HIV PROTEASE INHIBITORS

Abstract: The invention relates to HIV protease inhibitors wherein the compounds have a 2,4-dihydroxy isostere wherein the hydroxyl group in the 2-position is further substituted to create a tertiary alcohol. Also disclosed are pharmaceutically acceptable salts thereof, which inhibit HIV-I protease and are useful in the treatment of AIDS.

Description: TITLE HIV PROTEASE INHIBITORS BACKGROTTND 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 infection 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'- gag-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., Virology, 145, 280-92(1985), Crawford, et al., J. Virol . , 53, 899-907(1985) and Debouck, et al., Proc. Natl . Acad. Sci . USA, 84, 8903-6(1987). Inhibition 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 et al . , Science, 246, 1149 (1989). The method of isosteric replacement has been disclosed s 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. The compounds of this invention have a unique 2,4 dihydroxy isostere wherein the hydroxyl group in the 2 position is further substituted to create a tertiary alcohol. The compounds are potent inhibitors of retroviral protease and are able to penetrate affected cells. Dihydroxy isosteres have been reported as intermediates in the preparation of inhibitors of renin in Metternich et al . , Tet . Lett . , 29, 3923 (1988), Dellaria et al . , WO 87/04349, and Dellaria et. al . , J. Med. Chem. , 30, 1978, (1987) . SUMMARY OF THE INVENTION This invention comprises compounds, hereinafter described, 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) : SUBSTITUTE SHEET (I) wherein Rl is A, A-B or A-B-D A is R 11 , R 11 CO, R 11 - (CHR 11 ' ) n -CO, R 1:L OCO, R 1:L OCH (R 11 * ) CO, R^NHCH fR^ ' j CO, R^SCH fR^ ' j CO, R 1:L S02, R 1:L SO or R :L C (0) CO; R 5 B and D are NR'(CH 2 ) q « ^CO . R 2 and R 4 are Ci-βalkyl, optionally substituted with 1-5 fluorine atoms, C3_galkenyl, Cι_6alkyl-0-CH2 or (CH 2 )n~ T f wherein T is phenyl, naphthyl, Cs-βcycloalkyl or indolyl, optionally substituted with nitro, halogen, Cι_ 4 alkyl, Cι_ 4 alkoxy, Cι_ 4 alkylthio, provided that R 2 is not Cι-6 lkyl when R 4 is cyclohexylmethyl; R 5 is H, Ci-βalkyl, Cι_6alkyl-0-CH2 or J-CH 2 (CH 2 )nr wherein J is CONHR', C02R', NHR 1 , SR 1 , or phenyl, naphthyl, Cs-gcycloalkyl or indolyl, optionally substituted with nitro, halogen, hydroxy, Cι_ 4 al yl, Cχ_ 4 alkoxy, Cι_ 4 alkylthio or trifluoromethyl; R 3 is G, X-G or X-Y-G; R 5 X and Y are NR'^CO ; G is R 10 , NR'R 10 , NR'NR'-A, OR 10 or SR 10 ; R 10 is (CR 11 R 11 ') n -W; R 11 and R 11 ' are H, Alk, Ar, Het, Ar-Cι_ 5 alkyl, Het-Ci-salkyl, C3- 7 cycloalkyl, Ar-C3_ 7 cycloalkyl; W is H, CH 2 OR", COR", OR 11 , OCOR 11 , NR'R 11 , NR'COR 11 , SR 11 , Ar or Het; Alk is Ci-βal yl or Cι-6alkyl substituted by one or two hydroxy, nitro or Cι- 4 alkoxy groups, or one to five fluoro atoms; R' is H, Cι-6alkyl or (CH2)n _ Ar; R" is H, Cι-6alkyl or (CH 2 ) n -Ph; n is 0, 1 or 2; and SUBSTITUTE SHEET q is 0 or 1; or a pharmaceutically acceptable salt thereof. Suitably R 1 is A or A-B. Suitably R 2 is Ci-εalkyl or (CH 2 )n-phenyl. Suitably R 3 is G. Typically R 3 is NHCHfR 11 )-W, wherein R 11 is H or Alk and W is CH 2 OH, CONH2 or phenyl. Preferably R 1 is A. More suitably R 1 is Ci-βalkoxycarbonyl. Preferably R 2 is benzyl. Preferably R 3 is NHCH(i-pr)CH 2 θH. Preferably R 4 is benzyl. 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. Ar indicates aryl, Ar is phenyl or naphthyl, or phenyl or naphthyl substituted by one to three Cι- 4 alkyl, Cι- 4 alkoxy, Cι- 4 alkylthio, trifluoromethyl, nitro, mercapto, hydroxy, halogen, cyano, CO2R" or CON(R") 2 . Het indicates an optionally substituted heterocyclic ring, and is a saturated or unsaturated, five or six me bered ring or nine or ten- membered bicyclic ring, containing one to three heteroatoms chosen from the group of nitrogen, oxygen and sulfur, which are stable and available by conventional chemical synthesis. Illustrative heterocycles are pyridyl, furyl, thienyl, morpholinyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidininlyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, tetrazolyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, indolyl, quinolinyl, benzofuryl, benzisoxazolyl and benzothienyl. Het is optionally substituted with Cι- 4 alkyl, Cι- 4 alkoxy, C 1 -. 4 alkylt_.io, trifluoromethyl, nitro, mercapto, hydroxy, halogen, cyano, CO 2 R" or CON(R") 2 . Any accessible combination of up to three substituents on the phenyl, naphthyl or Het ring which is available by chemical synthesis and is stable is within the scope of this invention. SUBSTITUTESHEET Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of this invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem. 158, 9 (1984) . 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 natural amino acids (AA) are assumed to be of the L absolute configuration. Boc'refers to the t-butyloxycarbonyl radical, Z and Cbz refer to the carbobenzyloxy radical, BrZ refers to the o-bromobenzyloxy-carbonyl radical, C1Z is the p-chlorocarbobenzyloxy radical, C12 refers to the 2,4- dichlorocarbobenzyloxy radical, Bn refers to the benzyl radical, Ac refers to acetyl, Ph refers to phenyl, BrMgDA refers to bromomagnesium diisopropylamide, DCC refers to dicyclohexyl-carbodiimide, DMAP refers to dimethylamino- pyridine, HOBT refers to 1-hydroxybenzotriazole, OSU is 1-hydroxysuccinimide 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 formamide, HMPA is hexamethylphosphoramide, DMAPEC is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, DCC refers to dicyclohexylcarbodiimide, EDC 5 refers to N-ethyl-N' (dimethylaminopropyl)-carbodiimide, PPA refers to 1-propanephosphonic acid cyclic anhydride, DPPA refers to d±phenylphosphoryl azide, BOP refers to benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, TMS-Imid is N-trimethysilylimidazole, 10 valinol is (2S)-2-amino-3-methyl-butanol and THF is tetrahydrofuran. HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid. C^-galkyl as applied herein is meant to include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tertiary butyl, n-pentyl, 15 isopentyl arid hexyl. As used herein in the compounds of this invention. 