MXPA99004394A - N-(ARYL/HETEROARYL/ALKYLACETYL) AMINO ACID AMIDES, 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 treatingAlzheimer's disease both prophylactically and therapeutically with such pharmaceutical compositions. Said compounds are represented by formula (I), wherein R 1 is selected from the group consisting of:a) alkyl, alkenyl, alkaryl, alkcycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic;b) a substituted phenyl group of formula (II), wherein R is alkylene of from 1 to 8 carbon atoms, m is an integer equal to 0 or 1, and c) 1- or 2-naphthyl substituted at the 5, 6, 7 and/or 8 positions, R 2 is selected from the group consisting of hydrogen, alkyl of from 1 to 4 carbon atoms, alkylalkoxy of from 1 to 4 carbon atoms, alkylthioalkoxy of from 1 to 4 carbon atoms;and R 3 and R 3'are independently selected from the group consisting of:(a) hydrogen, (b) alkyl, (c) -(R 7) n(W) p, wherein R 7 is an alkylene group, W is selected from the group consisting of (i) formula (A);(ii) heteroaryl;and (iii) N-heterocyclic, and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3;(d) -CH(&phgr;)CH 2C(O)O-Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic;X'is hydrogen, hydroxy or fluoro;X''is hydrogen, hydroxy or fluoro, or X'and X''together form an oxo group, Z is selected from the group consisting of a bond covalently linking R 1 to -CX'X''-, oxygen and sulfur.

Description

AMIDAS DE N- (ARIL / HETEROARIL / ALQUILACETIL) AMINOÁCIDO, PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THE SAME, AND METHODS TO INHIBIT THE LIBERATION OF THE BETA-AMOLOID PEPTIDE? / 0 YOUR SYNTHESIS FOR THE USE OF SUCH COMPOUNDS REFERENCE FOUND FOR RELATED APPLICATIONS This application claims the benefit of the following U.S. Provisional Requests: 1. Provisional Application U.S. No. 60 /,, which became following the 37 C.F.R. § 1.53 (b) (2) (ii) of the U.S. Patent Application. No. 08 / 754,895, published November 22, 1996; and 2. Provisional Application U.S. No. 60 /,, which became following the 37 C.F.R. § 1.53 (b) (2) (ii) of the U.S. Patent Application. No. 08 / 7807,538, published on February 28, 1997, which are incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION Field of the Invention REF .: 30105 This application refers to compounds that inhibit the release of β-amyloid cell peptide and / or its synthesis, and, therefore, have utility in the treatment of Alzheimer's disease. This invention also relates to pharmaceutical compositions containing such compounds as well as methods for inhibiting the release of β-amyloid peptide.

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 Cerebral Novel Amyloid Protein ", Bi och., Bi ophys Res. Commun., 120: 885-890 (1984).

: Glenner, et al., "Polypept ide Marker for Alzheimer's Disease its Use for Diagnosis ", U. S. Pa t en t No. 4,666,829 published on 19 May 1987 Selkoe, "The Molecular Pathology of Alzheimer's Disease", Neuron, 6: 487-489 (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 Protecur Precursor Gene ", Na ture, 353: 844-846 (1989).

Murrell, et al., "A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease," Sci ence, 254: 97-99 (1991).

Mullan, et al., "A Pathogenic Mutation for Probable Alzheimer's Disease in the APP Gene at the N-Terminus of ß-Amyloid, Na ture Genet., 1: 345-347 (1992).

Schenk, et al., "Methods and Compositions for the Detection of Soluble ß-Amyloid Peptide", International Patent Application Publication No. WO 94/10569, published May 11, 1994. 9 Selkoe, "Amyloid Protein and Alzheimer's Disease ", Scientific American, pp. 2-8, November, 1991.

Tetrahedron Letters, 34 (48), 7685 (1993) Losse, et al., Tetrahedron, 27: 1423-1434 (1971) : - Citron, et al., "Mutation of the ß-Amyloid Precursor Protein in Familial Alzheimer's Disease Increases ß-Protein Production, Nature, 360: 672-674 (1992).

:? 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 extent as if each individual publication, patent or 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 progressive loss of memory, recognition, reasoning, judgment and emotional stability that gradually leads to deep mental deterioration and finally to death. AD is a very common cause of progressive mental failure (dementia) in older 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 represents one of the main public health problems nowadays and in the future. The disease is currently estimated to affect approximately two to three million individuals in the United States alone. AD is incurable in the present. Currently there is no known treatment to effectively prevent AD or reverse its symptoms and course.

The brains of individuals with AD exhibit characteristic lesions named senile plaques (or amyloid), amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary agglomerates. A large number of these lesions, particularly amyloid plaques and neurofibrillary agglomerates, are generally found in several areas of the human brain important for memory and recognition function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of older 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 (HCHWA-D). At present, 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 samples of brain tissue biopsies taken during an invasive neurosurgical procedure.

The main chemical constituent of amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and other malignancies mentioned above is a protein of approximately 4.2 kilodalton (KD) of approximately 39-43 amino acids designated β-amyloid peptide (βAP) 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 al.1 The isolation procedure and sequence results for the first 28 amino acids are described in U.S. Pat. No. 4,666,8292.

Molecular biology and protein chemistry analyzes have shown that 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 peptide fragment that is cut from APP by means of enzyme (s) protease (s). The precise biochemical mechanism by which the β-amyloid peptide fragment is cut from 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 indicates that the progressive cerebral deposition of β-amyloid peptide plays a seminal role in the pathogenesis of AD and may precede recognition symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that the nonsense mutations of DNA in amino acid 717 of the 770 amino acid isoform of APP can be found in affected members but not in unaffected members of several families with a genetically determined form (familial ) of AD (Goate, et al.4; Chartier Harían, et al.5; and Murrell, et al.6) 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 al.7). In the genetic linkage analysis it has been shown that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at 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 at amino acid 692 which causes a phenotype that resembles AD in some patients but to HCHWA-D in others. The discovery of these and other mutations in APP cases genetically based AD test that altering APP and subsequent deposition of its β-amyloid peptide fragment can cause AD.

Despite the progress that has been made to understand the outstanding 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 advantageously be based on drugs that are capable of inhibiting the release of the β-amyloid peptide and / or its synthesis in vi ve.

BRIEF DESCRIPTION OF THE INVENTION This invention is directed to the discovery of a class of compounds that inhibit the release of β-amyloid peptide and / or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and / or in the treatment of patients with AD to inhibit further deterioration in their condition. The class of compounds having the described properties are defined by the following formula I: wherein R1 is selected from the group consisting of a) alkyl, alkenyl, alkaryl, alkylenecycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy; b) a substituted phenyl group of formula II Rb 'Ra' II R- (R) - wherein R is alkylene of 1 to 8 carbon atoms, m is an integer equal to 0 or 1, Ra and Ra 'are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl; Rb and Rb 'are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C (0) R4 wherein R4 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy; and Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and wherein Rfc and R = are fused to form a methylenedioxy ring with the phenyl ring; and where R and / or Ri 'and / or Rr is fluoro, chloro, bromo and / or nitro, then Ra and / or R3' may also be chloro; Y (c) 1- or 2-naphthyl substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; R: is selected from the group consisting of hydrogen, alkyl, from 1 to 4 carbon atoms, alkylalkoxy from 1 to 4 carbon atoms, alkylthioalkoxy from 1 to 4 carbon atoms; and R3 and R3 'are independently selected for the group consisting of: (a) hydrogen with the proviso that R3 and R3' can not be hydrogen; (b) alkyl with the proviso that when R3 is hydrogen, then the alkyl group R3 has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom this chain can be optionally substituted with one or more alkyl groups with the additional proviso that R3 and R3 'are alkyl then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms this chain can be optionally substituted with one or more alkyl groups; (c) - (R7) n (W) p wherein R7 is an alkylene group, W is selected from the group consisting of: (i) where R5, R5 ', R9 and R9' are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl, heteroaryl and heterocyclic esters; and R6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters , heteroaryl, heterocyclic and wherein R6 and one of R5 or R5 'are fused to form a heterocyclic ring of 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; with the condition of when n is zero, R9 and R? ' they are hydrogen; (ii) heteroaryl; and (iii) N-heterocyclic with the proviso that when W is β -heterocyclic then n-is not zero; and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to 1, and (d) -CH (f) CH2C (0) 0-Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R: to -CX'X "-, oxygen and sulfur; with the proviso that when R1 is phenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R" 1 to -CX'X "-, m is zero, R3 is hydrogen, R3' is - (R ") (W) F where n is zero and p is one and W is then (i) R5, R5 ', R9, R9' and R6 are not all hydrogen and (ii) R5, R5 ', R9, R9' are hydrogen and R6 is methoxy; with the additional proviso that when R1 is 3,5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen , R3 'is - (R7) n (W) p where n is one and p is one, R7 is ethylene and W is then R5, R5 ', R9, R9' and R6 are not all hydrogen; Y even with the additional proviso that when R1 is 3, 5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, and m is zero, R3 is hydrogen, R3 'is - (R7) n (W) p where n is zero and p is one, W is and R5 ', R9, R9' are hydrogen, then R5 and R6 do not fuse to form, with the phenyl ring to which they are attached, an ft.alimido group.

Accordingly, in one of its aspects of the method, this invention is directed to the method for inhibiting the release of the β-amyloid peptide and / or its synthesis in a cell. This method comprises administering to said cell an amount of a compound or a mixture of compounds of formula I above effective to inhibit cell release and / or synthesis of β-amyloid peptide.

Because the generation in vi vo of the β-amyloid peptide is associated with the pathogenesis of the AD8'9, the compounds of the formula I can also be used in conjunction with a pharmaceutical composition to prevent and / or prophylactically and / or therapeutically treat AD. Accordingly, in another of its aspects 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 this method comprises administering to the patient a pharmaceutical composition containing a pharmaceutically inert carrier and an effective amount of a compound or mixture of compounds of formula I above.

In yet another aspect of the method, this invention is directed to a therapeutic method for the treatment of a patient with AD to inhibit further deterioration in the patient's condition. This method comprises administering to the patient a pharmaceutical composition containing a pharmaceutically inert carrier. and an effective amount of a compound or mixture of compounds of formula I above.

In formula I above, the preferred unsubstituted aryl groups R include, for example, phenyl, 1-naphthyl, 2-naphthyl, and the like.

Preferred R1 substituted aryl groups include, for example, monosubstituted phenyls having a simple substitution at positions 2, 3 or 4 where each of the particular substituents is governed by the respective Ra, Rb and Rc groups; disubstituted phenyls including those having two substituents in positions 2,3, positions 2,4, positions 2,5, positions 2,6, positions 3,4, positions 3,5 or positions 3,6 where each of these substituents are governed by respective Ra, Ra ', Rb, Rb' and Rc groups; and trisubstituted phenyls including those having three substituents at positions 2,3,4, positions 2,3,5, positions 2,3,6, positions 3,4,5 and positions 3,4,6 again where each one of these substituents are governed by respective Ra, Ra ', R, R *' and R groups. Preferably, the substituted phenyl groups do not include more than 3 substituents.

Examples of substituted phenyls include, for example, -fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nor rophenyl, -met-ilphenyl, 3-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, -bro ofhenyl, 3-ethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxy-phenyl, 2-methylphenyl, 2-fluorophenyl, 3,4-dichlorophenyl, 3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3, 5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-difluorophenyl.

Preferred R 1 alkaryl groups include, by way of example, benzyl, 3-phenylethyl, 4-phenyl-n-propyl, and the like.

Preferred alkyl, cycloalkyl and cycloalkenyl groups R1 include, by way of example, sec-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl, CH2-cyclobutyl, -CH2-cyclohexyl, -CH2 -cyclopentyl, -CH2CH2-cycloalkyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl, and the like.

Preferred substituted heteroaryls and R1 heteroaryls include, by way of example, pyrid-3-yl, pyrid-4-yl, thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazole- 5-yl, furan-2-yl, benzofuran-2-yl, thionaphth-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2- (thiophenyl) thiophen-5-yl, -metoxitionaften-2-yl, 3-phenyl-l, 2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.

Preferably R2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms and alkylthioalkoxy of 1 to 4 carbon atoms. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, -CH2CH2SCH3, and the like.

Preferably, R3 is hydrogen and R3 'is selected from the group consisting of 3-hydroxyphenyl, 3-methoxyphenyl, 3-ethoxycarbonylphenyl, n-hexyl, n-octyl, 4-ethoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-chlorophenyl, -cyanophenyl, 3, 5-dichlorophenyl, CH (CH:,) f (stereoisomer R), -CH (CH 3) f (stereoisomer S), phthal id-6-yl, 2-hydroxypi rid-3-yl, 2- (methoxycarbonylmethyl) benzyl, 3- (methoxycarbonyl) benzyl, 2- (2'-methoxycarbonylmethylphenyl) benzyl, and 2-phenylbenzyl.

Particularly preferred compounds for use in the methods and compositions of this invention include, by way of example, the following: N- (3-hydroxyphenyl) -N '- (phenylacetyl) -L-alaninamide N- (3-met oxy phenyl) -N' - (phenylacetyl) -L-alaninamide N- (3-ethoxy phenyl) -N '- (phenylacetyl) -L-alaninamide N- (4-ethoxycarbonylphenyl) -N' - (phenylacetyl) -L-alaninamide N- (n-hexyl) -N'- ( 3, 5-difluorophenylacetyl) -L-alaninamide N- (n-octyl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- (3-methoxy phenyl) -N' - (3, 5 difluoro phenylacetyl) -L-alaninamide N- (4-ethoxycarbon if in) - N '- (3, 5-difluoro phenylacetyl) -L-alaninamide N- (3-oxo ca rbon ilf eni l ) -N '- (3, 5-difluoro-phenylacetyl) -L-alaninamide N- (3-chlorophenyl) -N' - (3, 5-difluorof in useful lace) -L-alaninamide N- (3, 5) -dichlorophenyl) -N '- (3, 5-difluorophenylacetyl) -L-alani amide N- (3-cyanophenyl) -N' - (3, 5-difluoro-phenylacetyl) -L-alaninamide N- (ftalid-β- il) -N'- (3, 5-difluoro-phenylacetyl) -L-alaninamide N- [(4-methoxycarbonylphenyl) methyl] -N '- (3, 5 difluorophenylacetyl) -L-alaninamide N- (1-cyano) -phenyl-1-yl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- [(R) -l-phenylethyl] -N' - (3, 5-difluorophenylacetyl- alaninamide Nl (S) -l-phenylethyl] -N '- (3, 5-difluorophenylacetyl L-alaninamide N- [2 -hi drox ip i ridi n-3-yl] -N' - (3, 5 difluorophenylacetyl) - L-alaninamide N- [2-methoxycarbonyl-1-phenylethyl] -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- [-pyridin-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [1- (α-phthalamido) pent-2-yl] -N' - (3, 5 - difluorophenylacetyl) -L-alaninamide N- [2- (methoxycarbonylmethyl) benzyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [3- (methoxycarbonylmethyl) encyl] -N '- (3,5-di-fluoro-phenylacetyl) -L-alani-amide N- [2- (2'-methoxycarbonylmethyl) benzyl] -N '- (3,5-difluoro-phenylacetyl) -L-alaninamide N- [2-phenylbenzyl] -N '- (3, 5-di-fluoro-phenylacetyl) -L-alaninamide In addition, this invention provides novel compounds of formula I above. Preferred compounds are represented by formula II in Table I below: DETAILED DESCRIPTION OF THE INVENTION As before, this invention relates to compounds that 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 more detail, the following terms will be defined first.

Definitions The term "β-amyloid peptide" refers to a peptide of 39-43 amino acids having a molecular weight of about 4.2 kD, this peptide being substantially homologous to the protein form described by Glenner, et al.1 which includes mutations and post-translational modifications of the normal β-amyloid peptide. Either way, the β-amyloid peptide is a fragment of approximately 39-43 amino acids of a large glycoprotein that extends into the membrane, referred to as the β-amyloid precursor protein (APP). Its sequence of 43 amino acids is: 1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Wing Glu Asp Val Gly Ser Asn Lys Gly Wing 3_ lie lie Gly Leu Met Val Gly Gly Val Val 41 He Ala Thr (SEQ ID NO: 1) or a sequence that is substantially homologous to it.

"Alkyl" refers to monovalent alkyl groups preferably having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. 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, acyloxy, acylamino, amino, aminoacyl, esters of aminocarboxy, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxyl esters, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di- (substituted alkyl) amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and asymmetric di-substituted amides having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.

"Alkylene" refers to divalent alkylene groups preferably having 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms which may be straight or branched chain. 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 preferably having from 1 to 10 carbon atoms in the alkylene radical and from 6 to 14 carbon atoms in the aryl radical. Such alkaryl groups are exemplified by benzyl, phenethyl, and the like.

"Alkcycloalkyl" refers to -alkylene-cycloalkyl groups preferably having from 1 to 10 carbon atoms in the alkylene radical and from 3 to 8 carbon atoms in the cycloalkyl radical. Such alkylenecycloalkyl groups are exemplified by -CH2-cyclopropyl, -CH: CH-cyclohexyl, and the like.

"Alkoxy" refers to the group "alkyl-0-". 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 Similar.

"Substituted alkoxy" refers to the group "substituted-0-alkyl" where substituted alkyl is as defined above.

"Alkylalkoxy" refers to the group "-alkylene-O-alkyl" which includes, by way of example, methylenemethoxy (-CH20CH3), ethylenemethoxy (CH2CH20CH3), methylene-iso-propoxy (-CH2-0-CH (CH3) 2) and the like.

"Alkylthioalkoxy" refers to the group "-alkylene-S-alkyl" which includes by way of example, ethylenemethoxy (-CH2SCH:, ethylenethiomethoxy (-CH2CH2SCH3), methylene-iso-thiopropoxy (-CH2SCH (CH3) 2) and the like.

"Alkenyl" refers to alkenyl groups preferably having 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (-CH = CH2), n-propenyl (-CH: CH = CH2), iso-propenyl (-C (CH3) = CH2), and the like.

"Alkynyl" refers to alkynyl groups preferably 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 alkynyl unsaturation. Preferred alkynyl groups include ethynyl (-CH = CH2), propargyl (-CH2CH = CH2), and the like.

"Acyl" refers to the groups alkyl-C (0) -, alkyl-C (0) -substituted, cycloalkyl-C (0) -, aryl-C (O) -, and heterocyclic-C (0) - where alkyl, substituted alkyl, cycloalkyl, aryl and heteroaryl are as defined herein.

"Acylamino" refers to the group -C (0) NRR where each R is independently hydrogen or alkyl.

"Aminoacyl" refers to the group -NRC (0) R where each R is independently hydrogen or alkyl.

"Acyloxy" refers to the groups alkyl-C (0) 0-, alkyl-C (O) 0- substituted, cycloalkyl-C (0) 0-, aryl- C (0) 0-, heteroaryl-C (0) ) 0-, and heterocyclic-C (0) 0- where alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

"Aryl" refers to an unsaturated aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (eg, phenyl) or condensed multiple rings (eg, naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.

Unless otherwise restricted by the definition of the individual substituent, such aryl groups may be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, aryl, aryloxy, carboxyl, carboxyl esters, amino carboxyl esters, cyano, halo, nitro, heteroaryl, heterocyclic, thioalkoxy, trihalomethyl, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.

"Aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.

"Carboxyl" refers to the group -C (0) 0H; "carboxyl esters" refers to the groups -C (0) O-alkyl, -C (O) O-substituted alkyl, -C (0) O-aryl, -C (0) 0-heteroaryl, and -C (0) O-heterocyclic, and "aminocarboxyl esters" refers to the groups -NHC (0) 0R where R is alkyl, substituted alkyl, aryl, cycloalkyl, heteroaryl, or heterocyclic.

"Cycloalkyl" refers to cyclic alkyl groups of 3 to 10 carbon atoms having a single cyclic ring or condensed multiple rings which may optionally be substituted with 1 to 3 aryl groups. Such cycloalkyl groups include, by way of example, simple ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methyl-cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and Similar.

"Cycloalkenyl" refers to cyclic alkenyl groups of 4 to 10 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can 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 is preferably either fluoro 0 chlorine.

"Heteroaryl" refers to a monovalent aromatic carbocyclic group of 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur in the ring.

Unless otherwise restricted by the definition for the individual substituent, such heteroaryl groups may be optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, hydroxy, thioalkoxy, thioaryloxy, and the like. Such heteroaryl groups may have a single ring (eg, pyridyl or furyl) or multiple fused rings (eg, indonizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.

"Heteroaryloxy" refers to the group heteroaryl-O- where heteroaryl is as defined above and optionally includes substituted heteroaryl groups as defined above.

"Heterocycle" or "heterocyclic" refers to a monovalent saturated or unsaturated group having a single ring or condensed multiple rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, sulfur or oxygen in 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 alkyl, alkoxy, aryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy and similar. Such heterocyclic groups can have a single ring (eg, piperidinyl or tet rahidofuranyl) or condensed multiple rings.

Example of heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindol, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline , cinoline, pteridine, carba? ol, carboline, fenant ridine,. acridine, fenant rol ina, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydrosikinoline, 4, 5, 6, 7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

"Heterocyclyloxy" refers to the heterocyclic group -0- where heterocyclic is as defined above, optionally including substituted heterocyclic groups as defined above.

"Tiol" refers to the group -SH.

"Thioalkoxy" refers to the -S-alkyl groups wherein alkyl is as defined above.

"Alkoxy substituted with thio" refers to the alkoxy groups substituted with S wherein substituted alkoxy is as defined above.

"Thioaryloxy" refers to the group aryl-S- where the aryl group is as defined above and optionally includes substituted aryl groups as defined above.

"Thioheteroaryloxy" refers to the heteroaryl-S- group wherein the heteroaryl group is as defined above and optionally includes substituted aryl groups as defined above.

"Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of a compound of Formula I These salts 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, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic and inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.

Preparation of the Compound The compounds of formula I are easily prepared by various, divergent, synthetic routes selected with respect to the ease of preparation of the compound, commercial availability of starting materials, etc.

A first synthetic method involves the conventional coupling of an acid derivative with a primary amine of an esterified amino acid as shown in reaction (1) below: O O NCX "OH + 2 áí? R 'X' R2 (i) OR O R2 3 wherein R1, R2, X 'and X "are as defined above, and R' is preferably hydrogen or an alkyl group.

Reaction (1) only involves the coupling of a suitable acid derivative 1 with the primary amine of the amino acid / amino acid ester 2. under conditions that provide the N-acetyl derivative 3. This reaction is conventionally conducted for peptide synthesis and synthetic methods used here can also be used to prepare the N-acetyl amino acid / amino acid esters 3. For example, coupling reagents such as carbodiimides are well known with or without the use of Well-known additives such as? -hydroxysuccinimide, 1-hydroxybenzotriazole, etc. they can be used to facilitate the coupling. The reaction is conventionally conducted in an aprotic-metal diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.

Alternatively, in a preferred embodiment, the acid halide of compound 1 may be employed in reaction (1) and, when employed in this manner, it is typically employed in the presence of a suitable base to remove the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, α-methylmorpholine and the like.

The reaction (1) is preferably conducted from about 0 ° C to about 60 ° C until the completion of the reaction which typically occurs in 1 to about 24 hours. At the end of the reaction, the N-acetyl amino acid / amino acid ester 3. is recovered by conventional methods including precipitation, chromatography, filtration and the like or, alternatively in the case of the ester, is hydrolyzed to the corresponding carboxylic acid without purification and / or isolation different from the conventional technique (eg, aqueous extraction, etc.).

If an N-acetyl amino acid ester is formed, it is typically converted to the corresponding acid prior to coupling with an H? R3R3 'amine. Coupling is performed using well-known coupling chemistry with well-known coupling reagents such as carbodiimides with or without the use of well-known additives such as β-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. which can be used to facilitate the coupling. The reaction is conventionally conducted in a polar aprotic diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the ester group of 3 can, in some cases, be converted directly to an amide group via conventional ester / amide exchange reactions which are well known in the art.

