CN1094055A

CN1094055A - The new inhibitor of aspartyl protease

Info

Publication number: CN1094055A
Application number: CN93120823A
Authority: CN
Inventors: J·S·博格; H·V·迈耶尔斯; M·D·马利坎
Original assignee: Vertex Pharmaceuticals Inc
Current assignee: Vertex Pharmaceuticals Inc
Priority date: 1992-12-11
Filing date: 1993-12-11
Publication date: 1994-10-26
Also published as: MX9307821A; ZA939285B; AU5748194A; WO1994013629A1; IL107978A0

Abstract

The present invention relates to the new compound that a class is an aspartyl protease inhibitor.In one embodiment, the present invention relates to the new HIV aspartyl protease inhibitor that derives from mannitol of a class, it is characterized in that having ad hoc structure and physico-chemical property.The present invention also relates to contain the pharmaceutical composition of these compounds.The compounds of this invention and pharmaceutical composition are particularly useful for suppressing the activity of HIV aspartyl protease, thereby they can be used as antiviral agent, in order to tackle HIV virus, comprise HIV-1 and HIV-2 virus.

Description

The new inhibitor of aspartyl protease

The present invention relates to the new compound of a class, they are aspartyl protease inhibitors.In a preferred embodiment, the present invention relates to the new mannitol derivative of a class, it is characterized in that they have special structure and physico-chemical property as the HIV aspartyl protease inhibitor.The present invention also relates to contain the pharmaceutical composition of these compounds.Compound of the present invention and pharmaceutical composition are particularly useful for suppressing HIV aspartyl protease activity, thereby can be advantageously used for the antiviral agent that tackles the HIV virus that comprises HIV-1 and HIV-2 virus.

Human immunodeficiency virus (HIV) (retrovirus) is acquired immune deficiency syndrome (AIDS) (" acquired immune deficiency syndrome (AIDS) ")-a kind of immunity system that it is characterized in that, especially CD ₄+ T-cell (J.of NIH Res., 3, pp ^23-25(1991)) destroyed, be accompanied by the disease that is easy to suffer sporadic infection-and predecessor's AIDS related complex (ARC)-a kind of syndrome that it is characterized in that symptoms such as having persistent generalized lymphadenopathy, have a fever and lose weight; And the HIV of predecessor-asymptomatic infect-pathogenic agent.

As other several retrovirus, a kind of proteolytic enzyme that the HIV coding produces is translated the cutting (S.Crawforel etc. of back precursor polypeptide in forming the necessary process of infectious virus body, " A Deletion Mutation in the t ' part of the pol Gene of Moloney Murine Leukemia Virus Blocks Proteolyti Processing of the gagand pol polyproteins ", J.Virol., 53, P899(1985)).These gene products comprise pol and gag, the former encode virosome RNA dependent dna-polymerases (reversed transcriptive enzyme), endonuclease, hiv protease, the latter virosome core protein (people such as H.Toh that encodes, " Close Structural Resemlbance Between Putative Polymerase of a Drosophila Transposable Genetic Elemert 17.6 and pol gene Product of Moloney Murine Leukemia Virus ", EMBO J.4, P1267(1985)); People such as L.H.Pearl, " A Structural Model for the Retroviral Proteases ", Nature, PP329-351(1987); M.D.Power etc., " Nucleotide Sequence of SRV-1, a Type D Simian Acquired Immune Deficiency Syndrome Retrovirus ", Sciencc, 231, P1567(1986)).

A large amount of synthetic antiviral agents have been designed at each stage of HIV replicative cycle.These preparations comprise prevention virus and CD ₄+ T-lymphocyte bonded compound (as solubility CD4) and by suppressing the compound (as didanosine and zidovudine(AZT) of viral reverse transcriptase viral interference breeding) and suppress viral DNA and be attached to compound (M.S.Hirsh and R.T.D ' Agulia in the cell DNA, " Therapy for Human Immunod eficiency Virus infection ", N.Eng.J.Med., 328, P1686(1993)).But these preparations mainly are early stage at virus replication, can not suppress the generation of infectious virus body in the chronic infection cell.And, take part by significant quantity and cause cytotoxicity and adverse side effect behind these preparations, as anaemia and depressed marrow.

Recently, the focus of antiviral design transfers the processing created by the viral interference polyprotein precursor compound with the formation that suppresses the infectious virus body to.The processing of these precursor proteins need encoding viral the effect of duplicating necessary proteolytic enzyme (Science, 231, PP1580-1584(1986); Kohl, N.E.Deng, " Active HIV Protease is Requird for Viral Infectivity ", Proc.Natl.Acad.Sci.USA., 85, P4686(1988)).Utilize inhibitor peptides to confirm the antiviral efficacy that hiv protease suppresses.But this peptide compounds is generally complicated macromole, therefore demonstrates relatively poor bioavailability, and usually can not oral administration.Therefore, still need effectively to suppress the compound of virus protease effect, to be used as treatment and to prevent chronic and medicine acute viral infection.

The invention provides the new compound of a class and can make medicinal derivative, they are to aspartyl protease, and especially the HIV aspartyl protease has affinity.Based on this affinity, these compounds can be used as the inhibitor of these proteolytic enzyme.These compounds can use separately or with other therapeutical agent or preventive, be used in combination as antiviral agent, microbiotic, immunomodulator or vaccine etc., be used for the treatment of or prophylaxis of viral infections.

According to a preferred embodiment, The compounds of this invention can suppress HIV virus at people CD ₄Duplicate in+T-the cell, this is by the ability effect of the catalysis peptide bond hydrolysis that suppresses the HIV aspartyl protease.So these new compounds can be used to reduce initial and further infection that produces and can suppress host cell from the infective virus of chronic infection cell.Therefore, this compounds can be used as the treatment or the preventive of the infection that prevention or treatment cause by HIV-1 and correlated virus, and this viroid can cause symptomless infection, acquired immune deficiency syndrome (AIDS) dependency syndromes (" ARC "), dementia, acquired immune deficiency syndrome (AIDS) (acquired immune deficiency syndrome (AIDS)) or the similar disease of immune system relevant with AIDS.

Main purpose of the present invention provides the new mannitol derivative of a class, and it is an aspartyl protease inhibitor, especially the HIV aspartyl protease inhibitor.Mannitol derivative that such is new and medicinal derivative thereof (comprising its pharmaceutical salts) are represented by the formula I:

Wherein each n independently is selected from 0,1 and 2;

Each A and A ' independently are selected from natural a-amino acid or non-natural a-amino acid (as Ala, Asn, Cys, Gly.Gln, His, Ile, Leu, Met, Phe, Pro, Ser, Thr, Trp, Val or trifluoropropyl propylhomoserin), wherein the amino bonded of each A or A ' is to G or G ', or is bonded on the carboxyl of contiguous residue A or A ', this depends on that is more suitable for, and the carboxyl of A or A ' is bonded on the amino of contiguous residue A or A ', or is bonded on the Sauerstoffatom of this structure, and this depends on that is more suitable for; Each G and G ' are covalently bound independently to the amino of contiguous residue A or A ' or covalently bound to the Sauerstoffatom of this structure (if contiguous n=0), and each G and G ' are selected from following groups:

1) trityl;

2) hydrogen;

3) C _1-6Alkyl;

4）R ₃-CO-;

5) phthaloyl, wherein its aromatic nucleus can be by one or more substituent R ₄Replace arbitrarily;

6) R ₅(R ₆R ₇C) mCO-, wherein m=1-3;

7) R ₅(R ₆R ₇C) mW-, m=1-3 wherein, each W be selected from alone-OCO-and-SO ₂-, condition is that W is not-SO when W is connected on the Sauerstoffatom of this structure ₂-;

8) R ₈-W-, condition is that W is not-SO when W is connected on the Sauerstoffatom of this structure ₂-;

9) R ₅(R ₆R ₇C) (OR m-P(O) ₉)-, be m=1-3 wherein; With

10）R ₈-P（O）（OR ₉）-;

Each R ₃Be independently selected from:

1) hydrogen;

2) C _1-6Alkyl or C _2-6Alkenyl, this two can be selected from hydroxyl by one or more, the substituting group of chlorine and fluorine replaces arbitrarily; With

3) phenyl or naphthyl, the two can be by one or more substituent R ₄Replace arbitrarily;

Each R ₄Be independently selected from: C _1-4Alkyl, C _2-4Alkenyl, halogen (as F, Cl, Br or I), hydroxyl, nitro, C _1-3Alkoxyl group and-CO-N(R ₁₀) R ₁₀);

Each R ₅, R ₆And R ₇Independently be selected from hydroxyl; Hydrogen; Chlorine; Fluorine; C _1-3Alkoxyl group; The 5-7 element heterocycle; C _1-3Alkyl; Phenyl; And naphthyl; Described C _1-3Alkyl can be selected from chlorine by one or more, and the substituting group of fluorine and hydroxyl replaces arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇With separately or with any form that combines at random in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C _3-6Cycloalkyl, condition are if R ₅, R ₆Or R ₇Be present on the carbon atom of contiguous W, then R ₅, R ₆Or R ₇Not chlorine, fluorine or hydroxyl;

Each R ₈Be independently selected from phenyl, naphthyl and 5-7 element heterocycle (for example pyridyl, furyl or benzoisoxazole base), wherein said phenyl or naphthyl can be by one or more substituent R ₄Replace;

Each R ₉Independently be selected from C _1-4Alkyl and phenyl;

Each R ₁₀Independently be selected from hydrogen, C _1-4Alkyl and 5-7 element heterocycle (for example pyridyl, furyl or benzoisoxazole base);

Wherein each B and B ' independently are selected from oxygen and sulphur;

Wherein each D and D ' independently are selected from H ₂, oxygen and sulphur;

Wherein each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂);

Each R wherein ₁₁And R ₁₂Be independently selected from C _1-6Alkyl and C _2-6Alkenyl; With

Wherein each Ar is independently selected from phenyl, by one or more substituent R ₄Any phenyl that replaces and by one or more substituent R ₄5-7 element heterocycle (as the 3-pyridyl, 4-(1,2,3-the thiadiazoles)-Ji that replaces, or 4-morpholinyl arbitrarily).

Purpose of the present invention comprises pharmaceutical composition that formula I mannitol derivative also is provided and they using method as aspartyl protease (comprising the HIV aspartyl protease) inhibitor.

For the present invention described here is more fully understood, have been described in detail below.In specification sheets, used following abbreviation:

Name reagent or fragment

The Et ethyl

The Trityl trityl group

Ala D-or L-L-Ala

Asn D-or altheine

Cys D-or L-halfcystine

Gly D-or L-glycine

Gln D-or L-glutaminate

His D-or L-Histidine

Ile D-or L-Isoleucine

Leu D-or L-leucine

Met D-or L-methionine(Met)

Phe D-or L-phenylalanine

Pro D-or L-proline(Pro)

Ser D-or L-Serine

Thr D-or L-Threonine

Trp D-or L-tryptophane

Val D or L-Xie Ansuan

Cbz carbobenzoxy-(Cbz) (carbonyl benzyloxy)

EDC 1-(3-dimethylaminopropyl)-the 3-ethyl-carbodiimide hydrochloride

The TFA trifluoroacetic acid

The EtOAC ethyl acetate

The DMF dimethyl formamide

AZT Zidovudine

TIBO 4,5,6, and 7-tetrahydrochysene-5-Methylimidazole is (4,5,1-zk) (1,4) benzodiazepine also

-2(1H)-ketone

The IL-2 interleukin II

GM-CSF granular leukocyte macrophage clone stimulating factor

The rEPO recombiant erythropoietin

EtoH ethanol

MeoH methyl alcohol

The THF tetrahydrofuran (THF)

The DMAP 4-dimethylaminopyridine

Et ₂The O ether

Also used following term herein:

Unless stated otherwise, used term " P(O) (OR ₉)-", refer to phosphate derivative (promptly two subsidiary genes link to each other with P), rather than refer to phosphorous acid ester.

Term " Ar " refers to saturated or undersaturated part.Term " Sauerstoffatom on this structure " refers to oxygen on the primary hydroxyl of mannitol skeleton of The compounds of this invention.

Term " heterocycle " refers to stable 5-7 unit's monocycle or 5-7 unit bicyclic heterocycle, and they are saturated or unsaturated ring, and it can be by benzo-fused arbitrarily when for monocycle.Each heterocycle is formed by carbon atom and 1-4 the heteroatoms that is selected from N, O and S.Term " nitrogen and sulfur heteroatom " comprises the quaternized form of nitrogen and sulphur and any basic nitrogen of any oxidised form.This heterocycle can link to each other with the heteroatoms or the carbon atom of ring, causes the generation of rock steady structure.Preferred above-mentioned heterocycle (but being not limited thereto) comprising: benzimidazolyl-, imidazolyl, the tetrahydroglyoxaline ketone group, imidazolinyl, quinolyl, isoquinolyl, indyl, pyridyl, pyrryl, pyrrolinyl, pyrazolyl, pyrazinyl, quinoxalinyl, piperidyl, morpholinyl, thio-morpholinyl, furyl, thienyl, triazolyl, thiazolyl, the β-Ka Lin base, tetrazyl, thiazolidyl, benzofuryl, thio-morpholinyl sulfone benzoxazolyl, the oxo-piperidine base, the oxo-pyrrolidine base, the oxo azepine Base, azepine

Base, isoxazolyl, tetrahydrofuran base, thiadiazolyl group, benzo dioxolyl, thiophenyl, tetrahydrochysene sulfur phenenyl and nicotinoyl, morpholine-dithio carboxylic acyl group and tetramethylene sulfone.

Term " hiv protease " and " HIV aspartyl protease " are used alternatingly, and refer to the aspartyl protease by human immunodeficiency virus-1 or-2 codings.In the present invention's one preferred embodiment, this term refers to 1-type human immunodeficiency virus aspartyl protease.

Term " effectively dose " refers to effectively treat the amount that patient HIV infects.Term " effectively preventive dose " refers to effectively prevent the amount of patient HIV infection.Here, term " patient " refers to comprise the people by Mammals.

