PT98228A - PROCESS FOR THE PREPARATION OF INHIBITORS OF RETROVIRAL PROTEASES, THEIR INTERMEDIARIES AND PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

72 876 SB CASE 14515 -3

BACKGROUND OF THE INVENTION The present invention relates to the process of preparing compounds which are inhibitors of aspartic proteases, particularly retroviruses.

Retroviruses, that is, viruses of the Retroviridae family, are a class of viruses that carry their genetic material as ribonucleic acid instead of deoxyribonucleic acid. Also known as tumor RNA viruses, their presence has been associated with a wide variety of diseases in humans and animals. It is believed that they are the causative agents of pathological conditions associated with infections of 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 immune deficiency syndrome virus (SIDAS), human T-lymphotropic virus ( HTLV-I, -II) and the human immunodeficiency virus (HIV-1, HIV-2) which is the etiological agent of AIDS (acquired immunodeficiency syndrome) and AIDS-related complexes, and many others . Although pathogens have been isolated in many of these cases, no satisfactory method for the treatment of this type of infection has yet been developed. Of these viruses, HTLV and HIV have been especially well characterized. The production of functional viral proteins is critical for retrovirus replication. Protein synthesis is performed by translating the open reading frames into poly-protein constructs corresponding to the gaq reading frames. pol and env. The precursor proteins gaq and pol are processed by a viral protease into the functional proteins. 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 the processing of the polyproteins can not be provided by the host and is essential to the life cycle of the retrovirus. In fact, it has been demonstrated that infectivity is lacking to retroviruses lacking the protease 72 876 SB CASE 14515 -4-

or which contain a mutated form of protease. See Katoh et al., Viroloay. 145, 280-92 (1985), Crawford, et al., J. Virol., 53, 899-907 (1985), Debouck, et al., Proc. Natl. Acad. Know. USAr 84, 8903-6 (1987). Thus, inhibition of retroviral protease appears to be a therapy method for retroviral diseases. Methods for expressing retroviral proteases in E. coli have been described (Debouck, et al., Proc. Natl. Acad Sci USA 8903-06 (1987) and Tomasselli et al., Biochemistry, 29, 264-9 (1990 ), and references cited therein). Recombinant HIV protease inhibitors have been described (Dreyer et al., Proc Natl Acad Sci USA 86, 9752-56 (1989), Tomasselli et al., Supra, Roberts et al., Science, 248 , Et al., U.S. Patent No. 3,777,144; Dreyer et al., European Patent Application Ser. 352 000). In addition, some of these inhibitors have been shown to be potent inhibitors of viral proteolytic processing in HIV-1 infected T lymphocyte cultures (Meek et al., Nature ILondon). 343, 90 (1990) and Roberts et al. supra).

The limitations of current strategies for aspartic protease inhibition include (1) oral bioavailability, (2) plasma clearance times (e.g., by biliary excretion or degradation): (3) selectivity of inhibition; and (4) in the case of intracellular targets, membrane permeability or incorporation into cells. The present invention relates to novel retroviral aspartic protease inhibitors. Unlike the inhibitors described above, the compounds of the present invention are not analogues of peptidic substrates having a traceable mimetic dipeptide. They also deviate substantially from a peptide substrate-like structure in that they do not have a conventional amino-terminal, carboxy-terminal orientation.

SUMMARY OF THE INVENTION The present invention relates to the process of preparing compounds having the structures particularly indicated in

72 876 SB CASE 14515 and which are described hereinafter, which bind to retroviral proteases. These compounds are viral protease inhibitors and are useful in the treatment of diseases related to virus infection. The present invention also relates to the process for the preparation of a pharmaceutical composition comprising one of the abovementioned compounds and a pharmaceutically acceptable carrier thereof. The present invention further describes a method for the treatment of viral diseases comprising administering to a mammal in need thereof an effective amount of one of the abovementioned inhibitor compounds. DETAILED DESCRIPTION OF THE INVENTION The compounds of the invention have the structure I or II:

X 1 NH 2 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 selected from the group: Ala, Asn, Cys, Trp, Gly, Gin, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His or trifluoroalanine, in which the amino group of B is attached to A or the carboxyl group of the adjacent B residue, as appropriate, and the carboxyl group of B is attached to the amino group of the adjacent B residue or to I or II, as appropriate; and A is covalently attached to the amino group of the adjacent residue B or the amino group of I or II if n = 0, and is: 1) trityl, 2) hydrogen, 3) C1-4alkyl, 4) R3-CO -, wherein R 3 is: a) hydrogen,

B) unsubstituted or substituted alkyl, with one or more hydroxyl groups, chlorine atoms or fluorine atoms, c) unsubstituted or substituted phenyl or naphthyl, with one or more (ii) halogen, where halogen is F, Cl, Br or I, iii) hydroxyl, iv) nitro, v) C 1 -C 3 alkoxy, or vi) -CO -N (R 10) 2, wherein R 10 is independently H or C 1 -C 4 alkyl; or d) a 5-7 membered heterocycle, such as pyridyl, furyl or benzisoxazolyl; 5) phthaloyl in which the aromatic ring is unsubstituted or substituted with one or more substituents R4; 6) R 5 (R 6 R 7 C) m -CO-, where m = 1-3 and R 5, R 6 and R 7 are independently of one another: a) hydrogen, b) chlorine or fluorine, c) unsubstituted or substituted C 1 -C 3 alkyl , with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl, e) unsubstituted or substituted phenyl or naphthyl, with one or more substituents R 4, f) C 1 -C 4 alkoxy, g) a 5-7 heterocycle h) R 5, R 6 and R 7 may independently be attached to form a monocyclic, bicyclic or tricyclic ring system, each ring being a C 3 -C 6 cycloalkyl; 7) R 5 (R 6 R 7 C) mW-, where m = 1-3 and W is OCO or SO 2, and R 5, R 6 and R 7 are as previously defined, except R 5, R 6 and R 7 are not chlorine, fluorine or hydroxyl, if they are adjacent to W; 8) R 8 -W-, where R 8 is a 5-7 membered heterocycle, such as pyridyl, furyl or benzisoxazolyl; 9) R9 -W-. wherein R 9 is unsubstituted or substituted phenyl or naphthyl, with one or more substituents R 4; 10) R 5 - (R 6 R 7 C) m -P (O) (OR 11) -, where R 11 is C 1 -C 4 alkyl or phenyl; 72 876 SB CASE 14515 -7-

11) R8-P (O) (OR11) -; or 12) R9-P (O) (OR11) -; R1 and R2 are the same or different and are: 1) -CH2R12, where R12 is: a) NH-A, where A is as defined above, b) R5- (R6R7C) m-, c) R5- (R6R7C) mV -, where V is 0 or NH, except that R 5, R 8 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) R 5 - (R 6 R 7 C) m S (O) R6 and R7 are as defined above, except that R4, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to the sulfur, e) R8 -S (O) n -, f) R 9 -S (O) n -, g) (R 1 30) P (O) (OR 14) -, wherein R 13 and R 14 are independently of one another: i) C 1 -C 6 alkyl, ii) C 3 -C 6 cycloalkyl, iii) H , iv) R9, or v) R8, h) R13P (O) (OR14) -, i) N (R10) 2, j) NR15R16, where R15 and R16 are attached to form a saturated nitrogen heterocycle of 4-6 (i) azetidinyl, (ii) pyrrolidinyl, (iii) piperidinyl, or (iv) morpholinyl, (k) R17 OCH2 O, wherein R17 is i) C1-6 alkyl, or a 5-7 membered heterocycle, (1) r17och2ch2och2, m) N-imidazolyl, wherein the imidazole ring is unsubstituted or substituted with a R4 substituent, n) N-benzimidazolyl, wherein the condensed benzene ring

72 876 SB CASE 14515 -8 is unsubstituted or substituted with one or more substituents

2) hydrogen 3) C 1 -C 6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C 3 -C 7 cycloalkyl; and pharmaceutically acceptable salts thereof.

Preferred are the peptidic compounds of the foregoing description which are symmetrical at C-2, wherein X1 = X2 and R3 = R2.

Suitably, the compound has the structure I and R1 = R2 and X1 = X2.

Suitably, R 1 and R 2 are C 1 -C 6 alkyl. Preferably, R1 and R2 are benzyl.

Suitably, X 1 and X 2 are AlaAla, Val, Cbz-Val, Cbz or hydrogen. Preferably, X 1 and X 2 are Cbz-Val.

The compounds of the present invention are useful in the preparation of a pharmaceutical composition, in particular, of a pharmaceutical composition for the treatment of infections caused by retroviruses.

C-2 symmetrical peptidic compounds in which R 1 and R 2 are C 1 -C 6 alkyl or arylalkyl are preferred, and X 1 and X 2 are single amino acids or mono- or dipeptides; these groups may be terminally substituted by common acyl groups or by blocking groups commonly used in peptide synthesis, such as t-Boc or Cbz.

Also included in the present invention are pharmaceutically acceptable acid addition salts, complexes or prodrugs of the compounds of the invention. As pro-drugs we consider any 72 876

SB CASE 14515 covalently linked carriers which release the parent drug.

As used herein, and except where indicated, the term " alkyl " refers to a straight-chain or branched alkyl radical having 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 with the indicated number of carbon atoms attached through a bridging oxygen atom; it is intended that " cycloalkyl " includes saturated ring groups, such as, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; it is understood that " alkenyl " includes both linear and 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-methylpropenyl and the like; the term " alcinyl " refers to a straight or branched hydrocarbon chain with 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 propynyl, 2-butynyl, 4-pentynyl, 2-methyl-3-propynyl and the like.

As used herein, and except where indicated, 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, and S, and wherein the nitrogen or sulfur heteroatoms may be optionally oxidized and the nitrogen atom may be optionally quaternized, and including any bicyclic group in which any of the heterocyclic rings defined above is condensed with a benzene ring. The heterocyclic rings may be attached to any heteroatom or to any carbon atom which results in the creation of a stable structure. Examples of such heterocyclic elements include piperidinyl, piperazinyl,

2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolinedinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolylidyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolyl, quinuclidinyl, indolyl, quinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, thiamorpholinylsulfoxide, thiamorpholinylsulfoxide and oxadiazolyl.

When any variable (eg, A, B, R 1, R 2, R 3, -, R 17, heterocycle, substituted phenyl, etc.) occurs more than once in any constituent or in formulas I or II, is independent of its definition in each of the other cases. Combinations of substituents and / or variables are also permissible only if these combinations result in stable compounds. By the convention used herein, it is intended that a geminal diol, for example when R 6 and R 7 are both hydroxyl, is equivalent to a carbon-oxygen double bond.

Other abbreviations and symbols commonly used in the art used herein to describe peptides include the following: Amino Acid Codex Coding Three Letters Amino Acid Three Letters Alanine Ala Leucine Leu Arginine Arg Lysine Lys Asparagine Asn Methionine Met Aspartic Acid Asp Phenylalanine Phe Cysteine Cys Prolina Pro Glutamine Gin Serine Ser Glutamic Acid Glu Threonine Thr Glycine Gly Tryptophan Trp Histidine His Tyrosine Tyr Isoleucine Ile Valine Go Asparagine or Asx Aspartic Acid Glutamine or Glx Acid Glutamic

72 876 SB CASE 14515 -11-

According to the conventional embodiment, the amino terminus is on the left and the carboxyl terminus is on the right. All chiral amino acids (AA) can occur as racemates, racemic mixtures, or individual enantiomers or diastereomers, all the isomeric forms being included in the present invention. β-Ala refers to 3-aminopropanoic acid. Boc refers to the t-butoxycarbonyl radical, Cbz refers to the carbobenzyloxy radical, i-Bu refers to iso -butyl, Ac refers to acetyl, Ph refers to phenyl, DCC refers to dicyclo -hexylcarbodiimide, DMAP refers to dimethylaminopyridine, HOBT refers to 1-hydroxybenzotriazole, NMM is N-methylmorpholine, DTT is dithiothreitol, EDTA is ethylenediaminetetraacetic acid, DIEA is diisopropylethylamine, DBU is 1,8-diazabicyclo [5.4.0] undec-7-ene, DMSO is dimethylsulfoxide, DMF is dimethylformamide and THF is tetrahydrofuran. HF refers to hydrofluoric acid and TFA refers to trifluoroacetic acid.

