Patent Publication Number: US-2007111981-A1

Title: New (hetero)aryl compounds with MCH antagonistic activity and medicaments comprising these compounds

Description:
This application claims priority to EP 05 110 014, filed Oct. 26, 2005, which is incorporated herein in its entirety.  
      The present invention relates to new heteroaryl compounds, the physiologically acceptable salts thereof as well as their use as MCH antagonists and their use in preparing a pharmaceutical preparation which is suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way. The invention also relates to the use of a compound according to the invention for influencing eating behaviour and for reducing body weight and/or for preventing any increase in body weight in a mammal. It further relates to compositions and medicaments containing a compound according to the invention and processes for preparing them. Other aspects of this invention relate to processes for preparing the compounds according to the invention.  
     BACKGROUND TO THE INVENTION  
      The intake of food and its conversion in the body is an essential part of life for all living creatures. Therefore, deviations in the intake and conversion of food generally lead to problems and also illness. The changes in the lifestyle and nutrition of humans, particularly in industrialised countries, have promoted morbid overweight (also known as corpulence or obesity) in recent decades. In affected people, obesity leads directly to restricted mobility and a reduction in the quality of life. There is the additional factor that obesity often leads to other diseases such as, for example, diabetes, dyslipidaemia, high blood pressure, arteriosclerosis and coronary heart disease. Moreover, high body weight alone puts an increased strain on the support and mobility apparatus, which can lead to chronic pain and diseases such as arthritis or osteoarthritis. Thus, obesity is a serious health problem for society.  
      The term obesity means an excess of adipose tissue in the body. In this connection, obesity is fundamentally to be seen as the increased level of body fat which leads to a health risk. There is no sharp distinction between normal individuals and those suffering from obesity, but the health risk accompanying obesity is presumed to rise continuously as the level of body fat increases. For simplicity&#39;s sake, in the present invention, individuals with a Body Mass Index (BMI), which is defined as the body weight measured in kilograms divided by the height (in metres) squared, above a value of 25 and more particularly above 30, are preferably regarded as suffering from obesity.  
      Apart from physical activity and a change in nutrition, there is currently no convincing treatment option for effectively reducing body weight. However, as obesity is a major risk factor in the development of serious and even life-threatening diseases, it is all the more important to have access to pharmaceutical active substances for the prevention and/or treatment of obesity. One approach which has been proposed very recently is the therapeutic use of MCH antagonists (cf. interalia WO 01/21577, WO 01/82925).  
      Melanin-concentrating hormone (MCH) is a cyclic neuropeptide consisting of 19 amino acids. It is synthesised predominantly in the hypothalamus in mammals and from there travels to other parts of the brain by the projections of hypothalamic neurones. Its biological activity is mediated in humans through two different G-protein-coupled receptors (GPCRs) from the family of rhodopsin-related GPCRs, namely the MCH receptors 1 and 2 (MCH-1R, MCH-2R).  
      Investigations into the function of MCH in animal models have provided good indications for a role of the peptide in regulating the energy balance, i.e. changing metabolic activity and food intake [1,2]. For example, after intraventricular administration of MCH in rats, food intake was increased compared with control animals. Additionally, transgenic rats which produce more MCH than control animals, when given a high-fat diet, responded by gaining significantly more weight than animals without an experimentally altered MCH level. It was also found that there is a positive correlation between phases of increased desire for food and the quantity of MCH mRNA in the hypothalamus of rats. However, experiments with MCH knock-out mice are particularly important in showing the function of MCH. Loss of the neuropeptide results in lean animals with a reduced fat mass, which take in significantly less food than control animals.  
      The anorectic effects of MCH are presumably mediated in rodents through the G ∀S -coupled MCH-1R [3-6], as, unlike primates, ferrets and dogs, no second MCH receptor subtype has hitherto been found in rodents. After losing the MCH-1R, knock-out mice have a lower fat mass, an increased energy conversion and, when fed on a high fat diet, do not put on weight, compared with control animals. Another indication of the importance of the MCH system in regulating the energy balance results from experiments with a receptor antagonist (SNAP-7941) [3]. In long term trials the animals treated with the antagonist lose significant amounts of weight.  
      In addition to its anorectic effect, the MCH-1R antagonist SNAP-7941 also achieves additional anxiolytic and antidepressant effects in behavioural experiments on rats [3]. Thus, there are clear indications that the MCH-MCH-1R system is involved not only in regulating the energy balance but also in affectivity.  
      Literature: 
          1. Qu, D., et al., A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature, 1996. 380(6571): p. 243-7.     2. Shimada, M., et al., Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature, 1998. 396(6712): p. 670-4.     3. Borowsky, B., et al., Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-I receptor antagonist. Nat Med. 2002. 8(8): p. 825-30.     4. Chen, Y., et al., Targeted disruption of the melanin-concentrating hormone receptor-1 results in hyperphagia and resistance to diet-induced obesity. Endocrinology, 2002. 143(7): p. 2469-77.     5. Marsh, D. J., et al., Melanin-concentrating hormone 1 receptor-deficient mice are lean, hyperactive, and hyperphagic and have altered metabolism. Proc Natl Acad Sci U S A, 2002. 99(5): p. 3240-5.     6. Takekawa, S., et al., T-226296: A novel, orally active and selective melanin-concentrating hormone receptor antagonist. Eur J Pharmacol, 2002. 438(3): p.129-35.        

      In the patent literature certain amine compounds are proposed as MCH antagonists. Thus, WO 01/21577 (Takeda) describes compounds of formula  
                 
 
 wherein Ar 1  denotes a cyclic group, X denotes a spacer, Y denotes a bond or a spacer, Ar denotes an aromatic ring which may be fused with a non-aromatic ring, R 1  and R 2  independently of one another denote H or a hydrocarbon group, while R 1  and R 2  together with the adjacent N atom may form an N-containing hetero ring and R 2  with Ar may also form a spirocyclic ring, R together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity. 
 
      Moreover WO 01/82925 (Takeda) also describes compounds of formula  
                 
 
 wherein Ar 1  denotes a cyclic group, X and Y represent spacer groups, Ar denotes an optionally substituted fused polycyclic aromatic ring, R 1  and R 2  independently of one another represent H or a hydrocarbon group, while R 1  and R 2  together with the adjacent N atom may form an N-containing heterocyclic ring and R 2  together with the adjacent N atom and Y may form an N-containing hetero ring, as MCH antagonists for the treatment of obesity, inter alia. 
 
      WO 94/22809 (Pharmacia/Famitalia) describes substituted (arylalkylaminobenzyl)-aminopropionamide derivatives and their use as anti-epileptic, neuroprotective and antidepressant agents. Among many other examples the compounds 2-[[[4-[[3-(2-fluorophenyl)propyl]amino]phenyl]methyl]amino]-propanamide and 2-[[[4-[[3-(3-fluorophenyl)propyl]amino]phenyl]methyl]amino]-propanamide are mentioned.  
      U.S. Pat. No. 3,209,029 describes aminoalkyl-aromatic-ethylamines as difunctional amines capable of use in condensation reactions to provide novel polyamides.  
     AIM OF THE INVENTION  
      The aim of the present invention is to identify new (hetero)aryl compounds, particularly those which are especially effective as MCH antagonists. The invention also sets out to provide new (hetero)aryl compounds which can be used to influence the eating habits of mammals and achieve a reduction in body weight, particularly in mammals, and/or prevent an increase in body weight.  
      The present invention further sets out to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of symptoms and/or diseases caused by MCH or otherwise causally connected to MCH. In particular, the aim of this invention is to provide pharmaceutical compositions for the treatment of metabolic disorders such as obesity and/or diabetes as well as diseases and/or disorders which are associated with obesity and diabetes. Other objectives of the present invention are concerned with demonstrating advantageous uses of the compounds according to the invention. The invention also sets out to provide a process for preparing the amide compounds according to the invention. Other aims of the present invention will be immediately apparent to the skilled man from the foregoing remarks and those that follow.  
     OBJECT OF THE INVENTION  
      In a first aspect the present invention relates to (hetero)aryl compounds of general formula I  
                 
 
      wherein  
      R 1 , R 2  independently of one another denote H, C 1-8 -alkyl or C 3-7 -cycloalkyl, while the alkyl or cycloalkyl group may be mono- or polysubstituted by identical or different groups R 11 , and a —CH 2 — group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by —O—, —S— or —NR 3 —, or 
          R 2  denotes a C 1-3 -alkylene bridge which is linked to the group Y, wherein the alkylene bridge may be sustituted with one or more C 1-3 -alkyl-groups, and R 1  is defined as hereinbefore or denotes a group selected from C 1-4 -alkyl-CO—, C 1-4 -alkyl-O—CO—, (C 1-4 -alkyl)NH—CO— and (C 1-4 -alkyl) 2 N—CO— wherein alkyl-groups may be mono- or polyfluorinated; or     R 1  and R 2  form a C 3-8 -alkylene bridge, wherein a —CH 2 — group not adjacent to the N atom of the R 1 R 2 N group may be replaced by —CH═N—, —CH═CH—, —O—, —S——SO—, —(SO 2 )—, —CO—, —C(═CH 2 )—, —C(═N—OH)—, —C(═N—(C 1-4 -alkyl))- or —NR 13 —,     while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R 14 , and     the alkylene bridge defined hereinbefore may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in such a way that the bond between the alkylene bridge and the group Cy is made     via a single or double bond,     via a common C atom forming a spirocyclic ring system,     via two common adjacent C and/or N atoms forming a fused bicyclic ring system or     via three or more C and/or N atoms forming a bridged ring system;        

      X denotes a C 1-4 -alkylene bridge, while in the definition C 2-4 -alkylene one or two C atoms may be monosubstituted by R 10 , or 
          a C 3-4 -alkylene bridge, wherein a —CH 2 —CH 2 — group not directly adjacent to the N atom of the R 1 R 2 N— group is replaced by —CH 2 —O— or —CH 2 —NR 4 —,     while the meanings given for X hereinbefore may comprise one, two or three identical or different C 1-4 -alkyl substituents, while two alkyl groups may be joined together forming a 3 to 7-membered cyclic group; and        

      R 4  denotes H or C 1-3 -alkyl; and  
      R 10  denotes hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 -alkoxy or C 1-4 -alkoxy-C 1-3 -alkyl; and  
      Y is a 5- or 6-membered unsaturated or aromatic carbocyclic group which may contain 1, 2, 3 or 4 heteroatoms selected from N, O and/or S; and which cyclic group may be mono- or polysubstituted by identical or different substituents R 20 ;  
      Q, Z independently of one another denote a group selected from —CR 3a R 3b —, —O— and —NR N —,  
      R N  independently of one another denote H, C 1-4 -alkyl, formyl, C 1-3 -alkylcarbonyl or C 1-3 -alkylsulfonyl; and  
      R 3a R 3b R 4a ,  
      R 4b R 5a R 5b  independently of one another denote H or C 1-4 -alkyl; and  
      A is a 5- or 6-membered unsaturated or aromatic carbocyclic group which may contain 1, 2, 3 or 4 heteroatoms selected from N, O and/or S; which cyclic group may be mono- or polysubstituted by identical or different substituents R 20 ; and  
      B denotes a group Cy; and  
      W denotes a single bond, —CH 2 —, —O—, —NR N —; —O—CH 2 —, —NR N —CH 2 —, —CH 2 —O—, —CH 2 —NR N —, or —CH 2 —CH 2 —; 
          or        

      B is selected from the group consisting of halogen, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-6 -alkenyloxy, C 3-6 -alkynyloxy, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 3-7 -cycloalkenyl-C 1-3 -alkyl, C 1-6 -alkylcarbonyl, C 1-6 -alkylamino or di-(C 1-6 -alkyl)-amino, wherein one or more C atoms independently of one another may be mono- or polysubstituted by halogen and/ or monosubstituted by hydroxy, C 1-4 -alkoxy or cyano and/ or cyclic groups may be mono- or polysubstituted by identical or different groups R 20 ; and  
      W denotes a single bond; and  
      Cy denotes a carbo- or heterocyclic group selected from one of the following meanings 
          a saturated 3- to 7-membered carbocyclic group,     an unsaturated 4- to 7-membered carbocyclic group,     a phenyl group,     a saturated 4- to 7-membered or unsaturated 5- to 7-membered heterocyclic group with an N, O or S atom as heteroatom,     a saturated or unsaturated 5- to 7-membered heterocyclic group with two or more N atoms or with one or two N atoms and an O or S atom as heteroatoms,     an aromatic heterocyclic 5- or 6-membered group with one or more identical or different heteroatoms selected from N, O and/or S.     while the above-mentioned saturated 6- or 7-membered groups may also be present as bridged ring systems with an imino, (C 1-4 -alkyl)-imino, methylene, ethylene, (C 1-4 -alkyl)-methylene or di-(C 1-4 -alkyl)-methylene bridge, and     while the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R 20 , or in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R 21 , and     while in the above-mentioned saturated or unsaturated carbo- or heterocyclic groups a —CH 2 -group may be replaced by a —C(═O)— group;        

      R 11  denotes halogen, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—, R 15 —O—CO—, R 15 —CO—O—, cyano, R 16 R 17 N—, R 18 R 19 N—CO— or Cy, while in the above-mentioned groups one or more C atoms may be substituted independently of one another by substituents selected from halogen, OH, CN, CF 3 , C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-3 -alkyl;  
      R 13  has one of the meanings given for R 17 ,  
      R 14  denotes halogen, cyano, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—, R 15 —O—CO—, R 15 —CO—, R 15 —CO—O—, R 16 R 17 N—, HCO—NR 15 —, R 18 R 19 N—CO—, R 15 —O—C 1-3 -alkyl R 15 —O—CO—C 1-3 -alkyl, R 15 —SO 2 —NH, R 15 —SO 2 —N(C 1-3 -alkyl)—, R 15 —O—CO—NH—C 1-3 -alkyl, R 15 —SO 2 —NH—C 1-3 -alkyl, R 15 —CO—C 1-3 -alkyl, R 15 —CO—O—C 1-3 -alkyl, R 16 R 17 N—C 1-3 -alkyl, R 18 R 19 N—CO—C 1-3 -alkyl or Cy-C 1-3 -alkyl,  
      R 15  denotes H, C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, phenyl, phenyl-C 1-3 -alkyl, pyridinyl or pyridinyl-C 1-3 -alkyl,  
      R 16  denotes H, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, C 4-7 -cycloalkenyl, C 4-7 -cycloalkenyl-C 1-3 -alkyl, ω-hydroxy-C 2-3 -alkyl, ω-(C 1-4 -alkoxy)-C 2-3 -alkyl, amino-C 2-6 -alkyl, C 1-4 -alkyl-amino-C 2-6 -alkyl, di-(C 1 4 -alkyl)-amino-C 2-6 -alkyl or cyclo-C 3-6 -alkyleneimino-C 2-6 -alkyl,  
      R 17  has one of the meanings given for R 16  or denotes phenyl, phenyl-C 1-3 -alkyl, pyridinyl, C 1-4 -alkylcarbonyl, C 3-7 -cycloalkylcarbonyl, hydroxycarbonyl-C 1-3 -alkyl, C 1-4 -alkoxycarbonyl, C 1-4 -alkylaminocarbonyl, C 1-4 -alkoxycarbonyl-C 1-3 -alkyl, C 1-4 -alkylcarbonylamino-C 2-3 -alkyl, N—(C 1-4 -alkylcarbonyl)-N—(C 1-4 -alkyl)-amino—C 2-3 -alkyl, C 1-4 -alkylsulphonyl, C 1-4 -alkylsulphonylamino-C 2-3 -alkyl or N—(C 1-4 -alkylsulphonyl)-N(—C 1-4 -alkyl)-amino-C 2-3 -alkyl;  
      R 18 , R 19  independently of one another denote H or C 16 -alkyl wherein R 18 , R 19  may be linked to form a C 3-6 -alkylene bridge, wherein a —CH 2 — group not adjacent to an N atom may be replaced by —O—, —S—, —SO—, —(SO 2 )—, —CO—, —C(═CH 2 )— or —NR 13 —;  
      R 20  denotes halogen, hydroxy, cyano, nitro, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, R 22 —C 1-3 -alkyl or has one of the meanings given for R 22 ; and  
      R 21  denotes C 1-4 -alkyl, ω-hydroxy-C 2-6 -alkyl, ω-C 1-4 -alkoxy-C 2-6 -alkyl, ω-C 1-4 -alkyl-amino-C 2-6 -alkyl, ω-di-(C 1-4 -alkyl)-amino-C 2-6 -alkyl, ω-cyclo-C 3-6 -alkyleneimino-C 2-6 -alkyl, phenyl, phenyl-C 1-3 -alkyl, C 1-4 -alkyl-carbonyl, C 1-4 -alkoxy-carbonyl, C 1-4 -alkylsulphonyl, aminosulphonyl, C 1-4 -alkylaminosulphonyl, di-C 1-4 -alkylaminosulphonyl or cyclo-C 3-6 -alkylene-imino-sulphonyl,  
      R 22  denotes pyridinyl, phenyl, phenyl-C 1-3 -alkoxy, cyclo-C 3 - 6 -alkyleneimino-C 2-4 -alkoxy, OHC—, HO—N═HC—, C 1-4 -alkoxy-N═HC—, C 1-4 -alkoxy, C 1-4 -alkylthio, carboxy, C 1-4 -alkylcarbonyl, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylamino-carbonyl, di-(C 1-4 -alkyl)-aminocarbonyl, cyclo-C 3-6 -alkyl-amino-carbonyl, cyclo-C 3-6 -alkyleneimino-carbonyl, phenylaminocarbonyl, cyclo-C 3-6 -alkyleneimino-C 2-4 -alkyl-aminocarbonyl, C 1-4 -alkyl-sulphonyl, C 1-4 -alkyl-sulphinyl, C 1-4 -alkyl-sulphonylamino, C 1-4 -alkyl-sulphonyl-N—(C 1-4 -alkyl)amino, amino, C 1-4 -alkyl-amino, di-(C 1-4 -alkyl)-amino, C 1-4 -alkyl-carbonyl-amino, C 1-4 -alkyl-carbonyl-N—(C 1-4 -alkyl)amino, cyclo-C 3-6 -alkyleneimino, phenyl-C 1-3 -alkylamino, N—(C 1-4 -alkyl)-phenyl-C 1-3 -alkylamino, acetylamino, propionylamino, phenylcarbonyl, phenylcarbonylamino, phenylcarbonylmethylamino, hydroxy-C 2-3 -alkylamino-carbonyl, (4-morpholinyl)carbonyl, (1-pyrrolidinyl)carbonyl, (1-piperidinyl)-carbonyl, (hexahydro-1-azepinyl)carbonyl, (4-methyl-1-piperazinyl)carbonyl, aminocarbonylamino or C 1-4 -alkylaminocarbonylamino,  
      while in the above-mentioned groups and radicals, particularly in A, B, Q, W, X, Y, Z, R N , R 3a , R 3b , R 4 , R 4a , R 4b , R 5a , R 5b , R 10 , R 11 , R 13  to R 22 , in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br and/or in each case one or more phenyl rings may additionally comprise independently of one another one, two or three substituents selected from the group F, Cl, Br, I, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, acetyl-amino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl- and di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl and/or may be monosubstituted by nitro, and 
          the H atom of any carboxy group present or an H atom bound to an N atom may in each case be replaced by a group which can be cleaved in vivo, the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof;        

      with the proviso that the following compounds (D1) and (D2) are not included:  
      (D1) 2-[[[4-[[3-(2-fluorophenyl)propyl]amino]phenyl]methyl]amino]-propanamide; and  
      (D2) 2-[[[4-[[3-(3-fluorophenyl)propyl]amino]phenyl]methyl]amino]-propanamide.  
      The invention also relates to the compounds in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers and in the form of the free bases or corresponding acid addition salts with pharmacologically acceptable acids. The subject of the invention also includes the compounds according to the invention, including their salts, wherein one or more hydrogen atoms are replaced by deuterium.  
      This invention also includes the physiologically acceptable salts of the (hetero)aryl compounds according to the invention as described above and hereinafter.  
      Also covered by this invention are compositions containing at least one (hetero)aryl compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients.  
      Also covered by this invention are pharmaceutical compositions containing at least one (hetero)aryl compound according to the invention and/ or a salt according to the invention optionally together with one or more inert carriers and/or diluents.  
      This invention also relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for influencing the eating behaviour of a mammal.  
      The invention further relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for reducing the body weight and/ or for preventing an increase in the body weight of a mammal.  
      The invention also relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition with an MCH receptor-antagonistic activity, particularly with an MCH-1 receptor-antagonistic activity.  
      This invention also relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.  
      A further object of this invention is the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of metabolic disorders and/or eating disorders, particularly obesity, bulimia, bulimia nervosa, cachexia, anorexia, anorexia nervosa and hyperphagia.  
      The invention also relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of diseases and/or disorders associated with obesity, particularly diabetes, especially type II diabetes, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.  
      In addition the present invention relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of hyperlipidaemia, cellulitis, fat accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affective disorders, depression, anxiety, sleep disorders, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.  
      The invention also relates to the use of at least one (hetero)aryl compound according to the invention and/or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of urinary problems, such as for example urinary incontinence, overactive bladder, urgency, nycturia and enuresis.  
      The invention further relates to the use of at least one (hetero)aryl compound according to the invention and/ or a salt according to the invention, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, for preparing a pharmaceutical composition which is suitable for the prevention and/or treatment of dependencies and/or withdrawal symptoms.  
      The invention further relates to processes for preparing for preparing a pharmaceutical composition according to the invention, characterised in that at least one (hetero)aryl compound according to the invention and/ or a salt according to the invention is incorporated in one or more inert carriers and/or diluents by a non-chemical method.  
      The invention also relates to a pharmaceutical composition containing a first active substance which is selected from the (hetero)aryl compounds according to the invention and/or the corresponding salts, including the compounds (D1) and (D2) explicitly excluded hereinbefore or one of the physiologically acceptable salts thereof, as well as a second active substance which is selected from the group consisting of active substances for the treatment of diabetes, active substances for the treatment of diabetic complications, active substances for the treatment of obesity, preferably other than MCH antagonists, active substances for the treatment of high blood pressure, active substances for the treatment of dyslipidaemia or hyperlipidaemia, including arteriosclerosis, active substances for the treatment of arthritis, active substances for the treatment of anxiety states and active substances for the treatment of depression, optionally together with one or more inert carriers and/or diluents.  
      Moreover, in one aspect, the invention relates to a process for preparing (hetero)aryl compounds of formula (1-3)  
                 
 
 wherein R 1 , R 2 , X, Y, R 4a , R 4b , R 5a , R 5b , Q, A, W, and B are defined as hereinbefore and hereinafter, by reacting a compound of general formula (1-1)  
                 
 
 wherein R 1 , R 2 , X and Y are defined as hereinbefore and hereinafter, 
 
 with a compound of general formula (1-2)  
                 
 
 wherein R 4a , R 4b , R 5a , R 5b , Q, A, W and B are defined as hereinbefore and hereinafter, 
 
 in the presence of a palladium catalyst with or without ligands and/or copper iodide and in the presence of a base. 
 
      The starting materials and intermediate products used in the synthesis according to the invention are also a subject of this invention. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION  
      Unless otherwise specified, the groups, residues and substituents, particularly A, B, Q, W, X, Y, Z, Cy, R 1 , R 2 , R 3a , R 3b , R 4 , R 4a , R 4b , R 5a , R 5b , R 10 , R 11 , R 13  to R 22 , R N , have the meanings given hereinbefore.  
      If groups, residues and/or substituents occur more than once in a compound, they may have the same or different meanings in each case.  
      If R 1  and R 2  are not joined together via an alkylene bridge, R 1  and R 2  independently of one another preferably denote a C 1-8 -alkyl or C 3-7 -cycloalkyl group which may be mono- or polysubstituted by identical or different groups R 11 , while a —CH 2 — group in position 3 or 4 of a 5-, 6- or 7-membered cycloalkyl group may be replaced by —O—, —S— or —NR 3 —, while one or both of the groups R 1  and R 2  may also represent H.  
      Preferred meanings of the group R 11  are F, Cl, Br, C 1-6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, R 15 —O—, cyano, R 16 R 17 N, C 3-7 -cycloalkyl, cyclo-C 3-6 -alkyleneimino, pyrrolidinyl, N—(C 1-4 -alkyl)-pyrrolidinyl, piperidinyl, N—(C 1-4 -alkyl)-piperidinyl, phenyl, pyridyl, pyrazolyl, thiazolyl, imidazolyl, while in the above-mentioned groups and radicals one or more C atoms may be mono- or polysubstituted independently of one another by F, C 1-3 -alkyl, C 1-3 -alkoxy or hydroxy-C 1-3 -alkyl, and/or one or two C atoms may be monosubstituted independently of one another by Cl, Br, OH, CF 3  or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R 20 , or in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R 21 . If R 11  has one of the meanings R 15 —O—, cyano, R 16 R 17 N or cyclo-C 3-6 -alkyleneimino, the C atom of the alkyl or cycloalkyl group substituted by R 11  is preferably not directly connected to a heteroatom, such as for example to the group —N—X—.  
      Preferably the groups R 1 , R 2  independently of one another represent H, C 1-6 -alkyl, C 3-5 -alkenyl, C 3-5 -alkynyl, C 3-7 -cycloalkyl, hydroxy-C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, (hydroxy-C 3-7 -cycloalkyl)-C 1-3 -alkyl, hydroxy-C 2-4 -alkyl, ω-NC—C 2-3 -alkyl, C 1-4 -alkoxy-hydroxy-C 1-4 -alkoxy-C 2-4 -alkyl, C 1-4 -alkoxy-carbonyl-C 1-4 -alkyl, carboxyl-C 1-4 -alkyl, amino-C 2-4 -alkyl, C 1-4 -alkyl-amino-C 2-4 -alkyl, di-(C 1-4 -alkyl)-amino-C 2-4 -alkyl, cyclo-C 3-6 -alkylene alkyl, pyrrolidin-3-yl, N—(C 1-4 -alkyl)-pyrrolidin-3-yl, pyrrolidinyl-C 1-3 -alkyl, N—(C 1-4 -alkyl)-pyrrolidinyl-C 1-3 -alkyl, piperidin-3-yl, piperidin-4-yl, N—(C 1-4 -alkyl)-piperidin-3-yl, N—(C 1-4 -alkyl)-piperidin-4-yl, piperidinyl-C 1-3 -alkyl, N—(C 1-4 -alkyl)-piperidinyl-C 1-3 -alkyl, tetrahydropyran-3-tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, phenyl-C 1-3 -alkyl, pyridyl-C 1-3 -alkyl, pyrazolyl-C 1-3 -alkyl, thiazolyl-C 1-3 -alkyl or imidazolyl-C 1-3 -alkyl, while the above-mentioned groups and radicals one or more C atoms independently of one another may be mono- or polysubstituted by F. C 1-3 -alkyl or hydroxy-C 1-3 -alkyl, and/or one or two C atoms independently of one another may be monosubstituted by Cl, Br, OH, CF 3  or CN, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different radicals R 20 , in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R 21 . Preferred substituents of the above-mentioned phenyl or pyridyl groups are selected from the group F, Cl, Br, I, cyano, C 1-4 -alkyl, C 1-4 -alkoxy, difluoromethyl, trifluoromethyl, hydroxy, amino, C 1-3 -alkylamino, di-(C 1-3 -alkyl)-amino, acetylamino, aminocarbonyl, difluoromethoxy, trifluoromethoxy, amino-C 1-3 -alkyl, C 1-3 -alkylamino-C 1-3 -alkyl and di-(C 1-3 -alkyl)-amino-C 1-3 -alkyl, while a phenyl group may also be monosubstituted by nitro.  
      Particularly preferred definitions of the groups R 1  and/or R 2  are selected from the group consisting of H, C 1-4 -alkyl, hydroxy-C 1-4 -alkyl, C 3-5 -alkenyl, C 3-5 -alkynyl, C 3-7 -cycloalkyl, hydroxy-C 3-7 -cycloalkyl, dihydroxy-C 3-6 -alkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-yl methyl, tetrahydrofuran-3-ylmethyl, (hydroxy-C 3-7 -cycloalkyl)-C 1-3 -alkyl, C 1-4 -alkoxy-C 2-3 -alkyl, hydroxy-C 1-4 -alkoxy-C 2 - 3 -alkyl, C 1-4 -alkoxy-C 1-4 -alkoxy-C 2-3 -alkyl, di-(C 1-3 -alkyl)amino-C 2-3 -alkyl, pyrrolidin-N-yl-C 2-3 -alkyl and piperidin-N-yl-C 2-3 -alkyl, while an alkyl, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and/or hydroxy-C 1-3 -alkyl, and/or mono- or polysubstituted by F or C 1-3 -alkyl and/or monosubstituted by CF 3 , Br, Cl or CN.  
      Most particularly preferred groups R 1  and/or R 2  are selected from the group consisting of H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, but-2-enyl, prop-2-ynyl, but-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-C 3-7 -cycloalkyl, (hydroxy-C 1-3 -alkyl)-hydroxy-C 3-7 -cycloalkyl, dihydroxy-C 3-5 -alkyl, 2-hydroxy- 1-(hydroxymethyl)-ethyl, 1,1-di(hydroxymethyl)-ethyl, (1-hydroxy-C 3-6 -cycloalkyl)-methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methyl-propyl, hydroxy-C 1-4 -alkoxy-C 2-3 -alkyl, di-(C 1-3 -alkyl)aminoethyl, pyrrolidin-N-yl-ethyl and piperidin-N-ylethyl, while the above-mentioned groups may be mono- or polysubstituted by F and/or C 1-3 -alkyl.  
      Examples of most particularly preferred groups R 1  and/or R 2  are therefore H, methyl, ethyl, n-propyl, i-propyl, prop-2-enyl, prop-2-ynyl, 2-methoxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, hydroxy-cyclopentyl, hydroxy-cyclohexyl, (hydroxymethyl)-hydroxy-cyclopentyl, (hydroxymethyl)-hydroxy-cyclohexyl, 2,3-dihydroxypropyl, (1-hydroxy-cyclopropyl)-methyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-yl methyl, tetrahydrofuran-3-yl methyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methyl-propyl, hydroxyethoxyethyl and dimethylaminoethyl.  
      Particularly preferably, at least one of the groups R 1 , R 2  has a meaning other than H.  
      In case the group R 2  denotes a C 1-3 -alkylene bridge which is linked to the group Y, preferably the definition of R 1  is in accordance with a preferred definition as described hereinbefore or R 1  denotes a group selected from C 1-4 -alkyl-CO—, C 1-4 -alkyl-O—CO—, (C 1-4 -alkyl)NH—CO— or (C 1-4 -alkyl) 2 N—CO— wherein alkyl-groups may be mono- or polyfluorinated. In case R 2  is linked to the group Y, then R 2  preferably denotes —CH 2 — or —CH 2 —CH 2 —, wherein the alkylene bridge may be sustituted with one or more C 1-3 -alkyl-groups. In case R 2  is linked to the group Y, then R 1  preferably denotes H or C 1-3 -alkyl which may be mono- or polyfluorinated.  
      If R 1  and R 2  form an alkylene bridge, this is preferably a C 3 - 7 -alkylene bridge or a C 3-7 -alkylene bridge, wherein a —CH 2 — group not adjacent to the N atom of the R 1 R 2 N group is replaced by —CH═N—, —CH═CH—, —O—, —S—, —(SO 2 )—, —CO—, —C(═N—OH)—, —C(═N—(C 14 -alkyl))— or —NR 1-3 —,  
      while in the alkylene bridge defined hereinbefore one or more H atoms may be replaced by identical or different groups R 14 , and  
      the alkylene bridge defined hereinbefore may be substituted with a carbo- or heterocyclic group cy in such a way that the bond between the alkylene bridge and the group Cy is made 
          via a single or double bond,     via a common C atom forming a spirocyclic ring system,     via two common adjacent C- and/or N atoms forming a fused bicyclic ring system or     via three or more C- and/or N atoms forming a bridged ring system.        

