CN1871251A - Novel triterpene derivatives, preparation thereof and use thereof - Google Patents
Novel triterpene derivatives, preparation thereof and use thereof Download PDFInfo
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- CN1871251A CN1871251A CN 200480030801 CN200480030801A CN1871251A CN 1871251 A CN1871251 A CN 1871251A CN 200480030801 CN200480030801 CN 200480030801 CN 200480030801 A CN200480030801 A CN 200480030801A CN 1871251 A CN1871251 A CN 1871251A
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Abstract
The present invention relates to novel synthetic derivatives of triterpenes and the use of such derivatives as pharmaceuticals. In some embodiments, the present invention is directed to the use of derivatives of triterpenes of the present invention for inhibiting retroviral infections.
Description
Background of invention
Invention field
The present invention relates to the new synthesis of derivatives and of the application of this analog derivative of triterpenes as medicine.Association area
Retrovirus is little strand justice RNA viruses.Retroviral particle comprises two identical strand justice RNA molecules.Its genome contains the sequence of RNA-dependent dna-polymerases, is also referred to as reversed transcriptive enzyme etc.Many molecules of discovery reversed transcriptive enzyme are very relevant with the geneome RNA in the ripe virion.When entering cell, this reversed transcriptive enzyme produces virus genomic double-stranded DNA copy, and this copy is inserted into the chromatin of host cell then.In case insert, virus sequence is called provirus.Retrovirus is integrated and is directly depended on virus protein.Linear viral dna end (LTRs) is for integrating the early stage precursor of proviral DNA.On integration site, exist the feature of one section short sequence of host DNA to repeat.
By the host cell RNA polymerase from the provirus sequence transcripton that inserts for viral genome and mRNAs to transcribing the reaction of conditioning signal provirus sequence end region, long terminal repeat or the LTRs.The protein of host cell produces machine and is used to produce virus protein, and many in them be inactivation, till being processed by the proteolytic enzyme of encoding viral.In general, progeny virion is sprouted from cell surface in non-cracked mode.Retroviral infection not necessarily disturbs the normal life cycle of cells infected or organism.Yet with regard to host organisms, it is not to be benign all the time.Take place although the dna virus of most of type all may relate to tumour, retrovirus is the retrovirus family of carcinogenic RNA viruses.Miscellaneous retroviruses is such as several very rare disease of immune system that also can produce as the human immunodeficiency virus (HIV) who causes the pathogenic agent of people's acquired immune deficiency syndrome (AIDS) (AIDS) in the superior being.
Human immunodeficiency virus (HIV) belongs to lentivirus, i.e. member in the retrovirus subfamily.HIV infects and the intrusion immune system cell; It destroys the immunity system of health and makes opportunistic infection of patient's susceptible and tumour.The appearance of immune deficiency is progressively and irreversibly, wherein has the high mortality near 100% in several years.
HIV-1 to immune system cell T4 lymphocyte be nutrition with cytopathogenic, described immune system cell express cell surface is also referred to as differentiation antigen CD4, T4 and the leu3 of OKT4.Due to the interaction between due to illness malicious envelope glycoprotein gp120 of viral tropism and the cell surface CD4 molecule (Dalgleish etc., " nature " are 312:763-767 (1984) (Nature)).These interact and not only mediate HIV infection permissive cell, and produce the syzygy that infects and do not infect the virus induction of T cell.This cytogamy body causes interior huge multinucleated syncytia formation, necrocytosis and the cd4 cell of HIV-infected patient body progressively to exhaust.These results produce the immunosuppression of HIV-inductive and sequela subsequently, opportunistic infection and tumour.
Remove the CD4+T extracellular, the host range of HIV comprises mononuclear phagocyte system cell (Dalgleish etc., document is the same), comprises the dendritic reticulum cell in blood monocyte, tissue macrophages, skin Langerhans cell and the lymphoglandula.HIV also is neurophilic, and it can infect monocyte and scavenger cell in the central nervous system, causes serious nervous lesion.Monocytes/macrophages is the main reservoir of HIV.They can interact and with the T cytogamy that contains CD4, cause the T cell depleting and produce the pathogenesis of AIDS thus.
In the process, the medicine that is used for the HIV-1 therapy in research and development has been obtained significant progress in the past few years.The therapeutical agent that is used for HIV comprises, but be not limited at least a among AZT, 3TC, ddC, d4T, ddI, tynofovir, Abacavir, nevirapine, Delavirdine, emtricitabine, efavirenz, Saquinavir, ritonavir, Indinavir, nelfinavir, rltonavir, amprenavir, fosamprenavir and the atazanavir or each other combination of other antiretroviral agent or antibody or relevant arbitrarily, such as gp41-deutero-peptide class enfuvirtide (Fuzeon with therapeutical agent based on biology; Timeris-Roche) and T-1249 (Trimeris) or solubility CD4, to the conjugate of the antibody of CD4 and CD4 or anti--CD4 or additionally provide as this paper.The combination of these medicines especially effectively and the level of viral RNA can be reduced in blood plasma the generation of can not detected level and slowing down virus resistance makes patient's health and life-span improve.
Although exist these progressive, still have problems in the present obtainable pharmaceutical admixtures.Manyly in these medicines show serious toxicity, have the dosage regimen that other side effect (for example fat is redistributed) maybe needs to reduce compliance and limits the complexity of effect thus.The HIV resistant strain occurs in time limit time expand usually, or even when conjoint therapy.These medicines expensive also is the restriction to their widespread use, especially uses beyond developed country.
Still there is remarkable demand to the research and development that prevent the other medicines that these situations take place.Ideal situation is, the different steps of these medicines in can target virus life cycle, thus be conjoint therapy interpolation medical drugs, and show minimum toxicity, and have lower production cost.
Before this, betulinic acid and platanic acid have been separated as the anti-HIV composition from Syzigium claviflorum.Betulinic acid and platanic acid show the inhibition activity that HIV-1 in the H9 lymphocyte is duplicated, the EC that has
50Value is respectively 1.4 μ M and 6.5 μ M and T.I. value and is respectively 9.3 and 14.The hydrogenation betulinic acid produces dihydrobetulinic acid, and it shows appropriate more efficiently anti-HIV activity, the EC that has
50Value be 0.9 and the T.I. value be 14 (" natural product magazine " be 57:243-247 (1994) (J.Nat.Prod.) for Fujioka, T. etc.).
Acyl group with some replacements; such as 3 ', 3 '-dimethyl-penten diacyl and 3 ', 3 '-dimethyl succinyl esterification betulinic acid produces the derivative (Kashiwada with enhanced activity; Y. etc., " pharmaceutical chemistry magazine " (J.Med.Chem.) 39:1016-1017 (1996)).United States Patent (USP) 5,679 has also been described the betulinic acid and the dihydrobetulinic acid derivative of the acidylate that belongs to effective anti-HIV agent in 828.
R=H (betulinic acid)
United States Patent (USP) 5,468 has disclosed the 28-acylamino derivative of feather fan alkanes in 888, and it is described as having cytoprotection to the HIV-cells infected.
Disclosed the birch camphor and 3 that is used for anticancer field among the Japanese patent application JP 01 143,832,28-diester class.
(birch camphor)
United States Patent (USP) 6,172 has disclosed the discovery birch camphor in 110 and dihydro birch camphor derivative has effective anti-HIV activity.
(birch camphor and dihydro birch camphor derivative)
3 carbon generations with the succinic acid esterification birch camphor can suppress the active compound of HIV-1 (Pokrovskii, A.G. etc., Gos.Nauchnyi Tsentr Virusol.Biotekhnol. " Vector " 9:485-491 (2001)).
Disclosed the application in treatment fungi infestation of birch camphor and analogue thereof in the International Application No. WO of announcing 02/26761.United States Patent (USP) 6,369 has disclosed the application of allobetulin (allobetulin) derivative in the treatment herpesvirus infection in 101.United States Patent (USP) 3,903 has disclosed the application of ursolic acid derivative as anti-inflammatory compound in 089.
Have the demand that continues to having the active compound of effective antiretroviral activity, especially anti-HIV, they have the bio distribution characteristic and the different modes of action of improvement.Press for this compounds so that replenish in the existing anti-HIV therapy.Also exist the part is coated on the safety that vagina or other inner membrance infect with the HIV that prevents between the individuality and the demand of active compound.