The peptide moieties represented by X 1 and X 2 are generally dipeptides or smaller. However, it is believed that longer peptides, which include the residues defined herein, are also useful and are considered within the scope of the invention. The selection of residues or terminal groups can be used to give the compound favorable biochemical or physicochemical properties. Hydrophilic residues may be used to impart desirable solubility properties or D-amino acids at the carboxyl terminus may be used to impart resistance to exopeptidases. The synthesis of compounds I in which R 1 = R 12 CH 2, R 1 = R 2 and X 1 = X 2 is performed from D - (+) - arabitol (Schemes 1 and 2). Thus, D - (+) - arabitol is converted to the 1,2: 4,5-dianhydro-3- (O-benzyl) -D- (+) - arabitol (10) as described in SL Schreiber, T. Sam-nakia and DE Uehling, J. Now, chem. 54, 15-16 (1989). The diepoxide 10 can then be reacted with NaN 3 in DMF to give the resulting dihydroxy terminal diazide which is converted to the protected diaziridine, 1.2: 4,5-di- (N-benzyloxycarbonylimino) - -3- (O-benzyl) -pentanol by desmesylation of the dihydroxyl terminal diazide, followed by reduction with LiAlH 4, in vacuo. and Zn. Followed by reaction with benzyl chloroformate. The resulting diaziridine is reacted with the appropriate nucleophiles such as (CH3) 2 Clu, to introduce the R1 side chain groups (Scheme 1). This procedure is especially suitable for the preparation of a compound I wherein R 1 = CH 2 R 12 where R 12 is hydrogen or a group forming a stable and reactive cuprate reagent, such as methyl # butyl, isopropyl, or other alkyl, alkenyl or aryl which is optionally substituted, for example, with fluoro, alkoxy or protected hydroxyl.

Alternatively, the compounds represented by formula I in which R 1 = R 12 CH 2, R 1 = SR 2 and X 1 = X 2 may be prepared from the diepoxide 10 by reaction with the appropriate carbon nucleophiles, such as cuprate (R 12) 2 CuCl reagents or alkynylaluminum, to introduce the R1 side chain groups (Scheme 2). This procedure is especially suitable for the preparation of a compound I wherein R 1 = CH 2 R 12, where R 12 is a group forming a stable and reactive cuprate reagent, as previously described. The resulting diol product is converted to the corresponding diamine with inversion of the configuration in the alcohol carbons. One way of achieving this is by conversion of the diol into the dimesylate by reaction with methanesulfonyl chloride and triethylamine followed by elimination with NaN3 in DMF to give the substituted 2,4-diazido-3-benzyloxypentane: the conversion in the 2,4-diamino derivative is carried out by reduction with a hydride reagent such as LIAH4 or by catalytic hydrogenation with a catalyst such as Pd (O) or Raney-Ni to give the central structure I (Scheme 2 ). The introduction of the groups X 1 = X 2 is carried out by conventional condensation reactions, as is well known in the art. Compound I in which R 12 is NH-A may be prepared from diepoxide 10 by reaction with NaN 3 in DMF to give the resulting dihydroxy terminal diazide which is converted to the corresponding tetraazide, with inversion of the configuration in the alcohol carbons as described above and subsequently in the corresponding tetraamine. After the selective reaction of terminal amines with A groups or protecting groups, 72 876 SB CASE 14515

-13-

SC

such as Boc or Cbz, there follows the introduction of X 1 = X 2 groups. In a similar manner, R 1 = R 2 groups may be introduced into compounds I in which R 1 is N (R 10) 2, NR 15 R 16, R 5 - (R 6 R 7 C) m R 5 - (R 6 R 7 C) m S (O) n -, for reaction of the diepoxide 10 with the appropriate oxygen, nitrogen or thiol nucleophile with subsequent oxidation of the thiol as required. The reaction of the diepoxide 10 with the appropriate phosphorus nucleophile in a Arbuzov or Michaelis-Arbuzov reaction allows the introduction of R1 = R2 groups which are (r13o) P (o) (or14) - or r13p (O) (or14 -.

Alternatively, the compounds represented by I may be prepared from protected alpha-aminoaldehydes, P 2 NHCH- (R 3 -CH 2 O). The required N-protected alpha-amino aldehydes are readily preparable from the N-protected alpha amino acids, respective , by reduction of the corresponding esters with diisobutylaluminum hydride, by reduction of the N-methyl-N-methoxyamides derived, P 2 NHC (R 2) CONMe - (Ome), with LiAlH 4 (Fehrentz and Castro, Synthesis 676 (1983)) or by reduction of the protected N alpha amino alcohol followed by oxidation with DMSO- (COCl) 2 or SO 3 -pyridine (Revision: Jurczak and Go-lebiowski, Chem Rev. 89, 149 ), The amino protecting group, P2, is t-Boc-, Cbz-, p-toluenesulfonyl or other conventional protecting group chosen as is well known in the art of the peptides. Synthesis of I proceeds by the preparation of an intermediate, P2 NH (R1) CH (OH) CH (R2) COQ, by aldopa condensation with a deri acyl alcohol, R2CH2CO2, under conditions of Evans et al. (Evans, Ennis, and Mathre, J. Am. Chem. Soc., 104, 1737-39 (1982)), Evans, Nelson and Taber, in Topics in Stereochemistry, Vol. 13, Allinger, Eliel, Wilen, eds Wiley 1982, pp 1-114), where Q is a chiral auxiliary used to direct the stereochemical result of the aldol reaction and is often the oxazolidinone derivative of valinol, norephedrine or phenylalanol. By protecting the hydroxyl with a P 1 protecting group such as TBDMS or benzyl, and subsequent hydrolytic removal of the Q group, there is obtained the intermediate P 2 NH (R 1) CH (O P 1) CH (R 2) CO 2 H, which is subjected to Curtius rearrangement ( Revision: Banthorpe, Patai, " The Chemistry of the Azido Group, " pp. 397-405, Interscience Pu-blishers, NY, 1971; Smith, Req., 3, 337-449 (1946)) for The compound P2NH (R1) CH (OP1) CH (R2) NH2 which is a non-symmetrically protected form of I. This pathway is versatile in that it allows access to all stereoisomers of compounds I and to non-symmetric compounds I, in which R1 and R2 are different and X1 and X2 are different. The synthesis of the compounds represented by formula II is carried out by the oxidation of the central hydroxyl group to the corresponding compounds I as is well known in the art. Useful oxidation reagents include, but are not limited to, Jones reagent, (C0Cl) 2 " DMSO / pyridinium dichromate and pyridinium chlorochromate.

By the procedures shown in Schemes 1-2, any enantiomer of the compounds with structures I and II can be prepared from the respective arabitol enantiomer.

Scheme 1 Synthesis of I

(+) - Amino Acid

1) p-TsCl

2) NaH, DMF 3) Bn-Br

BnO

Bn * benzyl

1) NaN3. DMF 2) MsCl, Et 3 N 3) LiAlH 4 4) CbZ-CI

Cbz-N

(CH2) m R3,

X1 NH NH2

X1HN f R2 OBn NHX2

HO I 72 876 SB CASE 14515

-15-

Esauma 2 Synthesis of I

(1) MSCI, Et3 N o ..- > (BnO 2) NaN3 1 DMF BnO ------- 3) B1 = benzyl R 1 R 1 R 1 R 2 X 1 HN 2 OCH 2 O

HO

I

Thus, in a further aspect thereof, the present invention relates to a process for the preparation of a compound of the formula:

RÍVR " 'N

NR " 'Riv OR " in which R 'is 1) a) NH-A wherein A, R 5 -R 10 and m are as defined for formula I; b) R 5 - (R 6 R 7 C) m -; c) R5- (R6R7C) mV-, where V is 0 or NH, except that R5, R6 and R7 are not hydroxyl, chloro or fluoro, if they are adjacent to V, d) R5- (R6R7C) m -S-. where m = 1-3 and R5, R6 and R7 are as previously defined, except that R5, R6 and R7 are not hydroxyl, chlorine or fluorine, if they are adjacent to the sulfur, e) R8 -S-, f) (OR 14) -, where R 13 and R 14 are independently: i) C 1 -C 8 alkyl, 72 876 SB CASE 14515

(Ii) C3-C6 cycloalkyl, iii) H, iv) R9, or v) R8, h) R13P (O) (OR14) -, i) N (R10) 2f j) NR15R16, where R15 and R16 are joined to form a 4-6 membered saturated nitrogen heterocycle including: i) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, k) R17 OCH2 O, wherein R17 is i) C1-6 alkyl, ) R9, or iii) CH2 Ar, wherein Ar is phenyl, naphthyl or a 5-7 membered heterocyclic, 1) R17 OCH2 CH2 OCH2, m) N-imidazolyl, wherein the imidazole ring is unsubstituted or substituted with a substituent R4, n ) N-benzimidazolyl. wherein the condensed benzene ring is unsubstituted or substituted with one or more R4 substituents, (o) C2 -C6 alkynyl, optionally substituted with one or more R9 groups; or p) C2-C6 alkenyl, optionally substituted with one or more R9 groups; 2) hydrogen, 3) C1-6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C3-C7 cycloalkyl, and R " is a hydroxyl protecting group and R H and R 2 are hydrogen, an amino-protecting group or, together, N 2, which comprises 1) reacting a compound of formula: 87 876 SB CASE 14515

(1 → 0)

RO with a compound R'-Z, where Z is a moiety which renders R 'nucleophilic and R " is a hydroxyl protecting group, 2) converting the resulting hydroxyl groups into leaving groups, 3) reacting the leaving groups with a nitrogen nucleophile.

The hydroxyl protecting groups are those groups which are commonly used in the art to mask the reactivity of the hydroxyl group, but which, however, are also capable of being selectively removed to regenerate the hydroxyl group. Typically, the oxygen-hydrogen bond is replaced by an oxygen-carbon bond. In Greene, T.W., Protective Groups in Oraanic Synthesis. John Wiley & Sons, New York (1981) discloses useful hydroxyl protecting groups, although many others are known in the art. Substituted or unsubstituted arylmethyl ethers are a class of groups particularly useful for protecting the hydroxyl group. The benzyl protecting group, optionally having substituent groups on the aryl ring, is useful.

Typically, Z is hydrogen, an alkali metal such as Li, Na or K, an alkaline earth metal, such as magnesium, or a transition metal, such as copper, aluminum, titanium, zinc or cadmium, or a species thereof derivative. Representative R'-Z compounds include optionally substituted alkyl-, aryl- or heteroaryl-lithium, alkyl-, aryl- or heteroarylmagnesium halides (eg, Grignard reagents), dialkyl lithium cuprate, diaryl lithium cuprate, or the alkali metal salts of optionally substituted allyl alcohols, phenols or benzyl alcohols. Diphenyl lithium cuprate is especially useful.

Hydroxyls are converted to suitable leaving groups such as mesylate, tosylate, brosylate, benzoate, acetate and halide by processes common in the art. The tosyl group is es-

It is particularly suitable and is formed by reacting the hydroxyl groups with, for example, tosyl chloride.

Suitable nitrogen nucleophiles are those which are capable of reacting with a leaving group. Unhindered amines or heterocycles, amine metal salts, heterocycles or azide are useful. Generally, a nitrogen-containing group of the formula r '-vn-z, where Z is as defined above and R " and R'v are hydrogen, an amino protecting group or, together, N2 (P * e., azido). Preferred is a metal azide, such as sodium or potassium azide. Subsequent reduction of the azido groups yields the amino groups.

The particularly useful intermediates of the invention are:

where R # and R " are defined as before.

The compounds of the present invention are prepared by the Merrifield solid phase technique (J. Am. Chem. Soc., 85, 2149 (1964), or preferably by solution processes known in the art. synthesis in solution and in solid phase, such as in a convergent synthesis in which di-, tri- or tetra-peptide fragments can be prepared by solid phase synthesis, and are either coupled or further modified by synthesis in solution. The peptide synthesis processes are generally described in JM Stewart and JD Young, " Solid Phase Peptide Synthesis ". Pierce Chemical Company, Rockford, II (1984) or M. Bodonsky, YA Klauser and Μ (1977), or "The Peptides " Gross and Meienhoffer, eds., Acad., Press, 1979, Volts I-III, to produce the peptides of the invention and such processes are incorporated herein by reference. B CASE 14515 -19-

Each amino acid or peptide is suitably protected, as is known in the art of peptides. For example, the Boc- or carbobenzyloxy group is preferred for protecting the amino group, especially in the α-position. A suitable benzyl or benzyl substituted group is used to protect the mercapto group from cysteine or other thiol-containing amino acids; or the hydroxyl of the serine or threonine. Tosyl or the nitro group may be used for the protection of the guanidine of Arg or the imidazole of His, and a suitably substituted carbobenzyloxy or benzyl group may be used for the hydroxyl group of Tyr, Ser or Thr, or for the ε-amino group of the lysine. Suitable substitution of the carbobenzyloxy and benzyl protecting groups is an ortho and / or chloro, bromo, nitro or methyl substitution, and is used to modify the reactivity of the protecting group. Cysteine and other sulfur containing amino acids may also be protected by the formation of a disulfide having a thioalkyl or thioaryl group. With the exception of the Boc group, the protecting groups are most conveniently those which are not removed by moderate acid treatment. These protecting groups are removed by methods such as catalytic hydrogenation or treatment with sodium in liquid ammonia or with HF, as is well known in the art.

