Novel 2-mercaptomethylene-tetrahydronaphthalene and indane-2-carboxamide derivatives as enkephalinase inhibitors

Abstract: The present invention relates to novel 2-mercaptomethylene-tetrahydronaphthalene derivatives which are useful as enkephalinase inhibitors.

Description: Enkephalinase or, more specifically, neutral endopeptidase-24.11, is a mammalian ectoenzyme which is involved in the metabolic degradation of certain circulating regulatory peptides. This enzyme, which is a Zn⁺²-metallopeptidase, exerts its effect by cleaving the extracellular peptides at the amino group of hydrophobic residues and thus inactivates the peptides as regulatory messengers. Enkephalinase is involved in the metabolic degradation of a variety of circulating regulatory peptides including endorphins, such as β-endorphin and the enkephalins, atrial natriuretic peptide (ANP), and other circulating regulatory peptides. Endorphins are naturally-occurring polypeptides which bind to opiate receptors in various areas of the brain and thereby provide an analgesic effect by raising the pain threshold. Endorphins occur in various forms including α-endorphin, β-endorphin, γ-endorphin as well as the enkephalins. The enkephalins, i.e., Met-enkephalin and Leu-enkephalin, are pentapeptides which occur in nerve endings of brain tissue, spinal cord and the gastrointestinal tract. Like the other endorphins, the enkephalins provide an analgesic effect by binding to the opiate receptors in the brain. By inhibiting enkephalinase, the metabolic degradation of the naturally-occurring endorphins and enkephalins are inhibited, thereby providing a potent endorphin or enkephalin-mediated analgesic effect. Inhibition of enkephalinase would therefore be useful in a patient suffering from acute or chronic pain. Inhibition of enkephalinase would also be useful in providing an antidepressant effect and in providing a reduction in severity of withdrawal symptoms associated with termination of opiate or morphine administration. In addition, inhibition of enkephalinase would be useful in providing an antidiarrheal effect in a patient suffering therefrom. ANP refers to a family of naturally-occurring peptides which are involved in the homeostatic regulation of blood pressure, as well as sodium and water levels. ANP's have been found to vary in length from about 21 to about 126 amino acids with a common structural feature being one or more disulfide-looped sequences of 17 amino acids with various amino- and carboxy-terminal sequences attached to the cystine moiety. ANP have been found to bind to specific binding sites in various tissues including kidney, adrenal, aorta, and vascular smooth muscle with affinities ranging from about 50 pico-molar (pM) to about 500 nano-molar (nM) [Needleman, Hypertension 7 , 469 (1985)]. In addition, it is believed that ANP binds to specific receptors in the brain and possibly serves as a neuromodulator as well as a conventional peripheral hormone. The biological properties of ANP involve potent diuretic/natriuretic and vasodilatory/hypotensive effects as well as an inhibitory effect on renin and aldosterone secretion [deBold, Science 230 , 767 (1985)]. By inhibiting enkephalinase, the metabolic degradation of the naturally-occurring ANP are inhibited, thereby providing a potent ANP-mediated diuretic, natriuretic, hypotensive and hypoaldosteronemic effect. Inhibition of enkephalinase would therefore be useful in a patient suffering from disease states characterized by abnormalities in fluid, electrolyte, blood pressure, intraocular pressure, renin, or aldosterone homeostasis, such as, but not limited to, hypertension, renal diseases, hyperaldosteronemia, cardiac hypertrophy, glaucoma and congestive heart failure. By inhibiting enkephalinase, a cognition enhancing effect is also provided in patients suffering from disease states such as Alzheimer's Disease. In WO-A-91/09840, published on July 11, 1991, N-[2-(mercaptomethyl)-indane-2-carbonyl]-(S)-methionine, cis-4-carboxycyclohexaneamine, (S)-isoserine and their S-acetylethyl ester derivatives are disclosed. In EP-A-0 361 365 mercaptoaminobenzoic and mercaptoaminocyclohexane-carboxylic acid compounds are disclosed which inhibit the action of neutral endopeptidase. In EP-A-0 274 234 a "spiro-bound" 2-indanyl N-(cis-carboxycyclohexyl)-glutarmide is disclosed as being a neutral endopeptidase inhibitor. In EP-A-0 038 758, EP-A-0 393 441 and EP-A-0 136 883 carboxamides are described which are enkephalinase inhibitors. In J. Med. Chem. 32 (12) 2519-2526 (1989) enkephalinase inhibiting N-(3,4-dihydroxybenzyl)- and N-(3-methoxy-4-hydroxybenzyl)-2-benzyl-3-mercaptopropionamides are disclosed. The present invention provides novel compounds of the formula (I) wherein n is the integer 2, Z is the radical -C(O)OR, or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is H, C₁-C₄ alkyl, or benzyl, R₁ is H or -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, and B is a radical of the formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0. These compounds are useful as inhibitors of enkephalinase. In addition, the present invention provides a composition comprising an assayable amount of a compound of formula (I) in admixture or otherwise in association with an inert carrier. The present invention also provides a pharmaceutical composition comprising an effective enkephalinase inhibitory amount of a compound of formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. The compounds of formula (I) are mercaptomethylene and carboxamide derivatives of a fused bicyclic moiety. The fused bicyclic moiety represented in formula (I) is a tetrahydronaphthalene moiety. As used herein, the term "C₁-C₄ alkyl" refers to a saturated straight or branched chain hydrocarbyl radical of one to four carbon atoms and specifically includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tertiary butyl. As used herein, the term "C₁-C₄ alkoxy" refers to an alkyloxy radical made up of an oxygen radical bearing a saturated straight or branched chain hydrocarbyl radical of one to four carbon atoms and specifically includes methoxy, ethoxy, propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy and tertiary butyloxy. Z is defined as the radical -C(O)OR or a phenyl unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy. The representation "-C(O)OR" refers to a carboxylic acid or ester functionality. When Z is a substituted phenyl moiety, the phenyl may be substituted in the ortho, meta or para positions with from 1 to 3 substituents. It is of course understood that where the phenyl is substituted with methylenedioxy, the methylenedioxy moiety is attached to adjacent carbon atoms of the phenyl ring. Specifically included within the scope of the term "Z" are -COOH, -COOCH₃, -COOCH₂CH₃, phenyl, 2,3-dihydroxyphenyl, 2,4-dihydroxyphenyl, 2,5-dihydroxyphenyl, 2,6-dihydroxyphenyl, 3,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl and 3-hydroxy-4-methoxyphenyl. B is defined as a radical of the formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0. When B is the cyclohexylidene moiety, the amide linkage to B and the carboxy linkage to B are at the 1 and 4 positions of the cyclohexylidene moiety and are cis with respect to each other. When B is -(CH₂) m CH(R₂)- and m is 0, the moiety thus formed, i.e., -NH-CH(R₂)-C(O)-O-, resembles a naturally occurring amino acid unit with R₂ representing the amino acid side chain. Of course it is understood that the compounds of formula (I) may exist in a variety of isomeric configurations including structural as well as stereo isomers. These compounds can have one or more chiral centers. For example, the carbon in the bicyclic moiety to which the mercaptomethylene and the carboxamide groups attach, may exist in the (R) or the (S) form. In addition, the methylidene moiety of B may exist in the (R) or the (S) form. It is further understood that the present invention encompasses those compounds of formula (I) in each of their various structural and stereo isomeric configurations as individual isomers and as mixtures of isomers. When R₁ is -C(O)-A, the compounds of formula (I) bear a thiocarboxy moiety. In other words, the structure of this moiety is The partial structure formed by the designation -(CH₂) n -represents