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 20 replication is inhibited, hence, disease progression is retarded. Representative compounds of this invention are: (2S,4S,5S) and (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6- phenyl-2,4-dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, 25 (2S,4S,5S) and (2R, R,5R)-5-(benzyloxycarbonyl-D- alanyl)amino-6-pheny1-2,4-dihydroxy-2-benzyl-l-oxo-hexyl- (benzyl)amide, (2S, 4S, 5S) and (2R, 4R, 5R) -5- (benzyloxycarbonyl-i- alanyl) amino- 6-pheny 1-2 , 4-dihydroxy-2-benzyl-l-oxo-hexyl- 30 (benzyl) amide, (2S, 4S, 5S) and (2R, 4R, 5R) -5- (t-butyloxycarbonylamino) -6- phenyl-2, 4-dihydroxy-2-benzyl-l-oxo-hexyl- ( (2S) -2- (3-methyl- butanol) )amide, (2S,4S,5S) and (2R, R,5R)-5-(t-butyloxycarbonylamino)-6- 35 phenyl-2, -dihydroxy-2-methyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol) )amide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-valinamide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(2-(propan-1,3-diol))amide, N-((2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl)-N'-(benzyloxycarbonyl)- hydrazine, N-((2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl)-hydrazine, and (2S,4S,5S)-5-(benzoylformyl)amino-6-pheny1-2,4-dihydroxy-2- benzyl-1-oxo-hexyl-(benzyl)amide. Preferred compounds of this invention are: (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2, - dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-((2S)-2-(3-methyl- butanol))amide, and (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-valinamide. The chiral centers of the compounds of the invention may be racemic or nonracemic. Racemic mixtures, mixtures of diastereomers, as well as single diastereo ers and enantiomers of the compounds of the invention are included in the present invention. The terms "S" and "R" are used to denote the configuration of asymmetric carbons, and are used as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 45, 13 (1976). Where double bonds may be present in the compounds, these bonds may be of the Z (cis) or E (trans) configuration. When any variable substituent occurs more than once in formula (I), its definition in each occurrence is independent of its definition at every other occurrence. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. The peptides of this invention are prepared by conventional methods of peptide synthesis from the compounds (II) and (III) : SUBSTITUTE SHEET (II) (III) wherein Pr 1 is an amino protecting group, Pr 2 is a carboxy protecting group and Pr 3 and Pr^ are H or a hydroxy protecting group. These intermediate compounds are prepared by methods well known in the art, similar to those disclosed by Metternich et al . , Tet . Lett . , 29, 3923 (1988) and in WO 87/94349, which are incorporated fully herein by reference, and illustrated in Scheme 1. Acetyl, Boc or Cbz are representative protecting groups for the amino group, and acetyl or trialkylsilyl are representative protecting groups for the hydroxyl group. Pr2 is generally OH, O-alkyl, 0- benzyl or O-phenyl. Methods of general synthetic utility are found in U.S. Patents 4,661,473 and 4,713,445, published European Patent applications EP-A 352 000 and 337 714, Holladay et al . , J. Med. Chem. , 30, 374 (1987) and Kempf, D., J. Org. Chem . , 51, 21, 3921 (1986), all of which are incorporated fully herein by reference. The compounds of formula (I) are prepared by: 1) (i) reacting a compound of the formula: wherein Pr 3 is H or a hydroxy-protecting group, and A, B, D, R 4 and R 2 are as defined for formula (I) , with any reactive groups protected, with a coupling agent and a compound of the formula: H-X-Y-G wherein G, X and Y are as defined for formula (I) , with any reactive groups protected, and (ii) if necessary, removing any protecting groups; or 2) (i) reacting a compound of the formula: SUBSTITUTESHEET H-X-Y-G wherein G, X and Y are as defined for formula (I) , with any reactive groups protected, with a base and a compound of the formula: wherein Pr 5 is H or a hydroxy-protecting group, and A, B, D, R 4 and R 2 are as defined for formula (I) , with any reactive groups protected, and (ii) if necessary, removing any protecting groups; or 3) (i) reacting a compound of the formula: wherein Pr 3 is.H or a hydroxy-protecting group, and X, Y, G, R 2 and R 4 are as defined in formula (I), with any reactive groups protected, with a coupling agent and a compound of the formula: A-B-D-OH wherein G, X, Y, A and R 10 are as defined for formula (I) , with any reactive groups protected, and (ii) if necessary, removing any protecting groups. Typical coupling agents include carbodiimides, such as DCC, EDC, DMAPEC, DPPA, PPA, and the BOP reagent, and reagents which may be used to form activated esters, anhydrides and acid halides, such as oxalyl chloride, thionyl chloride, N-hydroxysuccinimide and 4-nitrophenol. Many other such reagents are well know in the art. When G is R 10 , coupling reagents would additionally include organometallic reagents, such as lithium dimethyl copper which could be reacted with an acyl halide to form a ketone. Typical bases include organic nitrogenous bases, such as triethylamine or diisopropylamine, or an alkali metal alkoxide. It will also be understood that when the reagent H-X-Y-G contains an amino group, it may act as the base itself and an additional base is not required. Typical reactive groups which may require protection during synthesis are the hydroxyl, amino, carboxyl, carbonyl and mercapto groups. Conventional methods for protection and deprotection of reactive groups are disclosed in Greene, Protective Groups in Organic Cheτni..try r John Wiley and Sons, New