If solid phase processes are used, the peptide is constructed sequentially from the carboxy terminus towards the amino terminus of the peptide. Solid-phase synthesis is initiated by covalently linking the C-terminus of a protected amino acid to a suitable resin, such as benzhydrylamine (BHA) resin, methylbenzhydrylamine (MBHA) resin or chloromethyl resin (CMR), such as generally describes in U.S. Patent 4,244,946. BHA or MBHA support resins are used if the carboxyl terminus of the product peptide is intended to be a carboxamide. Generally, a CMR support is used if the carboxyl terminus of the peptide produced is intended to be a carboxyl group, although this resin may also be used to produce a carboxamide or an ester. Modification of the terminal amino group of the peptide is accomplished by alkylation or acetylation, as is generally known in the ar-72-CAS 72456 CAS. Such modifications may be made to the amino acid prior to incorporation into the peptide or peptide after it has been synthesized and the terminal amino group has been released but prior to removal of the protecting groups.

Typically, the acetylation is carried out on the free amino group using an acyl halide, anhydride or activated ester, of the corresponding α-alkyl acid, in the presence of a tertiary amine. The monoalkylation is most conveniently accomplished by reductive alkylation of the amino group with an appropriate aliphatic aldehyde or ketone in the presence of a moderate reducing agent such as lithium or sodium cyanoborohydride. Dialkylation as well as quaternization can be carried out by treatment of the amino group with an excess of an alkyl halide in the presence of a base. The synthesis of peptides in solution is performed using standard procedures to form amide bonds. Typically, a Boc-protected amino acid having a free carboxyl group is coupled to a protected amino acid having a free amino group using a suitable carbodiimide coupling agent such as N, N-dicyclohexylcarbodiimide (DCC ), optionally in the presence of catalysts, such as 1-hydroxybenzotriazole (HOBT) and dimethylaminopyridine (DMAP). Other processes, such as the formation of activated acid esters, anhydrides and acid halides, of the free carboxyl of a Boc-protected amino acid, and subsequent reaction with the free amine of a protected amino acid, optionally in the presence of a base . For example, a Boc-protected amino acid or peptide is treated in an anhydrous solvent such as dichloromethane or tetrahydrofuran (THF) in the presence of a base such as N-methylmorpholine or a trialkylamine 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 prepared by these methods may be selectively deprotected, using conventional techniques, at the amino or carboxyl terminus, and coupled to other peptides or amino acids using similar techniques. After the peptide is complete, the protecting groups may be removed, as hereinbefore described, for example, by hydrogenation in the presence of a palladium or platinum catalyst, or by treatment with sodium in ammonia liquid, hydrofluoric acid, trifluoroacetic acid or an alkali metal base.

Often, the esters are used to protect the terminal carboxyl group of peptides in the solution synthesis. These 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 in the other esters may be converted via an activated acyl intermediate as described above.

The substituted amides and amides of the invention are prepared from carboxylic acids of the peptides in a similar manner. Thus, ammonia or an amine substituted with an activated acyl intermediate of an α-amino acid or a protected amino group oligopeptide can be reacted to produce the amide. It is convenient to use coupling agents, such as DCC, to form amides substituted from the carboxylic acid itself and a suitable amine.

In addition, the methyl esters of the invention may be converted to the amides or substituted amides either directly by treatment with ammonia or with a substituted amine in methanol solution. A methanolic solution of the methyl ester of the peptide is saturated with ammonia and stirred in a pressurized reactor to provide the simple carboxamide of the peptides.

Methods for determination of inhibition constant (Ki) are described in the art by Dixon analysis, e.g. in Dreyer, et al. Proc. Natl. Acad. Know. U.S.A. 86, 9752-9756 (1989). A peptidolytic assay using the substrate Ac-Arg-Ala-Ser-Gln-Asn-Tyr-Pro-Val-Val-NH 2 and recombinant HIV protease is used, as described in Stricker, et al., Proteins. 6, 134-154 (1989). A smaller Ki value indicates a higher affinity of

72 876 SB CASE 14515 connection.

Pharmaceutical compositions of the compounds of the invention, or derivatives thereof, may be formulated as solutions or post-opticized powders for parenteral administration. The powders may be reconstituted, prior to use, by addition of a suitable diluent or other pharmaceutically acceptable carrier. The liquid formulation is generally an aqueous, isotonic, buffered solution. Examples of suitable diluents include normal isotonic saline, dextrose, 5% standard in water or buffered sodium or ammonium acetate solution. This formulation is especially suitable for parenteral administration, but may also be used for oral administration or may be contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxycellulose, gum arabic, polyethylene glycol, mannitol, sodium chloride or sodium citrate.

A preferred composition for parenteral administration may additionally contain an amount of compound encapsulated in a liposomal carrier. The liposome can be prepared by dispersing the compounds in an aqueous phase with phospholipids, with or without cholesterol, using a variety of techniques, including conventional manual agitation, high pressure extrusion, reverse phase evaporation and microfluidization. A suitable method for preparing such compositions is described in more detail in co-pending application Ser. 06/763484 which is hereby incorporated by reference. Such a carrier may be optionally directed to its site of action by an immunoglobulin or a reactive protein, the viral particle or the infected cells. Of course, the choice of these proteins will be dependent on the antigenic determinants of the infecting virus. An example of such a protein is the T cell glycoprotein, CD-4, or a derivative thereof, such as sCD-4 (soluble CD-4), which is reactive with the human immunodeficiency virus glycoprotein layer ). These proteins are described in copending U.S. Pat. 07/160463 which is hereby incorporated by reference. Similar bleeding proteins may be designed by known methods. In the art, for other viruses and these are also contemplated within the scope of the invention.

Alternatively, these compounds may be encapsulated, prepared in tablet form or in the form of an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to improve or stabilize the composition, or to facilitate the preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline and water. Solid carriers include starch, lactose, calcium sulfate dihydrate, kaolin, magnesium stearate or stearic acid, talc, pectin, gum arabic, agar or gelatin. The carrier may also include a delayed release material, such as glycerol monostearate or glycerol distearate, alone or together with a wax. The amount of solid carrier will vary, but will preferably be from about 20 mg to about 1 g per dosage unit. The pharmaceutical compositions are prepared following conventional pharmacy techniques involving grinding, blending, granulation and pressing, as required, for tablet forms; or grinding, blending and filling, for hard gelatin capsule forms. When using a liquid carrier, the composition will be in the form of an aqueous or non-aqueous syrup, elixir, emulsion or suspension. Such a liquid formulation may be administered directly p.o. or it may be used for filling a soft gelatin capsule.

For rectal administration, a powdered powder of the compounds of the invention may be combined with an excipient, such as cocoa butter, glycerin, gelatin or polyethylene glycols, and molded into a suppository. Powdered powders may also be prepared with an ointment, gel, ointment or emulsion, buffered or unbuffered, and administered through a transdermal patch.

Also disclosed in the present invention is a method for the treatment of viral infections, particularly of retrovirus infections, which comprises administering a compound of formula I to a patient infected with a virus susceptible. The method is particularly applicable to human immunodeficiency virus type 1 infection. When the compounds of the invention are used to induce antiviral activity in patients who are infected with susceptible viruses and requiring such treatment, the method of treatment comprises orally, parenterally, buccally, transdermally, intravenously, intramuscularly, rectally or by insufflation, of an effective amount of the chosen compound, preferably dispersed in a pharmaceutical carrier. Dosage units of the active ingredient are selected in the range of 0.05 to 50 mg / kg body weight. Typically, the dosage units will be from 50 to 1000 mg. For acute or chronic infection, these dosage units may be administered from one to ten times a day. 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 is herein included, as described in European Patent Application Ser. 337714, on pages 42-47.

The following Examples serve to illustrate the present invention. The Examples are not intended to limit the scope of the invention in any way and are presented only to show how to prepare and use the compounds of the invention.

In the Examples all temperatures are in degrees Celsius. Amino acid analyzes were performed on a Dionex Autoion 100. Peptide content analysis is based on amino acid analysis. FAB mass spectra were run on a Vab Aab mass spectrometer using fast atom bombardment. NMR spectra were recorded at 250 MHz using a Bruker Am 250 Spectrotron. The indicated multiplicities are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br denotes a broad signal.

Purification of recombinant HIV protease

In Debouck, et al., Proc. Natl. Acad. Know. USA, 84, 8903-6 (1987) disclosed methods for expressing HIV protease

72 876 SB CASE 14515 recombinant in E. coli. The enzyme used to test the compounds of the invention was thus produced and purified from the cell pellet, as previously described by Stickler et al. Proteins. 6, 139-154 (1989).

EXAMPLES

Example 1

Preparation of (3S, 5S) -3,5-diamino-4-hydroxyheptane Preparation by the procedure of Scheme 1: a) 1.2: 4,5-dianhydro-D - (+) - arabitol 9

Benzyl trichloroacetimidate (29.1 mL, 201 mmol) was added to a solution of D- (+) - arabitol (13.9 g, 91.4 mmol, azeotropically dried with toluene) in dry acetonitrile (200 mL), under Ar, and the mixture was stirred overnight. The solution was concentrated by rotary evaporation, dissolved in ethyl acetate (500 ml), washed with 5% NaHCO 3 solution (2 x 30 ml) and brine (30 ml), dried over Na 2 SO 4 and concentrated . The residue was dissolved in dry THF (500 mL) and cooled to -10 ° C, and solid sodium methylate (11.1 g, 205 mmol) was added with mechanical stirring under Ar. After 20 minutes, the mixture was partitioned between ether (2.5 L), filtered through glass fiber filter paper to remove sodium methylate, and concentrated by rotary evaporation at 30 ° C. The residue was purified by flash chromatography " flash " (silica gel, ether: pentane 3: 2) to give the title compound 9. (3.96 g, 34.1 mmol, 37% yield). b) 1.2: 4,5-dianhydro-3- (O-benzyl) -D- (+) - arabitol 10

Benzyl bromide (8.92 mL, 75 mmol) was added to a suspension of NaH (1.8 g, 75 mmol) in THF (9 mL). The mixture was cooled to -10 ° C under Ar, and compound 9 (3.90 g, 34 mmol) in THF (9 mL) was added dropwise with stirring. The ice bath was removed and the mixture allowed to warm rapidly to 40 ° C and cooled again. The mixture was diluted with 1% acetic acid (100 mL) and extracted with ethyl acetate (2 x 250 mL). The organic extracts were washed with 5% NaHCO 3 solution (75 mL) and brine (75 mL), dried over Na 2 SO 4 and concentrated. By " flash chromatography " of the residue (gradient, 0-4% of 72 876 SB acetate CASE 14515

-26-ethyl pentane) the title compound 10 (3.88 g, 17.2 mmol, 55% yield) was obtained. 1 H-NMR (CDCl 3): δ 7.4-7.1 (5H, m), 4.75 (1H, d, J = 12Hz), 4.65 (1H, d, J = (2H, m), 2.65 (2H, m), 2.85 (2H, m). To 1,65 g (8.0 mmol) of compound 10 in 50 ml of water and 50 ml of dioxane was added sodium bicarbonate (50 ml) and sodium bicarbonate 6.5 g (100 mmol) of NaN 3 and 340 mg (1 mmol) of tetra-n-butylammonium bisulfate were added. The reaction mixture was refluxed for 4 h, cooled and concentrated to ca. 50 ml by rotary evaporation and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (Na 2 SO 4) and concentrated to an oil, which was combined with ether: hexane (1: 1) and allowed to crystallize at 4øC, yielding 1.76 g of the desired product. title compound 11 (69% yield). NMR (CDCl 3): δ 7.5-7.3 (5H, m), 4.6 (2H, dd, J = 12Hz), 4.0 (2H, m) Δ (6H, m). d) (2S, 4S) -1,5-diazido-2,4-di- (methanesulfonyloxy) -3-benzyloxypenanthane To 630 mg (2.15 mmol) bis-azido diol 11 in 6.0 ml of pyridine was added 350 μΐ (4.5 mmol) of methanesulfonyl chloride at 0 ° C. The reaction mixture was allowed to warm to 25 ° C and stirred for 20 h, then diluted with 6 N HCl (12 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with 3% NaHC0 3 solution, dried (Na 2 SO 4) and concentrated. By " flash chromatography " of the residue (95: 5 CH 2 Cl 2: ether) afforded 867 mg (90% yield) of the title compound 12. 1 H NMR (CDCl 3): δ 7.4-7.2 (5H, m) , 5.0-4.7 (4H, m), 4.02 (2H dd, J = 3Hz), 3.9-3.5 (4H, m), 3.15 (3H, s), 3.10 (3H, s). (310 mg, 0.69 mmole) of compound 12 from step (d) in 2 ml of dry THF , at 0øC, 1.5 ml (1.5 mmol) of 1M LiAlH 4 in THF was added. The mixture was allowed to warm to 25 ° C and stirred overnight. Water (0.1 ml) was added, followed by 0.1 ml of 15% NaOH solution and 0.4 ml of water. The mixture was stirred,