In reaction (1), each of the reagents (1-acetic acid derivative and amino acid / amino acid ester 2.) are well known in the art with a plurality of each which is commercially available.

Alternatively, the compounds of formula I can be prepared by first forming the amino acid amide then N '-acetylating these esters. That is to say that the amine NHR3H3 'is coupled to the amino acid Block NHCHRCOOH blocked in N' via conventional coupling conditions to provide the amino acid amide Block? HCHR2 (O)? R3R3 'blocked at N'. The blocking group is then removed via conventional conditions to provide the free amide which is then acetylated in the manner described above to provide the compounds of formula I.

After the coupling and the? -acetylation (in any order) is completed, the resulting amides can be derived by conventional chemical means to provide the derivatives of the synthesized compounds. For example, the reactive functionality that is blocked in groups R2 and / or R3 can be unlocked and then derived. For example, an amino group protected with Boc in R2 (eg, lysine side chain) can be deblocked after synthesis and the amino group acylated or otherwise derivatized.

The compounds described herein can also be prepared by the use of polymer supported forms of carbodiimide peptide coupling reagents. A supported form of EDC polymer, for example, has been described (Tetrahedron Letters, 34 (48), 7685 (1993)) 10. Additionally, a novel carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms are have been exposed and are very useful for the preparation of the compounds of the present invention.

Polymers suitable for use in the manufacture of a polymer-supported coupling reagent are commercially available or could be prepared by methods well known to those skilled in the art of polymers. A suitable polymer must possess pendant side chains that have reactive radicals with the terminal amine of the carbodiimide. Such reactive radicals include chlorine, bromine, iodine and methanesulfonyl. Preferably, the reactive radical is a chloromethyl group. Additionally, the polymer structure must be inert to the carbodiimide and reaction conditions under which the last coupling reagents bonded to the polymer will be used.

Certain hydroxymethylated resins could be converted into chloromethylated resins useful for the preparation of polymer-supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethyl-phenylacetamidomethyl resin (Pam resin) and resin 4-benzyloxybenzyl alcohol (Resin Wang) available in Advanced Chemtech from Louisville, Kentucky, USA (see Advanced Chemtech catalog 1993-1994, page 115). The hydroxymethyl groups of these resins could be converted to the desired chloromethyl groups by any number of methods well known to the person skilled in the art.

The preferred resins are the chloromethoxy styrene / divinylbenzene resins due to their easy commercial availability. As the name suggests, these resins are already chloromethylated and do not require any chemical modification before being used. These resins are commercially known as Merrifield resins and are commercially available from Aldrich Chemical Company of Milwaukee, Wisconsin, USA (see Aldrich catalog 1994-1995, page 899). The methods for the preparation of PEPC and its polymer-supported forms are highlighted in the following scheme.

Functional resin where (P) - an inert polymer and LG = Cl. Br. I or OS02CH3 = Such methods are more fully described in U.S. Patent Application. Serial No. 60 / 019,790 published on June 14, 1996, whose application is hereby incorporated by reference in its entirety. In summary, the PEPC is prepared by first reacting the ethyl isocyanate with 1- (3-aminopropyl) pyrrolidone. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer-supported form is prepared by reacting the PEPC with an appropriate resin under standard conditions to give the desired reagent.

The coupling reactions of the carboxylic acid employing these reagents develop at about room temperature to about 45 ° C, for about 3 to 120 hours. Typically, the product could be isolated by washing the reaction with CHCl, and concentrating the organic remnants under reduced pressure. As discussed above, the isolation of products from reactions where a reagent bound to the polymer has been used is simplified, requiring only filtration of the reaction mixture and then the concentration of the filtrate under reduced pressure.

Still other methods for the preparation of esters are provided in the examples below.

In these synthetic methods, the starting materials may contain a chiral center (e.g., L-alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R, S enantiomers. Alternatively, a chiral isomer of the starting material can be used 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 R, S enantiomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. Alternatively, the chiral products can be obtained by purification techniques that separate enantiomers from a R, S mixture to provide one or the other stereoisomer. Such techniques are well known in the art.

Pharmaceutical Formulations When employed as pharmaceuticals, the compounds of 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 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 containing, as an active ingredient, one or more of the compounds of the formula I associated above with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by means of an excipient or stored inside such a vehicle which may be in the form of a capsule, powder bag, paper or another container. When the excipient serves as a diluent, it can be solid, semi-solid, or liquid material, which acts as a vehicle, excipient or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, powder bags, patches, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

To prepare a formulation, it may be necessary to grind the active compound to provide the appropriate particle size before combining 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 distribution in the formulation, p. ex. , 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; preservative agents such as methyl- and propylhydroxy benzoates; 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 employing procedures known in the art.

The compositions are preferably formulated in a unit dosage 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 dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity 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 at not more than about 20 weight percent of the pharmaceutical composition, more preferably not more than about 15 weight percent, with the balance being the pharmaceutically inert carrier.

The active compound is effective over a broad dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound administered will actually be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the existing 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 preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it means that the active ingredient is dispersed uniformly throughout the composition such that the composition could be easily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The 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 could be coated or otherwise compounded to provide a dosage form that provides the long-acting advantage. For example, the tablet or pill may comprise an internal dosage component and an external dosage component, the latter being in the form of a wrapper over the first. The two components can be separated by means of an enteric layer which serves to resist disintegration in the stomach and allows the internal component to pass intact in the duodenum or to delay the release. A variety of materials can be used for such enteric coatings or coatings, such materials include a number of polymeric acids and mixtures of polymeric acids with such materials as lacquer, cetyl alcohol, and cellulose acetate.

Liquid forms in which new compositions of the present invention could be incorporated for oral administration or injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and emulsions flavored with edible oils such as cottonseed oil, oil of sesame, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. The compositions preferably in pharmaceutically acceptable solvents could be nebulized for the use of inert gases. The nebulized solutions could be inhaled directly from the nebulizer device or the nebulizer device could be adhered to a facial mask duct, or intermittent positive mechanical breathing pressure. The solution, suspension, or powder compositions could be administered, preferably orally or nasally, of devices that release the formulation in an appropriate manner.

The following formulation examples illustrate the pharmaceutical compositions of the present invention.

Formulation Example 1 Hard gelatin capsules containing the following ingredients are prepared: Ingredient Quantity (ms / capsule) Active Ingredient 30. 0 Starch 305 .0 Magnesium Stearate 5.0 The above ingredients are mixed and filled with hard gelatin capsules in amounts of 340 mg.

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

Formulation Example 3 A dry powder inhaler formulation is prepared which contains the following components: Ingredient% in Weight Active Ingredient 5 Lactose 95 The active mixture is mixed with the lactose and the mixture is added to a dry powder inhalation apparatus.

Formulation Example 4 Tablets are prepared, each containing 30 mg of active ingredient, as follows: Ingredient Quantity (mg / tablet) Active Ingredient 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone (as a 10% solution in sterile water) 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talcum 1.0 mg Total 120 mg The active ingredient, starch and cellulose are passed through a U.S. Do not. 20 and mix thoroughly. The solution of polyvinylpyrrolidone is mixed with the resulting powders, which are then passed through a U.S. 16. The granules thus produced are dried from 50 ° to 60 ° C and passed through a U.S. 16. Sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a U.S. No. 30, then added to the granules which, after mixing, are compressed in a machine to produce tablets each weighing 150 mg.

Formulation Example 5 Capsules each containing 40 mg of medicament are prepared as follows: Ingredient Quantity (mq / capsule) Active Ingredient 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 ms Total 150.0 mg The active ingredient, cellulose, starch, a magnesium stearate are mixed, passed through a U.S. No. 20, and filled into hard gelatin capsules in amounts of 150 mg.

Formulation Example 6 Suppositories are made, each containing one-25 mg of the active ingredient as follows: Ingredient Amount Active ingredient 25 mg Fatty acid glycerides 2,000 mg saturated to The active ingredient is passed through a U.S. No. 60 and is suspended in the saturated fatty acid glycerides from previously melted using the minimum necessary heat. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 7 Suspensions are made, each containing 50 mg of medication per 5.0 ml of dose as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Taste and Color q.v. Purified water up to 5.0 ml The medicament, sucrose and xanthan gum are mixed through a U.S. mesh screen. No. 10, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some water and added with agitation. Sufficient water is then added to produce the required volume.

Formulation Example 8 Ingredient Quantity (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg The active ingredient, cellulose, starch, and magnesium stearate were mixed, passed through a U.S. No. 20, and hard gelatine capsules were filled in amounts of 560 mg.

Formulation Example 9 A subcutaneous formulation could be prepared as follows: Ingredient Amount Active Ingredient 5.0 mg Corn oil 1 ml Formulation Example 10 A topical formulation could be prepared as follows: Ingredient Amount Active Ingredient 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin up to 100 g The white soft paraffin is heated until melted. The liquid paraffin and the emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and the stirring is continued until dispersed. The mixture is then allowed to cool until solidified.

Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches could 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, p. e j. , U.S. Patent 5,023,252, published June 11, 1991, incorporated herein by reference. Such patches could be constructed for continuous, pulsatile, or demand release of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, directly or indirectly. Direct techniques usually involve the placement of a drug delivery catheter into the host ventricular system to pass the blood-brain barrier. Such an implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Pat. 5,011,472 which is incorporated herein by reference.

Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide the latency of the drug 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 lipid and capable of transport through the blood-brain barrier. Alternatively, the release of hydrophilic drugs could be increased by intra-arterial infusion of hypertonic solutions that can transiently open the blood-brain barrier.

Other formulations suitable for use in the present invention can be found in Remi ngton 's Pha rma ceu ti ca l Sci en ces, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).

Utility The compounds and pharmaceutical compositions of the invention are useful for 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, to increase the serum half life of the administered compound, the compounds could be encapsulated, introduced into the liposome lumen, prepared as a colloid, or they could employ other conventional techniques that provide a long half-life of the serum of the compounds . A variety of methods are available to prepare liposomes, as described in, p. ex. , 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.

The amount of the compound administered to the patient will vary depending on which is to be administered, the purpose of the 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 who has already had AD in an amount sufficient to at least partially arrest the onset of more symptoms of the disease and its complications. A suitable amount to accomplish this is defined as "therapeutically effective dose". The effective amounts for this use will depend on the judgment of the attending physician depending on factors such as the degree of severity of the AD in the patient, the age, weight and general condition of the patient, and the like.

Preferably, for use as therapeutics, the compounds described herein are administered in dosages that are in the range of about 1 to about 500 mg / kg / day.

In prophylactic applications, the compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or family characteristic) 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 physician depending on factors such as age, weight and general condition of the patient, and the like. Preferably, for use as prophylactics, the compounds described herein are administered in dosages that are in the range of about 1 to about 500 mg / kg / day.

As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions could be sterilized by conventional sterilization techniques, or they could be sterilized by filtration. The resulting aqueous solutions could be packaged for use as is, or lyophilized, the lyophilized preparation is combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparations will typically be between 3 and 11, more preferably from 5 to 9 and more preferably from 7 and 8. It will be understood that the use of certain excipients, vehicles or stabilizers already mentioned will result in the formation of pharmaceutical salts .

The following synthetic and biological examples are offered to illustrate this invention and are not constructed 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 meaning. If an abbreviation is not defined, it has its generally accepted meaning. ac. = aqueous Boc = tert-butoxycarbonyl BOP = benzotriazole-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate bd = broad doublet bs = broad singlet c = concentration (g / mL) ce = cubic centimeter CDl = 1,1 '-carbonyldiimidazole d = doublet dd = doublet of doublets DMAP = dimet and laminopyridine DMF = dimethylformamide DMSO dimethisulfoxide EDC 1- (3-dimethylaminopropyl [3-ethylcarbodiimide EDTA] ethylen diamine tetraacetic acid eq. equivalents EtOAc ethyl acetate EtOH ethanol g grams h hour L liter m multiple M% percent mol max maximum MeOH methanol meq milliequivalent mg milligram mL milliliter mm milimeter mM millimolar mmol millimol mp melting point N normal ng nanogram nm nanometers OD optical density PEPC = l- (3- (l -pyrrolidinyl) propyl) -3- ethylcarbodiimide pg = picogram pM = picoMolar psi = pounds per square inch q = quartet quint. = quintet rpm = rotations per minute s = singlet t = triplet TFA = trifluoric acid acetic THF = tetrahydrofuran tic = thin layer chromatography μq = picogram uL = microliter UV = ultraviolet In the later examples, all temperatures are in Celcius degrees (unless otherwise indicated).

The following General Procedures A '-K', Examples A '-D' and Examples A1-A81 illustrate the synthesis of several N- (ary 1 / he e roa ri 1 to ce ti 1) amino acids which can be hydrolyzed to provide the N- (ary1 / heteroarylacetyl) amino acids which are useful as starting materials for the amide compounds of this invention.

GENERAL PROCEDURE A 'Coupling of RXC (X' MX ") C (0) C1 with HNCH (R2) C (0) XR3 To a stirred solution of (D, L) -alanine isobutyl ester hydrochloride (from Example B below) (4.6 mmol) in 5 mL of pyridine was added 4.6 mmol of an acid chloride. The precipitation occurred immediately. The mixture was stirred for 3.5 h, diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried with magnesium sulfate, filtered, and evaporated under reduced pressure to produce the product. Other amino acid esters could also be employed in this process.

GENERAL PROCEDURE B 'Coupling of R: C (X') (X ") C (0) OH with H-NCH (R2) C (0) XR3 To a solution of the acid (3.3 mmol) and CD1 in 20 mL of THF was stirred for 2 h. L-alanine iso-butyl ester hydrochloride (from Example B back) (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried with magnesium sulfate, filtered, and evaporated under reduced pressure to produce the product. Other amino acid esters could also be employed in this process.

GENERAL PROCEDURE C Esterification of RC (X ') (X ") C (O) HCH (R2) C (0) OH with HOR5 To a stirred solution of phenylacetylacline (1.6470 g, 7.0 mmol) in 20 mL of THF was added CDI (1.05 g, 6.5 mmol) and the mixture was stirred for 1.5 h. 2-Met-ilbutanol (0.53 g, 6 mmol) was added to the mixture, followed by the addition of NaH (0.16 g, 6.5 mmol). The bubbling came immediately. The reaction mixture was stirred overnight. The reaction mixture was diluted with 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried with magnesium sulfate, filtered, and evaporated under reduced pressure to produce the product. Other N-acyl amino acids and alcohols could also be employed in this process.

GENERAL PROCEDURE D 'Hydrolysis of Ester to Free Acid The hydrolysis of the ester to free acid was conducted by conventional methods. Below are two examples of such conventional methods of esterification.

To the ester in a 1: 1 mixture of CH3OH / H20 was added 2-5 equivalents of K2CO;,. The mixture was heated to about 50 C for about 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 under reduced pressure. The pH of the remaining aqueous solution was adjusted to approximately 2, and ethyl acetate was added to extract the product. The organic phase was then washed with saturated aqueous NaCl and dried with MgSO4. The solution was removed from the solvent under reduced pressure to produce 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 so 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 with EtOAc, the combined organics were dried with Na: S04 and the solvent was removed under reduced pressure after filtration. The residue was purified by conventional methods (eg, recrystallization).

The following exemplifies this last example. The methyl ester of phenylacetylanine of 3-N02 9.27 g (0.0348 moles) were dissolved in 60 mL of dioxane and 15 mL of H: 0 and adding LiOH (3.06 g, 0.0731 mol) that had been dissolved in 15 mL of H20. 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 with EtOAc (4 X 100 mL), The combined organics were dried with Na 2 SO 4 and the solvent was removed under reduced pressure after filtration. The residue was recrystallized with EtOAc / isooctane to give 7.5 g (85%) of 3-nitrophenylacetyl alanine. CnH12N2? 5 requires C = 52.38, H = 4.80, and N = 11.11. Found from the analysis C = 52.54, H = 4.85, and N = 11.08. [a] 23 = -29.9 @ 589 nm.

GENERAL PROCEDURE E 'BOP Coupling at Low Temperature of Acid and Alcohol A solution of methylene chloride containing the carboxylic acid (100 M%) and N-methyl morpholine (150 M%) was cooled to -20 ° C under nitrogen. BOP (105 M%) was added in one portion and the reaction mixture was maintained at -20 ° C for 15 minutes. The corresponding alcohol (120 M%) was added and the reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate (3x). The combined ethyl acetate portions were washed with saturated aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), brine (lx), dried with anhydrous magnesium sulfate or sodium sulfate and the solvent was removed under pressure reduced to produce the raw product.

GENERAL PROCEDURE F 'EDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 eq.), N-methylmorpholine (5 eq.), And hydroxybenzotriazole monohydrate (1.2 eq.) Were added in sequence. The reaction was cooled to about 0 ° C and then 1.2 eq. of hydrochloride of 1 - (3-d ime t i 1 ami n op rop i 1) -3-ethylcarbodiimide. The solution was allowed to stir overnight and arrived at room temperature under N2 under pressure. The reaction mixture was worked by washing the solution with Na C0 :. saturated aqueous, 0.1M citric acid, and brine before drying with Na2SO4 and removing the solvents to produce the crude product. The pure products were obtained by flash chromatography in an appropriate solvent.

GENERAL PROCEDURE G 'EDC Coupling of Acid and Amine A round bottom flask was charged with carboxylic acid (1.0 eq.), Hydroxy-benzotriazole hydrate (1.1 eq.) And amine (1.0 eq.) In THF under nitrogen atmosphere. An appropriate amount (1.1 eq. For three free amines and 2.2 eq. For amine hydrochloride salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring for 4 to 17 hours at room temperature the solvent was removed under reduced pressure, the residue was stored in EtOAc (or similar solvent) / water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, IN HCl, brine and dried with anhydrous sodium sulfate. In some cases, the isolated product was analytically pure in this state while, in other cases, purification via chromatography and / or recrystallization was required before biological evaluation.

GENERAL PROCEDURE H 'Coupling of R: C (X') (X ") C (O) Cl with H-, NCH (R2) C (O) XR3 An excess of oxalyl chloride in dichloromethane was added to the acid derivative together with a drop of DMF. The resulting mixture was stirred for about 2 hours or until bubbling ceased.

The solvent was then removed under reduced pressure and rediluted with dry methylene chloride. To the resulting solution was added about 1.1 eq. of the appropriate amino acid ester and triethylamine (1.1 eq in methylene chloride). The system was stirred at room temperature for 2 hours and then the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1N HCl followed by IN NaOH. The organic layer was dried with anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure to provide the desired product.

GENERAL PROCEDURE I 'P-EPC coupling The P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods of the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J 'below.

Specifically, the appropriate free base amino ester (0.0346 mmol) and substituted phenylacetic acid (0.069 mmol) were dissolved in 2.0 mL of CHC13 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23 ° C. The reaction was filtered through a cotton plug ", rinsed with 2.0 mL of CHC13 and the filtrate was evaporated under a stream of nitrogen.The purity of each sample was determined by XE NMR and was in the range of 50% at > 95% Between 8.0 and 15.0 mg of the final product was obtained from each reaction and tested without further purification.

GENERAL PROCEDURE J ' Synthesis of Amino Acid Esters of N-BOC Corresponding Amino Acid A. Esterification of the acid.

The N-BOC amino acid was dissolved in dioxane and treated with an excess of alcohol (-1.5 eq.) And catalytic DMAP (100 mg) at 0"'C. Agitation was continued until completion of the reaction of which the product was recovered by conventional methods.

B. Removal of the N-BOC group.

The amino acid protected with N-BOC was dissolved in methylene chloride (0.05M) and treated with 10 eq. from TFA at room temperature under a nitrogen atmosphere. The reaction was monitored by means of tic until the initial material was usually consumed in 1-5 hours. 10 eq. Additional TFAs were added to the reaction if the initial material was still present after 5 hours. The reaction was carefully neutralized with Na 2 CO 3, separated, the organic layer was washed with brine and dried with anhydrous Na 2 SO 4. The crude amine was then used without purification.

The specific exemplification of these procedures is as follows: 1. Racemic (+/-) -N-BOC-a-amino butyric acid (Aldrich) (9.29 g, 0.0457 mol) was dissolved in 100 mL of dioxane and treated with iso-butyl alcohol (6.26 mL, 0. 0686 mol), EDC (8.72 g, 0.0457) and catalytic DMAP (100 mg) at 0-'C. After stirring for 17 hours, the organics were evaporated under reduced pressure, the residue was diluted with EtOAc, washed with NaHCO3, brine and dried with Na2SO4. Evaporation yields 8.42 g (71%) of an oil. C: .H ^ N04 requires: C = 60.21, H = 9.72, and N = . 40. Found from the analysis: C = 59.91, H = 9.89, and N = 5.67.

The above N-BOC amino acid ester (8.00 g, 0.032 mol) was deprotected as above giving 3.12 g (61%) of the free base as a colorless oil that solidifies before standing. 2. L-N-BOC-alanine (Aldrich) was dissolved (8.97 g, 0. 047 mol) in 100 mL of CH2C12, iso-butyl alcohol (21.9 L, 0.238 mol) and treated with DMAP (100 mg) and EDC (10.0 g, 0.52 mol) at 0 ° C. The mixture was stirred for 17 hours, diluted with H20, washed with 1.0 N HCl, NaHCO3, then brine and the organics were dried with Na2SO4.

Filtration and evaporation produces 11.8 g (quantitative) of iso-butyl ester of L-N-BOC-alanine which is contaminated with a small amount of solvent. One sample was dried under vacuum for analytical analysis. C-_H2_, N0 requires: C = 58.79, H = 9. 38, and N = 5.71. Found from the analysis: C = 58.73, H = 9.55, and N = 5.96.

The above N-BOC amino acid ester (11.8 g, 0.0481 mol) was deprotected as before. The free base was converted to the corresponding HCl salt using saturated HCl (g) / EtOAc to give iso-butyl ester hydrochloride of L-N-alanine. 4.2 g (48%) of a colorless solid was obtained. C7H15N02. HCl requires: C = 46.28, H = 8.88, and N = 7.71. Found from the analysis: C = 46.01, H = 8.85, and N = 7.68.

GENERAL PROCEDURE K 'Formation of methyl ester from amino acids The amino acid (amino acid or amino acid hydrochloride) is suspended in methanol and cooled to 0 ° C. HCl gas is bubbled through this solution for 5 minutes. The solution is allowed to warm to room temperature then it is stirred for 4 hours. The solvents are then removed under reduced pressure to provide the desired amino acid methyl ester hydrochloride. This product is usually used without further purification.

Example A 'Synthesis of free PEPC and polymer bound N-ethyl-N '-3- (1-pyrrolidinyl) propylurea To a solution of 27.7 g (0.39 mol) of ethyl isocyanate in 250 mL of chloroform was added 50 g (0.39 mol) 3- (1-pyrrolidinyl) propylamine dropwise with cooling. Once the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 74.5 g (96.4%) of the desired urea as a clear oil. l- (3- (l-pyrrolidinyl) propyl) -3-ethylca bodiimide (P-EPC) To a solution of 31.0 g (0.156 mol) of N-ethyl-N'-3- (1-pi rrol idini 1) propi 1 -u rea in 500 mL of dichloromethane was added 62.6 g (0.62 mol) of triethylamine and the The solution was cooled to 0 ° C. To this solution were then added 59.17 g (0.31 mol) of 4-toluenesulfonyl chloride in 400 mL of dichloromethane dropwise at such a rate to maintain the reaction at 0-5 ': C. After the addition was completed, the reaction mixture was warmed to room temperature and then heated to reflux for 4 hours. After cooling to room temperature, the reaction mixture was washed with saturated aqueous potassium carbonate (3 x 150 L). The aqueous phases were combined and extracted with dichloromethane. All organic phases were combined and concentrated under reduced pressure. The resulting orange suspension was suspended in 250 L of diethyl ether and the solid was decanted from the solution. The suspension / decanting process was repeated 3 more times. The ether solutions were combined and concentrated under reduced pressure to give 18.9 g (67%) of the desired product as an orange crude oil. A portion of the oil was distilled under vacuum to give a colorless oil which distilled at 78-82 ° C (0.4 mm Hg).

