5-HT2 receptor ligands

• US 5,824,676 A
• Filed: 12/10/1996
• Issued: 10/20/1998
• Est. Priority Date: 12/12/1994
• Status: Expired due to Fees

• Current Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Original Assignee: Allelix Biopharmaceuticals, Inc. (NPS Allelix Corp.)
• Inventors: Tehim, Ashok, Fu, Jian-min, Rakhit, Sumanas
• Primary Examiner(s): Berch, Mark L.
• Application Number:
  US08/763,255
• Time in Patent Office: 679 Days
• Field of Search: 540/547, 514/220
• US Class Current: 514/220
• CPC Class Codes: C07D 243/38 [b, e]- or [b, f]-condensed with six-membered rings
• CPC Class Codes: C07D 267/20 [b, f]-condensed

Abstract

Described herein are 5-HT2 receptor-selective compounds of 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--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 is C_1-6 alkyl optionally substituted with a substituent selected from OH, halo, C_1-4 alkyl and C_1-4 alkoxy; and

R₂, R₃ and R₄ are independently selected from H and R₁ ; and acid addition salts, solvates and hydrates thereof. Their use as ligands for serotonin 5-HT2 receptor identification and in a drug screening program, and as pharmaceuticals to treat indications in which the 5-HT2 receptor is implicated, such as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, schizophrenia, sleep disorders and appetite disorders is also described.

Claims

1. A compound of Formula 1:

##STR13## wherein A and B are benzene unsubstituted or 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 CO--, 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 SO₂ NH₂, C_1-4,alkylseleno, and OSO₃ H;

X₁ is selected from O, and S;

X₂ --is N═

;

R₁ is C_1-6 alkyl unsubstituted or substituted with a substituent selected from OH, halo, C_1-4 alkyl and C_1-4 alkoxy; and

R₂, R₃ and R₄ are independently selected from H and R₁ ;

and acid addition salts, solvates and hydrates thereof.

2. The compound according to claim 1, wherein A and B are both 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 CO--, 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, SO₂ NH₂,C_1-4 alkylseleno, and OSO₃ H.

3. The compound according to claim 1, wherein A is benzene optionally substituted by 1 or 2 chloro substituents.

4. The compound according to claim 1 wherein B is benzene optionally substituted by 1 or 2 chloro substituents.

5. The compound according to claim 1, wherein X₁ and X₂ --with rings A and B form the tricycle dibenzo b,f! 1,4!oxazepine that is optionally 8-chloro-substituted.

6. The compound according to claim 1, wherein R₁ is C_1-6 alkyl and R₂, R₃ and R₄ are selected from H and C_1-6 alkyl.

7. The compound according to claim 6, wherein R₁ and R₃ are C_1-6 alkyl and R₂ and R₄ are H.

8. The compound according to claim 7, wherein R₁ and R₃ are methyl.

9. The compound according to claim 2, wherein R₁ and R₃ are methyl and R₂ and R₄ are H.

10. The compound according to claim 1, wherein said compound is selected from

8-chloro-11-(3,5-dimethyl-1-piperazinyl)-dibenz b,f! 1,4!oxazepine;

11-(3,5-dimethyl-1-piperazinyl)dibenz b,f! 1,4!oxazepine; and

11-(2,5-dimethyl-1-piperazinyl)-dibenz b,f! 1,4!oxazepine.

11. The compound according to claim 10, wherein said compound is 8-chloro-11-(3,5-dimethyl-1-piperazinyl)-dibenz b,f! 1,4!oxazepine.

12. The compound according to claim 10, wherein said compound is 11-(2,5-dimethyl-1-piperazinyl)-dibenz b,f! 1,4! oxazepine.

13. A pharmaceutical composition, comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition, comprising a compound according to claim 10, and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition, comprising a compound according to claim 11, and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition, comprising a compound according to claim 12, and a pharmaceutically acceptable carrier.

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