WO1991005796A1

WO1991005796A1 - Carboxyalkyl dipeptide inhibitors of endopeptidases

Info

Publication number: WO1991005796A1
Application number: PCT/US1990/005640
Authority: WO
Inventors: Martin F. Haslanger; Bernard R. Neustadt; Elizabeth M. Smith
Original assignee: Schering Corporation
Priority date: 1989-10-13
Filing date: 1990-10-10
Publication date: 1991-05-02
Also published as: EP0495822A1; AU6503390A; JPH05501247A; CA2069312A1

Abstract

Carboxyalkyl dipeptide inhibitors of endopeptidases of formula (I) or pharmaceutically acceptable salt thereof, wherein R1 is H, alkyl, arylalkyl or aryl; R2 is H, alkyl, alkenyl or alkynyl, wherein the alkyl portion is substituted with 0-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkoxyalkoxy, alkylthio, aryl, alkoxyalkylthio, arylalkoxy and arylalkylthio; R?3 and R4¿ are independently alkyl or arylalkyl; or R?3 and R4¿ together with the carbon to which they are attached form an optionally substituted 5-, 6- or 7-membered ring wherein said ring comprises 0 to 1 heteroatoms selected from the group consisting of sulfur and oxygen; R5 is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkoxyalkyl or arylalkylthioalkyl; R6 is hydroxy, alkoxy, or R5; R7 is hydroxy, alkoxy, aryloxy, arylalkoxy, amino, alkylamino or dialkylamino; m is 0 or 1; and n is 0, 1, 2, or 3, use of the compounds, alone or in combination with an ACE inhibitor or an ANF, in the treatment of cardiovascular disorders such as hypertension, congestive heart failure, edema and renal insufficiency, use of the compounds in the treatment of pain conditions, and pharmaceutical compositions containing said compounds are disclosed.

Description

CARBOXYALKYL DIPEPTIDE

INHIBITORS OF ENDOPEPTIDASES

BACKGROUND OF THE INVENTION

The present invention relates to carboxyalkyl dipeptide inhibitors of endopeptidases useful in the treatment of cardiovascular disorders and pain

conditions.

Cardiovascular conditions 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 as enkephalinases or endopeptidases, which are also naturally occurring, and is inactivated thereby.

A variety of compounds are known as

endopeptidase inhibitors useful as analgesics and/or in the treatment of hypertension. For example, European Patent Application 274,234, published July 13, 1988, discloses, inter alia, spiro-substituted glutaramide diuretic compounds of the formula

wherein R⁵ in the cited patent may be a variety of alkyl or amino derivatives or a heterocyclic.

U.S. Patent 4,513,009, issued April 23, 1985, discloses, inter alia, alpha amino acid derivatives of the formula

wherein R¹ is preferably hydrogen or phenyl and R² is preferably hydrogen, alkyl, benzyl or benzyloxyalkyl. The compounds are said to have enkephalinase inhibiting and hypotensive activity.

U.S. Patent 4,610,816, issued September 9, 1986, discloses, inter alia, substituted dipeptide enkephalinase- inhibitors of the formula

wherein R¹ and R³ are preferably phenylethyl and R⁴ is preferably hydrogen, methyl or benzyl.

Similarly, German Patent Application 3,819,539, published December 22, 1988, discloses, inter alia, carboxyalkyl compounds of the formula

wherein R₁ and R₈ are preferably benzyl and R₅ is preferably hydrogen or lower alkyl.

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

Homostasis", 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. 76-81.

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 angiotensin 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

wherein R¹ is H, alkyl, arylalkyl or aryl;

R² is H, alkyl, alkenyl or alkynyl, wherein the alkyl portion is substituted with 0-3 substituents

independently selected from the group consisting of hydroxy, alkoxy, alkoxyalkoxy, alkylthio, aryl,

alkoxyalkylthio, arylalkoxy and arylalkylthio;

R³ and-R⁴ are independently alkyl or arylalkyl; or R³ and R⁴ together with the carbon to which they are attached form a 5-, 6- or 7-membered ring wherein said ring comprises 0 to 1 heteroatoms selected from the group consisting of sulfur and oxygen, wherein said ring is unsubstituted or is substituted on a carbon atom ring member by an alkyl or aryl group, or wherein said ring is substituted by a fused benzene ring;

R⁵ is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkoxyalkyl or arylalkylthioalkyl;

R⁶ is H, hydroxy, alkoxy, alkyl, alkoxyalkyl,

alkylthioalkyl, arylalkoxyalkyl, arylalkylthioalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;

R⁷ is hydroxy, alkoxy, aryloxy, arylalkoxy, amino, alkylamino or dialkylamino;

m is 0 or 1;

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

A preferred group of compounds of the present invention is that wherein R² is arylalkyl, especially phenylethyl. Another preferred group is that wherein R³ and R⁴ together with the carbon to which they are

attached form a 5-, 6- or 7-membered ring, especially a carbocyclic ring; especially preferred is a 5-membered ring. Still another preferred group in that wherein R⁵ is hydrogen, R⁶ is hydroxy, m is 1 and n is zero. Other preferred compounds of formula I are those wherein R¹ is hydrogen or benzyl. Similarly, R⁷ is preferably hydroxy, ethoxy or benzyloxy.

The invention also relates to the treatment of cardiovascular diseases with a combination of a

carboxyalkyl dipeptide of the present invention and an atrial natriuretic factor (ANF) or with a combination of a carboxyalkyl dipeptide of the present invention and an angiotensin converting enzyme (ACE) inhibitor.

Other aspects of the invention relate to pharmaceutical compositions comprising a carboxyalkyl dipeptide of this invention, alone or in combination with an ANF or an ACE inhibitor, and to methods of treatment of cardiovascular diseases comprising administering a carboxyalkyl dipeptide of this invention, alone or in combination with an ANF or an ACE inhibitor, to a mammal in need of such treatment.

Still another aspect of this invention relates to a method of treating pain conditions by administering a carboxyalkyl dipeptide of this invention, thereby inhibiting the action of endopeptidases in a mammal and eliciting an analgesic effect. Analgesic pharmaceutical compositions comprising said carboxyalkyl dipeptide compounds are also contemplated.