      Preferably also, R 1  and R 2  form an alkylene bridge such that R 1 R 2 N— denotes a group which is selected from azetidine, pyrrolidine, piperidine, azepan, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, 2,3,4,7-tetrahydro-1H-azepine, 2,3,6,7-tetrahydro-1H-azepine, piperazine in which the free imine function is substituted by R 3 , piperidin-4-one morpholine thiomorpholine, 1-oxo-thiomorpholin-4-yl, 1,1-dioxo-thiomorpholin-4-yl, 4-C 1-4 -alkoxy-imino-piperidin-1-yl and 4-hydroxyimino-piperidin-1-yl; or  
      a group which is particularly preferably selected from pyrrolidine, piperidine, piperazine in which the free imine function is substituted by R 13 , and morpholine,  
      while according to the general definition of R 1  and R 2  one or more H atoms may be replaced by identical or different groups R 14 , and/ or the above-mentioned groups may be substituted by one or two identical or different carbo- or heterocyclic groups Cy in a manner specified according to the general definition of R 1  and R 2  while the group Cy may be mono- or polysubstituted by R 20 .  
      Particularly preferred groups Cy are C 3-7 -cycloalkyl, aza-C 4-7 -cycloalkyl, particularly cyclo-C 3-6 -alkyleneimino, as well as 1-C 1-4 -alkyl-aza-C 4-7 -cycloalkyl, while the group Cy may be mono- or polysubstituted by R 20 .  
      The C 3-8 -alkylene bridge formed by R 1  and R 2 , wherein —CH 2 — groups may be replaced as specified, may be substituted, as described, by one or two identical or different carbo- or heterocyclic groups Cy, which may be substituted as specified hereinbefore.  
      In the event that the alkylene bridge is linked to a group Cy through a single bond, Cy is preferably selected from the group consisting of C 3-7 -cycloalkyl, cyclo-C 3-6 -alkyleneimino, imidazol, triazol, thienyl and phenyl.  
      In the event that the alkylene bridge is linked to a group Cy via a common C atom forming a spirocyclic ring system, Cy is preferably selected from the group consisting of C 3-7 -cycloalkyl, aza-C 4-8 -cycloalkyl, oxa-C 4-8 -cycloalkyl, 2,3-dihydro-1H-quinazolin-4-one.  
      In the event that the alkylene bridge is linked to a group Cy via two common adjacent C and/or N atoms forming a fused bicyclic ring system, Cy is preferably selected from the group consisting of C 4-7 -cycloalkyl, phenyl, thienyl.  
      In the event that the alkylene bridge is linked to a group Cy via three or more C and/or N atoms forming a bridged ring system, Cy preferably denotes C 4-8 -cycloalkyl or aza-C 4-8 -cycloalkyl.  
      In the event that the heterocyclic group R 1 R 2 N— is substituted by a group Cy, the group Cy is preferably linked to the group R 1 R 2 N— through a single bond, while Cy is preferably selected from the group consisting of C 3-7 -cycloalkyl, cyclo-C 3-6 -alkyleneimino, imidazol, imidazolidin-2-one, and triazol, while these groups may be substituted as specified, preferably by fluorine, C 1-3 -alkyl, hydroxy-C 1-3 -alkyl and hydroxy. Particularly preferably the group  
                 
 
 is defined according to one of the following partial formulae  
                 
                 
                 
 
 wherein one or more H atoms of the heterocycle formed by the group R 1 R 2 N— may be replaced by identical or different groups R 14 , and 
 
      the heterocycle formed by the group R 1 R 2 N— may be substituted by one or two, preferably one C 3-7 -cycloalkyl group, while the cycloalkyl group may be mono- or polysubstituted by R 20 , and  
      the ring attached to the heterocycle formed by the group R 1 R 2 N— may be mono- or polysubstituted at one or more C atoms by R 20 , or in the case of a phenyl ring may also additionally be monosubstituted by nitro and  
      wherein R 13 , R 14 , R 20 , R 21  have the meanings given hereinbefore and hereinafter.  
      If the heterocycle formed by the group R 1 R 2 N— is substituted as specified by one or two cycloalkyl groups mono- or polysubstituted by R 20 , the substituents R 20  independently of one another preferably denote C 1-4 -alkyl, C 1-4 -alkoxy-C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, hydroxy, fluorine, chlorine, bromine or CF 3 , particularly hydroxy.  
      Most particularly preferably the group  
                 
 
 is defined according to one of the following partial formulae  
                 
 
 particularly  
                 
 
 where R 13  has the meanings given above and hereinafter, and 
 
      the heterocycle formed by the group R 1 R 2 N- may be substituted by C 3-6 -cycloalkyl, hydroxy-C 3-6 -cycloalkyl or (hydroxy-C 3-6 -cycloalkyl)-C 1-3 -alkyl, and  
      the heterocycle formed by the group R 1 R 2 N— may be mono-, di- or trisubstituted by identical or different groups R 14 .  
      The following definitions of the group R 1 R 2 N are particularly preferred: azetidinyl, pyrrolidinyl, piperidinyl, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, morpholinyl,  
      fluoroazetidinyl, fluoropyrrolidinyl, fluoropiperidinyl, methylpyrrolidinyl, methylpiperidinyl, hydroxyazetidinyl, hydroxypyrrolidinyl, hydroxypiperidinyl, hydroxyazepanyl, (hydroxymethyl)-pyrrolidinyl, (hydroxymethyl)-piperidinyl,  
      3,4-dihydroxypyrrolidinyl, 3,4-dihydroxypiperidinyl, 3,5-dihydroxypiperidinyl, (hydroxymethyl)-hydroxy-pyrrolidinyl, (hydroxymethyl)-hydroxy-piperidinyl,  
      dimethylaminopyrrolidinyl, dimethylaminopiperidinyl, aminocarbonylpyrrolidinyl, methylaminocarbonylpyrrolidinyl, dimethylaminocarbonylpyrrolidinyl, aminocarbonylpiperidinyl, methylaminocarbonylpiperidinyl, dimethylaminocarbonylpiperidinyl, formylaminopiperidinyl, (N-formyl-N-methylamino)-piperidinyl,  
      methylcarbonylaminopiperidinyl, methylcarbonylaminopyrrolidinyl, N-(methylcarbonyl)-N-methyl-aminopiperidinyl, N-(methylcarbonyl)-N-methyl-aminopyrrolidinyl, ethylcarbonylamino-piperidinyl, ethylcarbonylaminopyrrolidinyl, N-(ethylcarbonyl)-N-methyl-aminopiperidinyl, N-(ethylcarbonyl)-N-methyl-aminopyrrolidinyl, cyclopropylcarbonylaminopiperidinyl, cyclopropylcarbonylaminopyrrolidinyl, N-(cyclopropylcarbonyl)-N-methyl-aminopiperidinyl, N-(cyclopropylcarbonyl)-N-methyl-aminopyrrolidinyl,  
      methylcarbonylaminomethylpiperidinyl, methylcarbonylaminomethylpyrrolidinyl, N-(methylcarbonyl)-N-methyl-aminomethylpiperidinyl, N-(methylcarbonyl)-N-methyl-aminomethylpyrrolidinyl,  
      methylsulfonylaminopyrrolidinyl, methylsulfonylaminopiperidinyl, N-(methylsulfonyl)-N-methyl-aminopyrrolidinyl, N-(methylsulfonyl)-N-methyl-aminopiperidinyl,  
      methoxycarbonylpyrrolidinyl, methoxycarbonylpiperidinyl, N-methyl-piperazinyl, N-(methylcarbonyl)-piperazinyl,  
      (methyl-4H-triazolyl)-pyrrolidinyl, (methyl-4H-triazolyl)-piperidinyl,  
      (methyl-imidazolidin-2-on-yl)pyrrolidinyl, (methyl-imidazolidin-2-on-yl)piperidinyl, imidazolylpyrrolidinyl, imidazolylpiperidinyl,  
      while in the groups mentioned a hydroxymethyl group may be mono- or disubstituted at the C atom by methyl, while two methyl substituents may be joined together, forming a cyclopropyl group, and  
      in one or two hydroxy groups the H atom may be replaced by a methyl group, and  
      the groups R 1 R 2 N- mentioned have no further substituents or have one or two substituents selected independently of one another from fluorine, hydroxy, C 1-3 -alkyl, hydroxy-C 1-3 -alkyl, CF 3 .  
      The following partial formulae are most particularly preferred definitions of the heterocyclic group  
                 
 
 specified above:  
                 
                 
                 
                 
                 
                 
                 
 
 wherein the groups mentioned are not further substituted, or 
 
      wherein methyl or ethyl groups may be mono-, di- or trisubstituted by fluorine, and wherein one or more H atoms of the heterocycle formed by the group R 1 R 2 N— which are bound to carbon may be substituted independently of one another by fluorine, chlorine, CN CF 3  C 13 -alkyl, hydroxy-C 1-3 -alkyl, particularly C 1-3 -alkyl or CF 3  preferably methyl, ethyl, CF 3 .  
      Among the above-mentioned preferred and particularly preferred meanings of R 1 R 2 N, the following definitions of the substituent R 14  are preferred: F Cl Br, cyano, C 14 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 -alkoxy, ω-(C 1-4 -alkoxy)-C 13 -alkyl, C 1-4 -alkyl-carbonyl, carboxy, C 1-4 -alkoxycarbonyl, hydroxy-carbonyl-C 1-3 -alkyl, C 1-4 -alkoxycarbonyl-C 1-3 -alkyl, formylamino, formyl-N—(C 1-4 -alkyl)-amino, C 1-4 -alkyl-carbonylamino, C 1-4 -alkyl-carbonyl-N—(C 1-3 -alkyl)amino, C 3-7 -cycloalkyl-carbonylamino, C 1-4 -alkyl-aminocarbonylamino, C 1-4 -alkyl-carbonylamino-C 1-3 -alkyl, C 1-4 -alkyl-carbonyl-N—(C 1-3 -alkyl)amino-C 1-3 -alkyl, C 3-7 -cycloalkyl-carbonylamino-C 1-3 -alkyl, C 1-4 -aminocarbonylamino-C 1-3 -alkyl, C 1-4 -alkyl-sulfonylamino, C 1-4 -alkyl-sulfonyl-N—(C 1-3 -alkyl)amino, C 1-4 -alkoxy-carbonylamino, C 1-4 -alkoxy-carbonylamino-C 1-3 -alkyl, amino, C 1-4 -alkyl-amino, C 3-7 -cycloalkyl-amino, C 3-7 -cycloalkyl-N—(C 1-4 -alkyl)-amino, di-(C 1-4 -alkyl)-amino cyclo-C 3-6 -alkyleneimino, amino-C 1-3 -alkyl, C 1-4 -alkyl-amino-C 1-3 -alkyl, C 3-7 -cycloalkyl-amino-C 1-3 -alkyl, C 3-7 -cycloalkyl-N—(C 1-4 -alkyl)-amino-C 1-3 -alkyl, di-(C 1-4 -alkyl)-amino-C 1-3 -alkyl, cyclo-C 3-6 -alkyleneimino-C 1-3 -alkyl, aminocarbonyl, C 1-4 -alkyl-amino-carbonyl, C 3-7 -cycloalkyl-amino-carbonyl, C 3-7 -cycloalkyl-N—(C 1-4 -alkyl)-amino-carbonyl, di-(C 1-4 -alkyl)-amino-carbonyl and (aza-C 4-6 -cycloalkyl)-carbonyl.  
      Particularly preferred meanings of the substituent R 14  are F, Cl, Br, C 1-4 -alkyl, hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 -alkoxy, ω-(C 1-4 -alkoxy)-C 1-3 -alkyl, C 1-4 -alkoxycarbonyl, amino-C 1-3 -alkyl, C 1-4 -alkyl-amino-C 1-3 -alkyl, C 3-7 -cycloalkyl-amino-C 1-3 -alkyl, C 3-4 -alkyl)-amino-C 1-3 -alkyl, di-(C 1-4 -alkyl)-amino-C 1-3 -alkyl, cyclo-C 3-6 -alkyleneimino-C 1-3 -alkyl, aminocarbonyl, di-(C 1-4 -alkyl)-amino-carbonyl, (aza-C 4-6 -cycloalkyl)-carbonyl, di-(C 1-4 -alkyl)-amino, formylamino, formyl-N(C 1-4 -alkyl)-amino, C 1-4 -alkyl-carbonylamino, C 1-4 -alkyl-carbonyl-N—(C 1-3 -alkyl)amino, C 3-5 -cycloalkyl-carbonylamino, C 1-4 -alkyl-aminocarbonylamino, C 1-4 -alkyl-carbonylamino-C 1-3 -alkyl, N—(C 1-4 -alkyl-carbonyl)-N—(C 1-3 -alkyl)amino-C 1-3 -alkyl, C 3-5 -cycloalkyl-carbonylamino-C 1-3 -alkyl, C 1-4 -alkyl-sulfonylamino, and N—(C 1-4 -alkyl-sulfonyl)-N—(C 1-3 -alkyl)amino.  
      In the above-mentioned preferred meanings of R 14  in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms may independently of one another additionally be monosubstituted by Cl or Br. Thus, preferred meanings of R 14  also include, for example, —CF 3 , —OCF 3 , CF 3 —CO— and CF 3 —CHOH—.  
      Most particularly preferred meanings of the substituent R 14  are F, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy-C 1-3 -alkyl, methoxymethyl, hydroxy, CF 3 , C 1-3 -alkoxycarbonyl, aminocarbonyl, di(C 1-3 -alkyl)amino, formylamino, N-formyl-N(C 1-3 -alkyl)amino, C 1-3 -alkyl-carbonylamino, C 1-4 -alkyl-carbonyl-N-methyl-amino, C 3-5 -cycloalkyl-carbonylamino, C 1-3 -alkyl-aminocarbonylamino, C 1-3 -alkyl-carbonylaminomethyl, C 1-4 -alkyl-carbonyl-N-methyl-aminomethyl, C 3-5 -cycloalkyl-carbonylaminomethyl, C 1-3 -alkyl-sulfonylamino, C 1-4 -alkyl-sulfonyl-N—(C 1-3 -alkyl)amino, CF 3 —CHOH—.  
      Examples of most preferred meanings of R 14  are F, hydroxy, methyl, ethyl, CF 3 , methoxy, hydroxymethyl, 2-hydroxyethyl, methoxycarbonyl, dimethylamino, formylamino, N-formyl-N-methylamino, methylcarbonylamino, ethylcarbonylamino, methylcarbonyl-N-methyl-amino, cyclopropyl-carbonylamino, methylcarbonylaminomethyl, ethylcarbonylaminomethyl, methylcarbonyl-N-methyl-aminomethyl, cyclopropyl-carbonylaminomethyl, methylamino-carbonylamino, methylsulfonylamino, methylsulfonyl-N-methylamino.  
      The group X preferably denotes a —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —O— or —CH 2 —CH 2 —NR 4 — bridging group, wherein one or two hydrogen atoms may be replaced by identical or different C 1-3 -alkyl-groups, while two alkyl-groups may linked together to form a 3 to 6-membered cycloalkyl group; and wherein R 4  is as defined hereinbefore or preferably denotes H or methyl.  
      Most preferably the group X denotes a —CH 2 —, —CH 2 —CH 2 — or —CH 2 —CH 2 —O—.  
      In case the substituent R 2  denotes an alkylene bridge which is linked to the group Y, then the group X preferably denotes —CH 2 — or —CH 2 —CH 2 —.  
      The group Y preferably denotes a phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group which may be mono- or polysubstituted by identical or different substituents R 20 .  
      More preferably the group Y denotes phenyl, pyridyl or pyridazinyl, which may be mono- or polysubstituted, in particular mono- or disubstituted by identical or different substituents R 20 .  
      Most preferably the group Y denotes a group characterized by a subformula selected from  
                 
 
 which may be mono- or disubstituted by identical or different substituents R 20 . 
 
      Preferred substituents R 20  of the group Y are selected from halogen, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy and CF 3 ; in particular chlorine or bromine.  
      According to a first embodiment the groups Q. Z independently of one another preferably denote a group selected from —CH 2 —, —O— and —NR N — with the proviso that Q and Z do not both at the same time denote —CH 2 —.  
      According to a second embodiment the groups Q and Z denote —CH 2 —.  
      The groups R N  independently of each other preferably denotes H, methyl, ethyl or formyl; most preferably H.  
      The groups R 4a , R 4b , R 5a , R   5b  preferably denote H.  
      Therefore according to said first embodiment preferred meanings of the bridging group -Z-CR 4a R 4b —CR 5a R 5b -Q- are selected from the group of subformulae consisting of  
      (a) —NR N —CH 2 —CH 2 —CH 2 —,  
      (b) —NR N —CH 2 —CH 2 —NR N —;  
      (c) —NR N —CH 2 —CH 2 —O—,  
      (d) —CH 2 —CH 2 —CH 2 —NR N —,  
      (e) —O—CH 2 —CH 2 —NR N —, and  
      (f) —O—CH 2 —CH 2 —O—,  
      (g) —O—CH 2 —CH 2 —CH 2 —,  
      (h) —CH 2 —CH 2 —CH 2 —O—,  
      wherein R N  is defined as hereinbefore. The subformulae (a), (c), (d) and (g) are particularly preferred.  
      According to said second embodiment the bridging group -Z-CR 4a R 4b —CR 5a R 5b -Q- is preferably the group —CH 2 —CH 2 —CH 2 —CH 2 —.  
      The group A preferably denotes a phenyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group which may be mono- or polysubstituted by identical or different substituents R 20 .  
      More preferably the group A denotes phenyl, pyridyl or pyridazinyl, which may be mono- or polysubstituted, in particular mono- or disubstituted by identical or different substituents R 20 .  
      Most preferably the group A denotes a group characterized by a subformula selected from  
                 
 
                 
 
 which may be mono- or disubstituted by identical or different substituents R 20 . 
 
      Preferred substituents R 20  of the group Y are selected from halogen, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy and CF 3 ; in particular chlorine or bromine.  
      In case the group A is a phenyl group monosubstituted by R 20 , the position of the substituent R 20  is preferably ortho with respect to the group Q.  
      In case the group B denotes a group selected from Cy and any preferred meaning thereof as given hereinafter, the group W preferably denotes a single bond, —CH 2 —, —O—, —NR N —, —CH 2 —, —NR N —CH 2 —, —CH 2 —O— or —CH 2 —NR N —, wherein R N  preferably denotes H or C 1-4 -alkyl. According to this embodiment of the present invention the group W more preferably denotes a single bond, —O—, —CH 2 —, —O≦CH 2 — or —NH—CH 2 —. According to an alternative of this embodiment, the group W preferably denotes —CH 2 —CH 2 —.  
      In case the group B does not denote a group selected from Cy, the group W denotes a single bond.  
      In case the group B denotes a group Cy, it is preferably selected from the group consisting of phenyl and 5- to 6-membered unsaturated or aromatic heterocyclic groups which contain 1 to 4 heteroatoms selected from N, O and S wherein the phenyl or heterocyclic group may be mono- or polysubstituted by identical or different substituents R 20 .  
      More preferably in case the group B denotes a group Cy, it is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl and thienyl; in particular selected from phenyl, pyridyl and 1H-imidazolyl, wherein said group B may be mono- or polysubstituted, preferably mono- or disubstituted by identical or different substituents R 20 .  
      Most preferably the group B denotes a group characterized by a subformula selected from which may be mono- or polysubstituted, particularly mono- or disubstituted by identical or different substituents R 20 .  
      In case the group B is a 6-membered ring, in particular a phenyl or pyridyl group, it is preferably unsubstituted or mono- or disubstituted by identical or different groups R 20 , wherein the preferred position of a substituent is para with respect to the group A—W.  
      Preferred substituents R 20  of the group B are selected from halogen, hydroxy, nitro, C 1-3 -alkyl, C 1-3 -alkoxy, (C 1-3 -alkyl)-carbonyl-, di-(C 1-3 -alkyl)amino, aminocarbonyl, (C 1-3 -alkyl)-carbonylamino and (C 1-3 -alkyl)-sulfonylamino, wherein in each case one or more C atoms may additionally be mono- or polysubstituted by F. Preferred examples of fluorinated groups R 20  are CF 3  and —O—CF 3 . Particularly preferred meanings of R 20  are fluorine, chlorine, methyl, methoxy and dimethylamino.  
      In case the group B does not denote a group Cy, it is preferably selected from the group consisting of halogen, CN, C 1-4 -alkyl, C 1-6 -alkoxy, C 1-4 -alkylcarbonyl, C 1-4 -alkylamino or di-(C 1-4 -alkyl)-amino, wherein one or more C-atoms of said groups may additionally be mono- or polysubstituted by F; particularly selected from chlorine, bromine, iodine, CN, CF 3 , methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and methylcarbonyl.  
      The following are preferred definitions of other substituents according to the invention:  
      Preferably the substituent R 13  has one of the meanings given for R 16 . Particularly preferably R 13  denotes H, C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, ω-hydroxy-C 2-3 -alkyl, ω-(C 1-4 -alkoxy)-C 2-3 -alkyl, C 1-4 -alkylcarbonyl. Most particularly preferably R 13  denotes H, C 1-4 -alkyl or C 1-3 -alkylcarbonyl. The alkyl groups mentioned hereinbefore may be monosubstituted by Cl or mono- or polysubstituted by F.  
      Preferred meanings of the substituent R 15  are H, C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, while, as defined hereinbefore, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br. Particularly preferably R 15  denotes H, CF 3 , methyl, ethyl, propyl or butyl.  
      The substituent R 16  preferably denotes H, C 1-4 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, ωhydroxy-C 2-3 -alkyl or ω-(C 1-4 -alkoxy)-C 2-3 -alkyl, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br. More preferably R 16  denotes H, CF 3 , C 1-3 -alkyl, C 3-6 -cycloalkyl or C 3-6 -cycloalkyl-C 1-3 -alkyl; in particular H, methyl, ethyl, n-propyl and i-propyl.  
      Preferably the substituent R 17  has one of the meanings given for R 16  as being preferred or denotes C 1-4 -alkylcarbonyl or C 3-5 -cycloalkylcarbonyl. Particularly preferably R 17  denotes H, C 1-3 -alkyl, C 1-3 -alkylcarbonyl, or C 3-5 -cycloalkylcarbonyl.  
      Preferably one or both of the substituents R 18  and R 19  independently of one another denotes hydrogen or C 1-4 -alkyl, particularly hydrogen or methyl.  
      In general the substituent R 20  preferably denotes halogen, hydroxy, cyano, nitro, C 1-4 -alkyl, C 1-4 -alkoxy, hydroxy-C 1-4 -alkyl, (C 1-3 -alkyl)-carbonyl-, di-(C 1-3 -alkyl)amino, aminocarbonyl, (C 1-3 -alkyl)-carbonylamino, (C 1-3 -alkyl)-sulfonylamino or R 22 —C 1-3 -alkyl, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br.  
      The substituent R 22  preferably denotes C 1-4 -alkoxy, C 1-4 -alkylthio, carboxy, C 1-4 -alkylcarbonyl, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di-(C 1-4 -alkyl)-aminocarbonyl, amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, C 1-4 -alkyl-carbonyl-amino, aminocarbonylamino or C 1-4 -alkylaminocarbonyl-amino, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br. Most particularly preferred meanings for R 22  are C 1-4 -alkoxy, C 1-4 -alkylcarbonyl, amino, C 1-4 -alkylamino, di-(C 1-4 -alkyl)-amino, wherein one or more H atoms may be replaced by fluorine.  
      Preferred definitions of the group R 21  are C 1-4 -alkyl, C 1-4 -alkylcarbonyl, C 1-4 -alkylsulphonyl, —SO 2 —NH 2 , —SO 2 —NH—C 1-3 -alkyl, —SO 2 —N(C 1-3 -alkyl) 2  and cyclo-C 3-6 -alkyleneimino-sulphonyl, while, as hereinbefore defined, in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br. Most particularly preferably R 21  denotes C 1-4 -alkyl or CF 3 .  
      Cy preferably denotes a C 3-7 -cycloalkyl, particularly a C 3-6 -cycloalkyl group, a C 5-7 -cycloalkenyl group, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aryl or heteroaryl, and the above-mentioned cyclic groups may be mono- or polysubstituted at one or more C atoms by identical or different groups R 20 , or in the case of a phenyl group may also additionally be monosubstituted by nitro, and/or one or more NH groups may be substituted by R 21 ; and in the above-mentioned saturated or unsaturated carbo- or heterocyclic groups a —CH 2 -group may be replaced by a —C(═O)— group. Most particularly preferred definitions of the group Cy are C 3-6 -cycloalkyl, pyrrolidinyl, piperidinyl and piperidinonyl, which may be substituted as specified.  
      The term aryl preferably denotes phenyl or naphthyl, particularly phenyl.  
      The term heteroaryl preferably comprises pyridyl, pyridazinyl, indolyl, quinolinyl and benzoxazolyl.  
      Preferred compounds according to the invention are those wherein one or more of the groups, radicals, substituents and/or indices have one of the meanings given hereinbefore as being preferred.  
      Particularly preferred compounds according to the invention may be described by a general formula IIa1 to IIf9, wherein compounds of the formulae IIc1 to IIc9, in particular IIc1, IIc6 and IIc9 are even more preferred,  
                 
                 
                 
                 
                 
                 
                 
                 
 
 wherein 
 
      D and E independently of one another denote CH or N, wherein CH may be substituted with L1; and  
      G and M independently of one another denote CH or N, wherein CH may be substituted with L2; and  
      L1 are independently of one another selected from the meanings of R 20  as defined hereinbefore, in particular of the meanings of R 20  as a substituent of the group Y as defined hereinbefore; and  
      L2 are independently of one another selected from the meanings of R 20  as defined hereinbefore, in particular of the meanings of R 20  as a substituent of the group A as defined hereinbefore; and  
      k1, k2 independently of one another denote 0, 1 or 2; and  
      R 1 , R 2 , R N , W and B are defined as hereinbefore, in particular possess a preferred meaning as defined hereinbefore.  
      According to a preferred embodiment in the formulae IIa1 to IIf9 both groups D and E denote N or both groups D and E denote CH, or D denotes CH while E denotes N; and  
      both groups G and M denote N or both groups G and M denote CH, or G denotes N while M denotes CH.  
      Even more preferably in the formulae IIa1 to IIf9 both groups D and E denote CH; and both groups G and M denote N.  
      In particular in the formulae IIa1 to IIf9, preferably IIc1 to IIc9, even more preferably IIc1, IIc6 and IIc9,  
      R 1 , R 2  independently of one another denote C 1-4 -alkyl, hydroxy-C 1-4 -alkyl, C 3-5 -alkenyl, C 3-5 -alkynyl, C 3-7 -cycloalkyl, hydroxy-C 3-7 -cycloalkyl, dihydroxy-C 3-6 -alkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, (hydroxy-C 3-7 -cycloalkyl)-C 1-3 -alkyl, C 1-4 -alkoxy-C 2-3 -alkyl, hydroxy-C 1-4 -alkoxy-C 2-3 -alkyl, C 1-4 -alkoxy-C 1-4 -alkoxy-C 2-3 -alkyl, di-(C 1-3 -alkyl)amino-C 2-3 -alkyl, pyrrolidin-N-yl-C 2-3 -alkyl and piperidin-N-yl-C 2-3 -alkyl, while an alkyl, alkoxy, cycloalkyl or cycloalkyl-alkyl group may additionally be mono- or disubstituted by hydroxy and/or hydroxy-C 1-3 -alkyl, and/or mono- or polysubstituted by F or C 1-3 -alkyl and/or monosubstituted by CF 3 , Br, Cl or CN; and one or both, preferably one of the groups R 1  and R 2  may also represent H; or  
      R 1 , R 2  are joined together and form together with the N atom to which they are bound a heterocyclic group which is selected from azetidine, pyrrolidine, piperidine, 2,5-dihydro-1H-pyrrole, 1,2,3,6-tetrahydro-pyridine, piperazine, wherein the free imine function is substituted by R 13  piperidin-4-one, morpholine, thiomorpholine, 1-oxo-thiomorpholine and 1,1-dioxo-thiomorpholine; 
          wherein one or more H atoms may be replaced by identical or different groups R 14  and     the heterocyclic group defined hereinbefore may be substituted via a single bond by a carbo- or heterocyclic group Cy, while Cy is selected from the group comprising C 3-7 -cycloalkyl, cyclo-C 3-6 -alkyleneimino, 1H-imidazol, imidazolidin-2-one, 4H-triazol, while Cy may be mono- or polysubstituted by identical or different groups R 20  where R 20  is as hereinbefore defined and is preferably selected from fluorine, CF 3 , C 1-3 -alkyl, hydroxy-C 1-3 -alkyl and hydroxy, and        

      R 14  is selected from F, Cl, Br, cyano, C 1-4 -alkyl, C 2-4 -alkenyl, C 2-4 -alkynyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-3 -alkyl, hydroxy, hydroxy-C 1-3 -alkyl, C 1-4 -alkoxy, ω-(C 1-4 -alkoxy)-C 1-3 -alkyl, C 1-4 -alkyl-carbonyl, carboxy, C 1-4 -alkoxycarbonyl, hydroxy-carbonyl-C 1-3 -alkyl, C 1-4 -alkoxycarbonyl-C 1-3 -alkyl, formylamino, N-formyl-N—(C 1-4 -alkyl)-amino, C 1-4 -alkyl-carbonylamino, N—(C 1-4 -alkyl-carbonyl)-N—(C 1-4 -alkyl)amino, C 3-7 -cycloalkyl-carbonylamino, C 1-4 -alkyl-aminocarbonylamino, C 1-4 -alkyl-carbonylamino-C 1-3 -alkyl, N—(C 1-4 -alkyl-carbonyl)-N—(C 1-3 -alkyl)amino-C 1-3 -alkyl, C 3-7 -cycloalkyl-carbonylamino-C 1-3 -alkyl, C 1-4 -alkyl-aminocarbonylamino-C 1-3 -alkyl, C 1-4 -alkyl-sulfonylamino, N—(C 1-4 -alkyl-sulfonyl)-N—(C 1-3 -alkyl)amino, C 1-4 -alkoxy-carbonylamino, C 1-4 -alkoxy-carbonylamino-C 1-3 -alkyl, amino, C 1-4 -alkyl-amino, C 3-7 -cycloalkyl-amino, N—(C 3-7 -cycloalkyl)-N—(C 1-4 -alkyl)-amino, di-(C 1-4 -alkyl)-amino, cyclo-C 3-6 -alkyleneimino, amino-C 1-3 -alkyl, C 1-4 -alkyl-amino-C 1-3 -alkyl, C 3-7 -cycloalkyl-amino-C 1-3 -alkyl, N—(C 3-7 -cycloalkyl)-N—(C 1-4 -alkyl)-amino-C 1-3 -alkyl, di-(C 1-4 -alkyl)-amino-C 1-3 -alkyl, cyclo-C 3-6 -alkyleneimino-C 1-3 -alkyl, aminocarbonyl, C 1-4 -alkyl-amino-carbonyl, C 3-7 -cycloalkyl-amino-carbonyl, N—(C 3-7 -cycloalkyl)-N—(C 1-4 -alkyl)-amino-carbonyl, di-(C 1-4 -alkyl)-amino-carbonyl, while in the above-mentioned meanings in each case one or more C atoms may additionally be mono- or polysubstituted by F and/or in each case one or two C atoms independently of one another may additionally be monosubstituted by Cl or Br; and  
      B denotes a group Cy, which is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, 1H-imidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl and thienyl; in particular selected from phenyl, pyridyl and 1H-imidazolyl, wherein the group B may be mono- or polysubstituted, preferably mono- or disubstituted by identical or different substituents R 20 ; and  
      W denotes a single bond, —CH 2 —, —O—, —NR N —, —O—CH 2 —, —NR N —CH 2 —, —CH 2 —O—, —CH 2 —NR N —, or —CH 2 —CH 2 —, wherein R N  preferably denotes H or C 1-4 -alkyl; most preferably a single bond, —O—, —O—CH 2 —, —NH—CH 2 —, —CH 2 —, or —CH 2 —CH 2 —;  
      or  
      B denotes a group selected from halogen, CN, C 1-4 -alkyl, C 1-6 -alkoxy, C 1-4 -alkylcarbonyl, C 1-4 -alkylamino or di-(C 1-4 -alkyl)-amino, wherein one or more C-atoms of said groups may additionally mono- or polysubstituted by F; and  
      W denotes a single bond; or  
      R 20  independently of one another denote F. Cl, Br, hydroxy, cyano, nitro, C 1-3 -alkyl, C 1-3 -alkoxy, (C 1-3 -alkyl)-carbonyl-, di-(C 1-3 -alkyl)amino, aminocarbonyl, (C 1-3 -alkyl)-carbonylamino and (C 1-3 -alkyl)-sulfonylamino, wherein in each case one or more C atoms may additionally be mono- or polysubstituted by F; and  
      R N  independently of each other denotes H, C 1-3 -alkyl or formyl; more preferably H or methyl; and  
      L1 halogen, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy and CF 3 ; and  
      k1 is 0 or 1; and  
      L2 halogen, C 1-3 -alkyl, C 1-3 -alkoxy, hydroxy and CF 3 ; and  
      k2 isOor1.  
      According to a preferred embodiment characterized by the formulae IIa1 to IIa9, in particular by the formula IIa2, the group B denotes halogen, CN, C 1-4 -alkyl, C 1-6 -alkoxy, C 1-4 -alkylcarbonyl, C 1-4 -alkylamino or di-(C 1-4 -alkyl)-amino, wherein one or more C-atoms of said groups may additionally mono- or polysubstituted by F; and all other groups in said formulae are as defined hereinbefore.  
      According to a alternative preferred embodiment characterized by the formulae IIb1 to IIf9, in particular by the formula IId1 and IIc4, the group B denotes Cy, which is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, 1H-imidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl and thienyl; in particular selected from phenyl, pyridyl and 1H-imidazolyl, wherein the group B may be mono- or polysubstituted, preferably mono- or disubstituted by identical or different substituents R 20 ; and all other groups in said formulae are as defined hereinbefore.  
      In the formulae IIa1 to IIa9 the group W preferably denotes a single bond. In the formulae IIb1 to IIf9 the group W preferably denotes a single bond, —CH 2 —, —O—, —NR N —, —O—CH 2 —, —NR N —CH 2 —, —CH 2 —O— or —CH 2 —NRN— wherein R N  preferably denotes H or C 1-4 -alkyl; most preferably a single bond, —O—, —O—CH 2 — or —NH—CH 2 .  
      The compounds listed in the experimental section, including the tautomers, the diastereomers, the enantiomers, the mixtures thereof and the salts thereof, are preferred according to the invention.  
      Some expressions used hereinbefore and below to describe the compounds according to the invention will now be defined more fully.  
      The term halogen denotes an atom selected from among F, Cl, Br and 1, particularly F, Cl and Br.  
      The term C 1-n -alkyl, where n has a value of 3 to 8, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms. Examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.  
      The term C 1-n -alkylene, where n may have a value of 1 to 8, denotes a saturated, branched or unbranched hydrocarbon bridge with 1 to n C atoms. Examples of such groups include methylene (—CH 2 —), ethylene (—CH 2 —CH 2 —), 1-methyl-ethylene (—CH(CH 3 )—CH 2 —), 1,1-dimethyl-ethylene (—C(CH 3 ) 2 —CH 2 —), n-prop-1,3-ylene (—CH 2 —CH 2 —CH 2 —), 1-methylprop-1,3-ylene (—CH(CH 3 )—CH 2 —CH 2 —), 2-methylprop-1,3-ylene (—CH 2 —CH(CH 3 )—CH 2 —), etc., as well as the corresponding mirror-symmetrical forms.  
      The term C 2-n -alkenyl, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and at least one C═C-double bond. Examples of such groups include vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.  
      The term C 2-n -alkynyl, where n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C═C triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, iso-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc.  
      The term C 1-n -alkoxy denotes a C 1-n -alkyl-O— group, wherein C 1-n -alkyl is defined as above. Examples of such groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert-pentoxy, n-hexoxy, iso-hexoxy etc.  
      The term C 1-n -alkylthio denotes a C 1-n -alkyl-S— group, wherein C 1-n -alkyl is defined as above. Examples of such groups include methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, iso-pentylthio, neo-pentylthio, tert-pentylthio, n-hexylthio, iso-hexylthio, etc.  
      The term C 1-n -alkylcarbonyl denotes a C 1-n -alkyl —C(═O)— group, wherein C 1-n -alkyl is defined as above. Examples of such groups include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert-pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.  
      The term C 3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarbocyclic group with 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3,2,1]octyl, spiro[4,5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.  
      The term C 5-n -cycloalkenyl denotes a monounsaturated mono-, bi-, tri- or spirocarbocyclic, preferably monocarboxylic group with 5 to n C atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, etc.  
      The term C 3-n -cycloalkylcarbonyl denotes a C 3-n -cycloalkyl-C(═O) group, wherein C 3-n -cycloalkyl is as hereinbefore defined.  
      The term aryl denotes a carbocyclic, aromatic ring system, such as for example phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl, etc. A particularly preferred meaning of “aryl” is phenyl.  
      The term cyclo-C 3-6 -alkyleneimino denotes a 4- to 7-membered ring which comprises 3 to 6 methylene units as well as an imino group, while the bond to the residue of the molecule is made via the imino group.  
      The term cyclo-C 3-6 -alkyleneimino-carbonyl denotes a cyclo-C 3-6 -alkyleneimino ring as hereinbefore defined which is linked to a carbonyl group via the imino group.  
      The term heteroaryl used in this application denotes a heterocyclic, aromatic ring system which comprises in addition to at least one C atom one or more heteroatoms selected from N. O and/or S. Examples of such groups are furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,5-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), indazolyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinozilinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc. The term heteroaryl also comprises the partially hydrogenated heterocyclic, aromatic ring systems, particularly those listed above. Examples of such partially hydrogenated ring systems are 2,3-dihydrobenzofuranyl, pyrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl, etc. Particularly preferably heteroaryl denotes a heteroaromatic mono- or bicyclic ring system.  
      Terms such as C 3-7 -cycloalkyl-C 1-n -alkyl, heteroaryl-C 1-n -alkyl, etc. refer to C 1-n -alkyl, as defined above, which is substituted with a C 3-7 -cycloalkyl, aryl or heteroaryl group.  
      Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another. Thus, for example, in the group di-C 1-4 -alkyl-amino, the two alkyl groups may have the same or different meanings.  
      The term “unsaturated”, for example in “unsaturated carbocyclic group” or “unsaturated heterocyclic group”, as used particularly in the definition of the group Cy, comprises in addition to the mono- or polyunsaturated groups, the corresponding, totally unsaturated groups, but particularly the mono- and diunsaturated groups.  
      The term “optionally substituted” used in this application indicates that the group thus designated is either unsubstituted or mono- or polysubstituted by the substituents specified. If the group in question is polysubstituted, the substituents may be identical or different.  
      The style used hereinbefore and hereinafter, according to which in a cyclic group a bond of a substituent is shown towards the centre of this cyclic group, indicates unless otherwise stated that this substituent may be bound to any free position of the cyclic group carrying an H atom.  
      Thus in the example  
                 
 
 the substituent L1 where k1=1 may be bound to any of the free positions of the phenyl ring; where k1=2 selected substituents L1 may independently of one another be bound to different free positions of the phenyl ring. 
 
