HIV PROTEASE INHIBITORS

Abstract: Compounds of the formula A-(C)b-(D)c-M-(X)e-Y-Z wherein: A is BocNH, CbzNH, H, R'R''N, R''CONR', or if a, b and c are 0 and Y is a covalent bond, then A is H, Boc, Cbz, R'' or R''CO; C and D are the same or different and are Ala, beta -Ala, D-Ala, Phe, Phg or Val; X is Ala, Ile, Leu, Val; Y is Ala, Ile, Leu, Val or is a covalent bond; Z is CO2R'''', CONR'R'''' COR', CH2OR'''', CH2OC(O)R'' or H, or if e is 0 and Y is a covalent bond, Z is OR'''' or NR'R''''; b, c and e are each independently 0 or 1, provided that c and e are not simultaneously 0; M is ( alpha ), wherein: R1 is independently, C1-5Alk, C3-5alkenyl or benzyl; R' and R'' are H or C1-5Alk; R'''' is H, C1-5Alk, C3-6cycloalkyl, (CH2)nC6H5, (CH2)nC5H4N, (CH2)nOH, (CH2)nNH2, or (CH2)nNHC(NH)NH2; inhibit the HIV-1 protease and are useful in the treatment of AIDS.

Description: TITLE HIV PROTEASE INHIBITORS BACKGROUND Retroviruses, that is, viruses within the family of Retroviridae, are a class of viruses which transport their genetic material as ribonucleic acid rather than deoxyribonucleic acid. Also known as RNA-tumor viruses, their presence has been associated with a wide range of diseases in humans and animals . They are believed to be the causative agents in pathological states associated with ir.fection by Rous sarcoma virus (RSV) , murine leukemia virus (MLV) , mouse mammary tumor virus (MMTV) , feline leukemia virus (FeLV) , bovine leukemia virus (BLV) , Mason-Pfizer monkey virus (MPMV) , simian sarcoma virus (SSV) , simian acquired immunodeficiency syndrome (SAIDS) , human T- lymphotropic virus (HTLV-I, -II) and human immunodeficiency virus (HIV-1, HIV-2) , which is the etiologic agent of AIDS (acquired immunodeficiency syndrome) and AIDS related complexes, and many others. Although the pathogens have, in many of these cases, been isolated, no effective method for treating this type of infection has been developed. Among these viruses, the HTLV and HIV have been especially well characterized. Although diverse in detail, all retroviruses are rather similar in overall structure. The extracellular virus particle is composed of an outer membrane studded with viral glycoproteins, a core of structural proteins, and a genome of single stranded ribonucleic acid. The retroviral genome has a distinctive regional organization, referred to as the 5'- σaσ-pol-env-3 ' structure, wherein the gag region encodes the core structural proteins, the pol region encodes certain critical viral enzymes such as reverse transcriptase, integrase and protease, and the env region encodes the envelope glycoproteins . . Viral replication occurs only within host cells and is dependent upon host cellular functions . Critical to this replication is the production of functional viral proteins. Protein synthesis is accomplished by translation of the open reading frames into polyprotein constructs, corresponding to the gag, pol and env reading frames, which are processed, at least in part, by a viral protease into the functional proteins. The proteolytic activity provided by the viral protease in processing the polyproteins cannot be provided by the host and is essential to the life cycle of the retrovirus . In fact, it has been demonstrated that retroviruses which lack the protease or contain a mutated form of it, lack infectivity. See Katoh et al., Viroloσv. 145, 280-92(1985), Crawford, et al. , £_. Virol . , 53, 899-907(1985) and Debouk, et al. , Proc. Na l. Acad. Sci. USA. 84, 8903-6(1987) . Inhibiton of retroviral protease, therefore, presents a method of therapy for retroviral disease. Methods to express retroviral proteases in E. coli have been disclosed by Debouck, et al., Proc. Natl. Acad. Sci. USA, 8903-06(1987) and Graves, et al., Proc. Natl. Acad. Sci. USA. 85, 2449-53(1988) for the HIV-1 virus. The crystal structure of an HIV-1 protease has been disclosed by Miller St ai.j Science. 246, 1149 (1989) . The method of isosteric replacement has been disclosed as a strategy for the development of protease inhibitors for HIV-1. Published European Patent- applications EP-A 337 714, EP-A 352 000 and EP-A 357 332, EP-A 346 847, EP-A 342 541 and EP-A 393 445 are representative. Similar strategies have also been reported for inhibition of renin in U.S. Patents 4,713,445 and 4,661,473. There remains a need for protease- inhibiting compounds which have a favorable balance of potency and pharmacokinetics properties. SUMMARY OF THE INVENTION This invention comprises compounds, hereinafter, of the formula (I) , which inhibit the retroviral protease of HIV-1, and are useful for treating Acquired Immunodeficiency Syndrome (AIDS) . This invention is also a pharmaceutical composition, which comprises a compound of formula (I) and a pharmaceutically acceptable carrier. This invention further constitutes a method for treating retroviral disease, which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) . DETAILED DESCRIPTION OF THE INVENTION The peptides of this invention are illustrated by formula (I) : A- ( C ) b- ( D ) c-M- ( X ) e-Y-Z (I) wherein: A is BocNH, CbzNH, H, R'R"N, R"CONR*, or if a, b and c are 0 and Y is a covalent bond, then A is H, Boc, Cbz, R" or R"CO; C and D are the same or different and are Ala, β-Ala, D- Ala, Phe, Phg or Val; X is Ala, lie, Leu, Val; Y is Ala, lie, Leu, Val or is a covalent bond; Z is CO2R"", CONR'R"", COR 1 , CH2OR"", CH2θC(0)R" or H, or if e is 0 and Y is a covalent bond, Z is OR"" or NR'R""; b, c and e are each independently 0 or 1, provided that c and e are not simultaneously 0; wherein: Rl is independently , Cι_5 lk, C3_5alkenyl or benzyl; R' and R" are H or C__5 lk; R"" is H, Cι-_5Al , C3_gcycloalkyl, (CH 2 ) n C6H5, (CH 2 ) n C5H4N, (CH 2 ) n OH, (CH 2 ) n NH2, or (CH 2 ) n NHC (NH)NH ; and pharmaceutically acceptable salts thereof; provided that if b and e are 0, Y is a covalent bond and D is Val, then Ri is not isobutyl. The compounds of this invention are more potent than those reported previously and have favorable pharmaceutical properties. Also included in this invention are pharmaceutically acceptable addition salts, complexes or prodrugs of the compounds of this invention. Prodrugs are considered to be any covalently bonded carriers which release the active parent drug according to formula (I) in vivo. Inasmuch as it may differ from conventional notation, it should be noted in formula (I) that A comprises the terminal amino group of the peptide and Z comprises the terminal carboxyl group of the peptide. Thus, when A and Z are H, the terminal residues of the peptide are "des-amino" and "descarboxy" amino acids respectively. Employing this representation, A comprises the terminal amino group of the residue C; or, when b is 0, to D. When b, and c are both 0, the amino group of M is substituted by an acyl or alkyl group, as specially provided by A in formula (I) . In similar fashion, Z comprises the terminal carboxyl group of the amino acid residue corresponding to Y; or when Y is a covalent bond, to X. When Y is a covalent bond and d and e are 0, the terminal carboxyl group of M is substituted by Z as specially provided in formula (I) . Other abbreviations and symbols commonly used in the art are used herein to describe the peptides . In accordance with conventional representation, the amino terminus is on the left and the carboxy terminus is on the right. Unless specified otherwise, all chiral amino acids (AA) are assumed to be of the L absolute configuration. (4'R a )Phe refers to phenylalanine substituted in the 4 position of the phenyl ring by R a . Boc refers to the t- butyloxycarbonyl radical, Cbz refers to the carbobenzyloxy radical, BrZ refers to ' the o-bromobenzyloxycarbonyl radical, Clz is the p-chlorocarbobenzyloxy radical, CI2Z refers to the 2,4-dichlorocarbobenzyloxy radical, Bzl refers to the benyzl radical, Ac refers to acetyl, Alk or Cχ-5Alk refers to C ] __5alkyl, Ph refers to phenyl, DCC refers to dicyclohexyl- carbodiimide, DMAP refers to dimethylaminopyridine, HOBT refers to 1-hydroxybenzotriazole, NMM is N-methylmorpholine, DTT is dithiothreitol, EDTA is ethylenediamine tetraacetic acid, DIEA is diisopropyl ethylamine, DBU is 1,8 diazobicyclo [5.4.0]undec-7-ene, DMSO is dimethylsulfoxide, DMF is dimethyl for amide and THF is tetrahydrofuran. HF refers to hydrofluoric acid and.TFA refers to trifluoroacetic acid. Cι_5al yl as applied herein is meant to include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl and isopentyl. As used herein in the compounds of this invention. Especially preferred compounds of this invention are di-, tri- and tetrapeptides such as