MXPA97010225A - Calpain inhibitors for the treatment of neurodegenerative diseases - Google Patents

Abstract

ts. New amino acid analogs are provided, having the formula (I): Z-A3-A2-A1-Q, wherein Z is H or a protecting group: A3 and A2 are independently a valine, leucine, alanine, isoleucine, phenylalanine, tyrosine, glycine, optionally protected 2-arylglycine, having either D or L stereochemistry or a chemical bond: A1 is a valine, leucine, isoleucine, alanine, phenylalanine, tyrosine, 2-phenyl-glycine, 2-phenethyl-glycine, 2 optionally protected aryl glycine: Q is H, CH2OCOL, CH2OL, CH2SL, CH2X, NHNHCOCH2OCOL, NHNHCOCH2OL, NHNHCOCH2SL, wherein L is an optionally substituted aryl or optionally substituted heteroaryl, and X is CI, Br or F, and a salt pharmaceutically acceptable to

Description

CA PAIN INHIBITORS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES DESCRIPTION OF THE INVENTION This invention relates to a series of novel amino acid analogs which exhibit selective inhibition of Calpain I, compositions containing novel amino acid analogues and methods for therapeutic use. The Calpain I inhibitors described in this invention comprise novel amino acid derivatives which have particular utility in the treatment of neurodegenerative diseases Calpain is a cytosolic protease enzyme found in all types of tissue and cells of mammals. There are two forms of the enzyme with different sensitivities to calcium; the high sensitivity form, calpain I, is activated by a low calcium concentration (2-75 μM), and the low sensitivity form, calpain II, is activated by a higher calcium concentration (200-800 μM). Although calpain II is the predominant form, calpain I is concentrated in synapses and neuronal cell bodies and is thought to be involved in the phenomenon of long-term synaptic potentiation. The location of active calpain explains how calpain can promote: (l) down-regulation of the active protein kinase C associated with the membrane; (2) formation of a soluble activated calpain kinase; and (3) reorganization of the cytoskeleton (Melloni, E., and Pontremoli, S, (1989), the Calpains, Trends Neurosci, 12, 438-44). Inactivation of the kinase results in suppression of superoxide anion production, a process correlated to membrane protein phosphorylation mediated by protein kinase C. The formation of a fully active, soluble kinase, operating in association with active calpain, It results in a selective modification in the organization of the cytoskeletal proteins, which correlates with the extracellular discharge of granular contents. These conclusions have been obtained by direct and specific inhibition of proteinases, which results in: (1) a significant increase in the production of superoxide anion; (2) a marked decrease in down-regulation of protein kinase C activity; (3) reduced formation of the kinase protein activated by calpain; (4) decreased phosphorylation and proteolytic degradation mediated by phosphorylation of cytoskeletal proteins; and (5) inhibition of granular exocytosis.

In addition, studies of (Lee, KS, Vanderklish, P., Arai, A., and Lynch, G. (1991), Inhibition of Proteolysis Protects Hippocampal Neurons from Ischemia, Proc. Nat. Acad. Sci. USA: 88, 7233 ) suggests that inhibition of calpain may protect from various ischemia-induced neurodegeneration, essential hypertension, and beneficial CNS disorders, and attack.

A wide variety of apeptidylz analogues are reported to inhibit the action of proteases (Mehdi, Shujaath, Cell-Penetrating Inhibitors of Calpain, TIPS, 16,150 April 1991). These peptidyl analogs include: epoxysuccinates (E-64), leupeptin (CH CO-Leu-Leu-ArgH), and ketopeptides. However, these inhibitors suffer from some of the following disadvantages: weak specificity of the enzyme a, lack of inhibitory potency, wide variety of inhibition of proteases more than calpain I, and the multiinhibition of several enzymes limits its therapeutic applicability.

A limited number of peptidylmethyl ketone analogues constitute a well-known class of compounds having enzyme inhibition activity (papain, cathepsin B). These analogs, however, essentially lack potency and selectivity to inhibit calpain I.

Despite several known calpain inhibitors, no effective therapy has yet been developed for most ischemias induced by neurodegenerative diseases, CNS disorders, and seizures. Consequently there is a need for effective therapeutic agents in the treatment and prevention of these diseases. Novel amino acid analogs having the formula (I) Z-Aa-Az-A ^ Q (I) are provided where Z is H or a protection group; A3 and A2 are independently an optionally protected valine, leucine, alanine, isoleucine, phenylalanine, tyrosine, glycine, 2-arylglycine having either D or L stereochemistry or a chemical bond; Ax is optionally protected valine, leucine, isoleucine, alanine, phenylalanine, tyrosine, 2-phenylglycine, 2-phenylethylglycine, 2-arylglycine; Q is H, CH20C0L, CH20L, CH2SL, CH2X, NHNHC0CH20C0L; NHNHC0CH20L, NHNHC0CH2SL, where L is an optionally substituted aryl or optionally substituted heteroaryl; Y X is Cl, Br or F, and a pharmaceutically acceptable salt thereof.

As used herein, the following terms should be understood to have the following meanings, unless otherwise indicated.

"Alkyl" means a saturated or unsaturated aliphatic hydrocarbon may be either a straight or branched chain. Preferred groups have no more than about 12 carbon atoms and can be methyl, ethyl, and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, and dodecyl. "lower alkyl" means an alkyl group as above, having 1 to 7 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and n-heptyl.

"Aryl" means phenyl and substituted phenyl.

"Substituted phenyl" means a phenyl group in which one or more of the hydrogens has been replaced by the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, lower alkoxy, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholinosulfonyl, and carbobenzoxy-methylsulfamoyl.

"Heteroaryl" means pyridyl, pyrimidyl, tetrazolyl or thiadiazolyl.

"Substituted heteroaryl" means a heteroaryl group in which one or more of the hydrogens has been replaced by the same or different substituents including halo, lower alkyl, nitro, amino, acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, lower alkoxy, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholho-sulfinyl, and carbobenzoxymethylsulfamoyl. A "protection group" is a radical attached to an atom of oxygen, sulfur, nitrogen, respectively, in which the radical serves to protect oxygen, sulfur or nitrogen functionally against an undesired reaction. Such protection groups are well known in the art, many are described in "The Peptides", E. Gross and J. Meienhofer, Eds. Vol. 3 Academic Press NY (1981).

The protecting groups of N can be N-acyl, N-alkoxycarbonyl, N-arylmethoxycarbonyl and N-arylsulfonyl protecting groups.

Protecting groups of 0 include benzyl, tert-butyl, methyl, tosylated carbobenzoxy groups.

The protecting groups of S include methyl, tert-butyl, benzyl and carbobenzoxy groups.

The pharmaceutically acceptable salts include both acid or base addition salts. The pharmaceutically acceptable acid addition salt refers to those salts which retain the biological efficacy and properties of the free bases and which are not biologically or otherwise undesirable, formed with organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid and p-toluenesulfonic acid and the like. The pharmaceutically acceptable base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like salts. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary amines, secondary, and tertiary, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, tripropylamine, ethanolamine, 2-diethylethenoethanol, 2-dimethylaminoethanol, dicylohexylamine, lysine, arginine, histidine , caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromide, purines, pepriziner, piperidine, polyamine resins and the like. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanol-amine, dicyclohexylamine, choline and caffeine. This invention also contemplates the pharmaceutically acceptable acid addition salts of the compounds of Formula I. It is well known in pharmacological techniques that the non-toxic addition salts of pharmacologically active amines compounds do not differ in activities of their free base. All stereoisomers as well as optical isomers related to the novel calpain inhibitor amino acid analogs described herein are also considered to be within the scope of this invention. The amino acid analogs of the present invention are selective calpain inhibitors. More particularly, the amino acid analogs of the present invention are linked to the active site of the proteolytic enzyme, specifically calpain I. The present invention further provides pharmaceutical compositions of the novel amino acid analogue inhibitors described above and method for treating the scheme induced by neurodegenerative diseases, stroke, myocardial infarction, CNS disorders, and immunological diseases involving interleukin 1.