      The H atom of any carboxy group present or an H atom bound to an N atom (imino or amino group) may in each case be replaced by a group which can be cleaved in vivo. By a group which can be cleaved in vivo from an N atom is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C 1-16 -alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C 1-16 -alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C 1-6 -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C 1-3 -alkylsulphonyl-C 2-4 -alkoxycarbonyl, C 1-3 -alkoxy-C 2-4 -alkoxy-C 2-4 -alkoxycarbonyl or R e CO—O—(R f CR g )—O—CO— group wherein 
          R e  denotes a C 1-8 -alkyl, C 5-7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl group,     R f  denotes a hydrogen atom, a C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl group and     R g  denotes a hydrogen atom, a C 1-3 -alkyl or R e CO—O—(R f CR h )—O group wherein R e  and R f  are as hereinbefore defined and Rh is a hydrogen atom or a C 1-3 -alkyl group, 
 
 while the phthalimido group is an additional possibility for an amino group, and the above-mentioned ester groups may also be used as a group which can be converted in vivo into a carboxy group. 
       

      The residues and substituents described above may be mono- or polysubstituted by fluorine as described. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy. Preferred fluorinated alkylsulphinyl and alkylsulphonyl groups are trifluoromethylsulphinyl and trifluoromethylsulphonyl.  
      The compounds of general formula I according to the invention may have acid groups, predominantly carboxyl groups, and/or basic groups such as e.g. amino functions. Compounds of general formula I may therefore be present as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali or alkaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine inter alia.  
      The compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.  
                 
 
      To obtain a compound of general formula (1-3) according to Scheme 1, a compound of general formula (1-1) is reacted with a compound of general formula (1-2) in the presence of a palladium catalyst with or without ligands and/or copper iodide and in the presence of a base. In principal such a reaction and its suitable reaction conditions are known as Buchwald-Hartwig amination or Goldberg reaction. The reaction is preferably carried out in an inert organic solvent solvent such as for example dioxane, DMF, DME, DMSO, toluene, benzene, acetonitrile, ethyleneglycol, isopropanol or THF, or a mixture of solvents. Suitable bases are particularly amine bases such as for example triethylamine, butylamine or N-diisopropyl-ethylamine (Hunig base), or inorganic bases such as cesium carbonate, cesium acetate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide or potassium phosphate. Preferred reaction temperatures are between −60° C. and 200° C. Typical palladium catalysts are for example tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), palladium(II)-acetate, Pd(PPh 3 ) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 , Pd(dppf)Cl 2  or palladium(II)-chloride. Typical ligands are for example triphenylphosphine, triphenylarsine or 2-(di-tert-butylphosphino)biphenyl. Suitable leaving groups (LG) are preferably selected from fluoride, bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.  
                 
 
      To obtain a compound of general formula (2-3) according to Scheme 2, a compound of general formula (2-1), for example a phenol (Y denotes phenyl), is reacted with a compound of general formula (2-2) in the presence of a base. Suitable bases are particularly tertiary amines such as triethylamine or Hunig base as well as alkali metal carbonates, for example potassium carbonate or sodium carbonate. The reactions are preferably carried out in an inert organic solvent like DMF, methylene chloride, acetone or DMSO, or mixtures thereof. DMF is a preferred solvent. The reaction usually takes place in a period of from 2 to 48 hours. A preferred temperature range for this reaction is from 20° C. to 120° C., preferably from 60° C. to 100° C. Preferred leaving groups (LG) are selected from fluoride, bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.  
                 
 
      To obtain a compound of general formula (3-3) according to Scheme 3, a compound of general formula (3-1) is reacted with a compound of general formula (3-2), for example a phenol (A denotes phenyl), in the presence of a base. Suitable bases are particularly tertiary amines such as triethylamine or Hunig base as well as alkali metal carbonates, for example potassium carbonate or sodium carbonate. The reactions are advantageously carried out in an inert organic solvent like DMF, methylene chloride, acetone or DMSO, or mixtures thereof. DMF is a preferred solvent. Usually the reaction takes place in a period of from 2 to 48 hours. Preferably the reaction is carried out in in a temperature range from 20 to 120° C., preferably from 60° C. to 100° C. Preferred leaving groups (LG) are fluoride, bromide, chloride, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate and the like.  
                 
 
      To obtain a compound of general formula (4-2) according to Scheme 4, a compound of general formula (4-1) is reacted with a reducing agent. Suitable reducing agents are selected from metal hydrides, for example lithium aluminum hydride, diisobutyl aluminum hydride (DIBAL), and boranes, preferably borane-THF-complex or borane-dimethylsulfide-complex. The reactions are preferably carried out in an inert organic solvent like methylene chloride, diethylether, toluene, benzene or THF and mixtures thereof. THF is a preferred solvent. The reaction usually takes place in a period of from 2 to 24 hours. Preferably the reaction is carried out in a temperature range from 20 to 100° C.  
                 
 
      To obtain a compound of general formula (5-3) according to Scheme 5, a compound of general formula (5-2) is reacted with methanesulphonic acid chloride in the presence of a base to form the coresponding methanesulphonate derivative, followed by in situ reaction with an amine of general formula (5-1). The reaction conditions required are known to the skilled man as such. Advantageous solvents are halogenated hydrocarbons and ethers, such as for example dichloromethane, diethyl ether or THF. Suitable bases are particularly tertiary amines such as triethylamine or Hunig base as well as alkali metal carbonates, for example potassium carbonate or sodium carbonate. Suitable reaction temperatures are usually in the range from 0 to 90° C.  
      If the amine H—NR 1 R 2  has another primary or secondary amino function, this is advantageously provided with a protective group beforehand, which can be cleaved again after the reaction has ended, using methods known from the literature.  
                 
 
      To obtain a compound of general formula (6-3) by reductive amination according to Scheme 6, a compound of general formula (6-2) is reacted with an amine of general formula (6-1) in the presence of an acid, followed by addition of a reducing agent. Advantageously the reaction is carried in an inert organic solvent such as halogenated hydrocarbons or ethers, such as for example dichloromethane, 1,2-dichloroethane, diethyl ether or THF, or mixtures thereof. Suitable acids are mineral acids, such as acetic acid or hydrochloric acid, or organic acids, such as para-toluenesulfonic acid. Suitable reducing agents are metal hydrides, especially sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborhydride. Suitable reaction temperatures are usually in the range from 0 to 90° C. Typical reaction times are 1 to 24 hours.  
      If the amine H—NR 1 R 2  has another primary or secondary amino function, this is advantageously provided with a protective group beforehand, which can be cleaved again after the reaction has ended, using methods known from the literature.  
                 
 
                 
 
      To obtain a compound of general formula (7-2) or (7-4) according to the Scheme 7a and 7b, a compound of general formula (7-1) or (7-3) is reacted with formaline in the presence of an acid, followed by addition of a reducing agent. Advantageously the reactions are carried out in an inert organic solvent such as halogenated hydrocarbons or ethers, such as for example dichloromethane, acetonitrile, diethyl ether or THF, or mixtures thereof. Suitable acids are mineral acids, such as acetic acid or hydrochloric acid, or organic acids, such as para-toluenesulfonic acid. Suitable reducing agents are metal hydrides, especially sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborhydride. Suitable reaction temperatures are usually in the range from 0 to 90° C. Typical reaction times are 1 to 48 hours.  
                 
 
                 
 
      To obtain a compound of general formula (8-2) or (8-4) according to the Schemes 8a and 8b, a compound of general formula (8-1) or (8-3) is reacted with a mixture of acetic acid anhydride and formic acid. Suitable reaction temperatures are usually in the range from 0 to 200° C., preferably in the range of 20 to 130° C. Typical reaction times are 1 to 48 hours.  
                 
 
      To obtain a compound of general formula (9-3) by reductive amination according to Scheme 9, a compound of general formula (9-2) is reacted with an amine or aniline of general formula (9-1) in the presence of an acid, followed by addition of a reducing agent. Advantageously the reaction is carried in an inert organic solvent such as halogenated hydrocarbons or ethers, such as for example dichloromethane, 1,2-dichloroethane, diethyl ether or THF, or mixtures thereof. Suitable acids are mineral acids, such as acetic acid or hydrochloric acid, or organic 10 acids, such as para-toluenesulfonic acid. Suitable reducing agents are metal hydrides, especially sodium borohydride, sodium triacetoxyborohydride or sodium cyanoborhydride. Suitable reaction temperatures are usually in the range from 0 to 90° C. Typical reaction times are 1 to 24 hours.  
                 
 
      To obtain a compound of general formula (10-2) according to Scheme 10, a compound of general formula (10-1) is reacted with hydrogen in the presence of a suitable hydrogenation catalyst or any other suitable reducing agent. Suitable hydrogenation catalysts are selected from metals or metal salts like palladium/charcoal, Raney nickel, Rh(PPh 3 ) 3 Cl (Wilkinson catalyst) or platinum(IV) oxide with or without the presence of vanadyl(IV) acetylacetonate. The reactions are preferably carried out in an inert organic solvent like ethyl acetate, diethylether, methanol, ethanol, DMF or THF and mixtures thereof with or without the presence of acids or bases like hydrochloric acid or ammonia. The reaction usually takes place in a period of from 1 to 96 hours. Preferably the reaction is carried out in a temperature range from 20 to 100° C. and in a pressure range from 1 bar to 30 bar.  
      Stereoisomeric compounds of formula (I) may chiefly be separated by conventional methods. The diastereomers are separated on the basis of their different physico-chemical properties, e.g. by fractional crystallisation from suitable solvents, by high pressure liquid or column chromatography, using chiral or preferably non-chiral stationary phases.  
      Racemates covered by general formula (I) may be separated for example by HPLC on suitable chiral stationary phases (e.g. Chiral AGP, Chiralpak AD). Racemates which contain a basic or acidic function can also be separated via the diastereomeric, optically active salts which are produced on reacting with an optically active acid, for example (+) or (−)-tartaric acid, (+) or (−)-diacetyl tartaric acid, (+) or (−)-monomethyl tartrate or (+)-camphorsulphonic acid, or an optically active base, for example with (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine or (S)-brucine.  
      According to a conventional method of separating isomers, the racemate of a compound of formula (I) is reacted with one of the above-mentioned optically active acids or bases in equimolar amounts in a solvent and the resulting crystalline, diastereomeric, optically active salts thereof are separated using their different solubilities. This reaction may be carried out in any type of solvent provided that it is sufficiently different in terms of the solubility of the salts. Preferably, methanol, ethanol or mixtures thereof, for example in a ratio by volume of 50:50, are used. Then each of the optically active salts is dissolved in water, carefully neutralised with a base such as sodium carbonate or potassium carbonate, or with a suitable acid, e.g. with dilute hydrochloric acid or aqueous methanesulphonic acid and in this way the corresponding free compound is obtained in the (+) or (−) form.  
      The (R) or (S) enantiomer alone or a mixture of two optically active diastereomeric compounds of general formula (I) may also be obtained by performing the syntheses described above with a suitable reaction component in the (R) or (S) configuration.  
      As already mentioned, the compounds of formula (I) may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically and pharmacologically acceptable salts thereof. These salts may be present on the one hand as physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, in the case of acidically bound hydrogen, the compound of formula (I) may also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter-ion. The acid addition salts may be prepared, for example, using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Moreover, mixtures of the above mentioned acids may be used. To prepare the alkali and alkaline earth metal salts of the compound of formula (I) with acidically bound hydrogen the alkali and alkaline earth metal hydroxides and hydrides are preferably used, while the hydroxides and hydrides of the alkali metals, particularly of sodium and potassium, are preferred and sodium and potassium hydroxide are most preferred.  
      The compounds according to the present invention, including the physiologically acceptable salts, are effective as antagonists of the MCH receptor, particularly the MCH-1 receptor, and exhibit good affinity in MCH receptor binding studies. Pharmacological test systems for MCH-antagonistic properties are described in the following experimental section.  
      As antagonists of the MCH receptor the compounds according to the invention are advantageously suitable as pharmaceutical active substances for the prevention and/or treatment of symptoms and/or diseases caused by MCH or causally connected with MCH in some other way. Generally the compounds according to the invention have low toxicity, they are well absorbed by oral route and have good intracerebral transitivity, particularly brain accessibility.  
      Therefore, MCH antagonists which contain at least one compound according to the invention are particularly suitable in mammals, such as for example rats, mice, guinea pigs, hares, dogs, cats, sheep, horses, pigs, cattle, monkeys and humans, for the treatment and/or prevention of symptoms and/or diseases which are caused by MCH or are otherwise causally connected with MCH.  
      Diseases caused by MCH or otherwise causally connected with MCH are particularly metabolic disorders, such as for example obesity, and eating disorders, such as for example bulimia, including bulimia nervosa. The indication obesity includes in particular exogenic obesity, hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, central obesity. This range of indications also includes cachexia, anorexia and hyperphagia.  
      Compounds according to the invention may be particularly suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiation.  
      In addition, the diseases caused by MCH or otherwise causally connected with MCH also include hyperlipidaemia, cellulitis, fatty accumulation, malignant mastocytosis, systemic mastocytosis, emotional disorders, affectivity disorders, depression, anxiety states, reproductive disorders, sexual disorders, memory disorders, epilepsy, forms of dementia and hormonal disorders.  
      Compounds according to the invention are also suitable as active substances for the prevention and/or treatment of other illnesses and/or disorders, particularly those which accompany obesity, such as for example diabetes, diabetes mellitus, particularly type II diabetes, hyperglycaemia, particularly chronic hyperglycaemia, complications of diabetes including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, etc., insulin resistance, pathological glucose tolerance, encephalorrhagia, cardiac insufficiency, cardiovascular diseases, particularly arteriosclerosis and high blood pressure, arthritis and gonitis.  
      MCH antagonists and formulations according to the invention may advantageously be used in combination with a dietary therapy, such as for example a dietary diabetes treatment, and exercise.  
      Another range of indications for which the compounds according to the invention are advantageously suitable is the prevention and/or treatment of micturition disorders, such as for example urinary incontinence, hyperactive bladder, urgency, nycturia, enuresis, while the hyperactive bladder and urgency may or may not be connected with benign prostatic hyperplasia.  
      Generally speaking, the compounds according to the invention are potentially suitable for preventing and/or treating dependencies, such as for example alcohol and/or nicotine dependency, and/or withdrawal symptoms, such as for example weight gain in smokers coming off nicotine. By “dependency” is generally meant here an irresistible urge to take an addictive substance and/or to perform certain actions, particularly in order to either achieve a feeling of wellbeing or to eliminate negative emotions. In particular, the term “dependency” is used here to denote a dependency on an addictive substance. By “withdrawal symptoms” are meant here, in general, symptoms which occur or may occur when addictive substances are withdrawn from patients dependent on one or more such substances. The compounds according to the invention are potentially suitable particularly as active substances for reducing or ending tobacco consumption, for the treatment or prevention of a nicotine dependency and/or for the treatment or prevention of nicotine withdrawal symptoms, for reducing the craving for tobacco and/or nicotine and generally as an anti-smoking agent. The compounds according to the invention may also be useful for preventing or at least reducing the weight gain typically seen when smokers are coming off nicotine. The substances may also be suitable as active substances which prevent or at least reduce the craving for and/or relapse into a dependency on addictive substances. The term addictive substances refers particularly but not exclusively to substances with a psycho-motor activity, such as narcotics or drugs, particularly alcohol, nicotine, cocaine, amphetamine, opiates, benzodiazepines and barbiturates.  
      The dosage required to achieve such an effect is conveniently, by intravenous or sub-cutaneous route, 0.001 to 30 mg/kg of body weight, preferably 0.01 to 5 mg/kg of body weight, and by oral or nasal route or by inhalation, 0.01 to 50 mg/kg of body weight, preferably 0.1 to 30 mg/kg of body weight, in each case 1 to 3× daily.  
      For this purpose, the compounds prepared according to the invention may be formulated, optionally in conjunction with other active substances as described hereinafter, together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, lozenges, powders, granules, solutions, emulsions, syrups, aerosols for inhalation, ointments or suppositories.  
      In addition to pharmaceutical compositions the invention also includes compositions containing at least one alkyne compound according to the invention and/ or a salt according to the invention optionally together with one or more physiologically acceptable excipients. Such compositions may also be for example foodstuffs which may be solid or liquid, in which the compound according to the invention is incorporated.  
      For the above mentioned combinations it is possible to use as additional active substances particularly those which for example potentiate the therapeutic effect of an MCH antagonist according to the invention in terms of one of the indications mentioned above and/or which make it possible to reduce the dosage of an MCH antagonist according to the invention.  
      Preferably one or more additional active substances are selected from among 
          active substances for the treatment of diabetes,     active substances for the treatment of diabetic complications,     active substances for the treatment of obesity, preferably other than MCH antagonists,     active substances for the treatment of high blood pressure,     active substances for the treatment of hyperlipidaemia, including arteriosclerosis,     active substances for the treatment of dyslipidaemia, including arteriosclerosis,     active substances for the treatment of arthritis,     active substances for the treatment of anxiety states,     active substances for the treatment of depression.        

      The above mentioned categories of active substances will now be explained in more detail by means of examples.  
      Examples of active substances for the treatment of diabetes are insulin sensitisers, insulin secretion accelerators, biguanides, insulins, α-glucosidase inhibitors, β3 adreno-receptor agonists. 
          Insulin sensitisers include glitazones, particularly pioglitazone and its salts (preferably hydrochloride), troglitazone, rosiglitazone and its salts (preferably maleate), JTT-501, GI-262570, MCC-555, YM-440, DRF-2593, BM-13-1258, KRP-297, R-119702 and GW-1929.     Insulin secretion accelerators include sulphonylureas, such as for example tolbutamide, chloropropamide, tolazamide, acetohexamide, glyclopyramide and its ammonium salts, glibenclamide, gliclazide, glimepiride. Further examples of insulin secretion accelerators are repaglinide, nateglinide, mitiglinide (KAD-1229) and JTT-608.     Biguanides include metformin, buformin and phenformin.     Insulins include those obtained from animals, particularly cattle or pigs, semisynthetic human insulins which are synthesised enzymatically from insulin obtained from animals, human insulin obtained by genetic engineering, e.g. from  Escherichi coli  or yeasts. Moreover, the term insulin also includes insulin-zinc (containing 0.45 to 0.9 percent by weight of zinc) and protamine-insulin-zinc obtainable from zinc chloride, protamine sulphate and insulin. Insulin may also be obtained from insulin fragments or derivatives (for example INS-1, etc.).     Insulin may also include different kinds, e.g. with regard to the onset time and duration of effect (“ultra immediate action type”, “immediate action type”, “two phase type”, “intermediate type”, “prolonged action type”, etc.), which are selected depending on the pathological condition of the patient.     α-Glucosidase inhibitors include acarbose, voglibose, miglitol, emiglitate.     β 3  Adreno receptor agonists include AJ-9677, BMS-196085, SB-226552, AZ40140.     Active substances for the treatment of diabetes other than those mentioned above include ergoset, pramlintide, leptin, BAY-27-9955 as well as glycogen phosphorylase inhibitors, sorbitol dehydrogenase inhibitors, protein tyrosine phosphatase 1B inhibitors, dipeptidyl protease inhibitors, glipazide, glyburide.        

      Active substances for the treatment of diabetes or diabetic complications furthermore include for example aldose reductase inhibitors, glycation inhibitors and protein kinase C inhibitors, DPPIV blockers, GLP-1 or GLP-2 analogues and SGLT-2 inhibitors. 
          Aldose reductase inhibitors are for example tolrestat, epalrestat, imirestat, zenarestat, SNK-860, zopolrestat, ARI-50i, AS-3201.     An example of a glycation inhibitor is pimagedine.     Protein Kinase C inhibitors are for example NGF, LY-333531.     DPPIV blockers are for example LAF237 (Novartis), MK431 (Merck) as well as 815541, 823093 and 825964 (all GlaxoSmithkline).     GLP-1 analogues are for example Liraglutide (NN2211) (NovoNordisk), CJC1131 (Conjuchem), Exenatide (Amylin).     SGLT-2 inhibitors are for example AVE-2268 (Aventis) and T-1095 (Tanabe, Johnson&amp;Johnson).     Active substances other than those mentioned above for the treatment of diabetic complications include alprostadil, thiapride hydrochloride, cilostazol, mexiletine hydrochloride, ethyl eicosapentate, memantine, pimagedine (ALT-711).        

      Active substances for the treatment of obesity, preferably other than MCH antagonists, include lipase inhibitors and anorectics. 
          A preferred example of a lipase inhibitor is orlistat.     Examples of preferred anorectics are phentermine, mazindol, dexfenfluramine, fluoxetine, sibutramine, baiamine, (S)-sibutramine, SR-141716, NGD-95-1.     Active substances other than those mentioned above for the treatment of obesity include lipstatin.     Moreover, for the purposes of this application, the active substance group of anti-obesity active substances also includes the anorectics, of which the β 3  agonists, thyromimetic active substances and NPY antagonists should be emphasised. The range of substances which may be considered as preferred anti-obesity or anorectic active substances is indicated by the following additional list, by way of example: phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A (hereinafter referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as for example sibutramine), a sympathomimetic active substance, a serotonergic active substance (such as for example dexfenfluramine, fenfluramine, a 5-HT2C agonist such as BVT.933 or APD356, or duloxetine), a dopamine antagonist (such as for example bromocriptine or pramipexol), a melanocyte-stimulating hormone receptor agonist or mimetic, an analogue of melanocyte-stimulating hormone, a cannabinoid receptor antagonist (Rimonabant, ACOMPLIA TM), an MCH antagonist, the OB protein (hereinafter referred to as leptin), a leptin analogue, a fatty acid synthase (FAS) antagonist, a leptin receptor agonist, a galanine antagonist, a GI lipase inhibitor or reducer (such as for example orlistat). Other anorectics include bombesin agonists, dehydroepiandrosterone or its analogues, glucocorticoid receptor agonists and antagonists, orexin receptor antagonists, urocortin binding protein antagonists, agonists of the Glucagon-like Peptide-1 receptor, such as for example exendin, AC 2993, CJC-1131, ZP10 or GRT0203Y, DPPIV inhibitors and ciliary neurotrophic factors, such as for example axokines. In this context mention should also be made of the forms of therapy which produce weight loss by increasing the fatty acid oxidation in the peripheral tissue, such as for example inhibitors of acetyl-CoA carboxylase.        

      Active substances for the treatment of high blood pressure include inhibitors of angiotensin converting enzyme, calcium antagonists, potassium channel openers and angiotensin II antagonists. 
          Inhibitors of angiotensin converting enzyme include captopril, enalapril, alacepril, delapril (hydrochloride), lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine (hydrochloride).     Examples of calcium antagonists are nifedipine, amlodipine, efonidipine, nicardipine.     Potassium channel openers include levcromakalim, L-27152, AL0671, NIP-121.     Angiotensin II antagonists include telmisartan, losartan, candesartan cilexetil, valsartan, irbesartan, CS-866, E4177.        

      Active substances for the treatment of hyperlipidaemia, including arteriosclerosis, include HMG-CoA reductase inhibitors, fibrate compounds. 
          HMG-CoA reductase inhibitors include pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, lipantil, itavastatin, ZD-4522 and their salts.        

      Fibrate compounds include fenofibrate, bezafibrate, clinofibrate, clofibrate and simfibrate.  
      Active substances for the treatment of dyslipidaemia, including arteriosclerosis, include e.g. medicaments which raise the HDL level, such as e.g. nicotinic acid and derivatives and preparations thereof, such as e.g. niaspan, as well as agonists of the nicotinic acid receptor.  
      Active substances for the treatment of arthritis include NSAIDs (non-steroidal antiinflammatory drugs), particularly COX2 inhibitors, such as for example meloxicam or ibuprofen.  
      Active substances for the treatment of anxiety states include chlordiazepoxide, diazepam, oxozolam, medazepam, cloxazolam, bromazepam, lorazepam, alprazolam, fludiazepam.  
      Active substances for the treatment of depression include fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline.  
      The dosage for these active substances is conveniently 1/5 of the lowest normal recommended dose up to 1/1 of the normal recommended dose.  
      In another embodiment the invention also relates to the use of at least one alkyne compound according to the invention and/ or a salt according to the invention for influencing the eating behaviour of a mammal. This use is particularly based on the fact that compounds according to the invention may be suitable for reducing hunger, curbing appetite, controlling eating behaviour and/or inducing a feeling of satiety. The eating behaviour is advantageously influenced so as to reduce food intake. Therefore, the compounds according to the invention are advantageously used for reducing body weight. Another use according to the invention is the prevention of increases in body weight, for example in people who had previously taken steps to lose weight and are interested in maintaining their lower body weight. A further use may be the prevention of weight gain in a co-medication with a substance generally causing weight gain (such a glitazones). According to this embodiment it is preferably a non-therapeutic use. Such a non-therapeutic use might be a cosmetic use, for example to alter the external appearance, or an application to improve general health. The compounds according to the invention are preferably used non-therapeutically for mammals, particularly humans, not suffering from any diagnosed eating disorders, no diagnosed obesity, bulimia, diabetes and/or no diagnosed micturition disorders, particularly urinary incontinence. Preferably, the compounds according to the invention are suitable for non-therapeutic use in people whose BMI (body mass index), defined as their body weight in kilograms divided by their height (in metres) squared, is below a level of 30, particularly below 25.  
      The Examples that follow are intended to illustrate the invention:  
      Preliminary Remarks:  
      As a rule,  1 H-NMR and/or mass spectra have been obtained for the compounds prepared. The R f  values are determined using ready-made silica gel 60 TLC plates F 254  (E. Merck, Darmstadt, Item no.1.05714) without chamber saturation or using ready-made aluminium oxide 60 F 254  TLC plates (E. Merck, Darmstadt, Item no.1.05713) without chamber saturation. The ratios given for the eluents relate to units by volume of the solvent in question. The units by volume for NH 3  relate to a concentrated solution of NH 3  in water. Silica gel made by Millipore (MATREX™, 35-70 my) is used for chromatographic purification. Alox (E. Merck, Darmstadt, aluminium oxide 90 standardised, 63-200 μm, Item no.1.01097.9050) is used for chromatographic purification.  
      The HPLC data given are measured under the following parameters:  
      mobile phase A: water:formic acid 99.9:0.1  
      mobile phase B: acetonitrile:formic acid 99.9:0.1  
      method A: analytical column: X-terra™ MS C18; 2.5 μm, 4.6 mm×30 mm; column temperature: 25° C.  
      gradient:  
                                                           time in min   % A   % B   flow rate in ml/min                                                            0.00   95.0   5.0   1.00           0.10   95.0   5.0   1.00           3.10   2.00   98.00   1.00           4.50   2.00   98.00   1.00           5.00   95.0   5.0   1.00                      
 
      method B: analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond)—C18; 3.5 μm; 4.6 mm×75 mm; column temperature: 30° C.  
      gradient:  
                                                           time in min   % A   % B   flow rate in ml/min                                                            0.00   95.0   5.0   1.60           4.50   10.0   90.0   1.60           5.50   90.0   10.00   1.60                      
 
      method C: analytical column: Zorbax column (Agilent Technologies), SB (Stable Bond)−C18; 3.5 μm; 4.6 mm×75 mm; column temperature: 30° C.  
      gradient:  
                                                           time in min   % A   % B   flow rate in ml/min                                                            0.00   95.0   5.0   0.80           9.00   10.0   90.0   0.80           11.0   90.0   10.00   0.80                      
 
      method D: analytical column: Zorbax column (Agilent Technologies), SB (Stable bond)—C18; 3.5 μm; 4.6 mm×75 mm; column temperature: RT  
      gradient:  
                                                           time in min   % A   % B   flow rate in ml/min                                                            0.00   95.0   5.0   1.60           4.50   10.0   90.0   1.60           5.00   10.0   90.0   1.60           5.50   95.0   5.00   1.60                      
 
      method E: analytical column: Waters Symmetry—C18; 3.5 μm; 4.6 mm×75 mm; column temperature: RT  
      gradient:  
                                                           time in min   % A   % B   flow rate in ml/min                                                            0.00   95.0   5.0   1.60           4.00   50.0   50.0   1.60           4.50   10.00   90.00   1.60           5.00   10.00   90.00   1.60           5.50   95.0   5.0   1.60                      
 
      method F: analytical column: Zorbax column (Agilent Technologies), SB (Stable bond)—C18; 3.5 μm; 4.6 mm×75 mm; column temperature: RT  
      gradient:  
                                                           time in min   % A   % B   flow rate in ml/min                                                            0.00   95.0   5.0   1.60           4.00   50.0   50.0   1.60           4.50   10.0   90.0   1.60           5.00   10.0   90.0   1.60           5.50   95.0   5.0   1.60                      
 
      The following abbreviations for the eluent mixtures are used hereinafter when giving the R f  values:  
      (A): silica gel, methylene chloride/methanol/ammonia (9:1:0.01)  
      (B): silica gel, methylene chloride/methanol/ammonia (9:1:0.1)  
      (C): silica gel, methylene chloride/methanol (9:1)  
      (D): silica gel, methylene chloride/methanol/ammonia (5:2:0.01)  
      (D): silica gel, methylene chloride/methanol/ammonia (5:1:0.01)  
      (E): aluminum oxide, methylene chloride/methanol (30:1)  
      (F): silica gel, ethyl acetate/methanol/ammonia (95:5:0.5)  
      (G): silica gel, ethyl acetate/methanol/ammonia (90:10:0.5)  
      (H): silica gel, cyclohexane/ethyl acetate (2:1)  
      (I): aluminum oxide, methylene chloride  
      (K): aluminum oxide, methylene chloride/methanol (50:1)  
      (L): silica gel, methylene chloride/methanol/ammonia (5:1:0.1)  
      (M): silica gel, methylene chloride/methanol/ammonia (95:5:0.01)  
      (N): aluminum oxide, ethyl acetate/ethanol (50:1)  
      If there is no specific information as to the configuration, it is not clear whether there are pure enantiomers or whether partial or even total racemisation has taken place.  
      The following abbreviations are used above and hereinafter:  
      abs. absolute  
      Cbz benzyloxycarbonyl  
      conc. concentrated  
      DMF N,N-dimethylformamide  
      dppf 1,1′-bis(diphenylphosphino)ferrocene  
      EII electron impact ionisation  
      ether diethyl ether  
      EtOAc ethyl acetate  
      EtOH ethanol  
      Fmoc 9-fluorenylmethoxycarbonyl  
      HCl hydrochloric acid  
      MeOH methanol  
      Ph phenyl  
      RT ambient temperature (about 20° C.)  
      TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate  
      THF tetrahydrofuran  
      Preparation of the Starting Compounds:  
     EXAMPLE I.1  
     3-(4′-Chloro-biphenyl-4-yl)-propylamine  
     