A-C-D-M-X-Y-Z, A-C-D-M-X-Z, A-C-D-M-Z, A-D-M-X-Y-Z, A-D-M-X-Z, A-D-M-Z and A-M-X-Y-Z. X and Y are suitably valine. C and D are suitably alanine. Suitably C is Ala and X is Val. Suitably Ri is H, Ci-5alkyl, allyl or benzyl. In one preferred embodiment Ri is H, Cι_5alkyl, allyl or benzyl. Suitably,. i is propyl. Suitably Z is CO2CH3, CONH2, CH2OH or CH2OAC. Favorable pharmacokinetic properties may result when Z is CH 2 OH or CH 2 OAc. When administered to an animal infected or potentially infected with a virus, which is dependent upon a virally encoded protease for processing of viral polyproteins, viral replication is inhibited, hence, disease progression is retarded. Representative compounds of this invention are: (2R,4S,5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoyl-valyl valine methyl ester; (2R, 4S,5S)-2-propyl-4-hydroxy-5- (benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoyl-valyl valine methyl ester; (2R, 4S,5S)-5- (carbobenzyloxy-alanylalanyl)amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo) exyl-valine methyl ester; (2R,4S,5S)-2-propyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl-valine methyl ester; (2R,4S,5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl valine methyl ester; (2R,4S,5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo) exyl-valyl valine methyl ester; (2R,4S, 5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2- (1-propyl)- (1-oxo) exyl-valyl valine methyl ester; (2R,4S,5S)-5-carbobenzyloxy-alanylalanyl) amino-6-pheny1- 4-hydroxy-2-isobutyl-(1-oxo)hexyl-valyl valine methyl ester; (2R, 4S, 5S)-5- (carbobenzyloxy-alanyl) amino-6-phenyl-4- hydroxy-2-isobutyl- (1-oxo)hexyl-valyl valine methyl ester; (2R, 4S, 5S) -5- (alanylalanyl) amino-6-phenyl-4-hydroxy-2- benzyl- (1-oxo)hexyl-valyl valine methyl ester; (2R,4S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl)- alanyl-alanyl) amino-6-phenylhexanoyl-valinol; (2R,4S,5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanylalanyl) amino-6-phenylhexanoyl- (O-acetyl) valinol; (2R, 4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl valinol; (2R,4S, 5S)-2-methyl-4-hydroxy-5-(methoxycarbonyl- alanyl)-amino-6-phenylhexanoyl-valyl valinol; (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (methoxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl- (O-acetyl)valinol; (2R, 4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl-(O-acetyl) valinol; (2R, 4S, 5S)-5- (carbobenzyloxy-alanyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinol; (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alany1) amino-6-phenylhexanoy1-valinol; (2R,4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoy1- (O-acetyl) valinol; (2R, S,5S) -5-(carbobenzyloxy-phenylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valyl valinol; (2R, 4S,5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valyl valinol; (2R,4S, 5S)-5- (tert-butyloxycarbonyl)amino-6-phenyl-4- hydroxy-2-benzyl- (1-ox.o)hexyl-valinol; (2R, 4S,5S)-5- (carbobenzyloxy-alanylalanyl)amino-6- phenyl-4-hydroxy-2-benzyl-(1-oxo)hexyl-valinamide; (2R, 4S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl) - alanylalanyl) amino-6-phenylhexanoyl-valyl amide; (2R, 4S,5S)-2-methyl-4-hydroxy-5-propanoylamino-6- phenylhexanoyl-valyl valine methyl ester; (2R, S, 5S)-5- (carbobenzyloxy-alanyl)amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valine methyl ester; (2R,4S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl) - alanyl)amino-6-phenylhexanoyl-valyl methyl ester; (2R, 4S,5S)-2-propyl-4-hydroxy-5- ( (benzyloxycarbonyl)alanyl)amino-6-phenylhexanoyl-valyl amide; (2R, 4S,5S)-2-allyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl amide; (2R,4S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl) - alanyl) amino-6-phenylhexanoyl-valyl amide; (2R,4S,5S)-5- (carbobenzyloxy-alanyl)amino-6-phenyl-4- hydroxy-2-benzyl- (1—oxo)hexyl-valinamide; (2R, 4S, 5S)-5- (tert-butyloxycarbonyl) amino-6-pheny1-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinamide; (2R,4S, 5S)-5- (carbobenzyloxy-alanylalanyl)amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valine; (2R, 4S,5S)-5- (carbobenzyloxy-alanyl)amino-6-pheny1-4- hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl)amide; (2R,4S,5S)-5- (tert-butyloxycarbonyl) amino-6-pheny1-4- hydroxy-2-allyl- (1-oxo) hexyl-valinamide; (2R, S, 5S)-5- (carbobenzyloxyalanyl)amino-6-phen 1-4- hydroxy-2-isobutyl- (1-oxo)hexyl-valinamide; (2R, 4S,5S)-5- (tert-butyloxycarbonyl)amino-6-pheny1-4-r hydroxy-2-isobutyl- (1-oxo)hexyl-valinamide; (2R, 4S, 5S)-5- (carbobenzyloxy-D-alanyl-L-alanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl)amide; and (2R,4S, 5S)-5- (carbobenzyloxy-phenylglycyl-alanyl)amino- 6-phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl) amide. Certain preferred compounds are: (2R,4S,5S)-2-propyl-4-hydroxy-5-(benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl-valine methyl ester (2R,4S,5S)-2-propyl-4-hydroxy-5- (benzyloxycar-bonyl- alanyl-alanyl) amino-6-phenylhexanoyl-valyl valine methyl ester (2R,4S, 5S)-5- (carbobenzyloxy-alanyl)amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinamide, and (2R, 4S, 5S) -5- (carbobenzyloxy-phenylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valyl valinol. The compounds of this invention are prepared by conventional methods of peptide synthesis. The residue denoted by M is prepared by methods well known in the art, such as those disclosed in U.S. Patents 4,661,473 and 4,713,445 and published European Patent applications EP-A 352 000 and 337 714, all of which are incorporated herein by reference. Other methods are disclosed by Holladay j≥t. al ■ . J. Med. Chem.. 30, 374-83(1987) and Kempf, D., J. Qrσ. Chem , 51, 21, 3921-26(1986) . The amino acids or modified amino acids of this invention are generally available commercially or are prepared by conventional methods of organic chemistry. Solution synthesis of the peptides is accomplished using routine methods for coupling the appropriate amino acid residues and optionally removing any protective groups.. Typically, a protected Boc-amino acid which has a free carboxyl group is coupled to a protected amino acid which has a free amino group using a suitable carbodiimide coupling agent, such as N, N 1 dicyclohexyl carbodiimide (DCC) , optionally in the presence of catalysts such as 1- hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP) . Suitable protective groups for amino acids and intermediates are disclosed in Greene, Protective Groups in Organic Chemistry. John Wiley and Sons, New York, 1981. Other methods for forming peptide bonds, such as the formation of activated esters, anhydrides or acid halides, of the free carboxyl of a protected Boc-amino acid, and subsequent reaction with the free amine of a protected amino acid, optionally in the presence of a base, are also suitable. For example, a protected Boc-amino acid or peptide is treated in an anhydrous solvent, such as methylene chloride or tetrahydrofuran (THF) , in the presence of a base, such as N-methyl morpholine, DMAP or a trialkyl amine, with isobutyl chloroformate to form the "activated anhydride", which is subsequently reacted with the free amine of a second protected amino acid or peptide. The peptide formed by these methods may be deprotected selectively, using conventional techniques, at the amino or carboxy terminus and coupled to other peptides or amino acids using similar techniques . After the peptide has been completed, the protecting groups may be removed as hereinbefore described, such as by hydrogenation in the presence of a palladium or platinum catalyst, treatment with sodium in liquid ammonia, hydrofluoric acid or alkali. Esters are often used to protect the terminal carboxyl group of peptides in solution synthesis. They may be converted to carboxylic acids by treatment with an alkali metal hydroxide or carbonate, such as potassium hydroxide or sodium carbonate, in an aqueous alcoholic solution. The acids may be converted to other esters via an activated acyl intermediate as previously described. The amides and substituted amides of this invention are prepared from carboxylic acids of the peptides in much the same manner. Thus, ammonia or a substituted amine may be reacted with an activated acyl intermediate to produce the amide. Use of coupling reagents, such as DCC, is convenient for forming substituted amides from the carboxylic acid itself and a suitable amine. In addition, the methyl esters of this invention may be converted to the amides, or substituted-amides, directly by treatment with ammonia, or a substituted amine, in methanol solution. A methanol solution of the