York, 1981. Representative methods for making the compounds of this invention are illustrated in Scheme 1 hereinafter. Scheme 1 It will be apparent that, by starting the synthetic sequence with an appropriately substituted amino acid, such as (IV) , the substituent R 4 may be introduced into the isosteres (II) or (III) as any desired amino acid side chain, with any reactive groups suitably protected. Similarly, by choosing an appropriate electrophile, such as R 2 -X wherein X is an appropriate displaceable group (i.e., Cl, Br or I), R 2 may be introduced into the isostere and varied as appropriate. An α-substituted, α-amino-aldehyde, such as (IV) , is prepared by conventional means. For instance, a suitable α- amino acid may be reduced to its corresponding carboxaldehyde to initiate the preparation. Suitable methods are disclosed Coppola et al . , Asymmetric Synthesis. Construction of Chiral Molecules Usinσ Amino Acids f Wiley Interscience, New York, 1987. The aldehyde (IV) is condensed with .the enolate derived from methyl pyruvate (V) and a suitable base, such as bromomagnesium diisopropylamide or lithium diisopropylamide, to form an aldol adduct which undergoes intramolecular cyclization in situ to yield the dihydrofuran dione 1. This lactone exists exclusively as the enol lactone, as depicted in Scheme 1. It has been found that by using lithium diisopropylamide as the base, the stereogenic * integrity of the aldehyde is sometimes lost and the resulting enol lactone cannot reproducibly be obtained in enantiomerically pure form. The use of bromomagnesium diisopropylamide instead of lithium diisopropylamide affords lactone enaήtiomeri'cally pure. The stereochemistry of the two centers agrees with that described by Metternich et al . , Tet . Lett . , 29, 3923 (1988) , although little or no undesired isomeric lactone is detected. The enol lactone 1 is reduced with an appropriate reducing agent, such as hydrogen with a palladium catalyst to yield an α-hydroxy lactone as mixture of epimers at the hydroxyl position. The hydroxyl group is then protected with an appropriate protective group which is stable to strong base, such as a silyl ether. Subsequent treatment of the TITUTE SHEET lactone with a strong base, such as lithium alkyl or dialkylamide, and treatment with an electrophile R 2 -X, wherein X is a leaving group, such as chloride, bromide, iodide, or sulfonate, yields the appropriately α-R 2 substituted lactone 4 diastereomerically pure. Reaction of the lactone with an appropriate nucleophile, such as an amine or hydroxide, provides the 2,4-dihydroxy-isostere. Hydrolysis of the lactone yields the stable 2,4-dihydroxy carboxylic acid. The hydroxyl groups in the 2 and 4 positions can be protected, or the hydroxyl group at the 4 position can be selectively protected. A silyl ether is the most useful group for this purpose. The protected compound allows further modification of the carboxy terminus via amidation, esterification or coupling of an activated acyl intermediate, such as an acyl halide, with an organometallic reagent. Likewise, deprotecting the amino terminus allows further modification of the amine group by alkylation, acylation or sulfonylation. Solution synthesis of the peptide bonds is accomplished using conventional methods for coupling the appropriate amino acid residues and optionally removing any protective groups. Suitable methods are disclosed, for instance, in Bodansky et al . , The Practice of Peptide Synthesis, Springer-Verlag, Berlin, 1984. 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' dicyclohexyl carbodiimide (DCC) or l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (DMAPEC) , 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, STITUTE S H ιe_ E - T 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 or DMAPEC, 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 and alcohols are preferred embodiments of this invention due their enhanced stability relative to esters. TITUTE SHEET 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) are used to induce anti¬ viral activity in patients which are infected with susceptible viruses and require such treatment. In particular, the this invention is a method of treating disease resulting from infection by retroviruses by administering a compound of this invention. The Human Immunodeficiencey Virus, type 1 (HIV-1) has been show to be susceptible to inhibition by the compounds of this invention. Thus, in one preferred embodiment this invention is a method of treating Acquired Immune Deficiency Syndrome (AIDS) . 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 0.01 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 20 nM to about 60 μM. The following table is representative of the inhibition constants of the compounds of this invention. Compounds of this invention in which R 1 is A, and R 2 and R^ are benzyl, and have notably superior activity. 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. 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 mg 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, phosphonofor at , rifabutin, ribaviran, phosphonothioate oligodeoxynucleotides, castanospermine, dextran sulfate, alpha interferon and ampligen. Nucleoside analogues, which include 2',3'-dideoxycytidine(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. TITUTE SHEET The Examples which follow serve to further 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 novel 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 E. 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 min. 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 85-95% 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 TE SHEET 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 g E. coli cell pellet. Inhibition of HIV protease activity Assays for inhibition of HIV-1 protease activity are well known in the art and are disclosed for instance in Moore et al . , Biochem. Biophys . Res. Comm. , 159, 420 (1989) and Kohl et al . , Proc. Natl . Acad. Sci . USA, 85, 4686 (1988) . 