       
         
         
             
             
         
       
     
     I.1.a  
     3-(4′-Chloro-biphenyl-4-yl)-acrylamide  
      10.0 g (38.7 mmol) of 3-(4′-Chloro-biphenyl-4-yl)-acrylic acid are dissolved in 300 ml methylene chloride and 14.0 ml thionyl chloride are added. The mixture is stirred for 1.5 hours at reflux. After cooling the mixture is slowly poured into 200 ml of ammonia at 0° C. Stirring is continued for 30 minutes. After that time the residue is filtered off, recrystallised from methanol and dried at 85° C.  
      Yield: 7.60 g (76% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      C 15 H 12 ClNO  
      EII Mass spectrum: m/z=258/260 [M+H] +   
     I.1.b  
     3-(4′-Chloro-biphenyl-4-yl)-propionamide  
      5.15 g (20.0 mmol) of 3-(4′-chloro-biphenyl-4-yl)-acrylamide are dissolved in 100 ml DMF. 1.00 g Raney nickel is added and the mixture is hydrogenated (50 psi) for 6 hours at RT. After that time the catalyst is filtered off and the filtrate evaporated. The residue is recrystallised from ethanol and the product is dried in vacuo at 80° C.  
      Yield: 4.40 g (85% of theory),  
      R f  value: 0.70 (silica gel, methylene chloride/methanol=9:1)  
      C 15 H 14 ClNO  
      EII Mass spectrum: m/z=260/262 [M+H] +   
     I.1.c  
     3-(4′-Chloro-biphenyl-4-yl)-propylamine  
      3.00 g (11.6 mmol) of 3-(4′-chloro-biphenyl-4-yl)-propionamide are dissolved in 100 ml THF. Under protective gas a total of 11.6 ml (11.6 mmol) of a 1N lithium aluminum hydride solution in THF is added batchwise at −10° C. The mixture is stirred for 10 hours at RT. After that time water and a 1N NaOH-solution are added. The mixture is filtered and the filtrate evaporated. The residue is purified by silica gel column cromatography with methylene chloride/ethanol/ammonia (5:1:0.01) as eluent.  
      Yield: 1.20 g (42% of theory),  
      R f  value: 0.70 (aluminum oxide, methylene chloride/methanol=5:1)  
      C 15 H 16 ClN  
      The following compounds are synthesised analogously to the method described above:  
     (I.2) [3-(4′-Chloro-biphenyl-4-yl)-propyl]-methyl-amine  
     EXAMPLE II.1  
     3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamine  
     
       
         
         
             
             
         
       
     
     II.1.a  
     Trifluoro-methanesulfonic acid 6-(4-methoxy-phenyl)-pyridazin-3-yl ester  
      2.02 g (10.0 mmol) 6-(4-Methoxy-phenyl)-2H-pyridazin-3-one (Synthesis 1993, 334-342) are dissolved in 15 ml pyridine and 2.50 ml (15.0 mmol) trifluoromethanesulfonic acid anhydride are slowly added at 0° C. under argon atmosphere. The mixture is stirred for 2 hours at RT. After that time the mixture is slowly poured into ice water, the precipitate is filtered off and washed with water. Methylene chloride is added, the organic phase is separated and dried over sodium sulphate. The solvent is evaporated and dried in vacuo at 60° C.  
      Yield: 2.95 g (88% of theory),  
      R f  value: 0.90 (silica gel, methylene chloride/methanol=9:1)  
      C 12 H 9 F 3 N 2 O 4 S  
      EII Mass spectrum: m/z=335 [M+H] +   
     II.1.b  
     {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-prop-2- ynyl}-carbamic acid tert-butyl ester  
      11.7 g (35.0 mmol) Trifluoro-methanesulfonic acid 6-(4-methoxy-phenyl)-pyridazin-3-yl ester and 11.0 g (70.0 mmol) prop-2-ynyl-carbamic acid tert-butyl ester are dissolved in 250 ml THF and 98 mg (1.4 mmol) bis-(triphenylphosphine)palladiumdichloride, 1.00 g (5.25 mmol) copper-(I)-iodide and finally 80 ml diisopropylamine are added at −10° C. The mixture is stirred for 3 hours at 0° C. and for additional 2 hours at RT. After that time the solvent is evaporated and purified by silica gel column chromatography with methylene chloride/ethyl acetate (5:1) as eluent. The product is dried in vacuo at 60° C.  
      Yield: 9.20 g (78% of theory),  
      R f  value: 0.30 (silica gel, methylene chloride/ethyl acetate=5:1)  
      C 19 H 21  N 3 O 3    
     II.1.c  
     {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl]-carbamic acid tert-butyl ester  
      9.20 g (27.1 mmol) {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester are dissolved in 500 ml ethyl acetate and 200 ml ethanol. 2.00 g Palladium on charcoal(10%) are added and the mixture is hydrogenated (50 psi) for 24 hours at RT. After that time the catalyst is filtered off and the filtrate evaporated.  
      Yield: 7.50 g (81% of theory),  
      R f  value: 0.60 (silica gel, methylene chloride/methanol=9:1)  
      C 19 H 25 N 3 O 3    
      EII Mass spectrum: m/z=344 [M+H] +   
     II.1.d  
     3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamine  
      7.50 g (21.8 mmol) {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-carbamic acid tert-butyl ester are dissolved in 100 ml methylene chloride and 17.0 ml of trifluoroacetic acid are added. The mixture is stirred for 3 hours at RT. After that time the solvent is evaporated. The residue is taken up in methylene chloride and washed with a diluted ammonia-solution. The organic phase is dried over sodium sulphate.  
      Yield: 5.00 g (94% of theory),  
      R f  value: 0.10 (silica gel, methylene chloride/methanol/ammonia=5:2:0.01)  
      C 14 H 17 N 3 O  
      EII Mass spectrum: m/z=244 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (II.2) 3-[6-(4-Chloro-phenyl)-pyridazin-3-yl]-propylamine     (II.3) 3-[6-(4-Cyano-phenyl)-pyridazin-3-yl]-propylamine (using Raney-nickel instead of palladium on charcoal for step c)     (II.4) 3-[6-(4-Fluoro-phenyl)-pyridazin-3-yl]-propylamine (using Raney-nickel instead of palladium on charcoal for step c)        

     EXAMPLE III.1  
     1-(4-Iodo-benzyl)-4-methyl-piperidine  
     
       
         
         
             
             
         
       
     
      12.3 g (41.3 mmol) 1-Bromomethyl-4-iodo-benzene and 11.5 ml (82.7 mmol) triethylamine are dissolved in 125 ml methylene chloride and 4.10 ml (41.3 mmol) of 4-methyl-piperidine are added slowly. The mixture is stirred for 2 hours at ambient temperature. The organic phase is washed with water and dried over sodium sulphate. Lastly the solvent is eliminated.  
      Yield: 8.90 g (68% of theory),  
      R f  value: 0.70 (silica gel, cyclohexane/ethyl acetate=1:1)  
      C 13 H 18 INO  
      The following compounds are synthesised analogously to the method described above: 
      (III.2) 1-(4-bromo-benzyl)-4-trifluoromethyl-piperidine     (III.3) (4-bromo-benzyl)-dimethyl-amine     (III.4) 1-(4-bromo-benzyl)-piperidine     (III.4a) 1-(6-chloro-pyridin-3-ylmethyl)-4-trifluoromethyl-piperidin-4-ol     (III.5) 1-(6-chloro-pyridin-3-ylmethyl)-piperidine     (III.6) 1 -(6-chloro-pyridin-3-ylmethyl)-4-methyl-piperidine     (III.7) (6-chloro-pyridin-3-ylmethyl)-dimethyl-amine     (III.8) 1-(4-bromo-benzyl)-4-trifluoromethyl-piperidin-4-ol     (III.9) 1-(4-bromo-benzyl)-piperidin-4-ol     (III.10) 1 -(4-bromo-benzyl)-piperidin-3-ol     (III.11) 4-(4-bromo-benzyl)-morpholine     (III.12) 1-(4-bromo-benzyl)-4-methyl-piperidin-4-ol     (III.13) [1 -(4-bromo-benzyl)-piperidin-4-yl]-methanol     (III.14) 1-(4-bromo-benzyl)-piperidine-4-carboxylic acid amide     (III.15) N-[1 -(4-bromo-benzyl)-piperidin-4-yl]-acetamide     (III.16) (4-bromo-benzyl)-diethyl-amine     (III.17) 1-(4-bromo-benzyl)-4-methyl-piperidin-3,4-diol     (III.18) 1-(4-iodo-benzyl)-piperidin-3-ol     (III.19) 1-[(4-bromo-benzyl)-ethyl-amino]-2-methyl-propan-2-ol     (III.20) (R)-1-(4-bromo-benzyl)-piperidin-3-ol     (III.21) (S)-1-(4-bromo-benzyl)-piperidin-3-ol     (III.22) (4-bromo-benzyl)-methyl-amine     (III.23) 1-(4-bromo-benzyl)-pyrrolidine     (III.24) 1-[(4-bromo-benzyl)-(2-hydroxy-ethyl)-amino]-2-methyl-propan-2-ol     (III.25) N-[1-(4-bromo-benzyl)-pyrrolidin-3-yl]-acetamide     (III.26) 2-[(4-bromo-benzyl)-(2-hydroxy-ethyl)-amino]-ethanol     (III.27) (R)-[1-(4-bromo-benzyl)-pyrrolidin-2-yl]-methanol     (III.28) [1-(4-bromo-benzyl)-piperidin-4-yl]-dimethyl-amine     (III.29) 1-(4-bromo-benzyl)-piperidine-4-carboxylic acid methyl ester     (III.30) 1-(4-bromo-benzyl)-4-fluoro-piperidine     (III.31) (S)-1-(4-bromo-benzyl)-pyrrolidin-3-ol     (III.32) N-[1-(4-bromo-benzyl)-piperidin-4-yl]-N-methyl-acetamide     (III.33) 4-(4-bromo-benzyl)-thiomorpholine-1,1-dioxide     (III.34) (R)-1-(4-bromo-benzyl)-pyrrolidin-3-ol     (III.35) 1-(4-bromo-benzylamino)-propan-2-ol     (III.36) (S)-1-(4-bromo-benzyl)-2-methoxymethyl-pyrrolidine     (III.37) (R)-1-(4-bromo-benzyl)-2-methoxymethyl-pyrrolidine     (III.38) 1-(4-iodo-benzyl)-piperidine-3-carboxylic acid amide     (III.39) [2-(4-iodo-phenylethyl)]-dimethylamine     (III.40) N-[1-(4-bromo-benzyl)-piperidin-4-yl]-formamide     (III.41) 1-(4-bromo-benzyl)-4-(4-methyl-4H-[1,2,4]triazol-3-yl)-piperidine     (III.42) (S)-[1-(4-bromo-benzyl)-pyrrolidin-2-yl]-methanol     (III.43) [1-(4-bromo-benzyl)-pyrrolidin-3-yl]-methanol     (III.44) 2-[(4-bromo-benzyl)-methyl-amino]-ethanol     (III.45) 1-(4-bromo-benzyl)-azetidine     (III.46) N-[1-(4-bromo-benzyl)-pyrrolidin-3-yl]-N-methyl-acetamide     (III.47) (3S,4R)-1-(4-bromo-benzyl)-piperidin-3,4-diol     (III.48) (3R,4S)-1-(4-bromo-benzyl)-piperidin-3,4-diol     (III.49) 2-[2-(4-bromo-benzylamino)-ethoxy]-ethanol     (III.50) [1-(4-bromo-benzyl)-piperidin-2-yl]-methanol     (III.51) 1-(4-bromo-benzyl)-3-methoxy-piperidine     (III.52) [1-(4-bromo-benzyl)-piperidin-3-yl]-methanol     (III.53) 1-(4-bromo-benzyl)-1,2,3,6-tetrahydro-pyridine     (III.54) (3S,4S)-1-(4-bromo-benzyl)-pyrrolidine-3,4-diol     (III.55) 1-(4-bromo-benzyl)-4-methoxy-piperidine     (III.56) [1-(4-bromo-benzyl)-pyrrolidin-3-yl]-dimethyl-amine     (III.57) [2-(4-bromo-phenylethyl)]-dimethylamine     (III.58) 1-[1-(4-bromo-benzyl)-piperidin-4-yl]-3-methyl-urea     (III.59) 1-(4-bromo-benzyl)-4-methyl-piperazine     (III.60) N-[1-(4-bromo-benzyl)-piperidin-4-ylmethyl]-N-methyl-acetamide     (III.61) 1-(4-bromo-benzyl)-3,5-dimethyl-piperidine     (III.62) cyclopropanecarboxylic acid [1-(4-bromo-benzyl)-piperidin-4-yl]-amide     (III.63) N-[1-(4-bromo-benzyl)-piperidin-3-yl]-acetamide     (III.64) 1-[1-(4-bromo-benzyl)-piperidin-4-yl]-3-methyl-imidazolidin-2-one     (III.65) N-[1-(4-bromo-benzyl)-piperidin-4-yl]-propionamide     (III.66) N-[1-(4-bromo-benzyl)-piperidin-4-ylmethyl]-acetamide     (III.67) N-[1-(4-bromo-benzyl)-piperidin-4-yl]-methanesulfonamide     (III.68) 1-(4-bromo-2-methoxy-benzyl)-piperidin-4-ol     (III.69) N-[1-(4-bromo-benzyl)-piperidin-4-yl]-N-methyl-methanesulfonamide     (III.70) [1-(4-bromo-benzyl)-piperidin-3-yl]-dimethyl-amine     (III.71) 1-(4-bromo-2-fluoro-benzyl)-piperidin-4-ol     (III.72) 2-[(4-bromo-benzyl)-ethyl-amino]-ethanol     (III.73) N-[1-(4-bromo-benzyl)-piperidin-3-ylmethyl]-acetamide     (III.74) 1-(4-bromo-benzyl)-3-methoxy-piperidine     (III.75) 1-[4-(4-bromo-benzyl)-piperazin-1-yl]-ethanone     (III.76) 1-(4-bromo-benzyl)-piperidin-4-one     (III.77) N-[1-(4-bromo-benzyl)-piperidin-3-yl]-N-methyl-acetamide     (III.78) 1-(4-bromo-benzyl)-4-imidazol-1-yl-piperidine     (III.79) 1-(4-bromo-benzyl)-piperidine-4-carboxylic acid dimethylamide     (III.80) (R)-1-(4-bromo-benzylamino)-propan-2-ol     (III.81) (S)-1-(4-bromo-benzylamino)-propan-2-ol     (III.82) (S)-N-[1-(4-bromo-benzyl)-pyrrolidin-3-yl]-acetamide     (III.83) (R)-N-[1-(4-bromo-benzyl)-pyrrolidin-3-yl]-acetamide     (III.84) (R)-[1-(4-bromo-benzyl)-piperidin-3-yl]-methanol     (III.85) (S)-[1-(4-bromo-benzyl)-piperidin-3-yl]-methanol     (III.86) (S)-N-[1-(4-bromo-benzyl)-pyrrolidin-3-yl]-N-methyl-acetamide     (III.87) (R)-N-[1-(4-bromo-benzyl)-pyrrolidin-3-yl]-N-methyl-acetamide     (III.88) N-[1-(4-bromo-benzyl)-4-methyl-piperidin-4-yl]-acetamide    

     EXAMPLE IV.1  
     1-(6-iodo-pyridin-3-ylmethyl)-4-trifluoromethyl-pipieridin-4-ol  
     
       
         
         
             
             
         
       
     
      295 mg (1.00 mmol) 1-(6-chloro-pyridin-3-ylmethyl)-4-trifluoromethyl-piperidin-4-ol (educt III.4a) and 3.00 g (20.0 mmol) sodium iodide are dissolved in 5 ml of acetonitrile and 0.2 ml conc. HCl is added at RT. The mixture is stirred for 10 hours at reflux. After cooling, the solvent is evaporated, the residue is suspended in water and conc. ammonia is added. The water phase is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulphate. After evaporation of the solvent the product is purified by silica gel column chromatography with methylene chloride/methanol (9:1) as eluent.  
      Yield: 390 mg (100% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol=9:1)  
      C 12 H 14 F 3 IN 2 O  
      EII Mass spectrum: m/z=387 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
      (IV.2) 1-(6-iodo-pyridin-3-ylmethyl)-piperidin (synthesized from educt III.5)     (IV.3) (6-iodo-pyridin-3-ylmethyl)-dimethyl-amine (synthesized from educt III.7)  
                 
   

     EXAMPLE V.1  
     5-Bromo-2-piperidin-1-ylmethyl-pyridine  
      This compound was prepared as described in Organic Letters 2004, 6, 4905-4907.  
     EXAMPLE VI.1  
     3-(6-Benzyloxy-pyridazin-3-yl)-propylamine  
     
       
         
         
             
             
         
       
     
     VI1.a  
     3-Benzyloxy-6-chloro-pyridazine  
      33.92 g (205.5 mmol) 3,6-Dichloro-pyridazine are dissolved in 100 ml benzyl alcohol and 30.06 g (231.0 mmol) sodium benzylate are added. The mixture is stirred for 30 minutes at RT. After that time the mixture is slowly poured into ice water, the precipitate is filtered off and washed with water. The product is dried at 80° C.  
      Yield: 11.5 g (81% of theory),  
      R f  value: 0.60 (silica gel, cyclohexane/tehyl acetate=2:1)  
      C 11 H 10 N 2 O 2    
      EII Mass spectrum: m/z=243/245 [M+Na] +   
     VI.1.b  
     6-Benzyloxy-2H-pyridazin-3-one  
      15.5 g (70.0 mmol) 3-Benzyloxy-6-chloro-pyridazine are dissolved in 100 ml acetic acid and 6.3 g (77.0 mmol) sodium acetate are added. The mixture is stirred for 8 hours at 120° C. After that time the solvent is evaporated. The residue is taken up in methylene chloride and washed four times with 0.1N acetic acid. The organic phase is separated and the solvent is evaporated.  
      Yield: 40.21 g (89% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/methanol=9:1)  
      M.p. 170-173° C.  
      C 11 H 9 ClN 2 O  
     VI.1.c  
      Trifluoro-methanesulfonic acid 6-benzyloxy-pyridazin-3-yl ester 11.4 g (56.4 mmol) 6-Benzyloxy-2H-pyridazin-3-one are dissolved in 50 ml pyridine and 14.0 ml (84.6 mmol) trifluoromethanesulfonic acid anhydride are slowly added at 0° C. under argon atmosphere. The mixture is stirred for 1.5 hours at RT. After that time the mixture is slowly poured into ice water, the precipitate is filtered off and washed with water. Methylene chloride is added, the organic phase is separated and dried over sodium sulphate. Lastly the solvent is evaporated.  
      Yield: 17.0 g (90% of theory),  
      R f  value: 0.50 (silica gel, petrol ether/ethyl acetate=5:1)  
      M.p. 67-68° C.  
      C 12 H 9 F 3 N 2 O 4 S  
     VI1.d  
     N-[3-(6-Benzyloxy-pyridazin-3-yl)-prop-2-ynyl]-2,2,2-trifluoro-acetamide  
      16.7 g (50.0 mmol) Trifluoro-methanesulfonic acid 6-benzyloxy-pyridazin-3-yl ester and 15.1 g (100.0 mmol) 2,2,2-trifluoro-N-prop-2-ynyl-acetamide are dissolved in 150 ml THF and 75 ml triethyl amine. 1.4 g (2.0 mmol) bis-(triphenylphosphine)palladiumdichloride and 1.40 g (7.35 mmol) copper-(I)-iodide are added at −5° C. The mixture is stirred for 20 hours at RT. After that time the solvent is evaporated. The residue is taken up in ethyl acetate and washed with water. The organic phase is dried over sodium sulphate, the solvent is evaporated. The product is washed with tert-butyl methyl ether and dried at 80° C.  
      Yield: 9.50 g (57% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/ethyl acetate=5:1)  
      M.p. 163-166° C.  
      C 16 H 12 F 3 N 3 O 2    
     VI1.e  
     N-[3-(6-Benzyloxy-pyridazin-3-yl)-propyl]-2,2,2-trifluoro-acetamide  
      9.50 g (28.3 mmol) N-[3-(6-Benzyloxy-pyridazin-3-yl)-prop-2-ynyl]-2,2,2-trifluoro-acetamide are dissolved in 100 ml ethyl acetate and 100 ml ethanol. 1.00 g Raney nickel are added and the mixture is hydrogenated (50 psi) for 48 hours at RT. After that time the catalyst is filtered off and the filtrate evaporated. The residue is purified by aluminum oxide column chromatography with methylene chloride/ethyl acetate (5:1) as eluent. The product is dried in vacuo at 50° C.  
      Yield: 5.90 g (61% of theory),  
      R f  value: 0.60 (silica gel, methylene chloride/methanol=9:1)  
      C 16 H 16 F 3 N 3 O 2    
      EII Mass spectrum: m/z=340 [M+H] +   
     VI.1.f  
     3-(6-Benzyloxy-pyridazin-3-yl)-propylamine  
      5.90 g (17.4 mmol) N-[3-(6-Benzyloxy-pyridazin-3-yl)-propyl]-2,2,2-trifluoro-acetamide are dissolved in 100 ml methanol and 70.0 ml (69.6 mmol) 1N sodium hydroxide solution are added at 0° C. The mixture is stirred for 1 hour at RT. After that time the solvent is evaporated. The residue is taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulphate and the solvent is evaporated.  
      Yield: 4.00 g (95% of theory),  
      R f  value: 0.30 (silica gel, methylene chloride/methanol/ammonia=5:1:0.01)  
      C 14 H 17 N 3 O  
      EII Mass spectrum: m/z=244 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (VI.2) 3-(6-Methoxy-pyridazin-3-yl)-propylamine starting from 3-iodo-6-methoxy-pyridazine (see J. Org. Chem. 1963, 28, 218) in step d     (VI.3) 3-(6-Ethoxy-pyridazin-3-yl)-propylamine starting from 3-iodo-6-ethoxy-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) in step d     (VI.4) 3-(6-Propoxy-pyridazin-3-yl)-propylamine starting from 3-iodo-6-propoxy-pyridazine (prepared analogously to J. Org.        

      Chem. 1963, 28, 218) in step d 
          (VI.5) 3-(6-isopropoxy-pyridazin-3-yl)-propylamine starting from 3-iodo-6-isopropoxy-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) in step d     (VI.6) 3-[6-(4-Fluoro-benzyloxy)-pyridazin-3-yl]-propylamine starting from 3-iodo-6-(4-fluoro-benzyloxy)-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) in step d     (VI.7) 3-(6-Phenoxy-pyridazin-3-yl)-propylamine starting from 3-iodo-6-phenoxy-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) in step d        

     EXAMPLE VII.1  
     (4-{3-[5-(4-Chloro-phenyl)-pyridin-2-ylamino]-propyl}-phenyl)-methanol  
     
       
         
         
             
             
         
       
     
      3.07 g (15.0 mmol) 5-(4-Chloro-phenyl)-pyridin-2-ylamine (described in WO 04/039780) and 2.46 g (15.0 mmol) 3-(4-hydroxymethyl-phenyl)-propionaldehyde (described in WO 04/039780) are dissolved in 50 ml methanol and 1 ml conc. acetic acid. The mixture is stirred for 1 hour at RT. After that time 1.89 g (30.0 mmol) sodium cyanoborohydride are added and the mixture is stirred for additional 16 hours at RT. After that time the solvent is evaporated. The residue is taken up in ethyl acetate and water, the organic phase is separated and washed with brine. The organic phase is dried over sodium sulphate and the solvent is evaporated. The residue is purified by silica gel column chromatography with ethyl acetate/methanol/ammonia (99:1:0.1) as eluent.  
      Yield: 2.60 g (49% of theory),  
      retention time (HPLC): 3.4 min (method B)  
      C 21 H 21 ClN 2 O  
      EII Mass spectrum: m/z=353/355 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (VII.2) (4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-ylamino]-propyl}-phenyl)-methanol     (VII.3) (4-{2-[6-(4-Methoxy-phenyl)-pyridazin-3-ylamino]-ethoxyl}-phenyl)-methanol        

     EXAMPLE VIII.1  
     [4-(3-{[5-(4-Chloro-phenyl)-pyridin-2-yl]-methyl-amino}-propyl)-phenyl]-methanol  
     
       
         
         
             
             
         
       
     
      423 mg (1.20 mmol) (4-{3-[5-(4-Chloro-phenyl)-pyridin-2-ylamino]-propyl}-phenyl)-methanol (educt VII.1) and 3.00 ml (3.60 mmol) formalin (37%) are dissolved in 5 ml acetonitrile and 0.5 ml conc. acetic acid. The mixture is stirred for 1 hour at RT. After that time 150 mg (2.40 mmol) sodium cyanoborohydride are added and the mixture is stirred for additional 20 hours at RT. After that time the solvent is evaporated. The residue is taken up in water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and the solvent is evaporated. The residue is purified by silica gel column chromatography with cyclohexane/ethyl acetate (1:1) as eluent.  
      Yield: 190 mg (43% of theory),  
      retention time (HPLC): 3.3 min (method B)  
      C 22 H 23 ClN 2 O  
      EII Mass spectrum: m/z=367/369 [M+H] +   
     EXAMPLE IX  
      The following starting materials have been described in WO 2004/039764 or can be prepared analogously: 
          (IX.1) N-[3-Chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide     (IX.2) N-[3-Chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenylamino)-acetamide     (IX.3) 2-(2-Chloro-4-trifluoromethyl-phenoxy)-N-[4-(2-diethylamino-ethoxy)-2-dimethylamino-phenyl]-acetamide     (IX.4) 2-(3-Bromo-biphenyl-4-yloxy)-N-{3-bromo-4-[2-(4-methyl-piperidin-1-yl)-ethyl phenyl}-acetamide     (IX.5) 2-(3-Bromo-biphenyl-4-yloxy)-N-[3-bromo-4-(2-diethylamino-ethyl)-phenyl]-acetamide        

     EXAMPLE X.1  
     3-Chloro-4-(2-diethylamino-ethoxy)-phenol  
     
       
         
         
             
             
         
       
     
     X.1.a  
     [2-(2-Chloro-4-methoxy-phenoxy)-ethyl]-diethyl-amine  
      5.00 g (31.5 mmol) 2-Chloro-4-methoxy-phenol, 8.50 g (32.6 mmol) (2-bromo-ethyl)-diethyl-amine hydrobromide and 8.80 g (63.7 mmol) potassium carbonate are dissolved in 200 ml acetone. The mixture is stirred for 10 hours at reflux. After that time additional 3.00 g (11.5 mmol) (2-bromo-ethyl)-diethyl-amine hydrobromide and 3.00 g (21.7 mmol) potassium carbonate are added and the mixture is refluxed for 1 hour. After cooling, the mixture is filtered, the solvent is evaporated and the residue is taken up in methylene chloride. The organic phase is washed with water and dried over sodium sulphate. Lastly the solvent is evaporated.  
      Yield: 6.40 g (79% of theory),  
      R f  value: 0.10 (silica gel, methylene chloride/methanol=50:1)  
      C 13 H 20 ClNO 2    
      EII Mass spectrum: m/z=257/259 [M+Na] +   
     X.1.b  
     3-Chloro-4-(2-diethylamino-ethoxy)-phenol  
      3.00 g (11.6 mmol) [2-(2-Chloro-4-methoxy-phenoxy)-ethyl]-diethyl-amine and 30.0 g (260 mmol) pyridine hydrochloride are melted for 3 hours at 200° C. After that time the mixture is cooled to 90° C. and poured into water. The mixture is stirred for 30 minutes at RT and extracted with ethyl acetate. After drying over sodium sulphate, the solvent is evaporated.  
      Yield: 2.48 g (87% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol=50:1)  
      C 12 H 18 ClNO 2    
      EII Mass spectrum: m/z=244/246 [M+H] +   
     EXAMPLE XI.1  
     Methanesulfonic acid 2-(2-chloro-4-iodo-phenoxy)-ethyl ester  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     XI.1.a  
     2-(2-Chloro-4-iodo-phenoxy)-ethanol  
      50.09 g (60.00 mmol) 2-(4-Bromo-2-chloro-phenoxy)-ethanol (described in WO 2004/072016), 17.98 g (120.0 mmol) sodium iodide, 1.14 g (6.00 mol) copper(I) iodide and 1.28 ml (12.0 mmol) N,N-dimethyl ethylenediamine are dissolved in 60 ml 1,4-dioxane. The mixture is stirred for 48 hours at RT. After that time 200 ml diluted ammonia solution are added and the solution is extracted three times with methylene chloride. The combined organic layers are dried over magnesium sulphate. Lastly the solvent is evaporated.  
      Yield: 16.2 g (90% of theory),  
      C 8 H 8 CIIO 2    
      EII Mass spectrum: m/z=298/300 [M] +   
     XI.1.b  
     Methanesulfonic acid 2-(2-chloro-4-iodo-phenoxy)-ethyl ester  
      0.20 g (0.67 mmol) 2-(2-Chloro-4-iodo-phenoxy)-ethanol, 0.14 ml (1.0 mmol) triethylamine and 0.078 ml (1.0 mmol) methane sulfonyl chloride are dissolved in 10 ml methylene chloride. The mixture is stirred for 1 hour at RT. After that time water is added. The organic phase is separated and washed with water. After drying over sodium sulphate, the solvent is evaporated.  
      Yield: 0.25 g (100% of theory),  
      R f  value: 0.60 (silica gel, methylene chloride/methanol=50:1)  
      C 9 H 10 CIIO 4 S  
      EII Mass spectrum: m/z=376/378 [M+H] +   
     EXAMPLE XII.1  
     4-{2-[6-(4-Methoxy-phenyl)-pyridazin-3-yloxy]-ethoxyl-benzaldehyde  
      70 mg (3.01 mmol) sodium metal are suspended in 2.0 ml THF and 500 mg (3.01 mmol) 4-(2-hydroxy-ethoxy)-benzaldehyde in 2.0 ml THF are slowly added. The mixture is stirred for 2 hours at 60° C. After that time 664 mg (3.01 mmol) 3-chloro-6-(4-methoxy-phenyl)-pyridazine in 2.0 ml THF are added and the mixture is stirred for 10 hours at reflux. After that time the solvent is evaporated and the residue is taken up in water. Ethyl acetate is added, the organic phase is separated and dried over sodium sulphate. The solvent is evaporated and the residue is purified by silica gel column chromatography with cyclohexane/ethyl acetate (1:1) as eluent.  
      Yield: 100 mg (9% of theory),  
      R f  value: 0.40 (silica gel, cyclohexane/ethyl acetate=1:1)  
      C 20 H 18 N 2 O 4    
      EII Mass spectrum: m/z=351 [M+H] +   
     EXAMPLE XIII.1  
     {2-[4-(2-Bromo-ethoxy)-2-chloro-phenoxyl-ethyl}-diethyl-amine  
     
       
         
         
             
             
         
       
     
      1.23 g (5.05 mmol) 3-Chloro-4-(2-diethylamino-ethoxy)-phenol (educt X.1), 1.70 ml (19.7 mmol) 1,2-dibromo-ethane and 1.70 g (12.3 mmol) potassium carbonate are dissolved in 50 ml acetonitrile. The mixture is stirred for 10 hours at 90° C. After that time additional 1.70 ml (19.7 mmol) 1,2-dibromo-ethane and 1.7 g (12.3 mmol) potassium carbonate are added and the mixture is stirred for 3 hours at 90° C. After that time the mixture is filtered, the solvent is evaporated and the residue is taken up in ethyl acetate. The organic phase is washed with water and 0.1N HCl, the aqueous phases are combined, 0.1N NaOH is added and the solution is reextracted with ethyl acetate. The combined organic layers are dried over sodium sulphate. Lastly the solvent is evaporated.  
      Yield: 560 mg (32% of theory),  
      R f  value: 0.05 (silica gel, methylene chloride/methanol=9:1)  
      C 14 H 21  BrClNO 2    
      EII Mass spectrum: m/z=350/352 [M+H] +   
     EXAMPLE XIV.1  
     {4-[6-(3-Amino-propyl)-pyridazin-3-yl]-phenyl}-dimethyl-amine  
     
       
         
         
             
             
         
       
     
