ASPARTIC PROTEASE INHIBITORS

Abstract: Compounds useful as inhibitors of retroviral proteases characterized by structure (I) wherein X<1> and X<2> may consist of 0-2 alpha -amino acid groups terminally substituted by hydrogen or one of a number of end groups, R<1>, R<2> can be selected from a wide variety of hydrocarbon radicals.

Description: TITLE ASPARΗC PROTEASE INHIBITORS BACKGROUND OF THE INVENTION This invention relates to compounds which are inhibitors of aspartic proteases, particularly of retroviruses. 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 satisfactory method for treating this type of infection has been developed. Among these viruses, the HTLV and HIV have been especially well characterized. Critical to the replication of retroviruses 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 any reading frames. The g_ ~ and pol precursor proteins, are processed by a viral protease into the functional proteins. The HIV-1 protease has been classified as an aspartic acid protease (Meek et al., Proc. Natl. Acad. Sci. USA. 88, 1841 (1989)). 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), 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 (Debouck, et al., Proc. Natl. Acad. Sci. USA. 8903-06(1987) and Tomasselli et al, Biochemistry. 29, 264-9 (1990) and refs. therein). Inhibitors of recombinant HIV protease have been reported (Dreyer et al., Proc. Natl. Acad. Sci. USA. 86, 9752-56 (1989); Tomasselli et al. supra: Roberts et al., Science. 248. 358 (1990); Rich et al., J. Med. Chem.. 33, 1285-88 (1990); Sigal et al., Eur. Pat. Appl. No. 337 714; Dreyer et al. Eur. Pat. Appl. No. 352 000). Moreover, certain of these inhibitors have been shown to be potent inhibitors of viral proteolytic processing in cultures of HIV- 1 infected T-lymphocytes (Meek et al., Nature (London). 343, 90 (1990) and by Roberts et al. supra ). The limitations of current strategies for aspartic protease inhibition include (1) oral bioavailability; (2) plasma clearance lifetimes (e.g., through biliary excretion or degradation); (3) selectivity of inhibition; and (4) in the case of intracellular targets, membrane permeability or cellular uptake. The present invention relates to a new inhibitors of retroviral and aspartic proteases. Unlike previously described inhibitors , the compounds of this invention are not analogues of peptide substrates possessing a scissile dipeptide mimetic. They also deviate substantially from peptide substrate-like structure in that they do not possess a conventional amino-to-carboxyl terminus orientation. SUMMARY OF THE INVENTION This invention comprises compounds having the structures particularly pointed out in the claims and described hereinafter which bind to retroviral proteases. These compounds are inhibitors of viral protease and are useful for treating disease related to infection by viruses. This invention is also a pharmaceutical composition, which comprises an aforementioned compound and a pharmaceutically acceptable carrier therefor. This invention further constitutes a method for treating viral diseases, which comprises administering to a mammal in need thereof an effective amount of an aforementioned inhibitor compound. DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention have the structure: I wherein X 1 and X 2 are the same or different and are A-(B) n - where n = 0-2; and B is, independently, an α-amino acid chosen from the group: Ala, Asn, Cys, Tip, Gly, Gin, He, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A or the carboxy group of the adjacent residue B, whichever is appropriate, and the carboxy group of B is bonded to the amino group of the adjacent residue B or the structure, whichever is appropriate; and A is covalently attached to the amine group of the adjacent residue B or to the amine group of the structure if n=0, and is: 1) trityl, 2) hydrogen, 3) Ci-Cg alkyl, 4) R3-CO- wherein R 3 is: a) hydrogen, b) Cj-Cό alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms, c) phenyl or naphthyl unsubstituted or substituted with one or more substituents R^, wherein R^ is: O C1-C4 alkyl, ii) halogen, where halogen is F, Cl, Br or I, iii) hydroxyl, iv) nitro, v) C1-C3 alkoxy, or vi) -CO-N(R 10 )2 wherein R 10 is, independently, H or C1-C4 alkyl; or d) a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; 5) phthaloyl wherein the aromatic ring is unsubstituted or substituted with one or more substituents R^; 6) R 5 (R 6 R 7 C)m-CO- wherein m = 1-3 and R 5 , R 6 , and R 7 are independently: a) hydrogen, b) chlorine or fluorine, c) C1-C3 alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl, e) phenyl or naphthyl unsubstituted or substituted with one or more substituents R4, f) Ci - C3 alkoxy, g) a 5-7 member