Patent Publication Number: US-7223796-B2

Title: Acyl-4-carboxyphenylurea derivatives, processes for preparing them and their use

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application claims priority under 35 U.S.C. § 119 to DE 10215907.6 filed Apr. 11, 2002. This application also claims priority under 35 U.S.C. § 120 to U.S. Provisional No. 60/402,779, filed Aug. 12, 2002. Both of these documents are incorporated herein by reference in their entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The invention relates to acyl-4-carboxyphenylurea derivatives and to their physiologically tolerated salts and physiologically functional derivatives. 
     2. Description of the Prior Art 
     EP 0 193 249 (Duphar) describes acylcarboxyphenylurea derivatives which possess antitumor activity. 
     SUMMARY OF THE INVENTION 
     The instant invention provides compounds which can be used for preventing and treating diabetes type 2. In particular, the instant invention provides novel compounds which have an effect which is markedly superior to that of the compounds disclosed in EP 0 193 249. 
     In a preferred embodiment, the instant invention also provides pharmaceutical compositions comprising one or more compounds as described herein and a pharmaceutically acceptable excipient. The composition may further comprise one or more blood sugar-lowering active agents. The composition may further comprise one or more compounds as described herein and an HMGCoA reductase inhibitor. 
     In another embodiment, the instant invention also provides a method for treating type 2 diabetes comprising administering to a subject in need thereof, one or more compounds as described herein. The method may further comprise administering one or more agents which may be insulin or insulin derivatives, hypoglycemic compounds, an HMGCoA reductase inhibitor, a cholesterol absorption inhibitor, a PPAR gamma agonist, a PPAR alpha agonist, a mixed PPAR alpha/gamma agonist, a fibrate, an MTP inhibitor, a bile acid absorption inhibitor, a CETP inhibitor, a polymeric bile acid adsorber, an LDL receptor inducer, an ACAT inhibitor, an antioxidant, a lipoprotein lipase inhibitor, an ATP citrate lyase inhibitor, a squalene synthetase inhibitor, a lipoprotein(a) antagonist, a lipase inhibitor, a sulfonylurea, a biguanide, a meglitinide, a thiazolidinedione, an α-glucosidase inhibitor, a CART agonist, a NPY agonist, a MC4 agonist, a orexin agonist, a H3 agonist, a TNF agonist, a GLP-1 derivative, a CRF agonist, a CRF BP antagonist, a urocortin agonist, a β3 agonist, a MSH (melanocyt-stimulating hormone) agonist, a CCK agonist, a serotonin-reuptake inhibitor, a mixed serotonin and noradrenergic compound, a 5HT agonist, a bombesin agonist, a galanin antagonist, a growth hormone, a growth hormone-releasing compound, a TRH agonists, a decoupling protein 2- or 3-modulators, a leptin agonist, a DA agonists (bromocriptine, doprexin), a lipase/amylase inhibitor, a PPAR modulator, a RXR modulator a TR-β-agonist or an amphetamine and compounds which act on an ATP-dependent potassium channel of a beta cell. 
     In another preferred embodiment, the instant invention also provides a method for lowering blood sugar comprising administering to a subject in need thereof, one or compounds as described herein. The method may further comprise administering one or more blood sugar-lowering active agents. 
     In another embodiment, the instant invention also provides a method for inhibiting glycogen phosphorylase comprising administering to a subject in need thereof, an effective amount of one or more compounds as described herein. 
     In another embodiment, the instant invention also provides a method of reducing body weight comprising administering to a subject in need thereof, one or compounds as described herein. 
     Preferably, the subject is a mammal, such as a human. 
     Additional objects, features and advantages of the invention will be set forth in the description which follows, and in part, will be obvious from the description, or may be learned by practice of the invention. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The invention therefore relates to compounds of the formula I, 
                         
