Dopamine receptor ligands

• US 5,798,350 A
• Filed: 05/03/1996
• Issued: 08/25/1998
• Est. Priority Date: 12/23/1993
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Inventors: Tehim, Ashok, Fu, Jian-Min, Rakhit, Sumanas
• Primary Examiner(s): Grumbling, Matthew V.
• Application Number:
  US08/642,264
• Time in Patent Office: 844 Days
• Field of Search: 544/377, 544/378, 546/197, 546/202, 540/575, 540/596, 514/212, 514/218, 514/254, 514/321, 514/324
• US Class Current: 514/217.03
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Described herein are D4 receptor-selective compounds of the general formula: ##STR1## wherein: A and B are independently selected, optionally substituted, saturated or unsaturated 5- or 6-membered, homo- or heterocyclic rings;

X₁ is selected from CH₂, O, NH, S, C═O, CH--OH, CH--N(C_1-4 alkyl)₂, C═CHCl, C═CHCN, N--C_1-4 alkyl, N-acetyl, SO₂ and SO;

X₂ --is selected from N═, CH₂ --, CH═, C(O)--, O--, and S--;

R₁ represents C_1-4 alkyl;

Y is selected from CH and N;

n is 0, 1 or 2;

q is 1 or 2;

R₂ is C_1-6 alkyl optionally incorporating a heteroatom selected from N, O and S;

D is cyclohexane or benzene; and

E is a saturated or unsaturated 5- or 6-membered heterocycle incorporating 1, 2 or 3 heteroatoms selected from O, N, and S, wherein E is optionally substituted with 1 or 2 substituents selected from halogen, C_1-4 alkyl and halogen-substituted C_1-4 alkyl;

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

1. A compound of Formula I:

##STR30## wherein A and B both are optionally substituted benzene;

X₁ is selected from O, S, SO₂ and SO;

X₂ --is selected from CH═

;

Y is selected from CH and N;

R₁ represents C_1-4 alkyl;

n is 0, 1 or 2;

q is 1 or 2;

R₂ is C_1-6 alkylene optionally incorporating an intervening or terminating heteroatom selected from N, O and S;

D is cyclohexane or benzene; and

E is a saturated or unsaturated 5- or 6-membered heterocycle incorporating 1, 2 or 3 heteroatoms selected from O, N, and S, wherein E is optionally substituted with 1 or 2 substituents selected from halogen, C_1-4 alkyl and halogen-substituted C_1-4 alkyl;

and acid addition salts, solvates or hydrates thereof.

2. A compound according to claim 1, wherein rings A and B are imidazole, triazole, pyrazole, thiophene, thiazole, and pyran, optionally substituted with substituents selected independently from hydroxyl, halo, C_1-4 alkyl, amino, nitro, cyano, halo-substituted C_1-4 alkyl, C_1-4 alkoxy, halo-substituted C_1-4 alkoxy, C_1-4 alkoxycarbonyl, C_1-4 acyl, halo-substituted C_1-4 acyl, cyclo-C_1-7 alkyl, thio-C_1-4 alkylene, C_1-4 alkylthio, halo-substituted C_1-4 alkylthio, cyanothio, tetrazolyl, N-piperidinyl, N-piperazinyl, N-morpholinyl, acetamido, C_1-4 alkylsulfonyl, halosulfonyl, halo-substituted C_1-4 alkylsulfonyl, C_1-4 alkylsulfoxyl, sulfonamido, C_1-4 alkylseleno, and OSO₃ H.

3. A compound according to claim 2, wherein ring A is substituted with 1 or 2 substituents selected independently from hydroxyl, halo, C_1-4 alkyl, amino, nitro, cyano, halo-substituted C_1-4 alkyl, C_1-4 alkoxy, halo-substituted C_1-4 alkoxy, C_1-4 alkoxycarbonyl, C_1-4 acyl, halo-substituted C_1-4 acyl, cyclo-C_1-7 alkyl, thio-C_1-4 alkylene, C_1-4 alkylthio, halo-substituted C_1-4 alkylthio, cyanothio, tetrazolyl, N-piperidinyl, N-piperazinyl, N-morpholinyl, acetamido, C_1-4 alkylsulfonyl, halosulfonyl, halo-substituted C_1-4 alkylsulfonyl, C_1-4 alkylsulfoxyl, sulfonamido, C_1-4 alkylseleno, and OSO₃ H.

