JPH05508855A - Retroviral protease inhibitors - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Retroviral protease inhibitor Background of the invention The present invention particularly relates to compounds that are inhibitors of retroviral aspartic proteases. Regarding compounds.

Retroviruses, or viruses belonging to the Retroviridae family, are A class of viruses that transport substances as liponucleic acid rather than deoxyliponucleic acid. Ru. Also known as RNA tumor viruses, they exist in humans and animals. It is associated with a wide range of diseases in humans. They are Rous sarcoma virus (RS) V), murine leukemia virus (MLV), murine mammalian tumor virus (MMT) V), feline leukemia virus (FeLV), bovine leukemia virus (BLV), Mason-Pfizer monkey virus, monkey meat tumor virus (SSV), monkey acquired color gE deficiency syndrome W (SAI　ID　S), human T’) Mbaei 11L virus (HTL V-1,4) and AIDS (later Human immunodeficiency virus, which is the cause of AIDS-related syndromes (innate immunodeficiency syndrome) and AIDS-related syndromes (HIV-1, HIV-2), and many other diseases associated with infection. It is believed to be a causative factor for this condition. In many of these cases, the pathogen is simply Although isolated, no satisfactory method of treating this type of infection has been developed. child Among these viruses, HTLV and HIV are particularly well characterized. It is made clear.

Critical to retrovirus replication is the production of functional viral proteins.

Protein synthesis is performed using open libraries corresponding to m, animals and = ■ reading frames. This is accomplished by translating the coding frame into polyprotein components. . Womai and To1 precursor proteins are converted into functional proteins by viral proteases. Processed easily. HIV-1 protease is an aspartic acid protease. (Meek et al., Proceedings BUSUSI5NAL ACADEMY OF SCIENCES OF NININISU A (Proe.

Natl, Acad, Sci, USA), vol. 88, p. 1841 (19 1989)). Viral proteases are used to process polyproteins. The proteolytic activity conferred by It is essential for the life cycle of the virus. In fact, it lacks proteases or Alternatively, Retrolysul, including its variants, has been shown to lack infectivity. ing. Katoh et al., Virology, 14 5, pp. 280-92 (1985): Crawford et al. , Journal of VOOG (J, Vxrol, ), Volume 53, 8 pp. 99-907 (1985); Debouck et al., Proceedings. National Academy of Sciences -F, -A (Proc, Natl, Acad, Sci, U.S.A. ), vol. 84, p. J903-6 (1987). Therefore, retrovirus pro Inhibition of tease provides a therapy for retroviral diseases.

How to express retroviral protease in E. coli (Debouck et al., Proceedings of National Academy of Sciences of New York (P. roc, Natl, Acad recombinant HIV protease inhibitors have not been reported. (Dreyer et al., Proceedings of the Nation) National Academy of Sciences of Ninis A (Pro e, Natl, Aead, Sci, USA), vol. 86, 975 pp. 2-56 (1989): Tomaselli et al. (ibid.): Roberts et al., Scienceigal et al., European Patent Application No. 33 No. 7714 Dreyer et al., European Patent Application No. 352000) . Furthermore, some of these inhibitors have been tested in cultures of T lymphocytes infected with HIII. has been shown to be an effective inhibitor of viral proteolytic processing in (Meek et al., Nature (London)) ondon), vol. 343, p. 90 (1990) and Roberts. ts) et al. (supra)).

Current methods for aspartic protease inhibition include (1) oral biological Availability: (2) plasma clearance lifetime (e.g., due to biliary secretion or degradation) ): (3) Selectivity of inhibition: (4) In the case of intracellular targets, membrane permeability or cell uptake There are restrictions such as taking. The present invention relates to retroviral aspartic acid proteases. The present invention relates to novel inhibitors of enzymes. Unlike the above-mentioned inhibitors, the compounds of the present invention It is not an analogue of the peptide substrate processing possible dipeptide mimetics.

They also have a conventional orientation from the amino terminus to the carboxyl terminus. It differs substantially from the peptide substrate-like structure in that it does not.

Summary of the invention The present invention resides in a retrovirus program as set forth in the claims and as set forth below. Includes compounds having a structure that binds to rotease. These compounds is an inhibitor of rus protease and is used to treat diseases associated with viral infections. It is useful for

The present invention also provides a pharmaceutical composition comprising the above compound and a pharmaceutically acceptable carrier thereof. It is a thing.

Additionally, the present invention provides for administering an effective amount of the above-described inhibitor compound to a mammal in need thereof. constitutes a method for the treatment of viral diseases, which comprises administering.

Detailed description of the invention The compound of the present invention has structure I or ■: [wherein, XI and X2 are the same or different, A-(B), -(where n= o ~ 2); and B is independently AlaSAsn, CysSTrpSGly, Gin, I le, LeuSMet.

Phe, Pro, Ser, Thr, Tyr, Val, His, or an α-amino acid selected from the group consisting of trifluoroalanine, where The mino group is bonded to the appropriate carboxyl group of A or the adjacent residue B. The carboxyl group of B is the appropriate one of the adjacent residue B or the amino group of ); and A is covalently bonded to the amine group of the adjacent residue B, or if n=0 3) CI-Ca alkyl, 4) R'-Co-(, -, :t', Rs is: a) hydrogen, b) Unsubstituted or one or more hydroxyl groups, chlorine atoms, or C, -C, alkyl, C) substituted with fluorine atom, unsubstituted or one or more or more substituents R4, where R4 is: i) c, -c4 alkyl, ii) halogen (here, halogen is F, C1, Br or ■), 5) hydro Xyl, juice) nitro, V) CI-C! alkoxy, or 1) -Co-N(R'')2 (where Rle is independently H or C, -C, phenyl or naphthyl substituted with (alkyl): d) pyridyl, (furyl, or 5- to 7-membered heterocycle such as benzisoxacylyl): 5) Phthalolyl (here, the aromatic ring is unsubstituted or one or more substituted substituted with substituent R4) 6) R3 (R'R7C), -Co- (here, 1 = 1 to 3, R5, R6, and R7 independently.

a) Hydrogen, b) chlorine or fluorine; C) Unsubstituted or one or more chlorine or fluorine atoms or hydro C, -C3 alkyl substituted with xyl group, d) hydroxyl, e) Phenyl unsubstituted or monosubstituted with one or more substituents R4 or naphthyl, f) C, -C4 alkoxy, g) a 5- to 7-membered heterocycle; h) R5, R6, and R? independently or together can be monocyclic, bicyclic, or 7) R'(R 6R'C), W- (where -=1 to 3, W is OCO or Sol , R5, R6, and R7 have the same meanings as above; however, Rs, R6, and and R7, if they are adjacent to W, are chlorine, fluorine or hydroxy. ); 8) R”-W- (where Rs is pyridyl, furyl, or benzisoxane 5- to 7-membered heterocycles such as silyl).

9) R'-W- (where R9 is unsubstituted or one or more substituted phenyl or naphthyl) substituted with group R4; or phenyl); 11) R8-P(○XOR”)-: Or 12) R book-P(OXOR1- and: R1 and R1 are the same or different: 1)-CH2R'' (where R 12 is a) NH-A (where A has the same meaning as above): b) R'-(R'R'C ), −: c) R'-(R'R'C), V-(,:,:T, VlkO also 1tNH; L, R5, R6 and Rt, if adjacent to V, are hydroxy (not chlorine or fluorine), d) R'-(R・R'C), -3(0), -(where i=1 to 3 and n=o ~2, and R5, R- and R7 have the same meanings as above: However, Rs, Ra , and Rt are hydroxyl, chlorine or Rt if they are adjacent to sulfur. or fluoride), e) R”-6(0),-1 f) R'-5(0), -1 gXR"0)P(0)(OR")-(::T, Rt3 and R" are independent sites: 1) CrCs alkyl, 1i) Cs-C+cycloalkyl, Hl tv)R”, v) R”), h) RIIP(0)(OR14)-1 i) NCR”)z, 3) NRI "R" (here, R13 and R11 are - together: rapid) piperi Jinil, tv) forming a 4- to 6-membered saturated nitrogen heterocycle containing morpholinyl), k) R”0 CHzO (::T, Rt7 is:ro ring), 1) R”0CHzCHzOCHt, m) N-imidazolyl (here, the imidazole ring is unsubstituted or has a substituent R 4), n) N-benzimidazolyl (here, the fused benzene ring is unsubstituted or (substituted with one or more substituents R4):0) optionally one or more substituents R4) Cl-C, alkynyl substituted with more groups R1: or p) C, -C, Al3 optionally substituted with one or more groups R9 ) Unsubstituted or one or more chlorine or fluorine atoms or hydroxy C, -C, alkyl substituted with a sil group, 4) CrCt cycloalkyl; and pharmaceutically acceptable salts thereof.

Among the peptide compounds described above, XI=X2 and R,=R1, and C2 Those with symmetry are preferred.

Suitably, the compound has a bottle design, RI R1 and XI=X2.

Suitably R1 and R2 are Cl-Cs alkyl. R1 and B-x are It is preferable that it is undil.

Suitably, XI and X2 are AlaAla, VallCbz-Val, C bz or hydrogen. Preferably XI and X2 are Cbz-Val.

The compounds of the present invention are useful for the preparation of drugs, especially drugs for treating infections caused by retroviruses. Useful for construction.

In addition, in a peptide compound with C2 symmetry, R and R2 are C, -C, alkyl or aralkyl, and XI and X2 are single amino acids or or dipeptide: these groups can be ordinary acyl groups or t-Boc Or the terminal is substituted with a protecting group commonly used in peptide synthesis such as Cbz. ) is also preferred.

The present invention also includes pharmaceutically acceptable adducts, complexes or complexes of the compounds of the present invention. Also includes prodrugs. Prodrugs are covalently bonded drugs that release the patented drug. It is understood that it is a carrier.

As used herein, unless otherwise noted, "alkyl" The term means [H or a branched alkyl group of the indicated number of carbon atoms, methyl, Ethyl, n-propyl, isopropyl, n-butyl, 5ec-butyl, tert -butyl, n-pentyl, l-methylbutyl, 2,2-dimethylbutyl, 2-methylbutyl These include tylpentyl, 2゜2-dimethylpropyl, n-hexyl, etc. but not limited to: "Alkoxy J refers to the indicated carbon bonded through a bridging oxygen atom Represents an alkyl group with the number of atoms: "Cycloalkyl J is cyclopropyl, cyclobutyl Saturated cyclic groups such as tyl, cyclopentyl, cyclohexyl and cycloheptyl “Alkenyl” is intended to include ethynyl, propenyl, butenyl, pentenyl, 2-methylpropenyl, etc., present at appropriate positions along the chain Straight or branched hydrocarbons with one or more carbon-carbon double bonds "Alkynyl" is meant to include the chain: ethylyl, 2-propynyl, 2 - along the chain, such as butynyl, 4-pentynyl, 2-methyl-3-propynyl Straight chain or or a branched hydrocarbon chain.

As used herein, unless otherwise noted, "heterocycle" The term is saturated or unsaturated and contains carbon atoms and from the group consisting of N, I and S. 1 to 3 m of selected heteroatoms, nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. A bicyclic ring in which any of the above heterocycles is fused to a benzene ring represents a stable 5- to 7-membered monocyclic or bicyclic heterocycle containing a cyclic group. Heterocycles are safe. It may be attached to a heteroatom or a carbon atom so as to form a fixed structure.

Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-ol xoazepinyl, 2-oxoazepinyl, 2-oxoazepinyl, 2-oxoa Zepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazoli pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, lydiazinyl, oxasilyl, isoxasilyl, morpholinyl, thiazolyl, Quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazoli benzopyranyl, benzoxazoyl, furyl, tetrahydrofuryl, tet Lahydrofuryl, chenyl, thiamorpholinyl sulfoxide, thiamorpholinyl Includes nyl sulfone, and oxadiazolyl.

Variables (e.g., A, B5R1, R1, R1, ..., R'', heterocycles, substituted phenyl, etc.) appears one or more times in the constituent element or structure I or ■ , its definition for each occurrence is distinct from its definition for any other occurrence. It is a relationship. Additionally, combinations of substituents and/or variables are permissible only if it results in a stable compound. The conventions used here Thus, twin diols, e.g. when R6 and Rt are simultaneously hydroxyl means that it is equivalent to a carbon-oxygen double bond.

Other terms commonly used in the art and used herein to describe peptides Abbreviations and symbols include: According to conventional notation, the amino terminal is on the left, and the carboxy terminus is on the right. All chiral amino acids (AA) are , racemates, racemic mixtures, or individual enantiomers or diastereomers and all isomeric forms are encompassed by the present invention. β- Ala means 3-aminopropanoic acid. Boe is t-butyloxycarbonyl Cbz means carbobenzyloxy group, 1-Bu means isobutylene group, Cbz means carbobenzyloxy group, AC means acetyl, Ph means phenyl, DCC means disyl. Chlorhexylcarbodiimide, DMAP means dimethylaminopyridine, H OBT means 1-hydroxybenzotriazole, NMM means N-methyl mole holin, DTT is dithiothreitol, and EDTA is ethylenediamide. DIEA is diisopropylethylamine, and DBU is 1. 8diazobicyclo[5,4,01undec-7-ene, DMSO is dimethylene rusulfoxide, DMF is dimethylformamide, and THF is tetrasulfoxide. It is hydrofuran. HF means hydrofluoric acid, TFA means trifluoroacetic acid means.

