Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-07-16
1999-01-12
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514250, 514292, 544343, 546 81, 546 85, A01N 4358, A01N 4342, C07D24136, C07D47100
Patent
active
058590064
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of Pct/EP filed on Jan. 19, 1995.
This invention relates to a series of tetracyclic derivatives, to processes for their preparation, pharmaceutical compositions containing them, and their use as therapeutic agents. In particular, the invention relates to tetracyclic derivatives which are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having utility in a variety of therapeutic areas where such inhibition is thought to be beneficial, including the treatment of cardiovascular disorders.
Thus, according to a first aspect, the present invention provides compounds of formula (I) ##STR3## and salts and solvates (e.g. hydrates) thereof, in which: R.sup.0 represents hydrogen, halogen or C.sub.1-6 alkyl; 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; selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR4## 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 together represent a 3- or 4- membered alkyl or alkenyl chain.
There is further provided by the present invention a subgroup of compounds of formula (I), the subgroup comprising compounds of formula (Ia) ##STR5## and salts and solvates (e.g. hydrates) thereof, in which: R.sup.0 represents hydrogen, halogen or C.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; and selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR6## 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.
Within R.sup.1 above, the term "aryl" as part of an arylC.sub.1-3 alkyl group means phenyl or phenyl substituted by one or more (e.g. 1, 2 or 3) substituents. selected from halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and methylenedioxy. The term "heteroaryl" as part of a heteroarylC.sub.1-3 alkyl group means thienyl, furyl or pyridyl each optionally substituted by one or more (e.g. 1, 2 or 3) substituents selected from halogen, C.sub.1-6 alkyl and C.sub.1-6 alkoxy. The term "C.sub.3-8 cycloalkyl" as a group or part of a C.sub.3-8 cycloalkylC.sub.1-3 alkyl group means a monocyclic ring comprising three to eight carbon atoms. Examples of suitable cycloalkyl rings include the C.sub.3-6 cycloalkyl rings cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Within R.sup.2 above, optional benzene ring substituents are selected from one or more (e.g. 1; 2 or 3) atoms or groups comprising halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, --CO.sub.2 R.sup.b, haloC.sub.1-6 alkyl, haloC.sub.1-6 alkoxy, cyano, nitro and NR.sup.a R.sup.b, where R.sup.a and R.sup.b are each hydrogen or C.sub.1-6 alkyl, or R.sup.a may also represent C.sub.2-7 alkanoyl or C.sub.1-6 alkylsulphonyl. Optional substituents for the remaining ring systems are selected from one or more (e.g. 1, 2 or 3) atoms or groups comprising halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy and arylC.sub.1-3 alkyl as defined above. The bicyclic ring ##STR7## may, for example, represent naphthalene, a heterocycle such as benzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline, indole, benzothiophene or benzofuran or ##STR8## (where n is an integer 1 or 2 and X and Y may each represent CH.sub.2, O, S or NH).
In the above definitions, the term "alkyl" as a group or part of a group means a straight chain or, where available, a branched chain alkyl moiety. For example, it may represent a C.sub.1-4 alkyl
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patent: 3717638 (1973-02-01), Schulenberg
patent: 3917599 (1975-11-01), Saxena et al.
Dellouve-Courillon et al., Tetrahedron, 46(9), 3245-66 (1990).
Brana et al., Synth Comm., 20(12), 1793-1810 (1990).
Saxena et al., Journal of Medicinal Chemistry, 16(5), 1973, 560-564.
Ishida et al., Chem. Pharm. Bull., 33(8), 1985, 3237-3249.
ICOS Corporation
Ngo Tamthom T.
Shah Mukund J.
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