ENDOTHELIN CONVERTING ENZYME INHIBITORS

Abstract: Compounds are disclosed which inhibit endothelin converting enzyme. These compounds are useful for treating hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma and atherosclerosis.

Description: ENDOTHELIN CONVERTING ENZYME INHIBITORS This is a continuation-in-part of U.S. Patent Application Serial No. 649,649, filed January 31, 1991. Technical Field The present invention relates to compounds and compositions which inhibit endothelin converting enzyme (ECE) , processes for making such compounds, synthetic intermediates employed in these processes and methods for suppressing endothelin production, treating hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin-induced toxicity, asthma and atherosclerosis with such compounds. Background Art Endothelin (ET) is a 21 amino acid peptide that is produced by endothelial cells. ET is produced by enzymatic cleavage of a Trp-Val bond in the precursor peptide big endothelin (Big ET) . This cleavage is caused by an endothelin converting enzyme (ECE) . Endothelin has been shown to constrict arteries and veins, increase mean arterial blood pressure, decrease cardiac output, increase cardiac contractility in vitro, stimulate mitogenesis in vascular smooth muscle cells in vitro, contract non- vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in. vitro . increase airway resistance in vivo- induce formation of gastric ulcers, stimulate release of atrial natriuretic factor in vitro and in vivo f increase plasma levels of vasopressin, aldosterone and catecholamines, inhibit release of renin in vitro and stimulate release of gonadotropins in vitro. An agent which suppresses endothelin production or an agent which binds to endothelin would be expected to produce beneficial effects in a variety of therapeutic areas. In fact, an anti-endothelin antibody has been shown, upon intrarenal infusion, to ameliorate the adverse effects of renal ischemia on renal vascular resistance and glomerular filtration rate (Kon, et al., J. Clin. Invest. £2. 1762 (1989)) . In addition, an anti-endothelin antibody attenuated the nephrotoxic effects of intravenously administered cyclosporin (Kon, et al.. Kidney Int. 2 L 1487 (1990) ) and attenuated infarct size in a coronary artery ligation-induced myocardial infarction model ( atanabe, et al.. Nature 2Δ 114 (1990)) . An endothelin converting enzyme has been reported which can be inhibited by pepstatin A (Wu- ong, et al., Biochem. Biophys. Res. Commun. 171 1291 (1990)) . However, no other inhibitors of this endothelin converting enzyme are known. Disclosure of the Invention In accordance with the present invention there are endothelin converting enzyme inhibiting compounds of the formula (I) : wherein A is hydrogen, an N-protecting group or RχNHCH(R2)C (0) - wherein Ri is H or an N-protecting group and R2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ 2 C(CH 2 ) n C(0)- wherein n is 1 to 3; B is -N(R 4 )CH (R3)C(0) - wherein R is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R5)CH(R6)C(0)- wherein R5 is hydrogen or loweralkyl and Rβ is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; X is -CH2- or -C(0)-; D is 1) -OR7 wherein R 7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) -NR8R9 wherein R_ and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2)m -z wherein m is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO2R10 wherein Rio is hydrogen or loweralkyl or Z is - R11R12 wherein Rn and R12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri3)C(0)- wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Ri3)C(0)NHCH(Rι 4 )C(0)- wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R14 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR15 wherein R15 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) -NR16R17 wherein R16 and R17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2) -Y wherein p is 2 to 8 and Y is -OH, heterocyclic, -S03H, -CO2R18 wherein Riβ is hydrogen or loweralkyl or Y is -NR19R20 wherein R19 and R20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. In accordance with the present invention there are also endothelin converting enzyme inhibiting compounds of the formula (II) : wherein A is hydrogen, an N-protecting group, RiNHCH (R 2 )C (0) - wherein Ri is H or an N-protecting group and R2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ2C(CH2) n C(0)- wherein n is 1 to ' 3; B is -N(R 4 )CH(R3) C (0) - wherein R 4 is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R 5 ) CH (Rβ)C(0) - wherein R 5 is hydrogen or loweralkyl and Rβ is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; P 4 is hydrogen, loweralkyl or benzyl; X is -CH2- or -C(0)-; D is 1) -OR7 wherein R7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) -NRβRg wherein RQ and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2)m~Z wherein m is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO2R10 wherein Rio is hydrogen or loweralkyl or Z is -NR11R12 wherein Rn and R12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri3)C(0) - wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Rι 3 )C(0)NHCH(R 14 )C(0)- wherein R 13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R14 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR15 wherein R15 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) -NRιgRi7 wherein Rig and R17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2)p-Y wherein p is 2 to 8 and Y is -OH, heterocyclic, -SO3H, -CO2R18 wherein Rig is hydrogen or loweralkyl or Y is -NR19R20 wherein R19 and R20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. In accordance with the present invention there are also endothelin converting enzyme inhibiting compounds of the formula (III) : wherein A is hydrogen, an N-protecting group, R l NHCH (R2)C(0) - wherein R is H or an N-protecting group and R2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, alkoxycarbonylalkyl or arylalkoxycarbonylalkyl; or A is HO2C (CH2) n (0) - wherein n is 1 to 3; or A is Rι a C (0) - or Rι a S(0)2- wherein Rι a is heterocyclic; or A is (aminoalkyl) (alkyl)aminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, (dialkylaminoalkyl) (alkyl)aminocarbonyl, (aminoalkyl) (alkyl)aminosulfonyl, (alkylaminoalkyl) (alkyl)aminosulfonyl, (dialkylaminoalkyl) (alkyl)aminosulfonyl, (heterocyclicalkyl) (alkyl)aminocarbonyl or (heterocyclicalkyl) (alkyl)aminosulfonyl; B is -N(R 4 )CH (R 3 )C(0)- wherein R 4 is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R5)CH(Rg)C(0)- wherein R5 is hydrogen or loweralkyl and Rζ is loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; and R 21 is loweralkyl, cycloalkyl or cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. The chiral centers of the compounds of the invention can be racemic or asymmetric. Racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention are included in the present invention. The terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30. The terms "Ala", "Asn", "Asp", "lie" and "Val" as used herein refer to alanine, asparagine, aspartic acid, isoleucine and valine, respectively. In general, the amino acid abbreviations used herein follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature for amino acids and peptides (Eur. J. Biochem. 1984, lϋS., 9-31) . The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981)), which is hereby incorporated by reference. N-protecting groups comprise carbamates, amides, N-alkyl derivatives, amino acetal derivatives, N-benzyl derivatives, imine derivatives, enamine derivatives and N-heteroatom derivatives . In particular, N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) , benzyloxycarbonyl (Cbz) and the like. N-protecting groups also include an L- or D- aminoacyl residue, which can itself be N-protected. The term "O-protecting group" as used herein refers to a substituent which protects hydroxyl groups against undesirable reactions during synthetic procedures such as those O-protecting groups disclosed in Greene, "Protective Groups In Organic Synthesis," (John Wiley & Sons, New York (1981) ) . O-protecting groups comprise substituted methyl ethers, for example, methoxymethyl, 'benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, t-butyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; substituted ethyl ethers, for example, 2,2,2- trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like. The term "loweralkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, t-butyl, n-pentyl, 1-methylbutyl, 2,2- dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl and the like. The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring system having one or more aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and the like. Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, carboalkoxy and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The term "arylalkyl" as used herein refers to an aryl group appended to a loweralkyl radical, for example, benzyl and the like. The term "cycloalkyl" as used herein refers to an aliphatic ring having 3 to 7 carbon 'atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl and the like. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl. The term "carboxyalkyl" as used herein refers to a loweralkyl radical to which is appended a carboxyl (-COOH) group. The term "alkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an alkoxycarbonyl group (i.e., -C(0)OR3o wherein R30 is loweralkyl) . The term "arylalkoxycarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended an arylalkoxycarbonyl group (i.e., -C(0)ORso wherein R 50 is an arylalkyl group) . The term "aminocarbonylalkyl" as used herein refers to a loweralkyl radical to which is appended -C(0)NH 2 . The term "cyanoalkyl" as used herein refers to a loweralkyl radical to which is appended a cyano group (-CN) . The term "alkylamino" as used herein refers to R 51 NH- wherein R 51 is a loweralkyl group. The term "dialkylamino" as used herein refers to R 52 R 53 N- wherein R 52 and R 53 are independently selected from loweralkyl. The term "aminoalkyl" as used herein refers to a loweralkyl radical to which is appended an amino group <-NH 2 ) . The term "alkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended an alkylamino group. The term "dialkylaminoalkyl" as used herein refers to a loweralkyl radical to which is appended a dialkylamino grou . The term " (aminoalkyl) (alkyl)aminocarbonyl" as used herein refers to R 54 R 55 NC(0)- wherein R 54 is an aminoalkyl group and R 55 is a loweralkyl group. The term "(aminoalkyl) (alkyl)aminosulfonyl" as used herein refers to R 54 R 55 NS(0) _- wherein R 54 is an aminoalkyl group and R 55 is a loweralkyl group. The term "(alkylaminoalkyl) (alkyl)aminocarbonyl" as used herein refers to Rs Rs 7 NC(0) - wherein Rsg is an alkylaminoalkyl group and R 57 is a loweralkyl group. The term " (alkylaminoalkyl) (alkyl) aminosulfonyl" as used herein refers to Rs Rs 7 NS (0) 2 ~ wherein Rs is an alkylaminoalkyl group and R5 7 is a loweralkyl group. The term " (dialkylaminoalkyl) (alkyl) minocarbonyl" as used herein refers to R5 8 R5 9 NC(0) - wherein R 5 8 is a dialkylaminoalkyl group and Rs is a loweralkyl group. The term " (dialkylaminoalkyl) (alkyl)aminosulfonyl" as used herein refers to R 5 8R59NS(0) 2 ~ wherein R58 is a dialkylaminoalkyl group and R 5 9 is a loweralkyl group. The term " (heterocyclicalkyl) (alkyl)aminocarbonyl" as used herein refers to RgoRgiNC(0) - wherein Rgo is a heterocyclicalkyl group and Rgi is a loweralkyl group. The term "(heterocyclicalkyl) (alkyl)aminosulfonyl" as used herein refers to RgoRgiNS (0) _~ wherein Rgo is a heterocyclicalkyl group and Rgi is a loweralkyl group. The term "heterocyclic ring" or "heterocyclic" as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5- or 6-membered ring containing one, two or three nitrogen atoms; one nitrogen and one sulfur atom; or one nitrogen and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds . The nitrogen heteroatoms can be optionally quaternized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like) . Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl. Heterocyclics can be unsubstituted or monosubstituted or disubstituted with substituents independently selected from hydroxy, halo, oxo (=0) , alkylimino (R*N= wherein R* is a loweralkyl group) , amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl, cycloalkyl, aryl, arylalkyl, -COOH, -SO3H and loweralkyl. In addition, nitrogen containing heterocycles can be N-protected. The term "heterocyclicalkyl" as used herein refers to heterocyclic group appended to a loweralkyl radical. Representative compounds of the invention include: N-{ (S)-2-[ (tert-Butyloxycarbonyl)amino]-3,3- dimethylbutanoyl}-Isoleucyl-Statyl Ethyl ester; N-{ (S) -2- [ (tert-Butyloxycarbonyl)amino]-3,3- dimethylbutanoyl}-Isoleucyl-Statyl-OH; N-{ (S)-2-[ (tert-Butyloxycarbonyl)amino]-2- cyclohexylacetyl}-Isoleucyl-Statyl Ethyl ester; N-{ (S)-2-[ (tert-Butyloxycarbonyl)amino]-2- cyclohexylacetyl}-Isoleucyl-Statyl-OH; N-Boc-Isoleucyl-Isoleucyl-Statyl Carboxamide; N-Boc-Isoleucyl-Isoleucyl-Statyl (4- Hydroxybutyl) carboxamide; N-Boc-Isoleucyl-Isoleucyl-Statyl (5- Hydroxyamyl) carboxamide; N-Boc-Isoleucyl-Isoleucyl-Statyl (6- Hydroxyhexyl) carboxamide; [1-[ (N-Cbz-Isoleucyl-Isoleucyl) mino]-3- methybutyl (methoxy)phosphinyl]acetic acid tert-Butyl ester; N-Boc-Isoleucyl-Isoleucyl-Statyl-OH; N-Succinyl-Isoleucyl-Isoleucyl-Statyl-Valyl-OH; N-Boc-Cyclohexylalanyl-Isoleucyl-Statyl Ethyl ester; N-Boc-Isoleucyl-Isoleucyl-Statyl-β-Alanyl Ethyl ester; N-Boc-Isoleucyl-Isoleucyl-Statyl Isobutylcarboxamide; N-Boc-Cyclohexylalanyl-Isoleucyl-Statyl-OH; N-Boc-Isoleucyl-Isoleucyl-Statyl-β—Alanyl-OH; N-Boc-Isoleucyl-Isoleucyl-Tryptophanyl Carboxaldehyde; (4S)-4-(N-Boc-Isoleucyl-Isoleucyl-Amino)-5-(3-indolyl) -3- hydroxypentanoic acid; (4S)-4-(N-Succinyl-Isoleucyl-Isoleucyl-Amino)-5-(3- indolyl) -3-hydroxypentanoic acid Ethyl ester; N-[ (4S) -4-(N-Boc-Isoleucyl-Isoleucyl-Amino) -5- (3-indolyl) - 3-hydroxyρentanoyl]-Valyl-OH; N-[ (4S)-4-(N-Boc-Aspartyl-Isoleucyl-Isoleucyl-Amino) -5-(3- indolyl)-3-hydroxypentanoyl]-Valyl-OH; (4S)-4-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-5-(3- indolyl)-3-hydroxypentanoic acid; N-[ (4S)-4-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-5-(3- indolyl)-3-hydroxypentanoyl]-Valyl-OH; (2S,3R,4S)-2-(N-Boc-Isoleucyl-Isoleucyl-Amino) -1- cyclohexyl-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-(N-Succinyl-Isoleucyl-Isoleucyl-Amino) -1- cyclohexyl-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-(N-Boc-Aspartyl(β-O-Benzyl)-Isoleucyl- Isoleucyl-Amino)-l-cyclohexyl-3,4-dihydroxy-6- methylheptane; (2S,3R,4S)-2-(N-Acetyl-Isoleucyl-Isoleucyl-Amino)-1- cyclohexyl-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-1- cyclohexyl-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-(N-Boc-Isoleucyl-Isoleucyl-Amino) -1-(2- naphthyl)-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-1- (2-naphthyl)-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-1- (1-naphthyl)-3,4-dihydroxy-6-methylheptane; N-Boc-Isoleucyl-Isoleucyl-Statyl Isopropylcarboxamide; [1-[N-Cbz-Isoleucyl-Isoleucyl-Amino]-3- methylbutyl(hydroxy)phosphinyl]acetic acid tert-Butyl ester; N-Boc-Isoleucyl-Isoleucyl-Statyl Isoamylcarboxamide; N-Boc-Isoleucyl-Isoleucyl-Statyl Cyclohexylmethylcarboxamide; [1-[N-(N-Cbz-[ (S)-2-Amino-3,3-dimethylbutanoyl] )- Isoleucyl-Amino]-3-methylbutyl(hydroxy)phosphinyl]acetic acid tert-Butyl ester; [1-[N-Cbz-Isoleucyl-Isoleucyl-Amino]-3- methylbutyl(hydroxy)phosphinyl]acetyl Isobutylcarboxarrd.de; (2S,3R,4S)-2-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-1- (3-indolyl)-3,4-dihydroxy-6-methylheptane; N-Boc-Cyclohexylalanyl-Isoleucyl-Statyl Isobutylcarboxamide; N-Boc-Cyclohexylalanyl-Isoleucyl-Statyl N-(2-(2- Pyridyl)ethyl)Carboxamide; N-Boc-Cyclohexylalanyl-Isoleucyl-Statyl N- (2-N' ,N'- Dimethylaminoethyl)Carboxamide; N-Boc-Cyclohexylalanyl-Isoleucyl-Statyl N-(2-(Morpholin- 4-yl)ethyl)Carboxamide; (2S,3R,4S)-2-{ [N- (4-Methylpiperazin-l-yl-carbonyl)- Cyclohexylalanyl-Isoleucyl]amino}-l-(2-naphthyl) -3, 4- dihydroxy-6-methylheptane Hydrochloride; N-Boc-tert-Butylalanyl-Isoleucyl-Statyl-OEt; N-Boc-tert-Butylalanyl-Isoleucyl-Statyl-OH; (2S,3R,4S)-2-{ [N-Boc-Asρartyl(β-0-Benzyl)-Isoleucyl- Isoleucyl]amino}-l-(2-naphthyl)-3,4-dihydroxy-6- methylheptane; N-Boc-Isoleucyl-Isoleucyl-Statyl N-(2-(2- Pyridyl)ethyl)Carboxamide; (2S,3R,4S)-2-{ [N-Succinyl-Cyclohexylalanyl- Isoleucyl]amino}-l-(2-naphthyl)-3,4-dihydroxy-6- methylheptane; (2S,3R,4S)-2-{ [N-Boc-Cyclohexylalanyl-Isoleucyl]amino}- 1-(4-tert-butylphenyl)-3,4-dihydroxy-6-methylheptane; (2S,3R,4S)-2-{ [N-Acetyl-Cyclohexylalanyl- Isoleucyl]amino}-l-(4-tert-butylphenyl)-3,4-dihydroxy-6- meth lheptane; (2S,3R,4S)-2-{ [N-Acetyl-Cyclohexylalanyl- Isoleucyl]amino}-l-(2-naphthyl)-3,4-dihydroxy-6- methylheptane; N-Boc-Isoleucyl-Isoleucyl-Statyl N-Methyl-N- IsobutylCarboxamide; (2S,3R,4S)-2-{ [N-(Morpholin-1-yl-carbonyl)- Cyclohexylalanyl-Isoleucyl]amino}-l-(2-naphthyl)-3,4- dihydroxy-6-methylheptane; (2S,3R,4S)-2-{ [{N-(N,N-Dimethylaminoethyl)-N- methylamino}carbonyl-Cyclohexylalanyl-Isoleucyl]amino}- 1-(2-naphthyl)-3,4-dihydroxy-6-methylheptane; and (2S,3R,4S)-2-{ [N-(4-Methylpiperazin-l-yl-sulfonyl)- Cyclohexylalanyl-Isoleucyl]amino}-l-(2-naphthyl)-3,4- dihydroxy-6-methylheptane. The compounds of the invention can be prepared as shown in Schemes I-VII. Throughout the schemes, substituents A, B, C, D, E, X, R, Ri, R 2 , etc., are as defined herein-above. The general synthetic approach is depicted in Scheme I. The free amine or hydrochloride salt (which has been converted to its free base in situ) of the C-terminal residue 1 is coupled with the appropriately N-protected amino acid 2. through its carboxylic acid moiety using standard peptide coupling methods. The N-protecting group on the coupled product 2. is removed, and the residue is converted to its free base either in a separate step or in situ . The deprotected residue is then coupled to the carboxylic acid of an appropriately N-protected amino acid A using standard peptide coupling methods. Finally, peptide ϋ can converted to I (A is hydrogen, RiNHCH(R 2 )C(0)- or HO 2 C(CH 2 ) n C(0)-) by removal of the protecting group, optionally followed by coupling of the RiNHCH(R 2 )C(0)- or H0 2 C(CH 2 ) n C(0)- group. Alternatively, the process can begin at the the N- terminal end of the molecule. Thus, the carboxylic acid moiety of N-protected amino acid (wherein A is an N- protecting group or RiNHCH(R 2 )C(0)-) is coupled with 2. to provide peptide 2. (R 40 s loweralkyl or benzyl) . The ester 2. is converted to the carboxylic acid by hydrolysis or catalytic hydrogenation. The carboxylic acid derived from 2. is then coupled to 1 to provide I. In this alternative method when A is Hθ 2 C(CH 2 ) n C(0)-, this substitutent (i.e., A) is introduced during the last step of the sequence. The synthesis of statine and statine derivatives 1 is illustrated in Scheme II. The appropriate N-protected amino acid . is converted to its 3,5-dimethylpyrazolide using 3,5-dimethypyrazole and 1-hydroxybenzotriazole and l-(dimethylamino-propyl)-3-ethylcar-bodiimide or other appropriate coupling conditions and catalysts. The resultant pyrazolide 2. is reduced with lithium aluminum hydride or other appropriate reducing agent to give the amino acid carboxaldehyde Ul. The enol ether of an alkyl acetate (such as ethyl acetate) , prepared using lithium hexamethyldisilazide or other appropriate base, is reacted with the aldehyde to give the β-hydroxy ester ϋ. Hydroxy ester U can be further elaborated to provide 1. Compounds i wherein X is CH 2 are obtained via the acid derived from ester H. Hydrolysis of H provides the free acid which is converted to the 3,5- dimethylpyrazolide 11a as previously described. Reduction using lithium aluminum hydride or similar reducing agent provides the aldehyde lib. The aldehyde is reductively aminated with ReNH-E to provide ll£, which can be further elaborated to provide 1. The synthesis of the phosphorus derivatives of statine or statine derivatives 2Λ is shown in Scheme III. Derivatives of [ (benzyloxycarbonyl)amino-1- substituted(methoxy)-phosphinyl]acetic acid ester 12 ( 4 is loweralkyl, R 41 is loweralkyl) can be prepared as described in the literature: Bartlett, P. A.; Kezer, W. B.; J. Am. Chem. Soc, 106. 