Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1991-10-01
1993-06-15
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
560 16, 560147, 560153, 562426, 549 71, 549468, 549469, 549484, 549486, 549 58, 549 76, 549 77, 549493, 549496, 546335, 514538, 514539, 514560, 514563, A61K 31258, C07C32110
Patent
active
052198863
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to mercapto-acylamino acids useful in the treatment of cardiovascular disorders and pain conditions.
Cardiovascular disorders which may be treated with compounds of the present invention include hypertension, congestive heart failure, edema and renal insufficiency.
Human hypertension represents a disease of multiple etiologies. Included among these is a sodium and volume dependent low renin form of hypertension. Drugs that act to control one aspect of hypertension will not necessarily be effective in controlling another.
Enkephalin is a natural opiate receptor agonist which is known to produce a profound analgesia when injected into the brain ventricle of rats. It is also known in the art that enkephalin is acted upon by a group of enzymes known generically as enkephalinases, which are also naturally occurring, and is inactivated thereby.
A variety of mercaptoacylamino acids are known as enkephalinase inhibitors useful as analgesics and in the treatment of hypertension. Most are alpha amino acids, however European Patent Application 136,883, published Apr. 10, 1985, and U.S. Pat. No. 4,774,256 disclose, inter alia, compounds of the formula ##STR2## wherein n is 1-15 and R.sub.2 and R.sub.3 are various aryl, arylalkyl and heteroarylalkyl groups. The compounds are disclosed as having enkephalinase inhibiting activity.
It has recently been discovered that the heart secretes a series of peptide hormones called atrial natriuretic factors (ANF) which help to regulate blood pressure, blood volume and the excretion of water, sodium and potassium. ANF were found to produce a short-term reduction in blood pressure and to be useful in the treatment of congestive heart failure. See P. Needleman et al, "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid, Electrolyte and Blood-Pressure Homeostasis", N. Engl. J. Med., 314, 13 (1986) pp. 828-834, and M. Cantin et al in "The Heart as an Endocrine Gland", Scientific American, 254 (1986) pg. 7681.
A class of drugs known to be effective in treating some types of hypertension is ACE inhibitors, which compounds are useful in blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the formation of angiotension II from angiotensin I. For a review of ACE inhibitors, see M. Wyvratt and A. Patchett, "Recent Developments in the Design of Angiotensin Converting Enzyme Inhibitors" in Med. Res. Rev. Vol. 5, No. 4 (1985) pp. 483-531.
SUMMARY OF THE INVENTION
Novel compounds of the present invention are represented by the formula ##STR3## wherein Q is hydrogen or R.sup.7 CO--; with hydroxy, lower alkoxy, mercapto, lower alkylthio, aryl or heteroaryl; aryl; or heteroaryl; that when R.sup.4 and R.sup.9 are both hydrogen, R.sup.2 is biphenylyl, phenoxyphenyl, phenylthiophenyl, naphthyl, heteroaryl, or lower alkyl substituted with hydroxy, lower alkoxy, mercapto or lower alkylthio; hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl and aryl lower alkyl, or R.sup.5 and R.sup.6 together with the nitrogen to which they are attached form a 5-7 membered ring; or heteroaryl;
A preferred group of compounds of the present invention is that wherein t is zero, with compounds wherein p and t are both zero being more preferred. Another group of preferred compounds is that wherein R.sup.4 is hydrogen, hydroxy, methoxy, phenyl or benzyl. Still another preferred group is that wherein R.sup.2 is hydrogen or thienyl. Preferred amino acid portions of the compounds of formula I (i.e. the portion --NH--CH(R.sup.2)--CH(R.sup.4)--(CH.sub.2).sub.t --(CHR.sup.9).sub.p --COR.sup.3) are those wherein p and t are each 0, R.sup.2 is hydrogen and R.sup.4 is hydroxy or methoxy (e.g. isoserine or O-methyl isoserine); those wherein t is 1, p is 0, R.sup.2 is hydrogen and R.sup.4 is hydroxy (e.g. homo-isoserine); those wherein p and t are each 0, R.sup.2 is thienyl and R.sup.4 is hydrogen (e.g. .beta.-thienyl-.beta.-alanine); and those wherein p and t are each 0, R.sup.2 is hydrogen and R.su
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DeCapite Philip M.
Neustadt Bernard R.
Smith Elizabeth M.
Dicker Eric S.
Magatti Anita W.
Raymond Richard L.
Russell Mark W.
Schering Corporation
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