Benzyl-substituted compounds having dopamine receptor affinity

• US 5,814,628 A
• Filed: 12/10/1996
• Issued: 09/29/1998
• 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: Kirby, Robert A., Tehim, Ashok, Fu, Jian-Min
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US08/762,984
• Time in Patent Office: 658 Days
• Field of Search: 540/557, 514/220
• US Class Current: 514/220
• 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═CHCI, 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 CH and N;

Z is cyano

R₁ represents C_1-4 alkyl;

m is 0, 1, 2 or 3;

n is 0, 1 or 2;

q is 1 or 2; and

D is a 5, 6 or 7-membered, saturated or unsaturated, homo- or heterocyclic ring; 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. The compound of Formula 1:

##STR16## wherein;

A and B are benzene unsubstituted or substituted with 1-3 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, thiol-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 alkylSO--, sulfonamido, C_1-4 alkylseleno, and OSO₃ H;

X₁ is selected from NH, N--C_1-4 alkyl, and N-acetyl;

X₂ --is N═

;

Y is selected from CH and N;

Z is cyano;

R₁ represents C_1-4 alkyl;

m is 1, 2 or 3;

n is 0, 1 or2;

q is 1 or 2; and

D is benzene; and

acid addition salts or hydrates thereof.

2. The compound according to claim 1, wherein A is selected from benzene and B is selected from benzen wherein A and B are independently 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, thiol-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 alkylso-sulfonamido, C_1-4 alkylseleno, and OSO₃ H.

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

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

5. The compound according to claim 1, wherein X₁ is selected from NH.

6. The compound according to claim 1, wherein ring D is benzene and m is 1.

7. The compound according to claim 2, wherein ring D is benzene and m is 1.

8. The compound according to claim 3, wherein ring D is benzene and m is 1.

9. The compound according to claim 4, wherein ring D is benzene and m is 1.

10. The compound according to claim 5, wherein ring D is benzene and m is 1.

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