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WO2001085710A1 - Composes anticancereux, procede de fabrication, et compositions pharmaceutiques renfermant ces composes - Google Patents

Composes anticancereux, procede de fabrication, et compositions pharmaceutiques renfermant ces composes Download PDF

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Publication number
WO2001085710A1
WO2001085710A1 PCT/IB2001/000748 IB0100748W WO0185710A1 WO 2001085710 A1 WO2001085710 A1 WO 2001085710A1 IB 0100748 W IB0100748 W IB 0100748W WO 0185710 A1 WO0185710 A1 WO 0185710A1
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Prior art keywords
compound
formula
andrographolide
disorders
diabetes
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PCT/IB2001/000748
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English (en)
Inventor
Srinivas Nanduri
Sairam Pothukuchi
Sriram Rajagopal
Venkateswarlu Akella
Sunilkumar Bhadramma Kochunarayana Pillai
Ranjan Chakrabarti
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Dr. Reddy's Research Foundation
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Priority to AU2001256570A priority Critical patent/AU2001256570A1/en
Publication of WO2001085710A1 publication Critical patent/WO2001085710A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to novel anticancer agents, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.
  • the present invention more particularly relates to novel derivatives of andrographolide, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.
  • the novel derivatives of andrographolide have the general formula (I),
  • R 1 , R 2 and R 3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroafoyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group -(CO)- -R 5 where W represents O, S or NR 6 , wherein R 6 represents hydrogen or (CrC 6 )alkyl group, R 5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR 2 and OR 3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R 4 represents hydrogen, halogen or XR 7 where X represents O,
  • the andrographolide derivatives represented by general formula (I) defined above of the present invention are useful for treating cancer and other proliferative diseases including but not limited to herpes simplex virus types I and II (HSN I and HSN II) and human immunodeficiency (HIN).
  • the compounds of the present invention axe also useful in the treatment of psoriasis, restenosis, atherosclerosis and other cardiovascular disorders.
  • the compounds of the present invention are also useful as antiviral, antimalarial, antibacterial, hepatoprotective, immunomodulating agents and for the treatment of metabolic disorders.
  • the anticancer activity exhibited may be through cytotoxic activity, antiproliferation, cell cycle kinase inhibition or may be through cell differentiation.
  • novel compounds of formula (I) are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, body weight reduction, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
  • the present invention also relates to pharmaceutical compositions containing compounds of general formula (I) or mixtures thereof.
  • the present invention also relates to a process for the preparation of the above- defined compounds of general formula (I), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates.
  • the plant andrographis paniculata is extensively used in medicine as a bitter tonic, febrifuge and in bowel complaints (Glossary of Indian Medicinal Plants., Ed. R. ⁇ . Chopra, S. L. ⁇ ayar, I.C. Chopra, pl8, 1996; The useful plants of India, Ed. By S. B. Ambasta, p39, 1992).
  • the plant is useful in the treatment of bacterial infections (Int. J. Crude Drug Res. 1990, 28(4), p273-283; Drugs of the Future 1990, 15(8) p809-816). It is reported to possess antimalarial (Int. J. Pharmacognosy,f l992, 30(4), p263-274; J.
  • Cell cycle kiriases are naturally occurring enzy nes involved in regulation of the cell cycle (Progress in Cell Cycle Research, 1995, 1, p351-363).
  • Typical enzymes include the cyclin-depehdent kinases (cdk) cdkl, cdk2, cdk4, cdk5, cdk6 and Wee-1 kinase.
  • cdk cyclin-depehdent kinases
  • cdk cyclin-depehdent kinases
  • Japanese patent application JP 63-88124 discloses a mixture of at least two compounds of formula Via, VIb,
  • R 1 , R 2 , R 3 , R 4 and R 5 represent hydrogen or lower alkanoyl group and their activity as antitumorogenic agents.
  • DASM dehydroandrographolide succinic acid monoester prepared from andrographolide of the formula II is found to be inhibiting HIV virus and nontoxic to the H9 cell at the concentrations of 50-200 ⁇ g/ml and was inhibitory to HIV-l(IIIB) at the minimal concentration of 1.6-3.1 ⁇ g/ml (Proc. Soc. Exp. Biol. Med., 1991, 197, p59-66).