Term " can be made medicinal carrier or auxiliary " and " carrier of physiology purposes " refers to take to the patient and not destroy with The compounds of this invention the non-toxic carrier or the auxiliary of its pharmacologically active.

The compounds of this invention (comprising formula I compound) is defined as comprising that it can make medicinal derivative." medicinal derivative can be made " and refer to the salt of making medicinal salt, ester or this ester of The compounds of this invention or any other compound, after they are taken by the patient, (directly or indirectly) The compounds of this invention can be produced or it has the metabolite or the resistates of antiviral activity.

The salt that derives from appropriate base comprises basic metal (as sodium) salt, alkaline-earth metal (as magnesium) salt, ammonium salt and N-(C _1-4Alkyl) ₄+ salt.

The compounds of this invention contains one or more unsymmetrical carbons, therefore racemoid and racemic mixture, single enantiomer, non-enantiomer mixture and each diastereomer can occur.This class isomeric form of all of these compounds includes in the present invention.Each three-dimensional carbon can be R or S configuration.In addition, but The compounds of this invention C ₂-symmetric, wherein A=A ', B=B ', D=D ', E=E ' and G=G '.

Term " non-natural a-amino acid " refers at the non-existent a-amino acid of nature, but can obtain from natural a-amino acid or other chemical reagent by means known in the art.

The compounds of this invention contains one or more unsymmetrical carbons, therefore racemoid and racemic mixture, single enantiomer, non-enantiomer mixture and each diastereomer can occur.All these isomeric form of these compounds include in the present invention.Each three-dimensional carbon can be R or S configuration.In addition, but The compounds of this invention C ₂One is symmetric, wherein A=A ', B=B ', D=D ', E=E ' and G=G '.

Have only those substituent combination or variations of causing forming stable compound to be suitable for the present invention.The stability that refers to compound " stablized " in term should be enough to guarantee that it can make and take to Mammals by well-known process of the prior art.Usually can or be lower than under 40 ℃ the temperature and stablize at least one week at 40 ℃ at this compound under no moisture or other chemical reaction condition.

The compounds of this invention also can derive from the form of the salt of mineral acid or alkali, organic acid or alkali and use.The example of this class acid salt has: acetate, adipate, alginate, aspartate, benzoate, Phenylsulfonic acid, sulphite, butyrates, Citrate trianion, camphorate, camsilate, cyclopentane propionate, digluconate, the dodecyl sulphate hydrogen salt, dodecyl sulfate, esilate, formate, fumarate, gluceptate, glycerophosphate, glycollate, Hemisulphate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate, lactic acid salt, maleate, malonate, mesylate, the 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, embonate, pectinic acid salt, perchlorate, peroxydisulfate, 3-phenylpropionic acid salt, phosphoric acid salt, picrate, Pivalate, propionic salt, salicylate, succinate, vitriol, tartrate, thiocyanate-, tosylate and undecane hydrochlorate.

The present invention also is contemplated to the quaternized of any alkaline nitrogen-containing group in the disclosed compound.Any reagent that basic nitrogen atom can be known to a person skilled in the art is quaternized, and this class reagent comprises, elementary alkyl halide for example is as muriate, bromide and the iodide of methyl, ethyl, propyl group and butyl; Sulfuric acid dialkyl ester is as dimethyl, diethyl, dibutyl and diamyl sulfuric ester; Long-chain halogenide is as decyl, dodecyl, tetradecyl and octadecyl chlorination thing, bromide and iodide; And aralkyl halide, comprise benzyl, phenethyl bromide.

By this quaternized water or oil soluble or the dispersed product of obtaining.

The new mannitol derivative of the present invention is those compounds of formula I:

Wherein each n independently is selected from 0,1 and 2;

Each A and A ' independently are selected from natural a-amino acid or non-natural a-amino acid, wherein the amino bonded of each A or A ' is to G and G ', or be bonded on the carboxyl of contiguous residue A or A ', this depends on that is more suitable for, and the carboxyl of A or A ' is bonded on the amino of contiguous residue A or A ', or be bonded on the Sauerstoffatom of this structure, this depends on that is more suitable for; Each G and G ' are covalently bound independently to the amino of contiguous residue A or A ' or covalently bound to the Sauerstoffatom of this structure (if contiguous n=0), and each G and G ' are selected from trityl; Hydrogen; C _1-6Alkyl; R ₃-CO-;

R ₅(R ₆R ₇C) mCO-; R ₅(R ₆R ₇C) mW-; R ₅(R ₆R ₇C) (OR m-P(O) ₉)-; R ₈-P(O) (OR ₉)-; And phthaloyl, wherein its aromatic nucleus can be by one or more substituent R ₄Replace arbitrarily; M=1-3 wherein;

Each W independently is selected from-OCO-and-SO ₂-, condition is that W is not-SO when W is connected on the Sauerstoffatom of this structure ₂-;

Each R ₃Be independently selected from: hydrogen; C _1-6Alkenyl; Phenyl and naphthyl; Described C _1-6Alkyl and C _2-6Alkenyl can be selected from hydroxyl by one or more, and the group of chlorine and fluorine replaces; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₄Be independently selected from: C _1-4Alkyl, C _2-4Alkenyl, halogen, hydroxyl, nitro, C _1-3Alkoxyl group and-CO-N(R ₁₀) (R ₁₀);

Each R ₅, R ₆And R ₇Independently be selected from: hydrogen; Chlorine; Fluorine; C _1-3Alkoxyl group; The 5-7 element heterocycle; C _1-3Alkyl; Phenyl; And naphthyl; Described C _1-3Alkyl can be replaced arbitrarily by one or more substituting group that is selected from chlorine, fluorine and hydroxyl; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇With separately or with any form that combines at random in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C _3-6Cycloalkyl; Condition is if R ₅, R ₆And R ₇Be present on the carbon atom of contiguous W, then R ₅, R ₆Or R ₇Not chlorine, fluorine or hydroxyl;

Each R ₈Be independently selected from phenyl, naphthyl and 5-7 element heterocycle, wherein said phenyl or naphthyl can be by one or more substituent R ₄Replace;

Each R ₉Independently be selected from C _1-4Alkyl and phenyl;

Each R ₁₀Independently be selected from hydrogen, C _1-4Alkyl and 5-7 element heterocycle;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂);

Each R ₁₁And R ₁₂Be independently selected from C _1-6Alkyl and C _2-6Alkenyl; With

Each Ar is independently selected from phenyl, by one or more substituent R ₄Any phenyl that replaces and by one or more substituent R ₄5-7 element heterocycle (as the 3-pyridyl, 4-(1,2,3-the thiadiazoles)-Ji that replaces, or 4-morpholinyl arbitrarily).

Another specific embodiments of the present invention comprises aforesaid formula I compound, wherein, and substituting group n, A, A ', G, G ', R ₃, R ₄, R ₅, R ₆, R ₇, m, W, R ₈, R ₉, R ₁₀, B, B ', D, D ', E, E ', R ₁₁, R ₁₂With Ar as definition to the formula I, condition is when n=0, E and E ' they not all are 3-pyridyl or diethylin.

Except that stating separately here, A, A ', B, B ', D, D ', E, E ', G, G ', n, R ₃-R ₁₂, m, the definition of Ar and W is as mentioned above.

Another concrete scheme of the present invention comprises formula I compound,

Wherein each n independently is selected from 0,1 and 2;

Each A and A ' independently are selected from natural a-amino acid or non-natural a-amino acid, wherein the amino bonded of each A or A ' is to G or G ', or be bonded on the carboxyl of contiguous residue A or A ', this depends on that is more suitable for, and the carboxyl of A or A ' is bonded on the amino of contiguous residue A or A ', or be bonded on the Sauerstoffatom of this structure, this depends on that is more suitable for; Each G and G ' are covalently bound independently to the amino of contiguous residue A or A ' or covalently bound to the Sauerstoffatom of this structure (if contiguous n=0), and each G and G ' are selected from following groups: trityl; Hydrogen; C _1-6Alkyl; R ₃-CO-; R ₅(R ₆R ₇C) mCO-; R ₅(R ₆R ₇C) mW-, R ₈-W-, R ₅(R ₆R ₇C) (OR m-P(O) ₉)-, R ₈-P(O) (OR ₉)-and by one or more substituent R ₄Any phthaloyl that replaces; M=1-3 wherein;

Each W independently is selected from-OCO-and-SO ₂-, condition is that W is not-SO when W is connected on the oxygen of this structure ₂-;

Each R ₃Be independently selected from: hydrogen; C _1-6Alkyl, C _2-6Alkenyl, this two can be selected from hydroxyl by one or more, the substituting group of chlorine and fluorine replaces arbitrarily; Phenyl, naphthyl, the two can be by one or more substituent R ₄Replace arbitrarily;

Each R ₅, R ₆And R ₇Independently be selected from hydroxyl; Hydrogen; Chlorine; Fluorine; C _1-3Alkoxyl group; The 5-7 element heterocycle; C _1-3Alkyl; Phenyl; And naphthyl; Described C _1-3Alkyl can be selected from chlorine by one or more, and the substituting group of fluorine and hydroxyl replaces arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇With separately or with any form that combines at random in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C _3-6Cycloalkyl; Condition is if R ₅, R ₆And R ₇Be present on the carbon atom of contiguous W, then R ₅, R ₆And R ₇Not chlorine, fluorine or hydroxyl;

Each R ₉Independently be selected from C _1-4Alkyl and phenyl;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂);

Another concrete scheme of the present invention comprises formula I compound,

Substituting group n wherein, A, A ', G, G ', R ₃, R ₄, R ₅, R ₆, R ₇, m, W, R ₈, R ₉, R ₁₀, B, B ', D, D ', E, E ', R ₁₁And R ₁₂With Ar as definition to the formula I, condition is when n=0, E and E ' they not all are 3-pyridyl or diethylin.

Another concrete scheme of the present invention comprises the formula I compound of subclass:

Wherein each n independently is selected from 0,1 and 2;

Each A and A ' independently are selected from natural a-amino acid or non-natural a-amino acid, wherein the amino bonded of each A or A ' is to G or G ', or be bonded on the carboxyl of contiguous residue A or A ', this depends on that is more suitable for, and the carboxyl of A or A ' is bonded on the amino of contiguous residue A or A ', or be bonded on the Sauerstoffatom of this structure, this depends on that is more suitable for; Each G and G ' are covalently bound independently to the amino of contiguous residue A or A ' or covalently bound to the Sauerstoffatom of this structure (if contiguous n=0), and each G and G ' are selected from following groups: C _1-6Alkyl; R ₃-CO-; R ₅(R ₆R ₇C) mCO-; R ₅(R ₆R ₇C) mW-; And phthaloyl, it can be by one or more substituent R ₄Replace; M=1-3 wherein;

Each W is selected from alone-COC-and-SO ₂-, condition is that W is not-SO when W is connected on the Sauerstoffatom of this structure ₂-;

Each R ₃Be independently selected from: C _1-6Alkyl; Phenyl; And naphthyl; Described C _1-6Alkyl can be selected from hydroxyl by one or more, and the substituting group of chlorine and fluorine replaces arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₄Be independently selected from: C _1-4Alkyl, halogen, hydroxyl, nitro, C _1-3Alkoxyl group;

Each R ₅, R ₆And R ₇Independently be selected from hydrogen; Chlorine; Fluorine; The 5-7 element heterocycle; C _1-3Alkyl; Phenyl; And naphthyl; Wherein said C _1-3Alkyl can be selected from chlorine by one or more, and the substituting group of fluorine and hydroxyl replaces arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇With separately or with any form that combines arbitrarily in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C _3-6Cycloalkyl, condition are if R ₅, R ₆And R ₇Be present on the carbon atom of contiguous W, then R ₅, R ₆Or R ₇Not chlorine, fluorine or hydroxyl;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂);

Each R ₁₁And R ₁₂Be independently selected from C _1-6Alkyl; With

Each Ar is independently selected from phenyl and 5-7 element heterocycle; Wherein said phenyl and 5-7 element heterocycle can be by one or more substituent R ₄Replace arbitrarily.

The concrete scheme again according to the present invention, subclass compound is those compounds of formula I:

Wherein each n independently is selected from 0,1 and 2;

Each A and A ' independently are selected from natural a-amino acid or non-natural a-amino acid, wherein the amino bonded of each A or A ' is to G or G ', or be bonded on the carboxyl of contiguous residue A or A ', this depends on that is more suitable for, and the carboxyl of A or A ' is bonded on the amino of contiguous residue A or A ', or be bonded on the Sauerstoffatom of this structure, this depends on that is more suitable for; Each G and G ' are covalently bound independently to the amino of contiguous residue A or A ' or covalently bound to the Sauerstoffatom of this structure (if contiguous n=0), and each G and G ' are selected from following groups: hydrogen; C _1-6Alkyl; R ₃-CO-;

R ₅(R ₆R ₇C) mCO-; R ₅(R ₆R ₇C) mW-; And phthaloyl, it can be by one or more substituent R ₄Replace arbitrarily; M=1-3 wherein;

Each W is selected from alone-COC-and-SO ₂-, condition is that W is not-SO when W links on the Sauerstoffatom of this structure ₂-;

Each R ₅, R ₆And R ₇Independently be selected from hydroxyl; Hydrogen; Chlorine; Fluorine; C _1-3Alkoxyl group; C _1-3Alkyl; The 5-7 element heterocycle; Phenyl; And naphthyl; Described C _1-3Alkyl can be selected from chlorine by one or more, and the substituting group of fluorine and hydroxyl replaces arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇With separately or with any form that combines at random in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C _3-6Cycloalkyl, condition are if R ₅, R ₆And R ₇Be present on the carbon atom of contiguous W, then R ₅, R ₆Or R ₇Not chlorine, fluorine or hydroxyl;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂), when condition is n=0,

E and E ' are not 3-pyridyl or diethylamino amino;

Each R ₁₁And R ₁₂Be independently selected from C _1-6Alkyl; With

Each Ar is independently selected from phenyl and 5-7 element heterocycle, and wherein said phenyl and 5-7 element heterocycle can be by one or more substituent R ₄Replace arbitrarily.

