Abstract:
This invention is directed to compounds of the formula I  
                         
as defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula I, a method of treatment of a disorder or condition that may be treated by antagonizing histamine H3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above, and a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer&#39;s disease, attention-deficit disorder (ADD), attention-deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy-induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro-intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.

Description:
BACKGROUND OF THE INVENTION  
       [0001]     This invention is directed to compounds of formula I described herein, to a pharmaceutical composition comprising such compounds, and to methods of treatment of disorders or conditions that may be treated by antagonizing histamine-3 (H3) receptors using such compounds. The histamine-3 (H3) receptor antagonists of the invention are useful for treating anxiety disorders, including, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder; mood adjustment disorders, including depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood; age-associated learning and mental disorders, including Alzheimer&#39;s disease; attention adjustment disorders, such as attention-deficit disorders, or other cognitive disorders due to general medical conditions; attention-deficit hyperactivity disorder; psychotic disorders including schizoaffective disorders and schizophrenia; sleep disorders, including narcolepsy and enuresis; obesity; dizziness, epilepsy, and motion sickness. The H3 receptor antagonists of the invention are also useful for treating, for example, allergy, allergy-induced airway (e.g., upper airway) responses, congestion (e.g., nasal congestion), hypotension, cardiovascular disease, diseases of the GI tract, hyper- and hypo-motility and acidic secretion of the gastrointestinal tract, sleeping disorders (e.g., hypersomnia, somnolence, and narcolepsy), attention deficit hyperactivity disorder ADHD), hypo- and hyper-activity of the central nervous system (for example, agitation and depression), and other CNS disorders (such as schizophrenia and migraine).  
         [0002]     Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) that are commonly treated with antagonists of histamine or “antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as H1 and H2 receptors.  
         [0003]     A third histamine receptor (H3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, S32-837 (1983)). The existence of the H3 receptor has been confirmed by the development of selective H3 receptor agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of the neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.  
         [0004]     A number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H3 ligand may be an antagonist, agonist or partial agonist, see: (Imamura et al., Circulation Res., (1996) 78, 475-481); (Imamura et al., Circ. Res., (1996) 78, 863-869); (Lin et al., Brain Res. (1990) 523, 325-330); (Monti et al., Neuropsychopharmacology (1996) 15, 31-35); (Sakai et al., Life Sci. (1991) 48, 2397-2404); (Mazurkiewiez-Kwilecki and Nsonwah, Can. J. Physiol. Pharmacol. (1989) 67, 75-78); (Panula, P. et al., Neuroscience (1998) 44, 465-481); (Wada et al., Trends in Neuroscience (1991) 14,415); (Monti et al., Eur. J. Pharmacol. (1991) 205, 283); (Haas et al., Behav. Brain Res. (1995) 66, 41-44); (De Almeida and Izquierdo, Arch. Int. Pharmacodyn. (1986) 283, 193-198); (Kamei et al., Psychopharmacology (1990) 102, 312-318); (Kamei and Sakata, Japan. J. Pharmacol. (199 1) 57, 437-482); (Schwartz et al., Psychopharmacology; The Fourth Generation of Progress, Bloom and Kupfer (eds.), Raven Press, New York, (1995) 3, 97); (Shaywitz et al., Psychopharmacology (1984) 82, 73-77); (Dumery and Blozovski, Exp. Brain Res. (1987) 67, 61-69); (Tedford et al., J. Pharmacol. Exp. Ther. (1995) 275, 598-604); (Tedford et al., Soc. Neurosci. Abstr. (1996) 22, 22); (Yokoyama et al., Eur. J. Pharmacol. (1993) 234, 129); (Yokoyama and linuma, CNS Drugs (1996) 5, 321); (Onodera et al., Prog. Neurobiol. (1994) 42, 685); (Leurs and Timmerman, Prog. Drug Res. (1992) 39,127); (The Histamine H3 Receptor, Leurs and Timmerman (ed.), Elsevier Science, Amsterdam, The Netherlands (1998); (Leurs et al., Trends in Pharm. Sci. (1998) 19, 177-183); (Phillips et al., Annual Reports in Medicinal Chemistry (1998) 33, 31-40); (Matsubara et al., Eur. J. Pharmacol. (1992) 224, 145); (Rouleau et al., J. Pharmacol. Exp. Ther. (1997) 281, 1085); (Adam Szelag, “Role of histamine H3-receptors in the proliferation of neoplastic cells in vitro”, Med. Sci. Monit., 4(5): 747-755, (1998)); (Fitzsimons, C., H. Duran, F. Labombarda, B. Molinari and E. Rivera, “Histamine receptors signaling in epidermal tumor cell lines with H-ras gene alterations”, Inflammation Res., 47 (Suppl. 1): S50-S51, (1998)); (R. Leurs, R. C. Vollinga and H. Timmerman, “The medicinal chemistry and therapeutic potentials of ligand of the histamine H3 receptor”, Progress in Drug Research 45: 170-165, (1995)); (R. Levi and N. C. E. Smith, “Histamine H3-receptors: A new frontier in myocardial ischemia”, J. Pharm. Exp. Ther., 292: 825-830, (2000)); (Hatta, E., K Yasuda and R. Levi, “Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia”, J. Pharm. Exp. Ther., 283: 494-500, (1997); (H. Yokoyama and K. Iinuma, “Histamine and Seizures: Implications for the treatment of epilepsy”, CNS Drugs, 5(5); 321-330, (1995)); (K. Hurukami, H. Yokoyama, K. Onodera, K. Iinuma and T. Watanabe, AQ-0 145, “A newly developed histamine H3 antagonist, decreased seizure susceptibility of electrically induced convulsions in mice”, Meth. Find. Exp. Clin. Pharmacol., 17(C): 70-73, (1995); (Delaunois A., Gustin P., Garbarg M., and Ansay M., “Modulation of acetylcholine, capsaicin and substance P effects by histamine H3 receptors in isolated perfused rabbit lungs”, European Journal of Pharmacology 277(2-3):243-50, (1995)); and (Dimitriadou, et al., “Functional relationship between mast cells and C-sensitive nerve fibres evidenced by histamine H3-receptor modulation in rat lung and spleen”, Clinical Science 87(2):151-63, (1994). Such diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer&#39;s disease and attention deficit hyperactivity disorder; neurological disorders such as Parkinson&#39;s disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma,” medullary thyroid carcinoma and melanoma; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere&#39;s disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.  
         [0005]     H3 receptor antagonists have also been previously described in, for example, WO 03/050099, WO 02/0769252, and WO 02/12224. The histamine H3 receptor (H3R) regulates the release of histamine and other neurotransmitters, including serotonin and acetylcholine. H3R is relatively neuron specific and inhibits the release of certain monoamines such as histamine. Selective antagonism of H3R raises brain histamine levels and inhibits such activities as food consumption while minimizing non-specific peripheral consequences. Antagonists of the receptor increase synthesis and release of cerebral histamine and other monoamines. By this mechanism, they induce a prolonged wakefulness, improved cognitive function, reduction in food intake and normalization of vestibular reflexes. Accordingly, the receptor is an important target for new therapeutics in Alzheimer&#39;s disease, mood and attention adjustments, including attention deficit hyperactive disorder (ADHD), cognitive deficiencies, obesity, dizziness, schizophrenia, epilepsy, sleeping disorders, narcolepsy and motion sickness, and various forms of anxiety.  
         [0006]     The majority of histamine H3 receptor antagonists to date resemble histamine in possessing an imidazole ring that may be substituted, as described, for example, in WO 96/38142. Non-imidazole neuroactive compounds such as beta histamines (Arrang, Eur. J. Pharm. 1985, 111:72-84) demonstrated some histamine H3 receptor activity but with poor potency. EP 978512 and EP 982300 disclose non-imidazole alkylamines as histamine H3 receptor antagonists. WO 02/12224 (Ortho McNeil Pharmaceuticals) describes non-imidazole bicyclic derivatives as histamine H3 receptor ligands, and EP 1275647 (Les Laboratoires Servier) has disclosed novel octahydro-2H-pyrido[1,2-a]pyrazines that are selective H3 receptor antagonists. Other receptor antagonists have been described in WO 02/32893 and WO 02/06233.  
         [0007]     This invention is directed to histamine-3 (H3) receptor antagonists of the invention useful for treating the conditions listed in the preceding paragraphs. The compounds of this invention are highly selective for the H3 receptor (vs. other histamine receptors), and possess remarkable drug disposition properties (pharmacokinetics). In particular, the compounds of this invention selectively distinguish H3R from the other receptor subtypes H1R, H2R. In view of the increased level of interest in histamine H3 receptor agonists, inverse agonists and antagonists in the art, novel compounds that interact with the histamine H3 receptor would be a highly desirable contribution to the art. The present invention provides such a contribution to the art being based on the finding that a novel class of benzylic amino compounds exhibits a high and specific affinity to the histamine H3 receptor.  
       SUMMARY OF THE INVENTION  
       [0008]     This invention is directed to compounds of the formula I:  
                         
