MXPA96003347A - Derivatives of 1,3,5,5-tetrahydro-benzo [c] azepin-3-ona mercaptoacetilamido novedosos, useful as inhibitors of encephalinase and convertible enzyme of angiotens - Google Patents

Abstract

The present invention relates to certain novel 1,3,4,5-tetrahydro-benzo [c] azepin-3-one disulfide derivatives of mercaptoacetylamido (formula I) useful as inhibitors of enkephalinase and agiotensi-converting enzyme.

Description

DERULS OF DISULFIDE OF 1.3. , 5-TETRAHYDRO-BENZ? RC1 AZEPIN-3-ONA OF MERCAPTOACETILAMIDO NOVEDOSOS. USEFUL AS INHIBITORS OF ENCEPHALINASE AND ANGIOTENSIN CONVERTER ENZYME BACKGROUND OF THE INVENTION This application is a partial continuation of Application Serial Number 08 / 195,407, filed on February 14, 1994. Enkephalinase, or more specifically, endopeptidase-24.11, is a mammalian ectoenzyme that is involved in the metabolic degradation of certain circulation regulating peptides. This enzyme, which is a Zn + 2-metallopeptidase, exerts its effect by dissociating the extracellular peptides in the amino group of the hydrophobic residues and, therefore, 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 encephalinas, atrial natriuretic peptide (ANP), and other circulatory regulatory peptides. Endorphins are naturally occurring polypeptides that agglutinate with opiate receptors in different areas of the brain and, therefore, provide an analgesic effect by raising the pain threshold. Endorphins occur in different forms, including a-endorphin, β-endorphin, β-endorphin, as well as the enkephalins. The enkephalins, that is, et-encefaliña and Leu-encefaliña, are pentapeptides that occur in the nerve ends of brain tissue, the spinal cord, and the gastrointestinal tract. Like the other endorphins, the enkephalins provide an analgesic effect by agglutination with the opiate receptors in the brain. The inhibition of enkephalinase inhibits the metabolic degradation of naturally occurring endorphins and enkephalin, thus providing a potent endorphin-mediated or enkephalin-mediated analgesic effect. The inhibition of enkephalinase, therefore, would be useful in a patient suffering from acute or chronic pain. The inhibition of enkephalinase would also be useful to provide an antidepressant effect, and to provide a reduction in the severity of withdrawal symptoms associated with the termination of opiate or morphine administration. In addition, the inhibition of enkephalinase would also be useful in the treatment of irritable bowel syndrome. Auricular natriuretic peptide refers to a family of naturally occurring peptides, which are involved in the blood pressure regulation, as well as sodium and water levels. It has been found that atrial natriuretic peptides vary in length from about 21 to about 126 amino acids, with one common structural feature being one or more 17-amino acid disulfide sequences with different ino-terminal and carboxy-terminal sequences attached to the fraction of cisetin. It has been discovered that atrial natriuretic peptides bind with specific agglutination sites in different tissues, including the kidney, adrenal, aorta, and vascular smooth muscle, with affinities of approximately 50 pico-molar (pM) to approximately 500 nano- molar (nM) [Needle an, Hypertension 7, 469 (1985)]. In addition, it is believed that atrial natriuretic peptide binds to specific receptors in the brain, and possibly serves as a neuromodular, as well as a conventional peripheral hormone. The biological properties of atrial natriuretic peptide involve potent diuretic / natriuretic and vasodilatory / hypotensive effects, as well as an inhibitory effect on the secretion of renin and aldosterone [deBold, Science 230, 767 (1985)]. By the inhibition of enkephalinase, the metabolic degradation of naturally occurring atrial natriuretic peptide is inhibited., thus providing a powerful diuretic, natriuretic, hypotensive and hypoaldosteronemic effect mediated by the atrial natriuretic peptide. The inhibition of enkephalinase, therefore, would be useful in a patient suffering from disease states characterized by abnormalities in fluid, electrolytes, 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 addition, the compounds of the present invention are inhibitors of the Angiotensin Converting Enzyme (ECA). The angiotensin converting enzyme is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor that also stimulates the secretion of aldosterone by the adrenal cortex. The inhibition of angiotensin-converting enzyme, therefore, would be useful in a patient suffering from disease states, such as hypertension and congestive heart failure [see Illiam W. Douglas, "Polypeptides-Angiotensin, Plasma Kinins, and Others", Chapter 27, in Goodman and Gill in the Pharmacoloaical Basis of Therapeutics, 7th edition, 1985, pages 652-3, MacMillan Publishing Co., New York, New York]. In addition, it has been discovered that angiotensin-converting enzyme inhibitors are useful in the treatment of cognitive disorders [German Patent Application Number 3901-291-A, published on August 3, 1989. In addition, the compounds of the present invention invention are useful as inhibitors of the proliferation of smooth cells. The proliferation of smooth muscle cells in the intima of the muscular arteries is a primary cause of vascular stenosis in arteriosclerosis, after vascular surgery, and after coronary angioplasty. Several studies with animals have indicated that the renin-angiotensin system plays an important role in this response vascular to the lesions. Chronic treatment with angiotensin-converting enzyme (ACE) inhibitors reduced myointimal thickening following balloon injury in a carotid artery or rat aorta. Po ell, J.S., Muller, R.K.M. and Bau Gartner, H.R .; Suppression of the vascular response to injury: The role of angiotensin-converting enzyme inhibitors. J.A. Coll. Cardiol. 17: 137B-42B, 1991. More recently, it has been discovered that atrial natriuretic peptide (ANP) decreases myointimal proliferation. Atrial natriuretic peptide is rapidly metabolized through the release mediated by the receptor and by neutral endopeptidase (EPN). The inhibition of the neutral endopeptidase significantly reduces the proliferation in the vasculature of the balloon-injured rabbit. Davis H.R. , McGregor, D.C., Hoss, L., Mullins, D.E. and Sybertz, E.J .; 5 Atrial naturiuretic factor and the neutral inhibitor endopeptidase SCH42495 prevent myointimal proliferation after vascular injury. Cir. 86: 1-220, 1992. These studies imply that a double inhibitor of angiotensin converting enzyme and neutral endopeptidase should be therapeutically useful in the treatment of conditions that require the inhibition of the proliferation of smooth cells. Davis and Sybertz, European Patent Application Number 533084-A1, March 24, 1993.

SUMMARY OF THE INVENTION The present invention provides novel compounds of the Formula (I): where: R? and R2 are each independently hydrogen, hydroxy, -OR6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is an alkyl of 0 to 4 atoms of carbon; or wherein Rx and R2 join with the adjacent carbon atoms, R- ^ and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, -CH2OCH2CH2OCH3, or an Ar-Y- group; R is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCH3, 'CH20H, CH (0H) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the formula: Rc is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y-, or -CH20-C (0) C (CH3) 3 group; G is a radical selected from the group: where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (O) pCH3, or arylalkyl, wherein p is 0, 1 or 2; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -0C (0) R9, wherein R9 is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; R10 is 1 or 2 substituents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; R-L! is hydrogen, alkyl of 1 to 6 carbon atoms, or an Ar-Y- group; R12 is hydrogen or alkyl of 1 to 4 carbon atoms; Vj_ is O, S or NH? V2 is N or CH; V3 is a direct link or -C (0) -; or the stereoisomers or pharmaceutically acceptable salts thereof. The present invention further provides a method for inhibiting enkephalinase in a patient in need, which comprises administering to this patient an effective enkephalinase inhibitory amount of a compound of Formula (I). The present invention also provides a method for inhibiting the angiotensin-converting enzyme in a patient in need, which comprises administering to said patient an effective angiotensin-converting enzyme inhibitory amount of a compound of Formula (I). In addition, the present invention provides a composition comprising a test amount of a compound of Formula (I) mixed or otherwise in association with an inert carrier. The present invention also provides a pharmaceutical composition comprising an effective inhibitory amount of a compound of the Formula (I) admixed, or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

DETAILED DESCRIPTION OF THE INVENTION As used in this application: a) the term "C 1-6 alkyl" refers to a straight or branched chain, saturated, hydrocarbyl radical of from one to six carbon atoms, and includes methyl, ethyl, propyl, isopropyl, normal butyl, isobutyl, tertiary butyl, normal pentyl, cyclopentyl, normal hexyl, cyclohexyl and the like; b) the term "C 1 -C 4 alkyl" refers to a straight or branched, saturated hydrocarbyl radical of one to six carbon atoms, and includes methyl, ethyl, propyl, isopropyl, normal butyl, isobutyl, tertiary butyl; c) the designation "r" refers to a link that protrudes forward out of the plane of the page; d) the designation "" refers to a link that protrudes backwards out of the plane of the page; e) the designation < • N? W »refers to a link for which stereochemistry is not designated; f) the term "halogen" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; ~ g) the term "alkyl of 1 to 8 carbon atoms" refers to straight or branched chain hydrocarbyl radicals, saturated, from one to eight and from one to ten carbon atoms, respectively, including methyl, ethyl, propyl , isopropyl, normal butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, -methyl-3-heptyl and the like; h) the term "C 1 -C 4 alkoxy" refers to a straight or branched alkoxy group containing 1 to 4 carbon atoms, such as methoxy, ethoxy, normal propoxy, isopropoxy, normal butoxy, isobutoxy, butoxy tertiary, etc .; i) the designation "-C (O) -" refers to a carbonyl group of the formula: OR j) the term "Ar-Y-" refers to a radical wherein Ar is an aryl group, and Y is an alkyl of 0 to 4 carbon atoms; k) the term "C 0 -C 4 alkyl" refers to a straight or branched chain hydrocarbyl radical, saturated, of zero to four carbon atoms, and includes a bond, methyl, ethyl, propyl, isopropyl, normal butyl, isobutyl, tertiary butyl and the like; 1) the term "Ar" or "aryl group" refers to a phenyl or naphthyl group unsubstituted or substituted with one to three substituents selected from the group consisting of methylenedioxy, hydroxy, alkoxy of 1 to 4 carbon atoms, fluorine and chlorine; specifically included within the scope of the term "arylalkyl": phenyl, naphthyl, naphthylmethyl, phenylmethyl or benzyl, phenylethyl, p-methoxybenzyl, 3,4-methylenedioxybenzyl, p-fluorobenzyl and p-chlorobenzyl; m) the term "alkoxy group" and the alkoxy moiety of an alkoxycarbonyl group, can be straight or branched chain, and contains from 1 to 8 carbon atoms, preferably from 1 to 4 carbon atoms; are specifically included within the scope of the term "alkoxy group": methoxy, ethoxy, tertiary butoxy and the like; the specific examples of the alkoxycarbonyl groups are methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl and the like; n) the term "pharmaceutically acceptable salts" refers to either acid addition salts or base addition salts.

