STATINE-DERIVED TETRAPEPTIDE INHIBITORS OF BETA-SECRETASE

Abstract: Statine-derived peptide inhibitors of the beta -secretase enzyme are provided which are useful in the treatment of Alzheimer's disease and other diseases characterized by deposition of A beta peptide in a mammal. The compounds of the invention provide useful methods of treatment by administration of these inhibitors to reduce A beta peptide formation and pharmaceutical compositions.

Description: STATINE-DERIVED TETRAPEPTTDE INHIBITORS OF BETA-SECRETASE Field of the Invention This invention is directed to compounds useful in treatment of Alzheimer's disease and more specifically to compounds that are capable of β-secretase enzyme inhibition, thus interfering with cleavage of amyloid precursor protein to produce beta-amyloid, a major component of the amyloid plaques found in the brains of Alzheimer's sufferers. Background of the Invention Alzheimer's disease (AD) is a progressive degenerative disease of the brain primarily associated with aging which results in loss of memory and orientation. As the disease progresses, motor, sensory and linguistic abilities are also affected until there is global impairment of multiple cognitive functions of the brain. These cognitive losses occur gradually, but typically lead to severe impairment and eventual death in the range of four to twelve years. Alzheimer's disease is characterized by two major pathologic observations in the brain: neurofibrillary tangles and amyloid (or neuritic) plaques. Neurofibrillary tangles occur not only in Alzheimer's disease but also in other dementia-inducing disorders, while amyloid plaques are peculiar to AD. Smaller numbers of these lesions in a more restricted anatomical distribution are found in the brains of most aged humans who do not have clinical AD. Amyloidogenic plaques and vascular amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure. Neurofibrillary tangles are characterized as networks of microtubules and microfilaments which were once structural supports running symmetrically through the nerve cells that transported nutrients but have degenerated into dysfunctional tangled masses. They can be described histologically as non-membrane bound bundles containing paired, helically wound filaments (PHF) that are approximately 10 nm in length and located in the peπnuclear cytoplasm of certain neurons Major components of paired helical filaments are highly phosphorylated tau proteins (PHF-tau) of 60 kDa, 64 kDa and 68 kDa Aβ peptide is also a component of these tangles Tau belongs to the family of microtubule- associated proteins and plays a role in the microtubule assembly and stabilization In > certain other neurodegenerative disorders, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and Pick's disease, hyperphosphorylated tau proteins also accumulate m bram tissue in association with abnormal filaments Recent research indicates that the pattern of hyperphosphorylation and the resulting ultrastructure of the helical filaments are somewhat different in each type of disease 10 Amyloid plaques, on the other hand, are peculiar to and a defining feature of AD Amyloid plaques are predominantly composed of amyloid beta peptide (Aβ, also sometimes designated as βA4) Aβ is derived by proteolysis of the amyloid precursor protein (APP) and is comprised of 39-43 ammo acids Several proteases called secretases l are involved in the processing of APP It appears that the abnormal processing and deposition of Aβ in areas of the brain responsible for cognitive activities is a major factor in the development of AD Cleavage of APP at the N-termmus of the Aβ peptide by β- secretase and the C -terminus by one or more γ-secretases constitutes the amyloidogenic pathway, I e , the pathway by which Aβ peptide is formed Cleavage of APP by α- 0 secretase and the same or a different gamma secretase produces α-sAPP. a secreted form of APP that does not result in amyloid plaque formation This alternate pathway precludes the formation of AB It has been proposed that Aβ peptide accumulates as a result of the processing of APP by β-secretase and that therefore inhibition of the activity of this enzyme is desirable for treatment of AD See for example, β- Amvloid and Treatment ^ Opportunities for Alzheimer's Disease, Sabbagh, M , et al , Alz. Dis. Rev. 3, 1-19, (1997) Several lines of evidence indicate that progressive cerebral deposition of particular amyloidogenic proteins, β-amyloid proteins, (Aβ), play a seminal role m the pathogenesis 30 of AD and can precede cognitive symptoms by years or decades See, Selkoe, Neuron 6 487 (1991) Aβ is released from neuronal cells grown in culture and is present m cerebrospinal fluid (CSF) of both normal individuals and AD patients See. Seubert et al , Nature 359 325-327 (1992) Although diffuse deposition of Aβ peptide occurs in most all humans with aging, the formation of amyloid plaques occur only in AD patients. Formation of these plaques is believed to occur over a period of years or even decades. The Aβ peptide in amyloid plaques is always folded in a particular three-dimensional pattern called a beta-pleated sheet and appears to be chemically modified as well, which could explain the association of the Aβ peptides into the larger, denser plaques, rather than the diffuse deposits normally seen. Associated with this central core of Aβ peptide in the amyloid plaque are surrounding abnormal neurites and several types of altered glial cells. Glial cells normally associate with neurons and perform support and protective functions. On the outside of the plaque are reactive astrocytes, which are a type of glial cell typically found in injured brain areas. Additionally many other biochemical components, including enzymes, proteoglycans and apolipoproteins are present in the plaques. For a discussion of the formation of these plaques see for example: Sabbagh, M., et al, cited supra. The neurons touching the amyloid plaques are progressively debilitated and ultimately die. At present it is not known whether the Aβ peptide is neurotoxic in itself or if the secondary features of the amyloid plaques, e.g., the abnormal glial cells, cause the nerve cells to die. Researchers have demonstrated that the Aβ peptide has neurotoxic effects in vitro. Still other researchers have demonstrated that the 25-35 amino acid sequence of Aβ peptide is similar to that of substance P, an endogenous neuropeptide compound present in certain brain tissues and having neuroexcitatory effects. Co-administration of substance P in the study blocked the neurotoxic effect of Aβ peptide in rats. See: An in vivo model or the neurodegenerative effects of beta amyloid and protection by substance P. Kowall NW, et al., Proc Natl Acad Sci USA 88 (16) p7247-51 (1991). Another study reports that Aβ peptide is neurotoxic through its interference with Ca ++ homeostasis. Korotzer A.R., et al., Differential regulation by beta-amyloid peptides of intracellular free Ca2+ concentration in cultured rat microglia. Eur. J. Pharmacol., 288 (2):125-30 1995.. Further, some studies have proposed that Aβ peptide is responsible for the hypeφhosphorylation of tau, a microtubule associated protein, which results in formation of PHFs and neurofibrillary tangles as described above. Thus, with Aβ peptide clearly linked to the formation of amyloid plaques and implicated in the formation of neurofibrillary tangles in AD, there is a need for agents and methods for reduction of Aβ peptide in vivo. At present there are no published means for specifically inhibiting the β-secretase enzyme, or even structural identification of the β-secretase enzyme is or a peptide sequence of its active site. However, a commonly assigned application naming John Anderson, Guriqbal Basi, et al. as inventors and entitled: β-Secretase Enzyme Compositions and Methods, identifies the enzyme and methods of use thereof. Additionally, a commonly assigned application naming Varghese John, Jay Tung. Roy Horn and Larry Fang as inventors and entitled: Dipeptide Inhibitors of β-Secretase, describes and claims dipeptide inhibitors of the β-secretase enzyme. The two above- identified applications are being filed on the same day as the present application. The contents of these co-pending applications are hereby incoφorated by reference in their entirety for all puφoses. Additionally, US 4 636 491 to Bock, et al. discloses certain tetrapeptides having renin inhibitory activity. Some of the compounds disclosed in the broadest Markush description by Bock encompass some of the compounds of the present invention. However, all the specific examples of Bock are directed to the sequence: Phe- His-Sta-Leu or to the same sequence containing derivatives of statine . The sequence is neither claimed, nor operative in the β-secretase inhibition disclosed herein. It is believed that the compounds claimed herein are patentable as a selected subgenus of the broad Markush disclosure of Bock. Detailed Description of the Invention This invention is directed to the discovery of a class of compounds that inhibit β-amyloid peptide production by preferentially binding to and inhibiting the proteolytic function of the β-secretase enzyme. Inhibition of β-secretase enzyme stops or reduces the production of Aβ from APP and thus reduces or eliminates the formation of amyloid plaques and other types of Aβ deposition in the brain. Therefore, the compounds are useful in the prevention of Alzheimer's Disease in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deteπoration in their condition. Now it has been discovered that the compounds of the present invention provide inhibitors of the β- secretase enzyme. The invention relates to compounds of formula 1 Formula 1 wherem A is a straight or branched chain alkanoxy or alkenoxy of 1 to 5 carbon atoms, aryl, arylalkyl, the