MXPA01002977A - Hydroxamate-containing cysteine and serine protease inhibitors - Google Patents

Abstract

The present invention is directed to hydroxamate-containing inhibitors of cysteine and serine proteases. Methods for the use of the protease inhibitors are also described.

Description

INHIBITORS OF SERINE AND CYSTEINE PROTEASE CONTAINING HYDROXAMATE CROSS REFERENCE WITH RELATED APPLICATIONS This patent application claims the priority benefit of the Provisional Application of E.U. Series No. 60/101, 414, filed on September 22, 1998, the description of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION The present invention is directed to inhibitors of novel cysteine or serine proteases, referred to herein as hydroxamates. The present invention is also directed to methods for making these novel compounds, and methods for using same.

BACKGROUND OF THE INVENTION Numerous proteases of cysteine and serine have been identified in human tissues. A "protease" is an enzyme that breaks down proteins into smaller components (peptides). The terms "cysteine protease" and "serine protease" refer to proteases that are distinguished by the presence therein of a cysteine or serine residue that plays a critical role in the catalytic process. Mammalian systems, including humans, normally degrade and process proteins through a variety of enzymes that include cysteine and serine proteases. However, when they occur at high levels or when they are activated abnormally, the cysteine and serine proteases can be included in pathophysiogenic processes. For example, activated neutral calcium proteases ("calpains") comprise a family of intracellular cysteine proteases that are ubiquitously expressed in mammalian tissues. Two main calpains have been identified; Calpain I and Calpain II. Although calpain II is the predominant form in several tissues, it is thought that calpain I is the predominant form in the pathological conditions of nerve tissues. The calpain family of cysteine proteases has been implicated in several diseases and disorders, including neurodegeneration, apoplexy, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, thrombocyte agglomeration, cataracts and inflammation. Calpain I has been implicated in the excitatory amino acid induced neurotoxicity disorders that include ischemia, hypoglycemia, Huntington's disease, and epilepsy. Cathepsin B of lysosomal cysteine protease has been implicated in the following disorders: arthritis, inflammation, myocardial infarction, tumor metastasis, and muscular dystrophy. Other lysosomal cysteine proteases include cathepsins C, H, L and S. The conversion enzyme of interleukin-1β ("ICE") is a cysteine protease that catalyzes the formation of interleukin-1β. Interleukin-1β is a nanoregulatory protein involved in the following disorders: inflammation, diabetes, septic shock, rheumatoid arthritis, and Alzheimer's disease. ICE has also been linked to apoptotic cell death of neurons, which is implicated in a variety of neurodegenerative disorders including Parkinson's disease, ischemia, and amyotrophic lateral sclerosis (ALS). Cysteine proteases are also produced by several pathogens. Cysteine protease clostripain is produced by Clostridium histolyticum. Other proteases are produced by Tripanosoma cruzi "malaria parasites Plasmodium falciparum and P. vinckei and Streptocococcus. The HAV C3 viral protease of Hepatitis A is a cysteine protease essential for the processing of proteins and structural enzymes of picornavirus. Exemplary serine proteases involved in degenerative disorders include thrombin, human leukocyte elastase, pancreatic elastase, chymase and cathepsin G. Specifically, thrombin is produced in the blood coagulation cascade, opens the way for fibrinogen to form fibrin and activates the Factor VIII; Thrombin is involved in thrombophlebitis, thrombosis and asthma. Human leukocyte elastase is involved in degenerative tissue disorders such as rheumatoid arthritis, osteoarthritis, atherosclerosis, bronchitis, cystic fibrosis, and emphysema. Pancreatic elastase is involved in pancreatitis. Qutmase, an important enzyme in the synthesis of angiotensin, is involved in hypertension, myocardial infarction, and coronary heart disease. Cathepsin G is involved in the degradation of abnormal connective tissue, particularly in the lung. Hydroxamates that are structurally distinct from the compounds described herein have been described as inhibitors of glycogen phosphoryliase (International Patent Application Pub. No. WO 96/39385) and thrombin (U.S. Patent 5,563, 127). Given the binding between cysteine and serine proteases and various impairment disorders, compounds that inhibit these proteases would be useful and would provide an advance in both clinical and research medicine. The present invention addresses these, as well as others, important purposes.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed to novel cysteine and serine protease inhibitors referred to herein as hydroxamates. In the preferred embodiments, the novel compounds are represented by the following Formula I: I where: W is A-B-D; A is aryl (CH2) n, heteroaryl (CH2) n, alkyl having from one to about 14 carbons, alkenyl having from two to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, said group A being optionally substituted with one or more groups J; B is a bond or CO, SO, SO2, OCO, NR5CO, NR5SO2 or NR5SO; D is a bond, an amino acid residue, or a peptide composed of 2 to about 5 amino acid residues, said amino acid residue (s) are independently defined by the formula -NH-** CH (Rβ ) -CO-, in which ** indicate the possession of a carbon of an a-amino acid residue, where R6 is different from hydrogen, configuration D, configuration L, or a mixture of D- and L-; n is an integer from 0 to about 6; R1, R2, R3, R4, R5, and R6 are, independently, hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbons, said alkyl and cycloalkyl groups being optionally substituted with one or more groups J; and J is halogen, lower alkyl, aryl, heteroaryl, haloaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, amido, lower alkylamido, sulfonamido, lower alkyl sulfonamido, lower alkylsulfonyl, lower alkylsulfoxy, alkylthio lower, lower alkoxy, aryloxy, arylalkyloxy, hydroxy, carboxy, cyano, or nitro; and * denotes the possession of a carbon of an a-amino acid residue, where R2 is different from hydrogen, the D configuration, the L configuration, or a mixture of the D- and L- configurations. In some preferred embodiments, R1 is alkyl or alkyl substituted with J, wherein J is a lower alkoxy. In the most preferred embodiments, R 1 is benzyl, methoxymethyl, or butyl. In further preferred embodiments, R is alkyl or alkyl substituted with J where J is arylalkyloxy or aryl. In more preferred embodiments, R 2 is isobutyl or benzyloxymethyl. In further preferred embodiments, R3 is H. In some preferred embodiments, R4 is alkyl, J-substituted alkyl, cycloalkyl or cycloalkio substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl. More preferably, R 4 is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl) methyl, tert-butyl or 4-methylcyclohexyl. In some preferred embodiments, W is benzyloxycarbonyl, methanesulfonyl, benzoyl, tert-butoxycarbonyl, or benzyloxycarbonyl-leucyl. In some preferred embodiments, R3 is H, and R1 is alkyl or alkyl substituted with J, where J is lower alkoxy. In further preferred embodiments, R3 is H, and R2 is alkyl or alkyl substituted with J wherein J is arylalkyloxy or aryl. Still in more preferred embodiments, R3 is H, and R4 is alkyl, J-substituted alkyl, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, alkyl, haloaryl, or heteroaryl. Still in more preferred embodiments, R3 is H, R1 is alkyl or J-substituted alkyl, wherein J is lower alkoxy, and R2 is alkyl or J-substituted alkyl wherein J is arylalkyloxy or aryl. Still in more preferred embodiments, R3 is H, R1 is alkyl or J-substituted alkyl, wherein J is lower alkoxy, and R4 is alkyl, J-substituted alkyl, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl , alkyl or heteroaryl.

