N-(Mercaptoalkyl)amides

The present invention relates to N-(mercaptoalkyl)amides 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.

U.S. Pat. No. 4,513,009 to Roques et al discloses compounds having the formula ##STR2## wherein R.sup.1 includes alkyl and optionally substituted phenyl, n is 0 or 1 and R.sup.2 includes phenyl and substituted alkyl. The compounds are disclosed by Roques et al as principally having enkephalinase inhibitory activity, but are also said to be antihypertensives.

European Patent Application 161,769 discloses enkephalinase inhibitors of the formula ##STR3## wherein R.sub.2 includes alkyl, aryl and arylalkyl, R.sub.3 includes hydrogen, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, and n is 1-15.

It is known 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. U.S. Pat. No. 4,740,499 to Olins discloses a method of prolonging the effect of atrial peptides comprising co-administering thiorphan (a compound within the scope of U.S. Pat. No. 4,513,009) or kelatorphan with an atrial peptide.

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.

Novel compounds of the present invention are represented by the formula ##STR4## wherein R.sub.1 is lower alkyl, cyclolower alkyl, aryl or heteroaryl;

R.sub.2 is (COR.sub.3)-aryl, heteroaryl, substituted (COR.sub.3)-aryl or substituted heteroaryl, wherein the substituents are 1-3 substituents selected from the group consisting of carboxy, alkoxycarbonyl, lower alkyl, hydroxy, nitro halo, lower alkoxy, cyclolower alkyl, cyano, trifluoromethyl, phenyl, phenoxy and phenylthio;

R.sub.3 is --OR.sub.4 or --NR.sub.4 R.sub.5 ;

R.sub.4 and R.sub.5 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl and aryl lower alkyl, or R.sub.4 and R.sub.5 together with the nitrogen to which they are attached form a 5-, 6- or 7-membered ring;

Q is hydrogen or R.sub.6 CO--;

R.sub.6 is hydrogen, lower alkyl or aryl; and

m is 1 or 2;

and the pharmaceutically acceptable salts thereof.

A preferred group of compounds of formula I is that wherein R.sub.2 is (COR.sub.3)-phenyl, nitro or carboxy-substituted (COR.sub.3)-phenyl or pyridyl. Yet another preferred group of compounds of formula I is that wherein R.sub.3 is hydroxy, lower alkoxy or aryl lower alkoxy.

Preferred values for Q are hydrogen and acyl. Other preferred compounds are those wherein R.sub.1 is phenyl or lower alkyl-substituted phenyl, for example tolyl. A preferred value for m is 1.

Especially preferred compounds of formula I are those wherein R.sub.1 is phenyl or tolyl, m is 1, R.sub.2 is (COR.sub.3)-phenyl, nitro or carboxy-substituted (COR.sub.3)-phenyl, or pyridyl and R.sub.3 is hydroxy or alkoxy.

The invention also relates to the treatment of cardiovascular diseases with a combination of an N-(mercaptoalkyl)amide of the present invention and an atrial natriuretic factor (ANF) and with a combination of an N-(mercaptoalkyl)amide of the present invention and an angiotensin converting enzyme (ACE) inhibitor.

Other aspects of the invention relate to pharmaceutical compositions comprising an N-(mercaptoalkyl)amide of this invention, alone or in combination with an ANF or an ACE inhibitor, and to methods of treatment of cardiovascular diseases comprising administering an N-(mercaptoalkyl)amide 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 the invention relates to a method of treating pain conditions by administering an N-(mercaptoalkyl)amide of this invention, thereby inhibiting the action of enkephalinase in a mammal and eliciting an analgesic effect. Analgesic pharmaceutical compositions comprising said N-(mercaptoalkyl)amides are also contemplated.

An additional aspect of the invention relates to a method of treating nephrotoxicity resulting from immunosuppression therapy by administration of an N-(mercaptoalkyl)amide of this invention.

As used herein, the term "lower alkyl" means straight or branched alkyl chains of 1 to 6 carbon atoms, and "lower alkoxy" similarly refers to alkoxy groups having 1 to 6 carbon atoms. Cyclolower alkyl means cyclic alkyl groups of 3 to 6 carbon atoms.

