MXPA01006671A - Amidomalonamides and their use as inhibitors of matrix metalloproteinase - Google Patents

Abstract

The present application relates to novel aminomalonamides of formula (1) and pharmaceutical composition thereof which are useful for inhibiting matrix metallo-proteinases.

Description

AM1DOMALONAMIDAS AND THEIR USE AS INHIBITORS OF MMP MATRIX METALOPROTEINASE BACKGROUND OF THE INVENTION Matrix metalloproteinases (MMPs) are a family of zinc containing endopeptidases, which are capable of unfolding long biomolecules such as collagens, proteoglycans and gelatins. The expression is superregulated by pro-inflammatory cytokines and / or growth factors. The MMPs are secreted as inactive zymogens which, in the activation, are subjected to the control by means of the endogenous inhibitors, for example, metalloproteinase (TIMP) tissue inhibitor and a2-macroglobulin. Chapman, K.T. et al., J. Med. Chem. 36, 4293-4301 (1993); Beckett, R.P. et al., DDT 1, 16-26 (1996). The characteristic feature of diseases involving enzymes appears to be a stoichiometric imbalance between active enzymes and endogenous inhibitors, leading to excessive tissue disruption, and sometimes degradation. McCachren, S.S., Arthritis Rheum. 34, 1085-1093 (1991). The discovery of different matrix metalloproteinase families, their relationships, and their individual characteristics have been categorized in various reports. Emonard, H., et al. , Cell Molec. Bio. 36, 131-153 (1990); Birkedal-Hansen, H., J. Oral Pathol. 17, 445-451 (1988); Matnsian. L.M., Trends Genet. 6, 121-125 (1990); Murphy. G.J.P. et al., FEB Lett. 289, 4-7 (1991); Matrisian, L.M .. Bioessays 14, 455-463 (1992). Three groups of MMPs have been delineated: the collagenases that have triple helical mtesticial collagen as a substrate, the gelatmases that are proteasas of denatured collagen and Type IV collagen, and the stromelysms that are originally characterized as proteoglycanases but have now been identified as having a broad proteolytic spectrum. Examples of specific collagenases include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), and collagenase 3 (MMP-13). Examples of gelatinases include 72 kDa gelatinase (gelatinase A, MMP-2) and 92 kDa gelatinase (gelatinase B, MMP-9). Examples of stromelysms include stromelysm 1 (MMP-3), stromelysm 2 (MMP-10) and matrilysin (MMP-7). Other MMPs that do not fit neatly in the above groups include metalloelastase (MMP-12), membrane-type MMP (MT-MMP or MMP-14) and stromelysin 3 (MMP-11). Beckett, R.P. et al., supra. On the expression and activation of MMPs has been linked with a wide range of diseases such as cancer; rheumatoid arthritis; osteoarthritis; chronic inflammatory disorders, such as emphysema and emphysema induced by smoking; cardiovascular disorders, such as atherosclerosis; corneal ulceration; dental diseases such as gingivitis and periodontal disease; and neurological disorders, such as multiple sclerosis. For example, in adenocarcinoma, nearby invasive gastric cells that express the 72kDa form of Type IV collagenase, while not making non-invasive cells. Schwartz, G.K. et al., Cancer 73, 22-27 (1994). The rat embryo cells transformed by the Ha-ras and v-myc oncogenes or by the Ha-ras are only metastatic in mouse nest and are released from 92 kDa of gelatinase collagenase (MMP-9). Bernhard, E.J. et al., Proc. Nati Acad. Sci. 91, 4293-4597 (1994). The plasma concentration of MMP-9 was significantly increased (P <0.01) in 122 patients with gastrointestinal tract cancer and breast cancer. Zucker, S., et al., Cancer Res. 53, 140-146 (1993). In addition, intraperitoneal administration of batimastat, a synthetic MMP inhibitor, gives significant inhibition in the growth and metastatic spread and number of lung colonies that are produced by the intravenous injection of murine melanoma B16-BL6 in the C57BL / 6N mouse. Chirivi, R.G.S. et al., Int. J. Cancer 58, 460-464 (1994). Overexpression of TIMP-2, the endogenous tissue inhibitor of MMP-2, markedly reduced melanoma growth in the skin of mice is immunodeficient. Montgomery, A. M.P. et al., Cancer Res. 54, 5467-5473 (1994). The accelerated anomaly of the extracellular matrix of articular cartilage is a key feature in the pathology of rheumatoid arthritis and osteoarthritis. Current evidence suggests that the inappropriate synthesis of MMPs is the key case. Beeley, N.R.A. et al., Curr. Opin. Ther. Patents, 4 (1), 7-16 (1994). The entry of reliable diagnostic tools has allowed a number of search groups to recognize that stromelysin is a key enzyme in arthritis and joint trauma. Beeley, N.R.A. et al., Id.; Hasty, K.A. et al., Arthr. Rheum. 33, 388-397 (1990). It has been shown that stromelysin is important for the conversion of procollagenase into active collagenase. Murphy, G., et al., Biochem. J. 248, 265-268 (1987). In addition, a range of MMPs can hydrolyse the precursor attached to the tumor necrosis factor (TNF-α) membrane of pro-inflammatory cytokine. Gearing, A.J.H. et al., Nature 370, 555-557 (1994). This splitting produces soluble TNF-a in mature and inhibitors of MMPs can block TNF-production both in vi tro and in vivo. Gearing, A.J.H. et al., Id ^; Mohler, K.M. et al., Nature 370, 218-220 (1994); McGeehan, G.M. et al., Nature 370, 558-561 (1994). This pharmacological action is a likely contributor to the antiarthritic action of this class of compounds seen in animal models. Beckett, R.P. et al., supra. Stromelysin has been observed to degrade the proteinase inhibitor that regulates the activity of enzymes such as elastase, the excesses of which have been linked to chronic inflammatory disorders such as emphysema and chronic bronchitis. Beeley, N.R.A. et al., supra.; Wahl, R.C. et al., Annual Reports in Medicinal Chemistry 25, 177-184 (1990). In addition, a recent study indicates that MMP-12 is required for development in emphysema induced by smoking in mice. Science, 277, 2002 (1997). The inhibition of the appropriate MMP can thus enhance the inhibitory activity of endogenous inhibitors of this type. The high levels of mRNA corresponding to stromelysin have been observed in the atherosclerotic plaques extracted from heart transplant patients. Henney, A.M., et al., Proc. Nati Acad. Sci. 88, 8154-8158 (1991). It is proposed that the role of stromelysin in such plaques is to encourage rupture of the connective tissue matrix that encloses the plaque. This rupture is thought to be a key event in the cascade that leads to the formation of the type seen in coronary thrombosis. The MMP inhibition is thus a preventive measure for such thrombosis. Collagenase, stromelysin and gelatinase have been implicated in the destruction of the extracellular matrix of the cornea. It is thought to be an important mechanism of morbidity and visual loss in the number of ulcerative eye diseases, particularly those that follow infection or chemical damage. Burns, F.R. et al., Invest. Opthalmol. and Visual Sci. 32, 1569-1575 (1989). The MMPs present in the eye during ulceration are derived either endogenously from infiltrating leukocytes or fibroblasts, or exogenously from microbes. Collagenase and stromelysin activities have been identified in isolated fibroblasts from inflamed gingiva and enzyme levels have been correlated with the severity of gingivitis observed. Beeley, N.R.A. et al., supra.; Overall, C.M. et al., J. Periodontal Res. 22, 81-88 (1987). Obsessive levels of gelatinase-B in the cerebrospinal fluid have been linked with the incidence of multiple sclerosis and other neurological disorders. Beeley N.R.A. et al., supra.; Miyazaki, K. et al., Nature 362, 839-841 (1993). The enzyme can play a key role in the demyelination of neurons and the abnormality of the blood brain barrier that occurs in such disorders.

COMPENDIUM OF THE INVENTION The present invention provides novel aminomalonamides of the formula wherein Ri and R2 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, - (CH2) a-Ar ?, and - (CH2) b-Ar2; where a is an integer from 1 to 6; b is an integer from 2 to 6; Arx is a radical selected from the group consisting of wherein R 5 is 1 or 2 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C alkyl, hydroxy and C 1 -C 4 alkoxy; Rs is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C1-C4 alkoxy; Ar2 is the radical wherein Re is selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C? -C alkoxy; R3 is selected from the group consisting of C? -C6 alkyl, - (CH2) m-W, - (CH2) p-Ar3, - (CH2) ~ C02R9, (CH2) m-NR8-S02-Y? and (CH2) m-Z-Q where m is an integer from 2 to 8; p is an integer of 0-10, k is an integer from 1 to 9; W is phthalimido; Ar3 is selected from the group consisting of wherein R 23 is 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy; R8 is hydrogen or Ci-Cß alkyl; Rg is hydrogen or Ci-Ce alkyl; Yi is selected from the group consisting of hydrogen, - (CH2) -, - Ar4, and -N (R24) 2 where j is 0 or 1; R24 each time it is selected is independently hydrogen or Ci-Cß alkyl or taken together with the hydrogen to which they are attached form N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar4 is the radical wherein R 25 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, and C 1 -C 4 alkoxy; Z is selected from the group consisting of -O-, -NR8-, -C (0) NR8-, -NR8C (0) -, -NR8C (0) NH-, -NR8C (0) 0-, and -OC (0) NH-; wherein R8 is hydrogen or Ci-Cß alkyl; Q is selected from the group consisting of hydrogen, (CH2) n-Y2, and - (CH2) XY3; where n is an integer from 0 to 4; Y2 are selected from the group consisting of hydrogen, - (CH2) h-Ar5 and - (CH2) t-C (0) OR27 wherein rs is selected from the group consisting of wherein R26 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C? -C alkyl, and C? -C alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or C? -C6 alkyl; x is an integer from 2 to 4; Y3 are selected from the group consisting of -N (R28) 2, N-morpholino, N-piperidino, N-pyrrolidino, and N-isoindolyl; wherein R28 each time it is taken is independently hydrogen or Ci-Cß alkyl; R4 is selected. from the group consisting of hydrogen, -C (0) R 10 -C (0) - (CH 2) qK and -SG wherein Rio is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from the group consisting of , N-Ru -11 wherein V is selected from the group consisting of a bond, -CH2-, -0-, -S (0) r-, -NR-, and -NC. (0) R'-; wherein r is 0, 1 or 2; R is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and benzyl; R 'is selected from the group consisting of hydrogen, -CF3, C1-C10 alkyl, phenyl, and benzyl; R11 is selected from the group consisting of hydrogen, C? -C4 alkyl, and benzyl; R11 is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl; G is selected from the group consisting of where w is an integer from 1 to 3; R 2 are selected from the group consisting of hydrogen, Ci-Cß alkyl, -CH 2 CH 2 S (0) eCH 3, and benzyl; where e is 0, 1 or 2; Ri3 is selected from the group consisting of hydrogen, hydroxy, amino, Ci-Cß alkyl, N-methylamino, N, N-dimethylamino, -C02R ?7, and -OC (0) R ?8; wherein R 7 is hydrogen, -CH 20 -C (0) C (CH 3) 3, C 1 -C 4 alkyl, benzyl, or diphenylmethyl; Lanes are hydrogen, Ci-Cß alkyl or phenyl; R 14 is 1 or 2 substituents independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen; Vi is selected from the group consisting of -0-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C (0) -; V4 is selected from the group consisting of -0-, -S-, -NR19- and -NC (0) R20-; wherein R19 is hydrogen, C? -C alkyl, or benzyl; R20 is hydrogen, -CF3, C1-C10 alkyl, or benzyl; R15 is selected from the group consisting of hydrogen, Ci-Cß alkyl, and benzyl; R16 are selected from the group consisting of hydrogen and C? -C alkyl; and stereoisomers, pharmaceutically acceptable salts, and hydrates thereof. The present invention further provides a method for inhibiting the metalloproteinase (MMPs) matrix in a patient in need thereof comprising administering therein an effective matrix metalloproteinase inhibitory amount of a compound of the formula (1). As such, the present invention provides a method for treating a neoplastic disease state or cancer; rheumatoid arthritis; osteoartptis; osteoporosis; cardiovascular disorders, such as atherosclerosis; corneal ulceration, dental diseases, such as gingivitis or periodontal disease; and neurological disorders, such as multiple sclerosis; chronic inflammatory disorders, such as emphysema and especially emphysema induced by smoking. In addition, the present invention provides a composition comprising an amount to which a test of a compound of formula (1) in the mixture or otherwise in association with an inert carrier can be made. The present invention also provides a pharmaceutical composition comprising an effective MMP inhibitory amount of a compound of the formula (1) in the mixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients. As used in this application: a) the term "halogen" refers to a fluorine atom, chlorine atom, bromine atom, or iodine atom; b) the term "C6-C6 alkyl" refers to a straight or branched chain alkyl radical containing 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, etc.; c) the term "C?-C 4 alkyl" refers to a saturated straight or branched chain alkyl group containing from 1 to 4 carbon atoms and includes methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl , isobutyl, and t-butyl; d) the term "C" -Calkoxy "refers to a linear or branched alkoxy group containing 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t -butoxi, etc .; e) the term "Ci-Cio alkyl" refers to a straight or branched chain saturated alkyl group containing from 1 to 10 carbon atoms and include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl, etc .; f) as used in the examples and preparations, the following terms have the indicated meanings: "g" refers to grams, "mg" refers to milligrams, "" μg "refers to micrograms," mol "refers to moles, "mmol" refers to millimoles, "nmol" refers to nanomoles, "L" refers to liters, "mL" or "ml" refers to milliliters, "μL" refers to microliters, "° r" refers to degrees Centigrade, "Rf" refers to retention factor, "mp" refers to melting point, "dec" refers to decomposition, "bp" refers to boiling point, "mm Hg" is refers to the pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to nanometers, "brine" refers to the solution of saturated aqueous sodium chloride, "M" refers to molar, "M" "refers to millimolar," μL "refers to micromolar," NM "refers to nanomolar," HPLC "refers to highly-performed liquid chromatography," HRMS "refers to the mass spectrum of ta resolution, "DMF" refers to dimethylformamide, "μsi" refers to microcuries, "i.p." refers to intraperitoneally, "i.v." refers to intravenously, and "DPM" refers to disintegrations per minute.; g) the term "pharmaceutically acceptable salts" refers to either an acid addition salt or a basic addition salt. The term "pharmaceutically acceptable acid addition salts" is intended to be applied to any non-toxic organic or inorganic acid addition salts of the base compounds represented by the formula (1) or any of their intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, and phosphoric acid and acid metal salts such as sodium monoacid orthophosphate, and potassium acid sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymelic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic acid. , p-toluenesulfonic, and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts may exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which, in comparison to their free base forms, generally demonstrate high melting points. The expression "pharmaceutically acceptable basic addition salts" is intended to be applied to any non-toxic inorganic or organic basic addition salts of the compounds represented by the formula (1) or any of their intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium, or barium hydroxides; ammonium, and aliphatic, alicyclic or aromatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. As appreciated by one of ordinary skill in the art, the compounds of formula (1) exist as stereoisomers. Specifically, it is recognized that they exist as stereoisomers at the point of attachment of the substituents R3, R? 2, and -NHR15-. Where the compounds of this application were indicated, if the formula (1), starting materials, or intermediates, follow any of the designation (+) - and (-) - for the optical rotation, the designation (D) - and (L) ) - of the relative stereochemistry, or the designation Cahn-Ingold-Prelog of (R) - and (S) - for the stereochemistry. Any reference of this application in one of the compounds of the formula (1) is understood to encompass any specific stereoisomer or a mixture of stereoisomers. Specific stereoisomers can be prepared by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials which are well known in the art. Specific stereoisomers of the initial amino acid materials are commercially available or can be prepared by stereospecific synthesis as is well known in the art or analogously known in the art, such as D. A. Evans, et al. J. Am. Chem. Soc. , 112. 4011-4030 (1990); S. Ikegami et al. Tetrahedron, 44, 5333-5342 (1988); W. Oppolzer et al. Tet. Lets. 30 6009-6010 (1989); Synthesis of Optically Active a-Amino-Acids. R. M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed .: a-Amino-Acid Synthesis, Tetrahedron Symposia in print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schollkopf, PureAppl. Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem. 44, 3748-3752 (1979): M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al. J. Am. Chem. Soc., 110, 8520-8525 (1988). Specific stereoisomers of any starting materials or products can be resolved and recovered by techniques known in the art., such as chiral stationary phase chromatography, enzymatic resolution, or fractional recrystallization of the addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and described in Stereoche istry of Organic Compounds, E., L. Eliel and S. H. Wilen, Wiley (1994) and Enantiomers, Racemates. and Resolutions. J. Jacques, A., Collet. and S. H. Wilen, Wiley (1981). As with any group of structurally related compounds that propose a particular utility, certain groups and configurations of substituents are preferred for the compounds of formula (1). Preferred embodiments are given in the following: The compounds in which Ri and R2 are selected from the group consisting of Ci-Cd alkyl and - (CH2) a_Ar? they are preferred; The compounds in which Ri and R2 are - (CH2) a-AR? they are more preferred; The compounds in which Ri and R2 are - (CH2) a_AR? wherein a is 1 or 2 and ARi is phenyl or substituted phenyl are more preferred; The compounds in which R3 are selected from the group consisting of C? -C6 alkyl and - (CH2) P-Ar3 are preferred; Compounds in which R4 is selected from the group consisting of hydrogen, -C (0) R and S-G are preferred; The compounds in which R 4 is hydrogen are more preferred; and Compounds in which R4 is selected from the group consisting of -C (0) R and Rio is the most preferred C1-C4 alkyl. Examples of the compounds encompassed by the present invention include the following. It is understood that the examples encompass all isomers of the compounds and mixtures thereof. This list is significant to be representative only and is not intended to limit the scope of the invention in any way. N, N '-di- (3-diphenylpropyl) -2- ((S) -2-mercapto-4-phenylbutryrylamino) malonamide; N, N '-di- (4-diphenylbutyl) -2- ((S) -2-mercapto-4-phenylpropionylamino) malonamide; and N, '-di- (3-diphenylpropyl) -2- ((S) -2-mercapto-4-phenylbutyrylamino) malonamide.