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 O-0.1% TFA (15 min), 20% acetonitrile/H 2 0- 0.1% 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- NH 2 (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) . K-^ 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. Ultrasphere® and Ultrasphere® ODS are silica gel and octadecylsilane chromatographic supports, respectively, manufactured by Beckman Instruments Inc., Fullerton, CA. Microsorb® is a silica gel chromatographic support manufactured by Rainin Instruments Co., Woburn, Mass. Bakerbond® is a silica gel chromatographic support manufactured by J.T. Baker Chemical Co., Phillipsburg, N.J. Celite® is filter aid composed of acid washed diatomaceous silica manufactured by Mansville Corp., Denver, Colorado. FAB mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment.. 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 Prepara ion of (2S.4S.5SΪ -5- (t-butyloxycarbonylamino)-6- phenyl-2.4-dihydroxy-2-benzyl-l-oxo-hexy.1-(ben_y1 amide, and (2R.4R.5R) -5- (t-butyloxycarbonylamino) -6-phenyl-2.4- dihydroxy-2-benzyl-l-oxo-hexyl- (benzyl) amide (5) a) (5R)-5-( (lR)-l-t-butyloxycarbonylamino-2-phenyl)ethyl- 4H,5H-dihydrofuran-2,3-dione, and (5S)-5-( (IS)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-4H,5H- dihydrofuran-2,3-dione (1). A solution of Boc-(JC)-phenylalanine methyl ester (9.86 g, 0.0353 mol) in toluene (150 mL) under an argon atmosphere was cooled to -78° C. Diisobutyllithium aluminum hydride (1.0 M solution in hexane, 67 mL, 0.067 mol) was added dropwise by addition funnel over 2 h. After complete addition, the reaction mixture was quenched with methanol, and poured into a 10% solution of sodium potassium tartrate. The two layers were allowed to stir for 2 h and separated. The aqueous layer was extracted 3 X with ethyl acetate. The combined organic layers were washed twice with 0.05 M HCl, brine, dried over MgS0 4 and concentrated to a colorless oil, Boc-phenylalanine-carboxaldehyde. A solution of lithium diisopropylamide (2.5 M in hexane, 42.4 L, 0.106 mol) was diluted with THF (600 mL) and cooled to -78° C. To this mixture was added a solution of methyl pyruvate (10.8 g, 0.106 mol), HMPA (19 g, 0.106 mol) in THF (200 mL) over a 2 h period by addition funnel. After complete addition, the reaction mixture was allowed to stir an additional 30 min. To this reaction mixture was added a solution of Boc- phenylalanine-carboxaldehyde in THF (150 mL) via cannula. The reaction mixture was allowed to warm and stir to room temperature over 20 h. The mixture was poured into ice cold 1 N HCl. The aqueous layer was extracted 3 X with ethyl acetate. The combined organic layers were washed with cold IN HCl, brine, dried over MgSθ 4 and concentrated to an orange oil. The product was crystallized from methylene chloride/hexane, filtered and washed with hexane/Et 2 0 (2:1), to afford a fine white solid. Performing the same procedure, except using bromomagnesium diisopropylamide in place of lithium diisopropylamide as the base, yielded the enantiomerically pure product la, which was: (5S)-5-((IS)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-4H,5H- dihydrofuran-2,3-dione (la) . The product was determined to be enantiomerically pure by HPLC (Bakerbond ® OB, 3% ethanol/hexane, 0.8 mL/min) : ^-H NMR (CDCI 3 , 250 MHz) 51.38 (s, 9H) , 3.02 (m, 2H) , 4.19 (m, 1H), 4.89 (bs, 1H) , 6.15 (bs, 1H) , 7.3 (m, 5H) b) (5S)-5-( (lS)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-3- hydroxy-tetrahydrofuran-2-one, and (5R)-5-( (1R)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-3- hydroxy-tetrahydrofuran-2-one (2) To a solution of lactone 1 (10 g, 0.031 mol) in ethyl acetate (250 mL) was added 10% Pd/C (8 g) . The reaction mixture was degassed and one atmosphere of H was applied using a balloon. The reaction was allowed to stir at room temperature for 24 h, purged with Ar, and filtered through Celite ® washing with ethyl acetate. The organic layer was concentrated to a white solid (10 g, 99%) . The product was determined to be a 10:1 mixture of isomers at the alcohol position by NMR: -E NMR (CDCI 3 , 250 MHz, major isomer) δ 1.40 (s, 9H), 2,12 (m, IH), 2.49 (m, IH) , 2.95 (m, 2H) , 4.03 (m, IH), 4.36 (m, IH) , 4.49 (m, IH) , 4.75 (m, IH) , 7.3 (m, 5H) c) (5S)-5-( (lS)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-3- trimethysilyloxy-tetrahydrofuran-2-one, and (5R)-5-( (1R)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-3- trimethysilyloxy-tetrahydrofuran-2-one (3) A solution of (±)-hydroxylactone 2 (1 g, 3.12 mmol) in methylene chloride (25 mL) was treated with N- trimethylsilylimidazole (TMSImid) (0.873 g, 6 mmol). The reaction mixture was allowed to stir at room temperature for 24 h. The mixture was diluted with methylene chloride, washed with 0.05 M HCl, brine, dried over MgS0 4 , and concentrated to yield a white solid (1.2 g, 99%). -R NMR (CDCI 3 , 250 MHz) δ 0.19 (s, 9H) , 1.41 (s, 9H) , 2.10 (m, IH), 2.38 (m, IH) , 2.95 (m, 2H) , 3.99 (m, IH) , 4.28 (m, IH), 4.45 (m, IH) , 7.3 (m, 5H) Performing steps 1(b) and 1(c), except substituting the enantiomerically pure (5S)-5- ( (IS)-1-t-butyloxycarbonylamino- 2-phenyl)ethyl-4H,5H-dihydrofuran-2,3-dione la in step 1(b), (5S)-5-( (IS)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-3- trimethysilyloxy-tetrahydrofuran-2-one (3a) was prepared. d) (3S,5S)-5-( (IS)-l-t-butyloxycarbonylamino-2-phenyl)ethyl- 3-trimethysilyloxy-3-benzyl-tetrahydrofuran-2-one, and (3R,5R)-5-( (1R)-l-t-butyloxycarbonylamino-2-phenyl)ethyl-3- trimethysilyloxy-3-benzyl-tetrahydrofuran-2-one (4) A solution of lithium diisopropylamide (1.5 M solution in cyclohexane, 7.44 mL, 11.16 mmol) in THF (50 mL) was cooled to -78° C under an argon atmosphere. To this was added a solution of 3 (1.1 g, 2.79 mmol) in THF (25 mL) via cannula. The reaction mixture was allowed to