E. R. Squibb Sons, Inc.

Squibb & Sons, Inc.

Weller, Harold N., Iii

Gordon, Eric M.

Delaney, Norma G.

Norma G Delaney

Eric M Gordon

Miguel A Ondetti

George C Rovnyak

Melanie J Loots

Jollie D Godfrey, Jr

David W Cushman

Harold N Weller, Iii

Harold Norris Weller, Iii

Jack M DeForrest

Jack M Deforrest

Diuresis, natriuresis, and the lowering of blood pressure are produced in a host by administering one or more neutral endopeptidase inhibitors. An additional blood pressure lowering agent such as an angiotensin converting enzyme inhibitor can be administered along with the neutral endopeptidase inhibitor.

Inhibitors of neutral endopeptidase

Compounds of the formula ##STR1## wherein Z is ##STR2## proline, pipecolic acid, an indolecarboxylic acid or an isoquinolinecarboxylic acid. These compounds are useful as cardiovascular agents.

Trifluoromethyl mercaptan and mercaptoacyl derivatives and method of

Compounds of the formula ##STR1## wherein m is zero or 1; n is zero, 1 or 2; p is zero or 1 to 6 provided that m and p are not both zero; R.sub.3 is hydrogen, acyl, or benzyl; and R.sub.1 is hydrogen, alkyl, phenyl, substituted phenyl, phenyl-alkylene, heterocyclic-alkylene, etc. These compounds are useful as cardiovascular agents.

Compounds of the formula ##STR1## wherein Y can be tetrazolyl are disclosed. These compounds are useful as cardiovascular agents.

3,3,3-trifluoro-2-mercaptomethyl-N-tetrazolyl substituted propanamides

Compounds of the formula ##STR1## wherein Y is O or NH and X is ##STR2## will inhibit the action of neutral endopeptidase. As a result, such compounds produce diuresis, natriuresis, and lower blood pressure as well as being useful in the treatment of congestive heart failure, relieving pain, and diarrhea when administered to a mammalian host.

Phosphonate and phosphonamide endopeptidase inhibitors

Acylmercaptoalkanoyl compounds of the formula ##STR1## wherein n is an integer from one to fifteen possess enkephalinase inhibition activity and are useful as analgesic agents.

Certain [(lower alkanoyl-thio)methyl-1-oxo-3-phenyl propyl amino]benzene

Mercaptoalkanoyl and acylmercaptoalkanoyl compounds of the formula ##STR1## wherein n is an integer from one to fifteen possess enkephalinase inhibition activity and are useful as analgesic agents.

Use of enkephalinase inhibitors as analgesic agents

Enkephalinase inhibitors

Aminopeptidase inhibitory activity is exhibited by compounds having the formula ##STR1## and pharmaceutically acceptable salts thereof, wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, carboxyalkyl, halo-substituted alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylthioalkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, arylalkyl, carbamoylalkyl, guanidinylalkyl or heteroaryl;

Aminopeptidase inhibitors

An enkephalin-degrading aminopeptidase enzyme is inhibited by compounds having the formula ##STR1## and pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, carboxyalkyl, halo substituted alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylthioalkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, arylalkyl, carbamoylalkyl, guanidinylalkyl, or heteroaryl;

Use of diamino alcohols as analgesic agents

Analgesic and hypotensive activity is exhibited by compounds having the formula ##STR1## and pharmaceutically acceptable salts thereof, wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, carboxyalkyl, halo substituted alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylthioalkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, arylalkyl, carbamoylalkyl, guanidinylalkyl, or heteroaryl;

Amino thiol peptides

An enkephalin-degrading aminopentidase enzyme is inhibited by compounds having the formula ##STR1## and pharmaceutically acceptable salt thereof, wherein R.sub.1 and R.sub.2 are each independently hydrogen, alkyl, carboxyalkyl, halo substituted alkyl, hydroxyalkyl, aminoalkyl, mercaptoalkyl, alkylthioalkyl, (cycloalkyl)alkyl, (heteroaryl)alkyl, arylalkyl, carbamoylalkyl, guanidinylalkyl, or heteroaryl;

Use of diamino ketones as analgesic agents

Compounds of the formula ##STR1## wherein A is a cycloalkyl ring, a substituted cycloalkyl ring, a phenyl ring, or a substituted phenyl ring and ##STR2## are various dipeptide groups are disclosed. The compounds possess angiotensin converting enzyme inhibition activity and depending upon the terminal amino acid may also possess enkephalinase inhibition activity.

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Princeton, NJ, United States of America

Norma G Delaney