DETAILED DESCRIPTION

As used herein, the term "alkyl" means straight or branched lower alkyl chains of 1 to 6 carbon atoms; "alkenyl" similarly means lower alkenyl chains of 2 to 6 carbon atoms; "alkynyl" means lower alkynyl chains of 2 to 6 carbon atoms; and "alkoxy" similarly means lower alkoxy chains of 1 to 6 carbon atoms.

"Aryl" means a phenyl or. naphthyl ring; a phenyl or naphthyl ring substituted with 1-3 substituents selected from the group consisting of alkyl, hydroxy. alkoxy, halo, trifluoromethyl, phenyl, phenoxy and phenylthio; or a phenyl ring wherein adjacent alkyl or alkyl and alkoxy substituents form a 5- or 6-membered ring (for example indanyl, dihydrobenzofuranyl,

1,2,3,4-tetrahydronaphthyl and isochromanyl).

"Heteroaryl" means mono-cyclic or fused ring bicyclic aromatic groups having 5 to 10 ring members wherein 1-2 ring members are independently selected from the group consisting of oxygen, nitrogen and sulfur and wherein 1-3 carbon ring members may be substituted with substituents as defined above for aryl. Examples of heteroaryl groups are furanyl, thienyl, pyrrolyl, benzofuranyl, thianaphthenyl, indolyl and pyridyl.

All positional isomers of the aryl and heteroayl groups are contemplated, e.g. 2-pyridyl and 3- pyridyl, α-naphthyl and β-naphthyl.

Halo means fluoro, chloro, bromo or iodo radicals.

Compounds of the invention can form

pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art.

Certain compounds of the invention are acidic e.g., those compounds which possess a carboxyl group.

These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium and aluminum salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxy alkyl amines, N-methylglucamine and the like. The salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is

insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.

Compounds of formula I have at least one asymmetrical carbon atom and therefore include various stereoisomers. The invention includes all such isomers both in pure form and in admixture, including racemic mixtures.

An aspect of the present invention described above relates to the combination of a compound of formula I with an ANF. As indicated by Needleman et al., a number of ANF have been isolated so far, all having the same core sequence of 17 amino acids within a cysteine disulfide bridge, but having different N-termini

lengths. These peptides represent N-terminal truncated fragments (21-48 amino acids) of a common preprohormone (151 and 152 amino acids for man and rats, respectively). Human, porcine and bovine carboxy-terminal 28-amino acid peptides are identical and differ from similar peptides in rats and mice in that the former contain a methionine group at position 12 while the latter contain

isoleucine. Various synthetic analogs of naturally occurring ANF's also have been found to have comparable biological activity. Examples of ANF's contemplated for use in this invention are α human AP 21 (atriopeptin I), o human AP 28, α human AP 23 (atriopeptin II or APII), a human AP 24, α human AP 25, α human AP 26, o human AP 33, and the corresponding rat sequence of each of the above wherein Met 12 is lie. See Table 1 for a comparison of the peptides.

* lle is the rat p eptide

Another aspect of the invention is the administration of a combination of an ACE inhibitor and a compound of formula I.

Examples of ACE inhibitors are those disclosed in the article by Wyvratt et al., cited above, and in the following U.S. patents: U.S. Patents 4,105,776,

4,468,519, 4,555,506, 4,374,829, 4,462,943, 4,470,973, 4,470,972, 4,350,704, 4,256,761, 4,344,949, 4,508,729, 4,512,924, 4,410,520 and 4,374,847, all incorporated herein by reference; and the following foreign patents or published patent applications:

British Specification No. 2095682 published October 6, 1982 discloses N-substituted-N-carboxyalkyl amino carboxyl alkyl glycine derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula

either

(A) R^b and R₉ ^b are OH, 1-6C alkoxy, 2-6C alkonyloxy, di-(1-6C alkyl) amino- (1-6C) alkoxy, 1-6C hydroxy alkoxy, acylamino-(1-6C) alkoxy, acyloxy-(1-

6C) alkoxy, aryloxy, aryloxy-(1-6C)alkoxy, NH₂, mono- or di-(1-6C alkyl)amino, hydroxy amino or aryl-(1-

6C)alkylamino;

R₇ ^b-R₅ ^b, R₇ ^b and R₈ ^b are 1-20C alkyl, 2-20C alkonyl,

2-20C alkynyl, aryl, aryl-(1-6C) alkyl having 7-12C or heterocyclyl-(1-6C) alkyl having 7-12C;

R₆ ^b is cycloalkyl, polycycloalkyl, partly saturated cycloalkyl or polycycloalkyl, cycloalkyl- (1-6C) alkyl having 3-20C, 6-10C aryl, aryl-(1-6C) alkyl, aryl-(2-

6C)alkenyl or aryl-(2-6C) alkynyl; or

R₂ ^b and R₃ ^b together with the C and N atoms to which they are attached or R₃ ^b and R₅ ^b together with the N and C atoms to which they are attached form an N- heterocycle containing 3-5C or 2-4C and a S atom; all alkyl, alkonyl and alkynyl are optionally substituted by OH, 1-6C alkoxy, thio(sic), 1-6C alkylthio, NH₂, mono- or di(1-6C alkyl) amino, halogen or NO₂;

all 'cycloalkyl' groups (including poly and

partially unsaturated) are optionally substituted by halogen, 1-6C hydroxy alkyl, 1-6C alkoxy, amino-(1-

6C alkyl) amino, di-(1-6C alkyl)amino, SH, 1-6C alkylthio, NO₂ or CF₃; and

aryl groups are optionally substituted by OH, 1-6C alkoxy, NH₂, mono- or di-(1-6C alkyl) amino, SH, 1-

6C alkylthio, 1-6C hydroxy alkyl, 1-6C aminoalkyl, 1-6C thioalkyl, NO₂, halogen, CF₃, OCH₂O, ureido or guanidino; or

(B) R^b and R₉ ^b are H or 1-6C alkoxy;

R₁ ^b and R₂ ^b are H, 1-6C alkyl, aryl-(1-6C) alkyl having 7-12C or heterocyclyl-(1-6C) alkyl having 6-

12C;

R₃ ^b-R₅ ^b, R₇ ^b and R₈ ^b are H or 1-6C alkyl;