heterocycle, or h) R5, R , and R 7 may be independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is C3-C6 cycloalkyl; 7) R5(R6R7Qm W- wherein m = 1-3 and W is OCO or SO 2 and R 5 , R 6 , and R 7 are as defined above, except R^, R6, and R 7 are not chlorine, fluorine or hydroxyl if they are adjacent to W; 8) R8-W- wherein R- is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; 9) R9-W- wherein R^ is phenyl or naphthyl unsubstituted or substituted with one or more substituents R^; 10) R 5 -(R 6 R 7 C)m-P(O)(OR π )- wherein R 1 - is Ci - C4 alkyl or phenyl; 11) R8-P(0)(ORll)-; or 12) R9-P(O)(ORH)-; R- and R 2 are the same or different and are: 1) -CH2R 12 wherein R 12 is a) NH-A wherein A is defined as above; b) R5-(R6R7Q -; c) R 5 -(R 6 R 7 C)m V- wherein V is O or NH, except R 5 , R 6 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) N(RlO) 2 , e) NR15R16 wherein R-5 and R -~ are joined to form a 4-6 membered saturated nitrogens heterocycle including: i) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, f) R 17 OCH2θ wherein R 17 is: i) C -C 6 alkyl, ii) R9, or iii) CH 2 Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle, g) R 17 OCH 2 CH 2 OCH2, h) C 2 -Cg alkynyl, optionally substituted with one or more groups R 9 ; or i) C2~--6 alkenyl, optionally substituted with one or more groups R 9 ; 2) hydrogen, 3) Cj-Cg alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C3-C7 cycloalkyl; and R 18 is 1) hydrogen, 2) C C 6 alkyl, 3) phenyl; optionally substituted with chlorine, fluorine, or N0 2 , and 4) CH O 2 CR 19 wherein R 19 is a) hydrogen b) Cj-Cg alkyl, and c) phenyl; and pharmaceutically acceptable salts thereof. Oridinarily, χ = X 2 and Rl = R 2 , to produce truly symmetric compounds; however, the procedures allow for the preparation of pseudosymmetric compounds as well in which X 1 is different from X 2 and R 1 is different from R 2 . Peptide compounds of the foregoing description are preferred which are C2 symmetric wherein χl=X 2 , and Rl=R 2 . Suitably R- and R 2 are selected from C\-C alkyl, phenyl C j -Cg alkyl and C -Cg alkenyl. Preferably R- and R 2 are benzyl. Suitably X- and X 2 were selected from H, CbzVal, Val, Boc and Cbz. Suitably R- ~ is hydrogen, methyl or CH O CR 19 wherein C 19 is Ci-Cβ alkyl. The compounds of this invention are useful in the manufacture of a medicament, in particular, for a medicament for treating infection by retroviruses. C 2 symmetric peptide compounds wherein R- and R 2 are C\-C(- alkyl or aralkyl and X- and X 2 are single amino acids or mono- or dipeptides; these groups may be terminally substituted by common acyl groups or blocking groups commonly used in peptide synthesis, such as t-Boc or Cbz, are also preferred. 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 parent drug. Additionally within the scope of this invention are pharmaceutical compositions comprising a compound according to formula I and a pharmaceutically acceptable carrier. As used herein except where noted, the term "alkyl" refers to a straight or branched chain alkyl radical of the indicated number of carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, and the like; "alkoxy" represents an alkyl group of the indicated number of carbon atoms attached through a bridging oxygen atom; "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; "alkenyl" is meant to include either straight or branched hydrocarbon chains containing one or more carbon- carbon double bonds which may occur at any stable point along the chain, such as ethenyl, propenyl, butenyl, pentenyl, 2-methyl propenyl, and the like; "alkynyl" refers to either a straight or branched hydrocarbon chain of the indicated number of carbon atoms which contains a carbon-carbon triple bond which may occur at any stable point along the chain, such as ethynyl, 2-propynyI, 2-butynyl, 4-pentynyl, 2-methyl-3-propynyl, and the like. As used herein except where noted, the term "heterocycle" represents a stable 5- to 7-membered mono- or bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, furyl, tetrahydrofuryl,tetrahydropyranyl, thienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. When any variable (e.g., A, B, R*, R-, ..., R-7, heterocycle, substituted phenyl, etc.) occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By convention used herein, a geminal diol, for example when R6 and R7 are simultaneously hydroxyl, is meant to be equivalent with a carbon-oxygen double bond. Other abbreviations and symbols commonly used in the art used herein to describe the peptides include the following: In accordance with conventional representation, the amino terminus is on the left and the carboxy terminus is on the right. All chiral amino acids (AA) can occur as racemates, racemic