vigorously, with 10 ml of ether and filtered. Concentration of the ether phase gave the crude bis-aziridine which was dissolved in 5 ml of CH 2 Cl 2 and combined with 200 μ (1.4 mmol) of triethylamine and 200 μl (1.4 mmol) of benzyl. The mixture was stirred at 25 ° C for 3 h, and then filtered. The filtrate was concentrated and the residue was purified by flash chromatography " (ethyl acetate: hexanes 1: 5) to give 89 mg (28% yield) of the title compound 13. 1 H NMR (400 MHz, CDCl3): δ 7.4-7.2 (15H, m) J = 12Hz), 4.88 (1H, d, J = 12Hz), 4.84 (1H, d, J = J = 12 Hz), 4.82 (1H, t, J = 6 Hz), 2.39 (1H, d, J = (1H, m), 2.25 (1H, m), 2.25 (1H, d, J = 6Hz), 2.15 (1H, d, J = 6Hz) , d; J = 3Hz), 2.02 (1H, d, J = 3Hz). MS (DCI, NH 3): m / z 473.1 (M +). f) (3A.5S) -3,5-di- (carbobenzyloxyamino) -4-benzyloxyheptane To a suspension of Cul (72 mg, 0.375 mmol) in 1.5 mL of ether at -25 ° C 0.5 ml of 1.5 M choline in ether. The resulting colorless solution was cooled to -45 ° C and a solution of bis-aziridine 13 (10 mg, 0.02 mmol) in 0.5 ml ether was added. After stirring at -45 ° C for 1 h, the mixture was allowed to warm to 10 ° C over a period of 6 h and then stirred for a further 2 h. The mixture was diluted with 2 ml of saturated aqueous NH 4 Cl and 1 ml of saturated aqueous NH 3, and then extracted with ether. The organic layer was washed with brine, dried (Na 2 SO 4) and concentrated to give the title compound 14 (10 mg). NMR (CDCl 3): δ 7.2 (15H, m), 5.2-4.9 (4H, m), 4.93 (1H, d, J = 12Hz), 4.88 (1H, J = 12 Hz), 4.84 (1H, d, J = 12Hz), 4.7 (2H, d, J = 12Hz), 4.4 (2H, d, J = 12Hz), 3.7 (2H, m), 3.4 (1H, d, J = 2Hz), 1.6 (4H, m), 1.0 (3H, t, J = 7Hz), 0.9 (3H, t, J = 7Hz). g) (3S, 5S) -3,5-diamino-4-hydroxy-hentane 1

The product from step (f) is stirred with 20% Pd (OH) 2 on carbon (50% by weight) in 0.1N HCl methanolic solution under hydrogen atmosphere for 24 h. Filtration and removal of the solvents affords the title compound 1 as the dihydrochloride salt in which X 1 and X 2 are hydrogen and R 1 and R 2 are ethyl,

it

Preparation to Scheme 2 a) (3R, 5R) -3,5-Dihydroxy-4-benzyloxy-heptane To a suspension of Cul (143 mg, 0.75 mmol) in 3 ml of ether, 35 ° C was added methyl lithium (1 ml, 1.5M in ether, 1.5 mmol). The resulting colorless solution was stirred at -30 ° C for 30 minutes and then cooled to -78 ° C. A solution of bis epoxide 10 (78 mg, 0.37 mmol) in 2 ml of ether was added. The reaction mixture was allowed to warm to 25 ° C for 4 h, and saturated aqueous NH 4 Cl and concentrated aqueous NH 3 solution were added. The mixture was extracted with ether, the organic phase was dried over Na2 SO4 and the solvent was removed to give the title compound (93 mg, 100% yield). NMR (CDCl 3): δ 7.4-7.1 (5H, m), 4.7 (1H, d, J = 12Hz), 4.55 (1H, d, J = (2H, m), 3.2 (1H, dd), 2.5 (2H, b), 1.6-1.4 (4H, m), 1.0 (3H, t) J = 7Hz), 0.9 (3H, t, J = 7Hz). b) (3R, 5R) -3,5-methanesulfonyloxy-4-benzyloxy-heptane

Methanesulfonyl chloride (0.3 ml) was added dropwise to the diol 15 (93 mg) in pyridine (1 ml) at 0 ° C. The mixture was allowed to warm to 25 ° C. After 12 hours, the mixture was diluted with cold 6N HCl (10 ml) and extracted with CH 2 Cl 2. The organic extract was washed with 3% NaHC03 solution, dried over MgSO4 and concentrated. The residue was purified by flash chromatography to give the title compound (83 mg, 56% yield). NMR (CDCl3): δ 7.4-7.2 (5H, m), 4.75 (1H, m), 4.7 (1H, d, J = 12Hz), 4.6 (1H, d, J = 12Hz), 4.58 (1H, m), 3.9 (1H, dd, J = 2.6Hz), 3.0 (3H, s), 2.9 (3H, s) , 2.1-1.5 (4H, m), 1.05 (3H, t; J = 7Hz), 1.0 (3H, t, J = 7Hz). c) (3S, 5S) -3,5-diazido-4-benzyloxy-heptane

A mixture of bismesylate 16 (83 mg, 0.21 mmol) and sodium azide (0.5 g, 7.7 mmol) in 1.5 mL of dimethylformamide was heated at 70 ° C for 12 h. After cooling, ethyl acetate (20 ml) was added, the mixture was filtered and concentrated. By " flash chromatography " of the residue gave the title compound (54 mg, 90% yield). 1 H-NMR (CDCl3): δ 7.4-7.2 (5H, m), 4.65 72 876 SB CASE 14515

(2H, s), 3.5-3.2 (3H, m), 2.0-1.5 (4H, m), 1.1 (3H, t, J = 6Hz), , Δ (3H, t, J = 6Hz). d) (3S, 5S) -3,5-diamino-4-benzyloxyheptane To 328 mg (1.14 mmol) of bis-azide 17 in 5 ml of THF at 0 ° C was added 200 mg of LiAlH 4. The mixture was allowed to warm to 25 ° C and stirred for 5 h. The reaction was quenched by the addition of 0.5 ml of 15% NaOH solution, stirred for 15 minutes, diluted with ether (150 ml) and filtered. Concentration of the filtrate gave the title compound (278 mg, 100% yield). 1 H-NMR (CDCl 3): δ 7.26 (5H, m), 4.5 (2H, dd, J = 12Hz), 3.1 (1H, dd, J = 4.6Hz), 2.9 (1H, m), 2.75 (1H, m), 1.8-1.0 (10H, m), 0.9 (3H, t, J = 7Hz), 0.85 (3H, t; J = Hz). e) (3S, 5S) -3- (5-Diamino-4-hydroxyheptane 1

To the product diamine 18 (52 mg) in 4 ml of methanol was added 50 mg of 20% Pd (OH) 2 on carbon and 2 drops of concentrated aqueous HCl. The mixture was stirred under H2 atmosphere for 16 h, then filtered and concentrated to give the title compound 1 (53 mg) as the dihydrochloride salt.  € ƒâ € ƒâ € ƒ1 H-NMR (CD3 OD): Î'3.75 (1H, dd, J = 4.7Hz), 3.2-3.0 (2H, m), 1.8-1.4 (4H, m), 0.9 (6H, t; J = 7Hz).

Example 2

Preparation of (3S, 5S) -3,5-di (alanylalanyl) amino-4-hydroxyhepta-2a) (3S, 5S) -3,5-di- (carbobenzyloxyalanylalanyl) amino-4-benzyloxyheptane 19

To the product diamine 18 from Example 1, step k (87 mg, 0.37 mmol) in 6 ml of DMF was added 221 mg (0.75 mmol) of car-bobenzyloxyalanylalanine, 115 mg (0.75 mmol) HBOT and 154 mg (0.75 mmol) of DCC. The mixture was stirred overnight, then concentrated, taken up in ethyl acetate, filtered, washed with water and brine and dried (MgSO4). Removal of the solvent followed by MPLC (silica; 2% methanol in CH 2 Cl 2) provided the title compound (109 mg). NMR (DMSOd 6): δ 8.0-7.2 (21H, m), 5.0 (4H, bs), 4.6 (2H, dd, J = 12Hz), 4.2 ( 2H), 4.0 (2H, m), 3.8 (1H, m), 3.7 (1H, m), 3.5 (1H, dd, J = 7 - 1.3 (4H, m), 1.1 (12H, m), 0.75 (6H, t).

72 876 SB CASE 14515 b) (3S, 5S) -3,5-di (alanylalanyl) amino-4-hydroxyheptane 2

To the product 19 from step (a) (4.5 mg) in 1 ml of DMF was added 10 mg of 20% Pd (OH) 2 on carbon. The mixture was stirred under an atmosphere of H 2 for 6 h and then filtered and concentrated to afford the title compound 2 (3 mg) in which X 1 and X 2 are AlaAla and R 1 and R 2 are ethyl. NMR (CD3 OD): δ 4.3 (2H, m), 3.8 (2H, m), 3.7 (1H, m), 3.5 (1H, m) 2 (16H, m), 0.8 (6H, dt).

Example 3

Preparation of (3S, 5S) -3,5-di- (carbobenzyloxyvalyl) amino-4-hydroxyhetoxane To 133 mg (0.5 mmol) of Cbz-Val in 2 ml of THF at -40 ° C, 65 μΐ (0.5 mmol) of isobutyl chloroformate was added. After stirring for 10 minutes, a solution of 25 mg (0.17 mmol) of diamine hydrochloride 1 and 50 μM NMM in 1 ml of DMF was added. The mixture was slowly warmed to 20 ° C and stirred overnight, then diluted with ethyl acetate, washed with 5% HCl, 5% NaHCO 3 solution, and brine, and the organic layer was concentrated. The residue was purified by chromatography " flash " (ethyl acetate: hexanes) to give the title compound 3 (18 mg) in which X1 and X2 are Cbz-Val and R1 and R2 are ethyl. 1 H-NMR (CDCl 3): δ 7.5-7.3 (10H, m), 6.9 (1H, br d), 6.35 (1H, br d), 5.5 (H, br d) , 5.25 (1H, br d), 5.1 (4H, br s), 4.0-3.1 (6H, m), 2.4-2.1 (2H, m), 2.0 -1.4 (4H, m), 1.0-0.8 (18H, m). MS (FAB): m / z 613.2 (M + H) +.

Example 4

Preparation of (2S, 4S) -2,4-di- (alanylalanyl) amino-3-hydroxy-1,5-diphenylenane 4 (a) (2R, 4R) -2,4-dihydroxy-3-benzyloxy- diphenylpentane To a suspension of cyclo (191 mg, 1 mmol) in ether (5 mL) at -60 ° C was added phenyl lithium (4.0 mL, 2.0 mmol, 0.5 M in ether , freshly prepared from bromobenzene and lithium wire) The mixture was warmed to -50 ° C and then cooled again to -78 ° C. A solution of bis-epoxide 10 40 mg, 0.19 mmol) was dissolved in ether (1 ml) .The mixture was allowed to warm to -25 ° C for 6 h with stirring. After a further 12 h, 31-

with ether and washed with 20 ml of a 1: 1 mixture of concentrated aqueous ammonia solution: saturated NH 4 Cl solution. The organic phase was dried over MgSO4 and concentrated. The residue was purified by medium pressure liquid chromatography (1: 4 ethyl acetate: hexanes) to give the title compound 20 (22 mg, 30% yield) as a colorless solid. 1 H-NMR (CDCl 3): δ 7.5-7.0 (15H, m), 4.75 (1H, d, J = 12Hz), 4.55 (1H, d, J = , 2 (2H, m), 3.3 (1H, m), 3.0-2.7 (6H, m). b) (2S.4S) -2,4-di- (alanylalanyl) amino-3-hydroxy-1,5-diphenylpenta-4 The title compound 4, wherein X1 and X2 are AlaAla and R1 and R2 are PhCH2 is prepared from compound 20 by the procedures of Example 2.

