Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-23
1997-12-16
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142285, 5142328, 514248, 514253, 544 60, 544115, 544237, 544238, 544251, A61K 31505, A61K 31535, C07D48702, C07D41702
Patent
active
056985606
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/60497, filed Mar. 1, 1996.
1. Technical Field
The present invention relates to imidazoquinazoline derivatives or pharmaceutically acceptable salts thereof which have the cyclic guanosine 3',5'-monophosphate (cGMP)-specific phosphodiesterase (PDE) inhibitory activity and are useful for treating or ameliorating cardiovascular diseases such as thrombosis, angina pectoris, hypertension, heart failure, arterial sclerosis, as well as asthma and the like.
2. Background Art
cGMP plays an important role as a second messenger in intracellular signal transduction. An inhibitor of cGMP-specific PDE, an enzyme which degrades cGMP, increases the concentration of intracellular cGMP, enhances the effects of endothelium-derived relaxing factor (EDRF), nitro vasodilator or atrial natriuretic peptide, shows the antiplatelet activity, the anti-vasocontraction activity and the vasodilating activity, and are useful for treating angina pectoris, hypertension, congestive heart failure, post-PTCA restenosis, peripheral vascular diseases, bronchitis, chronic asthma, allergic asthma, allergic gravedo, glaucoma, alimentary canal diseases such as irritable intestine syndrome, and the like.
The PDE inhibitory activity and the adenosine receptor antagonistic Med. Chem., 29, 972 (1986), J. Med. Chem., 32, 2247 (1989), J. Org. Chem., 51, 616 (1986) and the references cited therein. However, these compounds are neither particularly strong PDE inhibitors nor selective cGMP-specific PDE inhibitors. are disclosed in EP635507.
The PDE inhibitors known so far inhibit not only cGMP-specific PDE but also the cyclic adenosine 3',5'-monophosphate (cAMP) PDE which is an enzyme similar thereto, and therefore cause the elevation of the concentration of cAMP as well as intracellular cGMP and may cause side effects and the like. Further, the inhibitory activities thereof are not yet sufficient, and compounds which are more potent and selective are expected and desired.
DISCLOSURE OF THE INVENTION
The present invention relates to imidazoquinazoline derivatives compounds of other formula numbers! represented by formula (I): ##STR2## wherein R.sup.1 represents hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heteroaryl, R.sup.2 and R.sup.3 represent independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heteroaryl, or R.sup.2 and R.sup.3 are combined to represent a substituted or unsubstituted heterocyclic group containing a nitrogen atom, R.sup.4 represents hydrogen or substituted or unsubstituted lower alkyl, X represents O or S, Y represents a single bond or O, n represents 0, 1, 2, or 3, or pharmaceutically acceptable salts thereof.
In the definitions of the groups of formula (I), the lower alkyl means a straight-chain or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, sec-pentyl, hexyl, isohexyl, heptyl, octyl, and isooctyl. The cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The lower alkenyl means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, propenyl, methacryl, butenyl, crotyl, pentenyl, and hexenyl. The aralkyl means an aralkyl group having 7 to 15 carbon atoms, such as benzyl, phenethyl, benzhydryl, and naphthylmethyl. The aryl means phenyl and naphthyl, and the heteroaryl means pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, triazolyl, tetrazolyl, benzothienyl, be
REFERENCES:
Schneller et al., J. Med. Chem., vol. 29, No. 6 (1986) 972-78.
Schneller et al., J. Med. Chem., vol. 32, No. 10 (1989) 2247-54.
Stevenson et al., J. Org. Chem., vol. 51, No. 5 (1986) 616-20.
Ichimura Michio
Kase Hiroshi
Machii Daisuke
Ohno Tetsuji
Onoda Yasuo
Coleman Brenda
Kyowa Hakko Kogyo Co. Ltd.
Shah Mukund J.
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