stir 15 min. HMPA (2 g, 11.16 mmol) was added via syringe and the reaction mixture was allowed to stir for 15 min. Benzyl bromide (1.9 g, 11.16 mmol) was added via syringe and the reaction mixture was allowed to stir for 3 h allowing the mixture to warm to -50°C. The reaction mixture was poured into 0.05 M HCl, and separated. The aqueous layer was extracted ethyl acetate (3X) , the combined organic layers were washed with 0.05 M HCl, brine, dried over MgS0 4 , and concentrated to a yellow oil. This was chromatographed (silica gel, 10:1 hexane:ethyl acetate) to afford a white crystalline solid (620 mg,46%) : ^-H NMR (CDC1 3 , 250 MHz) δ 0.18 (s, 9H) , 1.38 (s, 9H) , 2.13 (m, IH), 2.30 (m, IH), 2.70 (m, 2H) , 2.98 ( , 2H) , 3.53 (m, IH) , 3.82 (m, IH) , 4.60 (m, IH) , 7.2 (m, 10H) Performing steps 1(b) through 1(d) , except using the enantiomerically pure (5S)-5-((lS)-l-t-butyloxycarbonylamino- 2-phenyl)ethyl-4H,5H-dihydrofuran-2,3-dione, la, in step 1(b) , (3S,5S)-5-((IS)-l-t-butyloxycarbonylamino-2- phenyl)ethyl-3-trimethysilyloxy-3-benzyl-tetrahydrofuran-2- one (4a) was prepared. e) (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, and (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide (5) To a solution of benzylamine (212 mg, 1.98 mmol) in THF (20 mL) at -78° C under an argon atmosphere was added n-butyllithium (1.6M solution in hexane, 1.25 mL, 1.98 mmol). The reaction mixture was allowed to stir for 20 min. To this mixture was added a solution of 4 (240 mg, 0.495 mmol) in THF (10 mL) via cannula. The reaction mixture was allowed to stir for 1 h, poured into 0.05 M HCl, and extracted with ethyl acetate (3X) . The organic layers were washed with 0.05 M HCl, brine, dried over MgSθ 4 , and concentrated to a white solid. The solid was recrystallized from ethyl acetate, to afford the product (220 mg,86%) : -R NMR (CDC1 3 , 250 MHz) δ 1.39 (s, 9H) , 1.80 (m, IH) , 2.23 (m, IH) , 2.7-3.2 (m, 4H) , 3.39 (m, IH) , 3.90 (m, IH) , 4.32 (m, 2H), 4.76 (m, IH) , 5.02 (m, IH) , 7.2 (m, 15H) ; MS DCI/NH3 m/e 519[M+H]. + Performing steps 1(b) through 1(e), except using enantiomerically pure (5S)-5- ( (IS)-1-t-butyloxycarbonylamino- 2-phenyl)ethyl-4H, 5H-dihydrofuran-2,3-dione, la, in step 1 (b) , (2S, 4S, 5S)-5- (t-butyloxycarbonylamino)-6-phenyl-2, 4- dihydroxy-2-benzyl-l-oxo-hexyl- (benzyl)amide (5a) was prepared. Example 2 Preparation of (2S, 4S.5S)-..- (benzyloxycarbonyl-D- alanvl)amino-6-phenyl-2. -dihydroxy-2-benzyl-l-oxo-hexyl- (benzyl)amide, and (2R, 4R.5R) -5- (benzyloxγcarbonyl-D-alanγl) amino-6-pheny1-2.4- dihydroxy-2-benzyl-l-oxo-hexyl- (benzyl)amide ($) To a solution of 5 (73 mg, 0.141 mmol) in methylene chloride (3 mL) was added trifluoroacetic acid (3 mL) . The reaction mixture was allowed to stir for 1 h at room temperature. The mixture was concentrated and dried under high vacuum. The residue was diluted with methylene chloride (5 mL) and treated with triethylamine (16 mg, 0.15 mmol) . The reaction mixture was cooled to 0°C and Cbz-D-Ala (34 mg, 0.15 mmol), 1-hydroxybenzotriazole (HOBT) (21 mg, 0.15 mmol), and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (DMAPEC) (29 mg, 0.15 mmol) were added. The reaction mixture was allowed to stir at 0°C for 1 h, and the UBSTITUTESHEET ice bath removed. The mixture was allowed to warm and stir to room temperature for 16 h. The mixture was diluted with methylene chloride, washed with 10% NaHC0 3 , 0.05 M HCl, brine, dried over MgSθ 4 , and concentrated to an oily solid. The product was precipitated from methylene chloride/pentane, to afford a white powder (27 mg, 31%) . NMR shows that this is a mixture of two diastereomers. Partial resolution of the isomers can be obtained by HPLC (Rainin Microsorb® Si0 2/ 3% 2-propanol/methylene chloride) : -R NMR (mixture of diastereomers, DMSO, 250 MHz) δ 0.92 (d, 1.5H, J=6Hz) , 1.12 (d, 1.5H, J=6Hz) , 1.65 (m, IH) , 1.94 (m, IH), 2.55-3.1 (m, 4H) , 3.77 (m, 2H) , 4.02 (m, 2H) , 4.2 (m, IH) , 5.00 (2, 2H), 5.60 (m, IH), 7.2 (m, 20H) , 7.6 (m, IH) , 8. 13 (m, IH) Example 3 Preparation of (2S. S.5S)-5- (benzyloxycarbonyl-L- alanyl) amino- 6-pheny 1-2 r 4-dihydrQxy-2-_>en2yl-l-oxo-hexyl- (benzyl)amide r and (?R.4R. R)-5-(benzvloxycarbonyl-L-a]anyl) amino-6-phenyl-2.4- d.hydroxy-2-benzyl-1-oxo-hexyl-(benzyl) mide (7) To a solution of 5 (82 mg, 0.164 mmol) in methylene chloride (3 mL) was added trifluoroacetic " acid (3 mL) . The reaction mixture was allowed to stir for 1 h at room temperature. The mixture was concentrated and dried under high vacuum. The residue was diluted with methylene chloride (5 mL) and treated with triethylamine (18 mg, 0.18 mmol) . The reaction mixture was cooled to 0°C and Cbz-L-Ala (40 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol), and DMAPEC (35 mg, 0.18 mmol) were added. The reaction mixture was allowed to stir at 0°C for 1 h, and the ice bath was removed. The mixture was allowed to warm and stir to room temperature for 16 h. The mixture was diluted with methylene chloride, washed with 10% NaHC0 3 , 0.05 M HCl, brine, dried over MgS0 4 , and concentrated to an oily solid. The product was precipitated from methylene chloride/pentane, to afford a white powder (23 mg, 23%) NMR shows that this is a mixture of two diastereomers. Partial resolution of the isomers can be obtained by HPLC (Ranin Microsorb ® Si0 , 3% 2-propanol/ methylene chloride) : 1 H NMR (mixture of diastereomers, DMSO, 250 MHz) δ 0.92 (d, 3H, J=6Hz) , 1.12 (d, 1.5H, J=6Hz) , 1.65 (m, IH), 1.94 (m, IH) , 2.55-3.1 (m, 4H) , 3.77 (m, 2H) , 4.02 ( , 2H), 4.2 (m, IH) , 5.00 (2, 2H) , 5.60 ( , IH) , 7.2 (m, 20H), 7.6 (m, IH) , 8. 