CN101287744A - Antiviral compounds - Google Patents

Antiviral compounds Download PDF

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CN101287744A
CN101287744A CNA2006800221718A CN200680022171A CN101287744A CN 101287744 A CN101287744 A CN 101287744A CN A2006800221718 A CNA2006800221718 A CN A2006800221718A CN 200680022171 A CN200680022171 A CN 200680022171A CN 101287744 A CN101287744 A CN 101287744A
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alkyl
compound
virus
treatment
infection
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E·阿然兹普拉泽
K·M·耶格
D·A·格里什
M·B·安德森
I·C·金
D·V·库玛
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Myrexis Inc
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Myriad Pharmaceuticals Inc
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The present invention relates to compounds, pharmaceutical compositions and methods useful for treating viral infection.

Description

Antiviral compound
The mutual reference of relevant U. S. application
The application number that the present invention requires on June 22nd, 2005 to submit to is 60/692, the application number that 826 U.S. Provisional Application and on February 7th, 2006 submit to is 60/765,790 U.S. Provisional Application No., wherein the mode quoted in full of the content of each application is included this paper in.
Technical field
Present invention relates in general to be used for the treatment of method, compound and the pharmaceutical composition of virus infection (and delaying its morbidity).The present composition and method can be used for treating the virus infection that is caused by virus, and described virus is HIV, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, hsv 4 types (epstein-Barr virus), influenza virus, variola virus, coronavirus (being the SARS correlated virus) and west nile virus for example.
Background technology
Human virus infection is a major health, and the virus infection of performing animal is main economic problems.Resisting that virus infection has been proved to be is highly effective in some cases, smallpox for example, and this disease is along with the appearance of bovine vaccination is eradicated substantially.Though originally be uprooted to left and right sides smallpox hexyl in 1980, far no longer be possible owing to have this viral source and bioterrorism, but become reality, so have much smallpox popular is again worried.Other virus infection is more difficult antagonism always.B-mode and hepatitis C, Human Immunodeficiency Virus (HIV), hsv and influenza just cause the several outstanding member in a series of viruses of the remarkable health threat in the whole world.In addition, constantly the virus infection that occurs infects the SARS (Severe Acute Respiratory Syndrome) (SARS) that be associated as the existing quilt that breaks out recently with coronavirus along with human prevailing disease continues to threaten the world.It is current that effective treatment has harmful side effect usually to many virus infectiones.In addition, have the effect that causes selecting this class treatment is had the virus of resistance usually, and current methods of treatment is had the virus strain of resistance is a problem that day by day increases at the antiviral therapy of specific virus gene product.Therefore, new antiviral therapy had needs clear and definite and that always exist.
Summary of the invention
Present invention relates in general to treat the Compounds and methods for of virus infection.In addition, the outbreak that the present invention also relates to treat the symptom that causes by virus infection and/or postpone this symptom.The invention provides the compound that comprises formula I-IV formula I ' compound and contain the compound of one or more formulas I-IV and the pharmaceutical composition of one or more pharmaceutically useful vehicle.The compound of formula I ' and formula I-IV comprises following material and pharmaceutically useful salt and steric isomer:
Figure A20068002217100101
Figure A20068002217100111
Wherein:
Q is (CH 2) 1-2
L is an alkyl that 0-10 carbon atom arranged, and this alkyl can be saturated or fractional saturation; One or more carbon atoms of alkyl L can with-O-,-S-,-N-,-C (=O)-,-NC (=O)-,-C (=O) N-,-SO 2,-NSO 2,-SO 2N-, cycloalkyl reach-NC (=O) N-replacement; L can be selected from following substituting group and replaces with one or more: hydroxyl, halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) OH ,-C (=O) O (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
R1 be selected from hydrogen ,-C (=O)-(CH 2) m-CH 3,-C (=O)-(CH 2) m-C (CH 3) 2-COOH;
R2 is selected from cycloalkyl, aryl, heterocycle and heteroaryl, and above-mentioned group can be chosen wantonly with one or more and be selected from following substituting group and replace: hydrogen, hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
M is an integer that is selected from 0-10; And
R3 and R4 be independently selected from-H ,-CH 3,-(CH 3) 2,-CH (CH 3) 2With-C (=CH 2) CH 3
Therefore, the present invention provide in a related aspect by containing a kind of treatment (or prevention) thus a kind of pharmaceutical composition of the compound of the formula I-IV of significant quantity or medicament are administered to the method that the patient of needs treatment virus infection treats virus infection.
The present invention also provides the method that suppresses virus maturation on the other hand, and described method a kind ofly is enough to suppress be administered to the patient who needs this class treatment from a kind of pharmaceutical composition or the medicament of the formula I-IV compound of the amount of the virus maturation of the mankind or zooblast by containing.Of this embodiment of the present invention concrete aspect, the method that suppresses virus maturation comprises the mankind that the compounds for treating with a kind of formula I-IV is infected by the virus.
In addition, the present invention also provides the method that postpones the outbreak of virus infection symptom, comprises being administered to and being infected by the virus or having by the dangerous of virus infection or have the individuality of the danger that develops the virus infection symptom containing a kind of a kind of pharmaceutical composition of the formula I-IV compound that prevents significant quantity or medicament.Of this embodiment of the present invention concrete aspect, the method that suppresses or postpone the outbreak of virus infection symptom comprises the mankind that the compounds for treating with a kind of formula I-IV is infected by the virus.
A kind of method for the treatment of following people is provided in one aspect of the invention, described artificial any HIV retroviral carrier of family is infected by HIV promptly but does not also develop into AIDS (AIDS be defined as more serious AIDS define disease and/or circulation cd4 cell number drop under the level that effective immunologic function allows).This method comprises that this class that identification need treat is individual and will contain a kind of a kind of pharmaceutical composition or medicament for the treatment of the formula I-IV compound of significant quantity and is administered to this individuality.Therefore this method can be used for treating acute primary HIV infect syndromes (this syndromes can be asymptomatic or with the class influenza disease-related of for example having a headache with fever, uncomfortable, diarrhoea and nervous symptoms) or symptomless infection (symptomless infection is the latent period of the length that descends gradually with circulation cd4 t cell number).
On the other hand, the invention provides a kind of method of the such people of treatment, described people is infected by hepatitis B virus (HBV), hepatitis C virus (HCV) reactivity, or also do not form symptom (this symptom is defined as liver injury) that this viroid infects or the carrier who has lived through this viroid of subduing of this class symptom, or contacted this viroid recently.It is individual and will contain a kind of a kind of pharmaceutical composition or medicament for the treatment of the formula I-IV compound of significant quantity or prevention significant quantity and be administered to this individuality that this method comprises that this class of identification need treat.
In another aspect of this invention, a kind of method for the treatment of such people is provided, described people is infected by herpes simplex virus type 1, herpes simplex virus type 2 or hsv 4 types (being also referred to as epstein-Barr virus) reactivity, or also do not form symptom that this viroid infects or the carrier who has lived through this viroid of subduing of this class symptom, or contacted this viroid recently.It is individual and will contain a kind of a kind of pharmaceutical composition or medicament for the treatment of the formula I-IV compound of significant quantity or prevention significant quantity and be administered to this individuality that this method comprises that this class of identification need treat.
In another aspect of this invention, a kind of method for the treatment of such people is provided, described people is infected by influenza A virus, Influenza B virus or influenza virus C reactivity, or also do not form symptom that this viroid infects or the carrier who has lived through this viroid of subduing of this class symptom, or contacted this viroid recently.It is individual and will contain a kind of a kind of pharmaceutical composition or medicament for the treatment of the formula I-IV compound of significant quantity or prevention significant quantity and be administered to this individuality that this method comprises that this class of identification need treat.
In another aspect of this invention, a kind of method for the treatment of such people is provided, described people be subjected to poxvirus family any virus, be that the variola virus reactivity infects, or also do not form symptom (this symptom is defined as more serious smallpox and defines disease) that this viroid infects or the carrier who has lived through this viroid of subduing of this class symptom, or contacted this viroid recently.It is individual and will contain a kind of a kind of pharmaceutical composition or medicament for the treatment of the formula I-IV compound of significant quantity or prevention significant quantity and be administered to this individuality that this method comprises that this class of identification need treat.
In another aspect of this invention, a kind of method for the treatment of such people is provided, described people is infected by any viral reactivity in the coronavirus family, infected by the relevant coronavirus reactivity of a kind of SARS, or also do not form symptom (this symptom is defined as more serious SARS and defines disease) that this viroid infects or the carrier who has lived through this viroid of subduing of this class symptom, or contacted this viroid recently.It is individual and will contain a kind of a kind of pharmaceutical composition or medicament of the formula I-IV compound of significant quantity of preventing and be administered to this individuality that this method comprises that this class of identification need treat.
In another aspect of this invention, a kind of method for the treatment of such human or animal is provided, described human or animal is infected by the west nile virus reactivity, or also do not form symptom that this viroid infects or the carrier who has lived through the west nile virus of subduing of this class symptom, or nearest contacted west nile virus.It is individual and will contain a kind of a kind of pharmaceutical composition or medicament of the formula I-IV compound of significant quantity of preventing and be administered to this individuality that this method comprises that this class of identification need treat.
The compound of the formula I-IV of Shi Yonging can be used as a kind of pharmaceutical composition that contains one or more salt, carrier or vehicle in the present invention provides.Therefore some used compounds of the present invention have chiral centre, the present invention includes the use of all steric isomers, enantiomorph, diastereomer and composition thereof of described compound.
The present invention also provides and has been used for combination therapy medicine for treating viral infections composition or medicament.Said composition contains a kind of first compound and a kind of second antiviral compound for the treatment of significant quantity for the treatment of the formula I-IV of significant quantity, and this second compound is different from this first compound.The example of antiviral compound includes but not limited to proteinase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, fusion inhibitor, ripe inhibitor, immunomodulator and vaccine.
The compounds of this invention can be used for treating multiple other disease or symptom, for example hypertension, cancer (comprising cancer metastasis), immunity system relative disease, autoimmune disorder, infectation of bacteria (for example infectation of bacteria in the digestive tube), retinopathy and neurological disorder.
The mode of aforementioned content of the present invention and other advantage and feature and realization thereof is considering that it is clearer to become on the basis of following detailed description of the present invention together with appended examples, and embodiment has illustrated preferred and typical embodiment.
Unless otherwise prescribed, all technology used herein and scientific terminology have with the technical field of the invention technician's routine and understand identical implication.Though can be used for practice or test the present invention with the method and the material of method as herein described and materials similar or equivalence, suitable method and material are described hereinafter.Having under the situation of conflict, comprising that with the application's specification sheets definition is as the criterion.In addition, described material, method and embodiment only are not used in restriction the present invention for illustrating.
Other features and advantages of the present invention will become clearer by following detailed description and claim.
Embodiment
The invention provides the compound of the formula I ' that comprises formula I-IV compound, described compound can be used for treating virus infection and symptom thereof.The compound of formula I ' and formula I-IV comprises following compound and pharmaceutically useful salt and steric isomer:
Figure A20068002217100161
Wherein:
Q is (CH 2) 1-2
L is an alkyl that 0-10 carbon atom arranged, and this alkyl can be saturated or fractional saturation; One or more carbon atoms of alkyl L can with-O-,-S-,-N-,-C (=O)-,-NC (=O)-,-C (=O) N-,-SO 2,-NSO 2,-SO 2N-, cycloalkyl reach-NC (=O) N-replacement; L can be selected from following substituting group and replaces with one or more: hydroxyl, halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) OH ,-C (=O) O (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
R1 be selected from hydrogen ,-C (=O)-(CH 2) m-CH 3,-C (=O)-(CH 2) m-C (CH 3) 2-COOH;
R2 is selected from cycloalkyl, aryl, heterocycle and heteroaryl, and above-mentioned group can be chosen wantonly with one or more and be selected from following substituting group and replace: H, hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
M is an integer that is selected from 0-10; And
R3 and R4 be independently selected from-H ,-CH 3,-(CH 3) 2,-CH (CH 3) 2With-C (=CH 2) CH 3
In some embodiments of formula I-IV, R1 is-C (=O)-(CH 2) m-CH 3, and m is an integer that is selected from 0-10.In some embodiments of formula I-IV, R1 is-C (=O)-(CH 2) m-C (CH 3) 2-COOH, and m is an integer that is selected from 0-10.In the particular of formula I-IV, L is an alkyl that 0,1,2,3,4 or 5 carbon atom is arranged, and this alkyl can be saturated or fractional saturation; And as above described in the face of the definition of L, this carbon atom can be replaced and/or be had substituting group.