The compounds of the formula (1) can be prepared using techniques and procedures well known and appreciated by one of ordinary skill in the art. To illustrate, generally, synthetic scheme for preparing intermediates and the compounds of formula (1) are set forth in the following. In the following reaction schemes, the starting materials and reagents are readily available to one of ordinary skill in the art and all substituents are like Scheme of Reaction A 2 3) previously defined unless otherwise indicated In Scheme A, step 1, a suitable protected amino-ammonic acid derivative of the formula (2aa) is coupled with an appropriate amine to give a compound of the formula (2ab). A suitable protected aminomalonic acid derivative of the formula (2aa) is one in which the protecting group, Pgi, can be removed in the presence of the amide formulated in this step. The use of t-Boc for Pgi is preferred. Such amino-protected aminomalonic acid derivatives are readily prepared by amine-protected diethyl ammonium followed by ester hydrolysis.

An appropriate amine is one which gives Ri and R2 as desired in the final product of the formula (1). As appreciated by the person skilled in the art, the compounds of the formula (1) in which Ri and R2 are different can be prepared using protected mono-carboxy aminomalonic acid derivatives using this step, followed by the selective removal of the group. carboxy protector and the repeated amide formulation to give compounds of the formula (2ab) in which Ri and R2 are different. Such coupling reactions to form amides are carried out in suitable solvents, such as dichloromethane, tetrahydrofuran, diethyl ether, chloroform, and the like, and use suitable bases, such as triethylamine, N-methylmorpholine, N, N-disopropylethylamine, pyridine, and similar, and coupling reagents, as required, and are well known and appreciated in the art. The reactions are generally carried out from -10 ° C to the reflux temperature of the solvent and generally it is required from one hour to 2 days. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophilization, chromatography and recrystallization. The selection of an appropriate coupling reagent is within the skill of the art. Particularly suitable coupling reagents include l-ethyl-3- (3- (dimethylamino) propyl) carbodimide and 1-hydroxy-benzotriazole or N, N'-diisopropylcarbodiimide and 1-hydroxy-benzotriazole. Other coupling agents are the complex of benzotriazole-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate-complex of hexafluorophosphate pyridine benzotriazol-1-yloxytris (dimethylamino) phosphonium, carbodiimides (eg, N, '-dicyclohexylcarbodiimide); cyanamides (for example N, N-dibenzylcyanamide); (3) ketenimines; isoxazolium salts (for example, N-ethyl-5-phenyl-isoxazolium-3'-sulfonate); monocyclic nitrogen containing heterocyclic amides of aromatic character containing one to four ring nitrogens such as imidazolides, pyrazolides, and 1,2,4-triazoles. Specific heterocyclic amides that are useful include N, N'-carbonyldiimidazole and N, N-carbonyl-di-1,2-triazole; alkoxylated acetylene (e.g., ethoxyacetylene); reagents that form an anhydride mixed with the carboxyl portion of the amino acid (for example, ethylchloroformate and isobutylchloroformate). Other activation reagents and their use in peptide coupling are described by Kapoor, J. Pharm. Sci., 59, 1-27 (1970). In Reaction Scheme A, step 2, the amino protecting group, Pgi, of the compound of the formula (2ab) is selectively removed to give compounds of the formula (2ac). Such aminoselective deprotection reactions are well known and appreciated in the art. The product can be isolated and purified by techniques well known in the art, such as extraction or evaporation, salt formation, trituration, lyophilization, chromatography and recrystallization. In Reaction Scheme A, step 3, a compound of the formula (2ac) coupled with an appropriate acid derivative bearing R3, and Y (compound of the formula (3)) to give a compound of the formula (4). Such coupling reactions are well known and appreciated in the art and discussed in the foregoing. The product can be isolated and purified by techniques well known in the art such as extraction, evaporation, salt formation, trituration, lyophilization, chromatography and recrystallization. An appropriate compound of the formula (3) is one in which R3 is R3 as desired in the final product of the formula (1) or gives rise after deprotection to R3 as desired in the final product of the formula ( 1) and Y is a substituted protected thio or Y can be a hydroxy-protective or bromine substituent which gives rise under selective deprotection and displacement or displacement and further deprotection, and / or processing, if required, to -SR4 as desired in the final product of the formula (1). Alternatively, an appropriate compound of the formula (3) may also be one in which R3 <; gives rise to R "which, in the derivation, gives rise to R3 as desired in the final product of the formula (1) and Y is a protective thio substituent In addition, an appropriate compound of the formula (3) can be one in which the stereochemistry in R3 <and Y that supports carbon is as desired in the final product of the formula (1) or gives rise after displacement of the stereochemistry as desired in that carbon in the final product of the formula (1). The activation group (A) is one which undergoes an amidation reaction. As is well known in the art, an amidation reaction can proceed through an acid, A is -OH; or an acid can be first converted to an acid chloride, A is Cl; or an activated intermediary; such as an anhydride; a mixed anhydride or aliphatic carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroacetic acid, trifluoroacetic acid, and the like; the aromatic carboxylic acids such as benzoic acid and the like; of an activated ester, such as phenolyester, p-nitrophenolyester, 2-dinitrophenolyester, pentafluorophenol-ester, pentachlorophenolester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxy-lH-benztriazole ester, and the like; activated amide such as imizadol, dimethylpyrazole, triazole, or tetrazole: or an intermediate formed in the presence of coupling agents, such as dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide. Acid chlorides and activated intermediates can be prepared but not necessarily isolated before the addition of diethylaminomalonate. The use and selection of the appropriate protection groups are within the ability of those skilled in the art and will depend on the compound of formula (3) to be protected, the presence of other protective amino acid residues, other protecting groups, and the nature of the particular group or groups R3 and / or R4 are finally introduced. The compounds of the formula (3) in which Y is bromine and thio protecting are commercially available or can be prepared using materials, techniques, and procedures well known and appreciated by one of ordinary skill in the art or described herein. See PCT Application WO 96/11209, published April 18, 1996. Commercially available compounds of examples of formula (3) in which Y is bromine include 2-bromopropionic acid, 2-bromobutyric acid, 2-bromovaleric acid, 2-bromohexanoic acid, 6- (benzoylamino) -2-bromohexanoic acid, 2-bromoheptanoic acid, 2-bromooctanoic acid, 2-bromo-3-methylbutyric acid, 2-bromoisocaproic acid, 2-bromo-3- (5- imidazoyl) propionic, (R) - (+) -2-bromopropionic acid, (S) - (-) - 2-bromopropionic acid. The compounds of the formula (4) can also be prepared as set forth in the following in Reaction Scheme B.

Scheme of Reaction B In Scheme B, step 1, the diethylaminomalonate (formula (2ba) is coupled with an appropriate acid derivative of the formula (3) to give a compound of the formula (2bb) In Reaction Scheme B, an appropriate acid derivative of the formula (3) is one in which R3- is as described in the above in Reaction Scheme A and Y is a protected thio group which is stable to the hydrolysis reaction of step 2. In the Scheme of Reaction B, the use of the compounds in which Y is p-methoxybenzylmercapto is preferred, such coupling reactions are carried out in the appropriate solvents and use suitable bases in the coupling agents, as required, and are well known. and appreciated in the art and discussed in the above In Reaction Scheme B, step 2, the compound of the formula (2bb) is hydrolyzed to give a diacid of the formula (2bc) The hydrolysis of esters can be carried performed under acidic or basic conditions as is well known in the art. In Reaction Scheme B, step 3, a compound of the formula (2bc) is coupled with an appropriate amine as described in Reaction Scheme A, step 1, above, to give a compound of the formula (4). In Reaction Scheme C a compound of the formula (4) in which R3- is R3 as desired in the final product of the formula (1) or gives rise after deprotection to R3 as desired in the final product of the formula (1) and Y is a protected thio substituent or hydroxy or bromo gives rise to a final product of the formula (1).

Reaction scheme C (formula (1) or formula (1)) protected In Reaction Scheme C, step 1, a compound of formula (4) in which Y is a protected thio gives rise under selective deprotection to give a compound of the formula ). For example, the compounds of the formula (4) in which Y is a thio protecting substituent are selectively deprotected to give a thiol of the formula (5). Thio protecting substituents include thioesters, such as thioacetyl or thiobenzoyl, thioethers, such as thiobenzyl, thio-4-methoxybenzyl, thiotriphenylmethyl, or thio-t-butyl, or unsymmetrical sulfides, such as dithioethyl or dithio-t-butyl. The use and selective removal of such uncle protecting groups is well known and appreciated in the art and described in Protective Groups in Organic Synthesis, Theodora W. Greene (Wiley-Interscience, 2nd Edition, 1991). In Reaction Scheme C, step 2, a compound of formula (5) undergoes the modification reaction to give a compound of formula (1). Such modification reactions include, thiol esterification and disulfide formation. The compounds of the formula (1) in which R4 is a group -C (0) R? Oo -C (O) - (CH2) qX can be synthesized by thiol esterifications according to well known techniques and can be appreciated by one of ordinary skill in the art, such as that described in U.S. Patent No. 5,424,425, issued June 13, 1995. For example, in a thiol esterification a compound of the formula (5) is in contact with the above, an equimolar amount of an appropriate acid, such as H0-C (0) R? 0 or HO-C (0) - (CH2) qX in the presence of a suitable coupling agent to give a compound of the formula ( 1) in which R4 is -C (0) R? Oo -C (O) - (CH2) qX. The reaction is carried out in the presence of a coupling agent such as 2-fluoro-1-methylpyridinium p-toluensulfate, EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride), carbonyldiimidazole, EEDQ (1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, DCC, or diethyl cyanophosphonate in a suitable aprotic solvent such as methylene chloride. The reaction is usually carried out at a temperature between -20 ° C and the boiling point of the solvent.The reaction usually requires 1 to 24 hours.The product can be isolated and purified by techniques well known in the art, such as extract , evaporation, trituration, lyophilization, chromatography, and recrystallization The compounds of the formula (1) in which R4 is the -SG group can be synthesized according to techniques well known and appreciated by one of ordinary skill in the art, such as is described in PCT Application No. WO 95/21839, published August 17, 1995 and US Patents Nos. 5,491,143, issued February 13, 1996, and 5,731,306, issued March 24, 1998, and Roques. , B.P. et al., J. Med. Chem. 33, 2473-2481 (1992). For example, in a disulfide formulation, a compound of the formula (5) is in contact with an appropriate compound of the formula (7). (7) An appropriate compound of the formula (7) is one which gives G as desired in the final product of the formula (1) or gives origin under deprotection to G as desired in the final product of formula (1). In addition, the compound of formula (7) may have stereochemistry as desired in the final product of formula (1). 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 carried out. The reaction is carried out using 1.0 to 4.0 molar equivalents of an appropriate compound of the formula (7). 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 which is 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 and can be purified by chromatography and recrystallization. In reaction scheme C, step 3, a compound of the formula (4) in which Y is hydroxy or bromine can be displaced by an appropriate thiol, HSR4, to give a compound of the formula (1) or a protective compound of formula (1). In Reaction Scheme C, step 3, an appropriate thiol HSR4 is one which gives R4 as desired in the final product of formula (1) or gives rise under deprotection of R4 as desired in the final product of the formula (1) . In Reaction Scheme C, step 3, a compound of the formula (4) in which Y is hydroxy (obtained from the hydroxy protecting compounds of the formula (4) undergoes a displacement reaction with an appropriate thio introducing the reagent by means of a Mitsunobu method to give a compound of the formula (4) in which Y is a thio-protecting substituent or -SR4 as desired in the final compound of the formula (1) For example, a compound of the formula (4) in which Y is the hydroxy reactants with thioacetic acid or thiobenzoic acid, triphenylphosphine, and diethylazodicarboxylate in a suitable aprotic solvent, such as tetrahydrofuran to give a compound of the formula (4) in which Y is thioacetyl or thiobenzoyl. The selective removal of the thioacetic acid or thiobenzoic acid portion gives the desired compound of the formula (5) .The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation , trituration, lyophilization, chromatography, and recrystallization. Also, in Reaction Scheme C, step 3, a compound of the formula (4) in which Y is bromine undergoes a displacement reaction with an appropriate thio which introduces the reagent to give a compound of the formula (4) in which Y is the protective thio substituent which gives rise under deprotection and subsequent elaboration, if desired, the -SR4 as desired in the final compound of the formula (1). An appropriate thio introducing reagent is also one which introduces a -SR4 group as desired into the final compound of the formula (1). For example, a solution of p-methoxybenzyl mercaptan in a suitable organic solvent such as dimethylformamide is degassed and treated with a suitable base such as sodium hydride, sodium hydroxide, or cesium carbonate. After about 1 to 2 hours, a solution of a compound of the formula (4) in which Y is bromine is added. The reaction may benefit from the addition of a suitable catalyst, such as tetra-n-butylammonium iodide. The reaction mixture is carried out for 1 to 25 hours at temperatures averaging from 0 ° C to about 100 ° C. Selective removal of the 4-methoxybenzyl moiety gives the desired compound of the formula (1). The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, lyophilization, chromatography and recrystallization. In addition, in Reaction Scheme C, step 3, a compound of formula (4) in which Y is bromine can be displaced by an appropriate thioester, Ph3S-C (0) - (CH2) qX by well-known techniques and appreciated in the art, as described in U.S. Patent No. 5,424,425 issued June 13, 1995. In Reaction Scheme C, in an optional step, a protective compound of formula (1) is deprotected to give to give a compound of the formula (1). The deprotection reactions are well known and appreciated in the art and may include selective deprotections. In Reaction Scheme D a compound of the formula (4a) in which R3- gives rise to R3 <; and Y is -SR4 as desired in the final product of the formula (1) or a thio protecting substituent gives a compound of the formula (1).