13 (m, IH) ; MS DCI/NH 3 m/e 624[M+H]+ Example 4 Preparation of (2S.4S.5S)-5-(t-bπtyloxycarbonylamino)-6- phenyl-2.4-dihydroxv-2-benzyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol) )amide, and (2R. R.5R)-5-(t-butyloxycarbonylamino)-6- phenyl-2.4-dihydroxy-2-benzyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol) ) mide (9) a) (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-4- trimethylsilyloxy-2-hydroxy-2-benzyl-hexanoic acid, and (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6-phenyl-4- trimethylsilyloxy-2-hydroxy-2-benzyl-hexanoic acid (8) A solution of 4 (310 mg, 0.64 mmol) in THF/Water (1/1, 20 mL) was treated with 2.5 N NaOH (0.540 mL, 1.34 mmol) and allowed to stir at room temperature for 30 min. The mixture was concentrated to a white solid, diluted with 0.05N HCl, and extracted with ethyl acetate (3X) . The organic layers were washed with brine, dried over MgS0 and concentrated to a white solid. The solid was dissolved in TMSImid (3 mL) and was heated to 80°C for 16 h. The reaction mixture was cooled, diluted with ethyl acetate, washed with 0.05 N HCl (3X) , brine, dried over MgSθ 4 , and concentrated to an oil. The acid was precipitated from the oil with pentane to afford a white solid (278 mg, 87%) : -R NMR (CDCI 3 , 250 MHz) δ 0.21 (s, 8H) , 1.38 (bs, 9H) , 2.00 (m, IH), 2.22 (m, IH) , 2.7-3.1 (m, 4H) , 3.9-4.2 (m, 2H) , 4.72 (m, IH) , 7.2 (m, 10H) Performing the same reaction, except using the enantiomerically pure 4a, the compound (2S, 4S,5S)-5- (t- butyloxycarbonylamino)-6-phenyl-4-trimethylsilyloxy-2- hydroxy-2-benzyl-hexanoic acid (8a) was prepared. b) (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol) )amide, and (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl- ( (2S)-2-(3-methyl- butanol) )amide (9) To a solution of 8 (110 mg, 0.22 mmol) in methylene chloride (10 mL) at 0°C was added, HOBT (32 mg, 0.24 mmol), DMAPEC (46 g, 0.24 mmol), and valinol (25 mg, 0.24 mmol).. The reaction was allowed to stir at 0°C for 1 h, and allowed to warm to room temperature and stir for 16 h. The reaction mixture was diluted with methylene chloride, washed with 0.05 N HCl, brine, dried over MgS0 4 , and concentrated to a yellow oil. Crystallization from methylene chloride/pentane affords Isomer A (7 mg, 6%) . The mother liquor was concentrated and chromatographed (1:1 hexane:ethyl acetate) . The major fractions were the hydroxylactone, 4 (50 mg, 45%) and Isomer B. Isomer B was recrystallized from methylene chloride/pentane to afford a white solid (12 mg, 11%) . Isomer A ^-H NMR (CDCI3, 250 MHz) δ 0.70 (dd, 6H, J=7Hz, 28Hz) , 1.12 (m, IH), 1.39 (s, 9H), 1.62 (m, IH) , 1.85 (m, IH) , 2.17 (sm, IH), 2.7-3.1 (m, 3H) , 3.50 (m, 4H) , 3.90 (m, IH) , 4.77 (m, 2H), 5.12 ( , IH) , 6.7-7.4 (m, 10H) Isomer B -R NMR (CDCI3, 250 MHz) δ 0.80 (dd, 6H, J=7Hz, 22Hz) , 1.41 (s, 9H), 1.5-1.9 (m, 3H) , 2.27 (m, IH) , 2.7-3.1 (m, 3H) , 3.40 (m, 4H), 3.85 (m, IH) , 4.82 (m, 2H) , 5.57 (m, IH) , 6.7-7.4 (m, 10H) ; MS DCI/NH3 m/e 515[M+H] + Example 5 Preparation of ( S.4S. S)-5- (t-b tvloxycarbonylamino)-6- phenyl-2 r 4-dihydroxy-2-benzyl-l-oxo-hexyl- ( (2S)-2-(3-methyl- butanol) )amide (?) To a solution of (2S,4S,5S)-5- (t-butyloxycarbonylamino)- 6-phenyl-4-trimethylsilyloxy-2-hydroxy-2-benzyl-hexanoic acid 8a (320 mg, 0.64 mmol) in methylene chloride (10 mL) at 0°C was added, N-hydroxysuccinimide (80 mg, 0.7 mmol), DMAPEC (135 mg, 0.7 mmol), and valinol (72 mg, 0.7 mmol) . The reaction was allowed to stir at 0°C for 1 h, and allowed to warm to room temperature and stir for 16 h. The reaction mixture was diluted with methylene chloride, washed with 0.05N HCl, brine, dried over MgS04, and concentrated to a yellow oil. Crystallization from methylene chloride/pentane affords a white solid (15 mg, 5%) . The mother liquor was concentrated and chromatographed (1/1 hexane/ethyl acetate) to afford an additional 75 mg of product (27%) and 140 mg of 4a (52%) : -K NMR (CDCI3, 250 MHz) δ 0.80 (dd, 6H, J=7Hz, 22Hz), 1.41 (s, 9H), 1.5-1.9 (m, 3H) , 2.27 (m, IH) , 2.7-3.1 (m, 3H), 3.40 (m, 4H) , 3.85 (m, IH) , 4.82 (m, 2H) , 5.57 (m, IH), 6.7-7.4 (m, 10H) Example 6 Preparation of (2S. S, 5S)-5- (t-butyloxycarbonylamino)-6- phenvl-2.4-dihvdroxv-2-methvl-l-oxo-hexγ.1- ( (2S)-_- ..-methyl- bntanol) ) mide (12) a) (3S,5S)-5- ( (IS) -i-t-butyloxycarbonylamino-2-phenyl)ethyl- 3-trimethysilyloxy-3-methyl-tetrahydrofuran-2-one (10) A solution of lithium diisopropylamide (1.5 M solution in cyclohexane, 4.4 mL, 6.6 mmol) in THF (40 mL) was cooled to -78° C under an argon atmosphere. A solution of (2S,4S, 5S)-5- (benzyloxycarbonyl-L-alanyl) amin®-6-phenyl-2, 4- dihydroxy-2-benzyl-l-oxo-hexyl- (benzyl) amide 3a (0.65 g, 1.65 mmol) in THF (20 mL) was added via cannula. The reaction mixture was allowed to stir 15 min. HMPA (0.935 g, 6.6 mmol) was added via syringe and the reaction mixture was allowed to stir for 15 min. Methyliodide (1.2 g, 6.6 mmol) was added via syringe and the reaction mixture was allowed to stir for 3 h allowing the mixture to warm to -50°C. The reaction mixture was poured into 0.05 M HCl, and separated. The aqueous layer was extracted ethyl acetate (3X) , the combined organic layers were washed with 0.05 M HCl, brine, dried over MgSθ 4 , and concentrated to a yellow oil. This was chromatographed (silica gel, 7:1 hexane:ethyl acetate) to afford a white crystalline solid (280 mg, 41%) and 80 mg of a mixture of alkylated/unalkylated lactone: ^-H NMR (CDCI 3 , 250 MHz) δ 0.18 (s, 9H), 1.38 (s, 9H) , 1.43 (s, 3H) , 2.2 (m, 2H),.2.95 (m, 2H) , 3.98 ( , IH) , 4.25 (m, IH) , 4.68 (m, IH) , 7.25 (m, 5H) b) (2S,4S,5S)-5-(t-butyloxycarbonylamino).