methyl ester of the peptide is saturated with ammonia and stirred in a pressurized reactor to yield the simple carboxamide of the peptides. Carboxamides are preferred embodiments of this invention due their enhanced stability relative to esters . If the final peptide, after it has been deprotected, contains a basic group, an acid addition salt may be prepared. Acid addition salts of the peptides are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic or methanesulfonic. The acetate salt form is especially useful. If the final peptide contains an acidic group, cationic salts may be prepared. Typically the parent compound is treated with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation. Cations such as Na + , K + , Ca ++ and NH4 " are examples of cations present in pharmaceutically acceptable salts . Certain of the compounds form inner salts or zwitterions which may also be acceptable. The compounds of formula (I) , wherein M is -HNCHR; ] _R -, are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatmen . The method of treatment comprises the administration orally, parenterally, buccally, trans-dermally, rectally or by insufflation, of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier. Dosage units- of the active ingredient are generally selected from the range of 0.1 to 25 mg/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic infection. The protease inhibiting properties of the peptides of this invention, are demonstrated by their ability to inhibit the hydrolysis of a peptide substrate by rHIV protease in the range of about 0.1 nM to about 1.0 μM. The following table is representative of the inhibition constants of these peptides. Table I Inhibition of rHIV Protease Compound of _.- • _ Example No. (μM) 4 0.00068 5 0.0027 6(a) 0.00051 6(b) 0.018 7 0.0049 8(a) 0.037 8(b) 0.0025 Table I (cont'd) Inhibition of rHIV- Protease Compound of Example No. (μM) 9(b) 0.0022 ' 9(c) 0.8 9(d) 0.145 9(e) 0.05 9(f) 0.021 9(g) 1.60 9(h) 0.320 9 (j) 3.8 9(k) 0.95 10(d) 0.0007 10(g) 0.0012 10(h) 0.0017 10(i) 0.002 10(j) 0.02 10 (k) 0.077 10(1) 0.042 10 (m) 0.56 10 (n) <0.013 10(o) 0.022 Pharmaceutical compositions of the peptides of this invention, or derivatives thereof, may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. The liquid, formulation is generally a buffered, isotonic, aqueous, solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or buffered sodium or ammonium acetate solution. Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate. A preferred composition for parenteral administration may additionally be comprised of a quantity of the compound encapsulated in a liposomal carrier. The liposome may be formed by dispersion of the peptides in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional handshaking, high pressure extrusion, reverse phase evaporation and microfluidization. A suitable method of making such compositions is more fully disclosed in copending Application Serial No. 06/763,484 and is incorporated herein by reference. Such a carrier may be optionally directed toward its site of action by an immunoglobulin or protein reactive with the viral particle or infected cells. The choice of such proteins would of course be dependent upon the antigenic determinants of the infecting virus. An example of such a protein is the CD-4 T-cell glycoprotein, or a derivative thereof, such as sCD-4 (soluble CD-4), which is reactive with the glycoprotein coat of the human immunodeficiency virus (HIV) . Such proteins are disclosed in copending Application Serial No. 07/160,463, which is incorporated herein by reference. Similar targeting proteins could be devised, by methods known to the art, for other viruses and are considered within the scope of this invention. Alternately, these peptides may be encapsulated, tableted or prepared in a emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The'amount of solid carrier varies but, preferably, will be between about 20 g to about 1 g per dosage unit. The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule. For rectal administration, a pulverized powder of the peptides of this invention may be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository. The pulverized powders may also be compounded with an oily preparation, gel, cream or emulsion, buffered or unbuffered, and administered through a transdermal patch. Beneficial effects may be realized by co-administering, individually or in combination, other anti-viral agents with the protease inhibiting compounds of this invention. Examples of anti-viral agents include nucleoside analogues, phosphonoformate, rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen. Nucleoside analogues, which include 2 ' ,3 '-dideoxycytidme (ddC) , 2 ' ,3 '-dideoxyadenine (ddA) and 3 '-azido-2 ' ,3 '-dideoxythymide (AZT) , are especially useful. AZT is one preferred agent. Suitably pharmaceutical compositions comprise an anti-viral agent, a protease inhibiting peptide -of this invention and a pharmaceutically acceptable carrier. The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. Purification of Recombinant HIV Protease Methods for expressing recombinant HIV protease in E. coli have been described by Debouck, et al., Proc. Natl. Acad. Sci. USA, 84, 8903-6(1987) . The enzyme used to assay the peptide of this invention was produced in this manner and purified from the cell pellet as follows . The £__. coli cell pellet was resuspended in a buffer consisting of 50 mM Tris- HCl, pH 7.5; 1.0 mM each DTT, EDTA and PMSF (phenylmethylsulfonyl fluoride) . The cells were lysed by sonication and insoluble material was removed by centrifugation at 15,000 x g av, for 15 mi . The clarified supernatant was then brought to 40% of saturation with ammonium sulfate. This suspension was stirred at room temperature for 30 min. and then centrifuged as above. The resulting precipitate was redissolved/resuspended in a minimal volume of 20 mM Tris-HCl, pH 7.5; 200 mM NaCl; 0.1 mM each DTT and EDTA. The sample was centrifuged again before application (in 5 ml aliquots) to a Beckman TSK G2000SW preparative HPLC gel filtration column (2.1 cm x 60 cm.) . The column was equilibrated in the same buffer at a flow rate of 4 ml/min. The effluent of the column was monitored at 280 nm and 1 min. fractions collected. Typically, the rHIVPRT (recombinant HIV protease) eluted 45-46 min. into the run. At this stage, the protease was N85-95% pure. By immunoblot analysis >90% of the immunoreactive material was precipitated at the ammonium sulfate step. By activity assay, the highest peak of activity was found in the fractions collected at 45 and 46 minutes. Analysis of the TSK column fractions by RP- HPLC and SDS-PAGE indicated that the majority of the 11,000 Mr protein is also found in fractions 45 and 46. The activity itself cannot be used to obtain reliable recovery data as it is influenced by high salt, i.e., with increasing salt, increasing levels of activity were obtained. Thus, with each step in the purification, more total activity was recovered than was started with. The overall yield of rHIVPRT was Nl mg from a 50 gm E_ < _ coli cell pellet. Substrate Kinetics for HIV Protease Activity Initial rate data for oligopeptides were determined at pH 6.0, 37°C. Reaction mixtures (0.01-0.1 mL) contained 50 5 mM Mes (2-N-morpholino) ethanesulfonic acid) , 1 mM EDTA, 1 mM DTT, 0.2 M NaCl, 0.1% (v/v) Triton X-100 (pH 6.0), 10% DMSO, and variable concentrations of the peptides. After incubation at 37°C for several minutes, reaction was initiated by the addition of purified HIV protease (0.01-2 10 g) , and reactions were quenched after 10-30 min. with an equal volume of either ice-cold 0.6 N tricholoroacetic acid or 0.2% trifluoroacetic acid. Samples were centrifuged at 17,000 rpm for 5 min., and the peptide substrates and products were separated and quantified (by peak integration) 15. by reverse phase HPLC. Initial rates were determined as (mM peptide product formed) /min based on the percentage of conversion of substrate to. product for a given concentration of substrate. Typically, reaction rates were linear over the time course of the reaction, and less than 15-20% of the 20 substrate had been converted to product at reaction endpoint. Kinetic constants (Michaelis constants, maximal velocities) were determined by fitting initial rate data to the Michaelis-Menten equation (v = V max (S) / (K m + (S) ) ) using the Fortran program of Cleland (W. W. Cleland, Adv. Enzymol. 