The compounds of the present invention are prepared by the general synthesis methods described in Schemes 1, 2 and 3.

Scheme 1 Formula 5 Formula 6 Scheme 2 Scheme 3 The first step of this process involves the synthesis of N-protected dipeptide bromomethyl ketone (formula 2). Methods for the preparation of various dipeptides (formula 1) are well established in the art. The N-protected dipeptide (formula 1), which in some cases is commercially available, is then converted to the corresponding bromoketone (formula 2) by the hydrobromination or hydrohalogenation form of an intermediate diazomethylketone. A displacement reaction of bromomethyl or chloromethyl ketone by a carboxylic acid or aromatic alcohol (or thiol) then produces the desired arylcarboxymethyl ketone (formula 3) or aryloxy (or aryl thio) methyl ketone (formula 4) of the invention.

N-protected arylcarboxymethyl ketone dipeptide (formula 3) is deprotected by conventional hydrogenolysis and the free amino dipeptide analog (formula 5) is readily converted to the corresponding tripeptide arycoboxymethyl ketone (formula 6) under standard peptide coupling conditions as shown in Scheme 1.

The preparation of several amino acids of N-arycarboxyacetyl hydrazides (e.g. formula 8) involves the amino acid synthesis of bromoacetyl hydrazide by reacting the corresponding hydrazide amino acid (formula 7) with a haloacyl halide. The resulting haloacyl hydrazine is then readily converted to the arylcarboxylacetyl hydrazine (formula 8) or aryloxyacetyl hydrazine by coupling with the arylcarboxylic acid or aryl alcohol respectively (Scheme 2).

The peptide aldehydes (for example, formula 10) of this invention are easily prepared by synthesizing the corresponding N-methoxy-N-methylamide analogues (for example, formula 9) via standard synthesis followed by reduction with LAH of the above amides. The following examples will further illustrate the compounds of the present invention. Example 1 N-benzyloxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone (a) N-Benzyloxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylcellulose.

Dissolve N-benzyloxycarbonyl-L-leucyl-L-phenylalanine (10.16 g, 24.64 mmol) in dry THF (100 ml) under nitrogen. The solution is cooled to -15 ° C. N-methylmorpholine (2.98 ml 22.1 mmol) is added followed by dropwise addition of isobutyl chloroformate (3.35 ml, 25.86 mmol) over a period of 5 min. A solution of diazomethane in dry ether (50 mmol in 100 ml of dry ether with Na 2 SO 4, from Diazald-Aldrich) is poured into the reaction mixture. The reaction mixture (-15 ° C) is allowed to slowly warm to 0 ° C after one hour, and is then kept at room temperature for one hour.

The reaction mixture is cooled to 0 ° C, 47 ml of 50% Hbr / AcOH are added with stirring at 0 ° C, and the resulting mixture is transferred to the separatory funnel with 500 ml of water. The aqueous phase is extracted with ethyl acetate (3x) and the organic layer is washed successively with water, KHS04 0.3N, saturated NaHCO3 solution (water and brine) The organic layer is dried with MgSO4, filtered and concentrated to produce a white solid which is recrystallized from dichloromethane / hexane to give 10.35 g (86%) of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethylketone. (b) N-Benzyloxycarbonyl-L-leucylL-phenylalanine 2,6-difluorophenylcarboxymethylketone 2,6-difluorobenzoic acid (65 mg, 0.41 mmol) is added to a solution of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethylketone (200 mg, 0.41 mmol) and potassium fluoride in dry DMF under nitrogen. The reaction mixture is poured into the ether and the organic layer is washed successively with water, 5% NaHC03, water, and brine. Dry the ether solution with MgSO 4 and concentrate to yield a solid product which recrystallizes from ether / hexane to yield 165 mg (70%) of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone, p . of f. 108-9 ° C. (c) L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone A mixture of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenycarboxymethylketone (670 mg, 1.18 mmol) in anhydrous ethanol is added under 10% carbon palladium nitrogen (67 mg), and the mixture is cooled to 0 ° C. The nitrogen atmosphere is then replaced with hydrogen gas by equilibrating with hydrogen supplied from a balloon. When the atmosphere has been exchanged for hydrogen, 6N HCl solution (0.39 ml) is added to the solution and allowed to stir for 1.5 h at room trature. The reaction mixture is filtered through celite and the filtrate is concentrated in vacuo to yield the hydrochloride salt of L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone. (d) N-Benzyloxycarbonyl-D-alanyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone It is added to a mixture of L-leucyl-L-phenylalanine hydrochloride 2,6-difluorophenacyloxymethyl ketone (180 mg, 0.394 mmol, in azeotropic mixture with toluene), benzoxycarbonyl-D-alanine (97 mg, 0.43 mmol), benzotriazole hexafluorophosphate -1-yloxy-tripyrrolidinophosphonium (225 mg, 0.43 mmol) under nitrogen 5 ml of dichloromethane, and the resulting mixture at 0 ° C is cooled. N-methylmorpholine (117 mg, 1.06 mmol) to the mixture is added and the resulting reaction mixture is cooled to 0 ° C, and then stirred at room trature overnight. The mixture is poured into water, extracted with ethyl acetate, and the organic layer is washed successively with KHS04, saturated NaHCO3, and brine. Dry the organic layer with Na 2 SO 4 and concentrate in vacuo and purify the residue by chromatography eluting with 30-50% ethyl acetate / hexane to give 111 g (45%) of N-benzyloxycarbonyl-D-alanyl-L-leucyl -L-phenylalanine 2,6-difluorophenacyloxymethyl ketone, p. of f. 171-2 ° C.

The following calpain inhibitors are synthesized using the synthesis procedure described in Scheme 1 and Example 1.

