MXPA99004527A - N-(ARYL/HETEROARYL) AMINO ACID DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND METHODS FOR INHIBITING&bgr;-AMYLOID PEPTIDE RELEASE AND/OR ITS SYNTHESIS BY USE OF SUCH COMPOUNDS - Google Patents

Abstract

Disclosed are compounds which inhibit&bgr;-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits&bgr;-amyloid peptide release and/or its synthesis as well as methods for treating Alzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions.

Description

DERIVATIVES OF THE N- (ARYLO / HETEROARYL) AMINO ACID, PHARMACEUTICAL COMPOSITIONS THAT COMPRISE THE SAME, AND METHOD TO INHIBIT THE LIBERATION OF THE PEPTIDE BEGA MILOIDBO? / ° your SYNTHESIS THROUGH THE USE OF SUCH COMPOUNDS RECIPROCAL REFERENCE TO RELATED REQUESTS This application claims the benefit of the North American application, Provisional No. 60 /, which was converted in accordance with the 37 C.F.R. § 1.53 (b) (2) (ii) of the US patent application No. 08 / 755,334, filed on November 22, 1996, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION Field of the Invention This invention relates to compounds which inhibit the release of β-amyloid peptide and / or its synthesis, and, therefore, have utility in the treatment of Alzheimer's disease. This invention also relates to pharmaceutical compositions comprising such compounds as well as also to methods for inhibiting the release of β-amyloid peptide.

REF: 030050 References The following publications, patents and patent applications are cited in this application as superscript numbers: Glenner, et al., "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein", Biochem. Biophys. Res. Commun. , 120: 885-890 (1984). Glenner et al., "Polypeptide Marker for Alzheimer's Disease and its Use for Diagnosis", North American Patent No. 4, 666, 829 issued May 19, 1987. Selkoe, "The Molecular Pathology of Alzheimer's Disease," Neuron, 6 ^: 487-498 (1991). Goate, et al., "Segregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer's Disease", Na ture, 349: 704-706 (1990). Chartier-Harlan, et al., "Early-Onset Alzheimer's Disease Caused by Mutations at Codon 717 of the ß-Amyloid Protein Gene Precursor", Nature, 353: 844- 846 (1989). Murrell et al., "A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease", Science, 254: 97-99 (1991). Mullan et al., "A Pathogenic Mutation for Probable Alzheimer's Disease in the APP Gene at the N-Terminus of β-10 Amyloid, Nature Genet., 1: 345-347 (1992)." Schenk et al., "Methods and Compositions for the ction of Soluble ß-Amyloid Peptide ", International Patent Application Publication No. WO 94/10596, published May 11, 1994. Selkoe, "Amyloid Protein and Alzheimer's Disease", Scientific American, pp. 2-8, November 1991. 10 Yates et al., "N, N-Disubstituted Amino Acid Herbicides, "US Patent No. 3,598,859, issued August 10, 1971. 11 Citron et al.," Mutation of the ß-Amiloid Precursor Protein in Familial Alzheimer's Disease Increases ß-Protein Production, Na ture, 360 : 672-674 (1992). 12 Hansen et al., "Reexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth / Cell Kill", J. Immun. Meth. , 119: 203-210 (1989).

All prior publications, patents and patent applications are hereby incorporated by reference in their entirety to the same degree as if each publication, patent or individual patent application was specifically and individually indicated to be incorporated by reference in its entirety.

STATE OF THE ART Alzheimer's Disease (AD) is a degenerative disorder of the brain, characterized clinically by the progressive loss of memory, knowledge, reasoning, judgment and emotional stability that gradually leads to mental, deep rioration and finally death. AD is a very common cause of mental, progressive (dementia) failure in mature humans and is thought to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups around the world and presents a major public health problem of the present and future. It is currently estimated that the disease affects approximately two to three million individuals in the United States alone. AD is incurable today. He currently does not know of treatment that effectively prevents AD or reverses his symptoms and course. The brains of individuals with AD exhibit characteristic lesions called senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in the blood vessels) and neurofibrillary tangles. The large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in various areas of the human brain important for the function of memory and knowledge in patients with AD. The smaller numbers of these lesions in an anatomical, more restrictive distribution are also found in the brains of most mature humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCH A-D). Currently, a definitive diagnosis of AD usually requires observing the above-mentioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsy samples of brain tissue taken during an invasive neurosurgical procedure. . The chemical constituent, principal amyloid plaques and amyloid, vascular deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is a protein of approximately 4.2 kilodaltons (kD) of approximately 39-43 amino acids designated ß-amyloid peptide (ßAP, for its acronym in English) or sometimes Aß, AßP or ß / A4. The β-amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner et al1. The isolation procedure and sequence data for the first 28 amino acids are described in U.S. Patent No. 4,666,8292. Biological molecular and chemical analyzes of proteins have shown that the β-amyloid peptide is a small fragment of a much larger precursor protein (APP), which is normally produced by cells in many tissues of several animals, including humans.

Knowledge of the structure of the gene encoding the APP has shown that the β-amyloid peptide arises as a fragment of the peptide that is divided from the APP by protease enzyme (s). The precise biochemical mechanism by which the β-amyloid peptide fragment is split from the APP and subsequently deposited as amyloid plaques in the brain tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown. Several lines of evidence indicate that the progressive, cerebral deposition of β-amyloid peptide plays an original role in the pathogenesis of AD and may precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that nonsense DNA mutations in amino acid 717 of the 770 amino acid isoform of APP can be found in affected members but not in unaffected members of diverse families with a genetically determined form (family) of the AD (Goate et al4; Chartier Harían et al5; and Murrell et al6) and is referred to as the Swedish variant. A double mutation that changes lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan et al7). The genetic link analysis has shown that these mutations, as well as certain other mutations in the APP gene, are the molecular, specific cause of AD in affected members of such families. In addition, a mutation in amino acid 693 of the 770 amino acid isoform of APP has been identified as the cause of the deposition disease of the β-amyloid peptide, HCHWA-D, and a change from alanine to glycine in amino acid 692 cause a phenotype that resembles AD is some patients but to HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD proves that the alteration of APP and the subsequent deposition of its β-amyloid peptide fragment can cause AD. Despite the progress which has been made in the understanding of the fundamental mechanisms of AD and other diseases related to the β-amyloid peptide, there remains a need to develop methods and compositions for the treatment of the disease (s) . Ideally, the methods of treatment would be advantageously based on drugs which are capable of inhibiting the release of the β-amyloid peptide and / or its synthesis.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to the discovery of a class of compounds which inhibit the release of β-amyloid peptide and / or its synthesis and, therefore, are useful in the prevention of AD in susceptible patients. AD and / or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The class of compounds having the described properties are defined by formula I below: wherein: R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when R is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl , thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho (adjacent) to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and heteroaryl substituted with the proviso that the substituents are not ortho (adjacent) to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include the a-haloalkyl, a-diazoalkyl or -OC (0) alkyl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, and wherein R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X can also be -CR4R4Y 'where each R4 is independently selected from the group consisting of hydrogen, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl , heteroaryl and heterocyclic, and with the condition n that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derivative of D-phenylalanine, then X is not -C (0) OCH3. Accordingly, in one of its aspects of the method, this invention is directed to a method for inhibiting the release of the β-amyloid peptide and / or its synthesis in a cell, the method comprising administering to said cell an amount of a compound or a mixture of compounds of formula I above, effective to inhibit cell delivery and / or synthesis of β-amyloid peptide. Because the in vivo generation of the β-amyloid peptide is associated with the pathogenesis of AD8'9, the compounds of the formula I can also be used in conjunction with a pharmaceutical composition for preventing and / or treating the AD of prophylactic and / or therapeutic way. Accordingly, in another aspect of the method, this invention is directed to a prophylactic method for preventing the onset of AD in a patient at risk of developing AD, the method comprising administering to the patient a pharmaceutical composition comprising a carrier. pharmaceutically inert and an effective amount of a compound or a mixture of compounds of formula I above. In yet another aspect of the method, this invention is directed to a therapeutic method for treating a patient with AD in order to inhibit further deterioration in that patient's condition, the method comprising administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I above. In formula I above, phenyl substituted with R1 are preferably 4-substituted, 3,5-disubstituted or 3,4-disubstituted phenyl substituents wherein the substituents at positions 3 and / or 5 are defined by Rb, Rb ' as before and the substituents in the 4-position are defined by Rc as above. Particularly preferred 3, 5-disubstituted phenyls include, by way of example, 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (triflupromethyl) phenyl, 3,5-dimethoxyphenyl and the like. Particularly preferred 3,4-disubstituted phenyls include, by way of example, 3,4-dichlorophenyl, 3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro-4-cyanophenyl, 3- chloro-4-iodophenyl, 3,4-methylenedioxyphenyl and the like. Particularly preferred 4-substituted phenyls include, by way of example, 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl, 4- (phenylcarbonyl) phenyl, 4- (1-ethoxy) ethylphenyl and the like. Other preferred R1 substituents include, by way of example, 2-naphthyl, quinolin-3-yl, 2-methylquinolin-6-yl, benzothiazol-6-yl, benzothiazol-2-yl, 5-indolyl, phenyl, -naftilo, and similar. Preferably, R 2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the attachment of the aryl or heteroaryl atom to the carbon atom. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, -CH2CH2SCH3, phenyl and the like. Preferred R3 substituents include alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and the like; substituted alkyl groups such as a-hydroxyethyl, -CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo-4-hydroxybenzyl, -CH2-indol-3-yl, phenyl, - (CH2) -NH-BOC, - (CH2) -NH2, -CH2- (1-N-benzyl-imidazol-4-yl), -CH2-imide zol-4-yl, -CH2CH2SCH3, - (CH2) NHC (0) (CH2) 4CH3, - (CH2) and C (0) OR5 where y is 1 or 2 and R5 is hydrogen, methyl, tert-butyl, phenyl and the like. Preferred X substituents include groups -C (0) Y where Y is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, amino (-NH2), N- ( iso-butyl) amino, N-methylamino, N, -dimethylamino, N-benzylamino and the like as well as also where X is -CH20H and the like.

This invention also provides novel pharmaceutical compositions comprising a pharmaceutically inert carrier and a compound of formula I above. Particularly preferred compounds for use in the methods and compositions of this invention include, by way of example, the following wherein the stereochemistry of the groups R2 and R3 is derived from the L-amino acid: N- [N- (3,4-dichlorophenyl) -lanyl] valine methyl ester N- [N- (3,4-dichlorophenyl) alanyl] valine N- [N-] methyl ester N-isobutyl amide 3,4-dichlorophenyl) - alanyl] threonine N- [N- (3,4-dichlorophenyl) -lanyl] valine ethyl ester N- [N- (3,4-dichlorophenyl) -lanyl] valine tert-butyl ester N- [N- (3, 4-dichlorophenyl) alanyl] aline? - (l-hydroxy-3-methyl-2-butyl) amide of N- (3,4-dichlorophenyl) alanine?,? - dimethyl amide of N- [N- (3,4-dichlorophenyl) -lanyl] valine N- [N- (3,4- dichlorophenyl) -arylanyl] valine N- [N- (3,4-) methyl ester] N-methyl amide -dichlorophenyl) - alanyl] alanine methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] leucine methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] phenylalanine N-methyl ester [N- (3, -dichlorophenyl) -10 alanyl] isoleucine N- [N- (3,4- dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester N- [N- (3,4-) methyl ester dichlorophenyl) alanyl] -2-aminohexanoic acid methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] tryptophan a-methyl ester of N- [N- (3,4- dichlorophenyl) alanyl] aspartic ester β- (ester) a-methyl from N- [N- (3,4-Dicorophenyl) alanyl] aspartic acid N- [N- (3,4-dichlorophenyl) -arylanyl] -β-BOC-lysine methyl ester of N- [N-] benzothiazol-6-yl) alanyl] -2-aminohexanoic methyl ester of N * - [N- (3,4-dichlorophenyl) -lanyl] lysine N- [N- (3,4-dichlorophenyl) -lanyl] methyl ester] N- [N- (3,5-dichlorophenyl) -arylanyl] alanine methyl ester of N- [N- (3,5- dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester of N- [N-] (3,5- 10-dichlorophenyl) alanyl] phenylalanine ß- (methyl ester) α-methyl ester of N- [N- (3,4-dichlorophenyl) alanyl] aspartic acid methyl ester of N- [N- (3,4 - dichlorophenyl) alanyl] -1-benzylhistidine-N- [N- (3,4- (3, 4-dichlorophenyl) alanyl] glutamic acid ester N- (N- (3,4) -α- (tert-butyl) -methyl ester) -dichlorophenyl) alanyl] leucine-N- [N- (3,4- dichlorophenyl) alanyl] glutamic acid a-methyl ester N- [N- (3,4-d) methyl ester chloro-phenyl) -anthyl] - (3,5-diiodo) tyrosine methyl ester of N- [N- (3,4-dichlorophenyl) -alanyl] - (3-iodo) tyrosine methyl ester of N- [N- (3 , 5-25-dichlorophenyl) glycyl] -2-aminopentanoic methyl ester of N- [N- (3,4-dichlorophenyl) alanyl] -? E- (hexanoyl) lysine N- [N- (3,4-dichlorophenyl) amide ) alanyl] -phenylalanine N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N-methyl) -amide N- [N- (3,4-dichlorophenyl) -annil] - methyl ester - β-cyclohexylalanine N- [N- (3,4-dichlorophenyl) alanyl] -2- 10 aminohexanamide N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N, N-dimethyl) amide ester N- [N- (3,4-dichlorophenyl) -arylanyl] methionine methyl ester N- [N- (3,5-dichlorophenyl) alanyl] -2-aminohexan- (?,? -dimethyl) -amide N- [ N- (3,4-dichlorophenyl) alanyl] -2- aminohexanamide N- [N- (3,5-dithiorophenyl) alanyl] -2-aminohexan-20 (N-methyl) -amide N- [N-] methyl ester (3,4-dichlorophenyl) -arylanyl] histidine methyl ester of N- [N- (qui) acid nolin-3-yl) alanyl] -2-aminohexanoic acid methyl ester N- [N- (benzothiazol-2-yl) alanyl] -2-aminohexanoic methyl ester of N- [N- (3, 5-difluorophenyl) - alanyl] alanine N- [N- (3,5-difluorophenyl) alanyl] -2-aminohexanoic acid N- [N- (3,4-dichlorophenyl) alanyl] -2- aminohexanamide N - [N- (3,4-dichlorophenyl) alanyl] -2-aminohexan-10 (N-benzyl) -amide N- [N- (3,4-dichlorophenyl) alanyl] -2-amino-2-phenylethanol methyl ester of N- [N- (3,5-dichlorophenyl) -phenylglycinyl] alanine 15 N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexanol N- [N- (3,5-dichlorophenyl) alanyl] -2- Amino-2-phenylethanol N- [N- (3,5-dichlorophenyl) -anlanyl] -phenylglycine-tert-butyl ester N- [N- (3,5-di- (trifluoromethyl) tert-butyl ester ) phenyl) alanyl] -phenylglycine N- [N- (3,5-dimethoxyphenyl) alanyl] -2-aminohexanoic acid methyl ester and pharmaceutically acceptable salts of the same.

Still further, this invention provides novel compounds of the formula III: wherein R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy, and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo , cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl, and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include a-haloalkyl, a-diazoalkyl or a- groups OC (O) alkyl, (c) alkoxy or thioalkoxy (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "where R 'and R "are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and where R' and R" are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X may also be -CRR4Y 'where each R4 is independently selected from the group consisting of hydrogen, uilo, cycloalkyl, aryl, heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and with the proviso that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derived from D-phenylglycine, then X is not -C (0) OCH3, and even with the additional condition of excluding the following known compounds: when R1 is phenyl, R2 is methyl, X is -C (O) NH0, then R3 is not methyl, iso-propyl, isobutyl; and when R1 is phenyl, R2 is methyl, X is -C (0) NH2, then R3 is not benzyl.

Preferred compounds of formula III above include those set forth below in Table 1 below: neither TABLE I DETAILED DESCRIPTION OF THE INVENTION As above, this invention relates to compounds which inhibit the release of β-amyloid peptide and / or its synthesis, and, therefore, have utility in the treatment of Alzheimer's disease. However, before describing this invention in further detail, the following terms will be defined first.

Definitions The term "β-amyloid peptide" refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, the peptide that is substantially homologous to the protein form described by Glenner, and collaborators1 which includes mutations and post-transductional modifications of the β-amyloid peptide, normal. Either way, the β-amyloid peptide is approximately a fragment of 39-43 amino acids of a large glycoprotein that covers the membrane, referred to as the β-amyloid precursor protein (APP, for its acronym in English). Its sequence of 43 amino acids is: Asp Wing Glu Phe Arg His Asp Ser Gly Tyr 1 G1lu Val His His Gln Lys Leu Val Phe Phe 21 Wing Glu Asp Val Gly Ser Asn Lys Gly Wing 11 lie lie Gly Leu Met Val Gly Gly Val Val 41 He Wing Thr (ID. FROM SECTION NO: 1) or a sequence which is substantially homologous to the same "Alkyl" refers to monovalent alkyl groups preferably having 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. - carbon. This term is exemplified by groups such as * methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like. "Substituted alkyl" refers to an alkyl group, preferably 1 to 10 carbon atoms, having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, halogen, hydroxyl, carboxyl, carboxyalkyl, cycloalkyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro and mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono - and di-cycloalkylamino, mono- and di-arylamino, mono- and di-heteroaryl-amino, amino mono- and di-heterocyclic and disubstituted, asymmetric amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. "Alkylene" refers to alkylene, divalent groups preferably having 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2), ethylene (CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and CH (CH3) CH2-) and the like. "Alkaryl" refers to -alkylene-aryl groups which preferably have from 1 to 10 carbon atoms in the alkylene portion and from 6 to 10 carbon atoms in the aryl portion. Such alkaryl groups are exemplified by benzyl, phenethyl and the like. "Alkoxy" refers to the group "alkyl-O-d". Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n -pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like. "Substituted alkoxy" refers to the group "alkyl-O-substituted" wherein the substituted alkyl is as defined above. "Alkylalkoxy" refers to the group "-alkylene-O-alkyl" wherein alkylene and alkyl are as defined above. Such groups include, by way of example, methylenemethoxy (-CH2OCH3), ethylenemethoxy (-CH2CH2OCH3), n-propylene-iso-propoxy (-CH2CH2CH2? CH (CH3) 2), methylene ether-butoxy (-CH2-0- C (CH3) 3) and the like.

"Alkylthioalkoxy" refers to the group [beta] -alkylene-S-alkyl "wherein alkylene and aryl are as defined above, such groups include, by way of example, methylene-thiomethoxy (-CH2SCH3), ethylentiomethoxy (-CH2CH2SCH3), n-propylene-iso-thiopropoxy (-CH2CH2CH2SCH (CH3) 2) r methylenethio-tert-butoxy (-CH2SC (CH3) 3) and the like. "Alkenyl" refers to alkenyl groups having preferably 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably 1-2 alkenyl unsaturation sites . Preferred alkenyl groups include ethenyl (-CH = CH2), n-propenyl (-CH2CH = CH2), iso-propenyl (-C (CH3) = CH2), and the like. "Substituted alkenyl" refers to an alkenyl group as defined above having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, cycloalkyl, oxyacylamino, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and dialkylamino , mono- and di- (substituted alkyl) amino, mono- and di-cycloalkyl, mono- and di-arylamino, mono- and di-heteroarylamino, amino mono- and di-heterocyclic and di-substituted, asymmetric amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. "Alkynyl" refers to alkynyl groups in a preferable manner having from 2 to 10 carbon atoms and more preferably from 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of unsaturation of Alkynyl, Preferred alkynyl groups include ethynyl (-C = CH), propargyl (-CH2C = CH) and the like. "Substituted alkynyl" refers to an alkynyl group as defined above having 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, cyano, cycloalkyl, oxyacylamino, halogen, hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-cycloalkylamino, mono and di-arylamino, mono- and di-heteroarylamino, amino mono- and di-heterocyclic and di-substituted, asymmetric amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. "Acyl" refers to the groups alkyl-C (0) -, alkyl-C (0) -substituted, cycloalkyl-C (0) -, aryl-C (O) -, heteroaryl-C (O) -, and heterocyclic-C (O) - wherein alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Acylamino" refers to the group -C (0) NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and wherein each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic they are as defined in the present. "Aaminoacyl" refers to the group -NRC (0) R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and wherein each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Acyloxy" refers to the groups -0C (0) -alkyl, -OCH (0) -substituted alkyl, -0C (0) -cycloalkyl, -0C (0) -aryl, -C (0) -heteroaryl- , and -C (0) O-heterocyclic wherein alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

"Aminoacyloxy" refers to the groups -NRC (0) O-alkyl, -NRC (0) O-substituted alkyl, -NRC (0) 0-cycloalkyl, -NRC (0) O-aryl, -NRC (0) O-heteroaryl-, and -NRC (0) O-heterocyclic wherein R is hydrogen, alkenyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and wherein each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Oxyacylamino" refers to the groups -0C (O) NR-alkyl, -0C (0) NR-substituted alkyl, -0C (0) NR-aryl, -OC (0) R-heteroaryl-, and -OC ( 0) NR-heterocyclic wherein R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and wherein each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein. "Aryl" refers to a carbocyclic, aromatic, unsaturated group of 6 to 14 carbon atoms having an individual ring (for example phenyl) or multiple fused rings (for example, naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise restricted by the definition for the aryl substituent, such aryl groups may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, alkoxy substituted, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, acylamino, aminoacyloxy, oxyacylamino, aryl, aryloxy, carboxy, carboxylalkyl, cyano, halo, nitro, heteroaryl, trihalomethyl, thioalkoxy, substituted thioalkoxy, mono- and di- alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-cycloalkylamino, mono- and di-arylamino, mono- and di-heteroarylamino, amino mono- and di-heterocyclic and di-substituted, asymmetric amines having various substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. When substituted in this manner, such aryl groups are sometimes referred to herein as "substituted aryl". "Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above optionally including optionally substituted aryl groups as also defined above. "Carboxyalkyl" refers to the groups -C (O) O-alkenyl and -C (O) O-alkenyl substituted where alkenyl and substituted alkyl are as defined herein.

"Cycloalkyl" refers to cyclic alkyl groups of 3 to 20 carbon atoms having a cyclic ring, single or multiple fused rings (including aromatic rings fused to the cycloalkyl ring) which may be optionally substituted with 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl and the like, or multiple ring structures such as dibenzosuberane, adamantanyl and the like . "Cycloalkenyl" refers to cyclic alkenyl groups of 4 to 8 carbon atoms having an individual cyclic ring or multiple fused rings and at least one point of internal unsaturation which may optionally be substituted with 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like. "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.