-6-pheny1-4- trimethylsilyloxy-2-hydroxy-2-methyl-hexanoic acid (11) A solution of 10 (280 g, 0.64 mmol) in THF/water (1/1, 6 mL) was treated with 2.5N NaOH (0.540 mL, 1.34 mmol) and allowed to stir at room temperature for 30 min. The mixture was concentrated to a white solid, diluted with 0.05N HCl, and extracted 3 X with ethyl acetate. The organic layers were washed with brine, dried over MgSθ 4 and concentrated to a white solid. The solid was dissolved in TMSImid (3 mL) and was heated to 80°C for 16 h. The reaction mixture was cooled, diluted with ethyl acetate, washed 3 X with 0.05N HCl, brine, dried over MgSθ 4 , and concentrated to a yellow oil (225 mg, 77%) . NMR of the oil showed that this to be correct product although further attempts to purify it were unsuccessful. c) (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-methyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol))amide (12) To a solution of crude 10 (115 mg, 0.26 mmol) in methylene chloride (10 mL) at 0°C was added, hydroxysuccinimide (30 mg, 0.26 mmol), DMAPEC (50 mg, 0.26 mmol), and valinol (29 mg, 0.26 mmol) . The reaction was allowed to stir at 0°C for 1 h, and allowed to warm to room temperature and stir for 16 h. The reaction mixture was diluted with methylene chloride, washed with 0.05N HCl, brine, dried over MgSθ4, and concentrated to a yellow oil. Chromatography (silica gel, ethyl acetate) affords a white solid (6 mg, 5%) : -R NMR (CDC1 3 , 250 MHz) δ 0.92 (dd, 6H, J l =7Hz, J 2 =10Hz), 1.4 (s, 3H) , 1.41 (s, 9H) , 1.65-2.1 (m, 3H), 2.62 (m, IH) , 2.95 (m, 2H) , 3.44 (m, IH) , 3.61 (m, 2H) , 3.75 (m, IH) , 4.83 ( , IH) , 5.42 (m, IH) , 7.2 (m, 5H) ; MS (FAB) m/e 439 [M+H] + Example 7 Preparation of (2S. S.5S)-5-(t-butyloxycarbonylamino)-6- phenγl-2.4-dihydroxy-2-benzyl-1-oxo-hexyl-valinaττnde (13) To a solution of crude 4a (0.021 g, 0.043 mmol) in toluene (5 mL) , excess valineamide and sodium cyanide (0.001 g) were added. The reaction was heated to reflux for 36 h, cooled and concentrated. The residue was filtered through a short column of silica gel eluting with 10% methanol/methylene chloride followed by column chromatography (silica gel, 5% methanol/methylene chloride) to afford the title compound (5 mg) : -R NMR (CDCI3, 250 mhz) δθ.78 (d, J=6 Hz, 3H), 0.85 (d, J=6 Hz, 3H) , 1.46 (s, 9H) , 1.7-2.4 (m, 3H) , 2.8-3.5 (m, 4H), 3.8-4.2 ( , 3H) , 4.7 (m, IH) , 7.2-7.4 ( , 10H); MS DCI/NH3 m/e 528 {M+H] + . Example 8 Preparation of (2S. S. S)-5- (t-butyloxycarbonvlamino)-6- phenyl-2 f 4-dihydroxy-2-benzyl-2-oxo-hexyl-( (2)-propane- (1.3)-d_ol)amide (14) To a solution of 8a (0.02g, 0.041 mmol) in methylene chloride (10 mL) at 0°C, was added hydroxysuccmimide (0.005g, 0.04 mmol), DMAPEC (O.OOδg, 0.04 mmol), and serinόl (0.005g, 0.04 mmol) . The reaction was allowed to stir at 0°C for 1 h, and allowed to warm to room temperature and stir for 16 h. The reaction mixture was diluted with methylene chloride, washed with 0.05N HCl, brine, dried over MgSθ 4 , and concentrated to a yellow oil. Crystallization from methylene chloride/pentane affords the title compound as a white solid (10 mg, 48%) : IH NMR (CDC13, 250 Mhz) δ 1.38 (s, 9H) , 2.24 (m, 2H) , 2.6-3.1 (m, 4H), 3.6-3.9 (m, 6H), 4.7 (m, IH) 7-7.4 (m, 10H) . Example 9 Preparation of N- ( (2S.4S.5S) -5- (t-butγloxγoarbonvl- a ino)-6-phenyl-2. -dihydroxγ-2-methyl-l-oxo-hexγ] )-N'- (benzyloxycarbonyl) -hydrazine (15) To solid 4a (0.039g, 0.08 mmol) was added 5 mL of hydrazine hydrate and enough methanol to dissolve all the solid (~5 mL) . The reaction was stirred for 1 h at room temperature. The reaction was diluted with water, extracted with methylene chloride and concentrated to an oil. The residue was dissolved in THF/water (2:1, 10 L) , K Cθ 3 (0.022g, 0.167 mmol) and benzylchloroformate (0.014 g, 0.08 mmol) was added. The reaction mixture was stirred for 2 h at room temperature. The mixture was diluted with methylene chloride, washed with water and brine, dried and concentrated. The residue was chromatographed (1:1 hexane:ethyl acetate) to afford the title compound (0.01 gm, 22%): ~R NMR (CDCI 3 , 250 MHz) δ 1.36 (s, 9H) 1.85 (m, IH) , 2.1 (m, IH) , 2.6-3.2 (m, 5H) , 3.67 ( , IH) , 3.97 (m, IH) , 5.18 (m, 2H) , 7-7.5 (m, 15H) ; MS DCI/NH 3 m/e 577 M + Example 10 Preparation of N-( (2S r S r 5S)-5-(t-butyloxycarbonylamino)- 6-phenyl-2 r 4-dihydroxy-2-benzyl-l-oxo-hexyl)-hydrazine (lβ) To solid 4a (0.048 g, 0.1 mmol) was added 5 mL of hydrazine hydrate and enough methanol to dissolve the solid (~5 mL) . The reaction mixture was stirred for 1 h at room temperature. The reaction was diluted with water, extracted with methylene chloride and concentrated to an oil. The residue was dissolved in 0.05N HCl and extracted with methylene chloride. The aqueous phase was brought to basic pH with 2N sodium hydroxide, extracted with methylene chloride, dried with K Cθ 3 , and concentrated to an oily solid. The solid was dissolved in methylene chloride and pentane was added to precipitate the title compound as off white solid (0.018 mg, 43%): ^-H NMR (CDCI 3 , 250 MHz) δl.36 (s, 9H) , 1.67 (m, 2H) 2.7-3.1 (m, 4H) , 3.46 (m, IH) , 3.7-3.9 (m, 2H) , 4.79 (m, IH), 7.1-7.4 (m, 10H) Example 11 Preparation of (? .4S.5R)-5-(benzoylfor yl)amino-6-phenyl- 2.4-dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide (17) To a solution of 5 (0.023 g, 0.045 mmol) in methylene chloride(2mL) was added TFA (2mL) and the reaction mixture was stirred for 15 min. The mixture was concentrated in vacuo and the residue dissolved in methylene chloride. To this solution was added hydroxysuccinimide (1 mg, 0.01 mmol), DMAPEC (9 mg, 0.05 mmol), and benzoylformic acid (5 mg, 0.04 mmol) . The reaction mixture was stirred overnight at room temperature, diluted with methylene chloride, washed with NaHCθ 3 , HCl and brine. The organic phase was dried over MgSθ 4 and concentrated to an oil. The oil was purified by preparative thin layer chromatography (silica gel, 1:1 hexane:ethyl acetate) to yield the title compound as a white solid, which was recrystallized from methylene chloride/pentane: -R NMR (CDCI 3 , 250 Mhz) δl.8 (m, IH) , 2.24 (m, IH) , 2.8-3.3 (m, 4H), 4.0 (m, IH), 4.2-4.4 (m, 2H) , 6.9-7.3 (m, 17H) , 7.4 (m, IH), 7.53 (m, IH) , 8.18 (m, IH) Example 12 Liposomal Dosage Unit Composition Phosphatidylcholine (1.4 g) and phosphatidylglycerol (0.6g) 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 Parenteral Dosage Unit Composition A preparation which contains 250 mg of the compound of Example 5 is prepared as follows: 250 mg of the peptide is dissolved in 150 mL of distilled water. The solution is