Example 2 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichloro-3- [(2-morpholino) -ethoxy] phenylcarboxymethyl ketone Example 3 Benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-dichlorophenylcarboxymethyl ketone Example 4 Benzyloxycarbonyl-L-prolyl-L-leucyl-L-phenylalanine 2,6-dichlorophenylcarboxymethyl ketone Example 5 Benzyloxycarbonyl-L-prolyl-L-glycine 2,6-dichloro-3- (morpholinosulfonyl) phenylcarboxymethyl ketone Example 6 L-leucyl-benzyloxycarbonyl-L-phenylalanine 2, 6-dichloro-3- (morpholinosulfonyl) fenilcarboximetilcetona Example 7 Benzyloxycarbonyl-glycyl-L-leucyl-L-phenylalanine 2,6-difluoro-phenylcarboxymethyl ketone Example 8 L-leucyl-benzyloxycarbonyl-L-tyrosine 2, 6-dichloro-3- (morpholino-sulfonyl) fenilcarboximetilcetona Example 9 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- (morpholinesulfonyl) phenylcarboxymethyl ketone Example 10 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenylcarboxymethyl ketone Example 11 Benzyloxycarbonyl-L-valyl-L-phenylalanine 2, 6-Dichlorophenyl-carboxymethyl ketone Example 12 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone Example 13 Ter-butyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone Example 14 Benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-difluorophenylcarboxymethyl ketone Example 15 Benzyloxycarbonyl-L-leucyl-L-glycine 2,6-dichlorophenylcarboxymethyl ketone Example 16 Benzyloxycarbonyl-L-leucyl-L-glycine 3,6-dichloro-2-acetamidophenylcarboxymethyl ketone Example 17 p-Toluenesulfonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone Example 18 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dimethylphenylcarboxymethyl ketone Example 19 Benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-6-chlorophenylcarboxymethyl ketone Example 20 Benzyloxycarbonyl-L-leucyl-L-alanine 2-acetamido-6-chlorophenylcarboxymethylketone Example 21 Benzyloxycarbonyl-L-N-methyl-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone Example 22 Benzyloxycarbonyl-L-N-methyl-leucyl-L-f-enylalanine 2, 6-dichloro-3- [2- (morpholino) ethoxy] phenylcarboxymethyl ketone Example 23 Benzyloxycarbonyl-L-valyl-L-phenylalanine 2-acetamido-6-chlorophenylcarboxymethylketone Example 24 Benzyloxycarbonyl-LN-methyl-leucyl-L-phenylalanine 2.6 -dichloro- 3- (morpholinesulfonyl) phenylcarboxymethyl ketone Example 25 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethylketone Example 26 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3 - (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone Example 27 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- [2- (morpholino) ethoxy] phenylcarboxymethyl ketone Example 28 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dimethoxyphenylcarboxymethyl ketone Example 29 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichlorophenylcarboxymethyl-ketone Example 30 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-acetamido-6-chlorophenylcarboxymethyl ketone Example 31 Benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-3,6-dichlorophenyl-carboxymethyl ketone Example 32 Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-pyridylcarboxymethyl ketone Example 33 Benzyloxycarbonyl-L-leucyl-L-glycine 2,6-fluorophenylcarboxymethyl ketone Example 34 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-difluorophenylcarboxymethyl ketone Example 35 Benzyloxycarbonyl-L-valyl-1-alanine 2,6-bistrifluoromethylphenylcarboxymethyl ketone Example 36 p-Nitrobenzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluoropheni-carboxymethyl ketone Example 37 L-leucyl-benzyloxycarbonyl-L-phenylalanine 1- naftilcarboximetilcetona Example 38 L-leucyl-benzyloxycarbonyl-L-phenylalanine 2, 6-dichloro-3- benciloxifenilcarboximetilcetona Example 39 N-benzyloxycarbonyl-L-leucyl-N- (2, 6- diclorofenilcarboxiacetil ) it hydrazide to a solution of N-benzyloxycarbonyl-L-leucyl-N- (bromoacetyl) hydrazide (50 mg, 0.12 mmol) and 2,6-dichlorobenzoic acid (29 mg, 0.15 mmol) in dry DMF (5 ml) is added Potassium fluoride (18 mg) in one serving. The resulting mixture is poured into water, extracted with ether, and the organic layer is washed successively with water, 5% NaHC03, water, and brine. The organic layer is dried over MgSO4 and concentrated to yield 56 mg (88%) of N-benzyloxycarbonyl-L-leucyl-N- (2,6-dichlorophenylcarboxyacetyl) hydrazide, m.p. 103-5 ° C. The following compounds are made using the synthesis procedure described in Example 39. Example 40 N-benzyloxycarbonyl-L-leucyl-N-methyl, N- (2-acetamido-6-chlorophenicarboxy-acetyl) hydrazide Example 41 N-benzyloxycarbonyl-L-leucyl-N- (2-acetamido-6-chlorophenylcarboxy-acetyl) hydrazide Example 42 Benzyloxycarbonyl-L-leucyl-L-tyrosine 2, 6-dichloro-3- [2- (morpholino) ethoxy] Example 43 fenilcarboximetilcetona methoxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine 2, 6-dichloro-3 - [2- (morpholino) etoxijfenilcarboximetilcetona Ex 44 emplo Benzyloxycarbonyl-D-alanyl-L-leucyl-L-tyrosine 2-dichloro-3- [2- (morpholino) ethoxy] fenilcarboximetilcetona Example 45 Benzyloxycarbonyl-L-valyl-L- phenylalanine 2, 6-dichloro-3- [2- (orfolino) ethoxy] fenilcarboximetilcetona Example 46 Benzyloxycarbonyl-L-valyl-glycine 2, 6-dichloro-3- (methylsulfamoyl carbobenzoxy) fenilcarboximetilcetona Example 47 Benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- [2- (morpholino) -ethoxy] phenylcarboxymethyl ketone Example 48 Benzyloxycarbonyl-L-leucyl-glycine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethyl ketone Example 49 Methoxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone Example 50 Benzyloxycarbonyl-L-alanyl-L-glycine 2,6-dichloro-3- (carbobenzoxy-methylsulfamoyl) phenylcarboxymethyl ketone Example 51 Benzyloxycarbonyl-glycyl-L-phenylalanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone Example 52 Benzyloxycarbonyl-L-valyl-glycine 2,6-dichlorophenylcarboxymethyl ketone Example 53 Benzyloxycarbonyl-glycyl-L-phenylalanine 2,6-dichlorophenylcarboxymethyl ketone Example 54 Benzyloxycarbonyl-L-phenylalanyl-L-alanine 2,6-dichloro-3- [2- (morpholino) ethoxy] phenylcarboxymethyl ketone Example 55 L-phenylalanyl-benzyloxycarbonyl-glycine 2 diclorofenilcarboximetiIcetona Example 56 6- benzyloxycarbonyl-D-alanyl-L-leucyl-glycine 2, 6-dichloro-3- [2- (orfolino) etoxijfenilcarboximetilcetona Example 57 Benzyloxycarbonyl-L-leucyl-glycine 2,6-dichlorophenylcarboxymethyl ketone Example 58 Benzyloxycarbonyl-L-phenylalanyl-glycine 2,6-dichlorophenylcarboxymethylketone Example 59 Benzyloxycarbonyl-L-alanyl-glycine 2,6-dichlorophenylcarboxymethyl ketone Example 60 Benzyloxycarbonyl-L-phenylalanyl-L-alanine 2,6-bistrifluoromethylphenylcarboxymethyl ketone Example 61 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenoxymethylketone To a solution of benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethylketone (100 mg, 0.204 mmoles) 2,6-dichlorophenol 34 mg, 0.204 mmoles) and K2CO3 (29 mg, 0.204 mmoles) in 8 ml of DMF is added tetra-n-butyl-ammonium iodide (8 mg) and the resulting mixture is stirred for the night at room temperature. The mixture is diluted with ethyl acetate, washed with water and brine, and the organic layer is dried over Na2SO4. The solvent is concentrated in vacuo to yield 80 mg of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenoxymethylketone, as a white solid, m.p. 102-4 ° C.

Using the synthetic procedure described in Example 61 and Scheme 1, the following additional calpain inhibitors are synthesized.

Example 62 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [1- (3-pyridyl) tetrazolylphthiomethyl ketone Example 63 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(4-morpholinoethyl) tetrazolyl) thiomethyl ketone Example 64 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(5-methylthio) tetrazolyl] thiomethyl ketone Example 65 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(5-methylthio) tetrazolyl] thiomethyl ketone Example 66 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-6-difluorophenylthiomethyl ketone Example 67 N-benzyloxycarbonyl-L-valyl-L-phenylalanine 2-6-difluorophenoxymethyl ketone Example 68 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-pyrimidylthiomethyl ketone Example 69 N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- (1-phenyl) - tetrazoylthiomethyl ketone To a solution of benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethylketone (150 mg, 0.306 mmol) and 2-mercapto-phenyltetrazole (57.2 mg, 0.32 mmol) in 2 ml of DMF is added K2C03 (42.3 mg, 0.306 mmol) to Room temperature and the resulting reaction mixture is stirred overnight. The mixture is poured into 50 ml of water and then extracted with ethyl acetate. The organic layer is washed with 0.3 N KHS04, 5% NaHCO3, water, and brine and dried over Na2SO4. The solvent is concentrated in vacuo to yield 168 mg (94%) of N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- (1-phenyl) -tetrazolylthio-methylketone, as a white solid, m.p. 183-4 ° C.