R₆ ^b is cycloalkyl, polycycloalkyl, partly saturated cycloalkyl or polycycloalkyl, cycloalkyl-(1-6C) alkyl having 3-20C, aryl or aryl-(1-6C) alkyl; and aryl has 6-10C and is optionally substituted by 1-6C alkyl, 2-6C alkonyl, 2-6C alkynyl, OH, 1-6C alkoxy,

NH₂, mono- or di-(1-6C alkyl) amino, SH, 1-6C alkylthio, 1-6C hydroxy alkyl, 1-6C aminoalkyl, 1-6C thioalkyl, NO₂, halogen, CF₃, OCH₂O, ureido or guanidino;

European Patent Application 0 050 800 published May 5, 1982 discloses carboxy alkyl dipeptides

derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula

or a pharmaceutically acceptable salt thereof, wherein R^c and R^6c are the same or different and are hydroxy, lower alkoxy, lower alkonyloxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxy amino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy; R^1c is hydrogen, alkyl of from 1 to 10 carbon atoms,

substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, lower alkoxy carboxyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy, aralkylthio group is substituted with a group selected from halo, lower alkyl, hydroxy, lower alkoxy, amino, aminomethyl,

carboxyl, cyano, or sulfamoyl; R^2c and R^7c are the same or different and are hydrogen or lower alkyl; R^3c is hydrogen, lower alkyl, phenyl lower alkyl,

aminoethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkyl thio lower alkyl; R^4c and R^5c are the same or different and are hydrogen, lower alkyl or Z^c, or R^4c and R taken together form a group represented by Q^c, U^c,

Y^c, D^c or E^c, wherein;

is

wherein X^1c and X^2c independent of each other are O, S or CH₂, R^8c and R^9c independent of each other are lower alkyl, lower alkonyl, lower alkynyl, cycloalkyl having 3 to 8 carbon atoms, hydroxy lower alkyl, or -(CH₂)_n ^cAr^c, wherein n^c is 0, 1, 2 or 3 and Ar^c is unsubstituted or substituted phenyl, furyl, thienyl or pyridyl, wherein said substituted phenyl, furyl, thienyl or pyridyl groups are substituted with at least one group that is

independently selected from C₁ to C₄ alkyl, lower alkoxy, lower alkylthio, halo, CF₃ and hydroxy, or R^8c and R^9c taken together form a- bridge W^c , wherein W^c is a single bond or a methylene bridge or a substituted methylene bridge when at least one of X^1c and X^2c is methylene, or W^c is an alkylene or substituted alkylene bridge having 2 or 3 carbon atoms, said substituted methylene bridge or said substituted alkylene bridge having one or two substituents selected from lower alkyl, aryl and aryl lower alkyl groups, and p^c is 0, 1 or 2; with the proviso that at least one of R^4c and R^5c is Z^c, with the proviso that if R^4c is Z^c and p^c is 0 then X^1c and X^2c must both be methylene, and with the proviso that if X^1c and X^2c are both methylene then R^8c and R^9c must form an alkylene bridge W^c;

Q^c is

wherein R^8c, R^9c, X^1c and X^2c are as defined above, p^c is 0, 1 or 2, q^c is 0, 1 or 2, with the proviso that the sum of p^c and q^c must be 1, 2 or 3, with the proviso that if p^c is 0 then X^1c and X^2c must be methylene, and with the proviso that if X^1c and X^2c are methylene then R^8c and R^9c taken together form a bridge W^c, wherein W^c is as defined above; is

wherein R^8c, R^9c, X^1c and X^2c are as defined above, p^c is 0, l or 2 and q^c is 0, 1 or 2, with the proviso that the sum of p^c and q^c is 1, 2 or 3, with the proviso that if X^1c and X^2c are CH₂ then R^8c and R^9c taken together form a bridge W^c, wherein W^c is as defined above;

U^c is

wherein W^c is as defined above (except that W^c may also be a methylene bridge when X^1c and X^2c are oxygen or sulfur), X^1c and X^2c are as defined above, p^c is 0, 1 or 2, q^c is 0, 1 or 2, with the proviso that the sum of p^c and q^c is 1 or 2, and with the proviso that if p^c is 0, X^1c must be CH₂;

Y^c is

wherein G^c is oxygen, sulfur or CH₂, a^c is 2, 3 or 4 and b^c is 1, 2, 3, 4 or 5, with the proviso that the sum of a^c and b^c is 5, 6 or 7 or

G^c is CH₂, a^c is 0, 1, 2 or 3, b^c is 0, 1, 2 or 3 with the proviso that the sum of a^c and b^c is 1, 2 or 3, with the proviso that the sum of a^c and b^c may be 1, 2 or 3 only if R^1c is lower alkyl substituted with aralkylthio or aralkyloxy;

D^c is

wherein F^c is 0 or S,-j^c is 0, 1 or 2 and k^c is 0, 1 or 2, with the proviso that the sum of j^c and k^c must be 1, 2 or 3, and m^c is 1, 2 or 3 and t^c is 1, 2 or 3, with the proviso that the sum of m^c and t^c must be 2, 3 or 4;

is

wherein L^c is 0 or S, u^c is 0, 1 or 2 and v^c is 0, 1 or 2, with the proviso that the sum of u^c and v^c must be 1 or 2, and h^c is 1 or 2 and s^c is 1 or 2, with the proviso that the sum of h^c and s^c must be 2 or 3; European Patent Application 0 079 522 published May 25, 1983 discloses N-carboxymethyl(amidino) lysyl- proline compounds which are said to be angiotensin converting enzyme inhibitors and have the formula where <

wherein:

R^d and R^2d are independently hydrogen; loweralkyl; aralkyl; or aryl;