The present invention-subclass compound is those formula I compounds, wherein:

Each n=1;

Each A and A ' independently are selected from natural a-amino acid, wherein the amino bonded of each A or A ' is to G or G ', or be bonded on the carboxyl of contiguous residue A or A ', this depends on that is more suitable for, and the carboxyl of A or A ' is bonded on the amino of contiguous residue A or A ', or be bonded on the Sauerstoffatom of this structure, this depends on that is more suitable for; Each G and G ' are covalently bound independently to the amino of contiguous residue A or A ' or covalently bound to the Sauerstoffatom of this structure (if contiguous n=0), and each G and G ' are selected from following groups: hydrogen, R ₅(R ₆R ₇C) mW-, wherein W is-OCO-, m=1;

Each R ₅, R ₆And R ₇Independently be selected from hydroxyl; Hydrogen; Chlorine; Fluorine; C _1-3Alkyl; The 5-7 element heterocycle; Phenyl; And naphthyl; Described C _1-3Alkyl can be selected from chlorine by one or more, and the substituting group of fluorine and hydroxyl replaces arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇With separately or with any form that combines at random in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C _3-6Cycloalkyl, condition are if R ₅, R ₆Or R ₇Be present on the carbon atom of contiguous W, then R ₅, R ₆And R ₇Not chlorine, fluorine or hydroxyl;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂);

Each R ₁₁And R ₁₂Be independently selected from C _1-6Alkyl; With

A class preferred compound of the present invention is the compound of formula II:

Wherein:

Each B and B ' are selected from oxygen and sulphur separately;

Each D and D ' are selected from H separately ₂; Oxygen and sulphur;

Each E and E ' are selected from Ar and NEt separately ₂; And

Each Ar is independently selected from phenyl; The 3-hydroxy phenyl; The 3-pyridyl; 4-(1,2, the 3-thiadiazoles)-Ji; With the 4-morpholinyl.

The mannitol derivative of the preferred formula II of the present invention is wherein (A) n, (A ') n, G and the G ' Cbz Val that respectively does for oneself; B, D and E are selected from the compound of following groups together: 1) benzoic ether; 2) 3-hydroxybenzoate; 3) nicotinate; 4) 4-(1,2,3-thiadiazoles carboxylicesters); 5) benzyloxy; 6) thiobenzoic acid ester; 7) 4-morpholine dithiocarboxylic esters; With 8) N, N-diethyl-dithio carboxylicesters.1,1 ', the preferred configuration of 2 and 2 ' position is respectively (S), (S), (R) and (R), they are from starting raw material such as L-mannitol.These preferred compounds comprise the compound that the table I is described.

Table 1

Compound	B	D	E
				1 2 3 4 5 6 7 8	O O O O O S S S	0 0 0 0 H ₂O S S	Phenyl 3-hydroxy phenyl 3-pyridyl 4-1,2, the 3-thiazole)-Ji phenyl 4-morpholinyl diethylamino

Should be appreciated that, the compound of all formula I and formula II as defined herein, B, D and E are selected from following groups together: benzoic ether; The 3-hydroxybenzoate; Nicotinate; 4-(1,2,3-thiadiazine acid esters); Benzyloxy; The thiobenzoic acid ester; 4-morpholine dithiocarboxylic esters; And N, N-diethyl-dithio carboxylicesters.In addition, A and G can be the carbobenzoxy-(Cbz) Xie Ansuan together.

Preferred compound of the present invention is:

1,6-two-O-benzoyl-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 1);

1,6-two-O-(3-hydroxyl) benzoyl-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 2);

1,6-two-O-nicotinoyl-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 3);

1,6-two-O-(4-(1,2,3-thiadiazoles)-yl)-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 4);

1,6-two-O-benzyl-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 5);

1,6-two-S-benzoyl-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 6);

1,6-two-S-(4-morpholino thiocarbonyl)-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 7); And

1,6-two-S-(N, N-diethyl thiocarbonyl)-2,5-two-O-(N-carbobenzoxy-(Cbz) valyl)-L-mannitol (compound 8).

Compound of the present invention can be synthetic with routine techniques.Preferably synthetic easily from the starting raw material that is easy to get.

Compound of the present invention is to be easy to synthetic most in the known hiv protease inhibitor.The hiv protease inhibitor of Miao Shuing often contained six above chiral centres in the past, large-molecular peptides connects agent and/or their the synthetic airsensitive reagent (as organic metal composite) that needs.

The synthetic characteristic that is easy to relatively of The compounds of this invention has huge superiority when these compounds of mass production.

Generally can obtain the mannitol derivative of formula I and formula II easily from D-or L-mannitol.Available like this known technology is from commercially available D-or synthetic easily enantiomorph of L-mannitol or diastereomer mannitol derivative.

Although the present invention will comprise D-or L-mannitol or their racemic mixture as the skeleton that links various groups, preferred L-mannitol.

The using standard technology, can be to D-or L-mannitol derivatize according to following route I:

Route 1

D-or L-mannitol can change its single ketal (T.W.Greene into acetone or the known ketone of other those skilled in the art, Protective Groups in Organic Synthesis, John Wiley and Sons(1991) and the reference wherein quoted).Ketal is converted into diepoxide then, by the selectivity tosylation of primary hydroxyl, handles with alkali salt of wormwood then earlier, finishes diepoxyization, and tosylate is left away simultaneously.Epoxide group is used the nucleophilic reagent open loop of general formula E (CD) B on one side at the carbon atom of its steric restriction minimum then, and wherein E, D and B see the definition of the compound of formula I, form single adduct (pure epoxide).The hydroxyl that forms is then in the EDC(1-(3-dimethylaminopropyl)-the 3-ethyl-carbodiimide hydrochloride) and DMAP(4-methylamino pyridine) in the presence of, use general formula G-(A) the functionalized epoxide of a-amino acid of the N-protected of n-OH.Remaining epoxide group is used the nucleophilic reagent open loop of general formula E ' (CD ') B ' then; wherein E ', D ' and B ' see the definition of formula I compound; the glycol that generates carries out esterification with G '-(A ') n-OH; wherein G ' and A ' see the definition of formula I compound; slough ketal protectedly then with acidic aqueous solution, generate the compound of formula I.

The example for preparing the method for mapping or diastereoisomeric D-or L-mannitol derivative with the step of route I explanation is seen L.F.Wiggins, J.Chem.Soc., P.13(1946); Y.Le Merrer etc., Tetrahedron Lett., 26, pp.319-22(1985) and Y.Le Merrer etc., and Heterocy-cles, 25, pp.541-48(1987).In addition, suitable contain the ethylene linkage precursor and can (may unite use with perosmic anhydride with another oxygenant, as N-ethylmorpholine N-oxide compound) oxidation, obtain mapping or diastereomeric dibasic alcohol (is seen Van Rheenen etc., Tetr-ahedron Lett., pp.1973-76(1976) and Kaldor, J.Org.Chem., 55, pp.1698-1700(1990)).111, P.1123(1989) the perosmic anhydride oxidation also can be carried out in the presence of various chiral ligands, with asymmetric (as the selectivity of face) oxidation of promoting alkene (Wai etc., J.Am.Chem.Soc.).The another kind of method that makes up ethylene glycol nuclear is included in the aldehyde (can be identical or different) that reduction in quite which alcohol reaction connects two suitable derivatizes.This reacts available low price metal and carries out, and comprises titanium (J.E.McMurry, Acc.Chem.Res., 16, pp.405-411(1983)) and vanadium (Freudenberger etc., J.Am.Chem.Soc., 111, and various lanthanum iodide (Namy etc., Tetrahedron Lett., 24 pp.8014-16(1989)), pp.765-66(1983) and Imamoto etc., Tetrahed-ron Lett., 23, pp.1353-56(1982)).

Compound of the present invention can be synthetic with known technology.D-or L-mannitol can be with acid catalyst well known by persons skilled in the art and ZC(O) carbonyl compound of Z ' type is converted into the ketal of formula III; ZC(O) middle Z of Z ' and Z ' are selected from hydrogen, C separately _1-20Alkyl, C ₃-C ₈Cycloalkyl, phenyl, naphthyl and 5-7 unit heterocycle; C wherein ₁-C ₂₀Alkyl, C ₃-C ₈Cycloalkyl, phenyl, naphthyl and 5-7 unit heterocycle can be replaced arbitrarily by one or more substituting groups that are selected from hydrogen, hydroxyl, alkoxyl group, phenoxy group, nitro, carboxylate radical and sulfonate radical; Wherein Z and Z ' can be arbitrarily in conjunction with forming cyclic ketones.

Such ketone be commercially available or available currently known methods synthetic.During as catalysts, acetone is particularly preferred with sulfuric acid.

The ketal of formula III then can be on primary hydroxyl carries out selective esterification with the acid derivative of carboxylic acid or general formula E-C(D)-X, and wherein E and D see the compound definition of formula I, and X be the leavings group that suitably activates the C=D carbonyl.Such leavings group is known in the art, and comprises halogen ion, hydroxide radical, alcoholate ion, phenonium ion and sulfonate radical.Esterification can be carried out in the presence of organic bases, as triethylamine, diisopropylamine, ethyl diisopropyl amine, pyridine, 4-Dimethylamino pyridine or their mixture.Preferred leavings group comprises the halogen ion, and chlorine is particularly preferred.Preferred organic bases comprises pyridine and 4-Dimethylamino pyridine, especially preferably their mixture.In the preferred embodiment of the present invention, E-C(D) be benzoate anion together.In second kind of preferred embodiment, E-C(D) be 3-hydroxy-benzoic acid root.In the third preferred embodiment, E-C(D) be the nicotinic acid root.The 4th kind of preferred embodiment as, be 1,2 E-C(D), 3-thiadiazoles-4-carboxylate radical.The compound E-C(D of formula III)-compound of X esterification production IV:

Wherein Z and Z ' are with the definition of above-mentioned formula III.The glycol of formula IV general formula G-(A then) the further esterification of compound of n-X, the wherein definition of G, A and n cotype I compound, X is for strengthening G(when n=0) or the electrophilic leavings group of A.The leavings group that is fit to is well known in the art, includes, but is not limited to halogen ion, hydroxyl, alcoholate ion, phenonium ion and sulfonate radical.Esterification can be carried out in the presence of catalysts, as 4-Dimethylamino pyridine, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), DIC (DIC) and their mixture.In a kind of preferred embodiment of the present invention, leavings group is that hydroxyl, esterifying catalyst are the mixture of EDC and 4-Dimethylamino pyridine.In a kind of particularly preferred embodiment of the present invention, G=benzyloxycarbonyl (Cbz), A=Xie Ansuan (Val) and n=1.The compound G-(A of formula VI) compound of n-X esterification production V:

The wherein definition of Z, Z ', E, C and D cotype IV.The compound of formula V used water and acid treatment then is ketal protected to slough, the mannitol derivative of production I.It is known in the art being used to remove ketal protected acid, includes, but is not limited to: hydrochloric acid, sulfuric acid, acetate, tosic acid and trifluoroacetic acid.Preferred trifluoroacetic acid.

In addition, compound of the present invention can directly obtain from D-or L-mannitol.In preferred version of the present invention, select enantiomorph L-seminose.The effect of seminose available hydrogen negative ion donor is reduced to mannitol.The hydride ion donor is known in the art, and includes, but is not limited to sodium borohydride, sodium cyanoborohydride, Li-Al hydrogen, triisobutyl lithium borohydride and triisobutyl POTASSIUM BOROHYDRIDE.Seminose carries out in regular solution to the reduction of mannitol, as water, methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, tetrahydrofuran (THF) and their mixture.In preferred version of the present invention, the hydride ion donor is a sodium borohydride, and solvent is a methyl alcohol.

With aforesaid method mannitol is converted into ketal then.The ketal of formula III again on primary hydroxyl with the electrophilic reagent condensation, after electrophilic reagent and oxygen formed stable covalent linkage, itself was as a kind of leavings group.Such electrophilic reagent is known to those skilled in the art, includes, but is not limited to the carboxylic acid halides or the acid anhydrides of tosic acid, 4-bromobenzene acid iodide, methylsulfonic acid and trifluoromethanesulfonic acid.Preferred Tosyl chloride.Two adductss that generate can be used alkaline purification in usual vehicle (as above definition), to pass through residual hydroxyl attack terminal carbon, electrophilic group-oxygen leavings group is left away simultaneously, carries out intramolecularly dicyclo oxygenizement.Such alkali is well known to those skilled in the art, include, but is not limited to metal hydroxides such as sodium hydroxide, potassium hydroxide, carbonic acid metal salt such as yellow soda ash, salt of wormwood and Quilonum Retard and carbonic acid acid metal-salt such as sodium bicarbonate, saleratus and lithium bicarbonate.In the preferred version of the present invention, alkali salt of wormwood, usual vehicle are methyl alcohol.Such di-epoxide is suc as formula shown in the VI:

The wherein definition of Z and Z ' cotype III.The diepoxide of formula VI can use formula E-C(D hindering on the minimum carbon atom)-nucleophilic reagent of BH carries out alkylation, the wherein definition of E, D and B cotype I compound, generation glycol.In a kind of preferred embodiment of the present invention, E-C(D)-BH is a phenylformic acid.In second kind of preferred version, E-C(D)-BH is a thiobenzoic acid.In the third preferred version, E-C(D)-BH is a 4-morpholine dithionic acid.The glycol that obtains with this method is as shown in the formula shown in the VII:

Wherein Z, Z ', E, C and B such as above-mentioned formula IV define.The glycol of formula VII formula G-(A then) the further esterification of compound of n-X, the wherein definition of G, A and n cotype I compound, X is for strengthening G(when n=0) or the electrophilic leavings group of A.The leavings group that is fit to is known in the art, includes, but is not limited to halogen ion, hydroxyl, alcoholate ion, phenonium ion and sulfonate radical.Esterification may be carried out in the presence of catalysts, catalyzer such as 4-dimethylamino-pyridine, 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC), DIC (DIC) and their mixture.In a kind of preferred embodiment of the present invention, leavings group is a hydroxyl and esterifying catalyst is the mixture of EDC and 4-dimethylamino-pyridine.In the particularly preferred scheme of the present invention, G=benzoyloxy carbonyl (Cbz), A=Xie Ansuan (Val) and n=1.The compound G-(A of formula IV) the n-X esterification obtains the compound of formula VIII:

The wherein definition of Z, Z ', E, C, B, G, A and n cotype V.The compound of formula VIII is handled with the compound similar methods of formula V then, wherein discharges ketal protectedly, forms the mannitol derivative of formula I.In the preferred embodiment of the invention, unite the acid of using with water and be trifluoroacetic acid.