The term "pharmaceutically acceptable acid addition salts" is intended to be applied to any non-toxic organic or inorganic acid addition salt of a compound of the Formula (I) or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid, and acid metal salts, such as sodium acid monoorthophosphate, and potassium hydrogen sulfate. Illustrative organic acids that form suitable salts include mono-, di- and tri-carboxylic acids. Illustrative of these acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic acids, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroximic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, and sulphonic, such as p-toluenesulfonic acid, methanesulfonic acid, and 2-hydroxyethane sulfonic acid . These salts may exist, either in a hydrated or substantially anhydrous form. The term "pharmaceutically acceptable base addition salts" is intended to be applied to any non-toxic organic or inorganic base addition salts of a compound of Formula (I) or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia and organic aliphatic, cyclic or aromatic amines, such as methyl amine, dimethyl amine, tri-ethyl amine, triethyl amine, diethyl amine, isopropyldietyl amine, pyridine and picoline. As appreciated by one of ordinary skill in the art, compounds of Formula (I) can exist as stereoisomers. Any reference in this application to one of the compounds of Formula (I) means that it encompasses either specific stereoisomers or a mixture of stereoisomers. Specific stereoisomers can be prepared by stereospecific synthesis, or can be separated and recovered by techniques known in the art, such as chromatography, chromatography on chiral stationary phases, fractional recrystallization of addition salts formed by reagents used for that purpose, as described in Enantiomers, Race ates, and Resolutions, J. Jacques, A. Collet, and SH ilen, Wiley (1981). Examples of the compounds encompassed by the present invention include: amine disulfide (S) -Nl- (2-methylpropyl) -2- (thio) -ethyl 2- [4- (2-thio-3-phenyl- propionyl-amino) -3-oxo-1,3,4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric; amine disulfide (R) -1- (2-methylpropyl) -2- (thio) -ethyl 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3-ethyl ester , 4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric; L-cysteine ethyl ester disulfide 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo [c] azepin-2-yl ] -4-methyl-valeric; N-acetyl-L-cysteine ethyl ester disulfide 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo [c] azepin -2-il] -4-methyl-valeric; L-cysteine disulfide 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5-tetrahydrobenzo [c] azepin-2-yl] -4 -methyl-valeric; thiobenzyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl -valérico; '' 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1, 3,4,5-tetrahydrobenzo [c] azepin-2-yl] -4-thioethyl disulfide. -methyl-valeric; 2-hydroxythioethyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo [c] azepin-2-yl] disulphide] -4-methyl-valeric; 2-pyridylthiomethyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3,4,5-tetrahydrobenzo [c] azepin-2-tertiary butyl ester. il] -4-methyl-valeric; morpholino carboxamide disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1, 3,4,5-tetrahydrobenzo [c] azepin-2-2-thioacetic acid. il] -4-methyl-valeric; Thiobenzyl disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric; thioethyl disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5- 5-tetrahydrobenzo [c] azepin-2-yl] ] -4-methyl-valeric; 2-hydroxythioethyl disulfide of tertiary butyl ester disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5-tetrahydrobenzo [c] azepin 2-yl] -4-methyl- > -'- valerico; 0 2-pyridylthiomethyl disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3,4,5-tetrahydrobenzo [c] azepin-2] -yl] -4-methyl-valeric; morpholino carboxamide disulfide of 2-thioacetic acid tertiary butyl ester of 2- [4- (2-thio-3-5-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo] c] azepin-2-yl] -4-methyl-valeric. In Scheme 1 a general synthetic procedure for the preparation of the compounds of the Formula (I) is stipulated. In Scheme 1, all substituents, unless otherwise indicated, are as defined above. The starting materials, reagents, techniques, and procedures employed in Scheme 1 are well known and appreciated by one of ordinary skill in the art.

SCHEME 1 The disulfide of structure (b) can be obtained by methods known in the art, or by methods known analogously in the art, B.P. Roques et al., J. Med. Chem. 33. 2473-2481 (1992). The thiol of structure (a) is prepared according to Scheme A. In Scheme 1, step a, an appropriate disulfide of structure (b) is contacted with an appropriate thiol of structure (a) to give a disulfide of the Formula (I), or a protected disulfide of the Formula (I). A suitable disulfide of structure (b) is one in which G is as desired in the final product of Formula (I), or gives rise, on deprotection, to G, as desired in the final product of the Formula (I) An appropriate thiol of the structure (a) is one in which Rlf R2, R3, R4 and R5 are as desired in the final product of Formula (I), or give rise, after deprotection, to Rlf R2, R3, R and R5 as desired in the final product of Formula (I). For example, an appropriate disulfide of the structure (b) is contacted with an appropriate thiol of structure (a). The reaction is carried out in a suitable solvent, such as ethanol, methanol, dichloromethane, or mixtures of ethanol or methanol and dichloromethane. The solvent is degassed by passing a stream of nitrogen gas through it for 15 minutes before the reaction is performed. The reaction is carried out using 1.0 to 4.0 molar equivalents of an appropriate compound of structure (b). The reaction is carried out at temperatures from 0 ° C to the reflux temperature of the solvent, with a temperature of 10 ° C to 30 ° C being preferred. The reaction usually requires 1 to 48 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation and precipitation. The product can be purified by chromatography and recrystallization. In Scheme 1, optional step b, a protected disulfide of Formula (I) is deprotected to give a disulfide of Formula (I). The selection, use and removal of the protecting groups, and the removal of the protecting groups in a sequential manner using suitable protecting groups, such as those described in Protectin Groups in Orqanic Synthesis by T. Greene, are well known and appreciated by the experts in this field. The removal of the protecting groups, or the removal of the protecting groups in a sequential manner, as required, gives disulfides of the Formula (I). The following examples present typical syntheses, as described in Scheme 1. It is understood that these examples are illustrative only, and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the indicated meanings: "g" refers to grams, "mmol" refers to millimoles, "L" refers to milliliters, "° c" refers to degrees Celsius, "Rf" refers to retention factor, "pf" it refers to melting point, "des" refers to decomposition, "M" refers to molar, and "CCD" refers to thin layer chromatography.

PREPARATION 1 Tertiary butyl ester of 2-f4- (2-mercapto-3-phenyl-propionyl-aminol-3-oxo-l.3.4, 5-tetrahydrobenzorcl-azepin-2-yl] -4-methyl-valeric acid. combine tertiary butyl ester of 2- [4-benzoylsulphanyl-3-phenyl-propionyl-amino] -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -4-methyl ester -valérico (0.229 millimoles) in degassed methanol (3 milliliters), and cooled in an ice bath. It is treated with deionized aqueous lithium hydroxide (1.0 milliliters) and stirred, allowing the ice bath to gradually warm for 3 hours. With the reaction at 0 ° C, it is acidified with 5 percent hydrochloric acid. It is partitioned between methylene chloride and water, dried (Na2SO4), and purified by silica gel chromatography, to give the title compound.

EXAMPLE 1 Amine disulfide (S) -N- (tertiary butoxycarbonyl) -l- (2-methylpropyl) -2- (thio) -ethyl tertiary butyl ester of 2-T4- (2-thio-3-) acid phenyl-propionyl-amino) -3-oxo-l, 3, 4,5-tetrahydro-benzorc1azepin-2-yl-1-4-yl-valeric acid. Scheme 1, step a; Tertiary butyl ester of 2- [4- (2-mercapto-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] tertiary butyl ester is combined -4-methyl-valeric (1.20 mmol), and 2-thiopyridine disulfide of amine (S) -N- (tert-butoxy-carbonyl) -l- (2-methylpropyl) -2- (thio) -ethyl (1.46 mmol) ) in degassed ethanol (10 milliliters). It is stirred for 20 hours. It evaporates under vacuum. Chromatography is carried out on silica gel to give the title compound.

EXAMPLE 2 Amine disulfide (R) -N- • (tertiary butoxycarbonyl) -1- (2-methylpropyl) -2- (thio) -ethylliol = a tertiary butyl ester of 2-T4-thio-3-phenyl '-propionyl-amino) -3- OXO-1, 3, 4, 5-tetrahydro-benzorclazepin-2-yl-1-4-methyl -valérico. Scheme 1, step a: Tertiary butyl ester of 2- [4- (2-mercapto-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] is combined. azepin-2-yl] -4-methyl-valeric and 2-thiopyridine disulfide of amine (R) -N- (tert-butoxycarbonyl) -1- (2-methylpropyl) -2- (thio) -ethyl (1.46 millimoles) in degassed ethanol (10 milliliters). Stir for 18 hours. It evaporates under vacuum. Chromatography is carried out on silica gel to give the title compound.

EXAMPLE 3 Amine disulfide (S) -Nl- (methylpropyl) -2- (thio) -ethyl 2-f4-thio-3-phenyl-propionyl-amino acid) -3-oxo-l, 3,4,5 -tetrahydro-benzorcl zepin-2-ill -4-methyl-valeric. Scheme 1, step a; Amine disulfide (S) -N- (tertiary butoxycarbonyl) -1- (2-methylpropyl) -2- (thio) -ethyl tertiary butyl ester of 2- [4- (2-thio-3 phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -4-methyl-valeric (1.00 mmol) with methylene chloride (5 milliliters) , and treated with anisole (1.50 milliliters), and then with trifluoroacetic acid (1.0 milliliters). Stir at room temperature for 15 hours, and partition between ethyl acetate and brine. The organic layer is washed with brine, dried (Na2SO4), and purified by silica gel chromatography to give the title compound.

EXAMPLE 4 Amine (R) -1- (2-methylpropyl) -2- (thio) -ethyl 2-f4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1-ethyl ester disulfide 3, 4,5-tetrahydro-benzofc1azepin-2-ip-4-methyl-valeric. Scheme 1, step a: Combine amine disulfide (R) -N- (tertiary butoxy-carbonyl) -1- (2-methylpropyl) -2- (thio) -ethyl tertiary butyl ester of 2- [4- thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -4-methyl-valeric (1.2 mmol) with methylene chloride ( 5 milliliters), and treated with anisole (1.20 milliliters), and then with trifluoroacetic acid (1.0 milliliters). Stir at room temperature for 15 hours, and partition between ethyl acetate and brine. The organic layer is washed with brine, dried (Na2SO4), and purified by silica gel chromatography to give the title compound.

EXAMPLE 5 2-triopyridine disulfide of tertiary butyl ester of 2- r4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1 acid, 3, 4,5-tetrahydro-benzofc1azepin-2-ylT-4-yl-valeric. Tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] is combined. -4-methyl-valeric (4.0 mmol), and 2,2'-dithiodipyridine (16.0 mmol) in degassed ethanol (24 milliliters) and dichloromethane (6 milliliters). It is stirred under an inert atmosphere at room temperature for 20 hours. It is evaporated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound. In Scheme 2 for the preparation of the compounds of Formula (I), an alternative general synthetic procedure is stipulated. In Scheme 2, all substituents, unless otherwise indicated, are as defined above. The starting materials, reagents, techniques and procedures employed in Scheme 2 are well known and appreciated by one of ordinary skill in the art.

SCHEME 2 o Protected Formula (I) In Scheme 2, step a, an appropriate thiol of structure (d) is contacted with an appropriate disulfide of structure (4) to give a disulfide of Formula (I), or a protected disulfide of the Formula ( I), by the method described above in Scheme A, step a. A suitable thiol of structure (d) is one in which G is as desired in the final product of Formula (I), or gives rise, after deprotection, to G, as desired in the final product of the Formula, (I). A suitable disulfide of structure (c) is one in which R 1 R2, R 3, R 4 and R 5 are as desired in the final product of Formula (I), or give rise, after deprotection, to R 2 R 2, R3, R4 and R5 as desired in the final product of Formula (I). A suitable compound of structure (c) can be prepared by methods known analogously in the art, B.P. Roques et al., J. Med. Chem. 33, 2473-2481 (1992), from compounds of structure (a) prepared according to Scheme A. In Scheme 2, optional step b, a protected disulfide of Formula (I) is deprotected to give a disulfide of Formula (I) as described in Scheme 1, optional step b above. The following examples present typical syntheses, as described in Scheme 2. It is understood that these examples are illustrative only, and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the indicated meanings: "g" refers to grams, "mmol" refers to millimoles, "L" refers to milliliters, "° C" refers to degrees Celsius, "Rf" refers to retention factor, "pf" it refers to melting point, "des" refers to decomposition, "M" refers to molar, and "CCD" refers to thin layer chromatography.