R¹ is hydrogen; branched or straight chain C_1-12 alkyl and alkonyl; C₃-C₉ cycloalkyl and benzofused alkyl; substituted loweralkyl where the substituents are halo, hydroxy loweralkoxy, aryloxy, amino, mono- or diloweralkylamino, acylamino, arylamino,

guanidino, mercapto, loweralkylthio, arylthio, carboxy, carboxamido, or loweralkoxycarbonyl; aryl; substituted aryl where the substituents are

loweralkyl, loweralkoxy, or halo; arloweralkyl;

arloweralkenyl; heteroarloweralkyl;

heteroarloweralkenyl; substituted arloweralkyl, substituted arloweralkenyl, substituted

heteroarloweralkyl, or substituted

heteroarloweralkenyl where the aryl and heteroaryl substituents are halo, dihalo, loweralkyl, hydroxy, loweralkoxy, amino, aminoloweralkyl, acylamino. mono- or diloweralkylamino, carboxyl,

haloloweralkyl, nitro, cyano, or sulfonamido, and where the loweralkyl portion of arloweralkyl may be substituted by amino, acylamino, or hydroxyl;

where:

X^d and Y^d taken together are -CH₂-CH₂-;

R^4d is hydrogen; loweralkyl; aryl; substituted aryl; R^5d is hydrogen; loweralkyl; aryl or substituted aryl; n^d is 1 to 3;

W^d is absent; -CH₂-; or

Z^d is -(CH₂)_m ^d, where m^d is 0 to 2, provided that m^d may not be 0 and W^d may not be absent at the same time; and

R^6d is hydrogen; loweralkyl; halo; or OR^4d;

R^2d is ^___ (CH₂)_r ^d____B^{d ___}(CH₂)_s ^{d ____}NR^7dR^15d where

r^d and s^d are independently 0 to 3;

B^d is absent; -O-; -S-; or -NR^8d;

where R^8d is hydrogen; loweralkyl; alkanoyl; or aroyl; and

R^7d is

where

R^9d is loweralkyl; aralkyl; aryl; heteroaryl; or

heteroarloweralkyl and these groups substituted by hydroxy, lower alkoxy or halo; carboxyl;

carboxamido; nitromethenyl.

R^10d is hydrogen; loweralkyl; aryl; or amidino;

R^11d hydrogen; loweralkyl; cyano; amidino; aryl; aroyl; loweralkanoyl; NHR^13d;

OR^13d- - NO₂; -SO₂NH₂;

or

SO₂R^13d;

R^12d is hydrogen; loweralkyl; halo; aralkyl; amino; cyano; mono- or diloweralkylamino; or OR^4d;

R^13d is hydrogen; loweralkyl; or aryl;

R^15d is hydrogen; lower alkyl; aralkyl; or aryl;

constitute a basic heterocycle of 5 or 6 atoms or benzofused analogs thereof and optionally containing 1-3 N atoms, an oxygen, a sulfur, an S=O, or an SO₂ group optionally substituted by amino, lower alkyl amino, diloweralkyl amino, lower alkoxy, or aralkyl groups;

R^3d is C_3-8 cycloalkyl and benzofused C_3-8 cycloalkyl; perhydrobenzofused C_3-8 cycloalkyl; aryl;

substituted aryl; heteraryl; substituted heteroaryl;

R^14d is hydrogen or loweralkyl; and, a pharmaceutically acceptable salt thereof;

European Patent 79022 published May 18, 1983 discloses N-amino acyl-azabicyclooctane carboxylic acid derivatives which have the formula

hydrogen atoms at ring positions 1 and 5 are cis to each other and the 3-carboxy group has the endo orientation;

R₁ ^e is H, allyl, vinyl or the side chain of an optionally protected naturally occurring α-amino acid;

R₂ ^e is H, 1-6C alkyl, 2-6C alkonyl or aryl(1-4C alkyl);

Y^e is H or OH and Z^e is H, or Y^e and Z^e together oxygen;

X^e is 1-6C alkyl, 2-6C alkonyl, 5-9C cycloalkyl, 6-

12C aryl (optionally substituted by one to three 1- 4C alkyl or alkoxy, OH, halo, nitro, amino

(optionally substituted by one or two 1-4C alkyl), or methylenedioxy) or indol-3-yl);

European Patent 46953 published March 10, 1982 discloses N-amino acyl-indoline and tetrahydro

isoquinoline carboxylic acids which are angiotensin coverting enzyme inhibitors and have the formula

n^f is 0 or 1; is a benzene or cyclohexane ring:

R₁ ^f and R₂ ^f are each 1-6C alkyl, 2-6C alkonyl, 5-7C cycloalkyl, 5-7C cycloalkenyl, 7-12C

cycloalkylalkyl, optionally partially hydrogenated 6-10C aryl, 7-14C aralkyl or 5-7 membered monocyclic or 8-10 membered bicyclic heterocyclyl containing 1 or 2 S or O and/or 1-4N atoms; all R₁ ^f and R₂ ^f groups are optionally substituted,

R₃ ^f is H, 1-6C alkyl, 2-6C alkonyl or 7-14C aralkyl

The following Table II lists ACE inhibitors preferred fo use in the combination of this invention.

The compounds of the present invention can be produced by methods known to those skilled in the art, for example by one or more of the methods and subroutes described below. Reactive groups not involved in the condenε tions described below, e.g., amino, carboxy, etc., may be protected by methods standard in peptide chemistry prior to the coupling reactions and subsequently deprotected to obtain the desired products. In the formulae in the following description of the processes, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above for Formula I, including suitable

protection where applicable.

Process A: For the preparation of compounds of formula I, a ketoester (II) is condensed with a dipeptide (III) in the presence of a reducing agent:

The ketoester (II) can be condensed with the dipeptide (III) in aqueous solution, optimally near neutrality, or in a suitable organic solvent (for example, CH₃OH) in the presence of a reducing agent such as sodium

cyanoborohydride to give directly the desired compound I. Alternatively, the intermediate Schiff base, enamine, or aminol may be catalytically reduced to yield product I, for example, by hydrogen in the presence of palladium on carbon (e.g. 10% palladium on carbon) or of Raney nickel. The ratio of diastereomeric products formed may be altered by choice of catalyst.

Process B: A dipeptide (III) can be alkylated by means of a compound IV:

wherein X is chloro, bromo, iodo, alkylsulfonyloxy, including haloalkylsulfonyloxy (e.g. CF₃SO₂O-) or arylsulfonyloxy. The reaction can be carried out under basic conditions in water or in an organic solvent.