In preferred version of the present invention, from 3,4-O-isopropylidene-L-mannitol (1C) synthesizes the mannitol derivative, and the former is according to L.F.Wiggins, J.Chem.Soc., P13, (1946); LeMerrer etc., TetrahedronLett., 26 pp.319-22(1985) and Le Merrer etc., Hetero-cycles, 25, the pp.541-48(1987) method of (wherein using the D-mannitol) and describing (the seeing route 2-3) of deriving and from the L-mannitol.Diester karyonide row L-mannitol derivative 1-4 uses carboxyl acyl chloride by two primary hydroxyls of compound 1C in the presence of pyridine; or in the presence of EDC and DMAP, use carboxylic acid; carry out that selectively acylating obtains, there is lower link in glycol of Sheng Chenging and carbonyl benzyloxy-L-Xie Ansuan (Cbz Val-OH) at EDC and DMAP then.Handle with trifluoroacetic acid aqueous solution again,, produce L-mannitol derivative 1-4(route 2) to remove the acetonide protecting group.

L-seminose sodium borohydride reduction is used sulfuric acid and acetone three ketalizations then, removes terminal ketal with acetate and water again, obtains compound 1C, from then on compound similarly derivatize obtain L-mannitol derivative 5-8(route 3).

Route 3

Acetonide 1C handles in methyl alcohol with salt of wormwood then with Tosyl chloride optionally tosylation on each primary hydroxyl in pyridine, obtains di-epoxy compounds 5A(and sees L.F.Wiggins, J.Chem.Soc.p13, (1946); Le Merrer etc., Tetrahedron Lett., 26,319(1985) and Le Merrer etc., and Heterocycles, 25, P.541(1987)).Aluminum oxide is handled di-epoxy compounds 5A(as catalyzer with alcohol or thiocarboxylic acid and is seen Posner etc.; Tetrahedron Lett.; 42; P.3596(1975) and Posner etc., J.Am.Chem.Soc., 99; pp.25 and 8208(1977)); with the glycol Cbz Val-OH esterification in the presence of EDC and DMAP that generates, remove the acetonide protecting group with TFA/ water again, obtain N.F,USP MANNITOL derivative 5 and 6.In the presence of solvent dimethylformamide, handle di-epoxy compounds 5A, obtain mannitol derivative 7 and 8(, see Kempf etc., european patent application 402646A1) with of the similar reaction of mercaptan nucleophilic reagent to the open loop of N-acetylethyleneimine with the dithionate.The dithionate can directly use, or with amine alkali reaction on-site preparation.The glycol that generates with Cbz Val-OH esterification in the presence of EDC and DMAP, is sloughed the acetonide protecting group with TFA and water again.

Can recognize that as those skilled in the art above-mentioned synthetic method can not comprise can synthesize above-mentioned and all methods the application's claim compound.Other method is conspicuous to those of ordinary skills.

The compounds of this invention can connect suitable functional group and modify, to improve its biological selectivity.This modification known in the art, it comprises that raising penetrates into given biosystem (as blood, lymphsystem, central nervous system) ability, improves oral availability, improves solubleness with the energy drug administration by injection, improves metabolism and improves drainage rate.

As mentioned above, new compound of the present invention is an aspartyl protease, especially the fabulous ligand of HIV-1 and HIV-2 proteolytic enzyme.Therefore, these compounds can also suppress the last stages that HIV duplicates by targets, promptly by the processing of the viral polyprotein of HIV encoded protein enzyme control.The compounds of this invention has good inhibition HIV-1 virus infection persistent survival human T cell's ability in for some time, it is to measure by the outer P24 antigen (special marking of virus replication) of analysis of cells.(see, Meek etc., Nature, 343, pp.90-92(1990)).

The compounds of this invention is except being used for prevention or treatment HIV or HTLV infection, they also can be used as the inhibition or the agent interfering of other virus, and these viruses depend on the aspartyl protease (they play keying action in viral life circulation) that is similar to HIV or HTLV aspartyl protease.These compounds are by suppressing the hydrolytic process that aspartyl protease suppresses the polyprotein precursor.Because aspartyl protease is important for the production of ripe virus, therefore, by suppressing infectious virus, especially from the production and the breeding propagation of blocking virus effectively of the virus of chronic infection sexual cell.The compounds of this invention can suppress the enzymic activity of aspartyl protease well, and suppresses the ability of aspartyl protease catalysis peptide bond hydrolysis.

The compounds of this invention can be used for the treatment of or prophylaxis of viral diseases in a usual manner, and as HIV, HTLV and other depend on the virus (they play main effect in viral life circulation) of aspartyl protease.These methods of treatment, used dosage and other requirement can be selected from available method and technology by those of ordinary skills.For example, The compounds of this invention can be given to close with medicinal forms and the significant quantity that alleviates the severity of virus infection and deliver medicine to the virus infection patient with medicinal auxiliary.

Perhaps, The compounds of this invention can be used for vaccine and protects the method for individual immunity virus infection in a long time.These compounds can be by the conventional method of using proteinase inhibitor in vaccine, with vaccine or use separately or use with the form that other compound of the present invention uses.For example, a certain compound of the present invention can share with commonly used medicinal auxiliary in the vaccine and avoid virus infection with the administration of prevention significant quantity with protection individuality in the long duration, infects as HIV.Thus, the new proteinase inhibitor of the present invention can be used as treatment or prevents the mammiferous virus infection medicine of (comprising that HIV infects).

The compounds of this invention can single agent or is share form administration in healthy people or HIV infected patient with other antiviral agent that can disturb the HIV replication cycle.By with The compounds of this invention other antiviral agent Combined Preparation, can strengthen the therapeutic action of these compounds with the different steps of energy target virus life.But the antiviral agent target viral life cycle commitment that for example is used for co-administered (as enters cell, reverse transcription and viral DNA are integrated into cell DNA) medicine, the antiviral agent in these the early stage stages life history of target comprises: didanosine(ddI), alcitabine(ddC), d4T, Zidovudine(AZT), many vitriolic polysaccharide, the solvable CD4 of ST4(), their virus capable of blocking is adhered to or is adsorbed onto on the host cell; Can blocking virus be attached to compound on the lymphocytic CD4 acceptor of the T-that has CD4 with other.The reverse transcriptase inhibitors of other retroviral as the AZT derivative, can reduce or eliminate the virus infection and the clinical treatment of relevant symptom therewith thereby also can share to provide with The compounds of this invention.The example of other antiviral agent comprises: ganiclov-ir, dideoxycytidine, trisodium Phosphonoform-ate, eflornithine, ribavirin, acyclovir, alpha-interferon and trimenotrexate.In addition, the non-nucleosidic inhibitors of reversed transcriptive enzyme such as TIBO or nevirapine can be used as the uncoating inhibitor, the inhibitor of the inhibitor of Transactivation albumen such as tat or rev or viral integrase enzyme.These compounds also can share with other inhibitor of HIV aspartyl protease.

Because each pharmaceutical compositions of drug combination works at the different positions that HIV duplicates, so drug combination of the present invention treatment is duplicated and is demonstrated synergy suppressing HIV.Thisly unite use and compare with single agent administration advantageously to reduce and reach required treatment or prophylactic effect and the dosage of the degeneration-resistant virus drugs of used routine of needs.These drug combinations can reduce or eliminate conventional independent degeneration-resistant virus drugs and treat side effect that is produced and the degeneration-resistant virus activity that can not disturb these medicines.These drug combinations have also reduced the resistance ability to single therapy, make relevant toxicity drop to minimum simultaneously.These drug combinations also can not increase the drug effect that strengthens conventional medicine under the relevant toxicity.Specifically, play synergy aspect we have found these compounds HIV duplicates in stoping the human T cell.Preferred combination therapy comprises The compounds of this invention and AZT, ddI, and ddC or d4T be Combined Preparation together.

In addition The compounds of this invention also can with other hiv protease inhibitor such as RO31-8959(Roche), L-735; 524(Merck), XM323(Du-Pont Merck) and A-80,987(Abbott) together administration to strengthen treatment or prophylactic effect to various variant virals or the accurate class members of other HIV.

We preferably with The compounds of this invention with single medicine or with reverse transcriptase inhibitors such as AZT derivative or its HIV aspartyl protease inhibitor cooperative programs administration of retroviral.We think that the reverse transcriptase inhibitors of The compounds of this invention and retroviral or the Combined Preparation of HIV aspartyl protease inhibitor can demonstrate synergy, can stop thus, substantive reduce or eliminate virus infection or its relevant symptom fully.

The compounds of this invention also can with immunomodulator (as bropirimine, anti-human body interferon-alpha antibody, IL-2, GM-CSF, met-enkephalin, interferon-alpha, the former acetoacetic ester of two sulphurs, tumour necrosis factor, naltrexone and r EPO); Infect relevant infection or disease such as AIDS and ARC with microbiotic (as β-Pentamidne Isethonate) or vaccine Combined Preparation together with prevention or elimination and HIV.

When the treatment of The compounds of this invention and other medicines Combined Preparation, they can be in succession or deliver medicine to the patient simultaneously.In addition, medicine of the present invention or prevention composition can be constituted jointly by aspartyl protease inhibitor of the present invention and another treatment or prophylactic agent.

The compound that will disclose here is used for prevention and treatment HIV infects though the present invention concentrates on, and The compounds of this invention also can be used as other viral inhibitor, and these viruses are relevant with the similar aspartyl protease that plays a major role in viral life cycle.These viruses comprise as simian immunodeficiency virus and cause the retroviral of other similar AIDS disease, but are not limited to HTLA-I and HILV-II.In addition, The compounds of this invention also can be used for suppressing other aspartyl protease, especially comprises other human body aspartyl protease of the aspartyl protease of renin and processing endotheliotoxin (endothe-lin) precursor.

Pharmaceutical composition of the present invention contains The compounds of this invention and its pharmaceutical salts, pharmaceutical carrier, auxiliary or vehicle.The pharmaceutical carrier that in the present composition, uses, auxiliary or vehicle comprise (but being not limited thereto): ion-exchanger, aluminum oxide, aluminum stearate, Yelkin TTS, serum protein such as human serum haemproteins, buffer substance such as phosphoric acid salt, glycine, Sorbic Acid, potassium sorbate, the partial glycerol ester mixture of saturated vegetable fatty acid, water, salt or ionogen, as protamine sulfate, Sodium phosphate dibasic, sodium hydrogen phosphate, sodium-chlor, zinc salt, silica colloidal, Magnesium Trisilicate, polyvinylpyrrolidone, cellulosic material, polyoxyethylene glycol, Xylo-Mucine, polyacrylic ester, paraffin, polyethylene-polyoxypropylene-block polymer, polyoxyethylene glycol and lanolin.

The route of administration of pharmaceutical composition of the present invention has: oral, and non-enteron aisle, spraying sucks, part, rectum, nasal cavity, cheek, vagina or by implanting the storehouse.Our preferred oral and drug administration by injection.Pharmaceutical composition of the present invention can contain conventional non-toxicity pharmaceutical carrier, auxiliary or vehicle.Here used term " non-enteron aisle " is meant subcutaneous, intracutaneous, and vein, intramuscular, intraarticular, intrathoracic in the synovial membrane, in the film, intralesional and intracranial injection or drip infusion technique.

This pharmaceutical composition can aseptic injection preparation such as the aseptic injection aqueous solution or the use of oily form of suspension.This suspension can be by technology known in the art, and dispersion or wetting agent (as tween 80) and suspension agent are made into suiting.Aseptic injection preparation also can be with aseptic parenteral solution in diluent or the solvent or suspension, as the solution in 1,3 butylene glycol at the non-enteron aisle of non-toxicity.Spendable available vehicle and solvent have: mannitol, water, Ringer ' s solution and sodium-chlor isotonic solution.In addition, aseptic fixed oil generally is used as solvent or suspension medium.For this purpose, any tasteless fixed oil is synthetic list or double glyceride.Lipid acid such as oleic acid or its glyceride derivative can be used for the preparation of injection, if it is natural medicinal oil such as sweet oil or Viscotrol C, and the words of their the ethylating modifier of polyoxy especially.These oil solutions or suspension also can contain long-chain alcohol thinner or dispersion agent such as Ph.Helv or similarly pure.

Pharmaceutical composition of the present invention can the oral dosage form oral administration, and it comprises (but being not limited thereto): capsule, tablet, waterborne suspension and solution.The common carrier that is used for oral tablet comprises lactose and W-Gum.Lubricant also is to add usually as Magnesium Stearate.The used thinner of oral capsule is comprised lactose and exsiccant W-Gum.When the waterborne suspension oral administration, active ingredient can mix with emulsifying agent and suspension agent.As needs, also can add some sweeting agents and/or seasonings and/or tinting material.

Pharmaceutical composition of the present invention also can the suppository form rectal administration.These compositions can by with The compounds of this invention be solid-state and be liquid under rectal temperature and melt the suitable non-irritating excipient that discharges active compound at rectum and mix and prepare in room temperature.These materials comprise (but being not limited thereto): theobroma oil, beeswax and polyoxyethylene glycol.