The peptide moiety represented by Xl and X2 is generally a dipeptide or smaller than that. However, longer peptides containing the residues defined here are also considered to be active and are understood to be within the scope of this invention.

The choice of residues or terminal groups depends on the biochemical or physicochemical properties preferred for the above compounds. It may also be used to impart special properties. The use of hydrophilic residues imparts desirable solubility. The D-amino acid at the carboxy terminus may be used to give an exopeptidic acid. It may also be used to confer resistance to dasases.

Compound cutting (where R'=R"CH2, R'=R2, and X1=X combination is , D-(+)-arabitol (Scheme 1-2). Therefore, D- (+)-arabitol is Nis el Schreiber (S, L, 5chre iber), Tea Samnakia (T.

S amnakia) and D E-1-ring (D, E, Uehl ir+g) [Journal of Organic Chemistry (J, Org , Chet), vol. 54, pp. 15-16 (1989)]. 1.2:4.5-dianhydro-3-(O-benzyl)-D-(+ )-arabitol (10). Dieboxide 10 is then dissolved in DMF to give the resulting dihydroxy-terminated diazide. be able to. This dihydroxy-terminated diazide is synthesized by its dimesylation followed by L i A I H4 reduction and parallel diaziridine formation followed by benzyl By reaction with chloroformate, the protected diaziridine 1,2+4.5 -di(N-benzyloxycarbonylimino)-3-(0-benzyl)penta Converted to Nord. The obtained diaziridine can be treated with a suitable solution such as (CHs)zcuLi. A side chain group R1 is introduced by reacting with a suitable nuclear reagent (Scheme 1). This step is especially For compound cutting, R'=CHzR''' (R''' is hydrogen or a stable reactive Groups forming cuprate reagents, such as methyl, butyl, isopropyl, or other alkyl, alkenyl, or optionally, e.g. fluorine or alkoxy or protected hydroxy-substituted aryl)) There is.

Alternatively, Equation 1 (where R,' = R'2CH!, RI = R!, and Compounds represented by React with a salt reagent (R'CuLi or alkynylaluminum reagent to form a side chain can be prepared from diepoxide 10 by introducing the group R1 ( Scheme 2). This procedure also specifically applies to compounds I (where R1=C)1. R1 ! (R1! is a group that forms a stable reactive cuprate reagent, as described above) ) is suitable for the preparation of The resulting diol product has a configuration of the alcohol carbon is converted to the corresponding inverted diamine. One way to accomplish this is to Reaction with sulfonyl chloride and triethylamine followed by NaN in DMF 3 to give substituted 2,4-diazide-3-benzyloxypenkune : Conversion to 2,4-diamino derivatives followed by hydride reagents such as LiAlH4 or contacted with a catalyst such as Pd(0) or Raney Ni. Converting the diol to cymenlate by reduction to give core structure I (Scheme 2). The introduction of group X I = X 2 is This is achieved by standard condensation reactions known in the art.

Compound ① (here, R12 is NH-A) is reacted with NaN5 in DMF, and its to give the resulting dihydroxy-terminated diazide, which is Conversion to the corresponding tetraazide with the position reversed, followed by conversion to the corresponding tetramine It can be prepared from dieboxide 10 by: Then, the terminal amino Following selective reaction of the group A with a protecting group such as Boc or Cbz, the group X Introduce l=X2. Relatedly, compound I (where R'1iN( Rlo) 2, N RI S R+ 6, R5-(R'R)C), V4 or R5- (R@R'C), -8(0), -)+: i: The group RI=R1 is dieboxy 10 with appropriate oxygen, nitrogen, or nuclear reagents, if necessary, followed by Nidiepoxide 10 can be introduced by carrying out thiol oxidation, Arbuzov reaction or Michaelis Arbuzov reaction When reacted with an appropriate nuclear reagent in the eris-Arbuzov) reaction, ( R130) A group R that is P(OXOR1')- or R''P(0)(OR+4)- 1=R1 can be introduced.

Alternatively, a compound represented by a protected α-amino aldehyde P! It can be prepared from NHCH(R1)CHO. Necessary N-protected α-amino Noaldehyde can be prepared, for example, by converting the corresponding ester with diisobutylaluminum hydride. N-methyl, N-methoxyamide P”NHC derived by reducing Reacting H(R1)CONme(OMe) with LiAIH, (Fehren Fehrentz and Castro, Synthesis (S) 676 (1983)) or by N-protected α - reduction to amino alcohol followed by DMSO-(COCI)2 or 503- Oxidation with pyridine (review: J urczak and Go Revio can be prepared. Generally, the amino protecting group P2 is t-Boc-1 Cbz-1p-toluenesulfonyl or any selection known in the peptide art is another standard protecting group. ■The synthesis of Vans), Ennis and Mathre, Jar National Chemical Society (J, Am, Che t Soc, ) vol. 104, pp. 1737-39 (1982): Review: Kovan Evans, Nelson and Taver , Topics in Stereochemistry chemistry), Volume 13: Allinger, Edited by Elliere (Elze 1) and Wilen: Wiley (W acyl derivative R2C under the conditions of Intermediate P2NH(R')CH(OH)CH by aldol condensation with H2C0Q (R”)COQ, where Q is the leading stereochemical outcome of the aldol reaction. Chiral adjuvants used, often valinol, lufeedrin, or is an oxazolidinone derived from phenylalanol). proceed. Protect hydroxyl with protecting group P1 such as TBDMS or benzyl intermediate P”NH (R') CH(OP') CH(R COxHb"4utLru.

This is called the Curtius rearrangement (review: Banthor pe), Patai's ``The Chemistry of the Azid Guru'' The Chemistry of the Azide Group "Chemistry of Acyto Group", pp. 397-405, Interscience Publishers. Interscience Publishers, NY, 197 1st year; Smith (3with), Organic Reaxians (Org, Rea) ct, ), Vol. 3, pp. 337-449 (1946)), the compound P''N H(R’)CH(OP’)CH(R”)NHt. This protects I asymmetrically. It is a formalized form. This route covers all stereoisomers and asymmetric compounds of compound cutting. To approach the cutting (here, R1, R1 are different, ) (lS) (! is different) It is versatile in that it enables

The synthesis of compounds of formula This is accomplished by oxidizing the central hydroxyl group. Useful oxidizing reagents and methods pyridinium chlorochromate, and pyridinium chlorochromate. do not have.

Any enantiomer of the compound of structural engineering and ■ is shown in Scheme 1-2. Can be prepared from each enantiomer of arabitol by the procedure .

Scheme 1 0(・)-arabitol,. 1, >,,.

1) NaNz, DMF 4) Cbz-CI ■ 10　9n cod゛sigil ! Thus, in another aspect, the present invention provides the formula: C, where Ro is: 1) a) NH-A Nikode, ASR5 to RIO, and ``False'' have the same meaning as Claim 1): b) R5-(R'R7C), -: c) R'-(R'R'C), V-(2: where v is 0 or NH: However, R15 When R6 and R7 are adjacent to V, they are hydroxyl, chlorine or is not fluorine), d) R5-(R'R'C), -3- (where I = 1 to 3, R5, R1, and R7 have the same meanings as above, provided that R5, R6, and R7 are adjacent to the sulfur. if in contact, they are not hydroxyl, chlorine or fluorine), g )(R”0)P(OXORI4)-(where R13 and R14 are independently :i) C, -C@alkyl, 1f) C3-C@cycloalkyl, ff1)H.

fv) R', or v) R”), h) RI3P(OXORI4)-1 i) N(Rlo)z, j) NR"R" (,:,:, RI5 and RI6 are -o-ninatte:l) adze Tidinil, ii) pyrrolidinyl, piperidinyl, or iv) morpholinyl, ), k) RI70CH20 (where So, Rl? is i) C'-C' alkyl, 1f) R', or m) CH2Ar (where Ar is phenyl, naphthyl or a 5- to 7-membered heterocycle ), 1) R"0CH2CH20CH2, m) N-imidazolyl (here, the imidazole ring is unsubstituted or has a substituent R 4), n) N-benzimidazolyl (here, the fused benzene ring is unsubstituted or O) optionally substituted with one or more substituents R4): O) optionally substituted with one or more substituents R4 is C2-C, alkynyl substituted with more groups R9: or p) C, -C, a3 optionally substituted with one or more groups R9 ) Unsubstituted or 1 m or more chlorine or fluorine atoms or hydroxy CI-Ca alkyl substituted with a sil group, or 4) C3-C7 cycloa R'' is a hydroxyl protecting group, and R゛°° and R'' are hydrogen , an amino protecting group or taken together with N2] 1) Formula: The compound represented by R-Z (where Z is a moiety that imparts nuclear properties to Ro) 2) the resulting hydroxyl group is 3) reacting this substitutable group with a nitrogen nucleophile; This is a preparation method consisting of:

Hydroxyl protecting groups can be selectively removed to regenerate hydroxyl groups, but It is a group commonly used in the art to mask the reactivity of the droxyl group. Ru. Typically, oxygen-hydrogen bonds are replaced with oxygen-carbon bonds. useful information The droxyl protecting group is a Greene, T.W. W.), Protective Groups in Organic Synthesis (P. protective Groupsin Or anic 5ynthesis : Protecting Groups in Organic Synthesis), John Wiley & Sons Wiley & 5ons), New York (1981) However, many others are known in the art. Substituted or unsubstituted arylmethy Ethers are one particularly useful class of hydroxyl group-protecting groups. desired Therefore, a benzyl protecting group having a substituent on the aryl ring is useful.

Typically Z is hydrogen, an alkali metal such as Li, Na or is earth metal, e.g. magnesium, or transition metal, e.g. sea bream, aluminum. um, titanium, zinc or cadmium, or species derived therefrom. .

Representative examples of R-Z include optionally substituted alkyl, aryl or heteroaryl. lithium, alkyl, aryl or heteroaryl magnesium halide (e.g. Grignard reagent), lithium dialkyl cuprate salt, lithium diaryl cuprate, or optionally substituted alkyl alcohol Alkali metal salts of alcohol, phenol or benzyl alcohol. lithium di Phenylsterate is particularly useful.

Hydroxyl can be substituted with suitable substitutable groups by methods common in the art, e.g. Mesylate, tosylate, brosylate, benzoate, acetate and hala converted to id. Tosyl groups are particularly suitable, e.g. It is formed by reacting with chloride.

Suitable nitrogen nucleophiles include those capable of reacting with substitutable groups. steric hindrance organic amines or heterocycles, amines, heterocycles, or metal salts of It azide without Useful. Generally, the formula R"'R"N-Z, where Z has the same meaning as above, , R′′ and R” are hydrogen, an amino protecting group or together Nt (e.g. Nitrogen-containing groups such as azide) are useful. Metal azide, e.g. nat Preferred is lium or potassium azide. Subsequent reduction of the amide group results in amino give the base.

Particularly useful intermediate compounds of the invention are:

[In the formula, R' and R'' have the same meanings as above].

Compounds of the present invention are described by Merrifield [Journal ・Of American Chemical Society (J, Am, Chet) Soe, Vol. 85, p. 2149 (1964)]. or by solution methods known in the art. See, Tory, Ma or tetra-peptide fragments are prepared by solid-phase synthesis and then prepared by solution synthesis. Solid-phase synthesis, such as complex synthesis, in which coupling or further modification and solution synthesis may be used in combination. J.M. Steward (J, M, S tevart) and J.D. Young (, J, D, Young), [Solid Phase Peptide Analysis (Solid P Hase Peptide 5ynthesis, Solid Phase Peptide Synthesis)'', Pierce ・Chemical Company (Pierce Chemical Company) Rockford, II (1984) or M. Bodonsky (M, Bodonsky), Y.A. Crowther (Y, A, Klauser) and Y, M, Qnde tti), rPeptide Synthesis: Peptide Synthesis), John Wiley & Sons, Inc. Wiley &5ons, IDC,), -'-x-Yoke, N, Y, (19 1976), or “The Peptides” , gross and Meienhoffer Edited by: Acad, Press, 1979, No. T-■ The peptides of the present invention can be synthesized using methods of peptide synthesis generally described in Vol. may be synthesized (herein incorporated by reference).

Each amino acid or peptide is suitably protected as is known in the peptide art. . For example, a BOc group or a carbopencyloxy group can bind an amino group, especially in the α-position. preferred for protection. With a benzyl group or a suitably substituted benzyl group , the mercapto group of cysteine, or other thiol-containing amino acids; Protects hydroxyl of phosphorus or threonine. using tosyl or nitro groups The guanidine of Arg or the imidazole of His may be protected, as appropriate. Using a carbobenzyloxy or benzyl group substituted with TYr%Se The hydroxyl group of r or Thr or the ε-amino group of lysine may be protected. stomach. Suitable substitutions for carbobenzyloxy or benzyl protecting groups include chloro, bromo, ortho and/or parasubstitution by mono, nitro or methyl, and Used to modify reactivity. Cysteine and other sulfur-containing amino acids are , to form a disulfide using a thioalkyl group or a thioaryl group. Therefore, it may be protected. With the exception of the Boc group, protecting groups are most conveniently It cannot be removed by acid treatment. These protecting groups are known in the art. As you know, catalytic reduction, sodium in liquid ammonia or HF treatment, etc. removed by law.