Summary of the invention
First aspect of the present invention relates to the new compound of formula I:
Or its pharmaceutically acceptable salt or ester;
Wherein A be as shown in the formula fused rings:
Wherein in formula A among the ring carbon of called after x and y and the formula I ring carbon of called after x and y identical;
R
1Be the carboxyl alkyloyl, wherein the alkyloyl chain can be alternatively by one or more hydroxyls or halogen replaces or can be interrupted by nitrogen, sulphur or Sauerstoffatom or its combination;
R
2And R
3Independent be hydrogen, methyl, halogen, hydroxyl, carboxyl or-COOR
17
R
4Be hydrogen, methyl, halogen or hydroxyl;
R
5Be the carboxyl carbalkoxy, carbalkoxy, alkanoyloxymethyl, the carboxyl alkanoyloxymethyl, alkoxy methyl, the carboxyl alkoxy methyl, aminocarboxyl, alkyl amino-carbonyl, the dialkylamino carbonyl, the alkoxyl group alkyl amino-carbonyl, alkoxyl group alkoxyl group alkyl amino-carbonyl, alkoxycarbonyl amido alkoxyl group alkyl amino-carbonyl, the alkoxycarbonyl amido alkyl amino-carbonyl, the alkyl-carbonyl-amino alkyl amino-carbonyl, amino alkyl amino-carbonyl, the aminoalkoxy alkyl amino-carbonyl, one alkylamino alkyl amino-carbonyl, the dialkylamino alkyl amino-carbonyl, the heterocyclic radical carbonyl, the heterocyclic radical alkyl amino-carbonyl, the naphthene amino carbonyl, aromatic yl aminocarbonyl, the aryl alkane amino carbonyl, aryl-amino-carbonyl alkyl amino-carbonyl or heteroaryl amino carbonyl, any one in them are all replaced by one or more hydroxyls or halogen alternatively; Or R
5Be carboxyl or methylol; Or work as R
2Or R
3During for carboxyl, R
5Can be methyl;
R
6Be hydrogen, methyl, hydroxyl or halogen;
R
7And R
8Independent is hydrogen or C
1-6Alkyl;
R
9Be CH
2Or CH
3
R
10Be hydrogen, hydroxyl or methyl;
R
11Be methyl, methoxycarbonyl, carboxyl carbalkoxy, alkanoyloxymethyl, alkoxy methyl or carboxyl alkoxy methyl, any one in them all replaced by one or more hydroxyls or halogen alternatively;
R
12Be hydrogen or methyl;
R
13Be hydrogen or methyl;
R
14Be hydrogen or hydroxyl;
If C12 and C13 form singly-bound, R so
15Be hydrogen; If or C12 and C13 form two key, R so
15Do not exist;
R
16Be hydrogen or hydroxyl;
R
17Be alkyl or carboxyalkyl, wherein alkyl chain can be alternatively by one or more hydroxyls or halogen replaces or can be interrupted by nitrogen, sulphur or Sauerstoffatom or its combination; And
Wherein straight dotted line is represented optional pair of key between C12 and C13 or C20 and the C29;
Condition be when A for as the lower section time:
R
1Can not be glutaryl-or succinyl, have two keys this moment between C12 and the C13;
When A for (ii) and R
11During for methyl, R
1Can not be succinyl;
When A for (iii) and R
2, R
3And R
13When respectively doing for oneself hydrogen, R
1Can not be succinyl; And
Condition be A (i) can not for:
This moment R
2And R
3Be and have two keys between methyl and C12 and the C13.
In certain embodiments, R
1Be selected from the group that following groups is formed:
Second aspect of the present invention relates to pharmaceutical composition, and it comprises compound and pharmaceutically acceptable carrier or the thinner of one or more formulas I.One or more extra pharmaceutical active compounds also can be included in these compositions.
The compound of formula I is as antiretroviral agent.Therefore, the invention provides the method that suppresses retroviral infection in zooblast or the tissue, comprise the compound of the formula I that gives effectively to suppress the retrovirus consumption.Some embodiment relates to the method for the treatment of the patient who suffers from the disease relevant with retrovirus, comprises the pharmaceutical composition that comprises formula I compound that described patient is suppressed the retrovirus significant quantity.
The tetraterpene derivatives of formula I can be used for the conjoint therapy with one or more antiviral drugs.Therefore, the invention provides the method that treatment suffers from the patient of the disease relevant with retrovirus, comprise described patient is suppressed at least a formula I compound of retrovirus significant quantity and the combination of one or more antiviral drugs.In certain embodiments, described antiviral drug is used for the HIV-therapy in the U.S. through approval.The invention still further relates to by giving the method that the experimenter of HIV-1 has been infected at least a above-mentioned tetraterpene derivatives treatment, alternatively with known anti--any one or multiple combination in AIDS therapeutical agent or the immunostimulant carry out.
The present invention also provides the method for HIV transmission of infection between the prevention individuality.Especially, the invention provides prevention HIV and infect and to infect the pregnant woman from HIV and propagate method to fetus, be included in pregnancy duration before childbirth, during childbirth or the puerperium of branch at once described pregnant woman and/or described fetus are suppressed the compound of one or more formulas I of retrovirus significant quantity.
In addition, the invention provides prevention HIV and infect the method for propagating in the sexual intercourse process, be included in the preceding topical compositions to vagina or other mucosal administration inhibition retrovirus significant quantity of sexual intercourse, said composition comprises the compound of one or more formulas I.
In addition, the present invention relates to the method for preparation I compound.
Other embodiment of the present invention and advantage are listed in the following description and partial content obviously maybe can be learnt by implementing the present invention from this specification sheets.Can realize and obtain embodiment of the present invention and advantage by feature and the combination of in appending claims, pointing out especially.
Should understand above-mentioned general description and following detailed description all is to be indicative typically and only, is not to be used for limiting the present invention.
Describe in detail
Compound of the present invention has general expression I:
Or its pharmaceutically acceptable salt or ester;
Wherein A be as shown in the formula fused rings:
Wherein in formula A among the ring carbon of called after x and y and the formula I ring carbon of called after x and y identical;
R
1Be the carboxyl alkyloyl, wherein the alkyloyl chain can be alternatively by one or more hydroxyls or halogen replaces or can be interrupted by nitrogen, sulphur or Sauerstoffatom or its combination;
R
2And R
3Independent is hydrogen, methyl, halogen, hydroxyl, carboxyl or COOR
17
R
4Be hydrogen, methyl, halogen or hydroxyl;
R
5Be carboxyl carbalkoxy, carbalkoxy, alkanoyloxymethyl, carboxyl alkanoyloxymethyl, alkoxy methyl or carboxyl alkoxy methyl, any one in them all replaced by one or more hydroxyls or halogen alternatively; Or R
5Be carboxyl or methylol; Or work as R
2Or R
3During for carboxyl, R
5Can be methyl;
R
6Be hydrogen, methyl, hydroxyl or halogen;
R
7And R
8Independent is hydrogen or C
1-6Alkyl;
R
9Be CH
2Or CH
3
R
10Be hydrogen, hydroxyl or methyl;
R
11Be methyl, methoxycarbonyl, carboxyl carbalkoxy, alkanoyloxymethyl, alkoxy methyl or carboxyl alkoxy methyl, any one in them all replaced by one or more hydroxyls or halogen alternatively;
R
12Be hydrogen or methyl;
R
13Be hydrogen or methyl;
R
14Be hydrogen or hydroxyl;
If C12 and C13 form singly-bound, R so
15Be hydrogen; If or C12 and C13 form two key, R so
15Do not exist;
R
16Be hydrogen or hydroxyl;
R
17Be alkyl or carboxyalkyl, wherein alkyl chain can be alternatively by one or more hydroxyls or halogen replaces or can be interrupted by nitrogen, sulphur or Sauerstoffatom or its combination; And
Wherein straight dotted line is represented optional pair of key between C12 and C13 or C20 and the C29;
Condition be when A for as the lower section time:
If have two keys between C12 and the C13, R
1Can not be glutaryl-or succinyl;
When A for (ii) and R
11During for methyl, R
1Can not be succinyl;
When A for (iii) and R
2, R
3And R
13When respectively doing for oneself hydrogen, R
1Can not be succinyl; And
Condition is to work as R
2And R
3Be between methyl and C12 and the C13 and have two keys, A (i) can not for:
In certain embodiments, R
1Be carboxyl (C
2-10) alkyl-carbonyl or carboxyl (C
2-10) alkoxyl group (C
1-10) alkyl-carbonyl.In certain embodiments, R
1Be carboxyl (C
2-6) alkyl-carbonyl or carboxyl (C
2-6) alkoxyl group (C
1-6) alkyl-carbonyl.Suitable R
1Group is selected from the group that following groups is formed:
In certain embodiments, R
2And R
3Independent is hydrogen, methyl, halogen or hydroxyl.In certain embodiments, R
2And R
3Independent is carboxyl.In certain embodiments, R
2And R
3Independent is COOR
17
In certain embodiments, R
17Be carboxyl (C
2-10) alkyl or carboxyl (C
2-10) alkoxyl group (C
1-10) alkyl.In certain embodiments, R
17Be carboxyl (C
2-6) alkyl or carboxyl (C
2-6) alkoxyl group (C
1-6) alkyl.In certain embodiments, R
17Be selected from the group that following groups is formed:
The present invention in certain embodiments, described compound has formula II:
R wherein
1, R
4, R
5, R
6, R
7, R
8And R
14As above-mentioned formula I is defined.In one embodiment, R
6Be Beta-methyl, R
8Be hydrogen, R
5Be methylol and R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.In another embodiment, R
6Be hydrogen, R
7And R
8Be methyl, R
5Be carboxyl and R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.
