WO2014167581A2 - Procédé amélioré pour la préparation de promédicaments triptolides - Google Patents

Procédé amélioré pour la préparation de promédicaments triptolides Download PDF

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Publication number
WO2014167581A2
WO2014167581A2 PCT/IN2014/000203 IN2014000203W WO2014167581A2 WO 2014167581 A2 WO2014167581 A2 WO 2014167581A2 IN 2014000203 W IN2014000203 W IN 2014000203W WO 2014167581 A2 WO2014167581 A2 WO 2014167581A2
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formula
minnelide
compound
mixtures
sodium
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PCT/IN2014/000203
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English (en)
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WO2014167581A3 (fr
Inventor
Mani Bushan KOTALA
Venkata Lakshmi Narasimha Rao Dammalapati
Ravinder PALADI
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Laurus Labs Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present invention generally relates to an improved process for the preparation of disodium phosphonooxymethyl prodrug of triptolide (Minnelide).
  • the present invention also relates to minnelide in amorphous Form, processes for its preparation and pharmaceutical compositions containing the same.
  • Pancreatic cancer is one of the most lethal human malignancies with an all-stage 5- year survival frequency of ⁇ 5%,. which highlights the urgent need for more effective therapeutic strategies.
  • Triptolide a diterpenoid, is effective against pancreatic cancer cells in vitro as well as in vivo.
  • triptolide is poorly soluble in water, limiting its clinical use.
  • Minnelide a water-soluble analog of triptolide
  • Minnelide was tested both in vitro and in multiple independent yet complementary in vivo models of pancreatic cancer: an orthotopic model of pancreatic cancer using human pancreatic cancer cell lines in athymic nude mice, a xenograft model where human pancreatic tumors were transplanted into severe combined immune deficient mice, and a spontaneous pancreatic cancer mouse model.
  • Minnelide was highly effective in reducing pancreatic tumor growth and spread, and improving survival. Minnelide is presently under clinical trials.
  • Minnelide also known as disodium phosphonooxymethyl prodrug of triptolide, having the following formula 1 :
  • U.S. Patent No. 8,507,552 (“the '552 Patent”) discloses triptolide prodrugs such as minnelide.
  • the '552 patent further discloses a process for the preparation of minnelide, which includes the reaction of triptolide with dimethyl sulfoxide in high volume of acetic acid to yield thiomethyl intermediate, followed by phosphonylation and then deprotection and salt formation, which is schematically represented as follows:
  • the process of the present invention can be practiced on an industrial scale with minimizing the drawbacks associated with processes described in the art.
  • the main object of the invention is to provide a simple, cost effective process for the preparation of minnelide.
  • Another object of the invention is to provide a process for the preparation of minnelide in high yield and purity without the formation of undesired impurities and suitable for large scale production.
  • Another object of the invention is to provide a process for the preparation of minnelide, wherein the process excludes the use of excess quantity of reaction solvent, acetic acid thereby availability of acetyl group in the reaction is largely minimized so as to avoid the formation of acyl impurity, making the process simple and economical on an industrial scale.
  • Another object of the invention is to provide a process for the preparation of minnelide, which includes a base during the conversion of compound 3 in to compound 2 and a step of rapid silica gel chromatography of compound 2 under vacuum, thereby minimizing the acidic contact of product so as to avoiding the product degradation, making the process cost effective, particularly on large scale operations.
  • Yet another further object of the invention is to provide a process for the purification of minnelide by preparative High Performance Liquid Chromatography (HPLC) with a suitable eluent to minimize the process impurities.
  • Further object of the invention is to provide minnelide in an amorphous form obtained by the process of the present invention.
  • the present invention encompasses an improved process for the preparation of minnelide.
  • the present invention provides an improved process for preparation of minnelide of Formula 1,
  • the present invention provides an improved process for the preparation of minnelide of Formula 1 , comprising: reacting triptolide of Formula 4 with dimethyl sulfoxide in presence of acetic acid and acetic anhydride to obtain thiomethyl intermediate of formula 3, wherein the acetic acid is less than 20 volumes to the starting triptolide; and converting the compound of Formula 3 into minnelide of Formula 1.