mixtures, or individual enantiomers or diastereomers, with all isomeric forms being included in the present invention. β-Ala refers to 3-amino propanoic acid. Boc refers to the t-butyloxycarbonyl radical, Cbz or Z refers to the carbobenzyloxy radical, i-Bu refers to isobutyl, Ac refers to the acetyl, Ph refers to phenyl, DCC refers to dicyclohexylcarbodiimide, 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 formamide and THF is tetrahydrofuran. HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid. The peptide moieties denoted by X - and X 2 are generally dipeptides or smaller. However, longer peptides which encompass the residues defined herein are also believed to be active and are considered within the scope of this invention. The selection of residues or end groups may be used to confer favorable biochemical or physico-chemical properties to the compound. The use of hydrophilic residues may be used to confer desirable solubility properties or D-amino acids at the carboxy terminus may be used to confer resistance to exopeptidases. Compounds represented by the structure I of the invention can be prepared as follows: Condensation of an amino-protected alpha-amino phosphonoyl chloride, P 2 NHCH(R 1 )PO(OR)Cl, wherein R is typically methyl or phenyl and P 2 is a protecting group such as Cbz, with the enolate of an ester, R 2 CH2CO2 100 where R 100 is an hydrocarbon group, such as methyl, t-butyl or benzyl, produces the intermediate P 2 NHCH(R 1 )PO(OR)CH(R 2 )CO2R 1(X) . The ester is deprotected by removal of the group R 100 and the resulting acid is subjected to Curtius rearrangement via its corresponding acyl azide (Shiori et al., J. Am. Chem Soc. 94, 6203 (1972)) to produce P 2 NHCH(R 1 )PO(OR)CH(R 2 )NHR 101 , where R lϋl depends on the agent used to trap the intermediate isocyanate and is typically H, COCH2Ph, or CO(t-Bu). These groups are readily removed by methods well known in the art, such as treatment with acid or hydrogenolysis, to produce the compound wherein P 2 = R-~- = H. These compounds are a useful intermediates for the preparation of compounds of formula I. Thus, this invention is also an intermediate compound of the formula II: II wherein R 1 , R 2 and R 18 are as defined for formula I, and P 2 and R 101 are H or amino- protecting groups. Useful protecting groups are described in Greene, T.W., Protective Groups in Organic Synthesis. John Wiley & Sons, New York (1981), but many others are well known in the art. Boc and Cbz are typical amino protecting groups. The amino-protected alpha-amino phosphonoyl chloride, P 2 NHCH(R 1 )PO(OR)Cl, is prepared from the corresponding phosphonic diester, P 2 NHCH(R 1 )PO(OR)2, as described by Bartlett and Kezer, J. Am. Che . Soc. 106, 4282 (1984) and by Dreyer et al., European patent application EP 352 000. The phosphonic diester, P 2 NHCH(R 1 )PO(OR)2, is prepared by condensation of benzyl carbamate with P(OPh)3 and the aldehyde RϊCHO as described by Oleksyszyn et al., Synthesis. 985 (1979) to provide CbzNHCH(R 1 )PO(OPh)2, which can be converted to other compounds P 2 NHCH(R 1 )PO(OR)2 by simple exchange of protecting groups as described (Bartlett and Kezer, J. Am. Chem. Soc. 106, 4282 (1984); Dreyer et al., European patent application EP 352 000). Structure I (R 18 = H) is converted to structure I (R 18 = alkyl as described in the Claims) by reaction with an alkyl halide under basic conditions or by reaction with a diazoalkane, while structure I (R 18 = alkyl) is converted to structure I (R 18 = H) by treatment with trimethylsilyl bromide (McKenna and Schmidhauser, J. Chem. Soc. Chem. Commun.. 739 (1979)) or hydroxide ion or with a thiol nucleophile such as propanethiol in HMPA, or with tert-butylamine (Gray and Smith, Tet. Letters. 859 (1980)). Structure I (R 18 = H) is converted to Structure I (R 18 = CH2O2CR 19 as described in the Claims) by reaction with reagents of the formula CICH2O2CR ] 9 . The compounds of this invention are prepared by the solid phase technique of Merrifield, J. Am. Chem. Soc. 85, 2149 (1964), or preferably by solution methods known to the art. Generally, the compounds are prepared by acylation of the free amino group of the central phosphorous-containing unit. Accordingly, when R 1 = R 2 , this invention is also a process for preparing a compound of formula I, which comprises reacting a compound of formula III, III wherein R 1 and R 18 are as defined for formula I, with a compound of formula (IV), Xl-Z, wherein χ l is defined as above for formula I, and Z is OH or a displaceable activating group, and optionally removing any protecting groups. When X 1 and X 2 are different, the coupling reactions are performed sequentially. Thus, an amino-protecting group is maintained upon one amino