When required treatment comprises that can reach the zone of treatment or organ by the topical application medicine time, the topical of pharmaceutical composition of the present invention is useful especially.For the topical application on skin, pharmaceutical composition should be made into and contain the suitable paste that suspends or be dissolved in active ingredient in the carrier.The carrier that is used for the The compounds of this invention topical comprises (but being not limited thereto): mineral oil, liquid petroleum, white oil, propylene glycol, polyoxyethylene glycol, polyoxyethylene polyoxypropylene compound, emulsive paraffin and water.In addition, this pharmaceutical composition can be made into and contain solution or the ointment that suspends or be dissolved in the active ingredient in the carrier.Suitable carrier comprises (but being not limited thereto): mineral oil, Stearinsaeure sorbitan ester, polysorbate 60, hexadecanol ester type waxes, hexadecanol, 2-Standamul G, benzyl alcohol and water.Pharmaceutical composition of the present invention also can rectal suppository or suitable enema forms be applied topically to lower enteron aisle.Local paste through skin is also included among the present invention.

Pharmaceutical composition of the present invention can pass through nose aerosol or inhalation form administration.These compositions can and be made salts solution by technology preparation known in the art, and this wherein can add benzylalcohol or other suitable sanitas, absorption enhancer, and fluorohydrocarbon and/or other solvating agent known in the art or dispersion agent are to strengthen bioavailability.

The active ingredient compound dosage that is used to prevent or treats the virus infection that comprises that HIV infects is: the about 25mg/ kg body weight of about 0.01-/sky, the about 25mg/ kg body weight of preferably about 0.5-/sky.About 1-5 time of general administration every day of pharmaceutical composition of the present invention, or continuous infusion.This form of medication can be used for chronic or acute treatment.The active ingredient amount of mixing to generate single dose form with carrier changes according to host who is treated and concrete form of medication.Preparation generally contains the about 95%(W/W of about 5%-) active ingredient, preferred about 80% active ingredient of 20-.

According to the improvement situation of patient's symptom, in case of necessity, can take the The compounds of this invention of maintenance dose, composition or binding substances.Alleviated to desired degree and treatment should stop the time when symptom subsequently,, dosage or number of times or the two have been reduced to the symptom level of having improved that is maintained to according to the symptom situation.But because the repetition of disease symptoms, the patient must ask secular periodicity treatment.

Those skilled in the art can see obviously that use is fine than above-mentioned low or high dosage.The concrete dosage that any concrete patient is treated depends on many factors, this comprises the concrete activity of compound used therefor, patient age, body weight, common healthy state, sex, diet, administration number of times, discharge rate, the medicine of coupling, the degree of infection and time length, the patient is to the sensation of infection and clinician's diagnosis.

The compounds of this invention also can be used as can be effectively and aspartyl protease, especially with the commercial reagent of HIV aspartyl protease bonded.As commercial reagent, The compounds of this invention and its derivative can be used for blocking the proteolysis of target peptide or can being used for affinity chromatography to combine with stabilized resins as the constraint substrate by derivation.Is conspicuous for being characterized as these or other purposes to those skilled in the art with commercial aspartyl protease inhibitor.

The present invention also comprises the synthetic method of aspartyl protease inhibitor.A kind of method comprises the following steps:

(a). in the presence of acid, handle mannitol, with the preparation ketal derivatives with carbonyl compound; This carbonyl compound is selected from acetone, cyclopentanone, pimelinketone, phenyl aldehyde, and this acid is selected from sulfuric acid, spirit of salt, acetate, trifluoroacetic acid and composition thereof;

(b). with SULPHURYL CHLORIDE the primary hydroxyl of above-mentioned ketal derivatives is carried out esterification, with the preparation disulfonate; This SULPHURYL CHLORIDE is selected from Tosyl chloride, 4-bromobenzene SULPHURYL CHLORIDE, methylsulfonyl chloride and trifluoromethanesulfchloride chloride;

(c). with above-mentioned disulfonate and alkali reaction, with the preparation diepoxide; This alkali is selected from metal hydroxides, metal carbonate and alkali metal bicarbonate salt, and this di-epoxide has two minimum positions of empty resistance;

(d). make above-mentioned di-epoxide in the minimum position open loop of its empty resistance, with the preparation glycol with nucleophilic reagent; This nucleophilic reagent is selected from aryl alcohol, aryl thioic acid sulfoacid and the acid of heterocycle dithio;

(e). with the infinite above-mentioned glycol of a-amino acid esterification that has the N-protected group, with the preparation diester; This N-protected group is selected from benzyloxy carbonyl and tert-butoxycarbonyl; With

(f). the above-mentioned diester of mixture process of the acid in water and the step (a), to prepare above-mentioned aspartyl protease inhibitor.

The method of another synthetic aspartyl protease inhibitor of the present invention comprises the following steps:

(a). in the presence of acid, handle mannitol, with the preparation ketal derivatives with carbonyl compound; This carbonyl compound is selected from acetone, cyclopentanone, pimelinketone and phenyl aldehyde, and this acid is selected from sulfuric acid, spirit of salt, acetate, trifluoroacetic acid and composition thereof;

(b). in each primary hydroxyl position of above-mentioned ketal derivatives it is carried out esterification with esterifying reagent, with the preparation glycol; This esterifying reagent is selected from the carboxylic acid halides and the carboxylic acid anhydride of carboxylic acid, carboxylic acid;

(c). have the above-mentioned glycol of a-amino acid esterification of N-protected group with indefiniteness ground, with the preparation diester; This N-protected group is selected from benzyloxy carbonyl and tert-butoxycarbonyl; With

(d). the above-mentioned diester of mixture process of the acid in water and the step (a), to prepare above-mentioned aspartyl protease inhibitor.

For more fully understanding the present invention, especially exemplified by going out the following example.These embodiment do not have any restriction to scope of the present invention just for the present invention is described.

Raw material and method

Make the reaction of oxirane ring open loop use Al with the heteroatoms nucleophilic reagent ₂O ₃, preferred Brockman Super I, Woelm 200 neutrality (deriving from ICN).Reduction available from the L-seminose of Sigma with preparation L-mannitol.Use the L-amino acid derivative in case of necessity.

Thin-layer chromatography (TLC) carries out on 0.25mm silicon gel E.Merck 60 F254 thin plates and with indicated solvent systems wash-out.Preparative chromatography is by flash chromatography, with silica gel 60(EM Science) and shown in solvent systems and N just ₂Depress wash-out, perhaps still use 0.5,1.0 or the thick-layer chromatography of the thick E.Merck 60 F254 thin plates of 2.0mm carry out.Unless otherwise indicated, analyze thin plate, heating immediately in 20% solution-treated of EtOH, carry out the detection of compound by wash-out thin plate (analyzing or preparation) is placed under the UV light and with phospho-molybdic acid.

With Waters Delta Pak, 5 μ M silica gel, C-18 reverse-phase chromatographic column, diameter 3.90mmID * 15cm, flow velocity 1.5ml/min.Have following moving phase and gradient shape, carry out all HPLC and analyze.

Moving phase: A=H ₂0.1% trifluoroacetic acid among the O;

B=CH ₃0.1% trifluoroacetic acid among the CN

Gradient: the T=0 branch, A(95%), B(5%);

The T=20 branch, A(0%), B(100%);

The T=22.5 branch, A(0%), B(100%)

On the Bruker AMX 500 of equipment upset or QNP probe, write down nucleus magnetic resonance (NMR) spectrum.For obtaining data, sample dissolution is in deuterochloroform or deuterated methanol and use corresponding inner protonic solvent frequency to be standard.This paper provide chemical shift (ppm) and multiplicity (S represents unimodal, bimodal, bimodal the bimodal of branch of splitting again of dd that d represents, t represents triplet; Q represents quartet, and m represents multiplet, and br represents broad peak), for all C ₂-symmetrical compound, listed number of hydrogen atoms are half of number of hydrogen atoms in the molecule.

With Le Merrer etc., Heterocycles, 25, pp.541-48, (1987) are gone up method of describing and are prepared following compounds from L-N.F,USP MANNITOL, and wherein D-N.F,USP MANNITOL is used to prepare compound 1B, 1C, 1D and 5A.

Embodiment 1

A.L-mannitol (compound 1A).

To at MeOH(700ml) in commercial L-seminose (mixture of anomer, 27.5g 0.15mol) add sodium borohydride (12.6g at 0 ℃ in batches, 0.33mol), in reaction, drip dense HCl at 0 ℃, make it be acidified to PH=1, add solid K then ₂CO ₃(excessive), MeOH filters solution decompression as quantitative transfer agent.Concentrated filtrate obtains white solid.With itself and benzene (2 * 200l) azeotropic.By reflux solution, make solid crystallization from alcohol (1.8L) subsequently, and filter immediately.L-N.F,USP MANNITOL obtains the 17.3g product with the rapid crystallization of white needle-like crystals, i.e. compound 1A(63% productive rate).TLC:Rf(9%NH ₄OH/18%MeOH/CH ₂Cl ₂)=0.6(develops the color with triketohydrindene hydrate); NMR(CD ₃OD): 3.86(dd, 1H, ABX), 3.82(S, 1H), 3.74(m, 1H).

B.1,2: 3,4: 5,6-three-oxygen-isopropylidene-L-mannitol.

(15.5g 0.09mol) with acetone (193ml) and sulfuric acid (1.55ml) dilution, at room temperature will react (whole process is always for heterogeneous) and stir 12 hours the L-mannitol.Use 30%NH ₄OH(5.6ml) and solid K ₂CO ₃(9.8g) neutralization, and continue stirring 2 hours, filtration under diminished pressure subsequently.Concentrated filtrate obtains white solid, by adding capacity EtOH and being heated to homogeneous phase, mixes then with vibration and drips H ₂O is muddy slightly to solution becomes, and this white solid is crystallized out from wet alcohol.After the crystallization, filtration under diminished pressure obtains white needle-like crystals compound 1B(21g).As needs, can from mother liquor, reclaim more polyvoltine compound.NMR（CDCl ₃）：4.16（m，1H），4.05（dd，1H，ABX），3.95（dd，1H，ABX），3.92（dd，1H），1.40（S，3H），1.35（S，3H），1.32（S，3H）。

C.3,4-O-isopropylidene-L-mannitol (compound 1C).

Under 40 ℃, in the mixture of distilled water (120mL) and glacial acetic acid (280mL), add compound 1B(19.8g, 0.66mol), be reflected under this temperature and kept 2.5 hours.Keep bathing temperature at 40-50 ℃, remove aqueous acetic acid under the vacuum immediately.With acetone (150ml) dilution gained white solid, filtration under diminished pressure is removed undissolved white precipitate (L-N.F,USP MANNITOL).Concentrated filtrate obtains transparent thickness oily matter, crystallization immediately under vacuum.Use the benzene recrystallization, obtain white crystals product compound 1C(8.3g).NMR（CD ₃OD）：3.98（dd，1H），3.81（dd，1H，ABX），3.66（dd，1H，ABX），3.69（m，1H），1.41（s，3H）。

D.1,6-two O-benzoyls-3,4-O-isopropylidene-L-mannitol (compound 1D).

At-78 ℃, N ₂Under the atmosphere to compound 1C(45mg, 0.20mmol) and pyridine (0.83mL is 10.26mmol) at CH ₂Cl ₂Add in the solution (1mL) Benzoyl chloride (47 μ L, 0.41mmol).After stirring 2 hours under this temperature, this reaction is warming up to 20 ℃ and the cold 6N HCl(2mL of impouring) in, CH used then ₂Cl ₂Extraction.Use saturated NaHCO ₃With dry MgSO ₄The washing organic layer.After filtration and after concentrating, enriched material is separated (9%Et with flash chromatography ₂O/CH ₂Cl ₂), make compound 1D(25mg).NMR（CDCl ₃）：8.04（d，2H），7.56（t，1H），7.41（t，2H），4.69（dd，1H，ABX），4.42（dd，1H，ABX），4.05（s，1H），3.98（m，1H），1.39（s，3H）。

E.1,6-two-O-benzoyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 1E).

At carbonyl benzyloxy Xie Ansuan (CbzVal-OH; 73mg, 0.29mmol), the 1-(3-dimethylamino-propyl)-hydrochloride (EDC of 3-ethyl carbodiimide; 56mg, 0.29mmol) and Dimethylamino pyridine (DMAP; Catalytic amount) exists down, with compound 1D(25mg, 0.06mmol) at CH ₂Cl ₂Stirring at room is 12 hours (2ml).Use CH then ₂Cl ₂Diluted reaction mixture is used saturated NaHCO ₃With dry MgSO ₄The washing organic layer.After filtering and concentrating, concentrated solution separates (10%Et with flash chromatography ₂O/CH ₂Cl ₂), make colorless oil compounds 1E(20mg).

NMR（CDCl ₃）：7.99（d，2H），7.51（t，1H），7.21-7.40（m，1H），5.31（m，2H），5.08（d，1H，AB），4.95（d，1H，AB），4.77（d，1H，ABX），4.41（dd，1H，ABX），4.35（m，1H），4.25（d，1H），2.17（m，1H），1.46（s，3H），0.93（d，3H），0.82（d，3H）.

F.1,6-two-O-benzoyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 1).

With compound 1E(5mg) and 90% moisture trifluoroacetic acid (TFA; 1ml) 0 ℃, stirred 70 minutes, remove under the vacuum then and desolvate, make this acetonide remove protecting group.With above-mentioned residue with the flash chromatography (25%Et that purifies ₂O/CH ₂Cl ₂As eluent), obtain compound 1(1.4mg).TLC:Rf(25%Et ₂O/CH ₂Cl ₂)=0.3; HPLC analyzes: Rt=19.1 minute.

Embodiment 2

A.3-t-butyldimethylsilyloxy yl benzoic acid (compound 2A).