Example 70 Benzyloxycarbonyl-L-leucyl-L-tyrosinal Benzyloxycarbonyl-L-leucyl-L-tyrosyl-N- (methoxy), N-methylamide (9,182 mmol) is dissolved in 4 ml of ether / THF (1: 1) under nitrogen and the solution is cooled to 0 ° C. The LAH ether solution (0.182 mmol) is added via syringe to the reaction mixture with stirring. The reaction mixture is quenched with KHS04 0.3N (0.6 ml) and the mixture transferred into a separatory funnel containing 50 ml of water and 50 ml of ether / ethyl acetate (1: 1). The aqueous layer is extracted with ether / ethyl acetate and the combined organic layer is washed with KHS04 0.3N, water, and brine. The organic solution is dried over Na 2 SO 4 and concentrated in vacuo to give 53 mg (70.6%) of benzyloxycarbonyl-L-leucyl-L-tyrosinal, m.p. 57-60 ° C.

Using the synthesis procedure described in Scheme 1, Scheme 2 and Scheme 3, the following additional calpain inhibitors are prepared.

Example 71 Benzyloxycarbonyl-L-valyl-L-tyrosinal Example 72 Benzyloxycarbonyl-L-leucyl-L-O-methyl-tyrosinal Example 73 Benzyloxycarbonyl-L-leucyl-L-phenylalaninal Example 74 Benzyloxycarbonyl-L-isoleucyl-L-tyrosinal Example 75 Benzyloxycarbonyl-L-valyl-DL-2- (2-naphthylmethyl) glycine Example 76 Benzyloxycarbonyl-L-isoleucyl-L-phenylalaninal Example 77 Benzyloxycarbonyl-L-valyl-DL- 2- (phenethyl) glycine Example 78 Benzyloxycarbonyl-L-2-neopentyl-glycyl-L-phenylalaninal Example 79 Benzyloxycarbonyl-L-valyl-DL-2- (1-naphthylmethyl) glycine Example 80 Benzyloxycarbonyl-L-2-phenylglycyl-L phenylalanine Example 81 Benzyloxycarbonyl-L-alanyl-L-phenylalaninal Example 82 Benzyloxycarbonyl-L-2-phenethylglycyl-L-phenylalaninal Example 83 Benzyloxycarbonyl-L-phenylalanyl-L-phenylalaninal Example 84 Benzyloxycarbonyl-L-2-tert-butylglycyl-L phenylalanine Example 85 Benzyloxycarbonyl-L-2- (1-naphthymethyl) glycyl-DL-phenylalaninal Example 86 Benzyloxycarbonyl-L-leucyl-N-chloroacetyl hydrazide Example 87 Benzyloxycarbonyl-L-leucyl-N-bromoacetyl hydrazide Example 88 Benzyloxycarbonyl-L-leucine chloromethyl ketone Example 89 Benzyloxycarbonyl-L-leucyl-L-leucyl-L-phenylalanine chloromethyl ketone Example 90 Benzyloxycarbonyl-L-leucyl-L-alanine chloromethyl ketone Example 9 Benzyloxycarbonyl-1-leucyl-L-phenylalanine chloromethyl ketone Example 92 Benzyloxycarbonyl-glycyl-L-leucyl-L-tyrosine chloromethyl ketone Example 93 Benzyloxycarbonyl-L-leucyl-L-phenylalanine chloromethyl ketone Example 94 Benzyloxycarbonyl-L-leucyl-glycine chloromethyl ketone Example 95 Benzyloxycarbonyl-L-leucyl-L-alanine bromomethylketone Example 96 Benzyloxycarbonyl-L-valyl-L-phenylalanine bromomethylketone Example 97 Benzyloxycarbonyl-L-leucyl-L-leucine bromomethylketone Example 98 Benzyloxycarbonyl-L- asparagil-L-phenylalanine chloromethyl ketone Example 99 Benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethylketone Example 100 Benzyloxycarbonyl-L-phenylalanyl-L-alanine chloromethyl ketone Example 101 Benzyloxycarbonyl-glycyl-L-phenylalanine bromoethyl ketone Example 102 Benzyloxycarbonyl-L-valyl-glycine broom ethyl ketone Example 103 Benzyloxycarbonyl-L-leucine chloromethyl ketone Example 104 Benzyloxycarbonyl-L-phenylalanyl-L-alanine bromomethylketone Example 105 Benzyloxycarbonyl-L-alanyl-glycine bromomethylketone Example 106 Benzyloxycarbonyl-L-2- (2-naphthylmethyl) glycine chloromethyl ketone Example 107 Benzyloxycarbonyl-L-phenylalanyl-glycine chloromethyl ketone Example 108 Benzyloxycarbonyl-L-phenylalanyl-L-phenylalanine chloromethyl ketone Example 109 Benzyloxycarbonyl-L-leucyl-N- (bromoacyl) hydrazide Example 110 Benzyloxycarbonyl-L-leucyl-L-tyrosine bromomethyl ketone The compounds of the present invention are tested for inhibition activity of calpain I using the following test method. Inhibition assay of Calpain Y It obtains human blood cells from Northeastern New York Chapter of the American Red Cross. The isolation of calpain from human erythrocytes is similar to that described by Wang et al., (1988). A unit of packed red cells dated with an equal volume of dilution / wash solution is diluted and centrifuged. The supernatant is removed and the procedure repeated. The washed cells are pooled, used with 700 ml of solution to be used and centrifuged to remove cell debris. The membrane-free hemolysate is added to 500 ml of DEAE-sephacel and the suspension is gently stirred at 4 ° C for one hour.

Batch elution is performed using DEAE-sephacel wash solution to remove a large amount of unwanted protein, most of which is hemoglobin. The suspension is emptied into a column connected in series to a CL-4B column of phenyl-sepharose. The material that elutes from the DEAE-sephacel is directly applied to CL-4B of phenyl-sepharose. The column of CL-4B of phenyl sepharose is washed first with 75 mM NaCl and then without salt. Calpain begins to dissociate from the DEAE-sephacel with 75 M NaCl but most adhere to the column until the salt is removed. Fractions (20 ml) are collected, tested for caseinolytic activity with and without calpastatin and are therefore pooled. The pooled fractions are concentrated using an Amicon stirred cell equipped with a YK-10 membrane. Calpain is stored at 4 ° C with 10 mM EDTA and 5 mM 2-mercaptoethanol and is stable for at least 6 months. Test procedure The assay titled is a modification of that described by Gopalakrishna, R. and Barsky, S.H., Anal. Biochem., 148, 413, 1985. All the reagents are combined, compound 25 ul, buffer HEPES 25 ul, CaCl2 50 ul, enzyme 50 ul, and Casein 3H-acetyl, in polystyrene Lml title plates. The plates are preincubated at 25 ° C for 5 min. with gentle agitation before the addition of the substrate. Incubation is continued for an additional two hours and the addition of 0.5 ml of 5% TCA cooled with ice is completed. Unlabelled casein is added, the samples are centrifuged and 0.5 ml of supernatant is counted in 5 ml of Ready Protein liquid scintillation cocktail. This assay measures the degradation of casein 3H-acetyl as the end point for calpain activity.