EXAMPLE 6 N- (tertiary-butoxycarbopyl) -l-cysteine tertiary butyl ester ethyl ester disulfide and 2- (4-thio-) 3-phenyl-p-ionic acid 1- amino) -3 -oxo- 1, 3, 4.5-t etra idr o-benzo fclazepin-2-ill-methy1-valeric. Scheme 2, step a; 2-thiopyridine disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo] is combined [c] azepin-2-yl] -methyl-valeric (1.4 mmol) and ethyl ester of N- (tertiary butoxy-carbonyl) -L-cysteine (2.0 mmol) in degassed ethanol / dichloroethane (10 milliliters) / (2 milliliters). Stir for 18 hours. It is evaporated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

EXAMPLE 7 Thiobenzyl disulfide of tertiary acid butyl ester 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3, 5-tetrahydro-benzo-re-azepin-2-yl-methyl-valeric. Scheme 2, step a; 2-thiopyridine disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo] is combined [c] azepin-2-yl] -methyl-valeric (1.4 mmol), and benzylthiol (1.7 mmol) in degassed ethanol / dichloromethane (15 milliliters) / (3 milliliters). Stir for 18 hours. Benzylthiol (1.7 mmol) is added and stirred for 24 hours. It is evaporated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

EXAMPLE 8 Thioethyl disulfide of tertiary butyl ester of 2-f 4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzorclazepin-2-ip- methyl-valeric. Scheme 2, step a; 2-thiopyridine disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo] is combined [c] azepin-2-yl] -ethyl-valeric (1.68 mmol) and ethylthiol (2.7 mmol) in degassed ethanol / dichloromethane (15 milliliters) / (3 milliliters). Stir for 18 hours. Ethylthiol (2.7 mmol) is added and stirred for 24 hours. It is evaporated in vacuo to obtain a residue. The residue is chromatographed on silica gel, eluting 30 percent ethyl acetate / hexane to give the title compound as a solid.

EXAMPLE 9 2-f- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3,4,5-tetrahydro-benzofclazepin-2-tertiary butyl ester disulfide 2-hydroxythioethyl disulphide -ilT-methyl-valeric. Scheme 2. step a; '2-thiopyridine disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] is combined. ] azepin-2-yl] -methyl-valeric (1.54 mmol), and 2-hydroxyethylthiol (2.85 mmol) in degassed ethanol / dichloromethane (15 milliliters) / (3 milliliters). Stir for 18 hours. It is diluted with dichloromethane and extracted with a saturated solution of sodium chloride. Dry the organic layer over MgSO, filter, and concentrate in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

EXAMPLE 10 2-pyridylthiomethyl disulfide of tertiary butyl ester of 2-4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzofclazepin-2-ylT -methyl-valeric. Scheme 2, step a: Combine 2-thiopyridine dieulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5- tetrahydro-benzo [c] azepin-2-yl] -methyl-valeric (1.40 mmol), and pyridylmethylthiol (2.10 mmol) in degassed ethanol / dichloromethane (10 milliliters) / (2 milliliters). Stir for 18 hours. Concentrate in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

PREPARATION 2 Morpholinocarboxamide of 2-thiolacetic acid. Preparation of the starting material for Scheme 2, step a: Chloroacetyl chloride (2.00 milliliters, 25.0 mmol) and N-methyl morpholine (2.76 milliliters, 25.0 mmol) in dichloromethane (100 milliliters) are combined. It cools in a cold bath. Morpholine (2.19 milliliters, 25.0 mmol) is added and stirred in the ice bath for 1 hour. Warm to room temperature and stir for 1 hour. It is extracted with a 5% cold aqueous solution of sulfuric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride. Dry the organic layer over Na 2 SO 4, filter and evaporate in vacuo to obtain morpholinocarboxamide of chloroacetic acid. The morpholino carboxamide of chloroacetic acid prepared above (2.88 grams, 17.6 millimoles), and thiolacetic acid (1.40 milliliters, 20.0 millimoles) in degassed dimethyl amide (10 milliliters) are combined. Slowly add cesium carbonate (3.26 grams, 10.0 mmol), providing cooling as necessary to maintain the temperature of the reaction mixture below 40 ° C. It is stirred at room temperature for 16 hours. The reaction mixture is partitioned between water and ethyl acetate. Dry the organic layer over Na 2 SO 4, filter and evaporate in vacuo to obtain a residue. The residue is chromatographed on silica gel, eluting in sequence with 40 percent ethyl acetate / hexane, and then 66 percent ethyl acetate / hexane, to give 2-acetylthioacetic acid morpholinocarboxamide. The morpholino carboxamide of 2-acetylthioacetic acid obtained above (2.50 grams, 12.0 mmol), and degassed methanol (50 milliliters) are combined. It cools in a cold bath. Lithium hydroxide hydrate (1.0 grams, 24.0 mmol) is added. Stir for 3 hours. The reaction mixture is acidified to pH = 1 with 6 M hydrochloric acid solution. The reaction mixture is partitioned between water and dichloromethane. The organic layer is extracted with a saturated aqueous solution of ammonium chloride. Dry the organic layer over Na 2 SO 4, filter, and evaporate in vacuo to obtain a residue. The residue is chromatographed on silica gel eluting with ethyl acetate to give the title compound.

EXAMPLE 11 Carboxamide 2-thioacetic acid morpholinic tertiary butyl ester of 2-T4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l acid, 3,4, 5-tetrahydro-benzo-fe] azepin-2-y1] -methyl-valeric. Scheme 2, step a: Combine 2-thiopyridine disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5- tetrahydro-benzo [c] azepin-2-yl] -methylvaleric (1.40 millimoles), and morpholinocarboxamide of 2-thiolacetic acid (2.0 millimoles) in degassed ethanol / dichloromethane (10 milliliters) / (2 milliliters). It is stirred for 16 hours. Concentrate in vacuo to obtain a residue. The residue is chromatographed on silica gel eluting with 50 percent ethyl acetate / dichloromethane to give the title compound.

EXAMPLE 12 Salt of ethyl ester disulfide trifluoroacetic acid of L-cysteine of 2-f- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3,3,5,5-tetrahydro-benzofcTazepin-2-in-methyl-valeric acid. Scheme 2, optional step b; N- (tertiary butoxycarbonyl) -L-cysteine ethyl ester disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxoyl] 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -methyl-valeric (1.20 mmol), anisole (13.0 mmol) and dichloromethane (15 milliliters). It cools in a cold bath. Trifluoroacetic acid (3 milliliters) is added. It is stirred for 2 hours in the ice bath, and then warmed to room temperature, and stirred for an additional 2 hours. It is evaporated in vacuo to obtain a residue. Carbon tetrachloride is added to the residue, and evaporated in vacuo to obtain a residue. Triturate with hexane, filter and dry in vacuo to give the title compound.

EXAMPLE 13 Thiobenzyl disulfide of 2-f4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzofcTazepin-2-yl-methyl-valeric acid. Scheme 2, optional step b: Thiobenzyl disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro] is combined. -benzo [c] azepin-2-yl] -methyl-valeric (1.02 mmol), anisole (10.0 mmol) and dichloromethane (10 milliliters). It cools in a cold bath. Trifluoroacetic acid (2.0 milliliters) is added. It is stirred for 2.5 hours in the ice bath. It is evaporated in vacuo to obtain a residue. The residue is dissolved in diethyl ether and extracted with a hydrochloric acid solution. The aqueous layer is extracted with dichloromethane. The organic layers are combined, dried over MgSO, filtered, and concentrated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

EXAMPLE 14 2-f- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,, 5-1-tetrahydro-benzo-clazepin-2-y1] -methyl-valeric acid thioethyl ester disulfide. Scheme 2, optional step b: Thioethyl disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3,4,5-tetrahydro) is combined -benzo [c] azepin-2-yl] -methyl-valeric (1.43 mmol), anieol (10.0 mmol) and dichloromethane (14 milliliters). It cools in a cold bath. Trifluoroacetic acid (2.0 milliliters) is added. It is stirred for 2.5 hours in the ice bath. It is evaporated in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

EXAMPLE 15 2- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1, 3,4,5-tetrahydro-benzofclazepin-2-yl] -me il- 2-hydroxythioethyl disulfide. valeric Scheme 2, optional step b: 2-hydroxythioethyl disulfide of tertiary butyl ester disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4 , 5-tetrahydro-benzo [c] - azepin-2-yl] -methyl-valeric acid (0.9 mmol), anisole (10.0 mmol) and dichloromethane (10 milliliters). It cools in a cold bath. Trifluoroacetic acid (2.0 milliliters) is added. It is stirred for 2.5 hours in the ice bath. HE _ ,. evaporate in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound.

EXAMPLE 16 2-f- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3, 4,5-tetrahydro-benzofc1azepin-2-pyridylthiomethyl-2-trifluoroacetic acid salt il] -methyl-valeric.

Scheme 2, optional step b: Combine 2-pyridylthiomethyl disulfide of tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5 -tetrahydro-benzo [c] azepin-2-yl] -methyl-valeric acid (0.5 mmol), anisole (6.9 mmol) and dichloromethane (15 milliliters). It cools in a cold bath. Trifluoroacetic acid (1.4 milliliters) is added. Stir for 3 hours in the ice bath. It is evaporated in vacuo to obtain a residue. Carbon tetrachloride is added to the residue, and evaporated in vacuo to obtain a residue. Triturate with hexane, filter and dry to give the title compound.

EXAMPLE 17 Morpholine carboxamide disulfide of 2-f4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1, 3, 4,5-tetrahydro-benzorclazepin-2-i 2-thioacetic acid. ] -methyl-valeric. Scheme 2, optional step b; Combine morpholinic carboxamide disulfide of 2-thioacetic acid tertiary butyl ester of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5-tetrahydro- benzo [c] azepin-2-yl] -methyl-valeric (0.68 mmol), anisole (6.9 mmol) and dichloromethane (7.5 milliliters). It cools in a cold bath. Trifluoroacetic acid (2.0 milliliters) is added. It is stirred for 2 hours in the ice bath. Evaporate in vacuo to obtain a residue. The residue is chromatographed on silica gel to give the title compound. The compounds of structure (a) can be prepared by using procedures and techniques well known and appreciated by one of ordinary skill in the art. Scheme A stipulates a general synthetic scheme for the preparation of these compounds, wherein all substituents, unless otherwise indicated, were defined above.