In some embodiments, L can have one or more be selected from halogen, alkyl, haloalkyl ,-C (=O) OH ,-C (=O) O (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-CHF 2,-CF 3Substituting group with-CN.In some embodiments, L can have one or more be selected from hydroxyl, alkoxyl group, halogenated alkoxy ,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-OCF 3,-OCHF 2With-SCF 3Substituting group.In certain embodiments, L can have one or more being selected from-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-NH 2With-NO 2Substituting group.
In some embodiments, R2 by one or more be selected from halogen, alkyl, C-carboxyl, haloalkyl ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-CHF 2,-CF 3A phenyl that replaces with the substituting group of-CN.
In some embodiments, R2 by one or more be selected from hydroxyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, O-formamyl, O-thiocarbamoyl, ester, halogenated alkoxy ,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-OCF 3,-OCHF 2With-SCF 3A phenyl replacing of substituting group.
In some embodiments, R2 by one or more be selected from N-formamyl, N-thiocarbamoyl ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-NH 2With-NO 2A phenyl replacing of substituting group.In certain embodiments, R2 is by one or more phenyl that are selected from cycloalkyl, aryl, heteroaryl and the replacement of heterocyclic substituting group.
In one embodiment, the invention provides compound and the pharmaceutically useful salt thereof of formula I (a)-IV (a):
Figure A20068002217100181
Figure A20068002217100191
Wherein:
R1 is-C (=O)-CH 2-C (CH 3) 2-COOH;
R2 is selected from cycloalkyl, aryl, heterocycle and heteroaryl ring, and above-mentioned group is optional to be selected from following substituting group and to be replaced by one or more: hydrogen, hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-C (=O) NH (C 1-3Alkyl) NHC (=O) (C 1-3Alkyl) ,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
N is selected from an integer of 0,1,2 and 3.
In one embodiment, the invention provides the compound of formula I (a)-IV (a) and contain the pharmaceutical composition of this compound and one or more pharmaceutically useful vehicle, in the formula, R1 is-C (=O)-CH 2-C (CH 3) 2-COOH; R2 optional is selected from the phenyl that following substituting group replaces by one or more, and described substituting group is: hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2And n is selected from an integer of 0,1,2 and 3.
In one embodiment, the stereochemical structure that has kept the betulin core.For example, a kind of compound of the present invention can have the stereochemical structure of formula I (b):
Figure A20068002217100201
Wherein, L, R1 and R2 as above define in the face of formula I.
A kind of pharmaceutically useful salt of The compounds of this invention is example with following salt: with the salt that a kind of mineral acid forms, described mineral acid is spirit of salt, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid etc. for example; And the salt that forms with a kind of organic acid, described organic acid is acetate, propionic acid, Succinic Acid, maleic acid, FUMARIC ACID TECH GRADE, phenylformic acid, citric acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid etc. for example.Their hydrate (1 hydrate, 2 hydrates, 3 hydrates, 1/2 hydrate, 3/2 hydrate, 1/4 hydrate, 4/5 hydrate, 1/5 hydrate, 3/4 hydrate, 1/3 hydrate, 5/3 hydrate, 5/4 hydrate etc.), solvate etc. are also included within the compound of the present invention.In addition, the N-oxide compound is also included within the compound of the present invention.
In addition, pharmaceutically useful salt comprises the acid salt of mineral alkali, for example contain alkali metal cation (Li+ for example, Na+ or K+), alkaline earth metal cation (Mg++ for example, Ca++ or Ba++), the salt of ammonium cation, and the acid salt of organic bases, comprise ammonium and quaternary ammonium cation that aliphatics and aromatic series replace, for example by triethylamine, N, the N-diethylamide, N, the N-dicyclohexylamine, pyridine, N, N-Dimethylamino pyridine (DMAP), 1,4-diazabicylo [2.2.2] octane (DABCO), 1,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-5-alkene (DBN) and 1, the ammonium and the quaternary ammonium cation of the replacement that the alkylating protonation of the mistake of 8-diazabicylo [5.4.0] 11-7-alkene (DBU) produces.
In addition, the compound of formula I-IV can comprise asymmetric carbon atoms and therefore can exist with the form of racemize and optically-active.Therefore, optical isomer or enantiomer, racemic modification and diastereomer are also included within the compound of formula I-IV.The inventive method comprises the use of all these class isomerss and composition thereof.The separation method of enantiomer and non-enantiomer mixture is conventionally known to one of skill in the art.The present invention includes the described compound of formula I-IV of any isolating racemic modification or optically active form form, or by its any mixture of forming, these materials all has antiviral activity.
In one embodiment of the invention, the stereochemical structure of formula I-IV compound is equivalent to the stereochemical structure of the natural product (for example betulinic acid) that this compound derives from.
Mark except as otherwise noted or with the symbol (short-term or dual short-term) of a key, the tie point of a given group will be at the rightmost of described group.Therefore, for example, a hydroxyalkyl is connected on the primary structure by alkyl, and hydroxyl is a substituting group on the alkyl.
Term used herein " alkyl " refers to the saturated aliphatic hydrocarbon that comprises straight chain base and branched group.Preferred this alkyl has 1-20 carbon atom, and (no matter when it occurs at this paper, and numerical range for example " 1-20 " refers to each interior integer of given range; For example " 1-20 carbon atom " mean this alkyl can be by 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until and comprise that 20 carbon atoms form).More preferably it is a medium sized alkyl with 1-10 carbon atom.More preferably it is the low alkyl group with 1-6 carbon atom again, and further more preferably 1-4 carbon atom.This alkyl can be substituted or unsubstituted.When it is substituted, preferably one or more cycloalkyl, aryl, heteroaryl, heterolipid ring, hydroxyl, alkoxyl group, aryloxy, sulfydryl, alkylthio, arylthio, cyano group, halogen, carbonyl, thiocarbonyl, O-formamyl, N-formamyl, O-thiocarbamoyl, N-thiocarbamoyl, C-amide group, N-amide group, C-carboxyl, O-carboxyl, cyanato-, different cyanato-, sulphur cyanato-, different sulphur cyanato-, nitro, silyl and the amino of being selected from separately of one or more substituting groups.
Term used herein " halogen " refers to chlorine, fluorine, bromine and iodine.
Term used herein " hydrogen " refers to a hydrogen atom (H yl).
Term used herein " hydroxyl " refers to one-OH base.
Term used herein " alkoxyl group " refers to one-O-alkyl as described herein and one-O-cycloalkyl.Lower alkoxy refers to-the O-low alkyl group.
Term used herein " aryloxy " refers to one-O-aryl as described herein and one-O-heteroaryl.
Term used herein " sulfydryl " refers to one-SH base.
Term used herein " alkylthio " refers to one-S alkyl as described herein and one-S-cycloalkyl.
Term used herein " arylthio " refers to one-S aryl as described herein and one-S-heteroaryl.
Term used herein " carbonyl " refer to one-C (=O) R " base, wherein R " is selected from hydrogen as described herein, alkyl, cycloalkyl, aryl, heteroaryl (by a ring bond with carbon) and heterocycle (encircling bond with carbon by).
It " is hydrogen that term used herein " aldehyde radical " refers to carbonyl, wherein a R.
Term used herein " cyclic ketones " refers to a cycloalkyl, and one of them forms one of bonding "=O " on the carbon atom of this ring; Be that one of ring carbon atom is one a-C (=O) base.
Term used herein " thiocarbonyl " refer to one-C (=S) R " base, R are " as defined herein.
Term used herein " O-carboxyl " refers to a R, and " (=O) O-base, R " as defined herein for C.
Term used herein " C-carboxyl " refer to one-C (=O) OR " base, R are " as defined herein.
Term used herein " ester " is C-carboxyl, wherein a R as herein defined " is any one of the outer listed group of dehydrogenation (for example methyl, ethyl, low alkyl group).
Term used herein " C-carboxyl salt " refers to one-C (=O) O -M +Base, wherein M +Be selected from lithium, sodium, magnesium, calcium, potassium, barium, iron, zinc and quaternary ammonium.
Term used herein " ethanoyl " refers to one-C (=O) CH 3Base.
Term used herein " carboxyalkyl " refers to-(CH 2) rC (=O) OR ", wherein r be 1-6 and R " as hereinbefore defined.
Term used herein " carboxyalkyl salt " refers to one-(CH 2) rC (=O) O -M +, M wherein +Be selected from lithium, sodium, potassium, calcium, magnesium, barium, iron, zinc and quaternary ammonium.
It " is hydrogen that term used herein " carboxylic acid " refers to C-carboxyl, wherein a R.
Term used herein " haloalkyl " refers to an alkyl that replaces with 1-6 halogen group, and preferred haloalkyl is one-CX 3Base, wherein X is a halogen group.This halogen group can independently be selected.
Term used herein " trihalomethyl group alkylsulfonyl " refers to an X 3CS (=O) 2-Ji, X are as hereinbefore defined.
Term used herein " cyano group " refers to one-C ≡ N base.
Term used herein " cyanato-" refers to one-CNO base.
Term used herein " different cyanato-" refers to one-NCO base.
Term used herein " sulphur cyanato-" refers to one-CNS base.
Term used herein " different sulphur cyanato-" refers to one-NCS base.
Term used herein " sulfinyl " refer to one-S (=O) R " base, R are " as defined herein.
Term used herein " alkylsulfonyl " refer to one-S (=O) 2" base, R are " as defined herein for R.
Term used herein " sulfonamido " refer to one-S (=O) 2NR 17R 18, R 17And R 18As defined herein.
Term used herein " trihalomethyl group sulfonamido " refers to an X 3CS (=O) 2NR 17-Ji, X and R 17As defined herein.
Term used herein " O-formamyl " refers to one-OC (=O) NR 17R 18Base, R 17And R 18As defined herein.
Term used herein " N-formamyl " refers to a R 18OC (=O) NR 17-Ji, R 17And R 18As defined herein.
Term used herein " O-thiocarbamoyl " refers to one-OC (=S) NR 17R 18Base, R 17And R 18As defined herein.
Term used herein " N-thiocarbamoyl " refers to a R 17OC (=S) NR 18-Ji, R 17And R 18As defined herein.
Term used herein " amino " refers to one-NR 17R 18Base, R 17And R 18The both is a hydrogen.
Term used herein " C-amide group " refers to one-C (=O) NR 17R 18Base, R 17And R 18As defined herein.One " N-amide group " refers to a R 17C (=O) NR 18-Ji, R 17And R 18As defined herein.
Term used herein " nitro " refers to one-NO 2Base.
Term used herein " quaternary ammonium " refer to one- +NR 17R 18R 19Base, wherein R 17, R 18And R 19Be independently selected from hydrogen and unsubstituted low alkyl group.
Term used herein " methylene-dioxy " refers to one-OCH 2The O-base, wherein Sauerstoffatom is bonded on the adjacent ring carbon atom.
Term used herein " ethylenedioxy " refers to one-OCH 2CH 2The O-base, wherein Sauerstoffatom is bonded on the adjacent ring carbon atom.
" heterocycle " used herein refers to monocycle or the dicyclo that contains 4-12 atom, and at least one is selected from nitrogen, sulphur or oxygen in the described atom, one-CH in the heterocycle 2-Ji can choose wantonly by one-C (=O)-replace, and an epithio atom can be chosen wantonly and is oxidized to one or more S-oxide compounds.The example of " heterocycle " or " heterocyclic " ring includes but not limited to morpholino, piperidyl, piperazinyl, pyrrolidyl, thiomorpholine generation, high piperazinyl, imidazolyl, imidazolidyl, pyrazolidyl, dioxacyclohexyl and dioxolanyl.When heterocyclic πDian Zi system total conjugated, " heterocycle " can comprise heteroaryl.
" heteroaryl " used herein refers to have in the ring and one or morely is selected from the atom of nitrogen, oxygen and sulphur and has monocycle of πDian Zi system of a total conjugated or condensed ring (promptly sharing several rings of a pair of adjacent atom) group.The example of heteroaryl is but is not limited to pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, pyrazoles, pyridine, pyrimidine, quinoline, isoquinoline 99.9, quinazoline, purine and carbazole.
Monocycle or the condensed ring that " aryl " used herein refers to the full carbon of the πDian Zi system with a total conjugated encircles (promptly sharing the adjacent right several rings of carbon atom) base more.The example of aryl is but is not limited to phenyl, naphthyl and anthryl.