"Aryl" means mono-cyclic or fused ring bicyclic carbocyclic aromatic groups having 6 to 10 ring members and "heteroaryl" means mono-cyclic or fused ring bicyclic aromatic groups having 5-10 ring members wherein 1-2 ring members are independently nitrogen, oxygen or sulfur, wherein the carbon ring members of the aryl and heteroaryl groups are substituted by zero to three substituents selected from the group consisting of carboxy, alkoxycarbonyl, nitro, lower alkyl, hydroxy, halo, lower alkoxy, cyclolower alkyl, cyano, trifluoromethyl, phenyl, phenoxy or phenylthio. Examples of carbocyclic aryl groups are phenyl, .alpha.-naphthyl and .beta.-naphthyl, and examples of heterocyclic aryl groups are furyl, thienyl, pyrrolyl, benzofuryl, benzothienyl, indolyl and pyridyl. All positional isomers, e.g. 2-pyridyl, 3-pyridyl, are contemplated.

"Halo" refers to fluorine, chlorine, bromine or iodine radicals.

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, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.

The salts may be formed by conventional means, as by reacting the free acid form of the product with one or more equivalents of the appropriate base 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 ANFs contemplated for use in this invention are .alpha. human AP 21 (atriopeptin I), .alpha. human AP 28, .alpha. human AP 23 (atriopeptin II or APII), .alpha. human AP 24, .alpha. human AP 25, .alpha. human AP 26, .alpha. human AP 33, and the corresponding rat sequence of each of the above wherein Met 12 is Ile. See Table I for a comparison of the peptides.

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. Pat. Nos. 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 Oct. 6, 1982 discloses N-substituted-N-carboxyalkyl aminocarbonyl alkyl glycine derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula ##STR6## either (A) R.sup.b and R.sub.9.sup.b are OH, 1-6C alkoxy, 2-6C alkenyloxy, di-(1-6C alkyl)amino-(1-6C) alkoxy, 1-6C hydroxyalkoxy, acylamino-(1-6C)alkoxy, acyloxy-(1-6C)alkoxy, aryloxy, aryloxy-(1-6C)alkoxy, NH.sub.2, mono- or di-(1-6C alkyl)amino, hydroxyamino or aryl-(1-6C)alkylamino;

R.sub.1.sup.b -R.sub.5.sup.b, R.sub.7.sup.b and R.sub.8.sup.b are 1-20C alkyl, 2-20C alkenyl, 2-20C alkynyl, aryl, aryl-(1-6C) alkyl having 7-12C or heterocyclyl-(1-6C)alkyl having 7-12C;

R.sub.6.sup.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

R.sub.2.sup.b and R.sub.3.sup.b together with the C and N atoms to which they are attached or R.sub.3.sup.b and R.sub.5.sup.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, alkenyl and alkynyl are optionally substituted by OH, 1-6C alkoxy, thio(sic), 1-6C alkylthio, NH.sub.2, mono-or di(1-6C alkyl)amino, halogen or NO.sub.2 ;

all `cycloalkyl` groups (including poly and partially unsaturated) are optionally substituted by halogen, 1-6C hydroxyalkyl, 1-6C alkoxy, amino-(1-6C alkyl)amino, di(1-6C alkyl)amino, SH, 1-6C alkylthio, NO.sub.2 or CF.sub.3 ; and aryl groups are optionally substituted by OH, 1-6C alkoxy, NH.sub.2, mono- or di-(1-6C alkyl) amino, SH, 1-6C alkylthio, 1-6C hydroxyalkyl, 1-6C aminoalkyl, 1-6C thioalkyl, NO.sub.2, halogen, CF.sub.3, OCH.sub.2 O, ureido or guanidino; or (B) R.sup.b and R.sub.9.sup.b are H or 1-6C alkoxy;

R.sub.1.sup.b and R.sub.2.sup.b are H, 1-6C alkyl, aryl-(1-6C) alkyl having 7-12C or heterocyclyl-(1-6C) alkyl having 6-12C;

R.sub.3.sup.b -R.sub.5.sup.b, R.sub.7.sup.b and R.sub.8.sup.b are H or 1-6C alkyl;

R.sub.6.sup.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 alkenyl, 2-6C alkynyl, OH, 1-6C alkoxy, NH.sub.2, mono-or di-(1-6C alkyl) amino, SH, 1-6C alkylthio, 1-6C hydroxyalkyl, 1-6C aminoalkyl, 1-6C thioalkyl, NO.sub.2, halogen, CF.sub.3, OCH.sub.2 O, ureido or guanidino;

