Aminoacyl-containing dipeptide derivatives useful as antihypertensives

• US 4,555,502 A
• Filed: 09/30/1982
• Issued: 11/26/1985
• Est. Priority Date: 09/30/1982
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Patchett, Arthur A., Wu, Mu T.
• Primary Examiner(s): Phillips, Delbert R.
• Application Number:
  US06/425,133
• Time in Patent Office: 1,153 Days
• Field of Search: 260/239.3 T, 260/112.5 R, 548/492, 424/177, 514/19
• US Class Current: 514/16.2
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/60 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/06 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/54 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07K 5/0222 with the first amino acid being heterocyclic, e.g. Pro, Trp
• CPC Class Codes: Y10S 530/80 Antihypertensive peptides

Abstract

The invention relates to aminoacyl-containing dipeptide derivatives and related compounds which are useful angiotensin converting enzyme inhibitors and as antihypertensives.

Claims

1. A compound of the formula:

##STR44## wherein;

R and R₇ are independently hydrogen, loweralkyl, aryl, aralkyl;

R¹ is hydrogen;

alkyl of from 1-12 carbon atoms which include branched and unsaturated groups and cyclic groups of 3-9 carbon atoms;

substituted lower alkyl of 2-8 carbon atoms wherein the substituent(s) are halo, hydroxy, carboxy, carboxamido, loweralkylthio, loweralkoxy, loweralkoxycarbonyl, arylthio, aryloxy, aralkylthio, aralkyloxy, amino, loweralkylamino, diloweralkylamino, arylamino, arloweralkylamino, acylamino, acyl loweralkylamino, acyl arylamino, acyl aralkylamino, ═

O, ═

S or ureido;

benzofused cycloalkyl and bicycloalkyl of 8 to 12 carbon atoms which can be substituted by one or more of the foregoing substituents;

aryl, arloweralkyl, heteroaryl, heteroarloweralkyl, and those groups substituted by one or more of the foregoing substituents, the aryl or heteroaryl portions thereof being optionally mono-, di- or trisubstituted by halo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, substituted aminoloweralkyl, hydroxyloweralkyl, acylamino, carboxy, halolower alkyl, nitro, cyano or sulfonamido;

all of said foregoing substituents containing an aryl or heteroaryl group in which the aromatic rings are partially or completely hydrogenated;

n is 1 to 5;

r is 0 to 3;

R₂ is hydrogen, loweralkyl;

R₃ is hydrogen, aryl, hydroxyaryl, loweralkyl, loweralkyl substituted with aryl, carboxy, heteroaryl, amino, hydroxy, guanidino, alkylthio, mercapto, or alkyloxy;

R₄ and R₅ are independently hydrogen, loweralkyl;

or,

R₃ and R₅ can be joined to form a 5- to 6-membered ring having the formula;

##STR45## wherein V is --CH₂ CH₂ --, --CH₂ --, S, --CH(OR₂)-- and wherein R₂ is the same as defined above;

A is loweralkyl, C₃ -C₈ cycloalkyl;

C₈ -C₁₂ bicycloalkyl;

benzofused C₃ -C₈ cycloalkyl;

perhydrobenzofused C₃ -C₈ cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

perhydroheteroaryl, or perhydroheteroaralkyl;

all of which can be substituted by loweralkyl, loweralkoxy, halo, hydroxy, amino or acylamino;

B is hydrogen or loweralkyl;

or, A and B can be joined, together with the N and C atoms to which they are attached to form a ring having the formulae ##STR46## wherein;

X and Y taken together are --CH₂ --CH₂ --, ##STR47## wherein R₆ is hydrogen or loweralkyl;

R₉ is hydrogen;

lower alkyl;

cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

loweralkyloxy;

loweralkylthio;

aryloxy;

arylthio;

arloweralkyloxy;

arloweralkylthio;

acyloxy;

amino;

mono- or disubstituted loweralkylamino and arloweralkylamino;

heteroarloweralkylamino;

acylamino in which the acyl group can be loweralkanoyl, arloweralkanoyl, aroyl, heteroaroyl, heteroarloweralkanoyl;

carbamoyloxy;

or, N-substituted carbamoyloxy;

the aromatic ring in said foregoing substituents being optionally mono-, di- or trisubstituted by loweralkyl, loweralkoxy, hydroxy, amino, loweralkylthio, halo, lowerhydroxyalkyl, loweraminoalkyl, sulfonamido, cyano, nitro, aryl, aryloxy, arylthio, or aralkyl;

the aromatic rings in said groups containing aryl or heteroaryl groups being completely or partially hydrogenated;

R₁₀ is hydrogen;

loweralkyl;

aryl;

substituted aryl;

aralkyl;

or, cycloalkyl;

or R₉ and R₁₀ taken together can form a 5 or 6 membered ring which can contain 0, 1 or 2 S or O atoms;

p is 1 to 3;

q is 1 to 3;

W is absent;

--CH₂, or ##STR48## Z is --(CH₂)_m -- wherein m is 0 to 2 provided that m is not 0 when W is absent;

R₈ is hydrogen;

loweralkyl;

loweralkoxy;

hydroxy, halo;

loweralkylthio;

or, amino; and

, the pharmaceutically acceptable salts thereof.

