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Claims for Patent: 5,859,006

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Claims for Patent: 5,859,006

Title: Tetracyclic derivatives; process of preparation and use
Abstract:A compound of formula (I) ##STR1## and salts and solvates thereof, in which: R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl; R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, haloC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkylC.sub.1-3 alkyl, arylC.sub.1-3 alkyl or heteroarylC.sub.1-3 alkyl; R.sup.2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR2## attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 and R.sup.3 together represent a 3- or 4-membered alkyl or alkenyl chain. A compound of formula (I) is a potent and selective inhibitor of cyclic guanosine 3', 5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having a utility in a variety of therapeutic areas where such inhibition is beneficial, including the treatment of cardiovascular disorders.
Inventor(s): Daugan; Alain Claude-Marie (Les Ulis, FR)
Assignee: ICOS Corporation (Bothell, WA)
Application Number:08/669,389
Patent Claims: 1. A compound of formula (I) ##STR20## or salts or solvates thereof, in which: R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl;

R.sup.1 represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, haloC.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkylC.sub.1-3 alkyl, arylC.sub.1-3 alkyl, wherein aryl is phenyl or phenyl substituted with one to three substituents selected from the Group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, methylenedioxy, and mixtures thereof, or heteroarylC.sub.1-3 alkyl, wherein heteroaryl is thienyl, furyl, or pyridyl, each optionally substituted with one to three substituents selected from the group consisting of halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, and mixtures thereof;

R.sup.2 represents an optionally substituted mono-cyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR21## attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R.sup.3 represents hydrogen or C.sub.1-3 alkyl, or R.sup.1 or R.sup.3 together represent a 3- or 4-membered alkyl or alkenyl chain component of a 5- or 6-membered ring.

2. A compound of formula (Ia) ##STR22## or salts or solvates thereof, in which: R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl;

R.sup.1 represents hydrogen, C.sub.1-6 alkyl, halo C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkylC.sub.1-3 alkyl, aryl C.sub.1-3 alkyl or heteroarylC.sub.1-3 alkyl; and

R.sup.2 represents an optionally substituted mono-cyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR23## attached to the rest of the molecule via one of the ben- zene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen.

3. A compound according to claim 1, wherein R.sup.0 represents hydrogen.

4. A compound according to any of claim 1, wherein R.sup.1 represents hydrogen, C.sub.1-4 alkyl, haloC.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 cycloalkylmethyl, pyridylC.sub.1-3 alkyl, furylC.sub.1-3 alkyl or optionally substituted benzyl.

5. A compound according to claim 1, wherein R.sup.1 and R.sup.3 together represent a 3-membered alkyl chain.

6. A compound according to claim 1, to wherein R.sup.3 represents hydrogen.

7. A compound according to claim 1, wherein R.sup.2 represents an optionally substituted benzene, thiophene, furan, pyridine or naphthalene ##STR24## where n is ring or an optionally substituted bicyclic ring 1 or 2 and X and Y are each CH.sub.2 or O.

8. A cis isomer of formula (I) represented by formula (Ib) ##STR25## and mixtures thereof with its cis optical enantiomer, including racemic mixtures, or salts or solvates of these compounds in which R.sup.0 is hydrogen or halogen and R.sup.1, R.sup.2 and R.sup.3 are as defined in claim 1.

9. A method of treating stable, unstable and variant angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, congestive heart failure, renal failure, atherosclerosis, conditions of reduced blood vessel patency, peripheral vascular disease, vascular disorders, inflammatory diseases, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility, in a human or non-human animal body, which method comprises administering to said body a therapeutically effective amount of a compound according claim 1.

10. A pharmaceutical composition comprising a compound of the according claim 1, together with a pharmaceutically acceptable diluent or carrier therefor.

11. 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.

12. Cis-2, 3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

Cis-2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyr azino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

Cis-2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2',1': 6,1]pyrido[3,4-b]indole-1,4-dione;

Cis-2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2',1':6,1] pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6(3,4-methlenedioxyphenyl)-p yrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopentyl-6-(3,4-methlenedioxyphenyl )-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)- pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-py razino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-py razino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2' ,1':6,1]pyrido[3,4-b]indole-1,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-[3,4]-methylenedioxyphenyl)-pyrazino[2 ',1':6,1]pyrido[3,4-b]indole-1,4-dione;

(5aR,12R,14aS)-1,2,3,5,6,11,12,14a-Octahydro-12-(3,4-methylenedioxyphenyl)- pyrrolo[1",2":4',5']pyrazino[2',1':6,1]pyrido[3,4-b]indole-5-1,4-dione;

or physiologically acceptable salts or solvates thereof.

13. (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-m ethylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione;

or physiologically acceptable salts or solvates thereof.

14. A process of preparing a compound of formula (I), wherein R.sup.3 represents hydrogen, which process comprises treating a compound of formula (II) ##STR26## in which Alk represents C.sub.1-6 alkyl and Hal is a halogen atom, with a primary amine R.sub.1 NH.sub.2 or the process as hereinbefore described followed by

i) an interconversion step; and/or either

ii) salt formation; or

iii) solvate formation.

15. Compounds of formulae (II).
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