a saturated hydrocarbyl radical of straight chain configuration having from 1 to 2 carbon atoms. The partial structure formed by the designation -(CH₂) m - represents a saturated hydrocarbyl radical of straight chain configuration having from 0 to 5 carbon atoms. The compounds of formula (I) can be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. A general synthetic procedure for preparing these compounds is set forth in Scheme A. In Scheme A, all substituents unless otherwise indicated are as previously defined. Scheme A provides a general synthetic procedure for preparing the compounds of formula (I). In step a, the appropriate carbomethoxy substituted bicyclic compound of structure (1) is alkylated with t-butyl chloromethylsulfide to give the corresponding carbomethoxy-t-butylthiomethyl disubstituted bicyclic compound of structure (2). For example, the appropriate carbomethoxy substituted bicyclic compound of structure (1) is first deprotonated with a molar equivalent of an appropriate non-nucleophilic base such as lithium diisopropylamide. The reactants are typically contacted under anhydrous conditions in a suitable aprotic organic solvent such as tetrahydrofuran. The reactants are typically stirred together for a period of time ranging from 15 minutes to 5 hours and at a temperature range of from -20°C to -70°C. A molar equivalent of trimethylsilyl chloride is then added. The reaction mixture is stirred for a period of time ranging from 1-30 minutes at a temperature range of from -70°C to 10°C. The intermediate silyl ketene acetal is recovered from the reaction zone by evaporation of the solvent. The intermediate silyl ketene acetal is then contacted with a catalytic amount of zinc bromide followed by a molar equivalent of t-butyl chloromethylsulfide. The reactants are typically contacted in a suitable organic solvent such as methylene chloride. The reactants are typically stirred together for a period of time ranging from 15 minutes to 1 hour. The carbomethoxy-t-butylthiomethyl disubstituted bicyclic compound of structure (2) is recovered from the reaction zone by extractive methods as is known in the art. It can be purified by silica gel chromatography and recrystallization. In step b, the methyl ester of the appropriate carbomethoxy-t-butylthiomethyl disubstituted bicyclic compound of structure (2) is hydrolyzed to give the corresponding carboxy-t-butylthiomethyl disubstituted bicyclic compound of structure (3). For example, the appropriate carbomethoxy-t-butylthiomethyl disubstituted bicyclic compound of structure (2) is contacted with a molar excess of an appropriate base such as lithium hydroxide. The reactants are contacted in a suitable protic solvent such as methanol. The reactants are typically stirred together for a period of time ranging from 1-24 hours and at a temperature range of from room temperature to reflux. The carboxy-t-butylthiomethyl disubstituted bicyclic compound of structure (3) is recovered from the reaction zone by acidification and extractive methods as is known in the art. It can be purified by silica gel chromatography and recrystallization. In step c, the carboxy functionality of the appropriate carboxy-t-butylthiomethyl disubstituted bicyclic compound of structure (3) is amidated with the appropriate amine or amino acid of structure (4) to give the N-[[2-[[(t-butyl)thio]methyl]bicyclic compound]carbonyl]-amine or amino acid of structure (5). For example, the carboxy functionality of the appropriate carboxy-t-butylthiomethyl disubstituted bicyclic compound of structure (3) is first contacted with a molar excess of oxalyl chloride. The reactants are typically contacted in a suitable organic solvent such as methylene chloride. The reactants are typically stirred together for a period of time ranging from 1-5 hours and at a temperature range of from 0°C to room temperature. The intermediate acid chloride is recovered from the reaction zone by evaporation of the solvent. The intermediate acid chloride is contacted with a molar equivalent of the appropriate amine or amino acid of structure (4) and two molar equivalents of an appropriate acid scavenger such as triethylamine or sodium hydrogen carbonate. The reactants are typically contacted in a suitable organic solvent such as methylene chloride, chloroform or acetone. The reactants are typically stirred together for a period of time ranging from 30 minutes to 24 hours. The N-([2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (5) is recovered from the reaction zone by extractive methods as is known in the art. It can be purified by silica gel chromatography. Alternatively, the appropriate carboxy-t-butylthiomethyl disubstituted bicyclic compound of structure (3) is contacted with a molar equivalent of a coupling agent, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, a molar equivalent of an appropriate amine or amino acid of structure (4) and a molar equivalent of an appropriate acid scavenger such as triethylamine. The reactants are typically contacted in a suitable organic solvent such as tetrahydrofuran. The reactants are typically stirred together at room temperature for a period of time ranging from 2-24 hours. The N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (5) is recovered from the reaction zone by extractive methods as is known in the art. It can be purified by silica gel chromatography. In optional step d₁, the t-butylsulfide functionality of the appropriate N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (5), wherein Z' is phenyl substituted or unsubstituted or -COOR', wherein R' is a C₁-C₄ alkyl or benzyl, is cleaved to give the corresponding N-[[2-[mercaptomethyl]bicyclic compound]carbonyl]-amine or amino acid ester of structure (6). For example, the appropriate N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (5), wherein R is a C₁-C₄ alkyl or benzyl, is contacted with a molar equivalent of mercuric acetate. The reactants are typically contacted in an appropriate acidic solvent such as trifluoroacetic acid. The reactants are typically stirred together at room temperature for a period of time ranging from 1-24 hours. Mercury is removed from the reaction mixture by the addition of excess hydrogen sulfide. The N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid, ester of structure (6) is recovered from the reaction zone by extractive methods as is known in the art. It can be purified by silica gel chromatography. In optional step d₂, the ester functionality of the appropriate N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (5), wherein Z is -COOR and R is a C₁-C₄ alkyl or benzyl, is cleaved to give the corresponding N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (7), wherein R is hydrogen. For example, the appropriate N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (5), wherein R is a C₁-C₄ alkyl or benzyl ester, is contacted with a catalytic amount of trifluoromethanesulfonic acid. The reactants are typically contacted in an appropriate organic solvent such as dimethylsulfide. The reactants are typically stirred together at room temperature for a period of time ranging from 2-25 hours. The N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (7), wherein R is hydrogen can be recovered from the reaction zone by extractive methods as is known in the art. It may be purified by silica gel chromatography. Alternatively, the ester functionality of the appropriate N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (5), wherein R is a C₁-C₄ alkyl or benzyl, is hydrolyzed to give the corresponding N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (7), wherein R is hydrogen as described previously in step b. In optional step e₁, the thiol functionality of the appropriate N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amine or amino acid, ester of structure (6) is acylated to give the appropriate N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (8). For example, the appropriate N-[(2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid, ester of structure (6) can be contacted with a molar equivalent of an appropriate acylating agent such as acetic anhydride and a catalytic amount of an acid such as sulfuric acid. The reactants are typically stirred together for a period of time ranging from 