Scheme A ADDITION / ELIMINATION (3) HYDROLYSIS Step d Scheme A (Cont.) H2N (6) (7) AND (8) PhthN (9) Scheme? (Cont.) PhthN (11) (12) VULNERABILITY PhthN Step k (13) Scheme A (Cont.) AMINATION (14) 15 CHJtS-Pg / R3 (16) Pg - acetyl or benzoyl In step a, an appropriate 2- (2-hydroxymethyl-phenyl) -ethanol derivative of structure (1) is functionalized to give the corresponding 2- (2-chloromethyl-phenyl) -ethyl ester derivative of methanesulfonic acid of the structure (2). For example, a suitable 2-2 (hydroxymethyl-phenyl) -ethanol derivative of structure (1) is initially treated with lithium chloride and a suitable non-nucleophilic base, such as collidine in a suitable aprotic organic solvent, such as formamide Dimethyl This is followed by a treatment with a suitable mesylating agent, such as silyl chloride. The reaction is typically conducted on a temperature scale of -30 ° C to room temperature, preferably at 0 ° C, and for a period of time of 2 to 10 hours. The corresponding 2- (2-chloromethyl-phenyl) -ethyl ester derivative of methanesulfonic acid of structure (2) is recovered from the reaction mixture by extraction methods, as are known in the art, and can be purified by chromatography . In step b, the methanesulfonate functionality of the appropriate 2- (2-chloromethyl-phenyl) -ethyl ester derivative of methanesulfonic acid of structure (2) is removed, and the chlorine is replaced with iodine to give the derivative of -iodomethyl-2-vinyl-benzene corresponding to structure (3). For example, the appropriate 2- (2-chloromethylphenyl) -ethyl ester derivative of methanesulfonic acid of structure (2) is treated with a suitable non-nucleophilic base, such as tertiary potassium butoxide in a suitable aprotic organic solvent, such as diethyl ether. The reaction is typically conducted on a temperature scale of -30 ° C to room temperature, preferably at 0 ° C, and for a period of time from 15 minutes to 5 hours. The corresponding l-chloromethyl-2-vinylbenzene derivative is recovered from the "*" reaction mixture by extraction methods, as is known in the art. Then the appropriate l-chloromethyl-2-vinylbenzene derivative is treated with a suitable iodinating agent, such as sodium iodide, in a suitable solvent, such as acetone. The reaction is conducted on a temperature scale from room temperature to the reflux temperature of the solvent, and for a period of time from 15 minutes to 5 hours. The corresponding l-iodomethyl-2-vinylbenzene derivative of structure (3) is recovered from the reaction mixture by extraction methods, as are known in the art. In step c, the appropriate l-iodomethyl-2-vinylbenzene derivative of structure (3) is subjected to an addition / elimination reaction with 2- (bis-methylsulfonyl-methyleneamino) -l- (10)., 10-dimethyl-3,3-dioxo-3-thia-4-azatricyclo [5.2.1.0 1, 5] dec-4-yl) -ethanone (4) to give the 2-bis-methylsulfonyl derivative methyleneamino) -1- (10, 10-dimethyl-3, 3-dioxo-3-thia-4-aza-tricyclo [5.2.1.01, 5] dec-4-yl) -3- (2-vinylphenyl) -propan -1-one corresponding to the structure (5). For example, the anion of 2- (bis-methylsulfonyl-methyleneamino) -1- (10,10-dimethyl-3, 3-dioxo-3-thia-4-aza-tricyclo [5.2.1.0 l, 5] dec- 4-yl) -ethanone (4) is formed by the treatment of 2- (bis-methylsulfonyl-methyleneamino) -1- (10,10-dimethyl-3, 3-dioxo-3-thia-4-aza-tricyclo [ 5.2.1.01, 5] dec-4-yl) -ethanone (4) with a suitable non-nucleophilic base, such as normal butyl ilthio in a suitable aprotic organic solvent, such as tetrahydrofuran. The reaction is conducted on a temperature scale of -78 ° C to -30 ° C, preferably at -78 ° C, and for a period of time from 30 minutes to 5 hours. The appropriate l-iodomethyl-2-vinylbenzene derivative of structure (3) is then added, and the reaction is conducted on a temperature scale of -78 ° C to room temperature for a period of time from 1 to 24 hours. The derivative of 2- (bis-ethylsulphonyl-methyleneamino) -1- (10,10-dimethyl-1,3-, 3-dioxo-3-thia-4-aza-tricyclo [5.2.1.01, 5] dec-4-il] -3- (2-vinyl-phenyl) -propan-1-one of structure (5) is recovered from the reaction mixture by extraction methods, as are known in the art, and can be purified by chromatography. step d, the derivative of 2- (bis-methylsulfonyl-methyleneamino) -1- (10,10-dimethyl-3, 3-dioxo-3-thia-4-aza-tricyclo [5.2.1.01,5] dec-4 -yl] -3- (2-vinyl-phenyl) -propan-1-one of the structure (5) is hydrolyzed to give the corresponding 2-amino-3- (2-vinyl-phenyl) -propionic acid derivative of structure (6) For example, the derivative of 2- (bis-methylsulfonyl-methyleneamino) -1- (10,10-dimethyl-3, 3-dioxo-3-thia-4-aza-tricyclo [5.2. 1.01, 5] dec-4-yl] -3- (2-vinyl-phenyl) -propan-1-one of the structure (5) is treated with a suitable acid, such as aqueous hydrochloric acid in a suitable organic solvent , such as tetrahydrofuran. The reaction is conducted on a temperature scale of -10 ° C to room temperature, and for a period of time from 30 minutes to 20 hours. The solvent is evaporated, followed by treatment with an inorganic base, such as aqueous lithium hydroxide in a suitable organic solvent, such as tetrahydrofuran. The reaction is conducted on a temperature scale of -10 ° C to room temperature, and for a period of time from 30 minutes to 10 hours. After acidification, the corresponding 2-amino-3- (2-vinyl-phenyl) -propionic acid derivative of structure (6) is isolated by evaporation of the solvents. In step e, the amino functionality of the appropriate 2-amino-3- (2-vinyl-phenyl) -propionic acid derivative of structure (6) is protected to give the derivative of 2- (1, 3) acid. -dioxo-l, 3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic corresponding to the structure (7). For example, the appropriate 2-amino-3- (2-vinyl-phenyl) -propionic acid derivative of structure (6) is treated with an appropriate italic imide protective agent, such as N-carbethoxytallic imide in the presence of a suitable non-nucleophilic baee, such as aqueous sodium carbonate. The reaction is conducted on a temperature scale of -10 ° C to room temperature, and for a period of time of 1 to 10 hours. The corresponding 2- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid derivative of structure (7) is recovered from the zone of reaction by extraction methods, as are known in the art, and can be purified by chromatography. In step f, the carboxylic acid functionality of the 2- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid derivative is esterified from structure (7), to give the 2-trimethylsilylethyl ester derivative of 2- (1) acid, Corresponding 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic of structure (8). For example, the 2- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid derivative of the structure (7) is treated with 2. - (trimethylsilyl) ethanol in the presence of a suitable non-nucleophilic base, such as pyridine, in a suitable organic solvent, such as tetrahydrofuran. The reaction is conducted on a temperature scale of -30 ° C to room temperature, and for a period of time from 5 minutes to 2 hours. Then a coupling agent, such as carbodiimide 1- (3-dimethyl-aminopropyl) -3-ethyl (EDC), is added, and the reaction is conducted on a temperature scale of -30 ° C to room temperature over a period of time. of time from 10 to 48 hours. The corresponding 2-trimethylsilylethyl ester derivative of 2- (1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid of structure (8) is it recovers from the reaction zone by extraction methods, as are known in the art, and can be purified by chromatography. In step g, the vinyl functionality of the 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) 2-trimethylsilylethyl ester derivative is oxidized. ) -propionic appropriate structure (8), to give the derivative 2-trimethylsilylethyl ester of 2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (2-formyl) -phenyl) -propionic corresponding structure (9). For example, the 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid derivative of the appropriate 2-trimethylsilanyl ester of the structure (8), is treated with ozone in a suitable organic solvent, such as methylene chloride and methanol. The reaction is conducted on a temperature scale of -78 ° C to -50 ° C, and for a period of time necessary for a blue color to persist. After purging the reaction with nitrogen and quenching by methods known in the art, such as addition of dimethyl sulfide and pyridine, the 2-trimethylsilylethyl 2-l, 3-dioxo-1, 3-ester derivative is recovered. -dihydro-isoindol-2-yl) -3- (2-formyl-phenyl) -propionic corresponding to the structure (9) of the reaction zone by extraction methods, as are known in the art, and can be purified by chromatography In step h, the 2-trimethylsilylethyl ester derivative of appropriate 2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3- (2-formyl-phenyl) -propionic acid of the structure (9), is subjected to reductive amination with an appropriate tertiary butyl ester derivative of amino acid of structure (10), to give the tertiary butyl ester derivative of 2- acid. { 2- [1,3-dioxo-l, 3-dihydro-isoindol-2-yl) -2- (2-trimethylsilanyl-ethoxycarbonyl) -ethyl] -benzylamino} - corresponding acoustic structure (11). For example, the 2-trimethylsilanyl ethyl derivative of 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-formyl-phenyl) -propionic acid ester appropriate from the structure (9), is treated with an appropriate tertiary amino acid butyl ester derivative of structure (10) in an appropriate polar organic solvent, such as methanol, under dehydration conditions, such as with molecular sieves. The reaction is conducted on a temperature scale of -10 ° C to the reflux temperature of the solvent, preferably at room temperature, and for a period of time from 30 minutes to 10 hours. Then a suitable reducing agent, such as sodium cyanoborohydride, is added, and the reaction is conducted on a temperature scale of -10 ° C to the reflux temperature of the solvent, preferably at room temperature, and over a period of time. from 30 minutes to 24 hours. The tertiary butyl ester derivative of 2- acid. { 2- [1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -2- (2-trimethylsilanyl-ethoxycarbonyl) -ethyl] -benzylamino} The corresponding acetic structure (11) is recovered from the reaction zone by extraction methods, as are known in the art, and can be purified by chromatography. As would be appreciated by one skilled in the art, the tertiary amino acid butyl ester derivatives of structure (10), wherein R 4 has a reactive functionality, the reactive functionality can be protected prior to the reductive amination reaction of step h. The selection and use of suitable protecting groups are well known to one of ordinary skill in the art, and are described in "Protective Groups in Orqanic Synthesis". Theodora W. Greene, Wiley (1981). In step i, the ester functionality of the tertiary butyl ester derivative of 2- acid is hydrolyzed. { 2- [1, 3-dioxo-1, 3-dihydro-isoindol-2-yl) -2- (2-trimethylsilanyl-ethoxycarbonyl) -ethyl] -benzylamino} - appropriate acetic structure (11), to give the tertiary butyl ester derivative of 2- acid. { 2- [1,3-dioxo-l, 3-dihydro-isoindol-2-yl) -ethyl] -benzylamino} - corresponding acoustic structure (12). For example, the tertiary butyl ester derivative of 2- acid. { 2- [1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -2- (2-trimethylsilane-1-ethoxycarbonyl) -ethyl] -benzylamino} The appropriate acetic structure (11) is treated with an appropriate fluoride reagent, such as tetrabutyl ammonium fluoride in a suitable organic solvent, such as tetrahydrofuran. The reaction is conducted on a temperature scale of -10 ° C to room temperature, and for a period of time from 30 minutes to 5 hours. The tertiary butyl ester derivative of 2- acid. { 2- [1,3-dioxo-l, 3-dihydro-isoindol-2-yl) -ethyl] -benzylamino} The corresponding acetic of the structure (12) is recovered from the reaction zone by extraction methods, as are known in the art, and can be purified by chromatography. In step j, the tertiary butyl ether derivative of 2- acid. { 2- [l, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -ethyl] -benzylamino} The appropriate acetic structure (12) is subjected to a ring closure amination reaction to give the tertiary butyl ester derivative of 2- [4- (1,3-dioxo-1,3-dihydroisoindole) -2-yl) -3-oxo-l, 3, 4, 5-tetrahydro-benzo [c] azepin-2-yl] -acetic corresponding to structure (13). For example, the tertiary butyl ester derivative of 2- acid. { 2- [1,3-dioxo-l, 3-dihydro-isoindol-2-yl) -ethyl] -benzylamino} The appropriate acetic of the structure (12) is treated with a suitable activating agent, such as isobutyl chlorofor-ato, in the presence of a suitable non-nucleophilic base, such as N-methyl morpholine in a suitable organic solvent, such as tetrahydrofuran. . The reaction is conducted on a temperature scale from -10 ° C to the reflux temperature of the solvent, and for a period of time from 30 minutes to 10 hours. The tertiary butyl ester derivative of 2- [4- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -3-oxo-l, 3, 4, 5-tetrahydro-benzo [c] ] azepin-2-yl] -acetic acid of the structure (13) is recovered from the reaction zone by evaporation, and can be purified by chromatography. In step k, the phthalic imide protecting group is removed from the tertiary butyl ester derivative of 2- [4- (1, 3-dioxo-1,3-dihydro-isoindol-2-yl) -3-oxo- 1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -acetic appropriate structure (13), to give the tertiary butyl ester derivative of 2- (4-amino-3-oxo) - 1, 3, 4, 5-tetrahydrobenzo- [c] azepin-2-yl) -acetic corresponding to structure (14). For example, the appropriate imide-protecting groups can be removed using hydrazine monohydrate in a suitable protic solvent, such as methanol. The reaction is conducted on a temperature scale of -10 ° C to room temperature, and for a period of time from 2 hours to 4 days. The tertiary butyl ester derivative of 2- (4-amino-3-oxo-l, 3, 4, 5-tetrahydrobenzo [c] azepin-2- '<)- il) - corresponding acetic of structure (14) is recovered from the reaction zone by filtration and evaporation. In step 1, the tertiary butyl ester derivative of 2- (4-amino-3-oxo-; 3,4,5-tetrahydrobenzo [c] azepin-2-yl) -acetic acid appropriate to the structure ( 14), is subjected to an amination reaction with the appropriate thioacetate or thiobenzoate derivative of structure (15), to give the tertiary butyl ester derivative of 2- (4- (2-acetyle-sulfanyl-3-phenyl-propionyl) -amino-3-oxo-l, 3, 4, 5-tetrahydro-benzo [c] azepin-2-yl) -acetic corresponding, or the tertiary butyl ester derivative of 2- (4- (2-benzoylsulfani 1 -3-phenyl-propionyl and 1-amino-3-oxo-1, 3,4,5-tetrahydro-benzo [c] azepin-2-yl) -acetic corresponding to structure (16). of tertiary butyl ester of 2- (4-amino-3-oxo-l, 3, 4, 5-tetrahydro-benzo [c] azepin-2-yl) -acetic acid appropriate to structure (14) can be made react with the appropriate thioacetate or thiobenzoate derivative of the structure (15), in the presence of a reagent coupling, such as EEDQ (l-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline), DCC (carbodiimide 1,3-5 dicyclohexyl), or diethyl cyanophosphonate in a suitable aprotic solvent, such as methylene chloride. The reaction is conducted on a temperature scale of -10 ° C to room temperature, and for a period of time from 1 hour to 2 days. The tertiary butyl ester derivative of 2-0 (4- (2-benzoylsulfanyl-3-phenyl-propionyl-amino-3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl) The corresponding acetic of the structure (16) is recovered from the reaction zone by extraction methods, as is known in the art, and can be purified by chromatography.5 As would be appreciated by one skilled in the art, the derivative of tertiary butyl ester of 2- (4- (2- ... acetylsulfanyl-3-phenyl-propionyl-amino-3-oxo-l, 3, 4, 5-tetrahydro-benzo [c] azepin-2-yl) ) -acetic, or the tertiary butyl ester derivative of 2- (4- (2-benzoylsulfanyl-3-0 phenyl-propionyl-amino-3-oxo-l, 3,4, 5-tetrahydro-benzo [c]) azepin-2-yl) -acetic of structure (16), wherein Pg is an acetyl or benzoyl protecting group, can be hydrolyzed using techniques and procedures well known in the art, to give the compounds of structure (a) The 5 selection and use of agents d Suitable deprotection is well known to one of ordinary skill in the art, and is described in "Protective Groups in Orqanic Synthesis." Theodora W. Greene, iley (1981). For example, the thioacetate or thiobenzoate functionality of the appropriate thioacetate or thiobenzoate compound of structure (a), wherein R5 is tertiary butyl, can be removed with lithium hydroxide in a suitable solvent mixture, such as tetrahydrofuran and ethanol, to give the appropriate thio compound of the structure (a) used as starting material in Scheme 1. The tertiary butyl ester functionality of the appropriate thioacetate or thiobenzoate compound of structure (a), wherein R5 is tertiary butyl , can be removed using trifluoroacetic acid to give the appropriate thioacetate or thiobenzoate carboxylic acid compound of structure (a), wherein R5 is hydrogen. Alternatively, the carboxylic acid functionality of the appropriate thioacetate or thiobenzoate carboxylic acid compound of structure (a) can be re-esterified using techniques and procedures well known and appreciated in the art. For example, a thioacetate or thiobenzoate compound of structure (a), wherein R5 is alkyl of 1 to 4 carbon atoms, or an Ar-Y- group, or -CH20-C (0) C (CH3) 3 it can be prepared by treating the thioacetate or thiobenzoate carboxylic acid compound of structure (a), wherein R5 is hydrogen, with the alkyl halide of 1 to 4 carbon atoms, the halide of Ar-Y, or the appropriate chloromethyl pivalate, in a suitable aprotic solvent, such as dimethyl formamide, together with a non-nucleophilic base, such as cesium carbonate. The thioacetate or thiobenzoate functionalities of the appropriate thioacetate or thiobenzoate compound of structure (a), wherein R5 is alkyl of 1 to 4 carbon atoms or an Ar-Y- group, or -CH20-C (?) C ( CH3) 3 can be hydrolysed in the corresponding thiol compounds of structure (a) with ammonia, in a suitable protic solvent, such as methanol. The starting materials to be used in the general synthetic procedures illustrated in the Scheme A, they are readily available to an ordinary expert in this field. For example, 2- (bis-methylsulfanyl-methyleneamino) -1- (10,10-dimethyl-3, 3-dioxo-3-thia-4-aza-tricyclo [5.2.1.0 1, 5] dec-4- il] -ethanone is described in Tetrahedron Letters, page 6009, 1989. The following examples present typical syntheses, as described in Scheme A. It is understood that these examples are illustrative only, and are not intended to limit the scope of the present invention to As used herein, the following terms have the indicated meanings: "g" refers to grams, "mmol" refers to millimoles, "mL" refers to milliliters, "pe" refers to point of boiling; "° c" refers to degrees Celsius; "mm Hg" refers to millimeters of mercury, "μl" refers to microliths, "μg" refers to micrograms, and "μM" refers to micromolar.