Example 5

Preparation of (4R, 6R) -4,6-diamino-5-hydroxy-2,8-dimethyl-1,8-nona-no 5a) (4R, 6R) -4,6-dihydroxy-5-benzyloxy-2- (192 mg, 1.0 mmol) in ether (2 mL) at -60 ° C was added isopropenyl lithium (5.2 mL, 2.0 mmol; 0.38M in ether, freshly prepared from 2-bromopropene and lithium wire). The mixture was warmed to -45 ° C and then refluxed to -78 ° C. A solution of bis-epoxide 10 (60 mg, 0.29 mmol) in ether (5 mL) was added. The mixture was allowed to warm to 0 ° C for 2 h with stirring. The mixture was diluted with ether and washed with 5 ml of a 1: 1 mixture of concentrated aqueous ammonia: saturated NH 4 Cl solution. The organic phase was dried over MgSO4 and concentrated to give the title compound 21 (81 mg, 96% yield) as a colorless solid. NMR (CDCl3): δ 7.3 (5H, m), 4.9 (1H, bs), 4.85 (1H, bs), 4.80 (1H, bs), 4.65 (1H, d, J = 12 Hz), 4.0 (2H, m), 3.3 (1H, dd, J = 2.5 Hz), 2.55 (1H, d, J = 6Hz), 2.55 (1H, d, J = 4Hz), 2.5-2.1 (4H, m), 1.7 (1H, s). b) (4R, 6R) -4,6-dihydroxy-5-benzyloxy-2,8-dimethylnonane

To product 21 from step (a) (105 mg, 0.38 mmol) in CH2 Cl2 72 876 SB CASE 14515

(1 ml) was added Ir (COD) Py (PCy) 3 PF6 (Crabtree's catalyst). The mixture was stirred for 6 h under an H2 atmosphere, then filtered and concentrated to give the title compound 22 (110 mg, 100% yield). NMR (CDCl 3): δ 7.3 (5H, m), 4.6 (1H, dd, J = 12Hz), 4.0 (2H, m), 3.1 (1H, br s), 2.7 (2H, br s), 2.0-1.1 (6H, m), 1.0-0.8 (12H, m). c) (4R, 6R) -4,6-di- (methanesulphonyloxy) -5-benzyloxy-2,8-dimethylno-nano

Methanesulfonyl chloride (0.25 ml) was added dropwise to the diol 22 (93 mg) in pyridine (1 ml) at 0 ° C. The mixture was allowed to warm to 25 ° C. After 10 h the mixture was diluted with cold 6 N HCl (10 ml) and extracted with CH 2 Cl 2. The organic extract was washed with 3% NaHC03 solution, dried over MgSO4 and concentrated. The residue was purified by " flash " yielding the title compound 23 (210mg). NMR (CDCl 3): δ 7.4 (5H, m), 5.0 (1H, d, J = 12Hz), 4.7 (1H, m), 4.6 (1H, d, J = 3.0 (3H, s), 2.0 (3H, s), 2.0-1.1 (6H, m), 3.0 (3H, s) 1.0-0.9 (12H, m). d) (4R, 6R) -4,6-diazido-5-benzyloxy-2,8-dimethylnonane

To product 23 from step (c) (210 mg) in 2 ml of DMF was added 870 mg (15 mmol) of NaN3. The mixture was heated at 70 ° C for 7 h, then cooled and diluted with ethyl acetate. The filtrate was concentrated and the residue was purified by MPLC (ethyl acetate: hexane 1:20) to give the title compound 24 (52mg). 1 H-NMR (CDCl 3): δ 7.3 (5H, m), 4.55 (2H, dd, J 12 HZ), 3.4-3.15 (3H, m) 1 (6H, m), 1.0-0.75 (12H, m). e) (4S, 6S) -4,6-diamino-5-benzyloxy-2,8-dimethylnonane

To the product 24 from step (d) (52 mg, 0.15 mmol) in THF (3 mL) was added 80 mg of LiAlH 4 (2 mmol) at 0 ° C. The mixture was stirred at 25 ° C overnight, then quenched with 1N NaOH and diluted with ether (50 ml). Filtration and concentration gave the title compound 25 (44 mg) as a colorless oil. NMR (CDCl 3): δ 7.3 (5H, m), 4.6 (2H, dd, J = 12Hz), 3.1 (1H, m), 3.05-2.95 (2H, m), 1.9-1.1 (16H, m), 1.0-0.8 (12H, m).

72 876 SB CASE 14515 f) (4R, 6R) -4,6-diamino-5-hydroxy-2,8-dimethyl-1,8-nonane dihydrochloride To 165 mg of the diamine 25 from step (e) in 10 ml of methanol containing 5 drops of conc. 100 mg of 20% Pd (OH) 2 on carbon was added. The mixture was stirred overnight under H2 atmosphere, then filtered and concentrated to afford the title compound 5 (75 mg) in which X1 and X2 are hydrogen and R1 and R2 are isobutyl . NMR (CD3 OD): Î'3.7 (1H, m), 3.2 (1H, m), 1.8-1.0 (6H, m), 0.99-0.8 (12H, m) ).

Example 6

Preparation of (4R, 6R) -4- A) (4R, 6R) -4,6-di- (carbobenzyloxyalanylalanyl) amino-5-benzyloxy-2,8-dimethyl-6,8-dimethyl- 1,8-nonane

To the product 25 of Example 5, step (e) (44 mg, 0.15 mmol) in 2 ml of DMF was added 110 mg of Cbz-AlaAla (0.375 mmol), 58 mg (0.375 mmol) HOBT and 72 mg (0.375 mmol) DCC. The mixture was stirred for 48 h at 25 ° C, then diluted with 20 ml of ethyl acetate and filtered. The filtrate was concentrated and purified by MPLC (gradient, 0-5% methanol in CH 2 Cl 2) to give the title compound 26 (24 mg). NMR (CD3 OD): δ 8.0-7.2 (21H, m), 5.0 (4H, dd overlapping), 4.2 (2H, m), 4.0 (4H, m), 3 , Δ (1H, br s), 1.7-1.15 (18H, m), 0.9-0.7 (12H, br t). b) (4R, 6R) -4,6-di (alanylalanyl) amino-5-hydroxy-2,8-dimethyl-1,8-nonane 6

To product 26 from step (a) (12 mg) in 2 ml of DMF was added 50 mg of 20% Pd (OH) 2 on carbon. The mixture was stirred under an atmosphere of H2 for 10 h, then diluted with methanol, filtered and concentrated to give the title compound 6 (7.5 mg) in which X1 and X2 are AlaAla and R1 and R2 are isobutyl. NMR (CDCl3): δ 4.25 (2H, m), 3.8 (1H, m), 3.65 (2H, m), 3.1 (1H, br d) 1.1 (18H, m), 0.7 (12H, br d). 72 876 SB CASE 14515 Example 7 -34-

Preparation of (4R, 6R) -4,6-di- (carbobenzyloxy) amino-5-hydroxy-2,8-dimethyl-1,8-nonane To 6.0 mg of the product bis- 5 ml of CH2 Cl2 at 20 " was added 5 ml of triethylamine and 10 ml of benzyl chloroformate. After 3 h of stirring, the mixture was applied to a silica column and eluted with CH 2 Cl 2 / followed by ether to give the title compound 7 (4.6 mg) in which X 1 and X 2 are Cbz and R 1 and R2 are isobutyl. 1 H-NMR (CDCl 3): δ 7.3 (10H, bs), 5.1-4.9 (6H, m), 3.9-3.7 (2H, m), 3.5-3.35 (2H, m, 1H exchangeable with D2 O), 1.7-1.5 (4H, m), 1.3-1.2 (2H, m), 1.1-0.8 (12H, m).

Example 8

Preparation of (4R, 6R) -4,6-di- (carbobenzyloxivalyl) amino-5-hydroxy-2,8-dimethyl-1,8-nonane The title compound 8, wherein X1 * and X2 are Cbz-Val and R1 and R2 are isobutyl, was prepared by the procedure of Example 3 except that compound 5 was used in place of compound 1. 1 H-NMR (250 MHz, CDCl 3) 7.5-7.28 ( m), 6.8 (br s, 1H), 6.3 (br d, 1H), 5.6 (br s, 1H), 5.25 (br d, 1H), 5.1 (br s, 4H), 4.5-3.5 (m, 6H), 1.5-2.5 (m, 6H), 0.6-1.0 (m, 24H).

Example 9

Preparation of (2S, 4S) -1,5-diphenyl-3-hydroxy-2,4-bis-benzyloxycarbonylaminovalinylamino) pentane a) (2R, 4R) -1,2,3,5-Dianhydro-3-benzyloxyarabitol To a solution of 15.2 g (100 mole) of D (+) - arabitol in 350 ml of pyridine cooled in an ice bath was added 38.8 g (203.5 mmol) of p-toluenesulfonyl chloride in small portions , Stirred for 3 h, warmed to room temperature and added to 500 ml of ether.The ether phase was separated and the aqueous phase was extracted with 800 ml of ether.The organic phases were washed combined with 400 ml of 3% sodium bicarbonate solution, dried over anhydrous magnesium sulfate and the solvents removed in vacuo to give 34.17 g (74%) of the ditosylate 32. NMR (D, 4 H, J = 7 Hz), 7.25 (d, 4 H, J = 7 Hz), 4.4-3.5 (m, 7 H), 3.2 (b, 3 H), 2.5 (s, 6 H) 72 876 SB CASE 14515 -35-

To 10 g (55-60% in oil, 230 mmol) of sodium hydride in 300 ml of THF was added at 0øC a solution of the bistosylate 32 in 200 ml of THF and stirred vigorously for 1 h . The reaction mixture was treated dropwise with 12 ml of benzyl bromide in 10 ml of THF and stirred at 0 ° C for 1 h. The mixture was allowed to warm to room temperature and stirred overnight. It was quenched with 50 ml of water dropwise at 0 ° C. Extracted with ether, washed with water, dried over anhydrous sodium sulfate and the solvents removed in vacuo. The residual oil was filtered through silica gel (eluted first with hexane to remove unreacted benzyl bromide and then with ethyl acetate: hexane 1: 4) to give 9.0 g of bis-epoxide in the form of a slightly oily liquid. Further purification was performed by " flash chromatography " (silica, ethyl acetate: hexane 1:10) to give 6.10 g of diepoxide 33. KMN-H1 (CDCl3, 250 MHz) δ 7.4-7.7 (m, 5H), 4.75 (d, 1H, J = 12Hz), 4.65 (d, 1 H, J = 12Hz), 3.2 (m, 1H), 3.05 (m, 1H), 2.9 (t, 1 H, J = 7 Hz), 2.8 (m, 2 H), 2.65 (m, 2 H). b) (2R, 4R) -1,5-Diphenyl-3-benzyloxy-2,4-dihydroxypentane To a suspension of 2.99 g (15.5 mmol) of copper (I) iodide in 30 ml of THF, was added 18 ml of 1.8 M phenyl lithium solution in cyclohexane (freshly opened vial). The reaction mixture was warmed to -50 ° C and cooled again to -78 ° C, a solution of The solution of 1.01 g (4.9 mmol) of the bis-epoxide 33 in 10 ml of THF was allowed to warm to room temperature and stirred overnight. (1.75 g, 82%) of a colorless solid was obtained as a white solid (1.75 g, 82%) as a white solid. MS (DCI, NH 3) (M + H) + 364.5 1 H-NMR (CDCl 3, 250 MHz): δ 7.4-6.8 (m, 15H), 4.62 (d, 1 H, J = 12 Hz), 4.5 (d, 1 H, J = 12 Hz), 4.2 (m, 2H), 3.3 (dd, 1 H, J =), 2.8 (m, 4 H), 72 876 SB CASE 14515-36-

c) (2R, 4R) -1,5-diphenyl-3-benzyloxy-2,4-bis (methanesulfonyloxy) -pentane To 400 mg of the diol in 5 ml of pyridine at 0 ° C was added 1 ml of methanesulfonyl chloride and stirred for 18 h at room temperature. To ice cold 3N hydrochloric acid (20 ml) was added, extracted with 50 ml of methylene chloride, washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulfate and removed the solvents were dried in vacuo to give 1.20 g of 35 as an oil.

The above crude product was dissolved in 5 ml of DMSO and 1.05 g (16 mmol) of sodium azide was added. The reaction mixture was heated at 80 ° C for 6 h and then at 100 ° C for a further 8 h. The reaction mixture was cooled, diluted with ether and the unreacted sodium azide was removed by filtration. The combined solvents were removed in vacuo and the residue was chromatographed " flash " obtaining 285 mg of an inseparable mixture of the monoazide 36, (2S, 4S) -1,5-diphenyl-3-benzyloxy-4-azidopent-1-ene and bis-azide 37, in a ratio of 70:30 as determined by1 H-NMR. d) (2S, 4S) -1,5-diphenyl-3-benzyloxy-2,4-diaminopentane To 279 mg of the azide product mixture (36 + 37) obtained above in 10 ml of diethyl ether at 0Â ° C, 3 ml of a 1M solution of lithium aluminum hydride in THF was added over 10 minutes. It was stirred at 0 ° C for 30 minutes, warmed to room temperature and stirred for 3 h. It was cooled in an ice bath and quenched with 1 ml of 10% sodium hydroxide solution, diluted with ether and stirred for 2 h. The precipitate was removed by filtration through celite and washed with ether. Removal of the solvents followed by chromatography on 10 g of Florisil (hexane, ethyl acetate: hexane 1: 4 and then methanol) gave pure diamine (112 mg). 1 H NMR (CDCl 3, 250 MHz) δ 7.2 (m, 15 H), 4.7 (d, 21 H, J = 12 Hz), 4.5 (d, , 1 (m, 1H), 2.3-3.2 (m, 6 H). 72 876 SB CASE 14515 -37-

e) (2S.4S) -1,5-diphenyl-3-hydroxy-2,4-diaminopentane

62 mg of the diamino compound were hydrogenated in 10 ml of methanol containing 75 mg of concentrated hydrochloric acid over 25 mg of Pd / C. The catalyst was removed by filtration and washed with methanol. Removal of the solvents gave 68 mg of a solid from which, on trituration with hexane: ether, 48 mg of pure diamine was obtained as the hydrochloride. 1 H-NMR (CD 3 OD, 250 MHz) δ 7.4-6.9 (m, 10 H), 4.1 (bd, 1H, J = 6 Hz), 3.5-3.7 (m, 2 H ), 2.5-3.4 (m, 4 H). f) (2S.4S) -1,5-diphenyl-3-hydroxy-2,4-bis (benzyloxycarbonylamino-valinylamino) pentane The title product was prepared by the mixed anhydride method from 37 mg (0.107 mmol) of diamine hydrochloride, 150 mg of Cbz-Val, 98 μl of N-methylmorpholine and 80 μl of isobutyl chloroformate to give 68 mg of a white solid. Analytical samples were prepared by flash chromatography " flash " (silica, 10% MeOH / CH 2 Cl 2). MS (ES / MS) (M-H) + 735; 1 H NMR (CDCl 3, 250 MHz) δ 7.4-7.0 (m, 20 H), 6.1 (d, 1H, J = 7 Hz), 5.5 (d, 1H, J = 7). (M, 2 H), 3.6 (m, 2 H), 2.8-3.4 (m, 4 H), 2.2 (m, 1H), 1.85 (m, 1H), 0.9 (d, 3H, J = 7Hz), 0.86 (d, 3H, J = 7Hz), 0.7 (d , 3 H, J = 7 Hz), 0.55 (d, 3 H, J = 7 Hz).