Diagram of Reaction D (formula (1) or formula (1)) protected In Reaction Scheme D, step 1, an appropriate compound of formula (4a) is deprotected, hydrolyzed or reduced to give a compound of formula (4b). In Reaction Scheme D, step 1, an appropriate compound of the formula (4a) is one in which R3- gives rise to a compound of the formula (4b) in which R3"is R3 as desired in the product end of formula (1) or R3 .. further undergoes the derivation (step 2) to give a compound of formula (4a) in which R3 is desired in the final product of formula (1). Reaction D, step 1, an appropriate compound of the formula (4a) is one in which Y is -SR4 as desired in the final compound of the formula (1) or Y is protective thio that gives rise under deprotection or deprotection and further functionalization to give -SR4, as desired, in the final product of formula (1) as described in Reaction Scheme C, step 2, above For example, in a deprotection a compound of formula (4a) wherein R3 is - (CH2) mW (phthalimido group) is in contact with a molar excess of hydrazine monohydrate to give a compound of the formula ula (4b) in which R3 .. is - (CH2) m-NHR8 in which R8 is hydrogen. The reaction is typically carried out in a protic organic solvent, such as methanol or ethanol. The reaction is generally carried out at room temperature for a period of time ranging from 5-24 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. Alternatively, for example, in a deprotection a compound of the formula (4a) in which R3 > is - (CH2) m-NR8-t-Boc makes contact with a molar excess of a suitable acid to give a compound of the formula (4b) in which R3 .. is - (CH2) m-NHR8. The reaction is typically carried out in an organic solvent, such as methanol, ethanol, ethyl acetate, diethyl ether, or dioxane. Suitable acids for this reaction are well known in the art, including hydrochloric acid, hydrobromic acid, trifluoroacetic acid, and methanesulfonic acid. The reaction is generally carried out at room temperature for a period of time ranging from 1-10 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. For example, in a hydrolysis a compound of the formula (4a) in which R3. is - (CH2) mC (O) OPg3 and Pg3 is methyl or ethyl is contacted with about 1 to 2 molar equivalents of lithium hydroxide, sodium hydroxide, or potassium hydroxide to give a compound of the formula (4b) in wherein R3"is - (CH2) m-C02H. The reaction is carried out in a suitable solvent, such as a mixture of methanol, ethanol, methanol / water, ethanol / water mixtures, or tetrahydrofuran / water mixtures and generally they require 1 to 24 hours.The reaction is carried out at temperatures from about 0 ° C to the reflux temperature of a solvent.The resulting acid is isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, and precipitation and can be purified by trituration, precipitation, chromatography, and recrystallization, For example, in a reduction a compound of the formula (4b) in which R3> is - (CH2) m -? _ C02-Pg3 in which Pg3 is methyl or ethyl is in contact with an agent suitable reduction, such as lithium borohydride, diisobutylamino hydride, 9-borabicyclo [3.3.1] nonane, preferably lithium borohydride to give a compound of the formula (4b) in which R3 .. is - (CH2) ra _? - CH20H. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran or toluene, with tetrahydrofuran being preferred. The reaction is carried out at a temperature from about -30 ° C to about 50 ° C and generally requires from 2 to 12 hours. The product can be isolated by tempering, extraction, evaporation and precipitate and can be purified by trituration, chromatography, and recrystallization. In Reaction Scheme D, step 2, a compound of the formula (4b) undergoes a derivatization reaction to give a compound of the formula (4) in which R3 is as desired in the final product of the formula (1) ). Such derivatization reactions include hydrolysis of esters and ester formations as are well known in the art, ether formation, amine alkylation, amide formation, urea formation, carbamate formation and sulfonamide formation. In Reaction Scheme D, step 2, the compound of formula (4b) is one in which Y is a thio protecting group, such as thioacetyl, thiobenzoyl, 4-methoxybenzylthiol or t-butylthiol. For example, in an ether formation a compound of the formula (4b) in which R3 .. is - (CH2) m _? - CH20H is contacted with 1 to 10 molar equivalents of a suitable alkylating agent to give a compound of the formula (4) in which R3 is - (CH2) mZQ in which Z is -0-. A suitable alkylating agent is one which transfers Q or Q protected as desired in the final product of the formula (1), such as benzyl bromide, benzyl chloride, substituted benzyl bromide, substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoacetate, ethyl 3-chloropropionate, ethyl 3-bromopropionate, 5-bromovalerate ethyl, ethyl 4-bromobutyrate, 3-chloropropionamide, 2-bromoethylbenzene, substituted 2-bromoethylbenzene, l-chloro-3-phenylpropane, l-bromo-4-phenylbutane, and the like, or nitrogen mustard, including 2-chlorobenzene dimethylaminoethyl, 2-diethylaminoethyl chloride, and 3-dimethylaminopropyl chloride. The reaction is carried out in a suitable solvent, such as diethylether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or acetonitrile, and using a suitable base, such as sodium hydride, potassium hydride, potassium t-butoxide, and diisopropylamide of lithium. The reaction is generally carried out at temperatures of -70 ° C and room temperature and requires approximately 1-24 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. Alternatively, as appreciated by those skilled in the art, an ether formation can also be carried out by a similar procedure to a previous one using a compound of the formula (4b) in which R3"- is - (CH2) m_? -CH2OH in which the hydroxy group is first converted to a leaving group, such as chlorine, bromine or mesylate and a suitable alcohol which transfers Q or Q protected as desired in the final product of the formula (1), such as alcohol benzyl, substituted benzyl alcohol, phenol, substituted phenol, and the like. The conversion of hydroxy to the leaving groups, such as chloro bromo and mesylate are well known and appreciated in the art. For example, in an alkylation of amine a compound of the formula (4b) in which R3 > - is - (CH2) m-NHR8 is in contact with 1 to 10 molar equivalents of a suitable alkylating agent to give a compound of the formula (4) in which R3 is - (CH2) mZQ in which Z is - NR8-. The reaction can be carried out after the protection of the amine function of R3 > . wherein R8 is hydrogen by a suitable protecting group, such as benzyl or t-Boc. For an alkylation of amine a suitable alkylating agent is one as described above by the ether formulation and also include alkyl halide, such as methyl iodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride, butyl bromide, butyl chloride and the like. The reactions are carried out in a suitable solvent such as methanol, ethanol, dimethylformamide, or pyridine and using a suitable base, such as sodium carbonate, triethylamine, N, N-diisopropylethylamine or pyridine. The reaction is generally carried out at temperatures from room temperature to the reflux temperature of the solvent and require from about 1-24 hours. The product can be isolated by techniques well known in the art such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. Alternatively, for example, in an amine alkylation a compound of the formula (4b) in which R3- < is - (CH2) m-NHR8 is in contact in a reduction alkylation with a suitable aldehyde to give a compound of the formula (4) in which R3 is - (CH2) m-Z-Q in which Z is -NR8-. A suitable aldehyde is one that transfers protective Q or Q as desired in the final product of formula (1), such as benzaldehyde and substituted benzaldehydes. The reaction is carried out in a suitable solvent, such as methanol, ethanol, tetrahydrofuran, or mixtures of methanol or ethanol and tetrahydrofuran. The reaction can be carried out in the presence of a drying agent, such as sodium sulfate or molecular sieves. The reaction is carried out in the presence of 1.0 to 6.0 molar equivalents of an appropriate reducing agent, such as, sodium borohydride or sodium cyanoborohydride with sodium cyanoborohydride which is preferred. This may be advantageous for maintaining the pH in the range from about 4 to 6. The reaction is generally carried out at temperatures from 0 ° C to the reflux temperature of the solvent. Generally, reactions require 1 to 72 hours. The product can be isolated by techniques well known in the art such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. For example, in an amide formation in a compound of the formula (4b) in which R3- "is - (CH2) m-C02H is in contact with a suitable amine in an amide formation to give a compound of the formula (4) in which R3 is - (CH2) mZQ in which Z is amide. Such reactions of amide formation using carboxy activation or in suitable coupling agents are well known in the art and described in the foregoing. A suitable amine, HNR8Q gives rise to R8 and Q as desired in the final product of formula (1), such as methylamine, ethylamine, propylamine, butylamine, N-methyl benzylamine, benzyl-alanine, 4- (3- aminopropyl) morpholine and the like. For example, in an amide formation a compound of the formula (4b) in which R3O is - (CH2) m-NHR8 is in contact with a suitable carboxylic acid in an amide formation to give a compound of the formula (4) wherein R3 is - (CH2) m ~ ZQ in which Z is amide. Such amide formation reactions using carboxy activation or suitable coupling agents are well known in the art as described above. Suitable carboxylic acids, QC (0) -0H are those which give rise to Q as desired in the final product of the formula (1), such as benzoic acid, substituted benzoic acids, phenylacetic acids, substituted phenylacetic acids, mono- t-butyl malonate, and the like. For example, in a urea formation a compound of the formula (4b) in which R3 .. is - (CH2) m-NHR8 is in contact with an appropriate isocyanate, 0 = C = NQ, to give a compound of the formula (4) in which R3 is - (CH2) mZQ in which Z is urea. A suitable isocyanate is one which gives rise to Q as desired in the final product, such as phenyl isocyanate, substituted phenyl isocyanate, naphthyl isocyanate, isocyanate-ethyl acetate, and the like. The reaction is carried out by the addition of an equivalent of, or a light molar excess of, an appropriate isocyanate, is added to a solution of a compound of the formula (4b) in which R3 .. is - (CH2) m-NHR8 in a suitable solvent, such as diethyl ether, benzene, or toluene. The reaction is carried out at a temperature from about 0 ° C to the reflux temperature of the solvent and requires about 1-24 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, extraction, evaporation, trituration, chromatography, and recrystallization. For example, in a N-carbamoyl formation a compound of the formula (4b) which R3- is - (CH2) m-NHR8 is in contact with an appropriate chloroformate to give a compound of the formula (4) in which R3 is - (CH2) m ~ ZQ in which Z is N-carbamoyl. An appropriate chloroformate is one which gives rise to Q as desired in the final product of formula (1). Examples of chloroformate include benzyl chloroformate, naphthyl chloroformate, phenyl chloroformate, and substituted phenyl chloroformates, such as 4-chlorophenyl chloroformate, 4-methylphenyl chloroformate, 4-bromophenyl chloroformate, 4-fluorophenyl chloroformate, chloroformate 4-chloroformate. -methoxyphenyl and the like. The reaction is carried out by adding an equivalent of, or a light molar excess of, an appropriate chloroformate in a solution of a compound of the formula (4b) in which R3"is - (CH2) m-NHR8 in a suitable solvent , such as toluene, tetrahydrofuran, dimethylformamide, dichloromethane, pyridine, or chloroform. The reaction is carried out in the presence of an excess of a suitable base, such as triethylamine, sodium carbonate, potassium bicarbonate, pyridine or N, N-diisopropylethylamine. The reaction is carried out at a temperature from about -70 ° C to the reflux temperature of the solvent and generally requires from 30 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography, and recrystallization. For example, in an O-carbamoyl formation a compound of the formula (4b) in which R3 >; is - (CH2) m_? -CH20H is in contact with an appropriate isocyanate, as defined above by the formation of urea, to give a compound of the formula (4) in which R3 is - (CH2) mZQ in which Z is O-carbamoyl . The reaction mixture is carried out in a suitable solvent, such as diethyl ether tetrahydrofuran, dimethylformamide, or acetonitrile. The reaction can be facilitated by the use of the catalytic amount of a suitable base, such as sodium hydride, potassium hydride, or potassium t-butoxide. The reaction is generally carried out at temperature from -20 ° C to room temperature and requires from about 1-24 hours. The product can be isolated by techniques well known in the art, such as extraction, evaporation, and precipitation and can be purified by chromatography and recrystallization. For example, in a sulfonamide formation to prepare a compound wherein R3 is - (CH2) m-S02NR8-Y ?, a compound of the formula (4b) in which R3"is - (CH2) m-NHR8 is in contact with an appropriate sulfonamide-forming reagent: A suitable sulfonamide-forming reagent, such as a sulfonyl chloride, Y? S (0) 2CI, or sulfonyl anhydride, Yi (0) 2S-0-S (0) ) 2 Yi, is one which gives origin to Yi as desired in the final product Examples of the appropriate sulfonamide-forming reagents are benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, dansyl chloride, N-morpholinylsulfonyl, N-piperidinylsulfonyl chloride, 2,4,5-trichlorobenzenesulfonyl chloride, 2,5-dichlorobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-mesitylenesulfonyl chloride, 4-bromobenzene chloride sulfonyl, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-methoxybenzyl chloride ensulfonyl, 4-t-butylbenzenesulfonyl chloride, p-toluenesulfonyl chloride, 2,3,4-trichlorobenzenesulfonyl chloride, 2,5-dimethoxybenzenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 3-dimethoxybenzenesulfonyl chloride, 2-chlorobenzenesulfonyl chloride, , 6-dichlorobenzenesulfonyl, 3-bromobenzenesulfonyl chloride, 4-n-butylbenzenesulfonyl chloride, benzenesulfonic anhydride, 4-toluenesulfonic anhydride chloride, and 2-mesitylenesulfonic anhydride. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dichloromethane, pyridine or chloroform and in the presence of an excess of a suitable base, such as triethylamine, sodium carbonate, pyridine, or N, N-diisopropylethylamine. The reaction is carried out at a temperature from -50 ° C to the reflux temperature of the solvent. The reaction usually requires from 30 minutes to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, chromatography and recrystallization. In Reaction Scheme D, step 3, a compound of the formula (4) in which R3 is as desired in the final product of the formula (1) undergoes a selective thiol deprotection to give a compound of the formula ( 4) . Such selective thiol deprotections using suitable protecting groups are well known and appreciated in the art as discussed in Reaction Scheme C, step 1, above. In Reaction Scheme D, step 4, a compound of formula (4) undergoes a modification reaction to give the compound of formula (1) or protected compound of formula (1) as described in the Scheme of Reaction C, stage 2, previous. In Reaction Scheme D, step 5, a compound of formula (4a) in which Y is a protected thio is deprotected to give the compound of formula (1) or a protected compound of formula (1). In Reaction Scheme D, an optional step, a protected compound of formula (1) is deprotected to give a compound of formula (1). Such deprotection reactions are well known and appreciated in the art and may include selective deprotections. Alternative routes for preparing the compounds of the formula (3) in which Y is bromine, are present in Reaction Schemes F.l and F.2.

