CN102443043B - N-substituted-14 beta -(aminomethyl) triptodiolide derivative and preparation method and application thereof - Google Patents
N-substituted-14 beta -(aminomethyl) triptodiolide derivative and preparation method and application thereof Download PDFInfo
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- CN102443043B CN102443043B CN2010105076418A CN201010507641A CN102443043B CN 102443043 B CN102443043 B CN 102443043B CN 2010105076418 A CN2010105076418 A CN 2010105076418A CN 201010507641 A CN201010507641 A CN 201010507641A CN 102443043 B CN102443043 B CN 102443043B
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- lldt
- phenyl
- compound
- aminomethyl
- epitriptolide
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- 0 CC(C)[C@](*)(C[C@](C)[C@]([C@@]12O[C@@]1C1)([C@@](C)(CC3)[C@@]1C(CO1)=C3C1=O)O)[C@]2(C)O Chemical compound CC(C)[C@](*)(C[C@](C)[C@]([C@@]12O[C@@]1C1)([C@@](C)(CC3)[C@@]1C(CO1)=C3C1=O)O)[C@]2(C)O 0.000 description 13
- QUMRYCKECINDLQ-XESGGTJHSA-N CC(C)[C@]1([C@]([C@]23O[C@H]2C2)(C=O)O)O[C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]2C(CO2)=C1C2=O Chemical compound CC(C)[C@]1([C@]([C@]23O[C@H]2C2)(C=O)O)O[C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]2C(CO2)=C1C2=O QUMRYCKECINDLQ-XESGGTJHSA-N 0.000 description 3
- SWOVVKGLGOOUKI-ZHGGVEMFSA-N CC(C)[C@]1(C([C@]23O[C@H]2C2)=O)O[C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]2C(CO2)=C1C2=O Chemical compound CC(C)[C@]1(C([C@]23O[C@H]2C2)=O)O[C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]2C(CO2)=C1C2=O SWOVVKGLGOOUKI-ZHGGVEMFSA-N 0.000 description 1
- TXBVPQZUNXEIMH-OFMZVLJESA-N CC(C)[C@]1([C@@](CNc2c(C)cccc2)([C@]23O[C@H]2C2)O)[U][C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]2C(CO2)=C1C2=O Chemical compound CC(C)[C@]1([C@@](CNc2c(C)cccc2)([C@]23O[C@H]2C2)O)[U][C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]2C(CO2)=C1C2=O TXBVPQZUNXEIMH-OFMZVLJESA-N 0.000 description 1
- UHQIMBJGUQRSPC-AFXPCSBYSA-N CC(C)[C@]1([C@@](CO)([C@]23OC4C2)O)O[C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]4C(CO2)=C1/C2=[O]\C(C)C Chemical compound CC(C)[C@]1([C@@](CO)([C@]23OC4C2)O)O[C@H]1[C@@H]1O[C@]31[C@@](C)(CC1)[C@@H]4C(CO2)=C1/C2=[O]\C(C)C UHQIMBJGUQRSPC-AFXPCSBYSA-N 0.000 description 1
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Abstract
The invention provides a tripterygium diterpenoid lactone derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, a drug combination thereof and an application thereof in preparation of drugs for treatment of tumors. Particularly, the invention provides a tripterygium diterpenoid lactone derivative shown in Formula II-4 or a pharmaceutically acceptable salt thereof, a preparation method thereof, a drug combination thereof and an application thereof in preparation of drugs for treatment of tumors, in particular to ovarian cancer or prostate cancer.
Description
Technical field
The present invention relates to field of medicaments, in particular to a class tripterygium wilfordii diterpenes diterpenoids lactones derivative and pharmacy acceptable salt thereof, its preparation method with and application in the medicine for the preparation for the treatment of tumour, particularly genital system tumor.
Background technology
Trypterygine, the popular name Graceful Jessamine Herb, be Celastraceae (Celastraceae) Thunder God Calamus bejuco, is that the resource that has of China is than a more rich kind of plant.Thunder God Calamus (Tripterygium) plant has four kinds, be trypterygine (Tripterygium wilfordiiHook f.), Tripterygium hypoglaucum (Tripterygium hypoglaucum Levl.Hutch), northeast trypterygine (black climing) (Tripterygiumregelii Sprague et Takeda) and Cangshan trypterygine (Tripterygium forretii Dicls), in China, distribution all arranged.Trypterygine is recorded the earliest in " Dragon Lord book on Chinese herbal medicine warp ", and its main chemical compositions has diterpene, triterpene, sesquiterpene, alkaloid etc., from tripterygium plant, has isolated so far nearly 200 kinds of compound.The research that recent two decades comes shows that it has antitumor, anti-inflammatory, immunosuppression, antifertility, the various active such as antibiotic.
The trypterygine plant is in the existing history for many years of tumour that is used for the treatment of among the people, and wherein one of activeconstituents is triptolide.Triptolide, except obtaining antitumor action research widely, also once entered clinical trial, was used for the treatment of leukemia, but the larger toxic side effect of triptolide, too narrow treatment window, limited it in clinical middle application.The structure of modification of triptolide was confined in the introduction of water soluble group mostly in the past, and there is no essence on agent structure and change.After this class prodrug enters in body, by after hydrolysis or metabolism, still changing triptolide into and bring into play in vivo drug action, this has just determined that they can not fundamentally improve the toxic side effect of triptolide.Therefore, Pharmaceutical Chemists expect triptolide to be transform as always there is good aqueous solubility, high reactivity, hypotoxic antitumor drug candidate.
Summary of the invention
The inventor is by the further investigation to the triptolide structure activity relationship, its structure has been carried out being different to transformation and the modification of prior art, obtained the tripterygium wilfordii diterpenes diterpenoids lactones derivative of a collection of novel texture, mainly to introduce a series of phenyl aminess and heterocyclic aromatic amine micromolecular side chain in the C14 position, but also the C14 β-OH that will in the past think essential groups transform C14 α-OH as, thereby obtained a series of derivatives, and the preparation method of this analog derivative is provided.External genital system tumor suppresses experiment and shows that this analog derivative has good antitumour activity, can effectively suppress the propagation of genital system tumor cell.And, due to the introducing of phenyl amines and heterocyclic aromatic amine micromolecular side chain, making this analog derivative be easy to form all kinds of salt with acid, this will increase substantially the water-soluble of this analog derivative.
An object of the present invention is to provide novel tripterygium wilfordii diterpenes diterpenoids lactones derivative or its pharmacy acceptable salt of a class as shown in general formula (I).
Another object of the present invention is to provide the preparation method of a kind of described tripterygium wilfordii diterpenes diterpenoids lactones derivative or its pharmacy acceptable salt.
Another purpose of the present invention is to provide a kind of pharmaceutical composition for the treatment of tumour, and it comprises one or more described tripterygium wilfordii diterpenes diterpenoids lactones derivatives or its pharmacy acceptable salt and the pharmaceutically acceptable auxiliary material for the treatment of significant quantity.
A further object of the present invention is to provide described tripterygium wilfordii diterpenes diterpenoids lactones derivative or the purposes of its pharmacy acceptable salt in the medicine for the preparation for the treatment of tumour, particularly genital system tumor, especially ovarian cancer or prostate cancer.
According to an aspect of the present invention, provide the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in following general formula (I) or its pharmacy acceptable salt:
Wherein, Z means the aromatic heterocycles such as phenyl, thienyl, furyl, pyridyl, pyrryl, pyridazinyl, pyrimidyl, pyrazinyl, benzofuryl, indyl, benzothienyl, quinolyl or isoquinolyl;
Above-mentioned group is not necessarily replaced by one or more substituting group, described substituting group be F, Cl, Br ,-NH
2,-NHR ,-NRR ' ,-OH ,-(CH
2)
ncOOM, R, CF
3,-NO
2,-CN ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, wherein M is H, K, Na or R, the integer that n is 0-6, e is 0,1,2 or 3; Preferably, described substituting group be F, Cl ,-NH
2,-NHR ,-NRR ' ,-OH ,-(CH
2)
ncOOM, R or-OR;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
6cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, shown in general formula (I), tripterygium wilfordii diterpenes diterpenoids lactones derivative or its pharmacy acceptable salt are specially the compound shown in general formula (II-1) or its pharmacy acceptable salt:
Wherein,
By a methyl substituted phenyl A, not necessarily by one or more substituting group, replaced, described substituting group be F, Cl, Br, R ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR " ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3in one for H, another is not H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl;
R " is C
2-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R " is C
2-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt are specially the compound shown in general formula (II-2) or its pharmacy acceptable salt:
Wherein,
Phenyl A by a methoxy substitution is not necessarily replaced by one or more substituting group, described substituting group be Cl, Br, R ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3in one for H, another is not H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl;
R " is C
2-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R " is C
2-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt are specially the compound shown in general formula (II-3) or its pharmacy acceptable salt:
Wherein,
The phenyl A replaced by a fluorine atom is not necessarily replaced by one or more substituting group, and described substituting group is F, Cl, Br, R " ,-CH
2r ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3in one for H, another is not H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl;
R " is C
2-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R " is C
2-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt are specially the compound shown in general formula (II-4) or its pharmacy acceptable salt:
Wherein,
The phenyl A replaced by a chlorine atom is not necessarily replaced by one or more substituting group, and described substituting group is Cl, Br, R " ,-CH
2r ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR " ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3in one for H, another is not H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl;
R " is C
2-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R " is C
2-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt are specially the compound shown in general formula (II-5) or its pharmacy acceptable salt:
Wherein,
R
0mean OH or H;
By a R
0the phenyl A replaced is not necessarily replaced by one or more substituting group,
Work as R
0while meaning OH, described substituting group is F, Br, R " ,-CH
2r ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er,
Work as R
0while meaning H, described substituting group is Br, R " ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR " ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er,
The integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3in one for H, another is not H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl;
R " is C
2-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R " is C
2-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt are specially the compound shown in general formula (II-6) or its pharmacy acceptable salt:
(II-6)
Wherein,
R
1mean NH
2perhaps NHCOCH
3;
By a R
1the phenyl A replaced is not necessarily replaced by one or more substituting group, and described substituting group is Br, R, CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3in one for H, another is not H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
Preferably, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt are specially the compound shown in general formula (II-7) or its pharmacy acceptable salt:
Wherein,
M means Na, K, H, R;
By one-(CH
2)
nthe phenyl A that COOM replaces is not necessarily replaced by one or more substituting group, described substituting group be F, Cl, Br ,-(CH
2)
ncOOM, R ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3;
R
2, R
3be H, C independently of one another
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl ,-COR or-S (O)
ir, wherein i is 1 or 2; Preferably, R
2and R
3be H simultaneously, or R
2and R
3when different, be H;
Wherein, R, R ' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl; Preferably, R, R ' are identical or different C
1-C
4straight or branched alkyl, C
2-C
4straight or branched thiazolinyl, C
3-C
5cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
More preferably, tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention or its pharmacy acceptable salt are:
(1-1) (14S)-14 β-N-(2 '-tolyl)-aminomethyl Epitriptolide (LLDT-201)
(1-2) (14S)-14 β-N-(3 '-tolyl)-aminomethyl Epitriptolide (LLDT-202)
(1-3) (14S)-14 β-N-(4 '-tolyl)-aminomethyl Epitriptolide (LLDT-203)
(1-4) (14S)-14 β-N-(4 '-tolyl)-aminomethyl Epitriptolide hydrochloride (LLDT-228)
(2-1) (14S)-14 β-N-(2 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-208)
(2-2) (14S)-14 β-N-(3 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-209)
(2-3) (14S)-14 β-N-(4 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-210)
(2-4) (14S)-14 β-N-(4 '-p-methoxy-phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-229)
(3-1) (14S)-14 β-N-(2 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-215)
(3-2) (14S)-14 β-N-(3 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-216)
(3-3) (14S)-14 β-N-(4 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-217)
(3-4) (14S)-14 β-N-(4 '-fluorophenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-227)
(4-1) (14S)-14 β-N-(2 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-218)
(4-2) (14S)-14 β-N-(3 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-219)
(4-3) (14S)-14 β-N-(4 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-220)
(4-4) (14S)-14 β-N-(4 '-chloro-phenyl-)-aminomethyl Epitriptolide hydrochloride (LLDT-231)
(5-1) (14S)-14 β-N-(2 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-211)
(5-2) (14S)-14 β-N-(3 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-212)
(5-3) (14S)-14 β-N-(4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-213)
(5-4) (14S)-14 β-N-(4 '-hydroxy phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-230)
(5-5) (14S)-14 β-N-(3 '-trifluoromethyl)-aminomethyl Epitriptolide (LLDT-235)
(5-6) (14S)-14 β-N-(4 '-trifluoromethyl)-aminomethyl Epitriptolide (LLDT-236)
(5-7) (14S)-14 β-N-(3 '-nitrophenyl)-aminomethyl Epitriptolide (LLDT-237)
(5-8) (14S)-14 β-N-(4 '-nitrophenyl)-aminomethyl Epitriptolide (LLDT-238)
(5-9) (14S)-14 β-N-phenyl-aminomethyl Epitriptolide hydrochloride (LLDT-239)
(5-0) (14S)-14 β-N-phenyl-aminomethyl Epitriptolide (LLDT-214)
(6-1) (14S)-14 β-N-(2 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-204)
(6-2) (14S)-14 β-N-(3 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-205)
(6-3) (14S)-14 β-N-(4 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-206)
(6-4) (14S)-14 β-N-(4 '-acetylamino phenyl)-aminomethyl Epitriptolide (LLDT-207)
(6-5) (14S)-14 β-N-(4 '-acetylamino phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-226)
(7-1) (14S)-14 β-N-(2 '-methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-221)
(7-2) (14S)-14 β-N-(3 '-methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-222)
(7-3) (14S)-14 β-N-(3 '-methoxycarbonyl-4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-223)
(7-4) (14S)-14 β-N-(2 '-methoxycarbonyl-4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-224)
(7-5) (14S)-14 β-N-(3 '-amino-5 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-225)
(7-6) (14S)-14 β-N-(2 '-methoxycarbonyl-4 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-232)
(7-7) (14S)-14 β-N-(2 '-hydroxyl-4 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-233)
(7-8) (14S)-14 β-N-(2 '-hydroxyl-5 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-234)
As shown in reaction stream formula (I), the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (I)
(1) take Triptonide (LLDT-1) is initiator, in aprotic polar solvent, utilizes chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) compound (4) and reagent N H
2reductive amination process, under the effect of sodium triacetoxy borohydride, occurs in-Z, generates the compound shown in general formula (I-i);
(5) not necessarily, under alkaline condition, the compound shown in general formula (I-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs generate the compound shown in general formula (I-ii);
W means Cl or Br;
It is identical that Z and general formula (I) define, R
2and R
3except not by being defined identical with general formula (I) H;
Described aprotic polar solvent is selected from one or more in methyl-sulphoxide, DMF, methylene dichloride, trichloromethane, tetrahydrofuran (THF) and dioxane ethylene glycol bis methyl ether;
Described oxygenant be selected from two hydration sodium dichromate 99s, potassium bichromate, chromium trioxide, pyridinium dichromate, pyridinium chloro-chromate, ruthenium tetroxide, ceric ammonium nitrate, Collins reagent (chromium trioxide two pyridinium salts) and TEMPO-trichloroisocyanuric acid complex reagent one or more (wherein, TEMPO is 2,2,6,6-tetramethyl piperidine nitrogen oxygen free radical).