group, while the other amino group is acylated, to arrive at a structure of the formula V, IV wherein p3 is an amino protecting group. Then the amino-protecting group is selectively removed to arrive at a compound of the formula V. Accordingly, this invention is also a process for preparing a compound of the formula I, which comprises reacting a compound of the formula V, V with a compound X*-Z, wherein X 1 is defined as above for formula I, and Z is OH or a displaceable activating group. Suitable activating groups for carboxylic acids are acyl halides, such as an acid chloride or bromide, activated esters, such as the nitrophenyl esters or N-hydroxy-succinimide esters, activated anhydrides, such as isobutyl anhydride and the like. It will be readily apparent that Z may also be OH, or a carboxylic acid, when a suitable activating reagent, such as a carbodiimide or other coupling reagent, is used to effect the reaction (eg. the activation may occur in situ). Activating groups for sulfonic acids are typically sulfonyl halides. Activating groups for the alkyl group are groups such as the alkyl halide, alkyl sulfonate esters, for example mesylate, tosylate and brosylate, and alkyl acetates or benzoates. Other activating groups for these groups are well known and will be readily apparent to one skilled in the art depending upon the choice of X 1 . The methods of peptide synthesis generally set forth in J. M. Stewart and J. D. Young, "Solid Phase Peptide Synthesis". Pierce Chemical Company, Rockford, II (1984) or M. Bodansky, Y.A. Klauser and M. A. Ondetti, "Peptide Synthesis" . John Wiley & Sons, Inc., New York, N.Y. (1976), or "The Peptides" gross and Meienhoffer, eds.; Acad. Press, 1979, Vols I-III, may be used to produce the peptides of this invention and are incorporated herein by reference. Each amino acid or peptide is suitably protected as known in the peptide art. For example, the Boc- or carbobenzyloxy-group is preferred for protection of the amino group, especially at the α position. A benzyl group or suitable substituted benzyl group is used to protect the mercapto group of cysteine, or other thiol containing amino acids; or the hydroxyl of serine or threonine. The tosyl or nitro group may be used for protection of the guanidine of Arg or the imidazole of His, and a suitably substituted carbobenzyloxy group or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or the ε-amino group of lysine. Suitable substitution of the carbobenzyloxy or benzyl protecting groups is ortho and/or para substitution with chloro, bromo, nitro or methyl, and is used to modify the reactivity of the protective group. Cysteine and other sulfur-containing amino acids may also be protected by formation of a disulfide with a thioalkyl or thioaryl group. Except for the Boc group, the protective groups are, most conveniently, those which are not removed by mild acid treatment. These protective groups are removed by such methods as catalytic hydrogenation, sodium in liquid ammonia or HF treatment as known in the art. If solid phase methods are used, the peptide is built up sequentially starting from the carboxy terminus and working toward the amino terminus of the peptide. Solid phase synthesis is begun by covalentiy attaching the C terminus of a protected amino acid to a suitable resin, such as a benzhydrylamine resin (BHA), methylbenzhydrylamine resin (MBHA) or chloromethyl resin (CMR), as is generally set forth in U.S. Patent No. 4,244,946. A BHA or MBHA support resin is used for the carboxy terminus of the product peptide is to be a carboxamide. A CMR support is generally used for the carboxy terminus if the produced peptide is to be a carboxyl group, although this may also be used to produce a carboxamide or ester. Modification of the terminal amino group of the peptide is accomplished by alkylation or acetylation as is generally known in the art. These modifications may be carried out upon the amino acid prior to incorporation into the peptide, or upon the peptide after it has been synthesized and the terminal amino group liberated, but before the protecting groups have been removed. Typically, acetylation is carried out upon the free amino group using the acyl halide, anhydride or activated ester, of the corresponding alkyl acid, in the presence of a tertiary amine. Mono-alkylation is carried out most conveniently by reductive alkylation of the amino group with an appropriate aliphatic aldehyde or ketone in the presence of a mild reducing agent, such as lithium or sodium cyanoborohydride. Dialkylation as well as quaternization may be carried by treating the amino group with an excess of an alkyl halide in the presence of a base. Solution synthesis of peptides is accomplished using conventional methods used to form amide bonds. 