aryl being optionally substituted with 1 to 2 carbon atoms or halogen, adamantyloxy, or 4-ammobutanoιc acid, B is selected from the group consisting of hydroxy. wherem a dithered line represents a point of attachment at B of formula 1 , D is H or an oxo group, L is a 5 or 6 membered saturated, unsaturated or aromatic heterocycle having from 1 to 3 heteroatoms chosen from nitrogen, oxygen or sulfur, or a saturated, unsaturated or aromatic carbocycle of 3 to 6 carbon atoms, any group represented by L having optional substitution with R', OR', or halogen, Q is a bond, or is a straight chain linking group of 1 to 3 non-hydrogen atoms chosen from the group consisting of-CH 2 -, -O-, and -NH- wherein O and N may not be adjacent, πng M is a stable 5 to 7-membered saturated, unsaturated or aromatic heterocycle having ^ up to 2 additional N atoms and optionally having 1 to 2 atoms of O and S, T is independently selected from the group consisting of H, OH, NO?, C(O)N(R) 2 , F, Ci-Ci alkoxy, hydroxymethyl and CF 3 , wherein at least one T is other than H, x is an integer of 1 to 3, y is an integer of 1 to 6, R' is independently H, -OH, C|-C ? alkyl or phenyl, R is independently H, d- C alkyl, or phenyl, and E is H. or Ci-C ? alkyl, R, is C-C- alkyl, R 2 is 2-propyl, 2- methylpropyl- or phenyl optionally substituted with R', OR' or halogen, R 3 is phenyl, CpC-, alkyl, or l-(2-methylthιo-)ethyl-, R is 2-propyl, 2-butyl or 2-methylpropyl, and stereoisomers, hydrates or pharmaceutically acceptable salts or esters thereof to 0 reduce the formation of Aβ peptide Still further, it is an object of the present invention to provide pharmaceutical compositions containing such β-secretase inhibitors in a pharmaceutically acceptable earner Other objects of the invention will become apparent from reading the ^ specification and appended claims Detailed Description of the Invention Natural amino acids are available in abundance, and a great array of non-naturally 0 occuπng ammo acids have been prepared by techniques well known to those skilled m the art of organic synthesis Roberts and Vellaccio provide a comprehensive listing of non- natural amino acids, and techniques for the synthesis of many - ariations thereof m The Peptides, Vol 5 Analysis, Synthesis, Biology, Academic Press. NN 1983 A more recent descπption of additional routes to chirally pure non-natural ammo acids is in Asvmmetric svnthesis of a-amino acids from carbohvdrates as chiral templates, Cintas, P Tetrahedron, 47 (32), 6079-1 1 1 (1991) Thus one skilled in the art can synthesize the amino acid precursors used the preparation of the compounds of the invention by a judicious selection of one or more of the methods outlined above, which articles are ■ hereby incoφorated by reference Statme is a non-standard ammo acid residue present m pepstatin that provides this peptide its inhibitory activity (Rich, D H , J Med Chem 28, p 262 (1985) Interestingly, pepstatin has no inhibitory activity in assays with β-secretase Statme has the chemical 10 name (3S, 4S)-4-ammo-3-hydroxy-6-methylheptanoιc acid, and is further identified m the Merck Index (1 l l ed ) at monograph no 8759, and is available commercially, such as through the Sigma- Aldπch catalog The three letter abbreviation given to statme in the peptide art is Sta The (3S, 4S) stereoisomer is designated Sta(s) or statιne(s) Statme deπvatives are also well known in the literature and can be prepared by methods l-> disclosed in United States Patent 4,397,786 Other methods are descnbed in the senes cited above (The Peptides, Vol 5 Analysis, Synthesis, Biology, Academic Press, NY 1983] and b Bnngmann et al in Synlett (5), pp 253-255 (1990), by Kessler and Schudok m Synthesis (6) pp 457-8 (1990), and by Nishi and Monsawa in Heterocycles 29(9), 1835-42 (1989) 20 Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of skill in the art to which this invention belongs All patents and publications referred to herein are hereby incoφorated b\ reference in their entirety for all puφoses ^ Optical Isomers-Diastereomers-Geometπc Isomers Some of the compounds descnbed herein contain one of more asymmetric centers and may thus e nse to enantiomers, diastereomers, and other stereoisometnc forms which 0 may be defined in terms of absolute stereochemistry as (R)- or (S)- . or as (D)- or (L)- for ammo acids The present invention is meant to include all such possible diastereomers and enantiomers as well as their racemic and optically pure forms Optically actι\ e (R)- and (S), or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques When the compounds descnbed herein contain olefinic double bonds or other centers of geometnc asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometnc isomers Likewise, all tautomenc forms are intended to be included Stereoisomers refer to molecules wherein the same atoms attach to one other in the same order, but the positioning of the attachment vanes so that two molecules may not be spatially identical, they are classified according to the number and symmetry of the chiral centers m each molecule Chiral centers are atoms to which the same kinds of atoms are attached but have more than one possibility for arrangement around the chiral center lι atom There are two types of stereoisomers diastereomers and enantiomers Diastereomers are two molecules which are stereoisomers that have the same connectivity but are not mirror images of each other Chiral centers in diastereomers are ananged so that an internal plane of symmetry exists m the molecule The chemical and physical 1" properties of diastereomers tend to differ because different spatial shape changes the ways in which the molecules interact Enantiomers are are two molecules which are exact minor images of one other, because each chiral center is a reflection of the chiral center of the other enantiomer Enantiomers 20 have identical chemical and physical properties, which make separations based on their physical properties extremely difficult Enantiomers are usually labeled R and S (for nght-handed and left-handed) to distinguish them Racemic mixtures are defined as mixtures of two minor image forms of the same -^ molecule (enantiomers) in equal amounts Although stereoisomers may not vary greatly on a chemical level, on the biological level, different stereoisomers isomers "fit" differently into the vanous protein receptors that e biochemical processes and thus stereoisomers, and frequently even enantiomers, do "0 not bind equally Therefore, enantiomers of the same compound can have different effects w ithin the human body Many of the embodiments of the present invention embrace the residue -or side chain- of a naturally occurnng α-amino acid, it is to be noted that each α-ammo acid has a charactenstic "R-group". the R-group being the residue -or side chain- attached to the α- carbon atom of the amino acid. For example, the residue of glycine is H, for alanine it is methyl, for valine it is 2-propyl, for methionine it is methylthioethyl. The specific residues of the naturally occurring α-amino acids are well known to those of skill in the art. See, e.g, A. L. Lehninger, Biochemistry: The Molecular Basis of Cell Structure and Function, 1975 (or any edition thereafter), Worth Publishers, NY, see, particularly Chapter 4). As used herein, the residues of naturally occurring α-amino acids are the residues of those about twenty α-amino acids found in nature which are incoφorated into a protein by the specific recognition of the tRNA molecule with its cognate m NA codon in humans. Those non-naturally occurring α-amino acid residues embraced by the present invention are known to those of skill in the art. Statine, as discussed above in the background of the art is a commercially available γ-amino acid. In the compounds herein the preferred stereoisomer is the S configuration and the absolute stereochemistry is (3S, 4S). Other modified or non-usual amino acids are 2-aminobutyric acid (Abu) and phenylglycine (Phg), In amino acids of this type a change is made in the side chain of the amino acid, usually by varying the length or substitution thereon. For instance, 2- aminobutyric acid is an α-amino acid that varies from valine by the removal of one of the methyl groups from the side chain. Phenylglycine is a homolog of the naturally-occurring amino acid phenylalanine, which lacks the methylene linkage between the peptide backbone and the phenyl group found in phenylalanine. Norleucine (Nle) is a slightly different example where the branching methyl group of leucine is shifted rather than deleted to make a non-branching (normal) chain having the same number of carbon atoms as leucine. These unusual amino acids can be incoφorated into peptide chains using the standard peptide linkage synthetic procedures described below for the naturally-occurring amino acids. As used herein, the term "alkyl" includes the straight, branched-chain and hydrocarbons, the number of carbons atoms being generally specified. Where not specified the alkyl groups preferably contain from about 1 up to about 12, more preferably 1 to 6. and most preferably 1 to 5 carbons. Exemplary of such moieties are methyl, ethyl, n-propyl. isopropyl, n-butyl, t-butyl, sec-butyl, pentyl, n-hexyl, n-nonyl, n-decyl, and the like. The term "lower alkyl " includes Ci -Cs alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, and the like. As used herein, "heteroatom(s)" is/are selected from O, N or S, unless otherwise specified. Alkenes are alkyl groups containing at least one C-C double bond (-C=C-). Exemplary of alkenyl moieties are 2-methyl-2-propenyl, 2-methyl-l-propenyl, propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 2,2-difluoroethenyl, as well as those straight and branched chained moieties having more than one double bond. The term "lower alkyl " includes Ci -C 5 alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, t-butyl, n-pentyl, and the like. The term "halo" and "halogen" refer to chloro, bromo, fluoro, and iodo. "Lower alkenyl" refers to those C 2 -C 6 unsaturated groups such as vinyl, l-propene-2-yl, 1 -butene-4-yl, l-pentene-5-yl, 2-methyl-2-butene-4-yl and the like. The term "alkanoxy" refers to those groups having an alkyl moiety from 1 to 6 carbon atoms linked to an oxygen atom. This oxygen is linked to the carbon atom of another group. Examples of alkanoxy groups are: methoxy, ethoxy, propoxy, butoxy, iso-butoxy, and the like. The term "alkenoxy" includes C 2 -C 6 groups having a C-C double bond and an oxygen atom, such as ethenyloxy, propenyloxy, iso-butoxyethenyl and the like. The term "amine" includes pirmary, secondary and tertiary amine which may be in straight or branched chains or, in the case of secondary and tertiary amines within rings, and are optionally substituted with, C\ -C acyloxy, Ci -C 6 alkyl, C] -C 6 alkoxy, nitro, carboxy, carbamoyl, carbanoyloxy, cyano halogen, amino and the like. The terms "carboxyl", "carboxylate" and "carbamoyl" are all terms referring to functional groups containing the a carbon atom double bonded to an oxygen as well as single bonded to another oygen. in the case of carbamoyl the carbon is addionally bonded to a nitrogen atom. These terms all include the corcesponding pharmaceutically acceptable C, -C alkyl and aryl esters. The term "aryl" includes 3 to 8 membered stable saturated or unsaturated organic monocyclic rings having 0 to 4 hetero atoms selected from S, O, and N; and 7 to 10 membered organic stable, saturated or unsaturated, bicyclic rings having 0 to 5 hetero atoms selected from S, O, N; both of which may be substituted by halo, Ci -C 6 alkyl, Ci - C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted Ci -C alkyl, d -C 6 substituted alkoxy, substituted C2 -C 6 alkenyl, or substituted C2 -C alkynyl, hydroxy, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, Ci -C 4 alkylthio, Ci -C 4 alkanoyloxy, carbamoyl, or halo-substituted Ci -C 6 alkyl. The term "aryl" also includes fused ring carbocyclic and heterocyclic moieties having at least one aromatic nucleus. The term "arylalkyl" refers to any of the above aryl groups also having an alkyl radical though which the group connects to the larger structure. Prefened aryl and aralkyl moieties are phenyl, benzyl, phenethyl, 1- and 2-naphthyl, naphthylmethyl, 5-, 6-, 7-, and 8- quinolinyl, benzofuryl, indenyl, or indanyl, benzimidazolyl, indolyl, benzothiophenyl, indole-3 -ethyl and 5-, 6-, 7-, and 8-tetrahydroisoquinoline. Other examples of such ring systems may be found in J. Fletcher, O. Dermer, R. Fox, Nomenclature of Organic Compounds, pp. 20-63 (1974), and in the Examples herein. The terms substituted alkyl, substituted alkenyl, substituted alkynyl and substituted alkoxy are these radicals substituted with halogen, hydroxy, amino, Ci -C 7 acyloxy, nitro, carboxy, carbamoyl, carbamoyloxy, cyano, or Ci -C 6 alkoxy, and may be substituted one or more times with the same or a different group, preferably substituted 1 to 3 times. A linking group is defined as a divalent linear chain facilitating the reach of a binding group, for example a carboxyl group to binding sites within the target enzyme. The facilitation occurs as a result of either or both the extension of the group at a particularly advantageous distance from another binding site on the molecule or in providing an advantageous flexibility to the group in being able to adopt a conformation that allows for optimal binding. Particular examples of the group Q which may be present in compounds of the invention include groups of formula: -CH 2 -(CH )n-; -O-(CH?)n-; NH-(CH 2 )n-; -O- CH 2 -O-; -O-CH 2 -NH-; NH-CH 2 -NH- wherein n=0, 1 or 2. A pharmaceutically acceptable salt is any salt which substantially retains the activity of the parent compound and does not impart any deleterious or undesirable effect on the subject to whom it is administered and in the context in which it is administered Such salts are those formed with pharmaceutically acceptable cations, e g , alkali metals, alkali earth metals, etc A pharmaceutically acceptable ester is any ester formed on a parent carboxyhc acid which substantially retains the activity of the parent compound and does ^ not impart any deletenous or undesirable effect on the subject to whom it is administered and in the context in which it is administered A pharmaceutically acceptable excipient or diluent is any excipient which retains the activity of the therapeutic compound with which it is admixed and does not impart any deletenous or undesirable effect on the subject to whom it is administered and in the context in which it is administered 0 Abbreviations used in this specification represent the following Ac= acetyl (methylcarbonyl) bd = broad doublet BOC=tert-butoxycarbonyl ^ bs = broad singlet CBZ=benzyloxycarbonyl d = doublet DMF = dimthylformaide EDC = ethyl- l-(3-dιmethylamιnopropyl)carbodnmιde 0 EtOAc = ethyl acetate eq = equivalents HOBT = 1-hydroxybenzotnazole IC 50 = inhibitory concentration of a compound where the enzyme activity is reduced by half ^ m = multιplet mass spec or MS= mass spectrum nmr = nuclear magnetic resonance spectrum R f = ratio of movement of a substance on a thin layer chromatogram in companson to the movement of the solvent front 0 s = s glet t = tnplet TEA = tnethylacetate TFA = tnfluoroacetic acid THF = tetrahydrofuran > TLC = thin layer chromatography δ = units of measurement for nuclear magnetic resonance spectroscopy which are relative to a standard, e g tnmethyl silane μL = micro ter μM = micromolar (an expression of concentration in micromoles/ liter) 0 The terms N-termmal or N-terminus refer to that terminal or end group of a peptide beanng the free or denvatized ammo group of an amino acid residue Likewise, C- terminal or C-terminus refers to that terminal or end group of a peptide beanng the free or derivatized carboxy group of an amino acid residue. The term "capping group" refers to a non-amino acid moiety bonded to the C- or N-terminal of the peptide chain. Examples of N-terminal capping groups used in peptide synthesis are BOC (t-butoxycarbonyl,) and CBZ (benzyloxycarbonyl) and glutamic acid. Other capping groups are acetyl and adamantyloxycarbonyl. Non-limiting examples of are shown in Table 1. Methods of Synthesis Reaction scheme 1 illustrates the construction of some of the peptides provided herein and the variety of reactions that may be used to prepare intermediates from which compounds for formula 1 may be prepared, and provides a generic method for the synthesis of the tetrapeptides. Although statine and valine are employed as the N-terminal amino acids. It is to be understood that other peptides may be also be substituted in place of valine and that derivatives of statine may be employed as alternatives in the steps below to provide further tetrapeptides as provided herein. Scheme 1 NH 2 -Val-OBzl HCl + Boc-statιne(s) ^ Boc-Sta(s)-Val-OBzl B Boc-AA r St<s)-Val-OBzl NH 3 -St s>Val-OBzl B 1) R-AA 2 -OH D NH A A r Sta(s>V al-OBzl R- A A, - A A ! - t s -V al-OBzl F R-A j -AA j -Sta -Val-NH-R * R-AA 2 -AA 1 -St s)-Val-OH H 2 N — KOH R-AA 2 -AA 1 -St s)-V8-1-NH-R-C0 2 CH 3 *~ R-AA 2 -AA,-Sta s)-Val-NH-R-CO 2 H This scheme may be varied as desired by selecting a different carboxy protected amino acid residue, for example, α-amino-butyric acid (Abu) or phenylglycine (Phg) in Step A to couple with statine. Or alternatively, selecting a different statine derivative, such as Phe-Sta, wherein the 2-methyl-propyl group is replaced by benzyl, to be coupled with the starting amino acid in Step A. Derivatives of statine are known in the art and described in United States Patent 4,397,786. Experimental Methods Step A: Coupling of the C-terminal amino acid with statine. Boc-Sta(s) ( 1.0 equiv.) was dissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.), H 2 N-Val-OBzl .HCl (1.0 equiv.) and TEA (5 equiv.) were added and the mixture was sthred for 20 minutes. EDC (1.2 equiv.) was then added and allowed to stir overnight under an atmosphere of nitrogen. The reaction was diluted with water and extracted with EtOAc (3x). The organic layers were washed with aqueous citnc acid (2x), sat. NaHCO3 (2x), brine, then dried with MgSO 4 . Step B: Removal of the Boc-protecting group from the resulting dipeptide. The Boc-protecting group of the dipeptide was dissolved in a trifluoroacetic acid/methylene chloride (1/1) solution. The reaction was monitored by TLC to confirm the consumption of starting material at which time the solvents were removed under vacuum to yield the free amine which was used without further purification. Step C: Coupling deprotected amine with a selected amino acid residue (AAi). Boc-AAi-OH (1.0 equiv.) is dissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.), H 2 N-Stat-Val-OBzl .HCl (1.0 equiv.) and TEA (5 equiv.) were added and all was stirced for 20 minutes. EDC (1.2 equiv.) is added and the mixture is stirred overnight under an atmosphere of nitrogen. The reaction is then diluted with water and extracted with EtOAc (3x). The organic layers are washed with aqueous citric acid (2x), sat. NaHCO3 (2x), brine, then dried over MgSO 4 . Removal of the Boc-protecting group from the resulting tripeptide is accomplished as in Step B above. Step D: Coupling of the tripeptide with a selected amino acid residue (AA 2 ). l -i R-AA?-OH (1.0 equiv.) is dissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.), H 2 N-AA, -Stat-Val-OBzl.HCl (1.0 equiv.) and TEA (5 equiv. ) are added and the reaction mixture is stined for 20 minutes. EDC (1.2 equiv.) is then added to the mixture and is allowed to stir overnight under an atmosphere of nitrogen. The reaction is diluted with water and extracted with EtOAc (3x). The organic layers are washed with aqueous citric acid (2x), sat. NaHCO3 (2x), brine, then dried over MgSO 4 . Step E: Removal of the Carboxybenzyl (Cbz) protecting group from the C- terminus R-AA.