It is F Reaction burning. l is bromine and A is -OH) In Reaction Scheme F.l, an appropriate α-amino carboxylic acid of formula (8) is deaminobrominated to give a compound of formula (3) in which Y is bromine and A is -OH. An appropriate α-amino carboxylic acid of the formula (8), and protective forms thereof in which R 3 > is R3 as desired in the final product of formula (1) or gives rise after deprotection in R3 as desired in the final product of formula (1). In the addition, O-amino carboxylic acid of the formula (8) may also be one in which the stereochemistry in the carbon bearing R3 'gives rise after displacement in the stereochemistry as desired in this carbon in the final product of the formula (1). Such an appropriate α-amino carboxylic acid of formula (8) are commercially available or can be readily prepared by techniques and procedures well known and appreciated by one of ordinary skill in the art. For example, L-alanine, D-alanine, L-valine, D-valine, D-norvaline, L-leucine, D-leucine, D-isoleucine, D-tert-leucine, glycine, L-glutamic acid, acid D-glutamic, L-glutamine, D-glutamine, L-lysine, D-lysine, L-ornithine, D-ornithine, (D) - (-) -2-aminobutyric acid, D-threonine, D-homoserine, D-Alotreonine, D-serine, D-2-aminoadipic acid, D-aspartic acid, D-glutamic acid, D-lysine hydrate, 2,3-diaminopropionic acid monobromhydride, D-ornithine hydrochloride, D-dihydrochloride, L-2,4-diaminobutyric acid, L-meta-tyrosine, D-4-hydroxyphenylglycine, D-tyrosine, L-phenylalanine, D-phenylalanine, D, L-2-fluorophenylalanine, beta-methyl-D hydrochloride, L- phenylalanine, D, L-3-fluorophenylalanine, 4-bromo-D, L-phenylalanine, L-phenylalanine, L-phenylglycine, D-phenylglycine, D, L-4-fluorophenylalanine, 4-iodo-D-phenylalanine, D- homophenylalanine, D, L-2-fluorophenylglycine, D, L-4-chlorophenylalanine, and the like, are all commercially available and the methods in D. A. Evans, et al. J. Am. Chem. Soc., 112, 4011-4030 (1990): S. Ikegami et al. Tetrahedron. 44, 5333-5342 (1988); W. Oppolzer et al. Tet. Lets. 30 6009-6010 (1989); Synthesis of Optically Active a-Amino-Acids, R.M. Williams (Pergamon Press, Oxford 1989); M. J. O'Donnell ed .: a-Amino-Acid Synthesis. Tetrahedrom Symposia in print, No. 33, Tetrahedro 44, No. 17 (1988); U. Schóllkopf, PureAppl. Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem., 44, 3748-3752 (1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J. O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al. J. Am. Chem. Soc, 110, 8520-8525 (1988). The deaminobromination described in Reaction Scheme F.l can be carried out using conditions described in Compagnone, R.S. and Rapoport, H .. J. Org. Chem., 51, 1713-1719 (1986); U.S. Patent No. 5,322,942, issued June 21, 1994; Overberger, C.G. and Cho, I., J. Org. Chem., 33, 3321-3322 (1968); or P fister, K. et al., J. Am. Chem. Soc, 71, 1096-1100 (1949). For example, an α-amino carboxylic acid of the formula (8) and a suitable bromide, such as hydrogen bromide or potassium bromide in an acid solution, such as sulfuric acid, is treated with sodium nitrite. The reaction temperature is carried out at temperatures from about -25 ° C to about room temperature and requires about 1 to 5 hours. The product can be isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, chromatography, and recrystallization to give the compound of the formula (3) in which Y is bromine and A is -OH. The product can be isolated and purified by techniques well known and appreciated in the art, such as acidification, basification, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.

Reaction Scheme F.2 (9) Br ((3) in which Y i is bromine and A is -OH) In Reaction Scheme F.2, an appropriate carboxylic acid of the formula (9) is brominated to give a compound of the formula (3) in which Y is bromine and A is -OH.

An appropriate carboxylic acid of the formula (9), and the protected formulas thereof, is one in which R3 < is R3 as desired in the final product of formula (1) or gives rise after deprotection to R3 as desired in the final product of formula (1). For example, a mixture of a carboxylic acid of the formula (9) and dried red phosphorus are treated dropwise with bromide at average temperature ranging from about -20 ° to about 10 ° C. The reaction mixture is then heated to room temperature and then heated to about 80 ° C for about 2-5 hours. The reaction mixture is then cooled to room temperature, poured into water containing sodium bisulfite, and neutralized using solid sodium carbonate. The aqueous layer is extracted and acidified with a suitable acid, such as a concentrated hydrochloric acid. The precipitate is collected by filtration and dried to give the compound of the formula (3) or formula (3b2) in which Y is bromine and A is -OH. The product can be isolated and purified by techniques well known and appreciated in the art, such as acidification, basification, filtration, extracting, evaporation, trituration, chromatography, and recrystallization. The compounds of the formula (8) and (9) in which R3. is a - (CH2) m-W for use in Reaction Schemes F.l and F.2 are prepared according to Reaction Schemes G.l and G.2.

Reaction scheme G. 1 (1 1) (9) in which R ,, is W- (CH2) m- In Reaction Scheme G.l, an appropriate α-amino carboxylic acid of the formula (11) is converted to a compound of the formula (9) in which R3 < is W- (CH2) m-. An appropriate α-amino carboxylic acid of the formula (11) is one in which m is as desired in the final product of the formula (1) and are available in the art. For example, the reaction is carried out in a suitable polar solvent, such as water, ethanol, diethyl ether, tetrahydrofuran, or a water / ether solvent mixture using the appropriate base, such as sodium carbonate and N-carbethoxyphthalimide. The reaction mixture is typically stirred at about room temperature for 1-5 hours. The product can be isolated and purified by techniques well known in the art, such as acidification, extraction, evaporation, chromatography and recrystallization to give the additional compound of the formula (9) in which R3. is W- (CH2) m.

Reaction scheme G. 2, W- (CH2) m- Reaction Scheme G.2, step 1, appropriate α, α-diamino acid of the formula (12) undergoes selective N-a-protection to give a N-α-protected-α-diamino acid of the formula (13). A suitable α, α-diamino acid of formula (12) is one in which m is as desired in the final product of formula (1).

For example, a selective Na-protection of a suitable α, β-diamino acid, such as L-lysine (formula 12 in which m is 4), is achieved by masking the α-amino group by forming an imine of benzylidene. The benzylidene imine is formed by dissolving L-lysine monohydrochloride in lithium hydroxide and cooling the solution in a temperature range from about 0 ° to 10 ° C. The sharply distilled benzaldehyde is then added and the solution shaken. N -? - benzylidene-L-lysine is recovered by filtration and evaporation. The a-amino group of N-β-benzylidene-L-lysine then undergoes protection, such as the introduction of a Cbz or t-Boc group followed by hydrolytic cleavage of the imine in itself to give Na-benzyloxycarbonyl-L -lisina. Consequently, N-β-benzylidene-L-lysine is added to a mixture of sodium hydroxide and ethanol cooled at a temperature from about -5 ° to about -25 ° C. Then, the pre-cooled solutions of the benzyloxycarbonyl chloride in a solvent, such as ethanol, is added to the reaction mixture. The temperature is maintained in a range from about -10 ° to about -25 ° C during the course of the addition, and may allow it to emerge later. The reaction mixture is then acidified using a suitable acid, such as pre-cooled hydrochloric acid and N-a-benzyloxycarbonyl-L-lysine, which corresponds to formula (13) wherein m is 4, recovered by filtration or evaporation and recrystallization. In Reaction Scheme G.2, step 2, Na-benzyloxycarbonyl-L-lysine or other compounds of formula (13) are converted to α-phthalimido-a-benzyloxycarbonyl-L-lysine or another carboxylic acid? -phthalimido -a-aminoprotected of the formula (14) by the method described in Reaction Scheme Gl, above. Reaction Scheme G.2, step 3, the? -phthalimido-a-aminoprotected carboxylic acid of the formula (14) is deprotected to give a compound of the formula (8) in which R3- is W- (CH2) m_ . For example, α-phthalimido-a-benzyloxycarbonyl-L-lysine is in contact with hydrogen in the presence of a hydrogenation catalyst, such as palladium / carbon at % The reagents are typically contacted in a suitable solvent mixture such as ethanol, methanol, water and ethanol / water mixtures, or methanol / water mixtures. Reagents are typically shaken under a hydrogen atmosphere of 35-45 psi at room temperature for a period of time averaged from 5-24 hours. The product is typically recovered by filtration and evaporation of the solvent. A route to prepare the compounds of the formula (3) and formula (3b2) in which Yi is protected thio is present in Reaction Scheme H. Reagents and starting materials are readily available to one of ordinary skill in the art. Reaction Scheme H all substituents, unless otherwise indicated, are as previously defined.

Reaction scheme H g5 (15) (17) stage 2 R, ((3) in which Y is (18) protected guy) In Reaction Scheme H, step 1, a bromoacetate of the formula (15) is contacted with an appropriate thiol to give a protected acetic acid ester of the formula (17). In a bromoacetate of the formula (15) Pg5 is a protecting group, such as methyl, ethyl, t-butyl, and benzyl. An appropriate thiol is one which gives rise to a protective thio group, Y, in the product of the formula (3b). In Reaction Scheme H, step 1, the use of 4-methoxybenzylmercaptan is preferred. For example, a bromoacetate of the formula (15) is in contact with an appropriate thiol in a suitable organic solvent, such as dimethylformamide. Advantageously, the solvent is degassed. The reaction is carried out using a suitable base, such as sodium hydroxide triethylamine, or N, N-diisopropylethylamine. The reaction is carried out at temperatures from about -50 ° to about room temperature and about 1 to 72 hours are required. The protected acetic acid ester of formula (17) can be isolated and purified by well-known methods appreciated in the art, such as extraction, evaporation, chromatography, and distillation, and recrystallization. In Reaction Scheme H, step 2, the protected acetic acid ester of formula (17) is alkylated with an appropriate alkylating agent to give a compound of formula (18). In Reaction Scheme H, step 2, an appropriate alkylating agent is one which transfers R3 < which is R3 as desired in the final product of formula (1) or gives rise after deprotection to R3 as desired in the final product of formula (1) or gives rise to R3 > > as defined in Reaction Scheme D, step 1. Appropriate alkylating agents include alkylhalides, such as methyl iodide, methyl bromide, ethyl bromide, propyl bromide, propyl chloride, butyl bromide, butyl, and the like; benzyl bromide, benzyl chloride, substituted benzyl bromide, substituted benzyl chloride, ethyl bromoacetate, t-butyl bromoacetate, ethyl 3-chloropropionate, ethyl 3-bromopropionate, ethyl 5-bromovalerate, ethyl 4-bromobutyrate, 3- chloropropionamide, 2-bromoethylbenzene, substituted 2-bromoethylbenzene, l-chloro-3-phenylpropane, l-bromo-4-phenylbutane, and the like, N- (2-bromoethyl) phthalimide, N- (3-bromopropyl) phthalimide, N- (4-bromobutyl) phthalimide and the like; l-bromo-2-phenylethane, l-bromo-3-phenylpropane, l-bromo-4-phenylbutane and the like. For example, a protected acetic acid ester of formula (17) is alkylated with an appropriate alkylating agent. The reaction is carried out in a suitable solvent, such as diethyl ester, tetrahydrofuran, dimethylformamide, and toluene using a suitable base, such as sodium hydride, potassium hydride, potassium t-butoxide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide or lithium diisopropylamide. The reaction is generally carried out at temperatures from about -70 ° C to about room temperature or requires from about 1-24 hours. The product can be isolated by techniques well known in the art, such as extraction on evaporation and precipitation and can be purified by chromatography and recrystallization. In Reaction Scheme H, step 3, the compound of the formula (18) the carboxy protective group Pg3 is selectively removed to give the compound of the formula (3) in which Y is a protected uncle. Such deprotection of esters to acids in the presence of suitable thio protecting groups are well known and appreciated in the art. The following examples and typical synthesis preparations present as described in the above Reaction Schemes. These examples and preparations are understood to be illustrative only and are not intended to limit the scope of the invention in any way.

PREPARATION 1.1 2- (t-Butoxycarbonylamino) malonic acid Compound diethyl ammonium hydrochloride (5.0 g 23.6 mmol), triethylamine (3.30 mL, 23.6 mmol), and dichloromethane (80 mL). Di-t-butyl dicarbonate (5.4 g, 24.8 mmol) is added. After 18 hours, it was extracted with a 5% sulfuric acid solution, a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na 2 SO 4, filter and evaporate in vacuo to give a residue. Chromatography of the residue on silica gel is eluted with 3/2 hexane / ethyl acetate to give diethyl t-butoxycarbonylaminomalonate (87%). Diethyl t-butoxycarbonylaminomalonate combined (4.55 g, 16.5 mmol), in a solution of 6 M aqueous sodium hydroxide (6.65 mL, 40 mmol), and ethanol (30 mL). After 18 hours, evaporate in vacuo to remove more of the ethanol, dilute in water (50 mL) and extract with diethyl ether. It is acidified to a pH of about 3 with aqueous 12M hydrochloric acid and extracted twice with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and concentrate in vacuo to give the title compound (61%).

PREPARATION 1.2- (t-Butoxycarbonylamino) malonic acid Compound diethylamine malonate hydrochloride (13.34 g, 63.0 mmol), triethylamine (8.8 mL, 63.0 mmol), and dichloromethane (220 mL). Di-t-butyl dicarbonate (14.4 g, 66.2 mmol) is added. After 18 hours, it is extracted with a 5% aqueous sulfuric acid solution, a saturated aqueous sodium bicarbonate solution and brine. The organic layer is dried over Na 2 SO 4, filtered and evaporated in vacuo to give t-butoxycarbonylaminomalonate (103%). The combined diethyl t-butoxycarbonylaminomalonate (22.72 g, 82.5 mmol), a 6 M aqueous sodium hydroxide solution (55 mL, 330 mmol / g, and ethanol (150 mL).

After 56 hours, evaporate in vacuo to remove more of the ethanol, dilute with water (40 mL). It is cooled and acidified to a pH of about 3 with concentrated hydrochloric acid. Dry freezing gives a title compound and sodium chloride as a powder.

PREPARATION 2 Combined 2- (R) -2-Bromo-3-methylbutyric acid D-valine (4.7 g, 40.0 mmol) and a 2.5 M aqueous sulfuric acid solution is cooled as follows -5 ° C. The aqueous hydrobromic acid is added to (13.9 g, 48%, 40 mmol). A solution of sodium nitride (2.8 g, 40 mmol) in water (20 L) is added. After 2 hours, warm to approximately 5 ° C. After 18 hours, it is extracted three times with ethyl acetate. Dry the combined organic layers over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. The residue is taken to silica gel chromatography eluting with 1/1/0 dichloromethane / ethyl acetate / acetic acid to give a residue. The silica gel residue is chromatographed with 1/1 / 0.5 dichloromethane / ethyl acetate / diethyl acetate / acetic acid to give the title compound (35%).

EXAMPLE 1 N, N'-DIF-2-methyl-2- ((S) -2-mercapto-3-methylbutyrylamino) -malonamide 1. 1 Synthesis of N, N '-diphenethyl-2- (t-butoxycarbonylamino) -malonamide Combine t-butoxycarbonylaminomalonic acid (0.465 g, 2.12 mmol), phenethylamino (0.715 mL, 5.70 mmol) and dichloromethane (25 mL). Add N-methylmorpholine (0.752 mL, 6.85 mmol). Cool in an ice bath. Add benzotriazol-1-yloxy-tris (pyrrolidino) -phosphonium hexafluorophosphate complex (3.15 g, 6.85 mmol). Remove the ice bath and allow to warm to room temperature. After 18 hours, dilute the reaction mixture with ethyl acetate, extract with a 5% aqueous sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layers over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2/1 ethyl acetate / hexane to give the title compound. 1. 2 Synthesis of trifluoroacetic acid salt of N, N'-diphenethyl-2-aptinomalonamide Combine N, N '-diphenethyl-2- (t-butoxycarbonylamino) -malonamide (0.571 g, 1.35 mmol) and dichloromethane (10 mL). Add trifluoroacetic acid (1.8 mL). After 2.5 hours evaporate in vacuo to give a residue. Add hexanes and carbon tetrachloride to co-evaporate residual trifluoroacetic acid and evaporate in vacuo to give the title compound (100%). XX Synthesis of N, N '-diphenethyl-2- ((R) -2-bromo-3-methylbutyrylamino) malonamide Combine trifluoroacetic acid salt of N, N'-diphenethyl-2-aminomalonamide (0.285 g, 0.655 mmol) and dichloromethane (5 mL). Add (R) -2-bromo-3-methylbutyric acid (0.118 g, 0.655 mmol), N-methylmorpholine (0.10 mL, 0.983 mmol), and hydrochloric acid salt of 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (0.14 g, 0.725 mmol), and 1-hydroxybenztriazole hydrate (0.10 g, 0.72 mmol). After 18 hours, evaporate the reaction mixture in vacuo, dilute the concentrated reaction mixture with ethyl acetate, extract with a 5% aqueous sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Saturate each of the aqueous layers with sodium chloride and extract four times with ethyl acetate.