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), optionally in the presence of catalysts such as 1 -hydroxybenzotriazole (HOBT) and dimethylamino pyridine (DMAP). Other methods, 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, or a trialkyl amine, with isobutyl chloroformate to form the mixed 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, trifluoroacetic acid or alkali. Esters are often used to protect the terminal carboxyl group of peptides in solution synthesis. They may be convened 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 of an amino-protected α-amino acid or oligopeptide 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. Procedures for the determination of the inhibition constant (Ki) by Dixon analysis are described in the art, e.g., in Dreyer, et al. Proc. Natl. Acad. Sci. U.S.A.. 86, 9752-9756 (1989). A peptidolytic assay is employed using the substrate Ac-Arg-Ala-Ser-Gln-Asn-Tyr- Pro-Val-Val-NH 2 and recombinant HIV protease as in Strickler, et al., Proteins. 6, 134-154 (1989). The lower Ki value indicates a higher binding affinity. Pharmaceutical compositions of the compounds 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 excipient 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 compounds 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. Alternatively, these compounds may be encapsulated, tableted or prepared in a emulsion or syrup or 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 dϊhydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glycerol monostearate or glycerol 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 compounds of this invention may be combined with excipient 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. This invention is also a method for treating viral infection, particularly infection by retroviruses, which comprises administering a compound of formula I to a patient infected with a susceptible virus. The method is particularly applicable to infection by the Human Immunodeficiency Virus, type 1. When the compounds of this invention are used to induce anti-viral activity in patients which are infected with susceptible viruses and require such treatment, the method of treatment comprises the administration orally, parenterally, bucally, trans-dermally, intravenously, intramuscularly, 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 selected from the range of 0.05 to 50 mg/kg of body weight. Dosage units will typically be from 50 to 1000 mg. These dosage units may be administered one to ten times daily for acute or chronic infection. The dosage will be readily determined by one skilled in the art and will depend upon the age, weight and condition of the patient, and the route of administration. Combination therapy as described in Eur. Pat. Appl. No. 337 714 at pages 42-47 are included herein. The F^amples 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 Celsius. 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 mass spectrometer using fast atom bombardment. NMR spectra 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. Purification of Recombinant HIV Protease Methods for expressing recombinant HIV protease in E.coli have bee described by Debouck, et al., Proc Natl. Acad. Sci. USA, 84, 8903-6 (1987). The enzyme used to assay the compounds of this invention was produced in this manner and purified from the cell pellet as previously described by Stickler et al. Proteins, 6, 139-154 (1989). Example 1 Preparation of (+)- and meso-diC2-phenyl-l-carbobenzyl-oxyamino)ethyl-phosphinate 6 and ___ (a) Methyl 2-phenyl-l-carbobenzyloxyaminoethyl phosponate 1. The title compound was prepared as described by Dreyer et al., European patent application EP 352 000. (b) Methyl 2-phenyl-l-carbobenzyloxyaminoethyl phosphonyl chloride 2. To a solution of compound 1 (11.8 g, 33.9 mmol) in dry methylene chloride (80 ml) under Ar was added SOCI2 (2.72 ml, 37.3 mmol). After 2 hr the solvent is removed under vacuum. Residual HC1 is removed by addition and re-evaporation of dry methylene chloride, followed by dry THF (100 ml each), to provide the gummy phosphonyl chloride 2. (c) Methyl (2-phenyl-l-carbobenzyloxyamino)ethyl-(2-phenyl-l-(tert-butyl)carboxy)ethyl- phosphinate 3. n-Butyllithium (67.5 ml, 1.51 M in hexane, 0.102 mol) was added to dry diisopropylamine (14.3 ml, 0.102 mol) in dry THF (200 ml) at -78 °C under Ar. After 5 min neat tert-butyl hydrocinnamate (21.0 g, 0.102 mol) was added dropwise over 10 min. After 15 min further stirring, the product of step (b) (33.9 mmol) was added as a solution in 125 ml THF over 5 min. The solution was stirred at -78 °C for 5 min then allowed to warm to ca. -10 °C over 30 min, after which excess 