Process C: An aminoacid V can be condensed with an aminoacid VI

This reaction is well known from peptide chemistry. The reaction can be carried out in the presence of a

condensing agent such as dicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA) or N,N-disuccinimidyl carbonate in an inert solvent such as CH₃CN. While, as mentioned above, reactive groups are protected before the coupling reaction is carried out, the carboxy group of compound V can be activated via the intermediacy of active esters such as that derived from

1-hydroxybenzotriazole, its mixed anhydride (derived from a chlorocarbonic acid ester) or its azide.

The starting compounds in this reaction are known compounds and/or can be prepared according to known methods. The compound of formula V can, for example, be prepared by reacting a keto compound II with an amino ester VII:

wherein R⁸ is an ester protecting group such as t-butyl, according to the conditions described in process A.

Alternatively, compound V can be prepared by condensing VII and IV:

under the conditions described for process B above (the radical X being as defined in process B).

It is evident that a compound of formula I obtained by any one of processes A to C can be

transformed into another compound of formula I by methods known in the art.

The above processes can be followed by removing protecting groups by known methods. Protected carboxy groups e.g. when -OR¹ and R⁷ are for example alkoxy

(methoxy, ethoxy, tert. butyloxy), nitrobenzyloxy or benzyloxy, are deprotected by hydrolysis or

hydrogenation. For example, reductive cleavage of a benzyl ester of formula I (where R⁷ is benzyloxy and R¹ is alkyl) will yield compounds of formula I wherein R¹ is alkyl and R⁷ is hydroxy, and compounds wherein R⁷ is alkoxy and R¹ is benzyl will yield compounds of formula I wherein R¹ is hydrogen and R⁷ is alkoxy.) Hydrolysis can be carried out under acidic conditions (using e.g. a halogen hydracid or trifluoroacetic acid) or under basic conditions. The amino group(s) can be protected by

protecting groups such as, for example, formyl,

t-butoxycarbonyl, carbobenzyloxy and triphenylmethyl.

These groups can be removed under acidic conditions, e.g. by means of a halogen hydracid and/or trifluoroacetic acid.

We have found that the novel compounds of the present invention are effective in treating

cardiovascular disorders such as congestive heart

failure, edema, renal insufficiency and various types of hypertension, particularly volume expanded

hypertension. These novel compounds enhance both the magnitude and duration of the antihypertensive and natriuretic effects of endogenous ANF. Administration of a combination of a carboxyalkyl dipeptide and an ACE inhibitor provides an antihypertensive effect greater than either the carboxyalkyl dipeptide or ACE inhibitor alone. Administration of a combination of a carboxyalkyl dipeptide of formula I and an exogenous ANF or ACE inhibitor is therefore particularly useful in treating hypertension.

In addition to the compound aspect, the present invention therefore also relates to treating

cardiovascular disorders with a carboxyalkyl dipeptide of formula I or with a carboxyalkyl dipeptide of formula I in combination with an ANF or an ACE inhibitor, which methods comprise administering to a mammal in need of such treatment an amount of the carboxyalkyl dipeptide or an amount of a combination of a carboxyalkyl dipeptide and ANF or ACE inhibitor effective to treat hypertension, congestive heart failure, edema or renal insuffiency.

The drug or combination of drugs is preferably

administered in a pharmaceutically acceptable carrier, e.g. for oral or parenteral administration. The

combinations of drugs may be co-administered in a single composition, or components of the combination therapy may be administered separately. Where the components are administered separately, any convenient combination of dosage forms may be used, e.g. oral carboxyalkyl

dipeptide/oral ANF, oral carboxyalkyl dipeptide/

parenteral ACE inhibitor, parenteral carboxyalkyl

dipeptide/oral ANF, parenteral carboxyalkyl

dipeptide/parenteral ACE inhibitor.

When the components of a combination of a carboxyalkyl dipeptide and an ANF are administered separately, it is preferred that the carboxyalkyl

dipeptide be administered first.

The present invention also relates to a

pharmaceutical composition comprising a carboxyalkyl dipeptide for use in treating hypertension, congestive heart failure, edema or renal insufficiency, to a

pharmaceutical composition comprising both a carboxyalkyl dipeptide and an ANF and to a pharmaceutical composition comprising both a carboxyalkyl dipeptide and an ACE inhibitor.

The antihypertensive effect of carboxyalkyl dipeptides was determined according to the following procedure:

Male Sprague Dawley rats weighing 100-150 g were anesthetized with ether and the right kidney was removed. Three pellets containing DOC acetate

(desoxycorticosterone acetate, DOCA, 25 mg/pellet) were implanted subcutaneously. Animals recovered from

surgery, were maintained on normal rat chow and were allowed free access to a fluid of 1% NaCl and 0.2% KCl instead of tap water for a period of 17-30 days. This procedure results in a sustained elevation in blood pressure and is a slight modification of published procedures (e.g. Brock et al., 1982) that have been used to produce DOCA salt hypertension in the rat. On the day of study, animals were again

anesthetized with ether and the caudal artery was cannulated for blood pressure measurement. Patency of the caudal artery cannula was maintained with a

continuous infusion of dextrose in water at a rate of 0.2 ml/hr. Animals were placed into restraining cages where they recovered consciousness. Blood pressure was

measured from caudal artery catheter using a Statham pressure transducer attached to a Beckman oscillographic recorder. In addition, a cardiovascular monitoring device (Buxco Electronics, Inc.) and a digital computer were used to calculate average blood pressures.

After an equilibration period of at least 1.5 hr., animals were dosed subcutaneously (1 ml/kg) with vehicle (methylcellulose, hereinafter MC) or carboxyalkyl dipeptide and blood pressure was monitored for the next 4 hours.

A similar procedure can be used to determine the effect of carboxyalkyl dipeptide in combination with ACE inhibitors.

The antihypertensive effect of carboxyalkyl dipeptides in combination with ANF can be determined according to the following procedures:

Male spontaneously hypertensive rats (SHR), 16- 18 weeks old, 270-350 g, are anesthetized with ether and the abdominal aorta is cannulated through the tail artery. The animals are then placed into restrainers to recover from anesthesia (in less than 10 min.) and remain inside throughout the experiments. Through a pressure transducer (Gould P23 series) analog blood pressure signals are registered on a Beckman 612 recorder. A Buxco digital computer is used to obtain mean arterial pressures. Patency of the arterial cannula is maintained with a continuous infusion of 5% dextrose at 0.2 ml/hr. Animals are allowed a 90-min equilibration period. The animals first undergo a challenge with an ANF such as atriopeptin II (AP II) or AP28 30 μg/kg iv and at the end of 60 min. are treated with drug vehicle or a

carboxyalkyl dipeptide subcutaneously. A second ANF challenge is administered 15 min. later and blood

pressure is monitored for the next 90 min.