In certain embodiments, R
5Be the carboxyl carbalkoxy, carbalkoxy, alkanoyloxymethyl, the carboxyl alkanoyloxymethyl, alkoxy methyl, the carboxyl alkoxy methyl, aminocarboxyl, alkyl amino-carbonyl, the dialkylamino carbonyl, the alkoxyl group alkyl amino-carbonyl, alkoxyl group alkoxyl group alkyl amino-carbonyl, alkoxycarbonyl amido alkoxyl group alkyl amino-carbonyl, the alkoxycarbonyl amido alkyl amino-carbonyl, the alkyl-carbonyl-amino alkyl amino-carbonyl, amino alkyl amino-carbonyl, the aminoalkoxy alkyl amino-carbonyl, one alkylamino alkyl amino-carbonyl, the dialkylamino alkyl amino-carbonyl, the heterocyclic radical carbonyl, the heterocyclic radical alkyl amino-carbonyl, the naphthene amino carbonyl, aromatic yl aminocarbonyl, the aryl alkane amino carbonyl, aryl-amino-carbonyl alkyl amino-carbonyl or heteroaryl amino carbonyl, any one in them are all replaced by one or more hydroxyls or halogen alternatively; Or R
5Be carboxyl or methylol.In certain embodiments, R
5Be carboxyl carbalkoxy, carbalkoxy, alkanoyloxymethyl, carboxyl alkanoyloxymethyl, alkoxy methyl, carboxyl alkoxy methyl.In certain embodiments, R
5Be selected from carboxyl, methylol ,-CO
2(CH
2)
nCOOH ,-CO
2(CH
2)
nCH
3,-CH
2OC (O) (CH
2)
nCH
3,-CH
2OC (O) (CH
2)
nCOOH ,-CH
2O (CH
2)
nCH
3With-CH
2O (CH
2)
nThe group that COOH forms.In certain embodiments, R
5Be selected from the group that following groups is formed:
In certain embodiments, R
5Be selected from the group that following groups is formed:
In certain embodiments, R
5Be methylol.In certain embodiments, R
5Be carboxyl.In certain embodiments, n is 0-20.In certain embodiments, n is 1-10.In certain embodiments, n is 2-8.In certain embodiments, n is 1-6.In certain embodiments, n is 2-6.
In certain embodiments, described compound has formula III:
R wherein
1, R
9, R
10And R
11As above-mentioned formula I is defined.In one embodiment, R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.
In certain embodiments, R
11Be methyl, methoxycarbonyl, carboxyl carbalkoxy, alkanoyloxymethyl, alkoxy methyl or carboxyl alkoxy methyl, any one in them all replaced by one or more hydroxyls or halogen alternatively.In certain embodiments, R
11Be selected from methyl ,-CO
2(CH
2)
nCOOH ,-CH
2OC (O) (CH
2)
nCH
3,-CH
2O (CH
2)
nCH
3With-CH
2O (CH
2)
nThe group that COOH forms.In certain embodiments, n is 0-20.In certain embodiments, n is 1-10.In certain embodiments, n is 2-8.In certain embodiments, n is 1-6.In certain embodiments, n is 2-6.In certain embodiments, R
11Be methyl.In certain embodiments, R
11Be methoxycarbonyl.In certain embodiments, R
11Be selected from the group that methoxymethyl and ethoxyl methyl are formed.In certain embodiments, at R
11Methyl in the definition can be replaced by halogen or hydroxyl.
In certain embodiments, described compound has formula IV:
R wherein
1, R
2, R
3, R
4And R
13As above-mentioned formula I is defined.In one embodiment, R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.In one embodiment, R
2And R
3Be methyl.
In certain embodiments, compound of the present invention has formula V:
R wherein
1, R
3, R
5, R
6, R
7And R
8As above-mentioned formula I is defined.In one embodiment, R
6Be hydrogen, R
7Be methyl, and R
8Be methyl.In certain embodiments, R
6Be methyl, R
7Be hydrogen, and R
8Be methyl.In certain embodiments, R
3Be carboxyl.In certain embodiments, R
3Be COOR
17, R wherein
17As above-mentioned formula I is defined.
In certain embodiments, compound of the present invention has formula VI:
R wherein
1And R
5As above-mentioned formula I is defined.
Can use any triterpene in the formula I scope.According to the present invention, in certain embodiments, the compound of formula I is selected from uvaol, ursolic acid, erythrodiol, Echinocystic acid, Oleanolic Acid, sumaresinolic acid, lupeol, dihydro lupeol, Betulinic acid methylester, dihydrobetulinic acid methyl esters, 17-Alpha-Methyl-androstanediol, androstanediol, gymnemic acid, α-masticinic acid, beta boswellic acid and 4, the group that the derivative of 4-dimethyl-androstanediol is formed.
In certain embodiments, compound of the present invention is defined as formula I, wherein R
2And R
3Be methyl.In certain embodiments, compound of the present invention is defined as formula I, wherein R
1Be 3 ', 3 '-the dimethyl succinyl.In certain embodiments, compound of the present invention is defined as formula I, wherein R
1Be succinyl, that is:
According to the present invention, in certain embodiments, the stereochemistry of side chain substituents is important.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is (i) and R
5Be positioned on the β position.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is (i) and R
6Be positioned on the β position.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is (i) and R
14Be positioned on the α position.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is (i), R
7Be Alpha-Methyl, and R
8Be hydrogen.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is (i), R
8Be Alpha-Methyl, and R
7Be hydrogen.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is (i) and R
7And R
8It all is methyl.In certain embodiments, compound of the present invention is defined as formula I, and wherein A is for (ii) and R
11Be positioned on the β position.
In certain embodiments, 3 ', 3 '-the dimethyl succinyl is positioned on the C3 position.In certain embodiments, the compound of formula II is: 3-O-(3 ', 3 '-the dimethyl succinyl) uvaol; 3-O-(3 ', 3 '-the dimethyl succinyl) erythrodiol; 3-O-(3 ', 3 '-the dimethyl succinyl) Echinocystic acid; Or 3-O-(3 ', 3 '-the dimethyl succinyl) sumaresinolic acid.In certain embodiments, the compound of formula III is: 3-O-(3 ', 3 '-the dimethyl succinyl) lupeol; 3-O-(3 ', 3 '-the dimethyl succinyl) the dihydro lupeol; 3-O-(3 ', 3 '-the dimethyl succinyl)-17 β-methyl esters-betulinic acid; Or 3-O-(3 ', 3 '-the dimethyl succinyl)-17 β-methyl esters-dihydrobetulinic acid.In certain embodiments, the compound of formula IV is: 3-O-(3 ', 3 '-the dimethyl succinyl)-4,4-dimethyl androstanediol; 3-O-(3 ', 3-dimethyl succinyl)-17 Alpha-Methyl androstanediols; Or 3-O-(3 ', 3 '-the dimethyl succinyl) androstanediol.In certain embodiments, the compound of formula V is: 3-O-(3 ', 3 '-the dimethyl succinyl)-α-masticinic acid; Or 3-O-(3 ', 3 '-the dimethyl succinyl)-beta boswellic acid.In certain embodiments, the compound of formula VI be 3-O-(3 ', 3 '-the dimethyl succinyl) gymnemic acid.
