# US 5,703,072 A · Bicyclic nonane and decane compounds having dopamine receptor affinity > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,703,072 A - Document ID: US5703072A - Status: Granted - Kind: A - Application number: 08/625,358 - Filed: 1996-04-01 - Granted: 1997-12-30 - Earliest claimed: 1994-12-12 - Assignees: Allelix Biopharmaceuticals Inc. - Inventors: Patricia L. Power; Sumanas Rakhit - Web page: https://patentgrep.com/patent/US5703072A ## CPC - C07D 471/04: Ortho-condensed systems - C07D 487/04: Ortho-condensed systems - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract Described herein are D4 receptor-selective compounds of the general formula: ##STR1## wherein: A and B are independently selected, substituted or unsubstituted, unsaturated 5- or 6-membered, homo- or heterocyclic rings; X.sub.1 is selected from O, S, SO, SO.sub.2, CH.sub.2, C.dbd.O, CH--OH, CH--N(C.sub.1-4 alkyl).sub.2, C.dbd.CHCl, and C.dbd.CHCN; X.sub.2 --- is selected from N.dbd., CH.sub.2 --, CH.dbd. and C(O)--; n is 1 or 2; R.sub.1 is selected from H and the .alpha.-carbon side chain of an amino acid; R.sub.2 and R.sub.3 are selected independently from H, OH, --NH.sub.2, --C(O)NH.sub.2 .dbd.O, .dbd.S,halo,cyano, C.sub.1-9 alkyl, C.sub.1-9 alkoxy, C.sub.1-4 alkylS--, C.sub.1-4 alkylSO--, C.sub.1-4 alkylSO.sub.2 --, phenoxy, benzyloxy and piperonyloxy; and H* is in either the R- or the S-configuration, and acid addition salts, solvates and hydrates thereof. Their use as ligands for dopamine receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the D4 receptor is implicated, such as schizophrenia, is also described. ## Claims ### Claim 1 A compound of Formula I: ##STR18## wherein: A and B are independently selected from substituted or unsubstituted benzene; X.sub.1 is selected from O, S, SO, and SO.sub.2 ; X.sub.2 --- is N.dbd.; n is 1 or 2; R.sub.1 is selected from H and the .alpha.-carbon side chain of an amino acid; R.sub.2 and R.sub.3 are selected independently from H, OH, --NH.sub.2, --C(O)NH.sub.2, .dbd.O, .dbd.S, halo, cyano, C.sub.1-9 alkyl, C.sub.1-9 alkoxy, C.sub.1-4 alkylS--, C.sub.1-4 alkylSO--, C.sub.1-4 alkylSO.sub.2 --, phenoxy, benzyloxy and piperonyloxy; and H* is in either the R- or the S-configuration, and acid addition salts, solvates and hydrates thereof. ### Claim 2 (depends on 1) The compound according to claim 1, wherein H* is in the S-configuration. ### Claim 3 (depends on 1) The compound according to claim 1, wherein R.sub.2 is selected from H, OH and benzyloxy. ### Claim 4 (depends on 1) The compound according to claim 1, wherein R.sub.3 is H. ### Claim 5 (depends on 1) The compound according to claim 1, wherein R.sub.1 is H. ### Claim 6 (depends on 1) The compound according to claim 1, wherein n is 1. ### Claim 7 (depends on 1) The compound according to claim 1, wherein R.sub.2 is selected from H and benzyloxy. ### Claim 8 (depends on 1) A compound according to claim 1, wherein R.sub.3 and R.sub.1 are H. ### Claim 9 (depends on 8) A compound according to claim 8, wherein H* is in the S-configuration. ### Claim 10 (depends on 9) A compound according to claim 9, wherein n is 1. ### Claim 11 (depends on 10) A compound according to claim 10, wherein R.sub.2 is selected from H, OH and benzyloxy. ### Claim 12 (depends on 1) A compound according to claim 1, wherein H*, R.sub.1, R.sub.2, R.sub.3 and n are selected to form the group (6S)-1,4-diazabicyclo›4.3.0!non4-yl. ### Claim 13 (depends on 1) The compound according to claim 1, wherein X.sub.1 is O or S. ### Claim 14 (depends on 1) The compound according to claim 1, wherein X.sub.2 is N.dbd.. ### Claim 15 (depends on 1) The compound according to claim 1, wherein A and B are independently selected from benzene and benzene substituted with 1 or 2 substituents selected independently from hydroxyl, halo, C.sub.1-4 alkyl, amino, nitro, cyano, halo-substituted C.sub.1-4 alkyl, C.sub.1-4 alkoxy, halo-substituted C.sub.1-4 alkoxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 acyl, cyclo-C.sub.1-7 alkyl, thio-C.sub.1-4 alkylene, C.sub.1-4 alkylthio, halo-substituted C.sub.1-4 alkylthio, cyanothio, tetrazolyl, N-piperidinyl, N-piperazinyl, N-morpholinyl, acetamido, C.sub.1-4 alkylsulfonyl, halosulfonyl, halo-substituted C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfoxyl, sulfonamido, C.sub.1-4 alkylseleno, and OSO.sub.3 H. ### Claim 16 (depends on 15) The compound according to claim 15, wherein said substituents are selected from fluoro, chloro, bromo, nitro, amino and cyano. ### Claim 17 (depends on 1) The compound according to claim 1, wherein A, B, X.sub.1 and X.sub.2 together are selected to form a tricycle which is an optionally substituted dibenz›b,f!-1,4-oxazepine. ### Claim 18 (depends on 17) The compound according to claim 17, wherein said tricycle is a 4-chlorodibenz›b,f!