The antihypertensive effect in SHR of

carboxyalkyl dipeptides and ACE inhibitors, alone and in combination, can be determined as follows:

Animals are prepared for blood pressure measurement as described above. After stabilization, animals are dosed subcutaneously or orally with test

drugs or placebo and blood pressure is monitored for the next 4 hr.

The compounds having structural formula I have also been found to inhibit the activity of enzymes

designated enkephalinases. The compounds are particularly useful for the inhibition of enkephalinase A, which is derived from the striata of both rats and humans. In in vitro tests, using test procedures for enkephalinase A inhibition well known to those skilled in the art, selected compounds having structural formula I have been found to inhibit the activity of the aforementioned enzyme.

Therefore, the present invention also relates to a method of inhibiting the action of enkephalinases in a mammal thereby to elicit an analgesic effect with a compound of formula I, and to analgesic pharmaceutical compositions comprising compounds of formula I.

The compositions of this invention comprise a carboxyalkyl dipeptide or a carboxyalkyl dipeptide and an ANF or a carboxyalkyl dipeptide and an ACE inhibitor in combination with a pharmaceutically acceptable carrier for administration to mammals. A variety of

pharmaceutical forms is suitable, preferably for oral or parenteral administration, although mechanical delivery systems such as transdermal dosage forms are also contemplated.

The daily dose of the compound or combinations of this invention for treatment of hypertension,

congestive heart failure, edema or renal insufficiency is as follows: for carboxyalkyl dipeptides alone the typical dosage is 1 to 100 mg/kg of mammalian weight per day administered in single or divided dosages; for the combination of carboxyalkyl dipeptide and an. ANF, the typical dosage is 1 to 100 mg of carboxyalkyl

dipeptide/kg mammalian weight per day in single or divided dosages plus 0.001 to 0.1 mg ANF/kg of mammalian weight per day, in single or divided dosages, and.for the combination of carboxyalkyl dipeptide and an ACE

inhibitor, the typical dosage is 1 to 100 mg of

carboxyalkyl dipeptide/kg mammalian weight per day in single or divided dosages plus 0.1 to 30 mg ACE

inhibitor/kg of mammalian weight per day in single or divided dosages. The exact dose of any component or combination to be administered is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient.

Generally, in treating humans having hypertension, congestive heart failure, edema or renal insufficiency, the compounds or combinations of this invention may be administered to patients in a dosage range as follows: for treatment with carboxyalkyl

dipeptides alone, about 10 to about 500 mg per dose given 1 to 4 times a day, giving a total daily dose of about 10 to 2000 mg per day; for the combination of carboxyalkyl dipeptide and ANF, about 10 to about 500 mg carboxyalkyl dipeptide per dose given 1 to 4 times a day and about 0.001 to about 1 mg ANF given 1 to 6 times a day (total daily dosage range of 10 to 2000 mg day and .001 to 6 mg/day, respectively); and for the combination of a carboxyalkyl dipeptide and an ACE inhibitor, about 10 to about 500 mg carboxyalkyl dipeptide per dose given 1 to 4 times a day and about 5 to about 50 mg ACE inhibitor given 1 to 3 times a day (total daily dosage range of 10 to 2000 mg/day and 5 to 150 mg/day, respectively). Where the components of a combination are administered

separately, the number of doses of each component given per day may not necessarily be.the same, e.g. where one component may have a greater duration of activity, and will therefore need to be administered less frequently.

To produce an analgesic effect, compounds of this invention will be administered .in a dosage range of from about 1 to about 100 mg/kg. The doses are to be administered at intervals of from 3 to 8 hours. However, the quantity and frequency of dosage will depend upon such factors as the severity of the pain, the general physical condition of the patient, the age and weight of the patient, and other factors recognized by the skilled clinician.

Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions. Typical injectable formulations include solutions and

suspensions.

The typical acceptable pharmaceutical carriers for use in the formulations described above are

exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol, starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate;

calcium sufate; polyvinylpyrrolidone, polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate, stearic acid. vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene gylcol polymers; beta- cyclodextrin; fatty alcohols and hydrolyzed cereal solids; as well as other nontoxic compatible fillers, binders, disintegrants, buffers, preservatives, anti- oxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations.

Since the present invention relates to treatment of hypertension with a combination of active ingredients wherein said active ingredients may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. That is, two kits are contemplated, each combining two separate units: a carboxyalkyl dipeptide

pharmaceutical composition and an ANF pharmaceutical composition in one kit and a carboxyalkyl dipeptide pharmaceutical composition and an ACE inhibitor

pharmaceutical composition in a second kit. The kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals.

PREPARATION 1

2 (R)-TRIFLUOROMETHANESULFONYLOXY-4 PHENYLBUTYRIC ACID BENZYL ESTER

Step A: 2(R)-Acetoxy-4-Phenylbutyric Acid: Add sodium nitrite (15.5 g) portionwise to 2(R)-amino-4- phenylbutyric acid (10. Og) in glacial acetic acid (560 ml) over 2 hours. Stir the reaction mixture for 1 hour and concentrate in vacuo. Partition the residue between water and diethyl ether. Dry (MgSO₄) and concentrate the ether in vacuo to obtain an amber oil,

[α]²⁶ _D=+12.1° (MeOH).

Step B: 2 (R)-Hydroxy-4-Phenylbutyric Acid: At 0°C, treat the product of step A (11.4 g) in methanol (100 ml) with 2N NaOH (52 ml), warm the resulting mixture to room termperature, and stir for 20 hours. Concentrate the reaction mixture in vacuo and partition with water and ethyl acetate. Acidify the aqueous solution with

concentrated hydrochloric acid and extract with ethyl acetate. Dry (MgSO₄) and concentrate the ethyl acetate solution in vacuo to obtain a light tan solid, m.p. 104- 105°C, [α]²⁶ _D=-6.7°(MeOH).