2. A compound of claim 1 which is:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -glycyl-L-lysyl]-L-proline.

3. A compound of claim 1 which is:

N-[N² -(1-carboxy-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline.

4. A compound of claim 1 which is:

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline.

5. A compound of claim 1 which is:

N-[N² -(carboxy-3-phenylpropyl)-N³ -L-alanyl-L-2,3-diaminopropyl]-L-proline.

6. A compound of claim 1 which is:

N-[N² -(ethoxycarbonyl-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline.

7. A compound of claim 1 which is:

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -β

-alanyl-L-2,3-diaminopropyl]-L-proline.

8. A compound of claim 1 which is:

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline.

9. A compound of claim 1 which is:

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -methyl-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline.

10. A compound of claim 1 which is:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(2-methylalanyl)-L-lysyl]-L-proline.

11. A compound of claim 1 which is:

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -(2-methylalanyl)-L-2,4-diamino-n-butyryl]-L-proline.

12. A compound of claim 1 which is:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-phenylalanyl)-L-lysyl]-L-proline.

13. A compound of claim 1 which is:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-prolyl)-L-lysyl-L-proline.

14. A compound of claim 1 which is:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -sarcosyl-L-lysyl]-L-proline.

15. A compound of claim 1 which is:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline.

16. A composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and an antihypertensively effective amount of a compound of the formula:

##STR49## wherein;

R and R₇ are independently hydrogen, loweralkyl, aryl, aralkyl;

R¹ is hydrogen;

alkyl of from 1-12 carbon atoms which include branched and unsaturated groups and cyclic groups of 3-9 carbon atoms;

substituted lower alkyl of 2-8 carbon atoms wherein the substituent(s) are halo, hydroxy, carboxy, carboxamido, loweralkylthio, loweralkoxy, loweralkoxycarbonyl, arylthio, aryloxy, aralkylthio, aralkyloxy, amino, loweralkylamino, diloweralkylamino, arylamino, arloweralkylamino, acylamino, acyl loweralkylamino, acyl arylamino, acyl aralkylamino, ═

O, ═

S or ureido;

benzofused cycloalkyl and bicycloalkyl of 8 to 12 carbon atoms which can be substituted by one or more of the foregoing substituents;

aryl, arloweralkyl, heteroaryl, heteroarloweralkyl, and those groups substituted by one or more of the foregoing substituents, the aryl or heteroaryl portions thereof being optionally mono-, di- or trisubstituted by halo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, substituted aminoloweralkyl, hydroxyloweralkyl, acylamino, carboxy, halolower alkyl, nitro, cyano or sulfonamido;

all of said foregoing substituents containing an aryl or heteroaryl group in which the aromatic rings are partially or completely hydrogenated;

n is 1 to 5;

r is 0 to 3;

R₂ is hydrogen, loweralkyl;

R₃ is hydrogen, aryl, hydroxyaryl, loweralkyl, loweralkyl substituted with aryl, carboxy, heteroaryl, amino, hydroxy, guanidino, alkylthio, mercapto, or alkyloxy;

R₄ and R₅ are independently hydrogen, loweralkyl;

or,

R₃ and R₅ can be joined to form a 5- to 6-membered ring having the formula;

##STR50## wherein V is --CH₂ CH₂ --, --CH₂ --, S, --CH(OR₂)-- and wherein R₂ is the same as defined above;

A is loweralkyl, C₃ -C₈ cycloalkyl;

C₈ -C₁₂ bicycloalkyl;

benzofused C₃ -C₈ cycloalkyl;

perhydrobenzofused C₃ -C₈ cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

perhydroheteroaryl, or perhydroheteroaralkyl;

all of which can be substituted by loweralkyl, loweralkoxy, halo, hydroxy, amino or acylamino;

B is hydrogen or loweralkyl;

or, A and B can be joined, together with the N and C atoms to which they are attached to form a ring having the formulae ##STR51## wherein;

X and Y taken together are --CH₂ --CH₂ --, ##STR52## wherein R₆ is hydrogen or loweralkyl;