Example 10

Preparation of (3S, 5S) -3,5-di-carbobenzyloxyalanylalanyl] amino-4-hydroxyheptane a) (2R, 4R) -1,5-diazido-2,4-dihydroxy-3-benzyloxypentane 41A 1, 65 g (8.0 mmol) of bis-epoxide 33 in 50 ml of water and 50 ml of dioxane was added 6.5 g (100 mmol) of NaN 3 and 340 mg (1 mmol) of tetra-bis -n-butylammonium chloride. The reaction mixture was refluxed for 4 h, cooled, concentrated to ca. 50 ml by rotary evaporation and extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were dried (Na 2 SO 4) and concentrated to an oil, which was combined with ether: hexane (1: 1) and allowed to crystallize at 4øC to give 1.76 g of the compound of title (69% yield). 1 H-NMR (CDCl 3): δ 7.5-7.3 (5H, m), 72 876 SB CASE 14515 -38

(2H, m), 3.6-3.0 (6H, m) b) (2R, 4R) -1,5-diazido- 4-di- (methanesulfonyloxy) -3-benzyloxy-pentane To 630 mg (2.15 mmol) of bis-azidediol 41 in 6.0 ml of pyridine was added 350 μΐ (4.5 mmol) methanesulfonyl chloride at 0 ° C. The reaction mixture was allowed to warm to 25 ° C and stirred for 20 h, then diluted with 6 N HCl (12 mL) and extracted with dichloromethane (100 mL). The organic phase was washed with 3% NaHC0 3 solution, dried (Na 2 SO 4) and concentrated. By " flash chromatography " of the residue (95: 5 CH 2 Cl 2: ether) afforded 867 mg (90% yield) of the title compound. NMR (CDCl3): δ 7.4-7.2 (5H, m), 5.0-4.7 (4H, m), 4.02 (2H, dd, J = 9-3.5 (4H, m), 3.15 (3H, s), 3.10 (3H, s). c) (2S.4S) -1,2,4-di-N-carbobenzyloxyimino) -3-benzyloxypentane To 310 mg (0.69 mmol) of compound 42 in 2 mL of dry THF at 0 ° C , 1.5 ml (1.5 mmol) of 1M LiAlH 4 in THF was added. The mixture was allowed to warm to 25 ° C and stirred overnight. Water (0.1 ml) was added, followed by 0.1 ml of 15% NaOH solution and 0.4 ml of water. The mixture was stirred vigorously with 10 ml of ether and filtered. Concentration of the ether phase gave the crude bis-aziridine which was dissolved in 5 ml of CH 2 Cl 2 and combined with 200 μ (1.4 mmol) of triethylamine and 200 μ (1.4 mmol) of benzyl. The mixture was stirred at 25 ° C for 3 h and then filtered. The filtrate was concentrated and the residue was purified by flash chromatography " (ethyl acetate: hexanes 1: 5) to give 89 mg (28% yield) of the title compound. NMR (400 MHz, CDCl3): δ 7.4-7.2 (15H, m), 5.0 (1H, d, J = 12Hz), 4.93 (1H, d, J = 12Hz) (1H, d, J = 12Hz), 4.84 (1H, d, J = 12Hz), 4.74 (1H, d, J = 12Hz), 4.39 (1H, J = 12Hz), 2.82 (1H, t, J = 6Hz), 2.6 (1H, m), 2.45 (1H, m), 2.25 (1H, d, J = 6 Hz), 2.15 (1H, d, J = 6Hz), 2.04 (1H, d, J = 3Hz), 2.02 (1H, d, J = 3Hz). MS (DCI, NH 3): m / z 473.1 (M +). To a suspension of Cul (72 mg, 0.375 mmol) in 1.5 ml of 72 876 SB CASE 14515 * μ vi

-25 DEG C., 0.5 ml of a 1.5M solution of CH3 Li in ether was added. The resulting colorless solution was cooled to -45øC and a solution of bis-aziridine 43 (10 mg, 0.02 mmol) in 0.5 ml ether was added. After stirring at -45 ° C for 1 h, the mixture was allowed to warm to 10 ° C over a period of 6 h and then stirred for an additional 2 hours. The mixture was diluted with 2 ml of saturated aqueous NH 4 Cl and 1 ml of brine and then extracted with ether. The organic layer was washed with brine, dried (Na 2 SO 4) and concentrated to give the title compound (10 mg). NMR (CDCl 3): δ 7.2 (15H, m), 5.2-4.9 (4H, m), 4.93 (1H, d, J = 12Hz), 4.88 (1H, d, J = 12Hz), 4.84 (1H, d, J = 12Hz), 4.7 (2H, d, J = 12Hz), 4.4 (2H, d, J = 12Hz), 3.7 (2H, m), 3.4 (1H, d, J = 2Hz), 1.6 (4H, m), 1.0 (3H, t, J = 7Hz), 0.9 ( 3H, t; J = 7Hz). MS (DCI, NH 3) (M + H) + 505.1. To a suspension of Cul (143 mg, 0.75 mmol) in ether (3 mL) at -35 ° C was added methyl (3R, 5R) -3,5-dihydroxy-4-benzyloxyheptane (1mL, 1.5M in ether, 1.5mmole). The resulting colorless solution was stirred at -30 ° C for 30 minutes and then cooled to -78 ° C. A solution of the bis epoxide 33 (78 mg, 0.37 mmol) in 2 ml of ether was added. The reaction mixture was allowed to warm to 25 ° C for 4 h and saturated aqueous NH 4 Cl and concentrated aqueous NH 3 were added. The mixture was extracted with ether, the organic phase was dried over Na 2 SO 4 and The solvent was collected, yielding the title compound (93 mg, 100% yield). NMR (CDCl 3): δ 7.4-7.1 (5H, m), 4.7 (1H, d, J = 12Hz), 4.55 (1H, d, J = (2H, m), 3.2 (1H, dd), 2.5 (2H, b), 1.6-1.4 (4H, m), 1.0 (3H, t) J = 7Hz), 0.9 (3H, t, J = 12Hz); MS (DCI, NH 3) (M + H) + 239.2. f) (3R, 5R) -3,5-methanesulfonyloxy-4-benzyloxyheptane

Methanesulfonyl chloride (0.3 ml) was added dropwise to the diol 45 (93 mg) in pyridine (1 ml) at 0 ° C. The mixture was allowed to warm to 25 ° C. After 12 h the mixture was diluted with cold 6N HCl (10 ml) and extracted with CH 2 Cl 2. The organic extract was washed with 3% NaHC03 solution, dried over MgSO4 and concentrated. The residue was purified by " flash " The title compound was obtained (83 mg, 56% yield). 1 H-NMR 72 876 SB CASE 14515

(CDCl3): δ 7.4-7.2 (5H, m), 4.75 (1H, b1), 4.7 (1H, d, J = 12Hz), δ (1H, m), 3.9 (1H, dd, J = 2.6Hz), 3.0 (3H, s), 2.9 (3H, s), 2.1-1.5 (4H, m), 1.05 (3H, t, J = 7Hz), 1.0 (3H, t, J = 7Hz). g) (3S, 5S) -3,5-diazido-4-benzyloxyheptane

A mixture of bismesylate 46 (83 mg, 0.21 mmol) and sodium azide (0.50 g, 7.7 mmol) in 1.5 ml of dimethylformamide was heated at 70 ° C for 12 h. After cooling, ethyl acetate (20 ml) was added and the mixture was filtered and concentrated. By " flash chromatography " of the residue gave the title compound (54 mg, 90% yield). 1 H-NMR (CDCl 3): δ 7.4-7.2 (5H, m), 4.65 (2H, s), 3.5-3.2 (3H, m), 2.0-1.5 (4H, m), 1.1 (3H, t; J = 6Hz), 1.05 (3H, t, J = 6Hz). To 328 mg (1.14 mmol) of bis-azide 47 from step (j) in 5 ml of THF at 0 ° C was added 200 mg of LiAlH4. The mixture was allowed to warm to 25 ° C and stirred for 5 h. The reaction was quenched by the addition of 0.5 ml of 15% NaOH solution, stirred for 15 minutes, diluted with ether (150 ml) and filtered. Concentration of the filtrate gave the title compound (278 mg, 100% yield). NMR (CDCl 3): δ 7.26 (5H, m), 4.5 (2H, dd, J = 12Hz), 3.1 (1H, dd, J = 4.6Hz), 2.9 (1H, m), 2.75 (1H, m), 1.8-1.0 (10H, m), 0.9 (3H, t, J = 7Hz), 0.85 (3H, t; J = 7Hz). i) (3S, 5S) -3,5-diamino-4-hydroxyheptane To 52 mg of diamine 48 in 4 ml of methanol was added 50 mg of 20% Pd (OH) 2 on carbon and two drops of concentrated aqueous HCl. The mixture was stirred under H2 atmosphere for 16 h, then filtered and concentrated to give the title compound (53 mg) as the dihydrochloride salt. 1 H-NMR (CD 3 OD): δ 3.75 (1H, dd, J = 4.7Hz), 3.2-3.0 (2H, m), 1.8-1.4 (4H, m), 0.9 (6H, t; J = 7Hz). j) (3S, 5S) -3,5-di- (carbobenzyloxyalanylalanyl) amino-4-hydroxy-heptane

To the product diamine 49 (87 mg, 0.37 mmol) in 6 mL of DMF,

72 876 SB CASE 14515 was added 221 mg (0.75 mmol) of carbobenzyloxyalanylalanine, 115 mg (0.75 mmol) of HOBT and 154 mg (0.75 mmol) of DCC. The mixture was stirred overnight, then concentrated, taken up in ethyl acetate, filtered, washed with water and brine and dried (MgSO4). Removal of the solvent followed by MPLC (silica, 2% methanol in CH 2 Cl 2) provided the title compound (109 mg). NMR (DMSOd 6): δ 8.0-7.2 (21H, m), 5.0 (4H, bs), 4.6 (2H, dd, J = 12Hz), 4.2 ( 2H), 4.0 (2H, m), 3.8 (1H, m), 3.7 (1H, m), 3.5 (1H, dd, J = 7 - 1.3 (4H, m), 1.1 (12H, m), 0.75 (6H, t). MS (FAB) (M + H) + 789.3.

Example 11

Preparation of (3S, 5S) -3,5-di-Alanylalanyl) amino-4-hydroxyhepta-no 51

To product 19 (4.5 mg) in 1 ml of DMF was added 10 mg of 20% Pd (OH) 2 on carbon. The mixture was stirred under H2 atmosphere for 6 h, then filtered and concentrated to give the title compound (3 mg). NMR (CD3 OD): δ 4.3 (2H, m), 3.8 (2H, m), 3.7 (1H, m), 3.5 (1H, m) 2 (16H, m), 0.8 (6H, dt).