Still in more preferred embodiments, R3 is H, R1 is alkyl or J-substituted alkyl, wherein J is lower alkoxy, and R4 is alkyl, J-substituted alkyl, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl , alkyl or heteroaryl, and R2 is alkyl or alkyl substituted with J wherein J is arylalkyloxy or aryl. In some particularly preferred embodiments, R 1 is benzyl, methoxymethyl, or butyl; R2 is isobutyl or benzyloxymethyl; R3 is hydrogen; R 4 is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl) methyl, tert-butyl, or 4-methylcyclohexyl; and W is benzyloxycarbonyl, methanesulfonyl, benzoyl, tert-butoxycarbonyl, or benzyloxycarbonyl-leucyl. In particularly preferred further embodiments, R1 is benzyl; R2 is isobutyl; * indicates the carbon of an a-amino acid residue that has the L- configuration; R3 is hydrogen, R4 is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl) methyl, tert-butyl, or 4-methylcyclohexyl; Y W is benzyloxycarbonyl or benzyloxycarbonyl-leucyl. In particularly preferred further embodiments, R1 is benzyl; R2 is benzyloxymethyl; * indicates the carbon of an a-amino acid residue having the D- configuration; R3 is hydrogen; R 4 is methyl, ethyl, or benzyl; and W is methanesulfonyl. Some especially preferred embodiments of the invention are described in Table 1, infra. The present invention also provides compositions for inhibiting a protease selected from the group consisting of serine proteases and cysteine proteases comprising a compound of the invention. Also provided by the present invention are methods for inhibiting a protease comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the invention, and methods for inhibiting a protease that it comprises contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a composition comprising a compound of the invention. The compounds of the invention are useful for the inhibition of cysteine and serine proteases. Beneficially, these compounds find utility in a variety of approaches. For example, in the field of research, the claimed compounds may be used, for example, in the discovery of agents to treat disorders associated with abnormal and / or aberrant activity of cysteine and / or serine proteases. In a clinical field, for example, the compounds can be used to alleviate, mediate, reduce, and / or prevent the disorders with which they are associated in the abnormal and / or aberrant activity of cysteine and / or serine proteases. Thus, in some preferred embodiments, the present invention further provides pharmaceutical compositions comprising a compound of the invention, preferably also containing a pharmaceutically acceptable carrier. Also provided according to the present invention are compositions for the treatment of a disorder, which is preferably neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, agglomeration of thrombocytes, cataracts and inflammation, comprising a compound of claim 1 and a pharmaceutically acceptable carrier. The present invention also provides methods for the treatment of a disorder, which is preferably neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, thrombocyte agglomeration, cataracts and inflammation, which comprises administering to a subject in need of such treatment an effective amount of a compound of the invention. Because the hydroxamates of the invention inhibit cysteine proteases and serine proteases, they can be used in both research and therapeutic approaches. These and other characteristics of the subject compounds of the invention are set forth in more detail below.

DETAILED DESCRIPTION The present invention provides novel inhibitors of cysteine and serine protease inhibitors. In preferred embodiments, the compounds of the invention have Formula I: wherein: W is A-B-D; A is aryl (CH2) n, heteroaryl (CH2) n, alkyl having from one to about 14 carbons, alkenyl having from two to about 14 carbons, cycloalkyl having from 3 to about 10 carbon, said group A being substituted optionally with one or more groups J; B is a bond or CO, SO, SO2, OCO, NR5CO, NR5SO2 or NR5SO; D is a bond, an amino acid residue, or a peptide composed of 2 to about 5 amino acid residues, said amino acid residue (s) are independently defined by the formula -NH-** CH (R6 ) -CO-, in which the ** indicate the possession of a carbon of an a-amino acid residue, where R6 is different from hydrogen, the one with figuration D, the configuration L, or a mixture of D- and L-; n is an integer from 0 to about 6; R1, R2, R3, R4, R5, and R6 are, independently, hydrogen, alkyl having from one to about 14 carbons, cycloalkyl having from 3 to about 10 carbon, said alkyl and cycloalkyl groups are optionally substituted with one or more groups J; and J is halogen, lower alkyl, aryl, heteroaryl, haloaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, amido, lower aicylamido, sulfonamido, lower alkyl sulfonamido, lower alkylsulfonyl, lower alkylsulfoxy, alkylthio lower, lower alkoxy, aryloxy, arylalkyloxy, hydroxy, carboxy, cyano, or nitro; and * denotes the possession of a carbon of an a-amino acid residue, where R2 is different from hydrogen, the D configuration, the L configuration, or a mixture of the D- and L- configurations. The compounds of the invention are useful in a variety of approaches. For example, in a research environment, preferred compounds having defined attributes can be used to select natural and synthetic compounds that exhibit similar characteristics in inhibitory protease activity. Inhibition of cysteine protease or serine protease activity can be measured by determining the rate of inactivation of a protease using a compound of the invention. The compounds can also be used in the refinement of in vitro and in vivo models to determine the effects of the inhibition of particular proteases on particular cell types or biological conditions. In a therapeutic approach, given the connection between cysteine proteases and certain defined disorders, and serine proteases and certain defined disorders, the compounds of the invention can be used to alleviate, mediate, reduce and / or prevent the disorders that are associated with abnormal and / or aberrant activity of cysteine proteases and / or serine proteases.