European Patent Application 0 050 800 published May 5, 1982 discloses carboxyalkyl dipeptides derivatives which are said to be angiotensin converting enzyme inhibitors and have the formula ##STR7## or a pharmaceutically acceptable salt thereof, wherein R.sup.c and R.sup.6c are the same or different and are hydroxy, lower alkoxy, lower alkenyloxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy; R.sup.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 carbonyl, 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.sup.2c and R.sup.7c are the same or different and are hydrogen or lower alkyl; R.sup.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.sup.4c and R.sup.5c are the same or different and are hydrogen, lower alkyl or Z.sup. c, or R.sup.4c and R.sup.5c taken together form a group represented by Q.sup.c, U.sup.c, V.sup.c, Y.sup.c, D.sup.c or E.sup.c, wherein;

Z.sup.c is ##STR8## wherein X.sup.1c and X.sup.2c independent of each other are O, S or CH.sub.2, R.sup.8c and R.sup.9c independent of each other are lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl having 3 to 8 carbon atoms, hydroxy lower alkyl, or --(CH.sub.2).sub.n.sup.c Ar.sup.c, wherein n.sup.c is 0, 1, 2 or 3 and Ar.sup.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 C.sub.1 to C.sub.4 alkyl, lower alkoxy, lower alkylthio, halo, CF.sub.3 and hydroxy, or R.sup.8c and R.sup.9c taken together form a bridge W.sup.c, wherein W.sup.c is a single bond or a methylene bridge or a substituted methylene bridge when at least one of X.sup.1c and X.sup.2c is methylene, or W.sup.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.sup.c is 0, 1 or 2; with the proviso that at least one of R.sup.4c and R.sup.5c is Z.sup.c, with the proviso that if R.sup.4c is Z.sup.c and p.sup.c is 0 then X.sup.1c and X.sup.2c must both be methylene, and with the proviso that if X.sup.1c and X.sup.2c are both methylene then R.sup.8c and R.sup.9c must form an alkylene bridge W.sup.c ;

Q.sup.c is ##STR9## wherein R.sup.8c, R.sup.9c, X.sup.1c and X.sup.2c are as defined above, p.sup.c is 0, 1 or 2, q.sup.c is 0, 1 or 2, with the proviso that the sum of p.sup.c and q.sup.c must be 1, 2 or 3, with the proviso that if p.sup.c is 0 then X.sup.1c and X.sup.2c must be methylene, and with the proviso that if X.sup.1c and X.sup.2c are methylene then R.sup.8c and R.sup.9c taken together form a bridge W.sup.c, wherein W.sup.c is as defined above;

V.sup.c is ##STR10## wherein R.sup.8c, R.sup.9c, X.sup.1c and X.sup.2c are as defined above, p.sup.c is 0, 1 or 2 and q.sup.c is 0, 1 or 2, with the proviso that the sum of p.sup.c and q.sup.c is 1, 2 or 3, with the proviso that if X.sup.1c and X.sup.2c are CH.sub.2 then R.sup.8c and R.sup.9c taken together form a bridge W.sup.c, wherein W.sup.c is as defined above;

U.sup.c is ##STR11## wherein W.sup.c is as defined above (except that W.sup.c may also be a methylene bridge when X.sup.1c and X.sup.2c are oxygen or sulfur), X.sup.1c and X.sup.2c are as defined above, p.sup.c is 0, 1 or 2, q.sup.c is 0, 1 or 2, with the proviso that the sum of p.sup.c and q.sup.c is 1 or 2, and with the proviso that if p.sup.c is 0, X.sup.1c must be CH.sub.2 ;

Y.sup.c is ##STR12## wherein G.sup.c is oxygen, sulfur or CH.sub.2, a.sup.c is 2, 3 or 4 and b.sup.c is 1, 2, 3, 4 or 5, with the proviso that the sum of a.sup.c and b.sup.c is 5, 6 or 7 or G.sup.c is CH.sub.2, a.sup.c is 0, 1, 2 or 3, b.sup.c is 0, 1, 2 or 3 with the proviso that the sum of a.sup.c and b.sup.c is 1, 2 or 3, with the proviso that the sum of a.sup.c and b.sup.c may be 1, 2 or 3 only if R.sup.1c is lower alkyl substituted with aralkylthio or aralkyloxy;