Using solid-phase methods, peptides are separated starting from their carboxy terminus and moving toward their amino terminus. si is performed in order. Solid phase synthesis is generally described in U.S. Patent No. 4.244.946. As described, the C-terminus of the protected amino acid is attached to a suitable resin, e.g. Benzhydrylamine resin (BHA), methylbenzhydrylamine resin (MB HA) or chloromethyl resin (CMR). . At the carboxy terminus of the peptide product, which should be a carboxamide, BHA or or MBHA carrier resin. Where the peptide product should be a carboxyl group For the carboxy terminus, a CMR carrier is commonly used; It may also be used to produce cyamides and esters.

Modification of the terminal amino group of a peptide can be accomplished by This is achieved by alkylation or acetylation. These modifications are introduced into the peptide. for the amino acid before it is added, or after the synthesis and release of the terminal amino group. However, it may be performed on the peptide before the protective group is removed.

Typically, acetylation involves converting the acyl of the corresponding alkyl acid in the presence of a tertiary amine. This is done on free amino groups using halides, anhydrides or activated esters.

Monoalkylation is most conveniently carried out using a mild reducing agent, e.g. cyanoborohydride. a suitable aliphatic aldehyde or ketone in the presence of lithium or sodium chloride. This is carried out by reductive alkylation of the amino group using Dialkylation and quaternization treat the amino group with an excess of alkyl halide in the presence of a base. This can be done by

Solution synthesis of peptides uses traditional methods used to form amide bonds. achieved. Typically, a protected Boc amino with a free carboxyl group The acids optionally include 1-hydroxybenzotriazole (HOBT) and dimethylene In the presence of a catalyst such as fluoraminopyridine (DMAP), a suitable carbodiimide compound is linking agent, such as N,N' synchrohexylcarbodiimide (DCC) is used to couple to a protected amino acid with a free amino group. others methods, e.g. activated esters of the free carboxyl of protected Boc amino acids, anhydrous the protected amine or acid halide, optionally in the presence of a base. It is also suitable to react no acids with free amines. For example, protected Boa amino The amino acid or peptide may be a base, such as N-methylmorpholine, or a trialkyl an anhydrous solvent, such as methylene chloride or tetrahydrofuran, in the presence of a amine. (THF) with inbutyl chloroformate to form a mixed anhydride. Ru. This is subsequently reacted with a second protected amino acid or free amine of the peptide. let Peptides formed by these methods can be purified using conventional methods. selectively deprotecting the terminal or carboxy terminus and using similar methods to protect other It may be coupled to a peptide or amino acid. After the peptide is completed, Protecting groups as described above, e.g., water in the presence of a palladium or platinum catalyst. in liquid ammonia, hydrofluoric acid, trifluoroacetic acid or alkali. It can be removed by treatment with sodium.

To protect the terminal carboxyl group of peptides during solution synthesis, esters are often used. Stell is used. They are the hydroxylation of alkali metals in aqueous alcohol solutions. or carbonates, such as potassium hydroxide or sodium carbonate. Therefore, it may be converted to carboxylic acid. These acids are activated as described above. It may be converted to other esters via an acyl intermediate.

The amides or substituted amides of the present invention can be used in much the same way as carbon atoms of peptides. Prepared from acid. Therefore, ammonia or substituted amines can be converted into amino-protected α- Reacts with activated acyl intermediates of amino acids or oligopeptides to generate amides. Just let it happen. The use of a coupling agent, e.g. It is convenient to form substituted amides from the compound and the appropriate amine.

Furthermore, the methyl ester of the present invention can be used in a methanol solution with ammonia or It can also be directly converted to an amide or substituted amide by treatment with a substituted amine. good. A methanol solution of the peptide methyl ester is saturated with ammonia, Stirring in a pressurized reactor yields the simple carboxamide of the peptide. dixo The procedure for determining the inhibition constant (Ki) by Dfxon analysis is known in the art. For example, Dreyer et al., Proceedings of the Nation Naru Academy of Sciences of! --Nis A (Pro c, Natl, Acad, Sci, US, A,), Volume 86, 9752- 9756 (1989). Peptide degradation analysis - (Stricker) et al., Proteins, Volume 6, 1 34-154 (1989), the substrate Ac-Arg-Ala-Set- Gin-Asn-Tyr-Pro-Val-Val-NH2 and recombinant HIV Recruited using proteases. A low Ki value indicates high binding affinity.

Pharmaceutical compositions comprising the compounds of the present invention or derivatives thereof may be prepared as solutions or for parenteral administration. Alternatively, it may be formulated as a lyophilized powder. Powders should be mixed with a suitable diluent or may be regenerated by adding other pharmaceutically acceptable carriers. made of liquid The agent is generally an isodominant aqueous buffer solution. Examples of suitable diluents include the usual Tonic saline solution, standard 5% dextrose or sodium acetate in water or is an ammonium buffer solution. Such formulations are particularly suitable for parenteral administration. may be used for oral administration or in a metered-dose inhaler or nebulizer for inhalation. You may. Polyvinylpyrrolidone, gelatin, hydroxycellulose, arabic Agam, polyethylene glycol, mannitol, sodium chloride or citric It may be desirable to add excipients such as sodium chloride.

Furthermore, preferred compositions for parenteral administration include an amount of the above compound borne in liposomes. It may consist of things encapsulated in the body. Liposomes can be used in traditional hands A variety of methods including agitation, high pressure extrusion, reverse phase evaporation and microfluidization can be used The compound described above is added to the aqueous phase together with phospholipids and optionally cholesterol. , it may be formed by dispersing it. suitable for producing such compositions The method is disclosed in more detail in co-pending application no. 06/763.484. and is incorporated herein by reference. Such carriers can optionally contain viral particles or or by immunoglobulins or proteins that are reactive against infected cells. All you have to do is direct it to the part. The choice of such a protein is, of course, dependent on the infectious virus. Depends on the antigenic determinants of the virus. Examples of such proteins include CD-4 T cell glycoproteins. proteins, or derivatives thereof, such as human immunodeficiency virus (HIV) glycoproteins. It is 5CD-4 (soluble CD-4) that is reactive against Pakneet. This way Eel protein is disclosed in co-pending application no. 07/160.463, which It is hereby incorporated by reference. Other viruses can also be tested using methods known in the art. Therefore, it is possible to devise a similar target protein, and therefore it is within the scope of the present invention. Understand.

Alternatively, these compounds may be filled into capsules, tablets, or Alternatively, it may be prepared into oral dosage forms such as emulsions and syrups. pharmaceutically acceptable A solid or liquid carrier may be added to enhance or stabilize the composition; Alternatively, it may facilitate preparation of the composition. Liquid carriers include syrup, peanuts Includes raw oil, olive oil, glycerin, saline and water. as a solid carrier Contains starch, lactose, calcium sulfate dihydrate, clay, stearic acid nesium or stearic acid, talc, pectin, gum arabic, agar or zebra One example is latin. Also, glycerin monostearate and glycerin distearate Also included in the carrier are sustained release materials such as waxes alone or in combination with waxes.

The amount of solid carrier varies, but preferably from about 20 mg to about 1 g per dosage unit. be. In tablet form, the drug preparation can be crushed, mixed, granulated, and as required. Also, in the form of hard gelatin capsules, involves grinding, mixing and filling. Manufactured according to conventional pharmaceutical methods with If a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, or aqueous or non-aqueous suspension. It is a state. Such liquid formulations can be administered directly orally or in soft gelatin capsules. It may also be filled into bottles.

For rectal administration, pulverized powder of the compound of the present invention is mixed with cocoa fat, glycerin, etc. It can be combined with excipients such as gelatin or polyethylene glycol, or made into suppositories. Just mold it. The ground powder can be combined with oil-based preparations, gels, creams or emulsions. may be administered by transdermal patch, with or without buffers. stomach.

The present invention also provides treatment for viral infections, particularly infections caused by retroviruses. A method comprising administering a compound of formula I to a patient infected with an infectious virus. This is a method consisting of: This method is particularly useful for infections caused by human immunodeficiency virus type 1. Applicable to The compounds of the present invention can be used to infect infectious viruses and This treatment method may induce antiviral activity in patients who require such treatment. orally, an effective amount of the selected compound, preferably dispersed in a pharmaceutical carrier. Parenterally, bucally, transdermally, intravenously, intramuscularly, rectally, or by inhalation It consists of administering by. The dosage unit of the active ingredient is per kg of body weight. It is selected within the range of 0.05 to 50 mg. Dosage units typically contain 50 to 1 000mg. For acute or chronic infections, use 1 of these dosage units. It may be administered 1 to 10 times per day. Dosages can be readily determined by those skilled in the art. and depends on the age, weight and condition of the patient, as well as the route of administration. European patent issued The combination therapy described on pages 42-47 of Application No. 337714 is included herein. It will be done.

The following examples serve to illustrate the invention. These examples are within the scope of the invention. The compounds of the present invention can be produced and used without any limitation. It is given to show how it is used.

In the examples, all temperatures are in degrees Celsius. Amino acid analysis is done by Dionex. The test was carried out using Dionex Autoion 100. Contains peptide Quantitative analysis is based on amino acid analysis. The FABji quantity spectrum is Performed on a VGAab mass spectrometer using child collisions. The NMR spectrum is Bruca Recordings were made at 250 MHz using a Bruker A@250 spectrometer. display The multiplicity of is: S=-multiplet, d-doublet, t-triplet, q-quartet, m-multiplet. Yes, br indicates a broad signal.

Debouck et al., Proceedings of the National ・Academy of Sciences of New York (Proc, Natl, Acad, Sci.

USA), Vol. 84, pp. 8903-6 (1987). present invention Enzymes used to analyze compounds are produced in this way and made into sticks. S tickler and others have already released Proteins. 4, pp. 139-154 (1989), cell pellets It was purified from

Example Example 1 Preparation of (3S, 55)-3,5-diamino-4-hydroxyhebutane l Preparation according to step 1: a) 1.2 + 4.5-dianhuman 1:1l-D-(+)-arabitol 9be A D-(+)-arabitol in dry acetonitrile (200 mL) under r. (13.9g.

91.4 o1: Form an azeotrope with toluene and dry). The mixture was stirred overnight. This solution was concentrated using a rotary evaporator. , dissolved in ethyl acetate (500 mL), 5% NaHCOs (2X30WL) and Washed with brine (3Q+L), dried over Na2S04, and concentrated. residue was dissolved in dry THF (500 mL), cooled to -10 °C, and stirred mechanically under Ar. While stirring, add solid sodium mesylate (11.1 g, 205 mmol). added. After 20 minutes, the mixture was poured into a nitil (2,51) and a glass fiber was added. Filtered through fiber filter paper to remove sodium mesylate, and rotary filtered at 30°C. It was concentrated using an evaporator. The residue was subjected to flash chromatography (silica gel , 3:2 ether; pentane) to give the title compound 9 (3,96 g, 34. 1 mmol, yield 37%) was obtained.

b) 1.2+4.5-dianhydro-3-(0-benzyl)-D-(+)-ara Vitol 10 bromide pencil (8.92 mL, 75 mmol) was added to THF (9 m A slurry of NaH (1°8 g, 75 ml) in L) was added. This mixture The mixture was cooled to −10° C. under Ar and poured into THF (9a+L) with stirring. Compound 9 (3.90 g, 341111101) was added dropwise. take a bath The mixture was briefly warmed to 40° C. and then cooled again. this mixture Diluted with 1% acetic acid (100 mL) and extracted with ethyl acetate (2×250 mL).

Wash the organic extract with 5% NaHCOs (751 L) and saline (75!!L) , dried over NazSOi, and concentrated. Flash chromatography of the residue = (gradient, 0-4% ethyl acetate in pentane) to give the title compound 10 (3,8 8g517.2mmol, yield 55%) was obtained. 'HNMR (CDC1g): δ 7.4-7.1 (5H, m), 4.75 (IH, d; J=12Hz), 4. 65 (IH, d; J=12Hz).

3.2 (IH, m), 3.05 (LH, m), 2.9 (IH, t; J=7H z), 2.8 (2H.

m), 2.65 (2H, m).

cX2S, 45)-1,5-diazide-2,4-dihydroxy-3-benzi 1,65 g in 50 g of dioxane and 50 QaL of dioxane 56.5 g of NaN (100 O1) and compound 10 of (8,0 O1,) and tetra-n-butylammonium hisulfate 349 mg (1 mmol) was added. The reaction mixture was heated to reflux for 4 hours, cooled and rotary evaporated. Concentrate volumetrically to 50 mL using a vacuum evaporator and extract with ethyl acetate (3X 50 sL). I put it out. The combined organic extracts were dried (Na2SO,) and concentrated to an oil. Then, combine this with ether:hexane (1:1) and crystallize at 4°C. 1.76 g of the title compound 11 was obtained (yield 69%). 'HNMR(C D C1g): 67.5-7.3 (5H, m), 4.6 (2H, dd; J = 12Hz).