  • the present invention provides an improved process for preparation of minnelide of Formula 1, comprising: reacting thiomethyl intermediate of formula 3 with dibenzyl phosphate and N-halo succinimide in presence of a base and a solvent to obtain a compound of Formula 2; and converting the compound of Formula 2 into minnelide of Formula 1.
  • the present invention provides an improved process for the preparation of minnelide of Formula 1, comprising:
  • step d) debenzylating the compound of Formula 2 of step c) with hydrogenation catalyst to obtain minnelide.
  • the present invention provides an improved process for preparation of minnelide of Formula 1 substantially free of one or more impurities of Formula A, Formula B, Formula C and Formula D, comprising:
  • step b) reacting the thiomethyl intermediate of formula 3 of step b) with dibenzyl phosphate and N-halo succinimide in presence of a base and a solvent to obtain a compound of formula 2 ;
  • step f) purifying the minnelide of formula 1 of step e) by preparative High Performance Liquid Chromatography (HPLC) using suitable solvent to obtain minnelide of Formula 1 substantially free of one or more of Formula A, Formula B, Formula C and Formula D.
  • HPLC High Performance Liquid Chromatography
  • the present invention provides an improved process for preparation of minnelide of Formula 1 substantially free of one or more of Formula A and Formula B, comprising:
  • the present invention provides a process for purification of minnelide of Formula 1, comprising:
  • the present invention provides a process for purification of minnelide of Formula 1 substantially free of one or more Formula C and Formula D, comprising:
  • the present invention provides an isolated compound of Formula A
  • the present invention provides an isolated compound of Formula C
  • the present invention provides an isolated compound of Formula D
  • the present invention provides minnelide having purity greater than about 98%, as measured by HPLC.
  • the present invention provides minnelide substantially free of one or more of Formula A, Formula B, Formula C and Formula D.
  • the present invention provides minnelide having total impurities less than 0.5%, as measured by HPLC.
  • the present invention provides minnelide having any single impurity less than 0.1%, as measured by HPLC. In a sixteenth embodiment, the present invention provides amorphous Form of minnelide.
  • the present invention provides amorphous Form of minnelide characterized by an X-Ray diffraction (XRD) pattern substantially in accordance with Figure 1.
  • XRD X-Ray diffraction
  • the present invention provides amorphous Form of minnelide characterized by thermo gravimetric analysis (TGA) thermogram substantially in accordance with Figure 2.
  • the present invention provides a pharmaceutical composition comprising minnelide prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Figure 1 is the characteristic powder X-ray diffraction (XRD) pattern of Minnelide.
  • Figure 2 is the characteristic thermo gravimetric analysis (TGA) of Minnelide.
  • the present invention encompasses an improved process for the preparation of minnelide with high product yield and quality.
  • the present invention encompasses an improved process to prepare minnelide, wherein the process includes one or more steps of using substantially less quantity of reaction solvent such as acetic acid to avoid formation of acyl impurity, use of base in the conversion of Formula 3 to Formula 2 and introducing rapid silica gel chromatography under vacuum to minimize the product degradation, thereby process more convenient and economical, particularly on commercial scale.
  • the present invention provides an improved process for preparation of minnelide of Formula 1,
  • minnelide of Formula 1 The starting material Triptolide of Formula 4 is known in the art and is a naturally occurring compound obtained from the plant Tripteygium wilfordii or commercially available from Aktin Chemicals, China.
  • the processes of preparation, isolation and purification of minnelide have an extraordinary economic significance as they make it possible to obtain a chemically pure substance that can be used for pharmaceutical purposes.
  • the chemical purity of the Active Pharmaceutical Ingredient (API) produced in an industrial scale is one of the critical parameters for its commercialization.
  • the step a) of foregoing process may be carried out with dimethyl sulfoxide in presence of acetic acid and acetic anhydride.