The alkali that described alkaline condition is used can be selected from one or more in imidazoles, triethylamine, pyridine, salt of wormwood, n-Butyl Lithium, sodium carbonate, NaH and KH.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-1) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-1)
(1) take Triptonide LLDT-1 as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurs, generate the compound shown in general formula (II-1-i), wherein, amino benzenes compounds
in, the phenyl A replaced by a methyl is not necessarily replaced by one or more substituting group, described substituting group be F, Cl, Br, R ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR " ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e be 0,1,2 or 3, R, R ', R " as general formula (II-1) is defined;
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-1-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-1-ii), wherein, W means Cl or Br;
R
2and R
3except not by being defined identical with general formula (II-1) H.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-2) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-2)
(1) take Triptonide LLDT-1 as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) compound (4) and amino benzenes compounds
under the sodium triacetoxy borohydride effect, reductive amination process occurs to be generated, the compound shown in general formula (II-2-i), wherein, amino benzenes compounds
in, the phenyl A replaced by a methoxyl group is not necessarily replaced by one or more substituting group, described substituting group be Cl, Br, R ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e be 0,1,2 or 3, R, R ', R " as general formula (II-2) is defined;
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-2-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-2-ii), wherein, W means Cl or Br;
R
2and R
3except not by being defined identical with general formula (II-2) H.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-3) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-3)
(1) take Triptonide LLDT-1 as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) by compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurs, generate the compound shown in general formula (II-3-i), wherein, amino benzenes compounds
in, the phenyl A replaced by a fluorine atom is not necessarily replaced by one or more substituting group, and described substituting group is F, Cl, Br, R " ,-CH
2r ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e be 0,1,2 or 3, R, R ', R " with general formula (II-3), define identical;
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-3-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-3-ii), wherein, W means Cl or Br;
R
2and R
3except not by being defined identical with general formula (II-3) H.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-4) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-4)
(1) take Triptonide (LLDT-1) is initiator, in aprotic polar solvent, utilizes chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurs, generate the compound shown in general formula (II-4-i), wherein, amino benzenes compounds
in, the phenyl A replaced by a chlorine atom is not necessarily replaced by one or more substituting group, and described substituting group is Cl, Br, R " ,-CH
2r ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR " ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e is 0,1,2 or 3; R, R ', R " define identical with general formula (II-4);
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-4-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-4-ii), wherein, W means Cl or Br;
R
2and R
3except not by being defined identical with general formula (II-4) H.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-5) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-5)
(1) take Triptonide LLDT-1 as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) by compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurs, generate the compound shown in general formula (II-5-i), wherein, at amino benzenes compounds
in, R
0mean OH or H; By a R
0the phenyl A replaced is not necessarily replaced by one or more substituting group,
Work as R
0while meaning OH, described substituting group is F, Br, R " ,-CH
2r ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er,
Work as R
0while meaning H, described substituting group is Br, R " ,-CF
3,-NO
2,-CN ,-NHR ,-NRR ' ,-NHCOR " ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OR " ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er,
The integer that wherein n is 0-6, e be 0,1,2 or 3, R, R ', R " with general formula (II-5), define identical;
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-5-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-5-ii), wherein, W means Cl or Br;
R
2and R
3except not by being defined identical with general formula (II-5) H.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-6) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-6)
(1) take Triptonide LLDT-1 as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) by compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurring, generates the compound shown in general formula (II-6-i), wherein, at amino benzenes compounds
in, R
1mean NH
2perhaps NHCOCH
3; By a R
1the phenyl A replaced is not necessarily replaced by one or more substituting group, and described substituting group is Br, R, CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e be 0,1,2 or 3, R, R ' with general formula (II-6), define identical;
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-6-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-6-ii), wherein, W means Cl or Br;
R
1with general formula (II-6) define identical, R
2and R
3except not by being defined identical with general formula (II-6) H.
Preferably, the invention provides the preparation method of tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (II-7) or its pharmacy acceptable salt, the method comprises the steps:
Reaction stream formula (II-7)
(1) take Triptonide LLDT-1 as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2),
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) by compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurring, generates the compound shown in general formula (II-7-i), at amino benzenes compounds
in,
By one-(CH
2)
nthe phenyl A that the COOM group replaces is not necessarily replaced by one or more substituting group, described substituting group be F, Cl, Br ,-(CH
2)
ncOOM, R ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR ' ,-NHCOR ,-NHCONHR ,-NHCONRR ' ,-NHCO (CH
2)
nnH
2,-NHSO
2r ,-OH ,-OR ,-OCOR ,-OCO (CH
2)
nnH
2,-OCONHR ,-OCONRR ' ,-OSO
2r ,-COR ,-CONHR ,-CONRR ' ,-CO (CH
2)
nnH
2,-SO
2nH
2,-SO
2nHR ,-SO
2nRR ' or-S (O)
er, the integer that wherein n is 0-6, e be 0,1,2 or 3, R, R ', M as general formula (II-7), defined;
(5) not necessarily, under alkaline condition, the compound shown in general formula (II-7-i) and reagent W-R
2and W-R
3nucleophilic substitution reaction occurs and generate the compound shown in general formula (II-7-ii), wherein, W means Cl or Br;
R
2and R
3except not defining identical for H with general formula (II-7).
Described " pharmacy acceptable salt " is the salt that forms of the mineral acids such as aniline group in molecule and hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, sodium pyrosulfate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC or the salt formed with organic acids such as formic acid, acetic acid, picric acid, methylsulfonic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acids, also comprises in molecule-(CH
2)
nthe salt that COOM group and mineral alkali form, as sodium, potassium, calcium, aluminium salt and ammonium salt, or the salt formed with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc.
Further, the present invention also provides the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula (I) and pharmacy acceptable salt thereof for the preparation of the treatment tumour, the preferably application in the medicine of human reproductive system's tumour, it is characterized in that, described tripterygium wilfordii diterpenes diterpenoids lactones derivative and pharmacy acceptable salt thereof are used with the amount of 0.001-30mg/kg.
According to the pharmaceutical composition that is used for the treatment of tumour of the present invention, it is characterized in that, the gross weight based on 100 weight part pharmaceutical compositions, described tripterygium wilfordii diterpenes diterpenoids lactones derivative and pharmacy acceptable salt content thereof are 0.001～99.9wt%.
The formulation of pharmaceutical composition of the present invention can be the formulation through gastrointestinal administration or non-through the gastrointestinal administration formulation.The described formulation through gastrointestinal administration can be solution, emulsion, tablet, capsule etc.Described parenteral administration dosage can be injection, comprises the injecting pathways such as intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection; Through percutaneous drug delivery, as external-use lotion, ointment, patch etc.; Mucosal, as hypogloeeis, nasal cavity, rectum, vagina, duct etc.
The active ingredient tripterygium wilfordii diterpenes diterpenoids lactones derivative of pharmaceutical composition of the present invention and pharmacy acceptable salt thereof can be by single medications, also can with other antitumor drug combination therapy.Therefore, pharmaceutical composition of the present invention may further include one or more other antitumor drugs, and described antitumor drug is for affecting the biosynthetic medicine of tumour cell nucleic acid; Directly destroy the medicine that DNA of tumor cell stops it to copy; Embed the medicine that disturbs transcription in DNA of tumor cell; Disturb mitotic division to affect the medicine of tumour cell protein synthesis; Or by suppressing the medicine of cyclooxygenase (COX-2) generation antitumor action.Wherein, the described biosynthetic medicine of tumour cell nucleic acid that affects can be 5 FU 5 fluorouracil (5-Fluorouracil), mercaptopurine (6-Mercaptopurine), methotrexate (Methotrexate), cytosine arabinoside (Cytarabine) and hydroxyurea (Hydroxyurea) etc., the medicine that described direct destruction DNA of tumor cell stops it to copy can be mustargen (Chlormethine Hydrochloride), endoxan (Cytoxam), thiophene is for sending (Thiotepa), busulfan (Busulfan), ametycin (Mitomycin C), bleomycin (Bleomycin), cis-platinum (Cisplatin), ormaplatin (OP), RP-54780 (Oxaloplatin), DWA2114R, CI-973, lobaplatin (Lobaplatin), camptothecine (Camptothecin), Etoposide (Etoposide) etc., disturbing the medicine of transcription in described embedding DNA of tumor cell can be dactinomycin (Actinomycin D), Zorubicin (ADM), darubicin (Idarubicin) and mitoxantrone (NVT), SN-11841 (mAMSA) etc., described interference mitotic division affects the medicine of tumour cell protein synthesis can be for as vinealeucoblastine(VLB) (VLB) and vincristine(VCR) (VCR), carbon vinealeucoblastine(VLB) (VRB), taxol (Taxol), taxotere (Taxotere), ASP (L-asparaginase) or harringtonine (Harringtonine) etc., the described medicine that produces antitumor action by suppressing cyclooxygenase (COX-2) can be acetylsalicylic acid (Aspirin), indomethacin (Indomethaein), Ibuprofen BP/EP (Spansule Capsulae Ibuprofeni), nimesulide (Nimesulide), celecoxib (Celecoxib), rofecoxib (Rofecoxib), the medicine that described inhibition tumour neovascularity generates can be micromolecular compound Sutent (sunitinib), Xarelto (sorafenib), rapamycin (rapamycin) and antibody Arastin (bevacizumab) etc., described angiolysis medicine can be combretastatin (combretastatin A4), dimethylbenzene pyrrole acid (5,6-Dimethylxanthenoneacetic acid, DMXAA) etc., described tyrosine kinase inhibitor can be the antitumor drugs such as micromolecular compound imatinib (imatinib), erlotinib (erlotinib), Gefitinib (gefitinib), lapatinibditosylate (lapatinib) and antibody Erbitux (cetuximab), Trastuzumab (trastuzumab).