10% HC1 was added. The mixture was extracted with ether, the organic layer was concentrated and the residue was purified by flash chromatography on 400 g silica (gradient: hexanes:ethyl acetate 4:1 (21), 1:1 (21), 1:2 (1.5 1)) to provide the titled compound as a mixture of isomers (12.23 g, 22.7 mmol, 67% yield). -H NMR (CDC1 3 , 250 MHz) δ 7.25 (m, 15H), 5.00 (m, 2H), 4.62 (m, 1H), 3.89- 3.70 (m, 3H), 3.35-3.10 (m, 4H), 2.95 (m, 1H). (d) (+)- and (meso)-Di-(2-phenyl-l-carbobenzyl-oxyamino)ethyl-phosphinate methyl ester 4 and 5a,b. Compound 3 (0.88 g, 1.64 mmol) was dissolved in 5 ml neat TFA. After 1 hr the mixture was concentrated under vacuum, then reconcentrated sequentially from solutions of methanol, methylene chloride and benzene, to yield a foam (0.8 g). The foam was stirred at reflux in 9 ml dry toluene with triethylamine (0.456 ml, 3.28 mmol) and diphenylphosphoryl azide (0.707 ml, 3.28 mmol) under Ar for 3 hr. Benzyl alcohol (0.682 ml, 6.6 mmol) was added and the mixture was heated for 12.5 hr further, then was cooled and extracted with 10% HC1, 5% sodium carbonate, and water. The organic layer was concentrated to a dark oil, which was purified by flash chromatography on 75 g silica (gradient: 1:1 to 2:1 ethyl acetate:hexanes) to provide the titled product as a brown foam (0.26 g, 27% yield). (e) (+)- and meso-di(2-phenyl-l-carbobenzyloxyamino)ethyl-phosphinate 6 and 7. To a mixture of 1.15g (1.96 mmol) of compounds 4 and 5a,b (prepared as in step (d)) in 15 ml methanol and 8 ml water was added NaOH (5 mmol) in 2 ml water. After 36 hr stirring the mixture was acidified with 10% HC1 and extracted with methylene chloride. The organic layer was dried (MgS0 4 ) and concentrated. The residue was dissolved in 10 ml methanol and allowed to sit overnight, during which crystals of isomerically pure 7 (0.30 g) precipitated. The supernatant was concentrated, redissolved in 30 ml 7:2: 1 :0.01 methanol :water:DMF: TFA, and purified in three portions by reversed phase HPLC (2" X 25 cm Beckman Ultrasphere ODS CI 8 column) with the same solvent mixture. Isomer 6 eluted first (0.330 g, 29 % yield), followed by isomer 7 (0.20 g). Assignment of stereochemistry for 6 and 7 was achieved by conversion to their methyl phosphinate derivatives (vide infra, Examples 2 and 3). For isomer 6: HPLC RT 13 min (Ultrasphere® ODS C18, 4.6 X 250 mm, 1 mL/min, A:0.2% TFA-water, B:10% DMF-methanol, 30% A - 70% B isocratic, UV detection at 254 nm). HNMR (CDCI3/CD3OD, 250 MHz) d 7.25-7.00 (m, 20H), 4.89-4.46 (m, 4H), 4.13 (m, 2H), 3.12 (dm, 2H), 2.70 (m, 2H). MS (ESI): m/z 573 [M+H] + . For isomer 7: HPLC RT 16 min (Ultrasphere® ODS CI 8, 4.6 X 250 mm, 1 mL/min, A:0.2% TFA-water, B:10% DMF-methanol, 30% A - 70% B isocratic, UV detection at 254 nm); iHNMR (CDC13/CD3UD, 250 MHz) d 7.10-6.97 (m, 20H), 4.80 (dd, 4H), 4.12 (m, 2H), 3.11 (dm, 2H), 2.55 (m, 2H). MS (ESI): m/z 573 [M+H]+. Example 2 Preparation of (+)- Methyl di-(2-phenyl-l-carbobenzyl-oxyamino ethyl-phosphinate 4. Compound 6 from Example 1 (117 mg, 0.204 mmol) was stirred as a suspension in 5 ml methanol at 0 °C. Excess ethereal diazomethane was added, the resulting yellow solution was stirred 1.5 hr, then acetic acid (1 ml) was added. Concentration and flash chromatography of the residue (1 cm X 6" silica, 2: 1 ethyl acetate exanes then 25: 1 chloroform:methanol) provided the titled compound (70 mg, 0.119 mmol, 59% yield) as a single diastereoisomer, thus proving nonstereogenicity at phosphorus. TLC Rf 0.45 (silica, 25:1 chlorofoπmmethanol); *H NMR (CDC13 , 250 MHz) δ 7.25 (m, 20H), 5.92 (d, IH), 5.32 (d, IH), 5.02 (dm, 2H), 4.90 (dm, 2H), 4.53 (m, IH), 4.43 (m, IH), 3.67 (d, 3H; J = 9.9 Hz), 3.24 (m, 2H), 2.96 (m, 2H). Example 3 Preparation of (meso)- Methyl di-(2-phenyl-l-carbobenzyl-oxyamino)ethyl-phosphinate 5a. b. Compound 7 from Example 1 (114 mg, 0.20 mmol) was converted to the titled compound (54 mg, 46% yield) by the procedure of Example 2. The titled compound was a 60:40 mixture of diastereoisomers (5a and 5b), thus establishing the meso assignment. TLC Rf 0.45, 0.50 (silica, 25:1 chloroform:methanol); ] H NMR (CDCI3, 250 MHz) δ 7.28-7.10 (m, 20H), 6.41 (d, 3/5 x IH), 5.52 (d, 2/5 x IH), 5.12-4.94 (m, 4H), 4.53 (m, 2H), 3.83 (d, 3/5 x 3H; J = 10.3 Hz), 3.57 (d, 2/5 x 3H; J = 9.6 Hz), 3.34 (m, 2H), 2.82 (m, 2H). Example 4 Preparation of methyl di-(nR)-2-phenyl-l -carbobenzyloxy valylamino)ethyl-phosphinate 8 and methyl di-((lS)-2-phenyl-l-carbobenzyloxyvalylamino)ethyl-phosphinate 9. (a) (-t-)-methyl di-(2-phenyl-l-amino)ethyl-phosphinate dihydrochloride. The product of Example 2, compound 4 (70 mg, 0.12 mmol), was stirred as a solution in methanol (5 ml) with 3N HC1 (0.1 ml) and 10% Pd/C (80 mg) under H 2 (1 atm) for 4 hr. Filtration