 
 or the pharmaceutically acceptable salt(s) thereof, wherein: 
        n=0, 1, 2, or 3;     R 1  and R 2  are independently selected from the group that includes:     hydrogen;     C 1 -C 6  alkyl; or R 1  and R 2  together with the carbon to which they are attached form a carbonyl group (C═O) or a 3-8 member ring, wherein from one to three of the carbons in the ring is optionally replaced by O, S, NR 6 , or CO, and the ring is optionally fused to a C 6 -C 10  arylene and is optionally substituted at available positions on a ring carbon with one or two C 1 -C 4  alkyl groups; wherein t is 0, 1 or 2;     R 3 , R 4  and R 6  are independently selected from the group consisting of hydrogen;     C 1 -C 8  alkyl, optionally substituted with 1-4 halogen (especially fluorine) or OH;     C 3 -C 7  cycloalkyl;     C 6 -C 14  aryl;     3-8 member heterocycloalkyl, optionally substituted with a C 1 -C 4  alkyl-carbonyl group;     C 6 -C 10  arylsulfonyl, optionally substituted with C 1 -C 2  alkyl; and     5-10 member heteroaryl; or     R 3  and R 4  together with the nitrogen to which they are attached form a 4-7 member ring containing nitrogen (N) and 0-3 heteroatoms selected from N, O, S (e.g., to form piperazine, morpholine, pyrrolidine, piperidine, thiomorpholine).     R 5  is selected from the group that includes:     aryl, optionally substituted with Z;     heteroaryl, optionally substituted with Z;     3-8 member cyclic amine, optionally with 0-3 heteroatoms selected from N, O, or S (e.g., azetidine, pyrrolidine, piperidine, homopiperidine, piperazine, morpholine, thiomorpholine);     X, Y and Z are independently selected from the group consisting of H, F, Cl, Br, I, CN, OH, NH 2 , CF 3 , C 2 F 5 , (C 1 -C 6 ) alkyl, (C 1 -C 6 )-alkoxy, (C 1 -C 6 )alkyl-S(O) q —, wherein q is 0, 1 or 2.        
 
         [0026]     Where cis and trans isomers are possible for an embodiment of the inventive compound of formula I, both cis and trans isomers are within the scope of the invention.  
         [0027]     The term “alkyl” refers to straight or branched chains of carbon atoms. Exemplary alkyl groups are C 1 -C 6  alkyl groups which include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and the like, including all regioisomeric forms thereof, and straight and branched chain forms thereof. The term “alkyl” is also used to denote straight or branched chains of carbon atoms having one or more carbon-carbon double bonds, such as vinyl, allyl, butenyl, and the like, as well as straight or branched chains of carbon atoms having one or more carbon-carbon triple bonds, such as ethynyl, propargyl, butynyl, and the like. The term “aryl” denotes a cyclic, aromatic hydrocarbon. Examples of aryl groups include phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. The terms “alkoxy” and “aryloxy” denote “O-alkyl” and “O-aryl”, respectively. The term “cycloalkyl” denotes a cyclic group of carbon atoms, where the ring formed by the carbon atoms may be saturated or may comprise one or more carbon-carbon double bonds in the ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. As used herein, the term “cycloalkyl” is also intended to denote a cyclic group comprising at least two fused rings, such as adamantanyl, decahydronaphthalinyl, norbornanyl, where the cyclic group may also have one or more carbon-carbon double bonds in one or both rings, such as in bicyclo[4.3.0]nona-3,6(1)-dienyl, dicyclopentadienyl, 1,2,3,4-tetrahydronaphthalinyl (tetralinyl), indenyl, and the like. The term “halogen” represents chloro, fluoro, bromo, and iodo. The term “heteroaryl” denotes a monocyclic or bicyclic aromatic group wherein one or more carbon atoms are replaced with heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Preferred heteroaryl groups are five- to fourteen-member rings that contain from one to three heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of preferred heteroaryl groups include benzo[b]thienyl, chromenyl, furyl, imidazolyl, indazolyl, indolizinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazinyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinolizinyl, quinolyl, quinoxalinyl, thiazolyl, thienyl, triazinyl, triazolyl, and xanthenyl.  
         [0028]     The term “heterocycloalkyl” denotes a cycloalkyl system, wherein “cycloalkyl” is defined above, in which one or more of the ring carbon atoms are replaced with a heteroatom selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of such heterocycloalkyl groups include azabicycloheptanyl, azetidinyl, benzazepinyl, 1,3-dihydroisoindolyl, indolinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, and, tetrahydro-2H-1,4-thiazinyl.  
         [0029]     A cyclic group may be bonded to another group in more than one way. If no particular bonding arrangement is specified, then all possible arrangements are intended. For example, the term “pyridyl” includes 2-, 3-, or 4-pyridyl, and the term “thienyl” includes 2- or 3-thienyl.  
         [0030]     The term “C 0 -C 4 ” includes the embodiment where there are no carbons in a chain. Thus, for example, the groups “C 3 -C 7  cycloalkyl-C 0 -C 4  alkyl,” “C 6 -C 14  aryl-C 0 -C 4  alkyl,” “5-10-membered heteroaryl-C 0 -C 4  alkyl,” and “C 6 -C 14  aryl-C 0 -C 4  alkylene-O—C 0 -C 4  alkyl” include C 3 -C 7  cycloalkyl, C 6 -C 14  aryl, 5-10-membered heteroaryl, and C 6 -C 14  aryl—O—C 0 -C 4  alkyl, respectively.  
         [0031]     The term “C 1 -C 4  dialkylamino” refers to a dialkylamino group in which each alkyl group is independently a C 1 -C 4 alkyl group.  
         [0032]     This invention is also directed to: 
        a pharmaceutical composition for treating, for example, a disorder or condition that may be treated by antagonizing histamine-3 receptors, the composition comprising a compound of formula I as described above, and optionally a pharmaceutically acceptable carrier;     a method of treatment of a disorder or condition that may be treated by antagonizing histamine-3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above; and     a pharmaceutical composition for treating, for example, a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer&#39;s disease, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), psychotic disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy-induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastrointestinal tract, the composition comprising a compound of formula I as described above, and optionally a pharmaceutically acceptable carrier.        
 