" cycloalkyl " used herein refers to the monocycle or the condensed ring radical (promptly sharing several rings of adjacent a pair of carbon atom) of full carbon, and one or more ring does not have the πDian Zi system of total conjugated.The example of cycloalkyl is but is not limited to cyclopropane, tetramethylene, pentamethylene, cyclopentenes, hexanaphthene, diamantane, cyclohexadiene, suberane and cycloheptatriene.
The method of treatment virus infection
The invention provides by with a kind of pharmaceutical composition that contains a kind of formula I-IV compound for the treatment of significant quantity or medicament administration most virus carrier's patient (people or other animal) thus the method for treatment virus infection.For example, the virus carrier can discern by routine diagnosis technology known in the art, and is as indicated above.With the compound of a kind of formula I-IV the carrier of identification is carried out administration, the compound of described formula I-IV preferably is present in a kind of pharmaceutical composition with pharmaceutically useful carrier.
Another aspect of the present invention provides by containing a kind of pharmaceutical composition of formula I-IV compound for the treatment of significant quantity or patient (people or other animal) that medicament is administered to the characteristic symptom that demonstrates virus infection thereby the method for treatment reactivity virus infection with a kind of.Perhaps, the existence of virus infection can be directly any appropriate means by this area detect or determine.With the compound of a kind of formula I-IV the infected individuality of determining is like this carried out administration, the compound of described formula I-IV preferably is present in a kind of pharmaceutical composition with pharmaceutically useful carrier.
Therefore, the inventive method can be used for usually treating or prevent animal especially human with virus infection diseases associated or obstacle.Above-mentioned virus infection can be caused by following virus, described virus includes but not limited to slow virus, for example Human Immunodeficiency Virus 1 type and 2 types (HIV), human T cell lymphotrophic virus's 1 type and 2 types (HTLV-I and HTLV-II), SIV, EIAV (equine infectious anemia virus), BIV, FIV, CAEV, VMV and MMLV (moloneys mouse leukosis virus).Above-mentioned virus infection also can be caused by following virus: hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, hepatitis G virus, Human foamy spumavirus or herpes virus hominis (herpes simplex virus type 1 for example, herpes simplex virus type 2, hsv 3 types (being also referred to as varicella zoster virus), hsv 4 types (being also referred to as epstein-Barr virus or EBV), hsv 5 types, hsv 7 types).Above-mentioned virus infection also can be caused by following virus: influenza virus (first type, B-mode or third type), the human parainfluenza virus, respiratory syncytial virus, variola virus (variola virus), monkey pox virus, virus vaccinicum, human papillomavirus, the lonely virus of the secondary intestines of people 2 (human parechovirus 2), mumps virus, Measles virus, rubella virus, Semliki Forest virus, west nile virus, colorado tick fever virus, foot and mouth disease virus, Ebola virus, Marburg virus, polyomavirus, TT virus, lassa virus, lymphocytic choriomeningitis virus, vesicular stomatitis virus, rotavirus, varicella virus, parvovirus, cytomegalovirus, encephalitis, adenovirus, Echovirus, rhinovirus, Filovirus, the husky base virus of bandit (coxachievirus), coronavirus (for example relevant coronavirus of SARS), dengue fever virus, yellow fever virus, Hantaan virus, the local hemorrhage fever virus, molluscum virus, poliovirus, rabies virus etc.In some embodiments, this method infection of being used for the treatment of or preventing to cause by enveloped virus.In specific embodiment, as mentioned below, known infection is human and cause that the concrete virus of disease treats with the inventive method.
HIV
Term used herein " HIV infection " generally include host animal especially human host be subjected to the infection of Human Immunodeficiency Virus (HIV) family in the retrovirus, Human Immunodeficiency Virus (HIV) family includes but not limited to, HIVI (being also referred to as HTLV-III), HIV II (being also referred to as LAV-1), HIV III (being also referred to as LAV-2) etc.This paper " HIV " is used in reference to any strain, form, hypotype, clade and the mutation in the HIV family.Therefore, treatment HIV infects carrier that will comprise any virus in the HIV family in the treatment retrovirus or the people who is diagnosed as active A IDS, and related indication treatment of AIDS or prevention among the above-mentioned patient.HIV carriers can be discerned by any means known in the art.For example, can be positive or symptom HIV-positive or that have an AIDS determines that it is HIV carriers according to the anti-HIV antibody of people.Promptly " treatment HIV infect " should be understood that to treat the patient in any one stage in the several stages that is in the HIV progression of infection, described progression of infection comprises that (this syndromes can be asymptomatic or with the fever of class influenza disease to for example acute primary infection syndromes, uncomfortable, diarrhoea and nervous symptoms are for example had a headache), symptomless infection (symptomless infection have long latent period and with the decline gradually of circulation cd4 t cell number) and AIDS (AIDS be defined as more serious AIDS define disease and/or circulation cd4 cell quantity drop under the level that effective immunologic function allows).
Term used herein " postpones the outbreak that HIV infects " and means the such individuality of treatment, described individuality has the danger of being infected by HIV for (1), or (2) are under a cloud is infected by HIV or contact HIV, or contacted HIV of (3) past under a cloud, postpone at least three months with outbreak with acute primary infection syndromes.As known in the art, comprise with fever, discomfort, nausea/diarrhoea, pharyngitis, lymphadenopathy, myalgia with the clinical picture of acute primary infection syndromes canonical correlation and nervous symptoms is for example had a headache, the class influenza disease of encephalitis etc.Individuality on the line can be the people who carries out any following behavior: the blood that contact is polluted by HIV, blood transfusion, body fluid exchange, " unsafe " sexual intercourse with infected people, unexpected pricking wound, carry out medicine with contaminated syringe needle or syringe and inject, tatoo or acupuncture or gestation, farrowing interval or the virus disseminating from the parent to baby soon thereafter with contaminated instrument.Term " postpone HIV infect outbreak " can comprise also that treatment also is not diagnosed as to be infected by HIV but considered to be in the danger of being infected by HIV or the people by contacted HIV such as contaminated blood.
In addition, term " postpone AIDS outbreak " means by treating following individuality that (AIDS is characterized as more serious AIDS and defines disease and/or circulation cd4 cell quantity and drop under the level that effective immunologic function allows with AIDS, under promptly about 200/ μ l) and/or the related indication outbreak of AIDS postpone at least six months, described individuality has by infect dangerous of HIV for (1) or suspects and infected by HIV, or (2) are infected by HIV but do not formed AIDS.Be in individuality in the danger of being infected by HIV and can be contacted HIV of those past under a cloud or be considered to now or have in the future the people of the danger of contact HIV, described contact is by for example contacting the blood that polluted by HIV, blood transfusion, transplanting, body fluid exchange, " unsafe " sexual intercourse with infected people, unexpected pricking wound, tatooing or acupuncture or gestation, farrowing interval or the virus disseminating from the parent to baby soon thereafter with contaminated instrument.
Term " treatment AIDS " means treatment and demonstrates more serious AIDS and define the patient that disease and/or circulation cd4 cell quantity drop to (being generally under about 200/ μ l) under the level that effective immunologic function allows.Term " treatment AIDS " also comprises treatment AIDS related symptoms, this symptom means to be followed AIDS or HIV to infect or infects relevant obstacle and disease with AIDS or HIV, AIDS related syndromes (ARC) for example, carrying out property general lymphadenopathy (PGL), anti-HIV antibody be positive symptom and HIV-positive symptom, AIDS related neural symptom (for example dull-witted or tropical paraparesis), Kaposi sarcoma, thrombopenic purpura and relevant opportunistic infection, for example pneumocystosis, the tuberculosis mycobacteria, candidiasis of the esophagus, brain toxoplasmosis, the CMV retinitis, the encephalopathic that HIV is relevant, the exhaustion syndrome that HIV is relevant etc.
HBV
Term used herein " HBV infection " generally includes the people and infects any strain or serotype hepatitis B virus, comprises that acute hepatitis B infects and chronic hepatitis B infects.Therefore, treatment HBV infects carrier who means any strain of treatment or serotype hepatitis B virus or the people who is suffered from active hepatitis B by diagnosis, infect and/or one or more relevant symptoms of hepatitis B to reduce the intravital HBV virus amount of carrying of this patient or to alleviate, comprise the blood content of the transaminase of for example nausea and vomiting, poor appetite, fatigue, muscle and arthralgia, rising, prothrombin time, jaundice (flavescence of eyes and health) and the urine color depth of increase with HBV.The carrier of HBV can be discerned by any method known in the art.For example, can according to the anti-HBV antibody of people be positive (for example according to hepatitis B core antibody or hepatitis B surface antibody) or HBV be positive (for example according to hepatitis B surface antigen(HBsAg) (HBeAg or HbsAg) or HBV RNA or DNA) thereby or the symptom with hepatitis B infection or hepatitis B determine that it is the HBV carrier.Therefore, " treatment HBV infects " is construed as the treatment to the patient in any one stage in the several stages that is in the HBV progression of infection.In addition, term " treatment HBV infect " also can comprise suspecting the treatment of the individuality that is infected by HBV behind the contact HBV under a cloud, and described contact for example contacts the blood that polluted by HBV, blood transfusion, body fluid exchange, " unsafe " sexual intercourse with infected people, unexpected pricking wound, tatoos or acupuncture or gestation, farrowing interval or the virus disseminating from the parent to baby soon thereafter with contaminated instrument.Term " treatment HBV infects " also comprises the treatment to the patient of the danger of not infected by HBV but being considered to be infected by HBV.
Aspect another one, thereby provide the method that is infected by the patient's of HBV and HIV co-infected HBV to patient's treatment by with a kind of formula I-IV compound administration for the treatment of significant quantity.Particularly, HIV infects increases relevant with the approximate triple of persistence hepatitis B development.The compound of formula I-IV especially is fit to by the patient of HIV and HBV co-infected.Present marketed drugs interferon alpha is invalid by the patient of HBV and HIV co-infected to treatment.Other reverse transcriptase inhibitors of lamivudine and some can be used for treating above-mentioned coinfection, but lamivudine especially has toxicity, can cause liver injury, thereby hepatitis B is worsened.In addition, above-mentioned reverse transcriptase inhibitors often must be used in the cocktail.By contrast, The compounds of this invention has much smaller toxicity, and it is less to cause developing the possibility that virus resistance.Therefore, according to the present invention, it is individually dosed or be administered to by Mammals, the especially people of HBV and HIV coinfection with the medication combined of anti-HIV of another kind or anti-HBV that the compound of a kind of formula I-IV can be treated significant quantity.This method can comprise with technology identification well known in the art by the patient's of HBV and HIV coinfection step.For example, the PCR test can be used for detecting HBV DNA or RNA and the HIV RNA from the blood sample that the experimenter obtains.Perhaps, the antibody of virus-specific or antigen also can be used for detecting HBV and HIV infection.
Term used herein " prevention hepatitis B " means patient that prevention suffers from patient that HBV infects, patient that the HBV of suffering under a cloud infects or have the danger that HBV infects to be developed and hepatitis B (feature of hepatitis B is that more serious hepatitis defines symptom), liver cirrhosis or hepatocellular carcinoma.
HCV
Term used herein " HCV infection " generally includes the hepatitis C virus that the people infects any kind or hypotype, wherein comprises acute hepatitis C infection and chronic hepatitis C infection.Therefore treat HCV and infect the carrier of the hepatitis C virus that means treatment any kind or hypotype or be diagnosed as the patient who suffers from active hepatitis C, with the HCV virus amount of carrying that reduces this patient or alleviate and HCV infects and/or one or more relevant symptoms of hepatitis C.The carrier of HCV can discern by any method known in the art.For example, can be positive according to the antibody of an anti-HCV of people or HCV be positive (for example according to HCV RNA or DNA) or have the symptom (for example serum transaminase of Sheng Gaoing) of hepatitis C infection or hepatitis C thus determine that it is the carrier of HCV.Therefore, " treatment HCV infects " is construed as the patient who treats any one stage in the several stages that is in the HCV progression of infection.In addition, term " treatment HCV infect " is suspected the individuality that is infected by HCV after also comprising treatment contacted HCV of past under a cloud, and described contact is for example passed through: the blood that contact is polluted by HCV, blood transfusion, body fluid exchange, " unsafe " sexual intercourse with infected patient, unexpected pricking wound, tatoo or acupuncture or gestation, farrowing interval or the virus disseminating from the parent to baby soon thereafter with contaminated instrument.Term " treatment HCV infect " comprises also that treatment is not infected by HCV but the people of the danger that is considered to be infected by HCV.The patient that term used herein " prevention HCV " means that prevention suffers from that HCV infects or the HCV of suffering under a cloud infects or have the danger that HCV infects is developed and hepatitis C (feature of hepatitis C is that more serious hepatitis defines symptom), liver cirrhosis or hepatocellular carcinoma.