As used herein, the term "alkyl" means that it includes straight, branched chain and cyclic hydrocarbon groups such as, for example, ethyl and isopropyl groups. Preferred alkyl groups have from 1 to about 10 carbon atoms. The term "lower alkyl" refers to alkyl groups of 1-6 carbon atoms. In general, the term "lower" refers to groups having above six carbon atoms. The term "cycloalkyl" denotes cyclic alkyl groups, such as, for example, cyclopropyl groups. The term "alkenyl" denotes alkyl groups containing at least one double bond. The "aryl" groups are aromatic cyclic compounds including but not limited to phenyl, tolyl, naphthyl, anthracyl, phenanthryl, pyrenyl, and xylyl. Preferred aryl groups include phenyl and naphthyl. In general, the term "hetero" when used as a prefix indicates the presence of one or more straight atoms such as O, N or S. In this manner, the term "heterocyclic" refers to cyclic groups in which the ring portion includes at least one heteroatom. The "heteroalkyl" groups are heterocycles that contain only individual bonds within the ring portions, ie, saturated heteroatomic ring systems. The term "heteroaryl" denotes the aryl groups where at least one ring carbon has been replaced with a hetero atom. The term "haloaryl" is meant to mean that an aryl group carries one or more halogen atoms. The term "halogen" refers to atoms F, Cl, Br, and I. As used herein, "alkoxy" groups are alkyl groups attached through an oxygen atom. Examples of alkoxy groups include methoxy (-OCH3) and ethoxy (-OCH2CH3) groups. In general, the term "oxy" when used as a suffix indicates the union through the oxygen atom. Thus, the alkoxycarbonyl groups are carbonyl groups containing an alkoxy substitute, ie, groups of the general formula -C (= O) -O-R, where R is alkyl. The term "aryloxy" denotes an aryl group linked through an oxygen atom. The term "arylalkyl" (or "aralkyl") denotes an alkyl group containing an aryl substitute. The term "arylalkyloxy" (or "aralkyloxy") denotes an aralkyl group attached through an oxygen atom. As used herein, the term "amino acid" denotes a molecule or residue thereof that contains both an amino group and a carboxyl group. As used herein, the term "α-amino acid" means an amino acid of the general formula HOOC-CH (side chain) -NH 2, or a residue of such an amino acid of the formula, eg, -C (= O) -CH (side chain) -NH-. In the preferred embodiments of the compounds of the invention, the a-carbon (i.e. the carbon carrying the side chain) of the constituent amino acids can be exclusively in the L-configuration, exclusively in the D-configuration, or in a mixture of the D and L configurations in any proportion. The functional groups present in the compounds of Formula I may contain protecting groups. For example, amino acid side chain substitutes of the compounds of Formula 1 can be substituted with protecting groups such as benzyloxycarbonyl or f-butoxycarbonyl groups. The protection groups are known per se as chemical functional groups that can be selectively appended and removed from the functionalities, such as hydroxyl groups and carboxyl groups. These groups are presented in a chemical compound to render such functionality inert to the chemical reaction conditions to which the compound is exposed. Any of a variety of protection groups can be employed with the present invention. One such protection group is the benzyloxycarbonyl group (Cbz; Z). Other preferred protection groups according to the invention can be found in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis" 2d. Ed., Wiley & amp; Sons, 1991. As used herein, the term "amido" has its usual meaning as a group of the formula -C (= O) -NH-. The term "alkylamido" denotes an amido group that contains an alkyl substitute. The term "sulfonamido" denotes a group of the formula -SO2-NH-. In general, the term "alkyl" or "aryl" when used as a prefix in such terms as "alkylsulfonamido", "alkylsulfonyl", "alkylsulfoxy" or "alkylthio" indicates that the sulfonamido, sulfonyl, sulfoxy or thio group contains a substitute for alkyl. Some constituent groups represented in the formulas described herein may be substituted. As used herein, the term "substituted" indicates that any available hydrogen atom of the element designated "substituted" may be replaced by the indicated group. In preferred embodiments, the compositions are provided to inhibit a serine protease or a cysteine protease comprising a compound of the invention. In other preferred embodiments, the methods are provided to inhibit serine proteases or cysteine proteases comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the invention. The described compounds of the invention are useful for the inhibition of cysteine proteases and serine proteases. As used herein, the terms "inhibit" and "inhibition" mean that they have an opposite effect on enzymatic activity. An "inhibitory amount" is an amount of a compound of the invention effective to inhibit a cysteine and / or serine protease. The pharmaceutically acceptable salts of the cysteine and serine protease inhibitors also fall within the scope of the compounds as described herein. The term "pharmaceutically acceptable salts" as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate . Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine. The compounds provided herein can be formulated in pharmaceutical compositions by a mixture with pharmaceutically acceptable non-toxic excipients and vehicles. As noted above, such compositions can be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, by means, for example, transdermal patches; or prepare in other suitable ways for these and other forms of administration that will be apparent to those skilled in the art. The composition can be conveniently administered in unit dose form and can be prepared by any of the methods known in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA, 1980) . Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and of vegetable origin, hydrogenated naphthalenes and the like. In particular, the biocompatible, biodegradable polymers of lactide, lactide / glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for the administration of inhalation contain as excipients, for example, lactose, or they can be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of drops nasal, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration. The formulations for the transdermal patches are preferably lipophilic emulsions. The materials of this invention can be used as the sole active agent in a pharmaceutical or can be used in combination with other active ingredients, for example, other growth factors that could facilitate axonal regeneration or survival in diseases or disorders. The concentrations of the compounds described herein in a therapeutic composition will vary depending on a number of factors, including the dose of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration. In general terms, the compounds of this invention can be provided in effective inhibitory amounts in an aqueous physiological buffer solution containing about 0.1 to 10% w / w of the compound for parenteral administration. Typical dose ranges are from about 1 mg / kg to about 1 g / kg of body weight per day; a preferred dose range is from about 0.01 mg / kg to about 1 g / kg of body weight per day; a preferred dose range is from about 0.01 mg / kg to 100 mg / kg of body weight per day. Such formulations typically provide inhibitory amounts of the compound of the invention. However, the preferred dose of the drug to be administered probably depends on variables such as the type and degree of progress of the disease or disorder, the overall health of the patient in particular, the relative biological efficacy of the selected compound, and the formulation of the excipient of the compound, and its route of administration. As used herein, the term "contact" means to originate directly or indirectly that at least two elements are physically associated with each other. Contacting in this way includes physical acts such as placing the items together in a container, or administering the items to a patient. Thus, for example, the administration of a compound of the invention to a human patient evidencing a disease or disorder associated with the abnormal and / or aberrant activity of such proteases falls within the scope of the definition of the term "contact". The invention is further illustrated by way of the following examples which are intended to clarify the invention. These examples do not pretend, nor are they interpreted, as limiting the scope of the description.