The representative results of the test are shown in the following tables Table 1 Inhibitors Calpain Acyloxyketone And Z-A3-A2-A? -CH2-0-CO-Q Example Z A3 A £ A ^ Q ICsp μM 1 CBZ D-Ala -Leu L-Fen 2, 6-dif luorofenyl. 046 2 CBZ - L-Leu L-Fen 2, 6-chloro-3- [2- 0. 14 (morpholino) ethoxyphyl 3 CBZ - L-Leu L-Tir 2, 6-dichlorophenyl 0.22 4 CBZ L.Pro L-Leu L-Fen 2, 6-fluorophenyl 0.08 CBZ - L-Leu Gli 2, 6-dichloro-3- 0.11 (morpholinosulfonyl) phenyl 6 CBZ - L-Leu L-Fen 2, 6-dichloro-3- 0.17 (morpholinosulfonyl) phenyl 7 CBZ Gli L-Leu L-Fen 2, 6-difluorophenyl 0.04 8 CBZ - L-Leu L-Tir 2, 6-dichloro-3- 0.17 (morpholinosulfonyl) phenyl 9 CBZ - L-Leu L-Ala 2,6-dichloro-3- 0.43 (morpholinosulfonyl) phenyl CBZ - L-Leu L-Fen 2, 6-dichlorophenyl 0.33 11 CBZ - L-Val L-Fen 2, 6-dichlorophenyl 0.55 12 CBZ - L-Leu L-Fen 2, 6-difluorophenyl 0.16 13 CtBu - L-Leu L-Fen 2, 6-difluorophenyl 0.42 14 CBZ - L-Leu L-Tir 2, 6-difluorophenyl 0.40 CBZ - L-Leu Gli 2, 6-dichlorophenyl 0.29 16 CBZ - L-Leu Gli 3, 6-dichloro-2- > 10 acetamidophenyl 17 Cough - L-Leu L-Fen 2, 6-difluorophenyl 0.16 18 CME - L-Leu L-Fen 2, 6-dimethylphenyl 0.63 19 CBZ - L-Leu Gli 2-acetamido-6-chlorophenyl 0.78 CBZ - L-Leu L-Ala 2-acetamido-6-chlorophenyl 0.36 Table 2 Calpain I aryloxyketone inhibitors Example Z 2 A = Q IC / uM 61 CBZ L-Leu L-Fen 2, 6-dichlorophenoxy 2. 3 62 CBZ L-Leu L-Fen 2- [l- (3-pyridyl) tetrazoyljthio 0. 53 63 CBZ L-Leu L-Fen 2- [(4- 3. 8 morpholinoethyl) tetrazoyljtio 64 CBZ L-Leu L-Fen 2- [(methylthio) tiadazoyljtio 2. 0 65 CBZ L-Leu L-Fen 2, 6-difluorophenoxy > 10 66 CBZ L-Leu L-Fen 2, 6-dichlorophenylthio > 10 67 CBZ L-Val L-Fen 2, 6-difluorophenoxy > 10 68 CBZ L-Leu L-Fen 2-pyrimidylthio > 10 69 CBZ L-Leu L-Fen 2- (l-phenyltetrazoyl) thio > 10 Table 3 Calpain peptide aldehyde inhibitors I Z ^ -AxH Example Z A2 Rx IC50 / uM 70 CBZ L-Leu L-Tirosinal 0.02 71 CBZ L-Val L-Tirosinal 0.026 72 CBZ L-Val L-Tyrosinal (o-methyl) 0. 03 73 CBZ L-Leu L-Fenialaninal 0. 037 74 CBZ L-Ile L-Tirosinal 0. 053 75 CBZ L-Val 0. 07 76 CBZ L-Ile L-Fenialaninal 0. 08 77 CBZ L-Val DL-2- 0. 10 (phenethyl) glycine 78 CBZ L-2- L-Fenialaninal 0.10 (neopoentil) Glycyl 79 CBZ L-Val DL-2- (l- 0.11 naphthylmethyl) glycine! 0 CBZ 2-phenylglycyl L-Fenialaninal 0.11 CBZ L-Ala L-Fenialaninal 0.17 32 CBZ L-2- L-Fenialaninal 0.27 (phenethyl) glycyl 33 CBZ L-Fen L-Fenialaninal 0.41 Table 4 Haloketone inhibitors of Calpain and CBZ-A2_-A1-CH2X Example A, X IC50 / uM 86 L-leu-NHNHCO Cl 2.2 87 L-leu-NHNHCO Br L-Leu Cl > 10 89 L-Leu L-Leu L-Fen Cl > 10 90 L-Leu L-Ala Cl > 10 91 L-Leu L-Fen Cl 43.3 92 Gli L-Leu L-Fen Cl 6.6 93 L-Leu L-Tir Cl 40 94 L-Leu L-Fen Cl > 10 95 L-Leu L-Ala Br > 10 96 L-Val L-Fen Br > 10 97 L-Leu I-Leu Br > 10 98 - L- L-Fen Cl > 10 Asp (NH2) 99 - L-Leu L-Fen Br 9.1 The present invention includes a calpain inhibitor of this invention formulated in compositions together with one or more of the physiologically acceptable non-toxic carriers, adjuvants, or vehicles which are collectively referred to herein as carriers, for parental injection or oral administration, in solid or liquid form, for rectal or topical administration or the like.

The compositions may be administered to humans and animals either orally, rectally, parentally (intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, locally (powders, ointments or drops), or as a buccal or nasal spray. Compositions suitable for parental injection can comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and esters. injectable organics such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting, emulsification and distribution agents. The preservation of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may be desirable to also include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the dosage form can be brought about by the use of absorption retardation agents, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one usual inert excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose , glucose, mannitol and silicic acid, (b) binders, such as, for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose and acacia, (c) humectants, such as, for example, glycerol, (d) disintegrating agents, for example , agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complexes of silicates and sodium carbonate, (e) solution retarders, such as paraffin, (f) absorption accelerators, such as quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, such as, for example, kaolin and bentonite, and (and) lubricants, such as, for example, talc, stearate, calcium, stearate of magnesium, solid polyethylene glycols, sodium lauryl sulphate or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise quenching agents.

Solid compositions of a similar type can also be employed as filling agents in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and others as is well known in the art. They may contain opacifying agents, and may also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions which may be used are polymeric substances and waxes. The active compounds may also be in the micro-encapsulated form, if appropriate, with one or more of the aforementioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water, or other solvents, solubilizing agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, acetate. of ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, walnut oil, corn germ oil, olive oil, castor oil and olive oil. safflower, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters or mixtures of these substances, and the like.

In addition to such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring and perfuming agents.

The suspensions, in addition to the active compounds, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures thereof. substances, and the like.

The compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoaq butter, polyethylene glycol or suppository wax, which are solids at ordinary temperatures but liquid at temperature body and, therefore, fuse in the rectal or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays and inhalants. The active component is mixed under sterile conditions with a physiologically stable carrier and any preservatives, buffers or propellants as required. Ophthalmic formulations, ointments for eyes, powders and solutions are also contemplated as being within the scope of this invention.

The current dose levels of the active ingredient in the compositions of the present invention can be varied to obtain an amount of the active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. The selected dose level depends therefore on the therapeutic effect, the route of administration, the desired duration of treatment and other factors. The total daily dose of the compounds of this invention administered to a host in single or divided doses may be in amounts, for example, from about 0.5 mg to about 10 mg per kg of body weight. The compositions of the dosage unit may contain such amounts of such submultiples thereof as may be used to form the daily dose. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including body weight, general health, sex, diet, time and route of administration, absorption and excretion rates, combination with other drugs. and the severity of the particular disease that is treated.

Claims (42)

1. A compound of the formula (i) Z-A3-A2-A? -Q (I) Where Z is H or a protection group; A3 and A2 are independently an optionally protected valine, leucine, alanine, isoleucine, phenylalanine, tyrosine, glycine, 2-arylglycine having either D or L stereochemistry or a chemical bond; Ax is optionally protected valine, leucine, isoleucine, alanine, phenylalanine, tyrosine, 2-phenylglycine, 2-phenylethylglycine, 2-arylglycine; Q is H, CH20C0L, CH20L, CH2SL, CH2X, NHNHC0CH20C0L; NHNHC0CH20L, NHNHC0CH2SL, where L is an optionally substituted aryl or optionally substituted heteroaryl; Y X is Cl, Br or F, and a pharmaceutically acceptable salt thereof.