10 minutes to 10 hours. The N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amino acid, ester of structure (8) can be recovered from the reaction zone by evaporation of the solvent. It can be purified by silica gel chromatography. Alternatively, the appropriate N-[[2-[mercaptomethyl]bicyclic compound]carbonyl]-amine or amino acid, ester of structure (6) can be contacted with a molar equivalent of an appropriate acylating agent such as benzoyl chloride and a molar equivalent of a base such as pyridine. The reactants are typically stirred together for a period of time ranging from 10 minutes to 10 hours. The N-[[2[(benzoylthio)methyl]-bicyclic compound]carbonyl]-amine or amino acid, ester of structure (8) can be recovered from the reaction zone by evaporation of the solvent. It can be purified by silica gel chromatography. In optional step e₂, the ester functionality of an appropriate N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid, ester of structure (6) is hydrolyzed to give the N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid of structure (9). For example, the appropriate N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid, ester of structure (6) is contacted with a molar excess of an appropriate acid such as trifluoromethanesulfonic acid. The reactants are typically contacted in a suitable non-polar organic solvent such as dimethylsulfide. The reactants are typically stirred together for a period of time ranging from 15 minutes to 5 hours. The N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid of structure (9) is recovered from the reaction zone by evaporation of the solvent. It can be purified by silica gel chromatography. In optional step e₃, the t-butylsulfide functionality of the appropriate N-[[2-[[(t-butyl)thio]methyl]-bicyclic compound]carbonyl]-amino acid of structure (7), wherein R is hydrogen, is cleaved to give the corresponding N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid of structure (9) as described previously in optional step d₁. In optional step f, the thiol functionality of the appropriate N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amino acid of structure (7) is acylated to give the appropriate N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amino acid or N-[[2-[(benzoylthio)methyl]-bicyclic compound]carbonyl]-amino acid of structure (10) as described previously in optional step e₁. Starting materials for use in Scheme A are readily available to one of ordinary skill in the art. For example, certain carbomethoxy substituted bicyclic compounds (1) are described in J.Med.Chem . 32 1988 1989 and t-butyl chloromethylsulfide is described in J.Am.Chem.Soc . 77 572 1955. Compounds of formula (I) may also be prepared as set forth in Scheme B, wherein all substituents unless otherwise indicated are as previously defined. Scheme B provides a general synthetic procedure for preparing compounds of formula (I). This procedure is preferred for the preparation of compounds bearing unsubstituted alcohols in the B or Z' portions of the molecule. The t-butylsulfide functionality of the appropriate carboxy-t-butylthiomethyl disubstituted bicyclic compound of structure (3), prepared according to Scheme A, is cleaved and the thiol thus formed is acylated to give the corresponding carboxy-acetylthiomethyl disubstituted bicyclic compound of structure (3a). The t-butylsulfide functionality may be cleaved according to the procedures described in Scheme A, step d₁. The resulting thiol may be acylated according to the procedure described in Scheme A, step e₁. The carboxy-acetylthiomethyl disubstituted bicyclic compound of structure (3a) is then amidated to give the corresponding N-[(2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amine or amino ester of structure (8) according to the procedures set forth in Scheme A, step c. The acetylthio functionality of the N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (8) may then be hydrolysed selectively to give the N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (6). This is accomplished by utilizing a reagent which will selectively hydrolyze the acetylthio moiety while not reacting with the amide or amino acid moiety. For example, the N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (8) may be reacted with ammonium hydroxide in a polar solvent such as dioxane or methanol to give the N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]-amine or amino ester of structure (6). Where compound of structure (6) is an amino ester, it may then be further reacted to give the corresponding N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]amino acid of structure (9) by reaction with trifluoromethanesulfonic acid as described in Scheme A, step e₂, or by reaction with lithium hydroxide. The acetylthio functionality and an amide functionality of a N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl] -amine of structure (8) may be hydrolysed at the same time to give the corresponding N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]amino acid of structure (9) by reaction with a base such as lithium hydroxide. The mercaptomethyl moiety of the N-[[2-[mercaptomethyl]-bicyclic compound]carbonyl]amino acid of structure (9) may then be acylated as described in Scheme A, step f, to give the corresponding N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]amino acid of structure (10). The ester functionality of the N-[[2-((acetylthio) methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (8) may then be hydrolysed selectively to give the corresponding N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]amino acid of structure (10). This is accomplished by utilizing a reagent which will selectively hydrolyze the ester moiety while not reacting with the acetylthio moiety. For example, the N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]-amine or amino acid of structure (8) may be reacted with trifluoromethanesulfonic acid to give the corresponding N-[[2-[(acetylthio)methyl]-bicyclic compound]carbonyl]amino acid of structure (10) as described in Scheme A, step d₂. The following examples present typical syntheses as described in Scheme A. These examples are understood to be illustrative only and are not intended to limit the scope of the present invention in any way. As used herein, the following terms have the indicated meanings: "g" refers to grams; "mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to boiling point; "mp" refers to melting point; "°C" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury; "µL" refers to microliters; "µg" refers to micrograms; and "µM" refers to micromolar. Example 1 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl[carbonyl]-glycine, benzyl ester Step a: 2-Carbomethoxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene Dissolve 1,2,3,4-tetrahydro-2-naphthoic acid (10g, 57mmol) in methanol (100mL) and add dimethoxypropane (3mL). Cool to 5°C and saturate with hydrogen chloride gas. Allow to stand overnight then evaporate the solvent in vacuo . Take the residue up in ethyl ether, wash with saturated sodium hydrogen carbonate and dry (MgS0₄). Evaporate the solvent in vacuo and distill to give 2-carbomethoxy-1,2,3,4-tetrahydronaphthalene; bp 90-96°C @ 0.25mm Hg). Dissolve diisopropylamine (2.31mL, 16.5mmol) in anhydrous tetrahydrofuran (10mL), cool to -70°C and place under an argon atmosphere. Add, by dropwise addition, n-butyllithium (6.6mL of a 2.5M solution in hexane, 16.5mmol). Stir at -70°C for 20 minutes then add, by dropwise addition, a solution of 2-carbomethoxy-1,2,3,4-tetrahydronaphthalene (2.85g, 15mmol) in anhydrous tetrahydrofuran (10mL). Stir an additional 30 minutes then add trimethylsilyl chloride (1.9mL, 15mmol). Evaporate the solvent in vacuo and suspend the residue in anhydrous methylene chloride (30mL). Treat with t-butyl chloromethylsulfide (2.08g, 15mmol) and 3 portions of zinc bromide (300mg each) over 15 minutes. The mixture spontaneously warms to reflux. Quickly bring to room temperature with an ice bath and wash with water then saturated sodium hydrogen carbonate. Dry (MgS0₄) and evaporate the solvent in vacuo to give a yellow oil. Purify by silica gel chromatography (30% methylene chloride/hexane then 70% methylene chloride/hexane) and recrystallize (methanol) to give the title compound (2.89g, 65.2%). Step b: 2-Carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene Dissolve 2-carbomethoxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (2.5g, 8.6mmol) in methanol (50mL) and add 1N lithium hydroxide (15mL, 15mmol). Stir at reflux for 12 hours and at room temperature for an additional 12 hours. Dilute with water (10mL) and concentrate in vacuo to 20mL. Wash with ethyl ether and acidify the aqueous phase with 2N hydrochloric acid. Extract with methylene chloride (2X25mL), dry (MgS0₄) and evaporate the solvent in vacuo to give the title compound as a crystalline solid (2.37g, 99%). Step c: N-[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-glycine, benzyl ester Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (997mg, 3.58mmol) in anhydrous methylene chloride (20mL) and add excess oxalyl chloride. Stir at room temperature for 3 hours then evaporate the solvent in vacuo to give the intermediate acid chloride. Dissolve the intermediate acid chloride in methylene chloride (20mL) and add glycine benzyl ester tosylate salt followed by triethylamine (0.94mL, 7.16mmol). Cool briefly with an ice bath then stir overnight at room temperature. Pour into water and separate the organic phase. Wash with 2N hydrochloric acid then saturated sodium hydrogen carbonate. Dry (MgS0₄) and evaporate the solvent in vacuo to give 1.5g crude product as a clear heavy oil. Purify by silica gel chromatography (25% ethyl acetate/hexane) to give the title compound as a crystalline solid (1.3g, 85.6%). Step d₁: N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine, benzyl ester Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-glycine, benzyl ester (1.11g, 2.60mmol) in trifluoroacetic acid (10mL) and add mercuric acetate (824mg, 2.6mmol). Stir at room temperature under an argon atmosphere for 4.5 hours then treat with gaseous hydrogen sulfide. Remove the resulting black solid by filtration and dilute the filtrate with methylene chloride to 100mL volume. Wash with water then with brine and dry (MgS0₄). Evaporate the solvent in vacuo and purify by silica gel chromatography (20-25% ethyl acetate/hexane) to give the title compound as a heavy white oil (905mg, 94%). Anal. Calcd for C₂₁H₂₃NO₃S: C, 68.27; H, 6.27; S; 8.68; Found: C, 67.96; H, 6.31; S, 8.40. Example 2 N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-glycine, benzyl ester Mix N-[[1,2,3,4-tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine, benzyl ester (2.24g, 6.07mmol) and sulfuric acid (0.1mL of a 10% solution in acetic acid). Add acetic anhydride (0.572mL, 6.07mmol) and stir for 2 hours. Dilute with ethyl ether, wash with water then saturated sodium hydrogen carbonate and brine. Dry (MgS0₄) and evaporate the solvent in vacuo to give 2.2g of a yellow oil. Purify by silica gel chromatography (5% ethyl ether/methylene chloride) to give the title compound as a light yellow oil (1.76g, 70.4%). Example 3 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine Dissolve N-[[1,2,3,4-tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine, benzyl ester (74mg, 0.2mmol) in dimethylsulfide (2mL) and add trifluoromethanesulfonic acid (0.2mL). Stir at room temperature under an argon atmosphere for 1 hour. Dilute to a volume of 50mL with methylene chloride and extract with brine. Dry (MgS0₄) and evaporate the solvent in vacuo to give 53mg crude product. Purify by silica gel chromatography (methylene chloride then with 0.1:1:1 acetic acid:ethyl acetate:hexane) and recrystallize (methylene chloride/hexane) to give the title compound as a crystalline solid (32mg, 50%); mp 136-145°C. Example 4 N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-glycine Mix N-[[1,2,3,4-tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine (18.7g, 67.2mmol) and sulfuric acid (0.3mL of a 10% solution in acetic acid). Add acetic anhydride (6.34mL, 67.2mmol) over 10 minutes. Allow to cool, pour into ethyl ether and wash with water three times. Separate the organic phase, dry (MgS0₄) and evaporate the solvent in vacuo to give the title compound. Example 5 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-valine Step c: N-[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-valine, benzyl ester Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278mg, 1.0mmol) in anhydrous tetrahydrofuran (10mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230mg, 1.2mmol), L-valine benzyl ester hydrochloride (244mg, 1.00mmol) and triethylamine (0.132mL, 1.00mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (256mg, 55%). Optional Step d₂: N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-valine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-valine, benzyl ester (256mg, 0.547mmol) in dimethylsulfide (3mL) and add trifluoromethanesulfonic acid (0.2mL). Stir at room temperature under an argon atmosphere for 6 hours. Dilute with water and extract into ethyl ether. Wash with water, then brine and dry (MgS0₄). Evaporate the solvent in vacuo to give the title compound. Optional Step e₃: N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-valine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-valine in trifluoroacetic acid (2mL) and add mercuric acetate (175mg, 0.547mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:10:10/acetic acid/ethyl acetate/hexane) to give the title compound as a viscous light yellow oil (138mg, 78%). Example 6 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-alanine Step c: N-[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-alanine, benzyl ester Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (278mg, 1.0mmol) in anhydrous tetrahydrofuran (10mL). Add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (230mg, 1.2mmol), L-alanine benzyl ester hydrochloride (216mg, 1.00mmol) and triethylamine (0.132mL, 1.00mmol). Stir at room temperature under an argon atmosphere overnight. Partition between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgSO₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (20% ethyl acetate/hexane) to give the title compound as a clear yellow oil (210mg, 48%). Optional Step d₂: N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-alanine Dissolve N-[[1,2,3,4-tetrahydro-2[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-alanine, benzyl ester (210mg, 0.48mmol) in dimethylsulfide (3mL). Add excess anisole and trifluoromethanesulfonic acid (0.5mL). Stir at room temperature under an argon atmosphere overnight. Dilute with water and extract into ethyl ether. Wash with water, then brine and dry (MgS0₄). Evaporate the solvent in vacuo to give the title compound. Optional Step e₃: N-[[1,2,3,4-Tetrahydro-2-(mercarptomethyl)-2-naphthalenyl]carbonyl]-L-alanine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-alanine in trifluoroacetic acid (2mL) and add mercuric acetate (175mg, 0.547mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:10:10/acetic acid/ethyl acetate/hexane) to give the title compound as a viscous light yellow oil (138mg, 78%). Example 7 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-leucine Step c: N-[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-leucine, methyl ester Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (997mg, 3.58mmol) in anhydrous methylene chloride (20mL) and add excess oxalyl chloride. Stir at room temperature for 3 hours then evaporate the solvent in vacuo to give the intermediate acid chloride. Dissolve the intermediate acid chloride (156mg, 0.5mmol) in anhydrous methylene chloride (2mL). Add L-leucine methyl ester hydrochloride (91mg, 0.5mmol) and triethylamine (0.132mL, 1.00mmol). Stir at room temperature under an argon atmosphere overnight and evaporate the solvent in vacuo. Partition the residue between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgS0₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (1:1 ethyl acetate/hexane) to give the title compound as a clear yellow oil (145mg, 71.5%). Optional Step d₂: N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-leucine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-leucine, methyl ester (146mg, 0.36mmol) in methanol (3mL). Add a solution of lithium hydroxide monohydrate (1mL in water, 1mmol) and stir at room temperature under argon for 16 hours. Evaporate the solvent in