in which
         R7, R8, R9 and R10 are, independently of each other, H, F, Cl, Br, OH, NO 2 , CN, O—(C 1 –C 6 )-alkyl, O—(C 2 –C 6 )-alkenyl, O—(C 2 –C 6 )-alkynyl, O—SO 2 —(C 1 –C 4 )-alkyl, (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl or (C 2 –C 6 )-alkynyl, where alkyl, alkenyl and alkynyl can be substituted, once or more than once, by F, Cl or Br;   R1 and R2 are, independently of each other, H, (C 1 –C 6 )-alkyl, where alkyl can be substituted by OH, O—(C 1 –C 4 )-alkyl, NH 2 , NH(C 1 –C 4 )-alkyl or N[(C 1 –C 6 )-alkyl] 2 , O—(C 1 –C 6 )-alkyl, CO—(C 1 –C 6 )-alkyl, COO—(C 1 –C 6 )-alkyl, (C 1 –C 6 )-alkylene-COOH or (C 1 –C 6 )-alkylene-COO—(C 1 –C 6 )-alkyl;   R3 is H, F, Cl, Br, NO 2 , CN, O—R11, O-phenyl, S—R11, COOR11, N(R12)(R13), (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 3 –C 7 )-cycloalkyl or (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, where alkyl, cycloalkyl and alkynyl can be substituted, once or more than once, by F, Cl, Br, OR11, COOR11 or N(R16)(R17);   R4 is H, F, Cl, Br, NO 2 , CN, O—R11, O-phenyl, S—R11, COOR11, N(R12)(R13), (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 3 –C 7 )-cycloalkyl or (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, where alkyl, cycloalkyl and alkynyl can be substituted, once or more than once, by F, Cl, Br, OR11, COOR11 or N(R16)(R17);   R5 is H, F, Cl, Br, NO 2 , CN, O—R11, O-phenyl, S—R11, COOR11, N(R12)(R13), (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 3 –C 7 )-cycloalkyl or (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, where alkyl, cycloalkyl and alkynyl can be substituted, once or more than once, by F, Cl, Br, OR11, COOR11 or N(R16)(R17);   R6 is H, F, Cl, Br, NO 2 , CN, O—R11, O-phenyl, S—R11, COOR11, N(R12)(R13), (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 3 –C 7 )-cycloalkyl or (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, where alkyl, cycloalkyl and alkynyl can be substituted, once or more than once, by F, Cl, Br, OR11, COOR11 or N(R16)(R17);   R11 is H, (C 1 –C 8 )-alkyl, (C 2 –C 8 )-alkenyl or (C 2 –C 8 )-alkynyl, where alkyl, alkenyl and alkynyl can be substituted, once or more than once, by F, Cl, Br, OH or O—(C 1 –C 4 )-alkyl;   R12 and R13 are, independently of each other, H, (C 1 –C 8 )-alkyl, (C 2 –C 8 )-alkenyl, (C 2 –C 8 )-alkynyl, (C 3 –C 7 )-cycloalkyl, (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, COO—(C 1 –C 4 )-alkyl, COO—(C 2 –C 4 )-alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring can be substituted, up to two times, by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 –C 6 )-alkyl or CONH 2 ;   or R12 and R13 form, together with the nitrogen atom to which they are bonded, a 3-7-membered, saturated heterocyclic ring which can contain up to 3 heteroatoms selected from the group consisting of N, O and S and where the heterocyclic ring can be substituted, up to four times, by F, Cl, Br, OH, Oxo, (C 1 –C 4 )-alkyl or N(R14)(R15);   R14 and R15 are, independently of each other, H, (C 1 –C 8 )-alkyl, (C 2 –C 8 )-alkenyl, (C 2 –C 8 )-alkynyl, (C 3 –C 7 )-cycloalkyl, (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, COO—(C 1 –C 4 )-alkyl, COO—(C 2 –C 4 )-alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring can be substituted, up to two times, by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 –C 6 )-alkyl or CONH 2 ;   R16 and R17 are, independently of each other, H, (C 1 –C 8 )-alkyl, (C 2 –C 8 )-alkenyl, (C 2 –C 8 )-alkynyl, (C 3 –C 7 )-cycloalkyl, (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, COO—(C 1 –C 4 )-alkyl, COO—(C 2 –C 4 )-alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring can be substituted, up to two times, by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 –C 6 )-alkyl or CONH 2 ;   or R16 and R17 form, together with the nitrogen atom to which they are bonded, a 3–7-membered, saturated heterocyclic ring which can contain up to 2 further heteroatoms from the group N, O or S and where the heterocyclic ring can be substituted, up to four times, by F, Cl, Br, OH, Oxo, (C 1 –C 4 )-alkyl or N(R14)(R15);   and the physiologically tolerated salts thereof.       
     Preference is given to compounds of the formula I in which one or more radicals have the following meaning:
         R7, R8, R9 and R10 are, independently of each other, H, F, Cl, Br, OH, NO 2 , CN, (C 1 –C 6 )-alkyl or O—(C 1 –C 6 )-alkyl, where alkyl can be substituted, once or more than once, by F;   R1 and R2 are H;   R3 is H, F, Cl, Br, NO 2 , CN, O—R11, O-phenyl, S—R11, COOR11, N(R12)(R13), (C 1 –C 6 )-alkyl, (C 2 –C 6 )-alkenyl, (C 2 –C 6 )-alkynyl, (C 3 –C 7 )-cycloalkyl or (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, where alkyl, cycloalkyl and alkynyl can be substituted, once or more than once, by F, Cl, Br, OR11 or COOR11;   R4 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl, where alkyl, can be substituted, once or more than once, by F;   R5 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl, where alkyl can be substituted, once or more than once, by F;   R6 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl where alkyl can be substituted, once or more than once, by F;   R11 is H, (C 1 –C 8 )-alkyl, (C 1 –C 8 )-alkylene-O—(C 1 –C 8 )-alkyl or (C 1 –C 8 )-alkyl-OH, where alkyl can be substituted, once or more than once, by F;   R12 and R13 are, independently of each other, H or (C 1 –C 8 )-alkyl;   or R12 and R13 form, together with the nitrogen atom to which they are bonded, a 3–7-membered, saturated heterocyclic ring which can contain up to 3 heteroatoms selected from the group N, O and S and where the heterocyclic ring can be substituted, up to four times, by F, Cl, Br, OH, Oxo, (C 1 –C 4 )-alkyl or N(R14)(R15);   R14 and R15 are, independently of each other, H, (C 1 –C 8 )-alkyl, (C 2 –C 8 )-alkenyl, (C 2 –C 8 )-alkynyl, (C 3 –C 7 )-cycloalkyl, (C 3 –C 7 )-cycloalkyl-(C 1 –C 4 )-alkylene, COO—(C 1 –C 4 )-alkyl, COO—(C 2 –C 4 )-alkenyl, phenyl or SO 2 -phenyl, where the phenyl ring can be substituted, up to two times, by F, Cl, CN, OH, (C 1 –C 6 )-alkyl, O—(C 1 –C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 –C 6 )-alkyl or CONH 2 ;   and the physiologically tolerated salts thereof.       

