Phosphorus containing renin inhibitors

Details Phosphorus containing renin inhibitors Phosphorus containing renin inhibitors

1991-08-02

1995-11-21

Warden, Jill

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530800, 558170, 562 14, 562 15, 568 15, 564 12, 564 14, A61K 3800, C07F 902, C07F 922, C07F 936

Patent

active

054687322

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The proteolytic enzyme renin, which has a molecular weight of about 40,000, is produced in and secreted into the blood by the kidney. It is known to be active in vivo in cleaving the naturally-occurring plasma glycoprotein angiotensinogen, in the case of human angiotensinogen at the bond between the leucine (10th) and valine (11th) amino acid residues at the N-terminal end of the angiotensinogen: ##STR1## The circuiting N-terminal decapeptide (angiotensin I) formed by the above cleaving action of renin is subsequently broken down by the body to an octapeptide known as angiotensin II. Antiotensin II is known to be a potent pressor substance, i.e., a substance that is capable of inducing a significant increase in blood pressure, and is believed to act by causing the constriction of blood vessels and the release of the sodium-retaining hormone aldosterone from the adrenal gland. Thus, the renin-angiotensinogen system has been implicated as a causative factor in certain forms of hypertension and congestive heart failure.
One means of alleviating the adverse effects of the functioning of the renin-angiotensinogen system is the administration of a substance capable of inhibiting the angiotensinogen-cleaving action of renin. A number of such substances are known, including antirenin antibodies, pepstatin and naturally-occurring phospholipid compounds.
Dellaria et al. [Tetrahedron Lett. 2337 (1986)] describes the synthesis of several phosphonate esters as antihypertensive agents.
European Patent Application 249,445A published Dec. 16, 1987 claims a series of phosphonate antihypertensive agents which act as enzyme inhibitors.


SUMMARY OF THE INVENTION

It has now been found that certain phosphorous containing polypeptides are useful as renin-inhibiting agents and have application in the treatment of hypertension and congestive heart failure.
This series of novel compounds consists of peptides of the formula ##STR2## and a pharmaceutically acceptable salt thereof, wherein R.sub.1 is (CH.sub.3 O).sub.2 PO--, (CH.sub.2).sub.3 O.sub.2 PO-- or X--Y--, where X is morpholino, N-methylpiperazino, piperidino, pyrrolidin-1-yl, pyrrolyl, 3-oxopyrrolidin-1-yl, imidazolyl, cis-4-hydroxycyclohexyl, trans-4-hydroxycyclohexyl, acetylalkyl having three to six carbon atoms, alkyl having one to three carbon atoms, 4-oxopiperidino, 4-oxocyclohexyl, alkoxy having one to five carbon atoms or 4-hydroxypiperidino and Y is CH.sub.2 C.dbd.O or C.dbd.O; R.sub.2 is hydrogen or methoxy; R.sub.3 is alkyl having one to four carbon atoms, methoxyalkyl said alkyl having one to three carbon atoms, methylthioalkyl said alkyl having one to three carbon atoms, hydroxymethyl, imidazol-4-ylmethyl, methylsulfonylmethyl, methylsulfinylmethyl or carbamylethyl; R.sub.4 and R.sub.5 when considered separately are each alkyl having one to three carbon atoms, benzyloxy, alkoxy having one to four carbon atoms, dimethylamino or hydroxy; and R.sub.4 and R.sub.5 when taken together are alkylene having four to six carbon atoms, alkylenedioxy having three to four carbon atoms or mono- or dimethylalkylenedioxy having four to six carbon atoms.
A preferred group of compounds are those where R.sub.1 is X--Y-- where X is morpholino, Y is C.dbd.O, R.sub.2 is hydrogen and R.sub.3 is methylthioalkyl said alkyl having one to three carbon atoms. Especially preferred within this group are compounds where R.sub.3 is methylthiomethyl and R.sub.4 is methoxy and R.sub.5 is isopropoxy, where R.sub.4 and R.sub.5 together are butylene and where R.sub.4 and R.sub.5 together are propylenedioxy.
A second group of preferred compounds are those where R.sub.1 is X--Y-- where X is 4-oxopiperidino, Y is C.dbd.O, R.sub.2 is hydrogen and R.sub.3 is methylthioalkyl said alkyl having one to three carbon atoms. Especially preferred within this group are compounds where R.sub.3 is methylthiomethyl and R.sub.4 and R.sub.5 are each methoxy, where R.sub.4 and R.sub.5 together are propylenedioxy and where R.sub.4 and R.sub.5 together are pentylene.
A third group of preferr

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