Examples General Methods: Thin layer chromatography was performed using sheets coated with silica gel (MK6F 60A, 1 x 3 inches in size, 250 μm layer thickness, Whatman Inc.). Preparative thin layer chromatography was performed using sheets coated with silica gel (20 x 20 cm in size, 1000 micron layer thickness, Analtech). The chromatography of the preparative column was carried out using Merck silica gel, 40-63 um, 230-400 sieve. The 1H NMR spectrum was recorded on the 300 MHz GE QE300 Plus spectrometer using tetramethylsilane as the internal standard. The electro-mass mass spectrum was recorded in the VG instrument of platform II (Fisons instruments). Examples 1-15 were prepared following General Method A or B.

General Method A 2 R? = - CHp33 - 1a R2 = L-CH2CH (CH3) 2 3 R7 = H + J W = CßH5CH2OCO BOP, HOBt H2 OR4 4a R ^ = CH3 Dess-Martin 5a Ri = CH2C6H5; R2 = L-CH2CH (CH3) 2 W = C6H5CH2OCO; R * = CH3 to R1 = CH2C6H5; Rs = tBOC; Re = H ~ Ri = CH2C6H5; R5 = H HCl; R6 = CH3 ^ General Method B 6b Ri = CH2OCH3 8 R4 = CH2OC6H5; Rs = tBOC 9 R4 = CH2OC6H5; R5 = H HCI EDCI, HOBt, NM 1b b Rz = D-CH2OCH2C6H5 W = CH3SO2 Dess-Martin 5b Ri = CH2OCH3; R2 = D-CH2OCH2C6H5 W = CH3SO2; R "= CH2C6H5 Compounds 6a, 6b and related hydroxy acids were synthesized following a general procedure of Harbeson et al. , J. Med. Chem. 1994, 37, 2918-2929.

Example 1 Cbz-Leu-Phe-CONHOCHs (General Method A).

