Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-01-31
1997-01-07
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514258, 544116, 544119, 544279, A61K 31535, A61K 31435, C07D41314, C07D48702
Patent
active
055917429
DESCRIPTION:
BRIEF SUMMARY
This is the national stage under 35 U.S.C. .sctn.371(c) of Internal Application No. PCT/EP93/02097, having an international filing data of Aug. 4, 1993, which was oridingally filed Aug. 28, 1992 as Great Britain Patent Application No. 9218322.7.
This invention relates to a series of pyrido[3,2-d]pyrimidin-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 (Prinzmental) 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 characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
European patent application EP-A-0347146 discloses certain pyrido[3,2-d]pyrimidin-4-ones which, unlike the compounds of the present invention, contain a monosubstituted phenyl moiety at the 2-position of the said heterobicyclic system. These compounds are reported to be selective cGMP PDE inhibitors with bronchodilator and vasodilator activity of value in combatting asthma, bronchitis, angina, hypertension and congestive heart failure. The compounds of the present invention contain a 2,5-disubstituted phenyl moiety at the 2-position of the pyrido[3,2-d]pyrimidin-4-one bicyclic system and are significantly more potent cGMP PDE inhibitors than the previously mentioned prior art compounds.
The compounds of the present invention have the formula (I): ##STR2## and pharmaceutically acceptable salts thereof, wherein R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, CN or CONR.sup.4 R.sup.5 ; NHSO.sub.2 R.sup.8 or N(SO.sub.2 R.sup.8).sub.2 ; OH pyridyl 5-isoxazolin-3-onyl, morpholino or 1-imidazolidin-2-onyl; or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 1-pyrazolyl or 4-(NR.sup.10)-1-piperazinyl group wherein any of said groups may optionally be substituted with one or two substituents selected from C.sub.1 -C.sub.4 alkyl, CO.sub.2 R.sup.9, NH.sub.2 and OH; alkyl.
In the above definition, unless otherwise indicated, alkyl groups having three or more carbon atoms may be straight chain or branched chain.
The compounds of formula (I) may contain one or more asymmetric centres and thus they can exist as stereoisomers, i.e. as enantiomers or as diastereoisomers. The invention includes both mixtures thereof and the separated individual stereoisomers.
The compounds of formula (I) may also exist in tautomeric forms and the invention includes both mixtures thereof and the separated 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 sal
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Bell Andrew S.
Terrett Nicholas K.
Benson Gregg C.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
Ronau Robert T.
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