     XIV.1.a  
     [3-(6-Chloro-pyridazin-3-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester  
      19.2 g (80.0 mmol) 3-Chloro-6-iodo-pyridazine (Tetrahedron 55, 1999,15067) and 13.7 g (88.0 mmol) prop-2-ynyl-carbamic acid tert-butyl ester are dissolved in 200 ml THF and 2.50 g (4.0 mmol) bis-(triphenylphosphine)palladiumdichloride, 2.80 g (14.8 mmol) copper-(I)-iodide and finally 60 ml diisopropylamine are added at 0° C. The mixture is stirred for 2 hours at 0° C. After that time ice-water is added and the mixture is extracted with ethylacetate. The organic phase is separated and dried over sodium sulphate. The solvent is evaporated and the residue is purified by silica gel column chromatography with methylene chloride/ethyl acetate (5:1) as eluent. The product is dried in vacuo at 50° C.  
      Yield: 12.8 g (60% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/ethyl acetate=5:1)  
      C 12 H 12 ClN 3 O 2    
      EII Mass spectrum: m/z=268/270 [M+H] +   
      M.p. 102-105° C.  
     XIV.1.b  
     [3-(6-Chloro-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester  
      27.8 g (29.1 mmol) [3-(6-Chloro-pyridazin-3-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester are dissolved in 250 ml ethyl acetate. 2.00 g Raney-nickel are added and the mixture is hydrogenated (25 psi) for 7 hours at RT. After that time the catalyst is filtered off and the filtrate evaporated. The residue purified by silica gel column chromatography with methylene chloride/ethyl acetate (1:1) as eluent. The product is dried in vacuo at 50° C.  
      Yield: 6.30 g (80% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/ethyl acetate=1:1)  
      C 12 H 18 ClN 3 O 2    
      EII Mass spectrum: m/z=272/274 [M+H] +   
      M.p. 96-98° C.  
     XIV.1.c  
     {3-[6-(4-Dimethylamino-phenyl)-pyridazin-3-yl]-propyl}-carbamic acid tert-butyl ester  
      5.50 g (20.2 mmol) [3-(6-Chloro-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester are dissolved in 100 ml dioxane and 1.40 g (2.00 mmol) bis-(triphenylphosphine)palladium-dichloride, 10 ml 2N sodium carbonate solution and finally 4.30 g (26.3 mmol) 4-dimethylamino-phenyl boronic acid (dissolved in 50 ml dioxane and 50 ml methanol) are added. The mixture is stirred for 4 hours at 110° C. After cooling down, water is added and the mixture is extracted with ethylacetate. The organic phase is separated and dried over sodium sulphate. The solvent is evaporated and the residue is purified by silica gel column chromatography with ethyl acetate as eluent. The product is dried in vacuo at 70° C.  
      Yield: 6.50 g (90% of theory),  
      R f  value: 0.30 (silica gel, petrol ether/ethyl acetate=2:1)  
      C 20 H 28 N 4 O 2    
      EII Mass spectrum: m/z=357 [M+H] +   
      M.p. 160-164° C.  
     XIV.1.d  
     {4-[6-(3-Amino-propyl)-pyridazin-3-yl]-phenyl}-dimethyl-amine  
      6.50 g (18.2 mmol) {3-[6-(4-Dimethylamino-phenyl)-pyridazin-3-yl]-propyl}-carbamic acid tert-butyl ester are dissolved in 250 ml methylene chloride and 14.0 ml of trifluoroacetic acid are added. The mixture is stirred for 4 hours at RT. After that time the solvent is evaporated. The residue is taken up in methylene chloride and washed with 1N NaOH-solution. The organic phase is dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at 70° C.  
      Yield: 4.30 g (92% of theory),  
      R f  value: 0.20 (silica gel, methylene chloride/methanol/ammonia=5:1:0.02)  
      C 15 H 20 N 4    
      EII Mass spectrum: m/z=257 [M+H] +   
      M.p. 146-150° C.  
      The following compounds are synthesised analogously to the method described above: 
          (XIV.2) 3-[6-(3-Cyano-phenyl)-pyridazin-3-yl]-propylamine     (XIV.3) 3-(6-Pyridin-4-yl-pyridazin-3-yl)-propylamine     (XIV.4) 3-(6-p-Tolyl-pyridazin-3-yl)-propylamine     (XIV.5) 3-[6-(3,4-Difluoro-phenyl)-pyridazin-3-yl]-propylamine     (XIV.6) 3-[6-(2,4-Difluoro-phenyl)-pyridazin-3-yl]-propylamine        

     EXAMPLE XV.1  
     (4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propoxyl}-phenyl)-methanol  
     
       
         
         
             
             
         
       
     
     XV1.a  
     4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-prop-2-ynyloxy}-benzoic acid ethyl ester  
      0.84 g (2.5 mmol) Trifluoro-methanesulfonic acid 6-(4-methoxy-phenyl)-pyridazin-3-yl ester and 1.0 g (4.9 mmol) 4-prop-2-ynyloxy-benzoic acid ethyl ester are dissolved in 30 ml THF and 88 mg (0.13 mmol) bis-(triphenylphosphine)palladiumdichloride, 47 mg (0.25 mmol) copper-(I)-iodide and finally 3.5 ml diisopropylamine are added at RT under inert gas. The mixture is stirred for 3 hours at RT and for additional 3 hours at 50° C. After that time the solvent is evaporated and purified by silica gel column chromatography with methylene chloride/methanol (95:5) as eluent. The product is washed with ether/methanol.  
      Yield: 0.57 g (59% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol=39:1)  
      C 23 H 20 N 2 O 4    
      EII Mass spectrum: m/z=389 [M+H] +   
     XV.1.b  
     4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propoxyl}-benzoic acid ethyl ester  
      0.55 g (1.42 mmol) 4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-prop-2-ynyloxy}-benzoic ethyl ester are dissolved in 50 ml ethyl acetate. 100 mg Raney nickel are added and the mixture is hydrogenated (3 bar) at RT until completion. After that time the catalyst is filtered off and the filtrate evaporated. The residue is purified by silica gel column chromatography with methylene chloride/ethyl acetate (9:1) as eluent and the product is dried in vacuo at 50° C.  
      Yield: 0.23 g (41% of theory),  
      R f  value: 0.35 (silica gel, methylene chloride/ethyl acetate=9:1)  
      C 23 H 24 N 2 O 4    
      EII Mass spectrum: m/z=393 [M+H] +   
     XV.1.c  
     (4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propoxy}-phenyl)-methanol  
      0.20 g (0.51 mmol) 4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propoxy}-benzoic acid ethyl ester are dissolved in 10 ml THF and added to 610 ml (0.61 mmol) of a 1M solution of lithium aluminum hydride in THF at −10° C. The cooling bath is removed and the mixture is stirred for 2 hours at RT. After that time 0.1 ml water are carefully added. After 5 minutes 0.1 ml 4M NaOH solution and finally 0.5 ml water are carefully added. The mixture is stirred for 30 minutes. The solution is filtered, the solvent evaporated and the residue taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulphate. After evaporation of the solvent, the product is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (95:5:0.5) as eluent.  
      Yield: 110 mg (62% of theory),  
      R f  value: 0.45 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      C 21 H 22 N 2 O 3    
      EII Mass spectrum: m/z=351 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (XV.2) (4-{3-[6-(4-Chloro-phenyl)-pyridazin-3-yl]-propoxy}-phenyl)-methanol     (XV.3) {4-[3-(6-Phenoxy-pyridazin-3-yl)-propoxy]-phenyl}-methanol starting from 3-iodo-6-phenoxy-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) in step a     (XV.4) (4-{3-[6-(4-Fluoro-phenyl)-pyridazin-3-yl]-propoxy}-phenyl)-methanol     (XV.5) {4-[3-(6-Benzyloxy-pyridazin-3-yl)-propoxy]-phenyl}-methanol starting from 3-iodo-6-benzyloxy-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) and (4-prop-2-ynyloxy-phenyl)-methanol in step a (omitting step b)        

     EXAMPLE XVI.1  
     5-Bromo-2-methyl-2,3-dihydro-1H-isoindole  
     
       
         
         
             
             
         
       
     
      1.27 g (5.29 mmol) of 5-Bromo-2-methyl-isoindole-1,3-dione (Chem. Ber. 94, 1961, 2494) are dissolved in 60 ml THF. 2.01 ml (26.5 mmol) of borane-dimethylsulfide adduct are slowly added at 0° C. The ice-bath is removed and the mixture is stirred for 5 hours at reflux. After that time another 1.00 ml (13.2 mmol) borane-dimethylsulfide adduct are added and the mixture is stirred for 3 hours at reflux. 20 ml of methanol and 7 ml conc. HCl are slowly added. The mixture is stirred for 4 hours at 80° C. The residue is taken up in 25 ml 4N NaOH and 25 ml brine. The solution is extracted with methylene chloride, the organic phase is separated and dried over sodium sulphate. After evaporation of the solvent, the residue is purified by silica gel column cromatography with methylene chloride/methanol (95:5) as eluent.  
      Yield: 0.76 g (68% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol=19:1) C g H 10 BrN  
      EII Mass spectrum: m/z=212/214 [M+H] +   
     EXAMPLE XVII.1  
     3-(6-Phenethyl-pyridazin-3-yl)-propylamine  
     
       
         
         
             
             
         
       
     
     XVII.1 .a  
     3,6-Diiodo-pyridazine  
      14.9 g (0.1 mol) 3,6-Dichloro-pyridazine and 120 ml (0.54 mol) hydroiodic acid are refluxed for 0.5 hours at 150° C. After that time the mixture is cooled down and poured into 0.4 N NaOH solution/ice water. The precipitate is filtered off, taken up in methylene chloride and dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at 50° C.  
      Yield: 28.3 g (85% of theory),  
      C 4 H 2 I 2 N 2    
      EII Mass spectrum: m/z=333 [M+H] +   
      M.p. 165-168° C.  
     XVII.1.b  
     3-Iodo-6-phenethyl-pyridazine  
      0.66 g (2.00 mmol) 3,6-Diiodo-pyridazine and 0.23 mg (0.2 mmol) tetrakis(triphenylphosphine)palladium(0) are dissolved in 5 ml THF and 5.00 ml (2.50 mmol) 0.5 N phenylethylzinc bromide in THF are added. The mixture is stirred for 3 hours at RT. After that time the mixture is poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is separated and dried over sodium sulphate. After removal of the solvent, the residue is purified by silica gel column chromatography with methylene chloride/ethyl acetate (20:1) as eluent. The product is dried in vacuo at 50° C.  
      Yield: 0.30 g (48% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/ethyl acetate=19:1) C 12 H 11 IN 2    
      EII Mass spectrum: m/z=311 [M+H] +   
      M.p. 120-122° C.  
     XVII.1.c  
     [3-(6-Phenethyl-pyridazin-3-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester  
      Prepared according to procedure II.1.b from 5.90 g (19.0 mmol) 3-iodo-6-phenethyl-pyridazine and 3.87 g (25.0 mmol) prop-2-ynyl-carbamic acid tert-butyl ester.  
      Yield: 6.00 g (94% of theory),  
      R f  value: 0.80 (silica gel, methylene chloride/methanol=9:1)  
      C 20 H 23 N 3 O 2    
     XVII.1.d  
     [3-(6-Phenethyl-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester  
      Prepared according to procedure II.1.c from 6.00 g (17.8 mmol) [3-(6-phenethyl-pyridazin-3-yl)-prop-2-ynyl]-carbamic acid tert-butyl ester using 2.00 g Raney nickel as hydrogenation catalyst.  
      Yield: 5.50 g (91% of theory),  
      R f  value: 0.80 (silica gel, methylene chloride/methanol=9:1)  
      C 20 H 27 N 3 O 2    
     XVII.1.e  
     3-(6-Phenethyl-pyridazin-3-yl)-propylamine  
      Prepared according to procedure II.1.d from 5.50 g (16.1 mmol) [3-(6-phenethyl-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester.  
      Yield: 2.20 g (57% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol/ammonia=5:1:0.02)  
      C 15 H 19 N 3    
      The following compounds are synthesised analogously to the method described above: 
          (XVII.2) 3-(6-Benzyl-pyridazin-3-yl)-propylamine  
                 
using 3,6-dichloro-pyridazine and benzylzinc bromide as starting materials in step (b)        

     EXAMPLE XVIII.1  
     2-Methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine  
      1.53 g (40.3 mmol) Lithium aluminum hydride are dissolved in 100 ml THF and cooled to −15° C. 2.00 g (8.05 mmol) of 7-amino-3,4-dihydro-1 H-isoquinoline-2-carboxylic acid tert-butyl ester dissolved in 100 ml THF are slowly added at −5° C. The ice-bath is removed and the mixture is stirred for 12 hours at reflux. After that time the mixture is cooled to room temperature and 22.7 g (80.5 mmol) potassium sodium tartrate tetrahydrate are added and the mixture is stirred for 3 hours at rt. After that time 1 ml water is added, the mixture is filtered over celite and the filtrate is evaporated.  
      Yield: 1.40 g (100% of theory),  
      C 10 H 14 N 2    
      EII Mass spectrum: m/z=163 [M+H] +   
     EXAMPLE XIX.1  
     3-[6-(4-Methoxy-Phenyl)-pyridazin-3-yl]-propionaldehyde  
     
       
         
         
             
             
         
       
     
     XIX.1.a  
     3-(2-[1,3]Dioxolan-2-yl-ethyl)-6-(4-methoxy-phenyl)-pyridazine  
      2.70 g (8.00 mmol) Trifluoro-methanesulfonic acid 6-(4-methoxy-phenyl)-pyridazin-3-yl ester (example II.1.b) and 490 mg (0.43 mmol) tetrakis(triphenylphosphine)palladium(0) are dissolved in 20 ml THF and 20.0 ml (10.0 mmol) 0.5 N (1,3-dioxolan-2-ylethyl)zinc bromide in THF are added. The mixture is stirred for 20 hours at reflux. After that time the mixture is poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phase is separated and dried over sodium sulphate. After removal of the solvent, the residue is purified by silica gel column chromatography with ethyl acetate as eluent. The product is dried in vacuo at 50° C.  
      Yield: 2.20 g (96% of theory),  
      R f  value: 0.50 (silica gel, ethyl acetate)  
      C 16 H 18 N 2 O 3    
      EII Mass spectrum: m/z=287 [M+H] +   
      M.p. 107-110° C.  
     XIX.1.b  
     3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propionaldehyde  
      0.90 g (3.1 mmol) 3-(2-[1,3]Dioxolan-2-yl-ethyl)-6-(4-methoxy-phenyl)-pyridazine are dissolved in 15 ml 4 N HCl. The mixture is stirred for 2 hours at RT. After that time ethyl acetate is added and the mixture is neutralized by addition of sodium hydrogen carbonate. The organic phase is separated and dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at 50° C.  
      Yield: 0.70 g (92% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol=9:1)  
      C 14 H 14 N 2 O 2    
      EII Mass spectrum: m/z=243 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (XIX.2) 3-(6-Phenoxy-pyridazin-3-yl)-propionaldehyde starting from 3-iodo-6-phenoxy-pyridazine (prepared analogously to J. Org. Chem. 1963, 28, 218) in step a        

     EXAMPLE XX.1  
     4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamino}-benzaldehyde  
     
       
         
         
             
             
         
       
     
     XX.1.a  
      (4-Dimethoxymethyl-phenyl)-{3-[6-(4-methoxy-phenyl)-pyridazin-3-yl]-propyl]-amine 200 mg (0.82 mmol) 3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamine (educt II.1) and 0.14 ml (0.82 mmol) 4-bromo-benzaldehyde dimethyl actetal are dissolved in 3.0 ml of dioxane and 10 mg (0.03 mmol) 2-(di-tert-butylphosphino)biphenyl, 22 mg (0.03 mmol) tris(dibenzylideneaceton)dipalladium(0) and 110 mg (1.2 mmol) sodium tert-butoxide are added. The mixture is stirred for 5 hours at 60° C. in a sealed tube under argon atmosphere. After cooling, the solvent is removed. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (92:8:0.1) as eluent.  
      Yield: 190 mg (59% of theory),  
      R f  value: 0.85 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      retention time (HPLC): 3.1 min (method A)  
      C 23 H 27 N 3 O 3    
      EII mass spectrum: m/z=394 [M+H] +   
     XX.1.b  
      4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamino}-benzaldehyde 150 mg (0.38 mmol) (4-Dimethoxymethyl-phenyl)-{3-[6-(4-methoxy-phenyl)-pyridazin-3-yl]-propyl}-amine are dissolved in 10 ml THF and 1 ml 1 N HCl is added. The mixture is stirred for 4 hours at RT. After that time ethyl acetate is added and the mixture is neutralized by addition of sodium carbonate solution. The organic phase is separated and dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at 50° C.  
      Yield: 0.11 g (83% of theory),  
      R f  value: 0.60 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      C 21 H 21  N 3 O 2    
      EII Mass spectrum: m/z=348 [M+H] +   
     EXAMPLE XXI  
      The following compounds are synthesised analogously to the method described in WO 2001/27081 (example XX): 
          (XXI.1) 1-(4-amino-benzyl)-azetidin-3-ol     (XXI.2) 1-(4-amino-benzyl)-piperidine-4-carboxylic acid dimethylamide        

     EXAMPLE XXII.1  
     [6-(3-Amino-propyl)-pyridazin-3-yl]-benzyl-amine  
     
       
         
         
             
             
         
       
     
     XXII.1.a  
     [3-(6-Benzylamino-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester  
      0.27 g (1.0 mmol) [3-(6-Chloro-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester (example XIV.1.b) are dissolved in 1.1 ml benzylamine and stirred for 5 hours at 140° C. After cooling down, the solvent is evaporated and the residue is purified by silica gel column chromatography with methylene chloride/methanol (9:1) as eluent. The product is dried in vacuo at 50° C.  
      Yield: 0.18 g (53% of theory),  
      R f  value: 0.70 (silica gel, methylene chloride/methanol (9:1)  
     XXII.1.b  
     [6-(3-Amino-propyl)-pyridazin-3-yl]-benzyl-amine  
      1.15 g (3.36 mmol) [3-(6-Benzylamino-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester are dissolved in 50 ml methylene chloride and 3.0 ml of trifluoroacetic acid are added. The mixture is stirred for 12 hours at RT. After that time the solvent is evaporated. The residue is taken up in methylene chloride and washed with 1N NaOH-solution. The organic phase is dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at 70° C.  
      Yield: 0.75 g (92% of theory),  
      R f  value: 0.10 (silica gel, methylene chloride/methanol/ammonia=5:1:0.02) C 14 H 18 N 4    
      EII Mass spectrum: m/z=243 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (XXII.2) [6-(3-Amino-propyl)-pyridazin-3-yl]-benzyl-methyl-amine        

     EXAMPLE XXIII.1  
     3-[6-(Pyridin-3-yloxy)-pyridazin-3-yl]-propylamine  
     
       
         
         
             
             
         
       
     
     XXIII.1.a  
     [3-(6-Benzylamino-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester  
      2.70 g (10.0 mmol) [3-(6-Chloro-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester (example XIV.1.b), 1.30 g (13.7 mmol) 3-hydroxy-pyridine, 4.25 g (1.00 mmol) potassium phosphate, 0.425 g (1.00 mmol) di-tert-butyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane and 460 mg (0.50 mmol) tris(dibenzylideneacetone)dipalladium(0) are dissolved in 30 ml dioxane under argon atmosphere. The mixture is stirred for 25 hours at 100° C. After that time the mixture is cooled down, filtered through celite and the solvent is removed. The residue is purified by silica gel column chromatography with methylene chloride/ethyl acetate (1:1) as eluent.  
      Yield: 1.80 g (55% of theory),  
      R f  value: 0.30 (silica gel, ethyl acetate)  
      C 17 H 22 N 4 O 3    
      EII Mass spectrum: m/z=331 [M+H] +   
     XXIII.1.b  
     3-[6-(Pyridin-3-yloxy)-pyridazin-3-yl]-propylamine  
      1.80 g (5.45 mmol) [3-(6-Benzylamino-pyridazin-3-yl)-propyl]-carbamic acid tert-butyl ester are dissolved in 50 ml methylene chloride and 4.0 ml of trifluoroacetic acid are added. The mixture is stirred for 12 hours at RT. After that time the solvent is evaporated. The residue is taken up in methylene chloride and washed with 1N NaOH-solution. The organic phase is dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at 50° C.  
      Yield: 0.80 g (64% of theory),  
      R f  value: 0.30 (silica gel, methylene chloride/methanol/ammonia=5:2:0.01)  
     EXAMPLE XXIV.1  
     4-[3-(6-Phenoxy-pyridazin-3-yl)-propoxy]-benzaldehyde  
     
       
         
         
             
             
         
       
     
      0.20 g (0.60 mmol) {4-[3-(6-Phenoxy-pyridazin-3-yl)-propoxy]-phenyl}-methanol (educt XV.3) are dissolved in 10 ml methylene chloride and 0.36 g (3.0 mmol) manganese dioxide are added. The mixture is stirred for 3 hours at RT. After that time, the mixture is filtered through celite and the solvent is removed.  
      Yield: 170 mg (86% of theory),  
      C 20 H 18 N 2 O 3    
      EII mass spectrum: m/z=335 [M+H] +   
      The following compounds are synthesised analogously to the method described above: 
          (XXIV.2) 4-[3-(6-Benzyloxy-pyridazin-3-yl)-propoxy]-benzaldehyde using {4-[3-(6-benzyloxy-pyridazin-3-yl)-propoxy]-phenyl}-methanol (educt XV.5) as starting material        

     EXAMPLE XXV  
      The following starting materials can be prepared analogously to procedures described in WO 2004/039780: 
          (XXV. 1) 1-(4-{4-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-but-3-ynyl}-benzyl)-piperidin-4-ol     (XXV.2) 1-{4-[4-(6-Benzyloxy-pyridazin-3-yl)-but-3-ynyl]-benzyl}-piperidin-4-ol        

     EXAMPLE XXVI.1  
     (6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-butyl}-pyridazin-3-yl)-methanol  
     
       
         
         
             
             
         
       
     
     XXVI.1.a  
     3-(6-Chloro-pyridazin-3-yl)-prop-2-yn-1-ol  
      42.0 g (175 mmol) 3-Chloro-6-iodo-pyridazine (Tetrahedron 55, 1999, 15067) and 11.2 ml (192 mmol) propargyl alcohol are dissolved in 400 ml THF and 1.23 g (1.75 mmol) bis-(triphenylphosphine)palladiumdichloride, 665 mg (3.49 mmol) copper-(I)-iodide and finally 49.4 ml diisopropylamine are added at 0° C. under inert gas. The mixture is stirred for 0.5 hours at 0° C. and for an additional hour at RT. After that time, ethyl acetate is added and the solution is washed with diluted ammonia solution twice. The organic phase is separated and dried over magnesium sulphate. The product is taken up in ethyl acetate/acetonitrile and filtered through charcoal. Finally, the solvent is removed in vacuo.  
      Yield: 19.5 g (66% of theory),  
      C 7 H 5 ClN 2 O  
      EII Mass spectrum: m/z=169 [M+H] +   
     XXVI.1.b  
     3-(6-Chloro-pyridazin-3-yl)-propan-1-ol  
      19.4 g (115 mmol) 3-(6-Chloro-pyridazin-3-yl)-prop-2-yn-1-ol are dissolved in 400 ml THF. 4.00 g Platinum(IV) oxide and 3.05 g vanadyl(IV) acetylacetonate are added and the mixture is hydrogenated (15 psi) at RT for 5 hours. After that time, the catalyst is filtered off and the filtrate evaporated. The residue is purified by silica gel column chromatography with ethyl acetate as eluent.  
      Yield: 9.80 g (49% of theory),  
      R f  value: 0.30 (silica gel, ethyl acetate)  
      C 7 H 9 ClN 2 O  
      EII Mass spectrum: m/z=173/175 [M+H] +   
     XXVI.1.c  
     3-(6-Chloro-pyridazin-3-yl)-propionaldehyde  
      5.30 ml (61.8 mmol) Oxalyl chloride are dissolved in 250 ml methylene chloride under inert atmosphere. The solution is cooled to −60° C. and 8.77 ml (124 mmol) anhydrous DMSO in 30 ml methylene chloride are added at −60° C. and stirred for additional 10 minutes at −60° C. After that time, 8.20 g (47.5 mmol) {3-(6-chloro-pyridazin-3-yl)-propan-1-ol dissolved in 100 ml methylene chloride are added. The mixture is stirred for 45 minutes at −55° C. After that time, 16.0 ml (115 mmol) triethylamine are carefully added, the cooling bath is removed and the mixture is stirred for 12 hours at RT. Methylene chloride is added and the organic phase is washed with water twice. The organic phase is dried over magnesium sulphate, the solvent is removed and the residue is purified by silica gel column chromatography with ethyl acetate as eluent.  
      Yield: 3.60 g (44% of theory),  
      R f  value: 0.50 (silica gel, ethyl acetate)  
      C 7 H 7 ClN 2 O  
      EII mass spectrum: m/z=171/173 [M+H] +   
     XXVI.1.d  
     3-But-3-ynyl-6-chloro-pyridazine  
      3.60 g (21.1 mmol) 3-(6-Chloro-pyridazin-3-yl)-propionaldehyde are dissolved in 150 ml methanol and 5.83 g (42.2 mmol) potassium carbonate and finally 4.87 g (25.3 mmol) dimethyl 1-diazo-2-oxopropylphosphonate are added. The mixture is stirred for 12 hours at RT. After that time, ethyl acetate is added and the organic phase is washed with water twice.  
      The organic phase is dried over magnesium sulphate, the solvent is removed and the residue is purified by silica gel column chromatography with petrol ether/ethyl acetate (1:1) as eluent.  
      Yield: 2.00 g (57% of theory),  
      R f  value: 0.60 (silica gel, petrol ether/ethyl acetate=1:1)  
      C 8 H 7 ClN 2    
      EII mass spectrum: m/z=167/169 [M+H] +   
     XXVI.1.e  
     3-Chloro-6-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-pyridazine  
      1.0 g (6.0 mmol) 3-But-3-ynyl-6-chloro-pyridazine and 1.9 g (6.0 mmol) 5-(4-chloro-phenyl)-2-iodo-pyridine (described in WO 2004/039780) are dissolved in 20 ml THF and 98 mg (0.12 mmol) PdCl 2 (dppf), 23 mg (0.12 mmol) copper-(I)-iodide and finally 1.7 ml diisopropylamine are added at RT under inert gas. The mixture is stirred for 3 hours at RT. After that time, methanol is added and the precipitate is filtered off. The filtrate is reduced in vacuo, methanol is added and the precpitate is filtered off. The combined precpitates are dried at RT.  
      Yield: 2.1 g (89% of theory),  
      R f  value: 0.50 (silica gel, petrol ether/ethyl acetate=2:8)  
      C 19 H 13 Cl 2 N 3    
      EII Mass spectrum: m/z=354/356/358 [M+H] +   
     XXVI.1.f  
      6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-but-3-ynyl]-pyridazine-3-carboxylic acid methyl ester 2.00 g (5.65 mmol) 3-Chloro-6-a4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-pyridazine are dissolved in 20 ml methanol and 20 ml DMF and 101 mg (0.452 mmol) palladium(II) acetate, 250 mg (0.452 mmol) dppf and 1.6 ml triethylamine are added under inert gas. The mixture is transferred to an autoclave and CO is added (4 bar). The mixture is shaken for 4 hours at 50° C. After cooling down, the precipitate is filtered off. The filtrate is reduced in vacuo and the residue is purified by silica gel column chromatography with ethyl acetate as eluent. The product and the precipitate are combined, dissolved in methylene chloride and some methanol and filtered through silica gel. Finally, the solvent is removed in vacuo.  
      Yield: 1.00 g (47% of theory),  
      C 21  H 16 ClN 3 O 2    
      EII Mass spectrum: m/z=378/380 [M+H] +   
     XXVI.1.q  
     6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-butyl}-pyridazine-3-carboxylic acid methyl ester  
      600 mg (1.59 mmol) 6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-pyridazine-3-carboxylic acid methyl ester-are dissolved in 60 ml ethyl acetate. 200 mg Raney nickel are added and the mixture is hydrogenated (3 bar) at RT until completion. After that time, methanol is added, the catalyst is filtered off and the filtrate evaporated. The residue is purified by silica gel column chromatography with ethyl acetate as eluent.  
      Yield: 400 mg (66% of theory),  
      C 21 H 20 ClN 3 O 2    
      EII Mass spectrum: m/z=382/384 [M+H] +   
     XXVI.1.h  
     6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-butyl}-pyridazine-3-carboxylic acid  
      500 mg (1.31 mmol) 6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-butyl}-pyridazine-3-carboxylic acid methyl ester are dissolved in 25 ml methanol and 4.0 ml 1N NOH are added. The mixture is stirred for 2 hours at RT. After that time, 4.0 ml 1N HCl are added. The solvent is almost removed in vacuo and the precipitate is filtered off. The precipitate is washed with water and dried at 40° C.  
      Yield: 480 mg (100% of theory),  
      C 20 H 18 ClN 3 O 2    
      EII Mass spectrum: m/z=368/370 [M+H] +   
     XXVI.1.i  
     (6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-butyl}-pyridazin-3-yl)-methanol  
      480 mg (1.31 mmol) 6-{4-[5-(4-Chloro-phenyl)-pyridin-2-yl]-butyl}-pyridazine-3-carboxylic acid are dissolved in 30 ml THF and 233 mg (1.44 mmol) 1,1′-carbonyl-diimidazole are added. The mixture is stirred for 1 hour at 50° C. After cooling down, the mixture is added to a solution of 148 mg (3.92 mmol) sodium borohydride in 40 ml water. The mixture is stirred for 30 minutes. The mixture is acidified by addition of 1 N potassium hydrogensulphate solution and stirred for 20 minutes. After that time, the mixture is neutralized by addition of sodium hydrogencarbonate solution. The aqueous phase is extracted with ethyl acetate twice. The organic phase is washed with water twice and dried over sodium sulphate. After evaporation of the solvent, the product is purified by silica gel column chromatography with ethyl acetate/methanol (9:1) as eluent.  
      Yield: 250 mg (54% of theory),  
      C 20 H 20 ClN 3 O  
      EII Mass spectrum: m/z=354/356 [M+H] +   
      Preparation of the End Compounds:  
     EXAMPLE 1.1  
     [3-(4′-Chloro-biphenyl-4-yl)-propyl]-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-amine  
     
       
         
         
             
             
         
       
     
      246 mg (1.00 mmol) 3-(4′-Chloro-biphenyl-4-yl)-propylamine (educt I.1) and 315 mg (1.00 mmol) 1-(4-iodo-benzyl)-4-methyl-piperidine (educt III.1) are dissolved in 1.5 ml of isopropanol and 112 ml (2.00 mmol) ethyleneglycol, 425 mg (2.00 mmol) potassium phosphate and 10 mg (0.05 mmol) copper-(I)-iodide are added. The mixture is stirred for 15 hours at 80° C. in a sealed tube under argon atmosphere. After cooling, water and ethyl acetate are added. The organic phase is separated and dried over sodium sulphate. After evaporation of the solvent, the residue is purified by silica gel column chromatography with methylene chloride/ethanol/ammonia (5:1:0.01) as eluent.  
      Yield: 190 mg (44% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      M.p. 69-71° C.  
      C 28 H 33 ClN 2    
      EII mass spectrum: m/z=433/435 [M+H] +   
     EXAMPLE 2  
      The following compounds of general formula II-1 are prepared analogously to Example 1.1, the educts used being shown in the column headed “Educts”:  
                                      (II-1)                                                                           Exam-               mass   M.p.           ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   R f -value                                               2.1                                               II.1 III.1   431 [M + H] +     133-135   0.50 (A)               2.2                                               II.1 III.1   435/437 [M + H] +     129-131   0.60 (A)               2.3                                               VI.1 III.18   433 [M + H] +     n.d.   0.40 (A)               2.4                                               VI.1 III.1   431 [M + H] +     n.d.   0.50 (A)               2.5                                               II.1 III.38   460 [M + H] +     n.d.   0.45 (B)               2.6                                               II.1 III.39   391 [M + H] +     n.d.   0.55 (B)                  
 
     
       
         
         
             
             
         
       