EXAMPLE 18 Preparation of tertiary butyl ester of 2 -r- (2-benzoylsulfanyl-3-phenyl-propionyl-amino) -3-oxo-1, 3,4, 5-tetrahydro-benzophe] azepin-2-ill- 4-me il-valeric.

Step to; 2- (2-Chloromethylphenyl) -ethyl ester of methanesulfonic acid. Homophthalic acid (22.2 grams, 0.123 mmol) is dissolved in tetrahydrofuran (250 milliliters), and added dropwise, at room temperature, to a paste of lithium-aluminum hydride (15.5 grams, 0.407 moles) in tetrahydrofuran (500 milliliters). ). Heat to reflux for 18 hours, cool in an ice bath, and carefully add, by dropwise addition, water (16 milliliters), followed by 50 percent sodium hydroxide (16 milliliters). The ice bath is removed, water is added slowly with stirring, and the mixture is stirred until the gray precipitate becomes white, and gas evolution ceases. Filter, wash the solids with methylene chloride, dry (MgSO 4) and evaporate the solvent in vacuo to give 2- (2-hydroxymethyl-phenyl) -ethanol as a viscous oil (18.4 grams, 98 percent). 2- (2-Hydroxymethyl-phenyl) -ethanol (12.0 grams, 78 mmol) and collidine (23 milliliters, 0.17 mol) are mixed, and treated with lithium chloride (7.35 grams, 0.173 mmol) in dimethyl formamide (125 milliliters) ). It is cooled in an ice bath, and treated, by dropwise addition, with mesyl chloride (13.4 milliliters). It is stirred at 0 ° C for 4 hours, divided between ice water (300 milliliters) and a 1: 1 mixture of ether: pentane (2 x 400 milliliters). The organic layer is washed with a saturated solution of CuSO (2 x 200 milliliters), dried (MgSO4) and purified by silica gel chromatography (2.5: 1, hexane / ethyl acetate, followed by 2: 1, hexane. ethyl acetate, followed by 3: 2, hexane / ethyl acetate), to give the title compound as a pale yellow oil (8.8 grams, 45 percent).

Step b: l-Iodomethyl-2-vinylbenzene 2- (2-chloromethyl-phenyl) -ethyl ester of methanesulfonic acid (8.8 grams, 35.4 mmol) in ether (80 milliliters) is dissolved and cooled to -35 ° C. Tertiary potassium butoxide (10 grams, 89 mmol) is added and stirred for 30 minutes. Water (50 milliliters) and ether (150 milliliters) are added, extracted, dried (Na2SO4), and purified by silica gel chromatography (2: 3, methylene chloride / pentane), to give l-chloromethyl- 2-vinylbenzene as a colorless oil (4.43 grams, 82 percent). L-chloromethyl-2-vinylbenzene (4.0 grams, 26 mmol) is dissolved in acetone (100 milliliters), and sodium iodide (4.5 grams, 30 mmol) is added. Heat to a slight reflux for 30 minutes. Cool, add water (150 milliliters) and extract with pentane (200 milliliters). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (95 percent).

Step c: 2- (Bis-methylsulfanyl-methyleneamino)) -1- (10,10-dimethyl-3,3-dioxo-3-thia-4-aza-trichloro5.2.1.0 l, 51dec-4-yl- 3- (2-vinyl-phenyl) -propan-1-one Dissolves 2- (bie-ethylsulfanyl-methyleneamino) -1- (10,10-dimethyl-3, 3-dioxo-3-thia-4-aza) -trip [5.2.1.0 1, 5] dec-4-yl] -ethanone (7.91 gram, 21.0 mmol) in tetrahydrofuran (100 milliliters), and cooled to -78 ° C. It is treated, by dropwise addition, with 1.6M normal butyl lithium in hexane (13.1 milliliters, 21 millimoles). The mixture is stirred for 1.5 hours, then phosphotrylamidahexamethyl (HMPA) (4.25 milliliters, 24.4 mmol) is added. It is stirred for 15 minutes, and a solution of 1-iodomethyl-2-vinylbenzene (6.1 grams, 25 mmol) in tetrahydrofuran (100 milliliters) is added by means of a cannula. It is stirred overnight at room temperature, divided between saturated ammonium chloride (2 x 75 milliliters) and ethyl acetate (100 milliliters). Dry (Na2SO), and purify by silica gel chromatography (2.5: 1 hexane / ethyl acetate) to give the title compound as a white solid (4.5 grams).