4282 (1984). N-deprotection and dealkylation of the phosphinic acid (for example, using potassium cyanide and 1,4,7,10,13,16- hexaoxacyclooctadecane in dimethyl sulfoxide) provides 12.. Compound 12. can also be elaborated to derivative 14., which can then be elaborated to the compounds of the invention II using the general methods outlined in Scheme I. Scheme IV illustrates the synthesis of 2-amino-l- substituted-3,4-dihydroxy-alkanes 12 and is based on a literature procedure (Luly, J. R.; Hsiao, C. N.; Ba aung, N.; Plattner, J. J.; J. Org. Chem. Jϋ, 6109 (1988)). The amino acid . is N-protected using di-tert-butyl- dicarbonate or some other N-protecting group to give 15. The carboxylic acid l≤. is reduced using borane- tetrahydrofuran complex or other appropriate reducing agent to give the alcohol 1£.Using appropriate oxidizing conditions such as oxalyl chloride/dimethyl sulfoxide/methylene chloride, followed by triethylamine, the intermediate aldehyde is obtained. Trimethylsilyl cyanide and zinc iodide treatment yields the trimethylsilyl cyanohydrin, which upon reaction with a Grignard reagent R 2 iMgCl (such as isobutylmagnesium chloride) affords the hydroxy ketone 11. Reduction using sodium borohydride or other appropriate reducing agent provides the diol IB.. Removal of the N-protecting group provides the amino-diol 19, which can be elaborated to the compounds of the invention III using the general methods outlined in Scheme I. Scheme V illustrates an alternative synthesis of 18. Reduction of ester 25. (R* is loweralkyl and the like) , for example, with sodium borohydride, provides 1£. Oxidation (for example, Swern oxidation) , followed by reaction with the appropriate Wittig reagent (for example, Ph.3P + CH2R2i Br~/KOtBu in dimethyformamide or P 3P + CH2 2i Br~/potassium hexamethydisilazide in tetrahydrofuran) provides olefin 26. Oxidation (for example, Osθ 4 /N-methylmorpholine N- oxide) , followed by purification (for example, recrystallization) , gives IS.. Scheme VI illustrates an alternative preparation of 19 wherein R2 1 is isobutyl. D-Isoascorbic acid 21 can be converted to the known lactol 2J3L (J.Am.Chem.Soc. 105 3661 (1983)). Reaction with Ph3P=CH(CH 3 ) 2 provides 2D.- Oxidation to aldehyde .21, followed sequentially by reaction with benzylamine and a Grignard reagent (i.e., RCH 2 MgBr/CeCl3) gives amine 22.. Deprotection of the amino group, reduction of the olefin and removal of the acetonide protecting group provides 12. wherein R2 1 is isobutyl. An alternative preparation of the reduced form of compound 2 (i.e., 22.) is shown in Scheme VII. Epoxyalco ol 34 (J.Am.Chem.Soc. 109 1525 (1987)) is protected and then reacted with isopropyl Grignard to give 35. Reaction with camphorsulfonic acid (CSA) , followed by ozonolysis, gives the aldehyde 22.- Compound 22. ca be converted to 12. by adapting the procedure outlined in Scheme VI . Scheme I P-NH^A 0H 2. I SCHEME II SCHEME III 11 SCHEME IV ιa 18 12 111 SCHEME V P s N-ProtβctIng dation tig reaction 1ft _\_\ Scheme VI 1. H 2_a 2_Ω 2_1 R 2 ι=isobutyl Bn « benzyl 2_2 Scheme VII Compounds useful as intermediates for the preparation of compounds of the formula (I) include compounds of the formula : wherein Pi is hydrogen or an N-protecting group; P 2 is hydrogen or an O-protecting group; and R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; or an ester, acid halide or activated ester derivative thereof. Compounds useful as intermediates for the preparation of compounds of the formula (II) include compounds of the formula: wherein Pi is hydrogen or an N-protecting group; P 4 is hydrogen, loweralkyl or benzyl; and R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; or an ester, acid halide or activated ester derivative thereof. Compounds useful as intermediates for the preparation of compounds of the formula (III) include compounds of the formula: wherein Pi is hydrogen or an N-protecting group; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; P 2 and P 3 are independently selected from hydrogen and an O-protecting group; and R 21 is loweralkyl, cycloalkyl or cycloalkylalkyl; or a salt thereof. The following examples will serve to further illustrate the preparation of the compounds of the invention. Example 1 N-f (Si -2- r ^erfr-Bu yloxycarbonyli aπ nol -3.3- dimethylbut.anoyll-Iaoleueyl-St-.at-.yl Ethyl ester Example la Boc-Leucyl- T3.5-dimethylpyrazolidel To Boc-Leu-OH monohydrate (25 g, 0.10 mol) , 3,5- dimethyl pyrazole (DMP) (11.6 g, 0.'12 mol), and 1- hydroxybenzotriazole hydrate (HOBT) (16.2 g, 0.12 mol) combined in methylene chloride (CH 2 C1 2 ) (550 mL) and cooled to 2 °C was added 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (21.4 g, 0.11 mol). The reaction mixture was allowed to warm to room temperature, stirred overnight, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (EtOAc) and washed with I H3PO4. The aqueous washes were back extracted with EtOAc and the combined EtOAc extracts were washed with 1 N H 3 PO 4 (2x) , saturated NaHC0 3 (3x) , and brine, dried (Na 2 S0 4 ), and concentrated in vacuo to afford the title compound as a white solid. The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS(DCI/NH 3 ) m/e 310 (M+H) + . Example lb Boc-Leucinal To the product of Example la (25 g, 81 mmol) dissolved in anhydrous tetrahydrofuran (THF) (350 mL) and cooled to -78 °C was added lithium aluminum hydride (LAH) (5 g, 132 mmol) in 5 portions over 70 minutes. Following the addition, the reaction mixture was maintained at -78 °C for an additional 60 minutes and then carefully poured with vigorous stirring into 10% citric acid (1200 mL) . This mixture was extracted with diethyl ether (Et 2 θ) (3x500 mL) and the combined organic extracts were washed with brine, dried (MgSθ 4 ) , and concentrated in vacuo to give a tacky residue. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS(DCI/NH 3 ) m/e 216 (M+H) + . Example lc Boc-Staty Ethyl ester Ethyl acetate, which had been dried by refluxing overnight over CaH 2 and distilled, (14 mL, 0.143 mol) was added to freshly distilled THF (450 mL) and cooled to -78 °C. A lΛf solution of lithium hexamethyldisilazide (LHMDS) (120 mL) was added over 30 minutes under a N 2 atmosphere. After one hour at -78 °C, the product of Example lb (8.5 g, 0.039 mol) in freshly distilled THF (50 mL) was added, and the reaction mixture was stirred at -78 °C for 70 minutes and then quenched by addition to ltfHCl (700 mL). This mixture was extracted with Et 2 θ (2x400 mL) and the organic extracts washed with saturated NaHCθ 3 solution (2x) , brine, dried (MgSθ 4 ) , and concentrated in vacuo to afford 11.6 g of an orange oil. Flash chromatography on silica gel (350 g) eluting with 15% EtOAc in hexanes afforded 4.9 g of the title compound. MS (DCI/NH 3 ) m/e 304 (M+H) + . The 300 MHz l E NMR spectrum was found to be consistent with the proposed structure. Example Id Statyl Ethyl ester HC1 salt The product of Example lc (203 mg, 0.67 mmol) dissolved in 4W HC1 in dioxane (3 mL) was stirred at room temperature for 1 hour and then concentrated in vacuo to give the title product as an oil. MS (DCI/NH 3 ) m/e 204 (M+H) + of the free base. The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. Example le N-Bor.-Tsolenf.y1 -Statyl Ethyl ester To the product of Example Id (152 mg, 0.63 mmol) dissolved in CH 2 CI 2 (3 mL) was added N-methylmorpholine (NMM) (0.07 g, 0.70 mmol) and the reaction mixture cooled to 0 °C. Boc-Ile-OH hemihydrate (152 mg, 0.63 mmol) was added followed by 1-hydroxybenzotriazole (HOBT) and EDCI (134 mg, 0.70 mmol) . The reaction mixture was stirred at 0 °C and allowed to warm to room temperature overnight. The reaction mixture was diluted with EtOAc, washed with IN H 3 PO 4 (3x) , saturated NaHCθ 3 (3 χ ) r and brine, dried (Na 2 S0 ) , and concentrated in vacuo to give a solid. Recrystallization from hexane afforded the title compound as a white crystalline solid in 73% yield. The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 417 (M+H) + , 434 (M+H+NH 3 ) + . Example If Isoleucyl-Statyl Ethyl ester HC1 salt The product of Example le (200 g, 0.48 mmol) was deprotected as described in Example Id to afford an oil which was dissolved in H 2 O (15 mL) and lyophilized to give the title compound as a white amorphous solid (169 mg, 100%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (FAB+) m/e 304 (M+H) + . Example lςr (SI-2-r(tert-Butyloxycarbonyl)aminol-3.3-dimethvlbutanoic acid To L-t-Butylglycine (1.00 g, 7.6 mmol) dissolved in 1 N NaOH (9.5 mL) and THF (8 mL) was added di-t-butyl- dicarbonate (1.67 g, 7.6 mmol) in THF (1.5 mL) . The reaction mixture was stirred overnight at room temperature and extracted with hexanes (3x) . The combined organic extracts were washed with saturated NaHCθ 3 (2x) . The combined aqueous layers were adjusted to pH 2 with 1.1N NaHSθ 4 and back-extracted with Et 2 θ (3x) . The combined organic extracts were washed with brine, dried ( a2S04) , and concentrated in vacuo to give the title compound as an oil (1.70 g) which solidified on standing. MS (DCI/NH 3 ) m/e 232 (M+H) + , 249 (M+H+NH 3 )\ The 300 MHz X R NMR spectrum was found to be consistent with the proposed structure. F.xample lh N- US ) -2- r (tert-Butyloxycarbonyl ) aminol -3■ 3- dimethylbutanoyll-Isoleucyl-Statyl Ethyl ester The product of Example If (95 mg, 0.27 mmol) was partitioned between EtOAc (20 mL) and saturated NaHCθ 3 solution (30 mL) . The aqueous phase was extracted with additional EtOAc (2x10 mL) and the combined organic extracts were washed with brine, dried (Na 2 S0 4 ) , and concentrated in vacuo to afford the free base (80 mg, 94%) as a white powder. To the free base dissolved in CH 2 CI 2 (8 mL) and cooled to 0 °C was added Example lg (58 mg, 0.25 mmol) followed by HOBT (41 mg, 0.3 mmol) and EDCI (53 mg, 0.28 mmol) . The reaction mixture was allowed to warm to room temperature overnight. EtOAc was added and the mixture washed with IN H 3 PO 4 (3x) , saturated NaHC0 3 (3x) , and brine (2x) , dried (Na 2 Sθ 4 ) , and concentrated in vacuo to give a glassy residue which was crystallized from hot hexane to afford the title compound (120 mg, 91%) as an off-white solid. X H NMR (CDCI 3 , 300 MHz) δ 0.8-1.0 (m, 12H) , 1.00 (s, 9H), 1.05-1.95 (m, 9H) , 1.44 (s, 9H) , 2.48 (d, 2H) , 3.4 (bd, 1H) , 3.75-4.3 (m, 6H) , 5.18 (m, 1H) , 6.25 (m, 2H) . Anal calcd for C 27 H 51 N 3 O 7 : C, 61.22; H, 9.70; N, 7.93; Found: C 60.94, H 9.78, N 8.14. MS(FAB+) m/e 530 (M+H) + . Example 2 N-( (S)-2-r (ter -Bπ yloxγcaτ-bonγli πnr.Ωl-3.3- dimethylbutanoyl>-Tsoleucy1-Statyl-OH The product of Example lh (46 mg, 0.087 mmol) in MeOH (2.5 mL) was treated with 2 N NaOH (0.1 mL) and stirred at room temperature for 3.5 hours. An additional aliquot of 2 NaOH (0.1 mL) was added and stirring continued for an additional 2.5 hours. The reaction mixture was concentrated in vacuo, dissolved in H2O, and acidified to pH 1 with 1M H3PO4. The product was extracted with EtOAc, washed with H 2 O (2x) , brine, dried (Na 2 Sθ 4 ) , and concentrated in vacuo to afford a white solid (44 mg) . !H NMR (CDCI3, 300 MHz) δ 0.83-1.03 (m,' 12H) , 1.00 (s, 9H) , 1.03-1.66 (m, 5H) , 1.44 (s, 9H) , 1.95 (bs, 1H) , 2.56 (bt, 2H) , 3.7-4.3 (m, 4H) , 5.16 (m, 1H) , 6.75 (m, 2H) . Anal calcd for C2 5 H 47 N3O 7 0.5 H 2 0: C, 58.80; H, 9.47; N, 8.23; Found: C, 58.63; H, 9.32; N. 8.20. MS(FAB+) m/e 502 (M+H) + , 519 (M+H+NH 3 ) + . Example 3 N-l (Sl-2-r ( ert-Butyloxyπarhonγlϊam-inol-2- cyclohexylacetyl -Tsoleucyl-Statyl Ethyl ester Example 3a (S) ^-Amino-g-πyr-lohexylacetic acid L-Phenylglycine (8.04 g, 53 mmol) was reduced by catalytic hydrogenation using Ptθ2 in 80% acetic acid (HOAc) (200 mL) . The catalyst was removed by filtration and the HOAc removed under reduced pressure to afford the title compound as a white solid (7.8 g, 94%). The 300 MHz ■ "Ή NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 158 (M+H) + . Example 3b (S)-2-r (tert-Butyloxycarbonyl)aminol-2-cyolohexylacetic acid To the product of Example 3a (974 mg, 6.2 mmol) dissolved in 1 N NaOH (8 mL) was added THF (7 mL) followed by di-t-butyl-dicarbonate (1.34 g, 6.2 mmol) in THF (2 mL) . The reaction was stirred overnight at room temperature and then 2N NaOH (2 mL) was added. The reaction mixture was extracted with hexanes (3x) and the combined organic extracts were washed with saturated NaHCθ 3 solution (2x) . The combined aqueous layers were acidified to pH 2 with l.lΛf NaHSθ 4 and extracted with Et 2 θ (2x) . The ether extracts were dried (Na 2 Sθ 4 ) and concentrated in vacuo to give the title compound (1.37 g, 86%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH 3 ) m/e 275 (M+H+NH 3 ) + . Example 3c N-f (S)-2-T (tert-Butyloxycarbonyl)aminol-2- cyolohexylacetγl)-Tsoleucyl-Statyl Ethyl ester To the product of Example If (47 mg, 0.15 mmol) dissolved in CH 2 CI 2 (5 mL) and cooled to 0 °C was added the product of Example 3b (38 mg, 0.15 mmol) followed by HOBT (24 mg, 0.18 mmol) and EDCI (31 mg, 0.16 mmol) . The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was diluted with EtOAc, washed with 1M H3PO 4 (3x) , saturated NaHCθ3 (3x) , and brine, dried ( a2Sθ 4 ) , and concentrated in vacuo to give a white solid (62 mg) , which was recrystallized from EtOAc/hexanes. X H NMR (CDCI 3 , 300 MHz) δ 0.9 (m, 12H) , 1.0-2.15 (m, 20H) , 1.45 (s, 9H) , 2.5 (bd, 2H) , 3.3-3.5 (d of d, 1H) , 3.8-4.3 (m, 6H) , 5.0 (bt, 1H) , 6.4 (m, 2H) . Anal calcd for C29H53N3O 7 : C, 62.67; H, 9.61; N, 7.56; Found: C, 62.41; H, 9.54; N, 7.51. MS (FAB) m/e 556 (M+H) + . Example 4 N-( (S)-2-r (tert-Butyloxycarbonyl)aminol-2- cyclohexylace yl}-Isoleucyl-Statyl-OH The product of Example 3c was hydrolyzed in analogy to Example 2 to give a solid which was recrystallized from CH2Cl2/hexane to give the title compound (24 mg, 81%) . X E NMR (CDCI3, 300 MHz) δ 0.85-1.00 (m, 12H) , 1.45 (s, 9H) , 1.00-2.05 (m, 17H), 2.55 (bt, 2H) , 3.80-4.30 (m, 4H) , 5.10 (m, 1H) , 6.7-6.95 (m, 2H) . Anal calcd for C27H 4 9N3O 7 H2O: C, 59.43; H, 9.42; N, 7.70; Found: C, 59.51; H, 9.13; N, 7.67. MS (FAB) m/e 528 (M+H) + . Example 5 N-Boc-Isoleucyl-Tsoleucyl-Statyl Carboxamide Example 5a N-Boc-Isoleucyl-Ispleucyl-Statyl Ethyl ester Coupling of the product of Example If (200 mg, 0.63 mmol) with Boc-Ile-OH hemihydrate (152 mg, 0.63 mmol) by the method described in Example le afforded crude material which was recrystallized from EtOAc/hexane to give the title compound as a white crystalline solid (280 mg, 84%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 530 (M+H) + . Example 5b N-Boc-Isoleucyl-Isoleu γl-Statyl-OH The product of Example 5a (274 mg, 0.52 mmol) was hydrolyzed by the method described in Example 2 to give the title compound as a white solid (240 mg, 93%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 502 (M+H) + . Example 5c N-BQC-Isoleucyl-ISQleucy -Staty Carboxamide To the product of Example 5b (40 mg, 0.08 mmol) dissolved in THF (4 mL) and cooled to -5 °C was added N- methylmorpholine (NMM) (9 μL, 84 μ ol) followed by isobutyl chloroformate (IBCF) (llμL, 84 μmol) . The reaction mixture was stirred for 20 minutes and concentrated NH 4 OH (25 μL, 0.36 mmol) was added. After 2.5 hours, the solvent was removed under reduced pressure, the residue was dissolved in MeOH and diluted with CHCI 3 and washed with lΛf H 3 PO 4 (2x) , saturated NaHC0 3 (2x) , and brine. Drying (Na 2 Sθ 4 ) and concentration in vacuo followed by flash chromatography eluting with 93.5/6.5 CHCl 3 /EtOH afforded the title compound (7 mg, 18%) as a white solid. λ H NMR (DMSO-D 6 , 300 MHz) δ 0.8 (m, 18H) , 1.4 (s, 9H) , 1.0- 1.8 (m, 9H) , 2.0-2.2 (m, 2H) , 3.6-3.9 (m, 3H) , 4.35 (d of d, 1H) , 6.8-7.7 (m, 4H) . Anal calcd for C 25 H 48 4 O 6 : C, 59.97; H, 9.66; N, 11.19; Found: C, 59.77; H, 9.46; N, 10.77. MS (FAB) m/e 501 (M+H) + . Example 6 N-Boc-Isoleucyl-Isoleucyl-Statyl (4- Hydroxybutyl)carboxamide By the method described in Example 5c, the product of Example 5b (40 mg, 0.08 mmol) and 4-amino-l-butanol (7.7μL, 84 μmol) were reacted to give crude material (32 mg, 70%) . Flash chromatography eluting with 93.5/6.5 CHCl3/EtOH afforded the title compound as a white solid (16 mg, 35%) . X H NMR (CDCI3 + CD3OD, 300 MHz) δ 0.85-1.00 (m, 18H) , 1.05-2.00 (m, 13H) , 1.45 (s, 9H) , 2.30 (m, 2H) , 3.60-4.20 (m, 8H) , 5.50 (d of d, 1H) , 7.10 (m, 2H) . Anal calcd for C29H 5 6 4 O 7 H 2 0: C, 58.96; H, 9.90; N, 9.48; Found: C, 58.67; H, 9.43; N, 9.26. MS (FAB) m/e 573 (M+H) + , 595 (M+Na) + . Example 7 N-Boc-Tsoleucyl-Tsoleucy -Statyl Hyriroxyamyl)carboxamide By the method described in Example 5c, the product of Example 5b (40 mg, 0.08 mmol) and 5-amino-l-pentanol (8.6 mg, 84 μmol) were reacted to give crude material (41 mg, 87%) . Flash chromatography eluting with 91.5/8.5 CHCl3/Et0H afforded the title compound as a white solid (16 mg, 34%) . X R NMR (CDCI3 + CD3OD, 300 MHz) δ 0.90 (m, 18H), 1.00-2.00 (m, 15H) , 1.45 (s, 9H) , 2.30 (m,2H), 3.20 (m, 2H), 3.60 (t, 2H) , 3.85 ( , 3H) , 4.15 (d of d, 1H) . Anal calcd for C30H58 O7 : C, 61.40; H, 9.96; N, 9.55; Found: C, 61.15; H, 9.97; N, 9.38. MS (FAB) m/e 587 (M+H) + . Example 8 N-Boc-Isoleucyl-Tsoleucyl-Statyl (6- Hydroxyhexyl)carboxamide By the method described in Example 5c, the product of Example 5b (40 mg, 0.08 mmol) and 6-amino-l-hexanol (9.8 mg, 84 μmol) were reacted to give crude product (40 mg, 83%). Flash chromatography eluting with 93.5/6.5 CHCl 3 /EtOH afforded the title compound as a white solid (22 mg, 46%). 