-AArStat-Val-OBz ( 1.2 g) is dissolved in 100 ml of MeOH and Pd/C (l g, 10%) is added. The reaction is subjected to a hydrogen gas atmosphere of 50psi for 2 hours. The resulting slurry is filtered through a pad of celite, and rotoevaporated to yield the desired material. Step F: Coupling of the C-terminal end of the tetrapeptide with a functionalized amine R-AA 2 -AAι-Stat-Val-OH (1.0 equiv.) is dissolved in 30 mL of dry dichloromethane, then HOBT (2.0 equiv.), H 2 N-R (1.0 equiv.) and TEA (5 equiv.) were added and the reaction mixture is stirred for 20 minutes. EDC (1.2 equiv.) is added and allowed to stir overnight under an atmosphere of nitrogen. The reaction is diluted with water and extracted with EtOAc (3x). The organic layers are washed with aqueous citric acid (2x), sat. NaHCO3 (2x), brine, then dried over MgSO 4 . The amine groups (R-NH2) of the examples shown below are commercially available unless otherwise indicated by reference to a citation in a journal. Some of the compounds are supplied as the methyl ester, if a carboxylic acid function is present. If only the free carboxylic acid group is available commercially, the methyl ester can be prepared as indicated in step H below. Step G: Cleavage of the C-terminal capping group methyl ester to provide free carboxylic acid or carboxylate salt The methyl ester (1 equiv.) is dissolved in a suitable solvent (MeOH/water, dioxane/water. or THF/water). Hydroxide (2-20 equiv., KOH. NaOH, or LiOH) is added and the reaction mixture is allowed to stir until the all of the ester is converted to acid as evidenced by TLC. Volatile solvents are removed and the reaction is acidified with citric acid The resulting precipitate is collected and charactenzed to insure the desired matenal is obtained Step H: Preparation of the methyl ester for the C-terminal capping reaction The selected acid is dissolved in dry methanol HCL (gas) is bubbled through the mixture for 5 minutes The reaction is then stnred overnight and rotoevaporated to yield the desired methyl ester Step J: Aminoaryl diesters to Aminocyclohexyl diesters An example of this nng hydrogenation is with dimethyl -aminophthalate The amino- phthalate in acetic acid (12%v/v) was added 1 25 g of 5% rhodium on alumina (50% w/w ), the mixed slurry was saturated with hydrogen at 55 PSI and shaken for a total of 72 hrs Upon completion of the hydrogenation the reaction was filtered through Celite and dned over anhydrous sodium sulfate Filtration and subsequent rotoevaporation yielded crude product, which was then subjected to silica gel chromatographic punfication to provide dimethyl ammocyclohexyldicarboxylate as a pale white solid See also Fieser &. Fieser, Reagents for Org Syn 4, 418 and Freifelder, M , Ng, Y H , Helgren, P F , J Org Chem 30, 2485-6 Step K: Formation of azide The Hahde (5 5 mmole) was dissolved in dry DMF and sodium azide ( 6 88 mmole) was added The reaction was stirred overnight under nitrogen at 40° C Workup the reaction was concentrated under vacuum and partitioned between ethyl acetate and water The organic layer was dned by MgSO The azide product was obtained in 89 % yield Step L: Reduction of Azide The azide (2 44 mmole) was dissolved in THF, and PtO 2 (catalytic amount) The reaction was shaken on a Pan shaker m the presence of hydrogen (20-30 psi) for one hour Workup Filtered through celite and was rinsed with methanol The filtrate was concentrated down to obtain the desired amine product ιn92% yield Step M: Proctection of amine The amine (9 9 mmole) and methylamine (9 9mole) was dissolved in dry dichloromethane and (Boc)?O was added The reaction was stmed overnight under nitrogen Workup: the reaction was concentrated on a rotary evaporator and the residue was taken up with ethyl acetate and then washed with water, citnc acid, sodium bicarbonate, and bnne The organic solvent was dned over MgSO (86%). Step N: N-methylation The amine (4 1 mmole) was dissolved in THF and methyl iodide was added, followed by sodium hydnde. The reaction was stmed overnight under nitrogen Workup: the reaction was concentrated on a rotary evaporator and the residue was taken up with ethyl acetate and then washed with water, citnc acid, sodium bicarbonate, and bnne The organic solvent was dned over MgSO 4 . Step O: Bromination The methyl ester (26 9 mmole), benzoyl peroxide (0 455 mmole), and NBS (26 9 mmole) were dissolved m benzene and kept at reflux overnight under N?, after which the solution was concentrated to dryness The remaining solid was filtered and washed with hot water, then dned on high vacuum overnight (81%). Steps K, L and O are employed in the order set forth below: incoφoration into dipeptide Mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, mto the pure final products or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances For the puφose of classification of the inhibitor activities of the compounds of the present invention, the Examples given below have been grouped by their IC 50 concentrations. Those compounds of Group IV have an IC 50 of greater than 200 μM. The compounds of Group III have an ICsoConcentration of from between 100 μM and 200 μM and are the prefened compounds of the invention. The compounds of Group II have an IC 50 concentration of from between 10 μM and 99 μM and are the more prefened compounds of the invention. The compounds of Group I have an ICsoConcentration of < 10 μM and are the most prefened compounds of the invention. Table 1 Enzyme inhibition assay results for structures having the peptide backbone: In Examples 1-26: R 2 is 2-methylpropyl, R 3 is methylthioethyl and A is tert- butyloxycarbonyl. III Table 1 continued for variations of amino acid substituents and/or N-terminal capping groups. -11 IC 50 Group Structure R is 2-methylpropyl. R is 3 phenyl. A is butyloxy- II carbonyl and B is 4-amino- methvlbenzoic acid The following non-limiting examples describe a method by which each of the compounds of Table 1 and as numbered therein w ere prepared following the procedure outlined generally in Scheme 1. Example 1 Steps A through F were employed, substituting H2N-Val-OMe (the methyl ester) for the benzyloxycarbonyl protected starting material, and selecting L-Met as AAi and L-Val as AA-. Example 2 The product of Example 1 was further subjected to Step G to remove the methyl ester. leaving the free C-terminal acid. Molecular Formula C sH, 2 4 O s S 1 Molecular Weight 604.80 H-nmr (solvent) (CD 3 OD) δ 8.33(d. 1H): 7.00(d. 1H): 4.55(m. 1H); 4.33(d. 2H): 4.1 -3.8(m. 4H): 2.50(m. 2H); 2.42(d. 2H): 2.10(m. 2H): 2.08(s. 2H): 2.00( s. 3H): 1.55(m. 3H ): 1 .44( s. 9H); 1.33(m. l H ): 0.99(m. 18H ) Example 3 Steps A through F were employed, selecting L-Met as AAi and L-Yal as AA and usim benzylamine as NH 2 in step F. Example 4 Steps A tlirough F were employed, selecting L-Met as AAi and L-Val as AA? and using 1-pentanamme as RNH 2 in step F. Example 5 Steps A through F were employed, selecting L-Met as AAi and L-Val as AA 2 and using ethylam e as RNH in step F. Molecular Formula C HvN,,O-S Molecular Weight 631.87 Example 6 Steps A through F were employed, selecting L-Met as AAi and L-Val as AA 2 and using methyl 4-aminobutanoate as RNH 2 in step F. Example 7 Steps A through F were employed, selecting L-Met as AA. and L-Val as AA 2 and using methyl 3-aminopropanoate as RNH in step F. Example 8 The product of Example 6 was further subjected to Step G to remove the methyl ester, leaving the free C-terminal acid. Example 9 The product of Example 7 was further subjected to Step G to remove the methyl ester leaving the free C-termmal acid. Molecular Formula CHrNOώ Example 10 Steps A through F were employed, selecting L-Met as AA . and L-Val as AA; and using methyl 2-amιnomethylfhiazole-5-carboxylate as RNH 2 in step F and then removal of the methyl ester according to step G. The methyl 2-aminomethy thizaole-5-carboxylate was prepared according to Synthesis 1986, page 992. Example 11 Steps A through F w ere employed, selecting L-Met as AA. and L-Val as AA; and using methyl 4-aminomethylbenzoate as RNH; in step F and then removal of the methyl ester according to step G. Example 12 Steps A tlirough F were employed, selecting L-Met as AAi and L-Val as AA; and using methyl 4-aminomethylpyridine as RNH 2 in step F. Example 13 Steps A through F were employed, selecting L-Met as AA. and L-Val as AA? and using methyl 4-amιnomethylbenzoxyacetate as RNH; in step F and then removal of the l ester according to step G. Methyl 4-aminomethylbenzoxyacetate was prepared according to the procedure provided in J. Med. Chem. 1998. Vol. 31. No. 10 C-nmr ( solvent) ( MeOD): ό 169.033. 16S.1 7S. 16 " .998. 167.873. 166.744. 153.686. 135.801. 124.671 . 124.61 " . 120.2 7 . 1 15.650. 108.690. 108.463. 74.839. 65.41 1. 59.815. 55.935. 53.802 54.548. 54.344. 48.403. 48.074. 46.067. 35.651. 35.463. 35.322. 26.489. 26.144. 25.642. 25.501. 25.345. 25.078. 24.819. 22.71 1. 19.741. 1 7.664. 16.206. 13.729. 13.588. 12.593. 12.216. 9.246 Mass soec ( MH-) 768 Example 14 Steps A through F were employed, selecting L-Met as AA. and L-Val as AA; and using methyl 3-aminomethylbenzoate as RNH; in step F and then removal of the methyl ester according to step G. Example 15 Steps A through F were employed, selecting L-.Met as AA , and L-Val as AA; and using methyl 4-ammocyclohexylcarboxylate as RNH 2 in step F and then removal of the methyl ester according to step G. 2S Example 1 Steps A through F were employed, selecting L-Met as AA. and L-Val as AA; and usins. 