Step d; 2-Amino-3- (2-vinyl-phenyl) -propionic acid Dissolves 2- (bis-methylene-sulfanyl-methyleneamino) -1- (10,10-dimethyl-3,3-dioxo-3-thia-4-aza) -trich [5.2.1.0 l, 5] dec-4-yl] -3- (2-vinyl-phenyl) -propan-1-one (5.21 grams, 10.6 millimoles) in tetrahydrofuran (100 milliliters), and hydrochloric acid 0.75 N (100 milliliters), stirring at room temperature for 24 hours, evaporate the solvent in vacuo to give the hydrochloride salt as a white solid, dissolve in tetrahydrofuran (200 milliliters) and water (50 milliliters), add lithium hydroxide monohydrate (1.9 grams, 4.5 mmol), and stirred at room temperature under a nitrogen atmosphere for 4 hours, extracted into methylene chloride (200 milliliters) and washed with 2N sodium hydroxide (50 milliliters) Acidify to a pH of 2-3 with cooling in an ice bath, and concentrate in vacuo to give the title compound as a white solid (3.40 grams, 100 percent) Step e: 2- (1, 3-di oxo-l, 3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid 2-Amino-3- (2-vinyl-phenyl) -propionic acid (3.40 grams) is dissolved in water (75 milliliters), and sodium carbonate (1.97 grams, 18.6 millimoles) and N-carbetoxtallic imide (2.81 grams, 12.8 millimoles) are added. It is stirred for 2.5 hours, washed with methylene chloride (200 milliliters), acidified to a pH of 1 with cold concentrated hydrochloric acid, and extracted with ethyl acetate (3 x 200 milliliters), dried (Na 2 SO 4), The solvent is evaporated in vacuo, and purified by silica gel chromatography (1: 1: 2 percent hexane / ethyl acetate / acetic acid), followed by recrystallization (isopropanol) to give the title compound as a solid. pale yellow (2.47 grams).

Step f; 2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid 2-trimethylsilalethyl ester. 2- (1, 3-Dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid (2.47 grams, 7.69 mmol) is dissolved in tetrahydrofuran (35 milliliters), and it cools in a cold bath. It is treated with pyridine (1.6 milliliters, 20 millimoles), and 2- (trimethylsilyl) ethanol (2.3 milliliters, 16 millimoles). Stir for 30 minutes, and add l- (3-dimethylaminopropyl) -3-ethyl (EDC) carbodiimide hydrochloride (2.21 grams, 11.5 mmol). It is stirred for 22 hours at 5 ° C, and then at room temperature for 1.5 hours. Cool to 0 ° C, add all the reagents 0.6 times and stir at room temperature overnight. Dilute with ethyl acetate (150 milliliters), wash with 5 percent sulfuric acid (40 milliliters), and saturated sodium acid carbonate (40 milliliters). Extract back with methylene chloride (100 milliliters), wash with brine (30 milliliters), and dry (Na S04). The solvent is evaporated in vacuo and purified by silica gel chromatography (2: 1 hexane / ethyl acetate) to give the title compound (2.61 grams, 81 percent).

Step q: 2- (1, 3-Dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-formyl-phenyl) -propionic acid 2-trimethylsilylethyl ester. 2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-vinyl-phenyl) -propionic acid ester (2.61 grams, 6.19 mmol) in chloride is dissolved in 2-trimethylsilylethyl ester. of methylene (70 milliliters) and methanol (75 milliliters). It is cooled to -78 ° C and treated with ozone until a blue color persists. Purge with nitrogen, and add dimethyl sulfide (7 milliliters) and pyridine (0.35 milliliters). Allow to warm to room temperature gradually overnight. It is divided between methylene chloride (100 milliliters) and water (40 milliliters). Extract the aqueous with methylene chloride (50 milliliters), dry (Na2SO4), and purify by silica gel chromatography (2.5: 1 hexane / ethyl acetate) to give the title compound as a colorless viscous oil ( 2.65 grams, 100 percent).

Step h: Tertiary 2- tertiary acid ester. { 2-f2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -2- (2-trimethylsilanyl-ethoxycarbonyl) -ethyl] benzylamino >; - -methyl-valeric. 2-Trimethylsilaylethyl 2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -3- (2-formyl-phenyl) -propionic acid ester (250 milligrams, 0.590 mmol) in methanol is dissolved (15 milliliters), and treated with hydrochloride-tertiary butyl ester L-leucine (0.66 grams, 3.0 millimoles). Stir at room temperature for 2 hours with 3A molecular sieves, add sodium cyanoborohydride (0.6 milliliters) of a 1.0M solution in tetrahydrofuran, 0.6 mmol), stir for 0.5 hours, add additional sodium cyanoborohydride (0.3 milliliters) ), and stirred for 5 hours. Filter through a filter aid, evaporate the solvent in vacuo, and partition the residue between methylene chloride (100 milliliters) and saturated sodium hydrogen carbonate (40 milliliters). Dry (N2SO4), evaporate the solvent in vacuo, and purify by silica gel chromatography (5: 1 hexane / ethyl acetate, followed by 3: 1 hexane / ethyl acetate), to give the title compound (221 milligrams, 63 percent).

Step i: Tertiary butyl ester of acid 2-. { 2-f2-carboxy-2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -ethyl-benzylamino} -4-methyl-valeric. Tertiary butyl ester of 2- acid is dissolved. { 2- [2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) -2- (2-trimethylsilanyl-ethoxycarbonyl) -ethyl] benzylamino} -4-methyl-valeric (221 milligrams, 0.372 mmol) in tetrahydrofuran (5 milliliters), and treated with tetrabutyl ammonium fluoride (0.43 milliliters) of a 1.0M solution in tetrahydrofuran, 0.43 millimole). Stir for 1.5 hours, evaporate the solvent in vacuo, and dissolve the residue in ethyl acetate (75 milliliters). Wash with IN hydrochloric acid (25 milliliters) and brine (25 milliliters). Dry (N2SO4) and evaporate the solvent in vacuo to give the title compound as a white solid (188 milligrams).

Step j; Tertiary butyl ester of 2-f4- ((1,3-dioxo-1,3, dihydro-isoindol-2-yl) -3-oxo-l, 3,4,5-tetrahydro-benzofc1azepin-2-yl '| - -methyl-valeric, tertiary butyl ester of 2- {2- [2-carboxy-2- (l, 3-dioxo-l, 3, dihydro-isoindo1-2-y1) -ethyl-benzylamine) is dissolved. .) -4-methyl-valeric (188 milligrams) in tetrahydrofuran (10 milliliters), and cooled in an ice-cold bath. N-methyl morpholine (86 microliters, 0178 mmol) is added in sequence, and isobutyl chloroformate (55 microliters, 0.43 mmol), stir for 2 hours, filter, wash the salts with dry tetrahydrofuran, evaporate the solvent in vacuo, and purify by silica gel chromatography (1: 1 hexane / ethyl acetate) to give the title compound as a white solid (64 milligrams, 93 percent).

Step K: 2- (4-Amino-3-oxoyl, 3,4,5-tetrahydro-benzorc-1azepin-2-yl-4-methyl-valeric acid tertiary butyl ester.) Tertiary butyl ester of 2-acid is dissolved [-4- ((1, 3-DIOXO-1, 3, dihydro-isoindol-2-yl) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] - 4-Methyl-valeric (160 milligrams, 0.336 mmol) in methanol (3 milliliters) and treated with a solution of hydrazine monohydrate (0.40 milliliters, 0.40 millimoles) in methanol, stirred at room temperature for 65 hours, filtered through a filter aid, it is washed with methylene chloride, filtered through the filter aid, and dried (MgSO 4). The solvent is evaporated in vacuo to give the title compound (93 milligrams, 80.2 percent). ).

Step 1: Tertiary butyl ester of 2-f4- (2-benzoylsulfanyl-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzofc1azepin-2-yl-4-methyl- valeric Tertiary butyl ester of 2- (4-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -4-methyl-valeric acid (93 milligrams, 0.27) is dissolved. millimoles) in methylene chloride (3 milliliters), and treated with (S) -3-phenyl-2-benzoylthiopropionic acid (115 milligrams, 0.40 millimoles) and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (100 millimoles). milligrams, 0.40 millimoles). Stir at room temperature for 18 hours, evaporate the solvent in vacuo, dissolve the residue in ethyl acetate (40 milliliters), and wash with 5 percent sulfuric acid (15 milliliters), and then with acid carbonate. of saturated sodium (15 milliliters). Dry (N2SO4), evaporate the solvent in vacuo, and purify by silica gel chromatography (6: 1 hexane / ethyl acetate, followed by 2.5: 1 hexane / ethyl acetate to give the title compound as a colorless oil (141 milligrams, 85 percent).

EXAMPLE 19 Preparation of 2-f4- (2-benzoylsulfanyl-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzorc-aazepin-2-yl-4-methyl-valeric acid. Tertiary butyl ester of 2-4 (2-benzoylsulfani1-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] -4- is dissolved. methyl-valeric (141 milligrams, 0.229 millimoles) in methylene chloride (5 milliliters), and treated with anisole (0.12 milliliters, 1.15 millimoles), and then with trifluoroacetic acid (1.5M). Stir at room temperature for 15 hours, partition between ethyl acetate (25 milliliters) and brine (15 milliliters). Wash the organic layer with brine (15 milliliters), dry (N2SO4), and purify by silica gel chromatography (1: 1 hexane / ethyl acetate, followed by 1: 1: 0.01 hexane / ethyl acetate acetic acid) to give the title compound as a white solid (157 milligrams).

EXAMPLE 20 Preparation of acid 2-f4- (2-mercapto-3-phenyl-propionyl-amino) -3-oxo-l, 3, 4, 5-tetra idro-benzofc] azepin-2-i1") - 4- methyl-valeric acid 2- [4- (2-Benzoylsulfanyl-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydro-benzo [c] azepin-2-yl] is dissolved -4-methyl-valeric (0.229 millimole) in degassed methanol (3 milliliters) and cooled in an ice bath, treated with deionized aqueous lithium hydroxide (1.0 milliliter), and stirred, allowing the ice bath to warm Gradually for 3 hours, with the reaction at 0 ° C, it is acidified with 5 percent hydrochloric acid, divided between methylene chloride (75 milliliters) and water (25 milliliters), dried (N2SO4), and purified by silica gel chromatography (3: 1: 0.01 hexane / ethyl acetate / acetic acid, followed by 1: 1: 0.01 hexane / ethyl acetate / acetic acid) to give the title compound as a white solid (84 milligrams, 80.8 percent.) As used in the present, 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 analgesic effect mediated by endorphin or encephalitis. 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 the homeostasis of fluids, electrolytes, blood pressure, intraocular pressure, renin, or aldosterone, such as, but not limited to, hypertension, renal diseases, hyperaldosteronemia, cardiac hypertrophy, glaucoma and congestive heart failure. In these cases, the patient is in need of a diuretic, natriuretic, hypotensive and hypoaldosteronemic effect mediated by atrial natriuretic peptide. The inhibition of enkephalinase would provide an analgesic effect mediated by endorphin or enkephalin by inhibiting the metabolic degradation of endorphins and enkephalins. The inhibition of enkephalinase would provide a diuretic, natriuretic, hypotensive and hypoaldosteronemic effect mediated by atrial natriuretic peptide, by inhibiting the metabolic degradation of atrial natriuretic peptide. The inhibition of enkephalinase would also modulate the contractility of intestinal smooth muscle, and would be useful in the treatment of irritable bowel syndrome. 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 the severity of withdrawal symptoms associated with termination of opiate or morphine administration. The identification of these patients who are in need of treatment to inhibit enkephalinase is well within the skill and knowledge of an expert in ^ this field. A clinician trained in the field can easily identify, through the use of clinical tests, a physical examination, and medical / family history, patients who are in need of an endorphin or enkephalin-mediated analgesic effect, or who are in need of a diuretic, natriuretic, hypotensive or hypoaldosteronemic effect mediated by atrial natriuretic peptide. An effective enkephalinase inhibiting amount of a compound of Formula (I) is an amount which is effective "to inhibit enkephalinase and, consequently, to inhibit the metabolic degradation of naturally occurring circulation regulatory peptides, such as endorphins, including enkephalins, and natriuretic peptides headphones Successful treatment is also understood to include prophylaxis in the treatment of a patient in cases such as, for example, in a preoperative procedure, wherein the patient will be suffering from pain - "'acute or chronic in the near future 0 An effective enkephalinase inhibiting amount of a compound of the Formula (I), is an amount that is effective to inhibit enkephalinase in a patient in need, resulting in, for example, endorphin or enkephalin-mediated analgesic effects, or a diuretic, natriuretic, hypotensive or hypoaldosteronemic effect mediated by atrial natriuretic peptide . "An effective dose of enkephalinase inhibitor can be easily determined by using conventional techniques, and by observing the results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered, including, but not limited to: the patient's species; its size, age, and general health; the specific disease involved; the degree or involvement or 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 selected dose regimen, and the use of a concomitant medicament, An effective enkephalinase inhibiting amount of a compound of Formula (I) generally it will vary from about 0.01 milligrams per kilogram of body weight per day (mg / kg / day) to about 20 mg / kg / day.A daily dose of about 0.1 mg / kg to about 10 mg / kg is preferred. In addition, the present invention further provides a method for inhibiting the angiotensin-converting enzyme in a patient in need, which comprises administering to this patient an inhibitory amount of converting enzyme.