1 H NMR (CDCI3 + CD3OD, 300 MHz) δ 0.9 (m, 18H) , 1.05-2.00 (m, 17H) , 1.45 (s, ' 9H) , 2.30 (m, 2H) , 3.10-4.20 (m, 8H) , 5.55 (m, exchangeable H) , 7.05-7.22 (m, exchangeable H) . Anal calcd for C 31 H 60 N 4 O 7 : C, 61.97; H, 10.07; N, 9.32; Found: C, 61.75; H, 9.82; N, 9.14. MS (FAB) m/e 601 (M+H) + , 623 (M+Na) + . Example 9 ri-r (N-Cbz-Tsoleucyl-Tsoleucyl) Aminol^- methybntyKmethoxy^hosphinynaoetic acid tert-Butyl ester Example 9a ri-Amino-3-methybutyl (methoxy)phosphinyll cetic acid tert- Butyl ester [1-(Benzyloxycarbonyl)amino-3-methybutyl(methoxy)- phosphinyl]acetic acid tert-butyl ester, prepared by the literature procedure: Bartlett, P.A.; Kezer, W.B.; J. Am. Chem. Soc, 106 f 4282 (1984), (357 mg, 0.86 mmol) was dissolved in MeOH (11 mL) and hydrogenolyzed under H 2 using 10% Pd/C (84 mg) for approximately one hour. The catalyst was removed by filtration and the solvent removed under reduced pressure to give the title product as an oil (230 mg, 100%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 280 (M+H) + . Example 9b ri-r (N-Cbz-Isoleucyl)Aminol-3- methybutyl(methoxγ)phosphinynaceti acid tert-Butyl ester By the method described in Example le, the product of Example 9a (213 mg, 0.76 mmol) and Cbz-Ile-OH (203 mg, 0.76 mmol) were coupled. Normal work up afforded the title compound as an oil (402 mg, 100%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 393 (M+H) + , 410 (M+H+NH3) + . Example 9c ri-r (H-Tsoleuoyl) Aminol-3- ethybutyl(methoxy)phosphiny11acetic acid tert-Butyl ester The product of Example 9b (390 g, 0.74 mmol) dissolved in MeOH (16 mL) was treated with 10% Pd/C (105 mg) under H 2 for 90 minutes. The catalyst was removed by filtration and the solution concentrated in vacuo to afford the title compound as an oil (260 mg, 90%) . The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 527 (M+H) + , 544 (M+H+NH3) + . Example 9d ri-r (N- bz-Tsoleucyl-Isoleucyl) minol -3- methybutyl (methoxy)phosphinyllacetic acid tert-Butyl ester By the method described in Example le, the product of Example 9c (250 mg, 0.64 mmol) and Cbz-Ile-OH (170 mg, 0.64 mmol) were coupled. Normal work up afforded crude product which was purified by silica gel column chromatography eluting with 1% MeOH in CHCI 3 to afford the title compound (287 mg, 71%) . λ R NMR (CDCI3, 300 MHz) δ 0.9 (m, 18H), 1.00-2.00 (m, 9H) , 1.45 (s, 9H) , 2.95 (m, 2H), 3.75 (t, 3H) , 4.00 (m, IH) , 4.4 (m, IH) , 4.6 (m, IH) , 5.10 (m, 2H), 5.5 (d of d, IH) , 6.40 (d of d, IH) , 6.90 (d of d, IH) , 7.35 (m, 5H) . Anal calcϊd for C 32 H 54 N 3 O 8 P: C, 60.08; H, 8.51; N, 6.57; Found: C, 59.90; H, 8.52; N, 6.56. MS (FAB) m/e 640 (M+H) + , 662 (M+Na) + . Example 10 N-Boc-Isoleucyl-Isoleucyl-Statγl-OH Example 10a N-Bpc-Isoleucyl-Isoleucyl Benzyl ester To a solution of Boc-Ile-OH • I/2H 2 O (3.00 g, 12.5 mmol) in THF (40 mL) cooled to -15 °C was added N-methylmorpholine (NMM) (1.51 mL, 1.39 g, 13.7 mmol) and isobutyl chloroformate (IBCF) (1.78 mL, 1.87 g, 13.7 mmol) ; the white suspension formed was stirred at -15 °C for 5 min and treated with a 0 °C solution of the p- toluene sulfonate salt of H-Ile-OBn (4.92 g, 12.5 mmol) and NMM (1.51 mL, 1.39 g, 13.7 mmol) in THF (10 mL)/dimethyl formamide (DMF) (5 mL) . The reaction mixture was stirred at -15 °C and gradually allowed to warm to room temperature. After 4 hours, EtOAc was added; the mixture was washed with lA H 3 PO 4 (3x) , saturated NaHCθ 3 (2x) , and brine, dried (MgS0 4 ) , and concentrated in vacuo to give the title compound (5.16 g, 95%) as an oil which solidified on standing. The 300 MHz R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 435 (M+H) + , 452 (M+H+NH3) + . Example lQb N-Boc-Isoleuπyl-Tsnleπcyl-OH A solution of the product of Example 10a (1.00 g, 2.30 mmol) in MeOH (25 mL) was treated with 10% Pd/C (0.50 g) and placed under H 2 . After one hour, the catalyst was removed by filtration through Celite and the filtrate concentrated in vacuo. The residue obtained was dissolved in EtOAc, washed with lΛf HCl and brine, dried (MgS0 ) / and concentrated in vacuo to give the title compound (729 mg, 92%) as a colorless oil. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 345 (M+H) + , 362 (M+H+NH3) + . Example lQc Statyl Ethyl ester HCl salt A solution of the product of Example lc (425 mg, 1.4 mmol) in HCl-HOAc (20 mL) was stirred at room temperature for 2 hours. Water was added and the solution lyophilized to give the title product as an oil (302 mg, 90%) . MS (DCI/NH3) m/e 204 (M+H) + . Example lQd N-Boc-Tsoleucyl-Tsoleucyl-Statγl Ethyl ester The product of Example 10c (150 mg, 0.63 mmol) and the product of Example 10b (150 mg, 0.62 mmol) were coupled by the method described in Example le to give the title compound (130 mg, 40%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 530 (M+H) + , 547 (M+H+NH3) + . Example lQe N-Boc-Isoleucyl-Isoleucyl-Statyl-OH To a solution of the product of Example lOd (122 mg, 0.23 mmol) in MeOH (10 ml) at 0 °C was added a solution of 1M NaOH (0.5 mL, .5 mmol) . The reaction mixture was stirred at 0 °C for 3 hours and concentrated in vacuo to remove the MeOH. EtOAc was added followed by washing with lΛ H 3 PO 4 and brine, drying (MgSθ 4 ), and concentrating in vacuo to give a solid which was purified by flash chromatography on silica gel to give Boc-Ile-Ile-Sta-OMe. The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. Anal calcd for C 26 H 49 N 3 O7: C 60.56; H, 9.58; N, 8.15; Found: C, 60.35; H. 9.76; N. 8.14. MS (DCI/NH3) m/e 516 (M+H) + , 533 (M+H+NH3) + . To a solution of this compound (33 mg, 0.064 mmol) in MeOH (7 mL) was added IN NaOH (0.,45 mL, 0.45 mmol); the reaction mixture was stirred overnight at room temperature. The MeOH was removed under reduced pressure, EtOAc was added, followed by 1M H 3 PO 4 and brine washes, drying (MgSθ 4 ) , and concentrating in vacuo to give a white solid which was purified by preparative HPLC using a 1% TFA/H 2 O and CH 3 CN gradient. The fractions containing the desired product were concentrated to remove CH 3 CN, frozen and lyophilized to give the title compound as a white solid (7 mg, 22%) . 1 H NMR (DMSO-d 6 , 300 MHz) δ 0.80 (m ,18H), 1.00-1.75 ( , 9H) , 1.37 (s, 9H) , 2.05-2.40 (m, 2H) , 3.60-3.90 (m, 3H) , 4.15 ( , IH) , 4.15 (m, IH) , 6.77 (d, IH) , 7.65 (m, 2H) . Anal calcd for C 25 H 4 7N 3 O7 0.25 trifluoroacetate (TFA): C, 57.77; H, 8.98; N, 7.93; Found: C, 57.77; H, 8.98; N, 8.05. MS (FAB) m/e 502 (M+H) + , 524 (M+Na) + Example 11 N-Succinyl-Isoleucyl-Isoleucyl-Statyl-Valyl-OH Example 11a ' Isoleucyl-Isoleucyl Benzyl ester HCl salt A solution of the product of Example 10a (2.00 g, 4.61 mmol) in HCl-HOAc (25 mL) was stirred at room temperature for 2 hours. An additional aliquot of HCl- HOAc (10 mL) was added and stirring continued for an additional 4 hours. The reaction mixture was diluted with H 2 O and lyophilized to give the title compound (1.67 g, 98%) as a white solid. The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 335 (M+H) + . Example lib N-(3-(Methnxycarbonyl)propionyl)-Isoleucvl-Isoleucvl Benzyl ester A solution of Example the product of 11a (1.00 g, 2.70 mmol), N-methylmorpholine (NMM) (0.33 mL, 0.30 g, 3.00 mmol), methyl succinate (380 mg, 2.88 mmol), EDCI (570 mg, 2.97 mmol) and HOBT (450 mg, 3.33 mmol) in CH Cl 2 (50 mL) was stirred at 0 °C allowing to warm to room temperature overnight. The CH 2 CI 2 was removed under reduced pressure, EtOAc was added followed by lΛ H 3 PO 4 (3x) , saturated NaHCθ 3 (3x) and brine washes. Drying (MgSθ 4 ) followed by concentration in vacuo afforded crude product which was purified by flash chromatography eluting with 3:1 then to 1:1 hexane/EtOAc to give the title compound (701 mg, 58%) as a white solid. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 449 (M+H) + , 466 (M+H+NH3) "1" . Example 11c - N-(3-(Methoxγcarbonyl)propionγl)-Isoleucyl-Iso1encyl-OH The product of Example lib (500 mg, 1.12 mmol) was debenzylated by the procedure described in Example 10b. The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 359 (M+H) + , 376 (M+H+NH3) + . Example lid N-Boc-Statyl-QH To a solution of the product of Example lc (257 mg, 0.85 mmol) in MeOH (7 mL) was added a solution of lΛf NaOH (1.7 mL, 1.7 mmol). The reaction mixture was stirred at room temperature for 2 hours and worked up by the procedure described in Example 2 to give the title compound (203 mg, 87%) as a white solid. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3 ) m/e 276 (M+H) + , 293 (M+H+NH3 ) "1" . Example lie N-Boc-Statyl-Valyl Benzyl ester The product of Example lid (150 mg, 0.59 mmol) and the p-toluene sulfonate salt of H-Val-OBn (212 mg, 0.56 mmol) were coupled by the method described in Example le to give the title compound (0.189 g, 75%). The 300 MHz λ R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 465 (M+H) + , 482 (M+H+NH3) + . Example llf N-(3- (Methoxycarbonyl) ropionyl) -Isoleucyl-Isoleucyl- Statyl-Valyl Benzyl ester The product of Example lie (125 mg, 0.27 mmol) was deprotected by the method described in Example 10c to give H-Sta-Val-OBn • HCl (104 mg, 97%) as a white solid. The 300 MHz i H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 365 (M+H) + . This dipeptide (83 mg, 0.21 mmol) was coupled with the product of Example lie (84 mg, 0.23 mmol) by the method described in Example le to give crude material which was purified by flash chromatography on silica gel eluting with 3% MeOH/CHCl 3 to give the title compound (11 mg, 80%) . The 300 MHz λ R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 705 (M+H) + . Example 11? N-Succinyl-Isoleucyl-Isoleυcyl-Statyl-Valyl-OH The product of Example llf (100 mg, 0.14 mmol) was debenzylated by catalytic hydrogenation by the method described in Example 10b and purified by preparative HPLC to give the carboxylic acid. The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. Anal calcd for C 30 H 54 N 4 O 9 -0.7 TFA: C, 54.30; H, 7.94; N, 8.07; Found: C, 54.44; H, 8.06; N, 8.32. MS (FAB) m/e 615 (M+H) + , 637 (M+Na) + . To a solution of the carboxylic acid (69 mg, 0.113 mmol) in CH3OH (5 mL) at 0 °C was added lΛf NaOH (0.23 mL, 0.23 mmol) . The reaction mixture was stirred at 0 °C allowing to warm to room temperature overnight. An additional aliquot of lΛf NaOH (0.1 mL, 0.1 mmol) was added and the reaction mixture again stirred overnight. The CH3OH was removed under reduced pressure, H2O was added, and the solution was lyophilized. The material obtained was dissolved in H2θ/acetone, filtered, and lyophilized to give the title compound (38.7 mg, 57%). 1 H NMR (DMSO-dε, 300 MHz) δ 0.85 (m, 24H) , 1.00-1.75 (m, 13H) , 2.00-2.55 (m, 6H), 3.65-3.90 (m, 2H) , 4.15 (m, 3H) , 7.5-7.9 (m, 4H) . Anal calcd for C 29 H 52 N 4 O 9 0.4 TFA 1.0 H 2 O: C, 53.87; H, 8.25; N, 8.43; Found: C, 53.87; H. 7.95; N. 8.62. MS (DCI/NH3) m/e 601 (M+H) + . Exa ple 12 N-Boc-Cyclohexylalanyl-Tsoleuπyl-Statyl Ethyl ester Example 12a N-Boc-Cyclnhexylalanyl-Tsoleucyl Benzyl ester Boc-Cha-OH (3.5 g, 12.9 mmol) and the p-toluene sulfonate salt of H-Ile-OBn (5.08 g, 12.9 mmol) were coupled using the method described in Example 10a to give crude material which was purified by flash chromatography on silica gel eluting with 15% EtOAc/hexane to give pure title compound. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 474 (M+H) + , 492 (M+H+NH3) + . Example 12b N-Boc-Cyclohexylalanyl-Tsoleucyl-Statyl Ethyl ester The product of Example 12a (500 mg, 1.055 mmol) was debenzylated using the method described in Example 10b to give the free carboxylic acid (405 mg, 100%) . The 300 MHz λ R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 385 (M+H) + , 402 (M+H+NH3) + . The carboxylic acid (172 mg, 0.45 mmol) and the product of Example 10c (107 mg, 0.45 mmol) were coupled using the method described in Example le crude product (232 mg, 91%) . Flash chromatography on silica gel using 3:1 hexane/EtOAc afforded the title compound (146 mg, 57%). ^-H NMR (DMSO-dβ, 300 MHz) δ 0.8 (m, 15H) , 1.00-1.73 (m, 19H), 1.40 (s, 9H) , 2.15-2.43 (m, 2H) , 3.65-4.20 (m, 6H), 4.90 (d of d, IH), 6.93 (d of d, IH) , 7.60 (d of t. 2H) . Anal calcd for C30H 5 5N3O 7 : C, 63.27; H, 9.70; N, 7.38; Found: C, 63.14; H, 9.71; N, 7.34. MS (FAB) m/570 (M+H) + . Example 13 N-Boc-Isoleucyl-Isoleucγl-Statvl-β-Alanyl Ethvl ester Example 13a N-Boc-Statyl-β-Alanvl Ethyl ester The product of Example lid (292 mg, 1.06 mmol) and β- Ala-OEt (196 mg, 1.27 mmol) were coupled by the method described in Example 10a to give the title compound (355 mg, 89%) as a white solid. The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 375 (M+H) + . Example 13b N-Boc-Isoleucγl-lsoleucyl-Statvl-β-Alanvl Ethvl ester The product of Example 13a (343 mg, 0.92 mmol) was deprotected by the method described in Example Id to give the HCl salt (279 mg, 98%) . The 300 MHz λ R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 274. The HCl salt (164 mg, 0.53 mmol) was coupled with the product of Example 10b (200 mg, 0.58 mmol) by the method described in Example 10a to give crude material (284 mg, 82%) . Flash chromatography on silica gel eluting with 2% CH3OH/CHCI3 afforded the title compound (141 mg, 41%) as a white solid. 1 H NMR <DMSO-d6, 300 MHz) δ 0.80 (m, 18H), 1.17 (t, 3H) , 1.37 (s, 9H) , 1.00-1.70 (m, 9H) , 2.10 ( , 2H), 2.40 (t, 2H) , 3.15-3.35 (m, 2H) , 3.65 (m, IH), 3.80 (bt, 2H), 4.03 (q, 2H) , 4.15 ( , IH) , 4.75 (d of d, IH), 6.75 (d, IH) , 7.47-7.82 (m, 3H) . Anal calcd for C30H 5 6N 4 O8 C, 60.00; H, 9.36; N, 9.33; Found: C, 59.98; H, 9.40; N, 9.33. MS (FAB) m/e 601 (M+H) + . Example 14 N-Boo-Tsoleucγl-Isoleucγl-Statyl Isobutyl arboxamide Example 14a N-Boc-Statyl Tsohutylcarboxamide. The product of Example lid (260 mg, 0.94 mmol) was coupled with isobutylamine (113 μL,-83 mg, 1.14 mmol) using the method described in Example 10a to give the title compound (280 mg, 90%) as a white solid. The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 331 (M+H) + . Example 14b N-Boo-Isolenoy -Tsoleuπyl-Statyl Tsobutylcarhoxamide The product of Example 14a (233 mg, 0.706 mmol) was deprotected by the method described in Example Id to give the HCl salt (188 mg, 100%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 231 (M+H) + . The HCl salt (90 mg, 0.34 mmol) was coupled with the product of Example 10b (128 mg, 0.37 mmol) by the method described in Example 10a to give crude material (119 mg, 63%) . Flash chromatography on silica gel eluting with 2% CH 3 OH in CHCI 3 gave pure title compound (27 mg, 14%) as a white solid. 1 H NMR (DMSO-d 6 , 300 MHz) δ 0.80 ( , 24H) , 1.35 (s, 9H) , 1.00-1.85 (m, 10H) , 2.10 (m, 2H) , 2.85 (m, 2H) , 3.75 (m, 3H) , 4.26 (m, IH) , 4.77 (m, IH) , 6.75-6.95 (d of d, IH) , 7.40-7.70 (m, 3H) . Anal calcd for C 29 H 56 N 4 O 6 0.5 H 2 O: C, 61.56; H, 10.15; N, 9.90; Found: C, 61.49; H, 10.03; N, 9.86. MS (FAB) m/e 557 (M+H) + . Example 15 N-Boπ-Cyclohexylalanyl-Isoleucyl-Statyl-OH The product of Example 12b (85 mg, 0.15 mmol) was hydrolyzed by the method described in Example 2 to give the title compound. ■ ' ■ H NMR (DMSO-d 6 , 300 MHz) δ 0.80 (m, 12H) , 1.35 (s, 9H), 1.00-1.73 (m, 19H) , 2.10-2.30 (m, 2H) , 3.67 (m, IH) , 3.83 (m, IH) , 3.95 (m, IH) , 4.13 (m, IH) , 6.92 (m, IH), 7.43-7.65 (m, 2H) . Anal calcd for C 28 H 51 N 3 O 7 0.5 H 2 O: C, 61.07; H, 9.52; N, 7.63; Found: C, 61.47; H, 9.49; N, 7.63. MS (FAB) m/e 542 (M+H) + , 564 (M+Na) + . Example 16 N-Boc-Isoleucγl-Isoleucγl-Statvl-β-Alanvl-OH The product of Example 13 (100 mg, 0.17 mmol) was hydrolyzed by the method described in Example 2 to give the title compound (68.7 mg, 71%) as a white solid. H NMR (DMSO-d 6 , 300 MHz) δ 0.80 (m, 18H) , 1.00-1.73 (m, 9H) , 1.40 (s, 9H), 2.10 (m, 2H) , 2.35 (t, 2H) , 3.20 (m, 2H) , 3.66 (m, IH), 3.80 (bt, 2H) , 4.15 (m, IH) , 4.75 (bd, IH) , 6.75 (d, IH), 7.45-7.80 (m, 3H) , 12.15 (bs, IH) . Anal calcd for C28H52N4O8: C, 58.72; H, 9.15; N, 9.78; Found: C, 58.47; H, 9.21; N, 9.67. MS (FAB) m/e 573 (M+H) + . Example 17 N-Boc-Tsoleucyl-Isoleucyl-Tryptophany Carboxaldehyde Example 17a Tryptnphanyl (N-Methoxy-N-met.hyl) carboxamide HCl sal To Boc-Trp-OH (5.00 g, 16.4 mmol) dissolved in CH2CI2 (100 mL) containing triethylamine (TEA) (2.75 mL, 1.2 equiv.) was added benzotriazol-1-yloxy- tris (dimethylamino)phosphonium hexafluorophosphate (BOP- reagent) (8.72 g, 1.2 equiv.), N,O-dimethylhydroxylamine hydrochloride (1.92 g, 1.2 equiv.), and TEA (2.75 mL, 1.2 equiv.). After one hour of stirring at room temperature, CH2CI2 (50 mL) was added and the mixture washed with 10% citric acid, saturated NaHCθ3, and brine, dried (Na2Sθ 4 ) , and concentrated in vacuo to afford a yellow oil which was crystallized from EtOAc/hexane. The Boc-protecting group was removed by the method described in Example Id to afford the title compound (5.02 g, 91%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. Example 17b N-Bnc-Tsoleucyl-Trγptophanγ3 (N~Met θXy-N- ethyl) carboxamide The product of Example 17a (2.45 g, 8.6 mmol) and Boc-Ile-OH (2.07 g, 8.6 mmol) were coupled using the procedure described in Example 10a to give crude material which was purified by flash chromatography on silica gel eluting with 1:1 EtOAc/hexane to afford the title compound (3.5 g, 88%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 461 (M+H) + . Example 17c N-Boc-Isoleucγl-Isoleucγl-Tryptophanyl (N-Methoxy-N- ethyl) carboxamide The Boc protecting group was removed from the product of Example 17b by the method described in Example Id to afford the hydrochloride salt (604 mg, 1.53 mmol) . This compound was coupled with Boc-Ile-OH hemihydrate (368 mg, 1.0 equiv.) by the method described in Example 10a to give crude product. Purification by flash chromatography on silica gel using 1:1 EtOAc/hexane afforded the title compound (576 mg, 66%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. Further purification was obtained by preparative reverse phase HPLC eluting with 0.1% TFA/H2O and CH3CN. Anal calcd for C30H 47 N5O6 0.25 TFA: C, 60.83; H, 7.91; N, 11.63; Found: C, 60.86; H, 8.05; N, 11.75. MS (FAB) m/e 574 (M+H) + . Example 17d N-Boc-Tsol ucyl-Isoleucyl-Tryptophanyl Carboxaldehyde To the product of Example 17c (100 mg, 0.1745 mmol) dissolved in THF (8 mL) under N2 and cooled to 0 °C in an ice bath was added lΛf lithium aluminum hydride (LAH) in THF (1.40 mL, 8.0 equiv) . After 20 minutes at 0 °C, the reaction mixture was poured into 10% citric acid (10 mL) . After stirring at room temperature for 30 minutes, 10% citric acid (10 mL) was added and the mixture was extracted with EtOAc (3x15 mL) . The combined organic extracts were washed with saturated NaHC0 3 , 10% citric acid, and brine, dried (Na 2 Sθ 4 ) , and concentrated in vacuo to give a semi-solid residue. This crude product was flash chromatographed on silica gel using 1:1 EtOAc/hexane as the eluant to give the title compound (16 mg, 18%) . H NMR (CDCI3, 300 MHz) δ 0.90 (m, 12H) , 1.05-2.00 (m 6H) , 1.45 (s, 9H), 3.30 (bt, 2H) , 3.90 (m, IH) , 4.30 (m, IH) , 4.90 (m, IH), 6.45 (bd, IH) , 6.60 (bs, IH) , 7.00-7.40 (m, 5H), 7.60 (bd, IH) , 8.20 (bs, IH) , 9.62 (s, IH) . Anal calcd for C 28 H 2 N 4 θs: C, 65.35; H, 8.23; N, 10.89; Found: C, 65.44; H, 8.53; N, 10.45. MS (FAB) m/e 515 (M+H) + , 537 (M+Na) + . Example 18 (4S)-4-(N-Boc-Tsoleucγl-Isoleucγl-Amino) -5-(3-indolγl) -3- hydroxypent noic acid Example 18a N-Boc-Tryptophanyl-T3.5-dimethylpyrazolidel Boc-Trp-OH (6.00 g, 24.3 mmol) was reacted with 3,5- dimethylpyrazole (2.33 g, 1 equiv) by the method described in Example la to give crude material which was flash chromatographed on silica gel eluting with 2:1 hexane/EtOAc