Compound 5a To a cooled (0 ° C) solution of compound 6a (500 mg, 1.69 mmol) in anhydrous methanol (25 ml) was added thionyl chloride (0.37 ml, 5.08 mmol). The mixture was then stirred at room temperature for 16 hours and concentrated under reduced pressure. Trituration with ethyl ether gave compound 7 which was dried and used directly in the next step. White solid; 1 H NMR (DMSO-d6) d 8.49 (br, 1 H), 8.15 (br, 2 H), 7.22 (m, 1 0 H), 6.52 (dd, 1 H), 4.35 (ddd, 1 H), 3.80 ( ddd, 1 H), 3.28 (d, 3H), 3.08 (dd, 1 H), 2.80 (dd, 1 H). MS m / e 210 (M + H). To a solution of compound 1 to (450 mg, 1.69 mmol) in anhydrous DMF (5 mL) was added 1-HOBt (229 mg, 1.69 mmol), BOP (899 mg, 2.03 mmol), and N-methylmorpholine (0.74 ml, 6.78 mmol). After 5 min. , compound 7 (416 mg, 1.69 mmol) dissolved in 5 ml of DMF was added. Stirring was continued 90 min at room temperature. The mixture was poured into water (50 ml) and extracted into ethyl acetate (3 x 20 ml). The organic layer was washed with 3% citric acid solution (10 ml), saturated sodium bicarbonate solution (10 ml), and saline (10 ml). The solution was dried over MgSO, filtered and concentrated under reduced pressure to obtain 700 mg of crude product. Chromatography of the preparative column (1-5% MeOH / methylene chloride) achieved 533 mg of compound 2 (69%). White amorphous solid; 1 H NMR (DMSO-d6) d 8.2 (d, 2H), 8.0 (m, 2H), 7.0 (s, 3H). MS m / e 457 (M + H). To a cooled (0 ° C) solution of compound 2 (533 mg, 1.17 mmol) in methanol (10 mL) was slowly added a solution of 1 N NaOH (2.92 mL, 2.92 mmol). The mixture was then stirred at room temperature for 90 minutes and concentrated under reduced pressure. Water (30 ml) was added and the mixture was extracted with diethyl ether (30 ml). The aqueous portion was acidified to pH = 4 with solid citric acid and extracted with ethyl acetate (3 x 20 mL). The solution was dried over MgSO, filtered and concentrated under reduced pressure to obtain 439 mg of compound 3 (85%). No further purification was necessary. White amorphous solid; 1 H NMR (DMSO-d6) d 7.73 (dd, 1 H), 7.31 (m, 10H), 5.07 (s, 2H), 4.17 (m, 1 H), 4.04 (m, 2H), 3.41 (m, 1 H), 2.88 (m, 1 H), 2.74 (m, 2H), 1.58 (m, 1 H), 1.33 (m, 2H), 0.85 (m, 6H). MS m / e 441 (M-H). To a solution of compound 3 (1 25 mg, 0.283 mmol) in anhydrous DMF (5 mL) was added 1-HOBt (38 mg, 0.283 mmol), BOP (150 mg, 0.339 mmol), and N-methylmorpholine (0.1 09 ml, 0.99 mmol). After 5 min H2NOMe HCl (27 mg, 0.283 mmol) dissolved in 5 ml of DMF was added. Stirring was continued 90 min at room temperature. The mixture was poured into water (50 ml) and extracted into ethyl acetate (3 x 20 ml). The organic layers were washed with 3% citric acid solution (10 ml), saturated sodium bicarbonate solution (10 ml), and saline (10 ml). The solution was dried over MgSO 4, filtered and concentrated under reduced pressure to obtain 10 mg of crude product. Chromatography with preparative thin layer films (5% MeOH / methylene chloride) achieved 79 mg of compound 4a (59%). White amorphous solid; MS m / e 472 (M + H). To a refrigerated (0 ° C) solution of compound 4a (79 mg, 0.168 mmol) in anhydrous methylene chloride (10 ml) was added slowly a Dess-Martin periodinane reagent (71 mg, 0.168 mmol). The cooling bath was removed and the mixture was stirred for an additional 90 minutes. The mixture was then washed with 1 0% sodium thiosulfate solution (2 x 10 ml), saturated sodium bicarbonate solution (5 ml), and saline (5 ml). The solution was dried in MgSO, filtered and concentrated under reduced pressure to obtain 60 mg of compound 5a (76%). White amorphous solid; 1 H NMR (CDCl 3) d 9.55 (br s, 1 H), 7.20 (m, 10 H), 6.82 (d, 1 H), 5.40 (m, 1 H), 5.03 (s, 2 H), 4.95 (br s) , 1 H), 4.14 (m, 1 H), 3.81 (s, 3H), 3.24 (dd, 1 H), 2.96 (dd, 1 H), 1.52 (m, 2H), 1 .39 (m , 1 H), 0.83 (m, 6H). MS m / e 470 (M + H).

Example 2 Cbz-Leu-Phe-CONHOEt.

This compound was prepared by the General Method A of the commercially available H2NOEt-HCI. 1 H NMR (DMSO-d 6) d 8.38 (d, 1 H), 7.25 (m, 10 H), 5.13 (m, 1 H), 5.03 (s, 2 H), 4.09 (m, 1 H), 3.83 (q, 2 H), 3.11 (dd, 1H), 2.87 (dd, 1H), 1.59 (m, 1H), 1.38 (m, 2H), 1.18 (t, 3H), 0.86 (m, 6H). MS m / e 484 (M + H). Example 3 Cbz-Leu-Phe-CONHOBn.

This compound was prepared by the General Method A of the commercially available H2NOBn-HCI. 1 H NMR (CDCl 3) d 9.39 (br s, 1 H), 7.25 (m, 15 H), 6.82 (d, 1 H), 5.45 (m, 1 H), 5.08 (s, 2 H), 5.03 (br, 1 H), 4.99 (dd, 2H), 4.18 (m, 1H), 3.32 (dd, 1H), 3.07 (dd, 1H), 1.86 (m, 2H), 1 44 (m, 1H), 0.85 (m, 6H). MS m / e 546 (M + H). Example 4 Cbz-Leu-Phe-CONHOCH2C6F5 This compound was prepared by the General Method A of commercially available H2NOCH2C6F5-HCI. 1 H NMR (CDCl 3) d 9.76 (br s, 1 H), 7.23 (m, 10 H), 6.74 (d, 1 H), 5.42 (br, 1 H), 5.42 (m, 1 H), 5.08 (m, 4 H), 4.18 (m, 1H), 3.24 (dd, 1H), 2.95 (dd, 1H), 1.60 (m, 2H), 1.42 (m, 1H), 0.82 (m, 6H). MS m / e 636 (M + H). Example 5 Cbz-Leu-Phe-CONHOtBu.

This compound was prepared by the General Method A of the commercially available H2NOtBu-HCI. 1 H NMR (CDCl 3) d 8.88 (br s, 1 H), 7.25 (m, 10 H), 6.62 (m, 1 H), 5.42 (m, 1 H), 5.08 (s, 2 H), 4.18 (m, 1 H), 3.35 (dd, 1H), 3.10 (dd, 1H), 1.60 (m, 3H), 1.38 (s, 9H), 0.85 (m, 6H). MS m / e 512 (M + H). Additional O-substituted hydroxylamines were prepared using the procedure of Mavunkel er al. Eur. J. Med. Chem. 1994, 29, 659-666. Example 6 Cbz-Leu-Phe-CONHO (4-methylcyclohexane) This compound was prepared by the General Method A of [(4-methylcyclohexyl) oxy] amine. 1 H NMR (CDCl 3) d 9.54 (d, 1 H), 7.25 (m, 10 H), 6.84 (m, 1 H), 5.44 (m, 1 H), 5.22 (m, 1 H), 5.08 (dd, 2 H), 4.18 ( m, 2H), 3.30 (m, 1H), 3.00 (m, 1H), 2.04 (m, 2H), 1.42 (m, 9H), 0.80 (m, 9H). MS m / e 552 (M + H).