Step C: 2 (R)-Hydroxy-4-Phenylbutyric Acid Benzyl Ester: Treat the product of step B (9.71 g) in dimethylformamide (85 ml) with cesium carbonate (18.1 g) and benzyl

chloride (6.5 ml) at room temperature for 18 hours.

Concentrate the reaction mixture in vacuo and partition between ethyl acetate and water. Dry (MgSO₄) and

concentrate the ethyl acetate solution in vacuo to obtain a yellow oil. Chromatograph this oil on silica gel (2000 ml) using dichloromethane as eluant. Concentrate the fractions containing the desired compound to obtain a pale yellow oil, [α]²⁶ _D=+0.4° (MeOH).

Step D: 2(R)-Trifluoromethanesulfonyloxy-4-Phenylbutyric Acid Benzyl Ester: At -22°C, add

trifluoromethanesulfonic anhydride (2.71 ml) to a

solution of pyridine (1.35 ml) in dichloromethane (30 ml) (dried over Molecular sieves 4 A). After 15 minutes, add the product of step C (4.35 g) in dichloromethane (30 ml) and stir for 15 minutes. Quench the reaction mixture with IN HCl and extract the mixture with

dichloromethane. Extract the dichloromethane solution with saturated NaHCO₃ solution. Dry (MgSO₄) and concentrate the dichloromethane solution in vacuo to obtain a light amber oil.

PREPARATION 2

1-AMINOCYCLOPENTANE-1-CARBOXYLIC ACID t-BUTYL ESTER

Step A: 1-(N-Benzyloxycarbonylamino)Cyclopentane-1- Carboxylic Acid t-Butyl Ester: Suspend 1-(N- benzyloxycarbonylamino) cyclopentane-1-carboxylic acid (2.0 g) in dichloromethane (25 ml) in a pressure bottle and cool to 0-5°C. Add concentrated H₂SO₄ (0.4 ml) and cool to -20°C. Condense isobutylene (10 ml), seal the pressure bottle (20 lb) and stir the reaction mixture at room temperature for 7 days. Pour the reaction mixture into dilute NaOH solution and stir for 10 min. Wash the dichloromethane solution with dilute NaOH and then water. Concentrate the dried (MgSO₄) ethyl acetate in vacuo to obtain an oil.

Step B: 1-Aminocyclopentane-1-Carboxylic Acid t-Butyl Ester: Hydrogenate the product of step A (1.8 g) in methanol (30 ml) containing 10% Pd/C (0.30 g) at 50 psi for 6.5 hours. Filter and concentrate the filtrate in vacuo to obtain an oil.

PREPARATION 3

1-[[1(S)-BENZYLOXYCARBONYL-3-PHENYLPROPYL]- AMINO]CYCLOPENTANE CARBOXYLIC ACID HYDROCHLORIDE

Step A: 1-[1(S)-Benzyloxycarbonyl-3-phenylpropyl]- aminocyclopentane Carboxylic Acid t-Butyl Ester: At 0- 5°C, add a solution of the product of Preparation 2 (2.6 g) and Proton Sponge® (1,8-bis(dimethylamino)naphthalene) (2.0 g.) in dichloromethane (40 ml) (dried over Molecular sieves 4A) dropwise to a solution of the product of

Preparation 1 (5.6 g) in dichloromethane (30 ml) and stir the resulting mixture at room temperature for 18 hours. Filter and concentrate the reaction mixture in vacuo.

Triturate the residue with diethyl ether (500 ml) and filter. Extract the diethyl ether solution (500 ml) with 200 ml portions of 5% of KHSO₄, H₂O, 5% NH₄OH, H₂O, 5% KHSO₄, H₂O, 5% NaHCO₃ and H₂O. Dry (MgSO₄) and

concentrate the diethyl ether solution to obtain a yellow oil. Chromatograph this oil on a column of silica gel (800 ml) using dichloromethane as eluant. Concentrate the desired fractions to obtain a pale yellow oil,

[α]²⁶ _D=+2.6° (MeOH).

Step B: 1-[1(S)-Benzyloxycarboxyl-3-Phenylpropyl] aminocyclopentane Carboxylic Acid Hydrochloride: Treat the product of step A (3.7 g) in dichloromethane (40 ml) with trifluoroacetic acid (25 ml), and stir the resulting mixture at room temperature for 19 hours. Concentrate the reaction mixture in vacuo, add dichloromethane (20 ml), and concentrate in vacuo. Add excess HCl in

dichloromethane to the residue and concentrate in

vacuo. Triturate the residue with diethyl ether and filter to obtain the title compound as a white

crystalline solid, m.p. 155-6°C, [α]²⁶ _D=+1.2° (MeOH).

EXAMPLE 1

N-[1-[[1(S)-BENZYLOXYCARBONYL-3-PHENYLPROPYL]AMINO]- CYCLOPENTYLCARBONYL]-(S)-ISOSERINE BENZYL ESTER

At 0-5°C, add triethylamine (1.7 ml) to the product of Preparation 3 (1.45 g), 1-(3-dimethylamino- propyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.8 g), 1-hydroxybenzotriazole (HOBT) (0.4g) and (S)-isoserine benzyl ester hydrochloride (0.9 g) in DMF (7 ml) and warm the resulting mixture to room temperature and stir for 72 hours. Concentrate the resulting mixture in vacuo, and partition between ethyl acetate and water (twice), IN NaHCO₃, dilute HCl, then brine. Dry (MgSO₄) and

concentrate the ethyl acetate solution to obtain an oil. Chromatograph this oil on a column of silica gel (300 ml, "Baker" 40 μ ) using ethyl acetate: hexane 1:4 (4L); 2:7 (1.5 L); 1:3 and then ethyl acetate.

Concentrate the fractions containing the title compound to obtain a colorless oil, [α]²⁶ _D=+11.8°.

EXAMPLE 2

N-[1-[[1(S)-CARBOXY-3-PHENYLPROPYL]AMINO]- CYCLOPENTYLCARBONYL]-(S)-ISOSERINE

Hydrogenate N-[1[[1(S)-benzyloxycarbonyl-3- phenylpropyl]amino]cyclopentyl-1-carbonyl](S)-isoserine (0.37 g) in glacial acetic acid (20 ml) in the presence of 5% Pd/C (0.22 g). After 5 hours, filter the mixture and concentrate in vacuo to obtain a residue. Dissolve the residue in dichloromethane/methanol, filter and evaporate to obtain a residue. Triturate the resultant residue with diethyl ether and filter to obtain the title compound as a white solid, m.p. 130-135°C, [α]²⁶ _D=+26.3 (MeOH).