Effective angiotensin of a compound of Formula (I). A patient is in need of treatment to inhibit the angiotensin-converting enzyme when the patient is suffering from hypertension, chronic congestive heart failure, hyperaldosteronemia, or cognitive disorders. The The inhibition of the angiotensin-converting enzyme reduces the levels of angiotensin II, and consequently, inhibits the vasopressor, hypertensive and hyperaldosteroneic effects caused thereby. An effective angiotensin-converting enzyme inhibitory amount of a compound of Formula (I), is the amount that is effective to inhibit the angiotensin-converting enzyme in a patient in need, which results, for example, in an effect hypotensive An effective anqiotensin converting enzyme inhibitory amount and an effective angiotensin-converting enzyme inhibitory dose are the same as described above for an effective amount and dose of enkephalinase inhibitor. In addition, the present invention further provides a method for the treatment of a patient suffering from proliferation of the smooth cells. An effective smooth cell proliferation inhibiting amount of a compound of Formula (I), is the amount that is effective to inhibit the proliferation of smooth cells in a patient in need, which results, for example, in thickening myointimal reduced after a vascular lesion. An effective inhibitory amount of smooth cell proliferation and an effective inhibitory dose of smooth cell proliferation are the same as described above for an effective enkephalinase inhibiting amount and dose. In effecting the treatment of a patient, the compounds of Formula (I) can be administered in any form or manner that puts the compound into biodisposition in effective amounts, including the 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 easily select the appropriate form and mode of administration, depending on the disease state to be treated, the stage of the disease, and other pertinent circumstances. The compounds of Formula (I) can be administered in the form of pharmaceutical compositions or drugs 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 selected administration route, and standard pharmaceutical practice. In another embodiment, the present invention provides compositions comprising a compound of Formula (I) mixed or otherwise in association with one or more inert carriers. These compositions are useful, for example, as test standards, as convenient elements for making bulk shipments, or as pharmaceutical compositions. An assayable amount of a compound of Formula (I) is an amount that can be easily measured by standard assay methods and techniques, as are well known and appreciated by those skilled in the art. The assayable amounts of a compound of Formula (I) will generally vary from about 0.001 percent to about 75 percent of the composition by weight. Inert carriers can be any material that does not degrade or otherwise react covalently with a compound of Formula (I). Examples of suitable inert carriers are water; aqueous pH regulators, such as those which are generally useful in the analysis of High Performance Liquid Chromatography (HPLC); organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable vehicles or excipients. More particularly, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of the Formula (I) mixed 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 vehicle or excipient can 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 can be adapted for oral or parenteral use, and can be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions, or the like.

The pharmaceutical compositions can be administered orally, for example, with an inert diluent or with an edible vehicle. They can be enclosed in gelatin capsules or can be compressed into tablets. For the purpose of oral therapeutic administration, the compounds of Formula (I) may be incorporated with excipients, and may be used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. . These preparations should contain at least 4 percent of the compound of Formula (I), the active ingredient, but can be varied depending on the particular form, and conveniently can be between 4 percent and about 70 percent by weight of the unit. The amount of the active ingredient present in the compositions is such that a suitable unit dosage form is obtained for administration. The tablets, pills, capsules, troches and the like may also contain one or more of the following auxiliaries: 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; brighteners, such as colloidal silicon dioxide; and sweetening agents, such as sucrose or saccharin, or flavoring agents, such as peppermint flavors, methyl salicylate, or orange. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other different materials that modify the physical form of the dosage unit, for example, as coatings. Accordingly, the tablets or pills can 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 dyes and flavorings. The materials used in the preparation of these different compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral administration, the compounds of Formula (I) can be incorporated into a solution or suspension. These preparations should contain at least 0.1 percent of a compound of the invention, but can be varied to be between 0.1 and about 50 percent of the weight thereof. The amount of the active ingredient present in these compositions is such that an adequate dosage is obtained. The solutions or suspensions may also include one or more of the following auxiliaries: sterile diluents, such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; pH regulators, such as acetates, citrates or phosphates, and agents for the adjustment of toxicity, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or in multi-dose vials made of glass or plastic. As with any group of structurally related compounds possessing a particular generic utility, certain groups and configurations are preferred for the compounds of Formula (I) in their end-use application. The compounds of Formula (I), wherein Rj is hydrogen or alkoxy are preferred. Preferred are compounds of Formula (I), wherein R 2 is hydrogen or alkoxy. In addition, the compounds of the Formula (I), wherein R3 is Preferred, are particularly preferred the following specific compounds of the Formula (I) in the end use application of the compounds of the present invention. amine disulfide (S) -Nl- (2-methylpropyl) -2- (thio) -eti-ethyl of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3-acid , 4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric; amine disulfide (R) -l- (2-methylpropyl) -2- (thio) -ethyl 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3-ethyl ester , 4,5-tetrahydrobenzo [c] azepin-2-y1] -4-methyl-valeric; L-cysteine ethyl ester disulfide 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo [c] azepin-2-yl ] -4-methyl-valeric; thiobenzyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl -valérico; thioethyl disulfide of 2-f 4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl -valérico; 2-hydroxythioethyl disulphide of acid disulfide 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1,3,4,5-tetrahydro-benzo [c] azepin-2-yl] -4-methyl-valeric; 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzo- [c] azepin-2-yl] - 2-pyridylthiomethyl disulfide 4-methyl-valeric; morpholino carboxamide disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1, 3,4,5-tetrahydrobenzo [c] azepin-2-2-thioacetic acid. il] -4-methyl-valeric; The following in vivo and ex vivo studies illustrate the utility of the compounds of the present invention as enkephalinase inhibitors and as inhibitors of angiotensin-converting enzyme. These studies are carried out by the method of J.F. French et al., J. Pharmacol. EXP. Ther .. 268 (1), 180-186 (1994). 5 Test compound or vehicle is administered (99/1, ethanol / 1 percent sodium bicarbonate solution) to fasted male Sprague-Dawley rats (Charles Rivers Breeding Laboratories Inc.). The administration is carried out , - by intraperitoneal injection. At 3 hours after 0 administration, the rats are sacrificed and the kidneys are removed and frozen. The whole kidneys are homogenized, and step P2 of the protocol of Booth and Kenny fBiochem is performed. J. 142. 575-581 (1974)] for the preparation of the microvilli fraction. The P2 material is resuspended in regulator 5 HEPES 50 M, pH 8.0, containing 0.3 M NaCl, and 0.5% Triton X-100, and maintained at -20 ° C before testing. The enzymatic activity can be measured by the fluorometric methods of Florentin et al., Anal. Biochem. 141, 62-69 (1984). The enzyme is assayed in 50 mM HEPES regulator (pH 7.4) in a 3.0 milliliter reaction volume containing 12 μM of the dansyl-D-AlaGly (p-nitro) PheGly-OH substrate (Km = 40 μM) at 25 ° C. The enzyme is added in a small volume to initiate the reaction, and the rate of fluorescence increase is continuously recorded using a fluorometer (excitation at 339 nanometers, emission, at 562 nanometers). Thiorpan (Sigma Chemical Co.) is used as a standard for the inhibition of atrial natriuretic peptide in vitro. The effectiveness of the test compound is determined by measuring the enzymatic activity of the kidneys obtained from the rats treated with the test compound, comparing with the enzymatic activity of the kidneys obtained from the vehicle-treated rats. The animal treated with Thiorphan serves as a positive control. The activity of the angiotensin converting enzyme is determined by the radiometric assay method of [J.W. Ryan, Methods in Enzymatic Analysis. 3rd edition, volume 5, pages 20-34; edited by J. Bergmeyer and M. Grasei, Verlag Chemie ', Weinheim 1983] using tritiated hypuryl glycine (Ventrex Laboratories, Portland ME). A pH regulator is used in the spectrophotometric assay of the angiotensin-converting enzyme. After quenching with acid, the tritiated product is extracted in a Ventrex Cocktail 1 [B. N. Swanson et al., Anal. Biochem. 148, 401-107 (1985)], and is counted in a Beckman scintillation counter. The inhibition of radioactive product formation is terminated by 1 μM enalaprilat in the assay, either from comptanted or vehicle-loaded rat kidney preparations, and taken to demonstrate the specificity for the angiotensin-converting enzyme. Male Sprague-Dawley rats (Charles Rivers Breeding Laboratories Inc.) weighing 230-290 grams were anaesthetized with methoxyfluorane and the marrow is punctured by inserting a stainless steel rod (2.2 millimeters in diameter) through the hollow of the right eye, through the brain, and down the spine to the sacral region. The lungs of the rat are ventilated through an endotracheal tube (Harvard Pump, Model 688). It is ventilated at a rate of 12.5 milliliters per minute provided in 50 strokes. The systemic blood pressure is recorded from a cannula (PE 50, which contains 0.01 percent heparin) inserted into the left carotid artery and connected to a pressure transducer (P23 DC). The systemic blood pressure is continuously recorded during the test in a polygraph (Grass Model 70). A 23 G hypodermic needle connected to a cannula (PE 50) is inserted into the lumen of the right femoral vein for injection of the test compound. Thirty minutes after the bone marrow, an intravenous injection of angiotensin I (0.3 micrograms) is given. Angiotensin I (human) is filled into a 0.01 percent ascorbic acid solution at a concentration of 0.3 micrograms / milliliter, from a material solution of 550 micrograms / milliliter in a 0.01 percent acetic acid solution. The intravenous injection of angiotensin I (0.3 micrograms) is repeated at 10 minute intervals, until two consecutive injections give responses that are within 10 percent of each other. It is administered by intraperitoneal or intravenous injection, either the test compound or the vehicle. An intravenous injection of angiotensin I (0.3 micrograms) is administered at 15, 30, 45, 60, 90 and 120 minutes following administration of the test compound or vehicle. The effectiveness of the test compound is determined by measuring the decrease in the angiotensin I-induced pressor response for the rats treated with the test compound, compared to the vehicle-treated rats.

Claims (43)

1. A compound of the Formula: Wherein: R and R2 are each independently hydrogen, hydroxy, -0R6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is 0 alkyl of 0 to 4 carbon atoms; or wherein R1 and R2 join with the adjacent carbon atoms, R1 and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, ~CH0CH2CH20CH3, or an Ar-Y- group; R is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCH3, CH20H, CH (0H) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the Formula: R5 is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y-, or -CH20-C (0) C (CH3) 3 group; G is a radical selected from the group: where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (0) pCH3, or arylalkyl, wherein p is 1, 2 or 3; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -OC (0) Rg, wherein R9 is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; R10 is 1 or 2 substituents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, 6 halogen; R1: L is hydrogen, alkyl of 1 to 6 carbon atoms, or an Ar-Y- group; R12 is hydrogen or alkyl of 1 to 4 carbon atoms; V-L is O, S or NH; V2 is N or CH; V3 is a direct link or -C (0) -; or the stereoisomers or pharmaceutically acceptable salts thereof.