Importantly, in all people that infected by HIV of the U.S., have an appointment 1/4th, promptly estimate 200,000 people, both also infected (referring to the report National Center for HIV on the webpage http://www.cdc.gov/hiv/pubs/facts/HIV-HCV_Coinfection.htm by HIV by HCV, STD and TB Prevention and Thomas, the Hepatology 36:S201-S209 (2002) of D.L.).Because by using highly active antiretroviral therapy to prolong the patient's who is infected by HIV life-span, hepatopathy has become a major reason of M ﹠ M, and be leading reason in some cases.All stages that the HIV infection shows the HCV infection have harmful effect.Particularly, HIV infects with the remarkable increase that develops into the persistence hepatitis C, higher HCV titre, to develop into liver cirrhosis (scarring) danger relevant with increasing HCV of the relevant hepatopathy of HCV more quickly relevant.And then HCV can influence the treatment of HIV infection, the hepatotoxic sickness rate that increase is caused by antiretroviral drugs.(Thomas, D.L. Hepatology 36:S201-S209, (2002) and the report National Center for HIV on the webpage http://www.cdc.gov/hiv/pubs/facts/HIV-HCV_Coinfection.htm, STD and TB Prevention)
In the U.S., two kinds of different methods of treatment have been approved for the treatment chronic hepatitis C: with the monotherapy of interferon-alpha with the conjoint therapy of interferon-alpha and ribavirin (ribavirin).In the chronic hepatitis C patient that HIV is negative, conjoint therapy produces the more sustained reaction of height ratio (30%-40%) than monotherapy (10%-20%) all the time.Conjoint therapy is enantiopathy virus gene 1 type and 2 types more effectively, and need the shorter course of treatment; But virogene 1 type is modal among the U.S. patient.Conjoint therapy has more side effect than monotherapy, but in most cases, conjoint therapy is more desirable.At present, the Interferon, rabbit monotherapy is specialized in using ribavirin to have patient's use of contraindication.(referring to http://www.cdc.gov/hiv/pubs/facts/HIV-HCV_Coinfection.htm)
Therefore, in the present invention aspect another, thereby provide the method that is infected by the patient's of HCV and HIV coinfection HCV to patient's treatment by with a kind of compound administration for the treatment of the formula I-IV of significant quantity.The compound of formula I-IV is specially adapted to by the patient of HCV and HIV coinfection.Particularly, this compound especially can effectively suppress the HCV infection and/or flow out from host cell.And this compound also can effectively suppress HIV and enters and/or flow out host cell.Compare with above-mentioned conjoint therapy, compound of the present invention has the possibility that much smaller toxicity and less causing produce virus resistance.Therefore, according to the present invention, that a kind of formula I-IV compound of treatment significant quantity is individually dosed or be administered to by Mammals, the especially people of HCV and HIV coinfection with the medication combined of anti-HIV of another kind or anti-HCV.This method can comprise with technology identification well known in the art by the patient's of HCV and HIV coinfection step.For example, the PCR test can be used for detecting HCV DNA or RNA and the HIV RNA from the blood sample that the experimenter obtains.Perhaps, special viral antibody or antigen also can be used for detecting HCV and HIV infection.
Simplexvirus
Simplexvirus is one of modal human pathogen.The member of simplexvirus family comprises herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella zoster virus (hsv 3 types or HSV-3; Be also referred to as varicella) and epstein-Barr virus (hsv 4 types or HSV-4).HSV-1 causes herpes labialis (being also referred to as herpes of mouth, cold sore, fever blster) usually, and herpes labialis is the open sore with hyperinfection, can form a scab before healing.HSV-1 can cause that also eye and brain infect.HSV-2 causes genital herpes usually.HSV-1 also can cause genital herpes, but frequency is much smaller than HSV-2.Through primary infection week after date, HSV-1 and HSV-2 form lifelong latent infection usually near the Sensory neurone of infection site.These latent infections do not show any S or S of infection or disease and exist, make this viral reactivation up to some incidents.Reactivate is causing sending out infringement near the position of primary infection or in the position identical with primary infection usually again.Reactivate as if occur in nervous during or during function of immune system reduces.
Except that herpes of mouth and genital herpes, HSV-1 and HSV-2 also can cause other disease.The example of this class disease comprises herpes simplex encephalitis-a kind of rare but possible fatal herpetic infection of brain; A kind of rare among newborn infant bleb-newborn infant but HSV that may be very serious infects (deriving from the virus disseminating of farrowing interval from the parent to baby); The HSV of herpetic whitlow-a kind of finger infects (deriving from the opposing party that infection is infected by HSCV from the transfer or the direct contact of health another part); And herpetic keratitis (herpes keratitis)---the HSV that plants eye infects (blind modal therefore former-).Therefore, Ren Lei herpes simplex infections is an important health problem.
Genital herpes mainly uses inhibition therapy and stage of attack therapy (episodic therapy) to treat.The inhibition therapy is used for their preictal treatments, and stage of attack therapy be used for the treatment in their whens outbreak.The treatment of use HCl valacyclovir (valacyclovir), acyclovir (acyclovir) and Famciclovir (famciclovir) both can be used in the inhibition therapy and also can be used in the stage of attack therapy.
The current known therapies that also HSV-1 is not infected.The available antiviral therapy is not in full force and effect and virus is become treatment is had resistance.Therefore, the method and composition that improves treatment HSV-1 there is clear and definite demand.
Epstein-Barr virus (hsv 4 types) worldwide exists hereinafter referred to as " EBV ".In fact, most of people can be infected by EBV in their life.Grownup at U.S.'s significant proportion is infected.As long as the provide protection of maternal antibody disappears during birth, the baby is with regard to easy infection EBV.Many children can infect EBV, and these infection do not cause symptom usually.The symptom that children EBV infects is difficult to distinguish with other typical children disease symptom.Not infected individuality has in pubescence or early stage infected danger of Adulthood during children, and this can cause infectious monocytosis (list) usually.The symptom of infectious monocytosis comprises fever, throat pain and lymph gland swelling, may form the spleen often do not followed or the swelling of liver.Cardiac problems or relate to the less generation of problem of central nervous system.Infectious monocytosis is almost never fatal.The symptom of infectious monocytosis usually 1 or 2 months in disappear, but EBV infected patient ensuing keep dormancy in life or some cells of hiding at throat and blood in.This virus is reactivate and finding in infected patient's saliva usually periodically.The generation of reactivate does not have disease symptoms usually.
It is relevant with many other diseases that EBV is considered to, and described disease comprises Burkitt lymphoma, nasopharyngeal carcinoma and Hokdkin disease.Especially common in the people that immunizing power reduces by the disease that EBV causes.EBV is relevant with the tumour of finding in organ transplantation patient body usually, and this tumour is called as transplants the back lympahadenism.Above-mentioned patient's immune system manually suppresses to help prevent body to repel neologism with pharmacotherapy usually.The individuality that is infected by HIV and suffer from AIDS also has the immunizing power of reduction and suffers from the oral cavity hairy leukoplakia usually, and this is a kind of along having the symptom that considerable EBV duplicates in the cell of lingual margin.Think also that in Burkitt lymphoma popular country the high incidence of malaria may be played a role by the immunity system that suppresses body in this lymphoma disease.
What scientist finds to be difficult to be interpreted as should virus can cause light relatively disease such as glandular fever and so in some, then cause malignant tumour in other people.Inherited genetic factors may be played a role.In any case, need treat to resist EBV.
Term used herein " hsv " or HSV refer to the hsv of any strain, include but not limited to HSV-1, HSV-2, HSV-3 (varicella zoster virus or varicella) and HSV-4 (or EBV).Therefore, " treatment HSV infects " will comprise the patient that treatment is infected by any virus activity in the HSV family of simplexvirus, or the carrier that any virus lays dormant sexuality is dyed in the HSV family of simplexvirus.
Term used herein " HSV infection " generally includes the infection of the hsv of any strain to the people, and has both comprised that active the infection also comprised latent infection.Therefore, " treatment HSV infects " means the carrier of the HSV of any strain of treatment.For example, thus can be positive or have the carrier that symptom that HSV infects determines that it is HSV according to the antibody of an anti-HSV of people.Therefore, " treatment HSV infects " should be understood that to treat the patient in any one stage in the several stages that is in the HSV progression of infection.In addition, term " treatment HSV infect " will suspect to suffer from the individuality that HSV infects after also will comprising treatment contact under a cloud HSV, the blood that described contact is for example polluted by HSV by contact, blood transfusion, body fluid exchange, " unsafe " sexual intercourse with infected people, unexpected pricking wound, tatoo or acupuncture or gestation, farrowing interval or the virus disseminating from the parent to baby soon thereafter with contaminated instrument.Term " treatment HSV infect " will comprise also that treatment is not infected by HSV but the people of the danger that is considered to be infected by HSV.
In another aspect of the present invention, thereby provide the method that a kind of compound administration for the treatment of the formula I-IV of significant quantity is infected by the patient's of HSV and HIV coinfection HSV to patient's treatment.Particularly, it is relevant with the active increase of infecting of HSV that HIV infects, and probably infects the immunocompromise state that is produced owing to HIV.The compound of formula I-IV is particularly suitable for by the patient of HIV and HSV coinfection.The marketed drug interferon alpha is invalid to treatment HBV and HIV coinfection at present.Other reverse transcriptase inhibitors of lamivudine and some can be used for treating above-mentioned coinfection, but lamivudine is especially toxic and can cause liver injury, and liver injury can make hepatitis B worsen.In addition, above-mentioned reverse transcriptase inhibitors often must be used in the cocktail.By contrast, The compounds of this invention has much smaller toxicity, and it is less to cause producing the possibility of virus resistance.Therefore, according to the present invention, can be with a kind of formula I-IV compound for the treatment of significant quantity individually dosed or be administered to by Mammals, the especially people of HSV and HIV coinfection with the medication combined of anti-HIV of another kind or anti-HSV.This method can comprise with technology identification well known in the art by the patient's of HSV and HIV coinfection step.For example, PCR test can be used for detecting HSV DNA or RNA and the HIV RNA in the blood sample that obtains from the experimenter.Perhaps also can use antibody or the Detection of antigen HSV and the HIV infection of virus-specific.
It is that the patient of the patient who prevents to suffer from the HSV infection, the HSV of suffering under a cloud infection or the patient that contact HSV risk of infection is arranged are developed outlet plenum bleb, genital herpes, varicella or zoster or chronic EBV infection that term used herein " postpone the related indication outbreak of HSV " to look like.
Influenza
Only follow the hospital care of average 36,000 example death and 114,000 examples in the annual influenza of the U.S..Though three kinds of generally acknowledged influenza virus types are arranged, i.e. influenza A, second type influenza virus and influenza C, influenza A and second type influenza virus are the reasons of annual influenza pandemic in winter.Influenza A also infects many different animal species except that infected person, comprise duck, chicken, pig, whale, horse and sea dog.Common infected person of second type influenza virus.
All three kinds of influenza virus types all have the genome of being made up of eight different RNA spirals, and this spiral coding individual gene also connects described nucleoprotein decision Virus Type: first type, B-mode or third type by nucleoprotein.In fact, the influenza genome is made of eight isolating nucleic acid fragments, when cell by more than a kind of Virus Type coinfection the time, this nucleic acid fragment is assembled to form and is had the virus of the new virus assortment of genes.Two kinds of virus surface proteins that coding is important in these RNA spirals: hemagglutinin and neuraminidase, this hemagglutinin and neuraminidase are embedded in the lipid bilayer of ripe virion.
Variation in viral hemagglutinin and the neuraminidase determines the hypotype that this is viral.Hemagglutinin is responsible for making virus to enter host cell, and neuraminidase discharges from infected cell the virus that makes firm formation and has vital role.Can neutralize virus and be the main determining factor of immunity of hemagglutinin antibody.Can not neutralize virus but can limiting virus duplicate and course of infection of neuraminic acid enzyme antibody.The hemagglutinin of particular type also improves the situation that will be infected by identical viral kind from now on usually with host's antibody prevention of neuraminidase.But, because the heredity of viral kind constitutes and to be dynamic and constantly to change, so may be invalid to the mutational variety a kind of new, reorganization of resisting next year from infecting the immunizing power that is obtained during back 1 year to a kind of successful resistibility of virus.