R₉ is hydrogen;

lower alkyl;

cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

loweralkyloxy;

loweralkylthio;

aryloxy;

arylthio;

arloweralkyloxy;

arloweralkylthio;

acyloxy;

amino;

mono- or disubstituted loweralkylamino and arloweralkylamino;

heteroarloweralkylamino;

acylamino in which the acyl group can be loweralkanoyl, arloweralkanoyl, aroyl, heteroaroyl, heteroarloweralkanoyl;

carbamoyloxy;

or, N-substituted carbamoyloxy;

the aromatic ring in said foregoing substituents being optionally mono-, di- or trisubstituted by loweralkyl, loweralkoxy, hydroxy, loweralkylthio, halo, lowerhydroxyalkyl, loweraminoalkyl, sulfonamido, cyano, nitro, aryl, aryloxy, arylthio, or aralkyl;

the aromatic rings in said groups containing aryl or heteroaryl groups being completely or partially hydrogenated;

R₁₀ is hydrogen;

loweralkyl;

aryl;

substituted aryl;

aralkyl;

or, cycloalkyl;

or R₉ and R₁₀ taken together can form a 5 or 6 membered ring which can contain 0, 1 or 2 S or O atoms;

p is 1 to 3;

q is 1 to 3;

W is absent;

--CH₂, or ##STR53## Z is --(CH₂)_m -- wherein m is 0 to 2 provided that m is not O when W is absent;

R₈ is hydrogen;

loweralkyl;

loweralkoxy;

hydroxy, halo;

loweralkylthio;

or, amino; and

,

the pharmaceutically acceptable salts thereof.

17. The composition of claim 16 wherein said compound is a member of the group:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -glycyl-L-lysyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline;

N-[N² -(carboxy-3-phenylpropyl)-N³ -L-alanyl-L-2,3-diaminopropyl]-L-proline;

N-[N² -(ethoxycarbonyl-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -β

-alanyl-L-2,3-diaminopropyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -methyl-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(2-methylalanyl)-L-lysyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -(2-methylalanyl)-L-2,4-diamino-n-butyryl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-phenylalanyl)-L-lysyl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-prolyl)-L-lysyl-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -sarcosyl-L-lysyl]-L-proline; and

,

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline.

18. A composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier;

an antihypertensively effective amount of a compound of the formula;

##STR54## wherein;

R and R₇ are independently hydrogen, loweralkyl, aryl, aralkyl;

R¹ is hydrogen;

alkyl of from 1-12 carbon atoms which include branched and unsaturated groups and cyclic groups of 3-9 carbon atoms;

substituted lower alkyl of 2-8 carbon atoms wherein the substituent(s) are halo, hydroxy, carboxy, carboxamido, loweralkylthio, loweralkoxy, loweralkoxycarbonyl, arylthio, aryloxy, aralkylthio, aralkyloxy, amino, loweralkylamino, diloweralkylamino, arylamino, arloweralkylamino, acylamino, acyl loweralkylamino, acyl arylamino, acyl aralkylamino, ═

O, ═

S or ureido;

benzofused cycloalkyl and bicycloalkyl of 8 to 12 carbon atoms which can be substituted by one or more of the foregoing substituents;

aryl, arloweralkyl, heteroaryl, heteroarloweralkyl, and those groups substituted by one or more of the foregoing substituents, the aryl or heteroaryl portions thereof being optionally mono-, di- or trisubstituted by halo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, substituted aminoloweralkyl, hydroxyloweralkyl, acylamino, carboxy, halolower alkyl, nitro, cyano or sulfonamido;

all of said foregoing substituents containing an aryl or heteroaryl group in which the aromatic rings are partially or completely hydrogenated;

n is 1 to 5;

r is 0 to 3;

R₂ is hydrogen, loweralkyl;

R₃ is hydrogen, aryl, hydroxyaryl, loweralkyl, loweralkyl substituted with aryl, carboxy, heteroaryl, amino, hydroxy, guanidino, alkylthio, mercapto, or alkyloxy;

R₄ and R₅ are independently hydrogen, loweralkyl;

or,

R₃ and R₅ can be joined to form a 5- to 6-membered ring having the formula;

##STR55## wherein V is --CH₂ CH₂ --, --CH₂ --, S, --CH(OR₂)-- and wherein R₂ is the same as defined above;

A is loweralkyl, C₃ --C₈ cycloalkyl;

C₈ --C₁₂ bicycloalkyl;

benzofused C₃ --C₈ cycloalkyl;

perhydrobenzofused C₃ --C₈ cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

perhydroheteroaryl, or perhydroheteroaralkyl;

all of which can be substituted by loweralkyl, loweralkoxy, halo, hydroxy, amino or acylamino;