     Very particular preference is given to compounds of the formula I in which one or more radicals have the following meaning:
         R7, R8, R9 and R10 are, independently of each other, H, F, Cl, Br, CH 3  or CF 3 ;   R1, R2, R5 are H;   R3 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl, where alkyl can be substituted once or more than once by F;   R4 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl, where alkyl can be substituted once or more than once by F;   R6 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl, where alkyl can be substituted once or more than once by F;   R11 is H or (C 1 –C 8 )-alkyl, where alkyl can be substituted once or more than once by F,   R12 and R13 are H or (C 1 –C 8 )-alkyl;   or the two radicals R12 and R13 form, together with the nitrogen atom to which they are bonded, a 5–6-membered, saturated heterocyclic ring which can contain a further oxygen atom;   and the physiologically tolerated salts thereof.       

     Very particular preference is furthermore given to compounds of the formula I in which one or more radicals have the following meaning:
         R7, R8, R9 and R10 are, independently of each other, H, F, Cl, Br, CH 3  or CF 3 ;   R1, R2, R4, R5 and R6 are H;   R3 is H, F, Cl, NO 2 , O—R11, N(R12)(R13) or (C 1 –C 6 )-alkyl, where alkyl can be substituted once or more than once by F;   R11 is H or (C 1 –C 8 )-alkyl, where alkyl can be substituted once or more than once by F,   R12 and R13 are H or (C 1 –C 8 )-alkyl;   or the two radicals R12 and R13 form, together with the nitrogen atom to which they are bonded, a 5-6-membered, saturated heterocyclic ring which can contain a further oxygen atom;   and the physiologically tolerated salts thereof.       