29, 25 1, (1967)) . The turnover number (k ca -t-) was obtained as k ca t = rnax/E-f-, where it is assumed that one active site is present per 22-kD dimer of HIV protease. An estimate of substrate viability was obtained by determination of a relative initial velocity (rel V D ) . This 30 assay was run in the same manner, except the percent hydrolysis of substrate after 10-20 min. was compared to the percent hydrolysis of Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val- NH 2 (control) after a similar incubation. This established a comparison of initial reaction velocity at one time point 35 relative to the control peptide. Inhibition of HIV protease activity A typical assay contained 10 mL MENDT buffer (50 mM Mes (pH 6.0; 2- (N-morpholino)ethanesulfonic acid), 1 mM EDTA, 1 mM dithiothreitol, 200 mM NaCl, 0.1% Triton X-100) ; 2, 3, or 6 mM N-acetyl-L-arginyl-L-alanyl-L-seryl-L-glutaminyl-L- asparaginyl-L-tyrosyl-L-prolyl-L-valyl-L-valinamide (Ac-Arg- Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH2; K m =7 mM) ; and micromolar and sub-micromolar concentrations of synthetic compounds . Following incubation at 37°C for several minutes, the reaction was initiated with purified 0.01-1 mg HIV protease. Reaction mixtures (37°C) were quenched after 10-20 minutes • with an equal volume of cold 0.6 N trichloroacetic acid, and, following centrifugation to remove precipitated material, peptidolysis products were analyzed by reverse phase HPLC (Beckman Ultrasphere ODS, 4.5 mm x 25 mm; mobile phase: 5-20% acetonitrile/H 2 0 - .1% TFA (15 min), 20% acetonitrile/H2θ - .1% TFA (5 min) at 1.5 mL/min, detection at 220 nm. The elution positions of Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val- NH2 (17-18 min) and Ac-Arg-Ala-Ser-Gln-Asn-Tyr (10-11 min) were confirmed with authentic material. Initial rates of Ac- Arg-Ala-Ser-Gln-Asn-Tyr formation were determined from integration of these peaks, and typically, the inhibitory properties of the synthetic compounds were determined from slope/intercept analysis of a plot of 1/v vs. [inhibitor] (Dixon analysis) . Kj_ values resulting from this type of primary analysis are accurate for competitive inhibitors only, and under conditions in which the Michaelis constant of the substrate used is well-determined. The Examples which follow serve to illustrate this invention. The Examples are intended to in no way limit the scope of this invention, but are provided to show how to make and use the compounds of this invention. In the Examples, all temperatures are in degrees Centigrade. Amino acid analyses were performed upon a Dionex Autoion 100. Analysis for peptide content is based upon Amino Acid Analysis. FAB mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment. The abbreviations used to represent th eluent composition for thin layer chromatography and counter current distribution are B: n-butanol, A: acetic acid, W: water, E: ethyl acetate and IP: isopropanol. NMR were recorded at 250 MHz using a Bruker AM 250 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Example 1 Preparation of (2R, S, 5S)-2-propyl-4- (t-butyldimethyl) siloxy- 5 (t-butyloxy-carbonyl) amino-6-phenylhexanoic acid a) t-butyloxycarbonyl-phenylalanine N,0- dimethylhydroxylamide N-methyl piperidine (24.4 ml, 0.206 mol) was added via addition funnel to a stirring suspension of N,0- dimethylhydroxylamine hydrochloride (19.56 g, 0.2 mol) in methylene chloride (118 ml) at 0°C, forming a clear solution, A. Boc-phenylalanine (53 g, 0.2 mol), THF (230 ml) and methylene chloride (900 ml) were combined and cooled to - 20°C, and N-methyl piperidine (24.4 ml) was added dropwise with stirring. Methyl chloroformate (15.5 ml, 0.2 mol) was then added rapidly via addition funnel with good stirring, the temperature being maintained below -10°C. Two minutes later solution A was added. The solution was allowed to warm to room temperature with stirring overnight. The mixture was cooled to 5°C and extracted with two 250 ml portions of cold 0.2 N HC1, two 250 ml portions of 0.5 N NaOH, and 250 ml brine, the was dried over MgS0 4 and concentrated to give 60.37 g of the titled compound. [«]l36 5 = 31° (c = 0.958, ethanol; 20°C) . b) t-butyloxycarbonyl-phenylalanal To a fine suspension of Li lH 4 (0.912 g, 24.0 mol) in ether (80 ml) at -45°C under Ar was added a solution of the amide of Example 1(a) (6.16 g, 20.0 mmol) in ether (20 ml) in a steady stream. After 5 min the mixture was allowed to warm to +10°C over 30 min, then was recooled to -45°C and a solution of 5.30 g KHSO 4 (39 mmol) in 15 ml water was added cautiously with stirring. The cooling bath was removed and the thick mixture was stirred for 30 min. Ether (100 ml) and methylene chloride (100 ml) were added, the mixture was filtered through Celite®, and the filter cake was rinsed with 100 ml each of ether and methylene chloride. The filtrate was extracted with three 50-ml portions of ice cold 1 N HC1, two 50-ml portions of ice cold 5% a2C03, and 100 ml brine, then dried over MgS0 4 , filtered and concentrated by rotary evaporation at 30°C to provide 4.18 g (16.8 mmol, 84% yield) of the titled compound as a white solid, mp : 82-83.5°C [α] D = +35.3° (c=1.00, CH C1 2 , 25°C) NMR (CDCI3) : δ 9.62(1H, s) , 7.33-7.17 (5H, m) , 5.07(1H, br) , 4.42(1H, q) , 3.12(2H, d) , 1.45(9H, s) . c) (5RS, 6S) -7-phenyl-6- (tert-butyloxycarbonylamino) -5- hydroxyhept-1-ene A 200 ml flask fitted with reflux condenser under Ar was charged with dry ether (35 ml) and Mg turnings (2.16 g, 90 mmol) . 4-bromo-l-butene (7.61 ml, 75 mmol) was added over 25 min to a stirred suspension of Mg, causing vigorous reflux. After the reflux had subsided, the mixture was heated to gentle reflux for an additional 20 min, then cooled to 0°C. (The yield of Grignard reagent was typically 65-70%) . A solution of the aldehyde of Example 1(b) (5.26 g, 21.1 mmol) in dry toluene (40 ml) was added over 10 min. After 1.5 hr at 0°C the clear, homogeneous reaction mixture was quenched cautiously with 3N HCl. The ether layer was separated, the aqueous layer was extracted once with ethyl acetate, the combined organic layers were washed with water and concentrated. The resulting yellow solid was dissolved in 50 ml methanol and stirred with NaBH 4 (200 ' mg) for 10 min. The mixture was diluted with 3N HCl and water, extracted with methylene chloride and concentrated. The residue was dissolved in a minimal volume of " methylene chloride and purified by flash chromatography (150 g silica, gradient elution; 20% to 40% ethyl acetate in hexanes) to provide 5.03 g of the titled product as a white solid (16.5 mmol, 78%) .' Analytical HPLC (Rainin Dynamax® silica, 15% ethyl acetate in hexanes) indicated a diastereomer ratio (5S) : (5R) of 7.20:1.00. d) (5S)-( (1*S)- (t-butyloxycarbonyl)amino-2'-phenylethyl)- tetrahydrofuran-2-one To a solution of the alcohols of Example 1(c) (5.00 g, 16.4 mmol) in ethyl acetate (50 ml) were added triethylamine (4.56 ml, 32.8 mmol), acetic anhydride (3.09 ml, 32.8 mmol), and 4-dimethylaminopyridine (50 mg, 0.41 mmol) . After 3 hr excess ethanol was added, and several minutes later the mixture was washed three times with 3N HCl, once with 5% NaHCQ 3 , and once with water, and concentrated to a thick residue. The crude acetates were dissolved in benzene (35 ml) , and stirred rapidly at 0°C with 35 ml water and 7 ml acetic acid. Tetra-n-butylammonium bromide (160 mg, 0.5 mmol) and KMnθ 4 (7.9 g, 50 mmol) were added. The mixture was allowed to warm to room temperature with vigourous stirring and intermittent cooling. After 2 hr, the thick black mixture was cooled to 0°C and saturated aqueous NaHSθ3 (75 m l) was added. After 15 min stirring, the resulting white mixture was filtered through Celite®, the aqueous layer was separated and extracted with ether. The combined organic layers were washed with water and concentrated to a foam (6.9 g) . The resulting crude 4-acetoxy acids were dissolved in 100 ml methanol and sodium methoxide (ca. 10 g) was added. The mixture was stirred at 25°C for two days then at 60°C for 18 hr. The thick mixture was concentrated, diluted with methylene chloride and extracted with 10% HCl. The aqueous layers were extracted twice with methylene chloride. The combined organic layers were washed with water, dried over MgSθ 4 , and filtered. The resulting solution of 4-hydroxy acids was stirred with 80 mg p-toluenesulfonic acid and several grams of 3 A molecular sieves for 24 hr. The mixture was filtered through Celite® and. concentrated to a thick oil. Flash chromatography on 100 g silica (gradient elution: 20% to 30% ethyl acetate in hexanes) provided the titled lactone (2.59 g, 8.49 mmol, 52% yield) . NMR (CDCI3) : δ 7.25(5H, m) , 4.68(1H, d; J = 9.7 Hz), 4.47(1H, dt), 4.01(1H, q) , 2.91(2H, m) , 2.51(2H, m) , 