"Heteroaryl" refers to an aromatic, monovalent group of 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Unless otherwise restricted by the definition for the heteroaryl substituent, such heteroaryl groups may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxyacyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, acylamino, aminoacyloxy, oxyacylamino, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl , trihalomethyl, thioalkoxy, substituted thioalkoxy, mono- and di-alkylamino, mono- and di (substituted alkyl) amino, mono- and di-cycloalkylamino, mono- and di-arylamino, mono- and di-heteroarylamino, amino mono- and di-heterocyclic and disubstituted, asymmetric amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and the like. The heteroaryl groups can have an individual ring (for example pyridyl, furyl, etc.) or multiple fused rings (for example indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl. When substituted in this manner, such heteroaryl groups are sometimes referred to herein as "substituted heteroaryl". "Heterocycle" or "heterocyclic" refers to a saturated or unsaturated, monovalent group having an individual ring or multiple fused rings, from 1 to 12 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen within the ring . Unless otherwise restricted by the definition for the heterocyclic substituent, such heterocyclic groups may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, substituted alkyl, alkoxy, substituted alkoxy , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amino, aminoacyl, acylamino, aminoacyloxy, oxyacylamino, aryl, aryloxy, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, trihalomethyl, thioalkoxy, substituted thioalkoxy, mono- and di-alkylamino , mono- and di (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, amino mono- and di-heterocyclic and disubstituted, asymmetric amines having different substituents selected from alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and the like. The heterocyclic groups may have an individual ring or multiple fused rings. Preferred heterocyclics include morpholino, piperidinyl and the like. Examples of heterocycles and heteroaryls include, but are not limited to, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, indazole, purine, quinolizine, isoquinoline, quinoline , phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3 , 4-tetrahydroisoquinoline, 4, 5, 6, 7-tetrahydrobenzo- [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. "Tiol" refers to the group -SH. "Thioalkoxy" refers to the group -S-alkyl. "Substituted thioalkoxy" refers to the group -S-substituted alkyl. "Thioaryloxy" refers to the aryl-S- group wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above. "Thioheteroaryloxy" refers to the heteroaryl-S- group wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above. In the compounds of the formula I, R and Rc can be fused to form a heteroaryl or heterocyclic ring with the phenyl ring. Fusing in this way results in a bicyclic, fused ring structure of the formula: where R is as as to dexfine above and A is the heteroaryl or heterocyclic group, fused as these terms are as defined above wherein the two atoms of the phenyl ring are included in the total atoms present in the heteroaryl or heterocyclic group. Examples of such fused ring systems include, for example, indol-5-yl, indole-6-yl, thionaphten-5-yl, thionaphten-6-yl, isothionephth-5-yl, isothionaphth-6-yl, indoxazin- 5-yl, indoxazin-6-yl, benzoxazol-5-yl, benzoxazol-6-yl, anthranil-5-yl, anthranil-6-yl, quinolin-6-yl, quinolin-7-yl, isoquinolin-6 ilo, isoquinolin-7-yl, cinolin-6-yl, cinolin-7-yl, quinazolin-6-yl, quinazolin-7-yl, benzofuran-5-yl, benzofuran-6-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, and the like. "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of Formula I, salts that are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium , magnesium, ammonium, tetraalkyl ammonium, and the like; and when the molecule contains a basic functionality, the salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of the Compound The compounds of the formula I above are easily prepared by means of several synthetic routes, divergent with the particular route selected relative to the ease of preparation of the compound, the commercial availability of the starting materials, and the like. In a synthetic method, the R1 group of the amino acid NH2CH (R2) COOH or an ester thereof is first introduced into the molecule. Then, conventional coupling of the first R1NHCH (R2) COOH or ester thereof with the amine of NH2CH (R3) C (O) Y yields the compounds of the formula I wherein X is -C (0) Y. Similarly, the conventional reduction of the group -C (0) Y leads to the -CH2OH groups and the like. The introduction of the group R1 into the amino acid NH2CH (R2) COOH or ester thereof can be carried out using various methods. For example, conventional coupling of a haloacetic acid with a primary amine forms an amino acid as shown in reaction (1) below: wherein R1 and R2 are as defined above and X 'is preferably a halo group such as chlorine or bromine. Alternatively, different halo groups such as triflate, mesylate, tosylate and the like may be employed. Additionally, suitable esters of 1_ can be employed in this reaction. Reaction (1) involves coupling a suitable haloacetic acid derivative with a primary aryl / heteroarylamine 2 under conditions that provide amino acid 3_. This reaction is described in, for example, Yates et al. 10 and proceeds by combining approximately stoichiometric equivalents of haloacetic acid 1 with the primary aryl / heteroarylamine 2 in a suitable inert diluent such as water, dimethyl sulfoxide (MDSO) and the like. The reaction employs an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to eliminate the acid generated by the reaction. The reaction is preferably conducted from about 25 ° C to about 100 ° C until the completion of the reaction which typically occurs within 1 to about 24 hours. This reaction is further described in U.S. Patent No. 3,598,859, which is incorporated herein by reference in its entirety. At the termination of the reaction, the N-aryl / N-heteroaryl 3 amino acid is recovered by conventional methods including precipitation, chromatography, filtration and the like. In reaction (1), each of the reactants (Haloacetic acid 1, primary aryl / heteroarylamine 2 and alcohol 3) are well known in the art with a plurality of each that is commercially available. In an alternative modality, - the R1 group can be coupled to an alanine ester (or other suitable amino acid ester) by conventional N-arylation. For example, a stoichiometric equivalent or slight excess of the amino acid ester can be dissolved in a suitable diluent such as DMSO and coupled with a haloaryl compound, X-R1 where X is a halo group such as fluoro, chloro or bromo and R1 is as is defined above. The reaction is conducted in the presence of an excess of a base such as sodium hydroxide to remove the acid generated by the reaction. The reaction typically proceeds from 15 ° C to about 250 ° C and is completed in about 1 to 24 hours. At the termination of the reaction, the N-aryl amino acid ester is recovered by conventional methods including chromatography, filtration and the like.

In yet another alternative embodiment, the esterified amino acids of formula I above can be prepared by reductive amination of a suitable 2-oxocarboxylic acid ester (such as a pyruvate ester) in the manner illustrated in Reaction (2) below : 6 wherein R1 and R2 are as defined above. In reaction (2), the approximately stoichiometric equivalents of a 2-oxocarboxylic acid ester 6 and arylamine 2 are combined in an inert diluent such as methanol, ethanol and the like and the reaction solution is treated under conditions which provide for the formation of imina (not shown). The formed imine is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H2 / palladium on carbon and the like to form the amino acid ester of N-aryl 5. In a particularly preferred embodiment, the reducing agent is H2 / pala'dio on carbon which is incorporated in the initial reaction medium which allows the reduction of imine in si tu in a container process to provide the amino acid ester of N-aryl 5. The reaction is conducted from preferably from about 20 ° C to about 80 ° C at a pressure of 1 to 10 atmospheres until the completion of the reaction which typically occurs within 1 to about 24 hours. At the termination of the reaction, the N-aryl 5 amino acid ester is recovered by conventional methods including chromatography, filtration and the like. Subsequent hydrolysis of the ester 5 leads to the corresponding carboxylic acid derivative. A further embodiment for preparing the N-aryl amino acids includes the nucleophilic, aromatic substitution of fluorobenzenes for the amine group of an amino acid. The carboxylic acid derivative is then coupled under conventional conditions well known in the art with a compound of the formula NH 2 CH (R 3) C (O) Y wherein R 3 and Y are as defined above. Such coupling leads to compounds of formula I. Subsequent modifications (eg, reduction) lead to additional compounds of formula I. When Y is an ester group, conventional transesterification techniques can be used to prepare a variety of different ester groups in the compounds of formula I. Numerous techniques are known in the ability to effect transesterification and each technique only replaces the ester group with a different ester group derived from the corresponding alcohol or thioalcohol and, in some cases, a catalyst such as titanium iso-propoxide (IV) is used to facilitate the completion of the reaction. In one technique, the alcohol or thioalcohol is first treated with sodium hydride in a suitable diluent such as toluene to form the corresponding alkoxide or sodium thioalkoxide which is then used to effect the transesterification. The efficiency of this technique makes it particularly useful with high boiling and / or expensive alcohols. In another transesterification technique, the ester to be transesterified is placed in a large excess of the alcohol or thioalcohol which carries out the transesterification. Then a catalytic amount of sodium hydride is added and the reaction proceeds rapidly under conventional conditions to provide the desired transesterified product. Because this protocol requires the use of a large excess of alcohol or thioalcohol, this procedure is particularly useful when alcohol is not expensive. Transesterification provides an easy means to provide a multiplicity of different ester substituents in the compounds of formula I above. In all cases, the alcohols and thioalcohols used to effect the transesterification are well known in the art with a significant number that is commercially available. Other methods for preparing the esters of this invention include, by way of example, first hydrolyze the ester to the free acid followed by 0-alkylation with, for example, a haloalkyl group in the presence of a base such as potassium carbonate. Still other methods for the preparation of compounds of the formula I are provided in the following examples. Compounds where X is -CR4R4Y 'are readily prepared by coupling, for example, an amino alcohol H2NCHR3CR4R4OH, to the carboxyl group of R1NHCHR2C (0) OH under normal coupling conditions well known in the peptide coupling chemistry that can be used well-known coupling reagents such as carbodiimides with or without the use of well-known additives such as N-hydroxysuccinimide, 1-hydroxybenzothiazole, etc. If necessary, the blocking groups well known in Y 'can be used to protect the group during coupling. Such blocking groups are particularly desirable when Y 'is an amino group. The reaction is conventionally conducted in an aprotic, inert diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. At the termination of the reaction, any blocking group in Y 'is selectively removed to provide the desired compound. When Y 'is -OH or -SH, the post-synthetic conversion of those groups to the corresponding esters (ie, -0C (0) R5), disulfides (ie, -SSR5) and -SSC (0) groups R5 be done using well-known chemistry. For example, the synthesis of the ester requires only the reaction with a suitable acid such as acetic acid (R7 = methyl), acid halide (for example acid chloride) or acid anhydride under suitable esterification conditions. When one of the R4 groups is hydrogen, the post-synthetic oxidation of the -CHR40H group leads to the ketone derivatives. Alternatively, such ketones can be prepared by coupling the appropriate amino ketone-HCl salt with the carboxyl terminal group of the amino acid. In these synthetic methods, the. starting materials may contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of diastereomers or R, S enantiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols may involve reversal of the chiral center during synthesis. Accordingly, unless otherwise indicated, the products of this invention are a - mixture of diastereomers (if two or more chiral centers are present) or R, S enantiomers (if only one chiral center is present). However, preferably when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. Alternatively, the chiral products are obtained by means of purification techniques which separate the diastereomers or enantiomers from a mixture of R, S to provide one or another stereoisomer. Such techniques are well known in the art.

Pharmaceutical Formulations When used as pharmaceutical formulations, the compounds of the formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In preparing the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. In this way, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatine capsules, suppositories, injectable solutions, sterile and packaged, sterile powders. In the preparation of a formulation, it may be necessary to grind the active compound to provide the appropriate particle size to combine with the other ingredients. If the active compound is substantially insoluble, it is ordinarily milled to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size is usually adjusted by grinding to provide a substantially uniform in the formulation, for example approximately 40 mesh. Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone , cellulose, sterile water, syrup and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl- and propylhydroxybenzoates, sweetening agents; and flavoring agents. The compositions of the invention can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art. The compositions are preferably formulated in a unit dose form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term "unit dose forms" refers to physically discrete units suitable as unit doses for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect., in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed in no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the remainder being carrier (s) ) pharmaceutically inert (s). ' The active compound is effective over a wide range of doses and is generally administered in a pharmaceutically effective amount. However, it will be understood that the amount of the compound currently administered will be determined by a physician or practitioner, in view of the pertinent circumstances, which include the condition to be treated, the route of administration selected, the current compound administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like. To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid formulation composition containing a homogeneous mixture of a compound of the present invention. When referring to such preformulation compositions as homogeneous, it is implied that the active ingredient is equally dispersed throughout the composition so that the composition can be easily subdivided into equally effective unit dose forms such as tablets, pills and capsules This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form that gives the long-acting advantage. For example, the tablet or pill may comprise an internal dose component and an external dose component, the latter being in the form of a wrapper over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and allows the inner component to pass intact in the duodenum or be delayed in the release. A variety of materials can be used for such enteric layers, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as lacquer or rubber, cetyl alcohol and cellulose acetate. Liquid forms in which the novel compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups or aqueous or oily suspensions, and emulsions flavored with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Compositions for inhalation or insufflation include solutions and suspensions in aqueous or organic, pharmaceutically acceptable solvents or mixtures thereof, and powders. The liquid or solid compositions may contain pharmaceutically acceptable excipients, suitable as described supra. Preferably, the compositions are administered by the oral or nasal respiratory route for the local or systemic effect. Preferred pharmaceutically acceptable solvent compositions can be nebulized by the use of inert gases. The nebulized solutions can be inhaled directly from a nebulization device or the nebulization device can be attached to a face mask chamber, or an intermittent, positive pressure breathing machine. The compositions in solution, suspension or powder can be administered preferentially orally or nasally, from devices which supply the formulation in an appropriate manner. The following formulation examples illustrate pharmaceutical compositions, representative of the present invention.

Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: Amount Ingredient (mg / capsule) Active ingredient 30.0 Starch 305.0 Magnesium stearate 5.0 The above ingredients are mixed and filled into hard gelatin capsules in amounts of 340 mg.

Formulation Example 2 A tablet formula is prepared using the ingredients below: Quantity Ingredient (mg / tablet) Active ingredient 25.0 Microcrystalline cellulose 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0 The components are mixed and compressed to form tablets, each weighing 240 mg.

Formulation Example 3 A formulation for dry powder inhaler is prepared containing the following components: Ingredient% by Weight Active ingredient 5 Lactose 95 The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhalation device.

Formulation Example 4 The tablets, each containing 30 mg of active ingredient, are prepared as follows: Quantity Ingredient (mg / tablet) Active ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as 10% solution in sterile water) 4.0 mg Carboxymethyl starch 4.5 mg sodium Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a US No. 20 mesh screen and all are mixed. The polyvinylpyrrolidone solution is mixed with the resulting powders, which are then passed through a 16 mesh US sieve. The granules thus produced are dried at 50 ° to 60 ° C and passed through a United States mesh screen 16. Sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a US No. 30 mesh screen, are then added to the granules which, after mixing, they are compressed into a tabletting machine to produce tablets each weighing 120 mg.

Formulation Example 5 The capsules, each containing 40 mg of medicament are made as follows: Amount Ingredient (mg / capsule) Active ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mq Total 150.0 mg The active ingredient, magnesium stearate and stearate are mixed, passed through a No. 20 mesh US sieve, and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 The suppositories, each containing 25 mg of active ingredient, are made as follows: Ingredient Quantity Active ingredient 25 mg Fatty acid glycerides 2,000 mg saturated for The active ingredient • passed through a US sieve No. 60 mesh and suspended in the saturated fatty acid glycerides previously melted using the minimum necessary heat. The mixture is then emptied into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 The suspensions, each containing 50 mg of medication per 5.0 mL of dose, are made as follows: Ingredient Quantity Active ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) ) 50.0 mg Sucrose 1.75 mg Sodium Benzoate 10.0 mg Flavor and Color cs Purified water for 5.0 mL The active ingredient, sucrose and xanthan gum are mixed, passed through an E.U. No. 10 mesh, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. Sodium benzoate, the taste and color are diluted with some water and added with agitation. Then enough water is added to produce. the volume required.

Formulation Example 8 Amount Ingredient (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, the starch and the magnesium stearate are mixed, passed through a sieve of E.U. No. 20 mesh, and filled into hard gelatin capsules in the amount of 425.0 mg.

Formulation Example 9 A subcutaneous formulation can be prepared as follows: Ingredient Quantity Active ingredient 5.0 mg Corn oil 1.0 mg Formulation Example 10 A topical formulation can be prepared as follows; Ingredient Quantity Active ingredient 1-10 g Emulsifying wax 30 g Liquid paraffin 20 g Soft, white paraffin for 100 g 'The soft, white paraffin is heated until it melts. The liquid paraffin and the emulsifying wax are incorporated and are stirred until they dissolve. The active ingredient is added and the stirring is continued until it disperses. The mixture is then cooled until it is solid. Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such patches can be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See for example, U.S. Patent No. 5,023,252, filed June 11, 1991, incorporated herein by reference. Such patches can be constructed for the continuous, pulsatile or on-demand supply of pharmaceutical agents. Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve the placement of a drug delivery catheter into the host ventricular system to avoid the blood-brain barrier. Such an implantable delivery system used for the transport of biological factors to anatomical, body-specific regions is described in U.S. Patent No. 5,011,472 which is incorporated herein by reference. Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide drug latency by converting hydrophilic drugs into lipid soluble drugs. Latency is generally achieved by blocking the hydroxy, carbonyl, sulfate and primary amine groups present in the drug to render the drug more soluble in lipids and docile for transport through the blood-brain barrier. Alternatively, the supply of hydrophilic drugs can be increased by the intra-arterial infusion of hyopertonic solutions which can transiently open the blood-brain barrier. Other formulations suitable for use in the present invention can be found in Remington Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

Utility The compounds and pharmaceutical compositions of the invention are useful in inhibiting the release of β-amyloid peptide and / or its synthesis, and, therefore, have utility in the treatment of Alzheimer's disease in mammals including humans. As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to increase the in vivo serum shelf life of the compound administered, the compounds can be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques can be used which provide a life span in serum, extended of the compounds.

A variety of methods are available for the preparation of liposomes, as described in, for example, Szoka et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference. incorporated herein by reference. The amount of compound administered to the patient will vary depending on what is being administered, the purpose of administration, such as prophylaxis or therapy, the condition of the patient, the manner of administration, and the like. In therapeutic applications, the compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest the further onset of the symptoms of the disease and its complications. An adequate amount to accomplish this is defined as "therapeutically effective dose". The amounts effective for this use will depend on the judgment of the attending clinician depending on factors such as the degree or severity of the AD in the patient, the age, weight and general condition of the patient, and the like. Preferably, for use as therapeutic substances, the compounds described herein are administered in doses ranging from about 0.1 to about 500 mg / kg / day.

In prophylactic applications, the compositions are administered to a patient at risk for the development of AD (determined for example by genetic selection or a family trait) in an amount sufficient to inhibit the onset of disease symptoms. An adequate amount to accomplish this is defined as "prophylactically effective dose". The effective amounts for this use will depend on the judgment of the attending clinician depending on factors such as age, weight and general condition of the patient, and the like. Preferably, for use as prophylactic substances, the compounds described herein are administered in dosages ranging from about 0.1 to about 500 mg / kg / day. As noted, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or they can be sterile filtered. When aqueous solutions are employed, they can be packaged for use as is, or lyophilized, the lyophilized preparation that is combined with an aqueous, sterile carrier prior to administration. The pH of the compound preparations will typically be between 3 and 11, more preferably 5 to 9 and much more preferably 7 and 8. It will be understood that the use of certain of the above excipients, carriers or stabilizers will result in Result the formulation of pharmaceutical salts. The following synthetic and biological examples are offered to illustrate this invention and should not be construed in any way as limiting the scope of this invention. Unless stated otherwise, all temperatures are in degrees Celsius'.

EXAMPLES In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its meaning generally accepted.

BOC tert-butoxycarbonyl db wide double bs singlet wide Cbz carbobenzyloxy c cubic centimeter CDI 1, 1 '-carbonyldiimidazole d double double d doublets DMF dimethylformamide DMSO dimethyl sulfoxide EDC 1- (3-dimethylaminopropyl) ethylcarbodiimide hydrochloride EDTA acid tetraacetic of ethylene diamine eq. equivalents ether diethyl ether g grams 10 L liter multiplet M max max mg mg 15 min. minutes mL milliliter mM millimolar mmol millimole N normal 20 ng nanogram nm nanometers OD optical density pg picograms pM picomolar 25 psi pounds per square inch q quartet quint. quintet rpm rotations per minute rt temperature environment singlet sept septeto t triplet THF tetrahydrofuran tic thin layer chromatography μg microgram μL microlitre UV ultraviolet w / v weight to volume Additionally, the term "Aldrich" indicates that the compound or reagent used in the following processes is commercially available from Aldrich Chemical Company, Inc., 1001 West St. Paul Avenue, Milwaukee, Wl 53233 USA; the term "Bachem" indicates that the compound or reagent is commercially available from Bachem Biosciences Inc., 3700 Horizon Drive, Renaissance at Gulph Mills, King of Prussia, PA 19406 USA; the term "Fluka" indicates that the compound or reagent is commercially available from Fluka Chemical Corp., 980 South 2nd Street, Ronkonkoma, NY 11779 USA; the term "Lancaster" indicates that the compound or reagent is commercially available from Lancaster Synthesis, Inc., P.O. Box 100, Windham; NH 03087 EUA; the term "Sigma" indicates that the compound or reagent is commercially available from Sigma, P.O. Box 14508, St. Louis, MO 63178 USA; and the term "Sennchem" indicates that the compound or reagent is commercially available from Senn Chemicals AG, P.O. Box 267, CH-9157 Dielsdorf, Switzerland. In the following examples, all temperatures are in degrees Celsius (unless otherwise indicated) and the following general procedures were used to prepare the compounds as indicated.

GENERAL PROCEDURE A Reductive Amination To a solution of arylamine in ethanol in a hydrogenation flask was added 1 equivalent of the 2-oxocarboxylic acid ester (eg, pyruvate ether), followed by 10% palladium on carbon (25 weight percent based on the arylamine). The reaction was hydrogenated at 1,404 kg / cm 2 (20 psi) of H2 on a Parr shaker until the complete reaction was indicated by tic (30 minutes to 16 hours). The reaction mixture was then filtered through a pad of Celite 545 (available from Aldrich Chemical Company, Inc.) and distilled solvent free in a rotary evaporator. The residue of the crude product was then further purified by chromatography.

GENERAL PROCEDURE B N-Heteroarylation of Alanine A solution of 1.1 equivalents of L-alanine and 2 equivalents of NaOH in DMSO was stirred at room temperature for 1 hour, then 1 equivalent of 2-chlorobenzotriazole was added. The mixture was heated at 100 ° C for 4 hours, then cooled to room temperature and emptied on ice. The pH of the resulting aqueous solution was adjusted to ~2, and the precipitated solid was removed by filtration. This solid was then dissolved in IN NaOH and the resulting solution was filtered through a pad of Celite 545. The pH of the filtrate was adjusted to ~2, and the white precipitate was filtered off and washed with water to give the product.