  • the plant Andrographis paniculata is also reported to inhibit proprotein convertases-1, -7 and furin possibly by suppressing the proteolytic cleavage of envelops glycoprotein gp 160 of HIV, which is known to be PC-mediated, particularly by furin and PC (Biochem. J., 1999, 338, 107-113)
  • compositions containing one or more ingredients obtained from the plants Valeariana officinalis and / or A. paniculata were disclosed to have antiviral, antineoplastic, antibacterial and immunomodulatory activity.
  • novel andrographolide derivatives have been prepared, screened and reported in the above said prior-art literature for their anticancer activity, they are not showing interesting activity.
  • novel andrographolide derivatives useful for treating cancer, HSN, HIV, psoriasis, restenosis, atherosclerosis, cardiovascular disorders also useful ds antiviral, antimalarial, antibacterial, hepatoprotective, immunornodulating agents arid for treatment of metabolic disorders, which are potent at lower doses arid havirig better efficacy with lower toxicity ⁇ we focussed our research efforts in preparing the novel andrographolide derivatives of the formula (I) as defined above.
  • the main objective of the present invention is, therefore, to provide novel andrographolide derivatives of the formula (I) as defined above, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions co ⁇ taihirig them or their mixtures.
  • Another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates containing them or their mixtures in combination with suitable carriers, solvents, diluents and other media normally erhployed in preparing such compositions.
  • Still another objective of the present invention is to provide pharmaceutical compositions containing compounds of formula (I), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, containing them or their mixtures in combination with one or more pharmaceutically acceptable active compounds with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • Still another objective of the present invention is to provide a process for the preparation of novel Andrographolide derivatives of the formula (I) as defined above, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activity with little or no toxic effect or reduced toxic effect.
  • R 1 , R 2 and R 3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroaralkenoyl, sulfonyl group or a group -(CO)-W-R 5 where W represents O, S or NR 6 , wherein R 6 represents hydrogen or (d-C 6 )alkyl group, R 5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR 2 and OR 3 together form a substituted or unsubstituted 6 or 7 membered cyclic structure containing carbon and oxygen atoms; R 4 represents hydrogen, halogen or XR 7 where X represents O, S,
  • Suitable groups represented by R 1 , R 2 and R 3 include hydrogen, substituted or unsubstituted, linear or branched (C Cs) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; heteroaryl group such as pyridyl, furyl, thiophenyl and the like, the heteroaryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; heteroaralkyl group such as pyridylmethyl, pyridylethyl, furanmethyl, furanethyl and the like, the heteroaralkyl group may be substituted; (C 2 -C 8 ) alkanoyl group such as ethanoyl, propanpyl, butano
  • the substituerits oh R 9 and R 10 include hydroxy, halogen such as fluorine, chlorine, bromine and the like; nitro, cyano or amino, (Ci-C 6 )alkyl, (Q-C ⁇ alkoxy, aryl or aroyl groups.
  • Suitable groups represented by R 4 include hydrogen, halogen such as fluorine, chlorine, bromine arid the like; or XR 7 where R 7 represents hydrogen or linear or branched (Q-Cs) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like, the alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group rnay be substituted; aralkyl such as benzyl, pheriethyl and the like, the aralkyl group r ⁇ ay be substituted; (C 3 -C 8 ) alkenoyl group such as propenoyl, butenoyl, pentenoyl and the like, the alkenoyl group may be substituted; (C 2 -C 8 ) alkanoyl group such as ethanoyl, pr ⁇ pahoyl, butanoyl
  • Suitable groups represented by R 5 include ( -C ⁇ alkyl such as methyl, ethyl, n- propyl and the like, the (CrC 6 )alkyl group may be substituted; aryl group such as phenyl, naphthyl and the like, the aryl group may be substituted; aralkyl such as benzyl, phenethyl and the like, the aralkyl group may be substituted; aroyl group such as benzoyl and the like, the aroyl group may be substituted.