filtered under sterile conditions in to a multi-dose ampoule and lyophilized. The powder is reconstituted by addition of 200 mL of 5% dextrose in water (D5W) for intravenous injection. The dosage is thereby determined by the injection volume. This solution is also suitable for use in other methods for administration, such as in 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 350 mg of the compound of Example 5 with 750 mg of lactose and 50 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: (I) wherein Rl is A, A-B or A-B-D; A is R 11 , R ι: CO, R 1:L OCO, R ι:L OCH(R 11 ') CO, R^NHCHfR 11 ')^ R 11 SCH(R 11 ')CO, R 1:L S0 2 , R 1:L SO or R 1:L C(0)CO; R 5 B and D are NR'(CH 2 ) q ^CO . R 2 and R 4 are Ci-βalkyl, optionally substituted with 1-5 fluorine atoms, C3_6alkenyl, Cι_6alkyl-0-CH 2 or (CH 2 ) n _ T, wherein T is phenyl, naphthyl, Cs-gcycloalkyl or indolyl, optionally substituted with nitro, halogen, Cι_4alkyl, Cχ_4alkoxy, Cχ_4alkylthio, provided that R 2 is not Cl-6alkyl when R 4 is cyclohexylmethyl; R 5 is H, Ci-galkyl, Cι_6alkyl-0-CH 2 or J-CH 2 (CH 2 ) n , wherein J is CONHR 1 , C0 2 R', NHR*, SR', or phenyl, naphthyl, Cs-gcycloalkyl or indolyl, optionally substituted with nitro, halogen, hydroxy, Cι-4alkyl, Cχ_4alkoxy, Cι_4alkylthio or trifluoromethyl; R 3 is G, X-G or X-Y-G; R 5 X and Y are NR'^ O ; G is R 10 , NR'R 10 , NR 'NR ' -A, OR 10 or SR 10 ; R 10 is (CR 11 R 11 ' ) n -V!; R 11 and R 11 ' are H, Alk, Ar, Het, Ar-Ci-salkyl, Het-Ci-salkyl, C3_ 7 cycloalkyl, Ar-C3-7cycloalkyl; W is H, CH 2 OR", COR" , OR 11 , OCOR 11 , NR'R 11 , NR' COR 11 , SR 11 , Ar or Het; Alk is Ci-ςalkyl or Cι_6alkyl substituted by one or two hydroxy, nitro or Cι- 4 alkoxy groups, or one to five fluoro atoms ; R' is H, Ci-βalkyl or (CH ) n -Ar; R" is H, Ci-βalkyl or (CH 2 ) n -Ph; n is 0, 1 or 2; and q is 0 or 1; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 in which R 1 is A. 3. A compound according to claim 1 in which R 2 is Ci-βalkyl or (CH ) n -phenyl. . A compound according to claim 1 in which R 3 is NHCH(R 1:L )-W, wherein R 11 is H or Alk and W is CH 2 OH, CONH or phenyl. 5. A compound according to claim 2 in which R 3 is NHCH(i-pr)CH 2 OH. 6 A compound according to claim 4 in which R 2 and R 4 are benzyl. 7. A compound according to claim 2 which is: (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2S,4S,5S)-5-(benzyloxycarbonyl-D-alanyl)amino-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2R,4R,5R)-5-(benzyloxycarbonyl-D-alanyl)amino-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2S,4S,5S)-5-(benzyloxycarbonyl-L-alanyl)amino-6-pheny1-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2R,4R,5R)-5-(benzyloxycarbonyl-L-alanyl)amino-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(benzyl)amide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol) )amide, (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-( (2S)-2-(3-methyl- butanol))amide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-methyl-l-oxo-hexyl-((2S)-2-(3-methyl- butanol) )amide, (2R,4R,5R)-5-(t-butyloxycarbonylamino)-6-phenyl-2, - dihydroxy-2-methyl-l-oxo-hexyl-((2S)-2-(3-methyl- butanol) )amide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-valinamide, (2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl-(2-(propan-1,3-diol) )amide, N-((2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-phenyl-2,4- dihydroxy-2-benzyl-l-oxo-hexyl)-N'-(benzyloxycarbonyl)- hydrazine, N-((2S,4S,5S)-5-(t-butyloxycarbonylamino)-6-pheny1-2,4- dihydroxy-2-benzyl-l-oxo-hexyl)-hydrazine, or (2S,4S,5S)-5-(benzoylformyl)amino-6-pheny1-2,4-dihydroxy-2- benzyl-1-oxo-hexyl-(benzyl)amide. 8. A pharmaceutical composition which comprises a compound according to claim 1 and a pharmaceutically acceptable carrier. 9. A pharmaceutical composition which comprises a compound according to claim 7 and a pharmaceutically acceptable carrier. 10. A method for treating retroviral infection which comprises administering an effective amount of a compound according to claim 1. 11. A method according to claim 10 for treating infection by HIV-1 which comprises administering an effective amount of a compound according to claim 1. 12. A method according to claim 10 for treating AIDS which comprises administering an effective amount of a compound according to claim 1. 13. The use of a compound according to claim 1 in the manufacture of a medicament. 14. A process for preparing a compound of the formula (I) : (I) wherein R 1 , ϊ\- , R3 and R 4 are as defined in claim 1, which comprises: 1) (i) reacting a compound of the formula: wherein Pr 3 is H or a hydroxy-protecting group, and A, B, D, R 4 and R 2 are as defined in claim 1, with any reactive groups protected, with a coupling agent and a compound of the formula: H-X-Y-G wherein G, X and Y are as defined in claim 1, with any reactive groups protected, and (ii) if necessary, removing any protecting groups; or 2) (i) reacting a compound of the formula: H-X-Y-G wherein G, X and Y are as defined in claim 1, with any reactive groups protected, with a base and a compound of the formula: wherein Pr 5 is H or a hydroxy-protecting group, and A, B, D, R 4 and R 2 are as defined in claim 1, with any reactive groups protected, and (ii) if necessary, removing any protecting groups; or 3) (i) reacting a compound of the formula: wherein Pr 3 is H or a hydroxy-protecting group, and X, Y, G, R 2 and R 4 are as defined in claim 1, with any reactive groups protected, with a coupling agent and a compound of the formula: A-B-D-OH wherein G, X, Y, A and R 10 are as defined for formula (I) , with any reactive groups protected, and (ii) if necessary, removing any protecting groups.

Inventors: GLEASON JOHN GERALD, LUM ROBERT THOMAS, GLEASON, JOHN, GERALD, LUM, ROBERT, THOMAS
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1992
Main classification: A61K37
IPC codes: A61K31, A61K38, A61P31, A61P37, A61P43, C07C221, C07C225, C07C233, C07C237, C07C271, C07C311, C07K5