2.14(2H, m) , 1.38(9H, s) . e) (3R,5S) - ( (1'S)- (t-butyloxycarbonyl)amino-2 '-phenylethyl)- 3-allyl-tetrahydrofuran-2-one To a solution of lithium diisopropyl amide (1.2 mL, 1.5 M solution) in tetrahydrofuran (1 mL) was added the lactone of Example 1(d) (.250 g, .82 mmol) in anhydrous THF (2 mL) at -78°C. After stirring for 15 min at -78°C, hexamethylphosphoramide (.285 mL, 1.64 mmol) was added to the solution. The solution was stirred for several min and allyl bromide (.142 mL, 1.8 mmol) was added. After 2 hr, the reaction mixture was quenched with a 10% solution of HCl and extracted with diethyl ether (3X) . The organic extracts were combined and evaporated to a clear oil. The oil was chromatographed (silica gel, 4:1 hexane:ethyl acetate) to give the titled compound as a white foam. (.175 g, 62%) . NMR(CDC13) : δ 7.35-7.10 (5H, m) , 5.80-5.55 (1H, m) , 5.09(1H, d) , 5.00 (1H, s), 4.62(1H, d(br)), 4.45(1H, dd) , 3.95(1H, dd) , 2.87(2H, d) , 2.70(1H, m) , 2.46(1H, ) , 2.21(2H, m) , 1.90(1H, m) , 1.3K9H, s) . MS(DCI/NH3) : m/z : (M+NH4) 363.3; 307.2 ; 290.2; 246.2; 154.1; 120.1. f) (3R, 5S)- ( (l'S)- (t-butyloxycarbonyl) amino-2'-phenylethyl) - 3-propyl-tetrahydrofuran-2-one To a solution of the lactone of Example 1(e) (.175 g, .507 mmol) in methanol (5 mL) was introduced 10% Pd on activated carbon (.020 g) . Hydrogen gas was bubbled through the solution for 1 hr and the solution was then maintained under a hydrogen atmosphere for 12 hr. The mixture was filtered through a pad of Celite with methanol and the solvents evaporated to give the titled compound as a white solid (.166 g, 94%) . NMR(CDCl3) : δ 7.20-7.05 (5H, m) , 5.37 (1H, d) , 4.35 (1H, dd) , 3.70(1H, dd), 2.73(2H, d) , 2.48(1H, m) , 2.15(1H, m) , 1.76(1H, m) , 1.58( 1H, m) , 1.41-1.05 (12H, m) , 0.72(3H, t) . 5 g) (2R,4S, 5S)-2-propyl-4- (t-butyldimethyl) siloxy-5 (t- butyloxycarbonyl) amino-6-phenylhexanoic acid The lactone of Example 1(f) (.166 g, .45 mmol) was dissolved in 1,4-dioxane (2 mL) and distilled water (1 mL) . To this cloudy solution was added 1 N NaOH (.523 mL, 1.1 eq.) 10 dropwise over 5 min. The solution cleared after addition, and after 30 min the reaction was quenched with a 10% citric acid solution. The solution was extracted (3X) with diethyl ether and the combined " organic extracts were washed once with water, dried over magnesium siilfate, filtered,and evaporated 15. to a white foam (.197 g) . The white foam was stirred in dimethylformamide (1.5 L) at 25°C and to this solution was added tert-butyl dimethylsilylchloride (.407 g, 5 eq.) and imidazole (.367 g, 10 eq.) . The mixture was allowed to stir under an argon 20 blanket for 16 hr, was diluted with 10% aq. citric acid and extracted with diethyl ether(3X) . The combined organic extracts were washed with water, dried over magnesium sulfate, filtered and evaporated to an oil. The resultant oil was stirred in tetrahydrofuran (9 mL) , 25 acetic acid (9 mL) , and water (3 mL) for 3 hr. The THF was evaporated in vacuo and the remaining solution diluted with water and extracted with diethyl ether (3X) . The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give a white foam, which was 30 chromatographed (silica gel, 50:1 dichloromethane: ethanol) . The titled compound was isolated as a white solid (.135 g, 59%) . NMR(CDC13) : δ 7.35-7.08 (5H, m) , 4.70(1H, d) , 3.91(1H, dd) , 3.70 (2H, m) , 2.95-2.60(2H, m) , 2.42 (2H, m) , 1.70 (1H, ) , 35 1.5K2H, m) , 1.35-1.10 (12H, m) , 0.90(9H, s) , 0.79(3H, t) , 0.07 (6H, d) . MS(DCI/NH3) : (M+H) + 480.4 ; 441 3; 424.3; 380.3; 362.3; 322.2; 248.2. Example 2 By the procedure set forth in Example 1, except substituting in step 1(e), in place of allyl bromide, either: (a) methyl iodide, (b) benzyl bromide, (c) methallyl bromide or (d) isobutyl bromide, the following compounds were prepared: (a) (2R,4S,5S) -2-methyl-4- (tert-butyldimethylsilyloxy) - 5- (tert-butyloxycarbonyl) amino-6-phenylhexanoic acid; (b) (2R, 4S,5S)-2-phenylmet__y1-4- (tert- butyldimethylsilyloxy) -5- (tert-butyloxycarbonyl) amino-6- phenylhexanoic acid; (c) (2R, S, 5S) -2-methallyl-4- (tert- butyldimethylsilyloxy) -5- (tert-butyloxycarbonyl) amino-6- phenylhexanoic acid; and (d) (2R, 4S, 5S)-2-isobutyl-4- (tert- butyldimethylsilyloxy) -5- (tert-butyloxycarbonyl) amino-6- phenylhexanoic acid. Example 3 Preparation of (2R, 4S, 5S) -2-allyl-4- (t-butyldimethylsilyl- oxy) -5 (t-butyloxy-carbonyl) amino-6-phenylhexanoic acid The titled compound was prepared according to the procedure of Example 1, except omitting the hydrogenation step 1(f) . Example 4 Preparation of (2R, S, 5S) -2-propyl-4-hydroxy-5- (benzyloxycar- bonyl-alanyl) amino-6-phenylhexanoy1-valyl-valine methyl ester a) (2R, 4S, 5S) -2-propyl-4- (t-butyldimethylsilyloxy) -5- (t- butyloxycarbonyl) amino-6-phenyIhexanoyl-valyl-valine methyl ester To a solution of the acid of Example 1(g) (.080 g, .167 mmol) in tetrahydrofuran (1 mL) at -40°C under argon was added N-methyl morpholine (.027 mL, .25 mmol) and isobutyl chloroformate (.022 mL, .167 mmol) . After stirring for 15 min at -40°C, N-methyl orpholine (.027. mL, .00025 mole) and Valine valine methyl ester hydrochloride (.049 g, .183 mmol) were added. The mixture was warmed to 25°C and allowed to stir under argon for 14 hr. The mixture was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and evaporated to a white semi-solid residue. The residue was chromatographed (silica gel, 20:1 dichloromethane: methanol) to give the titled compound as a white foam (.073 g, 63%) . NMR(CDCl3) : δ 7.32-7.05 (5H, ) , 6.68(2H, d) , 6.29(1H, d) , 5.30 (1H, d) , 4.73 (1H, d) , 4.50 (2H, m) , 4.15-3.72 (5H, m) , 3.63 (3H, s) , 2.71 (1H, m) , 2.30-0.65 (38H, m) , 0.10 (6H, d) . MS(DCI/NH3) : (M+H) + 692.7; 592.5; 578.5; 331.2; 257.2; 231.2; 216.2; 120.1; 72.1. b) (2R, 4S, 5S)-2-propyl-4- (t-butyldimethyl) siloxy-5- ( (benzyloxy-carbonyl) alanyl) amino-6-phenylhexanoyl-valyl- valine methyl ester The compound of Example 4(a) (.073 g, .106 mmol) was stirred in neat trifluoroacetic acid (1 mL) for 5 min, diluted with methanol, and treated with 2 drops of concentrated hydrochloric acid. The solvents were removed in vacuo to give the hydrochloride salt as a white foam(.071 g) . To a solution of Cbz-alanine (.014 g, .0613 mmol) in tetrahydrofuran (2 mL) at -40°C was added N-methyl morpholine (.009 mL, 1.5 eq.) and- isobutyl chloroformate (.008 mL, 1 eq.) . The mixture was stirred at -40°C for 15 min, then N- methyl morpholine (.009 mL, 1.5 eq.) and the previously prepared hydrochloride salt (.035 g, .9 eq.) were added. The mixture was warmed to 25°C and stirred under argon for 14 hr. The reaction was diluted with ethyl acetate and washed successively with 5% HCl, 5% aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered,and evaporated to a white solid which was chromatographed (silica gel, 40:1 dichloromethane:methanol) to give the titled compound as a white solid (.020 g, 45%) . NMR(CDCl3) : δ 7.40-7.12 (10H, m) , 6.61-6.40 (2H, m) , 5.15(2H, m) , 4.52-3.73(3H, m) , 3.62(3H, d) , 2.80(1H, m) , 2.12(2H, m) , 1.55(2H, m) , 1.21(1H, d) , 0.98-0.65 (32H, m) , 0.10(6H, d) . MS (FAB) : (M+H) + 797.8 c) (2R, 4S, 5S)-2-propyl-4-hydroxy-5- ( (benzyloxycarbonyl)- alanyl)amino-6-phenylhexanoyl-valyl-valine methyl ester. The compound of Example 4(b) (.020 g, .0251 mmol) was dissolved in 1 mL of neat trifluoroacetic acid and stirred for 10 min. The solution was diluted with dichloromethane and shaken with 5% aqueous sodium bicarbonate. The organic layer was removed and washed with water. The solvents were removed in vacuo and the resultant white solid was triturated with diethyl ether to give the titled compound as a white foam (.013 g, 76%) . NMR (DMSO-d 6 ) : δ 8.18 (1H, d) , 7.61(1H, d) , 7.53 (1H, d) , 7.36(5H, m) , 7.19(5H, m) , 5.04(2H, s) , 4.88(1H, d) , 4.30-4.04(3H, m) , 3.81(1H, d) , 3.60(3H, s) , 2.82(1H, m) , 2.05(1H, m) , 1.89(1H, m) , 1.55-1.20 (3H, m) , 1.20-1.05 (3H, m) , 0.95-0.7K16H, m) . MS(DCI/NH3) : (M+H) + 683.6, 665.6, 575.5, 549.5, 531.4, 461.3, 357.3, 339.3, 327.2, 257.2, 231.2, 216.2, 132.1. Example 5 Preparation of (2R, 4S, 5S) -5- (tert-butyloxycarbonyl) amino-6- phenyl-4-hydroxy-2- (1-propyl) - (1-oxo)hexyl-valyl valine methyl ester Following the procedure of Example 4 (a) , valyl valine methyl ester is acylated with the compound of Example 1 (g) . Treatment of the resulting product with tetrabutyl ammonium fluoride in tetrahydrofuran yields the titled compound. NMR (CDCI3) : δ 7.18 (5H, m) , 6.31 (1H, d) , 6.26 (1H, d) , 4.83(1H, q) , 4.51(1H, m) , 4.16(1H, m) , 3.69(3H, s) , 2.84(2H, d) , 2.48(1H, m) , 2.16(2H, m) , 1.63(4H, m) , 1.3K9H, s) , 1.28- 