to give the title compound (6.95 g, 75%). The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. Example 18b N-Boc-Tryptophanyl Carboxaldehyde The product of Example 18a (4.00 g, 10.47 mmol) was reduced by the method described in Example lb to give crude aldehyde which was purified by by flash chromatography on silica gel eluting with 2:1 hexane/EtOAc to give the title compound (2.44 g, 81%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. Example 18π (4S) -4-N-Boc-Amino-5- (3-indolγl) -3-hydroxypentanoic acid Ethyl ester Using the procedure described in Example lc, the product of Example 18b (2.44 g, 8.46 mmol) was converted to crude product which was purified by flash chromatography on silica gel eluting with 2:1 hexane/EtOAc to afford the title compound (1.91 g, 60%). The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. Example fid (4S) -4- (N-Boc-Tsolencyl-Tsoleucyl-Amino) -5- (3-indolγl) -3- hydroxypentanoic acid Ethyl ester The product of Example 18c (1.00 g, 2.66 mmol) was deprotected using the procedure described in Example Id to give the hydrochloride salt (786 mg, 95%) . This hydrochloride salt (604 mg, 1.94 mmol) was converted to its free base using saturated NaHCθ 3 (50 mL) and extracted after 30 minutes using EtOAc. The EtOAc was removed under reduced pressure to afford the free base as an oil. To the product of Example 10b (666 mg, 1 equiv) dissolved in CHCI 3 (8 mL) was added EDCI (445.6 mg, 1.2 equiv) and HOBT (314 mg, 1.2 equiv) . After stirring for 30 minutes, the free a ine in CHCI 3 (2 mL) /DMF (3 mL) was added and the reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo and EtOAc was added. Washing with saturated NaHCθ 3 , H 2 O, IN H 3 PO 4 , and brine, drying (Na 2 S0 4 ) , and concentrating under reduced pressure afforded the product as an oil which was purified by flash chromatography on silica gel eluting with 1:1 EtOAc/hexane to give the title product (381 mg, 33%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 603 (M+H) + . Example 18e 4S)-4-(N-Boc-Isoleucγl-lBθleucyl-Amino)- -(3-indo1 )-3- hydroxypentanoic acid The product of Example 18d (61 mg, 101.3 mmol) was hydrolyzed using the method described in Example 2 to give crude material which was purified by preparative HPLC to give the title compound. λ R NMR (CDCI3 + CD3OD, 300 MHz) δ 0.70-1.00 (m, 12H), 1.00-1.90 (m, 6H) , 1.45 (s, 9H) , 1.70 (m, 2H), 2.30 (m, 2H) , 2.90-3.15 (m, 2H) , 3.97 (m, 3H), 4.32 (bd, IH), 7.10 (m, 3H) , 7.33 (d, IH) , 7.70 (bt, IH) . Anal calcd for C 30 H 46 N 4 O 7 0.7 TFA: C, 57.62; H, 7.19; N, 8.56; Found: C, 57.49; H, 7.25; N, 8.94. MS (DCI/NH3) m/e 575 (M+H) + , 592 (M+H+NH3) + . Example 19 (4S)-4-(N-Succinyl-Isoleucyl-Isoleucyl-Amino)-5-(3- indolyl) -3-hydroxypentanoic acid Ethyl ester The product of Example 18d (41.1 mg, 68.3 mmol) was deprotected using the method described in Example Id to give the hydrochloride salt. To this hydrochloride salt dissolved in DMF (1 mL) was added 4- (dimethylamino) - pyridine (DMAP) (20 mg) , triethylamine (TEA) (5 drops) , and succinic anhydride (8.2 mg, 1.2 equiv) . The reaction mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound 1 H NMR (CDCI3, 300 MHz) δ 0.85 (m, 1-2H) , 1.00-2.10 (m, 12H) , 1.23 (t, 3H), 2.40-3.10 (m, 4H) , 3.03 (d of d, IH) , 3.70 (m, IH) , 4.12 (q, 2H) , 4.00-4.50 ( , 2H) , 6.30-7.30 (m, 5H), 7.33 (bd, IH) , 7.66 (bd, IH) , 8.10 (bs, IH) . Anal calcd for C3ιH 6 N 4 θ8 0.75 TFA: C, 56.72; H, 6.85; N, 8.14; Found: C, 57.08; H, 7.01; N,8.18. MS (FAB) m/e 603 (M+H) + . Example 20 N-r (4S) -4- (N-Boc-Isoleucyl-Isoleucyl-Amino)-5- (3-indolyl) - 3-hydroxypentanoyl 1-Valyl-OH Example 2Qa N-r (4S)-4-(N-Boc-Amino)-5-(3-indolyl)-3-hydroxypentanoyll- Valyl Benzyl ester The product of Example 18c (90.2 mg, 0.24 mmol) was hydrolyzed by the procedure described in Example 2 to give crude product which was purified by preparative HPLC to give the desired carboxylic acid. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 349 (M+H) + , 366 (M+H+NH3) + . This carboxylic acid (83.6 mg, 0.24 mmol) was coupled with the p-toluene sulfonate salt of Val-OBn (91.2 mg, 1.0 equiv) by the procedure described in Example 10a to give crude material which was flash chromatographed on silica gel using 1:1 EtOAc:hexane as the eluant to give the title compound (47.3 mg, 37%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 538 (M+H) + , 555 (M+H+NH3) "1" . Example 20b N-r (4S)-4-(N-Boc-Isoleucyl-Amino)-5-(3-indolyl)-3- hydroxypentanoyn-Va yl Benzyl ester The product of Example 20a was deprotected by the method described in Example Id to give the hydrochloride salt. This salt (205 mg, 0.434 mmol) was coupled with Boc-Ile-OH hemihydrate (104 mg, 1.0 equiv) by the method described in Example le to give a semi-solid residue which was purified by flash chromatography on silica gel eluting with 1:1 EtOAc/hexane to give after crystallization from 1:1 EtOAc/hexane the title compound (197 mg, 70%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. Anal calcd for C 36 H 50 N 4 O7 0.25 TFA: C, 64.54; H, 7.46; N, 8.25; Found: C, 64.76; H, 7.11; N, 8.25. MS (DCI/NH3) m/e 651 (M+H) + . Exa ple 2Qc N- r (4S) -4- (N-Boc-Isoleucγl-Isoleucγl-Ami.no) -5- (3-jndolyl ) 3-hγdroxypentanoyll-Valγl Benzyl ester The product of Example 20b (104 mg, 0.16 mmol) was deprotected by the method described in Example Id to give the hydrochloride salt. This salt was coupled with Boc- Ile-OH hemihydrate (38.4 mg, 1.0 equiv) by the method described in Example le and purified by the method described in Example 20b to give the title compound (58 mg, 47%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. Anal calcd for C 2 H 61 N 5 O 8 0.8 EtOAc: C, 65.12; H, 8.14; N, 8.44; Found: C, 65.18; H, 7.87; N. 8.86. MS (DCI/NH3) m/e 764 (M+H) + , 781 (M+H+NH3) + . Example 20d N- r (4S) -4- (N-Boc-Isolencγl-Isoleucvl-Amino) -5- (3-indolyl) • 3-hydroxypentanoyl1 -Valyl-OH To 10% Pd/C (21 mg) in acetic acid (HOAc) under N 2 was added ammonium formate (10.8 mg, 3 equiv) . After 10 minutes, the product of Example 20c (43.4 mg, 56.9 μmol) was added in HOAc (3 mL) . The reaction mixture was stirred overnight at room temperature. The catalyst was removed by filtration and the HOAc removed under reduced pressure. The residue was taken up in H 2 O/CH 3 CN and lyophilized to afford the title compound. 1 H NMR (DMSO- d 6 , 300 MHz) δ 0.80 (m, 18H) , 1.00-1.50 (m, 3H) , 1.35 (s, 9H), 1.70 (m, 2H), 2.00 (m, 2H) , 2.30 (m, IH) , 2.70 (m, IH), 3.00 (m, IH) , 3.70-4.30 (m, 6H) , 6.80-7.90 (m, 6H) , 10.70 (m, IH) . Anal calcd for C 35 H 55 N 5 O 8 0.5 TFA: C, 58.58; H, 7.55; N, 9.44; Found: C, 58.67; H, 7.64; N, 9.34. MS (FAB) m/e 674 (M+H) + , 696 (M+Na) + . Example 21 N-r (4S)-4-(N-Boc-Aspartyl-Isoleucyl-Isoleucyl-Amino)-5-(3- indolyl) -3-hydroxypentanoyll-Valyl-OH Example 21a N-r (4S) -4-(N-Boc-Aspartyl(β-O-Benzyl) -Isoleucyl-Isoleucyl- Amino)-5-(3-indolγl)-3-hγdroxypentanoγl1-Valyl Benzyl ester The product of Example 20c (60.8 mg, 79.7 μmol) was deprotected using the method described in Example Id to give the hydrochloride salt. This salt was coupled with Boc-Asp(βOBn)-OH (30.9 mg, 1.2 equiv) by the method described in Example le to give crude material which was purified by flash chromatography on silica gel eluting with 1:1 EtOAc/hexane to give the title product (25.1 mg, 33%) . Example 21b N-r (4S)-4-(N-Boc-Aspartyl-Isolencyl-Tsolenoyl-Amino)-5-(3- indolyl)-3-hydroxypentanoyll-Valyl-OH Catalytic transfer hydrogenation of the product of Example 21a (25.1 mg, 26 μmol) by the method described in Example 20d afforded after preparative HPLC and lyophilization the title compound. 1 H NMR (CDCI3 + CD3OD, 300 MHz) 0.74-1.00 (m, 18H) , 1.45 (s, 9H) , 1.85 (m, IH) , 2.00 (m, IH), 2.10-2.50 (m,4H) , 2.60-3.20 (m, 10H) , 3.95- 4.50 (m, 10H), 6.90-7.15 (m, 6H) , 7.60 (m, IH) . Anal calcd for C39H60N6O11 1 . 0 TFA : C, 54 . 54 ; H, 6 . 81 ; N, 9 . 31 ; Found : C, 54 . 32 ; H, 6 . 78 ; N, 9 . 38 . MS (FAB) m/e 789 (M+H) + , 811 (M+Na) + , 833 (M+2Na-H) + . Example 22 (4S) -4- (N-Boc-Cyclohexylalanyl-Isoleucyl-Amino) -5- (3- indolyl)-3-hydroxypentanoic acid Example 22a (4S) -4- (N-Boc-Cyclohexylalanyl-Isoleucyl-Amino) -5- (3- indolyl)-3-hydroxγpentanoic acid Ethyl ester Tthe product of Example 18c (255 mg, 0.678 mmol) was deprotected by the method described in Example Id and converted to its free base as described in Example 18d. The product of Example 12a was debenzylated as described in Example 12b to give the carboxylic acid. The free amine was coupled with the carboxylic acid (312.4 mg, 1.2 equiv) by the method described in Example le to give, after flash chromatography on silica gel using 1:1 EtOAc/hexane as the eluant, the title compound (337 mg, 90%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 643 (M+H) + . Example 22b (4S)-4-(N-BQC-Cyclohexylalanyl-Isoleucyl-ftmino)-5-(3- indolyl)-3-hydroxypentanoic acid The product of Example 22a (50 mg, 0.078 mmol) was hydrolyzed by the method described in Example 2 to give 1 after preparative HPLC the title compound. H NMR (CDCI3, 300 MHz) δ 0.70-1.05 (m, 6H) , 1.40 (2s, 9H) , 1.05-2.60 (m, 13H), 3.1 (m,2H), 4.00-4.45 (m, 3H) , 4.90 (m, IH) , 6.60- 7.20 (m, 4H) , 7.33 (d, IH) , 7.60 (2d, 2H) , 8.20 (m, IH) . Anal calcd for C 33 H 5θ N 0 7 0.65 TFA: C, 59.80; H, 7.41; N, 8.13; Found: C, 59.82; H, 7.37; N, 8.14. MS (FAB) m/e 615 (M+H) + , 637 (M+Na) + . Example 23 N- r (4S)-4-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino) -5-(3- indolyl) -3-hydroxypentanoyll-Valyl-OH Example 23a N- r (4S)-4-(N-Boc-Cyclohexylalanyl-Isoleucyl-Amino)-5-(3- indolyl)-3-hydroxypentanoy11-Valyl Benzyl ester The product of Example 20a (493 mg, 0.918 mmol) was deprotected by the method described in Example Id to give the hydrochloride salt. The product of Example 12a was debenzylated as described in Example 12b to give the carboxylic acid (423 mg, 1.2 equiv) . The amine hydrochloride salt and the carboxylic acid were coupled using the method described in Example le to give, after flash chromatography on silica gel eluting with 1:1 EtOAc/hexane, the title compound (217 mg, 30%) . The 300 MHz X R NMR spectrum was found to be consistent with the proposed structure. Example 23b N-r (4S)-4-(N-Boo-Cyclohexylalanyl-Tsoleucyl-Amino) -5-(3- indolyl)-3-hydroxγpentanoyll-Valvl-OH Catalytic transfer hydrogenation of the product of Example 23a (40 mg, 0.05 mmol) by the method described in Example 20d afforded, after preparative HPLC, the title co pound. 1 H NMR (CDCI3, 300 MHz) δ 0.65 (m, 6H) , 1.02 (t, 6H) , 0.85-1.50 (m, 6H) , 1.45 (2s, 9H) , 1.70 (m, 7H) , 2.25 (m, 2H), 2.30-3.20 (m, 4H) , 3.40 (m, IH) , 4.03 (m, 2H) , 4.20 (m, IH) , 4.35 (m, 2H) , 4.95 ( , IH) , 6.60 (bs, IH) , 6.90-7.50 (m, IH) , 8.40 (m, 10H) . Anal calcd for C 38 H 59 N 5 O 8 0.6 TFA: C, 60.18; H, 7.68; N, 8.95; Found: C, 60.35; H, 7.74; N, 9.06. MS (FAB) m/e 714 (M+H) + , 736 (M+Na) + . Example 24 (2S.3R.4S) -2- (N-Boo-Tsoleuoyl-Isoleucyl-Amino) -1- cyclohexyl-3 ,4-dihydroxy-6-me hylheptane Example 24a - (2S.3 .4S)-2-Amino-l-r.yclohexy1-3.4-dihydroxy-6- methylheptane (2S,3R,4S)-2-[ (tert-Butyloxycarbonyl)amino]-1- cyclohexyl-3,4-dihydroxy-6-methylheptane was prepared as described in the literature: Luly, J.R.; Hsiao, C.N.; BaMaung, N.; Plattner, J.J. J. Org. Chem. 1988, 53, 6109 This compound (413 mg, 1.2 mmol) was deprotected by the method described in Example Id to give the hydrochloride salt, which was dissolved in THF (2 mL) and treated with IN NaOH to pH 12. The mixture was extracted with CH2CI 2 (5x5 mL) . The combined organic extracts were dried (K 2 CO 3 ) and concentrated in vacuo to afford the title compound (294 mg, 99%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. F.xample 24b (2S.3R.4S)-2-(N-Boc-Isoleucyl-Amino)-l-cyclohexyl-3.4- dihydroxy-6-methylheptane The product of Example 24a (330 mg, 1.42 mmol) and Boc-Ile-OH hemihydrate (342 mg, 1.42 mmol) were coupled by the procedure described in Example 10a to give the title compound (558 mg, 86%) . ^Η NMR (CDCI3 + CD3OD, 300 MHz) δ 0.85-1.00 (m,12H), 1.10-2.00 (m, 19H) , 1.45 (s, 9H) , 3.20 (d of d, IH), 3.30 (d of t, IH), 3.92 (t, IH), 4.36 (d of t, IH), 4.90 (bs, IH), 6.20 (d, IH) . Anal calcd for C 25 H 48 N 2 O 5 0.25 H 2 O: C, 65.11; H, 10.60; N, 6.07; Found: C, 65.09; H, 10.48; N, 6.03. MS (FAB) m/e 457 (M+H) + . Example 24c (2S f 3Rr4S)-2-(N-Boc-Isoleucyl-Isoleucyl-Amino)-1- r.yclohexγl- .4-dihydroxy-6-methylheptane The product of Example 24b (156 mg, 0.34 mmol) was deprotected by the method described in Example Id to give the hydrochloride salt. The salt was converted to its free base using the procedure described in Example 24a to give the free amine (121 mg, 100%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 357 (M+H) + . To a stirred solution of Boc-Ile-OH hemihydrate (81 mg, 0.34 mmol) in THF (2 mL) at -20 °C was added NMM (37 μL, 0.34 mmol) followed by IBCF (44 μL, 0.34 mmol) maintaining the temperature at or below -17 °C. After 20 minutes, a solution of the free base from above in THF (2 mL) was added continuing to maintain the temperature below -17 °C. The reaction mixture was then allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the residue partitioned between EtOAc and saturated NaHCθ 3 . The organic phase was washed with IN H 3 PO 4 and brine, dried (MgSθ 4 ) , and concentrated in vacuo to afford a residue which was crystallized from 1:1 THF/EtOAc to give the title compound (181 mg, 93%) . mp 178-179 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.94 (m, 18H) , 1.00-2.25 (m, 13H) , 1.45 (s, 9H) , 3.18 (t, IH) , 3.35 (m, IH), 3.88 (t, IH) , 4.22-4.45 (m, 3H) , 5.02 (bs, IH) , 6.56 (bs, IH) , 6.80 (bd, IH) . Anal calcd for C 31 H 59 N 3 O 6 : C, 65.37; H, 10.40; N, 7.38; Found: C, 65.02; H, 10.13; N, 7.38. MS (DCI/NH3) m/e 570 (M+H) + , 587 (M+H+NH3) + . Example 25 (2S.3R.4S) -2- (N-Succinyl-Isoleucyl-Isoleucvl-Amino) -1- cyclohexyl-3.4-dihydroxγ-6-τnethγlheptane The product of Example 24c (67 mg, 0.11 mmol) was deprotected by the method described in Example Id to give the hydrochloride salt. The salt was converted to its free base using the procedure described in Example 24a to give the free amino compound (55 mg, 100%) . The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 470 (M+H) + . The amine (50 mg, 0.10 mmol) was reacted with succinic anhydride (12 mg, 0.127 mmol, 1.2 equiv) by the method described in Example 19 to give the title compound, mp 253-254 °C. ^Ε NMR (DMSO-d 6 , 300 MHz) δ 0.70-1.00 (m, 18H) , 1.00-1.83 (m, 22H) , 2.40 (m, 4H) , 2.92 (bd, IH) , 3.09 (bt, 1H) , 4.05-4.25 (m, 3H) , 4.49 (bd, 1H) , 4.70 (bs, 1H) , 7.52 (d, 1H) , 7.80 (d, 1H) , 7.92 (d, 1H) . Anal calcd for C30H5 5 N3O 7 H 0: C, 61.30; H, 9.77; N, 7.15; Found: C, 60.95; H, 9.30; N, 7.19. MS (FAB) m/e 570 (M+H) + , 592 (M+Na) + . Example 26 (2S r Rr 4S) -2- (N-Boc-ftspartyl (β-Q-Benzyl) -Isoleucyl- Isole cyl-Aim'no)-l-oyclohexyl-3.4-dihydroxy-6- methylheptane The product of Example 24c was deprotected and converted to its free base by the method described in Example 25 to give the amino compound. The amino compound (100 mg, 0.21 mmol) was coupled with N-(t- butyloxycarbonyl) -β-benzyl-aspartic acid (69 mg, 0.21 mmol) by the method described in Example 10a to give crude material which was flash chromatographed on silica gel eluting with a 45 to 60% gradient of EtOAc/hexanes to give, after lyophilization, the title compound (145 mg, 88%) . mp 175-184 °C. X H NMR (CDCI3, 300 MHz) δ 0.85-1.00 (m, 18H), 1.05-2.10 (m, 24H) , 1.46 (s, 9H) , 2.51 (d, IH) , 2.90 (m, 2H), 3.12 (t, IH) , 3.28 (m, IH) , 4.10 (t, IH) , 4.35 ( , 4H), 5.59 (d, IH) , 6.53 (d, IH) , 6.72 (d, IH) , 6.78 (d, IH), 7.35 (m, 5H) . Anal calcd for C 4 2H 7 0N 4 O9 0.5 H2O: C, 64.36; H,9.10; N, 7.15; Found: C, 64.42; H, 8.89; N, 7.10. MS (FAB) m/e 775 (M+H) + . Example 27 (2S.3R.4S) -2- (N-Acetyl-Tsoleucy -Isoleucy -Amino) -1- cyclohexyl-3.4-dihydroxy-6-mβthylheptane The product of Example 24c was deprotected and converted to its free base by the method described in Example 25 to give the amino compound. To a stirred solution of the amine (56.5 mg, 0.12 mmol) in THF was added acetylimidazole (14.6 mg, 0.13 mmol) . The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue dissolved in EtOAc. This solution was washed with H2O and brine, dried, and concentrated in vacuo to give a residue which was flash chromatographed on silica gel to give the title compound (52.3 mg, 85%) as colorless crystals, mp 247-248 °C. • ' " H NMR (DMSO-d 6 , 300 MHz) δ 0.83 (m, 18H) , 1.00-1.80 (m, 22H), 1.83 (s, 3H) , 2.92 (m, IH) , 3.08 (m, IH), 4.10 (m, IH) , 4.20 (q, 2H) , 4.50 (d, IH) , 4.71 (d, IH), 7.52 (d, IH) , 7.82 (d, IH) , 7.91 (d, IH) . Anal calcd for C28H53N3O 5 0.25 H 0: C, 65.17; H, 10.41; N, 8.14; Found: C, 64.92; H, 10.35; N, 8.00. MS (DCI/NH3) m/e 512 (M+H) + Example 28 (2S.3R.4S) -2- (N-Bon- yclohexγlalanyl-Isoleu yl-A ino) -1 - cyclohexyl-3. -dihydroxy-6-methylheptane The product of Example 12a was debenzylated as described in Example 12b to give the free carboxylic acid. To a stirred solution of the product of Example 24a (38.9 mg, 0.16 mmol) in anhydrous CH2CI2 (3 mL) at 0 °C was added successively the carboxylic acid described above (61.4 mg, 0.16 mmol, 1 equiv), HOBT (33 mg, 0.21 mmol), and EDCI (33 mg, 0.172 mmol, 0.08 equiv) . The mixture was stirred overnight allowing to warm to room temperature. The solvent was removed in vacuo and the residue taken up in EtOAc which was washed with IN H3PO 4 (2x) , saturated ΝaHCθ3 (2x) , and saturated NaCl (2x) , dried (MgS0 4 ) , and concentrated in vacuo to give a residue which was flash chromatographed to give the title compound (18 mg, 29%) . mp 181-182 °C. 1 H NMR (DMS0-d 6 , 300 MHz) δ 0.83 (m, 12H) , 1.00-1.80 (m, 30H), 1.37 (2s, 9H) , 2.90-3.15 (m, 3H) , 3.99 (m, IH), 4.13 (m, IH) , 4.23 (t, IH) , 4.47 (d, IH) , 4.72 (d, IH) , 6.75 (d, IH) , 6.80 (d, IH) , 7.60 (d, 2H) . Anal calcd for C3 4 H63N3O6: C, 66.96; H, 10.41; N, 6.89; Found: C, 66.91; H, 10.35; N, 6.77. MS (DCI/NH3) m/e 610 (M+H) + . Example 29 (2S.3R.4S)-2-(N-Boc-Isoleucyl-Isoleucyl-Amino)-1- (2- naphthyl) -3.4-ddhydroxy-6-methylheptane Example 29a (2S) -2-T (tert-Butyloxycarbonvl)aminol-3- (2- naphthyl)propanol L-2-Naphthylalanine (1.00 g, 3.18 mmol) was protected by the method described in Example Ig to give the tert- butyloxy-carbonyl-protected compound (1.4 g, 96%) . To a stirred solution of the above acid (1.4 g, 4.4 mmol) in anhydrous THF (7 mL) at 0 °C was slowly added borane-tetrahydrofuran (BH3-THF) complex (13.2 mL, 13.2 mmol, 3-fold excess) . The cooling bath was removed and the mixture was allowed to warm to room temperature. After 10 min at 25 °C, the mixture was again cooled to 0 °C and a solution of IN ΝaOH (5 mL) was very cautiously added. The cold solution was extracted with Et 2 θ (4x) and the combined organic extracts were dried (MgS0 4 ) and concentrated in vacuo to afford the title compound (1.21 g, 90%) as colorless crystals. The 300 MHz l R ΝMR spectrum was found to be consistent with the proposed structure. MS (DCI/ΝH3) m/e 302 (M+H) + . Example 29b (2S.3R)-2-r (tert-Butvloxvcarbonvl)aminol-1-(2-naphthvl)-3- hydroxy-6-methylheptan-4-one To a