  • the '552' patent disclose use of about 50 volumes of acetic acid and reaction time about 5 days for step a) reaction. Use of excess quantity of acetic acid and extended period of reaction time in the conversion of compound 4 to compound 3 leads to formation of unwanted acyl and keto impurities, which are difficult to control. It has been observed that formation of the acyl and keto impurities in the step a) reaction may be dependent on the quantity of acetic acid used and the reaction time.
  • the inventors of the present invention tried various combinations of equivalents of acetic acid and reaction time to minimize the formation of the acyl and keto impurities. The inventors have found that use of less than 20 volumes of acetic acid to the starting triptolide and the reaction time of about 20 to 24 hours are considerably favorable.
  • the step a) of foregoing process can be carried out with dimethyl sulfoxide in presence of about 17 volumes of acetic acid and about 10 volumes acetic anhydride for a period of about 24 hours.
  • the reaction temperature should be sufficient to affect the step a) reaction.
  • the reaction temperature may be from about 0°C to about +60°C, preferably at about 20°C to about 30°C.
  • water may be added to the reaction mass for further dilution and extract the product with water immiscible organic solvent. Then the product containing water immiscible organic solvent can be evaporated under vacuum and then purified by a silica gel column chromatography system with a suitable eluent.
  • the water immiscible organic solvent include, but are not limited to esters such as ethyl acetate, isopropyl acetate and the like; ethers such as methyl tertiary butyl ether, diethyl ether and the like; aromatic hydrocarbons such as toluene, xylene and the like; halogenated solvents such as dichloromethane, chloroform and the like and mixtures thereof; preferably dichloromethane.
  • the suitable eluent for column chromatography includes, but are not limited to halogenated solvents, esters, hydrocarbons and the like and mixtures thereof.
  • halogenated solvents such as dichloromethane, chloroform and the like; esters such as methyl acetate, ethyl acetate, isopropyl acetate and the like; hydrocarbons such as hexane, cyclohexane, heptane and the like; and mixtures thereof.
  • column purification can be performed by using ethylacetate in hexane and the compound of Formula 3 can be eluted with about 0% to about 25% of ethyl acetate in hexane, preferably about 20% to about 25% and process impurities such as Acyl (Formula A) and Keto (Formula B) impurities can be eluted with about 25% to about 50% of ethyl acetate in hexane, preferably 30% to 40%».
  • impurities such as Acyl (Formula A) and Keto (Formula B) impurities
  • the compound of Formula 3 and process impurities such as Formula A and Formula B recovered using the process of the chromatography method of the invention can be characterized by various techniques like 1H-Nuclear magnetic resonance (NMR) and Mass spectrometry (MS).
  • NMR 1H-Nuclear magnetic resonance
  • MS Mass spectrometry
  • the present invention provides an isolated compound of Formula A:
  • the present invention provides an isolated compound of Formula A, wherein the compound of Formula A is characterized by:
  • the present invention provides an isolated compound of Formula B:
  • the present invention provides an isolated compound of Formula B, wherein the compound of Formula B is characterized by:
  • step b) of foregoing process can be carried out by reacting the thiomethyl intermediate of formula 3 obtained from step a) with dibenzyl phosphate and N-halo succinimide in presence of a base and a solvent to obtain a compound of Formula 2.
  • the N-halo succinimide can be selected from N-bromosuccinimide or N-iodo succinimide; preferably N-iodo succinimide.
  • the solvent of step b) includes, but is not limited to ethers, halogenated hydrocarbons, aromatic hydrocarbons, amides, nitriles and the like and mixtures thereof.
  • the ethers include, but are not limited to dimethyl ether, diethyl ether, methyl ethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 1,4-dioxane and the like and mixtures thereof;
  • halogenated hydrocarbons include, but are not limited to dichloromethane, ethylene chloride, chloroform and the like;
  • aromatic hydrocarbons include, but are not limited to toluene, xylene, chlorobenzene and the like; and mixtures thereof;
  • amides include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like and mixtures thereof;
  • nitriles include, but
  • a suitable base for use herein may be, for example, an inorganic base can be used and includes an alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate and the like; alkali metal bicarbonate such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride and the like; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; alkali metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium t-butoxide and the like.