4.0 (2H, m), 3.6-3.0 (6H, m).

dX2S, 45)-1,5-diazide-2,4-di(methanesulfonyl) xy)-3-benzyloxypentane 12 6.30+g (2.15 mmol) of bisazide in OmL of pyridine 350 μL (4,5a+mol) of methanesulfonyl chloride was added to Step 11 at 0°C. was added. The reaction mixture was warmed to 25°C and stirred for 20 hours, then 6N It was diluted with 12 sL of HCI and extracted with 10 QmL of methylene chloride. 3% organic layer Washed with NaHCOs, dried (N a 2 S04) and concentrated. Clean the residue. By applying rush chromatography (95:5CH, C12 ether) Thus, 867 mg of the title compound 12 was obtained (yield 90%). 'HNMR (CDC 13): δ7.4-7.2 (5H, m), 5.0-4.7 (4H, m), 4.0 2 (2H, dd, J=3Hz), 3.9-3.5 (4H, m), 3.15 (3H , s), 3.10 (3H, s).

eX2 S, 45)-1,2+ 4.5-di(N-carbon benzyloxy imino)-3-benzyloxypentane 13 Dry THF 2. □310 mg of compound 12 of step (d) in sL (0, LM LiAlH41,5+L in THF at 0° C. (1.5 wmol) was added.

The mixture was warmed to 25°C and stirred overnight. Add water (0,1 sL) and then Then, 15% NaOHO, 1L and 0.4mL of water were added. This mixture is Stir vigorously with 1QmL of water and filter. Concentrating the ether layer yields the crude of bisaziridine was obtained. Dissolve this in 51llL of CH2C1x and 200 μL (1.4 mmol) of ruamine and pendylchloroforme-1-20 Combined with 0 μL (1,4 sL). This mixture was stirred at 25°C for 3 hours. then Filtered. The filtrate was concentrated and the residue was subjected to flash chromatography (ethyl acetate). :hexane 1:5) to obtain 89 mg of the title compound 13 (harvested rate 28%). IHNMR (400MHz; CD C15): δ7.4-7 ．． 2 (15H, m). 5.0 (LH, d: J = 12Hz), 4゜93 (IH, d; J = 12Hz), 4.88 (IH, d; J = 12Hz), 4.84 ( IH, d; J = 12 Hz), 4.74 (LH, d; J = 12 Hz), 4.39 ( IH, d; J=12Hz).

2.82 (IH, t+J=6Hz), 2.6 (IH, m), 2.45 (IH, m ), 2.25 (IH, d: J = 6 Hz), 2.15 (IH, d; J = 6 Hz), 2.04 (IH, d:J=3Hz).

2.02 (IH, d; J=3Hz). MS (DCl, NHs): m/z473. 1 (M+).

f) (3A,5S)-3,5-di(carbonbenzyloxyimino)-4-be Zyloxypentane 14 Suspension of CuI (72 mg, 0.375 mmol) in 5 mL of ether 5 sL of 1.5M CHsLiO in ether was added to the solution at -25°C. . The resulting colorless solution was cooled to -45°C and dissolved in 5 mL of ether Q. A solution of Suaziridine 13 (10 mg, 0.02+wol) was added. -45℃ After stirring for 1 hour, the mixture was warmed to 10°C for 6 hours and then The mixture was further stirred for 2 hours. Add this mixture to 2 L of a saturated aqueous solution of NH4ClH4Cl and Diluted with water IIIL and then extracted with ether. Wash the organic layer with brine, Drying (over CNazSOa) and concentration afforded the title compound 14 ( 10+wg). 'HNMR (CDC1s): δ7゜2 (15H, m), 5.2- 4.9 (4H, m), 4.93 (IH, d, J=12Hz), 4.88 (LH, d: J = 12Hz), 4.84 (LH, d: J = 12Hz), 4.7 (2H, d ; J=12Hz), 4.4 (2H, d; J=12), 3.7 (2H, m), 3. 4 (IH, d; J = 2Hz), 1.6 (4H, m), 1.0 (3H, t; J = 7Hz), 019 (3H, t; J = 7Hz).

X3S,5S)-3,5-diamino-4-hydroxyhebutane 1 step (f) The composition was prepared under a hydrogen atmosphere at 0.0%. 20% P on carbon in IN methanolic HCI d (OH)! (50% by weight) for 24 hours. Filter and remove the solvent. The title compound 1 was converted into the dihydrochloride salt (where XI and X2 are hydrogen) by (R1 and R2 are ethyl).

Preparation according to the procedure of Scheme 2 aX3R,5R)-3,5-dihydroxy-4-benzyloxyhebutane 15 - Suspension of Cu I (143 mg 50.75 m + aol) in 3 mL of Add methyllithium (1 sL, 1.5 M in ether; 1.5 mmol) was added. The resulting colorless solution was stirred at -30°C for 30 min and then The mixture was then cooled to -78°C.

of bisepoxide 10 (78 mg, 0.37 o1) in 2 mL of ether. solution was added. The reaction was warmed to 25°C for 4 hours, then NH4C 1 saturated aqueous solution, concentrated NH, and water were added. This mixture was extracted with ether and the The title compound was obtained by drying the organic layer with Na2S○4 and removing the solvent. (93+g, yield 100%) o'HNMR (CDC13): 67.4-7. 1 (5H, m), 4.7 (LH, d; J-12Hz), 4.55 (IH, d; J=12Hz), 3.9-3.7 (2H, m), 3.2 (IH, dd), 2.5 (2H, b), 1.6-1.4 (4H, m), 1.0 (3H, t: J =7Hz).

0.9 (3H, t:J=7Hz).

Methanesulfonyl chloride (0,3+L) in pyridine (1sL) at 0°C The mixture was added dropwise to Diol 15 (93 mg) in the refrigerator. This mixture was warmed to 25°C.

After 12 hours, the mixture was diluted with cold 6N HCl (10 sL) and CH2Cl□ Extracted with. The organic extract was washed with 3% NaHC○, dried over MgSO4, Concentrated. The residue was purified by flash chromatography to give the title compound. (83 mg, yield 56%). 'HNMR(CDCb)+67.4-7.2 (5H, m), 4.75 (IH, m).

4.7 (IH, d: J=12Hz), 4.6 (IH, d; J=12Hz) , 4.58 (IH.

m), 3.9 (IH, dd+ J = 2.6Hz), 3.0 (3H, s), 2.9 (3H, s), 2.1-1.5 (4H, m), 1.05 (3H, t; J=7 Hz), 1.0 (3H, t; J=7Hz).

c) (33,55)-3,5-diazido-4-benzyloxyhebutane 17 dimethyl Bismesylate 16 (83 mg, 0.5 mg in 1.5 aL of chillformamide) 21111!1ot) and sodium azide (0.5g, 7.7mmol) The mixture was heated to 70°C for 12 hours. After cooling, add ethyl acetate (20 sL). and the mixture was filtered and concentrated. The residue was subjected to flash chromatography. The title compound was obtained (54 mg, yield 90%). 'HNMR(C DCIs): δ7.4-7.2 (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).

dX3S, 55)-3,5-diamino-4-benzyloxyhebutane 18T Bisazide 17 328 mg (1.14 mmol) in HF 5+L, At 0°C, 11 g of LiAlH4 was added. Warm this mixture to 25°C, Stirred for 5 hours.

Quench the reaction by adding 0.5 sL of 15% NaOH for 15 min. Stir for a while, dilute with 150 mL of ether, and filter. By concentrating the filtrate The title compound was obtained (278+g, yield 100%). 'HNMR (CDCIs ): δ7.26 (5H, m), 4.5 (2H, dd: J=12Hz), 3.1 (LH, dd; J=4.6Hz).

2.9 (IH, m), 2.75 (IH, m), 1.8-1.0 (10H, m), 0.9 (3H, t; J=7Hz), 0.85 (3H, t; J=Hz).

e) (3S, 55)-3,5-diamino-4-hydroxyhebutane 1 methanol Diamine product 18 (52+og) in 4+L was added to 20% Pd on carbon. 50 mg of (OH)z and 2 drops of concentrated HCI aqueous solution were added. This mixture was The title compound was obtained by stirring under atmosphere for 16 hours, then filtering and concentrating. 1 (53 mg) was obtained as the dihydrochloride. IHNMR (CDjOD): δ3.75 (IH, dd.

J = 4.7Hz), 3.2-3.0 (2H, m), 1.8-1.4 (4H, m ), 0.9 (6H, t; J=7Hz).

Example 2 (3S, 55)-3,5-di(alanylalanyl)amino-4-hydroxy fresh heptane 2 aX3S, 55)-3,5-di(carbobenzyloxyalanylalanyl ) amino-4-37-mol), carbobenzyloxyalanylalanine 22 1 g (0,75 m 01), HOBT 115 mg (0,75 m 101), and 154 mg (0.75 mmol) of DCC were added. Stir this mixture overnight then concentrated, taken up in ethyl acetate, filtered, washed with water and brine, ( (MgSOa). The solvent was removed, followed by MPLC (silica; CH, The title compound (109 mg) was prepared by subjecting the title compound (109 mg) to 2% methanol in C12. Obtained. IHNMR (DMSO-ds): δ8. O-7,2 (21H, m), 5゜0 (4H, bs), 4.6 (2H, dd; J=12Hz), 4.2 (2H, m), 4.0 (2H, m).

3.8 (IH, m), 3.7 (IH, m), 3.5 (IH, dd: J = 4.7 Hz), 1.7-1.3 (4H, m), 1.1 (12H, m), 0.75 (6H, t).

10 mg of (OH)z was added. The mixture was stirred for 6 hours under 1 atm R2. , then filtered and concentrated to yield the title compound 2 (where XI and x2 are AlaA 1a, R1 and R2 are ethyl, 83 mg) was obtained. 'HNMR(C DsOD): δ4.3 (2H, m), 3.8 (2, H, m), 3.7 (IH, m ), 3.5 (LH, m), 1.8-1.2 (16H, m), 0.8 (6H, dt ).

Example 3 (3S, 55)-3,5-di(carbobenzyloxyvalyl)amino-4- 65 μL (0.5 mmol) of hydroxybutyl chloroformate was added. . After stirring for 10 minutes, 25 mg of diamine hydrochloride in DMF IIL (0,171 uol) and 50 μL of NMM were added. Slowly stir this mixture. warmed to 20°C, then diluted with ethyl acetate, 5% HCI, 5% NaHCO x and brine, and the organic layer was concentrated. Flash chromatograph the residue Purification with filtrate (ethyl acetate:hexane) yielded the title compound 3 (where XI and and X2 are Cbz-Val, R1 and R1 are ethyl) (18+ag ) was obtained. IHNMR (CD30D): δ7.5-7.3 (10H, m), 6. 9 (IH, br d), 6.35 (LH, br d), 5.5 (H, br d) , 5-25 (IH, 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/z613.2 (M+H)1 ゜ Example 4 (2S, 45)-2,4-di(alanylalanyl)amino-3-hydroxy -Preparation of 1,5-diphenylpentane 4 aX2R,4R)-2,4-dihydroxy-3-benzyloxy-1,5-Schiff s nylpentane 20 Suspension of CuI (191 mg, 1 ausol) in ether (5 mL) Add phenyllithium (4.0 mL, 2.0 mmol) to the solution at -60°C. freshly prepared from bromobenzene and lithium wire) was added. The mixture was warmed to -50°C and then recooled to -78°C. workman Bisepoxide 10 (40 mg, 0.19 mmo in IIL) l) solution was added. The mixture was heated to 25°C over 6 hours while stirring. did. After a further 12 hours, the mixture was diluted with ether and diluted with 1:1 concentrated ammonia. Water: Washed with 20 iL of saturated NH4CL. Dry the organic layer over MgOA , concentrated. The residue was purified by medium pressure liquid chromatography (ethyl acetate:hexane 1:4). ) to give the title compound 20 (22 mg, 30% yield) as a colorless solid. Obtained. 'HNMR (CDCLs): δ7.5-7.0) 13H.

m), 4.75 (LH, d: J-12Hz), 4. ．． 15 (IH, d; J=1 2Hx), 4.2 (2H, m), 3.3 (IH, m), 3.0-2.7 (6H, m).

bX2 S, 45)-2,4-di(alanylalanyl)amino-3-hydro xy-1,5-diphenylpentane 4 Title compound 4 (Xl and X2 are AlaAla, R1 and R2 are PhC H2) was prepared from compound 20 by the procedure of Example 2.

Example 5 (4R,5R)-4,6-diamitu-5-hydroxy-2,8-dimethyl-1, 8-Town of Nonan 5 aX4R,5R)-4,6-cyhydroxy-5-benzyloxy-2,8-dime Chill-1,8-nonadiene 21 CuJ (192ttrg, 1.Ommol) in ether (2mL) Impropenyl lithium (5.2 mL, 2. Qam ol; in needle (Do, 38M; 2-bromopropene and lithium freshly prepared from wire) was added. The mixture was warmed to -45°C and then It was recooled to -78°C. Bisepoxide 10 (6) in ether (5 mL) 0mg, 0129. The solution of 1) was added. While stirring this mixture, The mixture was heated to 0°C over a period of time. This mixture was diluted with ether and diluted with 1:1 concentrated ammonia. Aqueous solution: Washed with 5 mL of saturated NH, C1. Dry the organic layer over MgSO4, Concentration gave the title compound 21 (81111 g, 96% yield) as a colorless solid. Obtained. 'HNMR (CDCL: δ7.3 (5H, m), 4.9 (IH, bs ).