Example 12

Preparation of (3S, 5S) -3,5-di-carbobenzyloxyvalyl) amino-4-hydroxyheptane To 133 mg (0.5 mmol) of Cbz-Val in 2 ml of THF at -40 ° C, 65 μl (0.5 mmol) of NMM and 65 μΐ (0.5 mmol) of isobutyl chloroformate were added. After stirring for 10 minutes, a solution of 25 mg (0.17 mmol) of diazine hydrochloride 1 and 50 μM NMM in 1 ml of DMF was added. The mixture was slowly warmed to 20 ° C and stirred overnight, then diluted with ethyl acetate, washed with 5% HCl solution, 5% NaHCO3 solution and brine, and the organic layer was concentrated. The residue was purified by " flash " (ethyl acetate: hexanes) to give the title compound (18 mg). NMR (CDCl 3): δ 7.5-7.3 (10H, m), 6.9 (1H, bd), 6.35 (1H, bd), 5.5 (1H, bd) 25 (1H, bd), 5.1 (4H, bs), 4.0-3.1 (6H, m), 2.4--2.1 (2H, m), 2.0-1.4 (4H, m), 1.0-0.8 (18H, m). MS (FAB): m / z 613.2 (M + H) +. 72 876 SB CASE 14515 -42-

Example 13

Preparation of (4S, 6S) -4,6-diamino-5-hydroxy-2,8-dimethyl-1,8-nonane dihydrochloride a) (4R, 6R) -4,6-dihydroxy -5-benzyloxy-2.8-dimethyl-1,8-nonadiene To a suspension of Cul (192 mg, 1.0 mmol) in ether (2 ml) at -60 ° C was added isopropenyl lithium 2 ml, 2.0 mmol, 0.38 M in ether, freshly prepared from 2-bromopropene and lithium wire). The mixture was warmed to -45 ° C and then cooled again to -78 ° C. A solution of bis-epoxide 33 (60 mg, 0.29 mmol) in ether (5 mL) was added. The mixture was allowed to warm to 0 ° C for 2 h with stirring. The mixture was diluted with ether and washed with 5 ml of concentrated aqueous ammonia solution: 1: 1 saturated NH 4 Cl solution. The organic phase was dried over MgSO4 and concentrated to give the title compound (81 mg, 96% yield) as a colorless solid. NMR (CDCl3): δ 7.3 (5H, m), 4.9 (1H, bs), 4.85 (1H, bs), 4.80 (1H, bs), 4.75 (1H, (1H, d, J = 12Hz), 4.0 (2H, m), 3.3 (1H, dd, J = 2.5 Hz), 2.55 (1H, d, J = 6Hz), 2.55 (1H, d, J = 4Hz), 2.5-2.1 (4H, m), 1.7 (1H, s). MS (DCI, NH 3) (M + H) + 291.4. b) (4R, 6R) -4,6-dihydroxy-5-benzyloxy-2,8-dimethylnonane 54

To product 53 (105 mg, 0.38 mmol) in CH2 Cl2 (1 mL) was added 55 mg of Ir (COD) Py (PCy) 3 PF6 (Crabtree's catalyst). The mixture was stirred for 6 h under an H2 atmosphere, then filtered and concentrated to give the title compound (110 mg, 100% yield). NMR (CDCl 3): δ 7.3 (5H, m), 4.6 (1H, dd, J = 12Hz), 4.0 (2H, m), 3.1 (1H, bs), 2 , 7 (2H, bs), 2.0-1.1 (6H, m), 1.0-0.8 (12H, m). MS (DCI, NH 3) (M + H) + 295.4. c) (4R, 6R) -4,6-di-methanesulfonyloxy-5-benzyloxy-2,8-dimethylnonane

Methanesulfonyl chloride (0.25 ml) was added dropwise to the diol 54 (93 mg) in pyridine (1 ml) at 0 ° C. The mixture was allowed to warm to 25 ° C. After 10 h, the mixture was diluted with cold 6 N HCl (10 mL) and extracted with CH 2 Cl 2. The organic extract was washed with 3% NaHC03 solution, dried over MgSO4 and concentrated.

SB CASE 14515-33- was stirred. The residue was purified by " flash " the title compound (210 mg) was obtained. NMR (CDCl 3) δ 7.4 (5H, m), 5.0 (1H, m), 4.8 (1H, d, J = 12Hz), 4.7 (1H, m), 4 , 3.85 (1H, dd, J = 4.7Hz), 3.0 (3H, s), 2.9 (3H, s), 2.0 (1H, - 1.1 (6H, m), 1.0-0.9 (12H, m). d) (4R, 6R) -4,6-diazido-5-benzyloxy-2,8-dimethylnonane

To product 55 (210 mg) in 2 ml of DMF was added 870 mg (15 mmol) of NaN3. The mixture was heated at 70 ° C for 7 h, then cooled and diluted with ethyl acetate. The filtrate was concentrated and the residue was purified by MPLC (1:20 ethyl acetate: hexanes) to give the title compound (52mg). 1 H-NMR (CDCl 3): δ 7.3 (5H, m), 4.55 (2H, dd, J = 12Hz), 3.4-3.15 (3H, m) 1 (6H, m), 1.0-0.75 (12H, m). e) (4S, 6S) -4,6-diamino-5-benzyloxy-2,8-dimethylnonane

To product 56 (52 mg, 0.15 mmol) in THF (3 mL) was added 80 mg of LiAlH 4 (2 mmol) at 0 ° C. The mixture was stirred at 25 ° C overnight, then quenched with 1N NaOH and diluted with ether (50 ml). Filtration and concentration gave the title compound (44 mg) as a colorless oil. NMR (CDCl3): δ 7.3 (5H, m), 4.6 (2H, dd, J = 12Hz), 3.1 (1H, m), 3.05-2.95 (2H , m), 1.9-1.1 (6H, m), 1.0-0.8 (12H, m). (f) (4S) 6S-4- (6-Diamino-5-hydroxy-2,8-dimethyl-1,8-nonane) dihydrochloride To 165 mg of diamine 57 in 10 ml of methanol containing 5 drops of concentrated HCl, 100 mg of 20% Pd (OH) 2 on carbon was added. The mixture was stirred overnight under H 2, then filtered and concentrated to give the title compound (75 mg). NMR (CD3 OD): δ 3.7 (1H, m), 3.35 (1H, m), 3.2 (1H, m), 1.8-1.0 (6H, m) 99-0.8 (12H, m). MS (DCI, NH 3) (M + H) + 203.2.

Example 14

Preparation of (4S, 6S) -4,6-di- (carbobenzyloxyalanylalanyl) amino-5-hydroxy-2,8-dimethyl-1,8-nonane 59

To product 58 (44 mg, 0.15 mmol) in 2 mL of DMF, add 72 876

110 mg of Cbz-AlaAla (0.375 mmol), 58 mg (0.375 mole) of HOBT and 72 mg (0.375 mmole) were added. ) of DCC. The mixture was stirred for 48 h at 25 ° C, then diluted with 20 ml of ethyl acetate and filtered. The filtrate was concentrated and the residue was purified by MPLC (gradient, 0-5% methanol in CH 2 Cl 2) to give the title compound (24 mg). NMR (CD3 OD): δ 8.0-7.2 (21H, m), 5.0 (4H, dd overlapping), 4.2 (2H, m), 4.0 (4H, m), 3 , Δ (1H, br s), 1.7-1.15 (18H, m), 0.9-0.7 (12H, br t).

Example 15

Preparation of (4S, 6S-4,6-di-falbanylalanyl) amino-5-hydroxy-2,8-dimethyl-1,8-nonane

To product 59 (12 mg) in 2 ml of DMF was added 50 mg of 20% Pd (OH) 2 on carbon. The mixture was stirred under H2 atmosphere for 10 h, then diluted with methanol, filtered and concentrated to give the title compound (7.5 mg). NMR (CD3 OD): δ 4.25 (2H, m), 3.8 (1H, m), 3.65 (2H, m), 3.1 (1H, bd) 1 (18H, m), 0.7 (12H, bd). MS (FAB) (M + H) + 487.

Example 16

Preparation of (S, 6S) -4,6-di-carbobenzyloxy) amino-5-hydroxy-2,8-dimethyl-1, 8-nonane To 6.0 mg of the product bis-amine hydrochloride 58 in 0.5 ml of CH2 Cl2 at 20 ° C, 5 ml of triethylamine and 10 ml of benzyl chloroformate were added. After 3 h of stirring, the mixture was applied to a silica column and eluted with CH 2 Cl 2 followed by ether to give the title compound (4.6 mg). 1 H-NMR (CDCl 3): δ 7.3 (10H, bs), 5.1-4.9 (6H, m), 3.9-3.7 (2H, m), 3.5-3.35 (2H, m, 1H exchangeable with D2 O), 1.7-1.5 (4H, m), 1.3-1.2 (2H, m), 1.1-0.8 (12H, m).

Example 17

Preparation of (2S.4S) -2,4-di- (p-toluenesulfonyl) amino-3-hydroxy-1,5-diphenylpentane The title product was prepared by sulfonylation of compound 40 (Example 9) with p-toluenesulfonyl chloride in dichloromethane and triethylamine. NMR (250 MHz, CDCl3) 8.0-6.8 (m, 18H), 5.5 (d, 1H, J = 7Hz), 5.2 (d, 1H, J = 7Hz), 3.2-3.7 D (m, 72 876 SB CASE 14515 -45-

4H), 2.4-2.7 (m, 4H), 2.5 (s, 3H), 2.45 (s, 3H).

Inhibition of Enzyme Inhibition of HIV protease activity The inhibition assay was previously described in Dreyer et al. Proc. Natl. Acad. Know. USA, 86, 9752-9756 (1989) and Moore et al. Bioch. Biooh. Res. Com .. 159, 420 (1989). A typical assay contained 10 ml of MENDT buffer (50 mM Mg (pH 6.0, 2- (N-morpholino) ethanesulfonic acid) 1 mM EDTA, 1 mM dithiothreitol, 200 mM NaCl, 0.1% Triton x-100) ; N-acetyl-L-aryl-L-valyl-L-valinimide (Ac-Arg-Ala-L-asparaginyl-L- Ser-Gln-Asn-Tyr-Pro-Val-Val-NH 2; Km = 7 mH) 2, 3 or 6 mM; and micromolar and submicromolar concentrations of the synthesized compounds. After incubation at 37øC for several minutes, the reaction was started with 0.001-0.10 mg of purified HIV protease. The reaction mixtures were quenched (37øC) 10-20 minutes later with an equal volume of cold trichloroacetic acid 0.6 N and, after centrifugation to remove the precipitated material, the peptidolysis products were analyzed by reverse phase HPLC (Beckman Ultrasphere ODS, 4.5 mm x 25 mm mobile phase, 5-20% acetonitrile / H20, 0.1% TFA (915 minutes), 20% acetonitrile / H2 O, 0.1% TFA 5 minutes) at 1.5 ml / minute, 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. The initial rates of formation of Ac-Arg-Ala-Ser-Gln-Asn-Tyr were determined by integration of these peaks, and typically the inhibitory properties of the compounds synthesized from the slope / in the origin of a 1 / v vs. [inhibitor] (Dixon analysis). The resulting values of this type of primary analysis are accurate, only for competitive inhibitors, and under conditions in which the Michaelis constant of the substrate used is well determined. It is desirable for the compounds of the invention to have values of less than 50 μΜ, preferably less than 10 μΜ and more preferably less than 1 μΜ. 72 876

'CASE 14515 -46-

Following the procedures described herein and the teachings of the foregoing examples, the compounds listed in the following Table, with the structure and substituent groups indicated therein, may be prepared.

R1 R2

Inhibition of HIV protease

Asosto ^ 50 3 50 6 80 8 80 40 0,123 52 50 60 80 62 1,000 NHX 2

1 HNMR

HO

X 1 and X 2 R1 e: 1 Ethyl 2 AlaAla ethyl 3-Cbz-Val ethyl 4 AlaAla PhCH2 5 H i-Bu 6 AlaAla i-Bu 7 Cbz-i-Bu 8 Cbz-Val i-Bu 101 Cbz-Ala i- Bu 2/3-Ala i-Bu 3 / J-AlaVal i-Bu 4 Cbz-AlaAla i-Bu 105 BocAla i-Bu 6 AcAlaAsn i-Bu 7 Ac-GlnAsn i-Bu-14515 X 1 and X 2 Cbz-PheAla trifluoroAlaAla Cbz-trifluoroAlaAlaAlaAlaAlaAlaAlaAb Cbz-trifluoroAla Ph (CH2) 2COO BOC Ac PhSO2 HCO Propionyl i-Butyryl Ph (CH2) 2C0 PhS02Val Phenyl-1-octoyl Phenyl lactoyl-Val-Cbz-Ala-Cbz-Val-Cbz-Val-Cbz-Val-Cbz-Val-Cbz -Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val R1 and R2 Bu-Bu-Bu-Bu-Bu-Bu-Bu-Bu-Bu-Bu-Bu-Bu-Bu-

i-Bu i-Bu

PhCH2 1- Butenyl 2-Propenyl 3-Butenyl n-Pentyl Ph (CH2) 2-Cyclohexyl-CH2-2-Naphthyl-CH2-3-Naphthyl-CH2-2-Butynyl 3-Indoylmethyl trans -3-phenyl-3- -propenyl N-Piperidinyl-CH2-N-Morpholinyl-CH2- (CH3) 2N-CH2 t-ButylNH-CH2-N-Imidazoyl-CH2 PhC0NH-CH2 N-Indoyl-CH2 t-ButylCNH-CH2 BocNHCH2 14515 X1 and X2 Cbz -Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Val Cbz-Ala