  • an organic base may be used and includes primary, secondary or tertiary amine.
  • amines include, but are not limited to, triethylamine, tributylamine, diisopropylethylamine, diethylamine, N-methylmorpholine, pyridine, N,N- dimethylaniline, N,N-diethylaniline and the like and mixtures thereof.; and mixtures thereof.
  • the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine and the like; more preferably sodium carbonate.
  • the compound of Formula 2 obtained in step (b) is very unstable in acidic medium and it converts back into starting material triptolide rapidly.
  • step b) of foregoing process can be carried out by reacting the thiomethyl intermediate of formula 3 obtained from step a) with dibenzyl phosphate and N-iodo succinimide in presence of a base such as sodium carbonate and a solvent such as tetrahydrofuran to obtain a compound of Formula 2.
  • a base such as sodium carbonate
  • a solvent such as tetrahydrofuran
  • the step b) reaction can be carried out in a single solvent system such as tetrahydrofuran to avoid the emulsions formed, where the same formed when a mixed solvent system (mixture of tetrahydrofuran and dichloromethane) used as in the '552 patent.
  • a mixed solvent system mixture of tetrahydrofuran and dichloromethane
  • the reaction mass may be filtered and the obtained filterate may be treated with a suitable aqueous base such as sodium bicarbonate, sodium thiosulphate, potassium carbonate and the like and then extracting the product with an water immiscible organic solvent such as ethyl acetate, dichloromethane and the like.
  • the product containing water immiscible organic solvent may be evaporated under vacuum and then may be purified by a silica gel column chromatography system with a suitable eluent.
  • the compound of Formula 2 is highly unstable in solvent medium over extended period of time; the '552 patent disclose the compound of Formula 2 is purified by silica gel flash chromatography, which involves prolonged period of time to complete elution of the solvent system, which results degradation of the product. Hence purification in column chromatography with rapid elution of solvent system is necessary for obtaining a pure compound to minimize the product degradation.
  • the inventors of the present invention have surprisingly found that silica gel flash chromatography under vacuum is favorable to speedy solvent elution so as to minimizing the product degradation.
  • the present invention provides a process for purification of Formula 2 with a column chromatography under vacuum with a suitable eluent.
  • the suitable eluent for column chromatography includes, but are not limited to halogenated solvents such as dichloromethane, chloroform and the like, esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like, hydrocarbons such as hexane, heptane, cyclohexane and the like and mixtures thereof; preferably dichloromethane, ethyl acetate, hexane, heptane and the like; more preferably dichloromethane followed by ethyl acetate.
  • halogenated solvents such as dichloromethane, chloroform and the like, esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like, hydrocarbons such as hexane, heptane, cyclohexane and the like and mixtures thereof; preferably dichloromethane, ethyl
  • the vacuum for use herein may be, for example, a normal vacuum from about 300 mm/Hg to about 760 mm/Hg, preferably about 500 mm/Hg.
  • step (c) of the foregoing process involves debenzylation of the compound of Formula 2 obtained from step b).
  • the step of debenzylation may be carried out by reduction, preferably hydrogenation, more preferably catalytic hydrogenation.
  • the catalyst used for the catalytic hydrogenation is selected from metal catalysts such as platinum, palladium on carbon, rhodium, ruthenium and nickel; preferably palladium on carbon.
  • the catalyst may be used either wet or dry medium; particularly, palladium on carbon under dry medium is preferred.
  • the organic solvent of step c) includes, but is not limited to ethers, halogenated hydrocarbons such as dichloromethane, chloroform and the like; aromatic hydrocarbons such as toluene, xylene and the like; amides such as dimethyl formamide, dimethyl acetamide and the like; nitriles such as acetonitrile, propionitrile and the like; alcohols such as methanol, ethanol, isopropanol and the like and mixtures thereof; preferably tetrahydrofuran, dichloromethane and the like and mixtures thereof; more preferably tetrahydrofuran.