GENERAL PROCEDURE G Hydrolysis of Ester to Free Acid The hydrolysis of ester to free acid was conducted by conventional methods. Below are two examples of such conventional de-esterification methods. To a carboxylic ester compound (prepared, for example, by reductive amination by means of General Procedure A to provide the amino acid ester of N-aryl) in a 1: 1 mixture of CH3OH / H20, 2-5 equivalents of K2CO3. The mixture was heated at 50 ° C for 0.5 to 1.5 hours until the tic showed the complete reaction. The reaction was cooled to room temperature and the methanol was removed in a rotary evaporator. The remaining aqueous solution was adjusted to pH ~ 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried over MgSO4. The solution was distilled free of solvents in a rotary evaporator to give the product. The amino acid ester was dissolved in dioxane / water (4: 1) to which was added LiOH (~ 2 eq.) Which was dissolved in water such that the total solvent - after the addition was about 2: 1 dioxane: water. The reaction mixture was stirred until the reaction was complete and the dioxane was removed under reduced pressure. The residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted again with EtOAc, the combined organics were dried over Na2SO4 and the solvent was removed under reduced pressure after evaporation. filtration. The residue was purified by conventional methods (e.g., recrystallization). The following exemplifies this last example.

The methyl ester of 3-N02 phenylacetylanine 9.27 g (0.0348 mol) was dissolved in 60 mL of dioxane and 15 mL of H2O and LiOH (3.06 g, 0.0731 mol) was added, which was dissolved in 15 mL of H2O. After stirring for 4 hours, the dioxane was removed under reduced pressure and the residue was diluted with EtOAc, the layers were separated and the aqueous layer was acidified to pH 2. The aqueous layer was extracted again with EtOAc (4 X 100 mL ), the combined organic substances were dried over Na2SO and the solvent was removed under reduced pressure after filtration. The residue was recrystallized with EtOAc / isooctane which gave 7.5 g (85%). C11H12 2O5 requires C, 52.38 H, 4.80 N, 11.11. Analysis found C, 52.54 H 4.85 N, 11.08. [a] 23 = -29.9 @ 589 nm.

GENERAL PROCEDURE D First EDC Coupling Procedure To a 1: 1 mixture of the desired acid and amino / amide ester in CH2C12 at 0 ° C was added 1.5 equivalents of triethylamine, followed by 2.0 equivalents of hydroxybenzotriazole monohydrate, then 1.25 equivalents of ethyl-3- (3-dimethylamino) -propyl carbodiimide-HCl (EDC). The reaction was stirred overnight at room temperature, then transferred to a separatory funnel and washed with water, NaHC03 aqueous, saturated, 1N HCl, and saturated aqueous NaCl, and then dried over MgSO4. The solution was distilled solvent-free in a rotary evaporation to give the crude product.

GENERAL PROCEDURE E Second EDC Coupling Procedure The carboxylic acid was dissolved in methylene chloride. The amino acid / amide ester (1 eq.), N-methylmorpholine (5 eq.) And hydroxybenzotriazole monohydrate (1.2 eq.) Were added in sequence. A bath was applied with cooling to the round bottom flask until the solution reached 0 ° C. At that time, 1.2 eq. of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC). The solution was allowed to stir overnight and reach room temperature under nitrogen pressure. The reaction mixture was prepared by washing the organic phase with saturated aqueous sodium carbonate, 0.1M citric acid, and brine before drying with sodium sulfate. The solvents- were removed to give the crude product. The pure products were obtained by flash chromatography in an appropriate solvent.

GENERAL PROCEDURE F Removal Procedure of BOC and Ter-Butyl Ester The BOC- or tert-butyl ester compound was added to a 1: 1 mixture of CH2Cl2 and trifluoroacetic acid, and stirred until the tic indicated complete conversion, typically 2 hours. The solution was then distilled to dryness and the residue was taken up in ethyl acetate. For the compounds protected with BOC the solution was washed with dilute HCl. The aqueous phase was adjusted to a basic pH, then extracted with ethyl acetate. For the tert-butyl ester compounds the solution was washed with saturated aqueous NaHCO3. The aqueous phase was then adjusted to pH 2 and extracted with ethyl acetate. The organic phase for any case was then washed with saturated aqueous NaCl and dried over MgSO4. The solution was distilled solvent-free in a rotary evaporator to produce the product.

GENERAL PROCEDURE G N-Alkylation To a solution of 3-aminoquinoline in CH 2 Cl 2 was added 1.1 equivalents of triethylamine, followed by a solution of CH 2 Cl 2 of p-nitrobencenesulfonyl chloride (nosyl). The reaction was stirred at room temperature for 5 hours, then the di-nosylated aminoguiline was isolated by filtration and washed with ethyl acetate. This material was then added to a 1: 1 mixture of dioxane and IN NaOH and this solution was heated at 60 ° C for 4 hours, at which time all solids had dissolved. The reaction was cooled to room temperature, then the pH was adjusted to ~4. The mono-nosylated aminoquinoline, precipitated, was removed by filtration and washed with H20. Then a solution of this compound in THF was added to a suspension at -78 ° C of NaH in THF, then 2-ethyl bromopropionate was added. The reaction was heated to rt, then heated to reflux for 4 days. The crude reaction mixture was filtered free of solvents in a rotary evaporator, and the nosylated, alkylated aminoquinoline was obtained by chromatography. This product was then dissolved in DMF and 3 equivalents of K2CO3 were added, followed by 1.2 equivalents of thiophenol. The reaction was stirred overnight at room temperature. The reaction was then quenched with water and ether, and the organic phase was washed with aqueous, saturated NaHC03 and saturated aqueous NaCl, then dried over MgSO4. The solution was distilled free of solvents in a rotary evaporator to produce the crude product, which was then purified through chromatography.

GENERAL PROCEDURE H Ester / Amide Exchange To a solution of 3 equivalents of the desired amine in 1,2-dichloroethane was added 5.2 equivalents of trimethylaluminum where the addition was conducted under the surface of the solution via syringe. After stirring for 30 minutes at room temperature, a solution of the desired ester dissolved in 1,2-dichloroethane was added. The reaction was heated to reflux until the tic showed complete conversion, typically 3 hours. The reaction was then cooled to 0 ° C and cooled rapidly with 10% HCl (Note: the acid must be added slowly when some foam occurs during its addition). For those products not soluble in aqueous acid, the mixture was transferred to a separatory funnel and the layers separated. The aqueous phase was washed with ethyl acetate and the organic phases were washed with saturated aqueous NaCl, dried over MgSO, and concentrated under reduced pressure to leave the crude product. For the products soluble in aqueous acid, after cooling the reaction, the volume of the reaction was reduced to ~ l / 3 of the initial volume under reduced pressure. To the resulting solution was added 20% aqueous sodium potassium tartrate (Rochelle's salt) and ethyl acetate. The pH of the solution was adjusted to ~ 13, and aluminum salts were dissolved in the aqueous solution. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The combined organic solution was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure to leave the crude product.

GENERAL PROCEDURE I Reduction of Ester to Alcohol To a solution at 0 ° C of the ester started in Anhydrous THF was added 1.0 equivalent of Li.BH4 in THF.

The reaction was stirred at room temperature overnight, and then rapidly cooled with water. The THF was removed on a rotary evaporator and ethyl acetate was added, and the phases were separated. The organic phase was washed with saturated aqueous NaCl, dried over MgSO, and concentrated under reduced pressure to leave the product.

GENERAL PROCEDURE J Displacement of Triflate To a solution at 0 ° C of R- (+) - isobutyl lactate in CH2C12 1.1 equivalents of trifluoromethanesulfonic anhydride were added. After stirring at room temperature for 20 minutes, 1.1 equivalents of 2,6-lutidine were added and the stirring was continued for 10 minutes. This solution was then transferred to a flask containing 1 equivalent of arylamine and 1 equivalent of diisopropylethylamine in CH 2 Cl 2 or CH 3 NO 2 at 0 ° C. The reaction was kept overnight at room temperature, then distilled free of solvents in a rotary evaporator. The residue was dissolved in ethyl acetate, washed with 5% citric acid, followed by aqueous, saturated NaCl, and then the solution was solvent-free distilled in a rotary evaporator to give the crude product, which was then purified by the chromatography.

GENERAL PROCEDURE K Formation of Methyl Amino Acid This amino acid (amino acid or amino acid hydrochloride) was suspended in methanol and cooled to 0 ° C. HCl gas was bubbled through this solution for 5 minutes. The reaction was allowed to warm to room temperature, then stirred for 4 hours. The solvents were then removed to give the desired amino acid methyl ester hydrochloride. This product is usually used without further purification.

Example A Synthesis of N- (3,4-dichlorophenyl) -D, -alanine Using the procedure set forth in U.S. Patent No. 3,598,859, the disclosure of which is hereby incorporated by reference in its entirety, the N was prepared - (3,4-dichlorophenyl) -D, L-alanine. Specifically, water (approximately 0.06 mL per mL of isopropane) and 2-chloropropionic acid are added to a solution of 3,4-dichloroaniline (1 eguivalent) (Aldrich) in isopropanol (approximately 500 mL per mole of 3,4-dichloroaniline). (2 equivalents) (Aldrich). This mixture was heated to 40 ° C and sodium bicarbonate (0.25 equivalents) was added in successive portions before heating under reflux for 4-5 days. After cooling, the reaction mixture is poured into water and the unreacted 3,4-dichloroaniline is removed by filtration. The filtrate is acidified to pH 3-4 with concentrated hydrochloric acid and the resulting precipitated product is filtered, washed and dried to yield the title compound, m.p. = 148-149 ° C. Alternatively, following General Procedure .A above and using 3,4-dichloroaniline (Aldrich) and ethyl pyruvate (Aldrich), the N- (3,4-dichlorophenyl) -D, L-alanine ethyl ester was prepared as an oil . The reaction was monitored by tic silica gel (Rf = 0.4 in 25% EtOAc / Hexanes) and purification was by preparative plate chromatography (silica gel using 25% EtOAc / Hexanes as an eluent). The NMR data were as follows: rmn-xH (CDC13): d = 7.2 (d, ÍH); 6.7 (d, ÍH); 6.4 (dd, ÍH); 4.30 (broad s, ÍH); 4.2 (q, 2H); 4.1 (q, ÍH); 1.5 (d, 3H); 1.3 (t, 3H). rmn-13C (CDC13): d = 175; 146.7; 133; 131; 121; 114.9; 112.6; 72.0; 52.4; 28.3; 19.5. CnH? 3Cl2N02 (MW = 262.14); mass spectroscopy (MH +) 263.

Hydrolysis of this ester by means of, for example, General Procedure C provides the title compound.

Example B Synthesis of N- (3, 5-dichlorophenyl) -D, L-alanine Using the procedure set forth in U.S. Patent No. 3,598,859 (or Example A above), N- (3,5-dichlorophenyl) - D, L-alanine using the .3, 5-dichloroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).

EXAMPLE C Synthesis of N- (3, 5-difluorophenyl) -D, L-alanine Using the procedure set forth in U.S. Patent No. 3,598,859 (or Example A above), N- (3,5-difluorophenyl) - D, L-alanine using 3, 5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).

Example D Synthesis of L-Valine N, N-dimethyl amide To a stirred solution of 2.51 g (10 mmol) of Cbz-L-Valine (Bachem) in 20 mL of DMF was added 1.46 g (9 mmol) of CDI and The mixture was stirred for 50 min. To this mixture was added 6 mL (12 mmol) of dimethylamine (Aldrich) in 5 mL of THF and the reaction mixture was stirred for 18 hours. The mixture was taken up in 100 mL of ethyl acetate, washed with 10% HCl (3 x 40 mL), 10 L of brine, and 20% of potassium carbonate (2 x 50 mL), and dried over MgSO4. . The mixture was filtered and concentrated to yield the Cbz-L-valine N, N-dimethyl amide, which was hydrogenated under normal conditions with 10% Pd / C as the catalyst to remove the Cbz group and provide the title compound as an oil. The NMR data were as follows: rmn ^ H (CDC13): d = 3.47 (d, J = 5.4 Hz, 1H), 3.03 (s, 3H), 2.96 (s, 3H), 1.83 (m, 1H) , 1.60 (s, 2H), 0.95 (d, J - = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H). rmn-13C (CDCl 3): d = 175.1; 56.2, 37.0, 35.7, 32.0, 19.9, 16.8.

Example E Synthesis of L-Valine N, N-dimethyl amide The title compound was prepared following the procedure described in Example D above and using methylamine instead of dimethylamine. The title compound was an oil.

The NMR data were as follows: rmn ^ H (CDC13): d = 7.27 (broad s, 1H), 3.20 (d, J = • 3.8 Hz, ÍH), '2.79 (d, J = 5.0 Hz, 3H), 2.27 (m, 2H), 1.40 (s broad, 2H), 0.96 (d, J = 7.1 Hz, 3H), 0.79 (d, J = 6.8 Hz, 3H). rmn-13C (CDC13): d = 175.0, 60.1, 30.7, 25.6, 19.7, 15.9.

EXAMPLE F Synthesis of BOC amide-Norleucine To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine (Bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate and 50 mL of dichloromethane at 0 ° C. They added 3.45 g (1.2 mmoles) of EDC. The resulting mixture was stirred at 0 ° C for 1 hour and then ammonia gas was bubbled through the mixture for 10 minutes. The cooling bath was allowed to warm to room temperature and the mixture was stirred for 18 hours. The mixture was evaporated to dryness, triturated with 20% a2C3. The resulting solid was collected by filtration and washed with water to yield 2.69 g (11.7 mmol, 78%) of the title compound.

Example G Synthesis of N- [3,5-di (trifluoromethyl) phenyl] -L-alanine Step A: Following General Procedure J and using 3, 5-di (trifluoromethyl) aniline (Aldrich) and R- (+) isobutyl lactate (Aldrich), the isobutyl ester of N- [3,5-di (trifluoromethyl) phenyl] -L-alanine was prepared as an oil. The reaction was monitored by silica gel twitch (Rf = 0.38 in 10% EtOAc / hexanes). Purification was by thin layer chromatography of preparative plate using 10% EtOAc / hexanes as an eluent. The NMR data were as follows: rmn-1H (CDC13): d = 7.13 (s, ÍH), 6.91 (s, 2H), 4.97 (d, J = 8.24 Hz, ÍH), 4.18 (m, ÍH) , 3.93 (d, J = 6.59 Hz, 2H), 1.93 (sept, J = 6.71 Hz, 1H), 1.49 (d, J = 7.02 Hz, 3H), 0.89 (d, J = 6.59 Hz, 6H). rmn-13C (CDC13): d = 174.4, 147.9, 133.6, 133. 2, 132.7, 132.3, 129.4, 125.8, 122.2, 118.6, 112.81, 112. 76, 111.42, 111.37, 111.32, 111.27, 111.22, 72.2, 52.0, 32.1, 28.24, 28.17, 23.2, 19.5, 19.3, 19.2, 18.9, 14. 6. Ci5H? 7F6N02 (MW = 357.30); mass spectroscopy (MH +) 358.

Step B: The isobutyl ester of N- [3,5-di (trifluoromethyl) phenyl] -L-alanine was then hydrolyzed according to General Procedure C using lithium hydroxide in THF.

EXAMPLE H Synthesis of N- (3, 5-dimethoxy-nyl) -D, L-alanine The title compound was prepared according to the procedure described in US Patent No. 3,598,859 (or Example A above) using 3, 5 -methoxyaniline (Aldrich) and 2-chloropropionic acid (Aldrich).

EXAMPLE I Synthesis of N- (3,4-dichloro-enyl) glycine Using the. In the procedure set forth in U.S. Patent No. 3,598,859, N- (3,4-dichlorophenyl) glycine was prepared using 3,4-dichloroaniline (Aldrich) and 2-chloroacetic acid (Aldrich).

EXAMPLE J Synthesis of N- (3, 5-dichlorophenyl) -D, L-phenylglycine The 3, 5-dichloroaniline was heated to reflux (1 eq.) (Aldrich) and methyl a-bromophenylacetate (1 eq.) (Aldrich) in ethanol with N-methyl morpholine (Aldrich) for 3 days. After the normal preparation, the residue was crystallized from ethyl acetate / hexane / ether / water to give methyl N- (3,5-dichlorophenyl) -D, L-phenylglycine. The methyl ester was then hydrolyzed using lM NaOH / water in methanol to give the title compound.

EXAMPLE 1 Synthesis of N- [N- (3,4-dichloro-enyl) -D, L-alanyl] -L-valine methyl ester Following General Procedure D (without washing with IN HCl) and using ester hydrochloride L-valine methyl ester (Sigma) and N- (3,4-dichlorophenyl) alanine (from Example A above), the title compound was prepared. The NMR data were as follows: rmn-1H (CDC13): d = 7.20 (m, ÍH), 6.92-7.03 (m, ÍH), 6.69 (m, ÍH), 6.44 (m, ÍH), 4.50 (m, 1H), 4.19 (m, ÍH), 3.78 (m, ÍH), 3.71 (s, 1.5H), 3.65 (s, 1.5H), 2.12 (m, ÍH), 1.50 (d, J = 7.0 Hz, 3H), 0.80-0.92 (m , 4.5H), 0. 71 (d, J = 6.8 Hz, 1.5H). rmn-13C (CDC13): d = 173.4, 173.0, 172.2, 171.8, 146.0, 145.8, 132.9, 132.8, 130.7, 130.6, 121.7. 115.1, 114.8, 113.5, 113.1, 56.9, 56.6, 55.1, 54.8, 52.2, 52.1, 31.1, 31.0, 30.9, 19.6, 19.4, 17.7, 17.4.

EXAMPLE 2 Synthesis of N- [N- (3,4- dichlorophenyl) -D, L-alanyl] -L-valine N-iso-butyl amide Following N General Procedure H above and using N- [N-methyl ester] - (3,4-dichlorophenyl) -D, L-alanyl] -L-valine (from Example 1 above) and isobutylamine (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic (Rf = 0.3 in 10% methanol / dichloromethane). The data of the MRI? were as follows: rmn-xH (CDC13): d = 7.2 (d, ÍH), 7.0 (m, ÍH), 6.7 (m, ÍH), 6.4 (m, ÍH), 4.6 (m, ÍH), 4.1 ( m, 1H), 3.8 (m, 3H), 3.6 (s, 3H), 1.9 (m, 2H), 1.4 (d, 3H), 1.1 (m, 6H), 0.9 (m, 6H). rmn-13C (CDC13): d = 173.8, 173.4, 172.9, 146.6, 133.6, 133.4, 131.3, 122.5, 122.4, 115.8, 113.8, 56.9, 55.7, 38.2, 25.6, 20, 16, 12.1. C? 8H27? 302Cl2 (MW = 388.3); mass spectroscopy (MH +) 389.

Example 3 Synthesis of N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-threonine methyl ester Following General Procedure D (without washing with IN HCl) and using N- (3 , 4-dichlorophenyl) -D, L-alanine (from Example A above) and L-threonine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction product was purified by silica gel chromatography using 50% ethyl acetate / hexane. The NMR data were as follows: rmn-xH (CDC13): d = 1.06 (d, J = 6.4) and 1.17 (d, J = 6.3; 3H total in a ratio of 2: 1) 1.53 (d, J = 7, 3H), 2.31 (d, J = 5.6) and 2.58 (d, J = 4.7, total HI in a ratio of 2: 1), 3.68 (s) and 3.75 (s) (3H total in a ratio of 1: 2), 3.8-3.9 (m, ÍH), 4.15-4.25 (m, 1H), 4.3-4.45 (m, ÍH), 4.5-4.6 (m, ÍH), 6.4-6.5 (m, ÍH), 6.65-6.7 (m, 1H), 7.4-7.55 (m, 2H). rmn-13C (CDC13): d = 19.96, 20.23, 20.39, . 49, 53.23, 53.28, 55.35, 55.59, 57.5, 68.13, 68.21, 113. 72, 114.20, 115.42 115.60, 122.25, 122.35, 131.22, 131. 33, 133.41, 133.55, 146.47, 146.6, 171.63, 171.80, 174.69, 174.86. C? H? 8N20 Cl2 (MW = 349.22); mass spectroscopy (MH +) 349.

Example 4 Synthesis of N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-valine ethyl ester Following General Procedure D (without washing with IN HCl) and using N- (3, 4-dichlorophenyl) -D, L-alanine (from Example A above) and L-valine ethyl ester HCl, the title compound was prepared as an oil. The reaction product was purified by chromatography on silica gel using 35% ethyl acetate / hexane. The data of the MRI? were as follows: rmn-xH (CDCI3): d = 0.7-1.0 (superimposed group of d, J = 7, 6H), 1.19 and 1.27 (pair of t, J = 7, 3H), 1.5 (d, J = 7, 3H), 2.05-2.2 (m, ÍH), 3.7-3.9 (m, ÍH), 4.0-4.3 (m, 3H), 4.5-4.6 (m, 1H), 6.4-6.5 ( m, 1H), 6.5-6.6 (m, ÍH), 6.9-7.1 (M, ÍH), 7.2-7.3 (M, 1H). rmn-13C (CDC13): d = 14.65, 14.77, 17.96, 18. 25, 19.56, 20.06, 20.31, 31.77, 31.81, 55.50, 55.73, 57. 22, 57.46, 61.88, 61.94, 113.76, 114.01, 115.48, 115.76, 122.40, 122.46, 131.30, 131.33, 133.48, 133.61, 146. 41, 146.60, 171.86, 172.36, 173.54, 173.84. C 16 H 22 2 O 3 Cl 2 (MW = 361.27); mass spectroscopy (MH +) 361.

EXAMPLE 5 Synthesis of N- [N- (3, 4-dichlorophenyl) -D, L-alanyl] -L-valine, tert-butyl ester Following General Procedure D (without the washing of IN HCl) and using the N- (3, 4-dichlorophenyl) -D, L-alanine (from Example A above) and L-valine tert-butyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction product was purified by silica gel chromatography using 25% ethyl acetate / hexane. The data of the MRI? were as follows: rmn-1H (CDC13): d = 0.7-1.0 (superimposed group of d, J = 7, 6H), 1.36 (s) and 1.45 (s) (9H), 1.5-1.54 (2 d, J = 7, 3H), 2.0-2.2 (m, ÍH), 3.7-3.85 (m, ÍH), 4.1-4.2 (m, ÍH), 4.3-4.5 (m, ÍH), 6.4-6.5 (m, ÍH) , 6.7 (s, ÍH), 6.9-7.1 (m, ÍH), 7.15-7.3 (m, 1H). rmn-13C (CDC13): d = 17.84, 18.25, 19.50, . 06, 20.29, 28.42, 28.62, 31.96, 32.16, 55.45, 55.65, 57. 53, 57.92, 82.72, 113.75, 114.00, 115.43, 115.65, 122.26, 122.32, 131.29, 131.50, 146.46, 146.65, 170.88, 171. 48, 173.39, 173.65. C18H26? 2O3Cl2 (MW = 38-9.33); mass spectroscopy (MH +) 38 9.