     
     EXAMPLE 3.1  
     {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-[4-(4-methyl)-phenyl]-amine  
      243 mg (1.00 mmol) 3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamine (educt II.1) and 322 mg (1.00 mmol) 1-(4-bromo-benzyl)-4-trifluoromethyl-piperidine (educt III.2) are dissolved in 2.0 ml of dioxane and 12 mg (0.04 mmol) 2-(di-tert-butylphosphino)biphenyl, 18 mg (0.02 mmol) tris(dibenzylideneaceton)dipalladium(0) and 135 mg (1.4 mmol) sodium tert-butoxide are added. The mixture is stirred for 26 hours at 80° C. in a sealed tube under argon atmosphere. After cooling, water is added. The precipitate is filtered off and purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.1) as eluent.  
      Yield: 290 mg (60% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      retention time (HPLC): 2.4 min (method A)  
      C 27 H 31 F 3 N 4 O  
      EII mass spectrum: m/z=485 [M+H] +   
      The following compounds of general formula III-1 are prepared analogously to Example 3.1, the educts used being shown in the column headed “Educts”:  
                                      (III-1)                                                                                                               ret. time           Exam-                   mass   M.p.   (HPLC)       ple   R 1 R 2 N-X-   -W-B   D   Educts   spectrum   [° C.]   [min]*   R f -value                                                                                                 3.2                                               CH   II.1 III.3   377 [M + H] +     n.d.   n.d.   0.50 (A)               3.3                                               CH   II.1 III.4   417 [M + H] +     85   n.d.   0.40 (A)               3.4                                               CH   II.1 III.9   433 [M + H] +     145-148   2.2   0.50 (D)               3.5                                               CH   II.1 III.10   433 [M + H] +     140-142   2.2   0.50 (D)               3.6                                               CH   II.1 III.8   501 [M + H] +     173-176   2.3   0.50 (A)               3.7                                               N   II.1 V.1   418 [M + H] +     160-162   2.2   0.60 (D)               3.8                                               CH   II.2 III.3   381/383 [M + H] +     126-130   2.4   0.30 (A)               3.9                                               CH   II.1 III.11   419 [M + H] +     n.d.   2.3   0.60 (B)               3.10                                               CH   II.1 III.12   447 [M + H] +     n.d.   2.2   0.45 (B)               3.11                                               CH   II.1 III.13   447 [M + H] +     n.d.   2.2   0.35 (B)               3.12                                               CH   VI.1 III.4   417 [M + H] +     n.d.   2.4   0.50 (A)               3.13                                               CH   II.2 III.4   421/423 [M + H] +     n.d.   2.6   0.50 (A)               3.14                                               CH   II.1 III.14   460 [M + H] +     n.d.   2.2   0.80 (B)               3.15                                               CH   II.2 III.9   437/439 [M + H] +     120-125   2.4   0.30 (A)               3.16                                               CH   II.2 III.8   505/507 [M + H] +     n.d.   2.6   0.50 (A)               3.17                                               CH   II.2 III.10   437/439 [M + H] +     90-95   2.5   0.50 (A)               3.18                                               CH   II.1 III.15   474 [M + H] +     n.d.   2.2   0.80 (B)               3.19                                               CH   II.1 III.16   405 [M + H] +     n.d.   2.2   0.85 (B)               3.20                                               CH   II.1 III.17   463 [M + H] +     n.d.   2.2   0.45 (B)               3.21                                               CH   VI.1 III.9   433 [M + H] +     70-73   2.4   0.20 (A)               3.22                                               CH   VI.1 III.8   501 [M + H] +     145-147   2.6   0.40 (A)               3.23                                               CH   VI.1 III.3   377 [M + H] +     n.d.   2.4   0.40 (A)               3.24                                               CH   II.1 III.19   449 [M + H] +     n.d.   2.5   0.80 (L)               3.25                                               CH   II.1 III.20   433 [M + H] +     n.d.   2.4   0.65 (L)               3.26                                               CH   II.1 III.21   433 [M + H] +     n.d.   2.4   0.65 (L)               3.27                                               CH   II.1 III.22   363 [M + H] +     n.d.   2.3   0.30 (L)               3.28                                               CH   II.1 III.23   403 [M + H] +     n.d.   2.4   0.50 (L)               3.29                                               CH   II.1 III.24   465 [M + H] +     n.d.   2.4   0.80 (L)               3.30                                               CH   II.1 III.25   460 [M + H] +     n.d.   2.3   0.50 (L)               3.31                                               CH   II.1 III.26   437 [M + H] +     n.d.   2.3   0.65 (L)               3.32                                               CH   II.1 III.27   433 [M + H] +     n.d.   2.4   0.80 (L)               3.33                                               CH   II.3 III.4   412 [M + H] +     180-182   2.4   0.40 (A)               3.34                                               CH   VI.2 III.4   341 [M + H] +     64-66   2.0   0.40 (A)               3.35                                               CH   VI.3 III.4   447 [M + H] +     64-67   2.2   0.40 (A)               3.36                                               CH   VI.4 III.4   369 [M + H] +     69-72   2.4   0.40 (A)               3.37                                               CH   II.1 III.28   460 [M + H] +     n.d.   2.3   0.40 (B)               3.38                                               CH   VI.5 III.4   369 [M + H] +     n.d.   2.2   0.40 (A)               3.39                                               CH   VI.5 III.10   385 [M + H] +     n.d.   2.1   0.40 (A)               3.40                                               CH   II.1 III.29   475 [M + H] +     n.d.   2.4   0.60 (B)               3.41                                               CH   II.1 III.30   n.d.   n.d.   2.4   0.70 (B)               3.42                                               CH   II.1 III.31   419 [M + H] +     n.d.   2.3   0.45 (B)               3.43                                               CH   II.1 III.32   488 [M + H] +     n.d.   2.3   0.60 (B)               3.44                                               CH   II.1 III.33   467 [M + H] +     n.d.   2.3   0.70 (B)               3.45                                               CH   II.1 III.34   467 [M + H] +     n.d.   2.3   0.70 (B)               3.46                                               CH   II.1 III.35   407 [M + H] +     n.d.   2.3   0.35 (B)               3.47                                               CH   II.1 III.36   447 [M + H] +     n.d.   2.4   0.30 (B)               3.48                                               CH   II.1 III.37   447 [M + H] +     n.d.   2.4   0.30 (B)               3.49                                               CH   VI.6 III.4   435 [M + H] +     95-98   2.6   0.50 (A)               3.50                                               CH   VI.6 III.9   451 [M + H] +     80-83   2.4   0.30 (B)               3.51                                               CH   II.2 III.15   478/480 [M + H] +     n.d.   2.5   0.45 (A)               3.52                                               CH   II.2 III.13   447 [M + H] +     n.d.   2.5   0.45 (A)               3.53                                               CH   VI.6 III.8   519 [M + H] +     132-135   2.6   0.50 (A)               3.54                                               CH   VI.6 III.10   451 [M + H] +     n.d.   2.4   0.40 (A)               3.55                                               CH   VI.6 III.3   395 [M + H] +     69-70   2.4   0.30 (A)               3.56                                               CH   VI.6 III.1   449 [M + H] +     75-78   2.6   0.40 (A)               3.57                                               CH   II.4 III.4   405 [M + H] +     112-115   2.4   0.40 (A)               3.58                                               CH   II.4 III.9   421 [M + H] +     142-144   2.3   0.40 (A)               3.59                                               CH   II.1 III.40   460 [M + H] +     n.d.   2.2   0.40 (B)               3.60                                               CH   II.1 III.41   498 [M + H] +     n.d.   2.2   0.25 (B)               3.61                                               CH   VI.6 III.15   492 [M + H] +     188-192   2.4   0.60 (D)               3.62                                               CH   II.4 III.15   462 [M + H] +     150-153   2.3   0.40 (A)               3.63                                               CH   II.1 III.42   433 [M + H] +     n.d.   2.4   0.30 (B)               3.64                                               CH   II.1 III.43   433 [M + H] +     n.d.   2.3   0.40 (B)               3.65                                               CH   II.1 III.44   407 [M + H] +     n.d.   2.3   0.35 (B)               3.66                                               CH   VI.6 III.11   437 [M + H] +     50   2.5   0.40 (A)               3.67                                               CH   XIV.1 III.4   430 [M + H] +     120-125   2.4   0.50 (A)               3.68                                               CH   XIV.1 III.9   446 [M + H] +     160-163   2.2   0.40 (D)               3.69                                               CH   II.1 III.45   389 [M + H] +     n.d.   2.2   0.40 (B)               3.70                                               CH   II.1 III.46   474 [M + H] +     n.d.   2.3   0.60 (B)               3.71                                               CH   II.1 III.47   449 [M + H] +     n.d.   2.2   0.40 (B)               3.72                                               CH   VI.6 III.13   465 [M + H] +     n.d.   2.4   0.20 (A)               3.73                                               CH   II.1 III.48   449 [M + H] +     n.d.   2.2   0.40 (B)               3.74                                               CH   II.1 III.49   447 [M + H] +     n.d.   2.2   0.25 (B)               3.75                                               CH   II.1 III.50   447 [M + H] +     n.d.   2.3   0.30 (B)               3.76                                               CH   II.2 III.32   492/494 [M + H] +     n.d.   2.5   0.30 (B)               3.77                                               CH   II.1 III.51   447 [M + H] +     n.d.   2.2   0.65 (B)               3.78                                               CH   II.1 III.52   447 [M + H] +     n.d.   2.3   0.40 (B)               3.79                                               CH   VI.1 III.20   433 [M + H] +     n.d.   2.4   0.30 (B)               3.80                                               CH   VI.1 III.21   433 [M + H] +     n.d.   2.4   0.30 (B)               3.81                                               CH   II.4 III.21   474 [M + H] +     n.d.   2.4   0.30 (B)               3.82                                               CH   II.1 III.53   415 [M + H] +     n.d.   2.4   0.50 (B)               3.83                                               CH   VI.7 III.9   419 [M + H] +     120-125   2.3   0.50 (A)               3.84                                               CH   VI.7 III.4   403 [M + H] +     90-92   2.4   0.40 (A)               3.85                                               CH   II.4 III.23   403 [M + H] +     n.d.   2.4   0.30 (B)               3.86                                               CH   II.1 III.54   435 [M + H] +     n.d.   2.2   0.10 (B)               3.87                                               CH   II.1 III.55   447 [M + H] +     n.d.   2.3   0.50 (B)               3.88                                               CH   II.4 III.13   447 [M + H] +     n.d.   2.4   0.35 (B)               3.89                                               CH   II.1 III.56   446 [M + H] +     n.d.   2.4   0.50 (B)               3.90                                               CH   XIV.2 III.4   412 [M + H] +     120-122   2.4   0.30 (B)               3.91                                               CH   II.4 III.57   391 [M + H] +     n.d.   2.2   0.40 (B)               3.92                                               CH   VI.6 III.11   419 [M + H] +     n.d.   2.4   0.40 (B)               3.93                                               CH   XIV.2 III.9   428 [M + H] +     120-122   2.2   0.60 (D)               3.94                                               CH   XIV.3 III.4   388 [M + H] +     135-138   1.8   0.50 (D)               3.95                                               CH   XIV.4 III.4   401 [M + H] +     128-130   2.5   0.50 (A)               3.96                                               CH   XIV.4 III.9   417 [M + H] +     133-135   2.3   0.20 (A)               3.97                                               CH   II.4 III.32   488 [M + H] +     n.d.   2.4   0.55 (B)               3.98                                               CH   XIV.5 III.4   423 [M + H] +     104-106   2.5   0.40 (A)               3.99                                               CH   XIV.5 III.9   439 [M + H] +     80-82   2.54   0.40 (D)               3.100                                               CH   VI.7 III.21   460 [M + H] +     145-148   2.3   0.60 (D)               3.101                                               CH   VI.7 III.3   363 [M + H] +     n.d.   2.3   0.30 (A)               3.102                                               CH   XIV.1 III.11   432 [M + H] +     143-145   2.3   0.70 (A)               3.103                                               CH   XIV.1 III.3   390 [M + H] +     135-137   2.2   0.40 (A)               3.104                                               CH   II.1 III.58   489 [M + H] +     n.d.   2.3   0.25 (B)               3.105                                               CH   II.1 III.59   432 [M + H] +     n.d.   2.2   0.35 (B)               3.106                                               CH   XIV.1 III.21   487 [M + H] +     176-178   2.3   0.80 (D)               3.107                                               CH   II.1 III.60   502 [M + H] +     n.d.   2.3   0.35 (B)               3.108                                               CH   II.1 III.61   445 [M + H] +     n.d.   2.7   0.45 (B)               3.109                                               CH   XVII.1 III.4   415 [M + H] +     80-85   2.5   0.40 (A)               3.110                                               CH   XIV.1 III.55   460 [M + H] +     120-122   2.3   0.40 (A)               3.111                                               CH   II.1 III.62   500 [M + H] +     n.d.   2.4   0.30 (B)               3.112                                               CH   II.1 III.63   474 [M + H] +     n.d.   2.3   0.35 (B)               3.113                                               CH   II.1 III.64   515 [M + H] +     n.d.   2.4   0.45 (B)               3.114                                               CH   II.1 III.65   488 [M + H] +     n.d.   2.4   0.45 (B)               3.115                                               CH   VI.6 III.32   506 [M + H] +     125-128   2.5   0.40 (A)               3.116                                               CH   II.1 III.66   488 [M + H] +     n.d.   2.4   0.35 (B)               3.117                                               CH   II.1 III.67   510 [M + H] +     n.d.   2.3   0.40 (B)               3.118                                               CH   II.2 III.25   464/466 [M + H] +     n.d.   2.5   0.40 (B)               3.119                                               CH   II.2 III.40   464/466 [M + H] +     n.d.   2.5   0.30 (B)               3.120                                               CH   II.2 III.31   423/425 [M + H] +     n.d.   2.5   0.30 (B)               3.121                                               CH   II.2 III.20   437/439 [M + H] +     n.d.   2.5   0.50 (B)               3.122                                               CH   II.2 III.34   423/425 [M + H] +     n.d.   2.6   0.30 (B)               3.123                                               CH   VI.6 III.20   451 [M + H] +     125-128   2.5   0.40 (A)               3.124                                               CH   VI.6 III.21   451 [M + H] +     125-128   2.5   0.40 (A)               3.125                                               CH   XIV.1 III.20   446 [M + H] +     123-125   2.3   0.60 (A)               3.126                                               CH   XIV.1 III.21   446 [M + H] +     125   2.3   0.60 (A)               3.127                                               CH   II.2 III.21   437/439 [M + H] +     n.d.   2.5   0.50 (B)               3.128                                               CH   XIV.1 III.13   460 [M + H] +     135-138   2.2   0.30 (A)               3.129                                               CH   XIV.1 III.32   501 [M + H] +     140-142   2.3   0.40 (A)               3.130                                               CH   II.2 III.33   471/473 [M + H] +     n.d.   2.7   0.55 (B)               3.131                                               CH   VI.6 III.25   478 [M + H] +     150-153   2.5   0.30 (A)               3.132                                               CH   VI.6 III.57   409 [M + H] +     75-78   2.4   0.30 (A)               3.133                                               CH   XIV.1 III.41   511 [M + H] +     155-160   2.2   0.60 (D)               3.134                                               CH   II.1 III.69   524 [M + H] +     n.d.   2.5   0.45 (B)               3.135                                               CH   II.1 III.70   460 [M + H] +     n.d.   2.2   0.30 (B)               3.136                                               CH   II.2 III.26   441/443 [M + H] +     n.d.   2.5   0.35 (B)               3.137                                               CH   II.2 III.41   502/504 [M + H] +     n.d.   2.6   0.40 (B)               3.138                                               CH   II.2 III.35   411/413 [M + H] +     n.d.   2.5   0.40 (B)               3.139                                               CH   II.2 III.12   451/453 [M + H] +     n.d.   2.5   0.40 (B)               3.140                                               CH   II.2 III.66   492/494 [M + H] +     n.d.   2.6   0.30 (B)               3.141                                               CH   XVII.2 III.4   401 [M + H] +     104-106   2.5   0.40 (A)               3.142                                               CH   XVII.2 III.9   417 [M + H] +     n.d.   2.2   0.20 (A)               3.143                                               CH   II.2 III.60   506/508 [M + H] +     n.d.   2.4   0.60 (B)               3.144                                               CH   XVII.2 III.21   458 [M + H] +     128-130   2.2   0.40 (A)               3.145                                               CH   II.2 III.72   425/427 [M + H] +     n.d.   2.5   0.40 (B)               3.146                                               CH   II.2 III.73   492/494 [M + H] +     n.d.   2.5   0.30 (B)               3.147                                               CH   II.2 III.74   451/453 [M + H] +     n.d.   2.5   0.40 (M)               3.148                                               CH   II.1 III.75   460 [M + H] +     n.d.   2.2   0.60 (B)               3.149                                               CH   VI.7 III.62   486 [M + H] +     168-173   2.4   0.40 (N)               3.150                                               CH   VI.7 III.32   474 [M + H] +     120-123   2.4   0.50 (N)               3.151                                               CH   VI.7 III.11   405 [M + H] +     116-120   2.3   0.70 (N)               3.152                                               CH   VI.7 III.23   389 [M + H] +     61-64   2.4   0.20 (A)               3.153                                               CH   VI.7 III.13   433 [M + H] +     n.d.   2.3   0.60 (D)               3.154                                               CH   VI.7 III.25   446 [M + H] +     n.d.   2.1   0.30 (A)               3.155                                               CH   VI.7 III.55   433 [M + H] +     n.d.   2.5   0.40 (A)               3.156                                               CH   II.2 III.76   435/437 [M + H] +     n.d.   2.5   0.55 (B)               3.157                                               CH   VI.7 III.20   419 [M + H] +     95-98   2.3   0.30 (A)               3.158                                               CH   VI.7 III.21   419 [M + H] +     95-98   2.3   0.30 (A)               3.159                                               CH   II.1 III.77   488 [M + H] +     n.d.   2.3   0.40 (B)               3.160                                               CH   XIV.6 III.4   423 [M + H] +     n.d.   2.5   0.40 (B)               3.161                                               CH   II.1 III.72   421 [M + H] +     n.d.   2.4   0.50 (B)               3.162                                               CH   XIV.6 III.21   480 [M + H] +     n.d.   2.4   n.d.               3.163                                               CH   XIV.6 III.9   439 [M + H] +     n.d.   2.3   n.d.               3.164                                               CH   XIV.6 III.3   383 [M + H] +     n.d.   2.3   n.d.               3.165                                               CH   II.1 III.73   488 [M + H] +     n.d.   2.1   0.40 (B)               3.166                                               CH   II.4 III.21   421 [M + H] +     n.d.   2.2   0.30 (B)               3.167                                               CH   II.4 III.20   421 [M + H] +     n.d.   2.2   0.30 (B)               3.168                                               CH   II.4 III.13   435 [M + H] +     n.d.   2.2   0.25 (B)               3.169                                               CH   II.4 III.32   476 [M + H] +     n.d.   2.2   0.30 (B)               3.170                                               CH   II.1 III.78   483 [M + H] +     n.d.   2.1   0.40 (B)               3.171                                               CH   II.1 III.79   488 [M + H] +     n.d.   2.3   0.50 (B)               3.172                                               CH   VI.7 III.75   377 [M + H] +     48-50   1.9   0.80 (D)               3.173                                               CH   II.4 III.11   407 [M + H] +     n.d.   2.2   n.d.               3.174                                               CH   II.4 III.62   488 [M + H] +     n.d.   2.2   n.d.               3.175                                               CH   II.4 III.23   391 [M + H] +     n.d.   2.1   n.d.               3.176                                               CH   II.4 III.75   379 [M + H] +     n.d.   2.0   n.d.               3.177                                               CH   VI.7 III.44   393 [M + H] +     n.d.   2.2   0.60 (D)               3.178                                               CH   VI.7 III.12   433 [M + H] +     n.d.   2.2   0.60 (D)               3.179                                               CH   II.2 III.44   411/413 [M + H] +     n.d.   2.4   0.50 (B)               3.180                                               CH   II.2 III.63   478/480 [M + H] +     n.d.   2.5   0.55 (B)               3.181                                               CH   II.1 III.80   407 [M + H] +     n.d.   2.3   0.35 (B)               3.182                                               CH   II.1 III.81   407 [M + H] +     n.d.   2.3   0.35 (B)               3.183                                               CH   VI.6 III.41   516 [M + H] +     132-135   2.3   0.80 (D)               3.184                                               CH   VI.6 III.44   425 [M + H] +     n.d.   2.2   0.40 (A)               3.185                                               CH   II.2 III.82   464/466 [M + H] +     n.d.   2.3   n.d.               3.186                                               CH   II.2 III.83   464/466 [M + H] +     n.d.   2.3   n.d.               3.187                                               CH   II.2 III.84   451/453 [M + H] +     n.d.   2.4   0.55 (B)               3.188                                               CH   II.2 III.85   451/453 [M + H] +     n.d.   2.4   0.55 (B)               3.189                                               CH   II.1 III.83   460 [M + H] +     n.d.   2.1   n.d.               3.190                                               CH   II.1 III.82   460 [M + H] +     n.d.   2.1   n.d.               3.191                                               CH   XVII.1 III.21   472 [M + H] +     166-168   2.1   0.30 (A)               3.192                                               CH   VI.6 III.82   478 [M + H] +     n.d.   2.3   0.45 (B)               3.193                                               CH   VI.6 III.83   478 [M + H] +     n.d.   2.3   0.45 (B)               3.194                                               CH   II.1 III.86   474 [M + H] +     n.d.   2.2   n.d.               3.195                                               CH   II.1 III.87   474 [M + H] +     n.d.   2.2   n.d.               3.196                                               CH   II.4 III.44   395 [M + H] +     n.d.   2.3   n.d.               3.197                                               CH   II.4 III.3   365 [M + H] +     n.d.   2.1   n.d.               3.198                                               CH   XVII.1 III.9   431 [M + H] +     n.d.   2.2   0.30 (A)               3.199                                               CH   XVII.2 III.66   472 [M + H] +     n.d.   2.1   0.50 (B)               3.200                                               CH   XVII.1 III.11   417 [M + H] +     n.d.   2.3   0.50 (A)               3.201                                               CH   XVII.1 III.41   496 [M + H] +     156-158   2.1   0.20 (A)               3.202                                               CH   XVII.1 III.62   498 [M + H] +     138-142   2.3   0.40 (A)               3.203                                               CH   II.1 III.84   447 [M + H] +     n.d.   2.2   0.25 (B)               3.204                                               CH   II.2 III.45   393/395 [M + H] +     n.d.   2.3   0.65 (B)               3.205                                               CH   XVII.2 III.21   417 [M + H] +     n.d.   2.2   0.45 (B)               3.206                                               CH   XVII.2 III.13   431 [M + H] +     n.d.   2.1   0.30 (B)               3.207                                               CH   XVII.2 III.32   472 [M + H] +     n.d.   2.3   0.40 (B)               3.208                                               CH   XVII.2 III.62   484 [M + H] +     n.d.   2.5   0.50 (B)               3.209                                               CH   II.1 III.85   447 [M + H] +     n.d.   2.2   n.d.               3.210                                               CH   VI.7 III.41   484 [M + H] +     n.d.   2.3   0.50 (D)               3.211                                               CH   XVII.2 III.44   391 [M + H] +     n.d.   2.0   0.60 (B)               3.212                                               CH   XVII.2 III.25   444 [M + H] +     n.d.   2.0   0.55 (B)               3.213                                               CH   XVII.2 III.20   417 [M + H] +     n.d.   2.2   0.50 (B)               3.214                                               CH   XVII.1 III.13   445 [M + H] +     110-113   2.2   0.30 (A)               3.215                                               CH   XVII.1 III.66   486 [M + H] +     111-115   2.2   0.30 (A)               3.216                                               CH   XVII.1 III.20   431 [M + H] +     118-121   2.2   0.30 (A)               3.217                                               CH   XVII.1 III.21   431 [M + H] +     119-121   2.2   0.30 (A)               3.218                                               CH   XVII.2 III.23   387 [M + H] +     n.d.   2.2   0.60 (B)               3.219                                               CH   XVII.2 III.41   482 [M + H] +     n.d.   2.3   0.40 (B)               3.220                                               CH   XII.1 III.4   416 [M + H] +     98-102   2.2   0.70 (D)               3.221                                               CH   XII.2 III.4   430 [M + H] +     n.d.   2.1   0.30 (A)               3.222                                               CH   XIII.1 III.4   404 [M + H] +     n.d.   2.1   0.50 (D)               3.223                                               CH   VI.7 III.66   474 [M + H] +     n.d.   2.1   n.d.               3.224                                               CH   VI.7 III.88   474 [M + H] +     n.d.   2.1   n.d.               3.225                                               CH   VI.7 III.82   446 [M + H] +     n.d.   2.1   n.d.               3.226                                               CH   VI.7 III.83   446 [M + H] +     n.d.   2.1   n.d.               3.227                                               CH   VI.7 III.40   446 [M + H] +     n.d.   2.1   n.d.               3.228                                               CH   II.1 III.88   488 [M + H] +     n.d.   2.1   n.d.               3.229                                               CH   II.2 III.88   492/494 [M + H] +     n.d.   2.3   n.d.               3.230                                               CH   VI.7 III.60   488 [M + H] +     n.d.   2.2   n.d.               3.231                                               CH   II.2 III.62   504/506 [M + H] +     n.d.   2.3   n.d.               3.232                                               CH   II.2 III.23   407/409 [M + H] +     n.d.   2.3   n.d.                 *HPLC method A             
 
      The following compounds are prepared analogously:  
     3.233  
     {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-amine  
                         
 from educts II.1/XVI.1 
 
      R f  value: 0.60 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      retention time (HPLC): 2.3 min (method A)  
      C 23 H 26 N 4 O  
      EII mass spectrum: m/z=375 [M+H] +   
     3.234  
     1-(4-{3-[6-(4-Chloro-phenyl)-pyridazin-3-yl]-propylamino}-2-methoxy-benzyl)-piperidin-4-ol  
                         
 from educts II.2/III.68 
 
      R f  value: 0.20 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      retention time (HPLC): 2.5 min (method A)  
      C 26 H 31  ClN 4 O 2    
      EII mass spectrum: m/z=467/469 [M+H] +   
     3.235  
     1-(4-{3-[6-(4-Chloro-phenyl)-pyridazin-3-yl]-propylamino}-2-fluoro-benzyl)-pipieridin-4-ol  
                         
 from educts II.2/III.71 
 
      R f  value: 0.30 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      retention time (HPLC): 2.5 min (method A)  
      C 25 H 28 ClFN 4 O  
      EII mass spectrum: m/z=455/457 [M+H] +   
     3.236  
     {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-6-yl)amine  
                         
 from educt II.1 and 6-bromo-2-methyl-1,2,3,4-tetrahydro-isoquinoline (J. Chem. Soc., Perkin Transactions 1, 1976, 757) 
 
      R f  value: 0.70 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      retention time (HPLC): 2.1 min (method A)  
      M.p. 163-166° C.  
      C 24 H 28 N 4 O  
      EII mass spectrum: m/z=389 [M+H] +   
     EXAMPLE 4  
      The following compounds of general formula IV-1 are prepared analogously to Example 3.1, the educts used being shown in the column headed “Educts”:  
                                      (IV-1)                                                                           Exam-               mass   M.p.           ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   R f -value                                               4.1                                               I.1 III.3    379/381 [M + H] +     85-90   0.70 (D)               4.2                                               I.1 III.4    419/421 [M + H] +     100-103   0.40 (A)               4.3                                               I.1 III.8    503/505 [M + H] +     n.d.   0.60 (A)                  
 
     EXAMPLE 5.1  
     1-{6-[3-(4′-Chloro-biphenyl-4-yl)-propylamino]-pyridin-3-ylmethyl}-4-methyl-piperidin-4-ol  
     
       
         
         
             
             
         
       
     
      400 mg (1.63 mmol) 3-(4′-Chloro-biphenyl-4-yl)-propylamine (educt I.1) and 386 mg (1.00 mmol) 1-(6-iodo-pyridin-3-ylmethyl)-4-trifluoromethyl-piperidin-4-ol (educt IV. 1) are dissolved in 1.0 ml of DMF and 190 mg (1.00 mmol) copper-(I)-iodide and 480 mg (2.5 mmol) cesium acetate are added. The mixture is stirred for 20 hours at 90° C. in a sealed tube under argon atmosphere. After cooling, ethyl acetate and water are added. The organic phase is separated and dried over sodium sulphate. The solvent is evaporated and the product is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.01) as eluent.  
      Yield: 120 mg (24% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      M.p. 170-172° C.  
      C 27 H 29 ClF 3 N 3 O  
      EII mass spectrum: m/z=504/506 [M+H] +   
      The following compounds of general formula V-1 are prepared analogously to Example 5.1, the educts used being shown in the column headed “Educts”:  
                                      (V-1)                                                                               Exam-                   mass   M.p.           ple   R 1 R 2 N-X-   -W-B   R N     Educts   spectrum   [° C.]   R f -value                                                   5.2                                               —H   I.1 IV.2   420/422 [M + H] +     102-105   0.80 (E)               5.3                                               —CH 3     I.2 IV.2   434/436 [M + H] +     n.d.   0.50 (A)               5.4                                               —CH 3     I.2 IV.1   447/449 [M + H] +     n.d.   0.40 (A)                  
 
     EXAMPLE 6.1  
     [3-(4′-Chloro-biphenyl-4-yl)-propyl]-[5-(4-methyl-piperidin-1-ylmethyl)-pyridin-2-yl]-amine  
     
       
         
         
             
             
         
       
     
      140 mg (0.57 mmol) 3-(4′-Chloro-biphenyl-4-yl)-propylamine (educt 1.1) and 128 mg (0.57 mmol) 1-(6-chloro-pyridin-3-ylmethyl)-4-methyl-piperidin (educt III.6) are dissolved in 3.0 ml of toluene and 6 mg (0.02 mmol) 2-(di-tert-butylphosphino)biphenyl, 1.3 mg (0.006 mmol) palladium(II) acetate and 77 mg (0.80 mmol) sodium tert-butoxide are added. The mixture is stirred for 15 hours at 110° C. in a sealed tube under argon atmosphere. After cooling, water and ethyl acetate are added. The organic phase is separated and dried over sodium sulphate. The solvent is evaporated and the product is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.01) as eluent.  
      Yield: 18 mg (7% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      C 27 H 32 ClN 3    
      EII mass spectrum: m/z=434/436 [M+H] +   
     EXAMPLE 7  
      The following compounds of general formula VII-1 are prepared analogously to Example 5.1, the educts used being shown in the column headed “Educts”:  
                                      (VII-1)                                                                           Exam-               mass   M.p.           ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   R f -value                                               7.1                                               II.1 IV.3   378 [M + H] +     120-122   0.40 (E)               7.2                                               II.1 IV.2   418 [M + H] +     140-145   0.50 (E)                  
 
     EXAMPLE 8.1  
     1-(4-{3-[5-(4-Chloro-phenyl)-pyridin-2-ylamino]-propyl}-benzyl)-pipieridin-4-ol  
     
       
         
         
             
             
         
       
     
      176 mg (0.50 mmol) (4-{3-[5-(4-Chloro-phenyl)-pyridin-2-ylamino]-propyl}-phenyl)-methanol (educt VII.1) and 0.10 ml (0.60 mmol) N-ethyl diisopropylamine are dissolved in 5.0 ml of THF and 0.05 ml (0.60 mmol) methane sulfonyl chloride are added at RT. After stirring for 2 hours at RT, 101 mg (1.00 mmol) 4-hydroxy-piperidine are added and the mixture is stirred for additional 10 hours at RT. After that time, water and ethyl acetate are added. The organic phase is separated, washed with water and dried over sodium sulphate. The solvent is evaporated and the product is purified by silica gel column chromatography with ethyl acetate/methanol/ammonia (9:1:0.1) as eluent.  
      Yield: 124 mg (57% of theory),  
      R f  value: 0.40 (silica gel, ethyl acetate/methanol/ammonia=9:1:0.1)  
      C 26 H 30 ClN 3 O  
      EII mass spectrum: m/z=436/438 [M+H] +   
      The following compounds of general formula VIII-1 are prepared analogously to Example 8.1, the educts used being shown in the column headed “Educts”:  
                                      (VIII-1)                                                                                                               ret. time           Exam-                   mass   M.p.   (HPLC)       ple   R 1 R 2 N-X-   -W-B   R N     Educts   spectrum   [° C.]   [min]*   R f -value                                                       8.2                                               —H   VII.1   436/438 [M + H] +     n.d.   2.7 (B)   0.50 (F)               8.3                                               —H   VII.1   466/468 [M + H] +     n.d.   2.7 (B)   0.10 (F)               8.4                                               —H   VII.1   422/424 [M + H] +     n.d.   2.7 (B)   0.50 (G)               8.5                                               —H   VII.1   434 [M + H] +     n.d.   7.4 (C)   n.d.               8.6                                               —CH 3     VIII.1   448/450 [M + H] +     n.d.   2.9 (B)   0.25 (H)                  
 
     EXAMPLE 9  
      The following compounds of general formula IX-1 are prepared analogously to Example 8.1, the educts used being shown in the column headed “Educts”:  
                                      (IX-1)                                                                                                       ret. time           Exam-               mass   M.p.   (HPLC)       ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   [min]*   R f -value                                                   9.1                                               VII.2   433 [M + H] +     n.d.   2.9   n.d.               9.2                                               VII.2   433 [M + H] +     n.d.   3.0   n.d.                 *HPLC method B             
 
      The following compounds of general formula IX-2 are prepared analogously to Example 8.1, the educts used being shown in the column headed “Educts”:  
                                      (IX-2)                                                                                                       ret. time           Exam-               mass   M.p.   (HPLC)       ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   [min]*   R f -value                                                   9.3                                               VII.3   405 [M + H] +     n.d.   2.6   n.d.                 *HPLC method A             
 
     EXAMPLE 10.1  
     [3-Chloro-4-(2-diethylamino-ethoxy)-phenyl]-[2-(2-chloro-4-trifluoromethyl-phenoxy)-ethyl]-amine  
     
       
         
         
             
             
         
       
     
      0.40 g (0.84 mmol) N-[3-Chloro-4-(2-diethylamino-ethoxy)-phenyl]-2-(2-chloro-4-trifluoromethyl-phenoxy)-acetamide (educt IX.1) are dissolved in 20 ml of THF and 4.0 ml of 1M borane-THF complex are added at RT. After stirring for 3 hours at RT, the solvent is evaporated. The residue is taken up in methanol and 0.5 ml conc. HCl are added. After stirring for 10 minutes at 1 00° C. the solvent is evaporated. The residue is taken up in 50 ml methylene chloride and 5.0 g sodium carbonate are added. The solution is filtered and the filtrate is evaporated. The residue is purified by aluminum oxide column chromatography with methylene chloride/methanol (8:2) as eluent.  
      Yield: 330 mg (85% of theory),  
      R f  value: 0.70 (aluminum oxide, methylene chloride/methanol=50:1)  
      C 21 H 25 Cl 2 F 3 N 2 O 2    
      EII mass spectrum: m/z=465/467/469 [M+H] +   
      The following compounds of general formula X-1 are prepared analogously to Example 10.1, the educts used being shown in the column headed “Educts”:  
                                      (X-1)                                                                                       Exam-                           mass   M.p.           ple   R 1 R 2 N-X-   -W-B   L 1     L 2     L 3     Educts   spectrum   [° C.]   R f -value                                                           10.2                                               —H   —Cl   —NMe 2     IX.3   474/476 [M + H] +     n.d.   0.75 (K)               10.3                                               —Br   —Br   —H   IX.4   571/573/ 575 [M + H] +     n.d.   0.65 (I)               10.4                                               —Br   —Br   —H   IX.5   545/547/ 549 [M + H] +     n.d.   0.55 (K)                  
 
     EXAMPLE 11  
      The following compounds of general formula XI-1 are prepared analogously to Example 10.1, the educts used being shown in the column headed “Educts”:  
                                      (XI-1)                                                                                       Exam-                           mass   M.p.           ple   R 1 R 2 N-X-   -W-B   L 1     L 2     L 3     Educts   spectrum   [° C.]   R f -value                                                           11.1                                               —Cl   —Cl   —H   IX.2   464/468/ 470 [M + H] +     n.d.   0.45 (K)                  
 
     EXAMPLE 12.1  
     (2-{2-Chloro-4-[2-(2-chloro-4-iodo-phenoxy)-ethoxy]-phenoxyl}-ethyl)-diethyl-amine  
     
       
         
         
             
             
         
       
     
      0.16 g (0.66 mmol) 3-Chloro-4-(2-diethylamino-ethoxy)-phenol (educt X.1) and 97 mg (0.70 mmol) potassium carbonate are dissolved in 20 ml of DMF and stirred for 45 minutes at 60° C. After that time 0.26 g (0.69 mmol) methanesulfonic acid 2-(2-chloro-4-iodo-phenoxy)-ethyl ester (educt XI.1) are added and the mixture is strirred for 10 hours at 80° C. After cooling the mixture is filtered and the filtrate is poured into 100 ml water. The solution is extracted with ethyl acetate and the organic phase is dried over sodium sulphate. The solvent is evaporated and the residue is purified by silica gel column chromatography with methylene chloride/methanol (9:1) as eluent.  
      Yield: 90 mg (26% of theory),  
      R f  value: 0.35 (silica gel, methylene chloride/methanol=9:1)  
      C 20 H 24 Cl 2 NO 3    
      EII mass spectrum: m/z=524/526 [M+H] +   
     EXAMPLE 13.1  
     1-(4-{2-[6-(4-Methoxy-phenyl)-pyridazin-3-yloxyl-ethoxy}-benzyl)-4-methyl-pipieridin-4-ol  
     