Example 7 CH3S02-D-Ser (Bn) -Ser (e) -CONHOBn (General Method B).

Compound 5b To a suspension of D-Ser (Bn) (2.0 g, 10.3 mmol) in water (10 mL) was added a 1 N solution of NaOH (20 mL). After the solids had dissolved, methanesulfonyl chloride (1.19 ml, 15.5 mmol) was slowly added. An additional 1 N NaOH (5 mL) was added to adjust the pH = 10. The mixture was stirred 16 hours at room temperature, and was thus acidified to pH = 2 with concentrated HCl solution. The mixture was extracted into ethyl acetate (3 x 50 mL) and washed with saline (30 mL). The mixture was dried over MgSO, filtered and concentrated under reduced pressure to obtain 1.9 g (68%) of compound 1b as a white solid. No further purification was necessary. White amorphous solid; 1 H NMR (CDCl 3) d 7.26 (m, 5H), 5.30 (d, 1 H), 4.55 (s, 2H), 4.37 (m, 1 H), 3.95 (dd, 1 H), 3.75 (dd, 1 H), 3.00 (s, 3H). MS m / e 272 (M-H). To a solution of compound 6b (185 mg, 0.743 mmol) in anhydrous DMF (5 mL) was added 1-HOBt (100 mg, 0.743 mmol), BOP (394 mg, 0.892 mmol), and N-methylmorpholine (0.285 mmol). mi, 2.60 mmol). After 5 min. , H2NOBn-HCl (1 19 mg, 0.743 mmol) dissolved in 5 ml of DMF was added. Stirring was continued 90 minutes at room temperature. The mixture was poured into water (30 ml) and extracted into ethyl acetate (3 x 20 ml). The organic layer was washed with 3% citric acid solution (5 ml), saturated sodium bicarbonate solution (5 ml), and saline (5 ml). The solution was dried over MgSO 4, filtered and concentrated under reduced pressure to obtain 400 mg of crude product. Chromatography with preparative thin layer films (5% MeOH / methylene chloride) achieved 189 mg of compound 8 (71%). White amorphous solid; 1 H NMR (CDCl 3) d 7.26 (m, 5 H), 5.30 (d, 1 H), 4.55 (s, 2 H), 4.37 (m, 1 H), 3.95 (dd, 1 H), 3.75 (dd, 1 H ), 3.00 (s, 3H). MS m / e 355 (M + H). To a cooled solution of compound 8 (189 mg, 0.534 mmol) in anhydrous ethyl acetate (10 mL) was slowly bubbled anhydrous HCl for a period of 15 seconds. The mixture was then stirred at room temperature for 60 minutes and concentrated under reduced pressure. Trituration with ethyl ether gave compound 9 which was dried and used directly in the next step. White amorphous solid; MS m / e 255 (M + H). A solution of compound 9 (82 mg, 0.282 mmol) and N-methylmorpholine (0.031 mL, 0.282 mmol) in anhydrous DMF (10 mL) was stirred for 5 minutes. To this solution was added compound 1 b (77 mg, 0.282 mmol), 1-HOBt (38 mg, 0.282 mmol), and EDCI (65 mg, 0.338 mmol). The mixture was stirred 16 hours at room temperature, poured into water (30 ml) and extracted into ethyl acetate (5 x 20 ml). The organic layer was washed with 3% citric acid solution (5 ml), saturated sodium bicarbonate solution (5 ml), and saline (5 ml). The solution was dried over MgSO, filtered and concentrated under reduced pressure to obtain 50 mg of crude product. Chromatography with preparative thin layer films (5% MeOH / methylene chloride) achieved 25 mg of compound 4b (17%). White amorphous solid; MS m / e 510 (M + H). To a refrigerated (0 ° C) solution of compound 4b (25 mg, 0.049 mmol) in anhydrous methylene chloride (10 ml) was added slowly a Dess-Martin periodinane reagent (31 mg, 0.074 mmol). The cooling bath was removed and the mixture was stirred for an additional 90 minutes. The mixture was then washed with 10% sodium thiosulfate solution (2 x 5 ml), saturated sodium bicarbonate solution (2 ml), and saline (2 ml). The solution was dried over MgSO 4, filtered and concentrated under reduced pressure to obtain 14 mg of compound 5b (56%). White amorphous solid; 1 H NMR (CDCl 3) d 9.09 (br, 1 H), 7.25 (m, 1 1 H), 5.45 (m, 1 H), 5.28 (m, 1 H), 4.94 (dd, 2 H), 4.55 (dd) , 2H), 4.1 5 (m, 2H), 3.88 (m, 1 H), 3.66 (m, 2H), 3.23 (s, 3H), 2.95 (s, 3H). MS m / e 508 (M + H). EXAMPLE 8 CH3SO2-D-Ser (Bn) -Phe-CONHOBn.

This compound was prepared by General Method A. 1 H NMR (CDCl 3) d 9.53 (m, 1 H), 7.25 (m, 1 6H), 5.49 (m, 1 H), 4.92 (m, 2H), 4.40 ( dd, 2H), 4.18 (m, 2H), 3.55 (m, 2H), 2.81 (s, 3H), 2.72 (m, 2H). MS m / e 554 (M + H). Example 9 CH3S02-D-Ser (Bn) -Ser (Me) -CONHOEt.

This compound was prepared by General Method A. 1 H NMR (CDCl 3) d 9.38 (d, 1H), 7.21 (m, 11H), 5.49 (m, 1H), 5.37 (m, 1H), 4.49 (dd, 2H) , 4.09 (q, 2H), 3.82 (m, 1H), 3.61 (m, 1H), 3.35 (m, 1H), 3.18 (m, 1H), 2.93 (s, 3H), 1.38 (t, 3H). MS m / e 492 (M + H). Example 10 Cbz-Val-Phe-CONHOBn.