         [0036]     This invention is also directed to a method of treatment of a disorder or condition selected from the group consisting of the disorders or conditions listed in the preceding paragraph, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.  
         [0037]     The histamine-3 (H3) receptor antagonists of the invention are useful for treating, in particular, ADD, ADHD, obesity, anxiety disorders and respiratory diseases. Respiratory diseases that may be treated by the present invention include adult respiratory distress syndrome, acute respiratory distress syndrome, bronchitis, chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, asthma, emphysema, rhinitis and chronic sinusitis.  
         [0038]     The pharmaceutical composition and method of this invention may also be used for preventing a relapse in a disorder or condition described in the previous paragraphs. Preventing such relapse is accomplished by administering to a mammal in need of such prevention a compound of formula I as described above.  
         [0039]     The disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H3 antagonist compound of general formula I and an effective dose of a histamine H1 antagonist, such as cetirizine (Zyrtec™), for the treatment of allergic rhinitis, nasal congestion and allergic congestion.  
         [0040]     The disclosed compounds may also be used as part of a combination therapy, including their administration as separate entities or combined in a single delivery system, which employs an effective dose of a histamine H3 antagonist compound of general formula I and an effective dose of a neurotransmitter reuptake blocker. Examples of neurotransmitter reuptake blockers will include the serotonin-selective reuptake inhibitors (SSRI&#39;s) like sertraline (Zoloft™), fluoxetine (Prozac™), and paroxetine (Paxil™), or non-selective serotonin, dopamine or norepinephrine reuptake inhibitors for treating depression and mood disorders.  
         [0041]     The compounds of the present invention may have optical centers and therefore may occur in different enantiomeric configurations. Formula I, as depicted above, includes all enantiomers, diastereomers, and other stereoisomers of the compounds depicted in structural formula I, as well as racemic and other mixtures thereof. Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.  
         [0042]     The present invention also includes isotopically labeled compounds, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as  2 H,  3 H,  13 C,  11 C,  14 C,  15 N,  18 O,  17 O,  31 P,  32 P,  35 S,  18 F, and  36 C 1 , respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as  3 H and  14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e.,  3 H, and carbon-14, i.e.,  14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.  
         [0043]     “Antagonizing histamine-3 (H3) receptors,” as used herein, refers to acting as a histamine-3 receptor antagonist.  
         [0044]     A “unit dosage form” as used herein is any form that contains a unit dose of the compound of formula I. A unit dosage form may be, for example, in the form of a tablet or a capsule. The unit dosage form may also be in liquid form, such as a solution or suspension.  
         [0045]     The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.  
         [0046]     For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).  
         [0047]     For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.  
         [0048]     The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.  
         [0049]     The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.  
         [0050]     For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.  
         [0051]     A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.  
         [0052]     Aerosol formulations for treatment of the conditions referred to above (e.g., attention deficit hyperactivity disorder) in the average human are preferably arranged so that each metered dose or “puff” of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 μg to 100 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.  
         [0053]     In connection with the use of an active compound of this invention with a histamine H1 antagonist, preferably cetirizine, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a histamine H1 antagonist, preferably cetirizine, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.  
         [0054]     A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a histamine H1 antagonist) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.  
         [0055]     A proposed daily dose of a histamine H1 antagonist, preferably cetirizine, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the histamine H1 antagonist per unit dose which could be administered, for example, 1 to 4 times per day.  
         [0056]     A preferred dose ratio of cetirizine to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.  
         [0057]     Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains from about 0.01 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.  
         [0058]     Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains from about 0.01 mg to about 2000 mg of a histamine H1 antagonist, preferably cetirizine, preferably from about 1 mg to about 200 mg of cetirizine. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.  
         [0059]     As previously indicated, a histamine H1 antagonist, preferably cetirizine, in combination with compounds of formula I are readily adapted to therapeutic use as antiallergy agents. In general, these antiallergy compositions containing a histamine H1 antagonist, preferably cetirizine, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a histamine H1 antagonist, preferably cetirizine, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of cetirizine; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.  
         [0060]     In connection with the use of an active compound of this invention with a 5-HT re-uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 95% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.  
         [0061]     A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT re-uptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.  
         [0062]     A proposed daily dose of a 5-HT re-uptake inhibitor, preferably sertraline, in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5-HT re-uptake inhibitor per unit dose which could be administered, for example, 1 to 4 times per day.  
         [0063]     A preferred dose ratio of sertraline to an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.00005 to about 20,000, preferably from about 0.25 to about 2,000.  
         [0064]     Aerosol combination formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains from about 0.01 μg to about 100 mg of the active compound of this invention, preferably from about 1 μg to about 10 mg of such compound. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.  
         [0065]     Aerosol formulations for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or “puff” of aerosol contains from about 0.01 mg to about 2000 mg of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 1 mg to about 200 mg of sertraline. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.  
         [0066]     As previously indicated, a 5-HT re-uptake inhibitor, preferably sertraline, in combination with compounds of formula I are readily adapted to therapeutic use as antidepressant agents. In general, these antidepressant compositions containing a 5-HT re-uptake inhibitor, preferably sertraline, and a compound of formula I are normally administered in dosages ranging from about 0.01 mg to about 100 mg per kg of body weight per day of a 5-HT re-uptake inhibitor, preferably sertraline, preferably from about 0.1 mg. to about 10 mg per kg of body weight per day of sertraline; with from about 0.001 mg. to about 100 mg per kg of body weight per day of a compound of formula I, preferably from about 0.01 mg to about 10 mg per kg of body weight per day of a compound of formula I, although variations will necessarily occur depending upon the conditions of the subject being treated and the particular route of administration chosen.  
         [0067]     Anxiety disorders include, for example, generalized anxiety disorder, panic disorder, PTSD, and social anxiety disorder. Mood adjustment disorders include, for example, depressed mood, mixed anxiety and depressed mood, disturbance of conduct, and mixed disturbance of conduct and depressed mood. Attention adjustment disorders include, for example, in addition to ADHD, attention deficit disorders or other cognitive disorders due to general medical conditions. Psychotic disorders include, for example, schizoaffective disorders and schizophrenia; sleep disorders include, for example, narcolepsy and enuresis.  
         [0068]     Examples of the disorders or conditions which may be treated by the compound, composition and method of this invention are also as follows: depression, including, for example, depression in cancer patients, depression in Parkinson&#39;s patients, post-myocardial Infarction depression, depression in patients with human immunodeficiency virus (HIV), Subsyndromal Symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, DSM-IV major depression, treatment-refractory major depression, severe depression, psychotic depression, post-stroke depression, neuropathic pain, manic depressive illness, including manic depressive illness with mixed episodes and manic depressive illness with depressive episodes, seasonal affective disorder, bipolar depression BP I, bipolar depression BP II, or major depression with dysthymia; dysthymia; phobias, including, for example, agoraphobia, social phobia or simple phobias; eating disorders, including, for example, anorexia nervosa or bulimia nervosa; chemical dependencies, including, for example, addictions to alcohol, cocaine, amphetamine and other psychostimulants, morphine, heroin and other opioid agonists, phenobarbital and other barbiturates, nicotine, diazepam, benzodiazepines and other psychoactive substances; Parkinson&#39;s diseases, including, for example, dementia in Parkinson&#39;s disease, neuroleptic-induced parkinsonism or tardive dyskinesias; headache, including, for example, headache associated with vascular disorders; withdrawal syndrome; age-associated learning and mental disorders; apathy; bipolar disorder; chronic fatigue syndrome; chronic or acute stress; conduct disorder; cyclothymic disorder; somatoform disorders such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated disorder, and somatoform NOS; incontinence; inhalation disorders; intoxication disorders; mania; oppositional defiant disorder; peripheral neuropathy; post-traumatic stress disorder; late luteal phase dysphoric disorder; specific developmental disorders; SSRI “poop out” syndrome, or a patient&#39;s failure to maintain a satisfactory response to SSRI therapy after an initial period of satisfactory response; and tic disorders including Tourette&#39;s disease.  
         [0069]     As an example, the mammal in need of the treatment or prevention may be a human. As another example, the mammal in need of the treatment or prevention may be a mammal other than a human.  
         [0070]     A compound of formula I, which is basic in nature, is capable of forming a wide variety of different salts with various inorganic and organic acids. The acid addition salts are readily prepared by treating the base compounds with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.  
         [0071]     The acids which are used to prepare the pharmaceutically acceptable acid salts of the active compound used in formulating the pharmaceutical composition of this invention that are basic in nature are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions. Non-limiting examples of the salts include the acetate, benzoate, beta-hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1,4-dioate, caproate, chloride, chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylenesulfonate, acid phosphate, acid citrate, bitartrate, succinate, gluconate, saccharate, nitrate, methanesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.  
         [0072]     Preferred embodiments of the present invention include the compounds of formula I in which 
        (A) R 1  is hydrogen; or     (B) R 1  and R 2  together with the carbon to which they are attached form a carbonyl; or     (C) R 3  and R 4  are each methyl; or     (D) R 3  and R 4  together with the nitrogen to which they are attached form a 5-member pyrrolidine ring; or     (E) R 3  and R 4  together with the nitrogen to which they are attached form a 6-member piperidine ring; or        
 
