Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1992-07-21
1994-11-08
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 25, 560 27, 560 39, 560 41, 562430, 562444, 562450, C07C31105, C07C31106, A61K 31215
Patent
active
053629027
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to a series of cycloalkyl-substituted glutaramide derivatives which are diuretic agents having utility in a variety of therapeutic areas including the treatment of various cardiovascular disorders such as hypertension, heart failure and renal insufficiency.
According to the specification of our European patent application EP-A-0274234 and our pending European patent application No 893051305, we describe and claim certain cycloalkyl-substituted glutaramide derivatives having an aminocycloalkanecarboxylate ring as diuretic agents. The present invention provides further related compounds in which the aminocycloalkanecarboxylate ring is replaced by a beta-alanine group or derivative thereof.
The compounds are inhibitors of the zinc-dependent, neutral endopeptidase E.C.3.4.24.11. This enzyme is involved in the breakdown of several peptide hormones, including atrial natriuretic factor (ANF), which is secreted by the heart and which has potent vasodilatory, diuretic and natriuretic activity. Thus, the compounds of the invention, by inhibiting the neutral endopeptidase E.C.3.4.24.11, can potentiate the biological effects of ANF, and in particular the compounds are diuretic agents having utility in the treatment of a number of disorders, including hypertension, heart failure, angina, renal insufficiency, premenstrual syndrome, cyclical oedema, Menieres disease, hyperaldosteronism (primary and secondary), pulmonary oedema, ascites, and hypercalciuria. In addition, because of their ability to potentiate the effects of ANF the compounds have utility in the treatment of glaucoma. As a further result of their ability to inhibit the neutral endopeptidase E.C.3.4.24.11, the compounds of the invention may have activity in other therapeutic areas including for example the treatment of asthma, inflammation, pain, epilepsy, affective disorders, dementia and geriatric confusion, obesity and gastrointestinal disorders (especially diarrhoea and irritable bowel syndrome), the modulation of gastric acid secretion and the treatment of hyperreninaemia and leukaemia.
SUMMARY OF THE INVENTION
The compounds of the present invention are of the formula: ##STR1## wherein A completes a 4 to 7 membered carbocyclic ring which may be saturated or mono-unsaturated and which may optionally be fused to a further saturated or unsaturated 5 or 6 membered carbocyclic ring; an alternative biolabile ester-forming group; -C.sub.6)alkyl, aryl(C.sub.2 -C.sub.6)alkenyl, aryl(C.sub.1 -C.sub.4)alkoxy(C.sub.1 -C.sub.4)alkyl, and hydroxy(C.sub.1 -C.sub.4)alkyl, or together with the carbon atom to which they are attached, form a 2-indanylidene group; and -C.sub.6 alkynyl, C.sub.3 -C.sub.7 cycloalkyl, or C.sub.7 cycloalkenyl, or -C.sub.6 alkoxy, C.sub.1 -C.sub.6 alkoxy(C.sub.1 -C.sub.6)alkoxy, C.sub.3 -C.sub.7 cycloalkyl, C.sub.7 cycloalkenyl, aryl, aryloxy, heterocyclyl, --NR.sup.6 R.sup.7, --NR.sup.8 COR.sup.9, --NR.sup.8 SO.sub.2 R.sup.10, --CONR.sup.6 R.sup.7 or R.sup.6 R.sup.7 N--(C.sub.1 -C.sub.6)alkoxy; or ##STR2## wherein R.sup.6 and R.sup.7 are each independently H, C.sub.1 -C.sub.4 alkyl, C.sub.3 -C.sub.7 cycloalkyl, aryl, aryl(C.sub.1 -C.sub.4)alkyl, C.sub.2 -C.sub.6 alkoxyalkyl, or heterocyclyl; or the two groups R.sup.6 and R.sup.7 are taken together with the nitrogen to which they are attached to form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N--(C.sub.1 -C.sub.4)alkyl-piperazinyl group; or R.sup.5 is a biolabile mono or di-ester derivative of S-lysylaminomethyl, N.sup.2 -acetyl acetyl-S-lysylaminomethyl or N.sup.2 -methanesulphonyl-S-lysylaminomethyl; -C.sub.4)alkyl, aryl(C.sub.1 -C.sub.4)alkoxy, heterocyclyl, C.sub.1 -C.sub.4 alkoxy or NR.sup.6 R.sup.7 wherein R.sup.6 and R.sup.7 are as previously defined; heterocyclyl; R.sup.16 R.sup.17 N--(CH.sub.2).sub.p --, or or by OH, C.sub.1 -C.sub.4 alkoxy, SH, SCH.sub.3, NH.sub.2, aryl(C.sub.1 -C.sub.6)alkyl--OCONH--, NH.sub.2 CO--, CO.sub.2 H, guanidino, aryl, or heterocyclyl; or the two groups R.sup.13 and R.sup.14 are joined togethe
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Barnish Ian T.
James Keith
Dees Jos,e G.
Frazier B.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
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