4.85 (IH, bs), 4.80 (IH, bs), 4.65 (IH, d:J= 12Hz), 4.58 (IH, d: J = 12Hz), 4.0 (2H, m ), 3.3 (IH, dd: J = 2.5Hz).

2.55 (IH, d; J, = 6Hz), 2.55 (LH, d; J = 4Hz) , 2.5-2.1 (4H, m), 1.7 (IH, s).

bX4　R,6R)-4,6-cyhydroxy-5-benzyloxy-2,8-di Methyl nonane dan 1 Product 21 of step (a) (105 mg, o, 38 mmol), Ir(COD)Py(PCy)sPFs 55mg( Crabtree catalyst) was added. This mixture was heated to 1 atm of R 2 for 6 hours, then filtered and concentrated to yield the title compound 22 (110 tg. , yield 100%). 'HNMR (CDCIs): δ7.3 (5H, m), 4.6 (IH, dd: J=12Hz), 4.0 (2H, m), 3.1 (IH, br s), 2.7 (2H, br s), 2.01-1.1 (6H, m), 1. 0-0.8 (12H.

m).

cX4　R,6R)-4,6-di(methanesulfonyloxy)-5-penxy Ruoxy-2゜8-dimethylnonane 23 Methanesulfonyl chloride (0.25 iL) was dissolved in pyridine (IIL) at 0°C. The mixture was added dropwise to Diol 22 (93 mg) in the refrigerator. This mixture was warmed to 25°C.

After 10 hours, the mixture was diluted with cold 6N HCl (10 iL) and C) (, CI , extracted with . The organic extracts were washed with 3% NaHCOs and dried over MgOa. The resulting residue was purified by flash chromatography to give the title compound. 23 (210IIg) was obtained.

IHNMR (CDC13): δ7.4 (5H, m), 5.0 (LH, d; J = 12Hz), 4°7 (IH, m), 4.6 (IH, d; J = 12Hz), 3.85 (IHxdd; J-4,7Hx).

3.0 (3H, s), 2.0 (3H, s), 2.0-1.1 (6H, m), 1. 0-0.9 (12H1m).

dX4R,6R)-4,6-diacido-5-benzyloxy-2,8-dimethyl Product of step (c) 23 (210o+g) in nonane 24DMF 2+1L ), 870 mg (15a+mol) of NaN* was added. 70% of this mixture ℃ for 7 hours, then cooled and diluted with ethyl acetate. Concentrate the filtrate and remove the residue. was purified by MPLC (ethyl acetate:hexane 1:20) to give the title compound 24 (5 2 mg) was obtained. 'HNMR (CDCh): δ7.3 (5H, m), 4. ．． 55 (2H, dd; J-12Hz), 3.4-3.15 (3H, m), 2°0-1 ．． 1 (6H, m), 1.0-0.75 (12H, m).

eX4S, 65)-4,6-diamy2-5-benzyloxy-2,8-dime Product of step (d) 24 (52 mgg, 0.15 m5 ol) at 0°C, LiAlH4 (2 mmol) 80 m g was added. The addition was stirred overnight at 25°C, then quenched with 1N NaOH. diluted with ether (50+iL). By filtering and concentrating, The title compound 25 (44 mg) was obtained as a colorless oil. IHNMR (CDC14): 67.3 (5H, m), 4.6 (2H, dd: J = 12Hz), 3.1 (LH .

m), 3.05-2.95 (2H, m), 1.9-1.1 (6H, m), 1.0 -0.8 (12H.

m).

165 mg of step (e) in 10 mL of methanol containing 5 drops of concentrated HCI To diamine 25 was added 1001 g of 20% Pd(OH) on carbon. this The mixture was heated to 1 atm H! Stir at room temperature overnight, then filter and concentrate to give the title compound 5. (Xl and X1+1 hydrogen, R+ and R2 are isobutylene/14'a6X75mg ) was obtained. 'HNMR (CD, OD): δ3.7 (IH, m), 3.2 (IH, m), 1.8-1.0 (6H, m), 0.99-0.8 (12H, m).

Product 25 of Example 5, step (e) in DMF 2a+L (44+g, 0 ．． 15 mmol), Cbz-AlaAla 110 + g (0,3751 + ao 1), 58 mg (0,375 mmol HOBT.

and 721 g (0,375111 mol) of DCC were added. Add this mixture to 2 Stir at 5° C. for 48 hours, then dilute with 20 mL of ethyl acetate and filter. filtrate Concentrate and MPLC the residue (gradient, 0-5% methanol in qHICI□) The title compound 26 (24 mg) was obtained. IHNMR (CD, O D): δ8. O-7,2 (21H, m), 5.0 (4H, overlap dd), 4.2 (2H, m), 4.0 (4H, m), 3.5 (LH, brs), 1.7-1.1 5 (18H, m), 0.9-0.7 (12H, br t).

The product 26 (12a+g) of step (a) in 2iL of DMF is 25011 g of 20% Pd(OH) was added. This mixture was heated under R1 of 1 atm. Stir for 0 h, then dilute with methanol, filter, and concentrate to give the title compound 6 ( Xl and Xz are AlaAla and R+ and R2 are inbutyl ．． 5g) was obtained. IHNMR (CDSOD): 64.25 (2H, m), 3. 8 (IH, m), 3.65 (2H, m), 3. HIH, br　d), 1.6-1 ．． 1 18H, m), 0.7 (12H, br d).

Example 7 (4R,6R)-4,6-cycarpobenzylodi)amino-5-hydroxy- Preparation of 2,8-dimethyl-1,8-nonane 7 6.0 mg of bis-amine hydrochloride product 5 in 0.5 iL of ChzCh , at 20°C, 5 mL of triethylamine and pendylchloroforme) 10! I L was added. After 3 hours, the mixture was applied to a silica column, CHiCb and then diluted with ether to give the title compound 7 (Xl and X2 are Cbz, R1 and and R1 is isobutyl, X4.6a+g) was obtained. 'HNMR(CDCIg ): δ7.3 (10H, bs), 5゜1-4.9 (6H, m), 3.9-3 ．． 7 (2H, m), 3.5-3.35 (2H, m: Can be exchanged to IH with DtO) , 1.7-1.5 (4H, rn), 1.3-12 (2H, m), 1.1-0.8 (12H, m).

Example 8 (4R,6R)-4,6-di(carbobenzyloxyvalyl)amino-5-hyperyl Preparation of droxy-2°8-dimethyl-1,8-nonane 8 Title compound 8 (X’ and and X2 are Cbz-Val and R1 and R2 are isobutyl) is the compound Prepared by the procedure of Example 3 except that Compound 5 was used in place of Compound 1.

'HNMR (250MHz, CDC14) 7.5-7.28 (m, 10H), 6゜8 (br s, IH), 6.3 (br d, LH), 5.6 (br s, IH), 5.25 (br　d, IH).

5, 1 (br　s, 4H), 4.5-3.5 (m, 6H), 1.5-2.5 (m, 6H), 016-1°0 (m, 24H).

Example 9 (2S, 45)-1,5-diphenyl-3-hydroxy-2,4-bis(ben Preparation of Zyloxycarbonylaminovalinylamino)pentane 40 a) 2R,4 R)-1,2,4,5-dianhydro-3-benzyloxyarabitol 33 ice 15.2 g (100 mmol) in 350 aL of pyridine cooled in a bath ) of D(+)-arabitol, 38.8 g (203,5+uol) of p-Toluenesulfonyl chloride was added portionwise. Stir for 3 hours and bring to room temperature. Warm and pour into 500aL of ether. Separate the ether layer and reduce the aqueous layer to 800aL. Extracted with ether.

The combined organic layers were washed with 400aL of 3% sodium bicarbonate and soaked in anhydrous magnesium sulfate. After drying with SiO and removing the solvent in vacuo, 34.17 g (74%) Sylate 32 was obtained. IHNMR (CDsCOCD3) δ7.75 (d, 4H, J=7Hz).

7.25 (d, 4H, J=7Hz), 4.4-3.5 (m, 7H), 3.2 (b , 3H), 2.5(s, 6H).

10 g of sodium hydride in 300 L of THF (55-60% in oil, bistocillation in 200+aL of THF at 0°C. The solution of Part 32 was added and stirred vigorously for 1 hour. This reaction mixture was added to 10 μL of Treated dropwise with 121 L of benzyl bromide in THF and stirred for 1 hour at 0°C. did. Warm to room temperature and stir overnight. Quench by dropping 50L of water at 0℃ did. Extract with ether, wash with water, dry over anhydrous sodium sulfate, and remove the solvent. Removed in vacuo. The residual oil was filtered through silica gel (first dissolved in hexane). to remove unreacted benzyl bromide, and then dissolve in ethyl acetate hexane, 1:4. 9.0 g of bisepoxide were obtained as a slight oil. flash Further chromatography (silica, ethyl acetate, hexane 1:10) 6.10 g of dieboxide 33 was obtained. 'HNMR (CDCIs, 250MHz) δ7.4-7゜1 (m, 5H), 4.75 (d, IH, J=1 2Hz), 4.65 (d, IH, J=12Hz).

3.2 (m, IH), 3.01 (m, IH), 2.9 (t, IHJ=7Hz), 2.8 (m, 2H), 2.65 (m, 2H).

bX2R,4R)-1,5-diphenyl, 3-benzyloxy-2,4-dihyde Roxypentane 34 2.99 g (15.5 mmol) of iodized steel in 30 L of THF ( 1) to the suspension in cyclohexane (newly opened bottle) of 1.8M phenyllithium was added. The reaction mixture was heated to -50°C, Recooled to -78°C and added 1,01 g (4,9 mmol) of bisepoxide 33, warmed to room temperature and stirred overnight. Ta. Conventional work-up gave 1.75 g of diol 34 as an oil. A Trituration with tel/hexane gave 1.45 g (82%) of a colorless solid.

Elemental analysis, calculated values (as Cz4HzsOx): C(79,53), H(7,2 3); Actual value: C (79,25), H (7,18); MS (DCl, NHsXM +H)″364.5;’HNMR (CDCIs, 250MH,)67.4-6 , 8 (m, 15H), 4.62 (d, IH, J = 12Hz), 4.5 (d, IH, J = 12Hz).

4.2 (m, 2H), 3.3 (dd, IH, J=), 2.8 (m, 4H).

eX2R,4R)-1,5-diphenyl-3-benzyloxy-2,4-bis( methanesulfonyloxy)pentane 35 and (2S, 45)-1,5-diph phenyl-3-benzyloxy-2,4-diazidopentane 365 mL pyridine Add 1 L of methanesulfonyl chloride at 0°C to 400+ og of diol in Added Ride and stirred at room temperature for 18 hours. in 20tiL of 3N hydrochloric acid cooled with water. Pour, extract with 50 μL of methylene chloride, wash with 3% sodium bicarbonate, After drying over anhydrous sodium sulfate and removing the solvent in vacuo, 1.20 g of 35 was obtained. Obtained as an oil.

The above crude product was dissolved in 5+aL of DMSO, and 1.05 g (16 mmol) of Sodium azide was added. The reaction mixture was heated at 80" for 6 hours, then at 100" ’ and heated for an additional 8 hours. Cool the reaction, dilute with ether, and remove any unreacted of sodium azide was filtered off. Remove the combined solvents in vacuo and flash By chromatography, monoazide 36, (25,45)-1,5-dife Nyl-3-benzyloxy-4-azido-pent-1-ene, and bisazide 285 mg of an inseparable mixture in the ratio 70:30 calculated from IHNMR of 37 I got it.

dX2S, 45)-1,5-diphenyl-3-benzyloxy-2,4-di The azide product obtained above in 1 Q mL of aminobentane in diethyl ether ( 279 mg of a mixture of 36+37) in THF at 0″ 31 L of a 1M solution of aluminum was added over 10 minutes. 30 minutes at 0℃ Stir, warm to room temperature, and stir for 3 hours. Cool in a water bath and Quenched with sodium chloride, diluted with ether and stirred for 2 hours. Remove the precipitate The mixture was filtered through a filter and washed with ether. Remove the solvent and then add 10 g of Florisil Chromatography on top (hexane, ethyl acetate:hexane 1:4, then methane) 112+ng of pure diamine 38 was obtained. ’ HNMR (CDCIs, 250MH,) 67.2 (m, 15H), 4.7 (d, 21H, J=12Hz), 4.5(d, 21H.