2. The compound according to claim characterized in that L is substituted aryl selected from the group consisting of phenyl or naphthyl optionally substituted by 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo, acetyl, acetamido, hydroxy, phenyl, morpholino-lower alkyloxy, morphorino lower alkyl, benzyl, benzyloxy, nitro, amino, lower alkylamino, morpholinosulfonyl, morpholinosulfamoyl, benzyloxycarbonyl-methylsulfamoyl, acetylamino or trifluoromethyl.

3. The compound in accordance with the claim Characterized in that L is substituted heteroaryl selected from the group consisting of thiazole, furan, thiadiazole, thiophene, tetrazole, pyridyl, pyrimidyl, triazole optionally substituted by 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo, acetyl , acetamido, hydroxy, phenyl, morpholino-lower alkyloxy, morphorino lower alkyl, benzyl, benzyloxy, nitro, amino, lower alkylamino, morpholinosulfonyl, morpholinosulfamoyl, benzyloxycarbonyl-methylsulfamoyl, acetylamino or trifluoromethyl.

. The compound according to claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2, 6 -dichloro-3- [(2-morpholino) ethoxy] phenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-prolyl-L-leucyl-L-phenylalanine 2,6-dichlorophenyl-carboxymethylketone , benzyloxycarbonyl-L-leucyl-glycine 2,6-dichloro-3- (morpholinesulfonyl) phenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichloro-3- (morpholinosulfonyl) phenylcarboxymethylketone, benzyloxycarbonyl-glycyl-L-leucyl -L-phenylalanine 2,6-difluorophenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-dichloro-3- (morpholinosulfonyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- ( morpholinosulfonyl) phenylcarboxymethyl ketone and benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenylcarboxymethylketone.

5. The compound in accordance with the claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-L-valyl-L-phenylalanine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone, tert-butyloxycarbonyl-L-leucyl- L-phenylalanine 2,6-difluorophenyl-carboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-difluorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-glycine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-glycine , 3,6-dichloro-2-acetamido-phenylcarboxymethyl ketone, p-toluenesulfonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone. Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dimethylphenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-6-chlorophenylcarboxymethylketone and benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-6-chlorophenylcarboxymethylketone.

6. The compound according to claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-L-N-methyl-leucyl-L-phenylalanine 2, 6-difluorophenylcarboxymethyl ketone, benzyloxycarbonyl-1-LN-methyl-leucyl-L-phenylalanine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenyl-chloro-methyl-ketone, benzyloxycarbonyl-L-valyl-L-phenylalanine 2-acetamido-6-chlorophenylcarboxymethylketone, benzyloxycarbonyl -LN-methyl-leucyl-L-phenylalanine 2,6-dichloro-3- (morpholinosulfonyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl -L-alanine 2, 6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- [2- (morpholino) ethoxyphenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L- alanine, 2,6-dimethoxyphenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-alanine, 2,6-dichlorophenylcarboxymethylketone and benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-acetamido-6-chlorophenylcarboxymethylketone.

7. The compound according to claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-3,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-pyridylcarboxymethylketone , L-leucyl-benzyloxycarbonyl-L-glycine 2, 6-fluorofenilcarboxi-methyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine 2, 6-difluorofenilcarboximetilcetona, L-valyl-benzyloxycarbonyl-L-alanine 2, 6-bistrifluorometilfenilcarboximetilcetona, p- Nitrobenzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 1-naphthylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine, 2,6-dichloro-3-benzyloxyphenylcarboxymethylketone, N- benzyloxycarbonyl-L-leucyl-N- (2,6-dichlorophenylcarboxiacetyl) hydrazide and N-benzyloxycarbonyl-L-leucyl-N-methyl, N- (2-acetamido-6-chlorophenylcarboxiacetyl) hydrazide.

8. The compound in accordance with the claim 1, characterized in that it is selected from the group consisting of: N-benzyloxycarbonyl-L-leucyl-N- (2-acetamido-6-chlorophenyl-carboxyacetyl) hydrazide, benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, methoxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine, 2,6-dichloro-3- [2- (morpholino-ethoxy] phenylcarboxymethyl] ketone, benzyloxycarbonyl- D-alanyl-L-leucyl-L-tyrosine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, benzyloxycarbonyl-L-valyl-L-phenylalanine 2,6-dichloro-3- [2- (morpholino) -etoxijfenilcarboximetilcetona, benzyloxycarbonyl-L-valyl-glycine 2, 6-dichloro-3- (carbobenzoxy-methylsulfamoyl) fenilcarboximetilcetona, L-leucyl-benzyloxycarbonyl-L-alanine 2, 6-dichloro-3- [2- (morpholino) etoxijfenilcarboximetilcetona, benzyloxycarbonyl-L-leucyl-glycine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, methoxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine, 2,6-difluorophenylcarboxymethylketone and benzyloxycarbonyl-L-alanyl-L -glycine 2, 6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone.

9. The compound in accordance with the claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-glycyl-L-phenylalanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethylketone, benzyloxycarbonyl-L-vallyl-glycine 2,6-dichlorophenyl-carboxymethylketone, benzyloxycarbonyl-glycyl -L-phenylalanine 2, 6-diclorofenilcarboximetilcetona, L-phenylalanyl-benzyloxycarbonyl-L-alanine 2, 6-dichloro-3- [2- (morpholino) etoxijfenilcarboximetilcetona, L-phenylalanyl-benzyloxycarbonyl-glycine 2, 6-diclorofenilcarboximetilcetona, benzyloxycarbonyl-D- alanyl-L-leucyl-glycine 2, 6-dichloro-3- [2- (morpholino) etoxijfenil-carboximetilcetona, benzyloxycarbonyl-L-leucyl-glycine 2, 6-diclorofenilcarboximetilcetona, L-phenylalanyl-benzyloxycarbonyl-glycine 2, 6-diclorofenilcarboximetilcetona , benzyloxycarbonyl-L-alanylglycine 2,6-dichlorophenylcarboxymethylketone and benzyloxycarbonyl-L-phenylalanyl-L-alanine 2,6-bistrifluoromethylphenylcarboxymethylketone.

10. The compound according to claim 1, characterized in that it is selected from the group consisting of: N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenoxymethylketone, N-benzyloxycarbonyl-1-L-leucyl-L-phenylalanine 2- [ 1- (3-pyridyl) tetrazoliljtiometilcetona, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(4-morpholinoethyl) tetrazoliljtiometilcetona, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(5-methylthio) tetrazoliljtiometilcetona , N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(5-methylthio) tetrazolyl-thiomethyl ketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylthiomethyl ketone, N-benzyloxycarbonyl-L-valyl-L-phenylalanine 2, 6-difluorofenoximetilcetona, N-benzyloxycarbonyl-1-leucyl-L-phenylalanine 2-pirimidiltiometilcetona, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- (1-phenyl) tetrazoliltiometilcetona and benzyloxycarbonyl-L-leucyl-L-tirosinal .

11. The compound according to claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-L-valyl-L-tyrosinal, benzyloxycarbonyl-L-leucyl-LO-methyl-tyrosinal, benzyloxycarbonyl-L-leucyl-L-phenylalaninal, benzyloxycarbonyl-L-isoleucyl-L -tyrosine, benzyloxycarbonyl-L-valyl-DL-2- (2-naphthymethyl) glycline, benzyloxycarbonyl-L-isoleucyl-L-phenylalaninal, benzyloxycarbonyl-L-valyl-DL-2- (phenethyl) glycine, benzyloxycarbonyl-L-2 -neoptenyl-glycyl-L-phenylalaninal, benzyloxycarbonyl-L-valyl-DL-2- (1-naphthylmethyl) glycine and benzyloxycarbonyl-L-2-phenylglycyl-L-phenylalaninal.