EXAMPLE 6 Synthesis of N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-valine Amide Synthesis Following General Procedure D (without washing IN HCl) and using N- (3, 4-dichlorophenyl) -D, L-alanine (from Example A above) and L-valine amide hydrochloride (Sigma), the title compound was prepared as a solid having a melting point of 15β-158 ° C. . The reaction product was purified by silica gel chromatography using 90: 10: 1 CH2Cl2: MeOH:? H4OH. The data of the MRI? were as follows: rmn-1H (DMSO-d6): d = 0.6-0.9 (m, 6H), 1.2-1.4 (superimposed d, 3H), 1.8-2.0 (m, ÍH), 3.9-4.2 (m, 2H ), 6.3-6.4 (m, ÍH), 6.35-6.4 (m, ÍH), 6.7-6.8 (m, ÍH), 7.0- 7.15 (m, ÍH), 7.2-7.3 (m, 1H), 7.4 (s) broad, 1H), 7.8 (d, J = 10) and 8.0 (d, J = 10) (total HI in a ratio of 3: 2). rmn-13C (DMSO- 6): d = 17.8, 18.2, 19.00, 19.25, 19.6, 19.7, 31.16, 31.20, 51.9, 52.7, 57.11, 57. 4, 113.46, 113.58, 113.67, 113.85, 117.20, 117.45, 130. 64, 130.76, 131.53, 131.56, 148.25, 148.45, 173.06, 173. 11, 173.38, 173.51. C? 4H? 9? 302Cl2 (MW = 331); mass spectroscopy (MH +) 332.

Example 7 Synthesis of N- (3, 4-dichlorophenyl) -L-alanine N- (l-hydroxy-3-methyl-2-butyl) amide Following General Procedure D (without washing with IN HCl) and using the N- (3,4-dichlorophenyl) -D, L-alanine - (from Example A above) and valinol (Sigma), the title compound was prepared as an oil. The reaction product was purified by silica gel chromatography using 45:55 EtOAc / hexanes and 90: 10: 1 CH2C12: MeOH:? H4OH. The data of the MRI? were as follows: rmn-1H (DMSO-d6): d = 0.86 (d, J = 7, 3H), 0.91 (d, J = 7, 3H), 1.50 (d, J = 7, 3H), 1.8-2.0 (m, ÍH), 2. 6 (s broad, ÍH), 3.5-3.8 (m, 4H), 4.1 (s broad, ÍH), 6.45 (dd, J = 2.8, 8.7, ÍH), 6.7 (d, J = 2.8, ÍH), 6.8 (broad d, 1H), 7.2 (d, J = 5, ÍH). rmn-13C (DMSO- 6): d = 19.3, 20.1, 20.2, 29.5, 55.8, 57.4, 64.1, 113.7, 115.7, 122.4, 131.4, 133.5, 146.6, 174.6. C 14 H 20 2 2 O 2 Cl 2 (MW = 319.23); mass spectroscopy (MH +) 319.

EXAMPLE 8 Synthesis of N- [N- (3,4-dichloroenyl) -D, L-alanyl] -L-valine N, N-dimethyl amide Following General Procedure D and using N, N-dimethyl amide Valine (from Example D above) and? - (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 145-160 ° C). The data of the MRI? were as follows: rmn-1H (CDC13): d = 7.38 (m, ÍH), 7.14 (m, ÍH), 6.66 (m, 1H), 6.41 (m, ÍH), 4.78 (m, ÍH), 3.88 ( m, ÍH), 3.10 and 3.09 (s, s, 3H), 2.94 and 2.90 (s, s, 3H), 1.96 (m, 1H), 1.43 (m, 3H), 0.88 and 0.67 (m, 6H). rmn-13C (CDC13): d = 173.6, 173.1, 171.4, 171.3, 146.3, 146.0, 132.7, 132.6, 130.52, 130.46, 120.9, 120.8, 114.5, 113.4, 113.0, 54.25, 54.15, 53.4, 53.2, 37.4, 35.6 , 31.4, 31.3, 19.50, 19.46, 19.2, 17.5, 17.0. C 16 H 23 3 O 2 Cl 2 (MW = 360.29); mass spectroscopy (MH +) 360.

Example 9 Synthesis of N- [N- (3,4-dichlorophenyl) -D, -alanyl] -L-valine N-methyl amide Following General Procedure D and using N-methyl amide of L-valine (from Example E above) and? - (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 145-160 °). The NMR data were as follows: rmn-xH (DMSO-d6): d = 8.10 and 7.90 (m, 2H), 7.23 (, 1H),. 6.76 and 6.69 (m, ÍH), 6.57 (m, ÍH), 6.34 (m, ÍH), 3.90-4.14 (m, 2H), 2.57 and 2.56 (s, s, 3H), 1.88 (m, 1H), 1.27 '(m, 3H), 0.65-0.86 (m, 6H). rmn-13C (DMSO-d6): d = 173.1, 171.2, 171.1, 148.1, 147.9, 131.19, 131.16, 130.4, 130.2, 116.8, 113.5, 113.2, 113.1, 57.5, 57.3, 52.2, 51.5, 30.9., 30.8, 25.4, 19.2, 19.1, 18.8, 18.6, 18.2, 17.9. Ci5H2? 302 Cl2 (MW = 346.26); mass spectroscopy (MH +) 346.

EXAMPLE 10 Synthesis of N- [N- (3,4-dichlorophenyl) -D, -alanyl] -L-alanine methyl ester Following General Procedure D (without the washing of IN HCl) and using the methyl ester hydrochloride of L-alanine (Sigmaj and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as an oil.The reaction was monitored by tic (Rf = 0.24 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent The NMR data were as follows: rmn-1H (CDC13): d = 7.15 (m, 2H), 6.63 (dd, ÍH), 6.40 (m, ÍH), 4.50 (m, 2H), 3.75 (m, ÍH), 3.67 (s, 1.5H), 3.61 (s, 1.5H), 1.45 (d, 3H), 1.31 (m, 3H), rmn-13C (CDCI3): d = 173.5, 173.2, 173.0, 172.8, 146.3, 146.2, 132.6, 130.6, 130.5, 121.2, 114.9, 114.7, 113.3, 113.0 , 54.6, 54.5, 52.43, 52.39, 48.9, 47.8, 19.3, 19.1, 17.9, 17.8, Ci3H? 6N203Cl2 (MW = 319.19); masses (MH +) 319.

Example 11 Synthesis of N- [N- (3,4-dichlorophenyl) -L-alanyl] -L-leucine methyl ester Following General Procedure D and using L-leucine methyl ester hydrochloride (Sigma) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (m.p. = 120-132 ° C). The reaction was monitored by tic (Rf = 0.49 in 1: 1 EtOAc: Hexanes) and the product was purified by silica gel chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-xH (CDC13): d = 7.18 (d, 1H), 6.95 (broad d, IH), 6.69 (d, IH), 6.43 (dd, 1H), 4.58 (m , ÍH), 4.32 (d, ÍH), 3.75 (m, ÍH), 3.61 (s, 3H), 1.54 (m, 6H), 0.90 (m, 6H). rmn-13C (CDCI3): d = 174.1, 173.4, 146.8, 133.3, 131.2, 122.2 115.7, 114.1, 55.5, 52.9, 51.1, 41.6, 25.5, 23.4, 22.2, 20.0. C 16 H 22 2 O 3 Cl 2 (MW = 361.27); mass spectroscopy (MH +) 361.1.

Example 12 Synthesis of N- [N- (3, -dichlorophenyl) -L-alanyl] -L-phenylalanine methyl ester Following General Procedure D and using L-phenylalanine methyl ester hydrochloride (Sigma) and N- ( 3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 122-14.5 ° C). The reaction was monitored by tic (Rf = 0.47 in 1: 1 EtOAc: Hexanes) and the product was purified by silica gel chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-1H (CDC13): d = 7.21 (m, 4H), 7.05 (m, 2H), 6.91 (d, ÍH), 6.64 (d, ÍH), 6.38 (dd, ÍH), 4.84 (q, ÍH), 4.05 (broad s, 1H), 3.71 (m, 4H), 3.20 (m, 1H), 3.04 (m, ÍH), 1.37 (d, 3H). rmn-13C (CDC13): d = 173.6, 172.1, 146.5, 136.2, 133.4, 131.2, 129.7, 129.1, 127.7, 122.3, 115.6, 113.9, 55.4, 53.3, 53.0, 38.1, 19.9. C19H20 2O3Cl2 (MW = 395.29); mass spectroscopy (MH +) 395.

Example 13 Synthesis of N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-isoleucine methyl ester Following General Procedure D (without washing with IN HCl) and using ester hydrochloride of L-isoleucine (Sigma) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 95.5-101.5 ° C). The reaction was monitored by tic (Rf = 0.62 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-1H (CDC13): d = 7.21 (d, ÍH), 6.98 (m, 1H), 6.70 (m, ÍH), 6.45 (m, ÍH), 4.55 (m, ÍH), 4.11 (m, ÍH), 3.79 (m, 1H), 3.72 (s, 1.5H), 3.67 (s, 1.5H), 1.87 (m, 1H), 1.51 (d, 3H), 1.10 (m , 8H). rmn-13C (CDC13): d = 173.8, 173.4, 172.9, 172.4 ,. 146.6, 146.4, 133.6, 133.4, 131.30, 131.28, 122.5, 122.4, 115.8, 115.4, 114.1, 113.8, 56.9, 56.8, 55.7, 55.5, 52.8, 52.7, 38.3, 38.2, 25.5, 20., 20.0, 16.05, 16.03, 12.1, 12.0. C 16 H 22 2 O 3 Cl 2 (MW = 361.27); mass spectroscopy (MH +) 361.1.

Example 14 Synthesis of N * - [N- (3,4-dichlorophenyl) -L-alanyl] - (S) -2-aminopentanoic acid methyl ester Following General Procedure D (without washing with IN HCl) and using the L-norvaline methyl ester hydrochloride (Sennchem) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 150-153 ° C). The reaction was monitored by tic (Rf = -0.57 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-xH (CDC13): d = 7.21 (d, 1H), 6.95 (broad d, IH), 6.70 (d, IH), 6.47 (dd, IH), 4.57 (m , ÍH), 4.13 (broad d, ÍH), 3.78 (m, ÍH), 3.67 (s, 3H), 1.81 (m, ÍH), 1.62 (m, ÍH), 1.51 (d, 3H), 1.30 (m , 2H), 0.9 (t, 3H). rmn-13C (CDC13): d = 173.8, 173.0, 146.6, 133.4, 131.3, 122.4, 115.7, 114.1, 55.6, 52.9, 52.4, 34.8, 20.2, 19.2, 14.2. C 15 H 20 N 2 O 3 Cl 2 (MW = 347.24); mass spectroscopy (MH +) 347.

Example 15 Synthesis of W- [N- (3,4-dichlorophenyl) -L-alanyl] - (S) -2-aminohexanoic acid methyl ester Following General Procedure D (without washing with IN HCl) and using the hydrochloride of methyl ester of L-norleucine (Sigma) and N- (3,4-dichlorophenyl) -alanine (from Example A above), the title compound was prepared as a solid (mp = 163-165 ° C). The reaction was monitored by tic (Rf = 0.55 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. ) The NMR data were as follows: rmn-1 !! (CDC13): d = 7.18 (d, 1H, J = 8.7 Hz), 6. 99 (broad d, ÍH, J = 8.2 Hz), 6.69 (d, ÍH, J = 2.7 Hz), 6.45 (dd, ÍH, J = 8.7 Hz, J = 2.7 Hz), 4.53 (m, ÍH), 4.23 (d, 1H, J = 4.2 Hz), 3.77 (m, 1H), 3.66 (s, 3H), 1.83 (m, ÍH), 1.62 (, ÍH), 1.48 (d, 3H, J = 7.0 Hz), 1.27 (, 4H), 0.85 (t, 3H). rmn-13C (CDC13): d = 173.9, 173.1, 146.7, 133.4, 131.2, 122.3, 115.7, 114.1, 55.5, 52.9, 52.6, 32.4, 28.0, 22.8, 20.1, 14.4. Ci 6 H 22 N 203 Cl 2 (MW = 361.27); mass spectroscopy (MH +) 361.

Example 16 Synthesis of N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-tryptophan methyl ester Following General Procedure D (without washing with IN HCl) and using methyl ester hydrochloride of L-tryptophan (Sigma) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 54-66 ° C). The reaction was monitored by tic (Rf = 0.43 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-1H (CDC13): d = 8.15 (broad s, 0.5H), 7.98 (broad s, 0.5H), 7.51 (d, 0.5H), 7.12 (m, 6H) , 6.60 (d, 0.5H), 6.53 (dd, ÍH), 6.24 (m, ÍH), 4.88 (m, ÍH), 3.90 (d, 0.5H), 3.70 (, 4.5H), 3.32 (m, 1H ), 3.22 (m, ÍH), 1.40 (m, 3H). . rmn-13C (CDC13): d = 173.8, 173.6, 172.8, 172.4, 146.4, 146.3, 136.6, 133.3, 133.2, 131.2, 131.1, 128.2, 127.7, 123.3, 122.8, 122.05, 122.02, 120.3, 120.2, 119.0, 118.7 , 115.5, 115.4, 113.8, 113.3, 112.1, 111.9, 110.2, 109.9, 55.3, 55.1, 53.5, 53.1, 53.0, 52.9, 27.9, 27.7, 19.8, 19.6. C 21 H 21 N 3 O 3 Cl 2 (MW = 434.33); mass spectroscopy '(MH +) 434.

Example 17 Synthesis of N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-aspartic acid β- (f-butyl ester) α-methyl ester Following General Procedure D (without washing with HCl IN) and using the β-methyl ester (tert-butyl ester) α-methyl ester hydrochloride of L-aspartic acid (Bachem) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example To above), the title compound was prepared. The reaction was monitored by tic (Rf = 0.56 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-1H (CDC13): d = '7.52 (d, 0.5H), 7.42 (d, 0.5H), 7.13 (m, ÍH), 6.66 (d, 0.5H), 6.60 (d, 0.5H), 6.40 (m, 1H), 4.76 (m, ÍH), 4.40 (d, 0.5H), 4.31 (d, 0.5H), 3.75 (m, ÍH), 3.69 (s, 1.5 H), 3.62 (s, 1.5H), 2.88 (m, ÍH), 2.62 (, ÍH), 1.47 (m, 3H), 1.32 (s, 4.5H), 1.21 (s, 4.5H). rmn-13C (CDCI3): d = 174.0, 173.7, 171.7, 171.4, 170.30, 170.27, 146.7, 146.6, 133.4, 133.3, 131.2, 131.1, 122.0, 115.6, 115.1, 114.0, 113.4, 82.4, 55.4, 55.2, 53.24 , 53.19, 49.0, 48.7, 37.9, 37.8, 28.4, 28.2, 19.9, 19.8. C18H2 N205C12 (MW = 419.31); mass spectroscopy (MH +) 418.

EXAMPLE 18 Synthesis of 27- [N- (3,4-dichlorophenyl) -D, -alanyl] -L-aspartic acid a-methyl ester The tert-butyl ester group of the β- (tert-butyl ester) a- N- [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-aspartic acid methyl ester (from Example 17 above) was removed by means of General Procedure F to provide the title compound as a solid ( mp = 53.5-56 ° C). The reaction was monitored by tic (Rf = 0.54 in 1: 1 EtOAc: Hexanes). The data of the MRI? were as follows: rmn ^ H (CDC13): d = 7.59 (d, ÍH), 7.18 (m, ÍH), 6.79 (d, 0.5 H), 6.69 (d, 0.5H), 6.58 (m, 0.5H) , 6.47 (m, 0.5H), 4.84 (m, ÍH), 3.82 (m, ÍH), 3.73 (s, 1.5H), 3.68 (s, 1.5H), 3.04 (m, 1H), 2.79 (m, 0.5H), 2.73 (m, 0.5H), 1.49 (m, 3H). rmn- JC (CDCI3) 175.7, 175.6, 175.14 175. 07, 171.1, 171.0, 145.0, 144.6, 133.6, 133.5, 131.44, 131.40, 124.2, 123.4, 55.9, 55.4, 53.8, 53.7, 49.05, 49.00, 36.1, 19.2, 19.1. C? 4Hi6 205 Cl2 (MW-363.20); mass spectroscopy (MH +) 363.

Example 19 Synthesis of N- [N- (3,4-dichloro-enyl) -D, L-alanyl] -Ne-BOC-L-lysine Following the General Procedure D and using the N- (3, 4- dichlorophenyl) -D, L-alanine (from Example A above) and Ne-BOC-L-lysine methyl ester hydrochloride (Bachem), the title compound was prepared as an oil. The reaction was monitored by tic (Rf = 0.23 in 45% ethyl acetate / hexanes). The data of the MRI? were as follows: rmn-xH (CDCI3): d - = 7.22 (m, 4H), 6.63 (q, ÍH), 6.43 (m, ÍH), 4.72 (t, 0.5H), 4.63 (t, 0.5H) , 4.53 (m, ÍH), 4.42 (q, 1H), 3.78 (m, ÍH), 3.68 (s, 1.5H), 3.62 (d, 1.5H), 3.00 (m, 2H), 1.90-1.05 (m , 4H), 1.48 (d, 3H), 1.42 (s, 9H). rmn-13C (CDC13): d = 174.2, 173.9, 173.1, 172.8, 156.7, 156.6, 146.8, 146.7, 133.4, 133.3, 131.2, 131.1, 121.9,. 121.8, 115.5, 115.1, 114.0, 113.8, 79.7, 79.6, 79.6, 60.9, 55.2, 55.1, 53.0, 52.9, 52.4, 52.1, 40.6, 40.5, 32.3, 32.2, 30.1, 28.9, 22.8, 21.6, 19.9, 14.7.

Example 20 Synthesis of N- [27- (benzothiazol-6-yl) -D, L-alanyl] - (S) -2-aminohexanoic acid methyl ester Step A: Synthesis of 27- [27-benzothiazol-6-yl] ) -D, L-alanine A solution of 1 gram of 6-aminobenzothiazole (Lancaster) in 60 mL of dichloromethane was treated with 0.63 grams of pyridine and then 2.1 grams of trifluoroacetic acid anhydride at room temperature. The reaction was stirred for 3 hours, during which time the initially hot reaction mixture was cooled to room temperature. The mixture was heated with an aqueous solution of 5% citric acid, dried with 'MgSO4 and the solvents were removed to provide a quantitative yield of trifluoroacetamide of 6- aminobenzotriazole as a cream colored solid which was used immediately in the next reaction.

A 300 mg portion of 6-aminobenzotriazole trifluoroacetamide was dissolved in 35 L of THF and added to 1.2 eq. of KH at room temperature. The solution was refluxed for 5 hours, cooled and an 18-crown-6 crystal (Aldrich) was added together with 331 mg of ethyl 2-bromopropionate (Aldrich) and the resulting mixture was heated to reflux for 36 hours. . The reaction mixture was cooled, the solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic substances were washed with water. The pH of the aqueous layer was adjusted to pH 5 and extracted with ethyl acetate. The organic substances were combined, dried with MgSO4 and the solvents were removed. The crude material was purified by tic using dichloromethane / methanol (94: 4) to give the ethyl ester of N- (benzothiazol-6-yl) -D, L-alanine (Rf = 0.5). This material was treated with methanol and 5 eg. of potassium carbonate to reflux, and then cooled and the solvents were removed. The residue was taken up in water and ethyl acetate. The aqueous layer was adjusted to pH 2 and extracted with ethyl acetate. The ethyl acetate extracts were dried and the solvents were removed to give N- (benzothiazol-6-yl) -D, L-alanine.

Step B: Synthesis of 27- [27-benzothiazol-6-yl] -D, L-alanyl] - (S) -2-aminohexanoic acid methyl ester Following General Procedure D (using DMF as the reaction solvent, acetate of ethyl for extraction and without washing with HCl IN) and using the methyl ester hydrochloride of L-norleucine (Sigma) and N- (benzothiazol-6-yl) -D, L-alanine (from Step A above), the title compound was prepared. The reaction was monitored by tic (Rf = 0.28 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-1 !! (CDC13): d = 8.74 (s, ÍH), 7.91 (s, ÍH, J = 8.8 Hz), 7.15 (m, ÍH), 7.06 (d, 0.5H, J = 2.3 Hz), 7.00 (d, 0.5H, J = 2.3 Hz), 6.87 (m, 1H), 4.58 (m, ÍH), 4.20 (s broad, 2H), 3.87 (m, ÍH), 3.70 (s, 1.5H), 3.59 (s, 1.5H), 1.30 (m, 10H), 0.84 (t, 1.5H, J = 6.9 Hz), 0.60 (t, 1.5H), J = 6.9 Hz). rmn-13C (CDC13): d = 174.3, 174.0, 173.4, 173.0. 151.1, 151.0, 147.2, 145.5, 145.3, 136.2, 136.1, 124.4, 124.2, 116.1, 115.9, 104.6, 103.9, 56.2, 55.69, 53.0, 52.9, 52.5, 52.2, 32.43, 32.36, 28.0, 27.7, 22.8, 22.6, 20.3, 20.1, 14.4, 14.2.

C17H23N3O3S2 (MW = 349.46); mass spectroscopy (MH +) 350.

Example 21 Synthesis of methyl ester of 27- [27- (3,4-dichlorophenyl) -D, -alanyl] -L-lysine Following General Procedure F and using N- [N- (3, -dichlorophenyl) methyl ester ) -D, L-alanyl] -? E-BOC-L-lysine (from Example 19 above), the title compound was prepared as an oil. The reaction product was purified by silica gel chromatography using 89: 10: 1 of CH2Cl2: MeOH:? H4OH. The data of the MRI? were as follows: rmn-xH (CDC13 - 2 diastereomers): d = 7.21 (d, ÍH), 7.09 (broad day, 1H), 6.68 (q, 1H), 6.46 (m, 1H), 4.56 (, ÍH), 4.22 (s, broad), 3.78 (m, ÍH), 3.70 (s, 1.5H), 3.67 (s, 1.5H), 2.66 (t, ÍH), 2.54 (t, ÍH), 1.80 (m, ÍH), 1.62 (m, ÍH), 1.51 (d, 1.5H), 1.50 ( d, 1.5H), 1.32 (m, 2H), 1.11 (m, ÍH). rmn-13C (CDC13 - 2 diastereomers): d = 174.8, 174.3, 173.1, 172.8, 171.8, 146.9, 146.7, 133.3, 133.1, 131.2, 131.1, 121.7, 121.5, 115.2, 115.1, 113.9, 113.8, 60.9, 55.0, 54.9, 53.1, 53.0, 52.5, 52.3, 32.d, 32.09, 32.05, 31.8, 23.1, 22.9, 21.6, 19.9, 19.8 and 14.7.