D.sup.c is ##STR13## wherein F.sup.c is O or S, j.sup.c is 0, 1 or 2 and k.sup.c is 0, 1 or 2, with the proviso that the sum of j.sup.c and k.sup.c must be 1, 2 or 3, and m.sup.c is 1, 2 or 3 and t.sup.c is 1, 2 or 3, with the proviso that the sum of m.sup.c and t.sup.c must be 2, 3 or 4;

E.sup.c is ##STR14## wherein L.sup.c is O or S, u.sup.c is 0, 1 or 2 and v.sup.c is 0, 1 or 2, with the proviso that the sum of u.sup.c and v.sup.c must be 1 or 2, and h.sup.c is 1 or 2 and s.sup.c is 1 or 2, with the proviso that the sum of h.sup.c and s.sup.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 ##STR15## wherein: R.sup.d and R.sup.2d are independently hydrogen; loweralkyl; aralkyl; or aryl;

R.sup.1d is hydrogen; branched or straight chain C.sub.1-12 alkyl and alkenyl; C.sub.3 -C.sub.9 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; ##STR16## where: X.sup.d and Y.sup.d taken together are --CH.sub.2 --CH.sub.2 --; --CH(R.sup.5d)--S--; --C(O)--CH.sub.2 --; --CH.sub.2 --C(O)--; --C(O)--O--; --C(O)--S--; --CH.sub.2 --CH(OR.sup.4d)--; --C(O)--N(R.sup.4d)--; or --CH.sub.2 --C(R.sup.4d)--R.sup.5d ;

R.sup.4d is hydrogen; loweralkyl; aryl; substituted aryl;

R.sup.5d is hydrogen; loweralkyl; aryl or substituted aryl;

n.sup.d is 1 to 3;

W.sup.d is absent; --CH.sub.2 --; or --C(O)--;

Z.sup.d is --(CH.sub.2).sub.m.sup.d, where m.sup.d is 0 to 2, provided that m.sup.d may not be 0 and W.sup.d may not be absent at the same time; and

R.sup.6d is hydrogen; loweralkyl; halo; or OR.sup.4d ;

R.sup.2d is --(CH.sub.2).sub.r.sup.d --B.sup.d --(CH.sub.2).sub.s.sup.d --NR.sup.7d R.sup.15d

where

r.sup.d and s.sup.d are independently 0 to 3;

B.sup.d is absent; --O--; --S--; or --NR.sup.8d;

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

R.sup.7d is ##STR17## where R.sup.9d is loweralkyl; aralkyl; aryl; heteroaryl; or heteroarloweralkyl and these groups substituted by hydroxy, lower alkoxy or halo; carboxyl; carboxamido; nitromethenyl.

R.sup.10d is hydrogen; loweralkyl; aryl; or amidino; R.sup.11d is hydrogen; loweralkyl; cyano; amidino; aryl; aroyl; loweralkanoyl; --C(O)--NHR.sup.13d ; --C(O)--OR.sup.13d ; --NO.sub.2 ; --SO.sub.2 NH.sub.2 ; or SO.sub.2 R.sup.13d;

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

R13d is hydrogen; loweralkyl; or aryl;

R15d is hydrogen; lower alkyl; aralkyl; or aryl; ##STR18## 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.dbd.O, or an SO.sub.2 group optionally substituted by amino, lower alkyl amino, diloweralkyl amino, lower alkoxy, or aralkyl groups;

R.sup.3d is C.sub.3-8 cycloalkyl and benzofused C.sub.3-8 cycloalkyl; perhydrobenzofused C.sub.3-8 cycloalkyl; aryl; substituted aryl; heteraryl; substituted heteroaryl;

R.sup.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 ##STR19## hydrogen atoms at ring positions 1 and 5 are cis to each other and the 3-carboxy group has the endo orientation;

R.sub.1.sup.e is H, allyl, vinyl or the side chain of an optionally protected naturally occurring .alpha.-amino acid;

R.sub.2.sup.e is H, 1-6C alkyl, 2-6C alkenyl or aryl(1-C alkyl);

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

X.sup.e is 1-6C alkyl, 2-6C alkenyl, 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 Mar. 10, 1982 discloses N-amino acyl-indoline and tetrahydro isoquinoline carboxylic acids which are angiotensin coverting enzyme inhibitors and have the formula ##STR20## R.sub.1.sup.f and R.sub.2.sup.f are each 1-6C alkyl, 2-6C alkenyl, 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-N atoms; all R.sub.1.sup.f and R.sub.2.sup.f groups are optionally substituted, R.sub.3.sup.f is H, 1-6C alkyl, 2-6C alkenyl or 7-14C aralkyl.