The following formulations exemplify some of the dosage forms of the compositions of this invention. In each, the term "active compound" designates a compound of formula I, preferably N-[1-[1(S)-carboxy-3- phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine. However, this compound may be replaced by equally

effective amounts of other compounds of formula I. Pharmaceutical Dosage Form Examples

Example A

Method of Manufacture

Mix Item Nos. 1 and 2 in suitable mixer for 10- 15 minutes. Granulate the mixture with Item No. 3. Mill the damp granules through a coarse screen (e.g., 1/4", 0.63 cm) if necessary. Dry the damp granules. Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1- 3 minutes. Compress the mixture to appropriate size and weight on a suitable tablet machine.

Example B

Capsules

No. Ingredient mg/capsule mg/capsule

1. Active compound 100 500

2. lactose USP 106 123

3. Com Starch, Food Grade 40 70

4. Magnesium Stearate NF 4 7

TOTAL 250 700 Method of Manufacture

Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into suitable two-piece hard gelatin capsules on a suitable encapsulating machine.

Example C

Parenteral Preparation

Ingredient mg/vial mg/vial

Active Compound Sterile Powder 100 500

For reconstitution add sterile water for injection or bacteriostatic water for injection.

Claims

We Claim:

1. A compound represented by the formula

wherein R¹ is H, alkyl, arylalkyl or aryl;

alkoxyalkylthio, arylalkoxy and arylalkylthio; R³ and R⁴ are independently alkyl or arylalkyl; or R³ and R⁴ together with the carbon to which they are attached form a 5-, 6- or 7-membered ring wherein said ring comprises 0 to 1 heteroatoms selected from the group consisting of sulfur and oxygen, wherein said ring is unsubtituted or is substituted on a carbon atom ring member by an alkyl or aryl group, or wherein said ring is substituted by a fused benzene ring; R⁵ is H, alkyl, alkoxyalkyl, alkylthioalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylalkoxyalkyl or arylalkylthioalkyl; R⁶ is H, hydroxy, alkoxy, alkyl, alkoxyalkyl,

R⁷ is hydroxy, alkoxy, aryloxy, arylalkoxy, amin o, alkylamino or dialkylamino;

m is 0 or 1;

n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein R² is arylalkyl.

3. A compound of claim 2 wherein R³ and R⁴ together with the carbon to which they are attached form a carbocyclic 5-, 6- or 7-membered ring.

4. A compound of claim 2 wherein R⁵ is hydrogen, R⁶ is hydroxy, m is 1 and n is zero.

5. A compound of claim 1, 3 or 4 wherein R¹ is hydrogen or benzyl and R⁷ is hydroxy or benzyloxy.

6. A compound of claim 1 which is:

N-[1-[[1(S)-benzyloxycarbonyl-3- phenylpropyl]amino]cyclopentylcarbonyl]-(S)-isoserine benzyl ester; or

N-[1-[[1(S)-carboxyl-3-phenylpropyl]amino]- cyclopentylcarbonyl]-(S)-isoserine.

7. A method for treating hypertension, congestive heart failure, edema or renal insufficiency in mammals comprising admnistering to a mammal in need of such treatment an effective amount of a compound of claim 1 alone or in combination with an atrial natriuretic peptide or an angiotensin converting enzyme inhibitor.

8. A pharmaceutical composition for treating hypertension, congestive heart failure, edema or renal insufficiency comprising an effective amount of a compound of claim 1, alone or in combination with an atrial natriuretic peptide or an angiotensin converting enzyme inhibitor in a pharmaceutically acceptable

carrier.

9. A composition of claim 8 wherein the atrial natriuretic peptide is chosen from o human AP 21, α human AP 28, α human AP 23, α human AP 24, α human AP 25, a human 26, a human AP 33, and the corresponding atrial peptides wherein the methionine at position 12 is

replaced by isoleucine.

10. A composition of claim 8 wherein the

angiotensin converting enzyme inhibitor is selected from: spirapril, enalapril, ramipril, perindopril, indolapril, lysinopril, quinapril, pentopril, cilazapril, captopril, zofenopril, pivalopril and fosinopril.

11. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat hypertension or congestive heart failure in mammals which comprises in one container a pharmaceutical composition comprising a carboxylalkyl dipeptide and in a second container a pharmaceutical composition comprising an atrial natriuretic peptide.

12. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat hypertension or congestive heart failure in mammals which comprises in one container a pharmaceutical composition comprising a carboxyalkyl dipeptide and in a second container a pharmaceutical composition comprising an angiotensin converting enzyme inhibitor.

13. A method for inhibiting the action of

endopeptidases in a mammal thereby to elicit an analgesic effect comprising administering to a mammal in need of such treatment an analgesic-effective amount of a

compound of claim 1.

14. An analgesic pharmaceutical composition

comprising an analgesic-effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.

15. A method for preparing a pharmaceutical

composition comprising admixing a compound of claim 1 with a pharmaceutically acceptable carrier.

16. The use of a compound of claim 1 for the manufacture of a medicament for treating hypertension, congestive heart failure, edema, renal insufficiency or pain conditions.

17. A process for the preparation of a compound of formula I as defined in claim 1, wherein the compound is prepared by an appropriate process selected from the following processes A, B and C, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, m and n are as defined in claim l, including suitable protection:

Process A: condensation of a ketoester of formula II with a dipeptide of formula III:

Process B: alkylation of a dipeptide of formula III with a compound of formula IV wherein X is chloro, bromo, iodo, alkylsulfonyloxy, haloalkylsufonyloxy or

arylsulfonyloxy:

Process C: condensation of an aminoacid of formula V or a reactive derivative thereof with an amino acid of formula VI:

wherein Processes A, B and C are followed by isolation of the preferred isomer, if desired, and removal of the protecting groups, if necessary, to yield the desired product, and if desired, preparation of a salt thereof.