J=IH), 4.1 (m, IH), 2.3-3.2 (m, 6H).

eX2S, 45)-1,5-diphenyl-3-hydroxy-2,4-diami 621 g of Nopentane 39 diamino compound was added to 1□+L containing 1 g of concentrated hydrochloric acid at 75°C. Hydrogenation over 25 mg of Pd/C in methanol. Stir for 8 hours and touch The medium was filtered off and washed with methanol. By removing the solvent, 68tng A solid substance was obtained. By rubbing this with hexane ether, 4811 g of pure diamine was obtained as the hydrochloride salt. IHNMR (CD30D, 250MH , ) 67, 4-6.9 (m, 10H), 4゜1 (bd, LH, J = 6Hz ), 3.5-3.7 (m, 2H), 2.5-3.4 (m, 4H).

fX2S,4S)-1,5-diphenyl-3-hydroxy-2,4-bis(ben Zyloxycarbonylaminovalylamino)pentane 40 by mixed anhydride method , 37 mg (0,107 mmol) diamine hydrochloride, 150 mg Cbz-V al, 98 μL N-methylmorpholine and 80 μL isobutylchloroform. The title product was prepared from Mate as 68 mg of a white solid. Flush the analysis sample Prepared by chromatography (silica, 10% MeOH/CH2Cl4). Manufactured. MS(ES/MSXM-H)”735;’HNMR(CDC1s , 250MHz) 67, 4-7.0 (m, 20H), 6. Hd, IH, J = 7Hz), 5.5 (d, IH, J = 7Hz), 5.0 (m, 8H), 4 ．． 0 (m, 2H), 3.6 (m, 2H), 2.8-3.4 (m, 4H).

2, 2 (m, IH), 1.85 (m, IH), 0.9 (d, 3H, J=7Hz ), 0.86 (d.

3H, J = 71 (z), 0.7 (d, 3H, J = 7Hz), 0.55 (d, 3H , J=7Hz).

Implementation Nl0 (3S, 55)-3,5-di(carbobenzyloxyalanylalanyl)a Preparation of mino-4-hydroxypentane 50 a) (2R,4R)-1,5-diazide-2,4-dihydroxy-3-benzyl Oxypentane 41 1,65 g (8,0 mmo 1), 56.5 g of NaN (10 α ol) and tetra -n-butylammonium bisulfate) 340+g (1+uol) was added. Ta. The reaction mixture was heated to reflux for 4 hours, cooled and rotary evaporated. Concentrate volumetrically to 50 mL and extract with ethyl acetate (3×50 μL). combined The organic extract was dried (Na, So) and concentrated to an oil, which was purified with ether. 1.76 g of the title compound was crystallized at 4° C. with 1:1 hexane: A product (yield 69%) was obtained. 'HNMR (CDCl2): 67.5-7.3 (5H , m), 4.6 (2H, dd; J=12Hz), 4.0 (2H, m), 3°6 -3.0 (6H, m).

bX2R,4R)-1,5-diazide-2,4-di(methanesulfonyloxy ) ~3-benzyloxypentane 42 30 mg (2,15 ml Iol) of 6 in 6,0+sL pyridine Add 350 μL of methanesulfonyl chloride (4,5 mmol) was added.

The reaction mixture was warmed to 25°C, stirred for 20 hours, then treated with 6N HCl 12 mL and diluted with 100a+L of methylene chloride. The organic layer was diluted with 3% NaHCO s, dried (Na2SOa) and concentrated. Flash chroma the residue 867 mg (yield) The title compound was obtained with a yield of 90%. 'HNMR (CDCIs): 67.4-7.2 (5H, m), 5.0-4.7 (4H.

m), 4.02 (2H, ddj=3Hz), 3.9-3.5 (4H, m), 3. 15 (3H-s).

3, 10 (3H, s).

cX2s, 4S)-1,2+4.5-di(N-carbobenzyloxyimino) -3-benzyloxypentane 43 310+g (0,69+uol) of compound 42 in 2mL of dry THF, LM LiAlH41,511L (1,5 mmol) in THF at 0 °C was added. The mixture was warmed to 25°C and stirred overnight. Water (0.1 L) and then 4 mL of 15% NaOH 0,IIIL and water Q. child The mixture was stirred vigorously with 10+L of ether and filtered. Concentrate the ether layer In this way, crude bisaziridine was obtained. Change this to CH2CI2Sr a Dissolved in L, 200 μL of triethylamine (1,4 dragon o1) and 200 μL of triethylamine Combined with μL (1,4×5eal) of benzyl chloroformate. this mixture The mixture was stirred at 25° C. for 3 hours and then filtered. Concentrate the filtrate and flash-crunch the residue. Purification by chromatography (ethyl acetate:hexane 1:5) yielded 89+g (yield 28%) of the title compound was obtained. 'HNMR (400MHz: CDC15): δ 7.4-7.2 (15H, m), 5.0 (IH, d; J=12Hz), 4. 93 (IH, d　: J=12Hz), 4.88 (IH, d　; J=12Hz) , 4.84 (LH, d; J=12Hz), 4.74 (LH, d; J=1 2Hz), 4.39 (IH, d; J=12Hz), 2.82 (IH, t; J=6Hz), 2.6 (LH, m), 2゜45 (IH, m), 2.25 (IH .

d: J = 6Hz), 2.15 (LH, d: J = 6Hz), 2.04 (I H, d; J=3Hz).

2.02 (IH, d: J=3Hz). MS (DCI, NHs): m/z47 3.1 (M)

dX3S, 55)-3,5-di(carbobenzyloxyamino)-4-be 1,5 M CH3Li O,5 L in ether at 5°C to was added. The resulting colorless solution was cooled to -45°C and dissolved in 0.5 L of ether. Add a solution of bisaziridine 43 (10 Il+g, 0.02 ml ol) in did. After stirring for 1 hour at -45°C, the mixture was heated to 10°C for 6 hours. Warm and then stir for an additional 2 hours. This mixture was mixed with 2 m of saturated aqueous NH4Cl solution. L and 1 mL of saturated aqueous NH3, then extracted with ether. eats the organic layer Washed with brine, dried (Na2SOa) and concentrated to give the title compound (10 mg ) was obtained. 'HNMR (CDC1g): δ7.2 (15H.

m), 5.2-4.9 (4H, m), 4.93 (IH, d; J = 12Hz), 4 ．． 88 (IH.

d: J=12) (z), 4.84 (IH, d: J=12Hz), 4.7 (2H, d; J=12Hz), 4.4 (2H, d; J=12Hz), 3 ．． 7 (2H, m), 3.4 (IH, d; J=2Hz), 1.6 (4H, m) , 1.0 (3H, t: J = 7Hz), 0.9 (3H, t; J = 7Hz).

MS (DCl, NHsXM+H)"505.1゜e　X3　R,5R)-3,5 C in 3 mL of -dihydroxy-4-benzyloxyhebutane-45-ter ul (143mg, 0.75+a+5ol) at -35℃. lithium (1 L, 1.5 M in ether; 1.5 + uol) was added. .

The resulting colorless solution was stirred at -30°C for 30 minutes and then cooled to -78°C.

Bisepoxide 33 (78 mg, 0.37 mmol) in ether 2+L ) was added. The reaction was warmed to 25 °C over 4 h and saturated NH4C 1 aqueous solution and concentrated NH3 water were added. This mixture was extracted with ether and the organic layer The title compound was obtained by drying with NagS04 and removing the solvent. (93 servings, yield 100%). IHNMR (CDCIs): δ7.4-7.1 (5H, m), 4.7 (IH, d; J=12Hz), 4.55 (IH, d; J=12Hz), 3.9-3.7 (2H, m), 3.2 (IH.

dd), 2.5 (2H, b), 1.6-1.4 (4H, m), 1.0 (3H, t : J=7Hz), 0°9(3H,t; J-7Hz); MS(DCl, NHsXM+H)”239.2°f X3 R,5R)-3,5-methanesulfo Nyloxy-4-benzyloxyhebutanemethanesulfonyl chloride (0,3■ L) to diol 45 (93+gg) in pyridine (1 sL) at 0°C. dripped. This mixture was warmed to 25°C. After 12 hours, cool the mixture with 6N Diluted with MCI (10a+L) and extracted with CH, C1. Organic extract with 3%N Washed with aHCOs, dried with MgSO4 and concentrated. Flash clone the residue Purification by matography gave the title compound (83 mg, 56% yield).

'HNMR (CDC1m): δ7.4-7.2 (5H, m), 4.75 (IH, m), 4.7 (IH, c+; J=12Hz), 4.8 (IH, d: J= 12Hz), 4.58 (lH, m), 3°9 (IH, 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).

gX3 S, 55)-3,5-diazo-4-benzyloxyhebutane 47 dimethyl Bismesylate 46 (83 mg, 0.0 mg in 1.51 L of chillformamide) 21 Mixture of o1) and sodium azide (0.50g, 7.7anol) The mixture was heated to 70°C for 12 hours. After cooling, add ethyl acetate (20WL), The mixture was filtered and concentrated. The residue was subjected to flash chromatography and the table The title compound (54+gg, yield 90%) was obtained. 'HNMR (CDCIs): δ7 ．． 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).

h) (33,55)-3,5-diamino-4-benzyloxyhebutane 48TH F　Bisazide 47　328+g(1,14an) of step (j) in SmL 2001 g of LiAlH4 was added to 0°C. Bring this mixture to 25℃ Warmed and stirred for 5 hours. This reaction was dissolved by adding 0.5 μL of 15% NaOH. quenched with water, stirred for 15 minutes, diluted with 150 mL of ether, and filtered. filter The title compound (278+g, yield 100%) was obtained by concentrating the liquid.

lHNMR (CDCIs): δ7.26 (5H, m), 4.5 (2H, dd; J = 12Hz), 3.1 (LH, dd; J = 4゜6Hz), 2.9 (LH , m), 2.75 (IH, m), 1.8-1.0 (10H, m), 019 (3H , t: J=7Hz), 0.85 (3H, t: J=7Hz).

1X3S,5S)-3,5-diamino-4-hydroxyhebutane 49 methanol 52 mg of diamine product 48 in 4 mL was charged with 20% Pd on carbon (CH ) z and 2 drops of concentrated MCI aqueous solution were added. This mixture was mixed under H2 atmosphere. Stir for 16 hours at Obtained as an acid salt. IHNMR (CDIOD) δ3.75 (IH, dd; J= 4.7Hz).

3.2-3.0 (2H, m), 1.8-1.4 (4H, m), 0.9 (6H, t : J=7Hz).

j　X3　S, 55)-3,5-di(carbobenzyloxyalanylalani) ) Amino-4-hydroxyheptane 50 Diamine product 49 (87mg, 0.37ano 221 g (0.75a + mo l), HOBT 115+g (0,75+mol), and DCC 154mg ( 0.75+nol) was added. The mixture was stirred overnight, then concentrated and acetic acid Taken up in ethyl, filtered, washed with water and brine, dried (MgSO4) . The solvent was removed followed by MPLC (silica, CH.

The title compound (109m g) was obtained. 'HNMR (DMSO-ds): δ8.0-7.2 (21H, m) , 5.0 (4H, bs).

4.6 (2H, dd; J=12Hz), 4.2 (2H, m), 4.0 (2H, m), 3.8 (LH.

m), 3.7 (LH, m), 3.5 (IH, dd; J = 4.7Hz), 1.7- 1.3 (4-H, m).

1.1 (12H, m), 0.75 (6H, t). MS (FABXM+H)′″7 89.3e Example 11 (3S, 55)-3,5-di(alanylalanyl)amino-4-hydroxy Heptane 512-! Product 19 (4,5 mg) in 1+mL DMF was added with 20% Pd on carbon (OH)! 10a+g was added. This mixture was heated to 1 atm H! Stir for 6 hours under , then filtered and concentrated to give the title compound (3+gg). 'HNMR (CD sOD): δ4.3 (2H, m).

3.8 (2H, m), 3.7 (IH, m), 3.5 (IH, m), 1.8-1. 2 (16H, m).

0.8 (6H, dt).

Example 12 (3S, 55)-3,5-di(carbobenzyloxybarerel)amino-4- Preparation of hydroxyheptane 52 Cbz-Val 133+g (Q, 5ma+ol) in 2ml THF At -40 °C, 65 μL (0.5 m + l1 ol) of NMM and 65 μL (0 , 5 01) of isobutyl chloroformate was added. After stirring for 10 minutes, DM F 125 mg (0,17 anol) of diamine hydrochloride and N in 1 L A solution of 50 μL of MM was added. The mixture was gradually warmed to 20°C and stirred overnight. then diluted with ethyl acetate, 5% HCI, 5% NaHCO3, and brine. The organic layer was concentrated. The residue was purified by flash chromatography (ethyl acetate). The title compound (18+g) was obtained. 'HNMR( CDC13): δ7.5-7.3 (10H, m), 6.9 (IH, bd).

6.35 (IH, bd), 5.5 (IH, bd), 5.25 (IH, 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(F.A. B): m/z613.2 (M+H)".

a) (4R,6R)-4,6-cyhydroxy-5-benzyloxy-2,8-di Methyl-1,8-nonadiene 53 Suspension of CuI (1921 g, 1.0 mmol) in ether (2 L) Add isopropenyl lithium (5.2 L, 2.Qvmol) to the solution at -60°C. ; 0.38M in ether: 2-bromopropene and lithium wire freshly prepared) was added. The mixture was warmed to -45°C and then to -78°C. Recooled. Bisepoxide 33 (60+g, 0 ．． A solution of 29-01) was added. While stirring, this mixture was heated to zero over 2 hours. Warmed to ℃. This mixture was diluted with ether and 1:1 concentrated aqueous ammonia:saturated. Washed with 5 sL of NH, CI. The organic layer was dried with MgSO4, concentrated and The title compound (81@g, 96% yield) was obtained as a colorless solid. 'HNMR(C DCIs): 67.3 (5H, m), 4.9 (IH, bs), 4°85 (IH, bs), 4.80 (IH, bs), 4.75 (IH, bs), 4.65 (IH, d: J=12Hz), 4.58 (IH, d: J=12Hz), 4.0( 2H, m). 3.3 (IH, dd.