B is hydrogen or loweralkyl;

or, A and B can be joined, together with the N and C atoms to which they are attached to form a ring having the formulae ##STR56## wherein;

X and Y taken together are --CH₂ --CH₂ --, ##STR57## wherein R₆ is hydrogen or loweralkyl;

R₉ is hydrogen;

lower alkyl;

cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

loweralkyloxy;

loweralkylthio;

aryloxy;

arylthio;

arloweralkyloxy;

arloweralkylthio;

acyloxy;

amino;

mono- or disubstituted loweralkylamino and arloweralkylamino;

heteroarloweralkylamino;

acylamino in which the acyl group can be loweralkanoyl, arloweralkanoyl, aroyl, heteroaroyl, heteroarloweralkanoyl;

carbamoyloxy;

or, N-substituted carbamoyloxy;

the aromatic ring in said foregoing substituents being optionally mono-, di- or trisubstituted by loweralkyl, loweralkoxy, hydroxy, loweralkylthio, halo, lowerhydroxyalkyl, loweraminoalkyl, sulfonamido, cyano, nitro, aryl, aryloxy, arylthio, or aralkyl;

the aromatic rings in said groups containing aryl or heteroaryl groups being completely or partially hydrogenated;

R₁₀ is hydrogen;

loweralkyl;

aryl;

substituted aryl;

aralkyl;

or, cycloalkyl;

or R₉ and R₁₀ taken together can form a 5 or 6 membered ring which can contain 0, 1 or 2 S or O atoms;

p is 1 to 3;

q is 1 to 3;

W is absent;

--CH₂, or ##STR58## Z is --(CH₂)_m --wherein m is 0 to 2 provided that m is not 0 when W is absent;

R₈ is hydrogen;

loweralkyl;

loweralkoxy;

hydroxy, halo;

loweralkylthio;

or, amino;

the pharmaceutically acceptable salts thereof; and

, an antihypertensive and/or diuretic compound selected from the group consisting of amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetate and cryptenamine tannates, deserpidine, diazoxide, ethacrynic acid, furosemide, guanethidene sulfate, hydralazine hydrochloride, hydrochlorothiazide, hydroflumethiazide, metolazone, metroprololtartate, methyclothiazide, methyldopa, methyldopate hydrochloride, minoxidil, (S)-1-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-3-{[4-(2-thienyl)-1H-imidazol-2-yl]phenoxy}-2-propanol, polythiazide, the pivalogloxyethyl ester of methyldopa, indacrinone and variable ratios of its enantiomers, nifedipine, verapamil, dilthiazam, flumethiazide, bendroflumethiazide, atenolol, (+)-4-{3-{-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl}propyl}benzoic acid, bumethanide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, spironolactone, timolol, trichlormethiazide, benzthiazide, quinethazone, tricrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, merethoxylline procaine, and the like, as well as admixtures and combinations thereof.

19. The composition of claim 18 wherein said antihypertensively effective compound is a member of the group:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -glycyl-L-lysyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline;

N-[N² -(carboxy-3-phenylpropyl)-N³ -L-alanyl-L-2,3-diaminopropyl]-L-proline;

N-[N² -(ethoxycarbonyl-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -β

-alanyl-L-2,3-diaminopropyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -methyl-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(2-methylalanyl)-L-lysyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -(2-methylalanyl)-L-2,4-diamino-n-butyryl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-phenylalanyl)-L-lysyl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-prolyl)-L-lysyl-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -sarcosyl-L-lysyl]-L-proline; and

,

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline.

20. A method of treating hypertension which comprises administering to a patient in need of such treatment an antihypertensively effective amount of a compound of the formula:

##STR59## wherein;

R and R₇ are independently hydrogen, loweralkyl, aryl, aralkyl;

R¹ is hydrogen;

alkyl of from 1-12 carbon atoms which include branched and unsaturated groups and cyclic groups of 3-9 carbon atoms;

substituted lower alkyl of 2-8 carbon atoms wherein the substituent(s) are halo, hydroxy, carboxy, carboxamido, loweralkylthio, loweralkoxy, loweralkoxycarbonyl, arylthio, aryloxy, aralkylthio, aralkyloxy, amino, loweralkylamino, diloweralkylamino, arylamino, arloweralkylamino, acylamino, acyl loweralkylamino, acyl arylamino, acyl aralkylamino, ═