4. A compound according to claim 3, wherein rings A and B are both substituted with 1 or 2 substituents selected independently from hydroxyl, halo, C_1-4 alkyl, amino, nitro, cyano, halo-substituted C_1-4 alkyl, C_1-4 alkoxy, halo-substituted C_1-4 alkoxy, C_1-4 alkoxycarbonyl, C_1-4 acyl, halo-substituted C_1-4 acyl, cyclo-C_1-7 alkyl, HS-C_1-4 alkylene, C_1-4 alkylthio, halo-substituted C_1-4 alkylthio, cyanothio, tetrazolyl, N-piperidinyl, N-piperazinyl, N-morpholinyl, acetamido, C_1-4 alkylsulfonyl, halosulfonyl, halo-substituted C_1-4 alkylsulfonyl, C_1-4 alkylsulfoxyl, sulfonamido, C_1-4 alkylseleno, and OSO₃ H.

5. A compound according to claim 1, wherein ring A is substituented by 1 or 2 substituents selected from chloro, methyl, methylthio, nitro and cyano.

6. A compound according to claim 1, wherein ring B is substituted by 1 or 2 substituents selected from fluoro, chloro, trifluoromethyl, methoxy, nitro and cyano.

7. A compound according to claim 1, wherein X₁ is selected from, NH.

8. A compound according to claim 1, wherein q is 1.

9. A compound according to claim 8, wherein Y is N.

10. A compound according to claim 1, wherein ring D is benzene.

11. A compound according to claim 1, wherein R₂ is --CH₂ --.

12. A compound according to claim 1, wherein ring E is a 5-membered heterocycle containing two heteroatoms.

13. A compound according to claim 12, wherein ring E contains two oxygen atoms.

14. A compound according to claim 1, wherein ring E is a six-membered heterocycle containing two heteroatoms.

15. A compound according to claim 14, wherein ring E contains two oxygen atoms.

16. A compound according to claim 12, wherein ring D is benzene.

17. A compound according to claim 16, wherein R₂ is --CH₂ --.

18. A compound according to claim 1, wherein R₂ together with rings D and E form a piperonyl group.

19. A compound according to claim 9, which is 2-nitro-10-(4-piperonyl)-1-piperazinyl)dibenzo b,f!thiepine.

20. A compound according to claim 9, which is 2-chloro-10-(4-piperonyl)-1-piperazinyl)dibenzo b,f!thiepine.

21. A compound according to claim 9, wherein X₁ and X₂ together with rings A and B form dibenzo b,f!thiepine.

22. A compound according to claim 9, wherein X₁ and X₂ together with rings A and B form 2-chlorodibenzo b,f!thiepine.

23. A compound according to claim 9, wherein X₁ and X₂ together with rings A and B form 2-nitrodibenzo b,f!thiepine.

24. A compound according to claim 9, wherein X₁ and X₂ together with rings A and B form 2-chlorodibenzo b,f!thiepine.

25. A compound according to claim 9, wherein R₂ --D/E is piperonyl.

26. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1, and a pharmaceutically acceptable carrier.

27. A compound according to claim 1, wherein X₁ is selected from O and S.

28. A compound according to claim 1, wherein substituents for A and B are selected independently from hydroxyl, halo, C_1-4 alkyl, amino, nitro, cyano, halo-substituted C_1-4 alkyl, C_1-4 alkoxy, halo-substituted C_1-4 alkoxy, C_1-4 alkoxycarbonyl, C_1-4 acyl, halo-substituted C_1-4 acyl, cyclo-C_1-7 alkyl, thio-C_1-4 alkylene, C_1-4 alkylthio, halo-substituted C_1-4 alkylthio, cyanothio, tetrazolyl, N-piperidinyl, N-piperazinyl, N-morpholinyl, acetamido, C_1-4 alkylsulfonyl, halosulfonyl, halo-substituted C_1-4 alkylsulfonyl, C_1-4 alkylsulfoxyl, sulfonamido, C_1-4 alkylseleno, and OSO₃ H.

29. A pharmaceutical composition for treating a condition mediated by the D4 receptor, comprising a compound according to claim 1 in an amount effective to inhibit the D4 receptor, and a pharmaceutically acceptable carrier therefor.

30. A method for the treatment of a condition mediated by the D4 receptor, comprising the step of administering to a mammal in need of such treatment a composition according to claim 29.

31. A pharmaceutical composition for treating schizophrenia, comprising a compound according to claim 1 in an amount sufficient to produce an antischizophrenia effect, and a pharmaceutically acceptable carrier therefor.

32. A method for the treatment of schizophrenia, comprising the step of administering to a mammal in need of such treatment, a composition according to claim 31.

33. A pharmaceutical composition for treating anxiety, comprising a compound according to claim 1, an amount sufficient to produce an anti-anxiety effect, and a pharmaceutically acceptable carrier therefor.

34. A method for the treatment of anxiety, comprising the step of administering to a mammal in need of such treatment, a composition according to claim 33.