It is believed that the influenza pandemic disease produces when viral kind changes in time by the antigenic drift process.Antigenic drift (sudden change by main virus antigen gene especially hemagglutinin or Neuraminidase Gene causes) causes a small amount of change of surface antigen, and continues basically to take place always.When the correct position of these changes in gene took place, the antibody of other influenza virus kind of antagonism that they produce when causing new antigen not by preceding single infection was discerned.
Flu outbreak (or worldwide being very popular) be the result of " antigenic drift ".Antigenic drift is the bigger change that influenza A virus takes place suddenly, and this change comes from a kind of new hemagglutinin and/or new hemagglutinin and the neuraminic acid zymoprotein that is occurred in the influenza A virus kind.Above-mentioned drift is considered to take place when a kind of new viral chromosome group RNA combination results usually, and this new combination may be to produce in the non-human species, and should new combination be passed to the mankind.When a kind of like this antigenic drift took place, most of people had seldom this virus or not opposing, and infection is proved to be fatal.
On human history, flu outbreak has caused mass mortality.The flu outbreak of 1918-1919 has caused the death of about 2 to 4,000 ten thousand populations.In order to support above-mentioned antigenic drift hypothesis, recent analysis of molecules has proved that to cause pandemic influenza virus of 1918-19 relevant with a kind of swine influenza virus, described swine influenza virus with now still can cause the influenza virus of people's parainfluenza to belong to identical family.
Two classes treatment/preventative strategy can be used for tackling influenza infection: inoculate " influenza vaccines " and give antiviral drug.Influenza vaccines comprise the vaccine that contains influenza virus deactivation or inactivation.The antiviral that can be used for treating influenza infection comprises Symmetrel, Rimantadine, zanamivir (zanamivir) and Tamiflu (osteltamivir).Symmetrel and Rimantadine are used for the treatment of and prevent influenza A to infect, and zanamivir is used for the treatment of the first type and second type influenza virus infects, and Tamiflu is used for the treatment of and prevent the first type and second type influenza virus infects.
Although have many medicines and vaccination, still need to improve the method and composition of treatment and flu-prevention infection.
Term used herein " influenza " and " influenza virus " refer to the influenza of any kind or hypotype, comprise first type, B-mode and third type and all hypotypes thereof.Therefore, term " influenza infection " comprises that by the influenza infection of any kind term " treatment influenza infection " is interpreted as meaning treatment by the animal of the influenza infection of any kind especially people.In addition, term " treatment influenza infection " also will comprise the treatment contact influenza under a cloud after the doubtful individuality of suffering from influenza infection.Term " treatment influenza infection " also will comprise on the treatment surface not by influenza infection but be considered to by the people of the danger of influenza infection.
Subcutaneous ulcer virus
Term used herein " variola virus " refers to the variola virus of any kind, comprises variola major and variola minor (being also referred to as alastrim).The example of above-mentioned people's alastrim virus strain isolated be well-known and the complete genome nucleotide sequence of a virus strain be determined (referring to, the 15th of Harrison the edition Principles of InternalMedicine for example, Braunwald et al.EDS.McGraw-Hill, United States, and at the NC_001611 that is numbered of Genbank database).The technician can diagnose and be infected by smallpox or suspect the individuality that is infected by smallpox.The symptom that term " treatment smallpox " or " treatment variola virus " had both referred to treat this disease also refer to reduce this virus amount of carrying, infectivity and/or should virus duplicate.Term used herein " postpones to infect with smallpox the outbreak of relevant symptom " and means the patient that treatment is not infected by smallpox, or treatment is considered to the patient of the danger infected by smallpox, or the patient that infected by smallpox of treatment, so that will infect the outbreak delay at least three months of one or more relevant symptoms with smallpox.Term " treatment smallpox " also comprises the such people of treatment: suffer from that smallpox infects or under a cloudly suffer from smallpox and infect or the people's (feature of smallpox is that more serious smallpox defines symptom, for example macula, fever, blister pathology and pustular pathology) who infects the danger that develops into smallpox from variola virus arranged.
Breaking out of monkeypox occurs in the U.S. for the first time in June, 2003.Pathogenic agent is a monkey pox virus, and monkey subcutaneous ulcer virus belongs to and comprises variola virus (smallpox), is used in virus (cowpox) and vaccinia virus one viroid in the antismallpox vaccine.In the mankind, though monkeypox is different with smallpox, can not cause swollen lymph node, the S﹠S of monkeypox is similar with smallpox, but lighter usually.In the Africa of the most of monkeypox cases of known generation, infect the death cause 1% to 10% infected individuality.The symptom that term used herein " treatment monkeypox " or " treatment monkey pox virus " had both referred to treat this disease also refer to reduce this virus amount of carrying, infectivity and/or should virus duplicate.Term used herein " prevention monkeypox infect " means that prevention is not infected by monkeypox but the patient's of the danger that is considered to be infected by monkeypox infection.Term used herein " postpones to infect with monkeypox the outbreak of relevant symptom " and means treatment not by the monkeypox infection or be considered to danger of being infected by monkeypox or the patient who has been infected by monkeypox, will infect the outbreak delay at least three months of one or more relevant symptoms with monkeypox.
Coronavirus
Term used herein " SARS-CoV ", " SARS " or " SARS be correlated with coronavirus " refer to the coronavirus of any kind relevant with the serious acute respiratory symptom.The example of above-mentioned human coronavirus strain isolated be known HCoV-OC43 and HCoV-229E (referring to, for example Marra et al.Science 300:1399 (2003) and Rota et al.Science300:1394 (2003) (at the AY278741 that is numbered of Genbank database)).The technician can diagnose the individuality by the relevant coronavirus of SARS infects or suspection is infected by the relevant coronavirus of SARS.Term " treatment SARS " or " the relevant coronavirus of treatment SARS " had both referred to that the symptom for the treatment of this disease also referred to reduce duplicating of infectivity and/or the relevant coronavirus of SARS.Term " treatment SARS " comprises also that treatment is not infected by SARS-CoV but the people of the danger that is considered to be infected by SARS-CoV.Term used herein " prevention SARS " means prevention to be suffered from SARS-CoV infection or the SARS-CoV of suffering under a cloud infection or has the people of the risk of SARS-CoV infection to develop into SARS (feature of SARS is that more serious SARS-CoV defines for example serious respiratory disease of symptom, fever, dry cough, shortness of breath and severe acute respiratory syndrome).
West nile virus
Xi Niluo (WN) virus occurred at the temperate zones of Europe and North America in recent years, showed the threat to the health of the public, horse and animal.The most serious performance of WN virus infection is human and fatal encephalitis (brain inflammation) of horse and the lethality of some poultry and wild fowl.The WN virus infection is a problem that increases gradually in the North America.2002 are only in the U.S. and the case of the human WN virus infection that 4,156 examples place on record are just arranged and 284 people's death are arranged.Term used herein " treatment west nile virus " " treatment Xi Niluo disease " refers to the known WN of the being subjected to virus infection of treatment and suspects and is subjected to WN to infect the symptom of this disease in two kinds of situations.
In one embodiment, described methods of treatment is generally used for treating and is just experiencing the individuality that is infected by any the acute or chronic challenge virus that causes in the above-mentioned virus.In another embodiment, described methods of treatment is generally used for treating the carrier of above-mentioned arbitrary virus, and this carrier is experiencing the challenge virus outbreak.In another embodiment, this method is generally used for treating known contacted or suspect the individuality of contacted arbitrary above-mentioned virus.In another embodiment, this method is generally used for prophylactic treatment may contacted arbitrary above-mentioned virus or the individuality of the danger of the arbitrary above-mentioned virus of contact is arranged, thus preventing infection or alleviate its symptom.
In a specific embodiment, this method is used for the treatment of and is diagnosed as the HIV carriers that also do not develop into AIDS (feature of AIDS be more serious AIDS define disease and/or circulation cd4 cell quantity be reduced under the level that effective immunologic function allows, under promptly about 200/ μ l).For example, this method can be used for treating the patient who is diagnosed as any HIV infective stage before the AIDS, comprises treatment acute HIV symptom (or acute primary HIV infection symptoms) and symptomless infection (symptomless infection have long latent period and with the decline gradually of circulation cd4 t cell number).
On the one hand, the invention provides the method for the virus infection in any stage of treatment in the patient who used or establishing received antiviral to treat with one or more, described virus infection is in any stage, and cause by arbitrary above-mentioned virus, especially cause by HIV.Other the example of antiviral compound of this class includes but not limited to proteinase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, fusion inhibitor and composition thereof.The compound of formula I-IV does not have patient's (for example, reactionless or develop virus tolerance) of sound response or with the patient of recurring behind one or more other antiviral or the medication therapy for treating to giving to other antiviral can for dispensing.As used herein, " reactionless patient " patient's patient meaning of " other antiviral not being had sound response " just is meant under the relevant medical standard or the conventional practice in anti-virus infection treatment field in doctor's the observation or the judgement of specialty.For example, under the situation of HIV, if treat the blood plasma HIVRNA level (or its equivalent parameter) of patient after sufficiently long for some time reduces in a large number with one or more other inverases, if or the reduction amount of blood plasma HIVRNA level (or its equivalent parameter) is less than 10 times of the reduction amount of initial therapy after 4 weeks, then he or she has reactionless or does not have the feature of sound response.The indication of other of reactionless patient can comprise, for example, and lasting decline, ADR or drug toxicity and the clinical deterioration rates of cd4 t cell quantity.Therefore, the inventive method comprises identification this class patient and will have a kind of pharmaceutical composition of formula I-IV compound for the treatment of significant quantity or the step that medicament is administered to this patient subsequently.
In another embodiment, with a kind of formula I-IV compound administration to having lived through one or more pharmacological agent---a kind of viral protein of described drug targeting is virus protease, reversed transcriptive enzyme, intergrase, envelope protein (for example, anti-gp120 and gp41 or its homologue that merges) for example---and to the patient of the no sound response of this treatment.Compound of the present invention belongs to the new class antiviral, this medicine be considered to target certain or some host cell proteins.Their mode of action is different from other antiviral.Therefore, they are to treating by virus infection and reactionless or especially effective with the patient who produces recurrence behind one or more another kind of antiviral treatments to one or more other another kind of antiviral.
In addition, the present invention also provides the method for the outbreak that postpones acute infection, and this method comprises and is administered to and suffers from acute viral infection or have the dangerous of virus infection or have the individuality of the danger that the symptom of developing into infects having a kind of a kind of pharmaceutical composition of the formula I-IV compound that prevents significant quantity or medicament.For example, when postponing the outbreak of symptom infection is arranged, can discern by a kind of virus infection or have by the individual of the danger of virus infection and give a kind of formula I-IV compound that prevents significant quantity, promptly be enough to the amount that the outbreak of this acute viral infection is postponed at least 6 months.Preferably postpone at least 12 months, 18 months or 24 months with outbreak with this acute viral infection with enough amounts.
In addition, the present invention also provides delay that the method for the outbreak of symptom virus infection is arranged, this method comprises that identification is individual, described individuality (1) has by a kind of danger of virus infection, or (2) are suspected by a kind of virus infection or a kind of virus of suspection contact, or (3) are suspected in the past contacted a kind of virus and will be had a kind of a kind of pharmaceutical composition or medicament of the formula I-IV compound of significant quantity of preventing and be administered to this individuality.
For prophylaxis of viral infections, treatment symptomless virus infect, postpone have the outbreak of symptom virus infection or treatment that the symptom virus infection is arranged, a kind of compound of the present invention and one or more other antiviral compounds can be united use, preferably unite use with other antiviral compound that works by the different mechanisms of action.The example of above-mentioned other antiviral compound includes but not limited to proteinase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, fusion inhibitor and composition thereof." administration altogether " means a part together administration of several active agents as same treatment or medical scheme.Active agents can be one day different time administration or administration at one time respectively.In addition, the present invention also provides a kind of pharmaceutical composition, and said composition has the compound of a kind of formula I and is selected from a kind of compound of proteinase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, fusion inhibitor, ripe inhibitor, immunomodulator, vaccine and composition thereof.But, should be appreciated that above-mentioned other antiviral compound should not disturb or poorly influence the desired result of active compound of the present invention.A kind of formula I-IV compound and one or more other antiviral compounds for the treatment of significant quantities for the treatment of significant quantity is administered to the individuality that needs treatment altogether, is a kind of method that the present invention provides in this respect.