During treated with combined medication, triptolide alcohol derivative and pharmacy acceptable salt thereof and other chemotherapeutics can be administrations simultaneously, can be sequential administration, can be also separately administrations.
The present invention also provide aforementioned pharmaceutical compositions for the preparation of the treatment tumour and with the medicine of the disease of Tumor-assaciated in application, wherein, medicine activity component is used with the amount of 0.001～30mg/kg.
Triptolide alcohol derivative of the present invention and pharmacy acceptable salt thereof can be used for the treatment of the warm-blooded animal that suffers from the proliferative diseases such as tumour.
Described " tumour " comprises innocent tumour and malignant tumour: innocent tumour mainly contains fibroma, lipoma, vascular tumor etc.; Malignant tumour mainly comprises that the malignant tumour occurred by epithelium is as squamous cell carcinoma, mammary cancer, ovarian cancer etc., by the histogenetic malignant tumour of mesoderm as fibrosarcoma, osteosarcoma, lymphosarcoma, neurospongioma etc., and by the histogenetic malignant tumour of embryonic cell, neurocyte or prematurity and the malignant tumour that occurred by hematopoietic cell etc.Be particularly useful for treatment the conventional cell cytotoxic drug is had to drug-fast tumour as Zorubicin, taxol, docetaxel, vinorelbine etc., the tumour with multidrug resistance particularly mediated by P-170 glycoprotein.
Described " warm-blooded animal " comprises people and other animal, as rodent and mammal.
The implication of described " proliferative disease " comprises tumour, atypical hyperplasia, but is not limited to tumour and atypical hyperplasia.
Triptolide alcohol derivative of the present invention and pharmacy acceptable salt thereof can also, for the disease with Tumor-assaciated, comprise the tumor diseases such as mammary cancer of the tumour with multidrug resistance of prostate cancer, human ovarian cancer, cancer of the stomach, myelocytic leukemia, colorectal carcinoma, mammary cancer, the mediation of P-170 glycoprotein as the anti-medicine of Zorubicin.
Preferably, triptolide alcohol derivative of the present invention and pharmacy acceptable salt thereof are used for the treatment of prostate cancer and ovarian cancer.
Beneficial effect
(application number: difference 200910048699.8) is in the application of the first submit of the application and applicant, substituent structure difference on C14, introduced phenyl amines small molecules side chain on the C14 position, make compound be easy to and various mineral acids and organic acid salify, and in molecule-(CH
2)
nthe COOM group is easy and mineral alkali or organic bases salify also, and this will improve the water-soluble of compound greatly.The effect experiment aspect, a large amount of compounds all show very potent cytotoxicity.
The present invention has synthesized tripterygium wilfordii diterpenes diterpenoids lactones derivative efficient, low toxicity, can be practically for the treatment of tumor disease.External drug effect result shows, although tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention and pharmacy acceptable salt thereof will be thought the C14 β-OH of essential groups and change C14 α-OH in the past, but still show very strong antitumor action, this provides larger development space for the direction of structure of modification undoubtedly, therefore makes medicine of the present invention have better application prospect.
Embodiment
Below in conjunction with example, the present invention is further elaborated, but these embodiment are never any limitation of the invention, scope of the present invention is determined by claim.
preparation Example
Instrument and main experiment material are as follows:
BrukerAM-400 type and Varian Mercury plus-400 type nuclear magnetic resonance analyser, MAT-711 and MAT-95 type mass spectrograph, H and 200-300 order column chromatography silica gel (Haiyang Chemical Plant, Qingdao), HSGF254TLC plate (Yantai City chemical research institute).
Starting raw material: the method preparation of describing in document [1] for Triptonide (LLDT-1).
Document [1]: Zhou, B.; Li, X.M.; Feng H.J.; Li, Y.C.Tetrahedron 2010,66, and 5396.
The preparation of Preparation Example 1 compound (3)
Under argon shield, the 50mL anhydrous tetrahydro furan is added in the reaction flask that is placed with magnesium chips (900mg, 37.5mmol), chloromethyl dimethyl isopropoxy silane (6mL) is added drop-wise in reaction system through constant pressure funnel.Finish this lead reaction system and stir 30min under 50 ℃, prepared Grignard reagent.The Grignard reagent that this is prepared dropwise adds in the Triptonide (LLDT-1) (3g, 8.4mmol) that has been dissolved in the 100mL dry tetrahydrofuran.Stopped reaction after back flow reaction 1.5h under room temperature, reaction system saturated ammonium chloride solution cancellation, the ethyl acetate extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, obtain thick product compound (2) after concentrating.Without further purifying, compound (2) is dissolved in 50mL methyl alcohol and 80mL tetrahydrofuran (THF), add KHCO
3(3.5g), KF (3.9g) and 30% hydrogen peroxide (10mL), react and add the sodium sulfite solution that 10ml is saturated after 3 hours, by the organic solvent evaporated under reduced pressure, add ethyl acetate and saturated aqueous common salt extraction, organic layer saturated common salt water washing, anhydrous sodium sulfate drying, the thick product after concentrating is through column chromatography purification (eluent: ethyl acetate: hexanaphthene=1: 2) obtain white solid compound (3) (2.28g, productive rate: 70%).
Compound 3:
1h NMR (CDCl
3, 300MHz) δ 4.67 (s, 2H), 4.26 (d, J=11.8Hz, 1H), 3.87-3.80 (m, 2H), (3.64 d, J=11.5Hz, 1H), 3.46 (d, J=3.3Hz, 1H), 2.76-2.64 (m, 1H), (2.45 sept., J=6.9Hz, 1H), 2.37-2.25 (m, 1H), 2.23-2.04 (m, 2H), 1.89 (t, J=14.1Hz, 1H), 1.55 (dd, J=12.6,5.2Hz, 1H), 1.25-1.13 (m, 1H), (1.07 s, 3H), 0.91 (d, J=6.9Hz, 3H), 0.89 (d, J=6.9Hz, 3H);
13cNMR (CDCl
3, 100MHz) δ 173.2 (C), 160.2 (C), 125.4 (C), 74.4 (C), 70.0 (CH
2), 67.5 (C), 65.3 (C), 65.2 (CH
2), 65.0 (C), 56.5 (CH), 56.1 (CH), 54.4 (CH), 40.3 (CH), 36.0 (C), 30.1 (CH
2), 25.5 (CH), 23.4 (CH
2), 20.9 (CH
3), 18.6 (CH
3), 17.1 (CH
2), 13.7 (CH
3); IR (KBr) 3415,3361,2966,2927,2875,1755,1724,1672,1439,1074,1018cm
-1; MS (EI, 70eV) m/z (%) 391 ([M+1]
+, 2), 372 (1), 71 (100); HRMS (EI) calcd.for C
21h
27o
7(M+H)
+391.1757, found 391.1752.Anal. (C
21h
26o
7) C, H.
The preparation of Preparation Example 2 compounds (4)
By compound 3 (420mg, 1.08mmol) be dissolved in the 15mL dichloromethane solvent, add trichloroisocyanuric acid (376mg in 0 ℃, 1.62mmol), add afterwards TEMPO (16mg, 0.108mmol) and with TLC, detect rapidly, react completely and add the sodium carbonate solution cancellation to react and regulate the pH value to neutral, use dichloromethane extraction, organic phase is water, saturated common salt water washing respectively, and concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound 4 (340mg, 0.87mmol, productive rate: 81%).
Compound 4:
1h NMR (CDCl
3, 300MHz) δ 10.03 (s, 1H), 4.76-4.59 (m, 2H), 3.97 (d, J=3.0Hz, 1H), (3.91 s, 1H), 3.75 (d, J=5.9Hz, 1H), 3.60 (d, J=3.0Hz, 1H), (2.79-2.67 m, 1H), 2.38-2.26 (m, 1H), (1.87 dd, J=14.7,13.6Hz, 1H), 1.58 (dd, J=12.6,4.0Hz, 1H), 1.03 (s, 3H), (0.83 d, J=6.9Hz, 3H), (0.79 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 198.3,173.2, and 160.1,125.4,81.7,69.9,65.9,65.5,62.1,56.3,55.8,54.0,40.4,36.0,30.2,26.6,23.3,19.8,17.3,17.1,13.6; IR v
max(KBr) 3448,2968,2933,2875,2254,1747,1728,1674cm
-1; MS (EI, 70eV) m/z (%) 389 ([M+1]
+, 4), 388 (M
+, 1), 371 (2), 343 (6), 327 (52), 299 (88), 71 (100).
The preparation of Preparation Example 3 (14S)-14 β-N-(2 '-tolyl)-aminomethyl Epitriptolide (LLDT-201)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add hydrochloric acid o-toluidine (72mg, 0.5mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (85mg, 0.4mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-tolyl)-aminomethyl Epitriptolide (LLDT-201) (26mg, 0.054mmol, productive rate: 54%).
LLDT-201:
1h NMR (300MHz, CDCl
3) δ 7.19-7.06 (m, 2H), 6.74 (dd, J=17.0,7.8Hz, 2H), 4.64 (s, 2H), 4.39 (brs, 1H), (3.86-3.80 m, 2H), 3.75 (s, 1H), 3.50 (d, J=3.0Hz, 1H), 2.78-2.67 (m, 1H), (2.53 sept, J=6.9Hz, 1H), 2.37-2.24 (m, 2H), 2.20-2.16 (m, 5H), 1.89 (t, J=14.1Hz, 1H), 1.55 (dd, J=12.4,4.9Hz, 1H), 1.25-1.14 (m, 1H), (1.07 s, 3H), 0.99 (d, J=6.9Hz, 3H), 0.91 (d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.5, and 145.9,130.2,127.0,125.3,124.2,118.7,111.1,73.6,70.0,68.2,65.3,64.5,56.0,55.7,54.4,49.4,40.3,36.1,29.9,25.6,23.4,21.2,18.7,17.7,17.1,13.6; IR v
max(KBr) 3386,2931,1751,1676,1604,1518,1450cm
-1; MS (EI, 70eV) m/z (%) 479 (M
+, 6), 450 (1), 120 (100), 91 (7); HRMS (EI) C
28h
33nO
6(M
+) calculated value: 479.2308, measured value: 479.2301.
The preparation of Preparation Example 4 (14S)-14 β-N-(3 '-tolyl)-aminomethyl Epitriptolide (LLDT-202)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add m-toluidine (53.5mg, 0.5mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (85mg, 0.4mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-tolyl)-aminomethyl Epitriptolide (LLDT-202) (26mg, 0.054mmol, productive rate: 54%).
LLDT-202:
1h NMR (300MHz, CDCl
3) δ 7.10 (t, J=7.5Hz, 1H), 6.67-6.56 (m, 3H), 4.67 (s, 2H), 4.24 (brs, 1H), 3.90-3.81 (m, 4H), 3.49-3.42 (m, 2H), 2.71 (m, 1H), 2.51 (sept, J=6.3Hz, 1H), 2.37-2.09 (m, 6H), (1.88 t, J=14.1Hz, 1H), 1.55 (dd, J=12.4,4.9Hz, 1H), 1.25-1.14 (m, 1H), 1.09 (s, 3H), (0.99 d, J=6.3Hz, 3H), (0.93 d, J=6.3Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.4, and 147.9,139.1,129.2,125.3,120.3,115.7,111.5,73.2,69.9,68.2,65.2,64.6,56.1,55.8,54.5,50.0,40.3,36.0,29.9,25.6,23.4,21.5,21.2,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 479 (M
+, 5), 120 (100); HRMS (EI) C
28h
33nO
6(M
+) calculated value: 479.2308, measured value: 479.2307.
The preparation of Preparation Example 5 (14S)-14 β-N-(4 '-tolyl)-aminomethyl Epitriptolide (LLDT-203)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add monomethylaniline (53.5mg, 0.5mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (85mg, 0.4mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-tolyl)-aminomethyl Epitriptolide (LLDT-203) (26mg, 0.054mmol, productive rate: 54%).
