Cyclic GMP-specific phosphodiesterase inhibitors

• US 5,981,527 A
• Filed: 05/15/1998
• Issued: 11/09/1999
• Est. Priority Date: 07/14/1995
• Status: Expired due to Term

• Current Assignee: ICOS Corporation (Eli Lilly and Company)
• Original Assignee: ICOS Corporation (Eli Lilly and Company)
• Inventors: Daugan, Alain Claude-Marie, Gellibert, Francoise
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): RAO, DEEPAK R
• Application Number:
  US09/000,192
• Time in Patent Office: 543 Days
• Field of Search: 514/250, 544/343
• US Class Current: 514/250
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/14 Ortho-condensed systems

Abstract

A compound having the formula (I) ##STR1## and solvates thereof, wherein: R⁰ represents hydrogen, halogen or C_1-6 alkyl;

R¹ represents hydrogen or C_1-6 alkyl;

R² represents the bicyclic ring ##STR2## which may be optionally substituted by one or more groups selected from halogen and C_1-3 alkyl; and

R³ represents hydrogen or C_1-3 alkyl is disclosed.

The compounds are potent and selective inhibitors of cGMP-specific PDE, and are useful in a variety of therapeutic areas where such inhibition is beneficial.

Claims

1. A compound of formula (I) ##STR11## and solvates thereof, in which:

R⁰ represents hydrogen, halogen or C_1-6 alkyl;

R¹ represents hydrogen or C_1-6 alkyl;

R² represents the bicyclic ring;

##STR12## and R³ represents hydrogen or C_1-3 alkyl.

2. A compound according to claim 1 wherein R⁰ represents hydrogen.

3. A compound according to claim 1 wherein R¹ is selected from hydrogen, methyl, and iso-propyl.

4. A compound according to claim 1 wherein R³ represents hydrogen or methyl.

7. A process for preparing a compound according to claim 1 ##STR13## comprising hydrogenating a compound of formula (III) ##STR14## in which Alk is defined as above and Cbz represents a carbobenzyloxy group, in the presence of a catalyst in a suitable solvent such as an alcohol, at elevated temperature;

optionally followed by

i) an interconversion step; and

/or

iii) solvate formation.

8. A pharmaceutical composition comprising a compound according to claim 1, together with a pharmaceutically acceptable diluent or carrier therefor.

9. A process of preparing a pharmaceutical composition comprising a compound according to claim 1, which process comprises mixing said compound together with a pharmaceutically acceptable diluent or carrier therefor.

10. A method of treating conditions where inhibition of cGMP specific PDE is of therapeutic benefit, in a human or non-human animal body, which comprises administering to said body a therapeutically effective amount of a compound according to claim 1.

11. The method of claim 10 wherein the condition is erectile dysfunction.

12. The method of claim 11 wherein the animal body is human.

13. The method of claim 11 wherein the compound is administered orally.

5. (6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-2-methyl-pyrazino[2'"'"',1'"'"':

6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-pyrazino[2'"'"',1'"'"';

6,1]pyrido[3,4-b]indole-1,4-dione;

(3S,6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-3-methyl-pyrazino[2'"'"',1'"'"';

6,1]pyrido[3,4-b]indole-1,4-dione;

(3S,6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-2,3-dimethyl-pyrazino[2'"'"',1'"'"';

6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-2-isopropyl-pyrazino[2'"'"',1'"'"';

6,1]pyrido[3,4-b]indole-1,4-dione;

and physiologically acceptable solvates thereof.

6. (6R,12aR)-2,3,6,7,12,1 2a-Hexahydro-6-(5-benzofuranyl)-2-methyl-pyrazino[2'"'"',1'"'"':

6,1]pyrido[3,4-b]indole-1,4-dione.