stirred solution of anhydrous dimethyl sulfoxide (DMSO) (394 μL, 5.47 mmol, 2.2 equiv) in anhydrous CH 2 CI 2 (7 L) at -70 °C was slowly added a 2Λf solution of oxalyl chloride (1.85 ml, 3.78 mmol, 1.5 equiv) at such a rate as to maintain the temperature below -65 °C. After 10 minutes, a solution of the product of Example 29a (750 mg, 2.48 mmol) in 10% DMSO in CH 2 CI 2 (5 mL) was added, again keeping the temperature less than or equal to -66 °C. The mixture was stirred 15 minutes, after which time dry triethylamine (1.41 mL, 9.95 mmol, 4 equiv) was slowly added to the precipitated sulfoxonium salt. After 3 minutes, anhydrous zinc iodide (183 mg, 0.49 mmol, 0.2 equiv) was added. The mixture was stirred vigorously for 5 minutes, then trimethylsilyl cyanide (TMSCN) (1.19 mL, 8.10 mmol, 3.5 equiv) was added and the mixture was allowed to warm to room temperature. After 60 minutes, the mixture was again cooled to 0 °C and a 2 solution of i-butylmagnesium chloride (13.5 mL, 27 mmol, 10.5 equiv) in ether was added maintaining the temperature equal to or lower than 0 °C. The mixture was allowed to warm to room temperature and stirred for 4 hours. The mixture was poured into EtOAc containing 1:1 ice/lN H 3 PO 4 . The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with IN H 3 PO 4 , H 2 O, and saturated ΝaCl, dried (MgSθ 4 ), and concentrated in vacuo. The residue obtained was flash chromatographed on silica gel eluting with 18% EtOAc/hexane to afford the title compound (486 mg, 51%) . The 300 MHz H ΝMR spectrum was found to be consistent with the proposed structure. MS (DCI/ΝH3) m/e 386 (M+H) + , 403 (M+H+NH3) + . Example 29c (25r3R f 4S)-2-r(tert-Butyloxycarbonyl) minol-1-(2- naphthvl)-3.4-dihvdroxv-6-methvlhePtane To a stirred solution of the product of Example 29b (480 mg, 1.24 mmol) in anhydrous THF (29 mL) at room temperature was added sodium borohydride (48 mg, 1.24 mmol) . The mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and poured into sodium chloride solution. This mixture was extracted with EtOAc, dried (MgSθ 4 ) , and concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel eluting with 30% EtOAc/hexanes to give the title compound (249 mg, 52%) . The 300 MHz l R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 388 (M+H) + , 405 (M+H+NH3) + . Exa ple 29d (2S. R.4S) -2- (N-Boc-Tsoleucyl-Amino) -1- (2-naphthyl) -3.4- dihydroxy-6-methylheptane The product of Example 29c (60 mg, 0.15 mmol) was deprotected by the method described in Example Id to give the hydrochloride salt. The salt was converted to its free base by dissolving in THF (1 mL) and adjusting the pH to 13 with IN ΝaOH. The mixture was poured into CH 2 CI 2 and the aqueous phase was extracted with CH 2 CI 2 • The combined organic extracts were dried over anhydrous K 2 CO 3 and concentrated in vacuo to afford the free amine (45 mg, 100%) . The free amine (45 mg, 0.155 mmol) and Boc-Ile-OH hemihydrate (37 mg, 0.155 mmol) were coupled by the method described in Example 10a to give the title compound (77 mg, 99%) as colorless crystals. The 300 MHz H ΝMR spectrum was found to be consistent with the proposed structure. MS (DCI/ΝH3) m/e 501 (M+H) + , 518 (M+H+NH3) + . Example 29e (2S.3R.4S) -2- (N-Boo-Tsol uoyl-Isoleucyl-A ino) -1- (2- naphthyl)-3.4-dihydroxy-6-methylheptane The product of Example 29d (70 mg, 0.139 mmol) was deprotected by the method described in Example Id and converted to its free base by the method described in Example 29d to give the free amine (56 mg, 100%) . Boc-Ile-OH hemihydrate (33.5 mg, 0.139 mmol) and the free amine (56 mg, 0.139 mmol) were coupled by the method described in Example 10a to give the title compound (85 mg, 99%) as a white solid. mp 168-169 °C. K NMR (CDCI3, 300 MHz) δ 0.68-0.95 (m, 18H) , 1.45 (s, 9H) , 1.00-1.50 (m, 6H), 1.80 ( , 3H) , 2.40 (bs, 3H) , 3.00-3.42 (m, 4H) , 3.82 (t, IH) , 4.16 (m, IH) , 4.40 (q, IH) , 5.23 (d, IH) , 6.91 (d, IH) , 7.20 (d, IH) , 7.40 (d, 3H) , 7.65-7.80 (m, 3H) . Anal calcd for C3 5 H 55 N3O 6 : C, 68.43; H, 9.03; N, 6.85; Found: C, 68.37; H, 8.92; N, 6.79. MS (FAB) m/e 614 (M+H) + . Example 3Q (2S. R.4S)-2-(N-Boc-Cyclohexylalanyl-Isolencyl-Amino)-1- (2-naphthyl) - .4-dihydroxv-6-methylheptane Boc-Cha-OH (34.6 mg, 0.127 mmol) was coupled with (2S,3R,4S)-2-N-(Ile-amino)-1-(2-naρhthyl)-3,4-dihydroxy-6- methylheptane (51 mg, 0.127 mmol), obtained from the deprotection of the product of Example 29d by the method described in Example 29e, by the method described in Example 10a to give, after recrystallization from EtOAc/hexanes, the title compound (57.6 mg, 70%) as a white crystalline solid, mp 173-174 °C. λ R NMR (CDCI3, 300 MHz) δ 0.70-1.05 (m, 12H) , 1.10-1.90 (m, 19H) , 1.47 (s, 9H), 3.20 (m, IH), 3.25 (d of d, IH) , 3.48 (m, 2H) , 4.00-4.20 (m, 2H) , 4.55 ( , IH) , 5.78 (bd, IH) , 7.22-7.50 ( 4H), 7.70-7.83 (m, 3H) . Anal calcd for C38H59N3O6: C, 69.80; H, 9.09; N, 6.43; Found: C, 69.47; H, 9.02; N, 6.38. S (FAB) m/e 654 (M+H) + . Example 31 (2S.3R.4S) -2- (N-Boπ-Cyr.l ohexylalanyl-Isoleucyl-Amino) -1- (l-naphthyl)-3.4-dihydroxy-6-methylheptane The product of Example 31 was prepared in analogy to the method described in Example 30 using 1-naphthylalanine instead of 2-naphthylalanine to give the title compound, mp 149-150 °C. 1 H NMR (CDCI3 + CD3OD, 300 MHz) δ 0.82- 1.90 (m, 31H), 1.44 (s, 9H) , 3.26 (d of d, IH) , 3.38 (m, 2H) , 4.05-4.23 (m, 3H) , 4.62 (q, IH) , 7.30 (bd, IH) , 7.45- 7.57 (m, 7H) , 7.72 (m, IH) , 7.83 (d of d, IH) , 8.19 (d, IH) . Anal calcd for C 38 H 59 N 3 O 6 0.5 H 2 0: C, 68.85; H, 9.12; N, 6.34; Found: C, 69.09; H, 9.10; N, 6.31. MS (DCI/NH3) m/e 654 (M+H) + , 671 (M+H+NH3) + . Example 32 N-Boc-Isoleucyl-Isoleucyl-Statyl Isopropylcarboxamide To the product of Example 5b (50 mg, 0.1 mmol) in freshly distilled THF (5 mL) cooled to -5 °C was added NMM (11.5 μL, 0.105 mmol) followed by IBCF (13.5 μL, 0.105 mmol) ; the reaction mixture was stirred at -5 °C for 15 minutes. Isopropylamine (25.5 μL, 0.15 mmol) was added and the reaction mixture was allowed to warm to room temperature overnight. EtOAc with a small amount of MeOH was added and the mixture was washed with lΛf H 3 PO 4 (3x) , saturated NaHC0 3 (3x) , and brine, dried (Na 2 S0 4 ) , and concentrated in vacuo to give a white solid (46 mg) which was flash chromatographed on silica gel eluting with 97/3 CHCl 3 /EtOH to give an amorphous solid. Crystallization from MeOH/H 2 θ afforded the title compound (32 mg, 59%) . 1 H NMR (CDCI3, 300 MHz) δ 0.86-1.05 (m, 18H) , 1.05-2.15 (m, 15H), 1.46 (2s, 9H) , 2.30 (m, 2H) , 2.50 (bd, IH) , 3.70 (d of t, IH) , 3.80-4.25 (m, 4H) , 4.86-4.97 (m, IH) , 6.40- 6.73 (m, 3H) . Anal calcd for C 2 8H 54 N 4 O6 0.25 H2O: C, 61.45; H, 10.04; N, 10.24; Found: C, 61.48; H, 9.80; N, 10.10. MS (FAB) m/e 543 (M+H) + , 565 (M+Na) + . Example 33 n-rN-Cbz-Isoleucyl-Isole oyl-Aminol-3- methylbut l (hydroxy) hosphinyl1acetic acid tert-Butyl ester The product of Example 9 (100 mg, 0.156 mmol) and KCN 1,4,7,10, 13,16-hexaoxacyclooctadecane (18-Crown-6) complex (48 mg, 0.146 mmol) were dissolved in anhydrous DMSO (5 mL) and heated at 70-80 °C for 5 h and stirred at room temperature overnight. EtOAc was added and the mixture was washed with 1M H3PO 4 and brine, dried (Na2Sθ 4 ) , and concentrated in vacuo to give an amorphous solid (91 mg) . Flash chromatography on silica gel eluting with 90/10/1 CHCl3/MeOH/NH OH gave the title compound (49 mg, 67% based on a 25 mg recovery of the product of Example 9) . H NMR (CD3OD, 500 MHz) δ 0.90 (m, 18H) , 1.10-1.90 (m, 9H) , 1.47 (2s, 9H), 2.51-2.76 (m, 2H) , 4.01 (t, IH) , 4.28 (m, 2H) , 5.09 (m, 2H), 7.31 (m, 5H) . Anal calcd for C3 1 H 5 2N3O8P 0.25 NH4OH: C 58.68; H, 8.46; N, 7.17; Found: C, 58.29; H, 8.44; N, 7.46. MS (FAB) m/e 626 (M+H) + , 648 (M+Na) + , 670 (M+2Na) + . Example 34 N-Boc-Isoleucyl-Isoleucyl-Statyl Isoamylcarboxamide The product of Example 5b (50 mg, 0.1 mmol) was reacted with isoamylamine (23 μt, 0.2 mmol) by the method described in Example 32 to give a white solid (50 mg, 88%) which was flash chromatographed on silica gel eluting with 97/3 CHCl 3 /EtOH to give an amorphous solid. Crystallization from MeOH/H 2 θ afforded the title compound (24 mg, 42%). X H NMR (CDCI3, 300 MHz) δ 0.94 (m, 24H) , 1.02-2.13 (m, 12H) , 1.47 (2s, 9H) , 2.23-2.57 ( , 3H) , 3.25 (m, 2H) , 3.71 (d of t, IH) , 3.90 (m, 2H) , 4.20 (m, IH) , 4.90 (2d, IH), 6.40-6.60 (m, 2H) , 6.70 (d, IH) . Anal calcd for C 3θ H 58 N4θ 6 0.4 H 2 0: C, 62.34; H, 10.25; N, 9.69; Found: C, 62.21; H, 9.85; N, 9.42. MS (FAB) m/e 571 (M+H) + , 471 (M+H-Boc) + . Example 35 N-Boc-Isoleuoyl-Isoleucyl-Statyl Cyclohexylmethylcarboxamide The product of Example 5b (50 mg, 0.1 mmol) was reacted with cyclohexanemethylamine (19.5 μL, 0.15 mmol) by the method described in Example 32 to give a white solid (50 mg) which was flash chromatographed on silica gel eluting with 96.5/3.5 CHCl 3 /EtOH to give an amorphous solid. Crystallization from MeOH/H 2 θ afforded the title compound (31 mg, 52%). 1 H NMR (CDCI3, 300 MHz) δ 0.95 (m, 18H), 1.03-2.12 (m, 20H) , 1.47 (2s, 9H) , 2.24-2.70 (m, 3H), 3.10 (q, 2H) , 3.68-4.04 (m, 3H) , 4.21 (m, IH) , 4.90 (2d, IH), 6.40-6.63 (m, 2H) , 6.77 (bd, IH) . Anal calcd for C 32 H 6 oN 4 0 6 0.25 H 2 0: C, 63.91; H, 10.14; N, 9.32; Found: C, 63.80; H, 9.88; N, 9.22. MS (FAB) m/e 597 (M+H) + , 619 (M+Na) + . Example 36 ri- TN- (N-Cbz- r (S) -2-Amino-3.3-dimet.hylbutano y π ) - T o ucy 1 -Aminol -3-methylbutyl (hydroxy) phosphinyl l acetic aci d tert-Butyl ester Example 36a n-TN-(N-Cbz-r(S)-2-ftmino-3,3-dimethylbutanoyll)- Isoleucyl-Aminol-3-methylbutyl(methoxy)phosphinyl1acetic acid tert-Butyl ester The product of Example 9c was coupled with (S)-2- (benzyloxycarbonyl)-amino-3,3-dimethylbutanoic acid by the method described in Example le to give the title compound. The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. Example 36b n-fN-(N-Cbz-r (S)-2-Amino-3.3-dimethylbutanoyl1 )- Tsol ucyl-Aminol-3-methylbutyl (hydroxy)phosphinyl1acetic acid tert-Butyl ester To the product of Example 36a (115 mg, 0.18 mmol) dissolved in anhydrous DMSO (5 mL) was added KCN:18- crown-6 (52 mg, 0.16 mmol). The reaction mixture was heated at 70-80 °C for 3 hours, cooled to room temperature, and then partitioned between lAf H 3 PO 4 and EtOAc. The organic phase was washed with brine, dried (Na 2 Sθ ), and concentrated under reduced pressure to afford a residue which was flash chromatographed eluting with 90/10/1 chloroform/methanol/ammonium hydroxide. The title compound was obtained as an amorphous solid (37 mg, 33%). X H NMR (CDCI3, 300 MHz) δ 0.95 ( , 21H) , 1.00-1.90 (m, 6H) , 1.45 (s, 9H) , 2.78 (m, 2H) , 3.95-4.66 (m, 3H) , 5.07 (bq, 2H) , 5.67 (bs, IH) , 6.70 (bs, IH) , 7.30 (m, 5H) , 7.55 (bs, IH) . MS (FAB) m/e 626 (M+H) + , 648 (M+Na) + . Example 37 ri- rN-Cbz-Isoleucyl-Isoleucyl-Aminol -3- ethylbutyl (hydroxy) phosphinyl 1 aoetyl Isobutylcarboxamide Example 37a n-JN-Chz-Tsoleucyl-Isoleuoyl -Aminol-3- methylbutyl (methoxy) hosphinyl1 aoetic Aπi The product of Example 9d (137' mg, 0.21 mmol) was dissolved in TFA (1.5 mL) and stirred at room temperature for one hour. The TFA was removed under reduced pressure and azeotroped with toluene (4x10 mL) to afford the title compound (125 mg, 100%) as a white solid. The 300 MHz λ R NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 584 (M+H) + . Example 37b ri-fN-Cbz-Isolenoyl-Tsoleucyl-Aminol-3- methylbutyl (methoxy)phosphinyl 1aoetyl Tsohntylc rboxamide To isobutylamine (32 μL, 0.32 mmol) dissolved in CH 2 CI2 and cooled to 0 °C was added the product of Example 37a (126 mg, 0.22 mmol) in CH 2 CI 2 followed by HOBT (36 mg, 0.26 mmol) and EDCI (46 mg, 0.24 mmol) . The reaction mixture was allowed to warm to room temperature overnight and then diluted with EtOAc. Washing with lΛf H3PO 4 (3x) , saturated NaHCθ3 (3x) , and brine, drying ( a 2 S0 4 ) , and concentrating under reduced pressure afforded crude material (125 mg, 91%) . Flash chromatography eluting with 1.75% MeOH in CHCI3 afforded the title compound (78 mg, 57%) . The 300 MHz X R NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 639 (M+H) + , 656 (M+H+NH3) + . Example 37c ri-rN-Cbz-Isoleucyl-Isoleucyl-Aminol-3- methylbutylfhydroxy)phosphinyl1acet.yl Isobutylcarboxamide The product of Example 37c (75 mg, 0.12 mmol) was demethylated by the procedure described in Example 36b and purified by flash chromatography to afford the title compound as an amorphous solid (13 mg, 17%) . H NMR (CD3OD, 300 MHz) δ 0.80-1.00 (m, 24H) , 1.05-1.90 (m, 10H) , 2.70 ( , 2H), 3.04 (m, 2H) , 4.00-4.28 (m, 3H) , 5.09 (m, 2H), 7.33 (m, 5H) . MS (FAB) m/e 625 (M+H) + , 663 (M+K) + . Example 38 (2S.3R.4S)-2-(N-Boc-Cyolohexylalanyl-Isoleucyl-Amino)-1- (3-indolyl) -3.4-dihydroxy-6-methylheptane Example 38a N-Boo-Trypt.ophanyl(N'-Boc) Benzvl ester To a suspension of L-tryptophan benzyl ester hydrochloride (1.00 g, 3.02 mmol) in benzene (100 mL) was added successively 50% aqueous sodium hydroxide (10 mL) , tetrabutylammonium bisulfate (100 mg) and triethylamine (1.25 mL, 8.9 mmol, 2.96 equiv) without stirring. Vigorous stirring was initiated and then di- t-butyl dicarbonate (1.97 g, 9.05 mmol, 3 equiv) was added. After stirring at room temperature for 90 minutes, water (50 mL) was added and the phases separated. The aqueous phase was extracted with benzene and the combined organic phases were washed with 10% aqueous citric acid and brine, dried (MgS0 4 ), and concentrated in vacuo. The residue obtained was flash chromatographed eluting with 15-25% gradient of EtOAc in hexanes to give the title compound (902 mg, 60%) as a white amorphous solid. The 300 MHz' X H NMR spectrum was found to be consistent with the proposed structure. Example 38b N-Boc-Tryptophanyl(N'-Boc)-QH To a suspension of 10% palladium on carbon (250 mg) in methanol (2 mL) was added 1,3-cyclohexadiene (200 μL, 2.02 mmol, 2 equiv). After the mixture was stirred at room temperature for 5 minutes, a solution of the product of Example 38a (500 mg, 1.01 mmol) in a 1:1 mixture of EtOAc and MeOH (2 mL) was added. After 2 hours, the catalyst was removed by filtration and the solvent removed in vacuo to afford the title compound as a white amorphous solid (334 mg, 82%) . The 300 MHz X H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 405 (M+H) + , 422 (M+H+NH3) "1" . Exa ple 38c (2S.3R.4S)-2- r (tert-Butyloxycarbonyl)aminol-1- ri-N- (tβrt-butyloxycarbonyl) indol-3-yll-3.4-dihydroxy-6- methylheptane The product of Example 38b was reduced using BH 3 - THF complex by the procedure described in Example 29a to give the alcohol; the 300 MHz 1 H NMR spectrum of which was found to be consistent with the proposed structure, MS (DCI/NH3) m/e 391 (M+H) + , 408 (M+H+NH3) "1" . By the procedure described in Example 29b, the alcohol was then carried on to the heptanone; the 300 MHz 1 H NMR spectrum of which was found to be consistent with the proposed structure, MS (DCI/NH3) m/e 475 (M+H) + , 492 (M+H+NH3) "1" . Sodium borohydride reduction for two hours by the procedure described in Example 29c afforded the dihydroxy title compound as an amorphous solid (324 mg, 68%) . The 300 MHz L H NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 477 (M+H) + , 494 (M+H+NH3) + . Example 38d (2S.3R.4S)-2-(N-Boo-Cyclohexy1a]any1-Isoleucyl-Amino)-l- n-N-(tert-butyloxycarbonyl) indol-3-yll-3.4-dihydroxv-6- methylheptane The product of Example 38c (251 mg, 0.52 mmol) was dissolved in 4N HCl in dioxane (2 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue partitioned between THF-CH 2 CI 2 and IN ΝaOH. The phases were separated and the aqueous layer further extracted with THF-CH 2 CI 2 • The combined organic extracts were dried (K 2 CO 3 ) and concentrated in vacuo to afford the free amine (198 mg, 100%) . The free amine (198 mg, 0.52 mmol) was coupled with Boc-Ile-OH hemihydrate (127 mg, 0.52 mmol) by the procedure described in Example 10a to give Boc-Ile- [ (2S,3R,4S)-2-Amino-l-[1-(tert-butyloxycarbonyl)indol-3- yl]-3,4-dihydroxy-6-methylheptane] as an amorphous solid (75 mg, 24%); MS (DCI/NH3) m/e 590 (M+H) + . Deprotection and conversion to free base were performed as described above to afford the free amine (51 mg, 81%) . Boc-Cha-OH (28 mg, 0.102 mmol) was coupled with the free amine (51 mg, 0.102 mmol) by the procedure described in Example 10a to give the title compound (74 mg, 96%) . The 300 MHz 1 H NMR spectrum was found to be consistent with the proposed structure. MS (FAB) m/e 643 (M+H) + . Example 38e (2S. R.4S) -2- (N-Boc-Cyclohexylalanyl-Isoleucyl-Amino) -1- (3-indolyl) -3.4-dihydroxy-6-methylheptane To a stirred solution of the product of Example 38d (74 mg, 99 μmol) in THF (1 mL) was added 4N ΝaOH (1 mL) . The biphasic solution was stirred overnight at room temperature, diluted with MeOH (1 mL) to effect solution, and stirred overnight at room temperature. Concentration in vacuo afforded an aqueous residue which was extracted with CH 2 CI 2 /THF (8:2) . The aqueous phase was brought to neutrality with 1 . 1N ΝaHSθ 4 and further extracted with EtOAc. The combined organic extracts were dried (MgSθ 4 ) and concentrated in vacuo to afford a residue which was purified by flash chromatography and lyophilized to give the title compound (56 mg, 87%) . H NMR (CDCI3 + CD3OD, 300 MHz) δ 0.70 (m, 12H) , 0.80-1.70 (m, 19H), 1.28 (s, 9H) , 2.90 (d, 2H) , 3.15 (m, 2H) , 3.90-4.10 (m, 3H) , 4.34 (m, 1H),6.90 (m, 3H) , 7.17 (d, IH), 7.43 (d, IH) . MS (FAB) m/e 643 (M+H) + . Example 39 N-Boc-Cyclohexylalanyl-Tsoleucyl-Statyl Isobutylcarboxamide The compound resulting from Example 15 (47 mg, 0.087 mmol) was reacted with isobutylamine (21 μL, 0.22 mmol) by the procedure described in- Example 5c. The crude material (45 mg) was recrystallized from hot ethyl acetate and hexanes to afford the title compound (35 mg, 68%). 1 H NMR (CDCI3 + CD3OD, 300 MHz) δ 0.86-0.97 (m, 18H), 1.46 (s, 9H), 1.10-1.98 (m, 20H) , 2.29 (m, 2H) , 3.05 (m, 2H) , 3.91 (m, 2H) , 4.12 (m, 2H) . Anal calcd for C32H60 4 O6: C, 64.40; H, 10.13; N, 9.39. Found: C, 64.59; H, 9.95; N, 9.07. MS (FAB) m/e 597 (M+H) + . Example 4Q N-Boc-Cyolohexylalanyl-Tsoleucyl-Statvl N-(2-(2- Pyridyl)ethyl)Carboxamide To the compound resulting from Example 15 (30 mg, 55.45 μmol) dissolved in tetrahydrofuran (2 mL) and cooled to 0 °C was added 1-hydroxybenzotriazole (HOBT) (9 mg, 1.2 equiv) in DMF, 4-(dimethylamino)pyridine (DMAP) (8.1 mg, 1.2 equiv) and l-amino-2-(2- pyridyl)ethane (16.6 μL, 2.5 equiv) . After the mixture became homogeneous, EDCI (12.8 g, 1.2 equiv) was added. After stirring at room temperature for 3 days, the reaction mixture was concentrated at reduced pressure. The residue obtained was purified by preparative HPLC and lyophilized to give the title product (32.4 mg, 91%) . λ R NMR (CDCI3, 300 MHz) δ 0.87-1.00 ( , 12H) , 1.46 (s, 9H) , 1.20-1.82 (m, 19H) , 2.04 (bs, IH) , 2.27 (m, IH) , 2.38 (m, IH) , 3.41 (m, 2H) , 3.86 (m, 2H) , 4.13 (m, 2H) , 5.22 (m, IH) , 7.10 (m, IH) , 7.60-7.80 (m, 2H) , 7.85 (d, IH) , 8.32 (bt, IH) , 8.70 (m, IH) . Anal calcd for C3 5 H59N 5 0 6 -1.25 TFA: C, 56.99; H, 7.67; N, 8.87. Found: C, 57.13; H, 7.70; N, 8.88. MS (DCI/NH3) m/e 646 (M+H) + . Example 41 N-Boc-Cvclohexylalanyl-Isoleucyl-Statyl N-(2-N'.N'- Dimethylaminoethyl) arboxamide To the compound resulting from Example 15 (30 mg, 55.45 μmol) was reacted with N,N-dimethylethylenediamine (15 μL, 2.5 equiv) by the procedure described in Example 40. Purification by preparative HPLC and lyophilization afforded the title compound (31.8 mg, 94%) . 