         [0078]     The most preferred embodiment of the present invention include the compounds of formula I in which R 1  and R 2  are hydrogen, R 3  and R 4  are methyl and n is 1.  
         [0079]     Preferred embodiments of the present invention also include any combination of the foregoing embodiments (A)-(E).  
         [0080]     Preferred compounds of formula I in accordance with the present invention are the following: 
    1′-(4-piperidin-4-ylbenzyl)-[1,3′]bipyrrolidinyl;     4-[1-(4-piperidin-4-ylbenzyl)-pyrrolidin-3-yl]-morpholine;     diethyl-[1-(4-piperidin-4-ylbenzyl)-piperidin-3-yl]-amine;     1′-[4-(2,6-dimethylpiperidin-3-yl)-benzyl]-[1,3′]bipyrrolidinyl;     dimethyl-(1-{1-[4-(1-methylpiperidin-4-yl)-phenyl]-ethyl}pyrrolidin-3-yl)-amine;     dimethyl-(1-{1-methyl-1-[4-(1-methylpiperidin-4-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-amine;     dimethyl-(1-{1-[4-(1-methylpiperidin-4-yl)-phenyl]-cyclopropyl}pyrrolidin-3-yl)-amine;     dimethyl-{5-methyl-1-[4-(1-methylpiperidin-4-yl)-benzyl]-pyrrolidin-3-yl}amine;     dimethyl-{1-[4-(1-methylpiperidin-4-yl)-benzyl]-azepan-3-yl}-amine;     dimethyl-{1-[4-(1-methylpiperidin-4-yl)-benzyl]-azetidin-3-yl}-amine;     dimethyl-[1-(4-pyrimidin-4-ylbenzyl)-azetidin-3-yl]-amine;     dimethyl-[1-(4-pyridin-3-ylbenzyl)-azetidin-3-yl]-amine;     dimethyl-{1-[4-(2-methylpyrimidin-5-yl)-benzyl]-pyrrolidin-3-yl}-amine;     5-[4-(3-dimethylamino-pyrrolidin-1-ylmethyl)-phenyl]-pyrimidin-2-ol;     {1-[4-(2-methoxypyrimidin-5-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine;     {1-[3,5-difluoro-4-(2-methylpyrimidin-5-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine;     {1-[5-fluoro-2-methyl-4-(2-methylpyrimidin-5-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine;     1-(1-biphenyl-4-ylmethylpyrrolidin-3-yl)-4-methylpiperazine;     1-benzyl-4-(1-biphenyl-4-ylmethylpyrrolidin-3-yl)-piperazine;     1-benzenesulfonyl-4-(1-biphenyl-4-ylmethylpyrrolidin-3-yl)-piperazine;     1-(4-fluorophenyl)-4-[1-(4-pyridin-4-ylbenzyl)-pyrrolidin-3-yl]-piperazine; 1-[4-(2-methylpyrimidin-4-yl)-benzyl]-pyrrolidin-3-ylamine;     (3-dimethylaminopyrrolidin-1-yl)-(4-pyridin-4-ylphenyl)-methanone;     dimethyl-{1-[4-(2-methylthiazol-5-yl)-benzyl]-pyrrolidin-3-yl}-amine;     dimethyl-{1-[4-(5-methyl-[1,3,4]thiadiazol-2-yl)-benzyl]-pyrrolidin-3-yl}-amine;     [1-(4-benzothiazol-2-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine;     {1-[4-(1H-benzimidazol-2-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine;     {1-[4-(4,5-dimethylthiazol-2-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine;     N-cyclopentyl-N-methyl-[1-(4-pyrimidin-2-ylbenzyl)-pyrrolidin-3-yl]-amine;     {1-[2-chloro-4-(2-methylpyrimidin-5-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine; and     dimethyl-{1-[4-(4-methylmorpholin-2-yl)-benzyl]-pyrrolidin-3-yl}-amine.    
 
         [0111]     The most preferred examples of compounds according to the present invention include: 
    (R)-[1-(4-(4-pyridylbenzyl))-pyrrolidin-3-yl]-dimethylamine.     (S)-[1-(4-(4-pyridylbenzyl))-pyrrolidin-3-yl]-dimethylamine     4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-carboxylic acid dimethylamide.     { 1 -[4-(3-fluoropyridin-4-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine.     {1-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine.     {1-[4-(3-fluoropyridin-4-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine.     {1-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine.     {1-[4-(1-methyl-1H-indol-5-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine.     4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-carbonitrile.     4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-3-methoxy-biphenyl-2-carboxylic acid diisopropylamide.     4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-2-carboxylic acid diisopropylamide.     (1-biphenyl-4-ylmethyl-pyrrolidin-3-yl)-dimethylamine.     [1-(4′-fluorobiphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(3′,5′-bis-trifluoromethyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4′-phenoxybiphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4-thiophen-2-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4-thiophen-3-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4-benzofuran-2-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine.     [4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-yl]-methanol.     [1-(4-furan-2-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4-benzo[1,3]dioxol-5-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(3′,4′-dimethoxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     1-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-yl]-ethanone.     1-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-ethanone.     [1-(4-benzo[b]thiophen-2-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     [4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-methanol.     1-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-2-yl]-ethanone.     [1-(2′-phenoxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(2′-Benzyloxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4-furan-3-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(3′-methylsulfanyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     N-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-acetamide.     [1-(4′-benzyloxy-3′-fluorobiphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethyl-amine.     4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-ol.     [1-(4′-benzyloxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(2′-methylsulfanyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-carbonitrile.     [1-(4′-methanesulfonyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethyl-amine.     [1-(3′-benzyloxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     [1-(4-isoquinolin-5-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     1-(3′-pyrazol-1-ylbiphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     1-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-2-ylmethyl]-piperidin-4-one     {1-[4-(3-chloropyridin-4-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine.     [1-(4-pyrimidin-5-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     (S)-[1-(4′-methanesulfonyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     (R)-[1-(4′-methanesulfonyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine.     (S)-N-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-acetamide.     (R)-N-[4′-(3-dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-acetamide.     (R)-[1-(4-piperidin-4-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine.     (S)-[1-(4-piperidin-4-ylbenzyl))-pyrrolidin-3-yl]-dimethylamine,   
 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0162]     The compounds of formula I according to the invention may be prepared by the general procedure shown in Scheme 1-3.  
                         
 
         [0163]     According to Scheme 1, an amine of the general formula II, which may be commercially available or readily prepared using methods and procedures from the chemical or patent literature, is reacted with an appropriately substituted aldehyde (III, R 1 =H) or ketone (III, R 1  ≠ H) to produce the intermediate of general formula IV. This transformation is generally referred to as a reductive amination and can be performed under a variety of conditions known to one skilled in the art of chemistry. It may be performed in a single, concerted process (e.g., see A. F. Abdel-Magid, C. A. Maryanoff and K. G. Carson in Tetrahedron Letters, 1990, 39:5595-5598). In such conversions, the carbonyl compound of formula III and the intermediate amine of formula II are combined in a reaction inert solvent and treated with a reducing reagent such as sodium cyanoborohydride (NaBH 3 CN) or sodium triacetoxyborohydride (NaBH(OAc) 3 ). Suitable solvents include, among others, tetrahydrofuran (THF) and 1,2-dichloroethane (DCE) and the reactions may be conducted with or without the addition of an organic acid (e.g., acetic acid).  
         [0164]     The conversion of compounds of formula II and III into compounds of formula IV can also be completed using two or more individual steps, e.g., involving the initial formation of an imine intermediate such as V, followed by reduction of the C═N double bond to generate the compounds of general formula I. In some instances, this intermediate can be isolated and purified.  
                         
 
         [0165]     For example, the intermediate of formula II and the appropriate aldehyde (R 1  ═H) or ketone of formula III can be combined in the presence of a dehydrating reagent in a reaction neutral solvent like benzene, toluene, methanol or ethanol and stirred for a prescribed amount of time until the reaction is judged to be completed (e.g., using techniques like thin layer chromatography (tic), mass spectrometry (MS) or nuclear magnetic resonance spectrometry (NMR)). Such dehydrating reagents include, for example, p-toluenesulfonic acid (i.e., PTSA), titanium(IV) chloride (i.e., TiCl 4 ), titanium(IV) isopropoxide (i.e., Ti(OiPr) 4 ) or molecular sieves. The reaction can be conducted within the range of about 0° C. to about the boiling point of the solvent employed and at pressures of about one to about three atmospheres. The intermediate imine V so obtained can then be reduced with one or more reducing reagents under conditions familiar to one skilled in the art, e.g., hydrogen gas in the presence of a catalyst like palladium on carbon (Pd/C) or platinum on carbon (Pt/C), sodium borohydride (i.e., NaBH 4 ), sodium (triacetoxy)borohydride, sodium cyanoborohydride and the like. The use of hydrogen as the reducing agent is often conducted in a reaction inert solvent such as methanol, ethanol, THF, 1,4-dioxane or similar solvents at a pressure of about one atmosphere to a pressure of about five atmospheres of hydrogen and typically at a temperature from about room temperature to a temperature that is below or at the boiling point of the solvent employed. When using the hydride reagents, the choice of solvent can be made from, but not limited to, methanol, ethanol, isopropanol, 1,4-dioxane, THF and the like. The reaction can be carried out at atmospheric pressure and at temperatures ranging from about −40° C. to about the boiling temperature of the solvent employed, typically at 0-40° C. and most preferably at room temperature.  
         [0166]     When Y═R 5  for compound III, the desired compound of formula I may be prepared directly from II and III, eliminating the need to prepare the substituted intermediate of formula IV where Y≠R 5 , as defined for compound I. Otherwise, the Y group in compound IV can be converted to a group R 5  as defined above. This transformation can be made using several different procedures depending on the nature of the R 5  group. For example, when R 5  is aryl or heteroaryl, the intermediate of formula IV wherein Y is Br, Cl or I can be reacted with an aryl or heteroaryl boronic acid, using conditions described by Suzuki and others. This procedure, often referred to as the Suzuki reaction, has been described in numerous publications in the scientific literature, including Stanforth, S. P., “Catalytic Cross-coupling Reactions in Biaryl Synthesis.” Tetrahedron, 1998, 54:263-303; Watanabe, T. et al “Synthesis of Sterically Hindered Biaryls via the Palladium-catalyzed Cross-coupling Reaction of Arylboronic Acids or Their Esters with Haloarenes.” Synlett, 1992, 3:207-210; Ali, N. M. et al “Palladium-catalyzed Cross-coupling Reactions of Arylboronic Acids with π-Deficient Heteroaryl Chlorides.” Tetrahedron, 48(37):8117-8126; Saito, S. et al “Synthesis of Biaryls via a Nickel(0)-catalyzed Cross-coupling Reaction of Chloroarenes with Arylboronic Acids.” Journal of Organic Chemistry, 1997, 62(23):8024-8030; Indolese, A. F. “Suzuki-type Coupling of Chloroarenes with Arylboronic Acids Catalyzed by Nickel Complexes.” Tetrahedron Letters, 1997, 38(20):3513-3516; Zhang, H. et al, “Base and Cation Effects on the Suzuki Cross-coupling of Bulky Arylboronic Acid with Halopyridines. Synthesis of Pyridylphenols.” Journal of Organic Chemistry, 1988, 63(20):6886-6890; Wustrow, D. J. and Wise, L. D. “Coupling of Arylboronic Acid with a Partially Reduced Pyridine Derivative.” Synthesis, 1991, 11:993-995.  
         [0167]     Alternatively, the intermediate of general formula IV wherein Y is Br, Cl or I can first be converted to a boronic acid derivative which is then reacted under similar Suzuki conditions with an intermediate of general formula Y-R 5 , wherein Y and R 5  are as previously defined, to generate the compound of general formula I.  
                         