2-aminoglutaramide as RNH; in step F. Molecular Formula C ,H.,Λ ' -OQS Molecular Weight .96 H-nmr (solvent) (CD OD) δ S.44(d. IH) S.22(d. IH); 7.86(d. IH): 6.S8(m. IH): 4.56(m. IH): 4.33(m. IH): 4.0-3.9(m.3H): 3.33(m. 2H); 2.55(m.2H); 2.43(m.2H): 2.1-1.9(m.5H): 1.55(m. IH); 1.44(s.9H): 1.33(m. IH): 0.99(m.18H) C-nmr (solvent) (CD;,OD) δ 174.129.96.505.80.711. " 1.549.61.971.59.440. 59.283.54.189.52.786.52.480.41.437.32.525.31.640. 28.700.25.785.23.786.22.211.22.140.19.7S1.19.475. 18.621.18.449.15.235 Mass spec (MH-) 731 Example 1" Steps A through F were employed, selecting L-Met as AAi and L-Val as AA; and using methyl 1-amιnocyclopropane-l-carboxylate as RNH; in step F and then removal of the methyl ester according to step G. Example 18 Steps A through F were employed, selecting L-Met as AAi and L-Yal as AA; and usi 3-amιno-dihydro-2(3H)-furanone as RNH; in step F. Molecular Formula C32H.--N.O0S Molecular Weight 687.90 Mass spec (MH-) 688.4 Example 19 Steps A through F were employed, selecting L-Met as AA; and L-Val as AA; and usim methyl 4-amιnobutan-l-ol as RNH; in step F. Molecular Formula ! C H„VO,S Molecular Weight 675. 2) Example 20 Steps A through F were employed, selecting L-Met as AAi and L-Yal as AA; and using methyl 3-ammobenzoate as RNH; in step F and then removal of the methyl ester according to step G. Example 21 Steps A through F were employed, selecting L-Met as AA] and L-Yal as AA; and usi methyl 4-pιpeπdine-acetate as RNH; in step F and then removal of the methyl ester according to step G. Example 22 Steps A through F were employed, selecting L-Met as AA. and L-Yal as AA; and using ethyl piperazine-X '-carboxylate as RNH; in step F and then removal of the ethyl ester according to step G. Example 23 Steps A through F were employed, selecting L-Met as AAi and L-Val as AA 2 and using l-acetamιdo-2-ammoefhane as R-NH 2 in step F. Example 24 Steps A through F were employed, selecting L-Met as AAi and L-Val as AA; and using 1 -ammo 4-fluorobenzene as RNH; in step F. Example 25 Steps A through F were employed, selecting L-Met as AAi and L-Y ' al as AA; and using 4-ammomethylbenzocarboxamιde as RNFL in step F Molecular Formula C ,H,,\ OsS Example 26 Steps A through F were employed, selecting L-Met as A ι and L-\ al as A. ; and using 3.5-dιcarbo\\c\clohe\\ tamine as RNH; in step F The amine was prepared as follows To 25 g oi dιmeth\l 5-amιnoιsophthalate in 40 ml ol methanol 48ml acetic acid ( added 125 g of 5° u rhodium on alumιna(50°o w w ). the mixed slum was saturated with hydrogen at 55 PSI and shaken for a total of 72 hrs Lpon completion of they h\drogenatιon the reaction w as filtered through Celite and dned o\ er anhydrous sodium sulfate Filtration ana subsequent rotoevaporation yielded 385g of crude product, which as then subjected to suica gel chromatographic purification to afford 076g of Di-Methyl l-Amιnocyclohe\>l-3, 5-Dι- Carboxy ate as a pale white solid See also Fieser & Fieser. Reagents for Org S\n 4.418 and Freifelder. M . Ng. V H . Helgren. P F . J Oi? Chem 30.2485-6 Molecular Formula C36H63N5O11S Molecular \\ eight " 73 tic Rf (sohent) Rf=005 (10%MeOH DCM) Punfication 1 Acid Base Washes 2 Tπturation w Ether Filtration Mass spec (MH-) 7723(ESI eg ) Synthetic Route Method A. B. E. J. F. G Description Method J Amino- Ar l Diesters to Amιno-C\clohe\\l Diesters Example 2"? Prepared in a manner similar to Example 26. except that dιmeth\l 6-amιnoterephthalate was utilized in the preparation of 1 Molecular Formula 1 C36H63N5O11S ! Molecular \\ eight 1773 I tic Rf (sohent) ! Rf=025 (lOVMeOH DCM) Purification 1 Acid Base \\ ashes 2 Tnturation w Ether Filtration Example 28 Prepared using methyl 4-aminoocyclhexylacetate. Example 29 Prepared according to the initial preparation used to prepare Example 1 1 but Steps M and N are inserted prior to the removal of the ester alcohol. Aminomethvlbenzoic acid was first protected with 1 equivalent of BOC and then the N-protected amine was methylated with methyl iodide. The BOC group was subsequently removed and the \-methy - aminomethylbenzoic acid was coupled with the tetrapeptide. Svnthetic Route Descπption | Method F. M.N.G Example 30 The amine utilized was dimethyl 1 -amino- 1.3-propane-dicarboxylate and then the dicarboxylate was saponified to provide the dicarboxylic acid. Example 31 The tetrapeptide was coupled to the N-terminal capping group. The capping groups was prepared by reacting l -bromo-l -(4-benzoic acid) ethane with sodium azide, reducing the resulting azide to the amine and coupling the product with the tetrapeptide. Example 32 Prepared in a manner similar to Example 26. except that dimethyl 5-ammophthalate was utilized in the preparation of 3.4-dicarboxycyclohexylamine. Molecular Formula C36H63N501 1 S Example 33 The tetrapeptide was coupled with l -ammo-indan-2-ol usmg step F. Example 34 The methyl ester of 2-carboxy-cyclohexylamine was prepared according to setp H. then coupled with the tetrapeptide and the free carboxlyic acid was generated according to step G. Example 35 The tetrapeptide was coupled with the methyl ester of phenylglycine and the ester group was subsequently removed. Example 36 The tetrapeptide w as coupled with 2-( 5-(2-hydroxynitrobenzene))- l -ethanamme. Example 37 The compound was prepared in a manner similar to Example 1 1 with the following vanations: Phenyl-statme (Phe-Sta) was employed in place of statine and phenylglycine (Phg) w as selected as AAi and N-Ac-L-Val was used as AA; Molecular Formula C39H49N5O8 Molecular Weight 715 Mass spec ( MH- ) I 716.3(APCI ) Example 38 The compound was prepared in a manner similar to Example 1 1 with the following vanations: Phenylglycine (Phg) was selected as AA] and carbobenzyloxy (Cbz)-L-Val Example 39 The compound was prepared in a manner similar to Example 1 1 with the following variation: Phenvlglvcme (Phg) was selected as AAi . Enzvme Inhibition Assay Purpose/Rationale: The MBP-C125 assay, determines relative inhibition of β-secretase cleavage of an MPB- C125 substrate by the compounds assayed. Human brain β-Secretase from the concentrated HiQ pool prepared 7/16/97 in 0.20% Triton is used in the assay . Inhibition data was obtained from an ELISA which uses an anti-MBP capture antibody (on precoated and blocked 96-well high binding plates) followed by incubation with diluted enzyme reaction supernatant, incubation with an anti-SW192 specific biotinylated reporter antibody and incubation with streptavidin alkahne phosphatase. Detection was effected by a fluorescent substrate signal on cleavage by the phosphatase. The ELISA only detected cleavage following Leu 596 at the substrate's Swedish APP 751 mutation site. Compounds were diluted in a 1 : 1 dilution series to a six-point concentration curve (two wells per concentration) which took up one 96-plate row per compound tested. Relative compound inhibition potency was determined by calculating the concentration of compound that showed a fifty- percent reduction in detected signal compared to the enzyme reaction signal in the control wells with no added compound. Procedure: Each of the test compounds was weighed out into a vial and DMSO was added to make up a lOmM solution. To obtain a final compound concentration of 200 μM at the high point of a 6-point dilution curve, 100 μL of the 10 mM solution was added to well CI of a 96-well V-bottom plate. Fifty μL of DMSO was added to odd wells of ro C across the plate and 1 : 1 serial dilutions were made. 10 μL of each dilution was added to each of two wells on row C of a conesponding V-bottom plate to which 190 μL of 52 mM NaOAc/7.9% DMSO, pH 4.5 were pre-added. The NaOAc diluted compound plate was spun down to pellet precipitant and 20 μL/well was transfened to a conesponding flat- bottom plate to which 30 μL of ice-cold enzyme-substrate mixture (2.5 μL MBP-C125 substrate, 0.03 μL enzyme and 24.5 ice cold 0.09% TXl 00 per 30 μl) was added. The compound concentration in the final enzyme reaction was thus 50 times less than the starting concentration. The final reaction mixture of 200 μM compound for the highest curve point was in 5% DMSO, 20 mM NaAc, 0.06% TXl 00, at pH 4.5. The enzyme reaction was started by warming the plates to 37° C. After 90 minutes at 37° C, 200 μL/well cold specimen diluent was added to stop the reaction and 20 μL/well was transfened to a corresponding α-MBP coated ELISA plate, containing 80 μL/well specimen diluent. This reaction was incubated overnight at 4oC and the ELISA was developed the next day using a 2 hr. incubation with α-192SW followed by Streptavidin- AP conjugate and flourescent substrate. The signal was read on a fluorescent plate reader. Methods for treating Alzheimer's disease and other diseases characterized bv deposition of Aβ peptide. This invention also relates to a method of treatment for patients suffenng from disorders or diseases which can be attnbuted to Aβ plaque formation as previously descnbed and, more specifically, a method of treatment involving the administration of the β-secretase inhibitors of formula 1 as the active constituents Accordingly, the compounds of formula lean be used among other things in the treatment Alzheimer's disease, and in diseases and indications resulting from the over-expression of Aβ-peptide such as found in certain genetic defect diseases such as plaque formation associated with Tnsomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage 0 with Amyloidosis of the Dutch-Type (HCHW A-D) As mentioned abov e, compounds of formula 1 are useful in medicine since they are active as inhibitors of β-secretase Accordingly another aspect, this - a method of management (by which is meant treatment or prophylaxis) of disease or conditions mediated by β-secretase m mammals, in particular in humans, which method compnses admmistenng to the mammal an effectiv e, amount of a compound of formula 1 above, or a pharmaceutically acceptable salt or ester thereof, and 0 a compound of formula (I) for use in human or