1 H NMR (CDCI3, 300 MHz) δ 0.85-1.00 (m, 18H) , 1.45 (s, 9H) , 1.00-1.80 (m, 19H), 2.25 (m, IH) , 2.45 (m, IH) , 3.01 (d, 2H), 3.22 (m, IH) , 3.50 (m, IH) , 3.93-4.20 (m, 4H) , 5.59 ( , IH), 7.40 (m, IH) , 8.03 (bd, IH) , 8.45 (m, IH) , 9.63 (m, IH) . Anal calcd for C32H6 1 N 5 O6 • 1.1 TFA: C, 55.97; H., 8.46; N, 9.29. Found: C, 55.71; H, 8.49; N, 9.50. MS (DCI/NH3) m/e 612 (M+H) + . Example 42 N-Boc-Cyclohexylalanyl-Isolβucyl-Statyl N- (2- (Morpholin- 4-y.l ) ethyl) Carboxamide The compound resulting from Example 15 (30 mg, 55.45 μmol) was reacted with N-(2-aminoethyl)morpholine (18 μL, 2.5 equiv) by the procedure described in Example 40. Purification by preparative HPLC and lyophilization afforded the title product (24 mg, 66%) . 1 H NMR (CDCI3, 300 MHz) δ 0.84-1.00 (m, 12H) , 1.45 (s, 9H) , 1.00-1.77 (m, 19H), 2.20-2.47 (m, 2H) , 2.40-3.05 (m, 7H) , 3.20 (bd, IH), 3.53 (bt, IH) , 3.85-4.28 (m, 7H) , 5.60 (bd, IH), 7.50 (bs, IH) , 8.20 (bd, IH) , 8.7 (m, IH) . Anal calcd for C 34 H 6 ιN 5 0 7 -1.3 TFA: C, 55.'36; H, 8.06; N, 8.35. Found: C, 55.16; H, 8.14; N, 8.38. MS (DCI/NH3) m/e 654 (M+H) + . Example 43 (2Sr3Rr4S)-2-f FN-(4-Methylpiperazin-l-yl-carbonyl)- Cyclohexylalanyl-Isoleucyllamino}-l-(2-naphthyl)-3,4- dihydroxy-6-methylheptane Hydrochloride Example 43a N-(4-Methy piperazin-l-yl-carbonyl) -Cyclohexylalanine To Cyclohexylalanine methyl ester hydrochloride salt (1.00 g, 4.51 mmol) suspended in toluene (25 mL) was added bis(trichloromethyl)carbonate (triphosgene) (669.2 mg, 0.5 equiv) . The reaction mixture was warmed at 100 °C for 3 hours and then concentrated under reduced pressure to afford a semi-solid residue. To this residue dissolved in methylene chloride (15 mL) and cooled to 0 °C was added N-methylpiperazine (0.50 mL, 1.0 equiv) . After stirring for 1 hour, the reaction mixture was concentrated at reduced pressure to afford a semi-solid residue. Flash chromatography on silica gel eluting with 4% methanol in chloroform afforded the title product (629 mg, 45%) . To the methyl ester (629 mg, 2.022 mmol) dissolved in tetrahydrofuran (16 mL) and water (2 mL) and cooled to 0 °C was added lithium hydroxide monohydrate (169.7 mg, 2.0 equiv) in water (2 mL) . After 90 minutes, the tetrahydrofuran was removed under reduced pressure and the aqueuous solution acidified to pH 3 by the careful addition of IN HCl. This solution was placed on a column of Dowex 1-X8 and 50W-X8 made acidic by packing and equilibrating with IN HCl. The column was eluted with 0 . 1N HCl and 1. ON HCl. The title product was obtained as an amorphous solid. MS (DCI/ΝH3) m/e 298 (M+H) + . The 300 MHz X R NMR spectrum was found to be consistent with the proposed structure. Example 43b (2S.3R.4Si -2--T TN- (4-Methylpiperazin-l-yl-carhonyl ) - Cyolohexylalanyl-Tsoleuoyl 1 amino ) -l - (2-naphthyl ) -3. 4- dihydroxy-6-methylheptane Hydrochloride The compound resulting from Example 29d (27.8 mg, 55.5 μmol) was deprotected as described in Example Id to afford (2S,3R,4S)-2-N-(Isoleucyl-amino)-1-(2-naphthyl)- 3,4-dihydroxy-6-methylheptane. The compound resulting from Example 43a (18.1 mg, 61 μmol) was coupled with the above amine (22.2 mg, 0.91 equiv) using the procedure described in Example le to afford crude product (31 mg, 76%) . Flash chromatography on silica gel eluting with 20% methanol in methylene chloride afforded pure material. The free amine was taken up in 4N HCl in dioxane (1.5 mL) and then concentrated at reduced pressure to afford the hydrochloride salt. """H ΝMR (DMSO-d6, 300 MHz) δ 0.62-0.89 (m, 12H) , 0.90-1.80 (m, 19H) , 2.23 (m, 3H), 2.90-3.20 (m, 4H) , 3.30 (s, 3H) , 3.40-3.74 (m, 3H) , 4.18 (m, IH), 4.32 (m, IH) , 5.00 (d, 0.5H) , 6.55 (d, 0.5H), 7.40-7.57 (m, 4H) , 7.70-7.88 (m, 4H) . Anal calcd for C3 9 H 62 ClΝ 5 0 5 -2.5 H 2 0: C, 61.52; H, 8.87; N, 9.20. Found: C, 61.37; H, 8.98; N, 9.14. MS (FAB) m/e 680 (M+H) + . Example 44 N-Boc-tert-Butvlalanvl-Isoleucyl-Statvl-OEt tert-Butylalanine (250 mg, 1.7 mmol) was protected by the procedure described in Example lg. The 300 MHz ■ "Ή NMR spectrum was found to be consistent with the proposed structure. MS (DCI/NH3) m/e 246 (M+H) + , 263 (M+H+NH3) " * " . The free base of Example If (69 mg, 0.22 mmol) was coupled with the above carboxylic acid (53 mg, 0.22 mmol) by the procedure described in Example 3c. The product was recrystallized from ethyl acetate and hexanes to afford the title compound (108 mg, 92%) . H NMR (CDCI3, 300 MHz) δ 0.86-0.99 (m, 21H) , 1.27 (d of t, 3H), 1.46 (s, 9H) , 1.00-2.07 (m, 8H) , 2.47 (m, 2H) , 3.40 (d of d, IH) , 3.97-4.27 (m, 6H) , 4.85 (m, IH) , 6.32 ( , IH), 6.60 (m, IH) . Anal calcd for C28H53N3O7: C, 61.85; H, 9.82; N, 7.73. Found: C, 62.05; H, 10.01; N. 7.52. MS (FAB) m/e 544 (M+H) + . Example 45 N-Boc-ter -Bu+yl 1any!-Tsole πyl-Statyl-OH The compound resulting from Example 44 (40 mg, 74 μmol) was hydrolyzed by the procedure described in Example 2 to give, after recrystallization from methylene chloride and hexanes, the title product (35 mg, 92%) . 1 H NMR (CDCI3, 300 MHz) δ 0.85-1.00 (m, 21H) , 1.46 (s, 9H), 1.03-2.03 (m 8H) , 2.53 (t, 2H) , 3.07-4.30 (m, 4H) , 5.00 (bd, IH) , 6.82 (bd, IH) . Anal calcd for C 2 βH 4 9 3θ 7 -1.0 H 2 0: C, 58.51; H, 9.63; N. 7.87. Found: C, 58.65; H, 9.66; N, 7.89. MS (FAB) m/e 516 (M+H) + , 538 (M+Na) + . Example 46 (2S.3R.4S) -2- i rN-Boc-Aspartyl (β-O-Benzyl) -Isoleucyl- Isoleucyl1amino)-l-(2-naphthyl)-3 r 4-dihydroxy-6- methylheptane The compound resulting from Example 29 was deprotected by the procedure described in Example Id to give (2S,3R,4S)-2-N-(Isoleucyl-Isoleucyl-amino)-1- (2- naphthyl)-3,4-dihydroxy-6-methylheptane] . This amine (41 mg, 0.079 mmol) was coupled with Boc-Aspartic(β- OBenzyl) acid (25.3 g, 0.079 mmol) by the procedure described in Example 10a to give crude product . Recrystallization from ethyl acetate and hexanes afforded the title compound (51 mg, 80%) as colorless crystals, m.p. 178-179 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.58 (m, 6H), 0.94 (m, 12H) , 1.48 (s, 9H) , 1.00-2.08 (m. 9H), 2.65 (bs, IH), 2.90-3.43 (m, 6H) , 4.07-4.23 ( , 3H), 4.40 (d of d, IH), 4.67 (d of d, IH) , 5.11 (d of d, 2H), 5.62 (d, IH) , 6.67 (d of d, IH) , 6.80 (d, IH) , 7.29-7.43 (m, 7H) , 7.64-7.78 (m, 4H) . Anal calcd for C, 67.46; H, 8.12; N, 6.84. Found: C, 67.24; H, 7.95; N, 6.59. MS (FAB) m/e 819 (M+H) + . Example 47 N-Boc-Isoleucyl-lsoleucyl-Statyl N-(2-(2- Pyridyl)ethyl)Carboxamide The compound resulting from Example lOe (48 mg, 95.8 μmol) was reacted with 2-(2-aminoethyl)pyridine (29 μL, 2.5 equiv) by the procedure described in Example 40. Purification by HPLC followed by lyόphilization afforded the title product. X H NMR (CDCI3, 300 MHz) δ 0.87-1.00 (m 18H), 1.46 (s, 9H) , 1.00-2.07 (m, 9H) , 2.28 (m, 2H) , 3.32 (t, 2H), 3.60-3.96 (m, 6H) , 4.14 (t, IH) , 5.28 (bd, IH), 6.92 (m, IH) , 7.50-7.82 (m, 3H) , 8.24 (t, IH) , 8.77 (bd, IH) . Anal calcd for C32H55N5O6*1• 65 TFA: C, 53.40; H, 7.19; N, 8.82. Found: C. 53.07; H, 7.10; N, 9.25. MS (FAB) m/e 606 (M+H) + . Example 48 (2S.3R.4S)-2-f rN-Suocinyl-Cγclohexylalany]- Tsoleuoyll mino1-1-(2-naphthyl)-3.4-dihydroxy-6- ethylheptane The compound resulting from Example 30 (250 mg, 0.38 mmol) was deprotected by the procedure described in Example Id. This amine hydrochloride was reacted with succinic anhydride (7 mg, 1.05 equiv) by the procedure described in Example 19. Purification by MPLC eluting with 10% methanol in methylene chloride containing 1% ammonium hydroxide and lyophilization afforded the title compound. m.p. 156-160 °C. 1 H NMR (DMSO-d 6 , 300 MHz) δ 0.60-0.87 (m, 12H) , 0.88-1.80 (m, 19H) , 2.25-2.47 (m, 4H) , 2.90-3.20 (m, 4H) , 3.32 (d, IH) , 4.15 (t, IH) , 4.33 (m, 2H) , 5.03 (bd, IH) , 7.45 (m, 3H) , 7.64-7.89 (m, 5H) , 8.04 (bd, IH) . Anal calcd for C 37 H 55 N 3 O7-H 2 0: C, 66.14; H, 8.55; N, 6.25. Found: C, 65.76; H, 8.61; N. 6.33. MS (FAB) m/e 654 (M+H) + . Example 49 (2S.3R.4S)-2-( rN-Boc-Cyclohexγlalanγl-Isoleucyl1amino)- 1- (4- er -but.ylphenyl)-3,4-dihydroxy-6-methylheptane Example 49a tert-Butyl 3-(4-tert-Butyl)phenvlnropionate To a stirred solution of anhydrous isopropylcyclohexylamine (5.18 mL, 31.5 mmol, 1.05 equiv) in anhydrous tetrahydrofuran (30 mL) at 0 °C was added n-butyllithium (13.0 mL, 30.3 mmol, 1.01 equiv). The resultant solution was cooled to -75 °C and anhydrous tert-butyl acetate (4.04 mL, 30 mmol) was added at a rate such that the temperature did not exceed -73 °C. The enolate solution was stirred for 1 hour and then 1,3-dimethyl,3,4,5,6-tetrahydro-2(IH)-pyrimidinone (DMPϋ) (3.80 mL, 30 mmol, 1 equiv) followed by a pre- cooled solution of freshly distilled 4-tert-butylbenzyl bromide (5.51 mL, 30 mmol, 1 equiv) in tetrahydrofuran (5 mL) was added at rate such that the temperature remained below -65 °C. The cooling bath was removed and the mixture warmed to room temperature and poured into 1.1M sodium bisulfate and ether. The phases were separated and the organic phase washed with solutions of sodium bicarbonate and sodium chloride (2x) , dried (magnesium sulfate) and concentrated in vacuo to afford crude material. Flash chromatography on silica gel eluting with 5% ether in hexanes gave the title compound (7.247 g, 92%) as a colorless oil. Example 49b tert-Butyl 3-(4-tert-Butyl) henylpropionic Acid To a stirred solution of the compound resulting from Example 49a (7.24 g, 27.6 mmol) in anhydrous methylene chloride (8 mL) at 0 °C was added TFA (4 mL, 52 mmol, 1.9 equiv) . The cooling bath was removed and the mixture stirred overnight at room temperature. The volatiles were moved in vacuo to afford a white crystalline solid. The product obtained was dissolved in 3N sodium hydroxide (60 mL) and washed with hexane (2x) . The aqueous layer was cooled to 10 °C and the pH adjusted to 1.0 by the careful additon of 3N HCl (70 mL) . The precipitated acid was extracted with ether (2 x 50 mL) ; the combined organic extracts were dried over magnesium sulfate and concentrated a in vacuo to afford the title compound (5.14 g, 90%). Example 49c (4S)-3-f3-(4-tert-Butylphenyl)-l-oxopropyl}-4- (phenylmethyl)-2-oxazolidinone To a stirred solution of the compound resulting from Example 49b (3.00 g, 14.54 mmol) in anhydrous tetrahydrofuran (100 L) at -78 °C was added successively anhydrous triethylamine (2.63 mL, 18.9 mmol, 1.3 equiv) and freshly distilled pivaloyl chloride (2 mL, 15.99 mmol, 1.1 equiv) . The reaction mixture was stirred at -78 °C for 15 minutes, 0 °C for 45 minutes, and then re-cooled to -78 °C. In a separate flask, n-butyllithium (2.22Λ solution in hexanes) (6.9 mL, 15.3 mmol, 1.05 equiv) was added to a stirred solution of the oxazolidinone (2.83 g, 15.99 mmol, 1.1 equiv) in anhydrous tetrahydrofuran (35 mL) at -78 °C at a rate such that the temperature did not exceed -72 °C. The cold oxazolidinide solution was transferred via cannula into the mixed anhydride solution, and the reaction mixture was stirred overnight allowing to gradually warm to room temperature. The reaction was quenched by the addition of IN sodium hydrogen sulfate (120 mL) , and most of the tetrahydrofuran was removed in vacuo. The resulting aqueous mixture was extracted with methylene chloride (3 x 50 mL) and the combined organic extracts washed with solutions of sodium bicarbonate and sodium chloride, dried over sodium sulfate, and concentrated in vacuo . The residue obtained was flash chromatographed on silica gel eluting with 10% ethyl acetate in hexanes to afford the title product (5.31 g, 76%) . The 300 MHz l R ΝMR spectrum was found to be consistent with the proposed structure. Exa ple 49d (3(2S) .4S)-3-f2-Azido-3-(tert-butylphenyl)-l-oxopropyl>- 4- (PhenyImethyl) -2-oxazolidinone To anyhydrous tetrahydrofuran (27 L) at -78 °C was added a solution of potassium hexamethyldisilazide (18.96 mL, 9.48 mmol, 1.1 equiv) followed by a solution of the compound resulting from Example 49c (3.10 g, 8.66 mmol) at -78 °C in anhydrous tetrahydrofuran (41 mL) such that the temperature did not exceed -75 °C. After 30 minutes, a pre-cooled solution of 2,4,6- triisopropylbenzenesulfonyl azide (Trysl azide) (3.37 g, 10.92 mmol, 1.2 equiv) in anhydrous tetrahydrofuran (29 mL) was added rapidly through a wide bore cannula. The mixture was stirred for 1 minute ' upon completion of the addition, and then acetic acid (2.27 mL, 39.8 mmol, 4.6 equiv) was added in one portion. The cooling bath was removed and replaced with a water bath at 40 °C allowing the reaction temperature to quickly rise to 32 °C. After 30 minutes at this temperature, the mixture was poured into brine and extracted with methylene chloride (2x) . The combined organic extracts were washed with sodium bicarbonate solution, dried over magnesium sulfate, and concentrated in vacuo to afford crude material. Purification by flash chromatography on silica gel eluting with 50% methylene chloride in hexanes afforded partially purified material which was rechromatographed eluting with a 45% to 100% gradient of methylene chloride in hexanes to afford the title compound (2.09 g, 59%). Example 49e (2S) -2-Azido-3- (4-tert-Butylphenyl) ropionic acid To the compound resulting from Example 49d (2.09 g, 5.14 mmol) dissolved in tetrahydrofuran (38 mL) and water (12.8 mL) and cooled to 0 °C was added lithium hydroxide monohydrate (430 mg, 10.2 mmol, 2.0 equiv). After 30 minutes, the mixture was poured into 0 .5N sodium bicarbonate (60 mL) and concentrated at reduced pressure to remove the tetrahydrofuran. The aqueous solution was extracted with methylene chloride (4x) and then adjusted to pH 1.0 by the careful addition of 3N sulf ric acid and extracted with ether (4x) . The combined ether extracts were dried 'over magnesium sulfate and concentrated in vacuo to afford the title compound (1.27 g, 99%) as colorless crystals. Example 49f (2S)-2-Boc-Amino-3-(4-tert-Butvlphenvl)propan-l-ol To a stirred suspension of lithium aluminum hydride (748 mg, 19.7 mmol, 4 equiv) in anhydrous tetrahydrofuran (50 mL) at 0 °C was added a solution of the compound resulting from Example 49e (1.22 g, 4.93 mmol) in tetrahydrofuran (5 mL) . The cooling bath was removed and the mixture warmed to room temperature. After 30 minutes, the mixture was heated under reflux for 2 hours. After cooling to room temperature, 4N sodium hydroxide was cautiously added. The solvent was removed in vacuo and the residue obtained extracted with methylene chloride (3x) . The combined organic extracts were dried over anhydrous potassium carbonate and concentrated in vacuo to afford the amino compound (883 mg, 86%) . The amino compound (836 mg, 4.03 mmol) was protected using the procedure described in Example Ig to afford crude material. Flash chromatography on silica gel eluting with with 40% ethyl acetate in hexanes afforded the title compound (957 mg, 77%) . The 300 MHz τ R NMR spectrum was found to be consistent with the proposed structure. Example g (2S.3R.4S)-2-Amino-l-(4-tert-butylphenyl)-3.4-dihydroxv- 6-methylheptane The compound resulting from Example 49f (235 mg, 0.77 mmol) was treated in analogy to the procedure described in the literature for the 1-cyclohexyl compound: Luly, J.R.; Hsiao, C.N.; BaMaung, N.; Plattner, J.J. J. Org. Chem. 1988, 53, 6109. This compound (58 mg, 0.147 mmol) was deprotected by the procedure described in Example Id to give the hydrochloride salt. The salt was partitioned between methylene chloride and IN sodium hydroxide. The aqueous layer was further extracted with methylene chloride and the combined organic extracts were dried over anhydrous potassium carbonate and concentrated in vacuo to afford the title compound (43.2 mg, 100%) as colorless crystals. Example 49h (?S.3R.4S)-?-f rH-Tsoleuoynamino -l-(4- er - mtylphenyl ) -3.4- ihydroxv-6-methy1heptane The compound resulting from Example 49g (43.2 mg, 0.147 mmol) was coupled with Boc-Ile-OH hemihydrate (35.4 mg, 0.147 mmol) by the procedure described in Example 10a to give the title compound as a white crystalline solid (74.7 mg, 100%). The protecting group was removed using the procedure described in Example Id to give the hydrochloride salt. The salt was treated as described in Example 49g to give the title compound (59.9 mg, 100%) as colorless crystals. Example 49i (2S.3R.4S) -2-f fN-Boc-Cyclohexylalanyl-Isoleucyllamino)- 1-(4-tert-butvlphenyl) -3.4-dihvdroxv-6-methylheptane The compound resulting from Example 49h (59.9 mg, 0.147 mmol) was coupled with Boc-Cha-OH (40.7 mg, 0.147 mmol) by the procedure described in Example 10a to give the title compound (94.3 mg, 97%) as white solid, which was recrystallized from ethyl acetate and hexanes. m.p, 171-172 °C. 1 H NMR (CDCI3, 300 MHz) δ 0.78-0.95 (m, 12H), 1.29 (S, 9H), 1.47 (s, 9H) , 0.95-2.20 (m, 19H) , 2.94 (m, 2H), 3.19-3.45 (m, 2H) , 4.00 (m, IH) , 4.17 (m, IH), 4.60 (d of d, IH), 4.86 (bd, IH) , 6.43 (d, IH) , 6.69 (bd, IH), 7.22 (d of d, 2H) . Anal calcd for C 38 H 65 N 3 O 6 : C, 69.16; H, 9.93; N, 6.37. Found: C, 69.66; H, 9.95; N, 6.07. MS (FAB) m/e 660 (M+H) + . Exa ple 50 (2S.3R.4S)-2--r TN-Acetyl-Cyclohexylalanyl- Isoleucyllamino -l-(4-tert-butylphenyl) -3.4-dihydroxy-6- methylheptane The compound resulting from Example 49 (30.7 mg, 46 μmol) was deprotected by the procedure described in Example Id to give the hydrochloride salt. The salt was treated as described in Example 49g to give the free amine (26 mg, 100%) as a white solid. The free amine (26 mg, 46 μmol) was reacted with acetyl imidazole (5.5 mg, 49 μmol) by the procedure described in Example 27 to give the N-acetyl compound. Flash chromatography on silica gel eluting with 85% ethyl acetate in hexanes afforded the title compound (18.7 mg, 67%) . m.p. 199-201 °C. 1 H NMR (DMSO-d 6 , 300 MHz) δ 0.64-0.90 (m, 12H) , 1.26 (s, 9H) , 0.90-1.80 (m, 19H) , 1.83 (s, 3H), 2.74 (m, IH) , 3.05 (m, 2H) , 3.05 ( , 2H), 3.32 (d, IH) , 4.10-4.40 (m, 4H) , 4.97 (d, IH) , 7.22 (d of d, 4H), 7.60 (d, IH), 7.77 (d, IH) , 8.03 (d, IH) . Anal calcd for C35H59N3O 5 : C, 69.85; H, 9.88; N, 6.98. Found: C, 70.03; H, 9.62; N, 6.19. MS (FAB) m/e 602 (M+H) + . Example 51 (2S.3R.4S) -2-f rN-Acetyl-Cyclohexylalanyl- Isoleucyπaminol-1-(2-naphthyl)-3.4-dihydroxy-6- methylheptane The compound resulting from Example 30 (33 mg, 50 μmol) was deprotected using the procedure described in Example Id and converted to its free base by the procedure described in Example 49g to give the free amine. The amine (27.9 mg, 0.050 mmol) was acetylated using acetyl imidazole (6.0 mg, 0.054 mmol, 1.08 equiv) using the procedure described in Example 27. Flash chromatography on silica gel eluting with ethyl acetate afforded the title product (25.7 mg, 85%). m.p. 192- 194 °C. X H NMR (DMSO-dβ, 300 MHz) δ 0.60-0.87 (m, 12H) , 0.88-1.80 (m, 19H), 1.83 (s, 3H) , 2.92-3.20 (m, 4H) , 4.16 (m, IH), 4.32 (d of d, 3H) , 5.07 (d, IH) , 7.45 (m, 3H) , 7.64-7.88 (m, 6H) , 8.01 (d, IH) . Anal calcd for C3 5 H 53 N3O 5 : C, 70.56; H, 8.97; N, 7.05. Found: C, 71.34; H, 8.81; N, 6.53. MS (FAB) m/e 596 (M+H) + . Example 52 N-Boc-Isoleucyl-Isoleucγl-Statyl N-Methyl-N-Tsobπt.yl Carboxamide To the compound resulting from Example 5b (37 mg, 0.074 mmol) was reacted with N-methyl-N-isobutylamine (8.8 μL, 0.074 mmol) by the procedure described in Example 3c to afford crude product (29 mg) . Flash chromatography on silica gel eluting with 3% ethanol in chloroform afforded the title product (16 mg, 38%) . H NMR (CDCI 3 , 300 MHz) δ 0.75-0.88 (m, 24H), 1.47 (s, 9H) , 0.90-2.00 (m, 12H), 2.32 (m, 2H) , 2.85 (m, 2H) , 3.10 (m, 2H), 3.81 (m, 3H) , 4.18 (m, IH) , 4.73 (m, IH) , 6.77 (m, IH) , 7.43-7.72 (m, 2H) . Anal calcd for C 3 oH 58 N 0 6 *0.5 H2O: C, 62.15; H, 10.26; N, 9.66. Found: C, 61.95; H, 9.79; N, 9.35. MS (FAB) m/e 571 (M+H) + . Exa ple 53 (2S r R r 4S)-2-f ΓN-(Morpholin-1-yl-carbonyl)- Cyclohexylalanyl-Isoleucyl1amino -l-(2-naphthyl)-3,4- dihydroxy-6-methylheptane Example 53a N- (Morpholin-l-yl-r.arbonyl ) -Cyclohexylalanin To Cyclohexylalanine methyl ester hydrochloride salt (200 mg, 0.902 mmol) suspended in toluene (5 mL) under nitrogen was added triphosgene (133.8 mg, 0.5 equiv) . The reaction mixture was warmed at 100 °C for 2 hours and then concentrated at reduced pressure. The residue obtained was taken up in methylene chloride (3 mL) , cooled to 0 °C, and treated with morpholine (79 μL, 1.0 equiv). After 10 minutes at 0 °C, the reaction mixture was concentrated at reduced pressure to afford the methyl ester as a semi-solid residue. MS (DCI/NH3) m/e 299 (M+H) + . The methyl ester (269 mg, 0.902 mmol) was hydrolyzed with lithium hydroxide by the procedure described in Example 43a to afford the title compound (234 mg, 91%) . Example 53b (2S.3R.4S)-2-f rN-(Morpholin-l-vl-carbonyl)- Cyolohexylalanyl-Isoleucyπamino -l- (2-naohthvl) -3.4- dihydroxy-6-methylheptane To the compound resulting from Example 53a (19.5 mg, 68.75 μmol) was coupled with the free amine (25 mg, 0.91 equiv) of Example 29d, which had been deprotected by the procedure described in Example Id and converted to its free base by the procedure described in Example 49g, by the procedure described in Example le to afford crude material (36.5 mg, 88%) . Flash chromatography on silica gel eluting with 1:1 ethyl acetate/hexanes to afford the title compound (22.7 mg, 50%). 