Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1992-12-14
1995-02-28
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514257, 514267, 544115, 544230, 544245, 544247, 544251, 544252, A61K 3152, C07D48714
Patent
active
053937554
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
The present invention relates to polycyclic guanine derivatives useful for treating cardiovascular and pulmonary disorders, as well as to their pharmaceutical compositions and methods for using the same.
SUMMARY OF THE INVENTION
The present invention is directed to novel polycyclic guanine derivatives of the formula: ##STR2## wherein
J is oxygen or sulfur,
R.sup.1 is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;
R.sup.2 is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamino, or --(CH.sub.2).sub.m TCOR.sup.20 wherein m is an integer from 1 to 6, T is oxygen or --NH-- and R.sup.20 is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;
R.sup.3 is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl, cycloalkyl, aryl, aminosulfonyl, amino, monoalkylamino, dialkylamino, hydroxyalkylamino, aminoalkylamino, carboxy, alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino;
R.sup.a, R.sup.b, R.sup.c and R.sup.d independently represent hydrogen, alkyl, cycloalkyl or aryl; or (R.sup.a and R.sup.b) or (R.sup.c and R.sup.d) or (R.sup.b and R.sup.c) can complete a saturated ring of 5- to 7-carbon atoms, or (R.sup.a and R.sup.b) taken together and (R.sup.b and R.sup.c) taken together, each complete a saturated ring of 5- to 7-carbon atoms, wherein each ring optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following: alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or such saturated ring can have two adjacent carbon atoms which are shared with an adjoining aryl ring; and
n is zero or one.
Preferred compounds are those of formula (I). Preferably, J is O. Also preferred is that R.sup.1 is alkyl, more preferably methyl. For R.sup.2, preferred substituents include hydrogen, benzyl, 4-chlorobenzyl, cyclohexylmethyl and trimethylacetoxymethyl. For R.sup.3, preferred substituents include hydrogen and alkyl such as methyl or ethyl. Preferably n is zero. Also preferred is that (R.sup.a and R.sup.b) form a saturated 5 membered ring, that (R.sup.b and R.sup.c) form a saturated 5, 6 or 7 membered ring or (R.sup.a and R.sup.b) and (R.sup.b and R.sup.c) each can complete a saturated ring and each ring contains 5 or 6 carbon atoms. When (R.sup.b and R.sup.c) form a saturated 5, 6 or 7 membered ring, generally the preferred stereochemistry is (R) at the carbon atom bearing R.sup.b and the preferred stereochemistry is (S) at the carbon atom bearing R.sup.c.
The compounds of formulas (I) and (I') are useful as antihypertensive, bronchodilating and blood platelet inhibiting agents. Compounds (I) and (I') are also useful in inhibiting phosphodiesterase enzymes. The inhibition of vascular phosphodiesterase is believed to induce antihypertensive activity. Compounds (I) and (I') can also serve as smooth muscle relaxants and are therefore useful in the treatment of bronchoconstriction. Such compounds also can inhibit platelet function and are useful in treating conditions benefitting from inhibiting platelet function.
The present invention is also directed toward a pharmaceutical composition containing at least one of compounds (I) and (I') in an amount effective to inhibit phosphodiesterase or relax smooth muscle. The present invention is also directed toward a pharmaceutical composition containing an anti-hypertensive, a bronchodilating or a platelet inhibiting effective amount of the compounds (I) and (I').
The present invention is also directed toward a method for treating hypertension, bronchoconstriction or diseases benefitting from platelet inhibition in a mammal comprising administering to a mammal in need of such treatment an amount of at least one of compounds (I) and (I') effective to treat any of the above diseases. The present invention is also directed toward a method for ma
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Lindo Neil A.
Mc Kittrick Brian A.
Neustadt Bernard R.
Dicker Eric S.
Grumbling Matthew G.
Majka Joseph T.
Schering Corporation
Shah Mukund J.
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