  • the substituents on the alkyl group, aromatic moiety of the aryl group, aralkyl group or aroyl group include halogen atom such as fluorine, chlorine and bromine; amino group, cyano, hydroxy, nitro, trifluoroethyl, (CrC 6 ) alkyl, (C ⁇ -C 6 ) alkoxy.
  • Suitable groups represented by R 6 include hydrogen, substituted or unsubstituted
  • ( -C ⁇ ) alkyl such as methyl, ethyl, n-propyl and the like.
  • the substituents on the alkyl group include halogen atom such as fluorine, chlorine and bromine; amino group, cyano, hydroxy, nitro, trifluoroethyl, ( -C ⁇ ) alkyl, (CrC 6 ) alkoxy.
  • R 1 , R 2 , R 3 , R 7 and R 8 may be selected from cyano, hydroxy, nitro, thio, halogen atom such as fluorine, chlorine, bromine and the like; substituted or unsubstituted groups selected from linear or branched (CpCg) alkyl group such as methyl, ethyl, n-propyl, iso-propyl and the like; amino, mono or disubstituted amino group; alkanoyl group such as ethanoyl, propanoyl, butanoyl and the like; thio(C 1 -C 8 )alkyl such as thiomethyl, thioethyl, thiopropyl and the like; (C 1 -C 6 )alkoxy group such as methoxy, ethoxy, propyloxy, butyloxy and the like; aroyl group such as benzoyl and the like; acyloxy group
  • (C C 8 )alkylthio group such as methylthio, ethylthio, propylthio and the like; heteroarylthio group such as pyridylthio, furylthio, thiophenylthio, benzothiazolethio, purinethio, benzimidazolethio, pyrimidinethio and the like; acylthio group such as acetylthio, propanoylthio, butanoylthio and the like; aralkylthio group such as benzylthio, phenylethylthio, phenylpropylthio and the like; arylthio group such as phenylthio, napthylthio and the like; ( -C ⁇ alkylseleno such as methylseleno, ethylseleno, propylselen
  • R 1 , R 2 , R 3 , R 5 , R 7 and R 8 represent disubstituted aryl
  • the two substituents on the adjacent carbon atoms form a linking group such as -X-CH 2 -Y-, -X- CH 2 -CH 2 -Y-, where X and Y may be same or different and independently represent O, NH, S or CH 2 .
  • salts forming part of this invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic bases such as N,N'-diacetylethylenediamine, betaine, caffeine, 2-diethylaminoethanol, 2-dimethylaminoethariol, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, diethanolamine, meglumine, ethylenediamine, N,N'- diphenylethylenediamine, N,N'-dibenzylethylenediamine, N-benzyl phenylethylamine, choline, choline,
  • Salts may include acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoate's, methanesulphonates, benzdates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • acid addition salts where appropriate which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoate's, methanesulphonates, benzdates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Particularly useful compounds according to present invention include:
  • the present invention also provides a process for the preparation of novel andrographolide of the general formula (I), where R 1 , R 2 and R 3 may be same or different and independently represent hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, heteroaroyl, aralkanoyl, aralkenoyl, heteroaralkanoyl, heteroalkenoyl, s ⁇ lf riyl group or a group -(CO)-W-R 5 where W represents O, S or NR 6 , wherein R 6 represents hydrogen or (d-C 6 )alkyl group, R 5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl or OR 2 arid OR 3 together for n a substituted or unsubstituted 6 or 7 membe e
  • R 1 , R 2 arid R 3 are as defined above and L represents hydroxy or a leaving group such as halogen atorri like fluorine, chlorine, bromine or iodine; p-tolueriesulforiate, methanesulfonate, trifluorornethanesulfonate and the like; or an alkanoate such as acetate, propanoate, butanoate arid the like, to produce a compound of formula (I), where all symbols are as defined earlier and R 4 represents hydrogen.
  • reaction of a compound of formula (VII) with R'-L and R 2 -L and R 3 -L, to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiirriide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like.