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

Compounds of the present invention can be made by methods well known to those skilled in the art. An example of a synthetic method is shown below. Acid II is converted into isocyanate III, for example by reaction with diphenylphosphorylazide at elevated temperatures (e.g. 80.degree. C.) in the presence of a base such as triethylamine in a solvent such as toluene. The isocyanate need not be isolated. The isocyanate III is treated with benzyl alcohol to produce the benzyl carbamate, IV. The carbamate IV is then converted to an amine salt, V, for example by treatment with HBr in acetic acid. The salt V is then reacted with a compound of formula VI in an inert solvent such as methylene chloride in the presence of a base such as triethylamine at room temperature to obtain compounds of formula I: ##STR36## wherein Q, R.sub.1, R.sub.2 and m are as defined above, and wherein Z is an acid activating group such as chloro, azido or alkoxycarbonyloxy. Alternatively, Z is hydroxy, in which case activation can be accomplished by a peptide coupling agent such as a carbodiimide.

It is apparent that using methods well known to those skilled in the art, compounds of formula I can be converted to different compounds of formula I by appropriate reaction of the Q and/or R.sub.3 variables, e.g. a thioester can be converted to a mercaptan, and an acid can be converted to an amide or an ester to an acid.

Compounds of formula II and VI are known in the art or can be prepared by methods well known in the art.

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 an N-(mercaptoalkyl)amide and an ACE inhibitor provides an antihypertensive and anti-congestive heart failure effect greater than either the N-(mercaptoalkyl)amide or ACE inhibitor alone. Administration of a combination of an N-(mercaptoalkyl)amide of formula I and an exogenous ANF or ACE inhibitor is therefore particularly useful in treating hypertension or congestive heart failure.

In addition to the compound aspect, the present invention therefore also relates to treating cardiovascular disorders with an N-(mercaptoalkyl)amide of formula I or with an N-(mercaptoalkyl)amide 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 N-(mercaptoalkyl)amide effective to treat hypertension or congestive heart failure or an amount of a combination of an N-(mercaptoalkyl)amide and ANF or ACE inhibitor effective to treat hypertension or congestive heart failure. 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 N-(mercaptoalkyl)amide/oral ANF, oral N-(mercaptoalkyl)amide/parenteral ACE inhibitor, parenteral N-(mercaptoalkyl)amide/oral ANF, parenteral N-(mercaptoalkyl)amide/parenteral ACE inhibitor.

When the components of a combination of an N-(mercaptoalkyl)amide and an ANF are administered separately, it is preferred that the N-(mercaptoalkyl)amide be administered first.

The present invention also relates to a pharmaceutical composition comprising an N-(mercaptoalkyl)amide for use in treating hypertension or congestive heart failure, to a pharmaceutical composition comprising both an N-(mercaptoalkyl)amide and an ANF, and to a pharmaceutical composition comprising both an N-(mercaptoalkyl)amide and an ACE inhibitor.

The antihypertensive effect of N-(mercaptoalkyl)amides 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 N-(mercaptoalkyl)amide and blood pressure was monitored for the next 4 hours.

A similar procedure can be used to determine the effect of N-(mercaptoalkyl)amides in combination with ACE inhibitors.

The antihypertensive effect of N-(mercaptoalkyl)amides 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 .mu.g/kg iv and at the end of 60 min. are treated with drug vehicle or an N-(mercaptoalkyl)amide 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 N-(mercaptoalkyl)amides 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.

Using the above test procedures, a 1 mg/kg dose (po) of 3-[N[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoic acid has been found to produce a 47 mmHg drop in blood pressure in the DOCA salt model and a 19 mm Hg drop in blood pressure (30 mg/kg sc) in the ANF potentiation procedure.