1.1 (7H, m) , 0.83 (12H, m) MS (FAB) : m/z 578.2 (M+H) + , 478.2, 391.1, 345.1, 231.1, 132.0, 91.0, 72.1, 57.1 Example 6 By the detailed procedures set forth herein, with particular reference to Example 4, the carboxyl group of the compound of Example 1 (g) was reacted with the appropriate hydrochloride of valylvaline methyl ester or valinamide, the amino group was deprotected and acylated with Cbz-alanine or Cbz-alanylalanine, and the t-butyldimethylsilyl-protecting group was removed to yield the following specific compounds: a) (2R,4S, 5S)-2-propyl-4-hydroxy-5- (benzyloxycar-bonyl- alanyl-alanyl)amino-6-phenylhexanoyl-valyl valine methyl ester NMR (DMSO-d 6 ) : δ 8.04 (1H, d) , 7.88 (1H, d) , 7.57 (2H, dd) , 7.45(1H, d) , 7.28(5H, m) , 7.16(5H, m) , 5.02(2H, s) , 4.85(1H, d) , 4.30-3.99 (4H, m) , 3.83 (1H, m) , 3.59 (3H, s) , 2.82 (2H, dd) , 2.61(2H, m) , 2.04 (1H, m) , 1.87 (1H, m) , 1.3(2H, q) , 1.15 (10H, m) , 0.82 (16H, m) . MS (FAB) :, m/z 75 .7 (M+H)+, 736.7, 623.6, 524.5, 489.5, 390.4, 309.2, 248.3, 231.3, 155.1. b) (2R,4S,5S)-2-propyl-4-hydroxy-5-(benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl amide NMR (DMSO-d6) : δ 7.50 (2H, dd) , 7.34 (5H, m) , 7.16(5H, m) , 6.96(1H, m) , 5.02(2H, s), 4.89(1H, d) , 4.04(2H, m) , 3.82 (1H, ) , 2.81 (1H, m) , 2.63(1H, m) , 1.85(1H, m) , 1.49-1.2K3H, ) , 1.14(7H, m) , 0.79(3H, t) , 0.72(12H, m) . Example 7 Preparation of (2R, 4S, 5S)-2-allyl-4-hydroxy-5- (benzyloxycarbonyl-alanyl)amino-6-phenylhexanoyl-valyl amide Using the procedure of Example 4, the carboxyl group of the compound of Example 3 was reacted with the hydrochloride of valinamide, the amino group was deprotected and acylated with Cbz-alanine, and the t-butyldimethylsilyl-protecting group was removed to yield the titled compound. NMR (DMSO-d6) : δ 7.56(2H, dd) , 7.37(6H, m) , 7.20 (5H, m) , 6.98(1H, s) , 5.67(1H, m) , 5.05-4.88 (4H, m) , 4.09(2H, dd) , 3.86(1H, m) , 2.84(1H, dd) , 2.61(2H, m) , 2.20(1H, m) , 2.03- 1.78(2H, m) , 1.40(2H, m) , 1.15(3H, s) , 0.84(2H, ) , 0.72 (6H, ) . Example 8 Following the procedure of Example 4 (a) , valinamide or valylvaline methyl ester was acylated with the compound of Example 3. Treatment of the resulting product with tetrabutyl ammonium fluoride in tetrahydrofuran yields the titled compounds : a) (2R, 4S, 5S) -5- (tert-butyloxycarbonyl) amino-6-pheny1- 4-hydroxy-2- (allyl) - (1-oxo) hexyl-valinamide, NMR (CDC1 3 ) : δ 7.16(5H, m) , 5.62 (1H, m) , 5.11(1H, d) , 4.89(2H, m) , 4.06(1H, dd) , 3.54(2H, m) , 2.91(1H, m) , 2.79(2H, d) , 2.28UH, m) , 2.04(1H, m) , 1.59(2H, dd) , 1.31(9H, s) , 0.84(6H, dd) MS (FAB) : m/z 362.0 (M+H)+, 246.0, 228.0, 186.1, 146.0, 117.0, 102.9, 91.0, 72.0, 57.0; b) (2R, 4S, 5S) -5- (tert-butyloxycarbonyl) amino-6-pheny1- 4-hydroxy-2- (allyl) - (1-oxo)hexyl-valyl valine methyl ester. Example 9 By the detailed procedures set forth herein, with particular reference to Example 4, the carboxyl group of the compound of Example 2 (a) is reacted with the hydrochloride of valine methyl ester, valyl-valine methyl ester, valinamide, valyl-valinamide, valinol or valyl-valinol, the amino group is deprotected and acylated with Cbz-alanine, Cbz-alanyl- alanine, Cbm-alanine or propanoic acid, and the t- butyldimethylsilyl-protecting group is removed to yield the following specific compounds. Valinols are acetylated in conventional fashion by treatment with triethylamine and acetic anhydride, acids are produced by hydrolysis with aq. methanolic potassium hydroxide of the corresponding methyl 5 esters. Carbobenzyloxy groups are removed by conventional hydrogenolysis with 5% palladium on carbon. a) 2R,4S,5S) ' -2~methyl-4-hydroxy-5-(ananylalanyl)amino- 6-phenylhexanoyl-valyl valine methyl ester, 10 b) (2R,4S,5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl valine methyl ester, NMR (CD3OD/CDCI3) : δ 7.12(10H, m) , .93 (2H, s) , 4.28 (IH, d) , 3.97(2H, ) , 3.80 " (2H, m) , 3.59(3H, s) , 3.42(1H, m) , 2.72(2H, m) , 2.43(1H, dd) , 2.10-1.79 (2H, ) , 1.61-1.27 (2H, m) , 15 . 1.13 (3H, d) , 0.93 (3H, d) , 0.78 (12H, d) ; c) (2R,4S, 5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl methyl ester, NMR (CDCI3) : δ 7.34-7.14(10H, m) , 6.59(1H, d) , 6.43(1H, d) , 5.37(1H, d) , 5.08(2H, s) , 4.48(1H, dd) , 4.19(2H, m) , 4.00(1H, 20 m) , 3.75(1H, m) , 3.71(3H, s) , 2.90 (2H, d) , 2.64(1H, ) , 2.11 (IH, m) , 1.87 (IH, m) , 1.65(2H, m) , 1.28 (3H, d; J=7.0 Hz), 1.10 (3H, d; J=7.0 Hz), 0.88 (6H, dd) . MS (DCI/NH3) : m/z 556 (M+H) + ; d) (2R, 4S, 5S) -2-methyl-4-hydroxy-5-propanoylamino-6- 25 phenylhexanoyl-valyl valine methyl ester, NMR (CD3OD/CDCI3) : δ 7.2 (5H, m) , 4.39 (IH, d; J=5.63 Hz), 4.14 (IH, d; J=7.9 Hz), 4.03 (IH, m) , 3.7 (3H, s) , 3.57 (IH, m) , 2.92 (IH, dd) , 2.80 (IH, dd) , 2.62(1H, ) , 2.17 (3H, m) , 2.04(1H, m) , 1.71(1H, m) , 1.49(1H, m) , 1.08(6H, m) , 0.94(12H, 30 m) MS (DCI/NH3) : m/z 506 (M+H) + ; e) (2R, S, 5S) -2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-ρhenylhexanoyl-valyl amide, NMR (CD3OD/CDCI3) δ 7.34-7.15 (10H, m) , 5.06 (2H, s) , 4.13- 35 3.94(3H, m) , 3.54(lH,m), 2.82(2H, m) , 2.58 (IH, m) , 1.97 (IH, ) , 1.65 (IH, m) , 1.46(1H, m) , 1.22 (3H, d; J=7.2 Hz), 1.02 (3H, d; J=7.1 Hz), 0.86(6H, t) . MS (FAB) : m/z 541.4 (M+H)+; f) (2R,4S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanylalany1)amino-6-phen lhexanoyl-valyl amide, MS (FAB) : m/z 612.3 (M+H) + NMR (DMS0-d6) δ 7.38-7.17 (10H, m) , 5.02(2H, s) , 4.24(m), 4.04(m), 2.80(m), 2.60 (m) , 1.48(1H, m) , 1.19(8H, m) , 0.91 (3H, d), 0.74 (6H, dd) ; g) (2R, S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoy1-valinol, NMR (CD 3 OD/CDCI 3 ) : δ 7.35-7.21 (10H, m) , 5.09(2H, s), 4.14 (IH, m) , 3.98(1H, m) , 3.57(4H, m) , 2.89(2H, ) , 2.55(1H, m) , 1.83(1H, m) , 1.69-1.44(2H, m) , 1.25(3H, d; J=7.0 Hz), 1.07 (3H, d; J=6.9 Hz), 0.88 (6H, m) . MS (FAB) : m/z 528.3 (M+H) + ; h) (2R, S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl-alanyl) amino-6-phenylhexanoyl-valinol, MS (FAB) : m/z 599.3 (M+H)+ NMR (CD3OD/CDCI3) : δ 7.35-7.2K10H, m) , 5.12(2H, s) , 4.27(1H, m) , 4.16-4.00(2H, m) , 3.58(4H, ) , 2.93 (IH, dd) , 2.81(1H, dd) , 2.56(1H, m), 1.84(1H, m) , 1.67(1H, .m) , 1.55(1H, m) , 1.3 (3H, d; J=7.1 Hz), 1.26 (3H, d; J=7.1 Hz), 0.91 (3H, d; J =6.7 Hz), 0.86(3H, d; J=6.8 Hz); i) (2R, 4S, 5S) -2-methyl-4-hydroxy-5- ( (methoxycarbonyl- alanyl) -amino-6-phenylhexanoyl-valyl valinol, NMR (CD3OD/CDCI3) : δ 7.15 (5H, m) , 3.90(3H, m) , 3.62-3.48 (4H, m), 3.59(3H, s) , 2.84(1H, dd) , 2.71(1H, dd) , 2.54(1H, m) , 1.93 (IH, m) , 1.80(1H, m) , 1.62(1H, m) , 1.39(1H, m) , 1.15(3H, d) , 0.98 (3H, d) , 0.83 (12H, m) ; j) (2R, 4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl- (O-acetyl) valinol, NMR (CDCI 3 ) : δ 7.33-7.17(10H, m) , 6.71(1H, d) , 6.11(1H, d) , 5.50(1H, d) , 5.07 (2H, s) , 4.30-3.90 (6H, m) , 3.68(1H, m) , 2.90(2H, m) , 2.58(1H, m) , 2.01 (3H, s) , 1.78(1H, m) , 1.62 (2H, m) , 1.27 (3H, d; J=6.9 Hz), 1.07 (3H, d; J=6.9 Hz), 0.88 (6H, t); k) (2R, S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoyl- (O-acetyl)valinol, MS (FAB) : m/z 641.4 (M+H)+ NMR (CD3OD/CDCI3) : δ 7.33-7.12 (10H, m) , 5.10 (2H, s) , 4.17- 3.95(5H, m) , 3.87 (IH, m) , 3.53 (IH, m) , 2.90(1H, dd) , 2.79 (IH, dd) , 2.02 (3H, s), 1.83-1.61 (2H, m) , 1.49 (IH, m) , 1.57 (3H, d; J=7.1 Hz), 1.09 (3H, d; J=7.1 Hz), 0.88 (3H, d; J =6.9 Hz), ' 0.7K6H, t) ; 1) (2R,4S, 5S)-2-methyl-4-hydroxy-5- ((methoxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl-(O-acetyl)valinol, NMR (CD3OD/CDCI3) : δ 7.08 (5H, m) , 4.07-3.83 (5H, m) , 3.52 (3H, s), 3.43(1H, m) , 2.74 (2H, m) , 2.46 (IH, m) , 1.91(3H, s) , 1.83(1H, m) , 1.67 (IH, m) , 1.55(1H, m) , 1.33(1H, m) , 1.13 (3H, d; J=7.0 Hz), 0.91(3H, d; J=6.9 Hz), 0.77 (12H, m) ; m) (2R,4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl)- alanyl) amino-6-phenylhexanoyl-valyl-(O-acetyl)valinol, NMR (CD3OD/CDCI 3 ) : δ 7.35-7.10(10H, m) , 5.05 (2H, s) , 4.17- 3.85(6H, m) , 3.52(1H, m) , 2.83(2H, m) , 2.55(1H, m) , 2.00(3H, s), 2.00 1.74(2H, m) , 1.65(1H, m) , 1.46(1H, m) , 1.22(3H, d; J=6.74 Hz), 1.00 (3H, d; J=6.90 Hz), 0.88 (12H, . m) ; n) (2R, S, 5S)-5- (carbobenzyloxy-alanylalanyl) amino-6- phenyl-4-hydroxy-2-methyl- (1-oxo)hexyl-valine; Example 10 Using (2R, 4S, 5S)-2-benzyl-4- (tert-butyldimethyl)-siloxy- 5- (tert-butyloxycarbonyl) amino-6-phenylhexanoic acid, the compound of Example 2(b), and employing the general procedures described herein in Example 4 and 9, the following specific compounds are prepared: a) (2R,4S,5S)-5- (carbobenzyloxy-alanylalanyl) arr_ino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valine methyl ester, b) (2R,4S, 5S)-5-(carbobenzyloxy-alanyl) amino-6-phen 1- 4-hydroxy-2-benzyl- (1-oxo)hexyl-valine