Preparation of a polymer supported form of l- (3- (1-pyrrolidinyl) propyl) -3-ethylcarbodiimide (P-EPC) A suspension of 8.75 g (48.4 mmol) l- (3- (l-pyrrolidin-yl) propyl) -3-ylcarbodiimide and 24.17 g (24.17 mmol) of Merrifield resin (2% cross-linked, 200- mesh) 400, chloromethylated styrene / divinylbenzene copolymer, 1 meq Cl / g) in dimethylformamide was heated at 100 ° C for 2 days. The reaction was cooled and filtered and the resulting resin was washed sequentially with 1L of DMF, 1L of THF and 1L of diethyl ether. The remaining resin was then dried under vacuum for 18 hours.

Example B 'Preparation of alanine isobutyl ester hydrochloride A mixture of 35.64 g (0.4 mol) of (D, L) -alanine (Aldrich) (or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of isobutanol were refluxed for 1.5 hours and the volatiles were completely removed in a rotary evaporator at 90 ° C under reduced pressure to give iso-butyl ester hydrochloride. (D, L) -alanine (or L-alanine iso-butyl ester hydrochloride), which was quite pure for use in further transformations.

Example C Preparation of 3,5-dichlorophenylacetic acid To a solution of 3.5 g of 3,5-dichlorobenzyl alcohol (Aldrich) in 75 mL of dichloromethane at 0: C was added 1.8 mL of methane sulphonylchloride followed by 3.5 mL of triethylamine added dropwise. After 2 hours the solution was diluted to 150 mL with dichloromethane, washed with 3N HCl, saturated aqueous NaHCO3 was dried with Na2SO4 and the solvents were removed to produce the desired 3,5-dichlorobenzyl methanesulfonate as a yellow oil which was used without purification.

The crude sulfonate was dissolved in 50 mL of DMF at 0 ° C and then 3 g of KCN were added. After 2 hours an additional 50 mL of DMF was added and the solution was stirred for 16 hours. The red solution was diluted with 1 L of H20 and acidified to pH 3 with 3N HCl. The aqueous solution was extracted with dichloromethane. The combined organics were washed with 3N HCl, dried with Na 2 SO 4 and the solvents were removed under reduced pressure to produce crude 3,5-dichlorophenylacetonitrile which was used without purification.

The nitrile was added to a mixture of 40 mL of concentrated sulfuric acid and 50 mL of H20 and heated to reflux for 48 hours, cooled to room temperature and stirred for 48 hours. The reaction was diluted in 1 L of ice ice, warmed to room temperature and extracted with 2 x 200 mL of dichloromethane and 2 x 200 mL of ethyl acetate. Both sets of organics were combined and washed with saturated aqueous NaHCO. The NaHCO3 fractions were combined and acidified to pH 1 with 3N HCl. The white solid was also too fine to filter and extracted with 2 x 200 mL of dichloromethane. The combined organics were dried with Na 2 SO 4 and the solvents removed under reduced pressure to yield crude 3,5-dichlorophenylacetic acid as a white solid. The solid was suspended with hexane and filtered to obtain 1.75 g of white solid.

NMR (CDC13): (in ppm) 3.61 (s, 2H), 7.19 (s, 1H); 7.30 (s, 1H) Example D 'Synthesis of N- (3-chlorophenylacetyl) alanine The title compound was prepared using L-alanine (Nova Biochem) and 3-chlorophenyl acetic acid (Aldrich) following General Procedures F 'or G', followed by hydrolysis using General Procedure D '.

Example To the Synthesis of N- (phenylacetyl) -D, L-alanine isobutyl ester Following General Procedure A 'above and using phenylacetyl chloride (Aldrich) and D, L-alanine isobutyl ester hydrochloride (from Example B' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl.

The NMR results were as follows:: H-rmn (CDC13): d = 7.23-7.36 (m, 5H), 6.18 (d, 1H), 4.58 (t, J = 7.3 Hz, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.90 (m, 1H), 1.34 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.8 Hz, 6H). : 3C-rmn (CDC13): d = 172.7, 170.3, 134.5, 129.2, 128. 8, 127.2, 71.3, 48.1, 43.4, 27.5, 18.8, 18.3. C: 5H 1N03 (MW = 263.34; Mass Spectroscopy (MH + = 264)) Example A2 Synthesis of N- (3-phenylpropionyl) -D, L-alanine iso-butyl ester Following General Procedure A 'above and using 3-phenyl Ipropioni chloride (Aldrich) and D, L-alanine isobutyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid which It has a melting point of 51 -54 ° C. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl.

The NMR results were as follows: "-H-rmn (CDC13): d = 7.25 (m, 2H), 7.19 (m, 3H), 6.28 (d, J = 7.2 Hz, 1H), 4.58 (quint., J = Hz, 1H), 3.89 (m, 2H), 2.95 (t, J = 1. 1 Hz, 2H), 2.50 (m, 2H), 1.92 (m, 1H), 1.33 (d, J = 7.1 Hz , 3H), 0.91 (d, J = 6.7 Hz, 6H), 13C-nm (CDC13): d = 173.0, 171.5, 140.6, 128.3, 128.1, 126.0, 71.2, 47.8, 37.9, 31.4, 27.5, 18.79, 18.77 , 18.3 C16H23N03 (MW = 277.37; Mass Spectroscopy (MH + = 278)) Example A3 Synthesis of N- (3-methylpentanoyl) -L-alanine iso-butyl ester Following General Procedure B 'and using 3-methylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with K ^ CO, aqueous and aqueous HCl.

The NMR results were as follows: 'H-rmn (CDC13): d = 6.08 (d, J = 5.9 Hz, 1H), 4.62 (quint., J = 7.3 Hz, 1H), 3.92 (m, 2H), 2.22 (m, 1H), 1.84-2.00 (m, 3H), 1.40 (d, J = 1. 2 Hz, 3H), 1.35 (m, 1H), 1.20 (m, 1H), 0.85-0.96 (m, 12H). 13C-rmn (CDCl3): d = 173.3, 172.1, 71.4, 47.9, 43.9, 32.3, 29.38, 29.35, 27.6, 19.10, 19.06, 18.93, 18.91, 18.72, 18.67, 11.3. C13H25N03 (MW = 243.35, Mass Spectroscopy (MH + = 244)) Example A4 Synthesis of N - [(4-chloro-enyl) -acetyl] -L-alanine iso-butyl ester Following General Procedure B 'and using 4-chlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 111 ° -113 ° C. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with K_CO ", aqueous and aqueous HCl.

The NMR results were as follows: xH-rmn (CDC13): d = 7.30 (d, = 8.2 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.18 (d, J = 5.5 Hz, 1H ), 4.57 (quint., J = 7.2 Hz, 1H), 3.88 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.36 (d, J = ll Hz, 3H), 0.90 ( d, J = 6.8 Hz, 6H). 13C-rmn (CDC13): d = 172.8, 169.8, 133.1, 133.0, 130. 6, 128.9, 71.4, 48.2, 42.6, 27.6, 18.85, 18.82, 18.4. C15H20N03C1 (MW = 297.78, Mass Spectroscopy (MH + = 298)) Example A5 Synthesis of isobutyl ester of JV - [(3,4-dischlorophenyl) acetyl] -L-alanine Following General Procedure B 'and using 3, 4-dichlorophenylacetic acid (Aldrich) and L-alanine isobutyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a fusion of 81 ° -83 ° C. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with K: C0? aqueous and aqueous HCl.

The NMR results were as follows: H-rmn (CDC1: d = 0.90 (d, J = 6.8 Hz, 6H), 1.38 (d, J = 7.1 Hz, 3H), 1.91 (m, 1H), 3.50 ( s, 2H), 3.90 (m, 2H), 4.57 (quint., J = 7.1 Hz, 1H), 6.31 (d, J = 4.9 Hz, 1H), 7.12 (m, 1H), 7.38 (m, 2H) 13C-NMR (CDC13): d = 18.4, 18.8, 18.9, 27.6, 42.2, 48.3, 71.5, 128.6, 130.6, 131.2, 131.3, 132.6, 134.7, 169.2, 172.8, C15H19N03C12 (MW = 332.23, Mass Spectroscopy ( MH '332)) EXAMPLE A6 Synthesis of N- [(4-ethylphenyl) acetyl] -D, -alanine isobutyl ester Following General Procedure B 'and using 4-methylphenylacetic acid (Aldrich) and D, L-alanine isobutyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a dot of fusion of 102 ° -104 ° C. The reaction was monitored by tic on silica gel (Rf = 0.6 in 33% ethyl acetate / hexane) and the purification was by extraction with Et: 0 followed by washes with K_CO. aqueous and aqueous HCl.

The NMR results were as follows:: H-rmn (CDCL,): d = 0.90 (d, J = 6.7 Hz, 6H), 1.35 (d, J = 7.2 Hz, 3H), 1.91 (m, 1H), 2.34 (s, 3H), 3.55 (s, 2H), 3.88 (m, 2H), 4.58 (m, 1H), 6.05 (bd, 1H), 7.16 (s, 4H). 13C-NMR (CDC13): d = 18.5, 18.85, 18.87, 21.0, 27.6, 43.1, 48.1, 71.3, 129.2, 129.6, 131.3, 136.9, 170.6, 172. 8. C16H23N03 (MW = 277.37, Mass Spectroscopy (MH + 278)) Example A7 Synthesis of N- [(3-pyridyl) acetyl] -D, L-alanine iso-butyl ester Following General Procedure F 'and using 3-pyridylacetic acid hydrochloride (Aldrich) and D-L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 62 ° -64 ° C. The reaction was monitored by tic on silica gel (Rf = 0.48% methanol / dichloromethane) and the purification was by chromatography on silica gel.

The NMR results were as follows:: H-rmn (CDCL3): d = 8.40 (d, J = 2.8, 2H); 7.6 (m, 1 H): 7.16 (m, 2H); 4.5 (quint., J = 7.2, 7.2, 1H); 3. 8 (m, 2H); 3.48 (s, 2H); 1.8 (m, 1H); 1.30 (d, J = 7.2, 3H); 0.81 (d, J = 6.7, 6H). 13C-NMR (CDC13): d = 173.4, 170.1, 150.6, 148.8, 137.4, 131.4, 124.1, 71.9, 48.9, 40.6, 28.1, 19.5, 19.4, 18.6. C14H20N2O3 (MW = 264, Mass Spectroscopy (MH + 265)) Example A8 Synthesis of N- [(1-naphthyl) acetyl] -L-alanine iso-butyl ester Following General Procedure B 'and using 1-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 69; -73: C. The reaction was monitored by tic on silica gel and the purification was by extraction with Et: 0 followed by washes with aqueous K2C03 and aqueous HCl.

The NMR results were as follows:: H-rmn (CDC1:: d = 0.83 (m, 6H), 1.25 (d, J = 7.1 Hz, 3H), 1.81 (m, 1H), 3 * .79 (m, 2H), 4.04 (2s, 2H), 4. 57 (quint., J = 7.3 Hz, 1H), 5.99 (d, J = 7.1 Hz, 1H), 7.44 (m, 2H), 7.53 (m, 2H), 7.85 (m, 2H), 7.98 (m, 1 HOUR) . 13C-NMR (CDC13): d = 18.2, 18.81, 18.83, 27.5, 41.5, 48.2, 71.3, 123.7, 125.6, 126.1, 126.6, 128.2, 128.5, 128.7, 130.7, 132.0, 133.9, 170.3, 172.5. C19H23N03 (MW = 313.40, Mass Spectroscopy (MH + 314)) Example A9 Synthesis of N- [(2-na) acetyl] -L-alanine iso-butyl ester Following General Procedure B 'and using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 128: -129 ° C. The reaction was monitored by tic on silica gel and the purification was by extraction with Et.O followed by washes with aqueous K: C03 and aqueous HCl.

The NMR results were as follows: H-rmn (CDC1 :.): d = 0.86 (m, 6H), 1.35 (d, J = 7.1 Hz, 3H), 1.78 (m, 1H), 3.76 (s, 2H ), 3.87 (m, 2H), 4.62 (quint., J = 7.2 Hz, 1H), 6.13 (d, J = 7.1 Hz, 1H), 7.41 (m, 1H), 7.48 (m, 2H), 7.74 ( s, 1H), 7.83 (m, 3H). 13C-NMR (CDC13): d = 18.4, 18.82, 18.85, 27.6, 43.7, 48.2, 71.4, 125.9, 126.3, 127.2, 127.6, 127.7, 128.2, 128.7, 132.0, 132.5, 133.5, 170.3, 172.8. C19H23N03 (MW = 313.40, Mass Spectroscopy (MH + 314)). ' Example A10 Synthesis of isobutyl ester of N- [(4-f enylbu year il] - L-alanine Following General Procedure B 'and using 4-phenylbutanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with aqueous K ^ C03 and aqueous HCl.

The NMR results were as follows:: H-rmn (CDC13): d = 0.92 (d, J = 6.7 Hz, 6H), 1.38 (d, J = 7.1 Hz, 3H), 1.96 (m, 3H), 2.21 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 7.3 H ?, 2H), 3.90 (m, 2H), 4.59 (quint., J = 7.2 Hz, 1H), 6.31 (d, 1H), 7.16 (m, 3H), 7. 24 (m, 2H). :? C-rmn (CDC13): d = 18.3, 18.75, 18.78, 26.8, 27.5, 34.9, 35.3, 47.8, 71.2, 125.7, 128.2, 128.3, 141.3, 172.1, 173.0. C17H25N03 (MW = 291.39, Mass Spectroscopy (MH + 292)).

Example All Synthesis of N- [(5-phenylpentanoyl) -L-alanine iso-butyl ester Following General Procedure B 'and using 5-phenylpentanoic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as an oil. The reaction was monitored by tic on silica gel and the purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl.

The NMR results were as follows:: H-rmn (CDC13): d = 7.23 (m, 2H), 7.17 (m, 3H), 6.30 (d, 1H), 4.59 (quint., J = 7.3 Hz, 1H), 3.91 (m, 2H), 2. 61 (t, J = 7.2 Hz, 2H), 2.22 (t, J = 7.2 Hz, 2H), 1.93 (m, 1H), 1.66 (m, 4H), 1.38 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.7 Hz, 6H). : 'C-rmn (CDC13): d = 173.1, 172.3, 142.0, 128.2, 128.1, 125.6, 71.2, 47.8, 36.1, 35.5, 30.8, 27.5, 25.0, 18.80, 18.77, 18.4. C18H27N03 (MW = 305.39, Mass Spectroscopy (MH + 306)).

Example A12, Synthesis of N- [(4-pyridyl) acetyl] -D, L-alanine isobutyl ester Following General Procedure F 'and using 4-pyridylacetic acid hydrochloride (Aldrich) and (D, L) -alanine isobutyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid which It has a melting point of 64 ° -66 ° C. The reaction was monitored by tic on silica gel (Rf = 0.43 10% methanol / dichloromethane) and the purification was by chromatography on silica gel.

The NMR results were as follows: '? -r n (CDC13): d = 8.51 (dd, J = 1.6, 2.8, 1.6, 2H); 7.23 (dd, J = 4.3, 1.6, 4.4, 2H); 6.71 (d, J = 6.8, 1 HOUR); 4.56 (quint., J = 7.3, 7.2, 1H); 3.88 (m, 2H); 3. 53 (s, 2H); 1.89 (m, 1H); 1.36 (d, J = 7.2, 3H); 0.88 (d, J = 6.7, 6H). :: 'C-rmn (CDC13): d = 173.5, 169.3, 150.5, 144.4, 125.1, 72.1, 48.9, 43.0, 28.2, 19.5, 18.9.

C14H20N203 (MW = 264, Mass Spectroscopy (MH + 265)) Example Al3 Synthesis of N- (phenylacetyl) -L-alanine iso-butyl ester Following General Procedure B1 and using phenylacetyl chloride (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B 'above), the title compound was prepared as a solid having a melting point of 45 °. -47 ° C. The reaction was monitored by tic on silica gel and the purification was by extraction with Et-0 followed by washes with aqueous K 2 CO 3 and aqueous HCl.

The NMR results were as follows:: H-rmn (CDC1,): d = 7.24-7.39 (m, 5H), 6.14 (d, 1H), 4.58 (t, J = 7.3 Hz, 1H), 3.88 (m , 2H), 3.58 (s, 2H), 1.90 (m, 1H), 1.35 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 6.7 Hz, 6H). : 3C-rmn (CDC15): d = 172.8, 170.4, 134.5, 129.3, 128. 9, 127.2, 71.3, 48.1, 43.5, 27.5, 18.9, 18.8, 18.4. C ^ H ^ .NO, (MW = 263.34, Mass Spectroscopy (MH + 264)).

Example To the Synthesis of 2- [(3,4-dichloro-enyl) acetamido] -butyl butyl ester Following General Procedure I 'above and using 3, 4-dichlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: H-rmn (CDC13): d = 7.36 (m, 3H), 6.03 (bd, 1H), 4.54 (m, 1H), 3.87 (, 2H), 3.49 (s, 2H) ), 1.93 (m, 2H), 1.72 (m, 1H), 0.88 (d, 6H), 0.80 (t, 3H).

Example A15 Synthesis of 2- [(3-methoxyphenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 3-methoxy phenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 6.75 (m, 4H), 5.93 (bd, 1H), 4. 51 (m, 1H), 3.83 (m, 2H), 3.75 (s, 2H), 3.52 (s, 2H), 1. 82 (m, 2H), 1.60 (m, 1H), 0.84 (d, 6H), 0.74 (t, 3H).

C17H25N04 (MW = 307.39, Species copied from Ma as as (MH + 309)).

Example 6 Synthesis of 2 - [(4-nitrophenyl) acetamido] butyric acid isobutyl ester Following General Procedure I 'above and using 4-nitric acid (Aldrich) and isobutyl 2-aminobutyric acid (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: ^ -rmn (CDC13): d = 8.16 (d, 2H), 7.44 (d, 2H), 6.04 (bd, 1H), 4.55 (m, 1H), 3.86 (m, 2H), 3.66 (s, 2H), 1. 86 (m, 2H), 1.67 (m, 1H), 0.85 (d, 6H), 0.81 (t, 3H).

C16H22N205 (MW = 322.36, Mass Spectroscopy (MH + 323)). ' Example Al 7 Synthesis of 2- [(3,4-methylenedioxyphenyl) acetamido] butyric acid isobutyl ester Following General Procedure I 'above and using 3, 4- (methylenedioxy) -phenyl acetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC1;.): d = 6.72 (m, 3H), 5.92 (b, 1H), 4.54 (m, 1H), 3.86 (m, 2H), 3.66 ( s, 2H), 1.86 (m, 2H), 1.66 (, 1H) 0.89 (d, 6H), 0.79 '(t, 3H).

Example A18 Synthesis of iso - butyl ester of 2 - [(thien-3-yl) acetic acid] Following General Procedure I 'above and using 3-thiopheneacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: '' H-rmn (CDC13): d = 7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1. 93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H).

Example Al 9 Synthesis of 2 - [(4-chlorofonyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 4-chlorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: "-H-rmn (CDC13): d = 7.22 (m, 2H), 7.11 (m, 2H), 5.80 (m, 1H), 4.44 (m, 1H), 3.78 (m, 2H), 3.43 (s, 2H), 1.77 (m, 2H), 1.56 (m, 1H), 0.83 (d, 6H), 0.71 ( t, 3H).

Example A20 Synthesis of 2 - [(3-nitrophenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 3-nitrophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rrnn (CDC13): d = 8.15 (m, 2H), 7.65 (m, 1H), 6.08 (m, 1H), 4.46 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 1.91 (m, 2H), 1.75 (, 1H), 0.98 (d, 6H), 0.71 (t, 3H).

Example A21 Synthesis of 2 - [(2-hydroxyphenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 2-hydroxyphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.14 (m, 1H), 7.01 (, 1H), 6.93 (m, 1H), 6.79 (m, 1H), 6.46 (m, 1H) ), 4.51 (m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 2.01 (m, 2H), 1.75 (m, 1H), 0.89 (d, 6H), 0.85 (t, 3H) .

Example A22 Synthesis of 2- [(2-naphthyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 2-naphthylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: xH-rmn (CDC13): d = 7.83 (m, 7H), 5.95 (m, 1H), 4.58 (m, 1H), 3.84 (m, 2H), 3.75 (s, 2H), 1.89 (m, 2H), 1.63 (m, 1H), 0.91 (d, 6H), 0.81 (t, 3H). C20H25NO3 (MW = 327.42, Mass Spectroscopy (MH + 328)).

Example A23 Synthesis of 2- [(2,4-dichlorophenyl) acetamido] butyric acid isobutyl ester Following General Procedure I 'above and using 2,4-dichlorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrates (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: "-H-rmn (CDC13): d = 7.49 (m, 1H), 7.22 (m, 2H), 5.98 (m, 1H), 4.52 (m, 1H), 3.86 (m , 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H), 0.87 (d, 6H), 0.80 (t, 3H).

Example A24 Synthesis of 2 - [(4-bromo enyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.43 (d, 2H), 7.19 (d, 2H), 5.85 (m, 1H), 4.51 (m, 1H), 3.81 (m, 2H), 3.47 (s, 2H), 1.84 (m, 2H), 1.61 (m, 1H), 0.84 (d, 6H), 0.76 (t, 3H). C: 6H. N0; .Br (MW = 356.26, Mass Spectroscopy (MH * 358)).

Example A25 Synthesis of 2 - [(3-chlorophenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 3-chlorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: H-rmn (CDC13): d = 7.25 (m, 3H), 7.12 (m, 1H), 5.80 (, 1H), 4.52 (m, 1H), 3.86 (m, 2H ), 3.50 (s, 2H), 1.87 (m, 2H), 1.67 (m, 1H), 0.88 (d, 6H), 0.77 (t, 3H). C: eH21N03Cl (MW = 311.81 Mass Spectroscopy (MH + 313)).

Example A26 Synthesis of 2 - [(3-fluorophenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 3-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:! H-rmn (CDC13): d = 7.31 (m, 1H), 7.01 (m, 3H), 5.95 (m, 1H), 4.54 (m, 1H), 3.84 (m, 2H), 3.54 (s, 2H), 1.88 (, 2H), 1.65 (m, 1H), 0.87 (d, 6H), 0.81 (t, 3H). C16H2N03F (MW = 295.35 Mass Spectroscopy (MH + 296)).

Example A27 Synthesis of 2- [(benzothiazol-4-yl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 4-benzothiazol-4-yl-1-acetic acid (Chemservice) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.82 (m, 1H), 7.51-7.21 (m, 4H), 5.84 (m, 1H), 4.51 (m, 1H), 3.90 ( s, 2H), 3.79 (m, 2H), 1.78 (m, 2H), 1.58 (m, 1H), 0.80 (d, 6H), 0.66 (t, 3H).

Example A28 Synthesis of 2 - [(2-methylphenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.18 (m, 4H), 5.79 (m, 1H), 4.54 (m, 1H), 3.85 (m, 2H), 3.59 (s, 2H), 3.29 (s, 3H), 1.81 (m, 2H), 1.59 (m, 1H), 0.87 (d, 6H), 0.77 (t, 3H). C: -H: NO, (MW = 291.39 Mass Spectroscopy (M + 291)).

Example A29 Synthesis of 2 - [(2-fluorophenyl) acetamido] -butyl butyl ester Following General Procedure I 'above and using 2-fluorophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.28 (m, 1H), 7.09 (m, 3H), 6.03 (m, 1H), 4.54 (m, 1H), 3.87 (m, 2H), 3.57 (s, 2H), 1.89 (m, 2H), 1.64 (m, 1H), 0.88 (d, 6H), 0.80 (t, 3H).

Example A30 Synthesis of 2 - [(4-chlorophenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 4-fluoro-phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.20 (, 2H), 6.97 (, 2H), 5.87 (m, 1H), 4.492 (m, 1H), 3.83 (m, 2H), 3.48 (s, 2H), 1. 86 (m, 2H), 1.60 (m, 1H), 0.87 (d, 6H), 0.78 (t, 3H).

C16H22N03F (MW = 295.35 Mass Spectroscopy (MH + 296)).