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 use of atrial natriuretic peptides in the treatment of nephrotoxicity associated with the immunosuppressive cyclosporin was reported by Capasso et al in the American Journal of Hypertension, 3, 3 (1990), p. 204-210. Since compounds of this invention enhance endogenous ANF, they can be used alone to treat nephrotoxicity, or they can be administered in combination with exogenous ANF.

The compositions of this invention comprise an N-(mercaptoalkyl)amide, an N-(mercaptoalkyl)amide and an ANF or an N-(mercaptoalkyl)amide 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 or congestive heart failure is as follows: for N-(mercaptoalkyl)amides alone the typical dosage is 0.1 to 10 mg/kg of mammalian weight per day administered in single or divided dosages; for the combination of an N-(mercaptoalkyl)amide and an ANF, the typical dosage is 0.1 to 10 mg of N-(mercaptoalkyl)amide/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 an N-(mercaptoalkyl)amide and an ACE inhibitor, the typical dosage is 0.1 to 10 mg of N-(mercaptoalkyl)amide/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 or congestive heart failure, the compounds or combinations of this invention may be administered to patients in a dosage range as follows: for treatment with an N-(mercaptoalkyl)amide alone, about 5 to about 500 mg per dose given 1 to 4 times a day, giving a total daily dose of about 5 to 2000 mg per day; for the combination of an N-(mercaptoalkyl)amide and ANF, about 5 to about 500 mg N-(mercaptoalkyl)amide per dose given 1 to 4 times a day and about 0.01 to about 1 mg ANF given 1 to 6 times a day (total daily dosage range of 5 to 2000 mg day and 0.01 to 6 mg/day, respectively); and for the combination of an N-(mercaptoalkyl)amide and an ACE inhibitor, about 5 to about 500 mg N-(mercaptoalkyl)amide 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 5 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.

For treatment of edema, renal insufficiency or nephrotoxicity associated with immunosuppressive therapy, dosage ranges of the compounds of this invention are the same as for treatment of hypertension with the use of N-(mercaptoalkyl)amides alone or in combination with ANF.

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 sulfate; 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, antioxidants, lubricants, flavoring agents, and the like commonly used in pharmaceutical formulations.

Since the present invention relates to treatment of hypertension or congestive heart failure 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: an N-(mercaptoalkyl)amide pharmaceutical composition and an ANF pharmaceutical composition in one kit and an N-(mercaptoalkyl)amide 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.

Following are examples of procedures for preparing compounds of formula I.

Heat for 1 hr at 80.degree. C. a solution of 2(S)-acetylthiomethyl-3-(2-methylphenyl)propionic acid (6.0 g=24 mmol), diphenylphosphoryl azide (6.6 g=24 mmol) and triethylamine (2.4 g=24 mmol) in toluene (90 ml). Allow to cool, add benzyl alcohol (3.1 g=29 mmol) and heat at 80.degree. C. for 1 hr. Concentrate in vacuo and partition with EtOAc and 1.0N NaHCO.sub.3. Dry and concentrate to obtain crude benzyl N-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]carbamate. Purify by silica gel chromatography with 2:1 hexane/Et.sub.2 O to obtain a white solid, m.p. 73.degree.-80.degree. C., [.alpha.].sub.D.sup.26 =-2.0.degree. (EtOH).

Add the above carbamate (3.2 g=9.0 mmol) to 33% HBr/HOAc (20 ml). After 4.5 hr, concentrate in vacuo. Treat the solid with Et.sub.2 O (200 ml), filter and dry to obtain the title compound as a pale orange solid, m.p. 137.degree.-8.degree. C.

To the hydrobromide of Preparation 1 (0.45 g=1.5 mmol) and 4-(methoxycarbonyl)benzoyl chloride (0.29 g=1.5 mmol) in CH.sub.2 Cl.sub.2 (25 ml), add Et.sub.3 N (0.30 g=3.0 mmol) in CH.sub.2 Cl.sub.2 (10 ml). After 1 hr, concentrate and partition between EtOAc and 1.0N HCl. Dry over MgSO.sub.4 and concentrate. Chromatograph the solid on silica, eluting with 1:1 Et.sub.2 O/hexane to obtain the title compound as a white solid, m.p. 136.degree.-40.degree. C., [.alpha.].sub.D.sup.26 =-19.3.degree. (EtOH).