LLDT-203:
1h NMR (300MHz, CDCl
3) δ 7.02 (d, J=8.1Hz, 2H), 6.69 (d, J=8.1Hz, 2H), 4.67 (s, 2H), (4.10 brs, 1H), 4.04 (s, 1H), (3.89-3.80 m, 3H), 3.49-3.38 (m, 2H), (2.71 m, 1H), 2.49 (sept, J=6.9Hz, 1H), 2.33-2.04 (m, 6H), 1.88 (t, J=13.8Hz, 1H), 1.55 (m, 1H), (1.25-1.14 m, 1H), 1.08 (s, 3H), (0.98 d, J=6.9Hz, 3H), (0.92 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.5, and 145.6,129.7,129.7,128.9,125.3,114.9,114.9,73.0,69.9,68.3,65.2,64.6,56.1,55.8,54.5,50.5,40.3,36.0,30.0,25.6,23.4,21.2,20.4,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 479 (M
+, 6), 120 (100); HRMS (EI) C
28h
33nO
6(M
+) calculated value: 479.2308, measured value: 479.2310.
The preparation of Preparation Example 6 (14S)-14 β-N-(2 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-208)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add ORTHO ANISIDINE (12.3mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-208) (34.6mg, productive rate: 70%).
LLDT-208:
1h NMR (CDCl
3, 300MHz) δ 6.92-6.73 (m, 4H), 4.75-4.62 (m, 3H), 3.90-3.80 (m, 7H), 3.54-3.45 (m, 2H), 2.72 (m, 1H), 2.51 (sept, J=6.9Hz, 1H), 2.34-2.10 (m, 3H), 1.90 (t, J=14.7Hz, 1H), 1.55 (dd, J=12.6,4.5Hz, 1H), 1.25-1.14 (m, 1H), 1.11 (s, 3H), (1.00 d, J=6.9Hz, 3H), (0.93 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.6, and 147.7,137.9,125.2,121.1,118.5,111.7,109.7,73.1,70.0,68.4,65.3,64.4,56.1,55.7,55.5,54.5,49.9,40.4,36.0,30.0,25.6,23.5,21.2,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 495 (M
+, 5), 136 (100); HRMS (EI) C
28h
33nO
7(M
+) calculated value: 495.2257, measured value: 495.2265.
The preparation of Preparation Example 7 (14S)-14 β-N-(3 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-209)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add m-anisidine (12.3mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-209) (34.6mg, productive rate: 70%).
LLDT-209:
1h NMR (CDCl
3, 300MHz) δ 7.11 (t, J=7.5Hz, 1H), (6.40-6.33 m, 3H), 4.67 (s, 2H), (3.91-3.76 m, 7H), 3.50-3.43 (m, 2H), (2.72 m, 1H), 2.50 (sept, J=6.9Hz, 1H), 2.33-2.10 (m, 3H), 1.89 (t, J=13.5Hz, 1H), 1.55 (dd, J=12.6,4.2Hz, 1H), 1.25-1.12 (m, 1H), 1.08 (s, 3H), (0.98 d, J=6.9Hz, 3H), (0.92 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.7, and 160.4,149.3,130.0,125.3,107.4,104.5,100.7,73.2,69.9,68.2,65.2,64.6,56.1,55.7,55.1,54.5,50.0,40.3,36.0,29.9,25.7,23.4,21.2,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 495 (M
+, 7), 136 (100); HRMS (EI) C
28h
33nO
7(M
+) calculated value: 495.2257, measured value: 495.2261.
The preparation of Preparation Example 8 (14S)-14 β-N-(4 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-210)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add P-nethoxyaniline (12.3mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-p-methoxy-phenyl)-aminomethyl Epitriptolide (LLDT-210) (34.6mg, productive rate: 70%).
LLDT-210:
1h NMR (CDCl
3, 300MHz) δ 6.82-6.73 (m, 4H), 4.67 (s, 2H), (4.26 s, 1H), 3.89-3.84 (m, 2H), 3.81 (d, J=3.0Hz, 1H), 3.75 (s, 3H), 3.48 (d, J=3.0Hz, 1H), 3.34 (d, J=13.2Hz, 1H), (2.70 m, 1H), 2.47 (sept, J=6.9Hz, 1H), 2.35-2.10 (m, 3H), 1.88 (t, J=13.8Hz, 1H), 1.55 (dd, J=12.6,4.8Hz, 1H), 1.25-1.12 (m, 1H), (1.09 s, 3H), 0.97 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.5, and 153.6,141.6,125.3,116.6,116.6,114.7,114.7,72.8,69.9,68.3,65.2,64.7,56.2,55.8,55.6,54.5,51.5,40.3,36.0,30.0,25.6,23.5,21.2,18.8,17.1,13.7; MS (EI, 70eV) m/z (%) 495 (M
+, 17), 136 (100); HRMS (EI) C
28h
33nO
7(M
+) calculated value: 495.2257, measured value: 495.2250.
The preparation of Preparation Example 9 (14S)-14 β-N-(2 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-215)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 2-fluoroaniline (11.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-215) (29mg, productive rate: 60%).
LLDT-215:
1h NMR (CDCl
3, 300MHz) δ 7.06-6.96 (m, 2H), 6.85 (t, J=8.1Hz, 1H), 6.77-6.69 (m, 1H), 4.67 (s, 2H), (4.54 brs, 1H), 3.92-3.80 (m, 3H), (3.63 s, 1H), 3.53-3.44 (m, 2H), (2.77-2.66 m, 1H), 2.50 (sept, J=6.9Hz, 1H), 2.36-2.10 (m, 3H), 1.91 (t, J=14.1Hz, 1H), 1.56 (dd, J=12.6,4.8Hz, 1H), 1.25-1.14 (m, 1H), (1.09 s, 3H), 0.99 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.4, and 153.5,151.1,136.4,136.3,125.3,124.5,118.8,118.7,114.8,114.7,113.7,73.5,69.9,68.2,65.2,64.4,56.1,55.7,54.5,49.6,40.3,36.0,29.9,25.7,23.4,21.1,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 483 (M
+, 4), 124 (100); HRMS (EI) C
27h
30nFO
6(M
+) calculated value: 483.2057, measured value: 483.2051.
The preparation of Preparation Example 10 (14S)-14 β-N-(3 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-216)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3-fluoroaniline (11.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-216) (29mg, productive rate: 60%).
LLDT-216:
1h NMR (CDCl
3, 300MHz) δ 7.17-7.08 (m, 1H), 6.53-6.41 (m, 3H), 4.67 (s, 2H), 4.45 (dd, J=9.6,3.6Hz, 1H), 3.91-3.81 (m, 3H), 3.51-3.38 (m, 3H), 2.76-2.66 (m, 1H), 2.48 (sept, J=7.2Hz, 1H), (2.36-2.12 m, 3H), 1.89 (t, J=14.4Hz, 1H), 1.55 (dd, J=12.9,5.4Hz, 1H), 1.25-1.13 (m, 1H), 1.09 (s, 3H), 0.99 (d, J=7.2Hz, 3H), (0.92 d, J=7.2Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.2,165.0, and 162.6,160.3,149.9,149.8,130.4,130.3,125.3,110.1,105.6,105.4,101.2,100.9,73.5,69.9,68.1,65.2,64.5,56.1,55.7,54.5,49.7,40.3,36.0,29.9,25.7,23.4,21.1,18.7,17.1,13.6; MS (EI, 70eV) m/z (%) 483 (M
+, 2), 124 (100); HRMS (EI) C
27h
30nFO
6(M
+) calculated value: 483.2057, measured value: 483.2058.
The preparation of Preparation Example 11 (14S)-14 β-N-(4 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-217)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 4-fluoroaniline (11.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-217) (29mg, productive rate: 60%).
LLDT-217:
1h NMR (CDCl
3, 300MHz) δ 6.91 (t, J=8.7Hz, 2H), 6.74-6.68 (m, 2H), 4.67 (s, 2H), 3.93 (brs, 1H), (3.89-3.80 m, 3H), 3.49 (d, J=2.4Hz, 1H), 3.36 (d, J=12.9Hz, 1H), (2.76-2.66 m, 1H), 2.46 (sept, J=6.6Hz, 1H), 2.36-2.12 (m, 3H), 1.88 (t, J=14.1Hz, 1H), 1.55 (dd, J=12.3,4.8Hz, 1H), 1.25-1.12 (m, 1H), (1.08 s, 3H), 0.98 (d, J=6.9Hz, 3H), 0.93 (d, J=6.6Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.4, and 158.0,155.6,144.2,125.3,115.9,115.8,115.8,115.6,73.1,69.9,68.2,65.2,64.6,56.2,55.8,54.5,50.9,40.3,36.0,30.0,25.6,23.4,21.2,18.8,17.1,13.7; MS (EI, 70eV) m/z (%) 483 (M
+, 4), 124 (100); HRMS (EI) C
27h
30nFO
6(M
+) calculated value: 483.2057, measured value: 483.2045.
The preparation of Preparation Example 12 (14S)-14 β-N-(2 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-218)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add Ortho-Chloro aniline (12.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-218) (30mg, productive rate: 60%).
LLDT-218:
1h NMR (CDCl
3, 300MHz) δ 7.28 (d, J=7.8Hz, 1H), 7.16 (t, J=7.5Hz, 1H), 6.81 (d, J=7.8Hz, 1H), 6.72 (t, J=7.5Hz, 1H), 5.00 (dd, J=9.3, 4.2Hz, 1H), 4.68 (s, 2H), 3.93-3.82 (m, 3H), 3.59-3.50 (m, 2H), 3.39 (s, 1H), 2.78-2.68 (m, 1H), 2.52 (sept, J=6.9Hz, 1H), 2.38-2.12 (m, 3H), 1.93 (t, J=14.1Hz, 1H), 1.57 (m, 1H), 1.25-1.14 (m, 1H), 1.10 (s, 3H), 1.00 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.3,160.4, and 144.1,129.3,127.8,125.3,120.9,118.9,112.4,73.7,69.9,68.2,65.3,64.3,56.0,55.6,54.4,49.5,40.4,36.1,29.9,25.7,23.5,21.1,18.7,17.1,13.6, MS (EI, 70eV) m/z (%) 499 (M
+, 3), 140 (100), HRMS (EI) C
27h
30nClO
6(M
+) calculated value: 499.1762, measured value: 499.1743.
The preparation of Preparation Example 13 (14S)-14 β-N-(3 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-219)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add m-chloro aniline (12.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-219) (30mg, productive rate: 60%).
LLDT-219:
1h NMR (CDCl
3, 300MHz) δ 7.10 (t, J=7.5Hz, 1H), 6.76 (d, J=9.0Hz, 1H), 6.72 (s, 1H), 6.61 (d, J=8.4Hz, 1H), 4.67 (s, 2H), 4.47 (brs, 1H), 3.89-3.80 (m, 3H), 3.51-3.40 (m, 3H), 2.76-2.66 (m, 1H), 2.48 (sept, J=6.6Hz, 1H), 2.36-2.10 (m, 3H), 1.89 (t, J=13.8Hz, 1H), 1.55 (dd, J=12.3, 4.8Hz, 1H), 1.25-1.12 (m, 1H), 1.08 (s, 3H), 0.98 (d, J=6.6Hz, 3H), 0.92 (d, J=6.6Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.2,160.3, and 149.2,135.0,130.2,125.3,118.9,114.2,112.5,73.6,69.9,68.1,65.2,64.5,56.1,55.7,54.5,49.7,40.3,36.0,29.9,25.7,23.4,21.1,18.7,17.1,13.6, MS (EI, 70eV) m/z (%) 499 (M
+, 3), 140 (100), HRMS (EI) C
27h
30nClO
6(M
+) calculated value: 499.1762, measured value: 499.1761.
The preparation of Preparation Example 14 (14S)-14 β-N-(4 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-220)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add p-Chlorobenzoic acid amide (12.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-chloro-phenyl-)-aminomethyl Epitriptolide (LLDT-220) (30mg, productive rate: 60%).
LLDT-220:
1h NMR (CDCl
3, 300MHz) δ 7.15 (d, J=8.1Hz, 2H), 6.68 (d, J=8.1Hz, 2H), 4.67 (s, 2H), 4.30 (brs, 1H), 3.89-3.81 (m, 3H), 3.61 (s, 1H), 3.49 (d, J=1.8Hz, 1H), 3.41 (t, J=9.9Hz, 1H), 2.76-2.66 (m, 1H), 2.47 (sept, J=6.9Hz, 1H), 2.36-2.10 (m, 3H), 1.89 (t, J=14.1Hz, 1H), 1.55 (dd, J=11.7, 4.2Hz, 1H), 1.25-1.12 (m, 1H), 1.09 (s, 3H), 0.98 (d, J=6.9Hz, 3H), 0.92 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.3,160.3, and 146.6,129.1,129.1,125.3,123.8,115.6,115.6,73.4,69.9,68.1,65.2,64.5,56.1,55.8,54.5,50.1,40.3,36.0,29.9,25.7,23.4,21.1,18.8,17.1,13.7, MS (EI, 70eV) m/z (%) 499 (M
+, 3), 140 (100), HRMS (EI) C
27h
30nClO
6(M
+) calculated value: 499.1762, measured value: 499.1764.