  • ethers halogenated hydrocarbons such as dichloromethane, chloroform and the like
  • aromatic hydrocarbons such as toluene, xylene and the like
  • amides such as dimethyl formamide, dimethyl acetamide and the like
  • nitriles such as acetonitrile, propionitrile and the
  • the reaction mass may be filtered and the obtained filterate may be diluted with water and treated with water immiscible organic solvent such as ethyl acetate, toluene, dichloromethane and the like and mixtures thereof; preferably dichloromethane.
  • the aqueous and the organic layers separated and the aqueous layer containing debenzylated product may be treated with a sodium base to obtain minnelide; the sodium base used in step c) is selected from sodium hydroxide, sodium carbonate, sodium methoxide or sodium bicarbonate, preferably sodium carbonate.
  • the minnelide product can be isolated from the resultant water by crystallization or lyophilization; preferably lyophilization.
  • the '552 Patent discloses addition of sodium carbonate solution to the reaction mass for saltification is done prior to the step of removal of impurities.
  • the impurities may not be removed completely once the same were saltified along with desired minnelide using sodium carbonate, which makes it is difficult to remove.
  • the solvent washings may be carried out using a water immiscible organic solvent such as ethyl acetate, dichloromethane, toluene and the like; preferably dichloromethane.
  • the present invention provides purification of crude minnelide obtained by the process of the present invention may contain about 3% to 4% of 0.5 RRT (Formula C) and 1.4 RRT (Formula D) impurities.
  • the quality of the crude minnelide can be improved by purifying the minnelide using preparative HPLC or solvent purification to remove such impurities.
  • the present invention provides, crude minnelide thus obtained may be purified by preparative HPLC method such as reverse phase chromatography.
  • the preparative HPLC can be performed using reverse phase chromatography and an eluent comprising an alcohol such as methanol, ethanol, isopropanol and the like, nitriles such as acetonitrile, propionitrile and the like; water and mixtures thereof; preferably mixture of methanol and water.
  • the reverse phase preparative chromatography column may be selected by any column known in the art, for example, 250x30 mm of Atlantis d-C18 with about 10 ⁇ particles with a flow rate of about 20 ml to 40 ml per minute, preferably about 30 ml per minute.
  • the present invention provides isolation of unwanted process impurities such as Formula C and Formula D formed during debenzylation of compound of formula 2 can be isolated by preparative HPLC. These impurities can be characterized by various techniques like H and C Nuclear magnetic resonance NMR) and Mass spectrometry (MS). isolated compound of
  • the present invention provides an isolated sodium salt of compound of Formula C, wherein the compound of Formula C is characterized by: 1H-NMR ⁇ , ppm (75 MHz, D 2 0): 4.89 (m, 2H), 4.79(m, 2H), 3.9(br, 1H), 3.9(br, 1H), 3.52(br, 1H), 3.39(br, 1H), 2.7(m, 1H), 2.25(m, 1H), 2.19(m, 1H), 2.14(m, lHa), 2.01(m, lHb), 1.89(m, lHb), 1.38(m, lHa), 1.24(m, lHb), 0.9(br, 3H), 0.84(br, 3H), 0.84(br, 3H).
  • the present invention provides an isolated compound of Formula D or a salt thereof.
  • the present invention provides minnelide prepared using the process of the invention having a purity greater than or equal to about 97%, as measured by HPLC, preferably about 98% as measured by HPLC, and more preferably about 99.5%, as measured by HPLC; substantially free of Formula A and Formula B impurities; wherein the word "substantially free” refers to minnelide having less than about 0.2% of Formula A, Formula B, Formula C or Formula D as measured by HPLC, preferably less than about 0.1% of Formula A, Formula B, Formula C or Formula, as measured by HPLC; more preferably less than about 0.05% of Formula A, Formula B, Formula C or Formula, as measured by HPLC.
  • the present invention provides minnelide having total impurities less than 0.5%, as measured by HPLC.