The alkyl of The compounds of this invention can be the straight or branched alkyl with the group that contains alkyl, preferably has 1-10 carbon atom.In certain embodiments, the alkyl of The compounds of this invention or contain the group of alkyl can be by C
3-7Cycloalkyl substituted.In certain embodiments, described cycloalkyl can include, but are not limited to cyclobutyl, cyclopentyl or cyclohexyl.
In addition, the avirulent pharmaceutically acceptable salt that comprises The compounds of this invention in the scope of the invention.Can separate and these salt of process made acid-stable in situ of purifying compounds final, the compound of free acid form that maybe can be by making purifying separately and suitable organic or inorganic alkali reaction and the salt that separates formation thus prepare these salt.They can comprise the positively charged ion based on basic metal and alkaline-earth metal, such as sodium, lithium, potassium, calcium, magnesium etc., and avirulent ammonium, quaternary ammonium and amine positively charged ion, include, but are not limited to ammonium, tetramethyl-ammonium, tetraethyl ammonium, methylamine, dimethylamine, Trimethylamine 99, ethamine, N-methylglucosamine etc.
In addition, the avirulent pharmaceutically acceptable ester class that comprises The compounds of this invention in the scope of the invention.Ester group preferably has the type that is easy to hydrolysis under physiological condition relatively.The example of the pharmaceutically acceptable ester class of The compounds of this invention comprises C
1-6Alkyl esters, wherein said alkyl are straight or branched.Acceptable esters also comprises C
5-7Cycloalkyl ester class and alkyl aryl class, such as, but be not limited to benzyl ester.Preferred C
1-4Alkyl esters.In certain embodiments, described ester class is selected from the group that following ester class is formed: alkyl carboxylic ester, such as acetate esters; With one-or the dialkyl phosphate class, such as methyl phosphorodithioate or dimethyl phosphoric acid ester.The ester class that can prepare The compounds of this invention according to ordinary method.
Some compound in formula I, II, III, IV, V and the VI scope is for being called the derivative of " prodrug ".Term " prodrug " refers to and passes through enzyme or chemical process in vivo, for example by hydrolysis in blood, changes into the compound of the parent compound of above-mentioned formula fast.Provide in the following document and gone through: Higuchi, T. and V.Stella " as the prodrug of new delivery system " (Pro-drugs as Novel Delivery Systems), Vol.14, A.C.S.Symposium Series; " bioreversible carrier in the medicinal design " (BioreversibleCarriers in Drug Design), Ed.Edward B.Roche, AmericanPharmaceutical Association, Pergamon Press, 1987.Useful prodrug can be the ester class of formula I, II, III, IV, V and VI.In the embodiment of some prodrug, low alkyl group is replaced by one or more hydroxyls or halogen group by suitable acid.Suitable acid comprises: for example carboxylic-acid, sulfonic acid class, phosphoric acid class or its lower alkyl esters class and phosphonic acids or its lower alkyl esters class.For example, suitable carboxylic-acid comprises: the alkyl carboxylic acid class, such as acetate; Aryl carboxylic acid class and aralkyl carboxylic acid's class.Suitable sulfonic acid class comprises that alkylsulphonic acid class, aryl sulfonic acid class and arylalkyl sulfonic acid class, suitable phosphoric acid ester and phosphonic acid ester are methyl esters class or ethyl ester class.
In certain embodiments, the C3 acyl group that has dimethyl or oxygen on C3 ' position can be the active compound of tool.This observations is pointed out the acyl group of these types, and active enhancing may be important to anti-HIV.
The invention still further relates to the method that has infected the experimenter of HIV-1 by at least a treatment that gives in the above-mentioned tetraterpene derivatives, alternatively with known anti--any one or multiple combination in AIDS therapeutical agent or the immunostimulant carry out.
Based on description provided herein, instruction and enlightenment, further feature of the present invention, advantage, embodiment, aspect and purpose are apparent for various equivalent modifications.
Analogue of the present invention can have the antiretroviral activity, the suitable compound and the composition that are used for treating with extra medicine activity component alternatively retroviral infection are provided thus, and described extra drug active ingredient is such as being antiretroviral, anti-HIV and/or immune-stimulating compound or antiviral antibody or its fragment.
So-called " antiretroviral activity " or " anti-HIV activity " is meant at least a ability that suppresses in the following situation:
(1) viral former-DNA is integrated into the host cell gene group;
(2) retrovirus and cell attachment;
(3) virus enters cell;
(4) cellular metabolism of permission virus replication;
(5) intercellular that suppresses virus is propagated;
(6) the synthetic and/or cell expressing of virus antigen;
(7) virus is germinateed or is ripe;
(8) enzymic activity of encoding viral (such as reversed transcriptive enzyme, intergrase and proteolytic enzyme); And/or
(9) any known reverse transcription or HIV pathogenic effects, such as, for example immunosuppression.Therefore, any activity of tending to suppress any of these mechanism is " antiretroviral activity " or " anti-HIV activity ".
Tetraterpene derivatives of the present invention can separately or be used for the treatment of retrovirus (for example HIV) with other therapeutic modality combination as known in the art to be infected.This class therapeutic modality can comprise use medicine chemotherapy, described medicine such as, but be not limited at least a in the following medicine: AZT, 3TC, ddC, d4T, ddI, tynofovir, Abacavir, nevirapine, Delavirdine, emtricitabine, efavirenz, Saquinavir, ritonavir, Indinavir, nelfinavir, rltonavir, amprenavir, fosamprenavir and atazanavir or any other antiretroviral agent or antibody combination each other, or with based on the associating of the therapeutical agent of biology, such as gp41-deutero-peptide class enfuvirtide (Fuzeon; Timeris-Roche) and T-1249 (Trimeris) or solubility CD4, to the antibody of CD4 and the conjugate of CD4 or anti--CD4, or provide in addition as this paper.
Tetraterpene derivatives of the present invention can be used for the processing blood goods, maintains blood products in the blood bank such as those.At present natural blood source is used to test antibody to HIV.Yet this sample of testing imperfection still and producing the negative test result may still contain HIV virus.Use tetraterpene derivatives processing blood of the present invention and blood products to add extra safety range by any reverse transcription disease cytotoxic activity that reduces or elimination may not be detected.
In addition, tetraterpene derivatives of the present invention can be as the preventive of HIV transmission of infection between the prevention individuality.For example, can by oral or by injection at pregnancy duration or before childbirth, when childbirth or divide the puerperium to give described derivative to pregnant woman and/or the fetus that HIV infects at once so that reduce the possibility of infection of newborn.In addition, can be before childbirth at once transvaginal give described derivative and prevent that the baby from passing through the infection in the birth canal process.In addition, can in the sexual intercourse process, use derivative of the present invention to propagate to prevent HIV, undertaken by the topical composition to vagina or other mucosal administration inhibition retrovirus significant quantity before sexual intercourse, said composition comprises one or more compounds among formula I, II, III, IV, V or the VI.For example, the derivative of the present invention male sex that can be used to protect from infection propagates HIV to not infected women or vice versa.
