# US 7,745,474 B2 · Imidazole derivatives for the treatment of gastrointestinal disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 7,745,474 B2 - Document ID: US7745474B2 - Status: Granted - Kind: B2 - Application number: 12/158,167 - Filed: 2006-12-21 - Published: 2009-01-01 - Granted: 2010-06-29 - Earliest claimed: 2005-12-23 - Assignees: AstraZeneca AB - Inventors: Udo Bauer; Wayne Brailsford; Linda Gustafsson; Tor Svensson; Maria Saxin - Web page: https://patentgrep.com/patent/US7745474B2 ## CPC - C07D 233/90: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals - A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system - A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants - A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia - A61P 1/10: Laxatives - A61P 1/12: Antidiarrhoeals - A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 405/12: linked by a chain containing hetero atoms as chain links - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to novel imidazole derivatives having a positive allosteric GABAB receptor (GBR) modulator effect, methods for the preparation of said compounds and to their use, optionally in combination with a GABAB agonist, for the inhibition of transient lower esophageal sphincter relaxations, for the treatment of gastroesophageal reflux disease, as well as for the treatment of functional gastrointestinal disorders and irritable bowel syndrome (IBS). The compounds are represented by the general formula (I) wherein R1, R2, R3 and Y are as defined in the description. For example, R1 may be phenyl, R2 may be dimethylamino, R3 may be alkoxy and Y may be a thioylamino- or methyl eneamino- linked substitutuent containing an aryl group. ## Claims ### Claim 1 A compound of the general formula (I), an enantiomer of the compound, or a pharmaceutically acceptable salt of the compound or the enantiomer, wherein: R1 represents C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, SO3R7, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R1 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; R2 represents C1-C6 alkyl, C1-C6 alkoxy or NR5R6; optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; R3 represents C1-C10 alkoxy, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R3 represents amino, optionally mono- or disubstituted with C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl or C3-C10 cycloalkyl; Y represents R4 represents C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; C1-C10 alkoxy; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, keto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, COR10, nitrile, SO2NR8R9, SO2R11, NR8SO2R9, NR8C═ONR9 or one or two aryl or heteroaryl groups; or R4 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, SO3R7, nitrile or one or two aryl or heteroaryl groups; R5 represents hydrogen, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R5 represents aryl or heteroaryl, each optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; R6 represents hydrogen, C1-C10 alkyl; C2-C10 alkenyl; C2-C10 alkynyl; or C3-C10 cycloalkyl, each optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R6 represents aryl or heteroaryl, each optionally substituted by C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; or R5 and R6 together form a ring consisting of from 3 to 7 atoms selected from the group consisting of C, N and O atoms, wherein said ring is optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, keto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups; R7 each and independently represents C1-C10 alkyl; R8 each and independently represents hydrogen, C1-C10 alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy; R9 each and independently represents hydrogen, C1-C10 alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy; R10 each and independently represents C1-C10 alkyl, optionally substituted by aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy; and R11 represents C1-C10 alkyl, aryl or heteroaryl, wherein said aryl or heteroaryl may optionally be further substituted by one or more of halogen(s), C1-C10 alkyl, C1-C10 alkoxy or C1-C10 thioalkoxy; wherein each alkyl, alkenyl, alkynyl and cycloalkyl group used in defining R1 and R3-R11 may independently have one or more carbon atom(s) replaced with an O, N or S atom, wherein none of the O, N or S atoms is in a position adjacent to any other O, N or S atoms; and wherein each alkyl, alkenyl, alkynyl, alkoxy and cycloalkyl group may independently have one or more carbon atom(s) substituted with fluoro; with the proviso that R2 may only represent alkoxy if Y represents NHSO2 or NHCS. ### Claim 2 (depends on 1) The compound according to claim 1, wherein R1 represents C1-C4 alkyl, optionally substituted by one aryl or two heteroaryl groups. ### Claim 3 (depends on 1) The compound according to claim 1, wherein R1 represents aryl, optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, SO3R7, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups. ### Claim 4 (depends on 3) The compound according to claim 3, wherein R1 represents unsubstituted phenyl. ### Claim 5 (depends on 1) The compound according to claim 1, wherein R2 represents C1-C4 alkyl. ### Claim 6 (depends on 1) The compound according to claim 1, wherein R3 represents C1-C4 