Combine the organic layers, dry over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate / hexane to give the title compound (67%). 1.4 Synthesis of N, N '-diphenethyl-2- ((S) -2-thioacetyl-3-methylbutyrylamino) malonamide Combine N, N' -difenetyl-2- ((R) -2-bromo-3-methylbutyrylamino) malonamide (0.20 g, 0.41 mmol), thioacetic acid (0.08 mL, 1.1 mmol), and dimethylformamide (8 mL). Degassing by repeated cycles of vacuum and filling with nitrogen gas. Add cesium carbonate (0.215 g, 0.664 mmol). After 18 hours, dilute with water and extract with ethyl acetate. Extract the organic layer with brine, dry over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 hexane ethyl acetate to give the title compound. 1.5 synthesis of N, N'-diphenethyl-2- ((S) -2-mercapto-3-methylbutyrylamino) malonamide Cool methanol (10 mL) in an ice bath and bubble with ammonia gas for approximately 15 minutes. Add a cooled solution (approximately 0 ° C) of N, N'-diphenethyl-2- ((S) -2-thioacetyl-3-methylbutyrylamino) malonamide (0.17 g, 0.35 mmol) in degassed methanol (10 mL). After 1 hour, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3/2 hexane-ethyl acetate and then 1/1 hexane-ethyl acetate to give the title compound (89%).

EXAMPLE 2 N, N'-DIFFENETYL-2- ((S) -2-mercapto-3-phenylpropionylamino) -malonamide 2. 1 Synthesis of N, N'-Difenethyl-2- ((R) -2-bromo-3-phenylpropionylamino) malonamide Prepare by the method of Example 1.3 using N, N'-diphenethyl-2-aminomalonamide trifluoroacetic acid salt ( 0.61 g, 0.600 mmol), (R) -2-bromo-3-phenylpropionic acid (0.137 g, 0.600 mmol), N-methylmorpholine (0.20 mL, 1.8 mmol), hydrochloric acid salt of l-ethyl-3- ( 3- (dimethylamino) propyl) carbodiimide (0.14 g, 0.72 mmol), and 1-hydroxybenztriazole hydrate (0.097 g, 0.72 mmol) in dichloromethane (10 mL). Purify by chromatography on silica gel eluting with 1/1 ethyl acetate / hexane to give the title compound (60%). 2.2 Synthesis of N, N '-diphenethyl-2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide Prepare by the method of Example 1.4 using N, N' -difenetyl-2- ((R) -2- bromo-3-phenylpropionylamino) malonamide (0.11 g, 0.21 mmol), thioacetic acid (0.05 mL, 0.62 mmol), and cesium carbonate (0.10 g, 0.31 mmol) in dimethylformamide (8 mL). Purify by chromatography on silica gel eluting with 1/1 hexane ethyl acetate to give the title compound (92%). 2.3 Synthesis of N, N '-diphenethyl-2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 1.5 using N, N' -difenetyl-2- ((S) -2- thioacetyl-3-phenylpropionylamino) -malonamide (0.10 g, 0.192 mmol).

Purify by chromatography on silica gel eluting with 1/1 hexane ethyl acetate to give the title compound (83%).

PREPARATION 3 2- (S) -2-Thioacetyl-4-phenylbutyric acid Combine D-homophenylalanine (5.0 g, 28.0 mmol) and a 2.5M aqueous sulfuric acid solution (28 mL). Cool to approximately -5 ° C. Add aqueous hydrobromic acid (6.35 L, 48%, 56 mmol). Add a solution of sodium nitrite (1.95 g, 28 mmol) in water (15 mL) for approximately 30 minutes. After 2 hours, heat to approximately 0 ° C. After 18 hours, extract three times with ethyl acetate. Dry the combined organic layers over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 9/1 / 0.5 dichloromethane / ethyl acetate / acetic acid to give 2- (R) -2-bromo-4-phenylbutyric acid (54%). Combine 2- (R) -2-bromo-4-phenylbutyric acid (0.486 g, 2.05 mmol), thioacetic acid (0.40 mL, 5.5 mmol), and dimethylformamide (40 mL). Degas by repeated cycles of vacuum and fill with nitrogen gas. Add cesium carbonate (1.08 g, .32 mmol). After 18 hours, dilute with water and extract with ethyl acetate. Extract the organic layer with brine, dry over Na 2 SO 4, filter, and evaporate in vacuo to give the title compound.

EXAMPLE 3 N, N'-DIFFENETYL-2- ((S) -2-mercapto-4-phenylbutyrylamino) -malonamide 3. 1 Synthesis of N, N '-diphenethyl-2- (t-butoxycarbonylamino) malonamide Combine a mixture of t-butoxycarbonylaminomalonic acid and sodium chloride of Preparation 1.2 (5.0 g, 13.7 mmol), phenethylamino (4.32 mL, 34.3 mmol) , and tetrahydrofuran (25 mL). Cool in an ice bath. Remove the ice bath. Add N-methylmorpholine (3.8 mL, 34.3 mmol), hydrochloric acid salt of l-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (6.58 g, 34.3 mmol), and 1-hydroxybenztriazole hydrate (4.63 g, 34.3 mmol). Allow to warm to room temperature. After 18 hours, dilute the reaction mixture with ethyl acetate, extract with a 5% aqueous sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on the silica gel eluting with 2/1 ethyl acetate / hexane to give the title compound (84%). 3.2 Synthesis of trifluoroacetic acid salt of N, N'-diphenethyl-2-aminomalonamide Combine N, N-diphenethyl-2- (t-butoxycarbonylamino) -malonamide (0.425 g, 1.00 mmol) and dichloromethane (7 mL). Add trifluoroacetic acid (1.5 mL). After 2.5 hours, evaporate in vacuo to give a residue. Repeatedly, add carbon tetrachloride to co-evaporate residual trifluoroacetic acid and evaporate in vacuo to give the title compound. 3.3 Synthesis of N, N '-diphenethyl-2- ((S) -2-thioacetyl-4-phenylbutylamino) malonamide Combine trifluoroacetic acid salt of N, N'-diphenethyl-2-aminomalonamide (0.50 g, 1.0 mmol) and dichloromethane (15 mL). Add (R) -2-thioacetyl-4-phenylbutyric acid (0.545 g, 1.0 mmol), N-methylmorpholine (0.22 mL, 2.0 mmol), and l-ethyl-3- (3- (dimethylamino) hydrochloric acid salt propyl) carbodiimide (0.23 g, 1.2 mmol), and 1-hydroxybenztriazole hydrate (0.16 g, 1.2 mmol). After 18 hours, evaporate the reaction mixture in vacuo, dilute the concentrated reaction mixture with ethyl acetate, extract with a 5% aqueous sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Extract each aqueous layer with ethyl acetate. Combine the organic layers, dry over a2SO4, filter, and evaporate in va cuo to give a residue. Chromatograph the residue on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (92%). 3.4 Synthesis of N, N '-diphenethyl-2- ((S) -2-mercapto-4-phenylbutyrylamino) malonamide Cool methanol (15 mL) in an ice bath and bubble with ammonia gas for approximately 15 minutes. Add a cooled solution (approximately 0 ° C) of N, N '-diphenethyl-2- ((S) -2-thioacetyl-4-phenylbutyrylamino) -malonamide (0.50 g, 0.92 mol) in degassed methanol (15 mL). After 1 hour, evaporate in vacuo to give a residue. Chromatograph the residue on the silica gel eluting with 3/2 hexane ethyl acetate to give the title compound (28%).

EXAMPLE 4 N, N'-Dibenzyl-2- ((S) -2-mercapto-3-phenylpropionylamino) -malonamide 4. 1 Synthesis of N, N'-dibenzyl-2- (t-butoxycarbonylamino) -malonamide Combine t-butoxycarbonylaminomalonic acid (0.438 g, 2.00 mmol), benzylamino (0.436 mL, 4.0 mmol), and dichloromethane (10 mL). Add N-methylmorpholine (0.55 mL, 5.00 mmol), hydrochloric acid salt of l-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (0.96 g, 5.0 mmol), and 1-hydroxybenztriazole hydrate (0.67 g) , 5.0 mmol). After 18 hours. Concentrate in vacuo, dilute the concentrated reaction mixture with ethyl acetate, extract with a 5% aqueous sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (52%). 4.2 Synthesis of trifluoroacetic acid salt of N, N'-dibenzyl-2-aminomalonamide trifluoroacetic acid salt Combine N, N'-dibenzyl-2- (t-butoxycarbonylamino) -malonamide (0.415 g, 1.04 mmol) and dichloromethane (7 mL). Add trifluoroacetic acid (1.0 mL). After 2.5 hours, evaporate in vacuo to dry under high vacuum to give the title compound. 4.3 Synthesis of N, N'-dibenzyl-2- ((R) -2-bromo-3-phenylpropionylamino) malonamide Combine trifluoroacetic acid salt of N, N'-dibenzyl-2-aminomalonamide (0.41 g, 1.04 mmol), (R) -2-bromo-3-phenylpropionic acid (0.262 g, 1.15 mmol), N-methylmorpholine (0.23 mL, 2.08 mmol), hydrochloric acid salt of l-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (0.22 g, 1.15 mmol), and 1-hydroxybenztriazole hydrate (0.155 g, 1.15 mmol) in dichloromethane (5 mL). After 18 hours, extract with a solution of 5% aqueous sulfuric acid, a solution of saturated sodium bicarbonate, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate / hexane to give the title compound. 4.4 Synthesis of N, N'-dibenzyl-2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide Combine N, N'-dibenzyl-2- ((R) -2-bromo-3-phenylpropionylamino) malonamide (0.49 g, 0.97 mmol) and thioacetic acid (0.172 mL, 2.42 mmol) in dimethylformamide (15 mL). Degass by repeated cycles of vacuum and fill with nitrogen. Add cesium carbonate (0.473 g, 1.45 mmol). After 18 hours, dilute the reaction mixture with water and extract twice with ethyl acetate. Combine the organic layers. Extract with brine, dry over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (46%). 4.5 Synthesis of N, N'-dibenzyl-2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Cool methanol (12 mL) in an ice bath and bubble with ammonia gas for approximately 15 minutes. Add a cooled solution (approximately 0 ° C) of N, N'-dibenzyl-2- ((S) -2-thioacetyl-3-phenylpropionylamino) -malonamide (0.224 g, 0.445 mmol) in degassed methanol (12 mL). After 1 hour, evaporate in va cuo to give a residue. Chromatograph the residue on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound.

EXAMPLE 5 N, N'-Di- (3-phenylpropyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide . 1 Synthesis of N, N '-di- (3-phenylpropyl) -2- (t-butoxycarbonylamino) malonamide Prepare by the method of Example 4.1 using 3-phenylpropylamino (0.54 mL, 4.0 mmol). Add by purification by chromatography on silica gel eluting with 2/1 ethyl acetate / hexane to give the title compound (27%). 5.2 Synthesis of trifluoroacetic acid salt of N, N'-di- (3-phenylpropyl) -2-aminomalonamide Prepare by the method of Example 4.2 using N, N '-di- (3-phenylpropyl) -2- (t- butoxycarbonylamino) malonamide (0.24 g, 0.53 mmol) to give, after evaporation in vacuo and drying under high vacuum, the title compound. . 3 Synthesis of N, N '-di-3- (phenylpropyl) -2- ((R) -2-bromo-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.3 using trifluoroacetic acid salt of N, N'- di- (3-phenylpropyl) -2-aminomalonamide. Purify by chromatography on silica gel eluting with 1/1 ethyl acetate / hexane to give the title compound. 5.4 Synthesis of N, N '-di- (3-phenylpropyl) -2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.4 using N, N'-di- (3- phenylpropyl) -2- ((R) -2-bromo-3-phenylpropionyl-amino) alonamide (0.124 g, 0.575 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound. 5.5 Synthesis of N, N '-di- (3-phenylpropyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.5 using N, N'-di- (3- phenylpropyl) -2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide (0.156 g, 0.289 mmol). After 1 hour, evaporate in va cuo to give a residue. Purify by chromatography on silica gel eluting with 5% acetone / dichloromethane to give the title compound.

EXAMPLE 6 N, N '-Di- (4-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionyl-amino) malonamide; • 6.1 Synthesis of N, N '-di- (4-methoxyphenethyl) -2- (t-butoxycarbonylamino) malonamide Prepare by the method of Example 4.1 using 4-methoxyphenethylamino (0.585 mL, 3.8 mmol). Add by purification by chromatography on silica gel eluting with 2/1 ethyl acetate / hexane to give the title compound (27%). 6.2 Synthesis of trifluoroacetic acid salt of N, N'-di- (4-methoxyphenethyl) -2-aminomalonamide Prepare by the method of Example 4.2 using N, N '-di- (4-methoxyphenethyl) -2- (t- butoxycarbonylamino) malonamide (0.20 g, 0.412 mmol) to give, after evaporation in vacuo and drying under high vacuum, the title compound. 6.3 Synthesis of N, N '-di- (4-methoxyphenethyl) -2- ((R) -2-bromo-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.3 7S using trifluoroacetic acid salt of N, N'-di- (4-methoxyphenethyl) -2-aminomalonamide. Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound. 6.4 Synthesis of N, N '-di- (4-methoxyphenethyl) -2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.4 using N, N' -di- (4 - methoxyphenethyl) -2- ((R) -2-bromo-3-phenylpropionyl-amino) malonamide (0.133 g, 0.223 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (54%). 6.5 Synthesis of N, N '-di- (4-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) alonamide Prepare by the method of Example 4.5 using N, N' -di- (4- methoxyphenethyl) -2- ((S) -2-thioacetyl-3-phenyl-propionylamino) malonamide (0.071 g, 0.12 mmol). After 1 hour, evaporate in va cuo to give a residue. Chromatograph the residue on the silica gel eluting with 1/1 ethyl acetate / hexane to give the title compound.

EXAMPLE 7 N, N'-Dipentil-2- (2-mercapto-3-phenylpropionylamino) malonamide 7. 1 Synthesis of N, N'-dipentil-2- (t-butoxycarbonylamino) -malonamide Prepare by the method of Example 4.1 using pentylamine (1.50 L, 12.8 mmol). Purify by chromatography on silica gel eluting sequentially with 1/1 ethyl acetate / hexane, 3/1 ethyl acetate / hexane, and then 5/1 ethyl acetate / hexane to give the title compound (68%). 7.2 Synthesis of N, N'-dipentyl-2-aminomalonamide trifluoroacetic acid salt Combine N, N'-dipentyl-2- (t-butoxycarbonylamino) -malonamide (1.49 g, 4.17 mmol). After 1.5 hours, evaporate in vacuo and triturate with carbon tetrachloride to give the title compound. 7.3 Synthesis of N, N'-dipentil-2- ((R) -2-bromo-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.3 using N trifluoroacetic acid salt, N'-dipentil-2-aminomalonamide. Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound. 7.4 Synthesis of N, N'-dipentyl-2- ((S) -2-thioacetyl-3-phenylpropionylamino) alonamide Prepare by the method of Example 4.4 using N, N'-dipentil-2- ((R) -2- bromo-3-phenylpropionylamino) malonamide (0.45 g, 0.961 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (62%). 7.5 Synthesis of N, N'-dipentyl-2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.5 using N, N'-dipentil-2- ((S) -2- thioacetyl-3-phenylpropionylamino) malonamide (0.277 g, 0.60 mmol). Purify by chromatography on silica gel eluting sequentially with 5% acetone / dichloromethane and then 10% acetone / dichloromethane to give the title compound.

