Muscarinic receptor ligands

• US 5,561,127 A
• Filed: 12/19/1994
• Issued: 10/01/1996
• Est. Priority Date: 12/19/1994
• Status: Expired due to Fees

• Current Assignee: NPS Pharmaceuticals Incorporated (Shire plc)
• Original Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Inventors: Tehim, Ashok, Rakhit, Sumanas
• Primary Examiner(s): Datlow, Philip I.
• Application Number:
  US08/358,471
• Time in Patent Office: 652 Days
• Field of Search: 540/551, 540/557, 514/211, 514/220
• US Class Current: 514/211.13
• CPC Class Codes: C07D 487/08 Bridged systems

Abstract

Described herein are D4 receptor-selective compounds of the general formula I: ##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--NEt₂, 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; and

Z is selected from C_1-6 alkyl optionally substituted with a substituent selected from OH, halo, C_1-4 alkyl and C_1-4 alkoxy;

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 M1/M2 receptor is implicated, such as schizophrenia, is also described.

Claims

1. A compound of Formula I:

##STR12## 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_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;

X₁ is selected from O, NH, S, N--C_1-4 alkyl, N-acetyl, SO₂ and SO;

X₂ --is N═

,

n is 1 or 2; and

Z is selected from C_1-6 alkyl unsubstituted or substituted with a substituent selected from OH, halo, C_1-4 alkyl and C_1-4 alkoxy;

and acid addition salts, solvates and hydrates thereof.

2. A compound according to claim 1, wherein Z is C_1-6 alkyl.

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

4. A compound according to claim 3, wherein Z is C_1-6 alkyl.

5. A compound according to claim 4, wherein ring A is benzene unsubstituted or substituted by 1 or 2 chloro substituents.

6. A compound according to claim 4, wherein ring B is benzene.

7. A compound according to claim 4, wherein X₁ is selected from O and NH.

8. A compound according to claim 7, wherein X₁ and X₂ --with rings A and B form the tricycle dibenzo[b,f][1,4]oxazepine that is unsubstituted or 8-chloro-substituted.

9. A compound according to claim 7, wherein X₁ and X₂ --with rings A and B form the tricycle dibenzo[b,e][1,4]diazepine that is unsubstituted or 7,8-dichloro-substituted.

10. A compound according to claim 2, wherein Z is methyl.

11. A compound according to claim 4, wherein Z is methyl.

12. A compound according to claim 8, wherein Z is methyl.

13. A compound according to claim 9, wherein Z is methyl.

14. A compound according to claim 1 selected from

8-chloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenzo[b,f][1,4]thiazepine;

11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenzo[b,f][1,4]thiazepine;

8-chloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenz[b,f][1,4]oxazepine;

11-(2-benzyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenz[b,f][1,4]oxazepine; and

7,8-dichloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenzo[b,e][1,4]diazepine.

15. A compound according to claim 14 selected from

11-(2-benzyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenz[b,f][1,4]oxazepine;

8-chloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenz[b,f][1,4]oxazepine; and

7,8-dichloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenzo[b,e][1,4]diazepine.

16. A compound according to claim 15 selected from

8-chloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenz[b,f][1,4]oxazepine;

and

7,8-dichloro-11-(2-methyl-2,5-diazabicyclo(2.2.1)hept-5-yl)-dibenzo[b,e][1,4]diazepine.

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

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

19. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 16, and a pharmaceutically acceptable carrier.