O, ═

S or ureido;

benzofused cycloalkyl and bicycloalkyl of 8 to 12 carbon atoms which can be substituted by one or more of the foregoing substituents;

aryl, arloweralkyl, heteroaryl, heteroarloweralkyl, and those groups substituted by one or more of the foregoing substituents, the aryl or heteroaryl portions thereof being optionally mono-, di- or trisubstituted by halo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, substituted aminoloweralkyl, hydroxyloweralkyl, acylamino, carboxy, halolower alkyl, nitro, cyano or sulfonamido;

all of said foregoing substituents containing an aryl or heteroaryl group in which the aromatic rings are partially or completely hydrogenated;

n is 1 to 5;

r is 0 to 3;

R₂ is hydrogen, loweralkyl;

R₃ is hydrogen, aryl, hydroxyaryl, loweralkyl, loweralkyl substituted with aryl, carboxy, heteroaryl, amino, hydroxy, guanidino, alkylthio, mercapto, or alkyloxy;

R₄ and R₅ are independently hydrogen, loweralkyl;

or,

R₃ and R₅ can be joined to form a 5- to 6-membered ring having the formula;

##STR60## wherein V is --CH₂ CH₂ --, --CH₂ --, S, --CH(OR₂)-- and wherein R₂ is the same as defined above;

A is loweralkyl, C₃ -C₈ cycloalkyl;

C₈ -C₁₂ bicycloalkyl;

benzofused C₃ -C₈ cycloalkyl;

perhydrobenzofused C₃ -C₈ cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

perhydroheteroaryl, or perhydroheteroaralkyl;

all of which can be substituted by loweralkyl, loweralkoxy, halo, hydroxy, amino or acylamino;

B is hydrogen or loweralkyl;

or, A and B can be joined, together with the N and C atoms to which they are attached to form a ring having the formulae ##STR61## wherein;

X and Y taken together are --CH₂ --CH₂ --, ##STR62## wherein R₆ is hydrogen or loweralkyl;

R₉ is hydrogen;

lower alkyl;

cycloalkyl;

aryl;

aralkyl;

heteroaryl;

heteroaralkyl;

loweralkyloxy;

loweralkylthio;

aryloxy;

arylthio;

arloweralkyloxy;

arloweralkylthio;

acyloxy;

amino;

mono- or disubstituted loweralkylamino and arloweralkylamino;

heteroarloweralkylamino;

acylamino in which the acyl group can be loweralkanoyl, arloweralkanoyl, aroyl, heteroaroyl, heteroarloweralkanoyl;

carbamoyloxy;

or, N-substituted carbamoyloxy;

the aromatic ring in said foregoing substituents being optionally mono-, di- or trisubstituted by loweralkyl, loweralkoxy, hydroxy, loweralkylthio, halo, lowerhydroxyalkyl, loweraminoalkyl, sulfonamido, cyano, nitro, aryl, aryloxy, arylthio, or aralkyl;

the aromatic rings in said groups containing aryl or heteroaryl groups being completely or partially hydrogenated;

R₁₀ is hydrogen;

loweralkyl;

aryl;

substituted aryl;

aralkyl;

or, cycloalkyl;

or R₉ and R₁₀ taken together can form a 5 or 6 membered ring which can contain 0, 1 or 2 S or O atoms;

p is 1 to 3;

q is 1 to 3;

W is absent;

--CH₂, or ##STR63## Z is --(CH₂)_m -- wherein m is 0 to 2 provided that m is not 0 when W is absent;

R₈ is hydrogen;

loweralkyl;

loweralkoxy;

hydroxy, halo;

loweralkylthio;

or, amino; and

,

the pharmaceutically acceptable salts thereof.

21. The method of claim 20 wherein said compound is a member of the group:

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -glycyl-L-lysyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline;

N-[N² -(carboxy-3-phenylpropyl)-N³ -L-alanyl-L-2,3-diaminopropyl]-L-proline;

N-[N² -(ethoxycarbonyl-3-phenylpropyl)-N⁵ -glycyl-L-ornithyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -β

-alanyl-L-2,3-diaminopropyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N³ -methyl-N³ -glycyl-D,L-2,3-diaminopropyl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(2-methylalanyl)-L-lysyl]-L-proline;

N-[N² -(1-carboxy-3-phenylpropyl)-N⁴ -(2-methylalanyl)-L-2,4-diamino-n-butyryl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-phenylalanyl)-L-lysyl]-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -(L-prolyl)-L-lysyl-L-proline;

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁶ -sarcosyl-L-lysyl]-L-proline; and

,

N-[N² -(1(S)-carboxy-3-phenylpropyl)-N⁴ -glycyl-L-2,4-diamino-n-butyryl]-L-proline.