 
         [0168]     As shown in Scheme 2, the compounds of formula I may also be prepared using standard conditions for the alkylation of a secondary amine. Thus, a compound of the general formula II can be reacted with an appropriately substituted compound of general formula VI, wherein X, Y, R 1  and R 2  are as previously defined and L 1  is defined as a leaving group selected from the group which includes (but is not limited to) Cl, Br, I, mesylate and tosylate, to generate a compound of general formula VII. In cases wherein Y═R 5 , the desired product of general formula I can be prepared in a single step. Otherwise, the group Y can be converted to a group R 5  as previously described above for Scheme 1.  
                         
 
         [0169]     For the preparation of compounds I, wherein R 1  and R 2  together with the carbon to which they are attached form a carbonyl group, an amine of the general formula II can be reacted with the appropriate L 2 -carbonyl reactant (wherein L 2  is selected from Cl, Br, mesylate or tosylate, among others) of formula VIII in a reaction inert solvent (e.g., chloroform, dichloromethane, THF, etc.) and in the presence of an acid scavenger such as sodium or potassium carbonate. This reaction may be conducted at temperatures from about −80° C. to about the boiling point of the reaction solvent used and at pressures from about one to about three atmospheres. The reaction may also be facilitated by the addition of pyridine or dimethylaminopyridine (DMAP) to form a reactive acylpyridinium ion (A. R. Fersht and W. P. Jencks, Journal of the American Chemical Society (1970) 92:5432-5442; G. Hofle et al, Angew. Chem. Intern. Ed. Engl. (1978) 17:569). Preparation of the intermediates of formula VIII (e.g., L 2 =Cl) from the corresponding carboxylic acid (e.g., L2=OH) are well precedented in the literature and known to one skilled in the art of organic synthesis. For example, compounds VII wherein L 2 =OH can be reacted with one or more equivalents of a reagent such as thionyl chloride (SOCl 2 ) or oxalyl chloride in a reaction inert solvent like chloroform or dichlormethane under a dry inert atmosphere (e.g., N 2  or Ar gas) to produce the acyl chloride of general formula VIII.  
         [0170]     When compounds of general formula VIII, where L 2  is as defined above, are not available or may be unstable or difficult to isolate or purify, the corresponding compound VIII wherein L 2 =OH may be reacted with an amine of general formula II to prepare the intermediate of formula IX. This would involve activation of the carboxyl group, e.g., in the presence of triphenylphosphine and bromotrichlormethane (CBrCl 3 ) or chloroform (L. E. Barstow and V. J. Hruby, Journal of Organic Chemistry (1971) 36:1305; H. J. Bestmann and L. Mott, Justig Liebig&#39;s Annalen der Chemie (1966) 693:132; J. B. Lee, Journal of the American Chemical Society (1966) 88:3440). Alternatively, the carboxyl group may be converted to an acyl imidazole by reacting the acid with carbonyldiimidazole (CDI) and then reacting the acylimidazole with the appropriate amine II to generate the intermediate IX (H. A. Staab and W. Rohr, Newer Methods Prep. Org. Chem. (1968) 5:61).  
         [0171]     Conversion of the intermediate of formula IX to the intermediate of formula X, i.e., replacing Y by R 5 , can be accomplished as described for the conversion of intermediate VII to compounds of formula I using Scheme 2.  
         [0172]     Conversion of the compounds of formula X to the compounds of general formula I can be accomplished using one of a number of available reducing reagents known to those skilled in the art, including lithium aluminum hydride (LiALH 4 ), sodium or lithium bis-(2-methoxyethoxy)aluminum hydride, diborane (B 2 H 6 ) or alane (AIH 3 ), among others. This procedure can be conducted using a reaction inert solvent such as diethyl ether or THF under a dry, inert atmosphere (e.g., N 2 , Ar) at temperatures from about −78° C. to about the boiling point of the solvent employed. There are many examples of this conversion in the literature including A. C. Cope et al, Organic Synthesis (1963) IV:339; R. B. Moffett, Organic Synthesis (1963) IV:354.  
         [0173]     In the examples that follow, the abbreviations used are intended to have the following, general meaning: 
        bm: broad multiplet (NMR)     bs: broad singlet (NMR)     dd: doublet of doublets (NMR)     d.e.: diatomaceous earth, filter agent     DMF: dimethylormamide     LRMS: low resolution mass spectrometry     calcd; calculated     d; doublet (NMR)     EtOAc: ethyl acetate     J: coupling constant (NMR)     LAH: lithium aluminum hydride     m: multiplet (in NMR)     min: minute(s)     m/z: mass to charge ratio (in mass spectrometry)     obsd: observed     Rf: retention factor (in chromatography)     Rt: retention time (in chromatography)     rt: room temperature     s: singlet (NMR), second(s)     t: triplet     THF: tetrahydrofuran     tlc: thin layer chromatography        
 