The preparation of Preparation Example 15 (14S)-14 β-N-(2 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-211)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add ortho-aminophenol (10.9mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-211) (28.8mg, productive rate: 60%).
LLDT-211:
1h NMR (CDCl
3, 300MHz) δ 6.90-6.67 (m, 4H), 4.67 (s, 2H), 3.89-3.80 (m, 3H), 3.52-3.43 (m, 2H), 2.76-2.64 (m, 1H), 2.51 (sept, J=6.6Hz, 1H), 2.36-2.06 (m, 3H), 1.87 (t, J=14.7Hz, 1H), 1.55 (dd, J=12.6,4.8Hz, 1H), 1.25-1.12 (m, 1H), 1.09 (s, 3H), (0.99 d, J=7.2Hz, 3H), (0.93 d, J=6.6Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.7,160.9, and 144.6,136.5,125.2,121.3,119.4,114.7,113.6,73.2,70.1,68.5,65.2,64.5,56.2,55.7,54.6,50.1,40.4,36.0,29.9,25.6,23.4,21.2,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 481 (M
+, 80), 120 (100); HRMS (EI) C
27h
31nO
7(M
+) calculated value: 495.2101, measured value: 481.2107.
The preparation of Preparation Example 16 (14S)-14 β-N-(3 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-212)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add a hydroxyanilines (10.9mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-212) (28.8mg, productive rate: 60%).
LLDT-212:
1h NMR (CDCl
3, 300MHz) δ 7.04 (t, J=7.8Hz, 1H), 6.33-6.28 (m, 3H), 5.64 (brs, 1H), 4.67 (s, 2H), (3.88-3.76 m, 4H), 3.50 (d, J=3.0Hz, 1H), 3.44 (d, J=13.2Hz, 1H), (2.72-2.65 m, 1H), 2.49 (sept, J=6.9Hz, 1H), 2.35-2.05 (m, 3H), 1.84 (t, J=13.8Hz, 1H), 1.53 (dd, J=12.6,4.5Hz, 1H), 1.25-1.12 (m, 1H), (1.06 s, 3H), 0.98 (d, J=6.9Hz, 3H), 0.92 (d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.6,160.7, and 156.9,149.5,130.2,125.2,107.0,106.3,101.6,73.4,70.1,68.4,65.2,64.6,56.2,55.7,54.6,50.0,40.3,36.0,29.9,25.7,23.4,21.2,18.8,17.1,13.7; MS (EI, 70eV) m/z (%) 481 (M
+, 10), 122 (100); HRMS (EI) C
27h
31nO
7(M
+) calculated value: 495.2101, measured value: 481.2080.
The preparation of Preparation Example 17 (14S)-14 β-N-(4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-213)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add para hydroxybenzene amine (10.9mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-213) (28.8mg, productive rate: 60%).
LLDT-213:
1h NMR (CDCl
3, 300MHz) δ 6.77-6.66 (m, 4H), 4.67 (s, 2H), 4.31 (brs, 1H), 3.85 (d, J=6.0Hz, 1H), 3.83 (s, 1H), 3.81 (d, J=3.3Hz, 1H), 3.49 (d, J=3.3Hz, 1H), 3.32 (d, J=13.5Hz, 1H), 2.75-2.65 (m, 1H), 2.46 (sept, J=6.9Hz, 1H), 2.36-2.06 (m, 3H), 1.86 (t, J=13.8Hz, 1H), 1.54 (dd, J=12.6, 4.5Hz, 1H), 1.24-1.12 (m, 1H), 1.07 (s, 3H), 0.97 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.5,160.7, and 149.6,141.3,125.3,116.9,116.9,116.0,116.0,72.8,70.1,68.4,65.2,64.7,56.3,55.8,54.6,51.6,40.3,36.0,30.0,25.6,23.4,21.2,18.8,17.1,13.7, MS (EI, 70eV) m/z (%) 481 (M
+, 100), HRMS (EI) C
27h
31nO
7(M
+) calculated value: 495.2101, measured value: 481.2100.
The preparation of Preparation Example 18 (14S)-14 β-N-phenyl-aminomethyl Epitriptolide (LLDT-214)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add aniline (9.3mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-phenyl-aminomethyl Epitriptolide (LLDT-214) (37.2mg, productive rate: 80%).
LLDT-214:
1h NMR (CDCl
3, 300MHz) δ 7.21 (t, J=7.8Hz, 2H), (6.85-6.75 m, 3H), 4.67 (s, 2H), (3.92-3.81 m, 4H), 3.49 (d, J=3.3Hz, 1H), 3.46 (d, J=13.8Hz, 1H), (2.76-2.65 m, 1H), 2.50 (sept, J=6.6Hz, 1H), 2.36-2.08 (m, 3H), 1.88 (t, J=12.9Hz, 1H), 1.55 (dd, J=12.6,4.8Hz, 1H), 1.25-1.12 (m, 1H), (1.09 s, 3H), 0.99 (d, J=6.6Hz, 3H), 0.93 (d, J=6.6Hz, 3H);
13cNMR (CDCl
3, 100MHz) δ 173.3,160.4, and 147.9,129.3,129.3,125.2,119.4,114.6,114.6,73.2,69.9,68.2,65.2,64.6,56.1,55.7,54.5,50.1,40.3,36.0,29.9,25.6,23.4,21.2,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 465 (M
+, 8), 106 (100); HRMS (EI) C
27h
31nO
6(M
+) calculated value: 465.2151, measured value: 465.2147.
The preparation of Preparation Example 19 (14S)-14 β-N-(2 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-204)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add adjacent amino aniline (10.8mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-204) (38.4mg, productive rate: 80%).
LLDT-204:
1h NMR (300MHz, CDCl
3) δ 6.81-6.71 (m, 4H), 4.66 (m, 2H), (3.90-3.81 m, 3H), 3.49 (d, J=3.0Hz, 1H), 3.38 (d, J=9.6Hz, 1H), (2.71 m, 1H), 2.49 (sept, J=6.6Hz, 1H), 2.32-2.03 (m, 3H), 1.87 (t, J=14.4Hz, 1H), 1.55 (dd, J=12.4,4.8Hz, 1H), 1.25-1.14 (m, 1H), 1.06 (s, 3H), (0.97 d, J=6.6Hz, 3H), (0.90 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.5, and 136.0,135.9,125.2,120.8,120.0,116.3,114.1,73.4,69.9,68.2,65.2,64.5,56.0,55.7,54.4,49.3,40.3,36.0,29.9,25.5,23.3,21.2,18.7,17.1,13.6; MS (EI, 70eV) m/z (%) 480 (M
+, 36), 121 (100); HRMS (EI) C
27h
32n
2o
6(M
+) calculated value: 480.2260, measured value: 480.2287.
The preparation of Preparation Example 20 (14S)-14 β-N-(3 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-205)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add m-aminophenyl amine hydrochlorate (18.8mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-205) (38.4mg, productive rate: 80%).
LLDT-205:
1h NMR (300MHz, CDCl
3) δ 6.99 (t, J=7.5Hz, 1H), 6.19-6.13 (m, 3H), 4.67 (s, 2H), 4.12-3.80 (m, 6H), 3.48-3.41 (m, 2H), 2.70 (m, 1H), 2.49 (sept, J=6.9Hz, 1H), 2.35-2.10 (m, 3H), (1.87 t, J=14.1Hz, 1H), (1.55 m, 1H), 1.25-1.14 (m, 1H), 1.08 (s, 3H), (0.98 d, J=6.9Hz, 3H), (0.92 d, J=5.7Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.5, and 149.0,147.5,130.1,125.3,106.8,105.3,101.4,73.2,69.9,68.2,65.2,64.6,56.1,55.7,54.5,50.0,40.3,36.0,29.9,25.6,23.4,21.2,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 480 (M
+, 7), 121 (100); HRMS (EI) C
27h
32n
2o
6(M
+) calculated value: 480.2260, measured value: 480.2251.
The preparation of Preparation Example 21 (14S)-14 β-N-(4 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-206)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add p-aminophenyl amine (10.8mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-aminophenyl)-aminomethyl Epitriptolide (LLDT-206) (38.4mg, productive rate: 80%).
LLDT-206:
1h NMR (300MHz, CDCl
3) δ 6.74-6.59 (m, 4H), 4.66 (s, 2H), (3.87-3.79 m, 3H), 3.47 (d, J=3.0Hz, 1H), 3.27 (d, J=12.9Hz, 1H), (2.70 m, 1H), 2.45 (sept, J=6.9Hz, 1H), 2.33-2.10 (m, 3H), (1.89 t, J=14.4Hz, 1H), (1.57 m, 1H), 1.25-1.14 (m, 1H), 1.07 (s, 3H), (0.96 d, J=6.9Hz, 3H), (0.92 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,160.5, and 140.4,139.7,125.2,117.1,117.1,116.4,116.4,72.7,69.9,68.4,65.2,64.6,56.2,55.8,54.5,51.6,40.3,36.0,30.0,25.6,23.4,21.2,18.8,17.1,13.7; MS (EI, 70eV) m/z (%) 480 (M
+, 3), 121 (100); HRMS (EI) C
27h
32n
2o
6(M
+) calculated value: 480.2260, measured value: 480.2258.
The preparation of Preparation Example 22 (14S)-14 β-N-(4 '-acetylamino phenyl)-aminomethyl Epitriptolide (LLDT-207)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add acetparaminosalol aniline (15.0mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-acetylamino phenyl)-aminomethyl Epitriptolide (LLDT-207) (41.7mg, productive rate: 80%).
LLDT-207：
1H NMR(300MHz，CDCl
3)δ7.31(d，J＝8.7Hz，2H)，7.21(s，1H)，6.72(d，J＝8.7Hz，2H)，4.67(s，2H)，4.19(brs，1H)，3.90-3.81(m，4H)，3.49(d，J＝3.3Hz，1H)，3.40(d，J＝13.5Hz，1H)，2.76-2.66(m，1H)，2.48(sept，J＝6.6Hz，1H)，2.36-2.11(m，6H)，1.88(t，J＝13.5Hz，1H)，1.55(dd，J＝12.3，4.2Hz，1H)，1.26-1.13(m，1H)，1.09(s，3H)，0.98(d，J＝6.6Hz，3H)，0.93(d，J＝6.6Hz，3H)；
13C NMR(CDCl
3，100MHz)δ173.3，168.2，160.4，144.9，130.0，125.3，121.9，121.9，115.0，115.0，73.2，69.9，68.2，65.2，64.6，56.1，55.8，54.5，50.5，40.3，36.0，30.0，25.7，24.2，23.4，21.2，18.8，17.1，13.7；MS(EI，70eV)m/z(％)522(M
+，20)，163(100).
The preparation of Preparation Example 23 (14S)-14 β-N-(2 '-methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-221)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 2-Methyl anthranilate (15.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(2 '-methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-221) (15.7mg, productive rate: 30%).
LLDT-221:
1h NMR (CDCl
3, 300MHz) δ 7.92 (d, J=8.1Hz, 1H), 7.42-7.36 (m, 1H), 6.97 (d, J=8.1Hz, 1H), 6.69 (t, J=8.1Hz, 1H), 4.67 (s, 2H), 3.96-3.81 (m, 6H), 3.50 (d, J=2.7Hz, 1H), 3.08 (s, 1H), 2.78-2.68 (m, 1H), 2.55 (sept, J=6.9Hz, 1H), 2.37-2.12 (m, 3H), 1.94 (t, J=13.5Hz, 1H), 1.57 (dd, J=11.4, 4.2Hz, 1H), 1.25-1.12 (m, 1H), 1.13 (s, 3H), 1.01 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.3,168.9, and 160.5,151.6,134.7,131.6,125.3,116.3,112.5,111.8,73.9,70.0,68.6,65.3,64.2,56.2,55.5,54.4,51.7,49.2,40.5,36.0,29.9,25.7,23.6,21.1,18.7,17.1,13.6, MS (EI, 70eV) m/z (%) 523 (M
+, 1), 164 (100), HRMS (EI) C
29h
33nO
8(M
+) calculated value: 523.2206, measured value: 523.2187.
The preparation of Preparation Example 24 (14S)-14 β-N-(3 '-methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-222)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3-Methyl anthranilate (15.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-222) (15.7mg, productive rate: 30%).