       
         
         
             
             
         
       
     
      100 mg (0.285 mmol) 4-{2-[6-(4-Methoxy-phenyl)-pyridazin-3-yloxy]-ethoxy}-benzaldehyde (educt XII.1) and 35 mg (0.30 mmol) 4-methyl-piperidin-4-ol are dissolved in 10 ml of THF and 0.20 ml conc. acetic acid are added. After 10 minutes 180 mg (0.855 mmol) sodium triacetoxyborohydride are added and the mixture is stirred for 20 hours at RT. After that time the mixture is filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (10:1:0.1) as eluent.  
      Yield: 50 mg (39% of theory),  
      R f  value: 0.25 (silica gel, methylene chloride/methanol/ammonia=10:1:0.1)  
      C 26 H 31  N 3 O 4    
      EII mass spectrum: m/z=450 [M+H] +   
      The following compounds of general formula XIII-1 are prepared analogously to Example 13.1, the educts used being shown in the column headed “Educts”:  
                                      (XIII-1)                                                                                                       ret. time           Exam-                   mass   (HPLC)       ple   R 1 R 2 N-X-   -W-B   D   Educts   spectrum   [min]*   R f -value                                                   13.2                                               CH   XII.1   434 [M + H] +     2.6   n.d.               13.3                                               CH   XII.1   436 [M + H] +     2.4   n.d.               13.4                                               CH   XII.1   406 [M + H] +     2.5   n.d.               13.5                                               CH   XII.1   380 [M + H] +     2.4   n.d.                 *HPLC method A             
 
      The following compounds of general formula XIII-2 are prepared analogously to Example 13.1, the educts used being shown in the column headed “Educts”:  
                                      (XIII-2)                                                                                                       ret. time           Exam-                   mass   (HPLC)       ple   R 1 R 2 N-X-   -W-B   D   Educts   spectrum   [min]*   R f -value                                                   13.6                                               CH   XX.1   401 [M + H] +     2.2   0.65 (B)                 *HPLC method A             
 
     EXAMPLE 14.1  
      3-Chloro-4-{2-[3-chloro-4-(2-diethylamino-ethoxy)-phenoxy]-ethoxy}-benzonitrile  
                 
 
      100 mg (0.285 mmol) {2-[4-(2-Bromo-ethoxy)-2-chloro-phenoxy]-ethyl}-diethyl-amine (educt XIII.1), 45 mg (0.29 mmol) 3-chloro-4-hydroxy-benzonitrile and 100 mg (0.724 mmol) potassium carbonate are dissolved in 5 ml of DMF. The mixture is stirred for 2 hours at 80° C. After that time the mixture is filtered and the solvent is evaporated. The residue is taken up in methylene chloride/methanol and washed with water and 0.1 N HCl. The organic phase is dried over sodium sulphate and the solvent is evaporated.  
      Yield: 38 mg (29% of theory),  
      R f  value: 0.45 (silica gel, methylene chloride/methanol=9:1)  
      C 21 H 24 Cl 2 N 2 O 3    
      EII mass spectrum: m/z=423/425 [M+H] +   
      The following compounds of general formula IVX-1 are prepared analogously to Example 14.1, the educts used being shown in the column headed “Educts”:  
                                      (IVX-1)                                                                                                               ret. time           Exam-                       mass   (HPLC)       ple   R 1 R 2 N-X-   -W-B   L 1     L 2     Educts   spectrum   [min]*   R f -value                                                       14.2                                               —Cl   —CH 3      XIII.1   420/422 [M + H] +     2.6   0.45 (C)               14.3                                               —Cl   —Cl   XIII.1   432/434/ 436 [M + H] +     3.0   0.45 (C)                 *HPLC method A             
 
     EXAMPLE 15.1  
     [3-(4′-Chloro-biphenyl-4-yl)-propyl]-(4-dimethylaminomethyl-phenyl)-methyl-amine  
     
       
         
         
             
             
         
       
     
      100 mg (0.264 mmol) [3-(4′-Chloro-biphenyl-4-yl)-propyl]-(4-dimethylaminomethyl-phenyl)-amine (compound 4.1) and 0.097 ml (1.30 mmol) formalin (37%) are dissolved in 5 ml of acetonitrile. The mixture is stirred for 30 minutes. After that time 0.037 ml (0.65 mmol) conc. acetic acid and 25 mg (0.39 mmol) sodium cyanoborohydride are added. The mixture is stirred for 10 hours at RT. After that time the solvent is evaporated. The residue is taken up in ethyl acetate and washed with diluted sodium hydrogen carbonate solution. The organic phase is dried over sodium sulphate and the solvent is evaporated. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.01) as eluent.  
      Yield: 37 mg (23% of theory),  
      R f  value: 0.30 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      C 25 H 29 ClN 2    
      EII mass spectrum: m/z=393/395 [M+H] +   
      The following compounds of general formula XV-1 are prepared analogously to Example 15.1, the educts used being shown in the column headed “Educts”:  
                                      (XV-1)                                                 Exam-               mass   M.p.           ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   R f -value                                               15.2                                               4.2   433/435 [M + H] +     n.d.   0.50 (A)               15.3                                               1.1   447/449 [M + H] +     n.d.   0.40 (A)                  
 
     EXAMPLE 16  
      The following compounds of general formula XVI-1 are prepared analogously to Example 15.1, the educts used being shown in the column headed “Educts”:  
                                      (XVI-1)                                                                                               ret. time           Exam-               mass   (HPLC)       ple   R 1 R 2 -N-X-   -W-B   Educts   spectrum   [min]*   R f -value                                               16.1                                               3.15   451/453 ]M + H] +     2.5   0.40 (A)               16.2                                               3.21   447 [M + H +     2.4   0.45 (A)                 *HPLC method A             
 
     EXAMPLE 17.1  
     N-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-N-(4-piperidin-1-ylmethyl-phenyl)-formamide  
     
       
         
         
             
             
         
       
     
      0.045 ml Acetic acid anhydride (0.48 mmol) are added to 2.0 ml formic acid (0.264 mmol) and strirred for 1.5 hours at RT. After that time 100 mg (0.24 mmol) {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-(4-piperidin-1-ylmethyl-phenyl)-amine (compound 3.3) are added and the mixture is stirred for 96 hours at RT and for 8 hours at 130° C. After that time the solvent is evaporated. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.01) as eluent.  
      Yield: 65 mg (40% of theory),  
      R f  value: 0.70 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      C 27 H 32 N 4 O 2    
      EII mass spectrum: m/z=445 [M+H] +   
     EXAMPLE 18  
      The following compounds of general formula XVIII-1 are prepared analogously to Example 8.1, the educts used being shown in the column headed “Educts”:  
                                      (XVIII-1)                                                                     ret. time           Exam-               mass   M.p.   (HPLC)   R f -       ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   [min]*   value                                                   18.1                                               XV.1   418 [M + H] +     n.d.   2.4   0.45 (B)               18.2                                               XV.2   422 [M + H] +     n.d.   2.6   0.40 (C)               18.3                                               XV.2   438/440 [M + H] +     n.d.   2.5   0.40 (B)               18.4                                               XV.2   480/482 [M + H] +     n.d.   2.5   0.35 (B)               18.5                                               XV.2   452/454 [M + H] +     n.d.   2.5   0.30 (B)               18.6                                               XV.2   493/495 [M + H] +     n.d.   2.5   n.d.               18.7                                               XV.2   424/426 [M + H] +     n.d.   2.5   n.d.               18.8                                               XV.2   382/384 [M + H] +     n.d.   2.6   n.d.               18.9                                               XV.2   438/440 [M + H] +     n.d.   2.5   n.d.               18.10                                               XV.2   438/440 [M + H] +     n.d.   2.5   n.d.               18.11                                               XV.3   404 [M + H] +     n.d.   2.3   n.d.               18.12                                               XV.4   406 [M + H] +     n.d.   2.3   n.d.               18.13                                               XV.3   420 [M + H] +     n.d.   2.3   n.d.               18.14                                               XV.3   461 [M + H] +     n.d.   2.2   n.d.               18.15                                               XV.4   422 [M + H] +     n.d.   2.3   n.d.               18.16                                               XV.5   418 [M + H] +     n.d.   2.5   0.75 (B)               18.17                                               XV.4   463 [M + H] +     n.d.   2.3   n.d.                 *HPLC method A             
 
     EXAMPLE 19.1  
     {3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propyl}-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-amine  
      540 mg (1.10 mmol) 3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propionaldehyde (educt XIX.1) and 178 mg (1.10 mmol) 2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylamine (educt XVIII.1) are dissolved in 20 ml of 1,2-dichloroethane and 0.25 ml conc. acetic acid are added. Finally 466 mg (2.2 mmol) sodium triacetoxyborohydride are added and the mixture is stirred for 4 hours at RT. After that time saturated sodium hydrogen carbonate solution is added and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and the solvent is evaporated. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.01) as eluent.  
      Yield: 150 mg (35% of theory),  
      R f  value: 0.60 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      M.p. 130-133° C.  
      C 24 H 28 N 4 O  
      EII mass spectrum: m/z=389 [M+H] +   
      The following compounds of general formula XIX-1 are prepared analogously to Example 19.1, the educts used being shown in the column headed “Educts”:  
                                      (XIX-1)                                                                                                       ret. time           Exam-               mass   M.p.   (HPLC)   R f -       ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   [min]*   value                                                   19.2                                               XIX.1 XXI.1   405 [M + H +     143-145   2.2   0.30 (D)               19.3                                               XIX.2 XXI.2   391 [M + H +     n.d.   2.2   n.d.               19.4                                               XIX.2 XXI.2   474 [M + H +     n.d.   2.3   n.d.                 *HPLC method A             
 
     EXAMPLE 20  
     
       
         
         
             
             
         
       
     
      The following compounds of general formula XX-1 are prepared analogously to Example 13.1, the educts used being shown in the column headed “Educts” 
                                      (XX-1)                                                                                                       ret. time           Exam-               mass   M.p.   (HPLC)   R f -       ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   [min]*   value                                                   20.1                                               XXIV.1   420 [M + H] +     n.d.   2.3   n.d.               20.2                                               XXIV.1   406 [M + H] +     n.d.   2.3   n.d.               20.3                                               XXIV.1   434 [M + H] +     n.d.   2.3   n.d.               20.4                                               XXIV.1   420 [M + H] +     n.d.   2.4   n.d.               20.5                                               XXIV.1   475 [M + H] +     n.d.   2.3   n.d.               20.6                                               XXIV.1   364 [M + H] +     n.d.   2.3   n.d.               20.7                                               XXIV.2   489 [M + H] +     n.d.   2.6   0.55 (C)                 *HPLC method A             
 
     EXAMPLE 21.1  
     1-(4-{3-[6-(4-Hydroxy-phenyl)-pyridazin-3-yl]-propylamino}-benzyl)-4-methyl-piperidin-4-ol  
     
       
         
         
             
             
         
       
     
      150 mg (0.30 mmol) 1-(4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamino}-benzyl)-4-methyl-piperidin-4-ol (educt 3.6) are dissolved in 10 ml methylene chloride and 0.33 ml (0.33 mmol) of a 1N solution of boron tribromide in methylene chloride are added at −65° C. under argon atmosphere. The mixture is stirred for 30 minutes at −65° C. and for 3 hours at RT. After that time another equivalent of boron tribromide solution (0.33 ml) is added and the mixture is stirred for 4 days at RT. After that time diluted ammonia solution is added. The organic phase is separated and dried over sodium sulphate and the solvent is evaporated. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.01) as eluent. The product is dried in vacuo at 80° C.  
      Yield: 85 mg (58% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/methanol/ammonia=9:1:0.01)  
      retention time (HPLC): 2.2 min (method A)  
      M.p. 200-204° C.  
      C 26 H 29 F 3 N 4 O 2    
      EII mass spectrum: m/z=487 [M+H] +   
     EXAMPLE 22.1  
     (4-Aminomethyl-phenyl)-{3-[6-(4-methoxy-phenyl)-pyridazin-3-yl]-propyl}-amine  
     
       
         
         
             
             
         
       
     
     22.1.a  
     4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamino}-benzonitrile  
      250 mg (1.00 mmol) 3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamine (educt II.1) and 164 mg (0.90 mmol) 4-bromo benzonitrile are dissolved in 2.0 ml of dioxane and 12 mg (0.04 mmol) 2-(di-tert-butylphosphino)biphenyl, 19 mg (0.021 mmol) tris(dibenzylideneaceton)dipalladium(0) and 122 mg (1.3 mmol) sodium tert-butoxide are added. The mixture is stirred for 24 hours at 80° C. in a sealed tube under argon atmosphere. After cooling, the solvent is removed. The residue is purified by silica gel column chromatography with methylene chloride/methanol/ammonia (9:1:0.1) as eluent.  
      Yield: 220 mg (71% of theory),  
      R f  value: 0.50 (silica gel, methylene chloride/methanol/ammonia=9:1:0.1)  
      retention time (HPLC): 3.0 min (method A)  
      C 21 H 20 N 4 O  
      EII mass spectrum: m/z=345 [M+H] +   
     22.1.b  
      (4-Aminomethyl-phenyl)-{3-[6-(4-methoxy-phenyl)-pyridazin-3-yl]-propyl}-amine 0.22 g (0.58 mmol) 4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-propylamino}-benzonitrile are dissolved in 5 ml methylene chloride and 12 ml ammonia solution in methanol. 60 mg Raney nickel are added and the mixture is hydrogenated (3 bar) at RT for 2 days. After that time the catalyst is filtered off and the filtrate evaporated. The residue is purified by silica gel column chromatography with methylene chloride/ethyl acetate/ammonia (9:1:0.1) as eluent.  
      Yield: 55 mg (27% of theory),  
      R f  value: 0.35 (silica gel, methylene chloride/ethyl acetate/ammonia=9:1:0.1)  
      retention time (HPLC): 2.2 min (method A)  
      C 21 H 24 N 4 O  
      EII Mass spectrum: m/z=349 [M+H] +   
     EXAMPLE 23.1  
     [4-(4-Methyl-piperidin-1-ylmethyl)-phenyl]-[3-(6-phenyl-pyridazin-3-yl)-propyl]-amine  
     
       
         
         
             
             
         
       
     
      0.15 g (0.35 mmol) {3-[6-(4-Chloro-phenyl)-pyridazin-3-yl]-propyl)-[4-(4-methyl-piperidin-1-ylmethyl)-phenyl]-amine (educt 1.1) are dissolved in 10 ml ethanol and 50 mg 10% palladium/charcoal are added. The mixture is hydrogenated (50 psi) at RT for 24 hours. After that time the catalyst is filtered off and the filtrate evaporated. The residue is purified by silica gel column chromatography with methylene chloride/ethyl acetate/ammonia (9:1:0.01) as eluent.  
      Yield: 32 mg (23% of theory),  
      R f  value: 0.40 (silica gel, methylene chloride/ethyl acetate/ammonia=9:1:0.01)  
      retention time (HPLC): 2.5 min (method A)  
      C 26 H 32 N 4    
      EII Mass spectrum: m/z=401 [M+H] +   
     EXAMPLE 24.1  
     1-(4-{4-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-butyl]-benzyl)-piperidin-4-ol  
     
       
         
         
             
             
         
       
     
      0.080 g (0.19 mmol) 1-(4-{4-[6-(4-Methoxy-phenyl)-pyridazin-3-yl]-but-3-ynyl}-benzyl)-piperidin-4-ol (educt XXV.1) are dissolved in 15 ml ethanol and 10 mg Rh(PPh 3 ) 3 Cl (Wilkinson catalyst) are added. The mixture is hydrogenated (50 psi) for 3 hours at RT. After that time the catalyst is filtered off and the filtrate evaporated. The residue is purified by HPLC chromatography (Zorbax column, Agilent Technologies, SB (Stable Bond)-C18; 5 μm; 30 mm×100 mm; column temperature: 30° C.) using a water/acetonitrile/formic acid gradient.  
      Yield: 8 mg (10% of theory),  
      retention time (HPLC): 3.2 min (method B)  
      C 27 H 33 N 3 O 2    
      EII Mass spectrum: m/z=432 [M+H] +   
     24.2  
     1-{4-[4-(6-Benzyloxy-pyridazin-3-yl)-butyl]-benzyl}-piperidin-4-ol  
                         
 prepared analogously to example 24.1 from 1-{4-[4-(6-benzyloxy-pyridazin-3-yl)-but-3-ynyl]-benzyl}-piperidin-4-ol (educt XXV.2) 
 
      retention time (HPLC): 3.2 min (method B)  
      C 27 H 33 N 3 O 2    
      EII mass spectrum: m/z=432 [M+H] +   
     EXAMPLE 25  
      The following compounds of general formula XXV-1 are prepared analogously to Example 8.1, the educts used being shown in the column headed “Educts”:  
                                      (XXV-1)                                                                                                       ret. time                                   (HPLC)       Exam-               mass   M.p.   [min]   R f -       ple   R 1 R 2 N-X-   -W-B   Educts   spectrum   [° C.]   (method)   value                                                   25.1                                               XXVI.1   407/409 [M + H] +     n.d.   3.2 (F)   n.d.               25.2                                               XXVI.1   405/407 [M + H] +     n.d.   3.2 (D)   n.d.               25.3                                               XXVI.1   437/439 [M + H] +     n.d.   3.1 (D)   n.d.               25.4                                               XXVI.1   409/411 [M + H] +     n.d.   2.7 (E)   n.d.               25.5                                               XXVI.1   437/439 [M + H] +     n.d.   3.2 (D)   n.d.                  
 
      The following compounds of general formula (A-1) can be prepared analogously to the foregoing examples:  
                                      (A-1)                                                                   Example   R 1 R 2 N-X-   D   R N     -W-B                                       A.1                         CH   —H                                     A.2                         CH   —H                                     A.3                         CH   —H                                     A.4                         CH   —H                                     A.5                         CH   —H                                     A.6                         CH   —H                                     A.7                         CH   —H                                     A.8                         CH   —H                                     A.9                         CH   —H                                     A.10                         CH   —H                                     A.11                         CH   —H                                     A.12                         CH   —H                                     A.13                         CH   —H                                     A.14                         CH   —H                                     A.15                         CH   —H                                     A.16                         CH   —H                                     A.17                         CH   —H                                     A.18                         CH   —H                                     A.19                         CH   —H                                     A.20                         CH   —H                                     A.21                         CH   —H                                     A.22                         CH   —H                                     A.23                         CH   —H                                     A.24                         CH   —H                                     A.25                         CH   —H                                     A.26                         CH   —H                                     A.27                         CH   —H                                     A.28                         CH   —H                                     A.29                         CH   —H                                     A.30                         CH   —H                                     A.31                         CH   —H                                     A.32                         CH   —H                                     A.33                         CH   —H                                     A.34                         CH   —H                                     A.35                         CH   —H                                     A.36                         CH   —H                                     A.37                         CH   —H                                     A.38                         CH   —H                                     A.39                         CH   —H                                     A.40                         CH   —H                                     A.41                         CH   —H                                     A.42                         CH   —H                                     A.43                         CH   —H                                     A.44                         CH   —H                                     A.45                         CH   —H                                     A.46                         CH   —H                                     A.47                         CH   —H                                     A.48                         CH   —H                                     A.49                         CH   —H                                     A.50                         CH   —H                                     A.51                         CH   —H                                     A.52                         CH   —H                                     A.53                         CH   —H                                     A.54                         CH   —H                                     A.55                         CH   —H                                     A.56                         CH   —H                                     A.57                         CH   —H                                     A.58                         CH   —H                                     A.59                         CH   —H                                     A.60                         CH   —H                                     A.61                         CH   —H                                     A.62                         CH   —H                                     A.63                         CH   —H                                     A.64                         CH   —H                                     A.65                         CH   —H                                     A.66                         CH   —H                                     A.67                         CH   —H                                     A.68                         CH   —H                                     A.69                         CH   —H                                     A.70                         CH   —H                                     A.71                         CH   —H                                     A.72                         CH   —H                                     A.73                         CH   —H                                     A.74                         CH   —H                                     A.75                         CH   —H                                     A.76                         CH   —H                                     A.77                         CH   —H                                     A.78                         CH   —H                                     A.79                         CH   —H                                     A.80                         CH   —H                                     A.81                         CH   —H                                     A.82                         CH   —H                                     A.83                         CH   —H                                     A.84                         CH   —H                                     A.85                         CH   —H                                     A.86                         CH   —H                                     A.87                         CH   —H                                     A.88                         CH   —H                                     A.89                         CH   —H                                     A.90                         CH   —H                                     A.91                         CH   —H                                     A.92                         CH   —H                                     A.93                         CH   —H                                     A.94                         CH   —H                                     A.95                         CH   —H                                     A.96                         CH   —H                                     A.97                         CH   —H                                     A.98                         CH   —H                                     A.99                         CH   —H                                     A.100                         CH   —H                                     A.101                         CH   —H                                     A.102                         CH   —H                                     A.103                         CH   —H                                     A.104                         CH   —H                                     A.105                         CH   —H                                     A.106                         CH   —H                                     A.107                         CH   —H                                     A.108                         CH   —H                                     A.109                         CH   —H                                     A.110                         CH   —H                                     A.111                         CH   —H                                     A.112                         CH   —H                                     A.113                         CH   —H                                     A.114                         CH   —H                                     A.115                         CH   —H                                     A.116                         CH   —H                                     A.117                         CH   —H                                     A.118                         CH   —H                                     A.119                         CH   —H                                     A.120                         CH   —H                                     A.121                         CH   —H                                     A.122                         CH   —H                                     A.123                         CH   —H                                     A.124                         CH   —H                                     A.125                         CH   —H                                     A.126                         CH   —H                                     A.127                         CH   —H                                     A.128                         CH   —H                                     A.129                         CH   —H                                     A.130                         CH   —H                                     A.131                         CH   —H                                     A.132                         CH   —H                                     A.133                         CH   —H                                     A.134                         CH   —H                                     A.135                         CH   —H                                     A.136                         CH   —H                                     A.137                         CH   —H                                     A.138                         CH   —H                                     A.139                         CH   —H                                     A.140                         CH   —H                                     A.141                         CH   —H                                     A.142                         CH   —H                                     A.143                         CH   —H                                     A.144                         CH   —H                                     A.145                         CH   —H                                     A.146                         CH   —H                                     A.147                         CH   —H                                     A.148                         CH   —H                                     A.149                         CH   —H                                     A.150                         CH   —H                                     A.151                         CH   —H                                     A.152                         CH   —H                                     A.153                         CH   —H                                     A.154                         CH   —H                                     A.155                         CH   —H                                     A.156                         CH   —H                                     A.157                         CH   —H                                     A.158                         CH   —H                                     A.159                         CH   —H                                     A.160                         CH   —H                                     A.161                         CH   —H                                     A.162                         CH   —H                                     A.163                         CH   —H                                     A.164                         CH   —H                                     A.165                         CH   —H                                     A.166                         CH   —H                                     A.167                         CH   —H                                     A.168                         CH   —H                                     A.169                         CH   —H                                     A.170                         CH   —H                                     A.171                         CH   —H                                     A.172                         CH   —H                                     A.173                         CH   —H                                     A.174                         CH   —H                                     A.175                         CH   —H                                     A.176                         CH   —H                                     A.177                         CH   —H                                     A.178                         CH   —H                                     A.179                         CH   —H                                     A.180                         CH   —H                                     A.181                         CH   —H                                     A.182                         CH   —H                                     A.183                         CH   —H                                     A.184                         CH   —H                                     A.185                         CH   —H                                     A.186                         CH   —H                                     A.187                         CH   —H                                     A.188                         CH   —H                                     A.189                         CH   —H                                     A.190                         CH   —H                                     A.191                         CH   —H                                     A.192                         CH   —H                                     A.193                         CH   —H                                     A.194                         CH   —H                                     A.195                         CH   —H                                     A.196                         CH   —H                                     A.197                         CH   —H                                     A.198                         CH   —H                                     A.199                         CH   —H                                     A.200                         CH   —H                                     A.201                         CH   —H                                     A.202                         CH   —H                                     A.203                         CH   —H                                     A.204                         CH   —H                                     A.205                         CH   —H                                     A.206                         CH   —H                                     A.207                         CH   —H                                     A.208                         CH   —H                                     A.209                         CH   —H                                     A.210                         CH   —H                                     A.211                         CH   —H                                     A.212                         CH   —H                                     A.213                         CH   —H                                     A.214                         CH   —H                                     A.215                         CH   —H                                     A.216                         CH   —H                                     A.217                         CH   —H                                     A.218                         CH   —H                                     A.219                         CH   —H                                     A.220                         CH   —H                                     A.221                         CH   —H                                     A.222                         CH   —H                                     A.223                         CH   —H                                     A.224                         CH   —H                                     A.225                         CH   —H                                     A.226                         CH   —H                                     A.227                         CH   —H                                     A.228                         CH   —H                                     A.229                         CH   —H                                     A.230                         CH   —H                                     A.231                         CH   —H                                     A.232                         CH   —H                                     A.233                         CH   —H                                     A.234                         CH   —H                                     A.235                         CH   —H                                     A.236                         CH   —H                                     A.237                         CH   —H                                     A.238                         CH   —H                                     A.239                         CH   —H                                     A.240                         CH   —H                                     A.241                         CH   —H                                     A.242                         CH   —H                                     A.243                         CH   —H                                     A.244                         CH   —H                                     A.245                         CH   —H                                     A.246                         CH   —H                                     A.247                         CH   —H                                     A.248                         CH   —H                                     A.249                         CH   —H                                     A.250                         CH   —H                                     A.251                         CH   —H                                     A.252                         CH   —H                                     A.253                         CH   —H                                     A.254                         CH   —H                                     A.255                         CH   —H                                     A.256                         CH   —H                                     A.257                         CH   —H                                     A.258                         CH   —H                                     A.259                         CH   —H                                     A.260                         CH   —H                                     A.261                         CH   —H                                     A.262                         CH   —H                                     A.263                         CH   —H                                     A.264                         CH   —H                                     A.265                         CH   —H                                     A.266                         CH   —H                                     A.267                         CH   —H                                     A.268                         CH   —H                                     A.269                         CH   —H                                     A.270                         CH   —H                                     A.271                         CH   —H                                     A.272                         CH   —H                                     A.273                         CH   —H                                     A.274                         CH   —H                                     A.275                         CH   —H                                     A.276                         CH   —H                                     A.277                         CH   —H                                     A.278                         CH   —H                                     A.279                         CH   —H                                     A.280                         CH   —H                                     A.281                         CH   —H                                     A.282                         CH   —H                                     A.283                         CH   —H                                     A.284                         CH   —H                                     A.285                         CH   —H                                     A.286                         CH   —H                                     A.287                         CH   —H                                     A.288                         CH   —H                                     A.289                         CH   —H                                     A.290                         CH   —H                                     A.291                         CH   —H                                     A.292                         CH   —H                                     A.293                         CH   —H                                     A.294                         CH   —H                                     A.295                         CH   —H                                     A.296                         CH   —H                                     A.297                         CH   —H                                     A.298                         CH   —H                                     A.299                         CH   —H                                     A.300                         CH   —H                                     A.301                         CH   —H                                     A.302                         CH   —H                                     A.303                         CH   —H                                     A.304                         CH   —H                                     A.305                         CH   —H                                     A.306                         CH   —H                                     A.307                         CH   —H                                     A.308                         CH   —H                                     A.309                         CH   —H                                     A.310                         CH   —H                                     A.311                         CH   —H                                     A.312                         CH   —H                                     A.313                         CH   —H                                     A.314                         CH   —H                                     A.315                         CH   —H                                     A.316                         CH   —H                                     A.317                         CH   —H                                     A.318                         CH   —H                                     A.319                         CH   —H                                     A.320                         CH   —H                                     A.321                         CH   —H                                     A.322                         CH   —H                                     A.323                         CH   —H                                     A.324                         CH   —H                                     A.325                         CH   —H                                     A.326                         CH   —H                                     A.327                         CH   —H                                     A.328                         CH   —H                                     A.329                         CH   —H                                     A.330                         CH   —H                                     A.331                         CH   —H                                     A.332                         CH   —H                                     A.333                         CH   —H                                     A.334                         CH   —H                                     A.335                         CH   —H                                     A.336                         CH   —H                                     A.337                         CH   —H                                     A.338                         CH   —H                                     A.339                         CH   —H                                     A.340                         CH   —H                                     A.341                         CH   —H                                     A.342                         CH   —H                                     A.343                         CH   —H                                     A.344                         CH   —H                                     A.345                         CH   —H                                     A.346                         CH   —H                                     A.347                         CH   —H                                     A.348                         CH   —H                                     A.349                         CH   —H                                     A.350                         CH   —H                                     A.351                         CH   —H                                     A.352                         CH   —H                                     A.353                         CH   —H                                     A.354                         CH   —H                                     A.355                         CH   —H                                     A.356                         CH   —H                                     A.357                         CH   —H                                     A.358                         CH   —H                                     A.359                         CH   —H                                     A.360                         CH   —H                                     A.361                         CH   —H                                     A.362                         CH   —H                                     A.363                         CH   —H                                     A.364                         CH   —H                                     A.365                         CH   —H                                     A.366                         CH   —H                                     A.367                         CH   —H                                     A.368                         CH   —H                                     A.369                         CH   —H                                     A.370                         CH   —H                                     A.371                         CH   —H                                     A.372                         CH   —H                                     A.373                         CH   —H                                     A.374                         CH   —H                                     A.375                         CH   —H                                     A.376                         CH   —H                                     A.377                         CH   —H                                     A.378                         CH   —H                                     A.379                         CH   —H                                     A.380                         CH   —H                                     A.381                         CH   —H                                     A.382                         CH   —H                                     A.383                         CH   —H                                     A.384                         CH   —H                                     A.385                         CH   —H                                     A.386                         CH   —H                                     A.387                         CH   —H                                     A.388                         CH   —H                                     A.389                         CH   —H                                     A.390                         CH   —H                                     A.391                         CH   —H                                     A.392                         CH   —H                                     A.393                         CH   —H                                     A.394                         CH   —H                                     A.395                         CH   —H                                     A.396                         CH   —H                                     A.397                         CH   —H                                     A.398                         CH   —H                                     A.399                         CH   —H                                     A.400                         CH   —H                                     A.401                         CH   —H                                     A.402                         CH   —H                                     A.403                         CH   —H                                     A.404                         CH   —H                                     A.405                         CH   —H                                     A.406                         CH   —H                                     A.407                         CH   —H                                     A.408                         CH   —H                                     A.409                         CH   —H                                     A.410                         CH   —H                                     A.411                         CH   —H                                     A.412                         CH   —H                                     A.413                         CH   —H                                     A.414                         CH   —H                                     A.415                         CH   —H                                     A.416                         CH   —H                                     A.417                         CH   —H                                     A.418                         CH   —H                                     A.419                         CH   —H                                     A.420                         CH   —H                                     A.421                         CH   —H                                     A.422                         CH   —H                                     A.423                         CH   —H                                     A.424                         CH   —H                                     A.425                         CH   —H                                     A.426                         CH   —H                                     A.427                         CH   —H                                     A.428                         CH   —H                                     A.429                         CH   —H                                     A.430                         CH   —H                                     A.431                         CH   —H                                     A.432                         CH   —H                                     A.433                         CH   —H                                     A.434                         CH   —H                                     A.435                         CH   —H                                     A.436                         CH   —H                                     A.437                         CH   —H                                     A.438                         CH   —H                                     A.439                         CH   —H                                     A.440                         CH   —H                                     A.441                         CH   —H                                     A.442                         CH   —H                                     A.443                         CH   —H                                     A.444                         CH   —H                                     A.445                         CH   —H                                     A.446                         CH   —H                                     A.447                         CH   —H                                     A.448                         CH   —H                                     A.449                         CH   —H                                     A.450                         CH   —H                                     A.451                         CH   —H                                     A.452                         CH   —H                                     A.453                         CH   —H                                     A.454                         CH   —H                                     A.455                         CH   —H                                     A.456                         CH   —H                                     A.457                         CH   —H                                     A.458                         CH   —H                                     A.459                         CH   —H                                     A.460                         CH   —H                                     A.461                         CH   —H                                     A.462                         CH   —H                                     A.463                         CH   —H                                     A.464                         CH   —H                                     A.465                         CH   —H                                     A.466                         CH   —H                                     A.467                         CH   —H                                     A.468                         CH   —H                                     A.469                         CH   —H                                     A.470                         CH   —H                                     A.471                         CH   —H                                     A.472                         CH   —H                                     A.473                         CH   —H                                     A.474                         CH   —H                                     A.475                         CH   —H                                     A.476                         CH   —H                                     A.477                         CH   —H                                     A.478                         CH   —H                                     A.479                         CH   —H                                     A.480                         CH   —H                                     A.481                         CH   —H                                     A.482                         CH   —H                                     A.483                         CH   —H                                     A.484                         CH   —H                                     A.485                         CH   —H                                     A.486                         CH   —H                                     A.487                         CH   —H                                     A.488                         CH   —H                                     A.489                         CH   —H                                     A.490                         CH   —H                                     A.491                         CH   —H                                     A.492                         CH   —H                                     A.493                         CH   —H                                     A.494                         CH   —H                                     A.495                         CH   —H                                     A.496                         CH   —H                                     A.497                         CH   —H                                     A.498                         CH   —H                                     A.499                         CH   —H                                     A.500                         CH   —H                                     A.501                         CH   —H                                     A.502                         CH   —H                                     A.503                         CH   —H                                     A.504                         CH   —H                                     A.505                         CH   —H                                     A.506                         CH   —H                                     A.507                         CH   —H                                     A.508                         CH   —H                                     A.509                         CH   —H                                     A.510                         CH   —H                                     A.511                         CH   —H                                     A.512                         CH   —H                                     A.513                         CH   —H                                     A.514                         CH   —H                                     A.515                         CH   —H                                     A.516                         CH   —H                                     A.517                         CH   —H                                     A.518                         CH   —H                                     A.519                         CH   —H                                     A.520                         CH   —H                                     A.521                         CH   —H                                     A.522                         CH   —H                                     A.523                         CH   —H                                     A.524                         CH   —H                                     A.525                         CH   —H                                     A.526                         CH   —H                                     A.527                         CH   —H                                     A.528                         CH   —H                                     A.529                         CH   —H                                     A.530                         CH   —H                                     A.531                         CH   —H                                     A.532                         CH   —H                                     A.533                         CH   —H                                     A.534                         CH   —H                                     A.535                         CH   —H                                     A.536                         CH   —H                                     A.537                         CH   —H                                     A.538                         CH   —H                                     A.539                         CH   —H                                     A.540                         CH   —H                                     A.541                         CH   —H                                     A.542                         CH   —H                                     A.543                         CH   —H                                     A.544                         CH   —H                                     A.545                         CH   —H                                     A.546                         CH   —H                                     A.547                         CH   —H                                     A.548                         CH   —H                                     A.549                         CH   —H                                     A.550                         CH   —H                                     A.551                         CH   —H                                     A.552                         CH   —H                                     A.553                         CH   —H                                     A.554                         CH   —H                                     A.555                         CH   —H                                     A.556                         CH   —H                                     A.557                         CH   —H                                     A.558                         CH   —H                                     A.559                         CH   —H                                     A.560                         CH   —H                                     A.561                         CH   —H                                     A.562                         CH   —H                                     A.563                         CH   —H                                     A.564                         CH   —H                                     A.565                         CH   —H                                     A.566                         CH   —H                                     A.567                         CH   —H                                     A.568                         CH   —H                                     A.569                         CH   —H                                     A.570                         CH   —H                                     A.571                         CH   —H                                     A.572                         CH   —H                                     A.573                         CH   —H                                     A.574                         CH   —H                                     A.575                         CH   —H                                     A.576                         CH   —H                                     A.577                         CH   —H                                     A.578                         CH   —H                                     A.579                         CH   —H                                     A.580                         CH   —H                                     A.581                         CH   —H                                     A.582                         CH   —H                                     A.583                         CH   —H                                     A.584                         CH   —H                                     A.585                         CH   —H                                     A.586                         CH   —H                                     A.587                         CH   —H                                     A.588                         CH   —H                                     A.589                         CH   —H                                     A.590                         CH   —H                                     A.591                         CH   —H                                     A.592                         CH   —H                                     A.593                         CH   —H                                     A.594                         CH   —H                                     A.595                         CH   —H                                     A.596                         CH   —H                                     A.597                         CH   —H                                     A.598                         CH   —H                                     A.599                         CH   —H                                     A.600                         CH   —H                                     A.601                         CH   —H                                     A.602                         CH   —H                                     A.603                         CH   —H                                     A.604                         CH   —H                                     A.605                         CH   —H                                     A.606                         CH   —H                                     A.607                         CH   —H                                     A.608                         CH   —H                                     A.609                         CH   —H                                     A.610                         CH   —H                                     A.611                         CH   —H                                     A.612                         CH   —H                                     A.613                         CH   —H                                     A.614                         CH   —H                                     A.615                         CH   —H                                     A.616                         CH   —H                                     A.617                         CH   —H                                     A.618                         CH   —H                                     A.619                         CH   —H                                     A.620                         CH   —H                                     A.621                         CH   —H                                     A.622                         CH   —H                                     A.623                         CH   —H                                     A.624                         CH   —H                                     A.625                         CH   —H                                     A.626                         CH   —H                                     A.627                         CH   —H                                     A.628                         CH   —H                                     A.629                         CH   —H                                     A.630                         CH   —H                                     A.631                         CH   —H                                     A.632                         CH   —H                                     A.633                         CH   —H                                     A.634                         CH   —H                                     A.635                         CH   —H                                     A.636                         CH   —H                                     A.637                         CH   —H                                     A.638                         CH   —H                                     A.639                         CH   —H                                     A.640                         CH   —H                                     A.641                         CH   —H                                     A.642                         CH   —H                                     A.643                         CH   —H                                     A.644                         CH   —H                                     A.645                         CH   —H                                     A.646                         CH   —H                                     A.647                         CH   —H                                     A.648                         CH   —H                                     A.649                         CH   —H                                     A.650                         CH   —H                                     A.651                         CH   —H                                     A.652                         CH   —H                                     A.653                         CH   —H                                     A.654                         CH   —H                                     A.655                         CH   —H                                     A.656                         CH   —H                                     A.657                         CH   —H                                     A.658                         CH   —H                                     A.659                         CH   —H                                     A.660                         CH   —H                                     A.661                         CH   —H                                     A.662                         CH   —H                                     A.663                         CH   —H                                     A.664                         CH   —H                                     A.665                         CH   —H                                     A.666                         CH   —H                                     A.667                         CH   —H                                     A.668                         CH   —H                                     A.669                         CH   —H                                     A.670                         CH   —H                                     A.671                         CH   —H                                     A.672                         CH   —H                                     A.673                         CH   —H                                     A.674                         CH   —H                                     A.675                         CH   —H                                     A.676                         CH   —H                                     A.677                         CH   —H                                     A.678                         CH   —H                                     A.679                         CH   —H                                     A.680                         CH   —H                                     A.681                         CH   —H                                     A.682                         CH   —H                                     A.683                         CH   —H                                     A.684                         CH   —H                                     A.685                         CH   —H                                     A.686                         CH   —H                                     A.687                         CH   —H                                     A.688                         CH   —H                                     A.689                         CH   —H                                     A.690                         CH   —H                                     A.691                         CH   —H                                     A.692                         CH   —H                                     A.693                         CH   —H                                     A.694                         CH   —H                                     A.695                         CH   —H                                     A.696                         CH   —H                                     A.697                         CH   —H                                     A.698                         CH   —H                                     A.699                         CH   —H                                     A.700                         CH   —H                                     A.701                         CH   —H                                     A.702                         CH   —H                                     A.703                         CH   —H                                     A.704                         CH   —H                                     A.705                         CH   —H                                     A.706                         CH   —H                                     A.707                         CH   —H                                     A.708                         CH   —H                                     A.709                         CH   —H                                     A.710                         CH   —H                                     A.711                         CH   —H                                     A.712                         CH   —H                                     A.713                         CH   —H                                     A.714                         CH   —H                                     A.715                         CH   —H                                     A.716                         CH   —H                                     A.717                         CH   —H                                     A.718                         CH   —H                                     A.719                         CH   —H                                     A.720                         CH   —H                                     A.721                         CH   —H                                     A.722                         CH   —H                                     A.723                         CH   —H                                     A.724                         CH   —H                                     A.725                         CH   —H                                        
 