Pharmaceutical composition
Pharmaceutical composition of the present invention can comprise at least a tetraterpene derivatives.Pharmaceutical composition of the present invention can further include other antiviral drug, such as, but not limited to AZT (zidovudine, RETROVIR, GlaxoSmithKline), 3TC (lamivudine, EPIVIR , GlaxoSmithKline), AZT+3TC, (COMBIVIR , GlaxoSmithKline), AZT+3TC+ Abacavir (abacvir) (TRIZIVIR , GlaxoSmithKline), ddI (didanosine, VIDEX , Bristol-Myers Squibb), ddC (zalcitabine, HIVID , Hoffmann-LaRoche), D4T (stavudine, ZERIT , Bristol-Myers Squibb), Abacavir (ZIAGEN , GlaxoSmithKline), nevirapine (VIRAMUNE , Boehringher Ingelheim), Delavirdine (Pfizer), efavirenz (SUSTIVA , DuPont Pharmaceuticals), tynofovir (VIREAD , GileadSciences), Saquinavir (INVIRASE , FORTOVASE , Hoffmann-La Roche), ritonavir (NORVIR , Abbott Laboratories), Indinavir (CRIXIVAN , Merck and Company), nelfinavir (VIRACEPT , Pfizer), amprenavir (AGENERASE , GlaxoSmithKline), Adefovir (PREVEON , HEPSERA , Gilead Sciences), atazanavir (REYATAZ , Bristol-Myers Squibb), fosamprenavir (LEXIVA , GlaxoSmithKline) and hydroxyurea (HYDREA , Bristol-Meyers Squibb) or arbitrarily each other combination of other antiretroviral agent or antibody or relevant with therapeutical agent based on biology is such as gp41-deutero-peptide class enfuvirtide (FUZEON ; Roche and Timeris) and T-1249 or solubility CD4, to the antibody of CD4 and the conjugate of CD4 or anti--CD4, or additionally provide as this paper.
Be suitable for most including, but are not limited to: amphotericin B (FUNGIZONE ) with other suitable antiviral drug that tetraterpene derivatives of the present invention uses; Polyinosinic-polycytidylic acid (the RNA of mispairing; Hemis pherx Biopharma); BETASERON (beta-interferon, Chiron); Butylated Hydroxytoluene; Carrosyn (polymannoacetate); Castanospermine; Contracan (stearic aeic derivative); Creme Pharmatex (containing benzalkonium chloride); The unsubstituted zidovudine derivative of 5-; Penciclovir (DENAVIR , Novartis); Famciclovir (FAMVIR , Novartis); Acyclovir (ZOVIRAX , GlaxoSmithKline); Cytofovir (VISTIDE , Gilead); Ganciclovir (CYTOVENE , Hoffman LaRoche); T 500; Beracilline (3-sulfydryl-D-Xie Ansuan); FOSCARNET (phosphonoformic acid; AstraZeneca); Fusidic acid; Potenlini (composition of Radix Glycyrrhizae); HPA-23 (ammonium-21-tungstyl-9-stibnate); ORNIDYL (eflornithine, Aventis); Nonoxynolum; Hydroxyethylsulfonic acid pentamidine (PENTAM-300); Peptide T (hot peptide sequence, Peninsula Laboratories); Phenytoin Sodium Salt (Pfizer); INH or vazadrine; Ribavirin (VIRAZOLE ; ValeantPharmaceuticals); Rifabutin (rifabutin), rifabutin (ansamycin) (MYCOBUTIN , Pfizer); CD4-IgG2 (Progenics Pharmaceuticals) or other contain CD4 or based on the molecule of CD4; Trimetrexate (Medimmune); Suramine and analogue thereof (Bayer); With WELLFERON (alpha-interferon, GlaxoSmithKline).
Pharmaceutical composition of the present invention can further include immunomodulator.According to the present invention, can with tetraterpene derivatives of the present invention alternatively the suitable immunomodulator of coupling can include, but are not limited to: ABPP (Bropririmine); Anti-Human's interferon-' alpha '-antibody; Xitix and derivative thereof; Interferon-beta; Ciamexon; Ciclosporin; Cimitidine Type A/AB; CL-246,738; G CFS comprises GM-CSF; Dinitrochlorobenzene; HE2000 (Hollis-EdenPharmaceuticals); Interferon-; Dextran; Hyperimmunization gamma globulin (Bayer); Immuthiol (sodium oiethyl dithiocarbamate); Interleukin 1 (Hoffmann-LaRoche, Amgen), interleukin II (IL-2) (Chiron); Isoprinosine (inosine pranobex); Krestin; LC-9018 (Yakult); Lentinan (Yamanouchi); LF-1695; Methionine enkephalin; Minophagen C; Muramyl-tripeptide, MTP-PE; TREXUPONT (Barr Laboratories); The RNA immunomodulator; REMUNE (ImmuneResponse Corporation); RETICULOSE (Advanced Viral ResearchCorporation); Shosaikoto; Genseng; Thymus humoral factor; Thymopentin; The Zadaxin factor 5; Thymus peptide 1 (ZADAXIN , SciClone); Thymostimulin; TNF (tumour necrosis factor, Genentech); And vitamin preparation.
In certain embodiments, animal subjects of the present invention is a Mammals.So-called " Mammals " is meant and belongs to mammiferous individuality.The present invention is used in particular for treating human patients.
Term " treatment " refers to and gives tetraterpene derivatives to the experimenter, and purpose can comprise the pathologic condition that prevention, improvement or healing are relevant with retrovirus.
Regard the medicine that provides as " combination " each other, condition is they to be offered the patient simultaneously or condition is to make biological activity overlapping such as the time between every kind of drug administration.
In certain embodiments, at least a tetraterpene derivatives comprises the single medicine composition.
The of the present invention at least a tetraterpene derivatives that the pharmaceutical composition that the present invention is used for administration can comprise the form of can accepting on the medicine alternatively with the combination of pharmaceutically acceptable carrier.Can give these compositions by the any-mode of realizing described purpose.The technician of the clinical field of treatment retrovirus pathologic condition is easy to determine the dosage and the scheme of tetraterpene derivatives of the present invention.
For example, can pass through non-enteron aisle, such as subcutaneous, intravenously, intramuscular, intraperitoneal, transdermal or suck by way of administration.On the other hand or simultaneously, can be by oral by way of administration.Dosage depends on recipient's age, health condition and body weight, previous tretament or the type of treatment simultaneously and the character of required effect.
Composition in the scope of the invention comprises all compositions of at least a tetraterpene derivatives of the present invention that contains the described purpose consumption of effective acquisition.Although individual need is variable, the scope of determining to belong to those skilled in the art of the optimum range of the significant quantity of every kind of composition.Typical doses comprises the about 100mg/kg body weight of about 0.1mg/kg-.In certain embodiments, described dosage comprises the active ingredient of the about 100mg/kg body weight of about 1mg/kg-.In certain embodiments, described dosage comprises the about 50mg/kg body weight of about 2.5mg/kg-.In certain embodiments, described dosage comprises the about 25mg/kg body weight of about 5mg/kg-.
That the therapeutic administration can also be included in is preceding, simultaneously, subsequently or auxiliaryly give the extra tetraterpene derivatives of at least a the present invention or other therapeutical agent, such as antiviral drug or immunostimulant.In these class means, the dosage of second kind of medicine can be identical or different with first kind of therapeutical agent.In certain embodiments, give described medicine next day of can be according to every kind of drug dose recommending.
The administration of The compounds of this invention can also comprise alternatively use immunity system reinforcer or immunomodulator in advance, simultaneously, subsequently or adjuvant therapy.Except that pharmaceutical active compounds, pharmaceutical composition of the present invention can also contain suitable pharmaceutically acceptable carrier, includes to be beneficial to vehicle and the auxiliary agent that described active compound is processed into the preparation that can use on medicine.In certain embodiments, described preparation, particularly can and can be used for those preparations of the administration of the above-mentioned type by oral administration, such as tablet, lozenge and capsule and in addition can be by the preparation of rectal administration, such as suppository, and by injection or the suitable solution used of oral administration, it is about 99% to contain the 1%-that has an appointment, active compound and the vehicle of preferably about 20%-about 75%.
According to self known mode, for example mixing, granulation, system ingot, dissolving or the lyophilization by routine prepares pharmaceutical preparation of the present invention.Therefore; can obtain the pharmaceutical preparation of oral application through the following steps: described active compound is mixed with solid excipient, grind the gained mixture alternatively, and if desired or necessary; add proper auxiliary agent post-treatment granular mixture, thereby obtaining tablet or ingot core.