LLDT-222:
1h NMR (CDCl
3, 300MHz) δ 7.48-7.40 (m, 2H), 7.26 (t, J=7.8Hz, 1H), 6.96-6.91 (m, 1H), 4.67 (s, 2H), (4.50 brs, 1H), 3.94-3.81 (m, 6H), (3.57 s, 1H), 3.52-3.47 (m, 2H), (2.76-2.66 m, 1H), 2.51 (sept, J=6.9Hz, 1H), 2.36-2.12 (m, 3H), 1.89 (t, J=13.5Hz, 1H), 1.56 (dd, J=12.0,5.4Hz, 1H), 1.26-1.13 (m, 1H), (1.09 s, 3H), 1.00 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.2,167.1, and 160.3,148.0,131.0,129.3,125.3,120.2,118.7,115.2,73.5,69.9,68.1,65.2,64.5,56.1,55.8,54.5,52.1,49.8,40.3,36.0,29.9,25.7,23.4,21.1,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 523 (M
+, 4), 164 (100); HRMS (EI) C
29h
33nO
8(M
+) calculated value: 523.2206, measured value: 523.2208.
Preparation Example 25 (14S)-14 β-N-(3 '-methoxycarbonyl-4 '-hydroxy phenyl)-preparation of aminomethyl Epitriptolide (LLDT-223)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 2-hydroxyl-5-Methyl anthranilate (16.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtain white solid compound (14S)-14 β-N-(3 '-methoxycarbonyl-4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-223) (32.3mg, productive rate: 60%).
LLDT-223:
1h NMR (CDCl
3, 300MHz) δ 10.26 (s, 1H), 7.24 (d, J=2.4Hz, 1H), 7.00-6.96 (m, 1H), 6.88 (d, J=8.7Hz, 1H), 4.67 (s, 2H), 4.08-3.81 (m, 8H), 3.50 (d, J=3.3Hz, 1H), 3.31 (d, J=13.5Hz, 1H), 2.76-2.66 (m, 1H), 2.47 (sept, J=6.9Hz, 1H), 2.36-2.12 (m, 3H), 1.88 (t, J=14.1Hz, 1H), 1.55 (dd, J=12.3, 4.8Hz, 1H), 1.25-1.12 (m, 1H), 1.09 (s, 3H), 0.98 (d, J=6.9Hz, 3H), 0.93 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.2,170.1, and 160.3,155.9,139.3,125.3,124.9,118.4,115.2,112.1,73.0,69.9,68.1,65.2,64.7,56.3,55.9,54.5,52.3,51.6,40.3,36.0,30.0,25.7,23.4,21.2,18.8,17.1,13.7, MS (EI, 70eV) m/z (%) 539 (M
+, 23), 180 (100), HRMS (EI) C
29h
33nO
9(M
+) calculated value: 539.2156, measured value: 539.2166.
Preparation Example 26 (14S)-14 β-N-(2 '-methoxycarbonyl-4 '-hydroxy phenyl)-preparation of aminomethyl Epitriptolide (LLDT-224)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 2-amino-5-methyl hydroxybenzoate (16.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtain white solid compound (14S)-14 β-N-(2 '-methoxycarbonyl-4 '-hydroxy phenyl)-aminomethyl Epitriptolide (LLDT-224) (32.3mg, productive rate: 60%).
LLDT-224:
1h NMR (CDCl
3, 300MHz) δ 7.40 (d, J=2.4Hz, 1H), (7.03-6.90 m, 2H), 4.67 (s, 2H), (3.86-3.79 m, 6H), 3.61 (d, J=14.4Hz, 1H), 3.49 (d, J=3.0Hz, 1H), (2.76-2.66 m, 1H), 2.51 (sept, J=6.9Hz, 1H), 2.36-2.10 (m, 3H), 1.90 (t, J=13.2Hz, 1H), 1.55 (dd, J=11.1,3.6Hz, 1H), 1.25-1.12 (m, 1H), (1.11 s, 3H), 1.00 (d, J=6.9Hz, 3H), 0.92 (d, J=6.9Hz, 3H);
13cNMR (CDCl
3, 100MHz) δ 173.6,168.4, and 160.8,147.0,145.8,125.2,123.1,116.8,115.1,113.0,73.5,70.1,68.7,65.3,64.3,56.4,55.5,54.4,51.9,50.6,40.4,36.0,29.9,25.6,23.5,21.1,18.7,17.1,13.6; MS (EI, 70eV) m/z (%) 539 (M
+, 15), 342 (100), 180 (60); HRMS (EI) C
29h
33nO
9(M
+) calculated value: 539.2156, measured value: 539.2158.
Preparation Example 27 (14S)-14 β-N-(3 '-amino-5 '-the methoxycarbonyl phenyl)-preparation of aminomethyl Epitriptolide (LLDT-225)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3, 5-diamino-methyl benzoate (16.6mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtain white solid compound (14S)-14 β-N-(3 '-amino-5 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-225) (32.3mg, productive rate: 60%).
LLDT-225:
1h NMR (CDCl
3, 300MHz) δ 6.84-6.79 (m, 2H), 6.26 (s, 1H), 4.66 (s, 2H), 4.12-3.79 (m, 7H), 3.49 (d, J=3.0Hz, 1H), (3.45 d, J=12.9Hz, 1H), 2.74-2.64 (m, 1H), 2.49 (sept, J=6.9Hz, 1H), (2.36-2.12 m, 3H), 1.87 (t, J=13.5Hz, 1H), 1.55 (m, 1H), 1.25-1.12 (m, 1H), 1.07 (s, 3H), (0.98 d, J=6.9Hz, 3H), (0.92 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.3,167.2, and 160.4,149.1,147.5,131.9,125.3,107.3,106.1,104.8,73.5,69.9,68.2,65.2,64.5,56.1,55.7,54.5,52.0,49.7,40.3,36.0,29.9,25.6,23.4,21.1,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 538 (M
+, 8), 342 (22), 179 (100); HRMS (EI) C
29h
34n
2o
8(M
+) calculated value: 538.2315, measured value: 538.2321.
Preparation Example 28 (14S)-14 β-N-(4 '-acetylamino phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-226)
LLDT-207 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filtration obtains white solid (14S)-14 β-N-(4 '-acetylamino phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-226) (40mg, productive rate: 93%).
LLDT-226：
1H NMR(300MHz，CDCl
3)δ7.70(d，J＝8.7Hz，2H)，7.49(d，J＝8.7Hz，2H)，4.70(s，2H)，4.23-4.17(m，2H)，4.05(d，J＝14.1Hz，1H)，3.93(d，J＝3.3Hz，1H)，3.76-3.71(m，1H)，3.49(d，J＝3.3Hz，1H)，2.80-2.70(m，2H)，2.40-2.10(m，6H)，1.98(t，J＝13.5Hz，1H)，1.85(dd，J＝12.3，4.2Hz，1H)，1.15(s，3H)，0.96(d，J＝6.3Hz，3H)，0.92(d，J＝6.3Hz，3H)；MS(EI，70eV)m/z(％)522(M
+，20)，163(100).
Preparation Example 29 (14S)-14 β-N-(4 '-fluorophenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-227)
LLDT-217 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filtration obtains white solid (14S)-14 β-N-(4 '-fluorophenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-227) (40mg, productive rate: 93%).
LLDT-227：
1H NMR(CDCl
3，300MHz)δ7.67-7.60(m，2H)，7.21(t，J＝8.1Hz，2H)，5.85(brs，1H)，4.71(s，2H)，4.28-4.08(m，3H)，3.94(d，J＝2.7Hz，1H)，3.49(d，J＝2.7Hz，1H)，2.84-2.72(m，2H)，2.42-2.10(m，3H)，1.98(t，J＝14.4Hz，1H)，1.57(dd，J＝12.3，4.8Hz，1H)，1.30-1.18(m，1H)，1.15(s，3H)，0.96(d，J＝6.3Hz，3H)，0.92(d，J＝7.2Hz，3H)；MS(EI，70eV)m/z(％)483(M
+，4)，124(100).
Preparation Example 30 (14S)-14 β-N-(4 '-tolyl)-aminomethyl Epitriptolide hydrochloride (LLDT-228)
LLDT-203 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filtration obtains white solid (14S)-14 β-N-(4 '-tolyl)-aminomethyl Epitriptolide hydrochloride (LLDT-228) (40mg, productive rate: 93%).
LLDT-228：
1H NMR(300MHz，CDCl
3)δ7.42(d，J＝8.1Hz，2H)，7.27(d，J＝8.1Hz，2H)，5.78(brs，1H)，4.70(s，2H)，4.21-4.00(m，3H)，3.91(d，J＝3.3Hz，1H)，3.48(d，J＝2.7Hz，1H)，2.80-2.70(m，2H)，2.40-2.08(m，6H)，1.96(t，J＝13.8Hz，1H)，1.55(m，1H)，1.28-1.18(m，1H)，1.14(s，3H)，0.94(d，J＝6.9Hz，3H)，0.91(d，J＝6.9Hz，3H)；MS(EI，70eV)m/z(％)479(M
+，6)，120(100).
Preparation Example 31 (14S)-14 β-N-(4 '-p-methoxy-phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-229)
LLDT-210 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filtration obtains white solid (14S)-14 β-N-(4 '-p-methoxy-phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-229) (40mg, productive rate: 93%).
LLDT-229：
1H NMR(CDCl
3，300MHz)δ7.53(d，J＝9.0Hz，2H)，6.98(d，J＝8.4Hz，2H)，5.96(brs，1H)，4.70(s，2H)，4.25-4.05(m，3H)，3.93(d，J＝3.6Hz，1H)，3.83(s，3H)，3.48(d，J＝3.0Hz，1H)，2.85-2.72(m，2H)，2.42-2.10(m，3H)，1.98(t，J＝13.8Hz，1H)，1.57(m，1H)，1.30-1.18(m，1H)，1.16(s，3H)，0.96(d，J＝6.3Hz，3H)，0.92(d，J＝6.9Hz，3H)；MS(EI，70eV)m/z(％)495(M
+，17)，136(100).
Preparation Example 32 (14S)-14 β-N-(4 '-hydroxy phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-230)
LLDT-213 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filtration obtains white solid (14S)-14 β-N-(4 '-hydroxy phenyl)-aminomethyl Epitriptolide hydrochloride (LLDT-230) (40mg, productive rate: 93%).
LLDT-230：
1H NMR(CDCl
3，400MHz)δ7.26-7.20(m，2H)，6.81(d，J＝8.8Hz，2H)，4.67(m，2H)，4.01(d，J＝5.6Hz，1H)，3.91(d，J＝12.8Hz，1H)，3.82(d，J＝3.6Hz，1H)，3.70-3.64(m，2H)，3.41(d，J＝3.2Hz，1H)，2.70-2.55(m，2H)，2.28-2.00(m，3H)，1.89(t，J＝13.6Hz，1H)，1.45(dd，J＝12.8，4.8Hz，1H)，1.20-1.10(m，1H)，1.04(s，3H)，0.84(d，J＝6.4Hz，3H)，0.82(d，J＝6.8Hz，3H)；MS(EI，70eV)m/z(％)481(M
+，100).
Preparation Example 33 (14S)-14 β-N-(4 '-chloro-phenyl-)-aminomethyl Epitriptolide hydrochloride (LLDT-231)
LLDT-220 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filtration obtains white solid (14S)-14 β-N-(4 '-chloro-phenyl-)-aminomethyl Epitriptolide hydrochloride (LLDT-231) (40mg, productive rate: 93%).
LLDT-231：
1H NMR(CDCl
3，300MHz)δ7.44-7.35(m，4H)，4.70(s，2H)，4.16-3.90(m，4H)，3.49(d，J＝3.3Hz，1H)，2.80-2.65(m，2H)，2.40-1.90(m，4H)，1.59-1.53(m，1H)，1.28-1.16(m，1H)，1.13(s，3H)，0.94(d，J＝6.3Hz，6H)；MS(EI，70eV)m/z(％)499(M
+，3)，140(100).
Preparation Example 34 (14S)-14 β-N-(2 '-methoxycarbonyl-4 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-232)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 2-amino-5-fluorobenzoic acid methyl esters (16.6mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtain white solid compound (14S)-14 β-N-(2 '-methoxycarbonyl-4 '-fluorophenyl)-aminomethyl Epitriptolide (LLDT-232) (32.3mg, productive rate: 60%).
