ARYL AND HETEROARYL TETRAHYDROBENZAZEPINE DERIVATIVES AND THEIR USE FOR TREATING GLAUCOMA

• US 20070293475A1
• Filed: 06/12/2007
• Published: 12/20/2007
• Est. Priority Date: 06/20/2006
• Status: Abandoned Application

• Current Assignee: Alcon Research Limited (Nestle SA)
• Original Assignee: Alcon Manufacturing Limited (Alcon Incorporated)
• Inventors: Hellberg, Mark R., Feng, Zixia, Mohapatra, Suchismita
• Application Number:
  US11/761,493
• Publication Number:
  US 20070293475A1
• Time in Patent Office: Days
• US Class Current: 514/217.01
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: C07D 223/16 Benzazepines; Hydrogenated benzazepines

Abstract

Aryl tetrahydrobenzazepine derivatives with minimal 5-HT_2B activity relative to 5-HT_2A and 5-HT_2C activity that are useful for treating glaucoma are disclosed.

Claims

1. A method for lowering or controlling intraocular pressure in a warm-blooded mammal'"'"'s eye, which comprises administering to the mammal a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula A:

2. The method of claim 1 wherein for the compound of formula A R₁═

H;

R₂═

OH, or OR, where R═

C_1-4 alkyl;

R⁴, R⁵═

H or C₁ alkyl;

R⁶, R⁷═

H or C₁ alkyl;

when R⁴ or R⁵═

C₁ alkyl, then R⁶═

R⁷═

H;

when R⁶ or R⁷═

C₁ alkyl, then R⁴═

R⁵═

H;

R⁸═

C_1-4 alkyl; and

Ar=phenyl, optionally mono- or di-substituted with F, Cl, Br, C_1-2 alkyl, OH, or OR⁸.

3. The method of claim 1 wherein the compound is selected from the group consisting of:

7-(3-Methoxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine fumarate;

8-(4-Hydroxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol hydrobromide; and

pharmaceutically acceptable salts thereof.

4. The method of claim 1 wherein the mammal is a human, the is composition is a topically administered ophthalmic composition, and the pharmaceutically effective amount of the compound is 0.01-5% (w/v).

5. The method of claim 4 wherein the pharmaceutically effective amount of the compound is 0.1-2% (w/v).

6. A method for treating glaucoma in a mammal, which comprises administering to the mammal a composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula A:

7. The method of claim 6 wherein for the compound of formula A R₁═

H;

R₂═

OH, or OR, where R═

C_1-4 alkyl;

R⁴, R⁵═

H or C₁ alkyl;

R⁶, R⁷═

H or C₁ alkyl;

when R⁴ or R⁵═

C₁ alky, then R⁶═

R⁷═

H;

when R⁶ or R⁷═

C₁ alkyl, then R⁴═

R⁵═

H;

R⁸═

C_1-4 alkyl; and

Ar=phenyl, optionally mono- or di-substituted with F, Cl, Br, C₁₂ alkyl, OH, or OR⁸.

8. The method of claim 6 wherein the compound is selected from the group consisting of:

7-(3-Methoxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine fumarate;

8-(4-Hydroxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol hydrobromide; and

pharmaceutically acceptable salts thereof.

9. The method of claim 6 wherein the mammal is a human, the composition is a topically administered ophthalmic composition, and the pharmaceutically effective amount of the compound is 0.01-5% (w/v).

10. The method of claim 9 wherein the pharmaceutically effective amount of the compound is 0.1-2% (w/v).

11. A compound of the formula:

12. The compound of claim 11 wherein R═

C₁ alkyl.

13. The compound of claim 11 selected from the group consisting of:

7-(3-Methoxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine fumarate;

8-(4-Hydroxy-benzyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol hydrobromide; and

pharmaceutically acceptable salts thereof.