1 H NMR (DMSO- dβ, 300 MHz) δ 0.63-0.87 (m, 12H) , 0.90-1.75 (m, 19H) , 2.90-3.20 (m, 3H) , 3.30 (m, 2H) , 3.53 (m, 2H) , 4.18 (m, IH), 4.32 (m, IH) , 5.02 (d, 0.5H), 6.50 (d, 0.5H), 7.45 (m, 1.5H), 7.60 (d, 0.5H), 7.71-7.87 (m, 2.5H). Anal calcd for C38H 58 N 4 O 6 *H 2 0: C, 66.64; H, 8.83; N, 8.18. Found: C, 66.69; H, 8.47; N, 8.06. MS (FAB) m/e 667 (M+H) + . Example 54 (2S.3R.4S) -2-f r IN- (N.N-Dimethylaminoethyl) -N- methylamino)carbony1-Cyclohexylalanyl-Isoleucyl1amino)- l-(2-naphthyl)-3.4-di ydroxy-6-methylheptane Example 54a (N- (N.N-Dimethylaminoethy1) -N-methyla ino1oarbony - Cyclohexylalanine To Cyclohexylalanine methyl ester hydrochloride (1.00 g, 4.51 mmol) suspended in toluene (25 mL) and warmed to 100 °C under nitrogen was added triphosgene (669 mg, 0.5 equiv). After 3.5 hours, the reaction mixture was concentrated at reduced pressure. The residue obtained was dissolved in methylene chloride and cooled to 0 °C. N,N-dimethyl-N'-methylethylenediamine (0.51 mL, 1.0 equiv) was added, and the reaction mixture was allowed to stir for 1 hour. The solvents were removed under reduced pressure to afford crude product. Flash chromatography on silica gel eluting with 1-10% methanol in chloroform gave the methyl ester (1.016 g, 72%) . The methy ester (1.016 g, 3.246 mmol) was hydrolyzed with lithium hydroxide (272 mg, 2 equiv) by the procedure described in Example 43a. Ion exchange chromatography eluting with 0. IN hydrochloric acid afforded the title compound as a white amorphous solid (710 mg, 73%) . Example 54b (2S.3R.4S) -2-f r (Ν- (Ν.Ν-Dimethy aminoethyl) -Ν- methylamino>oarhonyl-Cyclohexylalany1-Isoleuoy11amino)- l-(2-naphthyl)-3.4-dihydroxy-6-methylheptane To the compound resulting from Example 54a (20.6 mg, 68.75 μmol) was coupled with the free base of Example 29d (25 mg, 0.91 equiv), which had been deprotected by the procedure described in Example Id and converted to its free base by the procedure described in Example 49g, by the procedure described in Example le to give crude material. Flash chromatography on silica gel eluting with 2% methanol in chloroform followed by preparative HPLC followed by lyophilization afforded the title compound. 1 H ΝMR (DMSO-dβ, 300 MHz) δ 0.67-0.86 (m, 12H), 0.90-1.80 (m, 19H) , 2.78 (m, 5H) , 2.90-3.25 (m, 8H), 3.54 (m, 2H) , 4.15-4.38 (m, 2H) , 5.07 (d, IH) , 6.43 (d, IH), 7.45 (m, 2H) , 7.64-7.90 (m, 6H) . Anal calcd for C39H63Ν5O5 • 1.7 TFA: C, 58.15; H, 7.45; N, 8.00. Found: C, 58.22; H, 7.58; N, 7.96. MS (FAB) m/e 682 (M+H) + . Exa ple 55 (2S.3R.4S) -7- i TN- (4-Methylpiperazin-l-yl-sul fonyl ) - Cyclohexylalanyl-Tsoleucynamino -1- (2-naphthyl) -3.4- dihydroxy-6-methylheptane Example 55a N-(4-Methylpiperazin-l-yl-sulfonyl) -Cyclohexylalanine To a solution of N-methylpiperazine (1.48 mL, 13.3 mmol) in dioxane (6.7 mL) cooled to 0 °C was added 4N hydrochloric acid in dioxane (10 mL) . The reaction was very exothermic, and the mixture was stirred until the reaction cooled to room temperature. The solvent was removed under reduced pressure and chased with ether (2x) . The solid obtained was taken up in acetonitrile (7 mL) and sulfuryl chloride (3.53 mL, 3.3 equiv) was added. The mixture was warmed at relux for 24 hours and the product removed by filtration and washed with 1:1 acetonitrile/ether (100 mL) . This crude material was recrystallized from hot methanol and acetonitrile to afford 4-methylpiperazin-l-ylsulfonyl chloride (1.36 g, 44%) as a white crystalline solid. To Cyclohexylalanine methyl ester hydrochloride salt (1.00 g, 4.51 mmol) suspended in methylene chloride (6 mL) was added the above sulfonyl chloride (893 mg, 1.0 equiv) and triethylamine (2.01 mL, 3.2 equiv). The reaction mixture was stirred overnight at room temperature. The solvents were removed under reduced pressure, and the residue obtained was purified by flash chromatography on silica gel eluting with ethyl acetate to afford the methyl ester (409 mg, 29%) . MS (DCI/NH3) m/e 348 (M+H) + . The methyl ester (409 mg, 1.174 mmol) was hydrolyzed with lithium hydroxide (109 mg) by the procedure described in Example 43a to afford crude material which was purified by ion exchange chromatography to afford the title compound (341 mg, 87%) . Example 55b (?S.3R.4S)-2-f rN-(4-Methylpiperazin-l-yl-snlfonyl)- r.yol ohexyla lanyl-Isoleucyn amino 1 -1 - (2-naphthyl ) -3. 4- dihydroxy-6-methyl eptane To the compound resulting front Example 55a (22.9 mg, 68.75 μmol) was coupled with Example 29d (25 mg, 0.91 equiv) , which had been converted to its hydrochloride salt by the procedure described in Example Id and then converted to its free base by the procedure described in Example 49g, by the procedure described in Example le to afford crude product (25.4 mg, 57%) . Preparative HPLC afforded the title product. X H NMR (DMSO-dβ, 300 MHz) δ 0.70-0.87 (m, 12H) , 0.95-1.80 (m, 19H) , 2.27-2.70 (m, 2H) , 2.75-3.20 (m, 11H), 3.50-3.94 (m, 5H), 4.20-4.40 (m, 3H) , 5.15 (bd, IH), 7.40-8.03 ( , 11H) , 9.83 (bs, IH) . Anal calcd for C 38 H 6 ιN 5 0 6 S-1.55 TFA: C, 55.30; H, 7.06; N, 7.84. Found: C, 55.27; H, 7.07; N, 7.65. MS (FAB) m/e 716 (M+H) + . Tsolation and Characterization of Endothelin Converting Enzyme Rat lung plasma membranes were prepared and assayed for endothelin converting enzyme activity as previously described (Biochem. Biophys. Res. Commun. 171 1291 (1990)) . HPLC Fractionation on Mono O Rat lung plasma membranes (400 mg) were solubilized by stirring at 4°C for 45 minutes in 50 ml of 20 mM Tris- HCl, pH 7.7 containing 2 mM dithiothreitol and 46 mM NOG (Buffer C) . The unsolubilized materials were removed by centrifugation at 60,000 x g for 30 minutes. Solubilized materials were injected onto a Mono Q HR 10/10 column (Pharmacia) and eluted with concentration gradients of 0-1 M NaCl in 240 ml of Buffer C at 4 ml/minute. (Endothelin converting enzyme active fractions were eluted from 0.07 to 0.14 M NaCl) . Absorbance at 280 nm was monitored by a LKB 2150 UVICORD SD monitor. Fractions were analyzed for endothelin converting enzyme activity and by SDS-PAGE. Protein content was determined by the Bio-Rad Protein Assay kit. HPLC Fractionation on Superose 12 Mono Q fractions containing endothelin converting enzyme activity were pooled, concentrated to 25 mg/ml by Amicon Macrosolute Concentrators, and then a 200 μl sample was applied to Superose 12 (Pharmacia) . Buffer B (lOOmM NaCl, 50 mM Hepes, pH 7.4) was used as the mobile phase. The flow rate was 0.3 ml/minute and 0.6 ml/fraction was collected. Protein standards of known molecular mass and blue dextran were chromatographed in parallel. Absorbance at 280 nm was monitored as above. Fractions were assayed for endothelin converting enzyme acitivity. Fractions containing endothelin converting enzyme activity were concentrated and analyzed by SDS-PAGE. HPLC Fractionation on Mono P Superose 12 fractions containing endothelin converting enzyme activity were pooled and passed through PD-10 columns (Pharmacia) to change to the starting buffer (25 mM bis-Tris, pH 6.9 by CH 3 COOH) . Samples were injected onto a Mono P HR 5/20 column (Pharmacia) . After washing with the starting buffer, the column was eluted with a buffer containing 9.5% of Polybuffer 96 and 0.5% of Polybuffer 74 (both Pharmacia) adjusted to pH 5.9 by acetic acid. Values of pH in each fraction were determined. Absorbance at 280 nm was monitored. Fractions were assayed for endothelin converting enzyme activity SDS-PAGE Proteins were resolved by PhastGels (SDS-PAGE: 8-25 gradient; Isoelectric focusing: pH 5-8) in a Pharmacia Phastsystem. Gels were visualized by silver stain. The enzyme has an apparent molecular mass of 90 KD as estimated by SDS-PAGE or gel filtration and appears to be a single peptide protein. (Boiling the sample resulting from Mono Q purification under reducing conditions did not change the results of the SDS-PAGE analysis) . The enzyme may exist as isozymes with pis at 6.2 and 6.3. The endothelin converting enzyme activity after Mono Q purification was found to be optimal at pH 3.5 at 37°C. The endothelin converting enzyme activity in active Mono Q fractions was inhibited by pepstatin A with an IC 5 0 of 5 nM. The endothelin converting enzyme activity of solubilized endothelin converting enzyme (P3 from rat lung) is not inhibited at 40 mM by TLCK, aprotinin, PMSF, E-64, bestatin, phosphoramidon or thiorphan. The endothelin converting enzyme activity of active Mono Q fractions was stimulated by divalent metal cations in the order of Mn +2 > Zn +2 > Ca+ 2 > Mg+ 2 > Ba +2 = Co +2 . The ability of the compounds of the invention to inhibit a pepstatin A-inhibitable endothelin converting enzyme can be determined according to the following assay. ECE Inhibitor Screening Assay In a 1.5 mL tube, an assay cocktail containing 50 mM HEPES-100 mM NaCl buffer (pH 7.4 and containing 0.01% NaN 3 ) , MnCl 2 (40 μM) , pepstatin A (1 nM) , Bestatin (40 μM) , PMSF (40 μM) , test compound (100 μM in DMSO) and solubilized endothelin converting enzyme (P3 from rat lung, see Biochem. Biophys. Res. Commun. 171 1291 (1990)) were added and vortexed. The above mixture without the test compound was used as the control. Following a 15 minute preincubation at 37°C, benzyl succinate (100 μM) , NaOAc, and Big ET (3 μg> were added. The mixture was incubated for 30 minutes at 37°C, followed by addition of pepstatin (40 μM) and 10% TFA to stop the reaction. The mixture was vortexed, centrifuged and the supernatant retained for HPLC determination of Big ET, ET- 1 and CTF. The ET peaks were detected using absorbance at 226 nM. Percent inhibiton calculations were made with reference to controls based on quantitation of the ET-1 and Big ET peaks at the end of the incubation period. Table 1 shows the IC 50 (concentration at which the test compound inhibits enzyme activity by 50%) values for representative compounds of the invention. TABLE 1 Inhibition of Endothelin Converting Enzyme Compound of Example IΩ__{ (hM) 1 50 6 57 7 68 8 39 12 19 13 17 14 8 15 ' 47 16 30 23 24 24 7 25 17 26 7 27 29 28 9 30 3 33 33 34 19 35 17 39 9.5 40 10 41 18 42 16 43 6 44 21 45 51 46 4 47 20 48 7 49 6 50 4 51 4 52 10 53 3 54 5 55 5 The data indicate that the compounds inhibit endothelin converting enzyme. The ability of the compounds of the invention to lower blood pressure can be demonstrated according to the methods described in Matsumura, et al., Eur. J. Pharmacol. 185 103 (1990) and Takata, et al., Clin. Exp. Pharmacol. Physiol. IH 131 (1983).. The ability of the compounds of the invention to treat congestive heart failure can be demonstrated according to the method described in Margulies, et al.. Circulation £2.2226 (1990) . The ability of the compounds of the invention to treat myocardial infarction can be demonstrated according to the method described in Watanabe, et al.. Nature 344 114 (1990) . The ability of the compounds of the invention to treat coronary angina can be demonstrated according to the method described in Heistad, et al., Circ. Res. 2 711 (1984) . The ability of the compounds of the invention to treat cerebral vasospasm can be demonstrated according to the method described in Nakagomi, et al., J. Neurosurg. ___ 915 (1987) . The ability of the compounds of the invention to treat acute renal failure can be demonstrated according to the method described in Kon, et al., J. Clin. Invest. _2. 1762 (1989) . The ability of the compounds of the invention to treat gastric ulceration can be demonstrated according to the method described in Wallace, et al.. Am. J. Physiol. 256 G661 (1989) . The ability of the compounds of the invention to treat cyclosporin-induced nephrotoxicity can be demonstrated according to the method described in Kon, et al.. Kidney Int. 211487 (1990). The ability of the compounds of the invention to treat endotoxin-induced toxicity (shock) can be demonstrated according to the method described in Takahashi, et al.. Clinical Sci. 2 619 (1990). The ability of the compounds of the invention to treat asthma can be demonstrated according to the method described in Potvin and Varma, Can. J. Physiol. and Pharmacol. £L 1213 (1989). The ability of the compounds of the invention to treat atherosclerosis can be demonstrated according to the methods described in Bobik, et al.. Am. J. Physiol. 258 C408 (1990) and Chobanian, et al.. Hypertension 15.327 (1990) . The compounds of the present invention can be used in the form of salts derived from inorganic or .organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents'as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. The compounds of the present invention can also be used in the form of esters. Examples of such esters include a hydroxy1-substituted compound of formula I, II or III which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, or an acyl residue of the formula R**C(0)- or R**C(S)- wherein R** is hydrogen, loweralkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy. The amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used, including those wherein the amino acyl group is -C(O) CH2NR200 R 20l wherein R200 and R 20i are independently selected from hydrogen and loweralkyl or the group -NR 2 00 R 20 l forms a nitrogen containing heterocyclic ring. These esters serve as pro-drugs of the compounds of the present invention and serve to increase the solubility of these substances in the gastrointestinal tract. These esters also serve to increase solubility for intravenous administration of the compounds. The prodrugs of this invention are metabolized in vivo to provide the hydroxyl- substituted compound of formula I, II or III. The preparation of the prodrug esters is carried out by reacting a hydroxyl-substituted compound of formula I, II or III with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester. The compounds of the invention are useful for inhibiting pepstatin A-inhibitable endothelin converting enzyme in a human or other mammal. The compounds of the present invention are also useful for suppressing production of endothelin in a human or other mammal. In addition, the compounds of the present invention are -Ill- useful for the treatment or hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin-induced nephrotoxicity, endotoxin- induced toxicity, asthma and atherosclerosis in a human or other mammal. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more usually 1 to 500 mg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents . Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins) , both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more cardiovascular agents independently selected from diuretics, adrenergic blocking agents, vasodilators, calcium channel blockers, renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, angiotensin II antagonists, potassium channel activators and other cardiovascular agents. Representative diuretics include hydrochlorothiazide, chlorothiazide, acetazolamide, amiloride, bumetanide, benzthiazide, ethacrynic acid, furosemide, indacrinone, metolazone, spironolactone, triamterene, chlorthalidone and the like or a pharmaceutically acceptable salt thereof. Representative adrenergic blocking agents include phentolamine, phenoxybenzamine, prazosin, terazosin, tolazine, atenolol, metoprolol, nadolol, propranolol, timolol, carteolol and the like or a pharmaceutically acceptable salt thereof. Representative vasodilators include hydralazine, minoxidil, diazoxide, nitroprusside and the like or a pharmaceutically acceptable salt thereof. Representative calcium channel blockers include amrinone, bencyclane, diltiazem, fendiline, flunarizine, nicardipine, nimodipine, perhexilene, verapamil, gallopamil, nifedipine and the like or a pharmaceutically acceptable salt thereof. Representative renin inhibitors include enalkiren, RO 42-5892, PD-134672 and the like or a pharmaceutically acceptable salt thereof. Representative angiotensin II antagonists include DUP 753 and the like. Representative ACE inhibitors include captopril, enalapril, lisinopril and the like or a pharmaceutically acceptable salt thereof. Representative potassium channel activators include pinacidil and the like or a pharmaceutically acceptable salt thereof. Other representative cardiovascular agents include sympatholytic agents such as methyldopa, clonidine, guanabenz, reserpine and the like or a pharmaceutically acceptable salt thereof. The compounds of the invention and the antihypertensive agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient. The combination can be administered as separate compositions or as a single dosage form containing both agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature of the invention which are defined in the appended claims .