-1,4-oxazepine. ### Claim 19 (depends on 18) The compound according to claim 18, wherein R.sub.3 and R.sub.1 are H. ### Claim 20 (depends on 19) The compound according to claim 19, wherein H* is in the S-configuration. ### Claim 21 (depends on 20) The compound according to claim 20, wherein n is 1. ### Claim 22 (depends on 21) The compound according to claim 21, wherein R.sub.2 is selected from H, OH and benzyloxy. ### Claim 23 (depends on 17) A compound according to claim 17, wherein said tricycle is a 8-chlorodibenz›b,f!-1,4-oxazepine. ### Claim 24 (depends on 1) The compound according to claim 1, wherein said compound is selected from the group consisting of: 8-chloro-11-›(6R,S)-1,4-diazabicyclo›4.4.0!decan-4-yl!dibenzo›b,f!-1,4-oxaz epine; 4-chloro-11-›(6S)-1,4-diazabicyclo›4.3.0!non-4-yl!dibenzo›b,f!-1,4-oxazepin e; 8-chloro-11-›(6R)-1,4-diazabicyclo›4.3.0!non-4-yl!dibenzo›b,f!-1,4-oxazepin e; and 8-chloro-11-›(6R)-1,4-diazabicyclo›4.4.0!decan-4-yl!dibenzo›b,f!-1,4-oxazep ine. 25. ### Claim 25 (depends on 24) The compound according to claim 24, wherein said compound is 4-chloro-11-›(6S)-1,4-diazabicyclo›4.3.0!non-4-yl!dibenzo›b,f!-1,4-oxazepi ne. ### Claim 26 (depends on 1) A pharmaceutical composition, comprising a compound according to claim 1 in an amount effective to antagonize D4 receptor stimulation, and a pharmaceutically acceptable carrier. ### Claim 27 (depends on 2) A pharmaceutical composition, comprising a compound according to claim 2 in an amount effective to antagonize D4 receptor stimulation, and a pharmaceutically acceptable carrier. ### Claim 28 (depends on 12) A pharmaceutical composition, comprising a compound according to claim 12 in an amount effective to antagonize D4 receptor stimulation, and a pharmaceutically acceptable carrier. ### Claim 29 (depends on 25) A pharmaceutical composition, comprising a compound according to claim 25 in an amount effective to antagonize D4 receptor stimulation, and a pharmaceutically acceptable carrier. ### Claim 30 (depends on 1) A pharmaceutical composition, comprising a compound according to claim 1 wherein said compound is present in an amount sufficient to produce an anti-schizophrenia effect, and a pharmaceutically acceptable carrier. ### Claim 31 (depends on 2) A pharmaceutical composition, comprising a compound according to claim 2 wherein said compound is present in an amount sufficient to produce an anti-schizophrenia effect, and a pharmaceutically acceptable carrier. ### Claim 32 (depends on 12) A pharmaceutical composition, comprising a compound according to claim 12 wherein said compound is present in an amount sufficient to produce an anti-schizophrenia effect, and a pharmaceutically acceptable carrier. ### Claim 33 (depends on 25) A pharmaceutical composition, comprising a compound according to claim 25 wherein said compound is present in an amount sufficient to produce an anti-schizophrenia effect, and a pharmaceutically acceptable carrier. ### Claim 34 (depends on 1) A pharmaceutical composition comprising a compound according to claim 1, wherein said compound is present in an amount sufficient to produce an anti-anxiety effect, and a pharmaceutically acceptable carrier. ### Claim 35 (depends on 26) A method for the treatment of a medical condition mediated by D4 receptor stimulation, comprising administering to a mammal in need of such treatment, a composition according to claim 26. ### Claim 36 (depends on 27) A method for the treatment of a medical condition mediated by D4 receptor stimulation, comprising administering to a mammal in need of such treatment, a composition according to claim 27. ### Claim 37 (depends on 28) A method for the treatment of a medical condition mediated by D4 receptor stimulation, comprising administering to a mammal in need of such treatment, a composition according to claim 28. ### Claim 38 (depends on 29) A method for the treatment of a medical condition mediated by D4 receptor stimulation, comprising administering to a mammal in need of such treatment, a composition according to claim 29. ### Claim 39 (depends on 30) A method for the treatment of schizophrenia, comprising administering to a mammal in need of such treatment, a composition according to claim 30. ### Claim 40 (depends on 31) A method for the treatment of schizophrenia, comprising administering to a mammal in need of such treatment, a composition according to claim 31. ### Claim 41 (depends on 32) A method for the treatment of schizophrenia, comprising administering to a mammal in need of such treatment, a composition according to claim 32. ### Claim 42 (depends on 33) A method for the treatment of schizophrenia, comprising administering to a mammal in need of such treatment, a composition according to claim 33. ### Claim 43 (depends on 34) A method for the treatment of anxiety, comprising administering to a mammal in need of such treatment, a composition according to claim 34.