alkoxy, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups. ### Claim 7 (depends on 1) The compound according to claim 1, wherein R3 represents C1-C10 alkyl, optionally substituted by one or more of C1-C10 thioalkoxy, C3-C10 cycloalkyl, keto, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups. ### Claim 8 (depends on 1) The compound according to claim 1 wherein R4 represents C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl or C3-C7 cycloalkyl, optionally substituted by one or more of C1-C10 alkoxy, C3-C10 cycloalkyl, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile, SO2NR8R9, NR8SO2R9, NR8C═ONR9, or one or two aryl or heteroaryl groups. ### Claim 9 (depends on 8) The compound according to claim 8, wherein R4 represents C1-C4 alkyl, optionally substituted by one or two aryl or heteroaryl groups. ### Claim 10 (depends on 9) The compound according to claim 9, wherein R4 represents C1-C4 alkyl, substituted by one or two aryl or heteroaryl groups. ### Claim 11 (depends on 1) The compound according to claim 1, wherein R4 represents aryl or heteroaryl, optionally substituted by one or more of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C1-C10 alkoxy, C1-C10 thioalkoxy, halogen(s), hydroxy, mercapto, nitro, carboxylic acid, CONR8R9, NR8COR9, CO2R10, nitrile or one or two aryl or heteroaryl groups. ### Claim 12 (depends on 1) The compound according to claim 1, wherein R5 represents C1-4 alkyl. ### Claim 13 (depends on 12) The compound according to claim 12, wherein R5 represents methyl. ### Claim 14 (depends on 1) The compound according to claim 1, wherein R6 represents C1-4 alkyl. ### Claim 15 (depends on 14) The compound according to claim 14, wherein R6 represents methyl. ### Claim 16 (depends on 1) The compound according to claim 1, wherein R5 and R6 form a ring consisting of 5 or 6 atoms selected from C, O and N. ### Claim 17 (depends on 1) The compound according to claim 1, wherein Y represents ### Claim 18 (depends on 1) The compound according to claim 1, wherein Y represents ### Claim 19 (depends on 1) The compound according to claim 1, wherein: R1 represents aryl; R2 represents NR5R6; R3 represents C1-C10 alkoxy; Y represents R4 represents C1-C10 alkyl, optionally substituted by one aryl; or R4 represents aryl or heteroaryl, each optionally substituted by one halogen; R5 represents hydrogen, C1-C10 alkyl; and R6 represents hydrogen, C1-C10 alkyl; or R5 and R6 together form a ring consisting of from 3 to 7 atoms selected from C and N atoms; wherein the alkyl used in defining R4 may have one carbon atom replaced with an O atom. ### Claim 20 (depends on 1) The compound according to claim 1, wherein: R1 represents aryl; R2 represents NR5R6; R3 represents C1-C4 alkoxy; Y represents R4 represents C1-C10 alkyl, optionally substituted by one aryl; or R4 represents aryl or heteroaryl, each optionally substituted by one halogen; R5 represents C1-C4 alkyl; and R6 represents hydrogen, C1-C4 alkyl; or R5 and R6 together form a ring consisting of from 5 to 6 atoms selected from C and N; wherein the alkyl used in defining R4 may have one carbon atom substituted for an O atom. ### Claim 21 (depends on 1) The compound according to claim 1, wherein the compound is selected from the group consisting of: tert-butyl 4-{[(4-chlorophenyl)carbonothioyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate; tert-butyl 4-{[(1Z)-(4-chlorophenyl)(pyrrolidin-1-yl)methylene]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate; tert-butyl 4-[(2,3-dihydro-1,4-benzodioxin-2-ylcarbonothioyl)amino]-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate; and tert-butyl 4-{[2-(benzyloxy)ethanethioyl]amino}-2-(dimethylamino)-1-phenyl-1H-imidazole-5-carboxylate. ### Claim 22 (depends on 1) A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. ### Claim 23 (depends on 22) A method for the treatment of gastroesophageal reflux disease (GERD), the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 22, optionally in combination with a GABAB receptor agonist, to a patient in need thereof. ### Claim 24 (depends on 22) A method for the treatment of a functional gastrointestinal disorder, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 22, optionally in combination with a GABAB receptor agonist, to a patient in need thereof. ### Claim 25 (depends on 22) A method for the treatment of irritable bowel syndrome (IBS), the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 22, optionally in combination with a GABAB receptor agonist, to a patient in need thereof. ### Claim 26 (depends on 22) A method for the prevention of reflux, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 22, optionally in combination with a GABAB receptor agonist, to a patient in need thereof. ### Claim 27 (depends on 22) A method for the inhibition of transient lower esophageal sphincter relaxations (TLESRs), the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 22, optionally in combination with a GABAB receptor agonist, to a patient in need thereof. ### Claim 28 (depends on 25) The method according to claim 25, wherein the IBS is constipation predominant IBS, diarrhea predominant IBS, or alternating bowel movement predominant IBS. ### Claim 29 (depends on 24) The method according to claim 24, wherein the functional gastrointestinal disorder is functional dyspepsia.