2. A compound of claim 1, wherein R3 is phenylmethyl.

3. A compound of claim 2, wherein R5 is hydrogen.

4. A method for inhibiting enkephalinase in a patient in need thereof, which comprises administering to this patient an effective enkephalinase inhibitory amount of a compound of the Formula: wherein: Rx and R2 are each independently hydrogen, hydroxy, -OR6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is an alkyl of 0 to 4 carbon atoms; or where R ^ and R join with the adjacent carbon atoms, R.}. and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, -CH OCH2CH2OCH3, or an Ar-Y- group; R is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCH3, 'CH20H, CH (0H) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the formula: R. is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y- group, or -CH20-C (0) C (CH3) 3; G is a radical selected from the group: where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (0) CH3, or arylalkyl, wherein p is 1, 2 or 3; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -0C (0) R9, wherein R9 is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; R10 is 1 or 2 substituents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; R? l is hydrogen, alkyl of 1 to 6 carbon atoms, or an Ar-Y- group; R12 is hydrogen or alkyl of 1 to 4 carbon atoms; V_ is O, S or NH; V2 is N or CH; V3 is a direct link or -C (0) -; or the stereoisomers or pharmaceutically acceptable salts thereof.

5. A method according to claim 4, wherein the patient is in need of an analgesic effect mediated by endorphin or enkephalin.

6. A method according to claim 4, wherein the patient is in need of a hypotensive effect mediated by atrial natriuretic peptide.

7. A method according to claim 4, where the patient is in need of a diuretic effect mediated by atrial natriuretic peptide.

8. A method according to claim 4, wherein the patient is suffering from congestive heart failure.

9. A method according to claim 4, wherein the patient is suffering from irritable bowel syndrome.

10. A method for inhibiting the angiotensin-converting enzyme in a patient in need thereof, which comprises administering to this patient an effective angiotensin-converting enzyme inhibitory amount of a compound of the Formula: wherein: RJL and R2 are each independently hydrogen, hydroxy, -OR6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is an alkyl of 0 to 4 carbon atoms; or where R? and R2 are bonded with the adjacent carbon atoms, R1 and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, -CH20CH2CH20CH3, or an Ar-Y- group; R4 is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCH3, CH20H, CH (0H) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the Formula: R5 is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y-, or -CH20-C (0) C (CH3) 3 group; G is a radical selected from the group: R ?? where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (0) pCH3, or arylalkyl, wherein p is 1, 2 or 3; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -OC (0) Rg, wherein R9 is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; R 10 is 1 or 2 solvents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; R1; L is hydrogen, alkyl of 1 to 6 carbon atoms, or an Ar-Y- group; R12 is hydrogen or alkyl of 1 to 4 carbon atoms; Vx is O, S or NH; V2 is N or CH; V3 is a direct link or -C (0) -; or the pharmaceutically acceptable stereoisomers or saltse thereof.

11. A method according to claim 10, wherein the patient is in need of a hypotensive effect.

12. A method according to claim 10, wherein the patient is in need of a cognitive ability enhancing effect.

13. A method according to claim 10, wherein the patient is suffering from congestive heart failure.

14. A method for inhibiting the proliferation of smooth cells in a patient in need thereof, which comprises administering to this patient an effective smooth cell proliferation inhibiting amount of a compound of the Formula: where: R? and R2 are each independently hydrogen, hydroxy, -OR6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is an alkyl of 0 to 4 atoms of carbon; or where R? and R2 join with the adjacent carbon atoms, Rj ^ and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, -CH20CH2CH20CH3, or an Ar-Y- group; R is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCH3, 'CH20H, CH (0H) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the formula: R5 is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y-, or -CH20-C (0) C (CH3) 3 group; G is a radical selected from the group: where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (0) pCH3, or arylalkyl, wherein p is 1, 2 or 3; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -OC (0) R9, wherein Rg is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; R10 is 1 or 2 substituents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; R 1 is hydrogen, alkyl of 1 to 6 carbon atoms, or an Ar-Y- group; R12 is hydrogen or alkyl of 1 to 4 carbon atoms; V? is O, S or NH; V2 is N or CH; V3 is a direct bond or -C (O) -; or the stereoisomers or pharmaceutically acceptable salts thereof.

15. A composition comprising a test amount of a compound of claim 1, mixed or otherwise in association with an inert carrier.

16. A pharmaceutical composition comprising an effective immunosuppressive amount of a compound of claim 1, mixed, or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

17. A compound of claim 1, wherein the compound is amine disulfide (S) -Nl- (2-methylpropyl) -2- (thio) -etilic acid 2- [4- (2-thio-3- phenyl-propionyl-amino) -3-oxo-l, 3,4,5-tetrahydrobenzofc] azepin-2-yl] -4-methyl-valeric.

18. A compound of claim 1, wherein the compound is amine disulfide (R) -l- (2-methylpropyl) -2- (thio) -ethyl 2- [4- (2-thio-3- phenyl-pTopionyl-amino) -3-oxo-1,4,4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric acid.

19. A compound of claim 1, wherein the compound is L-cysteine ethyl ester disulfide 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3-cysteine. 4,5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric;

20. A compound of claim 1, wherein the compound is thiobenzyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5- tetrahydrobenzo [c] azepin-2-y1] -4-methyl-valeric.

21. A compound of claim 1, wherein the compound is thioethyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4,5- tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric.

22. A compound of claim 1, wherein the compound is 2-hydroxythioethyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4-acid disulfide, 5-tetrahydrobenzo [c] azepin-2-yl] -4-methyl-valeric.

23. A compound of claim 1, wherein the compound is 2-pyridylthiomethyl disulfide of 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-l, 3,4, 5-tetrahydrobenzo- [c] azepin-2-yl] -4-methyl-valeric.

24. A compound of claim 1, wherein the compound is morpholino acid carboxamide disulfide. 2-thioacetic acid 2- [4- (2-thio-3-phenyl-propionyl-amino) -3-oxo-1, 3,4, 5-tetrahydrobenzo [c] azepin-2-yl] • '-4 -methyl-valeric.

25. A pharmaceutical composition comprising a compound of claim 1, mixed or otherwise in association with one or more inert carriers.

26. A compound according to claim 1, for use as a pharmaceutically active compound.

27. A compound according to claim 1, for use as an enkephalinase inhibitor.

28. A compound according to the claim 1, to be used as an inhibitor of angiotensin-converting enzyme.

29. A compound according to claim 1, for use as an inhibitor of the proliferation of the smooth cells.

30. A compound according to claim 1, for use in the production of an analgesic effect, a hypotensive effect, a diuretic effect, or a cognitive capacity improving effect.

31. A compound according to the claim 1, for use in the treatment of congestive heart failure or irritable bowel syndrome.

32. A pharmaceutical composition according to claim 27 for the inhibition of enkephalinase.

33. A pharmaceutical composition according to claim 28 for the inhibition of angiotensin converting enzyme.

34. A pharmaceutical composition according to claim 29, for the inhibition of the proliferation of the smooth cells.

35. A pharmaceutical composition according to claim 30, for the production of an analgesic effect, a hypotensive effect, a diuretic effect, or a cognitive capacity improving effect.

36. A pharmaceutical composition according to claim 31, for the treatment of congestive heart failure or irritable bowel syndrome.

37. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the inhibition of enkephalinase.

38. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the inhibition of angiotensin converting enzyme.

39. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for inhibiting the proliferation of smooth cells.

40. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for producing an analgesic effect, a hypotensive effect, a diuretic effect, or a cognitive capacity enhancing effect. .

41. The use of a compound of claim 1, optionally in combination with a pharmaceutically acceptable carrier, for the preparation of a pharmaceutical composition for the treatment of congestive heart failure or irritable bowel syndrome.

42. A process for the preparation of a compound of the Formula: wherein: R1 and R2 are each independently hydrogen, hydroxyU, -OR6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is an alkyl of 0 to 4 carbon atoms; or wherein Rx and R2 join with the adjacent carbon atoms, R1 and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R3 is hydrogen, alkyl of 1 to 8 carbon atoms, -CH20CH2CH20CH3, or an Ar-Y- group; R is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCH3, CH2OH, CH (OH) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the Formula: R5 is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y-, or -CH20-C (0) C (CH3) 3 group; G is a radical selected from the group: where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (0) pCH3, or arylalkyl, wherein p is 1, 2 or 3; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -0C (0) R9, wherein R9 is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; < io is 1 or 2 substituents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; R11 is hydrogen, alkoyl of 1 to 6 carbon atoms, or an Ar-Y- group; R12 is hydrogen or alkyl of 1 to 4 carbon atoms; V-L is O, S or NH; V2 is N or CH; V3 is a direct bond or -C (O) -; or the stereoisomers or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the Formula: wherein R1 f R2, R4 and R5 were defined above, with a compound of the Formula: wherein G was defined above, and optionally deprotecting and optionally preparing a pharmaceutically acceptable salt by further reaction with an acceptable acid or an acceptable base.

43. A process for the preparation of a compound of the Formula: wherein: R1 and R2 are each independently hydrogen, hydroxy, -0R6, wherein R6 is an alkyl group of 1 to 4 carbon atoms or an Ar-Y- group, where Ar is aryl and Y is an alkyl of 0 to 4 carbon atoms; or where R? and R2 join with the adjacent carbon atoms, Rj and R2 can be taken together with those adjacent carbon atoms to form a benzene ring, or methylenedioxy; R is hydrogen, alkyl of 1 to 8 carbon atoms, -CH 2 OCH 2 CH 2 OCH 3, or an Ar-Y- group; R is hydrogen, alkyl of 1 to 6 carbon atoms, a group Ar-Y-, -CH2CH2SCI_3, CH2OH, CH (0H) CH3, CH2CH2C (= 0) NH2, CH2C (= 0) NH2, or a group of the Formula: R5 is hydrogen, an alkyl group of 1 to 4 carbon atoms, or an Ar-Y-, or -CH20-C (0) C (CH3) 3 group; G is a radical selected from the group: where: m is an integer from 1 to 3; R7 is hydrogen, alkyl of 1 to 6 carbon atoms, -CH2CH2S (0) pCH3, or arylalkyl, wherein p is 1, 2 or 3; R8 is hydrogen, hydroxy, amino, alkyl of 1 to 6 carbon atoms, N-methylamino, N, N-dimethylamino, -C02R5, or -0C (0) R9, wherein R9 is hydrogen, alkyl of 1 to 6 atoms carbon, or phenyl; R10 is 1 or 2 substituents independently selected from the group consisting of: hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen; Rl? is hydrogen, alkyl of 1 to 6 carbon atoms, or an Ar-Y- group; R1 is hydrogen or alkyl of 1 to 4 carbon atoms; Vx is O, S or NH; V2 is N or CH; V3 is a direct bond or -C (O) -; or the stereoisomers or pharmaceutically acceptable salts thereof, which comprises reacting a compound of the Formula: wherein R ', R2, R4 and R5 are defined above, with a compound of the Formula: wherein G was defined above, and optionally deprotecting and optionally preparing a pharmaceutically acceptable salt by further reaction with an acceptable acid or an acceptable base.