and removal of solvent provided the titled dihydrochloride (39.2 mg, 84%). -H NMR (CD 3 OD, 250 MHz) δ 7.35 (m, 10H), 3.82 (d, 3H; J = 10.2 Hz), 3.75 (m, 2H), 3.29 (m, 2H), 2.99 (m, 2H). (b) methyl di-((lR)-2-phenyl-l-carbobenzyIoxyvalylamino)ethyl-phosphinate 8 and methyl di-((lS)-2-phenyl-l-carbobenzyloxyvalylamino)ethyl-phosphinate 9. To a solution of Cbz-(L)-valine (75.4 mg, 0.300 mmol) and N-methylmorpholine (38 μl, 0.35 mmol) in 2 ml THF at -40 °C under Ar was added isobutyl chloroformate (39 μl, 0.300 mmol). After 10 min a solution of the dihydrochloride product of step (a) (39 mg) in 1.5 ml THF and 0.2 ml DMF was added along with more N-methylmorpholine (38 μl). The mixture was allowed to stir with warming to 25 °C, and after 11 hr 5% HCl was added. Extractive workup provided a 1 :1 mixture of the titled compounds as a solid (85 mg). Preparative HPLC (Dynamax silica 1 " X 25 cm, 2% methanol in chloroform 20 ml/min, UV detection at 254 nm) to provide compound 8 (22.9 mg, 23.8 % yield), which eluted first (RT = 14 min), followed by compound 9 (21.8 mg, 22.7% yield) (RT = 17 min). For compound 8: -U NMR (CDCI3, 250 MHz) δ 7.35-7.09 (m, 22H), 5.15-4.75 (m, 6H), 4.03 (m, IH), 3.95 (br, IH), 3.76 (br d, 3H; J = 9.7 Hz), 3.30 (m, 2H), 3.30-2.88 (m, 2H), 2.19-1.75 (m, 2H), 0.73 (m, 6H), 0.63-0.38 (m, 6H). For compound 9: -H NMR (CDCI3, 250 MHz) δ 7.38-7.24 (m, 20H), 5.23-4.93 (m, 7H), 4.76 (m, IH), 4.23 (dd, IH), 3.77 (m, IH), 3.63 (d, 3H; J = 10.3 Hz), 3.42 (br d, 2H), 2.96-2.68 (m, 2H), 1.68 (m, 2H), 0.75 ( , 6H), 0.54 (d, 3H; J = 6.8 Hz), 0.49 (d, 3H; J = 6.6 Hz). Example 5 Preparation of di-((lR)-2-phenyl-l -carbobenzyloxy valylamino)ethyl-phosphinic acid 10. A solution of compound 8 (20.3 mg, 25.3 μmol) in dry methylene chloride (1 ml) was added trimethylsilyl bromide (10 μL, 76 μmol). After 7 hr methanol (1 ml) was added, the solution was concentrated, and the residue was triturated with ether and dried to yield the titled compound as a solid (20 mg, 100 % yield). ] H NMR(CDCl3/CD 3 OD 250 MHz) δ 7.20-7.18 (m, 20H), 5.03 (dd, 4H), 4.54 ( , 2H), 3.86 (d, 2H; J = 6.4 Hz), 3.24 (m, 2H), 3.01 (m, 2H), 1.92 (m, 2H), 0.77 (apparent t, 12H); MS (FAB) m/e 771 [M+H] + , 637, 538. Example 6 Preparation of di-((lS)-2-phenyl-l-carbobenzyloxyvalylamino)ethyl-phosphinic acid 11. The titled compound was prepared from compound 9 (20.0 mg) in 100 % yield by the procedure of Example 5. ! H NMR(CDCl3/CD OD , 250 MHz) δ 7.33-7.15 (m, 20H), 5.06 (dd, 4H), 4.80 (m, 2H), 3.96 (d, 2H; J = 6.7 Hz), 3.35 (m, 2H), 2.98 (m, 2H), 1.69 (m, 2H), 0.59 (dd, 12H); MS(FAB) m/e 771 [M+H]+, 637. Example 7 Preparation of (IR, l'S)-(2-phenyl-l -carbobenzyloxy valylamino)ethyl-(2 '-phenyl- 1'- carbobenzyloxyvalylamino)ethyl-phosphinic acid 12 The titled compound was prepared from compound 5a,b by the procedures of Examples 4 and 5. MS(FAB) m/e 771 [M+HJ+, 637. The compounds of the forgoing Examples are given by the following structural formulas: 5 a,b - 7 8: R = Me 10: R = H 9: R = Me -j 2 11 : R = H ENZYME INHIBITION Inhibition of HIV protease activity The inhibition assay has been previously described in Dreyer et al. Proc. Natl. Acad. Sci. USA. .86, 9752-9756 (1989) and Moore et al. Bioch. Bioph. Res. Com.. 159. 420 (1989). 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 M 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 submicromolar concentrations of synthetic compounds. Following incubation at 37°C for several minutes, the reaction was initiated with 0.001-O.lOmg purified 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/H2θ - .1% TFA 915 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. It is desirable for the compounds of this invention to have Ki values less than 50 μM, preferably less than 10 μM and more preferably less than 1 μM. The following are representative of the inhibitory activity of the compounds of this invention. Inhibition of Purified HIV-1 Protease Compound No. Ki ( μM ) 10 0.0028 11 1.762 12 0.963 Following the procedures set forth herein and the teachings of the foregoing example the compounds set forth in the following Table can be prepared having the structure set forth hereinabove and the substituent groups as designated therein. In the compounds of Table I, R-~ in each case is hydrogen. Identical compounds to those in the Table can be prepared wherein R-~ is methyl or CH2θ2C-t-butyl. Table I