The 3-hydroxy-benzoic acid (219mg, 1.59mmol), (717mg stirred 12 hours 4.76mmol) and under the solution room temperature in the imidazoles (324mg is 4.76mmol) at DMF(3mL) tert-butyldimethylsilyl chloride.Use the EtOAC diluted reaction mixture, and with saturated NH ₄The Cl washing.Organic layer washes (2 times) with water, with MgSO ₄Dry.Obtain colourless liquid (831.4mg) after filtering and concentrating.Gained colourless liquid product (565mg) is dissolved in 60% acetate/20%H ₂O/20%THF(5ml) in, make reaction at room temperature proceed 90 minutes.Remove to desolvate under the vacuum and obtain solid chemical compound 2A(125mg).NMR（CDCl ₃）：7.70（d，1H），7.55（brs，1H），7.32（t，1H），7.07（d，1H），0.99（s，9H），0.21（s，6H）。

B.1,6-two-O-(3-(t-butyldimethylsilyloxy base) benzoyl)-3,4-O-isopropylidene-L-N.F,USP MANNITOL (compound 2B).

To 3-(t-butyldimethylsilyloxy base) (125mg is 0.50mmol) with compound 1C(55mg, 0.25mmol) at CH for phenylformic acid (compound 2A) ₂Cl ₂Solution (3ml) adds EDC(95mg, 0.50mmol) with the DMAP(catalytic amount), the gained mixture was stirred 12 hours.Remove under the vacuum and desolvate, residue separates (90%Et with flash chromatography ₂O/CH ₂Cl ₂Wash-out), obtain colourless residue compound 2B(78.4mg), need not purifying, be used for next step reaction.

C.1,6-two-O-(3-(t-butyldimethylsilyloxy base) benzoyl)-2,5-two-O-(N-carbonyl benzyloxy valyl)-3,4-oxygen-isopropylidene-L-mannitol (compound 2C).

Press the method for embodiment 1E, make compound 2B(28.4mg), CbzVal-OH(52mg, 0.21mmol), EDC(39mg is 0.21mmol) with the DMAP(catalytic amount, at 2ml CH ₂Cl ₂In) reaction.Obtain residue except that desolvating under the vacuum, with flash chromatography (9%Et ₂O/CH ₂Cl ₂Wash-out) with its separation, obtains colorless oil compounds 2C(51.5mg).TLC：Rf（9%Et ₂O/CH ₂Cl ₂）＝0.72。

D.1,6-two-O-(3-hydroxyl) benzoyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-N.F,USP MANNITOL (compound 2).

Press the method for embodiment 1F, 5%MeOH/CH ₂Cl ₂As eluent, through preparation TLC(0.25mm) after, compound 2C(44.1mg 0.05mmol) changes under the 22.5mg compound 2(reaction conditions, removes silyl and acetonide simultaneously).TLC:Rf(5%MeOH/CH ₂Cl ₂)=0.59; HPLC analyzes: Rt=17.0 minute.

Embodiment 3

A.1,6-two-O-nicotinoyl-3,4-O-isopropylidene-L-mannitol (compound 3A).

(324.1mg, 1.82mmol) the compound 1C(202.4mg of disposable adding-78 ℃ is 0.91mmol) at pyridine (3.6ml) and CH for the hydrochloride of nicotinoyl chlorine ₂Cl ₂In the solution (3.6ml).Stir to make in 5 hours to react and carry out, slowly be heated to room temperature around here.Reaction mixture impouring CH ₂Cl ₂(40ml), and use H ₂O(three times) and saturated NaCl solution washing, then with Na ₂SO ₄Drying concentrates under vacuum.15% Virahol/CH ₂Cl ₂As eluent, the flash chromatography separation makes compound 3A(209mg).NMR（CDCl ₃）：9.20（s，1H），8.72（d，1H），8.29（d，1H），7.38（m，1H），5.23（brs，1H），4.74（d，1H），4.47（m，1H），4.03（dd，2H），1.42（s，3H）。

B.1,6-two-O-nicotinoyl-2,5-two-O(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 3B).

At CH ₂Cl ₂CbzVal-OH(815.7mg (5ml) 3.25mmol) with compound 3A(200mg, 0.46mmol), stirs the gained mixture 48 hours.Use CH ₂Cl ₂(40ml) diluting reaction thing, and use H ₂Twice of O() and saturated NaCl solution washing, use Na then ₂SO ₄Dry and concentrated under vacuum.3.5% Virahol/CH ₂Cl ₂As eluent, separate with flash chromatography, obtain the compound 3B(340mg of white foam shape).NMR（CDCl ₃）：NMR（CDCl ₃）：9.20（s，1H），8.74（d，1H），8.23（d，1H），7.20-7.40（m，7H），5.32（m，2H），5.02（dd，2H），4.80（d，1H），4.50（m，1H），4.31（m，1H），4.23（d，1H），2.20（m，1H），1.45（s，3H），0.93（d，3H），0.84（d，3H）.

C.1,6-two-O-nicotinoyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 3).

With compound 3B(320mg, 0.36mmol) with 90% moisture trifluoroacetic acid (1.1ml) and CH ₂Cl ₂(2ml) stirred 18 hours under the room temperature, subsequently vacuum concentration.Preparation HPLC(anti-phase C-18 chromatographic column, 30mm * 30Cm, 100 dusts, 60 minutes gradient elutions of moving phase: 70%-20%A/B) make 59.6mg compound 3 and 158.8mg reclaims compound 3B.TLC:Rf(7% Virahol/CH ₂Cl ₂)=0.42; HPLC analyzes: Rt=14.9 minute.

Embodiment 4

A.1,6-two-O-(4-(1,2,3-thiadiazoles)-yl)-3,4-O-isopropylidene-L-mannitol (compound 4A).

Press embodiment 1D method, with 1,2,3-thiadiazoles-4-acyl chlorides (0.57mmol) is handled compound 1C(49.0mg, 0.22mmol).5%MeOH/CH ₂Cl ₂As eluent, with preparing TLC(0.5mm) make 20.9mg yellow solid compound 4A.NMR（CDCl ₃/DMSO_d ₆）：9.8（s，1H），5.63（brs，1H），4.67（d，1H），4.40（dd，1H），4.11（d，1H），4.01（brs，1H），1.41（s，3H）。

B.1,6-two-O-(4-(1,2,3-thiadiazoles)-yl)-2,5-two-O-(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 4B).

Use EDC(53.3mg, 0.28mmol) and DMAP(2.4mg, 0.02mmol) handle at DMF(1.2ml) in CbzVal-OH(72.3mg, 0.29mmol) and compound 4A(18mg, 0.04mmol), and the gained mixture stirred 24 hours.With EtOAc diluting reaction thing, and with twice of cold 3NHCl(), cold 5%NaHCO ₃The aqueous solution (twice), saturated NaCl solution washing are used Na then ₂SO ₄Drying, and vacuum concentration.4%MeOH/CH ₂Cl ₂As eluent, with preparing TLC(0.5mm) make the compound 4B of white foam shape.

NMR（CDCl ₃）：9.28（s，1H），7.20-7.40（m，5H），5.25-5.35（m，2H），4.98-5.15（m，2H），4.90（d，1H），4.51（dd，2H），4.30（m，1H），2.20（brs，1H），1.45（s，3H），0.97（d，3H），0.85（s，3H）.

C.1,6-two-O-(4-(1,2,3-thiadiazoles)-yl)-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 4).

Press the method for embodiment 3C, 5% Virahol/CH ₂Cl ₂As eluent, with preparation TLC(0.5mm) after, compound 4B(27.2mg 0.03mmol) changes the 5.7mg compound into.TLC:Rf(5% Virahol/CH ₂Cl ₂)=0.50; HPLC analyzes: Rt=16.9 minute.

Embodiment 5

A.1,2,5,6-two shrinks-3,4-O-isopropylidene-L-mannitol (compound 5A).

To pyridine (75ml, 0.93mol) the compound 1C(5.2g in, 0.02mol) under 0 ℃, add Tosyl chloride in batches.Under this temperature, stir after 3 hours the cold 6NHCl(160ml of reaction mixture impouring)/Et ₂O(72ml) in the mixture.Tell organic layer, and use 3%NaHCO ₃MgSO is used in solution (100ml) washing then ₄Dry.With concentrated, obtain desired xylene sulfonate after filtration, need not to purify, directly use it for next step reaction.

To above-mentioned product at anhydrous MeOH(150ml) solution in add anhydrous K ₂CO ₃(16.2g, 0.12ml), reaction was at room temperature carried out 3 hours.Use CH then ₂Cl ₂Diluted reaction mixture, and use H successively ₂O and saturated NH ₄MgSO is used in the Cl washing immediately ₄Dry.After filtration and after concentrating, make the crude product di-epoxide of weak yellow liquid, (～0.5mmHg) distillation obtains compound 5A, is colorless oil (b.p.:75-82 ℃) with its decompression.NMR（CDCl ₃）：3.80（dd，1H），3.08（dd，1H），2.81（t，1H），2.68（dd，1H），1.40（s，3H）。

B.1,6-two-O-benzyl-3,4-O-isopropylidene-L-mannitol (compound 5B).

To Al ₂O ₃(1.35g) at Et ₂O(3ml) (104 μ l 1.00mmol), stir after 5 hours, and (34.2mg is 0.18mmol) at Et to add compound 5A di-epoxide to add phenylcarbinol in the slurry in ₂O(2ml) solution in.Reaction was at room temperature carried out 12 hours, added MeOH(20ml then in reaction mixture), and with this solution placement 4 hours.This solution is passed through Celite

Behind the filtration under diminished pressure, concentrate residue, 90%Et ₂O/CH ₂Cl ₂As eluent, purify with thin-layer chromatography (0.5mm), make compound 5B(3.0mg).

C.1,6-two-O-benzyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 5C).

At CbzVal-OH(10mg, 0.04mmol), EDC(8mg, 0.04mmol) and the DMAP(catalytic amount) existence under, with compound 5B(3.0mg, 0.01mmol) at CH ₂Cl ₂Stirred 12 hours (2ml).Concentrated reaction mixture separates enriched material (9%Et with flash chromatography immediately ₂O/CH ₂Cl ₂Be eluent), obtain the link coupled product, i.e. compound 5C(1.9mg).

D.1,6-two-O-benzyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 5).

With compound 5C(1.9mg, 2.19 μ mol) under 0 ℃, stirred 75 minutes with 90% moisture trifluoroacetic acid (1.5ml), solvent removed in vacuo then, thus remove acetonide.17%Et ₂O/CH ₂Cl ₂As eluent,, obtain compound 5(1.6mg with thin-layer chromatography (0.5mm) purification gained residuum), be white solid.The TLC:Rf(50% hexane/EtoAc)=0.3;

NMR（CDCl ₃）：7.18-7.40（m，1OH），5.20（br d，1H），4.95-5.15（m，3H），4.49（m，2H），4.30（dd，1H），3.85（t，1H），3.75（br s，2H），2.98（d，1H），2.15（m，1H），0.93（d，3H），0.81（d，3H）.

Embodiment 6

A.1,6-two-S-benzoyl-3,4-O-isopropylidene-L-mannitol (compound 6A).

Thiobenzoic acid (136 μ l, 1.15mmol) and Al ₂O ₃(1.51g) at Et ₂O(2ml) form solution after 5 minutes, in to wherein adding epoxy compounds 5A(42.9mg, 0.23mmol) at THF(1ml) in solution, reaction is at room temperature stirred and was carried out 12 hours.Add MeOH(20ml), reaction mixture stirred 3 hours, filtration under diminished pressure.Except that after desolvating, mother liquor is dissolved in EtoAc, and uses saturated NaHCO under the vacuum ₃MgSO is used in washing then ₄Dry.Obtain compound 6A(77.1mg after filtering, concentrating), be red-purple oily matter, need not to purify, be directly used in next step reaction.The TLC:Rf(50% hexane/EtOAc)=0.63.

1,6-two-S-benzoyl-2,5-O-(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 6A).

At CbzVal-OH(293mg, 1.17mmol), EDC(224mg, 1.17mmol) and DMAP(4mg, 0.03mmol) have down compound 6A(77.1mg) sneak into CH ₂Cl ₂(2ml), the gained mixture was stirred 12 hours.Remove under the vacuum and desolvate, with the purifying resistates of preparation property TLC(3X * 1.0mm), the 25%EtOAc/ hexane obtains compound 6B(124mg as eluent).The TLC:Rf(50% hexane/EtOAc)=0.82.

C.1,6-two-S-benzoyl-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 6).

Press the method for embodiment 1F, 25%Et ₂O/CH ₂Cl ₂As eluent, through preparation TLC(0.5mm) purify after, compound 6B(23.4mg 0.03mmol) changes into 6.4mg compound 6.TLC:Rf(25%Et ₂O/CH ₂Cl ₂)=0.43; HPLC analyzes: Rt=19.8 minute.

Embodiment 7

A.1,6-two-S-(4-morpholinothio carbonyl)-3,4-O-isopropylidene-L-mannitol (compound 7A).

In the solution of 1: 1 mixture (239mg is 0.95mml) at DMF(1.5ml) of 4-morpholine dithionic acid and morpholine, add diepoxides 5A(59.2mg, 0.32mmol) at Et ₂O(0.5ml) solution in, reaction was at room temperature carried out 12 hours.After the EtOAc dilution, wash reaction mixture with water three times, with the water layer that the EtOAc extraction merges, use H again ₂EtOAc secondary after the O washing extraction.The organic layer MgSO that merges ₄Dry.After filtering and concentrating, EtOAc is as eluent, and residue is purified with the slab chromatography, obtains diol compound 7A(78mg), be white solid.TLC：Rf（EtOAc）＝0.63

B.1,6-two-S-(4-morpholine thiocarbonyl)-2,5-two-O-(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 7B).

At CbzVal-OH(133mg, 0.53mmol), EDC(102mg, 0.53mmol) and the DMAP(catalytic amount) exist down, with compound 7A(38.9mg, 0.08mmol) at CH ₂Cl ₂(1ml) stirred 48 hours.Reaction mixture CH then ₂Cl ₂Dilution, and use saturated NaHCO ₃MgSO is used in washing ₄Dry organic layer.After filtering and concentrating, 50% hexane/EtOAc is as eluent, and residue is purified with slab chromatography (1.00mm), obtains compound 7B(46mg).The TLC:Rf(50% hexane/EtOAc)=0.34.

C.1,6-two-S-(4-morpholine thiocarbonyl)-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 7).