methyl ester; c) (2R, S, 5S) -5- (carbobenzyloxy-alanylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo) exyl-valinamide; d) (2R, 4S, 5S) -5- (carbobenzyloxy-alanyl) amino-6-phenyl- 4-hydroxy-2-benzyl- (1-oxo)hexyl-valinamide, NMR (DMF-d7) : δ 7.31 (IH, dd) , 6.98 (15H, m) , 6.59 (IH, br s) , 4.81 (2H, d) , 3.92 (IH, m) , 3.71 (IH, q) , 3.42 (IH, m) , 2.29 (2H, m) , 1.71(1H, m) , 1.32(2H, m) , 0.97 (3H, d) , 0.52(6H, m) MS (FAB) : m/z 617.5 (M+H) + , 600.5, 550.8, 522.8, 492.5, 385.1, 355.2, 338.5, 329.1, 309.1, 281.2, 251.3, 233.1, 177.1, 157.1; e) (2R,4S, 5S)-5- (carbobenzyloxy-alanyl)amino-6-pheny1- 4-hydroxy-2-benzyl- (1-oxo)hexyl-valinol; f) (2R,4S, 5S)-5-(carbobenzyloxy-alanylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valine; g) (2R,4S, 5S)-5- (tert-butyloxycarbonyl) mino-6-pheny1- 4-hydroxy-2-benzyl- (1-oxo)hexyl-valyl valine methyl ester NMR (CDCI3/CD3OD) : δ 7.16(10H, ) , 5.07 (IH, d) , 4.27 (IH, d) , 3.92 (IH, d) , 3.68 (3H, s) , 3.53 (2H, m) , 2.73 (obsc. by H 2 0) , 1.96(2H, m) , 1.63 (2H, m) , 1.28(9H, s) , 0.79(12H, m) , MS (FAB) " : m/z 626.3 (M+H) + , 526.3, 439.2, 231.1, 155.0, 132.0, 119.0, 103.0, 91.0, 72.1, 57.1; h) (2R, S, 5S)-5- (tert-butyloxycarbonyl) amino-6-ρhenyl- 4-hydroxy-2-benzyl- (1-oxo)hexyl-valinamide, NMR (CD3OD) : δ 7.37 (IH, d) , 7.12 (10H, m) , 5.81 (IH, d) , 3.98(1H, m) , 3.57(1H, q) , 2.69(5H, m) , 1.89(1H, m) , 1.58 (3H, m) , 1.26(9H, s), 0.7K6H, dd) MS (FAB) : m/z 512.3 (M+H)+, 494.3, 456.2, 412.2, 357.2, 291.1, 273.1, 255.1, 181.1, 120.1, 102.1, 72.1; i) (2R,4S,5S)-5- (carbobenzyloxy-phenylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valyl valinol, MS (FAB) : m/z 779.4 (M+H) + , 761.4, 676.3, 577.2, 386.2, 296.1, 278.1, 242.3, 203.2; j) (2R, 4S, 5S)-5- (tert-butyloxycarbonyl) amino-6-pheny1- 4-hydroxy-2-benzyl- (1-oxα)hexyl-valyl valinol, NMR (CD3OD) : δ 7.20(10H, m) , 6.46(lH,d), 6.20(1H, d) , 4.71(1H, d) , 3.94(2H, ) , 3.55(4H, m) , 3.17(1H, dd) , 2.61(4H, m) , 2.03(1H, m) , 1.68 (3H, m) , 1.28(9H, s) , 0.83(12H, m) MS (FAB) : m/z 598.3 (M+H) + , 498.2, 296.1, 278.1, 203.1, 146.0, 117.0, 104.0, 91.0, 72.1, 57.0; k) (2R, 4S, 5S)-5- (carbobenzyloxy-alanyl) amino-6-pheny1- 4-hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl) amide, NMR (DMSO-dε) : δ 8.14 (IH, br s) , 7.54 (IH, d) , 7.20 (20H, m) , 6.93(2H, br dd) , 4.99(2H, s) , 4.84 (IH, m) , 4.23 (IH, m) , 4.01(2H, m) , 3.78(1H, m) , 3.44(2H, ) , 2.73(3H, m) , 1.52(1H, m), 1.30(2H, m), 1.08(3H, d) MS (FAB) : m/z 608 .2 (M+H) + , 590 .2 , 456 . 1 , 403 . 1, 386 . 1 , 368 . 1 , 308 . 9 , 296 . 0 , 278 . 0 , 242 . 2 ; 1) (2R,4S,5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl- 4-hydroxy-2-benzyl- (1-oxo)hexyl-valinol, NMR (CD 3 OD) : δ 7.38(1H, d) , 7.19 (10H, m) , 6.18(lH,d), 3.62 (IH, q) , 3.55 (2H, m) , 3.20 (2H, m) , 2.79 (2H, m) , 2.61 (2H, m) , 1.74(3H, m) , 1.56(1H, m) , 1.29(9H, s) , 0.76(6H, dd) MS (FAB) : m/z 499.3 (M+H)+, 481.3, 443.3, 425.3, 408.3, 399.3, 351.2, 278.2, 260.2, 183.1, 120.1, 91.1, 72.1; m) . (2R, S, 5S)-5-(alanylalanyl)amino-6-pheny1- -hydroxy- 2-benzyl- (1-oxo)hexyl-valyl valine methyl ester NMR (CD3OD) : δ 7.15(10H, m) , 4.30(1H, q) , 4.19(1H, d) , 4.12(1H, d) , 3.98(1H, q) , 3.63(3H, s) , 2.84(4H, m) , 2.53(1H, m) , 2.0K2H, m) , 1.58(2H, m) , 1.22(6H, dd) , 0.86(12H, m) MS (FAB) : m/z 682.5 (M+H)+, 668.4, 613.2, 537.4, 460.2, 443.2-, 329.1, 308.2, 290.1, 273.2; n) (2R, 4S, 5S) -5- (carbobenzyloxy-D-alanyl-L- alanyl) amino-6-phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl) amide, NMR (DMSO-d6) : δ 8.06 (IH, dd) , 7.70(1H, d) , 7.62 (IH, d) , 7.48(1H, d) , 7.31-6.86(20H, m) , 4.99(2H, q) , 4.20(2H, m) , 4.05(2H, m) , 3.73(1H, m) , 3.48(1H, d) , 3.30(1H, m) , 2.79(2H, m) , 2.58 (2H, m) , 1.63 (2H, m) , 1.16(3H, d) , 0.98(3H, d) MS (FAB) : m/z 679.1 (M+H) + , 661.1, 527.2, 456.1, 403.1, 386.1, 368.1, 296.1, 278.1; o) (2R, 4S,5S)-5- (carbobenzyloxy-phenylglycyl- alanyl) amino-6-phenyl-4-hydroxy-2-benzyl-(1-oxo)hexyl- (benzyl)amide, NMR (CDCI3/CD3OD) : δ 7.65(1H, d) , 7.41-7.01 (25H, m) , 6.91(1H, d), 6.90(1H, d), 6.54 (IH, d) , 5.11(1H, d) , 5.08(2H, s) , 4.41- 4.29(1H, m) , 4.25-4.17 (IH, t) , 4.15-3.92 (2H, m) , 3.62(1H, m) , 3.00-2.80(3H, m) , 2.79-2.58 (3H, m) , 1.86-1.51 (2H, m) , 1.11(3H, d) MS (FAB) : m/z 741.4 (M+H) + , 723.4, 296.2, 278.2, 235.1, 157.1, 146.1, 119.0, 106.1, 91.1, 79.0, 59.0; Example 11 Using the detailed procedures dexcribed herein, with particular reference to Example 4, and empoloying the compound of Example 2 (d) , the following specific compounds were prepared: a) (2R, S, 5S)-5- (carbobenzyloxyalanyl)amino-6-pheny1-4- hydroxy-2-isobutyl- (1-oxo)hexyl-valinamide, NMR (DMSO d 6 ) : δ 7.49(2H, dd) , 7.34-7.10 (10H, m) , 6.92(1H, s) , 4.98(2H, s) , 4.04(2H, m) , 3.37(2H, m) , 2.74(1H, m) , 1.69(3H, m) , 1.37(4H, ) , 1.14 (3H, d) , 0.76(12H, m) MS (FAB) : m/z 583.1 (M+H) + - b) (2R, 4S, 5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl- 4-hydroxy-2-isobutyl- (1-oxo)hexyl-valinamide, NMR (CD3OD) : δ 7.71(lH, d) , 7.18 (5H, s) , 6.19(1H, d) , 4.12(1H, m) , 3.64(1H, q) , 3.49(1H, d) , 2.8K1H, m) , 2.63 (2H, m) , 1.95(1H, m) , 1.68 (2H, m) , 0.97-0.74 (12H, m) , 1.26(9H, s) MS (FAB) : m/z 478.4 (M+H) + , 460.4, 422.3, 404.3, 387.3, 323.2, 305.2, 262.2, 239.2, 186.2, 117.1, 86.1; c) (2R, 4S, 5S) -5-carbobenzyloxy-alanylalanyl) amino-6- phenyl-4-hydroxy-2-isobutyl- (1-oxo)hexyl-valyl valine methyl ester, NMR (CDCI3/CD 3 OD) : δ 7.59(1H, d) , 7.50(1H, d) , 7.21-6.90 (10H, m) , 4.88(2H, s) , 3.86(2H, m) , 3.74(1H, m) , 3.49(3H, s) , 2.60(1H, m) , 1.33(3H, m) , 1.06(6H, dd) , 0.61(18H, m) MS (FAB) : m/z 768.6 (M+H)+, 750.6, 637.5, 553.4, 461.3, 277.2, 239.0, 185.1, 93.1; d) (2R,4S,5S)-5- (carbobenzyloxy-alanyl)amino-6-phenyl- 4-hydroxy-2-isobutyl- (1-oxo)hexyl-valyl valine methyl ester NMR (CDCI3/CD 3 OD) : δ 7.51(1H, d) , 7.28-6.94 (10H, m) , 4.92(2H, br s) , 4.24(1H, m) , 3.76(1H, m) , 3.54(3H, s) , 3.38(1H, br d) , 2.63(2H, m) , 2.36(1H, m) , 2.04-1.70 (2H, m) , 1.48-1.20 (2H, m) , 1.09(3H, d) , 0.72-0.5K18H, ) MS (FAB) : m/z 697.5 (M+H)+, 679.5, 566.4, 492.4, 467.3, 432.3. Example 12 Liposomal Dosage Unit Composition Phosphatidylcholine (1.4 g) and phosphatidylglycerol ( .6g) are dissolved in 300 ml of a 20% methanol in chloroform solvent and evaporated to dryness. A solution of the peptide (30 mg in 200 ml of phosphate buffered saline) is added to the dry phospholipid film which is allowed to equilibrate at room temperature for 1-2 hr. The liposome dispersion formed is then vortexed to insure uniform mixing. The resulting suspension is extruded through a 0.2μ polycarbonate filter five times to produce a uniform size distribution. If necessary the suspension can be dialysed or ultracentrifuged to remove non-encapsulated peptide. Example 13 Liposomal Dosage Unit Composition In a beaker, cholesterol (49 mg) and oleic acid (.358 g) are warmed to 65°C for 20-30 min. Maintaining the temperature, phospholipids (1 g) are added slowly, ensuring complete wetting by the oleic acid. A solution of arginine (.22 g in 3.37 g water) at 40°C is added in small aliquots and thoroughly mixed into the slurry. Mixing is maintained at 40°C- After equilibration for one week, the peptide (150 mg) is mixed thoroughly into the gel. The pH is adjusted to 7.0 with acetic acid if necessary. Phosphate buffered saline (pH 7.4) is added in small aliquots with vortexing to achieve a concentration of 200 mg of liposomal gel per ml. Liposomes form spontaneously. This procedure produces 5 g of liposomal suspension. A standard dosage unit is 1 g of liposomal suspension. Example 14 Parenteral Dosage Unit Composition A preparation which contains 25 mg of a peptide of this invention is prepared as follows: 25 mg of the peptide is dissolved in 15 ml of distilled water. The solution is filtered under sterile conditions in to a 25 ml multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 20 ml of 5% dextrose in water (D5W) for intravenous or intramuscular injection. The dosage is thereby determined by the injection volume. This solution is also suitable for use in other methods for administration, such as addition to a bottle or bag for IV drip infusion. Example 15 Oral Dosage Unit Composition A capsule for oral administration is prepared by mixing and milling 35 mg of the peptide with 75 mg of lactose and 5 mg of magnesium stearate. The resulting powder is screened and filled into a hard gelatin capsule. The above description fully discloses how to make and use this invention. This invention, however, is not limited to the precise embodiments described herein, but encompasses all modifications within the scope of the claims which follow.