  • the reaction may be carried out in the absence or presence of a base selected frofn triethylamine, pyridine, dimethyl aminopyridine and the like.
  • the reaction rnay be carried out in the presence of solvents such as dichlofomethane, chloroform, C 6 H 6 , dimethyl sulfoxide, r ⁇ ethanol, ethanol and the like or fnixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 200 °C, preferably at a temperature in the range of 20 °C to 160 °C and the reaction tin ⁇ e may range from 2 to 12 h, preferably from 2 to 10 h.
  • the compounds of formula (I) may also be prepared by a process, which comprises:
  • R 4 represents hydrogen
  • P 1 and P 2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl arid the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1 -phenyl ethylidene, carbonate and the like,
  • R -L (IX) where R 1 and L have the meanings given above to produce a compound of formula (X), where R 1 , R 4 , P 1 and P 2 are as defined above,
  • R 1 and R 4 have the meanirigs given above,
  • the protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like.
  • the reaction may be carried out in the presence of a suitable catalyst such as SOCl 2 , H 2 SO , HClO 4 , pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like.
  • the reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 60 °C, preferably at a temperature in the range of 20 °C to 40 °C.
  • the reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
  • the reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like.
  • the reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like.
  • the reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C 6 H 6 , dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 200 °C, preferably at a temperature in the range of 20 °C to 160 °C and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
  • the deprotection of a compound of formula (X) to produce a compound of formula (XI) r ⁇ ay be carried out using deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like.
  • the reaction may be carried in the presence of suitable solvent such as water, THF, dioxane, DCM, CHC1 3 , methanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 60 °C, preferably at a temperature in the range of 20 °C to 40 °C.
  • the reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
  • reaction of compound of formula (XI) with R 2 -L and R 3 -L, to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like.
  • the reaction may be carried out in the absence or preserice of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like.
  • the reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C 6 H 6 , dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 200 °C, preferably at a temperature in the range of 20 °C to 160 °C and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
  • the compound of formula (XII) represents a compound of formula (I) when X represents O.
  • Convertion the compound of formula (I) to produce a compound of formula (XII) may be carried out in the presence of reagents such as SeO , t-Bu0 2 H, H 2 O 2 and the like.
  • reagents such as SeO , t-Bu0 2 H, H 2 O 2 and the like.
  • the reaction may be carried out in the presence of solvents such as DCM, CHC1 3 , benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof.
  • the temperature and duration of the reaction may be maintained in the range of 0 to 30°C and 3 to 48 h respectively.
  • the reaction of compound of formula (XII) with R 7 -L to produce a compound of formula (I) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like.
  • the reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like.
  • the reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C 6 H 6 , dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 200 °C, preferably at a temperature in the range of 20°C to 160°C and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
  • the compound of formula (XII) represents a compound of formula (I) when X represents O.
  • (XII) may be carried out in the presence of reagents such as SeO 2 , t-Bu0 2 H, H 2 O 2 and the like.
  • the reaction may be carried out in the presence of solvents such as DCM, CHC1 3 , benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof.
  • solvents such as DCM, CHC1 3 , benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof.
  • the temperature and duration of the reaction may be maintained in the range of 0 to 30°C and 3 to 48 h respectively.
  • the conversion of coriipound of formula (XII) to compound of formula (I) may be carried out using halogenating agents such as thionyl chloride, thionyl bromide, phosphonyl chloride, PC1 5 , PBr 3) bromine trifluoride, N-bromosuccinimide-hydrogen fluoride(NBS-HF), cobalt(III)fluoride, lithium fluoride, potassium fluoride, sodium fluoride, ceasium fluoride, potassium iodide, sodium iodide, iodine, iodine cerium(IV)ammonium nitrate or R 7 -L where R 7 and L are as defined above.
  • halogenating agents such as thionyl chloride, thionyl bromide, phosphonyl chloride, PC1 5 , PBr 3) bromine trifluoride, N-bromosuccinimide-hydrogen fluoride(NBS-HF), cobalt(
  • the reaction may be carried out in the presence of solvents such as ether, dichloromethane, chloroform, DMF, DMSO and the like;
  • the reaction may be carried out in the range of- 40°C to 160°C.