vacuo without heat and acidify with 2N hydrochloric acid. Extract into methylene chloride (2X), dry (MgS0₄) and evaporate the solvent in vacuo to give the title compound as as white foam (142mg, 100%). Optional Step e₃: N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-leucine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-leucine (142mg, 0.36mmol) in trifluoroacetic acid (2mL) and add mercuric acetate (115mg, 0.36mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:10:10/acetic acid/ethyl acetate/hexane) to give the title compound as a viscous light yellow oil (107mg, 88%). Example 8 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-β-alanine Step c: N-[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-β-alanine, methyl ester Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (997mg, 3.58mmol) in anhydrous methylene chloride (20mL) and add excess oxalyl chloride. Stir at room temperature for 3 hours then evaporate the solvent in vacuo to give the intermediate acid chloride. Dissolve the intermediate acid chloride (148mg, 0.5mmol) in anhydrous methylene chloride (5mL). Add β-alanine methyl ester hydrochloride (60mg, 0.5mmol) and triethylamine (0.132mL, 1.00mmol). Stir at room temperature under an argon atmosphere for 45 minutes and evaporate the solvent in vacuo . Partition the residue between ethyl ether and 5% sulfuric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgS0₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (3:1 ethyl acetate/hexane) to give the title compound as a clear yellow oil (119mg, 65%). Optional Step d₂: N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbony]-β-alanine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-β-alanine, methyl ester (119mg, 0.33mmol) in methanol (3mL). Add an aqueous solution of lithium hydroxide hydrate (1mL, 1mmol) and stir at room temperature under argon overnight. Evaporate the solvent in vacuo to a volume of 1mL. Partition between 1N hydrochloric acid and methylene chloride. Separate the organic phase and extract the acidic phase with methylene chloride (2X10mL). Combine the organic phases, dry (MgS0₄) and evaporate the solvent in vacuo to give the title compound (106mg, 93%). Optional Step e₃: N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-β-alanine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-β-alanine (106mg, 0.30mmol) in trifluoroacetic acid (3mL) and add mercuric acetate (97mg, 0.30mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:10:10/acetic acid/ethyl acetate/hexane) to give the title compound as a clear yellow film (78mg, 88%). Example 9 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-phenylalanine Step c: N-[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-phenylalanine, methyl ester Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (997mg, 3.58mmol) in anhydrous methylene chloride (20mL) and add excess oxalyl chloride. Stir at room temperature for 3 hours then evaporate the solvent in vacuo to give the intermediate acid chloride. Dissolve the intermediate acid chloride (148mg, 0.5mmol) in anhydrous methylene chloride (5mL). Add L-phenylalanine methyl ester hydrochloride (108mg, 0.5mmol) and triethylamine (0.132mL, 1.00mmol). Stir at room temperature under an argon atmosphere for 45 minutes and dilute with ethyl ether (50mL). Wash with 5% sulfuric acid, then saturated sodium hydrogen carbonate (2X10mL). Dry (MgS0₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (1:3 ethyl acetate/hexane) to give the title compound as a yellow oil (158mg, 72%). Optional Step d₂: N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl)carbonyl]-L-phenylalanine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-phenylalanine, methyl ester (158mg, 0.36mmol) in methanol (3mL). Add a solution of lithium hydroxide hydrate (1mL in water, 1mmol) and stir at room temperature under argon overnight. Partition between 1N hydrochloric acid and methylene chloride. Separate the organic phase and extract the acidic phase with methylene chloride (2X10mL). Combine the organic phases, dry (MgS0₄) and evaporate the solvent in vacuo to give the title compound (149mg, 97%). Optional Step e₃: N-[[1,2,3,4-Tetrahydro-2-(mercarptomethyl)-2-naphthalenyl]carbonyl]-L-phenylalanine Dissolve N-[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]-L-phenylalanine (149mg, 0.35mmol) in trifluoroacetic acid (3mL) and add mercuric acetate (111mg, 0.35mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:8:12/acetic acid/ethyl acetate/hexane) to give the title compound as a viscous light yellow oil (121mg, 94%). Example 10 7-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-heptanoic acid Step c: 7-[[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]amino]-heptanoic acid Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (997mg, 3.58mmol) in anhydrous methylene chloride (20mL) and add excess oxalyl chloride. Stir at room temperature for 3 hours then evaporate the solvent in vacuo to give the intermediate acid chloride. Dissolve the intermediate acid chloride (200mg, 0.67mmol) in acetone (3mL). Add a solution of 7-amino heptanoic acid hydrochloride (120mg, 0.67mmol) in saturated sodium hydrogen carbonate. Stir at room temperature under an argon atmosphere for 30 minutes. Partition the residue between methylene chloride and 2N hydrochloric acid. Separate the organic phase and wash with water, saturated sodium hydrogen carbonate and brine. Dry (MgS0₄) and evaporate the solvent in vacuo . Purify by silica gel chromatography (1:4:15 acetic acid/ethyl acetate/hexane) to give the title compound as a clear yellow oil (140mg, 52%). Optional Step e₃: 7-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-heptanoic acid Dissolve 7-[[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]amino]-heptanoic acid (140mg, 0.345mmol) in trifluoroacetic acid (3mL) and add mercuric acetate (110mg, 0.345mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:6:15/acetic acid/ethyl acetate/hexane) to give the title compound as a viscous light yellow oil (101mg, 84%). Example 11 4-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid Step c: 4-[[[1,2,3,4-Tetrahydro-2-[[(t-butyl)thio]methyl]-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid Suspend 5% rhodium/carbon (2g) in water (50mL) and add 4-aminobenzoic acid (27.4g, 200mmol) and dilute to 200mL with water. Shake the mixture at 50 psi for 4 days, filter through glass fiber and evaporate the solvent in vacuo to a white solid. Mix the solid with diphenyl ether and heat quickly to reflux for 20 minutes. Cool and partition between hexane and water. Separate the organic phase and wash with water. Combine the aqueous phases, treat with sodium hydrogen carbonate and subject to continuous extraction with methylene chloride overnight. Evaporate the methylene chloride extracts in vacuo to give 3-isoquinuclidone as a white solid. Dissolve 3-isoquinuclidone (1.5g) in methanol (50mL) and saturated with HCl. Set stand overnight then warm to reflux for 16 hours. Evaporate the solvent in vacuo to give cis-4-amino-cyclohexanecarboxylic acid, methyl ester hydrochloride as a white foam. Dissolve cis-4-amino-cyclohexanecarboxylic acid, methyl ester hydrochloride (1.5g) in water (5mL) and add concentrated hydrochloric acid (5mL). Reflux under an argon atmosphere for 12 hours and evaporate the solvent in vacuo to give cis-4-amino-cyclohexanecarboxylic acid hydrochloride. Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (997mg, 3.58mmol) in anhydrous methylene chloride (20mL) and add excess oxalyl chloride. Stir at room temperature for 3 hours then evaporate the solvent in vacuo to give the intermediate acid chloride. Dissolve cis-4-amino-cyclohexanecarboxylic acid hydrochloride (121mg, 0.67mmol) in saturated sodium hydrogen carbonate (3mL). Add a solution of the intermediate acid chloride (200mg, 0.67mmol) in acetone (3mL) and stir at room temperature under an argon atmosphere for 30 minutes. Partition the residue between methylene chloride and 2N hydrochloric acid. Separate the organic phase, dry (MgS0₄) and evaporate the solvent in vacuo. Purify by silica gel chromatography (1:5:15 acetic acid/ethyl acetate/hexane) to give the title compound as a white crystalline solid (160mg, 59%). Optional Step e₃: 4-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid Dissolve 4-[[[1,2,3,4-tetrahydro-2-[[(t-butyl)thio]methyl]2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid (160mg, 0.40mmol) in trifluoroacetic acid (3mL) and add mercuric acetate (126mg, 0.40mmol). Stir at room temperature under an argon atmosphere overnight. Saturate the resulting solution with hydrogen sulfide, filter and wash with methylene chloride. Concentrate the filtrate in vacuo and purify by silica gel chromatography (1:4:15/acetic acid/ethyl acetate/hexane) to give the title compound as a white foam (130mg, 94%). Example 12 N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester 2-Carboxy-2-[(acetylthio)methyl]-1,2,3,4-tetrahydronaphthalene Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (5.36g, 20.0mmol) in trifluoroacetic acid (40mL) and add mercuric acetate (6.36g, 20.0mmol). Stir at ambient temperature under an atmosphere of argon for 4.5 hours, then treat with gaseous hydrogen sulfide. Remove the resulting black solid by filtration and dilute the filtrate to 100mL with methylene chloride. Wash with water, then with brine and dry (MgSO₄). Evaporate the solvent in vacuo to a residue. Mix the residue with sulfuric acid (0.3mL of 10% solution in acetic acid) and add acetic anhydride (2.04g, 20.0mmol). Stir the mixture for 2 hours under an atmosphere of argon at ambient temperature, then dilute with 100mL ethyl ether. Wash with water, brine then dry (MgSO₄). Concentrate the filtrate in vacuo to give the title compound. N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester Dissolve 2-carboxy-2-[(acetylthio)methyl]-1,2,3,4-tetrahydronaphthalene (2.88g, 10.0mmol) in dry dimethylformamide (20mL). To this solution add N-methyl morpholine (1.01g, 10.0mmol), isoserine benzyl ester tosylate salt (3.67g, 10.0mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92g, 10.0mmol). Stir the reaction mixture for 18 hours under an atmosphere of argon at ambient temperature then partition between ethyl acetate and dilute HCl. Wash the organic solution with water, saturated sodium hydrogen carbonate then brine. Dry the solution (MgSO₄) and concentrate in vacuo . Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound. Example 13 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl] carbonyl]-isoserine Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (4.41g, 10.0mmol) in deoxygenated tetrahydrofuran (50mL). To this solution add 1N LiOH (30mL, 30.0mmol) and stir under an atmosphere of argon for 4 hours. Concentrate the solution in vacuo then purify the residue by column chromatography (acetic acid:ethyl acetate:hexane) to give the title compound. Example 14 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-isoserine, benzyl ester Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (882mg, 2.00mmol) in tetrahydrofuran (20mL) then add NH₄OH (1mL). Stir at ambient temperature under an atmosphere of argon for 24 hours, then concentrate in vacuo . Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound. Example 15 N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester (882mg, 2.00mmol) in dimethylsulfide (2mL) and add trifluoromethane sulfonic acid (0.2mL). Stir at ambient temperature under an atmosphere of argon for 1 hour. Dilute to a volume of 50mL with methylene chloride and extract with brine. Dry (MgSO₄) and evaporate the solvent in vacuo to give the crude product. Purify the residue by column chromatography (acetic acid:ethyl acetate:hexane) to give the title compound. Example 16 N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine Dissolve 2-carboxy-2-[(acetylthio)methyl]-1,2,3,4-tetrahydronaphthalene (2.88g, 10.0mmol) in dry methylene chloride (20mL). To this solution add piperonyl amine (1.39g, 10.0mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.92g, 10.0mmol). Stir the reaction mixture for 18 hours under an atmosphere of argon at ambient temperature, then partition between ethyl acetate and dilute HCl. Wash the organic solution with water, saturated sodium hydrogen carbonate, then brine. Dry the solution (MgSO₄) and concentrate in vacuo . Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound. Example 17 N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine Dissolve N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-piperonylamine (1.92g, 5.00mmol) in deoxygenated tetrahydrofuran. To this solution add 1N LiOH (10.0mL, 10.0mmol) and stir under an atmosphere of argon for 4 hours. Partition between ethyl acetate and dilute HCl, wash with water and brine, dry (MgSO₄) then concentrate in vacuo . Purify the residue by column chromatography (ethyl acetate:hexane) to give the title compound. As used herein, the term "patient" refers to warm-blooded animals or mammals, including mice, rats and humans. A patient is in need of treatment to inhibit enkephalinase when the patient is suffering from acute or chronic pain and is in need of an endorphin- or enkephalin-mediated analgesic effect or is in need of an antidiarrheal effect. In addition, a patient is in need of treatment to inhibit enkephalinase when the patient is suffering from a disease state characterized by abnormalities in fluid, electrolyte, blood pressure, intraocular pressure, renin, or aldosterone homeostasis, such as, but not limited to, hypertension, renal diseases, hyperaldosteronemia, cardiac hypertrophy, glaucoma and congestive heart failure. In these instances the patient is in need of an ANP-mediated diuretic, natriuretic, hypotensive and hypoaldosteronemic effect. Inhibition of enkephalinase would provide an endorphin- or enkephalin-mediated analgesic effect by inhibiting the metabolic degradation of endorphins and enkephalins. Inhibition of enkephalinase would provide an ANP-mediated diuretic, natriuretic, hypotensive and hypoaldosteronemic effect by inhibiting the metabolic degradation of ANP. In addition, a patient is in need of treatment to inhibit enkephalinase when the patient is in need of an antidepressant effect or a reduction in severity of withdrawal symptoms associated with termination of opiate or morphine administration. A patient is also in need of treatment to inhibit enkephalinase when the patient is in need of an cognition enhancing effect due to a disease state such as Alzheimer's Disease. The identification of those patients who are in need of treatment to inhibit enkephalinase is well within the ability and knowledge of one skilled in the art. A clinician skilled in the art can readily identify, by the use of clinical tests, physical examination and medical/family history, those patients who are in need of an endorphin- or enkephalin-mediated analgesic effect, an antidiarrheal effect, a cognition enhancing effect or an ANP-mediated diuretic, natriuretic, hypotensive or hypoaldosteronemic effect. An effective enkephalinase inhibitory amount of a compound of formula (I) is an amount which is effective in inhibiting enkephalinase and in thus inhibiting the metabolic degradation of the naturally-occurring circulating regulatory peptides such as the endorphins, including enkephalins and ANP. Successful treatment is also understood to include prophylaxis in treating a patient in those instances such as, for example, in a preoperative procedure, where a patient will be suffering from acute or chronic pain in the near future. An effective enkephalinase inhibitory amount of a compound of formula (I) is an amount which is effective in inhibiting enkephalinase in a patient in need thereof which results, for example, in endorphin- or enkephalin-mediated analgesic effects, an antidiarrheal effect, a cognition enhancing effect or an ANP-mediated diuretic, natriuretic, hypotensive, hypoaldosteronemic effect. An effective enkephalinase inhibitory dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication. An effective enkephalinase inhibitory amount of a compound of formula (I) will generally vary from about 0.01 milligram per kilogram of body weight per day (mg/kg/day) to about 20 mg/kg/day. A daily dose of from about 0.1 mg/kg to about 10 mg/kg is preferred. In effecting treatment of a patient, compounds of formula (I) can be administered in any form or mode which makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, and the like. Oral administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the