Example A31 Synthesis of 2 - [(3-brodenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 3-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: "H-rmn (CDC13): d = 7.45 (m, 2H), 7.23 (m, 2H), 5.95 (m, 1H), 4.55 (m, 1H), 3.84 (m, 2H) 3.55 (s, 2H), 1.89 (m, 2H), 1.68 (m, 1H), 0.91 (d, 6H), 0.81 (t, 3H), C16H22N03Br (MW = 356.26 Mass Spectroscopy (MH + 357)) .

Example A32 Synthesis of 2 - [(3-trifluoromethylphenyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 3-trifluoromethyl-phenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC1;.): d = 7.52 (m, 1H), 7.47 (m, 2H), 6.01 (m, 1H), 4.56 (m, 1H), 3.86 ( m, 2H), 3.61 (s, 2H), 1.84 (m, 2H), 1.62 (m, 1H), 0.87 (d, 6H), 0.80 (t, 3H). C: -H_NO, F, (MW = 345.36 Mass Spectroscopy (M + 3. 4. 5) ) .

Example A33 Synthesis of 2 - [(2-thienyl) acetamido] butyric acid iso-butyl ester Following General Procedure I 'above and using 2-thiopheneacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 6.89 (m, 3H), 6.07 (bd, 1H), 4.50 (m, 1H), 3.82 (m, 2H), 3.71 (s, 2H), 1.85 (m, 2H), 1.62 (m, 1H), 0.81 (d, 6H), 0.75 (t, 3H). C14H21N03S (MW = 283.39 Mass Spectroscopy (MH + 284)).

Example A34 Synthesis of 2- (phenylacetate gone) butyric acid iso-butyl ester Following General Procedure H 'above and using phenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by chromatography on silica gel using 9: 1 toluene: EtOAc as eluent.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.17-7.28 (m, 5H), 6.23 (bd, 1H), 4.51 (m, 1H), 3.86 (m, 2H), 3.54 ( s, 2H), 1.87 (m, 2H), 1.62 (m, 1H), 0.87 (d, 6H), 0.78 (t, 3H). C16H23N03 (MW = 277.36, Mass Spectroscopy (M + 277)).

Example A35 Synthesis of N- (phenylacetyl) allyl 2-methylbutyl ester Step A. Preparation of N- (phenylacetyl) valine To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0 ° C was added 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich) dropwise. A colorless oil precipitated.The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL of diethyl ether, acidified to pH 2-3 with aqueous HCl.The white precipitate formed was filtered, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.

NMR results were as follows: xH-rmn (DMSO-d6): d = 12.63 (s, 1H), 8.25 (d, J = 8.6 Hz, 1H), 7.27 (m, 5H), 4.15 (m, 1H) , 3.56 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 2.05 (m, 1H), 0.87 (d, J = 6.8, Hz, 3H), 0.84 (d, J = 6.8 Hz, 3): 3C-rmn (DMSO-d6): d = 173.2, 170.4, 136.6, 129.0, 128.2, 126.3, 57.1, 41.9, 30.0, 19.2, 18.0 C13H: -NO :. (MW = 235.29; Mass Spectroscopy (MH + -236)) Step B. Synthesis of N- (phenylacetyl) val-2-methylbutyl ester Following General Procedure C and using the ? - (feni lace il) valine prepared in Step A above and 2-methybutan-1-ol (Aldrich), the title compound was prepared as a diastereomeric mixture. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: xH-rmn (CDC13): d = 7.25-7.40 (m, 5H), 5.95 (d, 1H), 4.56 (m, 1H), 3.84-4.00 (m, 2H), 3.61 (s, 2H), 2.10 (m, 1H), 1.68 (m, 1H), 1.38 (m, 1H), 1.15 (m 1H), 0.82-0.94 (m, 9H), 0.76 (d, 3H). 13C-rmn (CDC13): d = 171.84, 171.81, 170.7, 134.6, 129.31, 129.27, 128.9, 127.3, 69.8, 57.0, 43.7, 33.9, 31.3, 25.9, 25.8, 18.9, 17.4, 16.34, 16.27, 11.12, 11.07 . C16H27N03 (MW = 305.42, Mass Spectroscopy (MH 306)).

Example A36 Synthesis of N- (phenylacetyl) -L-methionine isobutyl ester L-Methionine (0.129 g, 0.869 mmol) (Aldrich) was saved in dioxane (5.0 mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 mL, 0.822 mmol ). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer was acidified to a pH of 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried with sodium sulfate, dried in vacuo and used without further purification.

N-Phenylacetyl-L-methionine (0.1285 g, 0.477 mmol) was dissolved in 3.0 mL of dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g) . After stirring for 17 hours at 23 ° C, the mixture was evaporated under reduced pressure for an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98: 2 CHCl 3 / MeOH as eluent afforded the crude product.

The NMR results were as follows:: H-rmn (CDClj): d = 7.4-7.23 (m, 5H), 6.14 (bd, 1H), 4.70 (m, 1H), 3.89 (d, 2H), 3.62. (s, 2H), 2.43 (m, 2H), 2.12 (m, 1H), 1.93 (m, 2H), 0.94 (d, 6H). C: 7H:., NO: .S (MW = 323.17, Mass Spectroscopy (M + 323) Example A37 Synthesis of N- (phenylacetyl) -L-leucine iso-butyl ester L-Leucine (Aldrich) (0.114 g, 0.869 mmol) was stored in dioxane (5.0 mL) and treated with a saturated solution of sodium bicarbonate (5.0 mL) followed by phenylacetyl chloride (Aldrich) (0.114 L, 0.822). mmoles). After stirring for 17 hours at room temperature the mixture was diluted with ethyl acetate, the layers were separated and the aqueous layer acidified to a pH of 2 with 5N HCl. The crude product was extracted into ethyl acetate, dried with sodium sulfate, dried in vacuo and used without further purification.

N-Phenylacetyl-L-leucine (0.0081 g, 0.048 mmol) was dissolved in 2.0 mL of CHC1;. (free of EtOH) and isobutyl alcohol (0.055 mL) and treated with P-EPC (100 mg, 0.87 milliequivalents). The mixture was rotated for 4 days, filtered through a cotton plug and the filtrate was evaporated under reduced pressure to an oil that was sufficiently pure to test.

The NMR results were as follows: H-rmn (CDC13): d = 7.22 (m, 5H), 5.57 (d, 1H), 4.35 (m, 1H), 3.35 (m, 3H), 1.35 (m , 4H), 0.68 (m, 9H).

C18H27N03 (MW = 305.40, Mass Spectroscopy (M + 305) Example A38 Synthesis of N- [(3-chloro-enyl) -acetyl] alanine 3-methylbut-2-enyl ester Following General Procedure C 'above and using N- (3-chlorophenylacetyl alanine (from Example D' above) and 3-methylbut-2-en-l-ol (Aldrich), the title compound was prepared.The reaction was monitored tic on silica gel and purification was by liquid chromatography using 30% EtOAc / hexane as eluent.

The NMR results were as follows:! Hr n (CDC13): d = 7.39-7.16 (m, 4H), 6.06 (bd, 1H), 5.38-5.29 (m, 1H), 4.63 (d, J = 9 Hz , 2H), 3.56 (s, 2H), 1.79 (s, 3H), 1.7 (s, 3H), 1.39 (d, J = 9 Hz, 3H).

Example A39 Synthesis of N - [(3-chlorophenyl) acetyl] alanine cyclopropylmethyl ester Following General Procedure C above, and using N- (3-chlorophenylacetylalanine (from Example D 'above) and cyclopropylmethanol (Aldrich), can be prepared The title compound The reaction was monitored by tic on silica gel and the purification was by liquid chromatography using 3: 7 EtOAc / hexane as eluent.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.2-7.1 (m, 4H), 6.09 (bs, 1H), 4.6 (dq, J = 9 Hz, 1H), 3.96 (dd, J = 9 Hz, 2H), 3.59 (s, 2H), 1.2 (d, J = 9 Hz, 3H), 1.2-1.0 (m, 1H), 0.60-0.50 (m, 2H), 0.30-0.20 (m , 2H).

Example A 0 Synthesis of N - [(3-chlorophenyl) acetyl] alanine 2-thienylmethyl ester Following General Procedure C above, and using N- (3-chlorophenylacetyl alanine (from Example D 'above) and 2-t-Iophenmethanol (Aldrich), the title compound can be prepared.The reaction was monitored by tic on silica gel and purification was by liquid chromatography using 3: 7 EtOAc / hexane as eluent.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.37-6.97 (m, 7H), 5.97 (q, J = 14 Hz, 2H), 4.6 (dq, J = 9 Hz, 1H), 3.76 (s, 2H), 1.38 (d, J = 9 Hz, 3H).

Example A41 Synthesis of N - [(3-chlorophenyl) acetyl] alanine (1-methylcyclopropyl) methyl ester Following General Procedure C 'above, and using N- (3-chlorophenylacetyl alanine (from Example D' above) and (1-met ilcyclopropyl) methanol (Aldrich), the title compound can be prepared.The reaction was monitored by tic in Silica gel and purification was by liquid chromatography using 3: 7 EtOAc / hexane as eluent.

The NMR results were as follows:: H-rmn (CDC13): d = 8.6 (bd, J = 9 Hz, 1H), 3.86 (q, J = 14 Hz, 2H), 3.4 (s, 2H), 2.29 (q, J = 9 Hz, 1H), 1.3 (d, J = 9 Hz, 3H), 1.03 (s, 3H), 0.5-0.4 (m, 2H), 0.4-0.28 (m, 2H).

Example A42 Synthesis of N - [(3-chloro-enyl) -acetyl] -lanine 3-thienylmethyl ester Following General Procedure C above, and using N- (3-chlorophenylacetylalanine (from Example D 'above) and 3-thiophenemethanol (Aldrich), the title compound can be prepared.The reaction was monitored by tic on silica gel and the purification was by liquid chromatography using 3: 7 EtOAc / hexane as eluent.

The NMR results were as follows:: H-rmn (CDC13): d = 8.03 (bd, J = 9 Hz, 1H), 7.56-7.5 (m, 1H), 7.47 (bs, 1H), 7.4-7.17 (m, 4H), 7.06 (d, J = 9 Hz, 1H), 5.1 (s, 2H), 4.3 (dq, 1H), 1.3 ( d, J = 9 Hz, 3H).

Example A43 Synthesis of N- [(3-chloro-enyl) -acetyl] -lanine 2-methylcyclopentyl ester Following General Procedure C 'above, and using N- (3-chlorophene lacetil alanine (from Example D' above) and 2-met ilcyclopentanol (Aldrich), the title compound can be prepared.The reaction was monitored by gel tic silica and purification was by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.39-7.16 (m, 4H), 6.3 (bd, 1H), 4.79-4.7 (m, 1H), 4.6-4.25 (m, J = 9 Hz, 1H), 3.58 (s, 2H), 2.09-1.8 (m, 2H), 1.74-1.6 (m, 2H), 1.74-1.6 (m, 2H), 1.39 (dd, J = 9 Hz, 3H), 1.2 (dt, J = 9 Hz, 1H), 0. 98 (dd, J = 9 Hz, 2H) C17H22N03C1 (MW = 323.82, Species copied from Mass (M + 323).

Example A4 4 Synthesis of 2-methylprop-2-enyl ester of iV - [(3-chlorophenyl) acetyl] alanine Following General Procedure C 'above, and using N- (3-chloropheni lacet i 1 alanine (from Example D' above) and 2-methylprop-2-en-l-ol (Aldrich), the title compound can be prepared. The reaction was monitored by tic on silica gel and the purification was by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

The NMR results were as follows: ? -rmn (CDC13): d = 7.39-7.16 (m, 4H), 6.03 (bs, 1H), 4.77 (s, 2H), 4.7-4.29 (m, 3H), 2.59 (s, 2H), 1.73 ( s, 3H), 1.43 (d, J = 9 Hz, 3H) C15H18N03C1 (MW = 295.76, Mass Spectroscopy (M + 296)).

Example A45 Synthesis of N- [(3-chlorophenyl) cetyl] alanine cyclohex-2-enyl ester Following the above General Procedure C ', and using N- (3-chlorophenylacetylalanine (from Example D' above) and cyclohex-2-en-l-ol (Aldrich), the title compound can be prepared.The reaction was monitored by tic on silica gel and the purification was by liquid chromatography using 3: 7 EtOAc: hexane as eluent.

The NMR results were as follows:: H-rmn (CDC1): d = 8.6 (d, J = 9 Hz, 1H), 7.4-7.2 (m, 4H), 6.05-5.8 (m, 1H), 5.7- 5.5 (m, 1H), 5.1 (bs, 1H), 4.13-4.29 (m, 1H), 3.5 (s, 2H), 2.1-1.9 (m, 2H), 1.8-1.69 (m, 1H), 1.69- 1.49 (m, 4H), 1.3 (dd, J = 9 Hz, 3H) C: -H; N0..C1 (MW = 321.8, Mass Spectroscopy (M + 321.2)).

Example A46 Synthesis of N- [(2-phenylbenzoxazol-5-yl) acetyl] alanine iso-butyl ester Following General Procedure I 'above, and using 5- (2-phenylbenzoxazole) -yl-acetic acid (CAS # 62143-69-5) and alanine iso-butyl ester (prepared following General Procedure J 'above), the title compound was prepared.

The NMR results were as follows:: H-rrt? N (CDC13): d = 8.24 (m, 3H), 7.68 (m, 1H), 7.51 (m, 5H), 6.04 (m, 1H), 4.58 (m, 1H), 3.85 (m, 2H), 3.68 (s, 2H), 1.9 (m, 1H), 1.35 (d, 3H), 0.87 ( d, 6H). C2CH: 4N: 04 (MW = 380, Mass Spectroscopy (MH + 381)).

Example A47 Synthesis of N- [(3-methylthioyl) acetyl] alanine iso-butyl ester Following General Procedure I 'above, and using 3-methylthiophenylacetic acid (CAS # 18698-73-2) and iso-butyl ester of alanine (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: 'H-rran (CDC13): d = 7.14 (m, 2H), 7.01 (m, 1H), 4.56 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.46 (s, 3H), 1.89 (m, 1H), 1.35 (d, 3H) 0.85 (d, 6H). C16H23N03S (MW = 309, Espect ros copi a de Mas as (MH + 31 0)).

Ex empl o A4 8 Synthesis of N-4- [(2-furyl) acetyl] alanine iso-butyl ester Following General Procedure I 'above, and using 2-furyl acetic acid (CAS # 2745-26-8) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.36 (m, 1H), 6.34 (, 1H), 6.21 (m, 1H), 4.56 (m, 1H), 3.91 (m, 2H ), 3.61 (s, 2H), 1.92 (m, 1H), 1.38 (d, 3H) 0.89 (d, 6H). C13H19N04 (MW = 253, Mass Spectroscopy (MH + 254)).

Example A49 Synthesis of N- [(benzofuran-2-11) acetyl] alanine iso-butyl ester Following General Procedure I 'above, and using benzofuran-2-ylacetic acid (Maybridge) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.51 (m, 1H), 7.44 (m, 1H), 7.25 (m, 2H), 6.67 (s, 1H), 4.60 (m, 1H), 3.87 (m, 2H), 3.77 (s, 2H), 1.88 (m, 1H), 1.38 (d, 3H), 0.87 (d, 6H). C-H_N0 (MW = 303, Mass Spectroscopy (MH + 304)).

Example A50 Synthesis of N- [(benzothiophen-3-11) acetyl] lanin iso-butyl ester Following General Procedure I 'above, and using t ianaphten-3-ylacetic acid (Lancastaer) and iso-butyl ester of alanine (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.89 (m, 1H), 7.76 (m, 1H), 7.38 (m, 3H), 6.07 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.82 (s, 4H), 1.84 (m, 1H), 1.32 (d, 3H), 0.85 (d, 6H). C17H21N03S (MW = 319, Mass Spectroscopy (MH + 320)).

Example A51 Synthesis of iso-butyl ester of iV- [(2-chloro-5-thienyl) acetyl] alanine Following General Procedure I 'above, and using 5-chloro-2-thienyl) acetic acid (CAS # 13669-19-7) and iso-butyl ester of alanine (prepared following General Procedure J' above), the composed of title. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: "-H-rmn (CDC13): d = 6.77 (m, 1H), 6.68 (d, 1H), 6.31 (bm, 1H), 4.59 (m, 1H), 3.91 (m , 2H), 3.38 (s, 2H), 1.90 (m, 1H), 1.39 (d, 3H) 0.89 (d, 6H), C3HI5N03SC1 (MW = 303, Mass Spectroscopy (MH + 303)).

Example A52 Synthesis of N- [(3-methylisoxazol-5-yl) acetyl] alanine isobutyl ester Following General Procedure I 'above, and using acid (3-methyl-isoxazol-5-yl) acetic acid (CAS # 19668-85-0) and iso-butyl ester of alanine (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: ^ -rmn (CDC13): d = 6.07 (s, 2H), 4.56 (m, 1H), 3.92 (m, 2H), 3.68 (s, 2H), 2.29 (s, 3H) ), 1.94 (m, 1H), 1.89 (d, 3H) 0.91 (d, 6H). C13H20N2O4 (MW = 268, Mass Spectroscopy (MH + 269)).

Example A53 Synthesis of iso-butyl ester of iV - [(2-entylthienyl) acetyl] lanin Following General Procedure I 'above, and using (2-phenyl-thiothienyl) acetic acid and iso-butyl ester of alanine (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.21-7.11 (m, 6H), 6.92 (d, 1H), 4.56 (m, 1H), 3.87 (m, 2H), 3.72 ( s, 2-H), 1.94 (m, 1H), 1.38 (d, 3H) 0.89 (d, 6H).

C19H23N03S2 (MW = 377, Mass Spectroscopy (MH + 378)).

Example A54 Synthesis of N - [(6-methoxybenzothiophen-2-yl) acetyl] alanine isobutyl ester Following General Procedure I 'above, and using alanine (6-methoxybenzothiophen-2-yl) acetic acid and iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: H-rmn (CDC1 :,): d = 7.59 (d, 1H), 7.33 (d, 1H), 7.16 (s, 1H), 7.03 (dd, 1H), 4.56 (m , 1H), 3.87 (s, 3H), 3. 84 (m, 2H), 3.76 (s, 2H), 1.85 (m, 1H), 1.30 (d, 3H) 0. 86 (d, 6H). C: -H23NO.S (MW = 349, Mass Spectroscopy (MH + 350)).

Example A55 Synthesis of N- [(3-phenyl-1, 2, 4-thiadiazol-5-yl) acetyl] alanine isobutyl ester Following General Procedure I 'above, and using acid (3-phenyl-1,2,4-thiadiazol-5-yl) acetic acid (CAS # 90771-06-5) and iso-butyl ester of alanine (prepared following the procedure General J 'above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.47 (m, 5H), 4.66 (m, 1H), 4.16 (s, 2H), 3.91 (m, 2H), 1.93 (m, 1H), 1.48 (d, 3H) 0.93 (d, 6H). C: -, H2: N303S (MW = 347, Mass Spectroscopy (MH + 348)).

Example A56 Synthesis of N- [(2-phenyloxazol-4-11) acetyl] alanine isobutyl ester Following General Procedure I 'above, and using (2-phenyloxazol-4-yl) acetic acid (CAS # 22086-89-1) and iso-butyl ester of. alanine (prepared following General Procedure J 'above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: Example A57 Synthesis of N- [(3-methylphenyl) acetyl] alanine iso-butyl ester Following General Procedure I 'above, and using 3-methylphenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.21 (m, 1H), 7.07 (m, 3H), 4.54 (, 1H), 3.83 (m, 2H), 3.52 (s, 2H) ), 2.35 (s, 3H), 1.87 (m, 1H), 1.32 (d, 3H), 0.88 (d, 6H). CItH, N0, (MW = 277, Mass Spectroscopy (MH + 278)).

Example A58 Synthesis of N- [(2,5-difluorophenyl) cetyl] alanine isobutyl ester Following General Procedure I 'above, and using 2, 5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: "-H-rmn (CDC13): d = 7.08-6.94 (m, 3H), 4.57 (m, 1H), 3.91 (m, 2H), 3.56 (s, 2H), 1.92 (m, 1H), 1.41 (d, 3H) 0.91 (d, 6H). C: 5H 19N03F2 (MW = 2 99, Mass Species Copy (MH + 300)).

Example A59 Synthesis of W - [(3,5-di-chlorophenyl) acetyl] alanine isobutyl ester Following General Procedure I 'above, and using 3,5-difluorophenylacetic acid (Aldrich) and alanine iso-butyl ester ( prepared following General Procedure J 'above), the title compound was prepared. The reaction was monitored by tic on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: H-rmn (CDC13): d = 6.81 (m, 2H), 6.74 (m, 1H), 6.06 (m, 1H), 4.57 (m, 1H), 3.92 (m, 2H), 3.51 (s, 2H), 1.94 (m, 1H), 1.36 (d, 3H) 0.87 (d, 6H). C: 5H: 9N03F2 (MW = 299, Mass Spectroscopy (MH + 300)).

Example A60 Synthesis of N - [(3-thienyl) acetyl] alanine iso-butyl ester Following General Procedure I 'above, and using 3-thiopheneacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tic in silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows: '-H-rmn (CDC13): d = 7.33 (m, 1H), 7.14 (m, 1H), 7.01 (, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). Opl Rotation: [a] 23 -52 (c 1 MeOH) @ 589 nm. C13H19N03S (MW = 269, Mass Spectroscopy (MH + 269)).

Example A61 Synthesis of N- [(4-methyl-enyl) -acetyl] -lanin iso-butyl ester Following General Procedure I 'above, and using 4-methyl-phenylaceacid (Aldrich) and α-butyl ester of alanine (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by on silica gel and the purification was by filtration as described in the general procedure.

The NMR results were as follows:: H-rmn (CDC13): d = 7.11 (s, 4H), 5.93 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.54 (s, 2H), 2.33 (s, 3H), 1.89 (m, 1H), 1.32 (d, 3H), 0.89 (d, 6H). C16H23N03 (MW = 277.35, Mass Spectroscopy (MH + 278)).

Example A62 Synthesis of N- (phenylacetyl) -L-alanine iso-butyl ester S-l- (methoxycarbonyl) Following General Procedure K 'and using (S) - (+) - 2-hydroxy-2-methylbutyric acid (Aldrich) in place of the amino acid, methyl (S) - (+) -2-hydroxy-methylbutyrate was prepared.

(S) - (+) -2-Hydroxy-methylbutyrate methyl was then coupled with carbobenzyloxy-L-alanine (Aldrich) using General Procedure E 'to provide iso-butyl ester of carbobenzyloxy-L-alanine Sl- (methoxycarbonyl) .

The isobenyl ester of carbobenzyloxy-L-alanine S-1- (methoxycarbonyl) (1.0 g) was then dissolved in 20 mL of methanol and 6N HCl (0.5 mL) and palladium on charcoal 10% (0.1 g) was added. . This reaction mixture was hydrogenated at 40 psi of hydrogen in a Parr apparatus for 5 hours at room temperature and then filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to provide the iso-butyl ester hydrochloride of L-alanine S-1- (methoxycarbonyl) (98% yield).

L-alanine S-l- (methoxycarbonyl) isobutyl ester hydrochloride was then coupled to the phenylaceacid using General Procedure G 'to provide the title compound.

The NMR results were as follows:: H-rmn (CDC13): d = 7.35-7.20 (m, 5H), 6.22 (bb, 1H), 4.83 (d, 1H), 4.65 (p, 1H), 3.68 (s, 3H), 3.55 (s, 2H), 2.21 (m, 1H), 1.40 (d, 3H), 0.97 (d, 3H) ), 0.93 (d, 3H). :? C-rmn (CDC13): d = 173.25, 171.18, 170.22, 135.11, 129.94, 129.50, 127.88, 52.67, 48.49, 43.98, 30.53, 19.21, 18.75, 17.58.