This compound was prepared by General Method B. 1 H NMR (CDCl 3) d 9.34 (br s, 1H), 7.25 (m, 15H), 6.82 (d, 1H), 5.45 (m, 1H), 5.08 (s, 2H) ), 5.03 (br, 1H), 4.99 (dd, 2H), 4.18 (m, 1H), 3.32 (dd, 1H), 3.07 (dd, 1H), 1.44 (m, 1H), 0.87 (m, 6H) . MS m / e 532 (M + H).

Example 11 Cbz-Val-Nle-CONHOBn.

This compound was prepared by General Method B. 1 H NMR (CDCl 3) d 9.46 (br s, 1 H), 7.20 (m, 10 H), 6.85 (d, 1 H), 5.45 (m, 1 H), 5.11 (s, 2H), 5.01 (br, 1H), 4.92 (m, 1H), 4.15 (m, 1H), 3.20 (br, 2H), 1.40 (m, 15H). MS m / e 498 (M + H). Example 12 Cbz-Leu-Leu-Phe-CONHOCH3.

This compound was prepared by General Method A. 1 H NMR (CDCl 3) d 9.48 (s, 1H), 7.24 (m, 10H), 6.92 (d, 1H), 6.50 (d, 1H), 5.38 (m, 1H) , 5.09 (s, 2H), 4.39 (m, 1H), 4.16 (m, 2H), 3.78 (s, 3H), 3.26 (dd, 1H), 3.02 (dd, 1H), 2.02 (m, 1H), 1.42 (m, 5H), 0.83 (m, 12H). MS m / e 583 (M + H).

Example 13 Cbz-Leu-Leu-Phe-CONHOBn.

This compound was prepared by General Method A. 1 H NMR (CDCl 3) d 9.48 (s, 1H), 7.24 (m, 15H), 6.78 (d, 1H), 6.58 (d, 1H), 5.43 (m, 1H) , 5.21 (m, 1H), 5.09 (s, 2H), 4.94 (dd, 2H), 4.42 (m, 1H), 4.16 (m, 1H), 3.26 (dd, 1H), 3.02 (dd, 1H), 2.02 (m, 1H), 1.42 (m, 5H), 0.83 (m, 12H). MS m / e 659 (M + H). Example 14 Cbz-Leu-Phe-CONHOBu.

This compound was prepared by General Method A. 1 H NMR (CDCl 3) d 9.21 (br s, 1 H), 7.26 (m, 10 H), 6.82 (d, 1 H), 5.40 (m, 1 H), 5.08 (s, 2H), 4.14 (m, 1H), 3.68 (m, 2H), 3.35 (m, 1H), 3.02 (m, 1H), 1.39 (m, 7H), 0.83 (m, 9H). MS m / e 512 (M + H). Example 15 PhCO-Phe-Nle-CONHOEt.

This compound was prepared by General Method B. 1 H NMR (CDCl 3) d 9.12 (d, 1 H), 7.40 (m, 10 H), 6.75 (d, 1 H), 5.38 (m, 1 H), 5.13 (m , 1 H), 4.87 (m, 1 H), 4.25 (m, 1 H), 4.17 (m, 1 H), 4.02 (m, 2 H), 3.20 (m, 2 H), 2.35 (m, 2 H), 1 .40 (m, 8H). MS m / e 454 (M + H). Example 16 Inhibition of Calpain To evaluate the inhibitory activity, concentrated (40-fold concentrated) solutions of each compound to be tested were prepared in 100% anhydrous DMSO and 5 μl of each inhibitor preparation was prorated in each of the three cavities of a sheet of 96 cavities. Recombinant human calpain I, prepared by the method of Meyer er al. (Biochem J. 1996, 314: 51-1 -519), was diluted in an assay buffer (ie, 50 mM Tris, 50 mM NaCl, 1 mM EDTA, 1 mM EGTA, and 5 mM ß-mercaptoethanol, pH 7.5, including 0.2 mM Succ-Leu-Tyr-MNA), and 175 μl was apportioned in the same cavities containing the concentrations of the independent inhibitor as well as the positive control cavities containing 5 μl of DMSO, but not compound. To initiate the reaction, 20 μl of 50 mM CaCl2 in a test buffer was added to all the cavities of the sheet, except for three, which were used as background baseline controls. Hydrolysis of the substrate is monitored every 5 minutes for a total of 30 minutes. Hydrolysis of the substrate in the absence of the inhibitor was linear for up to 15 minutes. The inhibition of calpain I activity was calculated as the percent reduction in the rate of hydrolysis of the substrate in the presence of the inhibitor relative to the velocity in its absence. The comparison between the control and inhibited rates were made within the linear range for the hydrolysis of the substrate. The IC50S of the inhibitors (production of 50% inhibition concentration) were determined from the percent reduction in rates of substrate hydrolysis in the presence of five to seven different concentrations of the test compound. The results were recorded as percent inhibition against the concentration of the inhibitor diagram, and the IC50 was calculated by fixing the data to the logistic equation of four parameters shown below using the GraphPad Prism program (GraphPad Software, Inc., San Diego, CA .). y = d + [(a-d) / (1 + (x / c)] The parameters a, b, c, and d are defined as follows: a is% inhibition in the absence of the inhibitor, b is the slope, c is the IC50, and d is the% inhibition at an infinite concentration of the inhibitor. The results are presented in Table I below, which lists the examples of the invention. Table I. Calpain Inhibitory Activity.

It is intended that each of the patents, applications, and printed publications mentioned in this patent document are hereby incorporated by reference in their entirety. As those skilled in the art will appreciate, numerous changes and modifications may be made to the preferred embodiments of the invention without departing from the spirit of the invention. It is intended that all such variations fall within the scope of the invention.