Claims: _ __J___ What is claimed is: 1. A method for inhibiting endothelin converting enzyme comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula: wherein A is hydrogen, an N-protecting group or RiNHCH(R 2 )C(0)- wherein Ri is H or an N-protecting group and R 2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is H0 2 C(CH 2 ) n C(0)- wherein n is 1 to 3; B is -N(R 4 )CH(R 3 )C(0)- wherein R 4 is hydrogen or loweralkyl and R 3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R 5 )CH(R 6 )C(0)- wherein R5 is hydrogen or loweralkyl and β is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; X is -CH 2 - or -C(0)-; D is 1) -0R 7 wherein R 7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) -NR8R9 wherein Re and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and "(CH2)m _z wherein m is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO2R10 wherein Rio is hydrogen or loweralkyl or Z is -NR11R12 wherein Rn and R12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri3)C(0)- wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Ri3)C(0)NHCH(Rι 4 )C(0)- wherein R 13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R14 is hydrogen, loweralkyl, cycloalkyl, ' cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR15 wherein R15 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) -NR16R17 wherein Riς and R17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2)p-Y wherein p is 2 to 8 and Y is -OH, heterocyclic, -SO3H, -CO2R18 wherein Riβ is hydrogen or loweralkyl or Y is -NR19R20 wherein R19 and R20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 2. The method of Claim 1 wherein X is -C (0) - and R is loweralkyl, cycloalkylalkyl or bicyclic heterocyclic. 3. A method for inhibiting endothelin converting enzyme comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula: wherein A is hydrogen, an N-protecting group, RiNHCH(R 2 )C(0)- wherein Ri is H or an N-prot.ecting group and R 2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ 2 C(CH 2 ) n C(0)- wherein n is 1 to 3; B is -N(R 4 )CH(R 3 )C(0)- wherein R 4 is hydrogen or loweralkyl and R 3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R 5 )CH(R 6 )C(0)- wherein R 5 is hydrogen or loweralkyl and Rζ is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; P is hydrogen, loweralkyl or benzyl; X is -CH 2 - or -C(0)-; D is 1) -OR 7 wherein R 7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) - Rβ g wherein Re and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH 2 )m-Z wherein m is 2 to 8 and Z is -OH, heterocyclic, -SO 3 H, -CO 2 R 10 wherein Rio is hydrogen or loweralkyl or Z is - R 11 R 12 wherein Rn and R 12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri 3 )C(0)- wherein R 13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Ri3)C(0)NHCH(Rι 4 )C(0)- wherein R i3 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R 1 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR 15 wherein 15 is hydrogen, 'loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) -NR 16 R 17 wherein Rig and R 17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH 2 ) P -Y wherein p is 2 to 8 and Y is -OH, heterocyclic, -SO 3 H, -CO 2 R 18 wherein Riβ is hydrogen or loweralkyl or Y is -NRιgR 2 0 wherein Ri and R 20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 4. The method of Claim 3 wherein X is -C(0)- and R is loweralkyl, cycloalkylalkyl or bicyclic heterocyclic. 5. A method for inhibiting endothelin converting enzyme comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula; wherein A is hydrogen, an N-protecting group, RiNHCH(R2)C(0)- wherein Ri is H or an N-protecting group and R2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, alkoxycarbonylalkyl or arylalkoxycarbonylalkyl; or A is HO2C(CH2)nC(0)- wherein n is 1 to 3; or A is Rι a C(0)- or Rι a S(0)2~ wherein Rι a is heterocyclic; or A is (aminoalkyl) '(alkyl)aminocarbonyl, (alkylaminoalkyl) (alkyl)aminocarbonyl, (dialkylaminoalkyl) (alkyl)aminocarbonyl, (aminoalkyl) (alkyl)aminosulfonyl, (alkylaminoalkyl) (alkyl)aminosulfonyl, (dialkylaminoalkyl) (alkyl)aminosulfonyl, (heterocyclicalkyl) (alkyl)aminocarbonyl or (heterocyclicalkyl) (alkyl)aminosulfonyl; B is -N(R 4 )CH(R3)C(0)- wherein R4 is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R5)CH(Rg)C(0)- wherein R5 is hydrogen or loweralkyl and Rg is loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; and R2 1 is loweralkyl, cycloalkyl or cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 6. The method of Claim 5 wherein wherein R is loweralkyl, cycloalkylalkyl, naphthyl or bicyclic heterocyclic. 7. A method for suppressing endothelin production comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula: wherein A is hydrogen, an N-protecting group or RiNHCH(R 2 )C(0) - wherein Ri is H or an N-protecting group and R2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ2C(CH2) n C(0)- wherein n is 1 to 3; B is -N(R ) CH(R3)C(0)- wherein R 4 is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R 5 )CH(Rg)C(0)- wherein R5 is hydrogen or loweralkyl and Rg is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; X is ' -CH2- or -C(0)-; D is 1) -OR7 wherein R7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) -NRβRg wherein Rg and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and _ (CH2) m -Z wherein is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO2R10 wherein Rio is hydrogen or loweralkyl or Z is -NR11R12 wherein Rn and R12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri3)C(0)- wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Ri3)C(0)NHCH(Ri4)C(0)- wherein R i3 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R 4 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR15 wherein R 5 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) -NRιgRi7 wherein Rig and R17 are independently selected from hydrogen, loweralkyl, "cycloalkyl, cycloalkylalkyl and -(CH2)p- wherein p is 2 to 8 and Y is -OH, heterocyclic, -SO3H, -CO2R18 wherein Riβ is hydrogen or loweralkyl or Y is -NR19R20 wherein R g and R20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. . 8. The method of Claim 7 wherein X is -C(0)- and R is loweralkyl, cycloalkylalkyl or bicyclic heterocyclic. 9. A method for suppressing endothelin production comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula: wherein A is hydrogen, an N-protecting group, RiNHCH(R2)C(0)- wherein Ri is H or an N-protecting group and R 2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ2C(CH2) n C(0)- wherein n is 1 to 3; B is -N(R 4 )CH(R3) C(0)- wherein R 4 is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R5)CH(Rg) C(0) - wherein R5 is hydrogen or loweralkyl and Rg is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; P4 is hydrogen, loweralkyl or benzyl; X is -CH 2 - or -C(0)-; D is 1) -OR7 wherein R 7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) -NRβRg wherein Re and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2) m -Z wherein m is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO2R 1 0 wherein Rio is hydrogen or loweralkyl or Z is - R 11 R 1 2 wherein Rn and R 12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri3)C(0)- wherein R 1 3 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Ri3)C(0)NHCH(Rι )C(0)- wherein R 1 3 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R 14 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR 15 wherein R 15 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) - RιgRi 7 wherein R g and R 17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH 2 ) p -Y wherein p is 2 to 8 and Ϋ is -OH, heterocyclic, -SO3H, -CO2 1 8 wherein Riβ is hydrogen or loweralkyl or Y is -NR 1 9R 20 wherein Rig and R20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 10. The method of Claim 9 wherein X is -C(0)- and R is loweralkyl, cycloalkylalkyl or bicyclic heterocyclic. 11. A method for suppressing endothelin production comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of the formula: wherein A is hydrogen, an N-protecting group, RiNHCH(R 2 )C(0)- wherein R is H or an N-protecting group and R 2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, alkoxycarbonylalkyl or arylalkoxycarbonylalkyl; or A is HO 2 C(CH 2 )nC(0)- wherein n is 1 to 3; or A is Rι a C(0)- or Rι a S(0) 2 ~ wherein Rι a is heterocyclic; or A is (aminoalkyl) * (alkyl)aminocarbonyl, (alkylaminoalkyl) (alkyl)aminocarbonyl, (dialkylaminoalkyl) (alkyl)aminocarbonyl, (aminoalkyl) (alkyl)aminosulfonyl, (alkylaminoalkyl) (alkyl)aminosulfonyl, (dialkylaminoalkyl) (alkyl)aminosulfonyl, (heterocyclicalkyl) (alkyl)aminocarbonyl or (heterocyclicalkyl) (alkyl) minosulfonyl; B is -N(R 4 )CH(R 3 )C(0)- wherein R 4 is hydrogen or loweralkyl and R 3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R 5 )CH(Rg)C(0)- wherein R 5 is hydrogen or loweralkyl and Rg is loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; and R 21 is loweralkyl, cycloalkyl or cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 12. The method of Claim 11 wherein wherein R is loweralkyl, cycloalkylalkyl, naphthyl or bicyclic heterocyclic. wherein A is hydrogen, an N-protecting group or RiNHCH(R 2 )C(0)- wherein Ri is H or'an N-protecting group and R 2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ 2 C(CH 2 ) n C(0)- wherein n is 1 to 3; B is -N(R 4 )CH(R 3 )C(0)- wherein R 4 is hydrogen or loweralkyl and R 3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(Rs)CH(Rg)C(0)- wherein R 5 is hydrogen or loweralkyl and Rg is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; X is -CH 2 - or -C(0)-; D is 1) -OR 7 wherein R 7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) -NRsRg wherein RQ and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2)m-Z wherein m is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO2R10 wherein Rio is hydrogen or loweralkyl or Z is -NR11R12 wherein Rn and R 2 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(Ri3)C(0)- wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Ri3)C(0)NHCH(Ri4)C(0)- wherein R13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R14 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR15 wherein R15 is hydrogen, ' loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) - RιgRi7 wherein Rig and R17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2)p-Y wherein p is 2 to 8 and Y is -OH, heterocyclic, -SO3H, -CO2R18 wherein Riβ is hydrogen or loweralkyl or Y is -NR19R20 wherein R19 and R20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. „ 14. The compound of Claim 13 wherein X is -C (0) - and R is loweralkyl, cycloalkylalkyl or bicyclic heterocyclic. 15. A compound of the formula: wherein A is hydrogen, an N-protecting group, RiNHCH(R 2 )C(0)- wherein R is H or an N-protecting group and R2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl or alkoxycarbonylalkyl; or A is Hθ2C(CH2) n C(0)- wherein n is 1 to 3; B is -N(R 4 )CH(R3)C(0)- wherein R 4 is hydrogen or loweralkyl and R3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R5)CH(Rg)C(0)- wherein R5 is hydrogen or loweralkyl and Rg is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; P4 is hydrogen, loweralkyl or benzyl; X is -CH2- or -C(0)-; D is 1) -OR 7 wherein R7 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; 2) ^ RβRg wherein Re and Rg are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and -(CH2) -Z wherein is 2 to 8 and Z is -OH, heterocyclic, -SO3H, -CO 2 R 1 0 wherein Rio is hydrogen or loweralkyl or Z is -NR 11 R 1 2 wherein Rn and 12 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; (3) -NHCH(R 3 )C(0)- wherein R 13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (4) -NHCH(Rι 3 )C(0)NHCH(Ri 4 )C(0)- wherein R 13 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl and R 1 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, aminocarbonylalkyl, cyanoalkyl, carboxyalkyl or alkoxycarbonylalkyl; and E is (1) absent; (2) -OR 15 wherein R 15 is hydrogen, loweralkyl, cycloalkyl or cycloalkylalkyl; or (3) -NRιgRi 7 wherein Rig and R 17 are independently selected from hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl and ~(CH 2 ) p -Y wherein p is 2 to 8 and Y is -OH, heterocyclic, -SO 3 H, -CO 2 R 18 wherein Riβ is hydrogen or loweralkyl or Y is -NR 19 R 20 wherein R 19 and R 20 are independently selected from hydrogen, loweralkyl, cycloalkyl and cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 16. The compound of Claim 15 wherein X is -C(0)- and R is loweralkyl, cycloalkylalkyl or bicyclic heterocyclic. 17. A compound of the formula: wherein A is hydrogen, an N-protecting group, RiNHCH(R 2 )C(O)- wherein Ri is H or an N-protecting group and R 2 is hydrogen, loweralkyl, cycloalkyl, cycloalkylalkyl, carboxyalkyl, alkoxycarbonylalkyl or arylalkoxycarbonylalkyl; or A is Hθ 2 C(CH 2 ) n C(0)- wherein n is 1 to 3; or A is Rι a C(0)- or Rι a S(0) 2 - wherein Rι a is heterocyclic; or A is (aminoalkyl) (alkyl)aminocarbonyl, (alkylaminoalkyl) (alkyl)aminocarbonyl, (dialkylaminoalkyl) (alkyl)aminocarbonyl, (aminoalkyl) (alkyl)aminosulfonyl, (alkylaminoalkyl) (alkyl)aminosulfonyl, (dialkylaminoalkyl) (alkyl)aminosulfonyl, (heterocyclicalkyl) (alkyl)aminocarbonyl or (heterocyclicalkyl) (alkyl)aminosul ' fonyl; B is -N(R 4 )CH(R 3 )C(0)- wherein R 4 is hydrogen or loweralkyl and R 3 is loweralkyl, cycloalkyl or cycloalkylalkyl; C is -N(R 5 )CH(Rg)C(0)- wherein R 5 is hydrogen or loweralkyl and Rg is loweralkyl, cycloalkyl or cycloalkylalkyl; R is loweralkyl, cycloalkyl, cycloalkylalkyl, aryl or bicyclic heterocyclic; and R 21 is loweralkyl, cycloalkyl or cycloalkylalkyl; or a pharmaceutically acceptable salt, ester or prodrug thereof. 18. The compound of Claim 17 wherein R is loweralkyl, cycloalkylalkyl, naphthyl or bicyclic heterocyclic. 19. A compound selected from the group consisting of: (2S,3R,4S)-2-{ (N-Acetyl-Cyclohexylalanyl- Isoleucyl)amino}-l-(4-tert-butylphenyl)-3,4-dihydroxy-6- methylheptane; (2S,3R,4S)-2-{ (N-Acetyl-Cyclohexylalanyl- Isoleucyl)amino}-l-(2-naphthyl)-3,4-dihydroxy-6- methylheptane; N-Boc-Isoleucyl-Isoleucyl-Statyl N-Methyl-N-Isobutyl Carboxamide; (2S,3R,4S)-2-{ (N-(Morpholin-1-yl-carbonyl)- Cyclohexylalanyl-Isoleucyl)amino}-l-(2-naphthyl)-3,4- dihydroxy-6-methylheptane; (2S,3R,4S)-2-{ ({N-(N,N-Dimethylaminoethyl)-N- methylamino}carbonyl-Cyclohexylalanyl-Isoleucyl)amino}- 1-(2-naphthyl)-3,4-dihydroxy-6-methylheptane; and (2S,3R,4S)-2-{ (N-(4-Methylpiperazin-l-yl-sulfonyl)- Cyclohexylalanyl-Isoleucyl)amino}-l-(2-naphthyl)-3, - dihydroxy-6-methylheptane. 20. A method for treating hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin- induced toxicity, asthma or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 13. 21. A method for treating hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin- induced toxicity, asthma or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 15. 22. A method for treating hypertension, congestive heart failure, myocardial infarction, reperfusion injury, coronary angina, cerebral vasospasm, acute renal failure, non-steroidal antiinflammatory drug induced gastric ulceration, cyclosporin induced nephrotoxicity, endotoxin- induced toxicity, asthma or atherosclerosis comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 17.

Inventors: OPGENORTH TERRY J, SHIOSAKI KAZUMI, TASKER ANDREW S, OPGENORTH, TERRY, J., SHIOSAKI, KAZUMI, TASKER, ANDREW, S.
Applicants: ABBOTT LAB, ABBOTT LABORATORIES
Application year: 1991
Main classification: C07K5
IPC codes: A61K38, A61P1, A61P9, A61P11, A61P13, A61P15, C07K5, C07K7, C08G59, C08J5, C09J163, H01L23