With compound 7B(12.6mg, 0.01mmol) with 90% moisture trifluoroacetic acid (1ml) 0 ℃ of stirring, and make reaction mixture rise to room temperature, to remove acetonide through 2.5 hours.Remove under the vacuum desolvate after, 5%MeOH/CH ₂Cl ₂As eluent,, obtain compound 7(7.4mg with slab chromatography (0.5mm) purification gained residue), be colorless oil.TLC:Rt(5%MeOH/CH ₂Cl ₂)=0.51; HPLC analyzes: Rt=18.1 minute.

Embodiment 8

A.1,1-two-S-(N, N-diethyl thiocarbamoyl)-3,4-O-isopropylidene-L-mannitol (compound 8A).

According to the method for embodiment 7A, the ammonium salt of diethyldithiocar bamic acid (133mg, 0.80mmol) with epoxy compounds 5A(49.8mg, 0.27mmol) reaction makes compound 8A(88mg) need not to purify, and is directly used in next step reaction.

B.1,6-two-S-(N, N-diethyl thiocarbamoyl)-2,5-two-O-(N-carbonyl benzyloxy is valyl)-3,4-O-isopropylidene-L-mannitol (compound 8B).

Compound 8A(88mg) at CH ₂Cl ₂Stirred 12 hours (3ml).Use CH then ₂Cl ₂Diluted reaction mixture, and with saturated NaHCO ₃Washing, organic layer MgSO ₄Dry.After filtering and concentrating, the 33%EtOAc/ hexane is as eluent, and flash chromatography purification residue obtains link coupled product, compound 8B(180mg).

The TLC:Rf(33%EtOAc/ hexane)=0.25.

C.1,6-two-S-(N, N-diethyl thiocarbamoyl)-2,5-two-O-(N-carbonyl benzyloxy is valyl)-L-mannitol (compound 8).

According to the method for embodiment 1F, 5%MeOH/CH ₂Cl ₂As eluent, after preparation TLC(2 * 0.25ml) separated, compound 8B(28.7mg 0.03mmol) changed 12.1mg compound 8 into.TLC:Rf(5%MeOH/CH ₂Cl ₂)=0.6; HPLC analyzes: Rt=19.8 minute.

Embodiment 9

Use M.W.Pennington etc. at Peptides 1990, Gimet, E.and D.Andrew, Eds., Escom; Leiden Nethertands(1990) goes up the method for describing, and we have measured the inhibition constant of all cpds of the present invention to HIV-1 proteolytic enzyme, the results are shown in the table II.

The table II

Compound K i(nm)

1 35

2 130

3 100

4 400

5 60

6 400

7 20

8 250

The table II shows that all compounds of test show and suppress and antiviral activity.

Though we have enumerated several embodiments of the invention, obviously, can be by on basic structure, improving to some extent, just can obtain using other embodiment of product of the present invention and method, therefore, the scope of the invention should limit with claim subsequently, rather than limits with the specific embodiment of enumerating as example.

Claims

1, the compound of formula I:

Wherein:

Each n is independently selected from 0,1 and 2;

Each A and A ' are selected from natural a-amino acid and non-natural a-amino acid separately, wherein A or A ' amino become with G or G ' suitably the time key or with the carboxyl Cheng Jian of adjacent residues A or A ', when the carboxyl of A or A ' is suitable and the amino Cheng Jian of adjacent residues A or A ', or with structure in oxygen Cheng Jian;

Each G and G ' separately with the amino of adjacent residues A or A ' or with structure in oxygen (when the n=0) covalent attachment, and be selected from trityl; Hydrogen; C ₁-C ₆Alkyl; R ₃-CO-; R ₅(R ₆R ₇C) _mCO-; R ₅(R ₆R ₇C) _m-W-; R ₈-W-; R ₅(R ₆R ₇C) _m-P (O) (OR ₉)-; R ₈-P (O) (OR ₉)-; And can be by one or more substituent R ₄Any phthaloyl that replaces; M=1-3 wherein;

Each W is selected from-OCO-and-SO ₂-, but condition is that W is not-SO when W links to each other with oxygen in the structure ₂-;

Each R ₃Be independently selected from hydrogen; C ₁-C ₆Alkyl; C ₂-C ₆Alkenyl; Phenyl; And naphthyl; Described C ₁-C ₆Alkyl and C ₂-C ₆One or more substituting groups that alkenyl can be selected from hydroxyl, atom and fluorine atom replace arbitrarily; Described phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₄Be selected from C ₁-C ₄Alkyl; C ₂-C ₄Alkenyl; Halogen atom; Hydroxyl; Nitro: C ₁-C ₃Alkoxyl group; With-CO-N (R ₁₀) (R ₁₀);

Each R ₅, R ₆And R ₇Be selected from hydroxyl separately; Hydrogen; Chlorine; Fluorine, C ₁-C ₃Alkoxyl group; Heterocycle: the C of 5-7 unit ₁-C ₃Alkyl; Phenyl; And naphthyl; Said C ₁-C ₃Alkyl can be replaced arbitrarily by one or more groups that are selected from chlorine, fluorine and hydroxyl; Said phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or separately or with the specific G of any bonded form or the R of G ' ₅, R ₆And R ₇Can be arbitrarily in conjunction with forming monocycle, dicyclo or three-ring system, each ring is C ₃-C ₆Cycloalkyl; Condition is if R ₅, R ₆Or R ₇On the adjacent carbon atom of W, then can not be chlorine, fluorine or hydroxyl;

Each R ₈Be independently selected from 5-7 unit heterocycle; Phenyl; And naphthyl; Said phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₉Be independently selected from C ₁-C ₄Alkyl and phenyl;

Each R ₁₀Be independently selected from hydrogen; C ₁-C ₄Alkyl; With 5-7 unit heterocycle;

Each B and B ' are independently selected from oxygen and sulphur;

Each D and D ' are independently selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N (R ₁₁R ₁₂), condition is when two n=0, E and E ' they are not 3-pyridyl or diethylamino;

Each Ar is independently selected from phenyl and 5-7 unit heterocycle; Wherein phenyl and heterocycle can be by one or more substituent R ₄Replace arbitrarily; And

Each R ₁₁And R ₁₂Be independently selected from C ₁-C ₆Alkyl and C ₂-C ₆Alkenyl.

2, according to the compound of claim 1, wherein

Each n is independently selected from 0,1 and 2;

Each A and A ' are selected from natural a-amino acid and non-natural a-amino acid separately, wherein each A or A ' amino become with G or G ' suitably the time key or with the carboxyl Cheng Jian of adjacent residues A or A ', the carboxyl appropriate amount of A or A ' and the amino Cheng Jian of adjacent residues A or A ', or with structure in oxygen Cheng Jian;

Each G and G ' separately with the amino of adjacent residues A or A ' or with structure in oxygen (when the n=0) covalent attachment, and be selected from trityl; Hydrogen; C ₁-C ₆Alkyl; R ₃-CO-R ₅(R ₆R ₇C) m-CO-; R ₅(R ₆R ₇C) m-W-; And can be by one or more substituent R ₄Any phthaloyl that replaces; M=1-3 wherein;

Each W is selected from-OCO-and-SO ₂-, condition is that W is not-SO when W links to each other with oxygen in the structure ₂-;

Each R ₃Be independently selected from hydrogen; C ₁-C ₆Alkyl; Phenyl; And naphthyl; C ₁-C ₆One or more substituting groups that alkyl can be taken from hydroxyl, chlorine atom and fluorine atom replace arbitrarily; Phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₄Be selected from C ₁-C ₄Alkyl; Halogen atom; Hydroxyl; Nitro; And C ₁-C ₃Alkoxyl group;

Each R ₅, R ₆And R ₇Be selected from hydrogen separately: chlorine; Fluorine; C ₁-C ₃Alkyl; C ₁-C ₃Alkoxyl group; 5-7 unit heterocycle; Phenyl; And naphthyl; Said C ₁-C ₃Alkyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇Separately or can be arbitrarily in conjunction with forming monocycle, dicyclo or three-ring system with any bonded form, each ring be C ₃-C ₆Cycloalkyl; Condition is if R ₅, R ₆Or R ₇On the adjacent carbon atom of W, then can not be chlorine, fluorine or hydroxyl;

Each B and B ' are independently selected from oxygen and sulphur;

Each D and D ' are independently selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂), condition is when two n=0, E and E ' they are not 3-pyridyl or diethylamino;

Each Ar is independently selected from phenyl and 5-7 unit heterocycle; Wherein phenyl and 5-7 unit heterocycle can be by one or more substituent R ₄Replace arbitrarily; And

Each R ₁₁And R ₁₂Be independently selected from C ₁-C ₆Alkyl.

3, the compound of formula I:

Wherein:

Each n is independently selected from 0,1 and 2;

Each A and A ' are selected from natural a-amino acid and non-natural a-amino acid separately, wherein A or A ' amino is suitably the time and G or G ' Cheng Jian, or with the carboxyl Cheng Jian of adjacent residues A or A ', when the carboxyl of A or A ' is suitable and the amino Cheng Jian of adjacent residues A or A ', or with structure in oxygen Cheng Jian;

Each G and G ' separately with the amino of adjacent residues A or A ' or with structure in oxygen (when the n=0) covalent attachment, be selected from trityl; Hydrogen; C ₁-C ₆Alkyl; R ₃-CO-; R ₅(R ₆R ₇C) mCO-; R ₅(R ₆R ₇C) m-W-; R ₈-W-; R ₅(R ₆R ₇C) (OR m-P(O) ₉)-; R ₈-P(O) (OR ₉)-; And can be by one or more substituent R ₄Any phthaloyl that replaces; M=1-3 wherein;

Each W is independently selected from-OCO-and-SO ₂-, but condition is that W is not-SO when W links to each other with oxygen in the structure ₂-;

Each R ₃Be independently selected from hydrogen; C ₁-C ₆Alkyl; C ₂-C ₆Alkenyl; Phenyl; And naphthyl; C ₁-C ₆Alkyl and C ₂-C ₆One or more substituting groups that alkenyl can be selected from hydroxyl, chlorine atom and fluorine atom replace arbitrarily; Phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₄Be independently selected from C ₁-C ₄Alkyl; C ₂-C ₄Alkenyl; Halogen atom; Hydroxyl; Nitro; C ₁-C ₃Alkoxyl group; With-CO-N(R ₁₀) (R ₁₀);

Each R ₅, R ₆And R ₇Be selected from hydroxyl separately; Hydrogen; Chlorine: fluorine, C ₁-C ₃Alkoxyl group; 5-7 unit heterocycle; C ₁-C ₃Alkyl; Phenyl; And naphthyl; Said C ₁-C ₃Alkyl can be replaced arbitrarily by one or more groups that are selected from chlorine, fluorine and hydroxyl; Said phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily; Or the R of special G or G ' ₅, R ₆And R ₇Separately or can be arbitrarily in conjunction with forming monocycle, dicyclo or three-ring system with any bonded form, each ring be C ₃-C ₆Cycloalkyl; Condition is if R ₅, R ₆Or R ₇On the adjacent carbon atom of W, then can not be chlorine, fluorine or hydroxyl;

Each R ₈Be independently selected from 5-7 unit heterocycle: phenyl; And naphthyl; Said phenyl and naphthyl can be by one or more substituent R ₄Replace arbitrarily;

Each R ₉Be independently selected from C ₁-C ₄Alkyl and phenyl;

Each B and B ' are independently selected from oxygen and sulphur;

Each D and D ' are independently selected from H ₂, oxygen and sulphur;

Each E and E ' are independently selected from Ar and N(R ₁₁R ₁₂), condition is when n=0, E and E ' they are not 3-pyridyl or diethylamino;

Each Ar is independently selected from phenyl and 5-7 unit heterocycle; Wherein phenyl and heterocycle can be by one or more substituent R ₄Replace arbitrarily (as 3-pyridyl, 4-(1,2, the 3-thiadiazoles) base or 4-morpholinyl); And

4, according to the compound of claim 3, wherein when two n=0, E and E ' are not 3-pyridyl or diethylamino.

5, according to the compound of claim 3 or 4, wherein:

Each n independently is selected from 0,1 and 2;

Each A and A ' independently are selected from naturally occurring a-amino acid and non-natural a-amino acid, wherein the amino of each A or A ' according to suitable situation and G or G ' or with the carboxyl bonding of adjacent residues A or A ', and the carboxyl of A or A ' look suitable the amino of situation and adjacent residues A or A ' or with this structure in the Sauerstoffatom bonding;

Each G and G ' independently with the amino of adjacent residues A or A ' or covalently bound with the oxygen (if n=0) of this structure, and be selected from: C ₁-C ₆Alkyl; R ₃CO-; R ₅(R ₆R ₇C) mCO-; R ₅(R ₆R ₇C) mW-; And phthaloyl, this group indefiniteness ground can be by one or more substituent R ₄Replace; M=1-3 wherein;

Each W independently is selected from-OCO-and-SO ₂-, condition is not to be-SO as W W when Sauerstoffatom in this structure links to each other ₂-;

Each R ₃Independently be selected from C ₁-C ₆Alkyl; Phenyl; And naphthyl; This C ₁-C ₆But alkyl indefiniteness ground is replaced by one or more substituting groups that are selected from hydroxyl, chlorine and fluorine; But this phenyl and naphthyl indefiniteness ground are by one or more substituent R ₄Replace;

Each R ₄Independently be selected from C ₁-C ₄Alkyl; Halogen; Hydroxyl; Nitro; And C ₁-C ₃Alkoxyl group;

Each R ₅, R ₆And R ₇At random and be independently selected from hydrogen; Chlorine; Fluorine; 5-7 unit heterocycle; Phenyl; Naphthyl; And C ₁-C ₃Alkyl, wherein said C ₁-C ₃But alkyl indefiniteness ground is by one or more substituent R ₄Replace; Perhaps individually or the specific G of any combination or the R on the G ' ₅, R ₆And R ₇Link together to indefiniteness, form monocycle, dicyclo or three-loop system, each ring is C ₃-C ₆Cycloalkyl; Condition is to work as R ₅, R ₆And R ₇They are not chlorine, fluorine or hydroxyl when being present on the carbon atom adjacent with W;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂; Oxygen; Or sulphur;

Each E and E ' independently are selected from Ar and N(R ₁₁R ₁₂);

Each Ar is selected from phenyl and 5-7 unit heterocycle; But wherein said phenyl and 5-7 unit heterocycle indefiniteness ground are by one or more substituent R ₄Replace; And

Each R ₁₁And R ₁₂Independent is C ₁-C ₆Alkyl.