vetennary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by β-secretase, and the use of a compound of formula (I) m the preparation of a composition for the ^ management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by β-secretase The disease or conditions refened to above include Alzheimer's disease, plaque formation associated with Tnsomy 21 (Down's Syndrome) and Hereditary Cerebral 0 Hemonhage with Amyloidosis of the Dutch-Type (HCHW A-D) For the treatment of diseases charactenzed by the overproduction and deposition of Aβ- ppeptide, the compunds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, mtrasternal injection or infusion techniques The compounds may be administered in an amount from about 0 1 mg/kg/day to about 500 mg/kg/day Preferced amounts for daily administration are from about 1 mg/ kg to about 50 mg/kg It will be understood however, that the amount of the compound actually administered will be determined by a physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight and response of the individual patient, the seventy of the patient's symptoms, and the like Formulation of pharmaceutical compositions Compositions are provided that contain therapeutically effective amounts of the compounds of formula 1 The compounds are preferably formulated into suitable pharmaceutical preparations such as tablets, capsules or elixirs, for oral administration or m stenle solutions or suspensions for parenteral administration Typically the compounds descnbed above are formulated into pharmaceutical compositions using techniques and procedures well known m the art About 1 to 500 mg of a compound or mixture of compounds for Formula 1 or a physiologically acceptable salt or ester is compounded with a physiologically acceptable vehicle, earner, excipient, binder, preservative, stabilizer, flavor, etc , in a unit dosage form as called for by accepted pharmaceutical practice The amount of active substance in those compositions or preparations is such that a suitable dosage in the range indicated is obtained The compositions are preferably formulated in a unit dosage form, each dosage containing from about 2 to about 100 mg, more preferably about 10 to about 30 mg of the active ingredient The term "unit dosage from" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active matenal calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carner(s) To prepare compositions, one or more compounds of formula 1 are mixed with a suitable pharmaceutically acceptable carrier. Upon mixing or addition of the compound(s), the resulting mixture may be a solution, suspension, emulsion or the like. Liposomal suspensions may also be suitable as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art. The form of the resulting mixture depends upon a number of factors, including the intended mode of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient for ameliorating the symptoms of the disease, disorder or condition treated and may be empirically determined. Pharmaceutical carriers or vehicles suitable for administration of the compounds provided herein include any such carriers known to those skilled in the art to be suitable for the particular mode of administration. In addition, the active materials can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action or have other action. The compounds may be formulated as the sole pharmaceutically active ingredient in the composition or may be combined with other active ingredients. In instances in which the compounds exhibit insufficient solubility, methods for solubilizing compounds may be used. Such methods are known to those of skill in this art, and include, but are not limited to, using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such as Tween®, or dissolution in aqueous sodium bicarbonate. Derivatives of the compounds, such as salts of the compounds or prodrugs of the compounds may also be used in formulating effective pharmaceutical compositions. The concentrations of the compounds are effective for delivery of an amount, upon administration, that ameliorates the symptoms of the disorder for which the compounds are administered. Typically, the compositions are formulated for single dosage administration. The compounds of formula 1 may be prepared with carriers that protect them against rapid elimination from the body, such as time release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems, The active compound is included in the pharmaceutically acceptable earner in an amount sufficient to exert a therapeutically useful effect m the absence of undesirable side effects on the patient treated The therapeutically effective concentration may be determined empirically by testing the compounds in known vitro and in vivo model systems for the treated disorder The compositions can be enclosed in ampoules, disposable synnges or multiple or single dose vials made of glass, plastic or other suitable matenal Such enclosed compositions can be provided m kits 10 The concentration of active compound in the drug composition will depend on absorption, mactivation and excretion rates of the active compound, the dosage schedule, and amount administered as well as other factors known to those of skill in the art l ^ The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at intervals of time It is understood that the precise dosage and duration of treatment is a function of the disease being treated and may be determined empincally using known testing protocols or by extrapolation from in vivo or in vitro test data It is to be noted that concentrations and dosage values may also vary 0 with the seventy of the condition to be alleviated It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person admmistenng or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the 5 claimed compositions If oral administration is desired, the compound should be provided in a composition that protects it from the acidic environment of the stomach For example, the composition can be formulated in an enteric coating that maintains its mtegnty in the stomach and releases 0 the activ e compound in the intestine The composition may also be formulated in combination with an antacid or other such ingredient Oral compositions will generally include an inert diluent or an edible carrier and may be compressed into tablets or enclosed in gelatin capsules. For the purpose of oral therapeutic administration, the active compound or compounds can be incoφorated with excipients and used in the form of tablets, capsules or troches. Pharmaceutically compatible binding agents and adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as, but not limited to, gum tragacanth. acacia, corn starch or gelatin; an excipient such as microcrystallme cellulose, starch and lactose, a disintegrating agent such as, but not limited to, alginic acid and corn starch; a lubricant such as, but not limited to, magnesium stearate; a gildant, such as, but not limited to, colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; and a flavoring agent such as peppermint, methyl salicylate, and fruit flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar and other enteric agents. The compounds can also be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The active materials can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include any of the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc. or a synthetic fatty vehicle like ethyl oleate or the like, polyethylene glycol, glycerine, propylene glycol or other synthetic solvent; antimicrobial agents, such as benzyl alcohol and methyl parabens; antioxidants, such as ascorbic acid and sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid (EDTA); buffers, such as acetates, citrates and phosphates, and agents for the adjustment of tomcity such as sodium chlonde or dextrose Parenteral preparations can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass, plastic or other suitable material Buffers, preservatives, antioxidants and the like can be incoφorated as required If administered intravenously, suitable earners include physiological saline or phosphate buffered saline (PBS), and solutions containing thickening and solubilizing agents, such as glucose, polyethylene glycol, and polypropyleneglycol and mixtures thereof Liposomal suspensions, including tissue-targeted hposomes, may also be suitable as pharmaceutically acceptable earners These may be prepared according to methods known to those skilled in the art For example, hposome formulations may be prepared as described m U S Pat No 4.522.811 The active compounds may be prepared with earners that protect the compound against rapid elimination from the body, such as time release formulations or coatings. Such earners include controlled release formulations, such as, but not limited to, implants and microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as collagen, ethylene vinyl acetate, polyanhydndes, polyglycohc acid, polyorthoesters, polylactic acid and others Methods for preparation of such formulations are known to those skilled in the art While this invention has been descnbed with respect to vanous specific examples and embodiments, it is to be understood that the invention is not limited thereby and should only be construed by mteφretation of the scope of the appended claims