12. The compound in accordance with the claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-L-alanyl-L-phenylalaninal, benzyloxycarbonyl-L-2-phenethylglycyl-L-phenylalaninal, benzyloxycarbonyl-L-phenylalanyl-L-phenylalaninal, benzyloxycarbonyl-L-2 tert-butylglycyl-L-phenylalaninal, benzyloxycarbonyl-L-2- (2-naphthylmethyl) glycyl-DL-phenylalaninal, benzyloxycarbonyl-L-leucyl-N-chloroacetyl-hydrazide, benzyloxycarbonyl-L-leucyl-N-bromoacetyl-hydrazide, benzyloxycarbonyl -L-leucine chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine chloromethyl ketone and benzyloxycarbonyl-L-leucyl-L-alanine chloromethyl ketone.

13. The compound according to claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-L-leucyl-L-phenylalanine chloromethyl ketone, benzyloxycarbonyl-glycyl-L-leucyl-L-tyrosine, chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L -phenylalanine chloromethyl ketone, benzyloxycarbonyl-L-leucylglycine chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine bromomethyl ketone, benzyloxycarbonyl-L-valyl-L-phenylalanine broom ethyl ketone, benzyloxycarbonyl-L-leucyl-L-leucine broom ethyl ketone, benzyloxycarbonyl-L-asparagyl- 1-phenylalanine chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethyl ketone and benzyloxycarbonyl-L-phenylalanyl-L-alanine chloromethyl ketone.

14. The compound according to claim 1, characterized in that it is selected from the group consisting of: benzyloxycarbonyl-glycyl-L-phenylalanine bromomethyl ketone, benzyloxycarbonyl-L-valyl glycine bromomethyl ketone, benzyloxycarbonyl-L-leucine chloromethyl ketone, benzyloxycarbonyl-L-phenylalanyl- L-alanine bromomethyl ketone, benzyloxycarbonyl-L-alanyl-glycine bromomethyl ketone, benzyloxycarbonyl-L-2- (2-naphthylmethyl) glycine chloromethyl ketone, benzyloxycarbonyl-L-phenylalanyl-glycine chloromethyl ketone, benzyloxycarbonyl-L-phenylalanyl-L-phenylalanine chloromethyl ketone, benzyloxycarbonyl- L-leucyl-N- (bromoacyl) hydrazide and benzyloxycarbonyl-L-leucyl-L-tyrosine bromomethylketone.

15. A pharmaceutical composition for the treatment or inhibition of a neurodegenerative disease in a mammal, characterized in that it comprises an effective amount of a compound of the formula (I) Z-A3-A2_A1-Q (I) where Z is H or a protecting group; A3 and A2 are independently an optionally protected valine, leucine, alanine, isoleucine, phenylalanine, tyrosine, glycine, 2-arylglycine having either a D or L stereochemistry or a chemical bond; Ai is an optionally protected valine, leucine, isoleucine, alanine, phenylalanine, tyrosine, 2-phenyl-glycine, 2-phenethyl-glycine, 2-aryl-glycine; Q is H, CH20C0L, CH20L, CH2SL, CH2X, NHNHC0CH20C0L, NHNHC0CH20L, NHNHC0CH2SL, wherein L is an optionally substituted aryl or an optionally substituted heteroaryl; Y X is Cl, Br or F, in a pharmaceutically acceptable vehicle.

16. The pharmaceutical composition according to claim 15, characterized in that L is substituted aryl selected from the group consisting of phenyl or naphthyl optionally substituted by 1 to 3 substituents selected from the group consisting of lower alkyl, lower alkoxy, halo, acetyl, acetamido, hydroxy, phenyl, morpholino-lower alkoxy, morpholino-lower alkyl, benzyl, benzyloxy, nitro, amino, lower alkylamino, morpholinosulfonyl, morpholinosulfamoyl, benzoxycarbonylmethylsulphamoyl, acetylamino or trifluoromethyl.

17. The pharmaceutical composition according to claim 15, characterized in that L is a substituted heteroaryl selected from the group consisting of thiazole, furan, thiadiazole, thiophene, tetrazole, pyridyl, pyrimidyl, triazole optionally substituted by 1 to 3 substituents selected from the group consisting of of lower alkyl, lower alkoxy, halo, acetyl, acetamido, hydroxy, morpholino-lower alkyloxy, morpholino-lower alkyl, encyl, benzyloxy, nitro, amino, lower alkylamino, morpholinosulfonyl, morpholinosulfamoyl, benzyloxycarbonylmethylsulphamoyl, acetylamino, phenyl or trifluoromethyl.

18. The pharmaceutical composition according to claim 15, wherein the compound is selected from the group consisting of: benzyloxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine 2, 6-difluorofenilcarboximetilcetona, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2, 6-dichloro-3- [(2-morpholino) etoxijfenilcarboximetilcetona, L-leucyl-benzyloxycarbonyl-L-tyrosine 2, 6-diclorofenilcarboximetilcetona, benzyloxycarbonyl-L-prolyl-L-leucyl-L-phenylalanine 2, 6-diclorofenil- carboximetilcetona, benzyloxycarbonyl-L-leucyl-glycine 2, 6-dichloro-3- (morpholinosulfonyl) fenilcarboximetilcetona, L-leucyl-benzyloxycarbonyl-L-phenylalanine 2, 6-dichloro-3- (morpholinosulfonyl) fenilcarboximetilcetona, benzyloxycarbonyl-glycyl-L- leucyl-L-phenylalanine 2,6-difluorofenilcarboximetilcetona, L-leucyl-benzyloxycarbonyl-L-tyrosine 2, 6-dichloro-3- (morpholinosulfonyl) fenilcarboximetilcetona, L-leucyl-benzyloxycarbonyl-L-alanine 2, 6-dichloro-3- (morpholinosulfonyl) phenylcarboxymethyl ketone and benzyloxycarbonate bonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenylcarboxymethyl ketone.

19. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-L-valyl-L-phenylalanine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2, 6- difluorophenylcarboxymethyl ketone, tert-butyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenyl-carboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-tyrosine 2,6-difluorophenylcarboxymethyl ketone, benzyloxycarbonyl-1-L-leucyl-L-glycine 2,6-dichlorophenylcarboxymethyl ketone , benzyloxycarbonyl-L-leucyl-L-glycine, 3,6-dichloro-2-acetamido-phenylcarboxymethylketone, p-toluenesulfonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone. Benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dimethylphenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-6-chlorophenylcarboxymethylketone and benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-6-chlorophenylcarboxymethylketone.

20. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-LN-methyl-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone, benzyloxycarbonyl-LN-methyl-leucyl-L-phenylalanine 2, 6-dichloro-3- [2- (morpholino) etoxijfenilcrboximetilcetona, L-valyl-benzyloxycarbonyl-L-phenylalanine 2-acetamido-6-clorofenilcarboximetilcetona, benzyloxycarbonyl-LN-methyl-leucyl-L-phenylalanine 2, 6-dichloro- 3- (morpholinosulfonyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone , L-leucyl-benzyloxycarbonyl-L-alanine 2, 6-dichloro-3- [2- (morpholino) etoxifenilcarboximetilcetona, L-leucyl-benzyloxycarbonyl-L-alanine, 2, 6-dimetoxifenilcarboximetilcetona, benzyloxycarbonyl-L-leucyl-L- alanine, 2,6-dichlorophenylcarboxime tylketone and benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-acetamido-6-chlorophenylcarboxymethylketone.

21. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-L-leucyl-L-glycine 2-acetamido-3,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 2-pyridylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-glycine 2,6-fluorophenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine 2,6-difluorophenylcarboxymethyl ketone, benzyloxycarbonyl-L-valyl-L-alanine 2,6-bistrifluoromethylphenylcarboxymethyl ketone , p-nitrobenzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine 1-naphthylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine, 2,6-dichloro-3-benzyloxyphenylcarboxymethylketone , N-benzyloxycarbonyl-L-leucyl-N- (2,6-dichlorophenylcarboxiacetyl) hydrazide and N-benzyloxycarbonyl-L-leucyl-N-methyl, N- (2-acetamido-6-chlorophenylcarboxiacetyl) hydrazide.

22. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: N-benzyloxycarbonyl-L-leucyl-N- (2-acetamido-6-chlorophenyl-carboxyacetyl) hydrazide, benzyloxycarbonyl-L-leucyl -L-tyrosine 2, 6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, methoxycarbonyl-D-alanyl-L-leucyl-L-phenylalanine, 2,6-dichloro-3- [2- (morpholino-ethoxy-phenylcarboxymethylketone, benzyloxycarbonyl-D-alanyl-L-leucyl-L-tyrosine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, benzyloxycarbonyl-L-valyl-L-phenylalanine 2,6-dichloro-3- [2- ( morpholino) -ethoxy-phenylcarboxymethylketone, benzyloxycarbonyl-1-L-valyl-glycine 2,6-dichloro-3- (carbobenzoxy-methylsulfamoyl) phenylcarboxymethylketone, benzyloxycarbonyl-L-leucyl-L-alanine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethyl ketone, benzyloxycarbonyl-L-leucyl-glycine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, methoxycarbonyl-D-alanyl-L-leucyl-L-phenyl alanine, 2,6-difluorophenylcarboxymethylketone and benzyloxycarbonyl-L-alanyl-L-glycine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethylketone.

23. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-glycyl-L-phenylalanine 2,6-dichloro-3- (carbobenzoxymethylsulfamoyl) phenylcarboxymethyl ketone, benzyloxycarbonyl-L-vallyl glycine 2 , 6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-glycyl-L-phenylalanine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-phenylalanyl-L-alanine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenylcarboxymethylketone, benzyloxycarbonyl-L-phenylalanyl-glycine 2, 6-dichlorophenyl-carboxymethylketone, benzyloxycarbonyl-D-alanyl-L-leucyl-glycine 2,6-dichloro-3- [2- (morpholino) ethoxy-phenyl-carboxymethylketone, benzyloxycarbonyl-L-leucyl-glycine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-phenylalanyl-glycine 2,6-dichlorophenylcarboxymethylketone, benzyloxycarbonyl-L-alanylglycine 2,6-dichlorophenylcarboxymethylketone and benzyloxycarbonyl-L-phenylalanyl-L-alanine 2,6-bistrifluoromethylphenylcarboxymethylcet ona

24. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-dichlorophenoxymethyl ketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [1- (3-pyridyl) -tetrazolyl-thiomethyl-ketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(4-morpholinoethyl) tetrazolyl-thiomethyl-ketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(5- methylthio) tetrazolyljthiomethyl ketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- [(5-methylthio) tetrazolylphthiomethylketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2,6-difluorophenylthiomethylketone, N-benzyloxycarbonyl-L-valyl- L-phenylalanine 2,6-difluorophenoxymethyl ketone, N-benzyloxycarbonyl-1-leucyl-L-phenylalanine 2-pyrimidylthiomethyl ketone, N-benzyloxycarbonyl-L-leucyl-L-phenylalanine 2- (1-phenyl) tetrazolylthiomethyl ketone and benzyloxycarbonyl-L-leucyl- L-tyrosinal.

25. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-L-valyl-L-tyrosinal, benzyloxycarbonyl-L-leucyl-LO-methyl-tyrosinal, benzyloxycarbonyl-L-leucyl- L-phenylalaninal, benzyloxycarbonyl-L-isoleucyl-L-tyrosinal, benzyloxycarbonyl-L-valyl-DL-2- (2-naphthymethyl) glycline, benzyloxycarbonyl-L-isoleucyl-L-phenylalaninal, benzyloxycarbonyl-L-valyl-DL-2 - (phenethyl) glycine, benzyloxycarbonyl-L-2-neoptenyl-glycyl-L-phenylalaninal, benzyloxycarbonyl-L-valyl-DL-2- (1-naphthylmethyl) glycine and benzyloxycarbonyl-L-2-phenylglycyl-L-phenylalaninal.

26. The pharmaceutical composition according to claim 15, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-L-alanyl-L-phenylalaninal, benzyloxycarbonyl-L-2-phenethylglycyl-L-phenylalaninal, benzyloxycarbonyl-L-phenylalanyl- L-phenylalaninal, benzyloxycarbonyl-L-2-tert-butylglycyl-L-phenylalaninal, benzyloxycarbonyl-L-2- (2-naphthylmethyl) glycyl-DL-phenylalaninal, benzyloxycarbonyl-L-leucyl-N-chloroacetyl-hydrazide, benzyloxycarbonyl-L -leucyl-N-bromoacetyl-hydrazide, benzyloxycarbonyl-L-leucine, chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine, chloromethyl ketone, and benzyloxycarbonyl-L-leucyl-L-alanine, chloromethyl ketone.

27. The pharmaceutical composition according to claim 1, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-L-leucyl-L-phenylalanine, chloromethyl ketone, benzyloxycarbonyl-glycyl-L-leucyl-L-tyrosine, chloromethyl ketone, benzyloxycarbonyl-L- leucyl-L-phenylalanine chloromethyl ketone, benzyloxycarbonyl-L-leucylglycine chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L-alanine bromomethyl ketone, benzyloxycarbonyl-L-valyl-L-phenylalanine broom ethyl ketone, benzyloxycarbonyl-L-leucyl-L-leucine broom ethyl ketone, benzyloxycarbonyl-L -asparagil-1-phenylalanine chloromethyl ketone, benzyloxycarbonyl-L-leucyl-L-phenylalanine bromomethyl ketone and benzyloxycarbonyl-L-phenylalanyl-L-alanine chloromethyl ketone.

28. The pharmaceutical composition according to claim 1, characterized in that the compound is selected from the group consisting of: benzyloxycarbonyl-glycyl-L-phenylalanine bromomethyl ketone, benzyloxycarbonyl-L-valyl glycine bromomethyl ketone, benzyloxycarbonyl-L-leucine chloromethyl ketone, benzyloxycarbonyl-L -phenylalanyl-L-alanine bromomethyl ketone, benzyloxycarbonyl-L-alanyl-glycine bromomethyl ketone, benzyloxycarbonyl-L-2- (2-naphthylmethyl) glycine chloromethyl ketone, benzyloxycarbonyl-L-phenylalanyl-glycine chloromethyl ketone, benzyloxycarbonyl-L-phenylalanyl-L-phenylalanine chloromethyl ketone , benzyloxycarbonyl-L-leucyl-N- (bromoacyl) hydrazide and benzyloxycarbonyl-L-leucyl-L-tyrosine bromomethylketone.

29. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it comprises administering to said mammal an effective amount of a composition according to claim 15.

30. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is understood to administer to said mammal an effective amount of a composition according to claim 16.

31. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is understood to administer to said mammal an effective amount of a composition according to claim 17.

32. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it comprises administering to said mammal an effective amount of a composition according to claim 18.

33. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is administered to administer to said mammal an effective amount of a composition according to claim 19.

34. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is understood to administer to said mammal an effective amount of a composition according to claim 20.

35. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is administered to administer to said mammal an effective amount of a composition according to claim 21.

36. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that copmrende administering to said mammal an effective amount of a composition according to claim 22.

37. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is administered to administer to said mammal an effective amount of a composition according to claim 23.

38. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is understood to administer to said mammal an effective amount of a composition according to claim 24.

39. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is administered to administer to said mammal an effective amount of a composition according to claim 25.

40. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is administered to administer to said mammal an effective amount of a composition according to claim 26.

41. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is administered to administer to said mammal an effective amount of a according to claim 27.

42. A method for treating or inhibiting a neurodegenerative disease in a mammal, characterized in that it is understood to administer to said mammal an effective amount of a composition according to claim 28.