J=2.5Hz), 2.55(1)1. d: J=6Hz), 2.55 (IH , d: J=4Hz).

2.5-2.1 (4H, m), 1.7 (LH, s). MS (DCl, NHsXM +H)”291゜4゜ bX4R,6R)-4,6-cyhydroxy-5-benzyloxy-2,8-dime Product 53 (105g+g, 0 ．． 38anol), Ir(COD)Py(PCy)sPFs(club 55 mg of Crabtree catalyst was added. This mixture was heated to 1 atm. Stir under H3 for 6 hours, then filter and concentrate to give the title compound (ilo+ag, Yield], 00%) was obtained. 'HNMR (CDC13): δ7.3 (5H, m).

4.6 (IH, dd: J = 12Hz), 4.0 (2H, m), 3.1 (IH, b s), 2.7 (2H.

bs), 2.0-1.1 (6H, m), 1.0-0.8 (12H, m).

MS (DCl, NHsXM+H)"295.4゜c　X4　R,6R)-4,6 -di(methanesulfonyloxy)-5-benzyloxy-2,8-dimethylno Naan 55 Methanesulfonyl chloride (0.25 L) was added in pyridine (1 L) at 0°C. was added dropwise to Diol 54 (93 mg). This mixture was warmed to 25°C . After 10 hours, the mixture was diluted with cold 6N HCI (10 WL) and CHIC1 Extracted with 2. The organic extract was washed with 3% N a HCOs and dried over MgO, and concentrated. The residue was purified by flash chromatography to give the title compound. (210 mg) was obtained. IHNMR (CDC13): δ7.4 (5H, m), 5 ．． 0 (LH, m), 4.8 (IH, d; J = 12Hz), 4.7 (LH, m), 4.6 (IH, d; J = 12Hz), 3.85 (IH, dd; J=4.7Hz), 3.0 (3H, s), 2.9 (3H, s), 2.0-1.1 (6H, m), 1.0-0, 9 (12H, m).

dX4　R,6R)-4,6-diacido-5-benzyloxy-2,8-dimethy Product 55 (210 mg) in lunonane 56DMF 2+iL was added with NaN 3870 mg (15 anol) was added. This mixture was heated to 70°C for 7 hours. , then cooled and diluted with ethyl acetate. The filtrate was concentrated and the residue was analyzed by MPLC (acetic acid Purification by ethyl:hexane 1:20 gave the title compound (52 g). . YiHNMR (CDCIg): δ7.3 (5H, m), 4.55 (2H, dd; J=12Hz), 3.4-3.15 (3H, m), 2.0-1.1 (6H, m ), 1°0-0.75 (12H, m).

eX4S, 65)-4,6-diamy2-5-benzyloxy-2,8-dime Product 56 (52 mg, 0.15 L) in tilnonane 57 THF (3 L) 480 mg (2 anol) of LiAlH was added to 1) at 0°C. This mixture The mixture was stirred at 25 °C overnight, then quenched with 1 N NaOH and diluted with ether (50 @ diluted with L). The title compound (44 mg) was freed by filtration and concentration. Obtained as a colored oil. 'HNMR (CDCIg): δ7.3 (5H, m), 4 ．． 6 (2H, dd: J=12Hz), 3.1 (IH, m).

3.05-2.95 (2H, m), 1.9-CI (6H, m), 1.0-0,8 (12H, m).

fX4S, 6S)-4,6-diamitu-5-hydroxy-2,8-dimethyl-1 ,8-nonane dihydrochloride 58 165 mg of diamine 57 in 10 layers of methanol containing 15 drops of concentrated HC. , 100 mg of 20% Pd(OH) on carbon was added. 1 atm of this mixture Stir overnight under H2, then filter and concentrate to give the title compound (75 mg). Ta. 'HNMR (CD30D) + 63.7 (IH, m), 3.35 (LH, m) , 3.2 (IH, m), 1.8-1.0 (6H, m), 0.99-0.8 (12 H, m). MS(DCl, NHsXM+H)-2(4S, 65)-4,6-di -(carbobenzyloxyalanylalanyl)amino-5-hydroxy-2,8 - Preparation of dimethyl-1,8-nonane 59 Product 58 in 2 mL of DMF ( 44+gSO, 15mmol), Cbz-A 1aA lal 10+ag( 0,375 mmol), HOBT 5 Seg (0,375 mmol), and 72 mg (0,375 mmol) of DCC was added. This mixture was heated at 25°C for 4 Stirred for 8 hours, then diluted with 20 mL of ethyl acetate and filtered. Concentrate the filtrate; The residue was purified by MPLC (gradient, 0-5% methanol in CHfCb). The title compound (24 mg) was obtained. 'HNMR (CDsOD): δ8 ．． 0-7.2 (21H, m), 5.0 (4H.

overlap dd), 4.2 (2H, m), 4.0 (4H, m), 3.5 (IH, br s), 1.7-1.15 (18H, m), 0.9-0.7 (12H, br t) .

Example 15 (4S, 65)-4,6-di(alanylalanyl)amino-5-hydroxy -Preparation of 2,8-dimethyl-1,8-nonane 60 Product 59 (12 mg) in 2 mL of DMF was added with 20% Pd(O H) 250@g was added. The mixture was stirred under 1 atm H1 for 10 h and then Diluted with methanol, filtered and concentrated to give the title compound (7,5a+g). Ta. IHNMR (CDsOD): δ4.25 (2H, m), 3.8 (IH, m) , 3.65 (2H, m), 3.1 (IH, bd), 1.6-1.1 (18H, m ), 0.7 (12H, bd), MS (FABXM+H)”487° Example 16 (4S, 65)-4,6-di(carbobenzyloxy)amino-5-hydro Preparation of xy-2,8-dimethyl-1,8-nonane 61 6,8a+g of bis-amine hydrochloride product 5 in 10.51 L of CH2Cl 8, at 20°C, add 5 mL of triethylamine and 10 @L was added. After stirring for 3 hours, the mixture was applied to a silica column and CH, Elution with CI and then ether gave the title compound (4.6 mg). 'HNM R (CDCIs): δ7, 3 (10H, bs), 5.1-4.9 (6H, m), 3.9-3.7 (2H, m), 3.5-3.35 (2H, m: IH with DhO (replaceable), 1.7-1.5 (4H, m), 1.3-1.2 (2H, m), 1. 1-0.8 (12H, m).

Example 17 (2S, 45)-2,4-di(p-toluenesulfonyl)amino-3-hydro Preparation of Roxy-1,5-diphenylpentane 62 p-)Luenesulfonylchloride in methylene chloride and triethylamine The title product was prepared by sulfonating compound 40 (Example 9) with did. 'HNMR (250MHz, CDC15) 8.04.8 (m, 18H), 5.5 (d.

IH, J = 7Hz), 5.2 (d, LH, J = 7Hz), 3.2-3.7D (m , 4H), 2.4-2.7 (m, 4H), 2.5 (s, 3H), 2.45 (s, 3H).

For inhibition analysis, the procedure of Dreyer et al. Goods of National Academy of Sciences of Ni Ni S.A. (Proc, Natl, Acad, Sci, U.S.A.)%8 6, pp. 9752-9756 (1989), and also by Moore et al. Biochemical and Biophysical Research Committee Bioch, Bioph, Res, Cow, Volume 159, 420 (1989). A typical analysis involves MENTT buffer (5 0mM Mes (pH 6, O; 2-(N-morpholino)ethanesulfonic acid), 1mM EDTA, 1mM dithiothreitol, 200mM NaC1,0,1 % Triton X-100); 2.3, or 6rxMN-acetyl-L~Arg Nyl-L-alanyl-L-seryl-glutaminyl-asparaginyl -Tyrosyl-L-prolyl-L-valyl-L-valinamide (Ac-Arg-A la-Ser-GIn-Asn-Tyr-Pro-Val-Vat-NH2; Km = 711M); and synthesis of micromolar and submicromolar concentrations contained compounds. After incubation for several minutes at 37°C, 0001-0. The reaction was started with 0.1 mg of purified HIV protease. Reaction mixture (37°C) After 10-20 minutes, quench with an equal volume of cold 0.6N trichloroacetic acid and centrifuge. After removing the precipitate, the peptide degradation products were analyzed by reverse phase HPLC (Beckman Ul Trusphere (Beckman Ultrasphere) OD 3% 4.5 ma+X25101; Mobile phase; 5-20% acetonitrile/H, O-, 1% TF A915 min), 20% acetonitrile 1H1o-91% TFA (5 min), Analyzed by detection at 22Qnm at 1.5mL/min. Ac-Arg-Al a-Ser-Gin-Asn-Tyr-Pro-Val-Val-N Hz (1 7-18 min) and Ac-Arg-Ala-8er-Gin-Asn-Tyr ( The elution portion (10 to 11 minutes) was confirmed with real Monoga. Ac-Arg-Ala- The initial rate of Ser-Gln-Asn-Tyr formation is determined from the integral value of these peaks. Therefore, the inhibitory properties of synthetic compounds are typically measured by plotting 1/V versus [inhibition 1flJ]. Combined with slope/intercept analysis (Dixon analysis). This type of primary analysis The values obtained for competitive inhibition are only for the substrate used, M. chaelis) is accurate under conditions where the constant is well defined.

The compounds of the invention have a K value of 50 HM or less, preferably 10 HM or less, more preferably 10 HM or less. More preferably, it is 1 μM.

If you follow the steps described here and the teachings of the examples above, you will achieve the results listed in the table below. Additionally, compounds having the structures and substituents shown therein can be prepared.

62 1.000 2 AlaAla ethyl 3 Cbz-Val ethyl , 4 AlaAla PhCH.

5 H1-Bu 6 A1aA1a'i-Bu 7 Cbz-i-Bu g Cbz-Val i-Bu lol Cbz-Ala 1-Bu 2 β-Ala 1-Bu 3 β-A1aVal i-Bu 4 Cbz-, AlaAla i-B u105 BocAla i-B u 6 AcAlaAsn i-Bu 7 AcGlnAsn i-Bu g Cbz-Phe Ala i-B u9 Trifluoro A1aAla i- B ullo Cbz-trifluoro A1aAla i-B ul trifluoro B A1a 1-Bu 2　Cbz-trifluoroA1a　1-Bu3　Ph(CHz)*COi-B　 u 4 Boc 1-Bu 115 Ac 1-Bu 6 Ph5o2 1-Bu 7 HCO1-Bu 8 Propynyl 1-Ba O2-butyryl i-Bu 120 Ph (CHz) 2co 1-BuI P hS 02Val i-B u2 Phenyl lactoyl 1-Bu 3 Phenyllactoyl-Val 1-Bu4 Cbz-Ala PhCH2 22Cbz-Val 1-7y Nyl 5 Cbz-Val 2-propenyl 7 Cbz-Val 3-butenuyl 8 Cbz-Vat n-pentyl 9 Cbz-Vat Ph (CHz)z-130Cbz-Val cyclohexy Ru-CH,-1Cbz-Val　2-naphthyl-CH2-2Cbz-Val　3 -Naphthyl-CH2-3Cbz-Val　2-1f2 4 Cbz-Val 3-indoylmethyl 135 Cbz-Val trans -3-Fs-3-propenyl 6 Cbz-Val N-piperidinyl-CH 2-7Cbz-Val　N-morpholinyl-CH2-8Cbz-Val　(CH 3) 2N-CH29Cbz-Val t-butylNH-CH, -140Cbz- Val N-imidazolylu CH.

I Cbz-Val PhC0NH-CH2-2Cbz-Val N-indoly Lu-CH.

3 Cbz-Val t-butyl CONH-CH.

4 Cbz-Val BocNHCHz145 Cbz-Val NHzCHz 6 Cbz-Val N-benzimidazolyl 7 Cbz-Val PhCHz O-CHs8 Cbz-Val Ph0-CHs 9 Cbz-Val CH3 (CHz) to CH2150Cbz-Val C H,0-CH.