Claims: Claims We claim: 1 ) A compound of formula 1 Formula 1 wherein A is a straight or branched chain alkanoxy or alkenoxy of 1 to 5 carbon atoms, aryl, arylalkyl. the aryl being optionally substituted with 1 to 2 carbon atoms or halogen, adamantyloxy, or 4-aminobutanoic acid; B is selected from the group consisting of hydroxy, wherein a dithered line represents a point of attachment at B of formula 1 ; D is H or an oxo group; L is a 5 or 6 membered saturated, unsaturated or aromatic heterocycle having from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur, or a saturated, unsaturated or aromatic carbocycle of 3 to 6 carbon atoms, any group represented by L having optional substitution with R', OR', or halogen, Q is a bond, or is a straight chain linking group of 1 to 3 non-hydrogen atoms chosen from the group consisting of-CH 2 -, -O-, and -NH- wherein O and N may not be adjacent, nng M is a stable 5 to 7-membered saturated, unsaturated or aromatic heterocycle having up to 2 additional N atoms and optionally having 1 to 2 atoms of O and S, T is independently selected from the group consisting of H, OH, NO 2 , C(O)N(R) 2 , F, Ci-Ci alkoxy, hydroxymethyl and CF 3 , wherein at least one T is other than H, x is an integer of 1 to 3, y is an integer of 1 to 6, R' is independently H, -OH, Ci-C 2 alkyl or phenyl, R is independently H, Ci- C 4 alkyl, or phenyl, and E is H, or Ci-C 2 alkyl, R] is Ci-Cs alkyl; R 2 is 2-propyl, l-(2- methylpropyl)- or phenyl optionally substituted with R', OR' or halogen, Ri is phenyl, CpCs alkyl, or l-(2-methylthιo-)ethyl-, R is 2-propyl, 2-butyl or 2-methylpropyl, and stereoisomers, hydrates and pharmaceutically acceptable salts and esters thereof 2) The compound of claim 1 wherem B is the group (1) wherem L is cyclohexane, x=0, z= 0 or 1, Q is -CH?- or a bond and E and R' are both H and R is H or C|-C alkyl 3) The compound of claim 2 wherem B is selected from the group consisting of 3,5- dicarboxycyclohexylamine, 3,4-dιcarboxycyclohexylamme and 2.4-dιcarboxycyclo- hexylamme and 2,5-dιcarboxycyclohexylamme 4) The compound of claim 1 wherem B is the group (1) wherein L is phenyl, x=l, z=0, Q is selected from a bond, -CH?- and -O-CH?-. R' is H and E is H or CH„ and R is H or d-X alkyl 5) The compound of claim 4 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid; 4-methylaminomethylbenzoic acid; 1 -amino- 1 -(4- carboxyphenyl)ethane; 2-aminomethylbenzoxyacetic acid; 2-aminobenzoic acid and 4-aminobenzoic acid. 6) The compound of claim 1 wherein B is the group (ii) wherein y is from 2 to 6 inclusive, z = 0 or 1 and R' and E are both H and R is H or C 1 - 5 alkyl. 7) The compound of claim 6 wherein B is selected from the group consisting of 4-aminobutanoic acid- 3-aminopropanoic acid and glutamic acid. 8) The compound of claim 1 wherein B is the group (v) wherein x = 1 and z = 0. 9) The compound of claim 8 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride. 10) The compound of claim 1 wherein B is the group (v) wherein ring M is a 6-membered heterocycle having 1 to 2 atoms of N, z = 0, Q is a bond or CH 2 and R is H or C 1 -C 5 alkyl. 11) The compound of claim 10 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid. 12) The compound of claim 1 wherein B is the group (iv) wherein L is phenyl and T is selected from the group consisting of H, OH, F, NO2, C(O)NH2, Ci-C? alkoxy and hydroxymethyl. 13) The compound of claim 12 wherein B is selected from the group consisting of 1 -amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethvlbenzene-4-carboxamide. 4? 14) The compound of claim 1 wherein B is selected from 2-ammomethylthιazole-5- carboxyhc acid and phenylglycine 15) The compound of claim 1 wherem B is selected from 3,5- dimethoxycyclo- ? hexylamine, 3,5-dιhydroxymethylcyclohexylamme and 3,4,5-tnmethoxycyclo- hexylamme 16) The compound of claim 1 wherein R \ is 2-propyl and R 2 is chosen from the group consisting of 2-methylpropyl and benzyl 0 17) The compound of claim 16 wherein B is the group (I) wherem L is cyclohexane, x=0, z= 0 or 1, Q is -CH 2 - or a bond and E and R' are both H and R is H or Ci-C? alkyl 18) The compound of claim 17 wherein B is selected from the group consisting of 3.5- 5 dicarboxycyclohexylamme, 3,4-dιcarboxycyclohexylamme and 2,4-dιcarboxycyclo- hexylamme and 2,5-dιcarboxycyclohexylamme 19) The compound of claim 16 wherem B is selected from the group consisting of 4-ammomethylbenzoιc acid, 4-methylammomethylbenzoιc acid 1 -ammo- 1 -(4- carboxyphenyl)ethane, 2-amιnomethylbenzoxyacetιc acid, 2-ammobenzoιc acid and 4-amιnobenzoιc acid 20) The compound of claim 16 wherem B is selected from the group consisting of 4-amιnobutanoιc acid- 3-ammopoφanoιc acid and glutamic acid 21) The compound of claim 16 wherem B is selected from the group consisting of 3-ammofuran-2-one and 2-amιnopentanedιoιc acid anhydnde 22) The compound of claim 16 wherein B is selected from the group consisting of 4-pιpendιneacetιc acid and pιperazme-4-carboxylιc acid 23) The compound of claim 16 wherem B is selected from the group consisting of 1 - amιno-2-(3-nιtro-4-hydroxyphenyl)ethane. 4-fluorobenzenamme. and ammomefhylbenzene-4-carboxamιde 24) The compound of claim 16 wherein B is selected from 2-aminomethylthiazole-5- carboxylic acid and phenylglycine. 25) The compound of claim 16 wherein B is selected from 3,5- dimethoxycyclo- hexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclo- hexylamine. 26) The compound of claim 1 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 27) The compound of claim 16 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 28) The compound of claim 17 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 29) The compound of claim 18 wherein R? is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 30) The compound of claim 19 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 31 ) The compound of claim 20 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 32) The compound of claim 21 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 33) The compound of claim 22 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 34) The compound of claim 23 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 35) The compound of claim 24 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 36) The compound of claim 25 wherem R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 37) The compound of claim 26 wherein Ri is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 38) A method of slowing the progression of a disease state charactenzed by deposition of Aβ peptide in a mammal compnsmg admmistenng to a mammal in need thereof an effective amount of a compound of Formula 1 wherem A is a straight or branched chain alkanoxy or alkenoxy of 1 to 5 carbon atoms, aryl, arylalkyl, the aryl being optionally substituted with 1 to 2 carbon atoms or halogen, adamantyloxy, or 4-ammobutanoιc acid, B is selected from the group consisting of hydroxy, wherem a dithered line represents a point of attachment at B of formula 1 , D is H or an oxo group; L is a 5 or 6 membered saturated, unsaturated or aromatic heterocycle having from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur, or a saturated, unsaturated or aromatic carbocycle of 3 to 6 carbon atoms, any group represented by L having optional substitution with R', OR', or halogen; Q is a bond, or is a straight chain linking group of 1 to 3 non-hydrogen atoms chosen from the group consisting of-CH 2 -, -O-, and -NH- wherem O and N may not be adjacent, nng M is a stable 5 to 7-membered saturated, unsaturated or aromatic heterocycle having up to 2 additional N atoms and optionally having 1 to 2 atoms of O and S, T is independently selected from the group consisting of H, OH, NO 2 , C(O)N(R) 2 , F, Cι-C 3 alkoxy, hydroxymefhyl and CF3, wherein at least one T is other than H, x is an integer of 1 to 3, y is an integer of 1 to 6, z is 0 (zero), 1 or 2, R' is independently H, -OH, Ci-C ? alkyl or phenyl, R is independently H, Ci- C alkyl, or phenyl, and E is H, or C]-C 2 alkyl, Rι is Ci-Cs alkyl, R is 2-propyl, l-(2- methylpropyl)- or phenyl optionally substituted with R', OR' or halogen, R 3 is phenyl, Ci-Cs alkyl, or l -(2-methylthιo-)ethyl-, R4 is 2-propyl, 2 -butyl or 2-methylpropyl, and stereoisomers, hydrates and pharmaceutically acceptable salts and esters thereof 39) The method of claim 38 wherein B is the group (1) wherem L is cyclohexane, x=0, z= 0 or 1, Q is -CH 2 - or a bond and E and R' are both H and R is H or Ci-C-, alkyl 40) The method of claim 39 wherein B is selected from the group consisting of 3,5- dicarboxycyclohexylamme, 3,4-dιcarboxycyclohexylamιne and 2,4-dιcarboxycyclo- hexylamine and 2,5-dιcarboxycyclohexylamιne 41) The method of claim 38 wherem B is the group (1) wherein L is phenyl, x=l, z=0, Q is selected from a bond, -CH 2 - and -O-CH 2 -, R' is H and E is H or CH 3 , and R is H or Ci-C- alkyl 42) The method of claim 41 wherem B is selected from the group consisting of 4-amιnomethylbenzoιc acid, 4-methylamιnomethylbenzoιc acid, 1 -amino- 1 -(4- carboxyphenyl)ethane, 2-amιnomethylbenzoxyacetιc acid, 2-ammobenzoιc acid and 4-ammobenzoιc acid 43) The method of claim 38 wherein B is the group (11) wherem y is from 2 to 6 inclusiv e, z = 0 or 1 and R' and E are both H and R is H or Ci -, alkyl 44) The method of claim 43 wherem B is selected from the group consisting of 4-amιnobutanoιc acid- 3-ammopropanoιc acid and glutamic acid 45) The method of claim 38 wherein B is the group (v) wherem x = 1 and z = 0 46) The method of claim 45 wherein B is selected from the group consisting of 3-amιnofuran-2-one and 2-amιnopentanedιoιc acid anhydnde 47) The method of claim 38 wherem B is the group (v) wherein nng M is a 6-membered heterocycle having 1 to 2 atoms of N, z = 0, Q is a bond or CH 2 and R is H or Ci-C-, alkyl 48) The method of claim 47 wherem B is selected from the group consisting of 4-pιpendmeacetιc acid and pιperazme-4-carboxyhc acid 49) The method of claim 38 wherem B is the group (iv) wherein L is phenyl and T is selected from the group consisting of H, OH, F, NO2, C(O)NH2 C]-C 2 alkoxy and hydroxym ethyl 50) The method of claim 49 wherem B is selected from the group consisting of 1-amιno- 2-(3-nιtro-4-hydroxyphenyl)ethane, 4-fluorobenzenamme, and ammomethylbenzene-4- carboxamide 51) The method of claim 38 wherem B is selected from 2-ammornefhylthιazole-5- carboxyhc acid and phenylglycine 52) The method of claim 38 wherem B is selected from 3,5- dimethoxycyclohexylamme, 3,5-dιhydroxymethylcyclohexylamιne and 3,4,5-tnmethoxycyclohexylamme 53) The method of claim 38 wherem Ri is 2-propyl and R 2 is chosen from the group consisting of 2-methylpropyl and benzyl 54) The method of claim 53 wherem B is the group (1) where L is cyclohexane, x=0, z= 0 or 1 , Q is -CH?