Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-05-06
1996-01-09
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514259, 544116, 544284, 544289, C07D23991, C07D41341, A61K 31505, A61K 31535
Patent
active
054829410
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/EP92/02746 filed Nov. 27, 1992.
This invention relates to a series of quinazolin-4-ones, which are potent and selective inhibitors of cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE), having utility in a variety of therapeutic areas including the treatment of cardiovascular disorders such as angina, hypertension, heart failure and atherosclerosis.
The compounds of the invention exhibit selectivity for inhibition of cGMP PDEs rather than cyclic adenosine 3',5'-monophosphate phosphodiesterases (cAMP PDEs) and, as a consequence of this selective PDE inhibition, cGMP levels are elevated, which in turn can give rise to beneficial anti-platelet, anti-neutrophil, anti-vasospastic and vasodilatory activity, as well as potentiation of the effects of endothelium-derived relaxing factor (EDRF) and nitrovasodilators. Thus the compounds have utility in the treatment of a number of disorders, including stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and diseases characterized by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
European patent application EP-A-0371731 discloses a group of quinazolin-4-ones as selective cGMP PDE inhibitors with bronchodilator and vasodilator activity of value in combatting asthma, bronchitis, angina, hypertension and congestive heart failure, but they are less potent as cGMP PDE inhibitors than those compounds hereinafter described.
The compounds of the present invention have the formula (I): ##STR2## wherein R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy or CONR.sup.5 R.sup.6 ; NR.sup.7 R.sup.8, (hydroxy)C.sub.2 -C.sub.4 alkyl optionally substituted with NR.sup.7 R.sup.8, CH.dbd.CHCO.sub.2 R.sup.9, CH.dbd.CHCONR.sup.7 R.sup.8, CH.sub.2 CH.sub.2 CO.sub.2 R.sup.9, CH.sub.2 CH.sub.2 CONR.sup.7 R.sup.8, SO.sub.2 NR.sup.7 R.sup.8, SO.sub.2 NH(CH.sub.2).sub.n NR.sup.7 R.sup.8 or imidazolyl; together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino or 4-(NR.sup.10)-1-piperazinyl group wherein any of said groups is optionally substituted with CONR.sup.5 R.sup.6 ; and alkyl or C.sub.1 -C.sub.4 alkoxy; and pharmaceutically acceptable salts thereof.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms may be straight chain or branched chain.
In addition, alkanoyl groups having four carbon atoms may be straight chain or branched chain.
The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as enantiomers or diastereoisomers. Furthermore certain compounds of formula (I) which contain alkenyl groups may exist as cis- or trans-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
The pharmaceutically acceptable salts of the compounds of formula (I) which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with organo-carboxylic acids, or with organo-sulphonic acids. Compounds of formula (I) can also provide pharmaceutically acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts.
A preferred group of compounds of formula (I) is that wherein R.sup.1 is H, methyl, methoxy or CONR.sup.5 R.sup.6 ; R.sup.2 is H or methyl; R.sup.3 is ethyl or n-propyl; R.sup.4 is H, acetyl optionally substituted with NR.sup.7
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Koizumi, Masuo et al., 4(3H)-Quinazolinones, Chem. Abstracts, 87:201571g (1977).
Benson Gregg C.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
Ronau Robert T.
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