     Preference is furthermore given to compounds of formula I in which R3 is not H. 
     If radicals or substituents can occur more than once in the compounds of the formula I, such as —O—R11, they can then all, independently of each other, have the given meanings and be identical or different. 
     The invention relates to compounds of the formula I, in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof. 
     The alkyl radicals in the substituents R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16 and R17 can be either straight-chain or branched. 
     Because of their higher solubility in water as compared with the starting compounds or basal compounds, pharmaceutically tolerated salts are particularly suitable for medical applications. These salts must possess a pharmaceutically tolerated anion or cation. Suitable pharmaceutically tolerated acid addition salts of the compounds according to the invention are salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and also of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaric acid. Suitable pharmaceutically tolerated basic salts are ammonium salts, alkali metal salts (such as sodium salts and potassium salts), alkaline earth metal salts (such as magnesium salts and calcium salts), trometamol (2-amino-2-hydroxymethyl-1,3-propanediol), diethanolamine, lysine or ethylenediamine. 
     Salts which contain an anion which is not pharmaceutically tolerated, such as trifluoroacetate, also belong within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically tolerated salts and/or for use in nontherapeutic, for example in-vitro, applications. 
     The term “physiologically functional derivative” which is used here denotes any physiologically tolerated derivative of a compound according to the invention of the formula I, e.g. an ester which is able, on being administered to a mammal, such as a human, to form (directly or indirectly) a compound of the formula I or an active metabolite thereof. 
     The physiologically functional derivatives also include prodrugs of the compounds according to the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull, 1994, 42, 57–61. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not themselves be active. 
     The compounds according to the invention can also be present in different polymorphic forms, e.g. as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds according to the invention belong within the scope of the invention and are another aspect of the invention. 
     In that which follows, all references to “compound(s) according to formula I” refer to compound(s) of the formula I as described above and to their salts, solvates and physiologically functional derivatives as described herein. 
     The compound(s) of the formula (I) can also be administered in combination with other active compounds. 
     The quantity of a compound according to Formula I which is required in order to achieve the desired biological effect depends on a number of factors, e.g. the specific compound which is selected, the intended use, the nature of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of bodyweight, e.g. 3–10 mg/kg/day. An intravenous dose can, for example, be in the range from 0.3 mg to 1.0 mg/kg, which dose can expediently be administered as an infusion of from 10 ng to 100 ng per kilogram per minute. Infusion solutions which are suitable for these purposes can, for example, contain from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Individual doses can, for example, contain from 1 mg to 10 g of the active compound. Thus, ampoules for injections can, for example, contain from 1 mg to 100 mg, and orally administrable individual dose formulations, such as tablets or capsules, can, for example, contain from 1.0 to 1000 mg, typically from 10 to 600 mg. While, for the therapy of the abovementioned conditions, the compounds according to formula I can be used themselves as compounds, they are preferably present, together with a tolerated excipient, in the form of a pharmaceutical composition. The excipient naturally has to be tolerated in the sense that it is compatible with the other components of the composition and is not harmful to the health of the patient. The excipient can be a solid or a liquid or both and is preferably formulated together with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances can also be present, including other compounds according to formula I. The pharmaceutical compositions according to the invention can be prepared using one of the known pharmaceutical methods, which essentially consist in the constituents being mixed with pharmacologically tolerated excipients and/or auxiliary substances. 
     Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, even though the most suitable mode of administration depends, in each individual case, on the nature and severity of the condition to be treated and on the nature of the compound according to formula I which is employed in each case. Coated formulations and coated delayed-release formulations also belong within the scope of the invention. Preference is given to formulations which are acid-resistant and gastric juice-resistant. Suitable gastric juice-resistant coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate. 
     Suitable pharmaceutical compounds for oral administration can be present in separate units, such as capsules, cachets, sucking tablets or tablets which in each case contain a defined quantity of the compound according to formula I; as powders or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared using any suitable pharmaceutical method which comprises a step in which the active compound and the excipient (which can be composed of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniformly and homogeneously mixing the active compound with a liquid and/or finely divided solid excipient, after which the product is molded, if required. Thus, a tablet, for example, can be prepared by pressing or molding a powder or granulate of the compound, where appropriate together with one or more additional constituents. Pressed tablets can be prepared by tableting the compound in freely flowing form, such as a powder or granulate, where appropriate mixed with a binding agent, lubricant, inert diluent and/or a (several) surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be prepared by molding the pulverulent compound, which is moistened with an inert liquid diluent, in a suitable machine. 
     Pharmaceutical compositions which are suitable for peroral (sublingual) administration include sucking tablets, which contain a compound according to formula I together with a flavoring agent, usually sucrose and gum arabic or tragacanth, and lozenges, which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic. 
     Suitable pharmaceutical compositions for parenteral administration preferably include sterile aqueous preparations of a compound according to formula I which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, even though the administration can also take place as an injection subcutaneously, intramuscularly or intradermally. These preparations can preferably be prepared by mixing the compound with water and making the resulting solution sterile and isotonic with the blood. In general, injectable compositions according to the invention comprise from 0.1 to 5% by weight of the active compound. 
     Suitable pharmaceutical compositions for rectal administration are preferably present as individual dose suppositories. These can be prepared by mixing a compound according to formula I with one or more conventional solid excipients, for example cocoa butter, and molding the resulting mixture. 
     Suitable pharmaceutical compositions for topical use on the skin are preferably present as an ointment, cream, lotion, paste, spray, aerosol or oil. Excipients which can be used are vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active compound is generally present at a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%. 
     Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal uses can be present as individual plasters which are suitable for long-term intimate contact with the epidermis of the patient. Such plasters expediently contain the active compound in an aqueous solution, which is, where appropriate, buffered, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active compound concentration is from approx. 1% to 35%, preferably from approx. 3% to 15%. As a particular possibility, the active compound can, as described, for example, in Pharmaceutical Research, 2(6): 318 (1986), be released by means of electrotransport or iontophoresis. 
     The following are suitable for use as additional active compounds for the combination preparations: 
     All antidiabetics which are named in the Roten Liste [Red List] 2001, Chapter 12 can be combined with the compounds according to the invention of the formula I, particularly for improving the effect synergistically. The active compound combination can be administered either by administering the active compounds separately to the patient or in the form of combination preparations in which several active compounds are present in one pharmaceutical preparation. Most of the active compounds which are listed below are disclosed in USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2001. 
     Antidiabetics include insulin and insulin derivatives, such as Lantus® (see www.lantus.com) or HMR 1964, rapidly acting insulins (see U.S. Pat. No. 6,221,633), GLP-1 derivatives, such as those which were disclosed in WO 98/08871 by Novo Nordisk A/S, and hypoglycemic active compounds which are effective orally. 
     The hypoglycemic active compounds which are effective orally preferably include sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, calcium channel openers, such as those which were disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes which are involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds, such as antihyperlipidemic active compounds and antilipidemic active compounds, which alter fat metabolism, compounds which decrease the intake of foodstuffs, agonists of PPAR and PXR, and active compounds which act on the ATP-dependent potassium channel of the beta cells. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin or rosuvastatin. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, such as ezetimibe, tiqueside or pamaqueside. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as rosiglitazone, pioglitazone, JTT-501 or GI 262570. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as GW 9578 or GW 7647. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as GW 1536, AVE 8042, AVE 8134 or AVE 0847, or as described in PCT/US 11833, PCT/US 11490 or DE10142734.4. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as fenofibrate, clofibrate or bezafibrate. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, such as implitapide, BMS-201038 or R-103757. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor (see, for example, U.S. Pat. Nos. 6,245,744 or 6,221,897), such as HMR 1741. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as JTT-705. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorber, such as cholestyramine or colesevelam. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor inducer (see U.S. Pat. No. 6,342,512), such as HMR1171 or HMR1586. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as avasimibe. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as OPC-14117. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as NO-1886. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor, such as SB-204990. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as BMS-188494. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as Cl-1027 or nicotinic acid 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as orlistat. 
     In one embodiment of the invention, the compounds of the formula I are administered in combination with insulin. 
     In one embodiment, the compounds of the formula I are administered in combination with a sulfonylurea, such as tolbutamide, glibenclamide, glipizide or glimepiride. 
     In one embodiment, the compounds of the formula I are administered in combination with a biguanide, such as metformin. 
     In yet another embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as repaglinide. 
     In one embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds which are disclosed by Dr. Reddy&#39;s Research Foundation in WO 97/41097, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione. 
     In one embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor, such as miglitol or acarbose. 
     In one embodiment, the compounds of the formula I are administered in combination with an active compound which acts on the ATP-dependent potassium channel of the beta cells, such as tolbutamide, glibenclamide, glipizide, glimepiride or repaglinide. 
     In one embodiment, the compounds of the formula I are administered in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. 
     In another embodiment, the compounds of the formula I are administered in combination with CART modulators (see “Cocaine-amphetamine-regulated transcript influences energy metabolism, anxiety and gastric emptying in mice” Asakawa, A, et al., M.:Hormone and Metabolic Research (2001), 33(9), 554–558), NPY antagonists, e.g. naphthalene-1-sulfonic acid {4-[(4-aminoquinazolin-2-ylamino)methyl]cylohexylmethyl}amide; hydrochloride (CGP 71683A)), MC4 agonists (e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid [2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]amide; (WO 01/91752)), orexin antagonists (e.g. 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea]; hydrochlorides (SB-334867-A)), H3 agonists (3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-one oxalic acid salt (WO 00/63208)); TNF agonists, CRF antagonists (e.g. [2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine (WO 00/66585)), CRF BP antagonists (e.g. urocortin), urocortin agonists, β3-agonists (e.g. 1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanol; hydrochloride (WO 01/83451)), MSH (melanocyte-stimulating hormone) agonists, CCK-A agonists (e.g. {2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}acetic acid trifluoroacetic acid salt (WO 99/15525)); serotonin reuptake inhibitors (e.g. dexfenfluramines), mixed serotonin compounds and noradrenergic compounds (e.g. WO 00/71549), 5HT agonists, e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO 01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g. human growth hormone), growth hormone-releasing compounds (tert-butyl 6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (WO 01/85695)), TRH agonists (see, for example, EP 0 462 884) uncoupling protein 2- or 3-modulators, leptin agonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as a potential approach to the treatment of obesity. Drugs of the Future (2001), 26(9), 873–881), DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors (e.g. WO 00/40569), PPAR modulators (e.g. WO 00/78312), RXR modulators or TR β-agonists. 
     In one embodiment of the invention, the additional active compound is leptin; see, e.g., “Perspectives in the therapeutic use of leptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert Opinion on Pharmacotherapy (2001), 2(10),1615–1622. 
     In one embodiment, the additional active compound is dexamphetamine or amphetamine. 
     In one embodiment, the additional active compound is flenfluramine or dexfenfluramine. 
     In yet another embodiment, the additional active compound is sibutramine. 
     In one embodiment, the additional active compound is orlistat. 
     In one embodiment, the additional active compound is mazindol or phentermine. 
     In one embodiment, the compounds of the formula I are administered in combination with bulk materials, preferably insoluble bulk materials (see, e.g., Carob/Caromax® (Zunft H J; et al., Carob pulp preparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY (2001 September–October), 18(5), 230–6), Caromax is a carob-containing product from Nutrinova, Nutrition Specialties &amp; Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)). The combination with Caromax® can be effected in one preparation or by administering compounds of the formula I and Caromax® separately. In this connection, Caromax® can also be administered in the form of foodstuffs, such as in bakery products or muesli bars. 
     Accordingly, the instant invention covers methods of treating type 2 diabetes and methods of lowering blood sugar levels with the instant compounds. Treating also covers alleviation of symptoms of type 2 diabetes or symptoms of high blood sugar. 
     It will be understood that each suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and, as desired, one or more further pharmacologically active substances, is regarded as coming within the protective scope of the present invention. 
     As described above, the following exemplary compounds and compounds of formula I may be administered in combination. 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     EXAMPLES 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Examples of formula I 
               