Claims (28)

1. CLAIMS 1. A compound of Formula I: I where: W is A-B-D; A is aryl (CH2) n, heteroaryl (CH2) n, alkyl having from one to about 14 carbons, alkenyl having from two to about 14 carbons, or cycloalkyl having from 3 to about 10 carbons, said group A being substituted optionally with one or more groups J; B is a bond or CO, SO, SO2, OCO, NR5CO, NR5SO2 or NR5SO; D is a bond, an amino acid residue, or a peptide composed of 2 to about 5 amino acid residues, said amino acid residue (s) are independently defined by the formula -NH-** CH (Rβ ) -CO-, in which the ** indicate the carbon possession of an a-amino acid residue, where R6 is different from hydrogen, the D configuration, the L configuration, or a mixture of D- and L-; n is an integer from 0 to about 6; R1, R2, R3, R4, R5, and R6 are, independently, hydrogen, alkyl having from one to about 14 carbons, or cycloalkyl having from 3 to about 10 carbons, said alkyl and cycloalkyl groups being optionally substituted with one or more groups J; and J is halogen, lower alkyl, aryl, heteroaryl, haloaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, amido, lower alkylamido, sulfonamido, lower alkyl sulfonamido, lower alkylsulfonyl, lower alkylsulfoxy, alkylthio lower, lower alkoxy, aryloxy, arylalkyloxy, hydroxy, carboxy, cyano, or nitro; and * denotes the carbon possession of an a-amino acid residue, where R2 is different from hydrogen, the D configuration, the L configuration, or a mixture of the D- and L- configurations.
2. 2. The compound according to claim 1, characterized in that R1 is alkyl or alkyl substituted with J, wherein J is lower alkoxy.
3. 3. The compound according to claim 2, characterized in that R1 is benzyl, methoxymethyl, or butyl.
4. 4. The compound according to claim 1, characterized in that R2 is alkyl or alkyl substituted with J, wherein J is arylalkyloxy or aryl.
5. 5. The compound according to claim 2, characterized in that R2 is isobutyl or benzyloxymethyl.
6. 6. The compound according to claim 1, characterized in that R3 is H.
7. The compound according to claim 1, characterized in that R4 is alkyl, J-substituted alkyl, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl.
8. The compound according to claim 7, characterized in that R 4 is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl) methyl, tert-butyl, or 4-methylcyclohexyl.
9. The compound according to claim 1, characterized in that W is benzyloxycarbonyl, methanesulfonyl, benzoyl, tert-butoxycarbonyl, or benzyloxycarbonyl-leucyl.
10. 10. The compound according to claim 1, characterized in that R3 is H, and R1 is alkyl or substituted alkyl with J, wherein J is lower alkoxy. eleven .
11. The compound according to claim 1, characterized in that R3 is H, and R2 is alkyl or alkyl substituted with J, wherein J is arylalkyloxy or aryl.
12. The compound according to claim 1, characterized in that R3 is H, and R4 is alkyl, alkyl substituted with J, cycloalkyl, or cycloalkyl substituted with J, wherein J is aryl, alkyl, haloaryl, or heteroaryl.
13. The compound according to claim 1, characterized in that R3 is H, and R1 is alkyl or alkyl substituted with J, wherein J is lower alkoxy, and R2 is alkyl or substituted alkyl with J wherein J is arylalkyloxy or aryl.
14. The compound according to claim 1, characterized in that R3 is H, R1 is alkyl or J-substituted alkyl, wherein J is lower alkoxy, and R4 is alkyl, J-substituted alkyl, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl.
15. The compound according to claim 1, characterized in that R3 is H, R1 is alkyl or J-substituted alkyl wherein J is lower alkoxy, R4 is alkyl, J-substituted alkyl, cycloalkyl, or cycloalkyl substituted with J wherein J is aryl, haloaryl, alkyl or heteroaryl, and R 2 is alkyl or substituted alkyl with J wherein J is arylalkyloxy or aryl.
16. The compound according to claim 1, characterized in that R is benzyl, methoxymethyl, or butyl; R2 is isobutyl or benzyloxymethyl; R3 is hydrogen; R 4 is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl) methyl, tert-butyl, or 4-methylcyclohexyl; and W is benzyloxycarbonyl, methanesulfonyl, benzoyl, tert-butoxycarbonyl, or benzyl oxycarbonyl-leucyl.
17. 17. The compound according to claim 1, characterized in that R1 is benzyl; R2 is isobutyl; * indicates the carbon of an a-amino acid residue that has the L configuration; R3 is hydrogen; R 4 is methyl, ethyl, propyl, butyl, benzyl, (pentafluorophenyl) methyl, tert-butyl, or 4-methylcyclohexyl; and W is benzyloxycarbonyl or benzyloxycarbonyl-leucyl.
18. 18. The compound according to claim 1, characterized in that R1 is benzyl; R2 is benzyloxymethyl; * indicates the carbon of an a-amino acid residue that has the D configuration; R3 is hydrogen; R 4 is methyl, ethyl, or benzyl; and W is methanesulfonyl.
19. 1 9. A compound as described in Table I, supra.
20. 20. A composition for inhibiting a protease selected from the group consisting of the serine proteases and cysteine proteases which comprise a compound of claim 1.
21. The composition according to claim 20, characterized in that said compound is selected from the group consisting of the compounds described in Table 1, supra.
22. 22. A method for inhibiting a protease comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of claim 1.
23. 23. The method according to claim 22, characterized in that said compound is selected from the group consisting of the compounds described in Table 1, supra.
24. 24. A method for inhibiting a protease comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a composition comprising a compound of claim 1.
25. 25. The method according to claim 24, characterized in that said compound is selected from the group consisting of the compounds described in Table 1, supra.
26. 26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
27. 27. A composition for the treatment of a disorder selected from the group consisting of neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, thrombocyte agglomeration, cataracts and inflammation , which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
28. 28. A method for the treatment of a disorder selected from the group consisting of neurodegeneration, stroke, Alzheimer's, amyotrophy, motor neuron damage, acute central nervous system injury, muscular dystrophy, bone resorption, thrombocyte agglomeration, cataracts, and inflammation , which comprises administering to a subject in need of such treatment an effective amount of a compound of claim 1.