Bicyclic nonane and decane compounds having dopamine receptor affinity

• US 5,576,314 A
• Filed: 12/12/1994
• Issued: 11/19/1996
• Est. Priority Date: 12/12/1994
• Status: Expired due to Term

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Inventors: Power, Patricia L., Rakhit, Sumanas
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): WONG, KING
• Application Number:
  US08/354,906
• Time in Patent Office: 708 Days
• Field of Search: 540/551, 540/550, 514/211
• US Class Current: 514/211.13
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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--;

n is 1 or 2;

R₁ is selected from H and an amino acid side chain;

R₂ is selected from H, OH, C_1-9 alkyl, C_1-9 alkoxy, and benzyloxy; and

R₃ is selected from H, OH, halo, cyano, C_1-4 alkyl, C_1-4 alkoxy, phenoxy, benzyloxy, ═O, ═S, C_1-4 alkylsulfonyl, C_1-4 alkylsulfonyl, C_1-4 alkylthio, amino, and aminocarbonyl;

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 II ##STR20## wherein:

A and B are independently benzene unsubstituted or 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, cyclo-C_1-4 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 alkylsulfoxyl, C_1-4 alkylsulfonyl, sulfonamido, C_1-4 alkylseleno, and OSO₃ H

either X₁ is O, S, SO or SO₂ and

X₂ is N;

or

X₁ is NH, N-C_1-4 alkyl or N-acetyl and

X₂ is O or S;

n is 1 or 2,

R₁ is selected from H and an α

carbon side chain of an amino acid;

R₂ is selected from H, OH, C_1-9 alkyl, C_1-9 alkoxy, and benzyloxy; and

R₃ is selected from H, OH, halo, cyano, C_1-4 alkyl, C_1-4 alkoxy, phenoxy, benzyloxy, ═

O, ═

S, C_1-4 alkylsulfoxyl, C_1-4 alkylsulfonyl, C_1-4 alkythio, amino, and aminocarbonyl;

and acid addition salts, solvates and hydrates thereof, wherein said compound is essentially free of any 6-R enantiomeric form thereof.

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

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

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

5. A compound according to claim 1, wherein X₂ - - - is N═

.

6. A compound according to claim 1, wherein X₁ and X₂ - - - with rings A and B form the tricycle dibenz[b,f]-1,4-oxazepine which is substituted or unsubstituted.

7. A compound according to claim 6, wherein the tricycle dibenz[b,f]-1,4-oxazepine is chloro-substituted at the 8-position.

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

9. A compound according to claim 8, wherein R₂ is selected from H or benzyloxy.

10. A compound according to claim 1, wherein n is 2.

11. A compound according to claim 1, selected from

8-chloro-11-(6S)-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenzo [b,f]-1,4-oxazepine;

8-chloro-11-(6S)-1,4-diazabicyclo[4.4.0]decan-4-yl]-dibenzo [b,f]-1,4-oxazepine;

8-chloro-11-[(6S)-8-benzyloxy-1,4-diazabicyclo[4.3.0]non-4-yl]-dibenzo[b,f]-1,4-oxazepine; and

8-chloro-11-[(6S)-8-hydroxy-1,4-diazabicyclo[4.3.0]non-4-yl]dibenzo[b,f]-1,4-oxazepine.

12. A compound according to claim 11, selected from

8-chloro-11-[(6S)-1,4-diazabicyclo[4.3.0]non-4-yl]dibenzo[b,f]-1,4-oxazepine;

and

8-chloro-11-[(6S)-1,4-diazabicyclo[4.4 .0]decan-4-yl]dibenzo[b,f]-1,4-oxazepine.

13. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 12, and a pharmaceutically acceptable carrier.

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

15. A pharmaceutical composition for treating a condition mediated by the D4 receptor, comprising a compound according to any one of claims 1-12 in an amount effective to inhibit the D4 receptor.

16. 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 15.

17. A pharmaceutical composition for treating schizophrenia, comprising a compound according to any one of claims 1-12, in an amount sufficient to produce an antischizophrenia effect, and a pharmaceutically acceptable carrier therefor.

18. 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 17.

19. A pharmaceutical composition for treating anxiety, comprising a compound according to any one of claims 1-12, in an amount sufficient to produce an antianxiety effect, and a pharmaceutically acceptable carrier therefor.

20. 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 19.