Claims: Claims: 1. A compound having the structure: wherein X- and X-- are the same or different and are A-(B) n - where n = 0-2; and B is, independently, an α-amino acid chosen from the group: Ala, Asn, Cys, Tφ, Gly, Gin, He, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is bonded to A or the carboxy group of the adjacent residue B, whichever is appropriate, and the carboxy group of B is bonded to the amino group of the adjacent residue B or the structure, whichever is appropriate; and A is covalentiy attached to the amine group of the adjacent residue B or to the amine group of the structure if n=0, and is: 1) trityl, 2) hydrogen, 3) Cι-C 6 alkyl, 4) R 3 -CO- wherein R3 is: a) hydrogen, b) Ci -C^ alkyl, unsubstituted or substituted with one or more hydroxyl groups, chlorine atoms, or fluorine atoms, c) phenyl or naphthyl unsubstituted or substituted with one or more substituents R^, wherein R^ is: D C1-C4 alkyl, ii) halogen, where halogen is F, CI, Br or I, iii) hydroxyl, iv) nitro, v) C1-C3 alkoxy, or vi) -CO-N(R l ϋ )2 wherein R 10 is, independently, H or C1-C4 alkyl; or d) a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; 5) phthaloyl wherein the aromatic ring is unsubstituted or substituted with one or more substituents R^; 6) R 5 (R 6 R 7 C)m-CO- wherein m = 1-3 and R 5 , R 6 , and R 7 are independently: a) hydrogen, b) chlorine or fluorine, c) C1-C3 alkyl unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl, e) phenyl or naphthyl unsubstituted or substituted with one or more substituents R^, f) Ci - C3 alkoxy, g) a 5-7 member heterocycle, or h) R-, R-, and R 7 may be independently joined to form a monocyclic, bicyclic, or tricycle ring system each ring of which is C3-C6 cycloalkyl; 7) R 5 (R 6 R 7 C)m W- wherein m = 1-3 and W is OCO or SO2 and R 5 , R 6 , and R 7 are as defined above, except R-, R6, and R 7 are not chlorine, fluorine or hydroxyl if they are adjacent to W; 8) R8-W- wherein R~ is a 5-7 member heterocycle such as pyridyl, furyl, or benzisoxazolyl; 9) R9-W- wherein is phenyl or naphthyl unsubstituted or substituted with one or more substituents R^; 10) R^R^Qm-PtOXOR 1 ] )- wherein R 1 - is C] - C4 alkyl or phenyl; 11) R8-P(O)(OR π )-; or 12) R9-P(O)(OR π )-; R- and R-* are the same or different and are: 1) -CH2R 12 wherein R 12 is a) NH-A wherein A is defined as above; c) R 5 -(R 6 R 7 C)m V- wherein V is O or NH, except R 5 , R 6 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) N(R10) 2 , e) NR15R16 wherein R -- and R- - are joined to form a 4-6 membered saturated nitrogens heterocycle including: i) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, or iv) moφholinyl, f) R 17 OCH2θ wherein R 17 is: i) C!-C6 alkyl, ii) R 9 , or iii) CH2Ar wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle, g) R 17 OCH 2 CH 2 OCH2, h) C2- j alkynyl, optionally substituted with one or more groups R 9 ; or i) C2-C ( 5 alkenyl, optionally substituted with one or more groups R 9 ; 2) hydrogen, 3) C]-C6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C3-C7 cycloalkyl; and R 18 is 1) hydrogen, 2) Cι-C 6 alkyl, 3) phenyl; optionally substituted with chlorine, fluorine, or NO2, and 4) CH2O2CR 19 wherein R 19 is a) hydrogen b) C1-C6 alkyl, and c) phenyl; and pharmaceutically acceptable salts thereof. 2. A compound as defined in claim 1 wherein R* = R- and X- = X-. 3. A compound as defined in claim 1 wherein R- and R 2 are selected from Cj-C6 alkyl, phenyl Cj-C alkyl and Cj-Cβ alkenyl. 4. A compound as defined in claim 1 wherein X- and X-- were selected from H, CbzVal, Val, Boc and Cbz. 5. A compound of claim 1 wherein R* ~ is hydrogen, methyl or CH2O2CRI 9 wherein C 9 is C1-C6 alkyl. 6. A compound according to any one of claims 1 to 5 wherein R 1 and R 2 are benzyl. 7. A compound as defined in claim 1 wherein the protease activity inhibitor constant is less than about 10 μM. 8. A compound according to claim 1 for use in a medicament. 9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmacetically acceptable carrier. 10. A method of treating infection by a retrovirus which comprises administering a compound according to claim 1. 11. A method according to claim IQ wherein the retrovirus is the Human Immunodeficiency Virus type 1. 12. A process for preparing a compound of formula I, as defined in claim 1, which comprises reacting a compound of formula III, III wherein, R 1 and R 18 are as defined in claim 1, with a compound of the formula: X--Z (IV) wherein X 1 is defined as above for formula I, and Z is OH or a displaceable activating group, and optionally removing any protecting groups. 13. A process for preparing a compound of formula I, as defined in claim 1, which comprises reacting a compound of formula V, V with a compound X--Z, wherein X 1 is defined as in claim 1 and Z is OH or a displaceable activating group, and optionally removing any protecting groups.

Inventors: DREYER GEOFFREY BAINBRIDGE, DREYER, GEOFFREY, BAINBRIDGE
Applicants: SMITHKLINE BEECHAM CORP, SMITHKLINE BEECHAM CORPORATION
Application year: 1991
Main classification: C07F9
IPC codes: A61K38, A61P31, C07F9, C07K1, C07K5, C07K14