Example A63 Synthesis of N- [(3-nitro-enyl) -acetyl] -L-alanine iso-butyl ester Following General Procedure H 'and using 3-nitrophenylaceacid (Aldrich) and L-alanine isobutyl ester hydrochloride (from Example B' above), the title compound was prepared. The reaction was monitored by on silica gel and the purification was by recrystallization with butyl chloride.

The NMR results were as follows: 'H-rinn (CDC13): d = 8.17 (m, 2H), 7.68 (d, 1H), 7.52 (d, 1H), 6.18 (, 1H), 4.48 (m, 1H ), 3.94 (m, 2H), 3.67 (s, 2H), 1.93 (, 1H), 1.42 (d, 3H), 0.91 (d, 3H). Opl Rotation: [] 23 -49 (c 5, MeOH).

Example A64 Synthesis of ethyl ester of N - [(3,5-difluorophenyl) acetyl] alanine Following General Procedure G 'and using 3,5-di-fluorophenylaceacid (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93 ° -95 ° C. The reaction was monitored by means of on silica gel (Rf = 0.8 in EtOAC) and the purification was by chromatography on silica gel using EtOAc as eluent followed by recrystallization with 1-chlorobutane.

The NMR results were as follows: xH-rmn (DMSO-d6): d = 1.30 (d, 3H); 3.52 (s, 2H). C13H15N03F2 (MW = 271.26, Mass Spectroscopy (M + 271)).

Example A65 Synthesis of N - [(3-nitrophenyl) acetyl] methionine ethyl ester Following General Procedure G 'above and using 3-nitrophenylaceacid (Aldrich) and methionine ethyl ester hydrochloride (Aldrich), the title compound was prepared. The reaction was monitored by means of on silica gel and the purification was by recrystallization with butyl chloride.

The NMR results were as follows:: H-rmn (CDC13): d = 8.18 (s, 1H), 8.15 (d, 1H), 7.66 (d, 1H), 7.48 (t, 1H), 6.30 (m, 1H), 4.67 (m, 1H), 4.21 (t, 2H), 3.67 (s, 2H), 2.47 (t, 2H), 2.47 (t, 2H), 2.12 (m, 2H), 2.08 (s, 3H) ), 1.27 (t, 3H). Optical Rotation: [a] 3 -30 (c 5, MeOH).

Example A66 Synthesis of N- [(3-chlorophenyl) acetyl] alanine iso-butyl ester Following General Procedure G 'above and using 3-chlorophenylacetic acid (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by means of tic on silica gel.

The NMR results were as follows:: H-rmn (CDC13): d = 7.29 (m, 3H), 7.18 (m, 1H), 6.0 (m, 1H), 4.56 (m, 1H), 3.89 (m, 2H), 3.53 (s, 2H), 1.91 (m, 1H), 1.39 (d, 3H), 0.91 (d, 3H). Optical Rotation: []; 3 -45 (c 5, MeOH). C15H2-N0; .C1 (MW = 297.78, Mass Spectroscopy (MH '297)).

Example A67 Synthesis of JV- [(3-chlorophenyl) acetyl] alanine 2- (2, JV-dimethylamino) ethyl ester Following General Procedure C above, and using N- (3-chlorophenyl-acetic) alanine acid (from Example D 'above) and 2- (N, N-dimethyl amino) ethanol (Aldrich), the title compound can be prepared. The reaction was monitored by means of tic on silica gel and the purification was by liquid chromatography using 0.1: 2: 0.79 NH40H: EtOH: CHC13 as eluent.

The NMR results were as follows: 'H-rmn (CDC13): 7.37 (s, 1H), 7.33-7.2 (m, 3H), 4. 675-4.6 (m, 1H), 4.5-4.37 (m, 1H), 4.25-4.13 (, 1H), 3.6 (d, J = 7 Hz, 2H), 2.86 (bs, 2H), 2.3 (s, 6H) ), 1.23 (d, J = 9 Hz, 3H). C, jH2: N203C l (MW = 3 13. 7 99, E spe ct ros copy of Masa s (MH * 313)).

Example A68 Synthesis of 2- [(3,5-dichlorophenyl) acetamido] hexanoic acid methyl ester Following General Procedure F 'above, and using 3,5-dichlorophenylacetic acid (from Example C above) and L-norleucine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid having a melting point from 77 ° -78 ° C. The reaction was monitored by silica gel tic (Rf = 0.70 in 40% EtOAC / hexanes) and the purification was by flash chromatography on silica gel using 40% EtOAc / hexanes as eluent.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.20 (s), 7.18 (s), 6. 6 (m), 4. 55 (m), 3.7 (s), 3.5 (s), 3.4 (s), 2.0 (s), 1.8 (m), 1.6 (), 1.2 (m), 0.8 (t). 13C-rmn (CDC13): d = 173.54, 169.67, 138.43, 135.72, 128.33, 128.07, 78.04, 77.62, 77.19, 53.04, 52.90, 43.14, 32.57, 27.87, 22.81, 14.41.

Example A69 Synthesis of N - [(3,5-dichlorophenyl) acetyl] -L-alanine iso-butyl ester Following General Procedure F 'above, and using 3, 5-dichlorophenoic acid (from Example C above) and L-alanine iso-butyl ester hydrochloride. (from Example B 'above), the title compound was prepared as a solid having a melting point of 115C-116- "C. The reaction was monitored by silica gel tic (Rf = 0.40 in 3% methanol / dichloromethane) and the purification was by flash chromatography on silica gel using 3% methanol / dichloromethane as eluent .

The NMR results were as follows: 'H-rpin (CDC13): d = 7.27 (d, J = 2 Hz, 1H), 7.19 (s, 2H), 6.22 (d, J = 6 Hz, 1H), 4.59 (quint., J = 7 Hz, 1H), 3.9 (q, J = 4 Hz, 2H), 3.5 (s, 2H), 1.9 (m , 1H), 1.4 (d, J = 7 Hz, 3H), 0.91 (d, < J = 7 Hz, 6H). 13C-rmn (CDC13): d = 173.45, 169.37, 138.31, 135.75, 128. 39, 128.11, 78.04, 77.61, 77.19, 72.19, 54.03, 48. 97, 43.12, 28.24, 19.52, 19.49, 19.09. C15H19N03C12 (MW = 331.9, Mass Spectroscopy (MH * 332)).

Example A70 Synthesis of N- (cyclohexylacetyl) -L-alanine iso-butyl ester Following General Procedure B 'above, and using cyclohexylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 92 ° -93 ° C. The reaction was monitored by means of tic on silica gel (Rf = 0.39 in 1: 3 EtOAc: hexane) and the purification was by extraction with Et20 followed by washes with aqueous K2CO3 and aqueous HCl.

The NMR results were as follows: xH-rmn (CDC13): d = 0.93 (d, J = 6.7 Hz, 6H), 0.85- 1.01 (m, 2H), 1.05-1.35 (m, 3H), 1.40 (d , J = l .1 Hz, 3H), 1.60-1.85 (m, 6H), 1.95 (m, 1H), 3.5 (s, 2H), 2.06 (d, J = 7.0 Hz, 2H), 3.92 (m, 2H), 4.61 (m, 1H), 6.08 (bd, 1H). : 3C-rmn (CDC13): d = 18.7, 18.9, 26.0, 26.1, 27.6, 33. 0, 35.3, 44.6, 47.9, 71.4, 171.8, 173.3. C15H N03 (MW = 269.39, Mass Spectroscopy (MH + 270)).

Example A71 Synthesis of N- (cyclopentylacetyl) -L-alanine iso-butyl ester Following General Procedure B 'above, and using cyclopentyl acetic acid (Aldrich) and isobutyl ester hydrochloride. of L-alanine (from Example B 'above), the title compound was prepared as a solid having a melting point of 62 ° -64 ° C. The reaction was monitored by means of tic on silica gel. { Rf = 0.37 in 1: 3 EtOAc: hexane) and the purification was by extraction with Et: 0 followed by washes with aqueous K2CO3 and aqueous HCl.

The NMR results were as follows: xH-rmn (CDC13): d = 0.87 (d, J = 6.8 Hz, 6H), 1.01-1.17 (m, 2H), 1.34 (d, J = 1 .2 Hz, 3H ), 1.40-1.62 (m, 4H), 1.70-1.83 (m, 2H), 1.89 (m, 1H), 2.15 (m, 3H), 3. 86 (m, 2H), 4.55 (m, 1H), 6.30 (d, J = 7.1 Hz, 1H). : 3C-rmn (CDC13): d = 18.4, 18.78, 18.80, 24.8 (very high), 27.5, 32.27, 32.32, 36.9, 42.5, 47.7, 71.2, 172.2, 173.2. Elemental Analysis-Calc (%): C, 65.85; H, 9.87; N, . 49; Found (%): C, 66.01; H, 10.08; N, 5.49. C ^ .H ^ NO;, (MW = 255.36, Mass Spectroscopy (MH + 256)).

Example A72 Synthesis of N- [(cyclohex-1-enyl) acetyl] -L-alanine iso-butyl ester Following General Procedure B 'above, and using cyclohex-1-enyl acetic acid (Alpha) and L-alanine iso-butyl ester hydrochloride (from Example B' above), the title compound was prepared as a solid having a melting point of 49 ° -51 ° C. The reaction was monitored by means of tic on silica gel (Rf = 0.40 in 1: 3 EtOAc: hexane) and the purification was by extraction with Et20 followed by washes with aqueous K2C03 and aqueous HCl.

The NMR results were as follows: 'H-rrpn (CDC13): d = 0.91 (d, J = 4.5 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 1.40 (d, J = 7.2 Hz, 3H), 1.52-1.70 (m, 4H), 1.97 (m, 3H), 2.06 (bs, 2H), 2.89 (s, 2H), 3.92 (m, 2H), 4.59 (m, 1H), 5.65 (s, 1H), 6.33 (d, J = 6.6 Hz, 1H). : 3C-rmn (CDC13): d = 18.7, 18.91, 18.93, 21.9, 22.7, . 3, 27.6, 28.3, 46.1, 47.9, 71.4, 127.1, 132.5, 170.6, 173.1. Elemental-Calc Analysis (%): C, 67.38; H, 9.42; N, 5.24; Found (%): C, 67.34; H, 9.54; N, 5.16. C.JH ^ JNO;, (PM = 267.37, Mass Spectroscopy (MH + 268)).

Example A73 Synthesis of N - [(3-chlorophenyl) acetyl] alanine 3-methylbut-2-enyl thioester Following General Procedure C above, and using N- [(3-chlorophenyl) acetyl] alanine and thioester of 3-methyl-2-butene (TCI), the title compound can be prepared. The reaction was monitored by means of tic on silica gel and the purification was by liquid chromatography using 3: 7 EtOAc: Hexane as eluent.

The NMR results were as follows:? -H-rmn (DMSO-d6): d = 5.2-5.075 (m, 1H), 4.37 (dq, J = 9 Hz, 1H), 3.56 (s), 3.43 (d, J = 12 Hz, 2H), 1266 (d, J = 12 Hz, 6H), 1.3 (d, = 9 Hz, 3H). C-.6H2CN02C1S (MW = 325.86, Mass Spectroscopy (MH * 325)).

Example A74 Synthesis of N- [(2-phenyl) -2-fluoroacetyl] alanine ethyl ester Following General Procedure F 'above, and using acid-fluorophenyl acetic (Aldrich), the title compound was prepared. The reaction was monitored by silica gel tic (Rf = 0.75 in 1: 1 EtOAC / hexane) and the purification was by silica gel chromatography using 1: 2 ethyl acetate / hexanes as eluent.

The NMR results were as follows:: Hr n (DMSO-d: d = 1.14 (q, 3H), 1.34 (d, 3H), 4.07 (m, 2H), 4.33 (m, 1H), 5.84 (d, 1H), 6.01 (d, 1H), 7.40-7.55 (m, 5H), 8.87 (m, 1H), C13H16N03F (MW = 253.27, Mass Spectroscopy (M + 353)).

Example A75 Synthesis of N- (3,5-difluorophenylacetyl) -L-phenylglycine methyl ester Following General Procedure F above, and using 3, 5-fluorophenyl acetic acid (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR results were as follows:: H-rmn (CDC13): d = 7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d 1H, 7.1 Hz), 5.56 (d 1H 7 Hz), 3.72 (s 3H), 3.57 (s 2H): 3C-rmn (CDC1: d = 197.6, 177.6, 171.8, 169.3, 136. 7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103. 8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3 C: -H:, NO F: (MW = 319.31, Mass Spectroscopy (MH + 320)).

Example A76 Synthesis of N- (3,5-difluorophenylacetyl) -L-enylglycine iso-butyl ester 3,5-difluorophenylacetic acid (Aldrich) was coupled EDC to L-phenylglycine methyl ester hydrochloride (Bachem) via General Procedure F above.

The resulting compound was placed in a large excess of the desired alcohol. A catalytic amount of dry NaH was added, and the reaction was followed by tic until the presence of initial material was no longer detected. The reaction was quenched with a few milliliters of 1N HCl, and after a few minutes of stirring saturated aqueous NaHCO3 was added. The volume of. the reaction mixture was reduced in a rotary evaporator until the excess alcohol was removed and then the remaining residue was saved in ethyl acetate and additional water was added. The organic phase was washed with saturated aqueous NaCl and dried with MgSO. The solution was separated from the solvent in a rotary evaporator, and the residue of the crude product was further purified by chromatography.

The NMR results were as follows: -rmn (CDC13): d = 7.35-7.3 (m 5H), 6.8-6.7 (m 3H), 6.60 (d 1H, 7 Hz), 5.55 (d 1H 7.1 Hz), 3.9 (m 2H), 3.60 (s 2H), 1.85 (m 1H 7 Hz), 0.8 (q 6H 7 Hz). 13C-rmn (CDC13): d = 171.3, 169.3, 165.4, 138.5, 137. 0, 129.5, 129.2, 127.6, 113.1, 113.0, 112.8, 112.7, 103.8, 103.5, 103.2, 75.5, 57.2, 43.4, 43.3, 28.2, 19.3 C20H2iNO3F2 (MW = 361.39, Mass Spectroscopy (MH + 362)).

Example A77 Synthesis of methyl ester of N- (cyclopentylacetyl) -L- f enligue ina Following General Procedure D 'above, and using cyclopentyl acetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.35 (s, 5H), 6.44 (bd, 1H), 5.6 (d, 1H), 3.72 (s, 3H), 2.24 (bs, 3H), 1.9-1.4 (m, 6H), 1.2-1.05 (m, 2H). "- • C-rmn (CDC13): d = 172.3, 171.7, 136.7, 129.0, 128.6, 127.3, 56.2, 52.7, 42.5, 36.9, 32.40, 32.38, 24.8 Example A78 Synthesis of N- (cyclopentylacetyl) -L-alanine methyl ester Following General Procedure D 'above, and using cyclopentyl acetic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.

The NMR results were as follows:: H-rmn (CDC15): d = 6.38 (d, 1H), 4.50 (m, 1H), 3.65 (s, 3H), 2.13 (bs, 3H), 1.80-1.00 (m (includes da 1.30, 3H), 11H) '-'C-rmn (CDC1: d = 173.7, 172.5, 52.1, 47.6, 42.3, 36.8 , 32.15, 32.14, 18.0 C :: H:, NO_, (MW = 213.28, Mass Spectroscopy (MH * 214)).

Example A79 Synthesis of N- (cyclopropylacetyl) -L-enylglycine methyl ester Following General Procedure D 'above, and using cyclopropylacetic acid (Aldrich) with L-phenylglycine methyl ester hydrochloride (Bachem), the compound of Title.

The NMR results were as follows:: H-rmn (CDC13): d = 7.35 (s, 5H), 6.97 (bd, J = 7.2 Hz, 1H), 5.59 (d, J = 1.8 Hz, 1H) , 3.71 (s, 3H), 2.17 (m, 2H), 1.05-0.95 (m, 1H), 0.62 (m, 2H), 0.02 (m, 2H). : 3C-rmn (CDC13): d = 171.9, 174.6, 136.6, 129.0, 128.5, 127.2, 56.1, 52.7, 41.0, 6.9, 4.37, 4.33 Example A80 Synthesis of N- (cyclopropylacetyl) -L-alanine methyl ester Following General Procedure D 'above, and using cyclopropyl lactic acid (Aldrich) with L-alanine methyl ester hydrochloride (Sigma), the title compound was prepared.

The NMR results were as follows:: H-rmn (CDC1.): D = 6.60 (d, 1H), 4.55 (m, 1H), 3.69 (s, 3H), 2.10 (m, 2H), 1.34 (d , 3H), 0.95 (m, 1H), 0.58 (m, 2H), 0.15 (m, 2H) 13C-rmn (CDC13): d = 173.7, 172.3, 52.3, 47.7, 41.0, 18.2, 6.7, 4.27, 4.22 Example A81 Synthesis of N - [(3-nitrophenyl) acetyl) -L-methionine isobutyl ester Following General Procedure H 'above, and using nitrophenylacetic acid (Aldrich) and L-methionine (Aldrich) the title compound was prepared as a tan oil. The reaction was monitored by means of tic on silica gel.

The NMR results were as follows:: H-rmn (CDC1:: d = 8.16 (m, 2H), 7.67 (d, 1H), 7.32 (t, 1H), 6.31 (bd, 1H), 4.69 (m, 1H), 3.90 (d, 2H), 3.68 (s, 2H), 2.47 (t, 2H), 2.15 (m, 1H), 2.02 (s, 3H), 1.90 (m, 2H), 0.91 (d, 6H) C: -H_N ^ OS (MW = 368.4, Mass Spectroscopy (M + 368)).

The following General Procedures A "-B" and Examples B1-B2 illustrate an alternative synthesis of N- (a r i 1 / he t eroa ri 1 ace i 1) amino acids useful as starting materials for the preparation of the amides of this invention.

GENERAL PROCEDURE A "Preparation of Acid Chloride 3, 5-difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0 ° C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) for a period of 5 minutes. The reaction was stirred for 3 h and then rotavaped under reduced pressure for a residue which was placed in a high vacuum pump for 1 h to provide 3,5-difluorophenylacetyl chloride as a yellow oil with low viscosity. Other acid chlorides can be prepared in a similar manner.

GENERAL PROCEDURE B "Procedure Schotten-Bauman 3,5-Di-fluorophenylacetyl chloride (from General Procedure A ") was added dropwise to a 0: C solution of L-alanine (Aldrich) (16.7 g, 0.187 mol) in 2N sodium hydroxide (215 mL, 0.43 mol) The reaction was stirred for 1 h at 0"JC and then overnight at room temperature. The reaction was diluted with water (100 mL), then extracted with ethyl acetate (3 x 150 mL). The organic layer was then washed with brine (200 mL), dried with MgSO 4, and rotary evaporated under reduced pressure to a residue. Recrystallization of the residue with ethyl acetate / hexanes gave the desired product (34.5 g, 82% yield). Other acid chlorides could be used in this process to provide the intermediates useful in this invention.

Example Bl Synthesis of N- (Phenylacetyl) -L-alanine Following General Procedure B "above, the title compound was prepared from phenylacetyl chloride (Aldrich) and L-alanine (Aldrich) as a solid having a melting point of 102-104 ° C.

The NMR results were as follows:: H-rmn (CDC13): d = 9.14 (br s, 1H), 7.21-7.40 (m, 5H), 6.20 (d, J = 7.0 Hz, 1H), 4.55 (m , 1H), 3.61 (s, 2H), 1.37 (d, J = 7.1 Hz, 3H). '••' C-rmn (CDC1,): d = 176.0, 171.8, 134.0, 129.4, 127.5, 48.3, 43.2, 17.9.

Example B2 Synthesis of N- (3,5-Difluorophenylacetyl) -L-alanine Following General Procedure B "above, the title compound was prepared from 3,5-difluorophenylacetyl chloride (from General Procedure A" above) and L-alanine (Aldrich).

The NMR results were as follows:: H-rmn (CD30D): d = 8.32 (br s, 0.3H), 6.71 (br, 1.7H), 6.71 (m, 2H), 6.60 (m, 1H), 4.16 (m, 1H), 3.36 (s, 2H), 1.19 (d, J = 7.3 Hz, 3H). : 3C-rmn (CD; .OD): d = 175.9, 172.4, 164.4 (dd, J = 13.0, 245.3 Hz), 141.1, 113.1 (dd, J = 7.8, 17.1 Hz), 102. 9 (t, J = 25.7 Hz), 49.5, 42.7, 17.5.

The compounds set forth in Examples 1-22 were prepared by one of the following General Procedures A-G, unless otherwise indicated.

GENERAL PROCEDURE A EDC Coupling Procedure I To a 1: 1 mixture of the corresponding carboxylic acid and amino / amide ester in CH2C12 at 0 ° C was added 1.5 equivalents of triethylamine, followed by 2.0 equivalents of hydroxybenzot riazole monohydrate, then 1.25 equivalents of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC). The reaction mixture was stirred overnight at room temperature and then transferred to a separatory funnel. The mixture was washed with water, saturated aqueous NaHCO3, saturated hydrochloric acid, and saturated aqueous sodium chloride, and then dried with MgSO4. The solution was separated from the solvent in a rotary evaporator to produce the crude product.

GENERAL PROCEDURE B EDC Coupling Procedure II A round bottom flask was charged with the appropriate carboxylic acid (1.0 eq.), Hydroxybenzotriazole hydrate (1..1 eq.) And the appropriate amine (1.0 eq.) In THF under nitrogen atmosphere. An appropriate amount (1.1 eq for the free amine and 2.2 eq for the amine hydrochloride salt) of a suitable base, such as Hunig's base was added to the stirred mixture, followed by 1-hydrochloride. { 3-dimet i laminopropyl) -3-ethylcarbodiimide (EDC) (1.1 eq.). After stirring for about 4 hours to 17 hours at room temperature, the solvent was removed under reduced pressure and the residue was stored in EtOAc (or a similar solvent) / H20. The extracts were washed with saturated NaHCO3, 1 N aqueous hydrochloric acid, brine and dried with Na2SO4. In some cases, the isolated product required additional purification using standard procedures, such as chromatography and / or recrystallization.

GENERAL PROCEDURE C EDC Coupling Procedure III A mixture of the appropriate carboxylic acid (1 eq.), 1-hydroxybenzothiazole (1.6 eq.), The appropriate amine (1 eq.), N-methyl ethylbenzene (3 eq.) And dichloromethane (or DMF for substrates). insoluble), cooled in an ice-water bath, was stirred until a clear solution was obtained. EDC (1.3 eq.) Was added to the reaction mixture and the cooling bath was allowed to warm to room temperature for 1-2 h. Then the reaction was stirred overnight. The reaction mixture was then evaporated to dryness in vacuo and 20% aqueous potassium carbonate was added to the residue. The mixture was stirred vigorously and allowed to stand for hours or overnight, if necessary, until the oily product solidified. The solidified product was then filtered, washed thoroughly with 20% potassium carbonate, water, 10% HCl, and water to give the product. No racemization was observed using this procedure.

GENERAL PROCEDURE D CDI Coupling Procedure I A solution of the appropriate acid (3.3 mmol) and 1,1'-carbodiimidazole (CDl) in 20 mL of THF was stirred for 2 hours. The amino acid ester hydrochloride (3.6 mmol) was added, followed by 1.5 mL (10.8 mmol) of triethylamine. The reaction mixture was stirred overnight and then dissolved in 100 mL of diethyl ether, washed with 10% HCl three times, brine once, 20% potassium carbonate once and brine once. The solution was dried with magnesium sulfate, filtered, and evaporated to produce the product.

GENERAL PROCEDURE E Reactions II of CDI Aq. A solution of the acid (1.08 mmol) and 1.1 carbodiimidazole (CDl, 0.972 mmol) in 10 mL of THF was stirred for 1-2 hours. The appropriate amine (1188 mmol) was added, and the reaction mixture was stirred overnight. The total reaction mixture was dissolved in 100 ml of ethyl acetate, washed with 10% HCl (50 X 2 ml), brine once, 20% potassium carbonate once and brine once. The solution was dried with magnesium sulfate, filtered and evaporated to produce the product.