disease state to be treated, the stage of the disease, and other relevant circumstances. Compounds of formula (I) can be administered in the form of pharmaceutical compositions or medicaments which are made by combining the compounds of formula (I) with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the chosen route of administration, and standard pharmaceutical practice. In another embodiment, the present invention provides compositions comprising a compound of formula (I) in admixture or otherwise in association with one or more inert carriers. These compositions are useful, for example, as assay standards, as convenient means of making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of formula (I) is an amount which is readily measurable by standard assay procedures and techniques as are well known and appreciated by those skilled in the art. Assayable amounts of a compound of formula (I) will generally vary from about 0.001% to about 75% of the composition by weight. Inert carriers can be any material which does not degrade or otherwise covalently react with a compound of formula (I). Examples of suitable inert carriers are water; aqueous buffers, such as those which are generally useful in High Performance Liquid Chromatography (HPLC) analysis; organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients. More particularly, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions, or the like. The pharmaceutical compositions may be administered orally, for example, with an inert diluent or with an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the compounds of formula (I) may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of formula (I), the active ingredient, but may be varied depending upon the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the active ingredient present in compositions is such that a unit dosage form suitable for administration will be obtained. The tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders, such as microcrystalline cellulose, gum tragacanth or gelatin; excipients, such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants, such as magnesium stearate or Sterotex; glidants, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin may be added or flavoring agents, such as peppermint, methyl salicylate or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example, as coatings. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral administration, the compounds of formula (I) may be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1 and about 50% of the weight thereof. The amount of the active ingredient present in such compositions is such that a suitable dosage will be obtained. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of glass or plastic. As with any group of structurally related compounds which possess a particular generic utility, certain groups and configurations are preferred for compounds of formula (I) in their end-use application. The compounds of formula (I) wherein n is 2 are preferred. The compounds of formula (I) wherein B is -(CH₂) m -CH(R₂)- are preferred. Compounds of formula (I) wherein m is 0 are preferred and compounds of formula (I) wherein B is a group represented by are preferred. The following specific compounds of formula (I) are particularly preferred in the end-use application of the compounds of the present invention: N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2 naphthalenyl]carbonyl]-glycine, benzyl ester; N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-glycine, benzyl ester; N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine; N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-glycine; N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-valine; N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2 naphthalenyl]carbonyl]-L-alanine; N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-leucine; N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-β-alanine; N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-phenylalanine; 8-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-heptanoic acid; 4-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid. N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl] carbonyl]-isoserine N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-isoserine, benzyl ester N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine. The following studies illustrate the utility of the compounds of the present invention as enkephalinase inhibitors. Enkephalinase is partially purified from rat kidney. The enzyme is extracted from the microvilli fraction by using Triton X-100 according to the method of Malfroy and Schwartz [ J.Biol.Chem. 259 , 14365-14370 (1984)] or by using a proteolytic treatment according to the method of Almenoff and Orlowski [ Biochem . 22 , 590-599 (1983)]. The enzyme is further purified by anion exchange chromatography (Mono Q™ column, Pharmacia) using a Pharmacia FPLC system. The enzyme activity may be measured by the fluorometric methods of Florentin et al. [Anal.Biochem. 141 , 62-69 (1984)] or of Almenoff and Orlowski [ J.Neurochemistry 42 , 151-157 (1984)]. The enzyme is assayed in 50mM HEPES buffer (pH 7.4) in a 3.0 mL reaction volume containing 12 µM of the substrate dansyl-D-AlaGly(p-nitro)PheGly (Km=40 µM) at 25°C. The substrate (and inhibitor) is added from a concentrated stock solution in DMSO (up to 0.1 mL DMSO final volume). The enzyme in a small volume (approximately 0.1 µg of FPLC purified protein) is added to initiate the reaction and the rate of fluorecense increase is recorded continuously using a fluorometer (excitation at 339nm, emission at 562nm). The results of the analysis of enzymatic activity as described in Table 1 indicate that the compounds of the present invention are inhibitors of enkephalinase. K i 's of Compounds of Formula (I) as Inhibitors of Enkephalinase Compound Enkephalinase, K i (nM) 100,250 0.4 101,890 0.3 101,782 2.0 100,552 0.6 100,185 ≦0.2 100,250 = N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine 101,890 = N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-alanine 101,782 = N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-valine 100,552 = 4-[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid 100,185 = N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-β-alanine

Claims: Claims for the following Contracting States : AT, BE, DE, DK, FR, GB, IT, NL, PT, SE A compound of the general formula wherein n is the integer 2, Z is -C(O)OR or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is H, C₁-C₄ alkyl, or benzyl, R₁ is H or -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, and B is a group of the general formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0. A compound according to Claim 1 wherein B is A compound according to Claim 2 wherein m is 0. A compound according to Claim 2 wherein m is 1. A compound according to Claim 1 wherein the compound of general formula I is N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-alanine, N-[[1,2,3,4,-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-valine, 4[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-β-alanine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine, N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-isoserine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-isoserine, benzyl ester, N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine or N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-napthalenyl]carbonyl]-isoserine, benzyl ester. A pharmaceutical composition containing a compound according to any of claims 1 to 5. A pharmaceutical composition according to claim 6 for inhibiting enkephalinase. A pharmaceutical composition according to claim 6 as an endorphin- or enkephalin-mediating analgesic agent. A pharmaceutical composition according to claim 6 as an ANP-mediating hypotensive agent. A pharmaceutical composition according to claim 6 as an ANP-mediating diuretic agent. A pharmaceutical composition according to claim 6 as an antidiarrheal agent. A pharmaceutical composition according to claim 6 for curing and/or preventing Alzheimer's Disease. A pharmaceutical composition according to claim 6 as an immunosuppressive agent. A composition comprising an assayable amount of a compound of