C? 6H23 3? 3Cl2 (MW = 376.28) EXAMPLE 22 Synthesis of methyl ester of 27- [27- (3,4-dichlorophenyl) -D, -alanyl] -L-tyrosine Following General Procedure D and using the methyl ester of L-tyrosine (Sigma) and N- ( 3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers on alanine. The reaction was monitored by tic (Rf = 0.29 in 10% MeOH / CH 2 Cl 2) and the purification was by flash chromatography (10% methanol / methylene chloride). The NMR data were as follows: rmn-1H (CDC13): d = 7.22 - 7.50 (m, 7H), 6.36 (dd, 0.5H), 6.28 (dd, 0.5H), 4.83 (m, 1H), 4.04 (dd, ÍH), 3.73 (s, 1.5H), 3.70 (m, ÍH), 3.68 (s, 1.5H), 3.14 (dd, 0.5H), 2.97 (m, 1.5H), 1.43 (d, 1.5H), 1.35 (d, 1.5H). rmn-13C (CDC13): d = 174.20, 174.08, 172.75, 172.26, 156.10, 155.99, 146.45, 146.32, 133.50, 133.38, 131.39, 131.26, 130.81, 130.67, 127.43, 127.00, 122.41, 122.22, 116.15, 116.12, 115.68 , 115.39, 113.94, 113.46, 55.47, 55.08, 53.54, 53.18, 37.62, 37.44, 19.91, 19.87.

Ci9H2o 204Cl2 (MW = 411.28) EXAMPLE 23 Synthesis of 27- [27- (3,5-dichlorophenyl) -D, L-alanyl] -L-alanine methyl ester Following General Procedure D and using N- (3, 5-dichlorophenyl) -D, L -alanine (from Example B above) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared as an oil. The reaction product was purified by silica gel chromatography using 50% ethyl acetate / hexane. The NMR data were as follows: rmn-1H (CDCI3): d = 1.3-1.55 (three sets of doublets in 1.34, 1.39 and 1.48, all J = 7, total 6H), 3.7-3.9 (m with singlet in 3.67 and 3.72, 4H), 4.3-4.4 (m, ÍH), 4.5-4.65 (m, ÍH), 6.4-6.6 (m, 2H), 6.73 (s, 1H), 6.95-7.1 (m, ÍH). rmn-13C (CDC13): d = 15.52, 15.59, 16.75, 16.87, 45.29, 45.39, 50.02, 51.89, 51.99, 108.9, 109.2, 109.5, 116.14, 116.19, 132.96, 133.96, 133.05, 145.67, 145.76, 170.13, 170.32 170.40, 170.63. Ci3H? 6N203Cl2 (MW = 319.19); mass spectroscopy (MH +) 319.

Example 24 Synthesis of N- [27- (3,5-dichlorophenyl) -L-alanyl] - (S) -2-aminopentanoic acid methyl ester Following General Procedure D and using N- (3,5-dichlorophenyl) -D, L-alanine (from Example B above). and L-norvaline methyl ester hydrochloride (Sennchem), the title compound was prepared. The reaction product was purified by silica gel chromatography using 50% ethyl acetate / hexane. The NMR data were as follows: rmn-1H (CDC13): d = 0.92 (t, J = 7, 3H), 1.2- 1.4 (m, 2H), 1.50 (d, J = 7, 3H), 1.5 -1.7 (m, 1H), 1.75- 1.9 (m, ÍH), 3.69 (s, 3H), 3.75-3.9 (m, ÍH), 4.2 (s broad, ÍH), 4.5-4.65 (m, ÍH), 6.5 (broad s, 2H), 6.73 (s, 1H), 6.85 (s broad, ÍH). rmn-13C (CDCl 3): d = 14.2, 19.25, 20.13, 34.8, 52.-4, 53.0, 55.2, 112.7, 119.5, 136.1, 148.7, 173.0, 173.5. C 4 H 2 O 203 Cl 2 (MW = 347.24); mass spectroscopy (MH +) 346.

Example 25 Synthesis of 27- [27- (3,5-dichlorophenyl) -L-alanyl] -L-phenylalanine methyl ester Following General Procedure D and using N- (3, 5-dichlorophenyl) -D, L-alanine and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction product was purified by silica gel chromatography using 50% ethyl acetate / hexane. The NMR data were as follows: .rmn ^ H (CDC13): d = 1.40 (d, J = 7, 3H), 3.10 (dd, J = 7.14, ÍH), 3.23 (dd, J = 5 , 14, ÍH), 3.74 (s, 3H), 3.75-3.9 (m, ÍH), 4.0 (s broad, ÍH), 4.8-4.95 (m, ÍH), 6.45 (s broad, 2H), 6.73 (s) , 2H), 7.0-7.2 (m, 2H), 7.2-7.3 (m, 5H). rmn-13C (CDCI3): d = 19.4, 37.5, 52.4, 52.7, 54.5, 112.0, 118.9, 127.1, 128.5, 129.1, 135.5, 135.6, 148.0, 171.4, 172.6. C? 9H2oN203Cl2 (MW = 395.29); e spectros copy of more as (MH +) 394.

EXAMPLE 26 Synthesis of β- (methyl ester) α-methyl acid ester 27- [27- (3, 4-dichlorophenyl) -D, L-alanyl] -L-aspartic Following General Procedure D (without washing with IN HCl) and using L-aspartic acid (methyl ester) α-methyl ester (Sigma) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp = 113.5-118 ° C). The reaction was monitored by tic (Rf = 0.29 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as the eluent. The NMR data were as follows: rmn-1H (CDC13): d = 7.47 (broad d, ÍH), 7.20 (m, ÍH), 6.69 (d, 0.5H), 6.60 (d, 0.5H), 6.44 (m, ÍH), 4.83 (, ÍH), 4.25 (s broad, 0.5H), 4.18 (s broad, 0.5H), 3.79 (m, ÍH), 3.72 (s, 1.5H), 3.67 (s, 1.5 H), 3.65 (s, 1.5H), 3.48 (s, 1.5H), 3.00 (m, ÍH), 2.79 (m, ÍH), 1.50 (, 3H). rmn-13C (CDCI3): d = 174.0, 173.6, 172.0, 171. 7, 171.4, 171.3, 146.6, 146.4, 133.43, 133.37, 131.22, 131.20, 122.2, 122.0, 115.5, 115.0, 114.1, 113.6, 55.4, 55.2, 53.46, 53.44, 52.7, 52.5, 48.8, 48.7, 36.4, 36.3, 19.9, 19.7. C? 5H? 8N2? 5Cl2 (MW = 377.23); mass spectroscopy (MH +) 377.

Example 27 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (27'-1-benzyl) -L-histidine methyl ester Following General Procedure D (without washing with HCl IN) and using the methyl ester hydrochloride of 1-benzyl-L-histidine (Sigma) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (pf = 49-51 ° C). The reaction was monitored by tic (Rf = 0. 21 in 5% methanol / methylene chloride) and the product was purified by flash chromatography using 5% methanol: methylene chloride as the eluent. The NMR data were as follows: rmn-1H (CDC13): d = 8.22 (d, 0.5H), 7.88 (d, 0. 5H), 7.29 (m, 3H), 7.08 (m, 4H), 6.65 (d, 0.5H), 6.44 (m, 2.5H), 4.90 (s, 1H), 4.86 (s, ÍH), 4.62 (m, ÍH), 4.47 (m, ÍH), 3.72 (m, ÍH), 3.61 (s, 1.5H), 3.47 (s, 1. 5H), 2.95 (m, '2H), 1.42 (d, 3H). rmn-13C (CDC1): d = 174.0, 173.9, 172.4, 172.0, 146.9, 138.1, 137.9, 137.6, 136.7, 136.5, 133.1, 133.0, 131.0, 130.9, 129.6, 129.5, 128.84, 128.79, 127.74, 127.71, 121.1 , 121.0, 117.3, 115.3, 115.1, 113.9, 113.6, 54.9, 54.8, 53.2, 52.9, 52.8, 52.7, 51.3, 51.2, 30.2, 29.8, 19.8. C 23 H 24 403 Cl 2 (MW = 475.38); mass spectroscopy (MH +) 475.

EXAMPLE 28 Synthesis of 27- [27- (3, 4-dichlorophenyl) -D, L-alanyl] -L-glutamic acid β- (tert-butyl ester) α-methyl ester Following General Procedure D (without the washed with IN HCl) and using ß- (tert-butyl ester) α-methyl ester hydrochloride of L-glutamic acid (Bachem) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example To above), the title compound was prepared as an oil. The reaction was monitored by tic (Rf = 0.52 and 0.59 in 1: 1 EtOAc: Hexanes) and the product was purified by flash chromatography using 1: 1 EtOAc: Hexanes as an eluent. The NMR data were as follows: rmn-xH (CDC13): d = 7.25 (m, 2H), 6.69 (m, ÍH), 6. 45 (m, ÍH), 4.54 (m, ÍH), 3.78 (m, ÍH), 3.70 (s, 1.5H), 3.65 (s, 1.5H), 2.10 (m, 4H), 1.49 (d, 3H) , 1.40 (s, 9H). rmn-13C (CDC13): d = 174.2, 173.9, 172.8, 172.7, 172.5, 172.3, 146.6, 146.5, 133.5, 133.3, 131.3, 131. 2, 122.16, 122.14, 115.7, 115.4, 114.0, 113.6, 81.6, 81. 5, 55.4, 55.2, 53.1, 53.0, 52.3, 51.9, 32.0, 31.7, 28. 6, 27.6, 27.3, 20.0, 19.8. C 19 H 26 N 2 O 5 Cl 2 (MW = 433.34); mass spectroscopy (MH +) 432.

Example 29 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] -L-glutamic acid a-methyl ester The tert-butyl ester group of the β- ester (tert-Joutyl ester) N- [N- (3,4-dichlorophenyl) alanyl] glutamic acid methylic acid (from Example 28 above), was removed by means of General Procedure F (washing with αHC03 was omitted and the product recovered with the ethyl acetate) to provide the title compound as a solid (mp = 42-45 °). The reaction was monitored by tic (Rf = 0.42 and 0.50 in 10% methanol / methylene chloride). The data of the MRI? were as follows: rmn-xH (CDC13): d = 7.57 (s broad, ÍH), 7.25 (d, ÍH), 6.75 (d, ÍH), 6.51 (m, 1H), 4.67 (m, ÍH), 3.91 (m, ÍH), 3.76 (s, 1.5H), 3.69 (s, 1.5H), 2.50-2.15 (m, 3H), 2.10-1.85 (m, ÍH), 1.51 (s broad, 3H). rmn-13C (CDCI3): d = 177.98, 177.73, 175.17, 174. 94, 172.64, 172.26, 146.60, 146.45, 133.52, 133.33, 131.41, 131.27, 122.32, 122.28, 115.68, 155.47, 113.98, 113. 59, 55.37, 55.17, 53.35, 53.29, 52.20, 51.85, 30.68, . 26, 27.29, 27.18, 19.86, 19.77. C15H? 8? 2? 5Cl2 (MW = 377.23).

EXAMPLE 30 Synthesis of amide of 27- [27- (3,4-dichlorophenyl) -L-alanyl] -L-leucine Following General Procedure D and using L-leucinamide hydrochloride (Sigma) and N- (3, 4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared. This compound was then purified by column chromatography, eluting first with 1: 1 EtOAc / hexane, then with 5% MeOH in methylene chloride. The NMR data were as follows: rmn ^ H (CDC13): d = 7.32 (d, 8.6, ÍH), 7.17 (d, 8.7, ÍH), 6.66 (d, 2.7, ÍH), 6.54 (s, 1H ), 6.41 (dd, 2.7, 8.7, ÍH), 6.13 (s, ÍH), 4.48 (m, ÍH), 4.33 (d, 5.3, ÍH), 3.83 (quintet, 6.9, ÍH), 1.58 (m, 3H ), 1.44 (d, 7.0, 3H), 0.89 (d, 6.0, 3H), 0.85 (d, 5.9, 3H). rmn- C (CDC13) 174.5, 173.9, 146.0, 132. 8, 130.7, 121.5, 114.7, 113.3, 54.3, 51.5, 40.8, 24.8, 22.9, 21.7, 19.2. C? 5H2? N302Cl2 (MW = 346.26); mass spectroscopy (MH +) 346.

Example 31 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (3,5-diiodo) -L-tyrosine methyl ester Following General Procedure D and using methyl ester hydrochloride of 3,5-diiodo-L-tyrosine (Bachem) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a mixture of stereoisomers on alanine. The reaction was monitored by the tick (Rf - 0.29 in 10% MeOH / CH2Cl2) and the purification was by flash chromatography (10% methanol / methylene chloride). The NMR data were as follows: rmn-1H (CDC13 - partially pure diastereomer A): d = 7.37 (s, 2H), 7.19 (d, ÍH), 6.99 (broad d, ÍH), 6.65 (d, ÍH), 6.40 (m, ÍH), 5.78 (s, ÍH), 4.73 (q, 1H), 3.72 (m, ÍH), 0.70 (s, 3H). rmn-13C (CDC13 - two diastereomers): d = 173. 86, 171.87, 171.41, 171.37, 170.90, 153.48, 150.74, 146.37, 146.30, 141.01, 140.09, 138.39, 133.50, 133.45, 132.14, 131.62, 131.34, 131.28, 122.80, 122.62, 121.82 115.89, 115.78, 115.72, 115.47 , 114.54, 113.79, 113.21, 82.92, 77.08, 61.01, 55.69, 53.32, 53.28, 53.18, 53.14, 52.97, 52.90, 52.76, 36.37, 36.15, 21.67, 20.20, 20.11, 19.76, 14.79. C? 9H18N20 Cl212 (MW = 663.08). mass spectroscopy (MH +) 663.

EXAMPLE 32 Synthesis of 27- [N- (3,4-dichlorophenyl) -D, L-alanyl] - (3-iodo) -L-tyrosine methyl ester Following General Procedure D and using methyl ester hydrochloride 3 -yodo-L-tyrosine (prepared following General Procedure K and using 3-iodo-L-tyrosine (Aldrich)) and N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above), prepared the title compound as a mixture of stereoisomers on alanine. The reaction was monitored by tic (Rf = 0.29 in 10% MeOH / CH 2 Cl 2) and the purification was by flash chromatography (10% methanol / methylene chloride). The NMR data were as follows: rmn-1H (CDC13): d = 7.37-7.20 (m, 3H), 6.97 -6.60 (m, 3H), 6.42 (dd, 1.5H), 6.32 (dd, 1.5H ), 5.52 (s broad, 0.5H), 5.43 (broad s, 0.5H), 4.80 (m, ÍH), 3.94 (dd, ÍH), 3.73 (s, 1.5H), 3.70 (s, 1.5H), 3.12 (dd, 0.5H), 2.94 (m, 1.5H), 1.48 (d, 1.5H), 1.43 (d, 1.5H). rmn-13C (CDC13): d = 173.56, 171.80, 171033, 154.52, 154.47, 145.69, 139.15, 138.74, 132.88, 132.71, 130.83, 130.61, 130.40, 130.26, 129.14, 128.81, 121.76, 121.73, 115.04, 114.97, 114.86 , 113.20, 112.71, 84.96, 84.68, 54.85, 54.65, 52.78, 52.60, 52.57, 52.51, 36.29, 36.08, 19.40, 19.27. C19H3.9 2O.1Cl2I '(MW = 537.18); mass spectroscopy (MH +) 538.

Example 33 Following the General Procedures and Examples described herein, the following compound could be prepared: N- [N- (4-chlorophenyl) -D, L-alanyl] -L-phenylalanine methyl ester Example 34 Synthesis of 27- [27- (3,4-dichlorophenyl) glycyl] - (S) -2-aminopentanoic acid methyl ester Following General Procedure D and using? - (3,4-dichlorophenyl) glycine (from Example I above) and L-norvaline methyl ester hydrochloride (Sennchem), the title compound was prepared. The reaction was monitored by tic (Rf = 0.32 in 50% ethyl acetate / hexanes) and the purification was by chromatography with silica gel using ethyl acetate / hexanes as the eluent. The data of the MRI? they were as follows-: rmn-aH. (CDC13): d = 7.21 (d, J = 8.7, ÍH), 6.94 (d, J = 7.8, 1H), 6.68 (d, J = 2.6, ÍH), 6.4 (m, 1H), 4.6 (m, 2H), 3.79 (d, J = 2.6, 2H), 3.71 (s, 3H), 1.7 (m, 2H), 1.2 (m, 2H), 0.88 (t, J = 7.3, 7.3, 3H) '. rmn-13C (CDC13): d = 173.3, 170.2, 147.2, 133.6, 131.3 ,. 122.2, 115.0, 113.6, 53.0, 52.3, 48.8, 34.8, 19.2, 14.1. C? H? 8 03Cl2 (MW = 333.22); mass spectroscopy (MH +) 334.

EXAMPLE 35 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] -NG- (hexanoyl) -L-lysine methyl ester Following the Procedure 'General D and using the N-methyl ester [N- (3,4-dichlorophenyl) -D, L-alanyl] -L-lysine (from Example 21 above) and hexanoic acid (Aldrich), the title compound was prepared.

The -reaction was monitored by tic (Rf = 0.38 in 60% CH2C12 / 10% hexanes / 27% EtOAc / 3% MeOH) and the purification was by flash chromatography using 60% CH2CH2 / 10% hexanes / 27% EtOAc / 3% MeOH as the eluent. The NMR data were as follows: rmn-xH (CDC13): d = 7.70 (d), 7.25 (m), 7.15 (m), 6.68 (m), 6.42 (m), 5.95 (s broad), 5.79 (broad), 4.70 (broad), 4.50 (m), 3.80 (m), 3.78 (s), 3.72 (s), 3.45 (), 3.20 (ra), 3.05 (m), 2.12 (m), 1.98 (m), 1.80 (m), 1.60 (m), 1.45 (m), 1.30 (m), 1.10 (m). rmn-13C (CDC13): d = 175.6, 174.4, 174.0, 173.9, 173.7, 173.1, 156.6, 146.9, 146.8, 133.5, 133.2, 131.2, 131.1, 121.7, 115.4, 115.23, 115.1, 114.0, 113.9, 79.6, 55.1 , 54.9, 54.8, 53.0, 52.9, 52.4, 52.0, 42.6, 40.9, 39.4, 37.1, 32.1, 31.7, 30.3, 29.4, 28.9, 28.5, 26.9, 25.9, 25.9, 23.0, 19.9, 19.7. C22H33 30 C12 (MW = 474.43); mass spectroscopy (MH +) = NA.

EXAMPLE 36 Synthesis of Amide of 27- [27- (3,4-dichloro-enyl) -D, L-alanyl] -L-phenylalanine Following General Procedure D and using the phenylalanine amide (Bachem) and N- (3, 4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a solid (mp 177-179 ° C). This compound was then purified by trituration with chloroform. The NMR data were as follows: rmn ^ H (DMSO-d6): d = 8.0-8.2 (d, ÍH), 7.45 (m, ÍH), 7.05-7.30 (m, 7H), 7.65-7.72 (m , 1H), 6.24-6.51 (m, 2H), 4.45 (m, 1H), 3.82 (m, 1H), 2.95 (m, ÍH), 2.78 (m, ÍH), 1.05-1.25 (m, 3H). rmn-13C (CDC13): d = 173.0, 172.9, 172.8, 172.7, 147.9, 137.7, 131.1, 130.3, 129.21, 129.15, 128.0, 127.9, 126.21, 126.19, 116.8, 113.5, 113.0, 112.6, 53.4, 53.3, 52.0 , 51.8, 37.92, 37.86, 18.9, 18.6. C? 8H? 9 302Cl2 (MW = 380.28); mass spectroscopy (MH +) 380.

Example 37 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (S) -2- aminohexan- (N-methyl) -amide Following General Procedure D and using N-methyl L-norleucine amide (prepared by coupling BOC-L-norleucine (Bachem) with methylamine (Aldrich) using General Procedure E, followed by removal of the BOC group using General Procedure F) and? - (3, 4-dichlorophenyl) -D, L-alanine, the title compound was prepared. This compound was then purified by washing with aqueous potassium carbonate. The data of the MRI? They were as follows: rmn-1 !! (CD3OD): d = 6.99 (t, ÍH), 6.48 (d, 10.8, ÍH), 6.32 (d, 8.7, ÍH), 4.09 (m, ÍH), 3.68 (q, 7.0, 0.5H), 3.59 ( q, 7.1, 0.5H), 2.50 (s, 1.5H), 2.47 (s, 1.5H), 1.28-1.60 (m, 2H), 1.23 (t, 6.5, 3H), 0.80-1.20 (m, 4H) , 0.68 (t, 6.7, 1.5H), 0.59 (t, 7.1, 1.5H). rmn-13C (CD3OD): d = 176.6 (superimposed), 174.54, 174.51, 148.8, 148.5, 133.6, 133.5, 131.7, 131.6, 121.0, 120.8, 115.2, 115.1, 114.5, 114.2, 55.3, 54.7, 54.3, 54.1, 33.3 (superimposed), 29.0, 28.8, 26.3, 26.2, 23.4, 23.3, 19.0 (superimposed), 14.3, 14.2. Ci 6 H 23 N 302 Cl 2 (MW = 360.29); mass spectroscopy (MH +) 360.

Examples 38 and 39 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - / J-cyclohexylalanine methyl ester Following General Procedure D and using α-cyclohexylalanine methyl ester (prepared at Starting from / J-cyclohexylalanine (Bachem) using General Procedure K) and N- (3,4-dichlorophenyl) -D, L-alanine, the title compound, as a mixture of diastereomers on alanine, was prepared as an oil . The reaction was monitored by tic (Rf = 0.27 (second isomer) and 0.30 (first isomer) in 35% EtOAc / hexanes) and the purification was by flash chromatography (35% EtOAc / hexanes).

The NMR data were as follows (First Isomer - Example 38): rmn -'- H (CD3OD): d = 7.21 (d, ÍH), 6.81. (broad d, HH), 6.70 (d, HH), 6.46 (dd, HH), 4.62 (m, HH), 4.19 (d, 1H), 3.77 (m, HH), 3.65 (s, 3H), 1.65 - 0.90 (m, 10H), 1.50 (d, 3H). • rmn-13C (CD3OD): d = 173.78, 173.48, 146.62, 133.45, 131.26, 122.51, 115.84, 114.17, 55.64, 52.91, 50.47, 40.18, 34.81, 34.04, 32.88, 26.86, 26.71, 26.55, 20.13. The NMR data were as follows (Second Isomer - Example 39): rmn- ^? (CD3OD) ': d = 7.23 (d, 1H), 6.83 (broad d, ÍH), 6.67 (d, ÍH), 6.45 (dd, ÍH), 4.63 (m, ÍH), 4.10 (d, ÍH), 3.69 (m, ÍH), 3.72 (s, 3H), 1.65 - 0.90 (m, 10H), 1.51 (d, 3H). rmn-13C (CD30D): d = 173.98, 173.56, 146.38, 133.65, 131.34, 122.49, 115.35, 113.78, 55.39, 52.95, 50.21, 40.26, 34.61, 34.10, 32.68, 26.82, 26.64, 26.41, 19.98. Ci9H26N203Cl2 (MW = 401.34); mass spectroscopy (MH +) 401.