6, formula I compound:

Wherein:

n＝1;

Each A and A ' are naturally occurring a-amino acid independently, wherein the amino of each A or A ' look suitable situation and G or G ' or with the carboxyl bonding of adjacent residues A or A ', and the carboxyl of A or A ' look suitable the amino of situation and adjacent residues A or A ' or with this structure in the oxygen bonding;

Each G and G ' independently with the amino of adjacent residues A or A ' or with this structure in oxygen (if adjacent n=0) coenosarc bonding, and be selected from hydrogen and R ₅(R ₆R ₇C) mW-, wherein W is-OCO-, m=1;

Each R ₅, R ₆And R ₇Be independently selected from hydrogen; Chlorine; Fluorine; C ₁-C ₃Alkyl; 5-7 unit heterocycle; Phenyl; And naphthyl; Described C ₁-C ₃But the one or more substituting groups that are selected to the alkyl indefiniteness chlorine, fluorine and hydroxyl replace; But described phenyl and naphthyl indefiniteness ground are by one or more substituent R ₄Replace; Perhaps, single that choose or the specific G of arbitrary combination or each R of G ' ₅, R ₆And R ₇Link together to indefiniteness, form monocycle, dicyclo or three-loop system, each this encircle and be C ₃-C ₆Cycloalkyl; Condition is to work as R ₅, R ₆Or R ₇They are not chlorine, fluorine or hydroxyl when being present in adjacent to W on carbon atom;

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂; Oxygen and sulphur;

Each E and E ' independently are selected from Ar and N(R ₁₁R ₁₂);

Each Ar independently is selected from phenyl and 5-7 unit heterocyclic radical; Wherein said phenyl and 5-7 unit heterocycle can be non-exclusively by one or more substituent R ₄Arbitrarily; And

Each R ₁₁And R ₁₂Independent is C ₁-C ₆Alkyl.

7, according to the compound of claim 6, this compound has the structural formula II:

Wherein:

Each B and B ' independently are selected from oxygen and sulphur;

Each D and D ' independently are selected from H ₂; Oxygen; And sulphur;

Each E and E ' independently are selected from Ar and NEt ₂; And

Each Ar independently is selected from phenyl; The 3-hydroxy phenyl; The 3-pyridyl; 4-(1,2, the 3-thiadiazoles)-Ji; With the 4-morpholinyl.

8, according to the compound of claim 1, wherein: B, D and E form benzoic ether jointly; The 3-hydroxybenzoate; Nicotinate; 4-(1,2,3-thiadiazoles carboxylicesters); Benzyloxy; The thiobenzoic acid ester; 4-morpholine dithiocarboxylic esters; And N, the N-diethyldithiocarbamate.

9, formula I compound

Wherein:

B, D and E form benzoic ether jointly; The 3-hydroxybenzoate; 4-(1,2,3-thiadiazoles carboxylicesters); Benzyloxy; The thiobenzoic acid ester; With 4-morpholine dithiocarboxylic esters, and wherein the definition of n, A, A ', G, G ', B, B ', D, D ', E and E ' is with claim 1, and different is when two n=0, and E and E ' are not 3-pyridyl or diethylamino.

10, the compound of formula I:

Wherein A and G form carbobenzoxy jointly, and wherein the definition of n, A, A ', G, G ', B, B ', D, D ', E and E ' is with claim 1, and different is when two n=0, and E and E ' are not 3-pyridyl or diethylamino.

11, the compound that has following structure

Wherein:

B is selected from oxygen and sulphur;

D is selected from H ₂; Oxygen; And sulphur;

E is selected from phenyl; The 3-hydroxy phenyl; The 3-pyridyl; And 4-(1,2, the 3-thiadiazoles)-Ji; The 4-morpholinyl.And diethylamino, and wherein the definition of n, A, A ', G, G ', B, B ', D, D ', E and E ' is with claim 1, and different is when two n=0, and E and E ' they are not 3-pyridyl or diethylamino.

12, be selected from following compound:

1,6-two-O-nicotinoyl-2,5-two-O-(N-carbobenzoxy-(Cbz) is valyl)-L-mannitol (compound 3);

1,6-two-O-(4-(1,2,3-thiadiazoles)-yl)-2,5-two-O-(N-carbobenzoxy-(Cbz) is valyl)-L-mannitol (compound 4);

1,6-two-O-benzyl-2,5-two-O-(N-carbobenzoxy-(Cbz) is valyl)-L-mannitol (compound 5);

1,6-two-S-benzoyl-2,5-two-O-(N-carbobenzoxy-(Cbz) is valyl)-L-mannitol (compound 6);

1,6-two-S-(4-morpholino thiocarbonyl)-2,5-two-O-(N-carbobenzoxy-(Cbz) is valyl)-L-mannitol (compound 7); With

1,6-two-S-(N, N-diethyl thiocarbonyl)-2,5-two-O-(N-carbobenzoxy-(Cbz) is valyl)-L-mannitol (compound 8).

13, each described compound among the claim 1-8 is applied to suppress the enzymatic activity of aspartyl protease.

14, the enzymatic that each described compound in the claim 9,12 is applied to suppress aspartyl protease advances activity.

15, formula I compound is applied to suppress the enzymatic activity of aspartyl protease, all substituent definition in the wherein said formula I are with claim 1, and different is when two n=0, and E and E ' are not 3-pyridyl or diethylamino.

16, each compound among the claim 1-8 is applied to suppress the ability of aspartyl protease catalysis peptide bond hydrolysis.

17, each compound among the claim 9-12 is applied to suppress the ability of aspartyl protease catalysis peptide bond hydrolysis.

18, formula I compound is applied to suppress the ability of aspartyl protease catalysis peptide bond hydrolysis, all substituent definition such as claims 1 in its Chinese style I, different is when two n=0, E and E ' they are not 3-pyridyl or diethylamino.

19, according to claim 13 or 16 described application, wherein said aspartyl protease is a hiv protease.

20, according to claim 14 or 17 described application, wherein said aspartyl protease is a hiv protease.

21, according to the application of claim 15 or 18, wherein said aspartyl protease is a hiv protease.

22, each described application of compound among the claim 1-8, it is used to suppress the breeding that the life cycle behavior of its obligate needs the virus of aspartyl protease.

23, each described application of compound among the claim 9-12, it is used to suppress the breeding that the life cycle behavior of its obligate needs the virus of aspartyl protease.

24, formula I compound is used to suppress the breeding that the life cycle behavior of its obligate needs the virus of aspartyl protease, wherein said all substituent definition of formula I are with claim 1, different is when two n=0, and E and E ' are not 3-pyridyl or diethylamino.

25, each described compound is as the application of therapeutical agent among the claim 1-8, and it is used to resist the infection that the life cycle behavior of its obligate needs the virus of aspartyl protease.

26, each described compound is as the application of therapeutical agent among the claim 9-12, and it is used to resist the infection that the life cycle behavior of its obligate needs the virus of aspartyl protease.

27, formula I compound is as the application of therapeutical agent, it needs the infection of the virus of aspartyl protease in order to resist the life cycle behavior of its obligate, all substituent definition are with claim 1 in its Chinese style I, different is when two n=0, and E and E ' are not 3-pyridyl or diethylamino.

28, each described compound is as the application of preventive among the claim 1-8, and it needs the infection of the virus of aspartyl protease in order to prevent the life cycle behavior of its obligate.

29, each described compound is as the application of preventive among the claim 9-12, and it needs the infection of the virus of aspartyl protease in order to prevent the life cycle behavior of its obligate.

30, formula I compound needs the application of preventive of infection of the virus of aspartyl protease as its obligate life cycle behavior, all substituent definition are with claim 1 in the wherein said formula I, unique different be when two n=0, E and E ' are not 3-pyridyl or diethylamino.

31, each described compound among the claim 1-8 is applied to destroy the life cycle that the life cycle behavior of its obligate needs the virus of aspartyl protease.

32, each described compound among the claim 9-12 is applied to destroy the life cycle that the life cycle behavior of its obligate needs the virus of aspartyl protease.

33, formula I compound is applied to suppress the life cycle that the life cycle behavior of its obligate needs the virus of aspartyl protease, all substituent definition are with claim 1 in the wherein said formula I, unique different be when two n=0, E and E ' are not 3-pyridyl or diethylamino.

34, according to each described application in the claim 22,25,28 or 31, wherein said virus is HIV-1, HIV-2 or HTLV-1.

35, according to each described application in the claim 23,26,29 or 32, wherein said virus is HIV-1, HIV-2 or HTLV.

36, according to each described application in the claim 24,27,30 or 33, wherein said virus is HIV-1, HIV-2 or HTLV.

37, each described compound among the claim 1-8 is applied to block the proteolysis of aspartyl protease.

38, each described compound among the claim 9-12 is applied to block the proteolysis of aspartyl protease.

39, formula I compound is applied to block the proteolysis of aspartyl protease, in the wherein said formula I all substituent definition with claim 1, unique different be when n=0, E and E ' are not 3-pyridyl or diethylamino.

40, among the claim 1-8 each described compound as the application of the matrix that links to each other with stable chromatographic resin in the affinity chromatography.

41, among the claim 9-12 each described compound as the application of the matrix that links to each other with stable chromatographic resin in the affinity chromatography.

42, formula I compound as with affinity chromatography in stablize the matrix that chromatographic resin links to each other application, in the wherein said formula I all substituent definition with claim 1, unique different be when two n=0, E and E ' are not 3-pyridyl or diethylamino.

43, a kind ofly can effectively resist the medicine for treating viral infections composition, it comprises among the claim 1-8 of effective dose each described compound and can make medicinal carrier, auxiliary or vehicle.

44, a kind ofly can effectively resist the medicine for treating viral infections composition, it comprises among the claim 9-12 of effective dose each described compound and can make medicinal carrier, auxiliary or vehicle.

45, a kind ofly can effectively resist the medicine for treating viral infections composition, it comprises the formula I compound of effective dose and can make medicinal carrier, auxiliary agent or vehicle, all substituent definition are with claim 1 in the wherein said formula I, unique different be when two n=0, E and E ' are not 3-pyridyl or diethylamino.

46, according to the described pharmaceutical composition of claim 43, it further comprises a kind of additional antiviral agent.

47, according to the described pharmaceutical composition of claim 44, it further comprises a kind of additional antiviral agent.

48, according to the described pharmaceutical composition of claim 45, it further comprises a kind of additional antiviral agent.

49, according to each described pharmaceutical composition among the claim 43-45, it further comprises a kind of immunomodulator.

50, a kind of method that prevents mammalian infections HIV, it comprises to described Mammals takes the claim 43 of effective dose, this step of pharmaceutical composition of 44 or 45.

51, a kind of method for the treatment of Mammals HIV infection, it comprises to described Mammals takes the claim 43 of effective dose, this step of pharmaceutical composition of 44 or 45.

52, according to claim 50 or 51 described methods, the pharmaceutical composition of wherein said effective dose contains the described compound of 0.01mg/kg body weight/day to the 25mg/kg body weight/day.

53, according to the described method of claim 50, wherein said dosing step comprises oral administration or drug administration by injection.

54, according to the described method of claim 51, wherein said dosing step comprises oral administration or drug administration by injection.

55, a kind of method of synthetic aspartyl protease inhibitor, it may further comprise the steps:

(a) in the presence of acid, handle mannitol, produce ketal derivatives with carbonyl compound; Described carbonyl compound is selected from acetone, cyclopentanone, pimelinketone and phenyl aldehyde; Described acid is selected from sulfuric acid, hydrochloric acid, acetate, trifluoroacetic acid and composition thereof;

(b) use SULPHURYL CHLORIDE at the described ketal derivatives of each primary hydroxyl site esterification, obtain the disulfonic acid ester; Described SULPHURYL CHLORIDE is selected from p-toluenesulfonyl chloride, 4-bromobenzene sulfonyl chloride, methylsulfonyl chloride and trifluoromethanesulfchloride chloride;

(c) with the described disulfonic acid ester of alkaline purification, produce di-epoxide; Described alkali is selected from metal hydroxides, metal carbonate and alkali metal bicarbonate salt; Described di-epoxide has two minimum sites of being obstructed;

(d) open described di-epoxide with nucleophilic reagent in each minimum site of being obstructed, produce glycol; Described nucleophilic reagent is selected from aryl alcohol, aryl thioic acid sulfoacid and the acid of heterocyclic radical dithio;

(e) with the described glycol of a-amino acid esterification that non-exclusively has the N-protected base, produce diester; Described N-protected base is selected from carbobenzoxy-(Cbz) such as uncle-butoxy carbonyl;

(f) the described diester of mixture process of the described acid of water and step (a) obtains described aspartyl protease inhibitor.

56, a kind of method of synthetic aspartyl protease inhibitor, it may further comprise the steps:

(a) in the presence of acid, handle mannitol, obtain ketal derivatives with carbonyl compound; Described carbonyl compound system is selected from acetone, cyclopentanone, pimelinketone and phenyl aldehyde; Described acid is selected from sulfuric acid, hydrochloric acid, acetate, trifluoroacetic acid and composition thereof;

(b) use esterifying agent at the described ketal derivatives of each primary hydroxyl site esterification, obtain glycol; Described esterifying reagent is selected from carboxylic acid, carboxylic acid halide and carboxylic acid anhydride;

(c) with the described glycol of a-amino acid esterification that non-exclusively has the N-protected base, produce diester; Described N-protected base is selected from carbobenzoxy-(Cbz) and uncle-butoxy carbonyl; With

(d) the described diester of mixture process of the described acid of water and step (a) obtains described aspartyl protease inhibitor.