GENERAL PROCEDURE F EDC Coupling Procedure IV A round bottom flask was charged with the appropriate carboxylic acid (1.0 eq.), Hydroxybenzotriazole hydrate (1.1 eq.) And the appropriate amine (1.0 eq.) In THF under nitrogen atmosphere. An appropriate amount (1.1 eq for the free amine and 2.2 eq for the amine hydrochloride salt) of a suitable base, such as Hunig's base was added to the stirred mixture, followed by 1 - (3-dimet i laminopropyl) hydrochloride -3-ylcarbodiimide (EDC) (1.1 eq.). After stirring for about 4 h at 50 h at room temperature, the solvent was removed under reduced pressure and the residue was stored in EtOAc (or a similar solvent) / H20. The extracts were washed with saturated NaHCO3, 1 N aqueous hydrochloric acid, brine and dried with Na2SO4. In some cases, the isolated product required additional purification using standard procedures, such as chromatography and / or recrystallization.

Example A Synthesis of 2-Amino-1-phthalimidopentane Hydrochloride 2-Amino-l-pentanol was stirred in a mixture of chloroform and saturated aqueous sodium bicarbonate. Di-tert-butyl dicarbonate (1.05 eq.) Was added in one portion and the mixture was stirred until the initial material was consumed. The organic portion was separated, dried (sodium sulfate) and concentrated. The crude material was purified by chromatography on silica gel using 1: 1 ethyl acetate / hexanes.

The product was dissolved in THF. Triethylamine (1.1 eq.) Was added and the mixture was cooled in an ice bath. Methanesulfonyl chloride (1.1 eq.) Was added dropwise and the mixture was stirred until the initial material was consumed. The mixture was concentrated under reduced pressure then partitioned between ethyl acetate and water. The organic portion was separated, dried (sodium sulfate) and concentrated to yield a white solid which was chromatographed on silica gel using 30% ethyl acetate in hexanes and finally crystallized with 1-chlorobutane / hexanes.

The crystalline product was stirred in dry DMF and potassium phthalimide (1.1 eq.) Was added. The mixture was stirred for 18 h then it was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic portion was dried and concentrated to yield a white solid. The solid was stored in chloroform and filtered through a plug of silica. The product containing eluent was concentrated to yield the crude product as a white solid.

The white solid was stored in dry diozan and the resulting solution was saturated with gaseous HCl. After stirring for 30 minutes, the mixture was concentrated to yield a white solid which was titrated in ether. The title compound was collected, washed with ether and dried in a vacuum oven.

Example B Synthesis of 5-Aminodibenzosuberane -Chlorodibenzosuberane (Aldrich) was heated to reflux in 7N NH3, in MeOH. After 18 hours, the reaction mixture was concentrated to a solid which was purified by chromatography on silica gel to yield the title compound.

Example 1 Synthesis of N- (3-Hydroxyphenyl) -N '- (phenylamethyl) -L-alaninamide Following General Procedure C and using N- (phenylacetyl) -L-alanine (Example Bl) and 3-hydroxyaniline . { Aldrich), the title compound was prepared as a solid (mp = 164-167 C). The product was purified by extraction with EtOAc and washing with aqueous NaHCO3 and HCl.

The NMR results were as follows:: H-rmn (DMSO-d,): d = 9.90 (s, 1H), 9.40 (s, 1H), 6. 41 (d, J = 7.4 Hz, 1H), 7.27 (m, 4H), 7.20 (m, 2H), 7. 0 *? . { , J = 8.0 Hz, IH), 6.98 (m, 1H), 6.46 (dd, J = 1.7, 7.1 Hz, 1H), 4.43 (m, 1H), 3.50 (s, 2H), 1.30 (d, J = 7.1 Hz, 3H). 13C-nm (DMS0-d6): d = 171.2, 170.0, 157.6, 140.0, 136.4, 129.4, 129.1, 128.2, 126.3, 110.5, 110.0, 106.4, 49.1, 41.9, 18.4. C17Hi8N203 (MW = 298.34); mass spectroscopy (MH +) 297 (M-H) +.

Example 2 Synthesis of N- (3-methoxy-enyl) -N'- (enylacetyl) -L-alaninamide Following General Procedure E and using N- (phenylacetyl) -L-alanine (Example Bl) and 3-methoxyaniline (Aldrich), the title compound was prepared as a solid (mp = 154-157"C).

The results of RM? were as follows:: H-rmn (CDC1,): d = 9.38 (s, 1H), 7-20-7.35 (m, 6H), 7.00-7.15 (, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.62 (dd, J = 2.2, 8.1 Hz, 1H), 4.85 (quint., J = 7.2 Hz, 1H), 3.70 (s, 3H), 3.57 (s, 2H), 1.42 (d, J = 7.0 Hz, 3H). '-'C-rmn (CDC1: d = 171.6, 171.0, 159.9, 139.1, 134.4, 129.5, 129.2, 128.8, 127.2, 112.2, 110.1, 105.5, 55.1, 49.8, 43.3, 18.5, C; .H_? _0. (MW = 312.37), mass spectroscopy (MH-) 313.

Example 3 Synthesis of N- (3-Ethoxycarbonylphenyl) -N'- (phenylacetyl) -L-alaninamide Following General Procedure E and using N- (phenylacetyl) -L-alanine (Example Bl) and 3-aminobenzoate (Aldrich), the title compound was prepared as a solid (mp = 142-145 ° C).

The results of RM? were as follows: H-rmn (CDC13): d = 9.44 (s, 1H), 8.16 (d, J = l.8 Hz, 1H), 7.74 (dd, J = 5.0, 8.0 Hz, 2H), 7.21 -7.36 (m, 6H), 6. 71 (d, J = 7.6 Hz, 1H), 4.86 (m, 1H), 4.35 (q, J = 7.1) Hz, 2H), 3.65 (s, 2H), 1.42 (d, J = 7.0 Hz, 3H), 1.35 (t, J = 7.8 Hz, 3H). : -C-rmn (CDC1,): d = 171.5, 171.8, 166.2, 138.2, 134.2, 131.0, 129.2, 129.0, 128.9, 127.4, 125.2, 124.2, 120.7, 61.1, 49.7, 43.5, 18.5, 14.3. C;? ^:?: 04 (PM = 354.41); mass spectroscopy (MH *) 355.

Example 4 Synthesis of N- (4-Ethoxycarbonylphenyl) -N '- (phenylacetyl) -L-alaninamide Following General Procedure E and using N- (phenylacetyl) -L-alanine (Example Bl) and 4-aminobenzoate (Aldrich), the title compound was prepared as a solid (mp = 175-178 ° C).

The results of RM? were as follows: 'H-rmn (CDC13): d = 9.61 (s, 1H), 7.91 (dd, J = 7.1, 8. 9 Hz, 2H), 7.50 (dd, J = 5.2, 8.7 Hz, 2H), 7.21-7.38 (m, 5H), 6.86 (d, J = 7.6 Hz, 1H), 4.88 (quint., J = 7.1) Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.62 (s, 2H), 1.36-1.44 (m, 6H). : 3C-rmn (CDC13): d = 171.7, 171.0, 166.1, 142.1, 134.2, 130.5, 129.2, 128.9, 127.5, 118.9, 60.8, 49.8, 43.3, 18.6, 14.3. C2-H: _? 04. { MW = 354.41); mass spectroscopy (MH ') 353 (M-H) -.

Example 5 Synthesis of N- (n-Hexyl) -Nf- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure B and using N- (3, 5-di fluorophenylacet il) -L-alanine (Example B2) and n-hexylamine. { Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic (Rf = 0.31 in 5% MeOH / CH2Cl2) and the product was purified by flash column chromatography using 5% MeOH / CH2Cl2 as eluent.

The NMR results were as follows:: H-rmn (CDC13): d = 7.62 (d, 1H), 7.14 (t, lH), 6. 80-6.60 (m, 3H), 4.62 (p, 1H), 3.44 (s, 2H), 3.23-3.01 (m, 2H), 1.41 (m, 2H), 1.39 (d, 3H), 1.23 (m, 8H), 0.83 (t, 3H). : 3C-rmn (CDC13): d = 173.0, 170.3, 165.1, 165.0, 161.8, 161.7, 139.47, 139.3, 139.2, 112.8, 112.7, 112.6, 112.5, 103.3, 103.0, 102.6, 49.5, 42.9, 40.1, 31.9, 29.8, 27.0, 23.0, 19.4, 14.5. C: -H; N-0; F (MW = 326.39); mass spectroscopy (MH *) 32 ^ 7.

Example 6 Synthesis of N- (n-Octyl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure B and using N- (3, 5-di f luorofeni lace il) -L-alanine (Example B2) and n-octylamine (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tic (Rf = 0. 35 in 5% MeOH / CH ^ Cl.) And the product was purified by flash column chromatography using 5% MeOH / CH2Cl2 as eluent.

The NMR results were as follows: 'H-rmn (CDC13): d = 7.50 (d, 1H), 7.03 (t, lH), 6.75-6.60 (m, 5H), 4.60 (p, 1H), 3.48 ( s, 2H), 3.24-3.04 (m, 2H), 1.40 (m, 2H), 1.38 (d, 3H), 1.23 (m, 10H), 0.86 (t, 3H). 13C-rmn (CDC13): d = 172.9, 170.2, 165.2, 165.0, 161.9, 161.7, 139.3, 139.2, 139.1, 112.8, 112.7, 112.6, 112.5, 103.4, 103.0, 102.7, 49.5, 43.0, 40.1, 32.3, 29.9 , 29.7, 27.4, 23.1, 19.4, 14.6. C: 9H2SN202F (MW = 354.44); mass spectroscopy (MH *) 355.

Example 7 Synthesis of N- (3-Methoxyphenyl) -N'- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure E and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and 3-methoxyani-1a (Aldrich), the title compound was prepared.

The results of RM? were as follows: ^ -rmn (DMSO-d: d = 1.30 (d, J = 7.0 Hz, 3H), 3.54 (s, 2H), 3.71 (s, 3H), 4.40 (quint., J = 7.0 Hz, 1H), 6.62 (d, J = 6.7 Hz, 1H), 6.96-7.26 (m, 5H), 7.29 (s, 1H), 8.51 (d, J = 7.1 Hz, 1H), 10.04 (s, 1H). 13C-rmn (DMSO-d6): d - 18.2, 41.2, 49.2, 54.9, 101.9 (t, J = 25.5 Hz), 104.9, 108.7, 111.4, 112.2 (dd, J = 7.3, 17.0 Hz), 129.5, 140.1, 140.7, 159.5, 162.1 (m), 168.9, 171.3. C18H1SN203F2 (MW = 348.35); mass spectroscopy (MH *) 349.

Example 8 Synthesis of N- (4-Ethoxycarbonylphenyl) - "" '- (3,5-di-chlorophenylacetyl) -L-alaninamide Following General Procedure E and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 4-aminobenzoate (Aldrich), the title compound was prepared.

The results of RM? were as follows:: H-rmn (DMSO-dJ: d = 1.32 (m, 6H), 3.55 (s, 2H), 4.27 (q, J = 7.0 Hz, 2H), 4.42 (quint., J = 7.0 Hz , 1 HOUR), 7. 00 (m, 2H), 7.08 (m, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7. 91 (d, J = 8.7 Hz, 2H), 8.57 (d, J = 6.7 Hz, 1H), 10.04 (s, 1H). 13C-nm (DMSO-d6): d = 14.2, 17.9, 41.1, 49.4, 60.5, 101.9 (t, J = 25.3 Hz), 112.2 (dd, J = 7.4, 16.9 Hz), 118.6, 124.3, 130.3, 140.6 , 140.8, 143.3, 162.1 (dd, J = 13.1 ', 243.7 Hz), 165.3, 169.0, 171.9. C20H2oN204F2 (MW = 390.39); mass spectroscopy (MH +) 391.

Example 9 Synthesis of N- (3-Ethoxycarbonylphenyl) -N'- (3, 5-difluoro-enylacetyl) -L-alaninamide Following General Procedure E and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and ethyl 3-aminobenzoate (Aldrich), the title compound was prepared.

The results of RM? were as follows: H-rmn (CDC13): d = 1.34 (t, J = 7.1 Hz, 3H), 1.47 (d, J = 6.9 Hz, 3H), 3.57 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4. 85 (quint, J = 7.1 Hz, 1H), 6.66 (m, lH), 6.78 (m, 2H), 7. 16 (d, J = 7.4 Hz, 1H), 7.30 (m, 1H), 7.74 (t, J = 7.8 Hz, 2H), 8.12 (d, J = 1.8 Hz, 1H), 9.38 (s, 1H) ). ::, C-rmn (CDC1 :.): d = 14.2, 18.6, 42.7, 49.9, 61.2, 102.8 (t, J = 25.1 Hz), 112.2 (dd, J = 8.0, 17.1 Hz), 120.9, 124.3, 125.4, 129.0, 131.1, 137.9, 138.0, 163.0 (dd, J = 12.6, 247.7 Hz), 166.2, 170.2, 171.0. C20H20N2O4F2 (MW = 390.39); mass spectroscopy (MH +) 391.

Example 10 Synthesis of N- (3-Chlorophenyl) -W- (3, 5-di-chlorophenylacetyl) -L-alaninamide Following General Procedure E and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and 3-chloroaniline (Aldrich), the title compound was prepared.

The results of RM? were as follows: H-rmn (DMSO-do): d = 1.31 (d, J = 7.1 Hz, 3H), 3.55 (s, 2H), 4.38 (quint., J = 7.1 Hz, 1H), 7.00 ( m, 2H), 7.09 (m, 2H), 7.33 (m, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.80 (s, 1H), 8.57 (d, 7.0 Hz, 1H), 10.26 (m, s, 1H). : 3C-nm (DMSO-de): d = 18.0, 41.2, 49.3, 101.9 (t, J = 25.5 Hz), 112.2 (dd, J = 7.3, 16.7 Hz), 117.6, 118.6, 123.0, 130.5, 133.1, 140.4, 140.5, 140.7, 162.2 (m), 169.0, 171.7. C: -H: í.? _ 0_FCl (MW = 352.77); mass spectroscopy (MH *) 353.

Example 11 Synthesis of N- (3,5-Dichlorophenyl) -N'- (3,5-difluorophenylacetyl) -L-alaninamide Following General Procedure E and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and 3,5-dichloroaniline (Aldrich), the title compound was prepared.

The results of RM? were as follows: xH-rmn (DMSO-d6): d = 1.31 (d, J = 7.0 Hz, 3H), 3.55 (s, 2H), 4.34 (m, 1H), 7.00 (m, 2H), 7.07 ( m, 1H), 7.27 (s, 1H), 7.66 (s, 2H), 8.59 (d, J = 6.6 Hz, 1H), 10.39 (s, 1H). "- • C-rmn (DMSO-d: d = 17.7, 41.1, 49.5, 101.9 (t, J = 25.5 Hz), 112.3 (dd, J = 7.7, 16.9 Hz), 117.3, 122.6, 134.1, 140.4, 140.6 , 140.7, 141.2, 162.1 (dd, J = 13.4, 243.9 Hz), 169.1, 172.0, C; -H:.? 0; FCl2 (MW = 387.22); mass spectroscopy (MH *) 387.

Example 12 Synthesis of N- (3-Cyanophenyl) -N '- (3,5-di-chlorophenylacetyl) -L-alaninamide Following General Procedure E and using N- (3,5-difluorophenylacetyl) -L-alanine (Example B2) ) and 3-cyanoaniline (Aldrich), the title compound was prepared.

The results of RM? were as follows: 'H-rmn (DMSO-d6): d = 1.32 (t, J = 7.1 Hz, 3H), 3.55 (s, 2H), 4.39 (quint, J = 7.0 Hz, 1H), 7.00 (m , 2H), 7.08 (m, 1H), 7.52 (m, 2H), 7.82 (m, 1H), 8.08 (s, 1H), 8.60 (d, J = 6.8 Hz, 1H), 10.42 (s, 1H) . 13C-nm (DMSO-d6): d = 17.9, 41.1, 49.4, 101.9 (t, J = 25.4 Hz), 112.2 (dd, J = 7.7, 17.0 Hz), 118.7, 121.8, 123.7, 126.9, 130.3, 139.7, 140.6, 140.8, 162.1 (dd, J = 13.3, 243.6 Hz), 169.1, 172.0. C: sH: f.? _, 02F2 (MW = 343.34); mass spectroscopy (MH *) 344.

Example 13 Synthesis of N- (Ftalid-6-yl) -? '- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure E and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and 6-aminophthalide (Aldrich), the title compound was prepared as a solid (mp = 241-245 (decomp) ° C). The reaction was monitored by tic (Rf = 0.11 in 1: 1 EtOAc / hexanes) and the product was purified by precipitation with water.

The NMR results were as follows: H-rmn (DMSO-d6): d = 1.34 (d, J = 7.1 Hz, 3H), 3.56 (s, 2H), 4.42 (m, 1H), 5.36 (s, 2H), 7.00 (d, J = 6.9 Hz, 2H), 7.08 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H) , 7.81 (m, 1H), 8.21 (s, 1H), 8.59 (d, J = 6.8 Hz, 1H), 10.42 (s, 1H). : 3C-rmn (DMSO-d6): d = 18.0, 41.2, 49.3, 69.8, 101.9 (t, J = 25.7 Hz), 112.3 (dd, J = 7.4, 16.9 Hz), 114.2, 123.4, 125.3, 125.5, 139.7, 140.6, 141.9, 162.1 (dd, J = 13.4, 243.7 Hz), 169.1, 170.8 , 171.8. C1? H: éN; O.F: (MW = 374.35); mass spectroscopy (MH *) 375.

Example 14 Synthesis of iV- [(4-Methoxycarbonylphenyl) ethyl] -N'- (3,5-difluorophenylacetyl) -L-alaninamide Following General Procedure D and using N- (3, 5-di fluorofen i lacet i 1) -L-alanine (Example B2) and methyl 4-amino-methylbenzoate (Aldrich), the title compound was prepared as a solid (mp = 191-192 ° C). The reaction was monitored by tic (Rf = 0.19 in 1: 1 EtOAc / hexanes) and the product was purified by precipitation with water.

The NMR results were as follows: -H-rmn (DMSO-d6): d = 1.25 (d, J = 7.0 Hz, 3H), 3.53 (s, 2H), 3.84 (s, 3H), 4.30 (m, 1H), 4.35 (d, J = 6.0 Hz, 2H), 6.99 (d, J = 6.9 Hz, 2H), 7.08 (t, J = 2.1 Hz, 1H), 7.35 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 8.43 (d, J = 7.2 Hz, 1H), 8.57 (t, 5.9 Hz, 1H) ). 13C-nm (DMSO-d6): d = 18.2, 41.3, 41.7, 48.5, 52.1, 101. 9 (t, 25.4 Hz), 112.2 (dd, J = 7.5, 17.0 Hz), 127.1, 128.1, 129.2, (140.6, 140.8 as multiplet), 145.2, 162.1 (dd, J = 13.4, 243.7 Hz), 166.1, 168.9, 172.5. C - H :: N; 0 F; (MW = 390.39); mass spectroscopy (MH *) 391.

Example 15 Synthesis of N- (1-Cyano-l-phenylmethyl) -2 i "- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure B and using N- (3, 5-di fluorophenylacetyl) -L-alanine (Example B2) and 1-cyano-l-phenylethylamine hydrochloride (Aldrich), the title compound was prepared as a solid (mp = 209-213 ° C). The reaction was monitored by tic (Rf = 0.5 in 10% MeOH / CHC13) and the product was purified by recrystallization with 1-chlorobutane / acetonitrile.

The NMR results were as follows: 'H-rmn (DMSO-d6): d = 3.50-3.55 (singlet, 2H); 6. 18 (d, 1H). C19H17F2 N302 (MW = 357.36); mass spectroscopy (MH *) 357.

Example 16 Synthesis of N- [(S) -1-Phenylethyl] -N'- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure B and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and (S) - (-) -1-phenylethylamine (Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.45 in 9: 1 CHCl _, / MeOH) and the product was purified by chromatography on silica gel using 95: 5 CHCl3 / MeOH as eluent.

The results of RM? were as follows:: H-rmn (CDC1;.): d = 7.18-7.28 (m, 5H), 6.81 (, 1H), 6.67 (m, 2H), 6.63 (m, 1H), 6.60 (m, 1H), 5.01 (m, 1H), 4.44 (m, 1H), 3.36 (m, 2H), 1.43 (d, 3H) ), 1.36 (d, 3H). Optical Rotation: [a] 23 -103 ° (c 1, MeOH). C19H20F2N2O2 (MW = 346.38); mass spectroscopy (M +) 346.

Example 17 Synthesis of N- [(R) -1-Phenylethyl] -N'- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure B and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and (R) - (+) - 1-phenylethylamine. { Aldrich), the title compound was prepared. The reaction was monitored by tic (Rf = 0.35 in 9: 1 CHCl 3 / MeOH) and the product was purified by chromatography on silica gel using 96: 4 CHCl 3 / MeOH as eluent.

The results of RM? were as follows:: H-rmn (CDC13): d = 7.31 (m, 5H), 6.78 (m, 2H), 6.71 (m, 1H), 6.32 (m, 1H), 5.01 (m, 1H), 4.46 (m, 1H), 3.45 (m, 2H), 1.43 (d, 3H), 1.30 (d, 3H). Optical Rotation: [] 2 :. + 5.97 ° (c 1, MeOH). C: oH; F ^? _ 0; (MW = 346.38); mass spectroscopy (M *) 346.

Example 18 Synthesis of N- [2-methoxycarbonyl-1-phenylethyl] -N'- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure B and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and methyl 3-amino-3-phenylpropionate hydrochloride, the title compound was prepared. The reaction was monitored by tic (Rf = 0.45 in 9: 1 CHCl3 / MeOH) and the product was purified by chromatography on silica gel using 95: 5 CHCl3 / MeOH as eluent.

The results of RM? were as follows:: H-rmn (CDC13): d = 7.28 (m, 5H), 6.89-6.67 (m, 2H), 6.37 (m, 1H), 5.36 (m, 1H), 4.52 (m, 1H) , 3.63 and 3.60 s, 3H), 3.51 and 3.45 (s, 2H), 2.80 (m, 2H), 1.37 (t, 3H). C_: H;: F. ?? ° 4 (MW = 404.41); mass spectroscopy (MH *) 404.

Example 19 Synthesis of N- [2-Hydroxypyridin-3-yl] -N '- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure C and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and 3-amino-3-hydroxypyridine (prepared by means of hydrogenation with Pd / C of 2-hydroxy-3-nitropyridine under standard conditions in EtOH / HOAc), the title compound was prepared.

The results of RM? were as follows: -H-rmn (DMSO-d6): d = 1.28 (d, J = 7 Hz, 3H), 3.55 (s, 2H), 4.51 (brq, J = 7 Hz, 1H), 6.20 (t , J = 7 Hz, 1H), 6.95-7.2 (m, 4H), 8.18 (dd, J = 1.7, 7.3 Hz, 1H), 8.64 (d, J = 7.0 Hz, 1H), 9.24 (s, 1H) . : 3C-nm (DMSO-d6): d = 17.9, 41.5, 49.7, 102.0, 102.3, 102.6, 105.6, 112.5, 112.6, 112.8, 112.9, 123.4, 128.20, 112.21, 129.2, 140.8,160.9, 164.0, 164.2, 169.6, 172.1. C? EH: iF? 503 (MW = 335).

Example 20 Synthesis of N-l- (Phthalimido) pent-2-yl-y "" '- (3, 5-di-chlorophenylacetyl) -L-alaninamide Following General Procedure F and using N- (3, 5-difluorophenylacetyl) -L-alanine (Example B2) and 2-amino-1-phthalimidopentane hydrochloride (from Example A above), the title compound was prepared. The reaction was monitored by tic (Rf = 0.3 in 5% MeOH / CHCl3) and the product was purified by chromatography on silica gel using 5% MeOH / CHCl3 as eluent, followed by recrystallization with chlorobutane / acetonitrile.

The NMR results were as follows:: H-rmn (DMSO-d6): d = 4.1 (m, 2H), 7.83 (bs, 4H). C 24 H 25 N 304 F 2 (MW = 457.48); mass spectroscopy (MH *) 457.