  • the duration of the reaction may range from 1 to 6 h.
  • a process for the preparation of the compound of formula (I) where R 4 represents halogen and other symbols are as defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates which comprises: reacting the compound of formula (I) where R 4 represents hydrogen and all other symbols are as defined earlier with suitable halogenating agent to produce a compound of formula (I), where R 4 represents halogen atom such as fluorine, chlorine, bromine or iodine
  • the reaction of compound of formula (I) where R 4 represents hydrogen with halogenating agents, to produce a compound of formula (I) where R 4 represents halogen may be carried out in the presence of reagents such as N-bromosucinimide(NBS), N- chlorosucinimide(NCS), N-iodosucinimide(NIS), bromine, chlorine, POCl 3 , PC1 3 , PBr 3 , SOCl , bromine trifluor
  • the reaction may be carried out in the presence of solvents such as DCM, CHC1 3 , benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof.
  • solvents such as DCM, CHC1 3 , benzene, THF, dioxane, DMF, methanol, ethanol and the like or mixtures thereof.
  • the temperature and duration of the reaction may be maintained in the range of -80 to 32°C and 3 to 48 h respectively.
  • R 1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl,, heteroaralkanoyl, heteroaralkenoyl, sulfonyl groups or a group -(CO)-W-R 5 where W represents O, S or NR , wherein R represents hydrogen or (C ⁇ -C 6 )alkyl group, R 5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or •aroyl; R 4 represents hydrogen; P 1 and P 2 may be same or different and independently represent trityl, t-butyldimethylsilyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or P 1 and P 2 together may
  • the present invention also provides a process for the preparation of the compound of formula (X), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises: (i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (Nil) with suitable protecting groups using conventional methods to produce a compound of formula (NIII), where R 4 represents hydrogen; P 1 and P 2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as acetate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1 -phenyl ethylidene, carbonate and the like,
  • R 1 , R 4 , P 1 and P 2 are as defined earlier.
  • the protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like.
  • the reaction may be carried out in the presence of a suitable catalyst such as SOCl 2 , H 2 SO , HClO , pyridinium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like.
  • the reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof.
  • the reactiori may be carried out ' at a temperature in the range of 0 °C to 60 °C, preferably at a temperature in the range of 20 °C to 40 °C.
  • the reaction tirr ⁇ e may range fr ⁇ rri 2 to 6 h, preferably frorn 2 to 4 h.
  • the reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a cor ⁇ pound of forrnula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like.
  • the reaction may be carried out in the absence or presence of a base selected from triethylamine, ' pyridine, dimethyl arniriopyridine and the like.
  • the reaction rfiay be carried out iri the presence of solvents such as dichloromethane, chloroform, C 6 H 6 , dirriethyl sulfoxide, methanol, ethariol and the like or ftiixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 200 °C, preferably at a temperature in the range of 20 °C to 160 °C arid the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
  • R 1 represents hydrogen or substituted or unsubstituted groups selected from alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, alkenoyl, aroyl, aralkanoyl, aralkenoyl, heteroaroyl,, heteroa alkarioyl, heteroaralkenoyl, sulfonyl groups or a group -(CO)-W- R 5 where W represents O, S or NR 6 , wherein R 6 represents hydrogen or (C ⁇ -C 6 )alkyl group, R 5 represents substituted or unsubstituted groups selected from alkyl, aryl, aralkyl or aroyl and R 4 represents hydrogen.
  • the present invention also provides a process for the preparation of the compound of formula (XI), their stereoisomers, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, which comprises: (i) protecting the hydroxy groups present on carbons 3 or 19 or 3 and 19 together in the compound of formula (VII) with suitable protecting groups using conventional methods to produce a compound of formula (VIII),
  • R 4 represents hydrogen
  • P 1 and P 2 may be same or different and represent hydrogen, trityl, t-butyl dimethyl silyl, pivaloyl and the like or esters such as ace ate, propionate, benzoate and the like or together may form methylene dioxy, isopropylidene, benzylidene, 1 -phenyl ethylidene, carbonate and the like,
  • R 1 and R 4 have the meanings given above.