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Ex. 
                 R7, R8, R9, R10 
                 R1 
                 R2 
                 R3 
                 R4 
                 R5 
                 R6 
                 Salt 
                 MS** 
                 M.p. 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 1 
                 2-Cl, H, H, H 
                 H 
                 H 
                 NO 2   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 240* 
               
               
                 2 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 NO 2   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 3 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 NO 2   
                 H 
                 H 
                 H 
                 TRIS 
                 ok 
               
               
                 4 
                 2-Cl, H, H, H 
                 H 
                 H 
                 OH 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 5 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 OH 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 7 
                 2-Cl, H, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 8 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 9 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 10 
                 2-Cl, 5-Cl, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 11 
                 2-Cl, 5-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 12 
                 2-F, H, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 13 
                 3-F, H, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 14 
                 3-Cl, H, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 15 
                 2-Cl, 5-CH 3 , H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 16 
                 2-Cl, 5-CH 3 , H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 17 
                 4-F, H, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 18 
                 3-Cl, 4-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 19 
                 2-CH 3 , H, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 20 
                 2-F, H, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 21 
                 3-F, H, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 22 
                 3-Cl, H, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 23 
                 3-Cl, 4-Cl, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 24 
                 2-CH 3 , H, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 25 
                 2-CH 3 , 4-CH 3 , H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 26 
                 2-CH 3 , 4-CH 3 , H, H 
                 H 
                 H 
                 OCH 3 H   
                 H 
                 H 
                 — 
                 ok 
               
               
                 27 
                 2-F, 4-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 28 
                 2-F, 4-Cl, H, H 
                 H 
                 H 
                 Ci 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 29 
                 2-F, 4-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 30 
                 2-F, 4-F, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 31 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 32 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 33 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 TRIS 
                 ok 
               
               
                 34 
                 2-F, H, H, H 
                 H 
                 H 
                 H 
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 35 
                 2-Cl, H, H, H 
                 H 
                 H 
                 H 
                 H 
                 H 
                 OH 
                 — 
                 ok 
               
               
                 36 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 H 
                 H 
                 H 
                 OH 
                 — 
                 ok 
               
               
                 37 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 H 
                 H 
                 H 
                 OH 
                 — 
                 ok 
               
               
                 38 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 OH 
                 — 
                 ok 
               
               
                 39 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 OH 
                 — 
                 ok 
               
               
                 40 
                 2-Cl, 5-Br, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 251 
               
               
                 41 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 268 
               
               
                 42 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 TRIS 
                 ok 
               
               
                 43 
                 2-Cl, 4-Cl, H, H 
                 H 
                 H 
                 OCF 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 44 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 OCF 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 45 
                 2-F, 6-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 46 
                 2-CH 3 , 6-CH 3 , H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 47 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 Cl 
                 H 
                 H 
                 H 
                 — 
                 ok 
                 262 
               
               
                 48 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 OCF 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 236 
               
               
                 49 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 OCF 3   
                 H 
                 H 
                 H 
                 TRIS 
                 ok 
               
               
                 50 
                 2-Cl, 4-Cl, 5-F, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 261 
               
               
                 51 
                 2-Cl, 5-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 273 
               
               
                 52 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 H 
                 H 
                 H 
                 NH 2   
                 — 
                 ok 
                 222 
               
               
                   
               
               
                 72 
                 2-Cl, 4-F, H, H 
                   
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 — 
                 ok 
                 258 
               