Therefore, the present invention also provides pharmaceutical composition and the medicament that can be used for above-mentioned treatment and prevention purpose, and said composition and medicament have a kind of formula I compound of significant quantity and other antiviral compound of one or more treatment significant quantities for the treatment of.Preferred above-mentioned other antiviral compound has a kind of and the different mode of action of formula I-IV compound.A kind of viral protein of more preferably above-mentioned other antiviral compound target.The example of this compounds includes but not limited to proteinase inhibitor, nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, fusion inhibitor and composition thereof.
The present invention also provides a kind of product, and this product comprises a kind of pharmaceutical composition or the medicament of the formula I-IV compound with a kind of treatment or prevention significant quantity.This pharmaceutical composition or medicament can be placed on container for example in bottle, gel capsule, bottle or the syringe.This product also can comprise this pharmaceutical composition or the medicament operation instruction in the above-mentioned various antiviral application that provides.This explanation can be printed on the paper or the form of brochure or book.Preferred product of the present invention also contains other antiviral compound of one or more treatments mentioned above or prevention significant quantity.
Usually, the compound-base of formula I-IV in overall restatement with every day about 0.01 μ g/kg serve as effective to the amount of about 100mg/kg.But the activeconstituents single administration maybe can be divided into some smaller doses with the predetermined time interval administration.The optimal dose unit of each administration can be for example from about 1 μ g to about 2000mg, preferably from about 5 μ g to about 1000mg.Under the situation of combination therapy, one or more other antiviral compounds of treatment significant quantity can maybe can be included in the pharmaceutical composition of the present invention that contains a kind of formula I-IV compound by dividing other pharmaceutical composition administration.The pharmacology of many above-mentioned other antiviral compounds and toxicology are well known in the art.Referring to, physicians Desk Reference for example, Medical Economics, Montvale, NJ; With The Merck Index, Merck ﹠amp; Co., Rahway, NJ.The treatment significant quantity of the employed described compound in this area and suitable unitary dose scope also can be equally applicable among the present invention.
Be construed as above-mentioned dosage range only as example and the non-desire restriction scope of the invention.The treatment significant quantity of every kind of active compound can change with multiple factor, described factor includes but not limited to the activity of compound used therefor, active compound is in the intravital stability of patient, the seriousness of the symptom that alleviates, the patient's that treats gross weight, the administration path, active compound absorbs in vivo, distribution and excretory difficulty or ease, patient's age for the treatment of and susceptibility etc., these will be conspicuous for a person skilled in the art.Dosage can be adjusted according to various factors change in time.
In pharmaceutical composition, described active ingredient can be the form of any pharmaceutically useful salt.Term used herein " pharmaceutically useful salt " refers to the nontoxic relatively organic or inorganic salt of described active compound, comprises the mineral acid or the organic acid addition salt of this compound.The example of the salt of alkalescence active compound component includes but not limited to hydrochloride, hydrobromate, vitriol, hydrosulfate, nitrate, acetate, phosphoric acid salt, oxalate, valerate, oleate, borate, benzoate, lauroleate, stearate, palmitate, lactic acid salt, tosylate, Citrate trianion, maleate, succinate, tartrate, naphthoate (napththylatesalt), fumarate, mesylate, lauryl sulfonate, gluceptate etc.Referring to for example, Berge, et al.J.Pharm.Sci., 66:1-19 (1997).The example of the salt of acidic active component compound comprises for example an alkali metal salt, alkaline earth salt and ammonium salt.Therefore, Shi Yi salt has aluminium salt, calcium salt, lithium salts, magnesium salts, sylvite, sodium salt and zinc salt.In addition, also can use organic salt, comprise for example Methionin, N, the salt of N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-methylglucosamine), PROCAINE HCL, PHARMA GRADE and Tutofusin tris.
For oral, active compound can be added in the preparation that comprises pharmaceutically acceptable carrier, and described carrier is tackiness agent (for example gelatin, Mierocrystalline cellulose, tragakanta), vehicle (for example starch, lactose), lubricant (for example Magnesium Stearate, silicon-dioxide), disintegrating agent (for example alginate, former rubber (primogel) and W-Gum) and sweeting agent or seasonings (for example glucose, sucrose, asccharin, wintergreen oil and peppermint) for example.Seal or the preparation of compressed tablets form can be oral with gelatine capsule.Capsule and tablet can prepare with any ordinary method.Capsule and tablet also can be coated smell, taste, the CF of various dressings known in the art to improve this capsule and tablet.In addition, liquid carrier for example fatty oil also can be included in the capsule.
Suitable oral preparations also can be forms such as suspension, syrup, chewing gum, disk, elixir.As needs, also can comprise the conventional reagent of the smell that is used to change particular form, taste, CF in the preparation.In addition, can not swallow the patient and carry out conventional administration, active compound can be dissolved in a kind of acceptable lipotropy vegetable oil carrier for example in sweet oil, the Semen Maydis oil and Flos Carthami oil by nutrient canal of intestine in order to give.
Active compound also can solution or the form of suspension or the lyophilized form that can be converted into solution or suspension before use carry out administered parenterally.In this class preparation, can use thinner or pharmaceutically useful carrier for example sterilized water and normal saline buffer solution.Other conventional solvent, pH buffer reagent, stablizer, antiseptic-germicide, tensio-active agent and antioxidant all can be included in the said preparation.For example, the available composition comprises sodium-chlor, acetate, Citrate trianion or phosphate buffered saline buffer, glycerol, glucose, non-volatile oils, methyl p-hydroxybenzoate, polyoxyethylene glycol, propylene glycol, sodium pyrosulfate, phenylcarbinol, xitix etc.Parenteral administration can be stored in any conventional containers for example in bottle and the ampoule.
The path of topical comprises intranasal administration, buccal administration, mucosa delivery, rectal administration or vagina administration.For topical, active compound can be mixed with washing lotion, emulsifiable paste, ointment, gel, powder, paste, spraying, suspension, drops and aerosol.Therefore, can comprise one or more thickening materials, wetting Agent for Printing Inks and stablizer in the preparation.The example of this class reagent includes but not limited to polyoxyethylene glycol, sorbyl alcohol, xanthan gum, vaseline, beeswax or mineral oil, lanolin, squalene etc.A specific form of topical is by carrying through the skin patch.Preparation is disclosed in for example Brown through the method for skin patch, et al., and Annual Review of Medicine, among the 39:221-229 (1988), its content is included this paper by reference in.
The subcutaneous implantation that is used to make active compound continue to discharge also can be used as a kind of suitable administration path.Under stomach wall before for example a kind of active compound in any appropriate formulation being implanted in the subcutaneous space, need a surgical procedures.Referring to for example, Wilson et al., J.Clin.Psych.45:242-247 (1984).Hydrogel can be used as the carrier that continues release of active compounds.Hydrogel is well known in the art.Normally thing prepares by the biocompatible crosslinked polymer of high-molecular weight is reticulated for they, and this reticulation expands in water and form a kind of gellike material.Preferred hydrogel is biodegradable or biological absorbable.For purposes of the invention, the hydrogel of being made by polyoxyethylene glycol, collagen or poly-(oxyacetic acid-altogether-L-lactic acid) may be useful.Referring to for example, Phillips et al., J.Pharmaceut.Sci., 73:1718-1720 (1984).
Active compound also can be conjugated on a kind of high-molecular weight polymer of non-peptide class of water-soluble non-immunogenicity, to form a kind of conjugate of polymkeric substance.For example, a kind of active compound is covalently bound forms a kind of conjugate to polyoxyethylene glycol.Usually, this class conjugate demonstrates solvability, the stability of raising and toxicity and the immunogenicity that reduces.Therefore, when being administered to the patient, the active compound in this conjugate can have the longer transformation period in vivo and demonstrate better therapeutic.Generally can be referring to Burnham, Am.J.Hosp.Pharm., 15:210-218 (1994).Pegylation albumen is used in the usefulness of albumen replacement therapy neutralization as other treatment at present.For example, Peg-Intron (PEG-INTRON
Figure A20068002217100421
) be used for the treatment of hepatitis B clinically.The Pegylation adenosine deaminase (
Figure A20068002217100422
) be used for the treatment of serious combined immunodeficiency disease (SCIDS).The Pegylation leunase ( ) be used for the treatment of acute lymphoblastic leukemia (ALL).This hydrolyzable degraded under physiological condition of covalent linkage between preferred polymers and the active compound and polymkeric substance.Above-mentioned conjugate is called as " prodrug ", it can be at an easy rate release of active compounds in vivo.Thereby also can by activeconstituents is added in the microcapsule well known in the art, in the Nano capsule or reach the controllable release of active compound in the hydrogel.
Liposome also can be used as the carrier of active compound of the present invention.Liposome is by various lipids---for example cholesterol, phosphatide, lipid acid and the derivative thereof---micelle of formation.Also can use the lipid of various modifications.Liposome can reduce the toxicity of active compound and increase their stability.Preparation is generally well known in the art comprising the method for the liposome suspension of activeconstituents.Referring to for example, U.S. Patent No. 4,522,811; Prescptt, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976).
Active compound also can with another promoting agent Combined Preparation, as long as effect, this another promoting agent Synergistic treatment or another disease or the symptom of preventing same symptom or can effectively treat the patient who is treated of active compound of the present invention are not interfered or poorly influenced to this another promoting agent.Above-mentioned other promoting agent includes but not limited to anti-inflammatory agent, antiviral agent, microbiotic, anti-mycotic agent, antithrombotic, cardiovascular drug, pravastatin, anticarcinogen, hypertension agents etc.In this combinational therapeutic methods, these two kinds of different pharmaceutical active compounds can be distinguished administration or in same administered in pharmaceutical compositions.
The example that suitable and The compounds of this invention one is used from the antiviral compound in the combination therapy includes but not limited to hiv protease inhibitor, nucleoside HIV-1 reverse transcriptase inhibitors, non-nucleoside HIV-1 reverse transcriptase inhibitors, hiv integrase inhibitor, HIV fusion inhibitor, the ripe inhibitor of HIV, immunomodulator and vaccine.
The example of nucleoside HIV-1 reverse transcriptase inhibitors comprises 3 '-(Zidovodine (Zidovudine) is also referred to as AZT and RETROVIR to azido--3 ' deoxythymidine
Figure A20068002217100424
), 2 ', 3 '-two dehydrogenations-3 '-deoxythymidine (stavudine (Stavudine), be also referred to as 2 ', 3 '-two dehydrogenations-3 '-deoxythymidine, d4T and ZERIT
Figure A20068002217100431
), (2R-cis)-4-amino-1-[2-(methylol)-1,3-oxathiolane-5-yl] (lamivudine (Lamivudine) is also referred to as 3TC and EPIVIR to-2 (1H)-pyrimidones
Figure A20068002217100432
), 2 ', 3 '-dideoxyinosine (ddI), and 9-[(R)-and two [[isopropoxy carbonyl] oxygen base] methoxyl groups of 2-[[] phosphinyl] methoxyl group] propyl group] VITAMIN B4 fumarate (fumaric acid tynofovir ester (Tenofovirdisoproxil fumarate) is also referred to as VireadTM).
The example of non-nucleosides HI V reverse transcriptase inhibitors comprises (-)-6-chloro-4-cyclopropyl acethlene base-4-Trifluoromethyl-1,4-dihydro-2H-3, and (Yi Feiweilun (efavirenz) is also referred to as DMP-266 or SUSTIVA to 1-benzoxazine-2-ketone ) (referring to U.S. Patent No. 5; 519; 021) amino, 1-[3-[(1-methylethyl)]-the 2-pyridyl]-the 4-[[5-[(methyl sulphonyl) amino]-1H-indoles-2-yl] carbonyl] piperazine (Delavirdine (Delavirdine); referring to application number is the pct international patent application of WO 91/09849); (1S, 4R)-cis-4-[2-amino-6-(cyclopropyl amino)-9H-purine-9-yl]-2-cyclopentenes-1-methyl alcohol (A Bokawei (Abacavir)).