Example 40 Synthesis of 27- [27- (3,4-dichlorophenyl) -L-alanyl] - (S) -2- to inohexanamide Following General Procedure D and using the amide of L-norleucine (prepared from the BOC amide -L-norleucine (from Example F above) using General Procedure F) and N- (3,4-dichlorophenyl) -D, L-alanine, the title compound was prepared as a solid (mp = 156-161 ° C ). The NMR data were as follows: rmn-1H (CD3OD): d = 6.49 (m, ÍH), 6.32 (m, ÍH), 1.14 (m, ÍH), 3.54-3.71 (m, ÍH), 0.80 -1.62 (m, 9H), 0.68 (m, 1.5H), 0.58 (m, 1.5H). rmn-13C (CD3OD): d = 176.3, 176.56, 148.8, 148.5, 133.6, 133.5, 131.71, 131.6, 120.8, 115.2, 115.1, 114.4, 114.2, 55.3, 54.7, 53.9, 53.7, 33.4, 33.3, 29.0, 28.6 , 23.4, 23.3, 19.03, 18.'99, 14.3, 14.2. C15H2? N302Cl2 (MW = 346.26); mass spectroscopy (MH +) 346.

Example 41 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (S) -2- aminohexan- (27,27-dimethyl) -amide Following General Procedure D and using N , N-methyl amide of L-norleucine (prepared by coupling BOC-L-norleucine (Bachem) with dimethylamine (Aldrich) using General Procedure E, followed by removal of the BOC group using General Procedure F) and N - (3,4-dichlorophenyl) -D, L-alanine, the title compound was prepared as a solid (mp = 137-160 ° C). The reaction was monitored by tic (0.20 and 0.24 (5% MeOH in CH2C12) and the purification of this compound was by precipitation of water. The NMR data were as follows: rmn-xH (CDC13): d = 0.77 (m, 3H), 1.11 (m, ÍH), 1. 24 (m, 3H), 1.47 (m, 3H), 1.40-1.80 (m, 2H), 2.92 and 2. 94 (two s, 3H), 3.07 (s, 3H), 3.84 (m, ÍH), 4.32 (d, J = 5.3 Hz, ÍH), 4.90 (m, ÍH), 6.44 (m, ÍH), 6.65 (s, ÍH), 7.17 (m, ÍH), 7.35 (m, ÍH). rmn-13C (CDC13): d = Í3.8, 13.9, 19.3, 19.4, 22.38, 22.45, 27.06, 27.14, 32.3, 32.5, 35.7 (possibly superimposed), 37.0, 37.1, 48.6, 48.8, 54.3, 54.5, 113.1, 113.5, 114.4, 114.7, 121.1, 121.3, 130.6 (superimposed), 132.7, 132.9, 146.0, 146.2, 171.4, 171.5, 172.6, 172.9. C? 7 H 25 N 302 Cl 2 (MW = 374.31); mass spectroscopy (MH +) 374.

Example 42 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, -alanyl] -L-methionine methyl ester Following General Procedure D and using L-methionine methyl ester hydrochloride (Sigma) and N - (3, 4-dichlorophenyl) -D, L-alanine (from Example A above), the title compound was prepared as a mixture of diastereomers. The reaction was monitored by tic (Rf = 0.35 in 43% EtOAc / hexanes) and purification of this compound was by flash chromatography with 43% EtOAc / hexanes. The NMR data were as follows: rmn-xH (CDC13): d = 7.21 (d, 2H), 6.68 (m, ÍH), 6.43 (m, ÍH), 4.68 (m, ÍH), 4.21 (dd, ÍH), 3.79 (m, ÍH), 3. 73 (s, 1.5H), 3.68 (s, 1.5H), 2.46 (m, ÍH), 2.31 (t, ÍH), 2.23 - 1.88 (, 2H), 2.06 (s, 1.5H), 1.93 (s, 1. 5H), 1.50 (d, 3H). rmn-13C (CDC13): d = 174.09, 173.81, 172.73, 172.38, 146.60, 146.47, 133.43, 131.37, 131.27, 122.36, 122. 33, 115.65, 115.31, 114.05, 113.65, 55.48, 55.32, 53. 19, 53.16, 51.99, 51.68, 31.74, 31.64, 30.62, 30.42, . 10, 19.92, 16.08, 15.91. 15H20 2O2Cl2S (MW = 379.31); mass spectroscopy (MH +) 379.

Example 43 Synthesis of 27- [27- (3,5-dichlorophenyl) -D, L-alanyl] - (S) -2-amino-exan- (27,7-dimethyl) -amide Following General Procedure E and using the N, N-dimethyl amide of L-norleucine (prepared by coupling BOC-L-norleucine (Bachem) with dimethylamine (Aldrich) using the General Procedure E, followed by removal of the BOC group using General Procedure F) and N- (3,5-dichlorophenyl) -D, L-alanine (from Example B above), the title compound was prepared. The reaction was monitored by tic (Rf = 0.25-0.30 in 3% methanol / dichloromethane) and the purification of this compound was by chromatography with 3% methanol / dichloromethane. The NMR data were as follows: rmn-1 !! (CDC13): d = 0.8-0.95 (t superimposed, 3H), 1.2-1.8 (m that contains d superimposed on 1.45 and 1. 48, 9H), 2.95 (s, 3H), 3.10 (s, 3H), 3.8-3.9 (m, ÍH), 4.3-4.4 (m, 1H), 4.8-4.95 (m, ÍH), 6.45 (s, 2H), 6.6-6.7 (my h) . C? 7 H 25 N 302 Cl 2 (MW = 374.31).

Example 44 Synthesis of 27- [27- (3, 5-dichlorophenyl) -D, L-alanyl] - (S) -2- aminohexanamide Following General Procedure D and using N- (3,5-dichlorophenyl) -D , L-alanine (from Example B above) and L-norleucine amide (from Example F above), the title compound was prepared. The reaction was monitored by tic (Rf = 0.15 in 3% methanol / dichloromethane) and the purification of this compound was by thin layer chromatography with 3% methanol / dichloromethane. The NMR data were as follows: rmn-1H (CD3OD): d = 0.9 (t, J = 7, 3H), 1.2-1.4 (m, 2H), 1.45 (d, J = 7, 3H), 1.5 -1.7 (m, HH), 1.75-1.9 (m, HH), 3.9-4.0 (m, HH), 4.1-4.3 (m, 1H), 4.3-4.4 (m, 1H), 6.5 (s broad, 2H ), 6.6 (s broad, ÍH). C15H2? N302Cl2 (MW = 346.26).

Example 45 Synthesis of 27- [27- (3,5-dichlorophenyl) -D, L-alanyl] - (S) -2- aminohexan- (N-methyl) -amide Following General Procedure D and using N- ( 3, 5-dichlorophenyl) -D, L-alanine and L-norleucine N-methylamide (prepared by coupling BOC-L-norleucine (Bachem) with methylamine (Aldrich) using General Procedure F, followed by removal of the BOC group using General Procedure F), the title compound was prepared. The reaction was monitored by tic (Rf = 0.25 in 3% methanol / dichloromethane) and the purification of this compound was by thin layer chromatography with 3% methanol / dichloromethane. The NMR data were as follows: rmn-xH (CD3OD): d = 0.9 (t, J = 7, 3H), 1.2-1.4 (m, 2H) ', 1.45 (d, J. = 7, 3H), 1.5-1.7 (m, ÍH), 1.75-1.9 (m, ÍH), 2.6-2.7 (m with s in 2.7, 4H), 3.8-4.0 (m, ÍH), 4. 1-4.3 (m, 2H), 6.5 (broad s, 2H), 6.6 (broad s, ÍH). C? 6H23N302Cl2 (MW = 360.29).

EXAMPLE 46 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] -L-histidine methyl ester Following General Procedure D (without washing with IN HCl) and using methyl ester hydrochloride of L-histidine (Sigma) and N- (3,4-dichlorophenyl) -D, L-alanine, the title compound was prepared as a solid (mp = 55-60 ° C). The reaction was monitored by tic (Rf = 0.52 in 10% methanol / methylene chloride) and the purification of this compound was by flash chromatography with 50% EtOAc / hexanes. The NMR data were as follows: rmn-1H (CDC13): d = 8.14 (broad d, J = 7.02 Hz, 0.5H), 7.79 (wide d, 7.57 Hz, 0.5H), 7.33 (s, ÍH) , 7.14 (m, ÍH), 6.73 (s, 0.5H), 6.69 (s, 0.5H), 6.59 (m, ÍH), 6.47 (m, 0.5H), 6.37 (m, 0.5H), 4.74 (m , ÍH), 4.33 (m, 1H), 3.79 (, ÍH), 3.69 (s, 1.5H), 3.62 (s, 1.5H), 3.05 (m, 2H), 1.47 (d, J = 7.02 Hz, 3H ). rmn-13C (CDC13): d = 174.35, 174.15, 172.45, 172.08, 146.80, 146.67, 135.48, 135.07, 134.65, 133.24, 133.12, 131.13, 131.04, 121.54, 121.49, 115.96, 115.78, 115.38, 115.05, 113.90, 113.72 , 61.04, 54.98, 53.11, 52.97, 52.71, 29.71, 19.43, 21.68, 19.86, 19.84, 14.77. C? 6H? 8N4? 3Cl2 (MW = 385.25); mass spectroscopy (MH +) 385.

Example 47 Synthesis of 27- [27- (quinolin-3-yl) -D, L-alanyl) - (S) -2-aminohexanoic acid methyl ester Using General Procedure G, followed by the hydrolysis set forth in the General Procedure C, N- (quinolin-3-yl) -D, L-alanine was prepared. This compound was then coupled to the L-norleucine methyl ester hydrochloride (Sigma) using General Procedure D to provide the title compound as an oil. The last reaction was monitored by tic (Rf = 0.76 in 10% methanol / methylene chloride and 0.07 in 1: 1 of EtOAcrHexans and the product was purified by chromatography - flash evaporation using 10% methanol / methylene chloride as the eluent The NMR data were as follows: rmn-xH (CDCl3): d = 8.53 (t, J = 2.8 Hz, HH), 7.95 (m, HH), 7.63 (m, HH), 7.46 (m, 2H), 7.20 (m, HH), 7.10 (d, J = 2.75 Hz, 0.5 H), 7.01 (d, J = 2.75 Hz, 0.5H), 4.60 (m, 2H), 3.94 (m, ÍH), 3.71 (s, 1.5H), 3.54 (s, 1.5H), 1.90-0.80 (m, 12H) ). rmn-13C (CDC13): d = 173.82, 173.50, 173.40, 172.96, 143.65, 143.60, 143.39, 143.32, 140.34, 140.26, 129.57, 129.49, 127.86, 127.78, 126.94, 126.78, 126.54, 113.39, 112.65, 55.69, 55.46 , 53.00, 52.86 ', 52.62, 52.28, 32.42, 32.35, 28.03, 27.79, 22.78, 22.62, 20.22, 20.01, 14.41, 14.12. C19H25N3O3 (MW = 343.43).

Example 48 Synthesis of N- [27- (benzothiazol-2-yl) -L-alanyl] - (S) -2-aminohexanoic acid methyl ester Following General Procedure B and using 2-chlorobenzothiazole (Aldrich) and L-alanine (Aldrich), N- (benzothiazol-2-yl) -L-alanine was prepared. This compound was then coupled to L-norleucine methyl ester hydrochloride (Sigma) using the General Procedure D (without washing with 1 HCl) to provide the title compound as a solid (p.f. = .99-120 ° C). The last reaction was monitored by tic (Rf = 0.42 in 1: 1 EtOAc: Hexanes) and the product was purified by preparative plate chromatography using 1: 1 EtOAc: Hexanes and :95 MeOH: dichloromethane as the eluent. The data of the MRI? were as follows: rmn-1H (CDC13): d = 7.66-7.03 (m, 6H), 4.69 (m, ÍH), 4.58 (m, ÍH), 3.72 (s, 1.9H), 3.61 (s, 1.1H ), 1.91-1.50 (m, 5H), 1.32-1.08 (m, 4H), 0.87-0.65 (m, 3H). rmn- .13, (CDC13) d = 175.8 170.3, 166, 160. 2, 152.3, 148.4, 132.1, 131.1, 126.8, 126.5, 124.5, 122.6, 122.0, 121.4, 120.9, 119.4, 54.3, 54.2, 53.0, 52.9, 3.5, 28.1, 28.0, 23.9, 22.9, 19.0, 18.8, 14.2. C? 7H23? 303S (MW = 34 9 .4 6); mass spectroscopy (MH + 350).

Example 49 Synthesis of 27- [27- (3, 5-difluorophenyl) -D, -alanyl] -L-alanine methyl ester Following General Procedure E and using L-alanine methyl ester hydrochloride (Sigma) and N- (3, 5-difluorophenyl) -D, L-alanine (from Example C above), the title compound was prepared as a solid (mp = 93-95 ° C). The reaction was monitored by tic (Rf = 0.4 in 3% methanol / methylene chloride) and the purification of this compound was by flash chromatography with 3% methanol / methylene chloride. The data of the MRI? were as follows: rmn-1H (CDC13): d = 6.9 (q), 6.25 (t), 6.10 (q), 5.3 (s), 4.6 (m), 4.25 (m), 33.7-3.8 (m), 1.8 (s), 1.5 (d), 1.4 (q), 1.25 (s). rmn "13C (CDC13): d = 173.78, 173.51, 173.44, 173. 27, 166.24, 166.09, 163.04, 162.83, 149.41, 149.37, 97. 47, 97.34, 97.20, 97.09, 96.82, 95.08, 95.03, 94.73, 94.69, 94.39, 94.34, 55.27, 55.22, 53.10, 53.02, 48.46, 48. 35, 19.99, 19.87, 18.72, 18.66. Ci3H? 6? 203F2 (MW = 28 6 .3); Mass copy spectra (MH +) 287.

Example 50 Synthesis of 27- [27- (3, 5-difluorophenyl) -D, L-alanyl] - (S) -2-aminohexanoic acid methyl ester Following General Procedure E and using L-methyl ester hydrochloride norleucine (Sigma) and N- (3,5-difluorophenyl) -D, L-alanine, the title compound was prepared as a solid (mp. = 93-95 ° C). The reaction was monitored by the tick (Rf = 0.6 in 3% methanol / methylene chloride) and purification of this compound was by flash chromatography with 3% methanol / methylene chloride. The data of the MRI? were as follows: rmn-1H (CDC13): d = 6.95 (d), 6.85 (d), 6.25 (t), 6.15 (t), 4.6 (m), 4.3 (m), 3.8 (m), 3.75 ( s), 3.70 (s), 1.8 (m), 1.65 (m), 1.55 (d), 1.3 (m), 1.1 (m), 0.85 (t), 0.80 (t). rmn-13C (CDC13): d = 173.64, 173.42, 173.35, 173. 04, 149.38, 149.23, 97.52, 97.21, 97.14, 96.83, 95.10, 95.05, 94.75, 94.70, 94.41, 77.61, 77.19, 55.34, 55. 25, 52.97, 52.87, 52.58, 52.25, 32.41, 27.96, 27.74, 22. 79, 22.68, 20.05, 19.87, 14.39, 14.25. C 16 H 22 2 O 3 F 2 (MW = 328.3); spectroscopy of more ace (MH +) 329.

Example '51 Synthesis of 27- [27- (3,4-dichlorophenyl) -L-alanyl] - (S) -2- aminohexanamide Following General Procedure D (using DMF as the solvent and ethyl acetate for extraction, and without washing with IN HCl) and using the L-norleucine amide (prepared from BOC-L-norleucine amide (from Example F above) using General Procedure F) and N- (3,4-dichlorophenyl) -L- alanine (prepared from 3,4-dichloroaniline (Aldrich) and R - (+) - isobutyl lactate (Aldrich) using General Procedure J, followed by hydrolysis using General Procedure C), the title compound was prepared as a solid (mp = 184-186 ° C). The reaction was monitored by tic (Rf = 0.48 in 12% methanol / methylene chloride) and the purification of this compound was by preparative plate chromatography using 12% methanol / methylene chloride as eluent. The NMR data were as follows: rmn-1 !! (CD3OD): d = 6.97 (d, J = 8.79 Hz, ÍH), 6.51 (d, J = 2.68 Hz, ÍH), 6.32 (dd, J = 8.73 Hz, J = 2.68 Hz, ÍH), 4.14 (m , ÍH), 3.67 (q, J = 6.96 Hz, 1H), 1.40 (m, 10H), 0.70 (m, 3H) rmn-13C (CDC13): d = 177.19, 177.11, 149.41, 134.05, 132.13, 121.38, 115.82, 114.96, 55.26, 54.48, 33.92, 29.54, 23.95, 19.58, 14.83. C? 5H2i 302Cl2 (MW = 346.26); mass spectroscopy (MH +) 346.

Example 52 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (S) -2- aminohexan- (27-benzyl) -amide 'Following General Procedure H above and using the ester N- [N- (3,4-dichlorophenyl) -D, L-alanyl) - (S) -2-aminohexanoic acid methyl ester (from Example 15 above) and benzylamine (Aldrich), the title compound was prepared as a solid (mp = 141-146 ° C). The reaction was monitored by tic on silica gel (Rf = 0.32 in 5% methanol / methylene chloride) and the purification was by preparative plate chromatography (silica gel using 5% methanol / methylene chloride as eluent). The data of the MRI? were as follows: rmn-1H (CDC13): d = 7.6 (m, 2H), 7.2 (m, 6H), 6.6 (m, HI), 6.3 (m, HI), 4.47 (m, 4H), 3.75 ( m, ÍH), 1.28 (m, 12H). rmn-13C (CDC13): d = 174.56, 174.50, 172.39, 172.32, 146.78, 146.65, 138.38, 133.43, 133.38, 131.22, 129.21, 128.06, 121.98, 121.72, 121.66, 115.21, 115.08, 113.73, 113.55, 54.94, 54.36 , 53.60, 53.22 ', 43.95, 33.10, 32.98, 28.24, 27.95, 22.96, 22.90, 19.78, 19.70, 14.49, 14.41. C22H27C12N302 (MW = 436.39); mass spectroscopy (MH +) 436.

Example 53 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (S) -2-amino-phenylethanol Following General Procedure E and using N- (3,4-dichlorophenyl) -D, L-alanine (from Example A above) and (S) - (+) -2-phenylglycinol (Aldrich), the title compound was prepared as a solid (m.p. = 66-70 ° C). The reaction was monitored by tic on silica gel (Rf = 0.25 in 5% methanol / methylene chloride) and the purification was by flash column chromatography (silica gel using 5% methanol / methylene chloride). as eluent). The NMR data were as follows: rmn - ^ - H (CDC13): d = 7.4-7.1 (m, 6H), 6.75 (d, J = 3 Hz, ÍH), 6.5-6.4 (m, ÍH), 5 (m, 1H), 4.2-4.0 (m, J = 4 Hz, ÍH), 3.8 (2H), 1.7 (s, ÍH), 1.55 (m, 3H). rmn "13C (CDC13): d = 174," 146, 139, 134, 131.8, 129.5, 128.5, 127, 123, 116, 114, 112, 67, 56.5, 55.5, 20. 16H18Cl2N2O2 (MW = 341); mass spectroscopy (MH +) 342.

Examples 54 and 55 Synthesis of 27- [27- (3,5-dichlorophenyl) -D, L-phenylglycyl] -L-alanine methyl ester Following General Procedure E and using N- (3, 5-dichlorophenyl) -D , L-phenylglycine (from Example J above) and L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared. The reaction was monitored by tic (Rf = 0.95 in 3% methanol / methylene chloride) and the purification of this compound was by recrystallization from EtOAc, hexane and ether. Two partially separated diastereomeric mixtures were obtained. The NMR data were as follows: rmn "1H (CDC13-75% isomer A / 25% isomer B): d = 7.45-7.35 (m, 5H), 6.7 (m, 2H), 6.47 (m, 2H), 5.1-5.0 (dd, J = 3 Hz, 1H), 4.75 (d, J = 3.5 Hz, 1H), 4.65-4.5 (m, 7.2 Hz 1H), 3.75-3.68 (2 s in a ratio of 3: 1, 3H), 1.43-1.3 (2 d in a ratio of 3: 1, J = 7.2 Hz, 3H) rmn ~ 13C (CDC13 - 75% of isomer A / 25% of isomer B): d = 173.27, 170.24, 148.61, 138.23, 136.07, 136.00, 130.11, 129.60, 129.58, 127.83, 127.69, 119.10, 112.68, 112.56, 78.03, 63.27, 53.20, 48.94, 18.85, rmn-1H (CDC13 - 25% of isomer A / 75% of isomer B): d = 7.45-7.35 (m, 5H), 6.7 (m, 2H), 6.47 (m, 2H), 5.1-5.0 (2xd, J = 3 Hz, 1H), 4.75 (d, J = 3.5 Hz, ÍH), 4.65-4.5 (m, J = 7.2 Hz, ÍH), 3.75-3.68 (2 s in a ratio of 1: 3, 3H), 1.43-1.3 (2 d in a ratio of 1 Rmn "13C (CDC13 - 25% of isomer A / 75% of isomer B): d = 173.27, 170.24, 148.61, 138.23, 136.07, 136.00, 130.11, 129.60, 129.58 , 127.83, 127.6 9, 119.10, 112.68, 112.56, 78.03, 63.27, 53.20, 48.94, 18.85. C? 8 H 18 N 203 Cl 2 (MW = 381.26); mass spectroscopy (MH +) 381.

Example 56 Synthesis of 27- [27- (3,4-dichlorophenyl) -D, L-alanyl] - (S) -2- aminohexanol Following General Procedure I above and using N- [N- (3-methyl) methyl ester, 4-dichlorophenyl) -D, L-alanyl] - (S) -2-aminohexanoic (from Example 15 above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel (Rf = 0.16 and 0.17 in 5% methanol / methylene chloride) and the purification was by preparative plate chromatography (silica gel using 5% methanol / chloride). methylene as the eluent). The NMR data were as follows: rmn_1H (CD3OD): d = 7.20 (d, ÍH), 6.79 (m, ÍH), 6. 68 (dd, ÍH), 6.43 (d, 1H), 4.42 (broad d, 0.6H), 4. 30 (broad d, 0.4H), 3.89 (m, ÍH), 3.75 (m, ÍH), 3. 70-3.40 (m, 2H), 1.60-0.95 (m, 9H), 0.90-0.70 (m, 3H) rmn "iJC (CD3OD): d 174.42, 174.17, 146.06, 145. 96, 132.89, 132.85, 130.74, 130.69, 121.64, 121.49, 114.98, 114.70, 113.14, 113.08, 65.42, 65.11, 55.00, 54.76, 51.69, 51.48, 30.67, 30.59, 28.16, 28.00, 22.48, 22.36, 19.44, 13.92, 13.82. C 15 H 22 Cl 2 N 2 O 2 (MW = 333.26); mass spectroscopy (MH +) 333.

Example 57 Synthesis of N- [27- (3,5-dichlorophenyl) -D, L-alanyl] - (S) -2-amino-2-enylethanol Following General Procedure E and using N- (3, 5-dichlorophenyl) ) -D, L-alanine (from Example B above) and (S) - (+) -2-phenylglycinol (Aldrich), the title compound could be prepared.