To the ester of Example 1 (0.14 g=0.36 mmol) in MeOH (8 ml, nitrogen-purged) add 1.00N NaOH (2.0 ml, nitrogen-purged). Stir 0.5 hr, concentrate in vacuo and add 1.0N HCl (2.0 ml). Collect the solid, wash with water and dry to obtain the title compound as a white solid, m.p. 195.degree.-7.degree. C., [.alpha.].sub.D.sup.26 =+64.9.degree. (EtOH).

In a fashion similar to Example 1, employ 3-(methoxycarbonyl)benzoyl chloride to prepare the title compound, a white solid, m.p. 118.degree. C., [.alpha.].sub.D.sup.26 =-22.5.degree. (EtOH).

In a manner similar to Example 2, convert the ester of Example 3 to the title compound, a white solid, m.p. 157.degree.-60.degree. C., [.alpha.].sub.D.sup.26 =+57.2.degree. (EtOH).

In a manner similar to Example 1, employ 2-(methoxycarbonyl)benzoyl chloride to prepare the title compound (eluted with Et.sub.2 O), a white solid, [.alpha.].sub.D.sup.26 =-12.2.degree. (EtOH).

In a manner similar to Example 2, convert the ester of Example 5 to the title compound, a white solid, [.alpha.].sub.D.sup.26 =+36.3.degree. (EtOH), FAB-MS: M+1=330.

Heat 3-methoxycarbonyl-5-nitrobenzoic acid (2.0 g=8.9 mmol) with SOCl.sub.2 (2.1 g=18 mmol) in toluene at reflux 1 hr. Concentrate to obtain 3-methoxycarbonyl-5-nitrobenzoyl chloride, m.p. 66.degree.-8.degree. C.

In a manner similar to Example 1, employ this acid chloride to prepare the title compound, a gum, [.alpha.].sub.D.sup.26 =-13.6.degree. (EtOH).

In a manner similar to Example 2, convert the ester of Example 7 to the title compound, a yellow solid, [.alpha.].sub.D.sup.26 =+61.5.degree. (EtOH).

To the hydrobromide of Preparation 1 (0.45 g=1.5 mmol) and 4-(chlorocarbonyl)phthalic anhydride (0.31 g=1.5 mmol) in CH.sub.2 Cl.sub.2 (25 ml), add Et.sub.3 N (0.30 g=3.0 mmol) in CH.sub.2 Cl.sub.2 (10 ml). After 2 hr, concentrate and partition between EtOAc and 1.0N HCl. Dry over MgSO.sub.4 and concentrate to obtain a white solid, m.p. 163.degree.-5.degree. C.

Treat this solid with 1:1 THF-H.sub.2 O (20 ml) for 18 hr. Concentrate to obtain the title compound, a white solid, [.alpha.].sub.D.sup.26 =-14.5.degree. (EtOH).

In a manner similar to Example 2, convert the acetyl compound of Example 9 to the title compound, a white foam, [.alpha.].sub.D.sup.26 =+54.5.degree. (EtOH).

To the hydrobromide of Preparation 1 (0.45 g=1.5 mmol), isonicotinoyl chloride hydrochloride (0.32 g=1.8 mmol), and 4-dimethylaminopyridine (0.18 g=1.5 mmol) in CH.sub.2 Cl.sub.2 (15 ml), add Et.sub.3 N (0.47 g=4.7 mmol) in CH.sub.2 Cl.sub.2 (5 ml). Stir 0.5 hr, concentrate and partition between EtOAc and H.sub.2 O. Dry over MgSO.sub.4 and concentrate. Chromatograph the oil on silica, eluting with 4% MeOH/CH.sub.2 Cl.sub.2 to obtain the title compound as a white solid, m.p. 132.degree. C., [.alpha.].sub.D.sup.26 =-24.1.degree. (EtOH).

In a manner similar to Example 2, convert the acetyl compound of Example 11 to the title compound, a white solid, [.alpha.].sub.D.sup.26 =+50.5.degree. (EtOH).

The following formulations exemplify some of the dosage forms of the compositions of this invention. In each, the term "active ingredient" designates a compound of formula I, preferably 3-[N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]aminocarbonyl]benzoic acid. However, this compound can be replaced by equally effective amounts of other compounds of formula I.

Mix Items 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.

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.

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