EXAMPLE 8 N, N '-Di- (2- (N-anilino) ethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide 8. 1 Synthesis of N, N '-di- (2- (N-anilino) ethyl) -2- (t-butoxycarbonylamino) malonamide Combine t-butoxycarbonylaminomalonic acid (0.730 g, 2.00 mmol), 2- (N-anilino) ethylamino (0.654 mL, 5.00 mmol) N-methylmorpholine (0.55 mL, 5.0 mmol)), hydrochloric acid salt l-ethyl-3- (3- (dimethylamino) propyl) -carbodiimide (0.958 g, 5.0 mmol), and hydrate 1-hydroxybenztriazole (0.67 g, 5.00 mmol) in dichloromethane (10 mL) and tetrahydrofuran (1 mL). After 18 hours, concentrate in vacuo, dilute the concentrated reaction mixture with ethyl acetate and extract with a saturated aqueous sodium bicarbonate solution and then brine. Extract each of the aqueous layers with ethyl acetate. Combine the organic layers, dry over Na2SO, filter, and evaporate in vacuo to give a residue. Combine the residue, methanol (10 mL), and celite and apply to a column of silica gel. Conduct chromatography eluting with 3/2 ethyl acetate / hexane to give the title compound (60%). 8.2 Synthesis of hydrochloric acid salt of N, N-di- (2- (N-anilino) ethyl) -2-a inomalonamide Combining N, N '-di- (2- (N-anilino) ethyl) -2- (t-butoxycarbonylamino) malonamide (0.55 g, 1.21 mmol) and tetrahydrofuran (7 mL) and diethyl ether (7 mL). Add a solution of hydrochloric acid in diethyl ether (10 mL, 1 M, 10 mmol) to give a solid. After 45 minutes, collect the solid by filtration to give the title compound. 8. 3 Synthesis of N, N '-di- (2- (N-anilino) ethyl) -2- ((R) -2-bromo-3-phenylpropionylamino) malonamide. Combine N, N '-di- (2- (N-anilino) ethyl) -2-aminomalonamide hydrochloric acid salt (0.474 g, 0.866 mmol) and dichloromethane (10 mL). Add (R) -2-bromo-3-phenylpropionic acid (0.26 g, 1.13 mmol). Add triethylamine (0.426 mL, 3.06 mmol). Add benzotriazole-1-yloxytris (dimethylamino) -phosphonium pyridine hexafluorophosphate complex (0.478 g, 1.13 mmol). After 18 hours, evaporate in vacuo and dilute the concentrated reaction mixture with ethyl acetate, extract with a 5% aqueous sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Extract each of the aqueous layers with ethyl acetate. Combine the organic layers and dry over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1/1 ethyl acetate / hexane and then 2/1 ethyl acetate / hexane to give the title compound (62%). 8.4 Synthesis of N, N '-di- (2- (N-anilino) ethyl) -2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.4 using N, N'- di- (2- (N-anilino) ethyl) -2- ((R) -2-bromo-3-phenylpropionyl-amino) malonamide (0.311 g, 0.549 mmol) and thioacetic acid (0.08 L, 0.010 mmol) in dimethylformamide (8 mL), and cesium carbonate (0.18 g, 0.549 mmol). Purify by chromatography on silica gel eluting sequentially with 1/1 ethyl acetate / hexane, 2/1 ethyl acetate / hexane, and then 3/1 ethyl acetate / hexane to give the title compound. 8.5 Synthesis of N, N '-di- (2- (N-anilino) ethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.5 using methanol (10 mL) and N, N '-di- (2- (N -anilino) ethyl) -2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide (0.151 g, 0.269 mmol) in degassed methanol (10 mL) and tetrahydrofuran (7 mL). After 2.5 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3/2 ethyl acetate / hexane and then 2/1 ethyl acetate / hexane to give the title compound.

PREPARATION 4 2- (S) -2-Thioacetyl-3-phenylpropionic acid Combine 2- (R) -2-bromo-3-phenylpropionic acid (2.85 g, 12.4 mmol), thioacetic acid (1.4 mL, 19.5 mmol), and dimethylformamide (30 mL). Degas by repeated cycles of vacuum and fill with nitrogen gas. Add cesium carbonate (4.25 g, 12.4 mmol). After 18 hours, add with a 5% aqueous sulfuric acid solution, dilute with water, and extract four times with ethyl acetate. Extract the combined organic layers with brine, dry over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1/1 / 0.02 hexane / ethyl acetate / acetic acid and then 1/1 / 0.02 hexane / ethyl acetate / acetic acid to give the title compound (43%) .

EXAMPLE 9 N, N'-Di- (pidrid-4-ylethyl) -2- (2-mercapto-3-phenylpropionyl-amino) malonamide 9. 1 Synthesis of N, N'-di- (pidrid-4-ylethyl) -2- (t-butoxycarbonylamino) malonamide Combine t-butoxycarbonylaminomalonic acid (0.438 g, 2.0 mmol), 2- (pyrid-4-yl) ethylamine ( 0.61 g, 5.0 mmol), N-methylmorpholine (0.55 L, 5.0 mmol)), hydrochloric acid salt l-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (0.96 g, 5.0 mmol), and hydrate of 1 -hydroxybenztriazole (0.68 g, 5.0 mmol) in dichloromethane (10 mL) and tetrahydrofuran (1 mL). After 18 hours, concentrate in vacuo, dilute the concentrated reaction mixture with ethyl acetate, and extract with a saturated aqueous sodium bicarbonate solution and then brine. Extract each of the aqueous layers with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol / dichloromethane to give the title compound (80%). 9.2 Synthesis of hydrochloric acid salt of N, N '-di- (pidrid-4-ylethyl) -2-aminomalonamide Combine N, N' -di- (pidrid-4-ylethyl) -2- (t-butoxycarbonylamino) malonamide (0.686 g, 1.61 mmol) and diethyl ether (20 mL). Add a solution of hydrochloric acid in diethyl ether (10 mL, 1 M, 10 mmol). After 1 hour, evaporate in vacuo to give the title compound. 9.3 Synthesis of N, N '-di- (pidrid-4-ylethyl) -2- ((R) -2-thioacetyl-3-phenylpropionylamino) malonamide Combine hydrochloric acid salt of N, N'-di- (pidrid- 4-ylethyl) -2-aminomalonamide (0.669 g, 1.63 mmol) and dichloromethane (10 mL), tetrahydrofuran (5 mL), and dimethylformamide (3 mL). Add an acid solution (S) -2-thioacetyl-3-phenylpropionic acid (0.43 g, 1.9 mmol) in dichloromethane (1.9 mL). Add N-methylmorpholine (0.357 mL, 4.90 mmol), hydrochloric acid salt of l-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (0.343 g, 1.8 mmol), and 1-hydroxybenztriazole hydrate (0.242 g, 0.18 mmol). After 18 hours, dilute the reaction mixture with ethyl acetate, extract with a saturated aqueous sodium bicarbonate solution, and then brine to give a residue. Chromatograph the residue on silica gel eluting with 10% methanol / dichloromethane and then 15% methanol / dichloromethane to give the title compound (63%). 9.4 Synthesis of N, N '-di- (pidrid-4-ylethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 4.5 using methanol (15 L) and N, N '-di- (pidrid-4-ylethyl) -2- ((S) -2-thioacetyl-3-phenylpropionylamino) malonamide (0.543 g, 1.02 mmol) in degassed methanol (15 mL). After 1.5 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/10 methanol / dichloromethane to give the title compound.

EXAMPLE 10 N, N'-DIFFENETYL-2- ((S) -2-mercaptopropionylamino) malonamide . 1 Synthesis of N, N '-diphenethyl-2- ((R) -2-bromopropionylamino) malonamide Prepare by the method of Example 4.3 using (R) -2-bromopropionic acid (0.109 mL, 1.2 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound. 10.2 Synthesis of N, N '-diphenethyl-2- ((S) -2-thioacetylpropionylamino) malonamide Prepare by the method of Example 4.4 using N, N' -diphenethyl-2- ((R) -2-bromopropionylamino) malonamide ( 0.175 g, 0.38 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (76%). 10.3 Synthesis of N, N '-diphenethyl-2- ((S) -2-mercaptopropionylamino) malonamide Prepare by the method of Example 1.5 using N, N' -diphenethyl-2- ((R) -2-thioacetylpropionyl-amino) malonamide (0.131 g, 0.29 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (98%).

EXAMPLE 11 N, N '-Difenetyl-2- (2-mercaptopropionylamino) malonamide 11. 1 Synthesis of N, N '-diphenethyl-2- (2-bromopropionylamino) -malonamide Prepare by the method of Example 4.3 using 2-bromopropionic acid (0.108 mL, 1.2 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound. 11.2 Synthesis of N, N '-diphenethyl-2- (2-thioacetylpropionylamino) malonamide Prepare by the method of Example 4.4 using N, N'-diphenethyl-2- (2-bromopropionylamino) alonamide (0.152 g, 0.33 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (96%). 11.3 Synthesis of N, N '-diphenethyl-2- (2-mercaptopropionylamino) malonamide Prepare by the method of Example 1.5 using N, N'-diphenethyl-2- (2-thioacetylpropionylamino) -malonamide (0.131 g, 0.29 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (100%).

EXAMPLE 12 N, N '-Difenetyl-2- (2-mercaptopentanoylamino) malonamide 12.1 Synthesis of N, N' -diphenethyl-2- (2-bromopentanoylamino) -malonamide Prepare by the method of Example 4.3 using 2-bromopentanoic acid (0.16) mL, 1.2 mmol). Purify by chromatography on silica gel eluting with 1/1 ethyl acetate / hexane to give the title compound. 12.2 Synthesis of N, N '-diphenethyl-2- (2-thioacetylpentanoylamino) malonamide Prepare by the method of Example 4.4 using N, N'-diphenethyl-2- (2-bromopentanoylamino) malonamide (0.162 g, 0.33 mmol). Purify by chromatography on silica gel eluting with 3/2 ethyl acetate / hexane to give the title compound (96%). 12.3 Synthesis of N, N '-diphenethyl-2- (2-mercaptopentanoylamino) -malonamide Prepare by the method of Example 1.5 using N, N'-diphenethyl-2- (2-thioacetylpentanoylamino) -malonamide (0.131 g, 0.29 mmol) . Purify by chromatography on silica gel eluting with 2/3 ethyl acetate / hexane and then 1/1 ethyl acetate / hexane to give the title compound.

PREPARATION 5 2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonic acid Combine (R) -2-bromo-3-phenylpropionic acid (3.44 g, 15 mmol), diethyl aminomalonate hydrochloride (4.23) g, 20 mmol), and N-methylmorpholine (5.5 mL, 50 mmol) in dichloromethane (50 mL). Add 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloric acid salt (3.83 g, 20 mmol) and 1-hydroxybenztriazole hydrate (2.70 g, 20 mmol). Add tetrahydrofuran (10 mL). After 20 hours, concentrate in vacuo and divide the concentrated reaction mixture between a solution of 5% aqueous sulfuric acid and methyl t-butyl ether. Separate the layers and extract the organic layer with a solution of saturated aqueous sodium bicarbonate and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 1/4 ethyl acetate / hexane, 1/3 ethyl acetate / hexane, and then 2.5 / 1 ethyl acetate / hexane to give 2- ((R) -2 -bromo-3-phenylpropionylamino) diethyl malonate. Combine 2- ((R) -2-bromo-3-phenylpropionylamino) -diethylmalonate (3.15 g, 8.16 mmol) and 4-methoxybenzyl mercaptan (2.6 mL, 19 mmol), and dimethylformamide (25 mL). Degassing by repeated application of emptying and filling the container with nitrogen. Add cesium carbonate (2.94 g, 9.9 mmol). After 16 hours, divide the reaction mixture between water and diethyl ether. Extract the organic layer with brine, dry over Na 2 SO 4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 3/1 hexane / ethyl acetate and then 2/1 hexane / ethyl acetate to give 2- ((S) -2- (p-methoxybenzimercapto) -3-phenylpropionylamino ) diethyl malonate. Combine diethyl 2- ((S) -2- (methoxybenzimercapto) -3-phenylpropionylamino) malonate (3.15 g, 6.85 mmol) and a solution of 6 M aqueous sodium hydroxide (4.6 mL, 28 mmol) in ethanol (15 mL ). After 24 hours, concentrate in vacuo, dilute the concentrated reaction mixture with water, adjust the pH to about 2.5 using a 6 M aqueous hydrochloric acid solution and lyophilize to give the title compound and sodium chloride.EXAMPLE 13 N, N '-Di- (4-chlorophenethyl) -2- (2-mercapto-3-phenylpropionyl-amino) malonamide 13.1 Synthesis of N,' -di- (4-chlorophenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide Combine 2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonic acid (prepared by the method of Preparation 5, 0.476 g, 63 % acid / 37% sodium chloride, 0.74, mmol), dichloromethane (9 mL), and tetrahydrofuran (1.5 mL). Add 4-chlorophenylethylamine (0.31 mL 2.23 mmol), N-methylmorpholine (0.25 mL 2.3 mmol), hydrochloric acid salt l-ethyl-3- (3- (dimethylamino) propyl) carbodiimide (0.427 g, 2.23 mmol) and hydrate of 1-hydroxybenztriazole (0.301 g, 2.23 mmol). After 3 days, concentrate in vacuo and partition the concentrated reaction mixture between a solution of aqueous sulfuric acid and ethyl acetate. Separate the layers and extract the organic layer with a solution of saturated aqueous sodium bicarbonate and then brine. Dry the organic layer over Na2S0. Filter, and evaporate in va cuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 2/3 ethyl acetate / hexane, 1/1 ethyl acetate / hexane, and then 1/2 ethyl acetate / hexane to give the title compound. 13.2 Synthesis of N, N '-di- (4-chlorophenethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide Combination of N, N' -di- (4-chlorophenethyl) -2- ((S) - 2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide (0.29 g, 0.43 mmol), mercury (II) acetate (0.171 g, 0.54 mmol), and anisole (0.47 mL) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying to the vacuum and filling the container with nitrogen. Add trifluoroacetic acid (4 mL). After 3 hours, purge with hydrogen sulfide (gas) for approximately 10 minutes. Filter and evaporate in va cuo to give a residue. Triturate the residue with diethyl ether to give the title compound as a solid (80%).

EXAMPLE 14 N, N '-Di- (2-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide 14. 1 Synthesis of N, N '-di- (2-methoxyphenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide Prepare by the method of Example 13.1 using 2-methoxyphenylethylamine (0.31 mL 2.93 mmol). Purify by chromatography on silica gel eluting sequentially with 2/3 ethyl acetate / hexane and then 1/2 ethyl acetate / hexane to give the title compound (50%). 14.2 Synthesis of N, N '-di- (2-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 13.2 using N, N'-di- (2- methoxyphenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide (0.24 g, 0.37 mmol). Purify by chromatography on silica gel eluting with 2/3 ethyl acetate / hexane to give the title compound (91%).

EXAMPLE 15 N, N '-Di- (4-methylphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide . 1 Synthesis of N, N '-di- (2-methylphenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide Combine acid 2- ((S) -2- (p- methoxybenzylmercapto) -3-phenylpropionylamino) malonic acid (prepared by the method of Preparation 5, 0.476 g, 63% acid / 37% sodium chloride, 0.74 mmol). and N-methylmorpholine (0.27 mL, 2.4 mmol), 2-methylphenylethylamine (0.25 mL, 1.7 mmol), dichloromethane (9 mL), and tetrahydrofuran (1 mL). Add 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloric acid salt (0.314 g, 1.64 mmol) and 1-hydroxybenztriazole hydrate (0.22 g, 1.64 mmol). After 1 day, concentrate in vacuo and partition the concentrated reaction mixture between a 5% aqueous sulfuric acid solution and ethyl acetate. Separate the layers and extract the organic layer with a solution of saturated aqueous sodium bicarbonate and then brine. Dry the organic layer over a2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 2/3 ethyl acetate / hexane and then 2/1 ethyl acetate / hexane to give the title compound. 15.2 Synthesis of N, N '-di- (2-methylphenethyl) -2- ((S) -2- (mercapto) -3-phenylpropylamino) malonamide Combination of N, N «-di- (2-methylphenethyl) -2- ((S ) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide (0.175 g, 0.274 mmol), mercury (II) acetate (0.108 g, 0.34 mmol), and anisole (0.3 mL) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add trifluoroacetic acid (4 mL). After 3 hours, purge with hydrogen sulfide (gas) for approximately 10 minutes. Filter and evaporate in va cuo to give a residue. Combine the residue with carbon tetrachloride and evaporate in va cuo to remove most of the trifluoroacetic acid. Chromatograph the residue on the silica gel eluting with 1/2 ethyl acetate / hexane and then 1/1 ethyl acetate / hexane to give the title compound.

EXAMPLE 16 N, N '-Di- (3-methoxyphenethyl) -2- (2-mercapto-3-phenylpropionyl-amino) malonamide 16. 1 Synthesis of N, N '-di- (3-methoxyphenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide Prepare by the method of Example 15.1 using 3-methoxyphenylethylamine (0.24 mL 1.7 mmol).