Example 58 Synthesis of tert-butyl ester of 27- [27- (3,5-dichloro-enyl) -L-alanyl] -L-phenylglycine Following General Procedure D (without washing with 1N HCl) and using N- ( 3, 5-dichlorophenyl) -L-alanine (prepared from 3,5-dichloroaniline (Aldrich) and R- (+) - isobutyl lactate (Aldrich) using General Procedure J, followed by hydrolysis using General Procedure C) and L-phenylglycine tert-butyl ester hydrochloride (Bachem), the title compound was prepared. The reaction was monitored by tic (Rf = 0. 39 in 25% EtOAc / Hexanes) and purification of this compound was by preparative plate chromatography using 25% EtOAc / Hexanes. The data of the MRI? were as follows: rmn ^ H (CDC13): d = 7.55 (d, J = 7.39 Hz, ÍH), 7.30 (s, 5H), 6.73 (t, J = 1.68 Hz, 1H), 6.46 (d, J = 1.71 Hz, 2H), 5.45 (d, J = 7.45 Hz, ÍH), 4.47 (d, J 5.19 Hz, 1H), 3.82 (, ÍH), 1.40 (d, J = 6.96 Hz, 3H), 1.34 (s) , 9H). rmn-13C (CDC13): d = 173.23, 169.92, 148.93, 137.43, 136.07, 129.40, 128.85, 127.40, 119.04, 112.48, 83.42, 57.37, 54.70, 28.29, 19.79. C2iH24N203Cl2 (MW = 423.34); mass spectroscopy (MH +) 423.

Example 59 Synthesis of tert-butyl ester of 27- [N- (3,5-di-trifluoromethyl) phenyl) -L-alanyl] -L-phenylglycine Following General Procedure D and using N- [3, 5-di- (trifluoromethyl) phenyl] -L-alanine (from Example G above) and L-phenylglycine tert-butyl ester hydrochloride (Bachem), the title compound was prepared. The reaction was monitored by tic (Rf = 0.46 in 25% EtOAc / Hexanes). The data of the MRI? were as follows: rmn ^ H (CDC13): d = 7.39 (d, J = 7.39 Hz, ÍH), 7.29 (s, 5H), 6.96 (s, 2H), 5.45 (d, J = 7.51 Hz, ÍH) , 4.69 (d, J = 5.31 Hz, ÍH), 3.95 (m, ÍH), 1.48 (d, J = 6.96 Hz, 3H), 1.33 (s, 9H). rmn-13C (CDC13): d = 172.7, 169.9, 147.9, 137. 3, 132.8, 132.4, 129.42, 129.34, 129.31, 128.9, 127.4, 127.2, 127, 122.1, 113.50, 113.47, 112.34, 112.29, 112.24, 83.5, 57.3, 54.6, 28.34, 28.30, 28.2, 19.8. C23H24N2? 3F6 (MW = 490.45).

Example 60 Synthesis of 27- [27- (3,5-di ethoxyphenyl) -D, L-alanyl] - (S) -2-aminohexanoic acid methyl ester Following General Procedure E (washing with dilute HCl and extracting with EtOAc ) and using N- (3, 5-dimethoxyphenyl) -D, L-alanine (from Example H above) and L-norleucine methyl ester hydrochloride (Sigma), the title compound was prepared as a light yellow oil. The reaction was monitored by tic (Rf = 0.3 in 30% EtOAc / Hexanes). The data of the MRI? were as follows: rmn-1H (CDC13): d = 0.6-0.9 (two triplets in 0. 72 and 0.82, J = 7 Hz, 3H), 1.0-1.9 (m, 9H), 3.6-3.7 (four singlet in 3.60, 3.65, 3.66 and 3.67, 10H), 3. 7-3.8 (m, ÍH), 4.6-4.7 (m, ÍH), 5.7-5.95 (m, 3H), 7.1-7.3 (m, ÍH). rmn-13C (CDC13): d = 14.21, 14.35, 19.8, 20.0, '22.69, 22.74, 27.8, 28.0, 32.20, 32.45, 52.18, 52.57, 52.65, 52.78, 55.31, 55.52, 55.59, 55.63, 91.6, 91.8, 92.86, 93.24, 149.02, 149.27, 162.11, 162.18, 173.02, 173.44, 174.47, 174.82.

C? 8H28N2? 5 (MW = 352.43) Example 61 Cell Selection for the Detection of / J-Amyloid Production Inhibitors Numerous compounds of the above formula I were tested for their ability to inhibit the production of / J-amyloid in a line of cells possessing the Swedish mutation. This selection test used cells (K293 = line of human kidney cells) which were stably transfected with the gene for amyloid precursor protein 751 (APP751) containing the double mutation Lys65iMet652 to sn65iLeu652 (numeration APP751) in the manner described in International Patent Application Publication No. 94/105698 and Citron et al11. This mutation is commonly called the Swedish mutation and the cells, designated "293 751 SWE", were plagued in 96-well plates, Corning at 1.5-2.5 x 104 cells per well in Dulbecco's minimal essential medium (Sigma, St. Louis, MO) plus 10% fetal bovine serum. The number of cells is important in order to achieve the results of β-amyloid ELISA without the linear range of the assay (~ 0.2 to 2.5 ng per mL).

After incubation overnight at 37 ° C in an incubator equilibrated with 10% carbon dioxide, the media was removed and replaced with 200 μL of a compound of the formula I (drug) containing the media per well during a pre-treatment period of two hours and the cells were incubated as before. The stock solutions of the drug were prepared in 100% DMSO such that in the final concentration of the drug used in the treatment, the concentration of dimethyl sulfoxide did not exceed 0.5% and, in fact, was usually equal to 0.1%. At the end of the pretreatment period, the media was removed again and replaced with fresh drug containing the media as before and the cells were incubated for an additional two hours. After the treatment, the plates were centrifuged in a GPR Beckman at 1200 rpm for five minutes at room temperature to pellet the cell waste from the conditioned media. From each well, 100 μL of the conditioned media or appropriate dilutions thereof were transferred into an ELISA plate precoated with antibody 266 [P. Seubert, Na ture (1992) 359: 325-327] against amino acids 13-28 of the? -aminoid peptide as described in International Patent Application Publication No. 94/105698 and stored at 4 ° C overnight . An ELISA assay that uses labeled antibodies 6C6 [P. Seübert, na ture (1992) 359: 325-327] against amino acids 1-16 of the peptide / J-amyloid was run the next day to measure the amount of the α-amyloid peptide produced. The cytotoxic effects of the compounds were measured by a modification of the Hansen et al. Method12. To the remaining cells in the tissue culture plate was added 25 μL of a stock solution of 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) (Sigma, St. Louis) , MO) (5 mg / mL) at a final concentration of 1 mg / mL. Cells were incubated at 37 ° C for one hour, and cell activity was stopped by the addition of an equal volume of the MTT lysis buffer (20% w / v sodium dodecyl sulfate in 50% dimethylformamide, pH 4.7) . Complete extraction was achieved by stirring overnight at room temperature. The difference in OD562nm and OD650nm was measured in a Molecular Device's UVmax microplate reader as an indicator of cell viability. The ELISA results of the β-amyloid peptide were adjusted to a normal curve and expressed as ng / mL of the β-amyloid peptide. In order to normalize cytotoxicity, these results were divided by MTT results and expressed as a percentage of the results of a drug-free control. All results are the average and normal deviation or error of at least six replicate trials. Test compounds were tested for inhibition activity of peptide / i-amyloid production in cells. The results of this test demonstrate that, each of the compounds of Examples 1-60 inhibit the production of β-amyloid peptide by at least 30% when compared to the control.

EXAMPLE 62 In Vivo Suppression of the Liberation of the α-amyloid and / or Synthesis This example illustrates how the compounds of this invention could be tested by the in vivo suppression of α-amyloid release and / or synthesis. For these experiments, PDAPP mice from 3 to 4 months of age were used [Games et al., (1995) Na ture 373: 532-527]. Depending on the compound being tested, the compound is usually formulated at either 5 or 10 mg / mL. Due to the low solubility factors of the compounds, these can be formulated with several vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% ethanol in corn oil; 2-hydroxypropyl- / J-cyclodextrin (Research Biochemicals International, Natick MA); and carboxymethylcellulose (Sigma Chemical Co., St. Louis MO). Mice were dosed subcutaneously with a measuring needle 26 and 3 hours later the animals were subjected to euthanasia by means of C02 narcosis and blood was taken by cardiac puncture using a syringe / tuberculin needle of 1c 25G 5 / 8"coated with 0.5 M EDTA solution, pH 8.0 The blood was placed in a Becton-Dickinson vacutainer tube containing EDTA and centrifuged for 15 minutes at 1500 x gravity at 5 ° C. The brains of the mice were then centrifuged. They removed and the cortex and hippocampus were dissected and placed on ice. 1. Brain Assay To prepare hippocampal and cortical tissue for enzyme-linked immunosorbent assays (ELISAs), each brain region was homogenized in 10 volumes of ice-cooled guanidine buffer (5.0 M guanidine-HCl, 50 mM Tris -HCl, pH 8.0) using a Kontes motor crusher or crusher (Fisher, Pittsburgh PA). The homogenized products were gently rocked on a rotating platform for three to four hours at room temperature and stored at -20 ° C before quantification of the / J-amylidene. Homogenate brain products were diluted 1:10 with ice-cold casein buffer [0.25% casein, phosphate buffered saline (PBS), 0.05% sodium azide, 20 μg / mL aprotinin, 5 mM EDTA , pH 8.0, 10 μg / mL of leupeptin], which reduces the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 x gravity for 20 minutes at 4 ° C. The? -aminoid standards (1-40 or 1-42 amino acids) were prepared such that the final composition was equal to 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA). The interspersed ELISA of the total / J-amyloids, which quantifies both the amyloid-α (1-40) and the α-amyloid (aa 1-42) consists of two monoclonal antibodies (mAb) for the α-amyloid . The capture antibody, 266 [P. Seubert, Na ture (1992) 359-325-327] is specific for amino acids 13-28 of? -aminoid. The 3D6 antibody [Johnson-Wood et al., PNAS USA (1997) 94-1550-1555], which is specific for amino acids 1-5 of /? -amyloid, is biotinylated and serves as the reporter antibody in the assay. The biotinylation procedure of the 3D6 employs the manufacturer's protocol (Pierce, Rockford IL) for the labeling with NHS-biotin of immunoglobulins except that 100 M sodium bicarbonate, buffer 8.4 is used. The 3D6 antibody does not recognize the precursor, amyloid, secreted protein (APP) or full-length APP but detects only the? -amyloid species with a terminal, amino acid aspartic acid. The assay has a lower limit of sensitivity of ~ 50 pg / mL (11 pM) and shows no cross-reactivity for the endogenous murine amyloid J peptide at concentrations up to 1 ng / mL. The configuration of the intercalated ELISA that quantifies the α-amyloid level (aa 1-42) employs mAb 21F12 [Johnson-Wood et al., PNAS USA (1997) 94: 1550-1555] (which recognizes amino acids 33- 42 of? -amyloid) as the capture antibody. Biotinylated 3D6 is also the reporter antibody in this assay that has a lower sensitivity limit of -125 pg / mL (28 pM). Capture mAbs 266 and 21F12 are coated at 10 μg / mL in 96-well immunoassay plates (Costar, Cambridge MA) overnight at room temperature. The plates are then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature, then stored dried at 4 ° C until use. The plates are rehydrated with wash buffer (saline buffered with Tris, 0.05% Tween 20) before use. Samples and standards are added to the plates and incubated overnight at 4 ° C. The plates are washed > 3 times with the wash buffer between each step of the test. Biotinylated 3D6, diluted to 0.5 μg / mL in casein incubation buffer (0.25% casein, PBS, 0.05% Tween 20, pH 7.4), is incubated in the well for 1 hour at room temperature. Avidin-HRP (Vector, Burlingame CA) diluted 1: 4000 in casein incubation buffer is added to the wells for 1 hour at room temperature. The colorimetric substrate, Slow TMB-ELISA (Pierce, Cambridge MA), is added and allowed to react for 15 minutes, after the enzymatic reaction is stopped with the addition of H S04 2 N. The reaction product is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) that measures the difference in absorbance at 450 nm and 650 nm. 2. Blood assay Plasma with EDTA was diluted 1: 1 in specimen diluent (0.2 g / L sodium phosphate * H2? (Monobasic), 2.16 g / L sodium phosphate * 7H20 (dibasic), 0.5 g / L of thimerosal, 8.5 g / L of sodium chloride, 0.5 mL of Triton X-405, 6.0 g / L of bovine serum albumin free of globulin, and water). Samples and standards in the specimen diluent were assayed using the total? -amyloid assay (266 capture / 3D6 reporter) described above for the brain assay, except that the specimen diluent was used in place of the casein diluents described . From the above description, various modifications and changes in composition and method will occur to those skilled in the art. It is proposed that all modifications that come within the scope of the appended claims are included therein.

SEQUENCE LIST (1) GENERAL INFORMATION (i) APPLICANTS: ATHENA NEUROSCIENCES, INC. ELI LILLY & COMPANY JAMES E. AUDIA BERVERLY K. FOLMER VARGHESE JOHN LEE H. LATIMER JEFFREY S. NISSEN WARREN J. PORTER EUGENE D. THORSETT JING WU (ii) TITLE OF THE INVENTION: AMINO ACIDS OF N- (ARIL / HETEROARYL), COMPOSITIONS PHARMACEUTICALS THAT THEY UNDERSTAND THE SAME, AND METHODS TO INHIBIT THE LIBERATION OF THE ß-AMYLOID PEPTIDE AND / OR ITS SYNTHESIS THROUGH THE USE OF SUCH COMPOUNDS (iii) NUMBER OF SEQUENCES: 1 (iv) CORRESPONDENCE DIRECTION: (A) DIRECTION: Burns, Doane, Swecker & Mathis, LLP (B) STREET: P.O. Box 1404 (C) CITY: Alexandria (D) STATE: Virginia (E) COUNTRY: E.U.A. (F) ZIP: 22313-1404 (v) COMPUTER LEADABLE FORM: (A) MEDIA TYPE: Flexible Disk (B) COMPUTER: IBM compatible PC (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) SOFTWARE: Patentln Reléase # 1.0, Version # 1.30 (vi) CURRENT REQUEST DATA: (A) APPLICATION NUMBER: Not assigned (B ') DATE OF SUBMISSION: Not assigned (C) CLASSIFICATION: (vii) PREVIOUS APPLICATION DATA: (A) NORTH AMERICAN PATENT APPLICATION NUMBER 08 / 755,334 (B) SUBMISSION DATE: November 22, 1996 (viii) INFORMATION OF THE POWDER / AGENT: (A) NAME: Swiss, Gerald F. (B) REGISTRATION NUMBER : 30,113 (C) REFERENCE NUMBER / REGISTRATION: 002010-057 (ix) TELECOMMUNICATION INFORMATION: (A) TELEPHONE: 650-854-7400 (B) TELEFAX: 650-854-8275 (2) INFORMATION FOR THE IDENT. SEC. NO: l: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 43 amino acids (B) TYPE: peptide (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (xi) DESCRIPTION OF. THE SEQUENCE: INDENT. FROM THE SEC. NO 1: Asp Ala Glu Phe Arg His Asp Ser Gly Tyr Glu Val His His 1 5 10 Gln Lys Leu Val Phe Phe Wing Glu Asp Val Gly Ser Asn Lys 15 20 25 Gly Ala lie lie Gly Leu Met Val Gly Gly Val Val lie Wing 30 35 40 Thr It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (77)

1. A method for inhibiting the release of β-amyloid peptide and / or its synthesis in a cell, the method is characterized in that it comprises administering to said cell an amount of a compound or a mixture of compounds effective in the inhibition of cell liberation and / or synthesis of the β-amyloid peptide wherein the compounds are represented by the formula I: wherein: R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: p wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkenyl, alkoxy, halo , cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl which contains 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the condition that the substituents are not ortho to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include the a-haloalkyl, a-diazoalkyl or -OC (0) alkyl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, and where R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X can also be -CR4R4Y 'where each R4 is independently selected from the group consisting of hydrogen, alkenyl, cycloalguyl, aryl, heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 wherein R5 is selected from the group consisting of alkyl, substituted alkenyl, cycloalguilo , aryl, heteroaryl and heterocyclic, and with the ion that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derived from D-phenylalanine, then X is not -C (0) OCH3.

2. A method to prevent the beginning of the AD in a patient at risk for developing AD, the method is characterized in that it comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I: wherein: R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the Phenyl ring, Rb and Rb are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb 'are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano , nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include the a-haloalkyl, a-diazoalkyl or -OC (0) alkyl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, and where R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X can also be -CR4R4Y 'where each R4 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl , heteroaryl and heterocyclic, and with the condition n that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derivative of D-phenylalanine, then X is not -C (0) OCH3.

3. A method for treating a patient with AD in order to inhibit deterioration in that patient's condition, the method is characterized in that it comprises administering to the patient a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of the formula I: wherein: R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the Phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl containing 1 to 3 'substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include the a-haloalkyl, a-diazoalkyl or -OC (O) alkyl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl , aryl, het-eroaryl, heterocyclic, and where R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting * of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X can also be -CR4R4Y 'where each R4 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl , heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 wherein R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and with the ion that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derived from D-phenylalanine, then X is not -C (0) OCH34.

The method according to claim 1, 2 or 3, characterized in that R1 is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazol-6-yl, and 5-indolyl.

5. The method according to claim 1, 2 or 3, characterized in that R1 is a substituted phenyl group of the formula: R * wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen.

6. The method according to claim 1, 2 or 3, characterized by R1 is a 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy , halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl.

7. The method according to claim 1, 2 or 3, characterized in that R1 is a substituted heteroaryl containing from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho to the heteroaryl linkage to the -NH group.

8. The method according to claim 7, characterized in that R1 is a phenyl 4-substituted, 3, 5-disubstituted or 3,4-disubstituted.

9. The method according to claim 8, characterized in that R1 is a 3,5-disubstituted phenyl.

10. The method according to claim 9, characterized in that the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (trifluoromethyl) phenyl and 3,5 -methoxyphenyl.

11. The method according to claim 8, characterized in that R1 is a 3,4-disubstituted phenyl.

12. The method according to claim 11, characterized in that the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro -4-cyanophenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl.

13. The method according to claim 8, characterized in that R1 is a phenyl 4-substituted.

14. The method according to claim 13, characterized in that the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl , 4- (phenylcarbonyl) phenyl and 4- (1-ethoxy) ethylphenyl.

15. The method according to claim 1, 2 or 3, characterized in that R1 is 2-methylquinolin-6-yl.

16. The method according to claim 1, 2 or 3, characterized in that R2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms and aril.

17. The method according to claim 16, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, -CH2CH2SCH3 and phenyl.

18. The method according to claim 1, 2 or 3, characterized in that R3 is an alkyl group.

19. The method according to claim 18, characterized in that the aryl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl.

20. The method according to claim 1, 2 or 3, characterized in that R3 is a substituted alkyl group.

21. The method according to claim 20, characterized in that the substituted alkyl group is selected from the group consisting of a-hydroxyethyl, -CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3, 5-diiodo -4-hydroxybenzyl, -CH2-indol-3-yl, - (CH2) 4-NH-BOC, - (CH2) 4-NH2, CH2- (lN-benzyl-imidazol-4-yl), -CH2-imidazole -4-yl, -CH2CH2SCH3, - (CH2) 4NHC (O) (CH2) 3CH3, and - (CH2) and C (O) OR5 where y is 1 or 2 and R5 is hydrogen, methyl or tert-butyl.

22. The method according to claim 1, 2 or 3, characterized in that X is -C (0) Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy.

23. The method according to claim 22, characterized in that Y is alkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy and tert-butoxy.

24. The method according to claim 1, 2 or 3, characterized in that X is -C (0) Y and Y is -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, alkyl substituted, cycloalkyl, aryl, heteroaryl, heterocyclic and where R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 further heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups.

25. The method according to claim 24, characterized in that Y is selected from the group consisting of amino (-NH2), N- (isobutyl) amino, N-methylamino, N, N-dimethylamino, and N-benzylamino.

26. The method according to claim 1, 2 or 3, characterized in that X is -CH 2 OH.

27. The method according to claim 1, 2 or 3, characterized in that the compound of the formula I is selected from the group consisting of: N- [N- (3,4-dichlorophenyl) -lanyl] valine N-methyl ester N- isobutyl amide of N- [N- (3,4-dichlorophenyl) alanyl] valine N- [N- (3,4- dichlorophenyl) -lanyl] threonine methyl ester N- [N- (3, 4-dichlorophenyl) -arylanyl] valine tert-butyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] valine amide of N- [N- (3,4-dichlorophenyl) alanyl] valine? - (l N- (3,4- dichlorophenyl) alanine?,? -dimethyl amide of N- [N- (3,4-dichlorophenyl) -lanyl] valine N-methyl amide of N- [N- (3, -dichlorophenyl) -lanyl] valine N- [N- (3,4-dichlorophenyl) -lanyl] alanine methyl ester N- [N- (3,4-dichlorophenyl) methyl ester ) - alanyl] leucine methyl ester of N- [N- (3,4-dichlorophenyl) -5-alanyl] phenylalanine methyl ester of N- [N- (3,4-dichlorophenyl) - alanyl] isoleucine N- [N- (3,4- dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester N-N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexanoic acid methyl ester of N- [N- (3,4-dichlorophenyl) -arylanyl] tryptophan a-methyl ester of N- [N- (3,4- 25 dichlorophenyl) alanyl] aspartic acid ester β- (tert-butyl ester) a- N- [N- (3, 4-dichlorophenyl) alanyl] aspartic acid methyl ester of N- [N- (3, 4-dichlorophenyl) - alanyl] -? - BOC-lysine N- [N-benzothiazol-6-yl] alanyl] -2-aminohexanoic acid methyl ester N- [N- (3,4-dichlorophenyl) methyl ester) - alanyl] lysine methyl ester of N- [N- (3,4-dichlorophenyl) -10 alanyl] tyrosine N- [N- (3,5-dichlorophenyl) -lanyl] alanine methyl ester N- [-] methyl ester N- (3,5-dichlorophenyl) alanyl] -2-aminopentanoic acid N- [N- (3,5-dichlorophenyl) alanyl] phenylalanine methyl ester N- [N- (N-methyl) methyl ester) - (3,4-dichlorophenyl) alanyl] aspartic N- [N- (3,4- 20-dichlorophenyl) alanyl] -1-benzylhistidine ester N- [N- (3,4- 20-dichlorophenyl) alanyl] - (methyl tert.-butyl ester) -methyl ester N- (3,4-dichlorophenyl) alanyl] glutamic amide of N- [N- (3,4-dichlorophenyl) alanyl] leucine a-methyl ester of N- [N- (3,4- 25 dichlorophenyl) alanyl] N - ['N- (3,4-dichlorophenyl) -arylanyl] - (3,5-diiodo) tyrosine methyl ester N- [N- (3,4-d) methyl ester chloro-phenyl) - alanyl] - (3-iodo) tyrosine N- [N- (3,5- dichlorophenyl) glycyl] -2-aminopentanoic acid methyl ester N- [N- (3,4-dichlorophenyl) alanyl methyl ester ] -? e- (hexanoyl) lysine amide of N- [N- (3,4-dichlorophenyl) alanyl] -10 phenylalanine N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N- methyl) -amide N- [N- (3,4-dichlorophenyl) -lanyl] -β-cyclohexylalanine methyl ester N- [N- (3,4-dichlorophenyl) alanyl] -2- aminohexanamide N- [N-] (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N, N-dimethyl) amide N- [N- (3,4-dichlorophenyl) -20 alanyl] methionine methyl ester N- [N- (3, 5-dichlorophenyl) alanyl] -2-aminohexan- (N, N-dimethyl) -amide N- [N- (3,5-dichlorophenyl) alanyl] -2- aminohexanamide N- [N- (3,5-dichlorophenyl) alanyl] -2-aminohexan- (N-methyl) -amide N- [N- (3,4-dichlorophenyl) -lanyl] histidine methyl ester of N- [N- (quinolin-3-yl) alanyl) ] -2-aminohexanoic acid methyl ester N- [N- (benzothiaz ol-2-yl) alanyl] -2-aminohexanoic methyl ester of N- [N- (3,5-difluorophenyl) -10 alanyl] alanine N- [N- (3,5-difluorophenyl) alanyl] methyl ester -2-aminohexanoic N- [N- (3,4-dichlorophenyl) -L-alanyl] -S-2-aminohexanamide 15 N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N- benzyl) -amide N- [N- (3, -dichlorophenyl) -D, L-alanyl] -2-amino-2-phenylethanol N- [N- (3,5-dichlorophenyl) -20-phenylglycinyl] alanine methyl ester N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexanol N- [N- (3,5-dichlorophenyl) alanyl] -2-amino-2-phenylethanol tert-butyl ester of N- [N-] (3, 5-dichlorophenyl) -25 L-alanyl] -L-phenylglycine N- [N- (3,5-di- (trifluoromethyl) phenyl) -L-alanyl] -L-phenylglycine methyl ester of N- [N- (3,5-dimethoxyphenyl) -L-alanyl] -2-aminohexanoic acid and pharmaceutically acceptable salts thereof.