Claim 1 in admixture or otherwise in association with an inert carrier. Use of a compound according to any of claims 1 to 5 for preparing a pharmaceutical composition. Claims for the following Contracting State : ES A process for preparing the compounds of general formula wherein n is the integer 2, Z is -C(O)OR, or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is H, C₁-C₄ alkyl, or benzyl, R₁ is H and B is a group of the general formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0, comprising reacting a compound of the general formula wherein n, Z and B are defined as above with mercuric acetate. A process for preparing the compounds of general formula wherein n is the integer 2, Z is -C(O)OR, or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is H, C₁-C₄ alkyl, or benzyl, R₁ is H and B is a group of the formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0, comprising reacting a compound of the general formula wherein n and B are defined as above, Z is -C(O)OR, or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is C₁-C₄ alkyl, or benzyl and R₁ is -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, with aqueous base. A process for preparing the compounds of general formula wherein n is the integer 2, Z is -C(O)OR, or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is H, C₁-C₄ alkyl, or benzyl, R₁ is -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, and B is a group of the general formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0, comprising reacting a compound of the general formula wherein n, Z and B are defined as above and R₁ is H with an acylating agent. A process for preparing the compounds of general formula wherein n is the integer 2 Z is -C(O)OR, or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is C₁-C₄ alkyl, or benzyl, R₁ is -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, and B is a group of the general formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0, comprising reacting a compound of the general formula wherein n and R₁ are defined as above with a compound of the general formula NH₂-B-Z wherein B and Z are defined as above in the presence of an activating agent. A process for preparing the compounds of general formula wherein n is the integer 2, Z is -C(O)OR, R is H, R₁ is H or -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, and B is a group of the general formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0, comprising reacting a compound of the general formula wherein n, R₁ and B are as defined above and Z is the radical -C(O)OR, wherein R is C₁-C₄ alkyl or benzyl with an appropriate acid or aqueous base. A process according to any of Claims 1 to 5 wherein B in general formula I is A process according to Claim 6 wherein m in general formula II is 0. A process according to Claim 6 wherein m in general formula II is 1. A process according to any of Claims 1 to 5 wherein the compound of general formula I is N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-glycine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-L-alanine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-L-valine, 4[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]amino]-cis-cyclohexanecarboxylic acid, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-β-alanine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-3,4-dihydroxybenzylamine, N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-isoserine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]-carbonyl]-isoserine, benzyl ester, N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine or N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine, benzyl ester. A process for preparing a pharmaceutical composition, comprising mixing of at least one compound obtainable according to the process of any of claims 1 to 9 with at least one pharmaceutically acceptable carrier or diluent. A process for preparing a pharmaceutical composition according to claim 10, which is useful in inhibiting enkephalinase. A process for preparing a pharmaceutical composition according to claim 10, which is useful as an endorphin- or enkephalin-mediating analgesic agent. A process for preparing a pharmaceutical composition according to claim 10, which is useful as an ANP-mediating hypotensive agent. A process for preparing a pharmaceutical composition according to claim 10, which is useful as an ANP-mediating diuretic agent. A process for preparing a pharmaceutical composition according to claim 10, which is useful as an antidiarrheal agent. A process for preparing a pharmaceutical composition according to claim 10, which is useful for curing and/or preventing Alzheimer's Disease. A process for preparing a pharmaceutical composition according to claim 10, which is useful as an immunosuppressive agent. A process for preparing a composition which comprises an assayable amount of at least one compound obtainable according to the process of any of claims 1 to 9 comprising mixing of at least one compound obtainable according to the process of any of claims 1 to 9 with at least one inert carrier. Claims for the following Contracting State : GR A compound of the general formula wherein n is the integer 2, Z is -C(O)OR or a phenyl group unsubstituted or substituted with from 1 to 3 substituents selected from the group consisting of OH, C₁-C₄ alkoxy, and methylenedioxy, R is H, C₁-C₄ alkyl, or benzyl, R₁ is H or -C(O)-A, wherein A is C₁-C₄ alkyl, or phenyl, and B is a group of the general formula wherein m is an integer 0 to 5, and R₂ is H, C₁-C₄ alkyl, -CH₂-OH, -CH(OH)-CH₃, -CH₂CH₂SCH₃, phenylmethyl, 4-hydroxy-phenylmethyl or OH, with the proviso that R₂ cannot be OH when m is 0. A compound according to Claim 1 wherein B is A compound according to Claim 2 wherein m is 0. A compound according to Claim 2 wherein m is 1. A compound according to Claim 1 wherein the compound of general formula I is N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-glycine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl)carbonyl]-L-alanine, N-[[1,2,3,4,-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-L-valine, 4[[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]amino]-cis-cyclohexanecarboxylic acid, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-β-alanine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine, N-[[1,2,3,4-tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-3,4-dihydroxybenzylamine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-isoserine, N-[[1,2,3,4-Tetrahydro-2-(mercaptomethyl)-2-naphthalenyl]carbonyl]-isoserine, benzyl ester, N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-naphthalenyl]carbonyl]-isoserine or N-[[1,2,3,4-Tetrahydro-2-[(acetylthio)methyl]-2-napthalenyl]carbonyl]-isoserine, benzyl ester. A process for preparing a pharmaceutical composition, comprising the mixing of at least one compound according to any of claims 1 to 5 with at least one pharmaceutically acceptable carrier or diluent. A process for preparing a pharmaceutical composition according to claim 6, which is useful in inhibiting enkephalinase. A process for preparing a pharmaceutical composition according to claim 6, which is useful as an endorphin- or enkephalin-mediating analgesic agent. A process for preparing a pharmaceutical composition according to claim 6, which is useful as an ANP-mediating hypotensive agent. A process for preparing a pharmaceutical composition according to claim 6, which is useful as an ANP-mediating diuretic agent. A process for preparing a pharmaceutical composition according to claim 6, which is useful as an antidiarrheal agent. A process for preparing a pharmaceutical composition according to claim 6, which is useful for curing and/or preventing Alzheimer's Disease. A process for preparing a pharmaceutical composition according to claim 6, which is useful as an immunosuppressive agent. A composition comprising an assayable amount of a compound of Claim 1 in admixture or otherwise in association with an inert carrier.

Inventors: BEIGHT DOUGLAS W, FLYNN GARY A, BEIGHT, DOUGLAS W., FLYNN, GARY A.
Applicants: MERRELL PHARMA INC, MERRELL PHARMACEUTICALS INC.
Application year: 1992
Main classification: C07C323
IPC codes: A61P1, A61P25, A61P37, A61K31, C12N9, C07C319, A61P7, C07C323, A61P9, C07D317, C07C327