Example 21 Synthesis of N- [-pyridin-2-yl-benzyl] -N '- (3, 5-difluorophenylacetyl) -L-alaninamide Following General Procedure F and using N- (3, 5-di fluorofeni lacet i 1) -L-alanine (Example B2) and.a- (2-? Iridi 1) benzylamine (Maybridge) the de-title compound was prepared. The product was purified by chromatography on silica gel using 5% MeOH / CHCl 3 as eluent, followed by recrystallization with n-chlorobutane / acetonitrile.

The results of RM? were as follows: "-H-rmn (DMSO-d6): d = 6.10 (d, 1H), 4.46 (m, 1H), C23H21F2N302 (MW = 409.44), mass spectroscopy (MH +) 409.

Example 22 Synthesis of N- [2- (methoxycarbonylmethyl) benzyl] -W- (3,5-difluorophenylacetyl) -L-alaninamide 2- (Aminomethyl) -benzeneacetate hydrochloride was stirred in dry methanol. Thionyl chloride (1.1 eq.) Was added dropwise and the mixture was stirred at room temperature overnight to yield methyl (2- (aminomethyl) -benzeneacetate hydrochloride as a white solid.

N '- (3,5-difluorophenylacetyl) -L-alanine (Example B2) in dichloromethane was coupled to methyl (2- (aminomethyl) -benzeneacetate hydrochloride using EDC, HOBT, DIEA to provide the title compound.

MS (M *) 404.1 EXAMPLE 23 Synthesis of N- [3- (methoxycarbonyl) benzyl] -Nf- (3,5-di luoro-enylacetyl) -L-alaninamide The title compound was prepared following the procedure set forth in Example 22 but substituting methyl (3- (aminomethyl) -benzene acetate acetate for methyl (3- (aminomethyl) -benzoate hydrochloride.

The NMR results were as follows: 'H-rmn (CDC13): d = 1410 (d, 3H), 3.56 (s, 2H). MS (M *) 390.

Example 24 Synthesis of N- [2 - (2'-ethoxycarbonylmethylphenyl) benzyl] -N'- (3, 5-difluorophenylacetyl) -L-alaninamide The title compound was prepared following the procedure set forth in Example 22 but substituting 2- (2'-methoxycarbonylmethylphenyl) benzyl amine for methyl (3- (aminomethyl) -benzoate hydrochloride.

Example 25 Synthesis of N- [2-phenylbenzyl] -N'- (3, 5-difluorophenylacetyl) -L-alaninamide The title compound was prepared following the procedure set forth in Example 22 but substituting 2-phenylbenzylamine for methyl (3- (aminomethyl) -benzoate hydrochloride.

The NMR results were as follows:! H-rmn (CDC13): d = 1.22 (d, 3H), 3.46 (s, 2H). MS (M *) 408.

Example 26 Cellular Screening for the Detection of β-Amyloid Production Inhibitors.

Numerous compounds of formula I above were tested for their ability to inhibit β-amyloid production of a cell line possessing the Swedish mutation. This screening test used cells (K293 = human kidney cell line) that was stably transfected with the 751 amyloid precursor protein gene (APP751) that contained the double mutation Lyséí: Mett._ to Asn6i; Leut52 (numbering APP751) in the manner described in International Patent Application Publication No. 94/105698 and Citron et al.12. This mutation is commonly referred to as the Swedish mutation and the cells, designated "293 751 SWE", were plated in 96-well Corning plates at 1.5-2.5 x 104 cells per well in minimal essential Dulbecco medium plus 10% serum of bovine fetus. The number of cells is important to obtain ß-amyloid ELISA results within the linear range of the test (-0.2 to 2.5 ng per mL).

After incubation overnight at 37: C in an incubator equilibrated with 10% carbon dioxide, the medium was removed and placed with 200 μL of a compound of formula I (drug) containing medium per well during a pre-treatment period of two hours and the cells were incubated as before. The stocks of drugs were prepared in 100% dimethylsulfoxide such that at the final concentration of the drug used in the treatment, the concentration of dimethylsulfoxide did not exceed 0.5% and, in fact, usually equaled 0.1%.

At the end of the pretreatment period, the medium was again removed and replaced with fresh drug containing the medium as before and the cells were incubated for an additional two hours. After the treatment, the plates were centrifuged in a Beckman GPR at 1200 rpm for five minutes at room temperature to form the cellular waste package of the conditioned medium. From each well, 100 μL of conditioned media or appropriate dilutions thereof were transferred into an ELISA plate precoated with antibody 26614 against amino acids 13-28 of the β-amyloid peptide as described in Patent Application Publication No. 94 / 105698 and stored at 4 ° C overnight. An ELISA test using the antibody labeled 6C614 against amino acids 1-16 of the β-amyloid peptide was run the next day to measure the amount of β-amyloid peptide produced.

The cytotoxic effects of the compounds were measured by means of a modification of the method of Hansen, et al.1 * -. To the remaining cells in the tissue culture plate, 25 μL of a stock solution of 3, (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (MTT) (5 mg / mL) was added. for a final concentration of 1 mg / mL. Cells were incubated at 37: C for one hour, and cell activity stopped by the addition of an equal volume of MTT lysis buffer (20% w / v sodium dodecyl sulfate in 50% dimethylformamide, pH 4.7). The complete extraction was achieved by stirring overnight at room temperature. The difference in OD562nm and OD650nm was measured in a microplate reader with Molecular Device for UVmax as an indicator of cell viability.

The β-amyloid peptide ELISA results were adjusted to a standard curve and expressed as ng / mL of β-amyloid peptide. To normalize cytotoxicity, these results were divided among MTT results and expressed as a percentage of the results of a control without drug. All results are the mean and the standard deviation of tests of at least six replicates.

The test compounds were tested for, the activity of inhibiting the production of β-amyloid peptide in cells that used this test. The results of this test demonstrate that, each of the compounds tested in this invention reduced the production of β-amyloid peptide by at least 30% compared to the control.

Example 27 In vivo Suppression of Release and / or Synthesis ß-Amyloid This example illustrates how the compounds of this invention could be tested for in vivo suppression and / or β-amyloid synthesis. For these experiments, PDAPP mice 3 to 4 months of age were used [Games et al., (1995) Na ture 373: 523-527]. Depending on the compound to be tested, the compound is usually formulated at 5 or 10 mg / ml. Due to the low solubility factors of the compounds, they could be formulated with several vehicles, such as corn oil (Safeway, South San Francisco, CA); 10% EtOH in corn oil (Safeway); 2-hydroxypropyl-β-cyclodextrin (Research Biochemicals International, Natick MA); and carboxymethyl 1-cellulose (Sigma Chemical Co., St. Louis MO). Specifically, for example 141 the vehicle was carboxymethyl cellulose (Sigma).

The mice were dosed subcutaneously with a 26-gauge needle and 3 hours later the animals were euthanized via C02 narcosis and the blood was taken by cardiac sting using a tuberculin syringe of 1c 25G 5/8"/ needle coated with 0.5 M EDTA solution, pH 8.0 The blood was placed in a Becton-Dickinson vaccination tube containing EDTA and rotated for 15 minutes at 1500 xg at 5 ° C. The brains of the mice are removed Afterwards, the cortex and hippocampus are dissected and placed on ice. 1. Brain Test To prepare hippocampal and cortex tissue for enzyme-linked immunosorbent assays (ELISA), each brain region is homogenized in 10 volumes of ice-cold guanidine buffer (5.0 M guanidine-HCl, 50 nM Tris-HCl, pH 8.0 ) using a motorized piston Kontes (Fisher, Pittsburgh PA). The homogenates were gently rocked on a rotating platform for three to four hours at room temperature and stored at -20 ° C before quantification of β-amyloid.

The brain homogenates are 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 leupeptidine], thus reducing the final concentration of guanidine to 0.5 M, before centrifugation at 16,000 kg for 20 minutes at 4 ° C. The ß-amyloid standards (amino acids 1-40 or 1-42) were prepared in such a way that the final composition was equal to 0.5 M guanidine in the presence of 0.1% bovine serum albumin (BSA).

The two-layer total β-amyloid ELISA, which quantifies β-amyloid (aa 1-40) and β-amyloid (aa 1-42) consists of two monoclonal antibodies (mAbs) for β-amyloid. The capture antibody, 26614, is specific for amino acids 13-28 of β-amyloid. The 3D615 antibody, which is specific for amino acids 1-5 of β-amyloid, biotinylates and serves as the reporter antibody in the test. The biotinylation procedure of 3D6 employs the manufacturer's protocol (Pierce, Rockford IL) to label NHS-biotin immunoglobulins except that 100 mM sodium bicarbonate, buffer pH 8.5, is used. The 3D6 antibody does not recognize the secreted amyloid precursor protein (APP) or full length APP but detects only the β-amyloid species with an amino terminal aspartic acid. The test has a lower sensitivity limit of -50 pg / ml (11 pM) and shows no cross-reactivity with the endogenous murine β-amyloid peptide at concentrations up to 1 ng / ml.

The configuration of the two-layer ELISA that quantifies the level of β-amyloid (aa 1-42) uses mAb 21F1215 (which recognizes amino acids 33-42 of β-amyloid) as it captures the antibody. Biotinylated 3D6 is also the reporter antibody in this test that have a sensitivity limit of less than -125 pg / ml (28 pM).

The mAbs of the captors 266 and 21F12 are coated with μg / ml in 96 well immunoprotein plates (Costar, Cambridge MA) overnight at room temperature. Plates are then aspirated and blocked with 0.25% human serum albumin in PBS buffer for at least 1 hour at room temperature, afterwards they are stored dissected at 4 * C until they are used. The plates are rehydrated with wash buffer (Tris-salt buffer, 0.05% Tween 20) before use. The samples and standards are added to the plates and incubated overnight at 4 ° C. The plates are washed = 3 times with wash buffer between each step of the test. The biotinylated 3D6 is diluted to 0.5 μg in casein incubation buffer (0.25% casein, PBS, 0.5% 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 which the enzymatic reaction stops with the addition of 2N H2SO4. The product of the reaction is quantified using a Molecular Devices Vmax (Molecular Devices, Menlo Park CA) which measures the difference in absorbance at 450 nm and 650 nm. 2. Blood test EDTA plasma is diluted 1: 1 in specimen diluent (0.2 gm / 1 sodium phosphate »H20 (monobasic), 2.16 gm / 1 sodium phosphate «H20 (dibasic), 0.5 gm / 1 of thimerosal, 8.5 gm / 1 of sodium chloride, 0.5 ml of TritonX-405, 6.0 g / 1 of globulin-free bovine serum albumin; and water) . Samples and standards in specimen thinner are tested using the total β-amyloid test (sensor 266 / reporter 3D6) described above for the brain test except that the specimen diluent was used instead of the casein diluents described.

From the above description, various modifications and changes in the composition and method will be presented by the experts in the art. All modifications that fall within the scope of the appended claims are projected to be included in them.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

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

Claims (65)

REI INDICATIONS

1. A method for inhibiting the release of the β-amyloid peptide and / or its synthesis in a cell in which this method comprises administering to said cell an amount of a compound or a mixture of compounds effective to inhibit the release and / or cellular synthesis of the β-amyloid peptide, characterized in that the compounds are represented by formula I: wherein R1 is selected from the group consisting of a) alkyl, alkenyl, alkaryl, alkylenecycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy; b) a substituted phenyl group of formula II wherein R is alkylene of 1 to 8 carbon atoms, i72 is an integer equal to 0 or 1, Ra and Ra 'are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl; Rb and Rb 'are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C (0) R4 wherein R4 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy; and Rc is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and wherein RD and Rc are fused to form a methylenedioxy ring with the phenyl ring; and when R- and / or Rb 'and / or R = is fluoro, chloro, bromo and / or nitro, then Ra and / or R3' may also be chloro; and (c) 1- or 2-naphthyl substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; Rz is selected from the group consisting of hydrogen, alkyl, from 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkyl-alkoxy of 1 to 4 carbon atoms; and R3 and R3 'are independently selected for the group consisting of: (a) hydrogen with the proviso that R3 and R3 'can not be hydrogen; (b) alkyl with the proviso that when R3 is hydrogen, then the alkyl group R3 has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom this chain can be optionally substituted with one or more alkyl groups with the additional proviso that R3 and R3 'are alkyl then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms this chain can be optionally substituted with one or more alkyl groups; (c) ~ (R7) n (W) p wherein R7 is an alkylene group, W is selected from the group consisting of: (i) (i) R 'Rí where R5, R5 ', R9 and R9' are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl, heteroaryl and heterocyclic esters; and R6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters , heteroaryl, heterocyclic and wherein R6 and one of R5 or R5 'are fused to form a heterocyclic ring of 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; with the proviso that when n is zero, R9 and R9 'are hydrogen; (ii) heteroaryl; Y (iii) N-heterocyclic with the proviso that when W is β -heterocyclic then n-is not zero; and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to i, and (d) -CH (f) CH ^ C (O) O-Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R' to -CX'X "-, oxygen and sulfur; the condition that when R1 is phenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen, R3' is - ( R7) n (W) p where n is zero and p is one and W is R9 R * R9 'R-- then (i) R5, R5 ', R9, R9' and R6 are not all hydrogen and (ii) R5, R5 ', R9, R9' are hydrogen and R6 is methoxy; with the additional proviso that when R1 is 3,5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R? is hydrogen, R? * is - (R7) n (W) p where n is one and p is one, R ^ is ethylene and W is R 'R' then R5, R5 ', R9, R9' and R6 are not all hydrogen; Y even with the additional proviso that when R1 is 3, 5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, and m is zero, R3 is hydrogen, R3 'is - (R7) n (W) p where n is zero and p is one, W is R9 R5 and R5 ', R9, R9' are hydrogen, then R5 and R6 do not fuse to form, with the phenyl ring to which they are attached, a phthalimido group.

2. A method for preventing the onset of AD in a patient at risk of developing AD, characterized in that the method comprises administering to the patient a pharmaceutical composition containing 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) alkyl, alkenyl, alkaryl, alkylenecycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy; b) a substituted phenyl group of formula II: wherein R is alkylene of 1 to 8 carbon atoms, m is an integer equal to 0 or 1, Ra and Ra 'are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl; Rb and Rb 'are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C (0) R4 wherein R4 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy; and R c is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and wherein R c and R c are fused to form a methylenedioxy ring with the phenyl ring; and when Rk and / or R * 7 'and / or Rc is fluoro, chloro, bromo and / or nitro, then R ° and / or Ra' can also be chloro; Y (c) 1- or 2-naphthyl substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; R: is selected from the group consisting of hydrogen, alkyl, from 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alky1-thioalkoxy of 1 to 4 carbon atoms; and R 'and R' are independently selected for the group consisting of: (a) hydrogen with the proviso that R3 and R3 'can not be hydrogen; (b) alkyl with the proviso that when R3 is hydrogen, then the alkyl group R3 has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom this chain can be optionally substituted with one or more alkyl groups with the additional proviso that R3 and R3 'are alkyl then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms this chain can be optionally substituted with one or more alkyl groups; (c) - (R7) n (W) p wherein R7 is an alkylene group, W is selected from the group consisting of: (i) R9 Rs R9 'R5 where R5, R5 ', R9 and R9' are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl, heteroaryl and heterocyclic esters; and R6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters , heteroaryl, heterocyclic and wherein Rf and one of R5 or R5 'are fused to form a heterocyclic ring of 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; with the proviso that when n is zero, R9 and R ° 'are hydrogen; (ii) heteroaryl; Y (iii) N-heterocyclic with the proviso that when W is N-heterocyclic then n-is not zero; and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to (d) -CH (f) CH2C (0) O-Q wherein Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R: to -CX'X "-, oxygen and sulfur; with the proviso that when R1 is phenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R: to -CX'X" -, m is zero, R3 is hydrogen, R3' is -. { R ~), (W) P where n is zero and p is one and is then (i) R5, R5 ', Ra, R9' and R6 are not all hydrogen and (ii) R5, R5 ', R9, R9' are hydrogen and R6 is methoxy; with the additional proviso that when R1 is 3,5-difluoro-phenyl, R: is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen, R3 'is - (R7) n () p where n is one and p is one, R ^ is ethylene and W is then R5, R: Rs R- and R6 are not all hydrogen; Y even with the additional proviso that when R1 is 3, 5-difluorophenyl, R: is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, and m is zero, R3 is hydrogen, R3 'is - (R) n (W) p where n is zero and p is one, W is and R5 ', R9, R9' are hydrogen, then R5 and R6 do not fuse to form, with the phenyl ring to which they are attached, a phthalimido group.

3. A method for treating a patient with AD to inhibit further deterioration in the condition of the patient, characterized in that the method comprises administering to the patient a pharmaceutical composition containing a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of formula I : wherein R: is selected from the group consisting of a) alkyl, alkenyl, alkaryl, alkylenecycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy; b) a substituted phenyl group of formula II: wherein R is alkylene of 1 to 8 carbon atoms, m is an integer equal to 0 or 1, Ra and Ra 'are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl; Rb and Rb 'are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C (0) R4 wherein R4 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy; and R c is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and wherein R b and R c are fused to form a methylenedioxy ring with the phenyl ring; and when Rb and / or Rb 'and / or Rc is fluoro, chloro, bromo and / or nitro, then Ra and / or Ra' can also be chloro; Y (c) 1- or 2-naphthyl substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; R: is selected from the group consisting of hydrogen, alkyl, from 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkyl thioalkoxy of 1 to 4 carbon atoms; and R? and R- 'are independently selected for the group consisting of: (a) hydrogen with the proviso that R3 and R3 'can not be hydrogen; (b) alkyl with the proviso that when R3 is hydrogen, then the alkyl group R3 has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom this chain can be optionally substituted with one or more alkyl groups with the additional proviso that R3 and R3 'are alkyl then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms this chain can be optionally substituted with one or more alkyl groups; (c) - (R7) n () p wherein R7 is an alkylene group, W is selected from the group consisting of: (i) R9 R5 where R-, R5 ', R? and R9 'are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, esters carboxyl, heteroaryl and heterocyclic; and R6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters , heteroaryl, heterocyclic and wherein R6 and one of R5 or R5 'are fused to form a heterocyclic ring of 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; with the proviso that when n is zero, R9 and RQ 'are hydrogen; (ii) heteroaryl; Y (iii) N-heterocyclic with the proviso that when W is N-heterocyclic then n-is not zero; and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to i, and (d) -CH (f) CH2C (O) OQ where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R1 to -CX'X "-, oxygen and sulfur; with the proviso that when R1 is phenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen, R3' is - (R7) R (W) P where n is zero and p is one and W is then (i) R ~, R ~ ', R9, Ra' and R6 are not all hydrogen and (ii) R :, R- ', R9, RQ' are hydrogen and R6 is methoxy; with the additional proviso that when R1 is 3,5-difluorophenyl, R: is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen, R3 'is - (R7) n () p where n is one and p is one, R7 is ethylene and W is then R5, R5 ', R9, R9' and R6 are not all hydrogen; Y even with the additional proviso that when R1 is 3, 5-difluorophenyl, R2 is methyl, X'.and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, and m is zero, R3 is hydrogen, R3 'is - (R7) n () p where n is zero and p is one, W is and R; R * Rc are hydrogen, then R5 and R6 do not fuse to form, with the phenyl ring to which they are attached, a phthalimido group.

4. The method according to claim 1, 2 or 3, characterized in that R1 is an unsubstituted aryl group.

5. The method according to claim 4, characterized in that the aryl group R 1 is unsubstituted is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.

6. The method according to claim 1, 2 or 3, characterized in that R: is a substituted aryl group.

7. The method according to claim 6, characterized in that the substituted aryl groups are substituted phenyl groups defined by the following: (a) monosubstituted phenyls having a simple substitution at positions 2, 3 or 4 wherein each of the particular substituents is governed by the respective R ", Rr and R" groups; (b) disubstituted phenyls having two substituents at positions 2,3, positions 2,4, positions 2,5, positions 2,6, positions 3,4, positions 3,5 or positions 3,6 where each of these substituents are governed by Ra, Ra ', R, Rb' and R = respective groups; Y (c) phenyls trisust ituidos having three substituents at positions 2,3,4, positions 2,3,5, positions 2,3,6, positions 3,4,5 and positions 3,4,6 where each one of these substituents are governed by the respective Rs, Ra ', Rb, Rb' and Rc groups.

8. The method according to claim 7, characterized in that the substituted phenyl groups are selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenol, 4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl. it, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxy-phenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-f luorofenyl, 3, 4-dichlorophenyl, 3,4-methylenedioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenol, and 2,5-difluorophenyl.

9. The method according to claim 1, 2 or 3, characterized in that R1 is an alkaryl group.

10. The method according to Claim 9, characterized in that the one alkaryl group R1 is selected from the group consisting of benzyl, phenylethyl, 3-phenyl-n-propyl and 4-phenyl-n-butyl.

11. The method according to claim 1, 2 or 3, characterized in that R1 is selected from the group consisting of the alkyl, alkenyl, cycloalkyl and cycloalkenyl groups.

12. The method according to claim 11, characterized in that R: is alkyl.

13. The method according to claim 11, characterized in that R: is cycloalkyl.

14. The method according to Claim 11, characterized in that R: is alkenyl.

15. The method according to claim 11, characterized in that R: is cycloalkenyl.

16. The method according to claim 11, characterized in that the alkyl, alkenyl, cycloalkyl and cycloalkenyl groups R1 are selected from the group consisting of sec-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2-cyclopropyl , -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2-cyclopentyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl.

17. The method according to claim 1, 2 or 3, characterized in that R1 is selected from the group consisting of heteroaryl and substituted heteroaryl groups.

18. The method according to claim 17, characterized in that the heteroaryl and substituted heteroaryl groups R: are selected from the group consisting of pyrid-3-yl, pyrid-4-yl, t-iofen-2-yl, t-iofen-3 ilo, benzothiazol- -i lo, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphten-2-yl, 2-chloro-iofen-5- i lo, 3-me ti 1 isoxa zol-5-i lo, 2- (thiophenyl) thiophen-5-yl, 6-methoxy-ioneften-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4 ilo.

19. The method according to claim 1, 2 or 3, 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 and alkylthioalkoxy of 1 to 4 carbon atoms.

20. The method according to claim 19, characterized in that R2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and -CH2CH2SCH3.

21. The method according to claim 1, 2 or 3, characterized in that X 'and X "are hydrogen and Z is a covalent bond linking R1 to -CX'X" -.

22. The method according to Claim 21, characterized in that R "'is hydrogen and R3' is selected from the group consisting of 3-hydroxyphenyl, 3-methoxy phenyl, 3-ethoxycarbonyl phenyl, n-hexyl, n-octyl, 4 - ethoxycarbon i 1 phenylo, 4-methoxycarbonylphenyl, 3-chlorophenyl, 3-cyanophenyl, 3,5-dichlorophenyl, CH (CH,) f (stereoisomer R), -CH (CH 3) f (stereoisomer S), ft a 1 id - 6- i 1 o, 2 -hi drox ip i rid- 3 - i 1 o, 2- (methoxycarbonylmethyl) benzyl, 3- (methoxycarbonyl) benzyl, 2- (2'-methoxycarboni lmethylphenyl) benzyl, and 2- phenylbenzyl.