The example of proteinase inhibitor comprises [5S-(5R *, 8R *, 10R *, 11R *)]-10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxy-8,11-two (phenyl methyl)-2,4,7,12-four azepines tridecane-13-acid 5-thiazolyl methyl esters (ritonavir (Ritonavir), by Abbott with NORVIR
Figure A20068002217100434
Be that trade mark sells), [3S-[2 (2S *, 3S *); 3a, 4ab, 8ab]]-N-(1; the 1-dimethyl ethyl) amino decahydro-2-[2-hydroxyl-3-[(3-hydroxy-2-methyl benzoyl)]-4-(thiophenyl) butyl]-3-1-isoquinolinecarboxylic acid oxamide list mesylate (viracept see nelfinaivr (Nelfinavir), by Agouron with VIRACEPT
Figure A20068002217100435
Be that trade mark sells), (2 (R)-hydroxyls-1 (S)-indanyl-2 (R)-phenyl methyl-4-(S)-hydroxyl-5-(1-(4-(2-benzo [b] furyl methyl)-2 (S)-N ' (tert-butylformamide base)-piperazinyl)) valeramide is (referring to U.S. Patent No. 5 for N-, 646,148), N-(2 (R)-hydroxyl-1 (S)-indanyl) 2 (R)-phenyl methyl-4-(S)-hydroxyl-5-(1-(4-(3-pyridylmethyl)-2 (S)-N '-(tert-butylformamide base)-piperazinyl))-valeramide (that Wei of indoles (Indinavir), by Merck with CRIXIVAN
Figure A20068002217100436
Be that trade mark sells), 4-amino-N-((2syn, 3S)-2-hydroxy-4-phenyl-3-((S)-tetrahydrofuran (THF)-3-base oxygen base carbonylamino)-butyl)-N-isobutyl--benzsulfamide (amprenavir (amprenavir), referring to U.S. Patent No. 5,585,397), with the N-tertiary butyl-decahydro-2-[2 (R)-hydroxy-4-phenyl-3 (S)-[[N-(2-quinolyl carbonyl]-left-handed asparaginyl group] amino] butyl] (4aS, 8aS)-isoquinoline 99.9-3 (S)-methane amide (Saquinavir (Saquinavir), by RocheLaboratories with INVIRASE
Figure A20068002217100441
For trade mark is sold).
The example of suitable hiv integrase inhibitor is in United States Patent (USP) 6,110,716; Open in 6,124,327 and 6,245,806, its content is included this paper by reference in.
Multiple other Anti-virus agent also can be used for combination therapy with The compounds of this invention, other Anti-virus agent include but not limited to 9-(2-'-hydroxyethoxy ylmethyl) guanine (acyclovir (acyclovir)), 2-amino-9-(2-'-hydroxyethoxy ylmethyl) purine, Suramine (suramin), ribavirin, antimony tungstate (antimoniotungstate) (HPA-23), Interferon, rabbit, interleukin-II and phosphonium mesitoyl formic acid ester (phosphorus formic acid (Foscarnet)).In addition, also can use other medicament for example can stimulate the LEVAMISOLE HCL or the thymosin of lymphocyte growth and/or performance function.
The example of HIV fusion inhibitor comprise antagonism HIV envelope protein (gp120 for example, gp41) and be derived from the antibody of the peptide of HIV envelope protein.For example, the III clinical trial phase has shown that (Trimeris limited-liability company, Durham NC) infect effectively treatment HIV the peptide that is derived from gp41 that is called as T-20.
Any suitable pharmaceutically useful derivative of above-claimed cpd, comprise that its pharmaceutically useful salt and ester also can use.
Embodiment
The synthetic of the compound of formula I-IV can be finished according to following general synthetic route.See Table representational structure and the relevant characterization data of 1-3.
Figure A20068002217100442
Figure A20068002217100451
Such scheme has been summed up the route of synthesis of the compound among the table 1-3, and reagent/condition wherein is: i.Ac 2O, DMAP, Py, Δ.Ii. oxalyl chloride (2M), CH 2Cl 2iii.NHR 1R 2、TEA、CH 2Cl 2。iv.NaOH(4M)、THF/MeOH。V.2,2-dimethyl succinyl oxide, DMAP, Py, Δ.vi.PtO 2、H 2(15psi)、AcOH。
Generally speaking, The compounds of this invention is synthetic according to the following step:
(i) a kind of protecting group of interpolation (is the C of betulinic acid to the select location of starting raw material 3The position);
(ii) forming an acyl chlorides on arbitrary desired location of synthetic compound in (i) step (is C 28The position);
(iii) make (ii) the acyl chlorides that forms in the step and the suitable required part (NH in the such scheme for example 2-R yl) reacts;
(iv) remove the protecting group of adding in (i) step; And randomly
(the dimethyl butyrate diacyl (is promptly added to C in the deprotection position of v) adding the compound that any part forms in (iv) step 3The position is shown in above-mentioned scheme).
Randomly reduce unsaturated link(age) to form compound of the present invention.Compound of the present invention also can follow these steps to synthesize:
(i) select location of activation starting raw material (is the C of betulinic acid 28The position);
(ii) make the compound that forms in (i) step and the suitable required part (NH in the such scheme for example 2-R yl) reacts; And
(iii) add other desired location of the material that any part forms in (ii) step and (promptly add the dimethyl butyrate diacyl to C 3The position is shown in above-mentioned scheme);
Protecting group refers to the part that the protection chemical group to avoid undesirable reaction.For example, protecting group comprises the known group of those skilled in the art, as ProtectiveGroups in Organic Synthesis, Greene, T., John Wiley ﹠amp; Sons, NewYork, those blocking groups described in the N.Y. (first version, 1981), protecting group wherein can or be removed with the interpolation of step described in this article.The example of protected hydroxyl includes but not limited to, silyl ether, for example by a hydroxyl and a kind of reagent---such as but not limited to TERT-BUTYL DIMETHYL CHLORO SILANE, trimethylchlorosilane, tri isopropyl chlorosilane, chlorotriethyl silane---those silyl ethers that reaction obtained; The methyl and the ethyl ether that replace are such as but not limited to methoxymethyl ether, methylthiomethyl ether, benzyloxy methyl ether, tert.-butoxy methyl ether, 2-methoxy ethoxy methyl ether, THP trtrahydropyranyl ether, 1-ethoxyethyl group ether, allyl ether, dibenzyl ether; The ester class is such as but not limited to formic acid benzoyl ester, manthanoate, acetic ester, trichloroacetic esters and trifluoro-acetate.The example of protected amido includes but not limited to, amides, for example methane amide, ethanamide, trifluoroacetamide and benzamide; Imide class, for example phthalimide and dithio succimide; And other.The example of protected sulfydryl includes but not limited to, thioether, for example S-phenmethyl thioether and S-4-picolyl thioether; The S-methyl-derivatives that replaces, for example hemimercaptol, dithio acetal and amino sulfo-acetal; And other.The example of the protecting group of protein synthesis includes but not limited to BOC, FMOC and CBZ (promptly being respectively: tertbutyloxycarbonyl, 9-fluorenyl methoxy carbonyl and benzyloxycarbonyl).
Group can add in building-up process or removes with means known in the art.For example, can be by adding a kind of activatory acid (for example diacetyl oxide) and a kind of organic bases (for example triethylamine or pyridine) thereby and heating gained mixture interpolation protecting group.The position of compound can be by activating with a kind of activator reaction known in the art, and described activator is dicyclohexylcarbodiimide, EDCI, HATU or PyBOP for example.Acyl chlorides can form by making carboxylic acid and a kind of chlorination reaction, and described chlorizating agent is thionyl chloride, oxalyl chloride, phosphoryl chloride and cyanuryl chloride for example.Acyl chlorides can for example primary amine and secondary amine reaction form for example amide group of required group with suitable part.
Protecting group can be removed by method known to those skilled in the art.For example, remove an acetic ester protecting group can by make this material and a kind of alkali for example aqueous sodium hydroxide solution contact and realize.Can add other parts in the desired location of this material,, thereby add a dimethyl butyrate diacyl to the C3 position in the presence of a kind of alkali (for example pyridine) for example by this material and dimethyl succinic acid acid anhydride are reacted.
The compound of formula II and III also can be according to above-mentioned general synthetic route by replacing betulinic acid to synthesize with suitable starting raw material.For example, the compound of formula II can be according to above-mentioned general synthetic route by replacing betulinic acid to synthesize with oleanolic acid; And the compound of formula III can replace betulinic acid to synthesize with ursonic acid.
The general procedure of HPLC purifying: with sample dissolution DMSO (～50mg/ml) in, then in Phenomenex Synergi Hydro-RP (00G-4376-P0) HPLC post (250 * 21.2mm, 10 μ sphere diameters, 80
Figure A20068002217100461
The aperture) go up purifying, solvent system is the aqueous solution (0.01% trifluoroacetic acid) of the acetonitrile of 50-90%, operation isocratic elution the most nearly 25 minutes.Carrying out flow point according to the extinction situation at 203 λ places collects.
(3 β)-3-(acetoxyl group) feather fan-20 (29)-alkene-28-acid (1)
Under nitrogen environment, use Ac 2O (0.26ml, 2.8mmol) and DMAP (0.14g, (0.50g, anhydrous pyridine solution (10ml) 1.1mmol) is then with this mixture backflow 1h 1.1mmol) to handle betulinic acid.Reaction mixture CHCl 3Dilution also washes with water.Use MgSO 4Dry organic layer and under reduced pressure concentrated 1 (0.42g, 76%) that obtains.
1H?NMR(DMSO-d 6，400MHz)δ0.79(s，6H，CH 3)，0.80(s，3H，CH 3)，0.87(s，3H，CH 3)，0.94(s，3H，CH 3)，1.25-1.62(m，18H，CH 2)，1.65(s，3H，CH 3)，1.75-1.85(m，2H，CH 2)，1.99(s，3H，CH 3CO)，2.08-2.14(m，1H)，2.18-2.27(m，1H)，2.90-3.00(m，1H)，4.36(dd，1H，J＝11.24Hz，J＝4.8Hz，H-3)，4.56(m，1H，CH＝)，4.69(d，1H，J＝2.15Hz，CH＝)，12.10(bs，1H，CO 2H)。
Preparation chloride of acid 3 (3 β)-3-(acetoxyl group) feather fan-20 (29)-alkene-28-acid (2)
(2M is dissolved in CH with oxalyl chloride solution 2Cl 2In, 4ml) add to 3-0-ethanoyl-betulinic acid (0.1g, 0.2mmol) in and stir 2h.Under reduced pressure be concentrated into this mixture dried.The anhydrous CH of residue 2Cl 2(3 * 1ml) dilutions under reduced pressure are concentrated into driedly, use then, need not to be further purified.
The general method of synthetic compound (3-34)
Under nitrogen environment, to the anhydrous CH of chloride of acid 2 (0.2mmol) 2Cl 2(5ml) add in the solution suitable amine (0.26mmol) and TEA (0.44mmol, 0.061ml).This reaction mixture at room temperature stirs and spends the night, and uses CH 2Cl 2H is used in dilution then 2O washes CH 2Cl 2Layer.Use MgSO 4Dry organic layer and under reduced pressure concentrate amide compound.In some cases, product is enough pure, can directly in next step, use, and some products HPLC purifying.
Table 1
Figure A20068002217100481
Figure A20068002217100491
Figure A20068002217100511
Figure A20068002217100531
Figure A20068002217100541
Figure A20068002217100561
Annotate: arom: aromatic series,
And: and.
The general method of synthetic compound (35-68)
With NaOH (4M, 0.27ml) THF (1.6ml) of processing suitable amide (0.21mmol) and methyl alcohol (1ml) solution.This mixture at room temperature stirs and spends the night, and vapourisation under reduced pressure falls solvent then.Resistates CH 2Cl 2Dilution is also washed with HCl solution (0.5N).Use MgSO 4Dry organic layer and under reduced pressure concentrate amide compound 35-68.
Table 2
Figure A20068002217100562
Figure A20068002217100571
Figure A20068002217100581
Figure A20068002217100591
Figure A20068002217100611
Figure A20068002217100621
Figure A20068002217100651
Annotate: arom: aromatic series,
And: and.
The general method of synthetic compound (69-121)
Under nitrogen environment, with 2,2-dimethyl succinic acid acid anhydride (0.109g, 0.85mmol) and DMAP (0.021g 0.17mmol) handles anhydrous pyridine (4ml) solution of suitable amide 35-68 (0.17mmol) and this mixture refluxed spend the night.Use CH 2Cl 2Diluted reaction mixture is also used H 2The O washing.Use MgSO 4Dry organic layer and under reduced pressure concentrate carboxylic acid product.Described crude product HPLC purifying.