Suitable vehicle is: for example, weighting agent, such as sugar, for example lactose or sucrose, mannitol or sorbyl alcohol; Cellulosics and/or calcium phosphate are such as tricalcium phosphate or secondary calcium phosphate; And tackiness agent, such as, for example use the starch paste of W-Gum, wheat starch, rice starch, yam starch, gelatin, tragakanta, methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone.If desired, can add disintegrating agent, such as above-mentioned starch and also have carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or its salt, such as Protanal TXF 200.The reagent of auxiliary agent, especially influence liquidity and lubricant be silicon-dioxide, talcum powder, stearic acid or its salt for example, such as Magnesium Stearate or calcium stearate; And/or polyoxyethylene glycol.If desired, give the suitable coatings of ingot core coating resistant to gastric juice.For this purpose, can use priming, it can contain Sudan Gum-arabic, talcum powder, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide, coating solution and appropriate organic solvent or solvent mixture alternatively.In order to produce the coatings of resistant to gastric juice, use suitable cellulosics solution, such as phthalic acid cellulose acetate or Hydroxypropyl Methylcellulose Phathalate.For example, dyestuff or pigment can be joined in tablet or the lozenge coatings, so that identify or be used to characterize the combination of active compound doses.
Can comprise the sucking fit capsule made by gelatin by the other medicines preparation that orally uses and by gelatin and softening agent, the soft seal capsule of making such as glycerine or sorbyl alcohol.Described sucking fit capsule can contain the active compound of particle form, can be mixed with weighting agent in this particle, such as lactose; Tackiness agent is such as starch; And/or lubricant, such as talcum powder or Magnesium Stearate; With optional stablizer.In using some embodiment of soft capsule, activated mixture is dissolved in or is suspended in the suitable liquid, such as fatty oil or whiteruss.In addition, can add stablizer.
Can comprise by the possible pharmaceutical preparation that rectum uses: the suppository of forming by active compound and suppository base for example.Suitable suppository base for example is natural or synthetic triglyceride or paraffinic.In addition, can also use the rectal capsule of forming by active compound and substrate combination.Possible substrate material comprises: for example liquid triglycerides class, polyethylene glycols or paraffinic.
The appropriate formulation that is used for parenterai administration comprises the active compound of water-soluble form, for example the aqueous solution of water-soluble salt.In addition, can give suspension as the active compound of suitable oily injection suspension form.Proper fat-soluble solvent or carrier comprise fatty oil, such as sesame oil; Or the Acrawax class, such as ethyl oleate or triglyceride.Moisture injection suspension can contain the material that increases suspension viscosity, comprising: for example carboxymethyl cellulose, sorbyl alcohol and/or dextran.This suspension can also contain stablizer alternatively.
Can prepare the whole body administrable preparation of the present invention that is used for enteron aisle, non-enteron aisle or topical.In fact, can use all preparations of three types simultaneously so that realize the whole body administration of active ingredient.
The appropriate formulation that is used for oral administration comprises: hard capsule or soft capsule; Lozenge; Pill; Tablet comprises coating tablet; Elixir; Suspension; Syrup or inhalation and controlled release form thereof.
Except that those formulations for the oral administration preparation, solid dosage also comprises rectal suppository.
Be used for preventing giving a birth or sexual intercourse process individuality between the prevention infected of HIV comprise one or more compounds and at least a pharmaceutically acceptable topical vehicle or thinner among formula I, II, III, IV, V and the VI with topical composition.For example, topical compositions can be ointment, gel, lotion, paste, jelly, sprays, foam or form of sponge.Formula I, II, III, IV, V and VI generally are lower than about 1,000 milligram and about in certain embodiments 0.01 milligram-Yue 100 milligrams in prevention with the dosage in the topical formulations.Topical preparation can comprise other preventative component.Described carrier and thinner should be acceptable, and its implication is and other component compatibility of preparation and harmless to the recipient.
Local prevention comprises that with preparation those are suitable for the preparation of vagina, rectum or topical.If suitable, these preparations can exist with the dispersive dose unit expediently and can be by the method preparation of pharmacy field any known.All these class methods include mixes promoting agent with liquid vehicle, gel or fine powder solid carrier, and then if necessary, makes product form required preparation.
The prevention that is suitable for vagina administration can be used as vaginal suppository, tampon, creme, gel, paste, jelly, foam or sprays or water or oil suspension, solution or emulsion (liquid preparation) with preparation and exists, they also contain suitable carrier well known in the art except that containing described promoting agent.Liquid preparation can contain typical additives, such as suspension agent; Emulsifying agent; Nonaqueous carrier comprises edible oil; Or sanitas.These preparations are used for preventing spreading through sex intercourse and the infection of baby by the birth canal process of HIV.In an example, can before sexual intercourse or before the childbirth, carry out vagina administration at once.
In certain embodiments, the prevention that is used for rectum or vagina administration that contains solid carrier provides as unitary dose suppository with preparation.Suitable carriers comprises material commonly used in theobroma oil and other this area.For example, can pass through one or more compounds and one or more carriers softening or fusing of hybrid I, II, III, IV, V and VI, form suppository with postcooling and in plastic film.
Prevention of the present invention can also be for using drops form moisture or the non-aqueous matrix preparation with preparation, and described matrix comprises one or more dispersion agents, solubilizing agent or suspension agent.Liquid spray can be sent from the pressurized drug packing.
Prevention of the present invention can be suitable for realizing continuing to send with preparation.In addition, described prevention can comprise other promoting agent with preparation, such as spermicide, biocide and antiviral drug.
When mixing, can also give tetraterpene derivatives of the present invention with the implant form with the Biodegradable sustained-release carrier.Perhaps, tetraterpene derivatives of the present invention can be mixed with the transdermal patch that is used for continuing to discharge active ingredient.
The appropriate formulation that is used for topical comprises creme, gel, jelly, mucilage, paste and ointment.Suitable Injectable solution comprises intravenously, subcutaneous and intramuscular Injectable solution.Perhaps, can be with transfusion with as the described tetraterpene derivatives of the form administration of nose inhalation or sprays.
Can use the method for well known to a person skilled in the art to prepare compound of the present invention.Various triterpene skeletons can be available from merchandise resources.Can be according to being the compound that the similar mode of typical method prepares accompanying drawing I of the present invention with as shown in scheme 1, modifying birch camphor.Can be in the anhydrous pyridine that under 95 ℃ the suitable acid anhydrides of birch camphor or dihydro birch camphor and 6 times is being had in the presence of 4-(dimethylamino) pyridine (DMAP) heated overnight.CH
2OR
zBe equivalent to as above-mentioned the (ii) defined R of A
11When tlc (TLC) shows that raw material consumption is complete, dilute this reaction system and use the 10%HCl solution washing with EtOAc.Use MgSO then
4Dry EtOAc layer and carry out column chromatography.
Scheme 1
Can be according to being the compound that the similar mode of typical method prepares accompanying drawing I of the present invention with as shown in scheme 2, modifying birch camphor.It is synthetic by way of, R wherein that scheme 2 has been described compound
1And R
11For replacing or unsubstituted carboxyl acyl group.CH
2OR
zBe equivalent to as above-mentioned the (ii) defined R of A
11
Scheme 2
Scheme 3 has been described by using the solid phase organic synthesis to synthesize other alternative method (Pathak of The compounds of this invention, A., Deng " combinatorial chemistry and high throughput screening " (Combinatorial Chem.and High Throughput Screening) 5,241-248 (2002)).Briefly, the triterpene skeleton can pass through at R
5, R
11Or R
13(by R
aExpression) going up formation ester or amido linkage is connected with resin.Can use and make that under mild conditions compound can any resin of cracked, for example 2-chlorine trityl chloride resin or Sieber amide resins.If desired, can introduce amino acid as the spacer between triterpene and the resin.In case triterpene is fixed on the resin support, just can be by adding the required R of sour form
1Substituting group is (by R
bExpression) on C3, introduces required derivatize.
Scheme 3
Can as shown in scheme 4, prepare tetraterpene derivatives of the present invention.28-hydroxyl with trityl ether moiety protection birch camphor (1) produces birch camphor 28-O-trityl ether (2), further handles its solution in pyridine with suitable dicarboxylic acid with having in the presence of the Dimethylamino pyridine under reflux state.Final passing through at CH
2Cl
2Reflux with the tosic acid pyridine among the-EtOH and remove the 28-protecting group and obtain required 3-O-acyl group birch camphor derivative.