      The following compounds of general formula (B-1) can be prepared analogously to the foregoing examples:  
                                      (B-1)                                                               Example   R 1 R 2 N-X-   D   -W-B                                   B.1                         CH                                     B.2                         CH                                        
 
      The following compounds of general formula (C-1) can be prepared analogously to the foregoing examples:  
                                      (C-1)                                                               Example   R 1 R 2 N-X-   D   -W-B                                   C.1                         CH                                     C.2                         CH                                     C.3                         CH                                     C.4                         CH                                     C.5                         CH                                     C.6                         CH                                     C.7                         CH                                     C.8                         CH                                     C.9                         CH                                     C.10                         CH                                     C.11                         CH                                     C.12                         CH                                     C.13                         CH                                     C.14                         CH                                     C.15                         CH                                     C.16                         CH                                     C.17                         CH                                     C.18                         CH                                     C.19                         CH                                     C.20                         CH                                     C.21                         CH                                     C.22                         CH                                     C.23                         CH                                     C.24                         CH                                     C.25                         CH                                     C.26                         CH                                     C.27                         CH                                     C.28                         CH                                     C.29                         CH                                     C.30                         CH                                     C.31                         CH                                     C.32                         CH                                     C.33                         CH                                     C.34                         CH                                     C.35                         CH                                     C.36                         CH                                     C.37                         CH                                     C.38                         CH                                     C.39                         CH                                     C.40                         CH                                     C.41                         CH                                     C.42                         CH                                     C.43                         CH                                     C.44                         CH                                     C.45                         CH                                     C.46                         CH                                     C.47                         CH                                     C.48                         CH                                     C.49                         CH                                     C.50                         CH                                     C.51                         CH                                     C.52                         CH                                     C.53                         CH                                     C.54                         CH                                     C.55                         CH                                     C.56                         CH                                     C.57                         CH                                     C.58                         CH                                     C.59                         CH                                     C.60                         CH                                     C.61                         CH                                     C.62                         CH                                     C.63                         CH                                     C.64                         CH                                     C.65                         CH                                     C.66                         CH                                     C.67                         CH                                     C.68                         CH                                     C.69                         CH                                     C.70                         CH                                     C.71                         CH                                     C.72                         CH                                     C.73                         CH                                     C.74                         CH                                     C.75                         CH                                     C.76                         CH                                     C.77                         CH                                     C.78                         CH                                     C.79                         CH                                     C.80                         CH                                     C.81                         CH                                     C.82                         CH                                     C.83                         CH                                     C.84                         CH                                     C.85                         CH                                     C.86                         CH                                     C.87                         CH                                     C.88                         CH                                     C.89                         CH                                     C.90                         CH                                     C.91                         CH                                     C.92                         CH                                     C.93                         CH                                     C.94                         CH                                     C.95                         CH                                     C.96                         CH                                     C.97                         CH                                     C.98                         CH                                     C.99                         CH                                     C.100                         CH                                     C.101                         CH                                     C.102                         CH                                     C.103                         CH                                     C.104                         CH                                     C.105                         CH                                     C.106                         CH                                     C.107                         CH                                     C.108                         CH                                     C.109                         CH                                     C.110                         CH                                     C.111                         CH                                     C.112                         CH                                     C.113                         CH                                     C.114                         CH                                     C.115                         CH                                     C.116                         CH                                     C.117                         CH                                     C.118                         CH                                     C.119                         CH                                     C.120                         CH                                     C.121                         CH                                     C.122                         CH                                     C.123                         CH                                     C.124                         CH                                     C.125                         CH                                     C.126                         CH                                     C.127                         CH                                     C.128                         CH                                     C.129                         CH                                     C.130                         CH                                     C.131                         CH                                     C.132                         CH                                     C.133                         CH                                     C.134                         CH                                     C.135                         CH                                     C.136                         CH                                     C.137                         CH                                     C.138                         CH                                     C.139                         CH                                     C.140                         CH                                     C.141                         CH                                     C.142                         CH                                     C.143                         CH                                     C.144                         CH                                     C.145                         CH                                     C.146                         CH                                     C.147                         CH                                     C.148                         CH                                     C.149                         CH                                     C.150                         CH                                     C.151                         CH                                     C.152                         CH                                     C.153                         CH                                     C.154                         CH                                     C.155                         CH                                     C.156                         CH                                     C.157                         CH                                     C.158                         CH                                     C.159                         CH                                     C.160                         CH                                     C.161                         CH                                     C.162                         CH                                     C.163                         CH                                     C.164                         CH                                     C.165                         CH                                     C.166                         CH                                     C.167                         CH                                     C.168                         CH                                     C.169                         CH                                     C.170                         CH                                     C.171                         CH                                     C.172                         CH                                     C.173                         CH                                     C.174                         CH                                     C.175                         CH                                     C.176                         CH                                     C.177                         CH                                     C.178                         CH                                     C.179                         CH                                     C.180                         CH                                     C.181                         CH                                     C.182                         CH                                     C.183                         CH                                     C.184                         CH                                     C.185                         CH                                     C.186                         CH                                     C.187                         CH                                     C.188                         CH                                     C.189                         CH                                     C.190                         CH                                     C.191                         CH                                     C.192                         CH                                     C.193                         CH                                     C.194                         CH                                     C.195                         CH                                     C.196                         CH                                     C.197                         CH                                     C.198                         CH                                     C.199                         CH                                     C.200                         CH                                     C.201                         CH                                     C.202                         CH                                     C.203                         CH                                     C.204                         CH                                     C.205                         CH                                     C.206                         CH                                     C.207                         CH                                     C.208                         CH                                     C.209                         CH                                     C.210                         CH                                     C.211                         CH                                     C.212                         CH                                     C.213                         CH                                     C.214                         CH                                     C.215                         CH                                     C.216                         CH                                     C.217                         CH                                     C.218                         CH                                     C.219                         CH                                     C.220                         CH                                     C.221                         CH                                     C.222                         CH                                     C.223                         CH                                     C.224                         CH                                     C.225                         CH                                     C.226                         CH                                     C.227                         CH                                     C.228                         CH                                     C.229                         CH                                     C.230                         CH                                     C.231                         CH                                     C.232                         CH                                     C.233                         CH                                     C.234                         CH                                     C.235                         CH                                     C.236                         CH                                     C.237                         CH                                     C.238                         CH                                     C.239                         CH                                     C.240                         CH                                     C.241                         CH                                     C.242                         CH                                     C.243                         CH                                     C.244                         CH                                     C.245                         CH                                     C.246                         CH                                     C.247                         CH                                     C.248                         CH                                     C.249                         CH                                     C.250                         CH                                     C.251                         CH                                     C.252                         CH                                     C.253                         CH                                     C.254                         CH                                     C.255                         CH                                     C.256                         CH                                     C.257                         CH                                     C.258                         CH                                     C.259                         CH                                     C.260                         CH                                     C.261                         CH                                     C.262                         CH                                     C.263                         CH                                     C.264                         CH                                     C.265                         CH                                     C.266                         CH                                     C.267                         CH                                     C.268                         CH                                     C.269                         CH                                     C.270                         CH                                     C.271                         CH                                     C.272                         CH                                     C.273                         CH                                     C.274                         CH                                     C.275                         CH                                     C.276                         CH                                     C.277                         CH                                     C.278                         CH                                     C.279                         CH                                     C.280                         CH                                     C.281                         CH                                     C.282                         CH                                     C.283                         CH                                     C.284                         CH                                     C.285                         CH                                     C.286                         CH                                     C.287                         CH                                     C.288                         CH                                     C.289                         CH                                     C.290                         CH                                     C.291                         CH                                     C.292                         CH                                     C.293                         CH                                     C.294                         CH                                     C.295                         CH                                     C.296                         CH                                     C.297                         CH                                     C.298                         CH                                     C.299                         CH                                     C.300                         CH                                     C.301                         CH                                     C.302                         CH                                     C.303                         CH                                     C.304                         CH                                     C.305                         CH                                     C.306                         CH                                     C.307                         CH                                     C.308                         CH                                     C.309                         CH                                     C.310                         CH                                     C.311                         CH                                     C.312                         CH                                     C.313                         CH                                     C.314                         CH                                     C.315                         CH                                     C.316                         CH                                     C.317                         CH                                     C.318                         CH                                     C.319                         CH                                     C.320                         CH                                     C.321                         CH                                     C.322                         CH                                     C.323                         CH                                     C.324                         CH                                     C.325                         CH                                     C.326                         CH                                     C.327                         CH                                     C.328                         CH                                     C.329                         CH                                     C.330                         CH                                     C.331                         CH                                     C.332                         CH                                     C.333                         CH                                     C.334                         CH                                     C.335                         CH                                     C.336                         CH                                     C.337                         CH                                     C.338                         CH                                     C.339                         CH                                     C.340                         CH                                     C.341                         CH                                     C.342                         CH                                     C.343                         CH                                     C.344                         CH                                     C.345                         CH                                     C.346                         CH                                     C.347                         CH                                     C.348                         CH                                     C.349                         CH                                     C.350                         CH                                     C.351                         CH                                     C.352                         CH                                     C.353                         CH                                     C.354                         CH                                     C.355                         CH                                     C.356                         CH                                     C.357                         CH                                     C.358                         CH                                     C.359                         CH                                     C.360                         CH                                     C.361                         CH                                     C.362                         CH                                     C.363                         CH                                     C.364                         CH                                     C.365                         CH                                     C.366                         CH                                     C.367                         CH                                     C.368                         CH                                     C.369                         CH                                     C.370                         CH                                     C.371                         CH                                     C.372                         CH                                     C.373                         CH                                     C.374                         CH                                     C.375                         CH                                     C.376                         CH                                     C.377                         CH                                     C.378                         CH                                     C.379                         CH                                     C.380                         CH                                     C.381                         CH                                     C.382                         CH                                     C.383                         CH                                     C.384                         CH                                     C.385                         CH                                     C.386                         CH                                     C.387                         CH                                     C.388                         CH                                     C.389                         CH                                     C.390                         CH                                     C.391                         CH                                     C.392                         CH                                     C.393                         CH                                     C.394                         CH                                     C.395                         CH                                     C.396                         CH                                     C.397                         CH                                     C.398                         CH                                     C.399                         CH                                     C.400                         CH                                     C.401                         CH                                     C.402                         CH                                     C.403                         CH                                     C.404                         CH                                     C.405                         CH                                     C.406                         CH                                     C.407                         CH                                     C.408                         CH                                     C.409                         CH                                     C.410                         CH                                     C.411                         CH                                     C.412                         CH                                     C.413                         CH                                     C.414                         CH                                     C.415                         CH                                     C.416                         CH                                     C.417                         CH                                     C.418                         CH                                     C.419                         CH                                     C.420                         CH                                     C.421                         CH                                     C.422                         CH                                     C.423                         CH                                     C.424                         CH                                     C.425                         CH                                     C.426                         CH                                     C.427                         CH                                     C.428                         CH                                     C.429                         CH                                     C.430                         CH                                     C.431                         CH                                     C.432                         CH                                     C.433                         CH                                     C.434                         CH                                     C.435                         CH                                     C.436                         CH                                     C.437                         CH                                     C.438                         CH                                     C.439                         CH                                     C.440                         CH                                     C.441                         CH                                     C.442                         CH                                     C.443                         CH                                     C.444                         CH                                     C.445                         CH                                     C.446                         CH                                     C.447                         CH                                     C.448                         CH                                     C.449                         CH                                     C.450                         CH                                     C.451                         CH                                     C.452                         CH                                     C.453                         CH                                     C.454                         CH                                     C.455                         CH                                     C.456                         CH                                     C.457                         CH                                     C.458                         CH                                     C.459                         CH                                     C.460                         CH                                     C.461                         CH                                     C.462                         CH                                     C.463                         CH                                     C.464                         CH                                     C.465                         CH                                     C.466                         CH                                     C.467                         CH                                     C.468                         CH                                     C.469                         CH                                     C.470                         CH                                     C.471                         CH                                     C.472                         CH                                     C.473                         CH                                     C.474                         CH                                     C.475                         CH                                     C.476                         CH                                     C.477                         CH                                     C.478                         CH                                     C.479                         CH                                     C.480                         CH                                     C.481                         CH                                     C.482                         CH                                     C.483                         CH                                     C.484                         CH                                     C.485                         CH                                     C.486                         CH                                     C.487                         CH                                     C.488                         CH                                     C.489                         CH                                     C.490                         CH                                     C.491                         CH                                     C.492                         CH                                     C.493                         CH                                     C.494                         CH                                     C.495                         CH                                     C.496                         CH                                     C.497                         CH                                     C.498                         CH                                     C.499                         CH                                     C.500                         CH                                     C.501                         CH                                     C.502                         CH                                     C.503                         CH                                     C.504                         CH                                     C.505                         CH                                     C.506                         CH                                     C.507                         CH                                     C.508                         CH                                     C.509                         CH                                     C.510                         CH                                     C.511                         CH                                     C.512                         CH                                     C.513                         CH                                     C.514                         CH                                     C.515                         CH                                     C.516                         CH                                     C.517                         CH                                     C.518                         CH                                     C.519                         CH                                     C.520                         CH                                     C.521                         CH                                     C.522                         CH                                     C.523                         CH                                     C.524                         CH                                     C.525                         CH                                     C.526                         CH                                     C.527                         CH                                     C.528                         CH                                     C.529                         CH                                     C.530                         CH                                     C.531                         CH                                     C.532                         CH                                     C.533                         CH                                     C.534                         CH                                     C.535                         CH                                     C.536                         CH                                     C.537                         CH                                     C.538                         CH                                     C.539                         CH                                     C.540                         CH                                     C.541                         CH                                     C.542                         CH                                     C.543                         CH                                     C.544                         CH                                     C.545                         CH                                     C.546                         CH                                     C.547                         CH                                     C.548                         CH                                     C.549                         CH                                     C.550                         CH                                     C.551                         CH                                     C.552                         CH                                     C.553                         CH                                     C.554                         CH                                     C.555                         CH                                     C.556                         CH                                     C.557                         CH                                     C.558                         CH                                     C.559                         CH                                     C.560                         CH                                     C.561                         CH                                     C.562                         CH                                     C.563                         CH                                     C.564                         CH                                     C.565                         CH                                     C.566                         CH                                     C.567                         CH                                     C.568                         CH                                     C.569                         CH                                     C.570                         CH                                     C.571                         CH                                     C.572                         CH                                     C.573                         CH                                     C.574                         CH                                     C.575                         CH                                     C.576                         CH                                     C.577                         CH                                     C.578                         CH                                     C.579                         CH                                     C.580                         CH                                     C.581                         CH                                     C.582                         CH                                     C.583                         CH                                     C.584                         CH                                     C.585                         CH                                     C.586                         CH                                     C.587                         CH                                     C.588                         CH                                     C.589                         CH                                     C.590                         CH                                     C.591                         CH                                     C.592                         CH                                     C.593                         CH                                     C.594                         CH                                     C.595                         CH                                     C.596                         CH                                     C.597                         CH                                     C.598                         CH                                     C.599                         CH                                     C.600                         CH                                     C.601                         CH                                        
 
      Some test methods for determining an MCH-receptor antagonistic activity will now be described. In addition, other test methods known to the skilled man may be used, e.g. by inhibiting the MCH-receptor-mediated inhibition of cAMP production, as described by Hoogduijn M et al. in “Melanin-concentrating hormone and its receptor are expressed and functional in human skin”, Biochem. Biophys. Res Commun. 296 (2002) 698-701 and by biosensory measurement of the binding of MCH to the MCH receptor in the presence of antagonistic substances by plasmon resonance, as described by Karlsson OP and Lofas S. in “Flow-Mediated On-Surface Reconstitution of G-Protein Coupled Receptors for Applications in Surface Plasmon Resonance Biosensors”, Anal. Biochem. 300 (2002),132-138. Other methods of testing antagonistic activity to MCH receptors are contained in the references and patent documents mentioned hereinbefore, and the description of the test methods used is hereby incorporated in this application.  
      MCH-1 Receptor Binding Test  
      Method: MCH binding to hMCH-1R transfected cells  
      Species: Human  
      Test cell: hMCH-1R stably transfected into CHO/Galphal 6 cells  
      Results: IC50 values  
      Membranes from CHO/Galphal6 cells stably transfected with human hMCH-1R are resuspended using a syringe (needle 0.6×25 mm) and diluted in test buffer (50 mM HEPES, 10 mM MgCl 2 , 2 mM EGTA, pH 7.00; 0.1% bovine serum albumin (protease-free), 0.021% bacitracin, 1 μg/ml aprotinin, 1 μg/ml leupeptin and 1 μM phosphoramidone) to a concentration of 5 to 15 μg/ml.  
      200 microlitres of this membrane fraction (contains 1 to 3 μg of protein) are incubated for 60 minutes at ambient temperature with 100 pM of  125 I-tyrosyl melanin concentrating hormone ( 125 I-MCH commercially obtainable from NEN) and increasing concentrations of the test compound in a final volume of 250 microlitres. After the incubation the reaction is filtered using a cell harvester through 0.5% PEI treated fibreglass filters (GF/B, Unifilter Packard). The membrane-bound radioactivity retained on the filter is then determined after the addition of scintillator substance (Packard Microscint 20) in a measuring device (TopCount of Packard).  
      The non-specific binding is defined as bound radioactivity in the presence of 1 micromolar MCH during the incubation period.  
      The analysis of the concentration binding curve is carried out on the assumption of one receptor binding site.  
      Standard:  
      Non-labelled MCH competes with labelled  125 I-MCH for the receptor binding with an IC50 value of between 0.06 and 0.15 nM.  
      The KD value of the radioligand is 0.156 nM.  
      MCH-1 Receptor-Coupled Ca 2+  Mobilisation Test  
      Method: Calcium mobilisation test with human MCH (FLIPR 384 )  
      Species: Human  
      Test cells: CHO/Galpha 16 cells stably transfected with hMCH-R1  
      Results: 1st measurement:: % stimulation of the reference (MCH 10 −6 M)  
      2nd measurement: pKB value  
                               Reagents:                                                HBSS (10x)   (GIBCO)           HEPES buffer (1M)   (GIBCO)           Pluronic F-127   (Molecular Probes)           Fluo-4   (Molecular Probes)           Probenecid   (Sigma)           MCH   (Bachem)           bovine serum albumin   (Serva)           (protease-free)           DMSO   (Serva)           Ham&#39;s F12   (BioWhittaker)           FCS   (BioWhittaker)           L-Glutamine   (GIBCO)           Hygromycin B   (GIBCO)           PENStrep   (BioWhittaker)           Zeocin   (Invitrogen)                      
 
      Clonal CHO/Galpha16 hMCH-R1 cells are cultivated in Ham&#39;s F12 cell culture medium (with L-glutamine; BioWhittaker; Cat.No.: BE12-615F). This contains per 500 ml 10% FCS, 1% PENStrep, 5 ml L-glutamine (200 mM stock solution), 3 ml hygromycin B (50 mg/ml in PBS) and 1.25 ml zeocin (100 μg/ml stock solution). One day before the experiment the cells are plated on a 384-well microtitre plate (black-walled with a transparent base, made by Costar) in a density of 2500 cells per cavity and cultivated in the above medium overnight at 37° C., 5% CO 2  and 95% relative humidity. On the day of the experiment the cells are incubated with cell culture medium to which 2 mM Fluo-4 and 4.6 mM Probenicid have been added, at 37° C. for 45 minutes. After charging with fluorescent dye the cells are washed four times with Hanks buffer solution (1×HBSS, 20 mM HEPES), which has been combined with 0.07% Probenicid. The test substances are diluted in Hanks buffer solution, combined with 2.5% DMSO. The background fluorescence of non-stimulated cells is measured in the presence of substance in the 384-well microtitre plate five minutes after the last washing step in the FLIPR 384  apparatus (Molecular Devices; excitation wavelength: 488 nm; emission wavelength: bandpass 510 to 570 nm). To stimulate the cells MCH is diluted in Hanks buffer with 0.1% BSA, pipetted into the 384-well cell culture plate 35 minutes after the last washing step and the MCH-stimulated fluorescence is then measured in the FLIPR 384  apparatus.  
      Data Analysis:  
      1st measurement: The cellular Ca 2+  mobilisation is measured as the peak of the relative fluorescence minus the background and is expressed as the percentage of the maximum signal of the reference (MCH 10 −6 M). This measurement serves to identify any possible agonistic effect of a test substance.  
      2nd measurement: The cellular Ca 2+  mobilisation is measured as the peak of the relative fluorescence minus the background and is expressed as the percentage of the maximum signal of the reference (MCH 10 −6 M, signal is standardised to 100%). The EC50 values of the MCH dosage activity curve with and without test substance (defined concentration) are determined graphically by the GraphPad Prism 2.01 curve program. MCH antagonists cause the MCH stimulation curve to shift to the right in the graph plotted.  
      The inhibition is expressed as a pKB value: 
 
 pKB =log( EC   50(testsubstance+MCH)   /EC   50(MCH) −1)−log  c   (testsubstance)  
 
      The compounds according to the invention, including their salts, exhibit an MCH-receptor antagonistic activity in the tests mentioned above. Using the MCH-1 receptor binding test described above an antagonistic activity is obtained in a dosage range from about 10 −10  to 10 −5  M, particularly from 10 −9  to 10 −6  M.  
      The following IC50 values were determined using the MCH-1 receptor binding test described above:  
                                       Compound               according to       IC50       Example no.   Name of substance   value                                            3.30   N-[1-(4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-    79 nM           yl]-propylamino}-benzyl)-pyrrolidin-3-yl]-           acetamide       9.1   1-(4-{3-[6-(4-Methoxy-phenyl)-pyridazin-3-   174 nM           ylamino]-propyl}-benzyl)-piperidin-4-ol       12.1   (2-{2-Chloro-4-[2-(2-chloro-4-iodo-phenoxy)-   172 nM           ethoxy]-phenoxy}-ethyl)-diethyl-amine                  
 
      Some examples of formulations will be described hereinafter, wherein the term “active substance” denotes one or more compounds according to the invention, including their salts. In the case of one of the combinations with one or more active substances described, the term “active substance” also includes the additional active substances.  
     EXAMPLE A  
      Capsules for Powder Inhalation Containing 1 mg Active Substance  
      Composition:  
      1 capsule for powder inhalation contains:  
                                                      active substance    1.0 mg           lactose   20.0 mg           hard gelatine capsules   50.0 mg               71.0 mg                      
 
 Method of Preparation: 
 
      The active substance is ground to the particle size required for inhalation. The ground active substance is homogeneously mixed with the lactose. The mixture is packed into hard gelatine capsules.  
     EXAMPLE B  
      Inhalable solution for Respimat® containing 1 mg active substance  
      Composition:  
                               1 spray contains:                                                    active substance   1.0   mg           benzalkonium chloride   0.002   mg           disodium edetate   0.0075   mg           purified water ad   15.0   μl                      
 
 Method of Preparation: 
 
      The active substance and benzalkonium chloride are dissolved in water and packed into Respimat® cartridges.  
     EXAMPLE C  
      Inhalable Solution for Nebulisers Containing 1 mg Active Substance  
      Composition:  
                                               1 vial contains:                                                        active substance   0.1   g           sodium chloride   0.18   g           benzalkonium chloride   0.002   g           purified water ad   20.0   ml                      
 
 Method of Preparation: 
 
      The active substance, sodium chloride and benzalkonium chloride are dissolved in water.  
     EXAMPLE D  
      Propellant Type Metered Dose Aerosol Containing 1 mg Active Substance  
      Composition:  
                                               1 spray contains:                                                        active substance   1.0   mg                             lecithin   0.1%                                 propellant gas ad   50.0   μl                      
 
 Method of Preparation: 
 
      The micronised active substance is homogeneously suspended in the mixture of lecithin and propellant gas. The suspension is transferred into a pressurised container with a metering valve.  
     EXAMPLE E  
      Nasal Spray Containing 1 mg Active Substance  
      Composition:  
                                                          active substance   1.0   mg           sodium chloride   0.9   mg           benzalkonium chloride   0.025   mg           disodium edetate   0.05   mg           purified water ad   0.1   ml                      
 
 Method of Preparation: 
 
      The active substance and the excipients are dissolved in water and transferred into a corresponding container.  
     EXAMPLE F  
      Injectable Solution Containing 5 mg of Active Substance Per 5 ml  
      Composition:  
                                                          active substance   5   mg           glucose   250   mg           human serum albumin   10   mg           glycofurol   250   mg           water for injections ad   5   ml                      
 
 Preparation: 
 
      Glycofurol and glucose are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.  
     EXAMPLE G  
      Injectable solution containing 100 mg of active substance per 20 ml  
      Composition:  
                                                          active substance   100   mg           monopotassium dihydrogen phosphate = KH 2 PO 4     12   mg           disodium hydrogen phosphate = Na 2 HPO 4 •2H 2 O   2   mg           sodium chloride   180   mg           human serum albumin   50   mg           Polysorbate 80   20   mg           water for injections ad   20   ml                      
 
 Preparation: 
 
      Polysorbate 80, sodium chloride, monopotassium dihydrogen phosphate and disodium hydrogen phosphate are dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules.  
     EXAMPLE H  
      Lyophilisate Containing 10 mg of Active Substance  
      Composition:  
                                                      Active substance   10 mg           Mannitol   300 mg            human serum albumin   20 mg                      
 
 Preparation: 
 
      Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into vials; freeze-dried.  
      Solvent for lyophilisate:  
                                                          Polysorbate 80 = Tween 80   20   mg           mannitol   200   mg           water for injections ad   10   ml                      
 
 Preparation: 
 
      Polysorbate 80 and mannitol are dissolved in water for injections (Wfl); transferred into ampoules.  
     EXAMPLE I  
      Tablets Containing 20 mg of Active Substance  
      Composition:  
                                                      active substance   20 mg           lactose   120 mg            maize starch   40 mg           magnesium stearate    2 mg           Povidone K 25   18 mg                      
 
 Preparation: 
 
      Active substance, lactose and maize starch are homogeneously mixed; granulated with an aqueous solution of Povidone; mixed with magnesium stearate; compressed in a tablet press; weight of tablet 200 mg.  
     EXAMPLE J  
      Capsules Containing 20 mg Active Substance  
      Composition:  
                                                      active substance   20 mg           maize starch   80 mg           highly dispersed silica    5 mg           magnesium stearate   2.5 mg                       
 
 Preparation: 
 
      Active substance, maize starch and silica are homogeneously mixed; mixed with magnesium stearate; the mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.  
     EXAMPLE K  
      Suppositories Containing 50 mg of Active Substance  
      Composition:  
                                                      active substance    50 mg           hard fat (Adeps solidus) q.s. ad   1700 mg                      
 
      Preparation:  
      Hard fat is melted at about 38° C.; ground active substance is homogeneously dispersed in the molten hard fat; after cooling to about 35° C. it is poured into chilled moulds.  
     EXAMPLE L  
      Injectable Solution Containing 10 mg of Active Substance Per 1 ml  
      Composition:  
                                                          active substance   10   mg           mannitol   50   mg           human serum albumin   10   mg           water for injections ad   1   ml                      
 
 Preparation: 
 
      Mannitol is dissolved in water for injections (Wfl); human serum albumin is added; active ingredient is dissolved with heating; made up to specified volume with Wfl; transferred into ampoules under nitrogen gas.