LLDT-232:
1h NMR (CDCl
3, 300MHz) δ 7.78 (brs, 1H), 7.61 (dd, J=9.9, 3.6Hz, 1H), 7.19-7.11 (m, 1H), 6.99-6.94 (m, 1H), 4.68 (s, 2H), 3.93-3.81 (m, 6H), 3.69-3.61 (m, 1H), 3.50 (d, J=3.0Hz, 1H), 3.14 (s, 1H), 2.79-2.69 (m, 1H), 2.51 (sept, J=6.6Hz, 1H), 2.38-2.10 (m, 3H), 1.94 (t, J=13.5Hz, 1H), 1.56 (m, 1H), 1.25-1.12 (m, 1H), 1.12 (s, 3H), 1.01 (d, J=6.6Hz, 3H), 0.93 (d, J=6.6Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.3,168.0, and 160.4,155.1,148.4,125.3,122.3,122.1,117.0,116.8,114.3,112.2,73.8,69.9,68.6,65.3,64.2,56.3,55.5,54.4,52.0,50.0,40.5,36.1,29.9,25.7,23.6,21.1,18.7,17.1,13.6, MS (EI, 70eV) m/z (%) 541 (M
+, 1), 182 (100), HRMS (EI) C
29h
32nFO
8(M
+) calculated value: 541.2112, measured value: 541.2121.
Preparation Example 35 (14S)-14 β-N-(2 '-hydroxyl-4 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-233)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3-hydroxy-4-aminobenzoic acid methyl esters (16.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtain white solid compound (14S)-14 β-N-(2 '-hydroxyl-4 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-233) (32.3mg, productive rate: 60%).
LLDT-233:
1h NMR (CDCl
3, 300MHz) δ 7.55 (d, J=9.0Hz, 1H), 7.53 (s, 1H), 7.27 (brs, 1H), 6.69 (d, J=8.4Hz, 1H), 4.66 (m, 2H), 3.90 (d, J=14.1Hz, 1H), 3.84 (s, 3H), 3.82 (d, J=3.3Hz, 1H), 3.77 (d, J=6.0Hz, 1H), 3.58 (d, J=14.4Hz, 1H), 3.51 (d, J=3.3Hz, 1H), 3.39 (s, 1H), 2.74-2.63 (m, 1H), 2.52 (sept, J=6.9Hz, 1H), 2.34-2.02 (m, 3H), 1.85 (t, J=14.1Hz, 1H), 1.53 (dd, J=11.7, 3.9Hz, 1H), 1.25-1.12 (m, 1H), 1.07 (s, 3H), 0.97 (d, J=6.9Hz, 3H), 0.91 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.6,167.7, and 160.7,143.2,141.8,125.2,124.0,118.6,114.9,109.7,74.0,70.1,68.3,65.3,64.3,56.0,55.6,54.5,51.8,49.0,40.3,36.0,29.8,25.7,23.4,21.0,18.7,17.0,13.6, MS (EI, 70eV) m/z (%) 539 (M
+, 24), 342 (100), HRMS (EI) C
29h
33nO
9(M
+) calculated value: 539.2155, measured value: 539.2154.
Preparation Example 36 (14S)-14 β-N-(2 '-hydroxyl-5 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-234)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3,4-AHBA methyl esters (16.7mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtain white solid compound (14S)-14 β-N-(2 '-hydroxyl-5 '-the methoxycarbonyl phenyl)-aminomethyl Epitriptolide (LLDT-234) (32.3mg, productive rate: 60%).
LLDT-234:
1h NMR (CDCl
3, 300MHz) δ 7.46 (s, 1H), 7.42 (d, J=7.5Hz, 1H), 6.82 (d, J=7.8Hz, 1H), 4.67 (s, 2H), 3.91-3.78 (m, 6H), 3.53-3.46 (m, 2H), 2.75-2.65 (m, 1H), 2.52 (sept, J=7.2Hz, 1H), (2.36-2.02 m, 3H), 1.85 (t, J=13.8Hz, 1H), 1.55 (m, 1H), 1.25-1.12 (m, 1H), 1.08 (s, 3H), (0.99 d, J=7.2Hz, 3H), (0.93 d, J=7.2Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.8,167.4, and 161.0,149.1,136.2,125.2,122.6,121.8,114.0,113.9,73.5,70.2,68.4,65.2,64.5,56.2,55.7,54.6,51.9,49.8,40.4,36.0,29.9,25.7,23.4,21.1,18.8,17.1,13.6; MS (EI, 70eV) m/z (%) 539 (M
+, 99), 342 (100); HRMS (EI) C
29h
33nO
9(M
+) calculated value: 539.2156, measured value: 539.2175.
Preparation Example 37 (14S)-14 β-N-(3 '-trifluoromethyl)-aminomethyl Epitriptolide (LLDT-235)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3-5-trifluoromethylaniline (16.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-trifluoromethyl)-aminomethyl Epitriptolide (LLDT-235) (42.6mg, productive rate: 80%).
LLDT-235:
1h NMR (CDCl
3, 300MHz) δ 7.30 (m, 1H), 7.03 (d, J=6.9Hz, 1H), 6.95 (s, 1H), 6.89 (d, J=8.4Hz, 1H), 4.67 (m, 3H), (3.93-3.81 m, 3H), 3.53-3.40 (m, 3H), (2.76-2.66 m, 1H), 2.50 (sept, J=7.2Hz, 1H), 2.38-2.10 (m, 3H), 1.90 (t, J=13.8Hz, 1H), 1.55 (dd, J=12.6,4.8Hz, 1H), 1.25-1.12 (m, 1H), (1.09 s, 3H), 0.99 (d, J=7.2Hz, 3H), 0.93 (d, J=7.2Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.2,160.3, and 148.3,132.0,131.7,131.4,131.1,129.7,125.4,122.7,117.1,115.4,110.7,74.4,69.9,68.1,65.2,64.5,56.1,55.8,54.5,49.7,40.3,36.0,29.9,25.7,23.4,21.1,18.7,17.1,13.6; MS (EI, 70eV) m/z (%) 533 (M
+, 4), 174 (100); HRMS (EI) C
28h
30nF
3o
6(M
+) calculated value: 533.2026, measured value: 533.2028.
Preparation Example 38 (14S)-14 β-N-(4 '-trifluoromethyl)-aminomethyl Epitriptolide (LLDT-236)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 4-5-trifluoromethylaniline (16.1mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-trifluoromethyl)-aminomethyl Epitriptolide (LLDT-236) (42.6mg, productive rate: 80%).
LLDT-236:
1h NMR (CDCl
3, 300MHz) δ 7.43 (d, J=8.7Hz, 2H), 6.75 (d, J=8.4Hz, 2H), 4.76-4.66 (m, 3H), 3.90 (d, J=13.2Hz, 1H), 3.85 (d, J=3.3Hz, 1H), 3.82 (d, J=5.4Hz, 1H), 3.56-3.46 (m, 2H), 3.19 (s, 1H), 2.78-2.68 (m, 1H), 2.50 (sept, J=6.9Hz, 1H), 2.38-2.12 (m, 3H), 1.90 (t, J=13.5Hz, 1H), 1.55 (dd, J=12.6, 4.8Hz, 1H), 1.25-1.12 (m, 1H), 1.09 (s, 3H), 0.99 (d, J=6.9Hz, 3H), 0.92 (d, J=6.9Hz, 3H),
13c NMR (CDCl
3, 100MHz) δ 173.2,160.2, and 150.7,126.6,126.6,126.0,125.4,123.3,120.8,120.6,120.2,120.0,113.2,113.2,73.9,69.9,68.0,65.2,64.4,56.1,55.8,54.5,49.3,40.3,36.0,29.9,25.7,23.4,21.1,18.7,17.1,13.7, MS (EI, 70eV) m/z (%) 533 (M
+, 4), 174 (100), HRMS (EI) C
28h
30nF
3o
6(M
+) calculated value: 533.2026, measured value: 533.2034.
Preparation Example 39 (14S)-14 β-N-(3 '-nitrophenyl)-aminomethyl Epitriptolide (LLDT-237)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 3-N-methyl-p-nitroaniline (13.8mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(3 '-nitrophenyl)-aminomethyl Epitriptolide (LLDT-237) (10.2mg, productive rate: 20%).
LLDT-237:
1h NMR (CDCl
3, 300MHz) δ 7.60-7.50 (m, 2H), 7.30 (t, J=8.7Hz, 1H), 7.02-6.98 (m, 1H), 4.93 (brs, 1H), (4.67 s, 2H), 3.91-3.81 (m, 3H), (3.54-3.46 m, 2H), 3.17 (s, 1H), (2.76-2.66 m, 1H), 2.51 (sept, J=6.9Hz, 1H), 2.36-2.12 (m, 3H), 1.90 (t, J=14.1Hz, 1H), 1.56 (dd, J=12.6,4.8Hz, 1H), 1.25-1.12 (m, 1H), (1.07 s, 3H), 0.98 (d, J=6.9Hz, 3H), 0.91 (d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.2,160.2, and 149.2,148.9,129.8,125.3,119.8,113.2,107.7,74.1,69.9,68.0,65.2,64.3,56.2,55.8,54.5,49.5,40.2,36.0,29.9,25.7,23.4,21.0,18.7,17.1,13.6; MS (EI, 70eV) m/z (%) 510 (M
+, 4), 151 (100); HRMS (EI) C
27h
30n
2o
8(M
+) calculated value: 510.2002, measured value: 510.2002.
Preparation Example 40 (14S)-14 β-N-(4 '-nitrophenyl)-aminomethyl Epitriptolide (LLDT-238)
By compound 4 (39mg, 0.1mmol) be dissolved in the 4mL acetonitrile solvent, add 4-N-methyl-p-nitroaniline (13.8mg, 0.1mmol), stirring at room 0.5h, add afterwards sodium triacetoxy borohydride (42mg, 0.2mmol), after reacting 4h under room temperature, stopped reaction, most of solvent decompression is steamed, after the residue thin up, be extracted with ethyl acetate, organic phase is water and saturated common salt water washing respectively, concentrated after anhydrous sodium sulfate drying, column chromatographic isolation and purification obtains white solid compound (14S)-14 β-N-(4 '-nitrophenyl)-aminomethyl Epitriptolide (LLDT-238) (10.2mg, productive rate: 20%).
LLDT-238:
1h NMR (CDCl
3, 300MHz) δ 8.10 (d, J=9.0Hz, 2H), (6.64 d, J=9.0Hz, 2H), 4.68 (s, 2H), 3.89 (d, J=3.3Hz, 1H), (3.86-3.79 m, 2H), 3.60-3.53 (m, 2H), (2.78-2.68 m, 1H), 2.51 (sept, J=6.9Hz, 1H), 2.38-2.12 (m, 3H), 1.92 (t, J=14.1Hz, 1H), 1.56 (m, 1H), (1.25-1.12 m, 1H), 1.09 (s, 3H), (0.97 d, J=6.9Hz, 3H), (0.91 d, J=6.9Hz, 3H);
13c NMR (CDCl
3, 100MHz) δ 173.1,159.9, and 153.2,138.8,126.3,126.3,125.5,111.9,111.9,74.9,69.9,67.9,65.3,64.2,56.2,55.8,54.6,48.8,40.3,36.1,29.9,25.8,23.4,20.9,18.6,17.1,13.6; MS (EI, 70eV) m/z (%) 510 (M
+, 4), 151 (100); HRMS (EI) C
27h
30n
2o
8(M
+) calculated value: 510.2002, measured value: 510.2031.
Preparation Example 41 (14S)-14 β-N-phenyl-aminomethyl Epitriptolide hydrochloride (LLDT-239)
LLDT-214 (40mg) is dissolved in the 4mL anhydrous diethyl ether, toward wherein passing into HCl gas, react after 2 hours, filter and obtain white solid (14S)-14 β-N-phenyl-aminomethyl Epitriptolide hydrochloride (LLDT-239) (40mg, productive rate: 93%).
LLDT-239：
1H NMR(CDCl
3，300MHz)δ7.65-7.49(m，5H)，6.00(brs，1H)，4.71(s，2H)，4.27-4.12(m，3H)，3.94(d，J＝3.0Hz，1H)，3.49(d，J＝3.3Hz，1H)，2.86-2.72(m，2H)，2.42-2.10(m，3H)，1.99(t，J＝13.8Hz，1H)，1.60-1.54(m，1H)，1.30-1.18(m，1H)，1.17(s，3H)，0.96(d，J＝6.6Hz，3H)，0.92(d，J＝6.9Hz，3H)；MS(EI，70eV)m/z(％)465(M
+，8)，106(100).