         [0196]     Solvents were purchased and used without purification. Yields were calculated for material judged homogenous by thin layer chromatography and NMR. Thin layer chromatography was performed on Merck Kieselgel 60 F 254 plates eluting with the solvents indicated, visualized by a 254 nm UV lamp, and stained with either an aqueous KMnO 4  solution or an ethanolic solution of 12-molybdophosphoric acid. Flash column chromatography was performed with using either pre-packed Biotage®) or ISCO® columns using the size indicated. Nuclear magnetic resonance (NMR) spectra were acquired on a Unity 400 or 500 at 400 MHz or 500 MHz for  1 H, respectively, and 100 MHz or 125 MHz for  13 C NMR, respectively. Chemical shifts for proton  1 H NMR spectra are reported in parts per million relative to the singlet of CDCl 3  at 7.24 ppm. Chemical shifts for  13 C NMR spectra are reported in parts per million downfield relative to the centerline of the triplet of CDCl 3  at 77.0 ppm. Mass spectra analyses were performed on a APCI Gilson 215, micromass ZMD (50% Acetonitrile/50% water) spectrometer.  
         [0197]     Reactions under microwave conditions were done using 2-5 mL round bottom vials, fitted with septa. The vials containing the reactants were inserted into the reaction chamber of a EMRYS™ Creator microwave apparatus (maximum power of 300 W) from Personal Chemistry Inc., 25 Birch St., Bldg C, Suite 304, Milford, Mass. 01757 and heated to the appropriate temperature for a the prescribed period of time. HPLC was performed according to the following methods:  
         [0198]     Method A: Preparative conditions (Waters 600 &amp; Waters 2767 Sample Manager); Column: Waters Symmetry C 18 , 5 μm, 30×150 mm steel column, part # WAT248000, serial # M12921A01; solvent A—0.1% Trifluoroacetic acid/water; solvent B—Acetonitrile; volume of injection: 850 μL; time 0.0, 100% solvent A, 0% solvent B, flow 20; time 2.0, 100% solvent A, 0% solvent B, flow 20; time 12.0, 0% solvent A, 100% solvent B, flow 20; time 15.0, 0% solvent A, 100% solvent B, flow 20; time 15.1, 100% solvent A, 0% solvent B, flow 20; time 20.0, 100% solvent A, 0% solvent B, flow 20.  
         [0199]     Mass spectral (micromassZO) conditions; Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. (° C): 120; Desolvation temp. (° C): 360; Desolvation gas flow (L/hr): 450; Cone gas flow (L/hr): 150; LM Resolution: 15; HM Resolution: 15; [Ion Energy: 0.2; Multiplier: 550.  
         [0200]     Splitter; Acurate by LC Packings, 1/10,000; Upchurch needle valve setting: 14; Make up pump (Waters 515) Flow (ml/min.): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1; Channels: TIC, 254 nm and 220 nm.  
         [0201]     Method B: Preparative conditions (Waters 600 &amp; Waters 2767 Sample Manager); Column: Waters Xterra PrepMS C 18  column, 5 μm, 30×150 mm steel column, part # 186001120, serial # T22881T 09; solvent A—0.1% Trifluoroacetic acid/water; solvent B—Acetonitrile; volume of injection: 1050 μL; time 0.0, 100% solvent A, 0% solvent B, flow 20; time 2.0, 100% solvent A, 0% solvent B, flow 20; time 12.0, 0% solvent A, 100% solvent B, flow 20; time 14.0, 0% solvent A, 100% solvent B, flow 20; time 14.1, 100% solvent A, 0% solvent B, flow 20; time 19.1, 100% solvent A, 0% solvent B, flow 20.  
         [0202]     Mass spectral (micromassZO) conditions; Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. (° C.): 120; Desolvation temp. (° C.): 360; Desolvation gas flow (L/hr): 450; Cone gas flow (L/hr): 150; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 550.  
         [0203]     Splitter; Acurate by LC Packings, 1/10,000; Upchurch needle valve setting: 14; Make up pump (Waters 515) Flow (ml/min.): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1; Channels: TIC, 254 nm and 220 nm.  
         [0204]     Method C: Preparative conditions (Waters 600 &amp; Waters 2767 Sample Manager); Column: Waters Symmetry C 18 , 5 μm, 30×150 mm steel column, part # WAT248000, serial # M12921A01; solvent A—0.1% Trifluoroacetic acid/water; solvent B—Acetonitrile; volume of injection: 850 μL; time 0.0, 90% solvent A, 10% solvent B, flow 20; time 10.0, 0% solvent A, 100% solvent B, flow 20; time 12.0, 0% solvent A, 100% solvent B, flow 20.  
         [0205]     Mass spectral (micromassZO) conditions; Capillary(kV): 3.0; Cone (V): 20; Extractor (V): 3.0; RF Lens (V): 0.5; Source temp. (° C.): 120; Desolvation temp. (° C.): 360; Desolvation gas flow (L/hr): 450; Cone gas flow (L/hr): 150; LM Resolution: 15; HM Resolution: 15; Ion Energy: 0.2; Multiplier: 550. Splitter; Acurate by LC Packings, 1/10,000; Upchurch needle valve setting: 14; Make up pump (Waters 515) Flow (ml/min.): 1. PDA (Waters 996) Settings; Start/End wavelength (nm): 200/600; Resolution: 1.2; Sample Rate: 1; Channels: TIC, 254 nm and 220 nm.  
         [0206]     The following intermediates may be prepared by the procedures described above:  
       Intermediate 1 
       [0207]    
       
                 
         
             
             
         
       
     
       (S)-[1-(4-Bromobenzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0208]     A mixture of 4-bromobenzaldehyde (1.04 g, 5.6 mmol, Aldrich Chemical Co.) and 3(S)-(-)-dimethylamino-pyrrolidine (0.80 g, 7.0 mmol) in 15 mL of dichloromethane was stirred under N 2  at rt for 15 min. Sodium triacetoxyborohydride (3.56 g, 16.8 mmol) was added portionwise over 5 min and the mixture was stirred at rt overnight. The reaction was quenched by addition of saturated aqueous NaHCO 3 , then extracted with additional CH 2 Cl 2 . The combined organic extracts were washed with water and saturated NaCl, dried over Na 2 CO 3  and filtered. Concentration in vacuo gave a dark oil which was chromatographed on silica gel, eluting with a gradient of 2% CH 3 OH in CH 2 Cl 2  to 0.5% NH 4 OH: 8% CH 3 OH: CH 2 Cl 2 . The product fractions were concentrated to a light brown oil.  
         [0209]     Mass spectrum (m/z) calcd for C 13 H 19 BrN 2 : 283.21; obsd 285 (M+2, 100%), 283 (M+, 100%).  
         [0210]      1 H-nmr (CDCl 3 , 400 MHz) δ1.74 (m, 1H), 2.03 (m, 1H), 2.23 (s, 6H), 2.35 (m, 1H), 2.51 (m, 1H), 2.67 (m, 1H), 2.78 (m, 2H), 3.53 (q, 2H), 7.19 (d, 2H), 7.43 (d, 2H).  
         [0211]     In the same manner, the corresponding (R)-isomer was prepared as an oil.  
         [0212]     Mass spectrum (m/z) calcd for C 13 H 19 BrN 2 : 283.21; obsd 285 (M+2, 100%), 283 (M+, 100%).  
       (R)-[1-(4-Bromobenzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0213]     The following compounds may be prepared by the procedures below:  
       EXAMPLE 1  
     General Procedure A  
       [0214]    
       
                 
         
             
             
         
       
     
       (R)-[1-(4-(4-pyridylbenzyl))-pyrrolidin-3-yl]-dimethylamine  
       [0215]     A solution of (R)-[1-(4-bromobenzyl)-pyrrolidin-3-yl]-dimethylamine (0.143 g, 0.5 mmol), pyridine-4-boronic acid (0.074 g, 0.6 mmol) and sodium carbonate (0.212 g, 2.0 mmol) in 4.0 mL ethanol containing 0.8 mL water was heated in a 5 mL microwave reaction tube.  
         [0216]     After degassing, the mixture was heated for 300 sec at 150° C., after which time a tic and mass spectrum indicated conversion to the product. The mixture was cooled to rt, diluted with water and extracted with ethyl acetate. The extracts were dried with Na 2 CO 3 , concentrated in vacuo and the residue purified using flash chromatography to give a white solid, 54 mg. This material was converted to the dihydrochloride salt using 1.0 M HCl in diethyl ether.  
         [0217]     Mass spectrum (m/z) calcd for C 18 H 23 N 3 : 281.40; obsd 282.1 (M+1, 100%).  
         [0218]      1 H-nmr (CDCl 3 , 400 MHz) δ1.82 (m, 1H), 2.06 (m, 1H), 2.30 (s, 6H), 2.51 (bs, 1H), 2.61 (m, 1H), 2.70 (m, 1H), 2.81 (q, 1), 2.96 (bs, 1H), 3.65 (q, 2H), 7.41 (d, 2H), 7.48 (d, 2H), 7.57 (d, 2H), 8.62 (d, 2H).  
         [0219]     In the same manner, (S)-[1-(4-(4-pyridylbenzyl))-pyrrolidin-3-yl]-dimethylamine was prepared and converted to the dihydrochloride salt, 57 mg.  
         [0220]     Mass spectrum (m/z) calcd for C 18 H 23 N 3 : 281.40; obsd 282.1 (M+1, 100%).  
         [0221]     Using the general procedure A, as described for Example 1 (with the exception of their conversion to the corresponding trifluoracetate salts), the following compounds were also prepared:  
       EXAMPLE 2 
       [0222]    
       
                 
         
             
             
         
       
     
       4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-carboxylic acid dimethylamide  
       [0223]     Mass spectrum (m/z) calcd for C 22 H 29 N 3 O: 351.231; obsd 352.11 (M+1, 100%)  
       EXAMPLE 3 
       [0224]    
       
                 
         
             
             
         
       
     
       {1-[4-(3-Fluoro-pyridin-4-yl)-benzyl]-Pyrrolidin-3-yl}-dimethylamine  
       [0225]     Mass spectrum (m/z) calcd for C 18 H 22 FN 3 : 299.179; obsd 300.06 (M+1, 100%)  
       EXAMPLE 4 
       [0226]    
       