               
                   
               
               
                 73 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 — 
                 ok 
                 274 
               
               
                   
               
               
                 74 
                 2-Cl, 4-Cl, 6-Cl, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 75 
                 2-Br, 4-CH 3 , H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 76 
                 2-Br, 4-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 77 
                 2-Br, 5-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 78 
                 2-F, 4-Cl, 5-F, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 79 
                 4-Cl, 5-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 80 
                 2-Cl, 4-Cl, 6-CH 3 , H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 81 
                 2-CF 3 , 4-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 82 
                 2-CF 3 , 6-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 83 
                 2-Cl, 3-CH 3 , H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 84 
                 2-Cl, 6-F, 5-CH 3 , H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 85 
                 2-Cl, 6-F, 3-CH 3 , H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 86 
                 2-Cl, 4-F, H, H 
                 H 
                 H 
                 N(CH 3 ) 2   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 247 
               
               
                 87 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 O(CH 2 ) 2 CH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 289 
               
               
                 88 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 O(CH 2 ) 3 CH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 275.5 
               
               
                   
               
               
                 89 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 — 
                 ok 
                 209.5 
               
               
                   
               
               
                 90 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 H 
                 H 
                 H 
                 — 
                 ok 
                 303 
               
               
                   
               
               
                 91 
                 2-CH 3 , 4-Br, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 92 
                 2-Cl, 4-Br, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 93 
                 2-Br, 5-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 94 
                 2-CH 3 , 5-CH 3 , H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 95 
                 2-CH 3 , 5-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 96 
                 2-F, 4-F, 5-F 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 97 
                 2-CH 3 , 4-F, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 98 
                 2-CH 3 , 5-Cl, H, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
               
               
                 99 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 NHCH 2 CH 3   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 300 
               
               
                 100 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 OCH 3   
                 H 
                 H 
                 NH 2   
                 — 
                 ok 
               
               
                 101 
                 2-Cl, 4-F, 5-F, H 
                 H 
                 H 
                 OCH(CH 3 ) 2   
                 H 
                 H 
                 H 
                 — 
                 ok 
                 261 
               
               
                   
               
               
                 *Decomposition 
               
               
                 **The information “MS is Ok” is means that a mass spectrum or HPLC/MS was measured and the molar peak (molar mass + H + ) was detected in this spectrum 
               
            
           
         
       
     
     Example 5 from EP 0 193 249 was synthesized as comparative example A. Example A has the structure: 
     
       
         
         
             
             
         
       
     
     The compounds of the formula I are characterized by advantageous effects on sugar metabolism; in particular, they lower the blood sugar level and are suitable for treating type 2 diabetes. The compounds can therefore be used on their own or in combination with other blood sugar-lowering active compounds (antidiabetics). 
     The compounds of formula I are furthermore suitable for treating late damage in diabetes, such as nephropathy, retinopathy, neuropathy and cardiac infarction, myocardial infarction, peripheral arterial occlusion diseases, thromboses, arteriosclerosis, syndrome X, obesity, inflammations, immune diseases, autoimmune diseases, such as AIDS, asthma, osteoporosis, cancer, psoriasis, Alzheimer&#39;s disease, schizophrenia and infectious diseases. 
     The activity of the compounds was tested as follows: 
     Glycogen Phosphorylase a Activity Test 
     The effect of compounds on the activity of the active form of glycogen phosphorylase (GPa) was measured in the reverse direction by monitoring the synthesis of glycogen from glucose 1-phosphate by determining the release of inorganic phosphate. All the reactions were carried out as duplicate determinations in 96-well microtiter plates (Half Area Plates, Costar No. 3696), with the change in absorption due to the formation of the reaction product being measured, at the wavelength specified below, in a Multiscan Ascent Elisa Reader (Lab Systems, Finland). In order to measure the enzymic activity of GPa in the reverse direction, the conversion of glucose 1-phosphate into glycogen and inorganic phosphate was measured in accordance with the general method of Engers et al. (Engers H D, Shechosky S, Madsen N B, Can J Biochem 1970 July;48(7): 746–754) but with the following modifications: Human glycogen phosphorylase a (for example containing 0.76 mg of protein/ml (Aventis Pharma Deutschland GmbH), dissolved in buffer solution E (25 mM β-glycerophosphate, pH 7.0, 1 mM EDTA and 1 mM dithiothreitol), was diluted with buffer T (50 mM Hepes, pH 7.0, 100 mM KCl, 2.5 mM EDTA, 2.5 mM MgCl 2 .6H 2 O), and addition of 5 mg of glycogen/ml, to a concentration of 10 μg of protein/ml. Test substances were prepared as a 10 mM solution in DMSO and diluted down to 50 μM with buffer solution T. 10 μl of 37.5 mM glucose, dissolved in buffer solution T and 5 mg/ml of glycogen, and also 10 μl of a solution of human glycogen phosphorylase a (10 μg of protein/ml) and 20 μl of glucose 1-phosphate, 2.5 mM, were added to 10 ml of the solution. The basal value of the activity of the glycogen phosphorylase a in the absence of test substance was determined by adding 10 μl of buffer solution T (0.1% DMSO). The mixture was incubated at room temperature for 40 minutes and the inorganic phosphate which was released was measured using the general method of Drueckes et al. (Drueckes P, Schinzel R, Palm D,  Anal Biochem Sep.  1, 1955;230(10):173–177) but with the following modifications: 50 μl of a stop solution of 7.3 mM ammonium molybdate, 10.9 mM zinc acetate, 3.6% ascorbic acid, 0.9% SDS are added to 50 μl of the enzyme mixture. After 60 minutes of incubation at 45° C., the absorption was measured at 820 nm. In order to determine the background absorption, the stop solution was added immediately after adding the glucose 1-phosphate solution in a separate assay. This test was carried out using a 10 μM concentration of the test substance in order to determine the respective inhibition of glycogen phosphorylase a by the test substance in vitro. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Biological activity 
               