The inhibited proliferation experiment of the outer tumour cell of pharmacological evaluation embodiment human body
In following examples, test-compound is provided by chemosynthesis embodiment of the present invention.
Reagent material
SK-OV-3 human oophoroma cell line and PC-3 human prostate cancer cell line are purchased from U.S. ATCC (American Type Culture Collection).
Method
Tumour cell is cultivated with RPMI 1640 or DMEM substratum (Gibco), includes 10% foetal calf serum, and culture condition is 37 ℃, 5%CO
2.Tumor cell inoculation, in the 96-orifice plate, after 24 hours, adds test-compound.Each concentration is established three multiple holes.And the solvent of establishing respective concentration contrasts and acellular zeroing hole.Test-compound is mixed with proper concn by dimethyl sulfoxide (DMSO), and in substratum, the final concentration of test-compound is 0.0001-100 μ M; In substratum, the final concentration of dimethyl sulfoxide (DMSO) is no more than 0.1%.After processing 72 hours with test-compound, discard nutrient solution, with cold Tricholroacetic Acid fixed cell.Then use sulphonyl rhodamine B (Sulforhodamine B, SRB) solution-dyed.Wash away not in conjunction with after SRB, dissolve and protein bound SRB with Tris, by microplate reader, measure the OD value under the 520nm wavelength, with following formula, calculate inhibitory rate of cell growth:
Inhibiting rate=(OD value control wells-OD value dosing holes)/OD value control wells * 100%
According to each control of the concentration rate, adopt Logit method calculation of half inhibitory concentration IC
50.
The cytotoxic effect of table one, cultured tumor cells in vitro
| Compound | Cell strain | Tumor type | IC 50(nM) | Cell strain | Tumor type | IC 50(nM) |
| LLDT-201 | SK-OV-3 | Ovarian cancer | 227 | PC-3 | Prostate cancer | 300 |
| LLDT-202 | SK-OV-3 | Ovarian cancer | 109 | PC-3 | Prostate cancer | 150 |
| LLDT-203 | SK-OV-3 | Ovarian cancer | 33 | PC-3 | Prostate cancer | 110 |
| LLDT-208 | SK-OV-3 | Ovarian cancer | 50 | PC-3 | Prostate cancer | 60 |
| LLDT-209 | SK-OV-3 | Ovarian cancer | 175 | PC-3 | Prostate cancer | 194 |
| LLDT-210 | SK-OV-3 | Ovarian cancer | 31 | PC-3 | Prostate cancer | 52 |
| LLDT-215 | SK-OV-3 | Ovarian cancer | 640 | PC-3 | Prostate cancer | 660 |
| LLDT-216 | SK-OV-3 | Ovarian cancer | 514 | PC-3 | Prostate cancer | 450 |
| LLDT-217 | SK-OV-3 | Ovarian cancer | 56 | PC-3 | Prostate cancer | 68 |
| LLDT-218 | SK-OV-3 | Ovarian cancer | 600 | PC-3 | Prostate cancer | 1000 |
| LLDT-219 | SK-OV-3 | Ovarian cancer | 800 | PC-3 | Prostate cancer | 800 |
| LLDT-220 | SK-OV-3 | Ovarian cancer | 180 | PC-3 | Prostate cancer | 270 |
| LLDT-211 | SK-OV-3 | Ovarian cancer | 112 | PC-3 | Prostate cancer | 107 |
| LLDT-212 | SK-OV-3 | Ovarian cancer | 109 | PC-3 | Prostate cancer | 109 |
| LLDT-213 | SK-OV-3 | Ovarian cancer | 10 | PC-3 | Prostate cancer | 35 |
| LLDT-214 | SK-OV-3 | Ovarian cancer | 76 | PC-3 | Prostate cancer | 122 |
| LLDT-204 | SK-OV-3 | Ovarian cancer | 120 | PC-3 | Prostate cancer | 183 |
| LLDT-205 | SK-OV-3 | Ovarian cancer | 30 | PC-3 | Prostate cancer | 41 |
| LLDT-206 | SK-OV-3 | Ovarian cancer | 10 | PC-3 | Prostate cancer | 36 |
| LLDT-207 | SK-OV-3 | Ovarian cancer | 20 | PC-3 | Prostate cancer | 47 |
| LLDT-221 | SK-OV-3 | Ovarian cancer | 1539 | PC-3 | Prostate cancer | 1796 |
| LLDT-222 | SK-OV-3 | Ovarian cancer | 2150 | PC-3 | Prostate cancer | 1091 |
| LLDT-223 | SK-OV-3 | Ovarian cancer | 240 | PC-3 | Prostate cancer | 51 |
| LLDT-224 | SK-OV-3 | Ovarian cancer | 177 | PC-3 | Prostate cancer | 68 |
| LLDT-225 | SK-OV-3 | Ovarian cancer | 170 | PC-3 | Prostate cancer | 224 |
| LLDT-226 | SK-OV-3 | Ovarian cancer | 22 | PC-3 | Prostate cancer | 50 |
| LLDT-227 | SK-OV-3 | Ovarian cancer | 60 | PC-3 | Prostate cancer | 60 |
| LLDT-228 | SK-OV-3 | Ovarian cancer | 30 | PC-3 | Prostate cancer | 80 |
| LLDT-229 | SK-OV-3 | Ovarian cancer | 30 | PC-3 | Prostate cancer | 40 |
| LLDT-230 | SK-OV-3 | Ovarian cancer | 10 | PC-3 | Prostate cancer | 30 |
| LLDT-231 | SK-OV-3 | Ovarian cancer | 150 | PC-3 | Prostate cancer | 230 |
| LLDT-232 | SK-OV-3 | Ovarian cancer | 700 | PC-3 | Prostate cancer | 1300 |
| LLDT-233 | SK-OV-3 | Ovarian cancer | 5000 | PC-3 | Prostate cancer | 825 |
| LLDT-234 | SK-OV-3 | Ovarian cancer | 1000 | PC-3 | Prostate cancer | 200 |
| LLDT-235 | SK-OV-3 | Ovarian cancer | 1625 | PC-3 | Prostate cancer | 1800 |
| LLDT-236 | SK-OV-3 | Ovarian cancer | 5000 | PC-3 | Prostate cancer | 2000 |
| LLDT-237 | SK-OV-3 | Ovarian cancer | 1100 | PC-3 | Prostate cancer | 1327 |
| LLDT-238 | SK-OV-3 | Ovarian cancer | 395 | PC-3 | Prostate cancer | 741 |
| LLDT-239 | SK-OV-3 | Ovarian cancer | 60 | PC-3 | Prostate cancer | 120 |
Annotate: IC
50concentration while for testing compound, growth of tumour cell being suppressed to reach half 50%.
According to the above results, test-compound has very significantly cytotoxicity to the tumour cell of vitro culture, so novel tripterygium wilfordii diterpenes diterpenoids lactones derivative of the present invention or its pharmaceutically acceptable propagation that can effectively suppress genital system tumor, can be for the preparation of the medicine for the treatment of genital system tumor disease.
Claims (6)
1. tripterygium wilfordii diterpenes diterpenoids lactones derivative or its pharmacy acceptable salt shown in general formula (II-4),
Wherein,
The phenyl A replaced by a chlorine atom is not necessarily replaced by one or more substituting group, described substituting group be Cl, Br, R'' ,-CH
2r ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR' ,-NHCOR ,-NHCONHR ,-NHCONRR' ,-NHSO
2r ,-OH ,-OR'' ,-OCOR ,-OCONHR ,-OCONRR' ,-OSO
2r ,-COR ,-CONHR ,-CONRR' ,-SO
2nH
2,-SO
2nHR ,-SO
2nRR' or-S (O)
er, wherein e is 0,1,2 or 3;
R
2, R
3be H independently of one another;
Wherein, R, R' are identical or different C
1-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl;
R'' is C
2-C
10straight or branched alkyl, C
2-C
10straight or branched thiazolinyl, C
3-C
10cycloalkyl, phenyl, thienyl, furyl, pyridyl or pyrryl.
2. tripterygium wilfordii diterpenes diterpenoids lactones derivative or its pharmacy acceptable salt shown in general formula according to claim 1 (II-4), wherein, the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in described general formula (II-4) or its pharmacy acceptable salt are (4-1) (14S)-14 β-N-(2'-chloro-phenyl-)-aminomethyl Epitriptolide
(4-2) (14S)-14 β-N-(3'-chloro-phenyl-)-aminomethyl Epitriptolide
(4-3) (14S)-14 β-N-(4'-chloro-phenyl-)-aminomethyl Epitriptolide
(4-4) (14S)-14 β-N-(4'-chloro-phenyl-)-aminomethyl Epitriptolide hydrochloride
3. the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in the described general formula of claim 1 (II-4) or the preparation method of its pharmacy acceptable salt, is characterized in that, comprises the following steps:
(1) take Triptonide LLDT-l as initiator, in aprotic polar solvent, utilize chloromethyl dimethyl isopropoxy silane and reactive magnesium to generate the C of attack triptolide after Grignard reagent
14the position carbonyl obtains compound (2);
(2) the thick product of step (1) gained can, without separation, directly generate dihydroxyl compound (3) under the oxygenizement of hydrogen peroxide;
(3) compound (3) is oxidized to compound (4) under the effect of oxygenant;
(4) compound (4) and amino benzenes compounds
under the effect of sodium triacetoxy borohydride, reductive amination process occurs, generate the compound shown in general formula (II-4-i), wherein, at amino benzenes compounds
in, the phenyl A replaced by a chlorine atom is not necessarily replaced by one or more substituting group, described substituting group be Cl, Br, R'' ,-CH
2r ,-CF
3,-NO
2,-CN ,-NH
2,-NHR ,-NRR' ,-NHCOR ,-NHCONHR ,-NHCONRR' ,-NHSO
2r ,-OH ,-OR'' ,-OCOR ,-OCONHR ,-OCONRR' ,-OSO
2r ,-COR ,-CONHR ,-CONRR' ,-SO
2nH
2,-SO
2nHR ,-SO
2nRR' or-S (O)
er, wherein e be 0,1,2 or 3, R, R', R'' as claim 1, defined.
4. the tripterygium wilfordii diterpenes diterpenoids lactones derivative shown in general formula according to claim 3 (II-4) or the preparation method of its pharmacy acceptable salt, wherein,
Described aprotic polar solvent is selected from one or more in methyl-sulphoxide, DMF, methylene dichloride, trichloromethane, tetrahydrofuran (THF) and dioxane ethylene glycol bis methyl ether;
Described oxygenant is selected from one or more in two hydration sodium dichromate 99s, potassium bichromate, chromium trioxide, pyridinium dichromate, pyridinium chloro-chromate, ruthenium tetroxide, ceric ammonium nitrate, chromium trioxide two pyridinium salts and TEMPO-trichloroisocyanuric acid complex reagent;
The alkali that described alkaline condition is used can be selected from one or more in imidazoles, triethylamine, pyridine, salt of wormwood, n-Butyl Lithium, sodium carbonate, NaH and KH.
5. a pharmaceutical composition that is used for the treatment of tumour, it comprises one or more tripterygium wilfordii diterpenes diterpenoids lactones derivatives claimed in claim 1 or its pharmacy acceptable salt and the pharmaceutically acceptable auxiliary material for the treatment of significant quantity.
6. tripterygium wilfordii diterpenes diterpenoids lactones derivative claimed in claim 1 or its pharmacy acceptable salt purposes in the medicine for the preparation for the treatment of ovarian cancer or prostate cancer.
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|---|---|---|---|---|
| CN1261602A (en) * | 1999-04-16 | 2000-08-02 | 成都地奥制药集团有限公司 | Alcohol derivative of Triperygium wilfordii lactone and its application |
| CN1511838A (en) * | 2002-12-27 | 2004-07-14 | �й���ѧԺ�Ϻ�ҩ���о��� | Triptolide alcohol derivative and its use |
| CN1753666A (en) * | 2003-02-25 | 2006-03-29 | 美国泛华医药公司 | Halogenated triptolide derivatives as immunomodulators and anticancer agents |
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2010
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261602A (en) * | 1999-04-16 | 2000-08-02 | 成都地奥制药集团有限公司 | Alcohol derivative of Triperygium wilfordii lactone and its application |
| CN1511838A (en) * | 2002-12-27 | 2004-07-14 | �й���ѧԺ�Ϻ�ҩ���о��� | Triptolide alcohol derivative and its use |
| CN1753666A (en) * | 2003-02-25 | 2006-03-29 | 美国泛华医药公司 | Halogenated triptolide derivatives as immunomodulators and anticancer agents |
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