23. The method according to claim 1, 2 or 3, characterized in that the compound of formula I is selected from the group consisting of: N- (3-hydroxyphenyl) -N'- (phenylacetyl) -L-alaninamide N- (3-methoxy phenyl) -N '- (phenylacetyl) -L-alaninamide N- (3-ethoxyphenyl) -N '- (phenylacetyl) -L-alaninamide N- (4-ethoxycarbonylphenyl) -N '- (phenylacetyl) -L-alaninamide N- (n-hexyl) -N'- (3, 5-difluorophenylacetyl) -L-alaninamide N- (n-octyl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- (3-methoxy phenyl) -A7 '- (3,5-difluorophenylacetyl) -L-alaninamide N - (4-oxo ca rbon i phen i) - N '- (3,5-difluorophenylacetyl) -L-alaninamide N- (3-ethoxycarbonyl) -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- (3-chlorophenyl) -N' - (3,5-difluoro-phenylacetyl) -L-alaninamide N- (3,5-dichloro-phenyl) -N '- (3,5-difluoro-phenylacetyl) -L-alaninamide N- (3-cyanophenyl) -N' - (3,5-difluorophenylacetyl) -L-alaninamide N- (ftalid) -6-yl) -N '- (3,5-difluorophenylacetyl) -L-alaninamide N - [(4-methoxycarbonyl phenyl) methyl] -N' - (3,5 difluorophenylacetyl) -L-alaninamide N - (1-cyano-l-phenylmethyl) -N '- (3,5-fluorophenylacetyl) -L-alaninamide ? - [(R) -l-phenylethyl] -? / '- (3, 5-di fluorophenylacetyl L-alaninamide N- [(S) -1-phenylethyl] -N' - (3, 5-difluorofenylacetyl) L-alaninamide N- [2-hydroxypyridin-3-yl] -N '- (3, 5 difluorophenylacetyl) -L-alaninamide N- [2-methoxycarbonyl-1-phenylethyl] -N '- (3, 5 difluorophenylacetyl) -L-alaninamide N- [α-pyridin-2-l-benzyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide i - [1- (? -phthalamido) pent-2-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2- (methoxycarbonylmethyl) benzyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [3- (methoxycarbonylmethyl) benzyl] -N '- (3,5-fluorophen-lacethyl) -L-alaninamide N- [2- (2'-methoxycarbonylmethylphenyl) benzyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2-phenylbenzyl] -? "- (3,5-difluorophenylacetyl) -L- alaninamide

24. A pharmaceutical composition, characterized in that it comprises a pharmaceutically inert carrier and a pharmaceutically effective amount of a compound of formula I: wherein R1 is selected from the group consisting of a) alkyl, alkenyl, alkaryl, alkylenecycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy; b) a substituted phenyl group of formula II: wherein R is alkylene of 1 to 8 carbon atoms, m is an integer equal to 0 or 1, Ra and Ra 'are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl; Rb and Rb 'are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C (0) R4 wherein R4 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy; and R c is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and wherein R b and R c are fused to form a methylenedioxy ring with the phenyl ring; and when Rb and / or R 'and / or Rc is fluoro, chloro, bromo and / or nitro, then Ra and / or Ra' may also be chloro; Y (c) 1- or 2-naphthyl substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; R2 is selected from the group consisting of hydrogen, alkyl, from 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkyl-alkoxy of 1 to 4 carbon atoms; and R3 and R3 'are independently selected for the group consisting of: (a) hydrogen with the proviso that R3 and R3 'can not be hydrogen; (b) alkyl with the proviso that when R3 is hydrogen, then the alkyl group R3 has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom this chain can be optionally substituted with one or more alkyl groups with the additional proviso that R3 and R3 'are alkyl then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms this chain can be optionally substituted with one or more alkyl groups; (c) - (R7), (W) wherein R7 is an alkylene group, W is selected from the group consisting of (i) where R5, R5 ', R9 and R9' are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl, heteroaryl and heterocyclic esters; and R6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters , heteroaryl, heterocyclic and wherein R6 and one of R5 or R5 'are fused to form a heterocyclic ring of 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; with the proviso that when n is zero, R9 and R9 'are hydrogen; (ii) heteroaryl; Y (iii) N - heterocyclic with the proviso that when W is? - heterocyclic then n - is not zero; and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to 1, and (d) -CH (f) CHC (O) O-Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R: to -CX'X "-, oxygen and sulfur; the condition that when Ra is phenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen, R3' is - ( R7) n () p where n is zero and p is one and W is R9 R5 then (i) R5, R5 ', R9, R9' and R6 are not all hydrogen and (ii) R5, R5 ', R9, R9' are hydrogen and R6 is methoxy; with the additional proviso that when R1 is 3,5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen , R3 'is - (R ") n () P where n is one and p is one, R7 is ethylene and is R9 Rs then R5, R5 ', R ?, R9' and R6 are not all hydrogen; Y even with the additional proviso that when R1 is 3, 5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, and m is zero, R3 is hydrogen, R3 'is - (R7) n (W) p where n is zero and p is one, W is R5 and R5 ', R9, R9' are hydrogen, then R5 and R6 do not fuse to form, with the phenyl ring to which they are attached, a phthalimido group.

25. The pharmaceutical composition according to Claim 24, characterized in that R1 is an unsubstituted aryl group.

26. The pharmaceutical composition according to Claim 25, characterized in that the aryl group R: not substituted is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.

27. The pharmaceutical composition according to Claim 24, characterized in that R1 is a substituted aryl group.

28. The pharmaceutical composition according to the Claim 27, characterized in that the substituted aryl groups are substituted phenyl groups defined by the following: (a) monosubstituted phenyls having a simple substitution at positions 2, 3 or 4 wherein each of the particular substituents is governed by the respective Ra, Rb and Rr groups; (b) disubstituted phenyls having two substituents at positions 2,3, positions 2,4, positions 2,5, positions 2,6, positions 3,4, positions 3,5 or positions 3,6 where each of these substituents are governed by respective Ra, Ra ', Rb, Rc' and R ~ groups; Y (c) trisubstituted phenyls having three substituents at positions 2,3,4, positions 2,3,5, positions 2,3,6, positions 3,4,5 and positions 3,4,6 where each of these substituents are governed by the respective Ra, Ra ', Rb, Rb' and Rc groups.

29. The pharmaceutical composition according to the Claim 28, characterized in that the substituted phenyl groups are selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl, 3-fluorophenyl , 3-chlorophenyl, 3-bromophenyl, 3-t-isomethoxy-phenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-p-halophenyl, 3,4-dichlorophenyl, 3, 4-me ti lendi oxi fen i lo, 3, 5-di f luorofeni lo, 3,5-dichloropheni lo, 2,4-dichlorophenyl, and 2,5-difluorophenyl.

30. The pharmaceutical composition according to Claim 24, characterized in that R1 is an alkaryl group.

31. The pharmaceutical composition according to Claim 30, characterized in that the one alkaryl group R is selected from the group consisting of benzyl, phenylethyl, 3-phenyl-n-propyl and 4-phenyl-n-butyl.

32. The pharmaceutical composition according to Claim 24, characterized in that R1 is selected from the group consisting of the alkyl, alkenyl, cycloalkyl and cycloalkenyl groups.

33. The pharmaceutical composition according to Claim 32, characterized in that R1 is alkyl.

34. The pharmaceutical composition according to Claim 32, characterized in that R1 is cycloalkyl.

35. The pharmaceutical composition according to Claim 32, characterized in that R1 is alkene lo.

36. The pharmaceutical composition according to Claim 32, characterized in that R1 is cycloalkenyl.

37. The pharmaceutical composition according to claim 32, characterized in that the alkyl, alkenyl, cycloalkyl and cycloalkenyl groups R1 are selected from the group consisting of sec-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH2- cyclopropyl, -CH2-cyclobutyl, -CH2-cyclohexyl, -CH2- cyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl.

38. The pharmaceutical composition according to Claim 24, characterized in that R1 is selected from the group consisting of heteroaryl and substituted heteroaryl groups.

39. The pharmaceutical composition according to claim 38, characterized in that the heteroaryl and substituted heteroaryl groups R1 are selected from the group consisting of pyrid-3-yl, pyrid-4-yl, t-iofen-2-yl, t-iofen-3. ilo, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thiophenten-2-yl, 2-cyothothiophen-5-yl, 3-methylisoxazol-5-yl , 2- (t-phenoyl) t-iofen-5-yl, 6-methoxy-ionephth-2-yl, 3-phenyl-1, 2, 4-1-iooxadiazol-5-yl and 2-phenyloxazol-4-yl.

40. The pharmaceutical composition according to claim 24, 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 and alkylthioalkoxy of 1 to 4 carbon atoms.

41. The pharmaceutical composition according to Claim 40, characterized in that R 2 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and CH 2 CH 2 SCH 3.

42. The pharmaceutical composition according to Claim 26, characterized in that X 'and X "are hydrogen and Z is a covalent bond linking R1 to -CX' X" -.

43. The pharmaceutical composition according to the Rei indication 42, characterized in that R3 is hydrogen and R "'is selected from the group consisting of 3-hydroxy phenyl, 3-methoxy phenol, 3-ethoxycarbonylphenyl, n-hexyl, n-octyl, -ethoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-chlorophenyl, 3-cyanophenyl, 3,5-dichlorophenyl, -CH (CH,) f (stereoisomer R), CH (CH;.) f (stereoisomer S), phthalo-6-yl , 2-hydroxypropyl-3-yl, 2- (methoxycarbonylmethyl) benzyl, 3- (toxic rb-onyl) benzyl, 2- (2'-methoxycarbonylmethylphenyl) encyl, and 2-phenylbenzyl.

44. The pharmaceutical composition according to claim 24, characterized in that the compound of formula I is selected from the group consisting of: N- (3-hydroxyphenyl) -N '- (phenylacetyl) -L-alaninamide N- (3-methoxyphenyl) -N '- (phenylacetyl) -L-alaninamide N- (3-ethoxyphenyl) -N '- (phenylacetyl) -L-alaninamide N- (4-ethoxycarbonylphenyl) -N '- (phenylacetyl) -L-alaninamide N- (n-hexyl) -A / '- (3,5-difluorophenylacetyl) -L-alaninamide N- (-octyl) - N '- (3,5-difluorophenylacetyl) -L-alaninamide ? t- (3-methoxy phenyl) -N '- (3,5-difluorophenylacetyl) -L-alaninamide T - (4-ethoxycarbonyl) - N '- (3,5-difluorophenylacetyl) -L-alaninamide N- (3-ethoxycarbonyl) in il) - N' - (3, 5 • difluorophenylacetyl) -L-alaninamide N- (3-chlorophenyl) -N '- (3,5-difluoro-phenylacetyl) -L-alaninamide N- (3,5-dichloro-phenyl) -N' - (3,5-difluoro-phenylacetyl) ) -L-alaninamide N- (3-cyanophenyl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- (phthalo-6-yl) -N' ~ (3,5-difluoro-phenylacetyl) -L -alaninamide N- [(4-methoxycarbonylphenyl) methyl] -N '- (3,5-fluorophenylacetyl) -L-alaninamide N- (1-cyano-1-phenylmethyl) -N' - (3,5-difluorophenylacetyl) -L-alaninamide N- [(R) -l-phenylethyl] -N '- (3, 5-difluorophenylacetyl) L-alaninamide N- [(S) -1-f -yl] -N '- (3, 5-difluorofenylacetyl) L-alaninamide N- [2-hydroxypyridin-3-yl] - N '- (3, 5 difluorophenylacetyl) -L-alaninamide N- [2-methoxycarbonyl-1-phenylethyl] -N' - (3, 5 difluorophenylacetyl) -L-alaninamide N- [a-pi ridin- 2 -i] -benz l] -N '- (3, 5 difluorophenylacetyl) -L-alaninamide N- [1- (α-phthalamido) pent-2-yl] -N' - (3,5-fluorophen-lacetil) -L- alaninamide N- [2- (methoxycarbonylmethyl) benzyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [3- (methoxycarbonylmethyl) benzyl] -N' - (3,5-fluorophenylacetate) 1-L -alaninamide N- [2- (2'-methoxycarbonylmethylphenyl) encyl] - N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2-pheobenzyl] -N' - (3,5-difluorophenylacetyl) -L-alaninamide

45. A compound of formula I characterized in that R1 is selected from the group consisting of a) alkyl, alkenyl, alkaryl, cycloalkyl, aryl, cycloalkyl, cycloalkylene, heteroaryl and heterocyclic wherein the heteroaryl or heterocyclic group is optionally substituted with 1 to 3 substituents selected from the group it consists of alkyl, alkoxy, aryl, aryloxy, halo, nitro, thioalkoxy, and thioaryloxy; b) a substituted phenyl group of formula II wherein R is alkylene of 1 to 8 carbon atoms, m is an integer equal to 0 or 1, R and Ra 'are independently selected from the group consisting of hydrogen, hydroxy, fluoro and methyl; Rfc and R 'are independently selected from the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy, cyano, cycloalkyl, halo, heteroaryl, heteroaryloxy, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, and -C (0) R4 wherein R4 is selected from the group consisting of alkyl, aryl, alkoxy, and aryloxy; and Rr is selected from the group consisting of hydrogen, alkyl, aryl, cyano, halo, nitro, and wherein Rr and R "are fused to form a methylenedioxy ring with the phenyl ring, and when RL and / or Rc 'and / or Rr is fluoro, chloro, bromo and / or nitro, then R * and / or Ra 'may also be chloro; (c) 1- or 2-naphthyl substituted at positions 5, 6, 7 and / or 8 with 1 to 4 substituents selected from the group consisting of alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; R- is selected from the group consisting of hydrogen, alkyl, from 1 to 4 carbon atoms, alkylalkoxy of 1 to 4 carbon atoms, alkylthioalkoxy of 1 to 4 carbon atoms; and R3 and R3 'are independently selected for the group consisting of: (a) hydrogen with the proviso that R3 and R3 'can not be hydrogen; (b) alkyl with the proviso that when R3 is hydrogen, then the alkyl group R3 has a linear carbon chain length of at least 5 carbon atoms from the nitrogen atom this chain can be optionally substituted with one or more alkyl groups with the additional proviso that R3 and R3 'are alkyl then at least one of the alkyl groups has a carbon chain length of at least 5 carbon atoms this chain can be optionally substituted with one or more alkyl groups; (c) - (R7) r () p wherein R "is an alkylene group, W is selected from the group consisting of: (i) R9 where R5, R5 ', R9 and R9' are independently selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl, heteroaryl and heterocyclic esters; and R6 is selected from the group consisting of hydrogen, hydroxyl, alkyl, substituted alkyl, amino, alkylamino, dialkylamino, aryl, acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, aminoacyl, cyano, cycloalkyl, halogen, carboxyl, carboxyl esters , heteroaryl, heterocyclic and wherein R6 and one of R5 or R5 'are fused to form a heterocyclic ring of 4 to 10 atoms having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur; with the proviso that when n is zero, R9 and R ° 'are hydrogen; (ii) heteroaryl; and (iii) N-heterocyclic with the proviso that when W is β -heterocyclic then n-is not zero; n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3 with the proviso that when n is zero then p is equal to 1, and (d) -CH (f) CH2C (0) 0-Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R1 to -CX'X "-, oxygen and sulfur; with the proviso that when R1 is phenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R: to -CX'X" -, m is zero, R3 is hydrogen, R3' is - (R7) n (W) p where n is zero and p is one and is R9 R5 then (i) R5, R5 ', R9, R9' and R6 are not all hydrogen and (ii) R5, R5 ', R9, R9' are hydrogen and R6 is methoxy; with the additional proviso that when R1 is 3,5-difluorophenyl, R2 is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, m is zero, R3 is hydrogen , R3 'is - (R7) n (W) p where n is one and p is one, R7 is ethylene and W is R9 R- then R5, R5 ', R9, R9' and R6 are not all hydrogen; Y even with the additional proviso that when R1 is 3, 5-di fluorophenyl, R: is methyl, X 'and X "are hydrogen, Z is a covalent group linking R1 to -CX'X" -, and m is zero, R3 is hydrogen, R3 'is - (R) n (W) p where n is zero and p is one, W is R9 R5 and R5 ', R9, R9' are hydrogen, then R5 and R6 do not fuse to form, with the phenyl ring to which they are attached, a phthalimido group.

46. The compound according to Claim 45, characterized in that R1 is an unsubstituted aryl group.

47. The compound according to Claim 45, characterized in that the unsubstituted aryl group R 1 is selected from the group consisting of phenyl, 1-naphthyl and 2-naphthyl.

48. The compound according to Claim 45, characterized in that R1 is a substituted aryl group.

49. The compound according to Claim 48, characterized in that the substituted aryl groups are substituted phenyl groups defined by the following: (a) monosubstituted phenyls having a simple substitution at positions 2, 3 or 4 wherein each of the particular substituents it is governed by the respective Ra, Rb and Rc groups; (b) disubstituted phenyls having two substituents at positions 2,3, positions 2,4, positions 2,5, positions 2,6, positions 3,4, positions 3,5 or positions 3,6 where each of these substituents are governed by respective Ra, Ra ', Rb, Rb' and R groups; Y (c) trisubstituted phenyls having three substituents at positions 2,3,4, positions 2,3,5, positions 2,3,6, positions 3,4,5 and positions 3,4,6 where each of these substituents are governed by the respective Ra, R3 ', Rb, Rb' and Rc groups.

50. The compound according to claim 49, characterized in that the substituted phenyl groups are selected from the group consisting of 4-fluorophenyl, 4-chlorophenyl, -bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxy-phenyl, 3-nitrophenyl , 3-f luorofeni lo, 3-chloropheni lo, 3-bromophenyl, 3-thiomethoxy-phenyl, 3-methylfl enyl, 3-trifluoromethylfl enyl, 2-hydroxyfl, 2-methylfl, 2-f luo-phenyl, 3, -dichlorofenyl, 3, 4-et i lendioxy f eni lo, 3, 5-di f luorofeni lo, 3,5-dichlorofenilo, 2,4-dichlorofenilo, and 2, 5-dif luorof enilo.

51. The compound according to Claim 45, characterized in that R1 is an alkaryl group.

52. The compound according to Claim 51, characterized in that the one alkaryl group R1 is selected from the group consisting of benzyl, phenylethyl, 3-f-enyl-n-propyl and 4-f-enyl-n-butyl.

53. The compound according to Claim 45, characterized in that R: is selected from the group consisting of the alkyl, alkenyl, cycloalkyl and cycloalkenyl groups.

54. The compound according to Claim 53, characterized in that R: is alkyl.

55. The compound according to Claim 53, characterized in that R: is cycloalkyl.

56. The compound according to Claim 53, characterized in that R1 is alkenyl.

57. The compound according to Claim 53, characterized in that R1 is cycloalkenyl.

58. The compound according to Claim 53, characterized in that the alkyl, alkenyl, cycloalkyl and cycloalkenyl groups R 1 are selected from the group consisting of sec-butyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, -CH 2 -cyclopropyl , -CH2-cyclobutyl, -CH2-cyclohexyl, -CH: -cyclopentyl, -CH2CH2-cyclopropyl, -CH: CH2-cyclobutyl, -CH2CH2-cyclohexyl, -CH2CH2-cyclopentyl.

59. The compound according to Claim 45, characterized in that R 'is selected from the group consisting of heteroaryl and substituted heteroaryl groups.

60. The compound according to Claim 59, characterized in that the heteroaryl and substituted heteroaryl groups R: are selected from the group consisting of pyrid-3-yl, pyrid-4-yl, thiophen-2-yl, thiophen-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphten-2-yl, 2-chlorotyl-iofen-5-yl, 3-methyl-1-yl - 5-i lo, 2- (thiophenyl) thiophen-5-yl, 6-methoxythin-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl and 2-phenyloxazol-4-yl.

61. The compound according to Claim 45, 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 and alkylthioalkoxy of 1 to 4 carbon atoms.

62. The compound according to Claim 61, characterized in that R: is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl and -CH2CH2SCH3.

63. The compound according to claim 45, characterized in that X 'and X "are hydrogen and Z is a covalent bond linking R; to -CX'X" -.

64. The compound according to Claim 45, characterized in that R "'is hydrogen and R3' is selected from the group consisting of 3-hydroxyphenyl, 3-methoxyphenyl, 3-ethoxycarbonylphenyl, n-hexyl, n-octyl, 4-ethoxycarbonyl nyl, 4-methoxycarbonylphenyl, 3-chlorophenyl, 3-cyanophenyl, 3,5-dichlorophenyl, CH (CH 3) f (stereoisomer R), -CH (CH 3) f (stereoisomer S), phthalid-6-yl, 2-hydroxypyrid -3-yl, 2- (me t ox i ca rb oni lmet il) ben cyl, 3 - (toxic rb onyl) benzyl, 2- (2 * -methoxycarbonylmethylphenyl) benzyl, and 2-phenylbenzyl.

65. The compound according to claim 24, characterized in that the compound of formula I is selected from the group consisting of: N- (3-hydroxyphenyl) -N '- (phenylacetyl) -L-alaninamide N- (3-methoxy phenyl) -N '- (phenylacetyl) -L-alaninamide N- (3-ethoxyphenyl) -N '-. { phenylacetyl) -L-alaninamide N- (4-ethoxycarbonylphenyl) -N '- (phenylacetyl) -L-alaninamide N- (n-hexyl) -A * '- (3, 5-difluorophenylacetyl) -L-alaninamide N- (n-octyl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- (3-methoxy phenyl) -N' - (3,5-difluoro-phenylacetyl) -L-alaninamide N- ( 4-ethoxycarbonyl) -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- (3-ethoxycarbonyl) enyl) -N' - (3,5-difluorophenylacetyl) -L-alaninamide N - (3-chlorophenyl) -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- (3,5-dichloro-phenyl) -N' - (3,5-difluoro-phenylacetyl) -L-alaninamide N- ( 3-cyanophenyl) -A7 '- (3, 5-difluorophenylacetyl) -L-alaninamide N-phthalo-6-yl) -N' - (3, 5-difluorophenylacetyl) -L-alanimamide N- [(4-methoxycarbonylphenyl) methyl] -N '- (3, 5 difluorophenylacetyl) -L-alaninamide N- (1-cy anole-1-methyl) -N' - (3, 5 difluorophenylacetyl) -L-alaninamide N - [( R) -l-phenylethyl] -N '- (3, 5-difluorofenylacetyl) L-alaninamide N - [(S) -l-phenylethyl] -N' - (3, 5-difluorofenylacetyl) L-alaninamide N- [2-hydroxy-di-n-3-yl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [2-methoxycarbonyl-1-phenylethyl] -N' - (3, 5-di-fluoro-phenylacetyl) -L-alaninamide N- [-pyridin-2-yl-benzyl] -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- [1- (α-phthalamido) pent-2 -yl] -N '- (3, 5' difluoropheni.lacetyl) -L-alaninamide N- [2- (methoxycarbonylmethyl) benzyl] -N '- (3,5-difluorophenylacetyl) -L-alaninamide N- [3-. { methoxycarbonylmethyl) benzyl] -N '- (3, 5-difluorophenylacetyl) -L-alaninamide N- [2- (2'-methoxycarbonylmethylphenyl) benzyl] -N' - (3,5-difluorophenylacetyl) -L-alaninamide N- [ 2-phenylbenzyl] -N '- (3, 5-difluorophenylacetyl) -L-alaninamide. SUMMARY OF THE INVENTION Compounds that inhibit the release of β-amyloid peptide and / or its synthesis are exposed and, therefore, have utility in the treatment of Alzheimer's disease. Also disclosed are pharmaceutical compositions containing a compound that inhibits the release of β-amyloid peptide and / or its synthesis as well as methods for the treatment of Alzheimer's disease prophylactically and therapeutically with such pharmaceutical compositions. The compounds are represented by the formula (I), wherein R1 is selected from the group consisting of: a) alkyl, alkenyl, alkaryl, alkalicycloalkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclic; b) a substituted phenyl group of formula (II), wherein R is alkylene of 1 to 8 carbon atoms, m is an integer equal to 0 or 1, and c) 1- or 2-naphthyl substituted at positions 5, 6 , 7 and / or 8, 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; and R- 'and R ~ "are independently selected from the group consisting of: (a) hydrogen, b) alkyl, (c) - (R7), (W) f_ where R ~ is an alkylene group, W is selected of the group consisting of (i) formula (A); (ii) heteroaryl; and (iii) N-heterocyclic, and n is an integer equal to 0 or 1, and p is an integer equal to 1 to 3; (d) -CH (f) CH2C (0) 0-Q where Q is selected from the group consisting of alkyl, aryl, heteroaryl and heterocyclic; X 'is hydrogen, hydroxy or fluoro; X "is hydrogen, hydroxy or fluoro, or X 'and X" together form an oxo group, Z is selected from the group consisting of a covalent bond linking R1 to -CX'X "-, oxygen and sulfur.