            
           
           
               
               
               
            
               
                   
                 Ex. 
                 % inhibition at 10 μM 
               
               
                   
                   
               
            
           
           
               
               
               
            
               
                   
                 1 
                 71 
               
               
                   
                 2 
                 85 
               
               
                   
                 3 
                 93 
               
               
                   
                 4 
                 56 
               
               
                   
                 5 
                 80 
               
               
                   
                 6 
                 89 
               
               
                   
                 7 
                 93 
               
               
                   
                 8 
                 96 
               
               
                   
                 9 
                 100 
               
               
                   
                 10 
                 95 
               
               
                   
                 11 
                 95 
               
               
                   
                 12 
                 82 
               
               
                   
                 13 
                 74 
               
               
                   
                 14 
                 70 
               
               
                   
                 15 
                 90 
               
               
                   
                 16 
                 89 
               
               
                   
                 17 
                 75 
               
               
                   
                 18 
                 64 
               
               
                   
                 19 
                 94 
               
               
                   
                 20 
                 85 
               
               
                   
                 21 
                 81 
               
               
                   
                 22 
                 79 
               
               
                   
                 23 
                 59 
               
               
                   
                 24 
                 87 
               
               
                   
                 25 
                 82 
               
               
                   
                 26 
                 81 
               
               
                   
                 27 
                 90 
               
               
                   
                 28 
                 91 
               
               
                   
                 29 
                 72 
               
               
                   
                 30 
                 95 
               
               
                   
                 31 
                 98 
               
               
                   
                 32 
                 98 
               
               
                   
                 33 
                 100 
               
               
                   
                 34 
                 59 
               
               
                   
                 35 
                 94 
               
               
                   
                 36 
                 96 
               
               
                   
                 37 
                 91 
               
               
                   
                 38 
                 103 
               
               
                   
                 39 
                 98 
               
               
                   
                 40 
                 92 
               
               
                   
                 41 
                 101 
               
               
                   
                 42 
                 99 
               
               
                   
                 43 
                 100 
               
               
                   
                 44 
                 101 
               
               
                   
                 45 
                 96 
               
               
                   
                 46 
                 92 
               
               
                   
                 47 
                 98 
               
               
                   
                 48 
                 99 
               
               
                   
                 49 
                 103 
               
               
                   
                 50 
                 108 
               
               
                   
                 51 
                 96 
               
               
                   
                 52 
                 96 
               
               
                   
                 53 
                 93 
               
               
                   
                 54 
                 91 
               
               
                   
                 55 
                 100 
               
               
                   
                 56 
                 96 
               
               
                   
                 57 
                 99 
               
               
                   
                 58 
                 91 
               
               
                   
                 59 
                 92 
               
               
                   
                 60 
                 41 
               
               
                   
                 61 
                 85 
               
               
                   
                 62 
                 59 
               
               
                   
                 63 
                 92 
               
               
                   
                 64 
                 40 
               
               
                   
                 65 
                 56 
               
               
                   
                 66 
                 97 
               
               
                   
                 67 
                 92 
               
               
                   
                 68 
                 54 
               
               
                   
                 69 
                 99 
               
               
                   
                 70 
                 100 
               
               
                   
                 71 
                 95 
               
               
                   
                 72 
                 99 
               
               
                   
                 73 
                 85 
               
               
                   
                 74 
                 47 
               
               
                   
                 75 
                 84 
               
               
                   
                 76 
                 98 
               
               
                   
                 77 
                 96 
               
               
                   
                 78 
                 69 
               
               
                   
                 79 
                 58 
               
               
                   
                 80 
                 65 
               
               
                   
                 81 
                 49 
               
               
                   
                 82 
                 40 
               
               
                   
                 83 
                 34 
               
               
                   
                 84 
                 98 
               
               
                   
                 85 
                 98 
               
               
                   
                 86 
                 99 
               
               
                   
                 87 
                 102 
               
               
                   
                 88 
                 99 
               
               
                   
                 89 
                 102 
               
               
                   
                 90 
                 95 
               
               
                   
                 91 
                 94 
               
               
                   
                 92 
                 95 
               
               
                   
                 93 
                 96 
               
               
                   
                 94 
                 88 
               
               
                   
                 95 
                 96 
               
               
                   
                 96 
                 90 
               
               
                   
                 97 
                 97 
               
               
                   
                 98 
                 95 
               
               
                   
                 99 
                 95 
               
               
                   
                 100 
                 95 
               
               
                   
                 101 
                 100 
               
               
                   
                   
               
            
           
         
       