                 
         
             
             
         
       
     
       {1-[4-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-benzyl]-Pyrrolidin-3-yl}-dimethylamine  
       [0227]     Mass spectrum (m/z) calcd for C 21 H 26 N 2 O 2 : 338.199; obsd 339.1 (M+1, 100%)  
       EXAMPLE 5 
       [0228]    
       
                 
         
             
             
         
       
     
       {1-[4-(1-methyl-1H-indol-5-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine  
       [0229]     Mass spectrum (m/z) calcd for C 22 H 27 N 3 : 333.22; obsd 334.12 (M+1, 100%)  
       EXAMPLE 6 
       [0230]    
       
                 
         
             
             
         
       
     
       4′-(3-Dimethylamino-Pyrrolidin-1-ylmethyl)-biphenyl-3-carbonitrile  
       [0231]     Mass spectrum (m/z) calcd for C 20 H 23 N 3 : 305.189; obsd 306.17 (M+1, 100%)  
       EXAMPLE 7 
       [0232]    
       
                 
         
             
             
         
       
     
       4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-3-methoxybiphenyl-2-carboxylic acid diisopropylamide  
       [0233]     Mass spectrum (m/z) calcd for C 27 H 39 N 3 O 2 : 437.304; obsd 438.3 (M+1, 100%)  
       EXAMPLE 8 
       [0234]    
       
                 
         
             
             
         
       
     
       4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-2-carboxylic acid diisopropylamide  
       [0235]     Mass spectrum (m/z) calcd for C 26 H 37 N 3 O: 407.293; obsd 408.3 (M+1, 100%)  
       EXAMPLE 9 
       [0236]    
       
                 
         
             
             
         
       
     
       (1-Biphenyl-4-methyl-pyrrolidin-3-yl)-dimethylamine  
       [0237]     Mass spectrum (m/z) calcd for C 19 H 24 N 2 : 280.193; obsd 281.18 (M+1, 100%)  
       EXAMPLE 10 
       [0238]    
       
                 
         
             
             
         
       
     
       [1-(4′-Fluoro-biphenyl-4-ylmethyl)-pyrrolidin-3-yl-dimethylamine  
       [0239]     Mass spectrum (m/z) calcd for C 19 H 23 FN 2 : 298.184; obsd 299.18 (M+1, 100%)  
       EXAMPLE 11 
       [0240]    
       
                 
         
             
             
         
       
     
       [1-(3′,5′-Bis-trifluoromethyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0241]     Mass spectrum (m/z) calcd for C 21 H 22 F 6 N 2 : 416.18; obsd 417.16 (M+1, 100%)  
       EXAMPLE 12 
       [0242]    
       
                 
         
             
             
         
       
     
       [1-(4′-phenoxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0243]     Mass spectrum (m/z) calcd for C 25 H 28 N 2 O: 372.22; obsd 373.21 (M+1, 100%)  
       EXAMPLE 13 
       [0244]    
       
                 
         
             
             
         
       
     
       [1-(4-thiophen-2-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0245]     Mass spectrum (m/z) calcd for C 17 H 22 N 2 S: 286.15; obsd 287.13 (M+1, 100%)  
       EXAMPLE 14 
       [0246]    
       
                 
         
             
             
         
       
     
       [1-(4-thiophen-3-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0247]     Mass spectrum (m/z) calcd for C 17 H 22 N 2 S: 286.15; obsd 287.13 (M+1, 100%)  
       EXAMPLE 15 
       [0248]    
       
                 
         
             
             
         
       
     
       [1-(4-Benzofuran-2-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0249]     Mass spectrum (m/z) calcd for C 21 H 24 N 2 O: 320.188; obsd 321.16 (M+1, 100%)  
       EXAMPLE 16 
       [0250]    
       
                 
         
             
             
         
       
     
       [4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-yl]-methanol  
       [0251]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 O: 310.204; obsd 311.19 (M+1, 100%)  
       EXAMPLE 17 
       [0252]    
       
                 
         
             
             
         
       
     
       [1-(4-Furan-2-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0253]     Mass spectrum (m/z) calcd for C 17 H 22 N 2 O: 270.173; obsd 271.17 (M+1, 100%)  
       EXAMPLE 18 
       [0254]    
       
                 
         
             
             
         
       
     
       [1-(4-Benzo[1,3]dioxol-5-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0255]     Mass spectrum (m/z) calcd for C 20 H 24 N 2 O 2 : 324.183; obsd 325.17 (M+1, 100%)  
       EXAMPLE 19 
       [0256]    
       
                 
         
             
             
         
       
     
       [1-(3′,4′-Dimethoxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0257]     Mass spectrum (m/z) calcd for C 21 H 28 N 2 O 2 : 340.215; obsd 341.2 (M+1, 100%)  
       EXAMPLE 20 
       [0258]    
       
                 
         
             
             
         
       
     
       1-[4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-yl]-ethanone  
       [0259]     Mass spectrum (m/z) calcd for C 21 H 26 N 2 O: 322.204; obsd 323.2 (M+1, 100%)  
       EXAMPLE 21 
       [0260]    
       
                 
         
             
             
         
       
     
       1-[4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-ethanone  
       [0261]     Mass spectrum (m/z) calcd for C 21 H 26 N 2 O: 322.204; obsd 323.19 (M+1, 100%)  
       EXAMPLE 22 
       [0262]    
       
                 
         
             
             
         
       
     
       [1-(4-Benzo[b]thiophen-2-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0263]     Mass spectrum (m/z) calcd for C 21 H 24 N 2 S: 336.166; obsd 337.17 (M+1, 100%)  
       EXAMPLE 23 
       [0264]    
       
                 
         
             
             
         
       
     
       [4′-(3-Dimethylamino-Pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-methanol  
       [0265]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 O: 310.204; obsd 311.22 (M+1, 100%)  
       EXAMPLE 24 
       [0266]    
       
                 
         
             
             
         
       
     
       1-[4′-(3-Dimethylamino-Pyrrolidin-1-ylmethyl)-biphenyl-2-yl]-ethanone  
       [0267]     Mass spectrum (m/z) calcd for C 21 H 26 N 2 O: 322.204; obsd 323.2 (M+1,100%)  
       EXAMPLE 25 
       [0268]    
       
                 
         
             
             
         
       
     
       [1-(2′-phenoxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0269]     Mass spectrum (m/z) calcd for C 25 H 28 N 2 O: 372.22; obsd 373.22 (M+1, 100%)  
       EXAMPLE 26 
       [0270]    
       
                 
         
             
             
         
       
     
       [1-(2′-Benzyloxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0271]     Mass spectrum (m/z) calcd for C 26 H 30 N 2 O: 386.235; obsd 387.24 (M+1, 100%)  
       EXAMPLE 27 
       [0272]    
       
                 
         
             
             
         
       
     
       [1-(4-Furan-3-yl-benzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0273]     Mass spectrum (m/z) calcd for C 17 H 22 N 2 O: 270.173; obsd 271.17 (M+1, 100%)  
       EXAMPLE 28 
       [0274]    
       
                 
         
             
             
         
       
     
       [1′-(3′-methylsulfanyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0275]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 S: 326.181; obsd 327.18 (M+1, 100%)  
       EXAMPLE 29 
       [0276]    
       
                 
         
             
             
         
       
     
       N-[4′-(3-Dimethylamino-Pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-acetamide  
       [0277]     Mass spectrum (m/z) calcd for C 21 H 27 N 3 O: 337.215; obsd 338.21 (M+1, 100%)  
       EXAMPLE 30 
       [0278]    
       
                 
         
             
             
         
       
     
       [1-(4′-Benzyloxy-3′-fluoro-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0279]     Mass spectrum (m/z) calcd for C 26 H 29 FN 2 O: 404.226; obsd 405.23 (M+1,100%)  
       EXAMPLE 31 
       [0280]    
       
                 
         
             
             
         
       
     
       4′-(3-Dimethylamino-Pyrrolidin-1-ylmethyl)-biphenyl-4-ol  
       [0281]     Mass spectrum (m/z) calcd for C 19 H 24 N 2 O: 296.188; obsd 297.17 (M+1, 100%)  
       EXAMPLE 32 
       [0282]    
       
                 
         
             
             
         
       
     
       [1-(4′-Benzyloxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0283]     Mass spectrum (m/z) calcd for C 26 H 30 N 2 O: 386.235; obsd 387.22 (M+1, 100%)  
       EXAMPLE 33 
       [0284]    
       
                 
         
             
             
         
       