Purify by chromatography on silica gel eluting sequentially with 2/3 ethyl acetate / hexane and then 2/1 ethyl acetate / hexane to give the title compound. 16.2 Synthesis of N, N '-di- (3-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 15.2 using N, N' -di- (3- methoxyphenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide (0.181 g, 0.27 mmol). Purify by chromatography on silica gel eluting with 1/2 ethyl acetate / hexane and then 1/1 ethyl acetate / hexane to give the title compound.

EXAMPLE 17 N, N'-Di- (3,4-dimethoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide 17. 1 Synthesis of N, N '-di- (3, 4-dimethoxyphenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide Combine 2- ((S) -2- ( p-methoxybenzylmercapto) -3-phenylpropionylamino) allyl (prepared by the method of Preparation 5. 0.476 g, 63% acid / 37% sodium chloride, 0.74 mmol) and N-methylmorpholine (0.27 mL, 2.4 mmol), hydrochloride 3,4-dimethoxyphenylethylamine (0.50 g, 2.3 mmol), dichloromethane (9 mL), and tetrahydrofuran (1 mL). Cool in ice bath. Add 1-ethyl-3- (3- (dimethylamino) propyl) carbodiimide hydrochloric acid salt (0.314 g, 1.64 mmol) and 1-hydroxybenztriazole hydrate (0.22 g, 1.64 mmol). After After 1 day, concentrate in vacuo and partition the concentrated reaction mixture between a 5% aqueous sulfuric acid solution and ethyl acetate. Separate the layers and extract the organic layer with a solution of saturated aqueous sodium bicarbonate and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 2/1 dichloromethane / ethyl acetate and then 1/1 dichloromethane / ethyl acetate to give the title compound. 17.2 Synthesis of N, N '-di- (3, -dimetoxifenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide Combination of N, N' -di- (3,4-dimethoxyphenethyl) - 2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) -malonamide (0.139 g, 0.19 mmol), mercury acetate (II) (0.076 g), and anisole (0.3 mL), and veratrol (0.24 mL) in dichloromethane (10 mL). Cool in an ice bath and degas by repeatedly applying vacuum and filling the vessel with nitrogen. Add trifluoroacetic acid (4 mL). After 3 hours, purge with hydrogen sulfide (gas) for approximately 10 minutes. Filter and evaporate m vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/1 dichloromethane / ethyl acetate / hexane and then 3/2 dichloromethane / ethyl acetate to give the title compound.

EXAMPLE 18 N, N'-D? - (3-chlorophenetyl) -2- (2-mercapto-3-phenylpropion l-ammo) malonamide 18. 1 Synthesis of N, N '-di- (3-chlorophenethyl) -2- ((S) -2- (p-methoxybenzyl ercapto) -3-phenylpropionylamino) malonamide Prepare by the method of Example 17.1 using 3-chlorophenylethylamine hydrochloride (0.50 g, 2.6 mmol). Purify by chromatography on silica gel eluting sequentially with 3/2 hexane / ethyl acetate and then 1/2 hexane / ethyl acetate to give the title compound. 18.2 Synthesis of N. N '-d? -3-chlorophenethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide Prepare by the method of Example 15.2 using N, N'-d? - (3-chlorophenethyl) -2- ((S ) -2- (p-methoxybenzylmercapto) -3-phenylpropionyl amino) malonamide (0.126 g, 0.186 mmol). Purify by chromatography on silica gel eluting sequentially with 2/1 hexane / ethyl acetate and then 1/1 hexane / ethyl acetate to give the title compound. EXAMPLE 19 N, N '-Di- (3, 4-d? Chlorophenet? L) -2- (2-mercapto-3-phenylpropionylamino) malonamide 19. 1 Synthesis of N, N '-di- (3, 4-d? Chlorophenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamine) alonamide Prepare by the method of Example 17.1 using hydrochloride 3, -d? Chlorophenylethylamine (0.50 g, 2.2 mmol). Purify by chromatography on silica gel eluting sequentially with 3/2 hexane / ethyl acetate and then 1/2 hexane / ethyl acetate to give the title compound. 19. 2 Synthesis of N, N '-di- (3,4-dichlorophenethyl) -2- (2-mercapto-3-phenylpropionylamino) alonamide Prepare by the method of Example 15.2 using N, N'-di- (3, 4 - dichlorophenethyl) -2- ((S) -2- (p-methoxybenzylmercapto) -3-phenylpropionylamino) malonamide (0.166 g, 0.222 mmol). Co-evaporation with carbon tetrachloride gives the title compound.

PREPARATION 6 Synthesis of (R) -2-bromo-6-phthalimidohexanic acid Combine ((R) -Na-Cbz-lysine) (R) -2-N-carbobenzyloxy-6-aminohexanoic acid (14.0 g, 50 mmol) and water (500 mL). Add sodium carbonate (5.65 g, 53 mmol) and N-carbethoxyphthalimide (13.15 g, 60 mmol). After 1.5 hours, acidify using 12M aqueous hydrochloric acid to give a solid. Collect the solid by filtration, rinse with water, and dry to give (R) -2-N-carbobenzyloxy-6-phthalamidohexanoic acid. Combine (R) -2-N-carbobenzyloxy-6-phthalamidohexanoic acid obtained in the above, methanol (200 mL), 10% palladium on carbon (1 g) and treat with hydrogen at atmospheric pressure. After 18 hours, filter, add to the filtrate a solution of hydrochloric acid in methanol (50 mL, 1 M, 50 mmol), and evaporate in va cuo to give hydrochloric (R) -2-amino-6-phthalamidohexanic acid salt acid.

EXAMPLE 20 N, N '-Difenet l-2- ((S) -2-mercapto-6-phthalimidohexanoylamino) -malonamide . 1 Synthesis of N, N'-d? Phenet? L-2- ((S) -2-bromo-6-phthalimidohexanoylamino) malonamide Prepare by the method of Example 3.3 using N, N'-difenet? Tfluoroacetic acid salt? l-2-ammomalonamide (20 mmol) and (R) -2-bromo-6-phthalimidohexanoic acid (25 mmol) to give the title compound. 20.2 Synthesis of N, N '-diphenethyl-2- ((S) -2- (p-methoxybenzylmercapto) -6-phthalimidohexanoylamino) malonamide Combine N, N'-d? Phenet? L-2- ((S) -2 -bromo-6-phthalimidohexanoylamino) malonamide (10 mmol), 4-methoxybenzyl mercaptan (3.48 mL, 25 mmol), and tetrabutylammonium iodide (approximately 50 mg) in dimethylformamide (10 mL). Degass by repeatedly applying vacuum and filling the container with nitrogen. Add cesium carbonate (4.10 g, 12.5 mmol). After 15 hours, divide the reaction mixture between water and methyl t-butyl ether, saturate the aqueous layer with sodium chloride. Extract the aqueous layer with brine, dry over Na 2 SO 4, filter, and evaporate in vacuo to give the title compound. 20.3 Synthesis of N, N '-diphenethyl-2- ((S) -2-mercapto-6-phthalimidohexanoylamino) malonamide Prepare by the method of Example 15.2 using N, N'-diphenethyl-2- ((S) -2- (p-methoxybenzylmercapto) -6-phthalimido-hexanoylamino) malonamide (5 mmol) to give the title compound. The present invention provides a method for inhibiting matrix metalloproteinase (MMP) in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibitory amount of a compound of formula (1). As used herein, the term "patient" refers to warm-blooded animals or mammals, including, pigs, dogs, rats, mice, hamsters, rabbits and primates, including humans. A patient is in need of treatment to inhibit MMP when it should be beneficial in the patient to reduce the physiological effect of active MMP. For example, a patient is in need of treatment to inhibit MMP when the patient is suffering from the disease state characterized by excessive tissue disruption or tissue degradation, such as, but not limited to, a neoplastic disease state or cancer, rheumatoid arthritis; osteoartptis; osteoporosis; cardiovascular disorders; such as atherosclerosis; corneal ulceration, dental diseases, such as gingivitis or periodontal disease; and neurological disorders; such as multiple sclerosis; chronic inflammatory disorders such as emphysema and especially emphysema induced by smoking. The identification of those patients who are in need of treatment to inhibit MMP is well known within the skill and knowledge of one skilled in the art. A clinician skilled in the art can easily identify, through the use of clinical tests, physical examination and medical / family history as those patients who suffer from disease states characterized by excessive tissue alteration or tissue degradation. An "effective matrix metalloproteinase inhibiting amount" and a compound of formula (1) is an amount which is effective, ba or single or multiple dose administration in the patient, in the rate of symptom release associated with MMP and it is thus effective in inhibiting the disruption of induced MMP tissue and / or induced MMP tissue degradation. As used in the present "symptom release" of conditions mediated by MMP refer to the decrease in severity over what is expected in the absence of treatment and does not necessarily indicate a total elimination or cure of the disease. Release of symptoms is also purported to include prophylaxis. An effective metalloproteinase matrix that inhibits the dose can already be determined by the use of conventional techniques and by observing the results obtained under analogous circumstances. In determining the effective dose, a number of factors are considered, which include, but are not limited to: all the patient's species; its size, age and general health; the specific disease involved; in the degree of involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailable characteristics of the preparation administered; the selected dose regimen; and the use of the concomitant medication. An effective matrix metalloproteinase that inhibits the amount of a compound of formula (1) which generally ranges from about 0.1 milligrams per kilogram of body weight per day (mg / kd / day) to about 300 milligrams per kilogram of body weight per day (mg / kg / day). A daily dose of about 1 mg / kg to about 100 mg / kg is preferred. A neoplastic disease state refers to an abnormal state or condition characterized by rapid proliferation of cell growth or neoplasm. The neoplastic disease states by which the treatment with a compound of the formula (1) will be particularly useful: Leukemias, such as, but not limited to, acute lymphoblastic, chronic lymphocytic, acute myeloblastic and chronic myelocytic; Carcinomas and adenocarcinomas, such as, but not limited to those of the cervix, esophagus, stomach, small intestines, colon, lungs (both large and small cells), breast and prostate; Sarcomas, such as, but not limited to, osteosome, osteosarcoma, lipoma, liposarcoma, hemangioma and hemangiosarcoma; Melanomas, which include amelanotic and melanotic; and novel tissue blending types such as, but not limited to, carcinosarcoma, lymphoid tissue type, follicular reticulum, cellular sarcomas, and Hodgkin's Disease. Neoplastic disease states for which treatment with a compound of formula (1) which will be particularly preferred includes carcinomas and adenocarcinomas, particularly breast, prostate and lung. Atherosclerosis is a disease state characterized by the development and growth of atherosclerotic lesions or platelets. The identification of these patients who are in need of treatment for atherosclerosis is very well within the skill and knowledge of someone with experience in the art. For example, individuals who are suffering from either clinically important atherosclerosis or those at risk of developing clinically important atherosclerosis are patients in need of atherosclerosis treatment. A clinician with ordinary skill in the art can easily determine, by the use of clinical tests, physical examination and medical / family history, whether an individual is a patient in need of treatment for atherosclerosis. The term "chronic inflammatory disease" refers to diseases or conditions characterized by persistent inflammation in the absence of an identifiable irritant or microbial pathogen. Inflammatory diseases for which treatment with a compound of formula (1) will particularly be useful include: emphysema, chronic bronchitis, asthma, and chronic inflammation, and especially emphysema induced by smoking. In the effective treatment of a patient, a compound of formula (1) can be administered in any form or manner that makes the compound bioavailable in effective amounts, including oral and parenteral routes. For example, the compound can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, topically, intranasally, rectally, by inhalation, and the like. Oral administration and inhalation are generally preferred.

One skilled in the art to prepare formulations can easily select the appropriate form and mode of administration depending on the state of the disease being treated, the stage of the disease and other relevant circumstances. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990) . A compound of the formula (1) can be administered in the form of pharmaceutical compositions or drugs which are made by combining a compound of the formula (1) with pharmaceutically acceptable carriers or excipients, the proportion and nature of which is determined via of management selection and standard pharmaceutical practice. The pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid or liquid material that 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, extensions, gels, ointments, aerosols or the like. The pharmaceutical compositions can be administered orally, for example, with an inert diluent or with a digestible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, a compound of the formula (1) can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewable gums and the like. These preparations should contain at least 4% of a compound of the formula (1), the active ingredient, although it can be varied depending on the particular form and may conveniently be between 4% to about 70% of the weight of the unit. The amount of the active ingredient present in the compositions is such that a suitable dosage form per unit will be obtained per administration. The tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcpstalin cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin can be added or a flavoring agent such as methyl, methyl salicylate or orange sabotage. When the dosage unit 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 various other materials that modify the physical form of the dosage unit, for example as a coating. In this way, the tablets or pills can be coated with sugar, shellac or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose, as a sweetening agent and certain preservatives, dyes and coloring and flavorings. Materials used in the preparation of these various compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations may contain at least 0.1% of a compound of the invention, but may be varied to be between 0.1% and about 50% of the weight thereof. The amount of the active ingredient present in such compositions is such that an adequate dose will be obtained. Preferred compositions and their preparations are capable of being determined by one skilled in the art. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water by injection, saline, 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 ethylenediaminetetracetic acid; buffers 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 capsules, disposable syringes, or multiple dose ampoules of plastic or glass. The compounds of the present invention can be administered by inhalation, such as aerosol or dry powder. The supply can be by means of a compressed liquefied gas or a suitable pumping system which disperses the compounds of the present invention or a formulation thereof. Formulations for administration for the inhalation of the compounds of the formula (1) can be delivered in single-phase, bi-phasic, or tri-phasic systems. A variety of systems are available for aerosol administration of the compounds of formula (1). The dry powder formulations are prepared either by pelletizing or by grinding the compound of the formula (1) until a suitable particle size is obtained or by mixing the pellets or grinding the compound of the formula (1) with a suitable carrier material, such as lactose and the like. Administration by inhalation includes the necessary containers, activators, valves, sub-containers and the like. The preferred aerosol and dry powder formulations for administration by inhalation can be determined by someone skilled in the art. The MMP inhibitors of the present invention can be evaluated with the procedures that follow.

EXAMPLE A Source and Activation of proMMP-1 ProMMP-1 (EC 3.4.24.7, interstitial collagenase) was purified from the culture medium of human rheumatoid synovial fibroblasts stimulated with the conditioned medium with the macrophage according to Okada, Y. et al., J. Biol. Chem. 261. 14245-14255 (1986). Active MMP-1 was obtained by treatment of proMMP-1 with trypsin (5 μg / mL) at 37 ° C for 30 minutes, followed by the addition of the soybean trypsin inhibitor (50 μg / mL). Determination of the Inhibition Constant (Kj) for MMP-1 The activated MMP-1 assay was made using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, Knight, C.G. et al., FEBS Lett. 296. 263-266 (1992), at 37 ° C in 2.0 mL of a test buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02% Brij-35. The increase in fluorescence due to the cleavage of the Gly-Leu peptide bond by MMP-3 was recorded with the Perkin-Elmer LS50B fluorometer (γ 328 nm, λ em 393 nm, excitation separation of 2.5, emission separation of 10 ). The substrate and the solution of inhibitor material were made in DMF. To determine the Ki values for the MMP-1 inhibitors, a series of intermediate inhibitor solutions were prepared in DMF and 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2 mM of the substrate solution in DMF in a quartz cuvette containing 2 mL of the assay buffer. The enzyme (10 μL of 2.0 μM of the dilution of MMP-3 in the assay buffer) was added at least at the start of the reaction. For the routine measurement of a K value? for a reversible, competitive inhibitor, the initial velocities in the presence of at least four inhibitory concentrations (Two previous concentrations of K- and two subsequent concentrations of KJ were measured using [S] = l μM (< < Km) and [MMP-1] = 0.8 nM. Under these conditions, the measured Kj.app approaches the K-. true Calculation of the K- Values. The Kx for a competitive inhibitor is calculated using: where o is the initial velocity in the absence of the inhibitor, vx is the initial velocity in the presence of the inhibitor and the concentration of [I], [S] is the substrate concentration, Km is the Michaelis constant. If a slow link is observed (ie the approach to slow link equilibrium), the final steady state velocity instead of the initial velocity is taken as v.