     
     Comparative Example A exhibits 3% inhibition at 10 μM. 
     It can be seen from the table that the compounds of the formula I inhibit the activity of glycogen phosphorylase a and are therefore well suited for lowering the blood sugar level. In particular, the compounds of formula I exhibit an effect which is from 14- to 36-fold higher than that of comparative example A. 
     The preparation of one example is described in detail below; The remaining compounds of formula I were obtained in an analogous manner, where appropriate using customary protective-group techniques: 
     EXPERIMENTAL SECTION 
     Example 1  
     a) 2-Chlorobenzoyl isocyanate 
     1.03 g (6.6 mmol) of 2-chlorobenzamide were suspended in 3 ml of dichloromethane. After 1.17 g (9.2 mmol) of oxalyl chloride had been added, the mixture was heated to reflux for 17 hours. The reaction mixture was then concentrated under high vacuum and reacted in step b without any further purification. 
     b) 3-[3-(2,4-Dichlorobenzoyl)ureido]-4-methoxybenzoic acid 
     2-Chlorobenzoyl isocyanate (step a) was taken up in 8 ml of acetonitrile, and a suspension of 1.1 g (6 mmol) of 4-amino-3-nitrobenzoic acid in 24 ml of acetonitrile was added. The mixture was heated to reflux for 3.5 hours and, after it had been cooled down, the precipitate was filtered off, washed with acetonitrile and dried in vacuo. 1.68 g (77%) of the desired product were obtained. 
     M.p.: 240° C. (decomposition) 
     Example 2  
     a) 4-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-3-trifluoromethoxybenzoic acid 
     The compound was prepared in a one-pot reaction. 30.0 g (155.8 mmol) of 2-chloro-4,5-difluorobenzoic acid were introduced under a protective-gas atmosphere into a 1 I round-bottomed flask with gas-tight mechanical stirrer and distillation attachment. After addition of 300 ml of toluene, 29.01 ml of thionyl chloride were added with stirring, and the batch was heated to 60° C. The reaction mixture was stirred at 60° C. for a further 1.5 hours, and 0.1 ml of pyridine was then added. After a further 1.5 hours at 60° C., 90 ml of liquid were distilled off from the batch under atmospheric pressure (maximum bath temperature 125° C.). The reaction solution was subsequently cooled to 20° C., and ammonia gas was passed in at 20–35° C. (cooling using an ice bath) until the solution was saturated. 160 ml of THF and 120 ml of deionized water were then added to the batch at 20° C. The aqueous phase was separated off, and the organic phase was washed with 5% aqueous sodium hydrogencarbonate solution. The organic phase was then dried by removal of 250 ml of liquid by azeotropic distillation under reduced pressure at 50° C. The reaction suspension was cooled to 20° C., and 17 ml of oxalyl chloride were added. The batch was stirred at 20° C. for a further 2 hours and subsequently stirred at 50° C. for 4 hours. 200 ml of liquid were removed from the batch by distillation under reduced pressure at 50° C., 200 ml of toluene were then added, and 200 ml of liquid were again removed by distillation under reduced pressure at 50° C. The batch was cooled to 20° C., and a solution of 26.49 g (119.8 mmol) of 4-amino-3-(trifluoromethoxy)benzoic acid in 75 ml of THF was added. The product was separated off by filtration via a glass suction filter and dried to constant weight under reduced pressure at 50° C. 52.6 g of the desired product were obtained. 
     m.p.: 236° C. 
     b) 4-[3-(2-Chloro-4,5-difluorobenzoyl)ureido]-3-trifluoromethoxybenzoic acid TRIS salt 
     A mixture of 10.0 g (22.79 mmol) of 4-[3-(2-chloro-4,5-difluorobenzoyl)ureido]-3-trifluoromethoxybenzoic acid and 3.0 g of α,α,α-tris(hydroxymethyl)methylamine was refluxed in 400 ml of 2-propanol until a clear solution was formed. The solution was filtered while hot and concentrated to a volume of 310 ml. On cooling to 20° C., the product crystallized out of the solution. 10.4 g of the desired product were obtained. 
     m.p.: 176° C. 
     The compounds of the formula I can be prepared by reacting ureas of the formula 2 or aniline derivatives of the formula 3 with aroyl isocyanates, with reactive acid derivatives, with acid chlorides or with anhydrides, of the formula 4, 
                         
in which R1 to R6 are as defined above. The resultant free acids of the formula I can then be reacted with the corresponding bases to give the corresponding physiologically tolerated salts of the compounds of the formula I.
 
     For explanation: if formula 4 represents an acid chloride, Y is Cl; if 4 represents an isocyanate, Y is N═C═O; and if 4 represents an anhydride, Y is 
     
       
         
         
             
             
         
       
     
     Preference is given to the preparation process for the compounds of the formula I via the aroyl isocyanate 4a, as depicted in the following scheme: 
     
       
         
         
             
             
         
       
     
     Formula I can generally be prepared in a one-pot process, which greatly simplifies large-scale industrial production. To this end, 4b is converted into the acid chloride by means of a suitable reagent, such as thionyl chloride or oxalyl chloride, in a suitable solvent, such as toluene. If necessary, a suitable catalyst, such as pyridine, NMP or DMF, is added in order to complete the reaction. After removal of the unreacted reagent (such as thionyl chloride), the acid chloride is converted into the acid amide 4b by means of suitable reagents, such as by passing ammonia gas into the reaction solution or addition of a solution of ammonia in a suitable solvent, such as THF. Sufficient water and a suitable solvent, such as THF, are added to the reaction mixture that all the solid dissolves. After phase separation and washing with sodium hydrogencarbonate solution, the organic phase is dried. The acid amide 4b is converted into the aroyl isocyanate 4a by addition of oxalyl chloride and subsequently heating the mixture. After unreacted oxalyl chloride has been removed, the aniline 3a is dissolved in a suitable solvent, such as THF, and added to the solution of the aroyl isocyanate 4a, during which the reaction product precipitates out of the solution. The compound of the formula I is separated off by filtration. After dissolution of the compound of the formula I with TRIS in a suitable solvent, such as 2-propanol, at the boil, the TRIS salt of the compound of the formula I crystallizes out on subsequent cooling of the solution. 
     All documents referred to herein are incorporated herein by reference in their entirety, including the priority documents, DE 10215907.6, filed Apr. 11, 2002, and U.S. Provisional No. 60/402,779, filed Aug. 12, 2002.