28. A pharmaceutical composition, characterized by comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of the formula I: R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the Phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, (c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl , thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include the a-haloalkyl, a-diazoalkyl or -OC (O) alkyl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and wherein R' and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X may also be - CRR4Y 'wherein each R4 is independently selected from the group consisting of hydrogen, alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, and with the proviso that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derivative of D-phenylalanine, then X is not -C (0) OCH3.

29. The pharmaceutical composition according to claim 26, characterized in that R1 is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazol-6-yl and 5-indolyl.

30. The pharmaceutical composition according to claim 26, characterized in that R1 is a substituted phenyl group of the formula: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the Phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen.

31. The pharmaceutical composition according to claim 26, characterized in that R1 is a 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo , cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl.

32. The pharmaceutical composition according to claim 26, characterized in that R1 is a substituted heteroaryl containing 1. to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the proviso that the substituents are not ortho to the heteroaryl linkage to the -NH group.

33. The pharmaceutical composition according to claim 30, characterized in that R1 is a 4-substituted, 3,5-disubstituted or 3,4-disubstituted phenyl.

34. The pharmaceutical composition according to claim 31, characterized in that R1 is a 3,5-disubstituted phenyl.

35. The pharmaceutical composition according to claim 32, characterized in that the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (trifluoromethyl) phenyl and 3, 5-dimethoxyphenyl.

36. The pharmaceutical composition according to claim 31, characterized in that R1 is a 3-disubstituted phenyl.

37. The pharmaceutical composition according to claim 34, characterized in that the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3- chloro-4-cyanophenyl, 3-chloro-4-iodophenyl and 3-methylenedioxyphenyl.

38. The pharmaceutical composition according to claim 31, characterized in that R1 is a 4-substituted phenyl.

39. The pharmaceutical composition according to claim 36, characterized in that the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4- iodophenyl, 4- (phenylcarbonyl) phenyl and 4- (1-ethoxy) ethylphenyl.

40. The pharmaceutical composition according to claim 26, characterized in that R1 is 2-methylquinolin-6-yl.

41. The pharmaceutical composition according to claim 26, characterized in that R2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms and aryl.

42. The pharmaceutical composition according to claim 39, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, -CH2CH2SCH3 and phenyl.

43. The pharmaceutical composition according to claim 26, characterized in that R3 is an alkyl group. .

44. The pharmaceutical composition according to claim 41, characterized in that the aryl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl.

45. The pharmaceutical composition according to claim 26, characterized in that R3 is a substituted alkyl group.

46. The pharmaceutical composition according to claim 43, characterized in that the substituted alkyl group is selected from the group consisting of a-hydroxyethyl, -CH2-cyclohexyl, benzyl, p-hydroxybenzyl, 3-iodo-4-hydroxybenzyl, 3, 5- diiodo-4-hydroxybenzyl, -CH2-indol-3-yl, - (CH2) 4-NH-B0C, - (CH2) 4-NH2, CH2- (lN-benzyl-imidazol-4-yl), -CH2- imidazol-4-yl, -CH2CH2SCH3, - (CH2) 4NHC (O) (CH) 3CH3, and - (CH2) and C (O) OR5 where y is 1 or 2 and R5 is hydrogen, methyl or tert-butyl.

47. The pharmaceutical composition according to claim 26, characterized in that X is -C (0) Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy.

48. The pharmaceutical composition according to claim 45, characterized in that Y is alkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy and tert-butoxy.

49. The pharmaceutical composition according to claim 26, characterized in that X is -C (0) Y and Y is -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic and wherein R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups.

50. The pharmaceutical composition according to claim 47, characterized in that Y is selected from the group consisting of amino (-NH2), N- (iso-butyl) amino, N-methylamino, N, -dimethylamino, and N-benzylamino.

51. The pharmaceutical composition according to claim 26, characterized in that X is -CH20H.

52. The pharmaceutical composition according to claim 26, characterized in that the compound of the formula I is selected from the group consisting of: N- [N- (3,4-dichlorophenyl) -lanyl] valine N-iss-butyl methyl ester N- [N- (3,4-dichlorophenyl) alanyl] valine N, N- [N- (3,4-dichlorophenyl) -annyl] threonine methyl ester, N- [N- (3,4-dichlorophenyl) ethyl ester ) - alanyl] valine tert-butyl ester of N- [N- (3,4- dichlorophenyl) -lanyl] valine amide of N- [N- (3,4-dichlorophenyl) alanyl] valine? - (1-hydroxy) 3-Methyl-2-butyl) N- (3,4-dichlorophenyl) alanine N, N, N-dimethyl amide of N- [N- (3,4-dichlorophenyl) -aryl] valine N-methyl amide of N- [N- (3,4-dichlorophenyl) -arylanyl] valine N- [N- (3,4-dichlorophenyl) -lanyl] alanine methyl ester methyl ester of N- [N- (3,4-dichlorophenyl) -alanil ] Leucine methyl ester of N- [N- (3,4-dichlorophenyl) -10 alanyl] phenylalanine N- [N- (3, 4-dicl) methyl ester orophenyl) - alanyl] isoleucine N- [N- (3,4- dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester N- [N- (3,4-dichlorophenyl) alanyl] methyl ester] -2- aminohexanoic N- [N- (3,4-dichlorophenyl) -lanyl] tryptophan methyl ester of N- [N- (3,4- 20 dichlorophenyl) alanyl] aspartic ester β- (tert-butyl ester) ) N- [N- (3,4-dichlorophenyl) alanyl] aspartic acid methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] -? - BOC-lysine methyl ethyl ester N- [N-benzothiazol-6-yl] alanyl] -2-aminohexanoic methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] lysine N- [N- (3,4-dichlorophenyl) methyl ester ) - alanyl] tyrosine methyl ester of N- [N- (3,5-dichlorophenyl) -lanyl] alanine methyl ester of N- [N- (3,5- 10-dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester of N- [N- (3,5- dichlorophenyl) alanyl] phenylalanine ester β- (methyl ester) α-methyl acid N- [N- (3,4-dichlorophenyl) alanyl] aspartic acid methyl ester of N- [N- (3,4-dichlorophenyl) alanyl] -1-benzylhistidine ester? - (tert-butyl ester) α-methyl N- [N- (3,4-dichlorophenyl) alanyl] leucine N- [N- (3, 4-dichlorophenyl) alanyl] glutamic acid amide 20 N- [N- (3,4- dichlorophenyl) alanyl] glutamic acid methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] - (3,5-diiodo) tyrosine ester N- [N- (3,4-dichlorophenyl) -25-alanyl] - (3-iodo) -tyrosine methyl ester of N- [N- (3,5- dichlorophenyl) glycyl] -2-aminopentanoic acid methyl ester N- [N- (3,4- dichlorophenyl) alanyl] -Ne- (hexanoyl) lysine N- [N- (3,4-dichlorophenyl) alanyl] -phenylalanine amide N- [N- (3,4-dichlorophenyl) ) alanyl] -2-aminohexan- (N-methyl) -amide methyl ester of N- [N- (3,4-dichlorophenyl) -10 alanyl] -β-cyclohexylalanine N- [N- (3,4-dichlorophenyl) alanyl] -2- aminohexanamide N- [N- (3, 4-dichlorophenyl) alanyl] -2-aminohexan- (N, N-dimethyl) -amide N- [N- (3,4-dichlorophenyl) methyl ester) - alanyl] methionine N- [N- (3,5-dichlorophenyl) alanyl] -2-aminohexan- (N, N-dimethyl) -amide N- [N- (3,5-dichlorophenyl) alanyl] -2- 20 aminohexanamide N- [N- (3, 5-dichlorophenyl) alanyl] -2-aminohexan- (N-methyl) -amide N- [N- (3,4-dichlorophenyl) -arylanyl] histidine methyl ester of N- [N- (quinoline- 3- il) alanyl] -2-aminohexanoic acid methyl ester N- [N- (benzothiazol-2-yl) alanyl] -2-aminohexanoic methyl ester of N- [N- (3,5-difluorophenyl) -lanyl] alanine N- [N- (3,5-difluorophenyl) alanyl] -2-aminohexanoic acid methyl ester N- [N- (3,4-dichlorophenyl) -L-alanyl] -S-2-aminohexanamide N- [ N- (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N-benzyl) -amide N- [N- (3,4-dichlorophenyl) alanyl] -D, L-alanyl] -2- 2-amino -2-phenylethanol 15 N- [N- (3, 5-dichlorophenyl) -phenylglycinyl] alanine methyl ester N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexanol N- [N- (3, 5-dichlorophenyl) alanyl] -2-amino-2-phenylethanol 20 N- [N- (3,5-dichlorophenyl) -L-alanyl] -L-phenylglycine ter-butyl ester of N- [N - (3, 5-di- (trifluoromethyl) phenyl) -L-alanyl] -L- phenylgli It contains N- [N- (3,5-dimethoxyphenyl) -L-alanyl] -2-aminohexanoic acid methyl ester and pharmaceutically acceptable salts thereof.

53. A compound of formula III characterized in that: R1 is selected from the group consisting of (a) phenyl, (b) a substituted phenyl group of formula II: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen, '(c) 2-naphthyl, (d) 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy , halo, cyano, nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl, (e) heteroaryl, and (f) substituted heteroaryl containing 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the proviso n that the substituents are not ortho to the heteroaryl linkage to the -NH group; R2 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms, aryl, heteroaryl, substituted aryl and substituted heteroaryl with the proviso that the substituents are not ortho to the union of the aryl or heteroaryl atom to the carbon atom; R3 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, substituted alkyl, substituted alkenyl, substituted alkynyl and heterocyclic; X is -C (0) Y where Y is selected from the group consisting of (a) alkyl, (b) substituted alkyl with the proviso that substitution in the substituted alkyl does not include the a-haloalguyl, a-diazoalkyl or -OC (O) alkyl, (c) alkoxy or thioalkoxy, (d) substituted alkoxy or substituted thioalkoxy, (e) hydroxy, (f) aryl, (g) heteroaryl, (h) heterocyclic, (i) -NR'R "wherein R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl , aryl, heteroaryl, heterocyclic, and wherein R 'and R "are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and when R3 contains at least 3 carbon atoms, X can also be -CR4R4Y 'where each R4 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y 'is selected from the group consisting of hydroxyl, amino, thiol, -OC (0) R5, -SSR5, -SSC (0) R5 where R5 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl , heteroaryl and heterocyclic, and with the condition n that when R1 is 3,4-dichlorophenyl, R2 is methyl, and R3 is benzyl derivative of D-phenylalanine, then X is not -C (0) OCH3. and even with the additional condition of excluding the following known compounds: when R1 is phenyl, R2 is methyl, X is -C (O) NH0, then R3 is not methyl, iso-propyl, isobutyl; and when R1 is phenyl, R2 is methyl, X is -C (0) NH2, then R3 is not benzyl.

54. The compound according to claim 51, characterized in that R1 is phenyl, 2-naphthyl, quinolin-3-yl, benzothiazl-6-yl and 5-indolyl.

55. The compound according to claim 51, characterized in that R1 is a substituted phenyl group of the formula: wherein Rc is selected from the group consisting of acyl, alkyl, alkoxy, alkylalkoxy, azido, cyano, halo, hydrogen, nitro, trihalomethyl, thioalkoxy, and wherein Rb and Rc are fused to form a heteroaryl or heterocyclic ring with the Phenyl ring, Rb and Rb 'are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, alkoxy and thioalkoxy with the proviso that when Rc is hydrogen, then Rb and Rb' are either both hydrogen or both substituents other than hydrogen.

56. The compound according to claim 51, characterized in that R1 is a 2-naphthyl substituted at positions 4, 5, 6, 7 and / or 8 with 1 to 5 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano , nitro, trihalomethyl, thioalkoxy, aryl and heteroaryl.

57. The compound according to claim 51, characterized in that R1 is a substituted heteroaryl containing from 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cyano, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy with the condition that the substituents are not ortho to the heteroaryl linkage to the -NH group.

58. The compound according to claim 55, characterized in that R1 is a 4-substituted, 3,5-disubstituted or 3,4-disubstituted phenyl.

59. The compound according to claim 56, characterized in that R1 is a 3,5-disubstituted phenyl.

60. The compound according to claim 57, characterized in that the 3,5-disubstituted phenyl is selected from the group consisting of 3,5-dichlorophenyl, 3,5-difluorophenyl, 3,5-di (trifluoromethyl) phenyl and 3, 5 -methoxyphenyl.

61. The compound according to claim 56, characterized in that R1 is a 3,4-disubstituted phenyl.

62. The compound according to claim 59, characterized in that the 3,4-disubstituted phenyl is selected from the group consisting of 3,4-dichlorophenyl, 3,4-difluorophenyl, 3- (trifluoromethyl) -4-chlorophenyl, 3-chloro 4-cyanophenyl, 3-chloro-4-iodophenyl and 3,4-methylenedioxyphenyl.

63. The compound according to claim 56, characterized in that R1 is a 4-substituted phenyl.

64. The compound according to claim 61, characterized in that the 4-substituted phenyl is selected from the group consisting of 4-azidophenyl, 4-bromophenyl, 4-chlorophenyl, 4-cyanophenyl, 4-ethylphenyl, 4-fluorophenyl, 4-iodophenyl , 4- (phenylcarbonyl) phenyl and 4- (1-ethoxy) ethylphenyl.

65. The compound according to claim 51, characterized in that R1 is 2-methylquinolin-6-yl.

66. The compound according to claim 51, characterized in that R 2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms and aryl.

67. The compound according to claim 64, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, -CH2CH2SCH3 and phenyl.

68. The compound according to claim 51, characterized in that R3 is an alkyl group.

69. The compound according to claim 66, characterized in that the aryl group is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and sec-butyl.

70. The compound according to claim 51, characterized in that R3 is a substituted alkyl group.

71. The compound according to claim 68, characterized in that the Substituted alkyl group is selected from the group consisting of a-hydroxyethyl, -CH2-cyclohexyl, benzyl, p-idroxybenzyl, 3-iodo-4-hydroxybenzyl, 3,5-diiodo -4-hydroxybenzyl, -CH2-indol-3-yl, - (CH2) 4-NH-B0C, - (CH2) 4-NH2, CH2- (lN-benzyl-imidazol-4-yl), -CH2-imidazole -4-yl, -CH2CH2SCH3, - (CH2) 4NHC (O) (CH2) 3CH3, and - (CH2) and C (O) OR5 where y is .1 or 2 and R5 is hydrogen, methyl or tert-butyl.

72. The compound according to claim 51, characterized in that X is -C (0) Y wherein Y is selected from the group consisting of alkoxy and thioalkoxy.

73. The compound according to claim 70, characterized in that Y is alkoxy selected from the group consisting of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy and tert-butoxy.

74. The compound according to claim 51, characterized in that X is -C (0) Y and Y is -NR'R ", where R 'and R" are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic and wherein R 'and R "are joined to form a cyclic group having 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy group.

75. The compound according to claim 72, characterized in that Y is selected from the group consisting of amino (-NH), N- (isobutyl) amino, N-methylamino, N, N-dimethylamino, and N-benzylamino.

76. The compound according to claim 51, characterized in that X is -CH 2 OH.

77. The compound according to claim 51, characterized in that the compound of the formula I is selected from the group consisting of: N- [N- (3,4-dichlorophenyl) -lanyl] valine methyl ester N-iso-butyl amide N- [N- (3,4-dichlorophenyl) alanyl] valine N- [N- (3,4-dichlorophenyl) -lanyl] threonine methyl ester N- [N- (3,4-dichlorophenyl) ethyl ester] - alanyl] valine tert-butyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] valine amide of N- [N- (3,4-dichlorophenyl) alanyl] valine? - (1-hydroxy-3) N- (3,4-dichlorophenyl) alanine N, N- (N- (3,4-dichlorophenyl) -lanyl] valine N- (3,4-dichlorophenyl) alanine N, N-N-dimethyl amide N- (3,4-dichlorophenyl) -arylanyl] valine N- [N- (3,4-dichlorophenyl) -lanyl] alanine methyl ester N- [N- (3,4-dichlorophenyl) -lanyl] methyl ester] Leucine methyl ester of N- [N- (3,4-dichlorophenyl) -lanyl] phenylalanine N- [N- (3,4-dichlorophenyl) -lanyl] methyl ester] Isoleucine N- [N- (3,4- dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester N- [N- (3,4- dichlorophenyl) alanyl] -2-aminohexanoic acid methyl ester of N- [N- (3,4-dichlorophenyl) -10-alanyl] tryptophan-α-methyl ester of N- [N- (3,4- dichlorophenyl) alanyl] aspartic acid β- (tert-butyl ester) α-methyl acid ester N- [N- (3,4-dichlorophenyl) alanyl] aspartic N- [N- (3,4-dichlorophenyl) -lanyl] -N-BOC-lysine methyl ester of N- [N-benzothiazol-6-yl] alanyl] -2-aminohexanoic acid N-methyl ester - [N- (3,4-dichlorophenyl) -20 alanyl] -lysine methyl ester of N- [N- (3,4-dichlorophenyl) -arylanyl] tyrosine N- [N- (3,5-dichlorophenyl) methyl ester) - alanyl] alanine N- [N- (3,5-dichlorophenyl) alanyl] -2-aminopentanoic acid methyl ester of N- [N- (3,5-dichlorophenyl) alanyl] phenylalanine ester β- (methyl ester) ) N- [N- (3,4-dichlorophenyl) alanyl] aspartic acid methyl ester of N- [N- (3,4- dichlorophenyl) alanyl] -1-benzylhistidine ester? - (tert-butyl ester) a-methyl from N- [N- (3,4-dichlorophenyl) alanyl] glutamic acid amide of N- [N- (3,4-dichlorophenyl) alanyl] leucine a-methyl ester of N- [N- (3,4- Dichlorophenyl) alanyl] glutamic methyl ester of N- [N- (3,4-dichlorophenyl) -5-alanyl] - (3,5-diiodo) tyrosine methyl ester of N- [N- (3,4-dichlorophenyl) - alanyl] - (3-iodo) tyrosine N- [N- (3,5-dichlorophenyl) glycyl] -2-aminopentanoic acid methyl ester N- [N- (3,4-dichlorophenyl) alanyl] methyl ester - Ne- (hexanoyl) lysine amide of N- [N- (3,4-dichlorophenyl) alanyl] -phenylalanine N- [N- (3, -dichlorophenyl) alanyl] -2-aminohexan-25 (N-methyl) -amide N- [N- (3,4-dichlorophenyl) -lanyl] -β-cyclohexylalanine methyl ester N- [N- (3,4-dichlorophenyl) alanyl] -2-aminshexanamide N- [N- (3, 4- dichlorophenyl) alanyl] -2-aminohexan- (N, N-dimethyl) -amide N- [N- (3,4-dichlorophenyl) -lanyl] methionine N- [N- (3,5-dichlorophenyl) alanyl methyl ester ] -2-aminohexan-10 (N, N-dimethyl) -amide N- £ N- (3, 5- dichlorophenyl) alanyl] -2- aminohexanamide N- [N- (3, 5-dichlorophenyl) alanyl] -2-aminohexan- (N-methyl) -amide N- [N- (3,4-dichlorophenyl) methyl ester) - alanyl] histidine N- [N- (quinolin-3-yl) alanyl] -2-aminohexanoic acid methyl ester N- [N- (benzothiazol-2-yl) -L-alanyl] -2 -aminohexanoic N- [N- (3,5-difluorophenyl) -lanyl] alanine methyl ester of N- [N- (3,5-difluorophenyl) alanyl] -2-aminohexanoic acid N- [N- (3 , 4-dichlorophenyl) -L-alanyl] -S-2-aminohexanamide N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexan- (N-benzyl) -amide N- [N- (3, 4-dichlorophenyl) -D, L-alanyl] -2-amino-2-phenylethanol methyl ester of N- [N- (3,5-dichlorophenyl) -phenylglycinyl] alanine N- [N- (3,4-dichlorophenyl) alanyl] -2-aminohexanol 10 N- [N- (3,5-dichlorophenyl) alanyl] -2-amino-2-phenylethanol tert-butyl ester of N- [N- (3,5-dichlorophenyl) -L-alanyl] -L-phenylglycine ester N- [N- (3, 5-di-15 (trifluoromethyl) phenyl) -L-alanyl] -L- phenylglycine N- [N- (3,5-dimethoxyphenyl) -L- methyl ester alanyl] -2-aminohexanoic and pharmaceutically acceptable salts of the 20 same.