- or a bond and E and R' are both H and R is H or -C-, alkyl 55) The method of claim 54 wherein B is selected from the group consisting of 3,5- dicarboxycyclohexylamine, 3,4-dιcarboxycyclohexylamme and 2,4-dιcarboxycyclo- hexylamme and 2,5-dιcarboxycyclohexylamme ? 56) The method of claim 53 wherem B is selected from the group consisting of 4-ammomethylbenzoιc acid, 4-methylammomethylbenzoιc acid 1 -ammo- 1 -(4- carboxyphenyl)ethane, 2-ammomethylbenzoxyacetιc acid, 2-ammobenzoιc acid and 4-amιnobenzoιc acid 0 57) The method of claim 53 wherem B is selected from the group consisting of 4-ammobutanoιc acid- 3-amιnopoφanoιc acid and glutamic acid 58) The method of claim 53 wherein B is selected from the group consisting of 3-ammofuran-2-one and 2-amιnopentanedιoιc acid anhydnde 5 59) The method of claim 53 wherem B is selected from the group consisting of 4-pιpendιneacetιc acid and pιperazιne-4-carboxyhc acid 60) The method of claim 53 wherem B is selected from the group consisting of 1-ammo- 2-(3-nιtro-4-hydroxyphenyl)ethane, 4-fluorobenzenamme, and amιnomethylbenzene-4- carboxamide 61) The method of claim 53 wherem B is selected from 2-ammomethylthιazole-5- carboxyhc acid and phenylglycine 62) The method of claim 53 wherem B is selected from 3,5- dimethoxycyclohexylamme, 3,5-dιhydroxymethylcyclohexylamme and 3,4,5-tnmethoxycyclohexylamme 63) The method of claim 38 wherem R is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 64) The method of claim 43 wherem R^ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 65) The method of claim 44 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 66) The method of claim 45 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 67) The method of claim 46 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 68) The method of claim 47 wherein R? is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 69) The method of claim 48 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 70) The method of claim 49 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 71) The method of claim 50 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 72) The method of claim 51 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 73) The method of claim 52 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 74) The method of claim 53 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 75) A pharmaceutical composition comprising a compound of formula 1 Formula 1 wherein A is a straight or branched chain alkanoxy or alkenoxy of 1 to 5 carbon atoms, aryl, arylalkyl, the aryl being optionally substituted with 1 to 2 carbon atoms or halogen, adamantyloxy, or 4-aminobutanoic acid; B is selected from the group consisting of hydroxy, wherein a dithered line represents a point of attachment at B of formula 1 ; D is H or an oxo group; L is a 5 or 6 membered saturated, unsaturated or aromatic heterocycle having from 1 to 3 heteroatoms chosen from nitrogen, oxygen and sulfur, or a saturated, unsaturated or aromatic carbocycle of 3 to 6 carbon atoms, any group represented by L having optional substitution with R', OR', or halogen; Q is a bond, or is a straight chain linking group of 1 to 3 non-hydrogen atoms chosen from the group consisting of -CH?-, -O-, and -NH- wherein O and N may not be adjacent; ring M is a stable 5 to 7-membered saturated, unsaturated or aromatic heterocycle having up to 2 additional N atoms and optionally having 1 to 2 atoms of O and S, T is independently selected from the group consisting of H, OH, NO 2 , C(O)N(R) 2 , F, C 1 -C 3 alkoxy, hydroxymethyl and CF 3 , wherein at least one T is other than H; x is an integer of 1 to 3, y is an integer of 1 to 6, z is 0 (zero), 1 or 2, R' is independently H, -OH, Ci-C 2 alkyl or phenyl, R is independently H, Ci- C 4 alkyl, or phenyl, and E is H, or CpC ? alkyl; Rι is C 1 -C 5 alkyl; R 2 is 2-propyl, l-(2- methylpropyl)- or phenyl optionally substituted with R', OR' or halogen; R 3 is phenyl, Cι-C alkyl, or l-(2-methylthio-)ethyl-; -R 4 is 2-propyl, 2-butyl or 2-methylpropyl; and hydrates, pharmaceutically acceptable salts and esters thereof and a pharmaceutically acceptable diluent. 76) The composition of claim 75 wherein B is the group (i) wherein L is cyclohexane, x=0, z= 0 or 1, Q is -CH 2 - or a bond and E and R' are both H and R is H or C]-C 5 alkyl. 77) The composition of claim 76 wherein B is selected from the group consisting of 3,5- dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclo- hexylamine and 2,5-dicarboxycyclohexylamine. 78) The composition of claim 75 wherein B is the group (i) wherein L is phenyl, x=l, z=0, Q is selected from a bond, -CH?- and -O-CH -, R' is H and E is H or CH 3 . and R is H or C1 -C 5 alkyl. 79) The composition of claim 78 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid; 4-methylaminomethylbenzoic acid; 1 -amino- 1 -(4- carboxyphenyl)ethane; 2-aminomethylbenzoxyacetic acid; 2-aminobenzoic acid and 4-aminobenzoic acid. 80) The composition of claim 75 wherein B is the group (ii) wherein y is from 2 to 6 inclusive, z = 0 or 1 and R' and E are both H and R is H or Cι_ > alkyl. 81) The composition of claim 80 wherein B is selected from the group consisting of 4-aminobutanoic acid- 3-aminopropanoic acid and glutamic acid. 82) The composition of claim 75 wherein B is the group (v) wherein x = 1 and z = 0. 83) The composition of claim 82 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride. 84) The composition of claim 75 wherein B is the group (v) wherein ring M is a 6-membered heterocycle having 1 to 2 atoms of N, z = 0, Q is a bond or CH 2 and R is H or C1-C5 alkyl. 85) The composition of claim 85 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid. 86) The composition of claim 75 wherein B is the group (iv) wherein L is phenyl and T is selected from the group consisting of H, OH, F, NO2, C(O)NH , C 1 -C 2 alkoxy and hydroxymethyl. 87) The composition of claim 86 wherein B is selected from the group consisting of l-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide. 88) The composition of claim 75 wherein B is selected from 2-ammomethylthιazole-5- carboxyhc acid and phenylglycine 89) The composition of claim 75 wherem B is selected from 3,5- dimethoxycyclo- hexylamme, 3,5-dιhydroxymethylcyclohexylamιne and 3,4,5-tnmethoxycyclo- hexylamine 90) The composition of claim 75 wherein is 2-propyl and R 2 is chosen from the group consisting of 2-methylpropyl and benzyl 91) The composition of claim 90 wherem B is the group (I) wherein L is cyclohexane, x=0, z= 0 or 1 , Q is -CH 2 - or a bond and E and R' are both H and R is H or C 1 -C 5 alkyl 92) The composition of claim 91 wherem B is selected from the group consisting of 3,5- dicarboxycyclohexylamme, 3,4-dιcarboxycyclohexylamιne and 2,4-dιcarboxycyclo- hexylamme and 2,5-dιcarboxycyclohexylamme 93) The composition of claim 90 wherem B is selected from the group consisting of 4-ammomethylbenzoιc acid, 4-methylammomethylbenzoιc acιdl-ammo-l-(4- carboxyphenyl)ethane, 2-ammomethylbenzoxyacetιc acid, 2-amιnobenzoιc acid and 4-ammobenzoιc acid 94) The composition of claim 90 wherem B is selected from the group consisting of 4-amιnobutanoιc acid- 3-ammopoφanoιc acid and glutamic acid 95) The composition of claim 90 wherem B is selected from the group consisting of 3-amιnofuran-2-one and 2-amιnopentanedιoιc acid anhydnde 96) The composition of claim 90 wherem B is selected from the group consisting of 4-pιpendιneacetιc acid and pιperazme-4-carboxylιc acid 97) The composition of claim 90 wherem B is selected from the group consisting of 1- amιno-2-(3-nιtro-4-hydroxyphenyl)ethane, 4-fluorobenzenamιne. and ammomethylbenzene-4-carboxamιde 98) The composition of claim 90 wherein B is selected from 2-amιnomethylthιazole-5- carboxyhc acid and phenylglycine ι 99) The composition of claim 90 wherem B is selected from 3,5- dimethoxycyclohexylamme, 3,5-dιhydroxymethylcyclohexylamme and 3,4,5-tnmethoxycyclo- hexylamine 100) The composition of claim 75 wherein R 3 is selected from the group consisting of 0 phenyl and 2-methylthioethyl and R4 is 2-propyl 101) The composition of claim 90 wherein R3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 5 102) The composition of claim 91 wherein Ri is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 103) The composition of claim 92 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 0 104) The composition of claim 93 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 105) The composition of claim 94 wherein R is selected from the group consisting of 5 phenyl and 2-methylthioethyl and R4 is 2-propyl 106) The composition of claim 95 wherein R is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 0 107) The composition of claim 96 where R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 108) The composition of claim 97 wherem R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 109) The composition of claim 98 wherein Ri is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl 110) The composition of claim 99 wherein R 3 is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl. 111) The composition of claim 100 wherein R is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

Inventors: FANG LAWRENCE, JOHN VARGHESE, MAMO SHUMEYE S, TUNG JAY, FANG, LAWRENCE, JOHN, VARGHESE, MAMO, SHUMEYE, S., TUNG, JAY
Applicants: ELAN PHARM INC, ELAN PHARMACEUTICALS, INC.
Application year: 2000
Main classification: C07K5
IPC codes: A61K38, A61P25, A61P43, C07K5, C07K7