Claims: What is claimed is : 1. A compound of the formula: A-(C ) b- ( D) c-M- (X ) e-Y-Z ' (I) wherein: A is BocNH, CbzNH., H, R'R"N, R"CONR', or if a, b and c are 0 and Y is a covalent bond, then A is H, Boc, Cbz, R" or R"CO; C and D are the same or different and are Ala, β-Ala, D- Ala, Phe, Phg or Val; X is Ala, lie, Leu, Val; Y is Ala, lie, Leu, Val or is a covalent bond; Z is C0 2 R"", CONR'R"", COR', CH20R"", CH 2 OC(0)R" or H, or if e is 0 and Y is a covalent bond, Z is OR"" or NR'R""; b, c and e are each independently 0 or 1, provided that c and e are not simultaneously 0; wherein: Rl is independently , C ] __5 lk, C3_5alkenyl or benzyl; • R' and R" are H or Cι_5 lk;' R"" is H, Cx-s lk, C 3 _ 6 cycloalkyl, (CH ) n C6H5, (CH 2 ) n C5H 4 N. (CH 2 ) n OH, (CH 2 ) n NH 2 , or(CH 2 ) n NHC(NH)NH 2; and pharmaceutically acceptable salts thereof; provided that if b and e are 0, Y is a covalent bond and D is Val, then Ri is not isobutyl. 2. A peptide according to claim 1 in which X and Y are Val. 3. A peptide according to claim 1 in which C and D are Ala. 4. A peptide according to claim 1 in which R • is H, Ci-salkyl, allyl or benzyl. 5. A peptide according to claim 1 in which Ri is propyl 6. A peptide according to claim 4 in which Z is CH2OH or CH2OAC. 7. A peptide according to claim 6 in which D is Ala and X is Val. 8. A peptide according to claim 1 in which the compound is: (2R, 4S,5S) -2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanylalanyl) amino-6-phenylhexanoyl-valyl valine methyl ester; (2R, 4S, 5S)-2-propyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl alanyl) amino-6-phenylhexanoyl-valyl valine methyl ester; (2R, S, 5S)-5- (carbobenzyloxy-alanylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valine methyl ester; (2R, 4S, 5S) -2-propyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl-valine methyl ester; (2R, 4S,5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl valine methyl ester; (2R, 4S, 5S) -5- (carbobenzyloxy-alanylalanyl)amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valine methyl ester; (2R, 4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoy1-valinol; (2R,4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanylalanyl)amino-6-phenylhexanoyl- (O-acetyl)valinol; (2R, 4S,5S) -2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl valinol; (2R,4S, 5S)-2-methyl-4-hydroxy-5- (methoxycarbonyl- alanyl) -amino-6-phenylhexanoyl-valyl valinol; (2R, 4S,5S)-2-methyl-4-hydroxy-5- (methoxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl- (O-acetyl) alinol; (2R,4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl- (O-acetyl)valinol; (2R,4S,5S)-5-(carbobenzyloxy-alanyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinol; (2R, 4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alany1)amino-6-phenylhexanoy1-valinol; (2R, S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl- (O-acetyl) alinol; (2R,4S,5S)-5-(carbobenzyloxy-alanylalanyl)amino-6- phenyl-4-hydroxy-2-benzyl-(1-oxo)hexyl-valinamide; (2R,4S, 5S)-2-methyl-4-hydroxy-5-(benzyloxycarbonyl- alanylalanyl) amino-6-phenylhexanoyl-valyl amide; (2R,4S, 5S) -2-methyl-4-hydroxy-5-propanoylamino-6- phenylhexanoyl-valyl valine methyl ester; (2R, 4S, 5S)-5- (carbobenzyloxy-alanyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valine methyl ester; (2R, 4S, 5S) -2-methyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl) amino-6-phenylhexanoyl-valyl methyl ester; (2R,4S, 5S) -2-propyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl amide; (2R,4S, 5S)-2-allyl-4-hydroxy-5- (benzyloxycarbonyl- alanyl)amino-6-phenylhexanoyl-valyl amide; (2R,4S, 5S)-2-methyl-4-hydroxy-5- (benzyloxycarbonyl) - alanyl) amino-6-phenylhexanoyl-valyl amide; (2R,4S,5S) -5- (carbobenzyloxy-alanyl)amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinamide; and (2R,4S,5S)-5- (carbobenzyloxy-alanylalanyl)amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo) exyl-valine. 9. A peptide according to claim 1 in which the compound is: (2R,4S, 5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valyl valine methyl ester; (2R, S,5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2- (1-propyl)-(1-oxo)hexyl-valyl valine methyl ester; (2R,4S, 5S)-5-carbobenzyloxy-alanylalanyl)amino-6-phenyl- 4-hydroxy-2-isobutyl- (1-oxo)hexyl-valyl valine methyl ester; (2R,4S, 5S) -5- (carbobenzyloxy-alanyl) amino-6-phenyl-4- hydroxy-2-isobutyl- (1-oxo)hexyl-valyl valine methyl ester; (2R, 4S, 5S)—5- (alanylalanyl)amino-6-phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valyl valine methyl ester; (2R, 4S,5S)-5- (carbobenzyloxy-phenylalanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl-valyl valinol; (2R,4S,5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valyl valinol; (2R,4S, 5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinol; (2R, S, 5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl-valinamide; (2R, S,5S) -5- (carbobenzyloxy-alanyl) amino-6-phenyl-4- hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl)amide; (2R, S, 5S)-5- (tert-butyloxycarbonyl) amino-6-phenyl-4- . hydroxy-2- (prop-2-ene)- (1-oxo)hexyl-valinamide; (2R, 4S, 5S)-5- (carbobenzyloxyalanyl)amino-6-phenyl-4- hydroxy-2-isobutyl-(1-oxo)hexyl-valinamide; (2R,4S,5S) -5-(tert-butyloxycarbonyl) amino-6-phenyl-4- hydroxy-2-isobutyl- (1-oxo)hexyl-valinamide; (2R,4S, 5S)-5- (carbobenzyloxy-D-alanyl-L-alanyl) amino-6- phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl) amide; and (2R,4S, 5S) -5- (carbobenzyloxy-phenylglycyl-alanyl)amino- 6-phenyl-4-hydroxy-2-benzyl- (1-oxo)hexyl- (benzyl)amide. 10. A pharmaceutical composition which comprises a peptide according to claim 1 and a pharmaceutically acceptable carrier. 11. A method of treating disease states associated with HIV infection which comprises administering an effective amount of a peptide according to claim 1. 12. A method of treating disease states associated with HIV infection which comprises administering an effective amount of a peptide according to claim 1 and azidothymidine.

Inventors: CARR THOMAS JOSEPH, DREYER GEOFFREY BAINBRIDGE, CARR, THOMAS, JOSEPH, DREYER, GEOFFREY, BAINBRIDGE
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1991
Main classification: C07K5
IPC codes: A61K31, A61K38, A61P31, C07C237, C07C271, C07C279, C07F7, C07K5, C07K7, C07K14