     
       [1-(2′-methylsulfanyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0285]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 S: 326.181; obsd 327.2 (M+1, 100%)  
       EXAMPLE 34 
       [0286]    
       
                 
         
             
             
         
       
     
       4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-4-carbonitrile  
       [0287]     Mass spectrum (m/z) calcd for C 20 H 23 N 3 : 305.189; obsd 306.2 (M+1, 100%)  
       EXAMPLE 35 
       [0288]    
       
                 
         
             
             
         
       
     
       [1-(4′-Methanesulfonyl-biphenyl-4-ylmethyl-pyrrolidin-3-yl]-dimethylamine  
       [0289]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 O 2 S: 358.171; obsd 359.18 (M+1, 100%)  
       EXAMPLE 36 
       [0290]    
       
                 
         
             
             
         
       
     
       [1-(3′-Benzyloxy-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0291]     Mass spectrum (m/z) calcd for C 26 H 30 N 2 O: 386.235; obsd 387.25 (M+1, 100%)  
       EXAMPLE 37 
       [0292]    
       
                 
         
             
             
         
       
     
       [1-(4-Isoquinolin-5-ylbenzyl)-Pyrrolidin-3-yl]-dimethylamine  
       [0293]     Mass spectrum (m/z) calcd for C 22 H 25 N 3 : 281.40; obsd 282.1 (M+1, 100%)  
       EXAMPLE 38 
       [0294]    
       
                 
         
             
             
         
       
     
       [1-(3′-pyrazol-1-ylbiphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0295]     Mass spectrum (m/z) calcd for C 22 H 26 N 4 : 346.215; obsd 347.22 (M+1, 100%)  
       EXAMPLE 39 
       [0296]    
       
                 
         
             
             
         
       
     
       1-[4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-2-ylmethyl]-piperidin-4-one  
       [0297]     Mass spectrum (m/z) calcd for C 25 H 33 N 3 O: 391.262; obsd 392.28 (M+1,100%)  
       EXAMPLE 40 
       [0298]    
       
                 
         
             
             
         
       
     
       {1-[4-(3-Chloro-pyridin-4-yl)-benzyl]-pyrrolidin-3-yl}-dimethylamine  
       [0299]     Mass spectrum (m/z) calcd for C 18 H 22 CIN 3 : 315.15; obsd 316.17 (M+1, 100%), 318.18  
       EXAMPLE 41 
       [0300]    
       
                 
         
             
             
         
       
     
       [1-(4-Pyrimidin-5-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0301]     Mass spectrum (m/z) calcd for C 17 H 22 N 4 : 282.184; obsd 283.2 (M+1, 100%)  
       EXAMPLE 42 
       [0302]    
       
                 
         
             
             
         
       
     
       (S)-[1-(4′-Methanesulfonyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0303]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 O 2 S: 358.171; obsd 359.18 (M+1, 100%)  
         [0304]      1 H-nmr (CDCl 3 , 400 MHz) δ1.82 (m, 1H), 2.04 (m, 1H), 2.30 (s, 6H), 2.51 (bs, 1H), 2.61 (m, 1H), 2.70 (m, 1H), 2.81 (q, 1H), 2.96 (bs, 1H), 3.07 (s, 3H), 3.65 (q, 2H), 7.41 (d, 2H), 7.54 (d, 2H), 7.75 (m, 2H), 7.97 (m, 2H).  
       EXAMPLE 43 
       [0305]    
       
                 
         
             
             
         
       
     
       (R)-[1-(4′-Methanesulfonyl-biphenyl-4-ylmethyl)-pyrrolidin-3-yl]-dimethylamine  
       [0306]     Mass spectrum (m/z) calcd for C 20 H 26 N 2 O 2 S: 358.171; obsd 359.18 (M+1, 100%)  
       EXAMPLE 44 
       [0307]    
       
                 
         
             
             
         
       
     
       (S)-N-[4′-(3-Dimethylamino-pyrrolidin-1-yl methyl)-biphenyl-3-yl]-acetamide  
       [0308]     Mass spectrum (m/z) calcd for C 21 H 27 N 3 O: 337.2; obsd 338.2 (M+1, 100%)  
       EXAMPLE 45 
       [0309]    
       
                 
         
             
             
         
       
     
       (R)-N-[4′-(3-Dimethylamino-pyrrolidin-1-ylmethyl)-biphenyl-3-yl]-acetamide  
       [0310]     Mass spectrum (m/z) calcd for C 21 H 27 N 3 O: 337.2; obsd 338.2 (M+1, 100%)  
         [0311]      1 H-nmr (CDCl 3 , 400 MHz) δ1.75 (m, 1H), 1.99 (m, 1H), 2.18 (s, 3H), 2.24 (s, 6H), 2.39 (t, 1H), 2.55 (q, 1H), 2.71 (m, 1H), 2.83 (m, 2H), 3.61 (q, 2H), 7.33 (m, 4H), 7.49 (m, 3H), 7.70 (bs, 1H).  
       EXAMPLE 46  
     General Procedure B  
       [0312]    
       
                 
         
             
             
         
       
     
       (R)-[1-(4-piperidin-4-ylbenzyl)-pyrrolidin-3-yl]-dimethylamine  
       [0313]     (R)-[1-(4-(4-pyridylbenzyl))-pyrrolidin-3-yl]-dimethylamine (40 mg, from Example 1) and platinum oxide (10 mg) in 10 mL CH 3 OH was hydrogenated on a Parr shaker apparatus at 45 p.s.i. for 4 hr. The solution was filtered through a pad of d.e., washed with additional CH 3 OH. The organic filtrates were concentrated in vacuo to a clear oil, 30 mg. This was converted to the hydrochloride salt as described above to give a white powder, 31 mg.  
         [0314]     Mass spectrum (m/z) calcd for C 18 H 29 N 3 : 287.45; obsd 288.2 (M+1, 100%).  
       EXAMPLE 47 
       [0315]    
       
                 
         
             
             
         
       
     
         [0316]     (S)-[1-(4-piperidin-4-ylbenzyl))-Pyrrolidin-3-yl]-dimethylamine was prepared in the same manner as Example 46 from (S)-[1-(4-(4-pyridylbenzyl))-pyrrolidin-3-yl]-dimethylamine to give the hydrochloride salt as a white powder.  
         [0317]     Mass spectrum (m/z) calcd for C 18 H 29 N 3 : 287.45; obsd 288.2 (M+1, 100%).  
         [0318]      1 H-nmr (CDCl 3 , 400 MHz) δ1.65 (m, 4H), 1.80 (d, 1H), 1.95 (m, 1H), 2.17 (s, 6H), 2.23 (t, 1H), 2.43 (m, 2H), 2.58 (m, 1H), 2.72 (m, 4H), 2.83 (m, 1H), 3.17 (d, 2H), 3.54 (q, 2H), 7.14 (d, 2H), 7.22 (d, 2H).  
       Determination of Biological Activity  
       [0319]     The in vitro affinity of the compounds in the present invention at the rat or human histamine H3 receptors can be determined according to the following procedure. Frozen rat frontal brain or frozen human post-mortem frontal brain is homogenized in 20 volumes of cold 50 mM Tris HCl containing 2 mM MgCl 2  (pH to 7.4 at 4 degrees C.). The homogenate is then centrifuged at 45,000 G for 10 minutes. The supernatant is decanted and the membrane pellet re-suspended by Polytron in cold 50 mM Tris HCl containing 2 mM MgCl 2  (pH to 7.4 at 4 degrees C.) and centrifuged again. The final pellet is re-suspended in 50 mM Tris HCl containing 2 mM MgCl 2  (pH to 7.4 at 25 degrees C.) at a concentration of 12 mg/mL. Dilutions of compounds are made in 10% DMSO/50 mM Tris buffer (pH 7.4) (at 10×final concentration, so that the final DMSO concentration is 1%). Incubations are initiated by the addition of membranes (200 microliters) to 96 well V-bottom polypropylene plates containing 25 microliters of drug dilutions and 25 microliters of radioligand (1 nM final concentration  3 H-N-methylhistamine). After a 1 hour incubation, assay samples are rapidly filtered through Whatman GF/B filters and rinsed with ice-cold 50 mM Tris buffer (pH 7.4) using a Skatron cell harvester. Radioactivity is quantified using a BetaPlate scintillation counter. The percent inhibition of specific binding can then be determined for each dose of the compound, and an IC50 or Ki value can be calculated from these results.  
                                           TABLE 1                           Rat H3 Binding for selected compounds                Example #   Rat H3 activity (K i , nM)                            42   55           43   72           44   139           45   75           46   136           47   33