EXAMPLE B ProMMP-2 source and activation Recombinant MMP-2 was purified from fermentation of yeast Pichia pas toris carrying the MMP-2 gene integrated into its chromosome. Briefly, the overall length of the cDNA for MMP-2 was obtained by reverse transcription of RNA from the A375M melanoma cell line by reverse transcriptase porase chain reaction (RT-PCR) using sequence specific oligonucleotides. The nucleotide sequence was confirmed by the Taq cycle sequence. The cDNA was ligated into the expression vector Pichia pastoris of pHIL-D2 in such a way that the expression of pro-MMP-2 is under the control of the alcohol oxidase promoter inducible in methanol. The expression construct was metabolized with Sali or Nsil and was used to transform the Pichia pastoris KM71 and SMD1168. A large-scale culture of a selected clone designed as 24S was performed in an elevated cell density fermenter and the recombinant MMP-2 was purified from the culture supernatant by gelatin-separating 4B (pharmacy). The enzyme is sufficiently pure at this stage for the routine measurement of inhibition. If desired, however, the enzyme can be further purified by gel filtration of AcA 44 (Spectra). Determination of the Inhibition Constant (Kj) of MMP-2. Active MMP-2 was obtained by the activation of proMMP-2 at 37 ° C for 1 hour with a 4-aminophenylmercuric acetate which was then removed by a Sephadex G-50 centrifugal column. The enzyme was assayed using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, at 37 ° C in 2.0 mL of a test buffer containing 50 mM Tris, pH 7.6, chloride 0.2 M sodium, 50 mM calcium chloride, 0.02% Brij-35, and 50 μM β-mercaptoethanol. The increase in fluorescence was recorded (? e: <328 nm,? em 393 nm). The substrate and the solutions of inhibitory material were made in DMF. The enzyme is added at least at the beginning of the reaction. For routine measurement, of a Ki value for a competitive reversible inhibitor, the initial rates in the presence of at least four inhibitory concentrations (two previous inhibitory concentrations of Ki and two following Ki concentrations) are measured using [S] = 1 μM (< < Km) &[MMP-2] = 0.4 nM. Under these conditions, the measurement Ki r app is close to the real Ki.

EXAMPLE C Source and Activation of proMMP-3 ProMMP-3 (EC 3.4.24.17; Stromelynsin-1) was purified from the culture media of human rheumatoid synovial fibroblasts stimulated by the conditioned macrophage medium according to Okada, Y . et al., J. Biol. Chem. 261, 14245-14255 (1986). Active MMP-3 was obtained by treating proMMP-3 with trypsin (5 μg / mL) at 37 ° C for 30 minutes, followed by the addition of the soybean trypsin inhibitor (50 μg / mL). Activated MMP-3 aliquots were stored at -20 ° C. Determination of the Inhibition Constant (Kj) for MMP-3 The MMP-3 activated assay using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, Knight, C.G. et al., FEBS Lett. 296. 263-266 (1992), at 37 ° C in a test buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02% Brij-35. The increase in fluorescence due to the cleavage of the Gly-Leu peptide bond by MMP-3 was recorded with the Perkin-Elmer LS50B fluorometer (? Ex 328 nm,? Was 393 nm, excitation separation of 2.5, emission separation of 10 ). The substrate and the solution of inhibitor material were made in DMF and 0.1% HC1-DMF, respectively. For the determination of the Kx values for the MMP-3 inhibitors, a series of intermediate inhibitory solutions were prepared in 0.1% HCl-DMF and 1 or 2 μL of the diluted inhibitor solution was mixed with 1 μL of 2 mM of the substrate solution in DMF in a quartz cuvette containing 2 mL of the assay buffer. The enzyme (10 μL of 0.2 μM of the dilution of MMP-3 in the assay buffer) was added at least at the start of the reaction. For the routine measurement of a K- value. for a reversible, competitive inhibitor, the initial rates in the presence of at least four inhibitory concentrations (two previous concentrations of Kx and two subsequent concentrations of Kx) were measured using [S] = l μM («Km) and [MMP-3] = 1 nM. Under these conditions, the measured K - .. app is close to the K -. true Calculations of the Values of K-. The K-. for a competitive inhibitor it is calculated using: where v0 is the initial velocity in the absence of the inhibitor, v-. is the initial velocity in the presence of the inhibitor and the concentration of [I], [S] is the concentration of the substrate, Km is the Michaelis constant. If a slow link is observed (ie the approach to slow link equilibrium), the final steady state velocity instead of the initial velocity is taken as v? . eleven! EXAMPLE D Source of MMP-12 (macrophage metalloelastase) MMP-12 (EC 3.4.24.65) was cloned, expressed and purified according to Shapiro, S.D. et al., J Biol. Chem. 268.23824-23829 (1993). Self-activation resulted in the fully processed active form of the above. The aliquots of MMP-12 were stored at -70 ° C. Determination of the Inhibition Constant (Ki) for MMP-12. The potency of the MMP-12 inhibitors was measured using quartz cuvettes or microtiter platelets. The activity of MMP-12 was measured using a fluorogenic substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, Knight, C.G. et al., FEBS Lett. 296, 263-266 (1992), at 25 ° C of a test buffer containing 50 mM Tris, pH 7.6, 0.2 M sodium chloride, 50 mM calcium chloride, and 0.02% Brij-35. The increase in fluorescence due to the cleavage of the Gly-Leu peptide bond by MMP-12 was recorded with the Perkin-Elmer LS50B fluorometer (? Ex 328 nm,? Em 393 nm, excitation separation of 2.5, emission separation of 10 ) for the assay in the cuvette and with a fluorescence platelet reader Molecular Devices Fmax (? ex 320 nm,? em 405 nm) for the assay of microtiter platelets. The substrate and solutions of inhibitory material were made in N, N, dimethylformamide (DMF) and 0.1% HCl-DMF, respectively.

The values of K-. were determined using the cuvette method by preparing a series of intermediate inhibitory solutions in 0.1% HCl-DMF and mixing the inhibitor with the substrate (final concentration of 2 μM) in a quartz cuvette containing 2 ml of the assay buffer . The MMP-12 was added at the start of the reaction at a concentration of 2nM and the curves were generated in progress. For the routine measurement of a Ki value for a reversible competitive inhibitor, the initial rates in the presence of at least four inhibitory concentrations (two previous concentrations and two subsequent Ki concentrations) were measured [S] = 2 μM (< <; Km) and [MMP-12] = 2 nM. Ba or these conditions, the measurement Ki, app is close to the real Ki. Ki values were determined using the microtitre plate method in a manner similar to that described for the cuvette method with some modification. Four different inhibitory concentrations (50 μl in a test buffer) of each compound were added to separate the wells from a microtiter plate and the substrate was added (100 μl) to achieve a final concentration of 4 mM. MMP-12 was added to a final concentration of 2 mM (50 μl) to initiate the reaction. Substrate splitting was recorded every 30 seconds for 30 minutes and curves were generated in progress.

Calculation of the Values for Ki. The Ki for a competitive inhibitor is calculated using: Vo / Vi = (l + [I] / Ki, app) and Ki = Ki, app / (l + [S] / Km =), where Vo is the initial velocity in absence of the inhibitor, Vi is the initial velocity in the presence of the inhibitor and the concentration of [I], [S] is the concentration of the substrate, Km is the Michaelis constant. If a slow link is observed (ie if the approach to link balance is slow), the final steady state velocity instead of the initial velocity is taken as Vi.

Claims (35)

1. REI INDICATIONS 1. A compound of the formula wherein Ri and R2 are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, - (CH2) a-Ar ?, and - (CH2) b-Ar2; where a is an integer from 1 to 6; b is an integer from 2 to 6; Ari is a radical selected from the group consisting of wherein Rs is 1 or 2 substituents independently selected from the group consisting of hydrogen, halogen, C? -C alkyl, hydroxy and C1-C4 alkoxy; Re is selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, and C 1 -C alkoxy; Ar2 is the radical wherein Re is selected from the group consisting of hydrogen, halogen, C? -C4 alkyl, and C? -C4 alkoxy; R3 is selected from the group consisting of Cx-Ce alkyl, - (CH2) m-W, - (CH2) p-Ar3, - (CH2) k-C02R9, (CH2) m-NR8-S02-Y? and (CH2) m-Z-Q where m is an integer from 2 to 8; p is an integer of 0-10, k is an integer from 1 to 9; W is phthalimido; Ar3 is selected from the group consisting of wherein R23 is 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, and C? -C alkoxy; R8 is hydrogen or C? -C6 alkyl; Rg is hydrogen or Ci-Cß alkyl; Yi is selected from the group consisting of hydrogen, - (CH2) j-Ar4, and -N (R24) 2 where j is 0 or 1; R24 each time it is selected is independently hydrogen or Ci-Cß alkyl or taken together with the hydrogen to which they are attached form N-morpholino, N-piperidino, N-pyrrolidino, or N-isoindolyl; Ar4 is the radical wherein R25 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C? -C alkyl, and C? -C4 alkoxy; Z is selected from the group consisting of -O-, -NR8-, -C (0) NR8-, -NR8C (0) -, -NR8C (0) NH-, -NR8C (0) 0-, and -OC (O) NH-; wherein R8 is hydrogen or C? -C6 alkyl; Q is selected from the group consisting of hydrogen, (CH2) n-Y2, and - (CH2) XY3; where n is an integer from 0 to 4; Y2 are selected from the group consisting of hydrogen, - (CH2) h-Ar5 and - (CH2) t-C (0) OR27 wherein Ar5 is selected from the group consisting of wherein R 26 is 1 to 3 substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C alkyl, and C 1 -C 4 alkoxy; h is an integer from 0 to 6; t is an integer from 1 to 6; R27 is hydrogen or C? -C6 alkyl; x is an integer from 2 to 4; Y3 are selected from the group consisting of -N (R2ß) 2, N-morpholino, N-piperidino, N-pyrrolidino, and N-isoindolyl; wherein R28 each time it is independently taken is hydrogen or Ci-Cß alkyl, "R 4 is selected, from the group consisting of hydrogen, -C (0) R 0, -C (0) - (CH 2) qK and -SG wherein Rio is selected from the group consisting of hydrogen, C1-C4 alkyl, phenyl, and benzyl; q is 0, 1, or 2; K is selected from the group consisting of wherein V is selected from the group consisting of a bond, -CH2-, -0-, -S (0) r-, -NR-, and -NC (0) R'-; wherein r is 0, 1 or 2; R is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, and benzyl; R 'is selected from the group consisting of hydrogen, -CF3, C1-C10 alkyl, phenyl, and benzyl; Rn is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl; Rn is selected from the group consisting of hydrogen, C1-C4 alkyl, and benzyl; G is selected from the group consisting of where is an integer from 1 to 3; R 12 are selected from the group consisting of hydrogen, C 1 -C 6 alkyl, -CH 2 CH 2 S (0) eCH 3, and benzyl; where e is 0, 1 or 2; Ri3 is selected from the group consisting of hydrogen, hydroxy, amino, Ci-Cß alkyl, N-methylamino, N, N-dimethylamino, -C02R ?7, and -OC (0) R ?8; wherein Ri7 is hydrogen, -CH20-C (0) C (CH3) 3, C1-C4 alkyl, benzyl, or diphenylmethyl; Lanes are hydrogen, C? -C6 alkyl or phenyl; R 14 is 1 or 2 substituents independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, or halogen; Vi is selected from the group consisting of -0-, -S-, and -NH-; V2 is selected from the group consisting of -N- and -CH-; V3 is selected from the group consisting of a bond and -C (0) -; V4 is selected from the group consisting of -0-, -S-, -NR19- and -NC (0) R20-; wherein R19 is hydrogen, C1-C4 alkyl, or benzyl; R20 is hydrogen, -CF3, C1-C10 alkyl, or benzyl; R15 is selected from the group consisting of hydrogen, Ci-Cß alkyl, and benzyl; Ri 6 are selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and stereoisomers, pharmaceutically acceptable salts, and hydrates thereof.
2. 2. The compound according to claim 1, wherein Rj. and R2 are Ci-C? alkyl.
3. 3. The compound according to claim 1, wherein Ri and R2 - (CH2) a_Ar? wherein a and Arx is as defined in claim 1.
4. 4. The compound according to claim 3, wherein a is 1 or 2.
5. 5. The compound according to claim 3, wherein Ar is phenyl or substituted phenyl.
6. 6. The compound according to claim 1, wherein R4 is hydrogen.
7. 7. The compound according to claim 1, wherein R4 are -S-G.
8. 8. The compound according to claim 1, wherein R4 is -C (0) R? 0.
9. 9. The compound according to claim 8, wherein Rio is C1-C4 alkyl.
10. 10. The compound according to claim 1, wherein the compound is N, N '-difenet? L-2- ((S) -2-mercapto-3-methylbutyrylammo) malonamide.
11. 11. The compound according to claim 1, wherein the compound is N, N-Difenet? L-2- ((S) -2-mercapto-3-phenylpropionylammo) malonamide.
12. 12. The compound according to claim 1, wherein the compound is N, N '-Difenet? L-2- ((S) -2-mercapto-4-phenylbutyrylaminojmalonamide 13. The compound according to claim 1 , wherein the compound is N, N'-d? benc? l-2- ((S) -2-mercapto-3-phenylpropionylammo) malonamide 14. The compound according to claim 1, wherein the compound is N, '-Di- (3-phenylpropyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide. 15. The compound according to claim 1, wherein the compound is N, N '-di-4-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide. 16. The compound according to claim 1, wherein the compound is N, N'-dipentil-2- (2-mercapto-3-phenylpropionylamino) malonamide. 17. The compound according to claim 1, wherein the compound is N, N '-di-4- (N-anilino) ethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide. 18. The compound according to claim 1, wherein the compound is N, N '-di- (pidrid-4-ylethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide. 19. The compound according to claim 1, wherein the compound is N, N '-diphenethyl-2- ((S) -2-mercaptopropionylamino) malonamide. The compound according to claim 1, wherein the compound is N, N '-diphenethyl-2- (2-mercaptopropionylamino) malonamide. 21. The compound according to claim 1, wherein the compound is N, '-diphenethyl-2- (2-mercaptopentanoylamino) malonamide. 22. The compound according to claim 1, wherein the compound is N, N '-di- (4-chlorophenethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide. 23. The compound according to claim 1, wherein the compound is N, N '-di (2-methoxyphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide. 24. The compound according to claim 1, wherein the compound is N, N '-di- (- (methylphenethyl) -2- ((S) -2-mercapto-3-phenylpropionylamino) malonamide. according to claim 1, wherein the compound is N, N '-di- (3-methoxyphenethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide 26. The compound according to claim 1, in where the compound is N, N '-di- (3,4-dimethoxyphenethyl) -2- ((S) 2 - . 2-mercapto-3-phenylpropionylamino) alonamide. 27. The compound according to claim 1, wherein the compound is N, N '-di- (3-chlorophenethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide. 28. The compound according to claim 1, wherein the compound is N, N '-di- (3,4-dichlorophenethyl) -2- (2-mercapto-3-phenylpropionylamino) malonamide. 29. A pharmaceutical composition comprising an effective matrix metalloproteinase inhibiting amount of a compound of claim 1. 30. A method for inhibiting matrix metalloproteinase in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibitory amount of a compound of claim 1. 31. A method for treating a neoplastic disease in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1. 32. A method for treating rheumatoid arthritis in a patient in need thereof. comprises administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of claim 1. 33. A method for treating osteoporosis in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibiting amount of a compound of the invention. claim 1. 34. 31. A method for treating chronic inflammatory disorders in a patient in need thereof comprising administering to the patient an effective matrix metalloproteinase inhibitory amount of a compound of claim 1. 35. The method according to claim 34, where the inflammat disorder Chronic orio is emphysema.