Scheme 4
Birch camphor (1) birch camphor 28-O-trityl ether (2)
3-O-acyl group birch camphor 28-O-trityl ethers 3-O-acyl group birch camphor derivative
Can according to the scheme of following foundation carry out the biological assessment that HIV-1 suppresses (Montefiori, D.C., etc., " clinical microbiology " (Clin.Microbiol.) 26,231-235 (1988)).People T-clone MT-2 maintained contain perfect medium (RPMI 1640 that contains the 1O% foetal calf serum that has replenished L-glutaminate is at 5%CO
2Under 37 ℃) continuous culture in.At first specimen is dissolved in methyl-sulphoxide to produce standard inventory solution with the concentration of 10mg/ml, it is diluted into tissue culture medium (TCM) obtains operating stock solution.Usually following drug level is used for screening: 100,20,4 and 0.8＜g/ml.With regard to being found to be active promoting agent, the refabrication diluent is used for test subsequently, so that can measure accurate EC
50Value (as giving a definition).The preparation specimen and in each sample well, add 90＜1 contain 3 * 10
5The substratum of the MT-2 cell of individual cell/ml and 45＜1 virus inoculation thing (HIV-1 IIIIB isolate), the concentration of wherein said virus inoculation thing is that (PI) causes killing and wounding the necessary concentration of 80% cellular targets in the time of 5 days after infection.The control wells of also having prepared only to contain virus and cell (no medicine) and only having contained cell (virus-free or medicine).Prepare identical with first group second group of sample and under the same terms that does not contain virus, join in the cell (simulated infection) to be used for toxicity test (as the IC that gives a definition
50).In addition, also in each experimentation with AZT as the positive drug control test.PI the 5th day, measure the cell killing rate that cell survival rate is determined virus induction by using the XTT method.By XTT, use the sample determination toxicity of compound of simulated infection.If specimen has inhibition ability and nontoxicity, report its effect: IC according to following term so
50, the MT-2 cell of the simulated infection to 50% has toxic specimen concentration; EC
50, can suppress HIV and duplicate the concentration that reaches 50% specimen; And therapeutic index (TI), IC
50With EC
50The ratio.
The following example is for to the interpretation that illustrates of method and composition of the present invention, has not been used for the qualification effect.Usually can run into and conspicuous to those skilled in the art other suitable modification and adaptive change to condition and parameter kind belongs to the spirit and scope of the invention.
Although one of ordinary skill in the art would recognize that and explain and described specific embodiment, can under the situation that does not break away from essence of the present invention and scope, carry out various modifications and change.
To those skilled in the art, according to drawing other embodiment apparently to the consideration of this specification sheets with from the implementation process of the present invention that this paper discloses.Only this specification sheets and embodiment are considered as typical example, scope that the present invention is definite and essence are represented by appended claim.All open source literatures, patent application and the patent of this paper citation intactly are incorporated herein by reference.
Claims (50)
1. the compound of formula I:
Or its pharmaceutically acceptable salt or ester;
Wherein A be as shown in the formula fused rings:
Wherein in formula A among the ring carbon of called after x and y and the formula I ring carbon of called after x and y identical;
R
1Be selected from the group that following groups is formed:
With
R
2And R
3Independent be hydrogen, methyl, halogen, hydroxyl, carboxyl or-COOR
17
R
4Be hydrogen, methyl, halogen or hydroxyl;
R
5Be the carboxyl carbalkoxy, carbalkoxy, alkanoyloxymethyl, the carboxyl alkanoyloxymethyl, alkoxy methyl, the carboxyl alkoxy methyl, aminocarboxyl, alkyl amino-carbonyl, the dialkylamino carbonyl, the alkoxyl group alkyl amino-carbonyl, alkoxyl group alkoxyl group alkyl amino-carbonyl, alkoxycarbonyl amido alkoxyl group alkyl amino-carbonyl, the alkoxycarbonyl amido alkyl amino-carbonyl, the alkyl-carbonyl-amino alkyl amino-carbonyl, amino alkyl amino-carbonyl, the aminoalkoxy alkyl amino-carbonyl, one alkylamino alkyl amino-carbonyl, the dialkylamino alkyl amino-carbonyl, the heterocyclic radical carbonyl, the heterocyclic radical alkyl amino-carbonyl, the naphthene amino carbonyl, aromatic yl aminocarbonyl, the aryl alkane amino carbonyl, aryl-amino-carbonyl alkyl amino-carbonyl or heteroaryl amino carbonyl, any one in them are all replaced by one or more hydroxyls or halogen alternatively; Or R
5Be carboxyl or methylol; Or work as R
2Or R
3During for carboxyl, R
5Can be methyl;
R
6Be hydrogen, methyl, hydroxyl or halogen;
R
7And R
8Independent is hydrogen or C
1-6Alkyl;
R
9Be CH
2Or CH
3
R
10Be hydrogen, hydroxyl or methyl;
R
11Be methyl, methoxycarbonyl, carboxyl carbalkoxy, alkanoyloxymethyl, alkoxy methyl or carboxyl alkoxy methyl, any one in them all replaced by one or more hydroxyls or halogen alternatively;
R
12Be hydrogen or methyl;
R
13Be hydrogen or methyl;
R
14Be hydrogen or hydroxyl;
If C12 and C13 form singly-bound, R so
15Be hydrogen; If or C12 and C13 form two key, R so
15Do not exist;
R
16Be hydrogen or hydroxyl;
R
17Be alkyl or carboxyalkyl, wherein alkyl chain can be alternatively by one or more hydroxyls or halogen replaces or can be interrupted by nitrogen, sulphur or Sauerstoffatom or its combination; And
Wherein straight dotted line is represented optional pair of key between C12 and C13 or C20 and the C29;
Condition be when A for as the lower section time:
If have two keys between C12 and the C13, R
1Can not be glutaryl-or succinyl;
When A for (ii) and R
11During for methyl, R
1Can not be succinyl;
When A for (iii) and R
2, R
3And R
13When respectively doing for oneself hydrogen, R
1Can not be succinyl; And
Condition is to work as R
2And R
3Be between methyl and C12 and the C13 when having two key, A (i) can not for:
Or
2. the described compound of claim 1, wherein R
2And R
3Be methyl.
3. the described compound of claim 1, wherein R
1Be 3 ', 3 '-the dimethyl succinyl.
4. the described compound of claim 1, wherein A is (i) and R
5Be positioned on the β position.
5. the described compound of claim 1, wherein A is (i) and R
6Be positioned on the β position.
6. the described compound of claim 1, wherein A is (i) and R
14Be positioned on the α position.
7. the described compound of claim 1, wherein A is (i), R
7Be Alpha-Methyl and R
8Be hydrogen.
8. the described compound of claim 1, wherein A is (i), R
8Be Alpha-Methyl and R
7Be hydrogen.
9. the described compound of claim 1, wherein A is (i) and R
7And R
8Be methyl.
10. the described compound of claim 1, wherein A is for (ii) and R
11Be positioned on the β position.
11. the compound of claim 1 has formula II:
R wherein
1, R
4, R
5, R
6, R
7, R
8And R
14As defined in claim 1.
12. the compound of claim 11, wherein R
6Be Beta-methyl, R
8Be hydrogen, R
5Be methylol and R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.
13. the compound of claim 11, wherein R
5For methylol ,-CO
2(CH
2)
nCOOH or-CO
2(CH
2)
nCH
3And n is 0-6.
14. the compound of claim 11, wherein R
5For-COC (O) (CH
2)
nCH
3Or-COC (O) (CH
2)
nCOOH and n are 0-6.
15. the compound of claim 11, wherein R
5For-CO (CH
2)
nCH
3Or-CO (CH
2)
nCOOH and n are 0-6.
16. the described compound of claim 11 is one of following compounds:
3-O-(3 ', 3 '-the dimethyl succinyl) uvaol;
3-O-(3 ', 3 '-the dimethyl succinyl) erythrodiol;
3-O-(3 ', 3 '-the dimethyl succinyl) Echinocystic acid; With
3-O-(3 ', 3 '-the dimethyl succinyl) sumaresinolic acid.
