Alkyl-substituted compounds having dopamine receptor affinity

• US 5,602,121 A
• Filed: 12/12/1994
• Issued: 02/11/1997
• Est. Priority Date: 12/12/1994
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Inventors: Fu, Jian-Min
• Primary Examiner(s): Datlow, Philip I.
• Application Number:
  US08/354,793
• Time in Patent Office: 792 Days
• Field of Search: 540/547, 540/551, 514/211
• US Class Current: 514/211.13
• CPC Class Codes: C07D 267/20 [b, f]-condensed

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--;

Y is selected from N and CH;

R₁ represents C_1-4 alkyl;

n is 0, 1 or 2;

q is 1 or 2; and

Z is C_5-10 alkyl optionally substituted with OH, halo, C_1-4 alkyl or C_1-4 alkoxy and optionally incorporating a heteroatom selected from O, N and S;

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:

##STR16## wherein;

A and B are independently selected from the group consisting of 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_3-7 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;

X₁ is O or S,

X₂ . . . is N═

;

Y is selected from N and CH;

R₁ represents C_1-4 alkyl;

n is 0, 1 or 2;

q is 1 or 2; and

Z is n-hexyl;

and acid addition salts, solvates or hydrates thereof.

2. A compound according to claim 1, wherein Y is N.

3. A compound according to claim 2, wherein n is O.

4. 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.

5. 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.

6. A compound according to claim 1, wherein X₁ and X₂ . . . with rings A and B form a tricycle selected from the group consisting of dibenz (b, f) (1,4)oxazepine, 4-chloro analog of dibenz (b, f) (1,4)oxazepine and 8-chloro analog of dibenz (b , f) (1,4) oxazepine.

7. A compound according to claim 1 selected from the group consisting of:

11-(4-hexyl-1-piperazinyl)dibenz(b,f)(1,4)oxazepine; and

4-chloro-11-(4-hexyl-1-piperazinyl)dibenz(b,f)(1,4)oxazepine.

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

9. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 6, and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 7, and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition for treating a condition mediated by the D4 receptor, comprising a compound according to any one of claims 1-7 in an amount effective to inhibit the D4 receptor, and a pharmaceutically acceptable carrier therefor.

12. A method for the treatment of a condition mediated by the D4 receptor, comprising administering to a mammal in need of such treatment, a composition according to claim 11.

13. A pharmaceutical composition for treating schizophrenia, comprising a compound according to any one of claims 1-7, in an amount sufficient to produce an antischizophrenic effect, and a pharmaceutically acceptable carrier therefor.

14. 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 13.

15. A pharmaceutical composition for treating anxiety, comprising a compound according to any one of claims 1-7, in an amount sufficient to produce an antianxiety effect, and a pharmaceutically acceptable carrier therefor.

16. 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 15.