  • the present invention provides minnelide having any single impurity less than 0.1 %, as measured by HPLC.
  • the present invention provides minnelide prepared by the process of the present invention is an amorphous Form.
  • the present invention provides amorphous Form of minnelide. In a further embodiment, the present invention provides amorphous Form of minnelide, characterized by powder X-ray diffraction pattern substantially in accordance with Figure. 1.
  • the present invention provides amorphous Form of minnelide, characterized by thermo gravimetric analysis (TGA) substantially in accordance with Figure. 2.
  • the present invention provides a process for the preparation of amorphous minnelide of formula 1, comprising removing water from a solution comprising minnelide using lyophilization technique.
  • the solution comprising water and minnelide can be obtained by the procedure described as above or dissolving any form of minnelide prepared from known processes in water medium and removing the water from the solution using lyophilization technique as per the procedure known from the person skilled in the art.
  • the present invention provides*a pharmaceutical composition
  • a pharmaceutical composition comprising minnelide prepared by the processes of the present invention and at least one pharmaceutically acceptable excipient.
  • Such pharmaceutical composition may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, injectable solution, etc.
  • the present invention provides minnelide and its intermediates, obtained by the above process, as analyzed using high performance liquid chromatography (“HPLC”) with the conditions are tabulated below:
  • Triptolide (75.0g) was dissolved in dimethyl sulfoxide (1.2 lit) at 25-30°C under nitrogen atmosphere.
  • Acetic anhydride (0.75 lit) and acetic acid (1.27 lit) were added at 25-30°C under nitrogen atmosphere.
  • the reaction mixture was stirred at 25-30°C for 24h (under nitrogen balloon pressure). After completion of the reaction the reaction mixture was poured into ice cold water (6.4 lit), and extracted thrice with dichloromethane (3x2.25 lit). Organic layers were combined and washed with water (2x1.5 lit), saturated aq sodium bicarbonate solution (2x1.8 lit) and brine solution. Organic layers was dried over anhydrous sodium sulphate and filtered off.
  • the solid was purified by quick flash silica gel using column chromatography under vacuum eluted with 100% dichloromethane (2.5 lit) followed by 100% ethyl acetate (5 lit). Both the fractions were collected separately and ethyl acetate fractions containing title compound were concentrated under reduced pressure to afford a foamy solid. Yield: 60 gms (80%).
  • the TGA is set forth in Figure-2

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Abstract

La présente invention concerne un procédé amélioré pour la préparation de Minnelide avec un rendement élevé et une pureté élevée.
PCT/IN2014/000203 2013-04-01 2014-04-01 Procédé amélioré pour la préparation de promédicaments triptolides WO2014167581A2 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111518157B (zh) * 2020-06-11 2021-02-23 山东大学 一种雷公藤甲素衍生物及其制备方法和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012483A1 (fr) * 1998-09-02 2000-03-09 Pharmagenesis, Inc. Promedicaments de triptolides a solubilite dans l'eau elevee
EP1552829A1 (fr) * 2002-09-18 2005-07-13 Farreach Lab. Derives de triptolide presentant un puissant effet immunosuppresseur et une forte solubilite dans l'eau, utilisations de ces derives de triptolide
WO2010129918A1 (fr) * 2009-05-07 2010-11-11 Regents Of The University Of Minnesota Promédicaments à base de triptolide

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012483A1 (fr) * 1998-09-02 2000-03-09 Pharmagenesis, Inc. Promedicaments de triptolides a solubilite dans l'eau elevee
EP1552829A1 (fr) * 2002-09-18 2005-07-13 Farreach Lab. Derives de triptolide presentant un puissant effet immunosuppresseur et une forte solubilite dans l'eau, utilisations de ces derives de triptolide
WO2010129918A1 (fr) * 2009-05-07 2010-11-11 Regents Of The University Of Minnesota Promédicaments à base de triptolide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111518157B (zh) * 2020-06-11 2021-02-23 山东大学 一种雷公藤甲素衍生物及其制备方法和应用

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