7 Cbz-Val CHsOCH20-CHs8 Cbz-Val CHsO CHzCHzOCHzOCH29Cbz-Val CHsS-CH2 150Cbz-Val　Ph5-CHl4　Cbz-Val　CH,S(○)- CH.

165　Cbz-Vat　CHsS(○)2-CH2■ 3 Cbz-Val Echini 4 A 1aA la P h CH! 5 H1-Bu 5 AlaAla i-Bu 7 Cbz-1-Bu 8Cbz-Val　i-B　u 201 Cbz-Ala i-Bu 2 β-Ala 1-Bu 3 β-A1aVal i-Bu 4 Cbz-AlaAla i-B u205 BocAla i-B u 6 AcAlaAsn i-Bu 7 AcGlnAsn i-Bu g Cbz-Phe Ala i-B u9 TrifluoroAlaA1a i- B u210Cbz-trifluoro A1aA1a i-B ul trifluoro Ala 1-Bu 2 Cbz4 Refluoro A1a 1-Bu3 Ph(CH2)2co 1-Bu 4 Boc 1-Bu 215 Ac 1-Bu 5 Ph5o2 1-Bu 7 HCO1-Bu 8 Propionyl 1-Ba O2-butyryl 1-Bu 220 Ph (CHz)tco i-B uI Ph5OtVal 1-Bu 2 Phenyl lactoyl 1-Bu 3 Phenyllactoyl-Val i-B u4 Cbz-Ala PhCH2 225Cbz-Val i-butenyl 6 Cbz-Val 2-propenyl 7 Cbz-Val 3-butenuyl 8 Cbz-Val n-pentyl 9 Cbz-Val Ph (CHz)z-230Cbz-Val cyclohexy Ru-CHl-I Cbz-Val 2-naphthyl-CHr2 Cbz-Val 3-naphthyl-CHz-3Cbz-Val 2-butynyl 4 Cbz-Val 3-indoylmethyl 235 Cbz-Val Tora:/ Su-3-7 di-3-phenyl 6 Cbz-Vat N-piperidinyl-C Hl-7Cbz-Val　N-morpholinyl-CHl-8Cbz-Val　(C Hx)zN-CHl9 Cbz-Val t-butylNH-CH, -240Cb z-Val　N-imidazolyl-CH3I　Cbz-Val　PhC0NH-C Hz-'l Cbz-Val N-indolyl-CH.

3 Cbz-Val 1-ButylCONH-CHl4 Cbz-Val BOC NHCH! 245 Cbz-Val NH, CHs5 Cbz-Val N-B Nzuimidazolyl 7 Cbz-Val PhC0NH-CHzg Cbz-Va l　Ph0-CHs 9 Cbz-Val CHs (CHz) to-CH210Cbz-Val CH sO-CHtI Cbz-Val (CHs)zcHo-CHs2 Cbz-V al t-butyl-0-CH.

3 Cbz-Val (CHs)zcHcHzo-CHs4 Cbz-Val CHsCHz(CH3)CHO-CH6　Cbz-Val　PhCHzOCH* 0-CHs7 Cbz-Val CHIOCH! 0-CHl8 Cbz-Val CHsOCHzCHzOCHzOCHt9 Cbz-Val CHsS-CH 210Cbz-Val　Ph5-CHzI　Cbz-Val　(CHs)zcH s-CHs2　Cbz-Val　CHx(CHz)zs-CHs3　Cbz-V al　CHs(CHz)sS-CHs4　Cbz-Val　CHsS(0)-C H2150Cbz-Val　CHsS(0)2-CHs6　Cbz-Val' PhS (0)z-CHz7 Cbz-Val i-propyl-5(0)-C H.

g Cbz-Val n-propyl-3(0)! -CHl9　Cbz-Val　 n-Butyl-8(0)t-CH2270Cbz-Vat (PhtO)zP(0 )-CHtI　Cbz-Val　(CHsO)zP(0)-CHl2　Cbz- Val　(n-butyl o)tP(0)-CHl3　Cbz-Val　(EtO) zP(0)-CHl4Cbz-Val(CHsO)iP(0)-CHt structure In (I) and (n), the XI and X2 groups are hydrogen or one of a number of terminal groups. It consists of 0 to 2 α-amino acid groups whose terminals are substituted by and R1 and R1 groups can be selected from a wide variety of hydrocarbon groups.] useful as inhibitors of retroviral proteases, characterized by Compound.

international search report

Claims (14)

[Claims] 1. Formula I or II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼I▲There are mathematical formulas, chemical formulas, tables, etc.▼II[ In the formula, X1 and X2 are the same or different, and A-(B)n- (where n=0 ~2); and B is independently Ala, Asn, Cys, Trp, Gly, Gln, Ile, Leu, Met, Phe, Pro, Ser, Thr, Tyr, Val, His, or an α-amino acid selected from the group consisting of trifluoroalanine, where The amino group of B is bonded to the appropriate carboxyl group of A or the adjacent residue B. The carboxyl group of B is the amino group of the adjacent residue B or I or II. A is covalently bonded to the amine group of the adjacent residue B or, if n=0, a covalent bond to the amine group of I or II. Has: 1) Trityl, 2) Hydrogen 3) C1-C6 alkyl, 4) R3-CO- (where R3 is: a) Hydrogen, b) Unsubstituted or one or more hydroxyl groups, chlorine atoms, or C1-C6 alkyl substituted with fluorine atoms, c) unsubstituted or one or more or more substituents R4, where R4 is: i) C1-C4 alkyl, ii) halogen (where halogen is F, Cl, Br or I), iii) hydrogen droxyl, iv) Nitro; v) C1-C3 alkoxy, or i) -CO-N(R10)2 (where R10 is independently H or C1-C phenyl or naphthyl substituted with 4alkyl); d) pyridyl , furyl, or a 5- to 7-membered heterocycle such as benzisoxazolyl); 5) Phthalolyl (here, the aromatic ring is unsubstituted or one or more substituted substituted with substituent R4); 6) R5(R6R7C)m-CO- (where m = 1 to 3, R5, R6, and R7 are independently: a) Hydrogen, b) chlorine or fluorine; c) Unsubstituted or one or more chlorine or fluorine atoms or hydro C1-C3 alkyl substituted with xyl group, d) hydroxyl, e) Phenyl unsubstituted or substituted with one or more substituents R4 or naphthyl, f) C1-C4 alkoxy, g) 5-7 membered heterocycle, h) R5, R6, and R7 are independently, together, monocyclic, bicyclic, or 7) R5 (R 6R7C) mW- (where m = 1 to 3, W is OCO or SO2 , R5, R6, and R7 have the same meanings as above; however, R5, R6, and and R7, if they are adjacent to W, are chlorine, fluorine or hydroxy. ); 8) R8-W- (where R8 is pyridyl, furyl, or benzisoxa 5- to 7-membered heterocycles such as zolyl); 9) R9-W- (where R9 is unsubstituted or one or more substituted phenyl or naphthyl substituted with group R4); 10) R5-(R6R7C ) m-P(O)(OR11)- (where R11 is C1-C4 alkyl or phenyl); 11) R8-P(O)(OR11)-; or 12) R9-P(O)(OR1 1) -; R1 and R2 are the same or different: 1) -CH2R12 (this Here, R12 is a) NH-A (where A has the same meaning as above); b) R5-(R 6R7C)m-; c) R5-(R6R7C)mV- (where V is O or NH; however, R5, R6 and R7, if adjacent to V, are hydroxyl, chlorine or or fluoride), d) R5-(R6R7C)m-S(O)n- (where m=1-3 and n=0 ~2, and R5, R6, and R7 have the same meanings as above; however, R5, R 6, and R7 are hydroxyl, chlorine when they are adjacent to sulfur. or not fluoride), e) R8-S(O)n-, f) R9-S(O)n-, g) (R13O)P(O)(OR14)- (where R13 and R14 are Standing: i) C1-C6 alkyl, ii) C3-C6 cycloalkyl, iii)H, iv) R9, v) is R8), h) R13P(O)(OR14)-, i) N(R10)2, j) NR15R16 (where R15 and R16 taken together: i) aze Tidinil, ii) pyrrolidinyl, iii) piperidinyl, iv) forming a 4- to 6-membered saturated nitrogen heterocycle containing morpholinyl), k) R17 OCH2O (where R17 is: i) C1-C6 alkyl, ii) R9, iii) CH2Ar (where Ar is phenyl, naphthyl or 5- to 7-membered (ro ring)), 1) R17OCH2CH2OCH2, m) N-imidazolyl (here, the imidazole ring is unsubstituted or has a substituent R 4), n) N-benzimidazolyl (here, the fused benzene ring is unsubstituted or o) optionally substituted with one or more substituents R4); C2-C6 alkynyl substituted with further groups R9; or p) C2-C6 alkenes optionally substituted with one or more groups R9 Nil; 2) Hydrogen, 3) Unsubstituted or one or more chlorine or fluorine atoms or hydro C1-C6 alkyl substituted with xyl group, 4) C3-C7 cycloalkyl and pharmaceutically acceptable salts thereof. 2. Claim 1 wherein said compound has structure I, R1=R2 and X1=X2. Compounds described. 3. 3. A compound according to claim 2, wherein R1 and R2 are C1-C6 alkyl. 4. 3. A compound according to claim 2, wherein R1 and R2 are benzyl. 5. X1 and X2 are AlaAla, Val, Cbz-Val, Cbz or 5. A compound according to claims 1-4, selected from hydrogen. 6. The compound according to claim 1, wherein the protease activity inhibitor constant Ki is about 10 μM or less. Compound. 7. 2. A compound according to claim 1 for use in medicine. 8. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 9. A retroviral infection comprising administering the compound according to claim 1. How to treat. 10. 10. The method according to claim 9, wherein the retrovirus is human immunodeficiency virus type 1. 11. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R' is: 1) a) NH-A (where A, R5 to R10 and m have the same meanings as in claim 1) ;b) R5-(R6R7C)m-; c) R5-(R6R7C)mV- (where V is O or NH; however, R5, When R6 and R7 are adjacent to V, they are hydroxyl, chlorine or is not a fluorine), d) R5-(R6R7C)m-S- (where m = 1 to 3, R5, R6, and R7 have the same meanings as above; provided that R5, R6, and R7 are adjacent to the sulfur. if in contact, they are not hydroxyl, chlorine or fluorine), e )R8-S-, f) R9-S-, g) (R13O)P(O)(OR14)- (where R13 and R14 are Standing: i) C1-C6 alkyl, ii) C3-C6 cycloalkyl, iii)H, iv) R9, or v) is R8), h) R13P(O)(OR14)-, i) N(R10)2, j) NR15R16 (where R15 and R16 taken together: i) aze Tidinil, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, ), k) R17OCH2O (wherein and R17 is: i) C1-C6 alkyl, ii) R9, or iii) CH2Ar (where Ar is phenyl, naphthyl or 5- to 7-membered (ro ring)), l) R17OCH2CH2OCH2, m) N-imidazolyl (here, the imidazole ring is unsubstituted or has a substituent R 4), n) N-benzimidazolyl (here, the fused benzene ring is unsubstituted or o) optionally substituted with one or more substituents R4); o) optionally substituted with one or more substituents R4; is C2-C6 alkynyl substituted with further groups R9; or p) C2-C6 alkyl optionally substituted with one or more groups R9 Kenil; 2) Hydrogen, 3) Unsubstituted or one or more chlorine or fluorine atoms or hydro C1-C6 alkyl substituted with xyl group, or 4) C3-C7 cyclo alkyl; R'' is a hydroxyl protecting group, and R'' and R'' are , hydrogen, an amino protecting group or taken together with N2] 1) Formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ The compound represented by R'-Z (where Z is a moiety that imparts nucleophilicity to R' minutes), 2) converting the obtained hydroxyl group into a substitutable group, and 3) converting this substitutable group into A method of preparation consisting of reaction with a nitrogen nucleophile. 12. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼III [In the formula, R' is: 1) a) NH-A (where A, R5 to R10 and m have the same meanings as in claim 1) ;b) R5-(R6R7C)m-; c) R5-(R6R7C)mV- (where V is O or NH; however, R5, When R6 and R7 are adjacent to V, they are hydroxyl, chlorine or is not fluorine), d) R5-(R6R7C)m-S- (where m = 1 to 3, R5, R6, and R7 have the same meanings as above; provided that R5, R6, and R7 are adjacent to the sulfur. if in contact, they are not hydroxyl, chlorine or fluorine), e )R8-S-, f) R9-S-, g) (R13O)P(O)(OR14)- (where R13 and R14 are Standing: i) C1-C6 alkyl, ii) C3-C6 cycloalkyl, iii)H, iv) R9, or v) is R8), h) R13P(O)(OR14)-, i) N(R10)2, j) NR15R16 (where R15 and R16 taken together: i) aze Tidinil, ii) pyrrolidinyl, iii) piperidinyl, or iv) morpholinyl, ), k) R17OCH2O (wherein and R17 is: i) C1-C6 alkyl, ii) R9, or iii) CH2Ar (where Ar is phenyl, naphthyl or 5- to 7-membered (ro ring)), l) R17OCH2CH2OCH2, m) N-imidazolyl (here, the imidazole ring is unsubstituted or has a substituent R 4), n) N-benzimidazolyl (here, the fused benzene ring is unsubstituted or o) optionally substituted with one or more substituents R4); o) optionally substituted with one or more substituents R4; is C2-C6 alkynyl substituted with further groups R9; or p) C2-C6 alkyl optionally substituted with one or more groups R9 Kenil; 2) Hydrogen, 3) Unsubstituted or one or more chlorine or fluorine atoms or hydro C1-C6 alkyl substituted with xyl group, or 4) C3-C7 cyclo alkyl; and R'' is a hydroxyl protecting group] . 13. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼IV [In the formula, R' and R'' are in claim 12 A compound represented by [has the same meaning as]. 14. formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼V A compound represented by the formula: [wherein R'' is a hydroxyl protecting group].