17. the compound of claim 1 has formula III:
R wherein
1, R
9, R
10And R
11As defined in claim 1.
18. the compound of claim 17, wherein R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.
19. the compound of claim 17, wherein R
11Be methyl, carboxyl carbalkoxy, alkanoyloxymethyl, alkoxy methyl or carboxyl alkoxy methyl.
20. the compound of claim 17, wherein R
11For methyl or-CO
2(CH
2)
nCOOH and n are 0-6.
21. the compound of claim 17, wherein R
11For-COC (O) (CH
2)
nCH
3And n is 0-6.
22. the compound of claim 17, wherein R
11For-CO (CH
2)
nCH
3Or-CO (CH
2)
nCOOH and n are 0-6.
23. the described compound of claim 17 is one of following compounds:
3-O-(3 ', 3 '-the dimethyl succinyl) lupeol;
3-O-(3 ', 3 '-the dimethyl succinyl) the dihydro lupeol;
3-O-(3 ', 3 '-the dimethyl succinyl)-17 β-methyl esters-betulinic acid; With
3-O-(3 ', 3 '-the dimethyl succinyl)-17 β-methyl esters-dihydrobetulinic acid.
24. the compound of claim 1 has formula IV:
R wherein
1, R
2, R
3, R
4And R
13As defined in claim 1.
25. the compound of claim 24, wherein R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl.
26. the compound of claim 24, wherein R
1Be 3 ', 3 '-dimethyl-penten diacyl, 3 ', 3 '-dimethyl succinyl, glutaryl-or succinyl and R
2And R
3Be methyl.
27. the described compound of claim 24 is one of following compounds:
3-O-(3 ', 3 '-the dimethyl succinyl)-4,4-dimethyl androstanediol;
3-O-(3 ', 3 '-the dimethyl succinyl)-17 Alpha-Methyl androstanediols; With
3-O-(3 ', 3 '-the dimethyl succinyl) androstanediol.
28. the compound of claim 1 has formula V:
R wherein
1, R
3, R
5, R
6, R
7And R
8As defined in claim 1.
29. the compound of claim 28, wherein R
6Be hydrogen, R
7Be methyl and R
8Be methyl.
30. the compound of claim 28, wherein R
6Be methyl, R
7Be hydrogen and R
8Be methyl.
31. the described compound of claim 28 is one of following compounds:
3-O-(3 ', 3 '-the dimethyl succinyl)-α-masticinic acid; With
3-O-(3 ', 3 '-the dimethyl succinyl)-beta boswellic acid.
32. the compound of claim 1 has formula VI:
R wherein
1And R
5As defined in claim 1.
33. the compound of claim 32, for 3-O-(3 ', 3 '-the dimethyl succinyl) gymnemic acid.
34. pharmaceutical composition comprises compound or its pharmaceutically acceptable ester or the salt and the pharmaceutically acceptable carrier of claim 1.
35. the pharmaceutical composition of claim 34 further comprises antiviral drug or immunostimulant.
36. the pharmaceutical composition of claim 35, wherein said antiviral drug are selected from by one or more groups formed in the following antiviral drug: zidovudine, lamivudine, zalcitabine, stavudine, didanosine, tynofovir, Abacavir, nevirapine, Delavirdine, emtricitabine, efavirenz, Saquinavir, ritonavir, Indinavir, nelfinavir, rltonavir, amprenavir, fosamprenavir, atazanavir, enfuvirtide, hydroxyurea, interleukin II, gamma Globulin, amantadine, guanidine hydroxy benzo imidazoles, interferon-' alpha ', interferon-beta, interferon-, thiosemicarbazone, Viruzona, Rifampin, ribavirin, pyrimidine analogue, purine analogue, phosphine formic acid, phosphonoacetic acid, acyclovir, di-deoxynucleoside and ganciclovir.
37. be used for suppressing the method for zooblast or tissue retroviral infection, comprise the pharmaceutical composition of the claim 34 that gives effectively to suppress the retrovirus consumption.
38. the described method of claim 37 wherein provides the described composition of described compound of the amount ranges of the about 100mg/kg body weight of about 0.1-.
39. the described method of claim 38 wherein provides the described composition of described compound of the amount ranges of the about 25mg/kg body weight of about 5-.
40. the described method of claim 39, wherein said animal is behaved.
41. pharmaceutical composition comprises claim 11,17,24,28 or 32 compound or its pharmaceutically acceptable ester or salt and pharmaceutically acceptable carrier.
42. the pharmaceutical composition of claim 41 further comprises the medicine that is selected from antiviral drug or immunostimulant.
43. the pharmaceutical composition of claim 42, wherein said antiviral drug is selected from by one or more groups formed in the following antiviral drug: zidovudine, lamivudine, zalcitabine, stavudine, didanosine, tynofovir, Abacavir, nevirapine, Delavirdine, emtricitabine, efavirenz, Saquinavir, ritonavir, Indinavir, nelfinavir, rltonavir, amprenavir, fosamprenavir, atazanavir, enfuvirtide, hydroxyurea, interleukin II, gamma Globulin, amantadine, guanidine hydroxy benzo imidazoles, interferon-' alpha ', interferon-beta, interferon-, thiosemicarbazone, Viruzona, Rifampin, ribavirin, pyrimidine analogue, purine analogue, phosphine formic acid, phosphonoacetic acid, acyclovir, di-deoxynucleoside and ganciclovir.
44. be used for suppressing the method for zooblast or tissue retroviral infection, comprise the pharmaceutical composition of the claim 43 that gives effectively to suppress the retrovirus consumption.
45. the described method of claim 44 wherein provides the described composition of described compound of the amount ranges of the about 100mg/kg body weight of about 0.1-.
46. the described method of claim 45 wherein provides the described composition of described compound of the amount ranges of the about 25mg/kg body weight of about 5-.
47. the described method of claim 46, wherein said animal is behaved.
48. by making cells contacting claim 1,11,17,24,28 or 32 compound suppress the method for retroviral infection.
49. prevention HIV infects and to infect the pregnant woman from HIV and propagate method to fetus, be included in pregnancy duration before childbirth, during childbirth or the puerperium of branch at once described pregnant woman and/or described fetus are suppressed the claim 1,11,17,24 of retrovirus significant quantity, 28 or 32 compound.
50. prevention HIV infects the method propagate in the sexual intercourse process, be included in before the sexual intercourse vagina or other mucosal administration are suppressed one or more compounds in the claim 1,11,17,24,28 or 32 of retrovirus significant quantity.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US50589903P | 2003-09-26 | 2003-09-26 | |
| US60/505,899 | 2003-09-26 | ||
| US60/559,358 | 2004-04-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1871251A true CN1871251A (en) | 2006-11-29 |
Family
ID=37444458
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480030801 Pending CN1871251A (en) | 2003-09-26 | 2004-09-27 | Novel triterpene derivatives, preparation thereof and use thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1871251A (en) |
| ZA (1) | ZA200602758B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102905529A (en) * | 2010-05-30 | 2013-01-30 | 莱拉营养食品有限公司 | Compositions comprising non-acidic boswellia oil fraction as bio-enhancer for enhancing the bioavailability of biological agents |
| CN103450319A (en) * | 2013-08-27 | 2013-12-18 | 青岛农业大学 | Separation method for erythrodiol in pittosporum leaf crude extract and new application of erythrodiol |
| CN110121334A (en) * | 2017-01-05 | 2019-08-13 | 加州大学董事会 | The contraceptive purposes of triterpene compound |
-
2004
- 2004-09-27 ZA ZA200602758A patent/ZA200602758B/en unknown
- 2004-09-27 CN CN 200480030801 patent/CN1871251A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102905529A (en) * | 2010-05-30 | 2013-01-30 | 莱拉营养食品有限公司 | Compositions comprising non-acidic boswellia oil fraction as bio-enhancer for enhancing the bioavailability of biological agents |
| CN103450319A (en) * | 2013-08-27 | 2013-12-18 | 青岛农业大学 | Separation method for erythrodiol in pittosporum leaf crude extract and new application of erythrodiol |
| CN110121334A (en) * | 2017-01-05 | 2019-08-13 | 加州大学董事会 | The contraceptive purposes of triterpene compound |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200602758B (en) | 2007-12-27 |
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