Table 3
Figure A20068002217100661
Figure A20068002217100671
Figure A20068002217100681
Figure A20068002217100701
Figure A20068002217100711
Figure A20068002217100721
Figure A20068002217100731
Figure A20068002217100741
Figure A20068002217100751
Figure A20068002217100761
Figure A20068002217100771
Annotate: arom: aromatic series,
Amide: acid amides,
And: and.
The general method of synthetic compound (122)
Figure A20068002217100781
(0.112g 0.15mmol) is suspended in the Glacial acetic acid (10ml) and feeds nitrogen with compound 73.Add platinum (IV) oxide compound (0.012g) of catalytic amount.Reactant is placed under 15psi hydrogen and is spent the night.Mixture is filtered and the vapourisation under reduced pressure solvent by a diatomite liner.With HPLC purifying gained crude product compound 122.
Compound 123 and 124 synthetic similar with compound 122.
Table 4
Figure A20068002217100782
Figure A20068002217100783
Annotate: arom: aromatic series.
The general method of synthetic compound (125)
Substitute starting raw material betulinic acid, the synthetic synthetic schemes that is similar to compound among the above-mentioned table 1-3 of compound 125 with ursonic acid.
Figure A20068002217100791
Embodiment 2: the mensuration of antiviral activity
Can in following detection, test compound of the present invention with determination of antiviral activity and general toxicity.
The detection of MT-4 cytoprotection
The T clone that HTLV-1 transforms, promptly MT-4 is very easily hiv-1-infected.Having assessed the anti-HIV-1 agent in this target cell system protects cell to avoid the ability of the cytopathic effect of HIV initiation.In this detection, in colorimetric estimation, the viability of HIV-1 cell and simulated infection cell to be assessed, the colorimetric estimation monitoring has the cell of metabolic activity to reduce the ability of tetrazolium salts WST-1.The WST-1 splitted positive findings that increases has shown the cytoprotection of antiviral compound.
In brief, the laboratory strains NL4-3 with HIV-1 carries out simulated infection or infection in batches with 0.0005 infection multiplicity to the MT-4 cell that is exponential growth.After carrying out two hours infection, wash this cell removing unconjugated virus, and insert flat board with compound that concentration increases progressively.After cultivation in four days, with the toxicity of compound in the cell of cytoprotection in the WST-1 check and analysis infected cells and simulated infection.
The PBMC drug susceptibility detects
With the antiviral activity of human peripheral blood mononuclear cells (PBMC) detection compound, as the index of clinical effectiveness.With the Ficoll-Hypaque density gradient PBMC is separated from two donors, merge, and stimulated three days with PHA-L.After the stimulation, wash this cell and remain in the substratum that contains IL-2.Use HIV-1 then IIIBVirus strain is carried out simulated infection with 0.01 infection multiplicity with post-stimulatory cell or was infected one hour in batches.Then cell (not washing) access is existed the flat board of the compound that concentration increases progressively, and cultivated seven days.Virus replication result in these substratum is the concentration of HIV-1p24 in the supernatant liquor, because PBMC is not subjected to the influence of the cytopathic effect that HIV brings out usually.The toxicity of compound detects with WST-1 and analyzes in the cell of simulated infection.
Detect discovery according to these, compound of the present invention has antiviral activity.Compound 71 has the EC50 (with the compound concentration (MT-4) (antiviral activity detection) of viral-induced cytopathic effect reduction by 50%) and the about 7.7 micromolar TC50 (TC50 is the compound concentration (toxicity measurement) that can cause the mortality ratio of host cell 50%) of about 126 nmoles.Compound 73 has the EC50 and the about 6.3 micromolar TC50 of about 8.1 nmoles.Compound 70 has the EC50 of about 2.9 nmoles and greater than 10 micromolar TC50.Compound 76 has the EC50 of about 11 nmoles and greater than 10 micromolar TC50.Compound 46 has about 8.6 micromolar EC50 and greater than 10 micromolar TC50.Representational compound of the present invention comprises that those EC50 are less than the compound of about 100 nmoles, for example compound 69,70,73-84,87,88,91-95,97,99-106,108-117,119-124.
All publications that this specification sheets is mentioned and applications for patents are understood those skilled in the art in the invention's level.This paper is all included in all publications and patent application by reference in, this equates particularly or point out seriatim that publication or patent application that each is independent include this paper by reference in.Mention publication and patent application merely and might not represent that they are prior aries of the application.
Though understand the present invention in order to know, some details that foregoing invention has been passed through elaboration and case description, clearly, the enforcement of some changes and improvements also belongs in the scope of the additional claim of the present invention.

Claims (23)

1. compound with following structure:
Figure A20068002217100021
And pharmaceutically useful salt and steric isomer,
Wherein,
Q is (CH 2) 1-2
L is an alkyl that 0-10 carbon atom arranged, and this alkyl can be saturated or fractional saturation; And
One or more carbon atoms of described alkyl L can with-O-,-S-,-N-,-C (=O)-,-NC (=O)-,-C (=O) N-,-SO 2,-NSO 2,-SO 2N-, cycloalkyl reach-NC (=O) N-replacement; And
L can be selected from following substituting group and replaces with one or more: hydroxyl, halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) OH ,-C (=O) O (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
R1 is-C (=O)-(CH 2) m-C (CH 3) 2-COOH;
R2 be selected from one or more be selected from hydrogen, hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2Optional cycloalkyl, aryl, heterocycle and the heteroaryl that replaces of substituting group;
R3 and R4 be independently selected from-H ,-CH 3,-(CH 3) 2,-CH (CH 3) 2With-C (=CH 2) CH 3And
M is an integer that is selected from 0-10.
2. the compound of claim 1, described compound has following structure:
Figure A20068002217100031
And pharmaceutically useful salt and steric isomer,
Wherein,
L is an alkyl that 0-10 carbon atom arranged, and this alkyl can be saturated or fractional saturation; And
One or more carbon atoms of described alkyl L can with-O-,-S-,-N-,-C (=O)-,-NC (=O)-,-C (=O) N-,-SO 2,-NSO 2,-SO 2N-, cycloalkyl reach-NC (=O) N-replacement; And
L can be selected from following substituting group and replaces with one or more: hydroxyl, halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) OH ,-C (=O) O (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
R1 is-C (=O)-(CH 2) m-C (CH 3) 2-COOH;
R2 be selected from available one or more be selected from hydrogen, hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2Optional cycloalkyl, aryl, heterocycle and the heteroaryl that replaces of substituting group; And
M is an integer that is selected from 0-10.
3. the compound of claim 1, wherein L is an alkyl that 0,1,2,3,4 or 5 carbon atom is arranged, described alkyl can be saturated or fractional saturation; And
One or more carbon atoms of described alkyl L can with-O-,-S-,-N-,-C (=O)-,-NC (=O)-,-C (=O) N-,-SO 2,-NSO 2,-SO 2N-, cycloalkyl reach-NC (=O) N-replacement; And
L can be selected from following substituting group and replaces with one or more: hydroxyl, halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) OH ,-C (=O) O (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2
4. the compound of claim 1, described compound has following structure:
And pharmaceutically useful salt and steric isomer,
Wherein,
R1 is-C (=O)-CH 2-C (CH 3) 2-COOH;
R2 be selected from usefulness-individual or a plurality of be selected from hydrogen, hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2Optional cycloalkyl, aryl, heterocycle and the hetero-aromatic ring that replaces of substituting group; And
N is one and is selected from 0,1,2 and 3 integer.
5. the compound of claim 4, wherein R2 be with one or more be selected from hydroxyl, halogen, alkyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, C-carboxyl, O-formamyl, O-thiocarbamoyl, N-formamyl, N-thiocarbamoyl, ester, haloalkyl, halogenated alkoxy, cycloalkyl, aryl, heteroaryl, heterocycle ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-CHF 2,-OCF 3,-OCHF 2,-SCF 3,-CF 3,-CN ,-NH 2And-NO 2The optional phenyl that replaces of substituting group; And
N is one and is selected from 0,1,2 and 3 integer.
6. the compound of claim 5, wherein n is 0 or 1.
7. the compound of claim 5, wherein n is 2 or 3.
8. the compound of claim 5, wherein R2 be with one or more be selected from halogen, alkyl, C-carboxyl, haloalkyl ,-C (=O) OH ,-CH (CH 3) C (=O) OH;-CH 2C (=O) OH ,-C (CH 3) 2C (=O) OH ,-C (CH 3) (CH 2CH 3) C (=O) OH ,-CH (CH 2CH 3) C (=O) OH ,-CH=C (CH 3) C (=O) OH ,-C (CH 2CH 3) 2C (=O) OH ,-C (=O) NH 2,-C (=O) NH (C 1-3Alkyl) ,-C (=O) N (C 1-3Alkyl) 2,-CHF 2,-CF 3A phenyl that replaces with the substituting group of-CN.
9. the compound of claim 5, wherein R2 be with one or more be selected from hydroxyl, alkoxyl group, alkylthio, arylthio, thiocarbonyl, O-carboxyl, O-formamyl, O-thiocarbamoyl, ester, halogenated alkoxy ,-S (=O) 2(C 1-3Alkyl) ,-S (=O) 2NH 2,-S (=O) 2N (C 1-3Alkyl) 2,-S (=O) 2NH (C 1-3Alkyl) ,-OCF 3,-OCHF 2With-SCF 3A phenyl replacing of substituting group.
10. the compound of claim 5, wherein R2 be with the one or more N-of being selected from formamyls, N-thiocarbamoyl ,-N (C 1-3Alkyl) 2,-NH (C 1-3Alkyl) ,-NH 2With-NO 2A phenyl replacing of substituting group.
11. the compound of claim 5, wherein R2 is a phenyl that is selected from cycloalkyl, aryl, heteroaryl and the replacement of heterocyclic substituting group with one or more.
12. the compound of claim 5, described compound has following structure
Figure A20068002217100061
13. the compound of claim 5, described compound has following structure
Figure A20068002217100062
14. the compound of claim 5, described compound has following structure
Figure A20068002217100063
15. the compound of claim 5, described compound has following structure
16. the compound of claim 5, described compound has following structure
Figure A20068002217100072
17. the compound of claim 5, described compound has one of following array structure:
Figure A20068002217100073
18. the compound of claim 5, described compound has one of following array structure:
Figure A20068002217100074
19. the compound of claim 1, described compound has following stereochemical structure:
Figure A20068002217100081
20. a pharmaceutical composition contains among the claim 1-19 each a kind of compound and one or more pharmaceutically useful vehicle.
21. each a kind of compound is used to produce a kind of purposes that can be used for treating the medicament of disease and obstacle among the claim 1-19.
22. the described purposes of claim 21, wherein said disease or obstacle are virus infectiones.
23. the method for each a kind of compound among the production claim 1-19 comprises:
(i) add the select location of a kind of protecting group to starting raw material;
(ii) the desired location of the compound that forms in (i) step forms an acyl chlorides;
The acyl chlorides of formation in (ii) going on foot and suitable required part are reacted;
(iv) remove the protecting group of adding in (i) step; And randomly
(v) add the deprotection position of the compound that a part forms in (iv) step.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102656180A (en) * 2009-07-14 2012-09-05 海特洛研究基金会 Lupeol-type triterpene derivatives as antivirals
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole derivatives as HIV inhibitors
US10370405B2 (en) 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102656180A (en) * 2009-07-14 2012-09-05 海特洛研究基金会 Lupeol-type triterpene derivatives as antivirals
US9067966B2 (en) 2009-07-14 2015-06-30 Hetero Research Foundation, Hetero Drugs Ltd. Lupeol-type triterpene derivatives as antivirals
CN102656180B (en) * 2009-07-14 2016-04-20 海特洛研究基金会 As the feather fan alcohol type triterpene derivative of antiviral drug
US9637516B2 (en) 2012-12-31 2017-05-02 Hetero Research Foundation Betulinic acid proline derivatives as HIV inhibitors
US9868758B2 (en) 2014-06-30 2018-01-16 Hetero Labs Limited Betulinic proline imidazole derivatives as HIV inhibitors
US10533035B2 (en) 2015-02-09 2020-01-14 Hetero Labs Ltd. C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US11034718B2 (en) 2015-02-09 2021-06-15 Hetero Labs Limited C-3 novel triterpenone with C-17 reverse amide derivatives as HIV inhibitors
US10370405B2 (en) 2015-03-16 2019-08-06 Hetero Labs Limited C-3 novel triterpenone with C-28 amide derivatives as HIV inhibitors

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