R and R 2 NH 2 CH 2 N-benzimidazolyl

PhCH2O-CH2

(CH3) 2 CHO-CH2 t-Butyl-O-CH2 (CH3) 2 CHCH2-CH2 CH3 CH2 (CH3) cho-ch2

Cyclohexyl-0-CH2

PhCH20CH20-CH2 ch3och2o-ch2 ch3och2ch2och2och2 ch3s-ch2

PhS-CH2 (CH3) 2CHS-CH2 CH3 (CH2) 2S-CH2 CH3 (ch2) 3s-ch2 CH3S (O) -CH2 CH3S (O) 2-CH2

Ph (0) 2-CH 2 n-Butyl-S (O) 2-CH 2 (Ph 2 O) 2 P (O) -CH 2 (CH 2) CH30) 2 P (O) -CH2 (n-Butyl) 2 P (O) -CH2 (EtO) 2 P (O) -CH2 (CH3) 2 P (O) -CH2 4: 72 876 SB CASE 14515

TABLE II R1 R2

NHX 2 if X 1 and X 2 0) 1 1 H ethyl 2 AlaAla ethyl 3 Cbz-Val ethyl 4 AlaAla PhCH 2 5 H i-Bu 6 AlaAla i-Bu 7 Cbz-i-Bu 8 Cbz-Val i-Bu 201 Cbz-Ala i 2-Ala-Bu-3-Ala-Val-Bu-4-Cbz-AlaAla i -Bu BocAla i-Bu 6 AcAlaAsn i-Bu 7 Ac-GlnAsn i-Bu 8 Cbz-PheAla i-Bu 9 trifluoroAlaAla i-Bu 210 Cbz-trifluoroAlaAla i-Bu-1-TrifluoroAla i-BU 2 Cb z-TrifluoroAla i -Bu 3 Ph (CH 2) 2 COO-Bu 4 Boc i-Bu 215 Ac-Bu 6 PhSO 2 i-Bu 7 HCO 8 Propionyl i-Bu 9 i -Butyryl i-Bu 220 Ph (CH 2) 2 CO i-Bu 1 PhSO 2 Val-i-Bu 2 Phenyl lactoyl i-Bu 72 876 0 SB CASE 14515 jj- 50- N2. X1 and X2 r! and R2 is 3-Phenyl-lactoyl-Val i-Bu 4 Cbz-Ala PhCH2 225 Cbz-Val i-Butenyl 6 Cbz-Val 2-Propenyl 7 Cbz-Val 3-Butenyl 8 Cbz-Val n-Pentyl 9 Cbz-Val Ph ( CH 2) 2-Cbz-Val 3-Naphthyl-CH 2 CH 3 -Bz-Val 2-Butynyl 4-Cbz-Val 3-Indoylmethyl 235 Cbz -Val trans-3-phenyl-3-propenyl 6-Cbz-Val N-Piperidinyl-CH 2 -7 Cbz-Val N-Morpholinyl-CH 2 -8 Cbz-Val (ch 3) 2n-ch 2 9 Cbz-Val t-ButHNH-CH 2 - 240 Cbz-Val-N-Imidazoyl-CH2 Cbz-Val PhC0NH-CH2 2 Cbz-Val N-Indoyl-CH2 3 Cbz-Val t-ButylCONH-CH2 4 Cbz-Val BocNHCH2 245 Cbz-Val NH2ch2 6 Cbz-Val N -benzimidazolyl Cbz-Val (CH3) 2 CHO-CH2 Cbz-Val-CH 2 -CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH (CH 3) CH 2 -CH 2 -CH 2 -CH 2 CHCH 2 -CH 2 CHCH 2 -CH 2 CH 2 OCH 2 -CH 2 CHCH 2 -CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O ch2 8 Cbz-Val ch3och2ch2och2och2 9 Cbz-Val ch3s-ch2> i 72 876 SB CASE 14515

-CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 2 -CH 2 CH 3 -CH 2 4 Cbz-Val-CH 3 S (O) -CH 2 265 Cbz-Val CH 3 S (O) 2 -CH 2 6 Cbz-Val PhS (O) Val (CH2) 2-CH2 (CH2) 2 P (O) -CH2-Cbz-Val (CH3) 2 P (O) ) -CH 2 Cbz-Val (n-Butyl) 2 P (O) -CH 2 Cbz-Val (EtO) 2 P (O) -CH 2 4 Cbz-Ala (CH 3) 2 P (O) -CH 2

Claims (10)

72 876 SB CASE 14515 -52- A process for the preparation of a compound of the formula: Wherein X1 and X2 are the same or different and are A- (B) n, wherein n = 0-2; and B is independently of the other an α-amino acid selected from the group: Ala, Asn, Cys, Trp, Gly, Gin, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or trifluoroalanine, wherein the amino group of B is attached to A or the carboxy group of adjacent residue B, where appropriate, and the carboxy group of B is attached to the amino group of adjacent residue B or I or II, choosing the appropriate one; and A is covalently attached to the amine group of adjacent residue B or to the amine group of I or II, if n = 0, and is: 1) trityl, 2) hydrogen, 3) C1-6 alkyl, 4) R3-CO - wherein R 3 is: a) hydrogen, b) C 1 -C 6 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 (ii) halogen, wherein halogen is F, Cl, Br or I, iii) hydroxyl, iv) nitro, v) C1-3 alkoxy, or vi) -CO-N (R10) 2, wherein R10 is, independently of the other, H or alkyl d) a 5-7 membered heterocycle, such as pyridyl, furyl or benzisoxazolyl, 5) phthaloyl, wherein the aromatic ring is unsubstituted or substituted with one or more R 4 substituents; 6) R 5 (R 8 R 7 C) m -CO-, wherein m = 1-3 and R 5, R 8 and R 7 are independently of the others: a) hydrogen, b) chlorine or fluorine, c) substituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, d) hydroxyl, e) phenyl or naphthyl, unsubstituted or substituted by one or more substituents R 4, f) C 1 -C 4 alkoxy, g) h) R 5, R 8 and R 7 may be independently of one another joined together to form a monocyclic, bicyclic or tricyclic ring system, each ring being C 3 -C 6 cycloalkyl; 7), wherein m = 1-3 and W is OCO or SO2 and R5, R6 and R7 are as defined above except that R5, R6 and R7 are not chlorine, fluorine or hydroxyl if they are adjacent a W; 8) R8 -W- wherein R8 is a 5-7 membered heterocycle, such as pyridyl, furyl or benzisoxazolyl; 9) R 9 -W- wherein R 9 is phenyl or naphthyl, unsubstituted or substituted with one or more substituents R 4; 10) R 5 - (R 6 R 7 C) m -P (O) (OR 11) - wherein R 11 is alkyl or phenyl; 11) R8-P (O) (OR11) - or 12) R9-P (O) (OR11) -; R 1 and R 2 are the same or different and are: 1) -CH 2 R 12 wherein R 12 is a) NH-A wherein A is as defined above b) R 5 (R 6 R 7 C) m-; c) R 5 (R 6 R 7 C) mV- wherein V is O or NH, except that R 5, R 8 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) R 5 (R 8 R 7 C) m S (O) -n, in R8 and R7 are as defined above, except that R5, R8 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to the sulfur, e) R8 -S (O) . are, independently of one another: i) C (O) -alkyl, - (C 1 -C 6) alkyl, - (C 1 -C 6) (i) n (r 10) 2, j) NR 15 R 16, wherein R 15 and R 16 are independently selected from the group consisting of: are linked together to form a saturated 4-6 membered nitrogenous heterocycle comprising: i) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, iv) morpholinyl, k) wherein R 17 is: (i) (ii) wherein Ar is phenyl, naphthyl or a 5-7 membered heterocycle, (1) wherein R 2, R 2, R 2, benzimidazolyl, wherein the condensed benzene ring is unsubstituted or substituted with one or more R4 substituents, (o) C2 -C6 alkynyl, optionally substituted with one or more R9 groups; or p) C2-C6 alkenyl, optionally substituted with one or more R9 groups; 2) hydrogen, 3) C 1 -C 6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C 3 -C 7 cycloalkyl, and R " is H or a hydroxyl protecting group and the pharmaceutically acceptable salts thereof, characterized in that it comprises reacting a compound of the formula: with a compound of formula X-OH and a coupling agent and removal of any hydroxyl-protecting group. 2) hydrogen, 3) C 1 -C 6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C 3 -C 7 cycloalkyl; and R77 is a hydroxyl protecting group, characterized in that it comprises: reacting a compound of structure: Wherein R7 is a displaceable group, with azide. 2. A process for the preparation of a compound of the formula: in which X 1, -, R 1, X 2 and R 2 are as defined in claim 1, characterized in that it comprises treating a compound A compound of the formula: wherein X 1, R 1, X 2 and R 2 are as defined in claim 1, with an oxidizing agent. A process according to claim 1 or 2, characterized in that ΧΧ = Χ2 and R1 = sR2. A process according to claim 1 or 2, characterized in that R1 and R2 are C1 -C6 alkyl. A process according to claim 1 or 2, characterized in that R1 and R2 are benzyl. Process according to Claims 1 to 4, ψ 72 876 " SB CASE 14515 wherein X1 and X2 are selected from AlaAla, Val, Cbz-Val, Cbz or hydrogen. 7. A process for the preparation of a pharmaceutical composition comprising combining a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier. 8. A process for the preparation of a compound of the formula: wherein R 1, R 2, R 3, R 4, in which R 'is 1) a) NH-A wherein A, R 1 -R 10 and m are as defined in claim 1; b) R 5 - (R 6 R 7 C) m -; c) R 5 - (R 8 R 7 C) mV-, wherein V is O or NH, except that R 1, R 6 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) R 5 - (R 6 R 7 C) m -S-- m is 1-3 and R 5, R 6 and R 7 are as defined above except that R 5, R 6 and R 7 are not hydroxyl, chlorine or fluorine if they are adjacent to the sulfur, e) R 8 -S-, f) R 9 -S-, g) (R130) P (O) (OR14) - wherein R13 and R14 are each independently of the other: i) C1-6 alkyl, ii) C3-6 cycloalkyl, iii) H, iv) R9, or v) R8, h) R13P (O) (OR14) -, i) N (R10) 2, j) NR15R16, where R15 and R16 are linked to form a saturated 4-6 membered nitrogen heterocycle, SB CASE 14515 including: i) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, k) wherein R 17 is: i) C 1 -C 6 alkyl or ii) R 9, or iii) CH 2 Ar where Ar is phenyl, naphthyl or a heterocycle m) N-imidazolyl, wherein the imidazole ring is unsubstituted or substituted with a substituent R4, n) N-benzimidazolyl, wherein the fused benzene ring is unsubstituted or substituted with one or more R4 substituents, o) C2 -C6 alkynyl, optionally substituted with one or more R9 groups; or P) C2 -C6 alkenyl, optionally substituted with one or more R9 groups; 2) hydrogen, 3) C1-6 alkyl, unsubstituted or substituted with one or more chlorine or fluorine atoms or hydroxyl groups, or 4) C3-C7 cycloalkyl; R 2 is a hydroxyl protecting group, R 3 and R 4 are hydrogen, an amino protecting group or taken together are N 2, characterized in that it comprises: 1) reacting a compound of the formula: with a compound R 2 -Z, wherein Z is a moiety which renders R 3 nucleophilic, 2) converting the resulting hydroxy groups into displaceable groups and 3) reacting the displaceable groups with a nitrogen nucleophile. 72 876 SB CASE 14515 • c -58- A process for the preparation of a compound of the formula: wherein R 1 is 1) a) NH-A wherein A, R 5 -R 10 and m are as defined in claim 1; b) R 5 - (R 6 R 7 C) m -; c) R5- (R6R7C) mV-, wherein V is O or NH, except that R5, R6 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to V, d) R5- (R6R7C) mS- wherein m = R3 and R5, R6 and R7 are as defined above except that R5, R5 and R7 are not hydroxyl, chlorine or fluorine if they are adjacent to the sulfur, e) R8 -S-, f) R9 -S-, g) (R130) P (O) (OR14) - wherein R13 and R14 are each independently of the other: i) C1-6 alkyl, ii) C3-6 cycloalkyl, iii) H, iv) R9, OR ) R8, h) R13P (O) (OR14) -, i) N (R10) 2, j) NR15R16, wherein R15 and R16 are linked to form a saturated 4-6 membered nitrogenous heterocycle comprising: ) azetidinyl, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, k) R17 OCH2 O wherein R17 is: i) C1-6 alkyl, ii) R9, or SB CASE 14515-59- (iii) CH 2 Ar where Ar is phenyl, naphthyl or a 5-7 membered heterocycle, (1) arylalkyl, m) N-imidazolyl, wherein the imidazole ring is unsubstituted or substituted with a substituent R 4, n) N-benzimidazolyl, wherein the condensed benzene ring is unsubstituted or substituted with one or more substituents A process for the preparation of a compound of the formula: In which R77 is H or a hydroxyl protecting group which comprises: 1) reacting a compound of the formula: with a sulfonyl halide, 2) treating the sulfonate with a base, 3) optionally reacting the compound with a hydroxyl protecting group. 1991 By SMITHKLINE BEECHAM CORPORATION = 0 OFFICIAL AGENT =