  • the protection of a compound of formula (VII) may be carried out using trityl chloride, t-butyldimethylsilyl chloride, pivaloyl chloride, dimethylsulfoxide, acetone, 2,2-dimethoxy propane, trimethyl ortho acetate, benzaldehyde, p-methoxy benzaldehyde and the like.
  • the reaction may be carried out in the preserice of a suitable catalyst such as SOCl 2 , H 2 SO , HClO 4 , pyridi ⁇ ium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like.
  • a suitable catalyst such as SOCl 2 , H 2 SO , HClO 4 , pyridi ⁇ ium p-toluene sulphonate, pyridine, p-toluene sulfonic acid, dimethyl aminopyridine, and the like.
  • the reaction may be carried out in the absence or presence of suitable solvent such as benzene, DMF, DMSO, acetonitrile, DCM, and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 60 °C, preferably at a temperature in the range of 20 °C to 40 °
  • the reaction time may range from 2 to 6 h, preferably from 2 to 4 h.
  • the reaction of a compound of formula (VIII) with a compound of formula (IX) to produce a compound of formula (X) may be carried out in the presence of dicyclohexylcarbodiimide (DCC), diethyl azadicarboxylate (DEAD), diisopropyl azadicarboxylate (DIAD) and the like.
  • the reaction may be carried out in the absence or presence of a base selected from triethylamine, pyridine, dimethyl aminopyridine and the like.
  • the reaction may be carried out in the presence of solvents such as dichloromethane, chloroform, C 6 H 6 , dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof.
  • solvents such as dichloromethane, chloroform, C 6 H 6 , dimethyl sulfoxide, methanol, ethanol and the like or mixtures thereof.
  • the reaction may be carried out at a temperature in the range of 0 °C to 200 °C, preferably at a temperature in the range of 20 °C to 160 °C and the reaction time may range from 2 to 12 h, preferably from 2 to 10 h.
  • the deprotection of a compound of formula (X) to produce a compound of formula (XI) may be carried out using deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like.
  • deprotecting agent such as acetic acid, hydrochloric acid, formic acid, trifluoroacetic acid and the like.
  • the reaction may be carried in the presence of suitable solvent such as water, THF, dioxane, DCM, CHC1 3 , methanol and the like or mixtures thereof.
  • the reaction may be carried out at a
  • the reaction time may range from 2 to 6 h* preferably from 2 to 4 h.
  • Suitable protecting groups in any of the above-mentioned reactions are those used conventionally in the art.
  • the methods of formation and removal of such protecting groups are those conventional methods appropriate to the fnolecule being protected.
  • the compound of formula (I) when produced through an intermediate compound, conventional functional group transformations such as hydrolysis, reduction or oxidation may be carried out.
  • the compound of formula (I) where R 1 , R 2 or R 3 are multi substituted and the two substituents may form a linking group -X-(CR ⁇ R 12 ) n -Y-, which may be converted to a compound of formula (I), where R 1 , R 2 or R 3 are multisubstituted and the substituents are independent.
  • the pharmaceutically acceptable salts are prepared by reacting the compounds of formula (I) wherever applicable with 1 to 4 equivalents of a base such as sodium hydroxide, sodium methoxide, sodium hydride, potassium t-butoxide, calcium hydroxide, magnesiui ⁇ hydroxide and the like, in solvents like ether, THF, methanol, t- butanol, dioxane, isopropanol, ethanol etc. Mixture of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, tromethamine, guanidine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
  • stereoisomers of the compounds of formula (I) forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid and the like or chiral bases such as brucine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al. in "Enantiomers, Recemates and Resolution” (Wiley Interscience, 1981).
  • polymorphs of cor ⁇ pound of general formula (I) forming part of this invention may be prepared by crystallization of compound of formula (I) under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperature ' s; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polyrhorphs may also be obtained by heating or melting the compound followed by gradual or slow cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray data or such other techniques.
  • Pharmaceutically acceptable solvates of compound of formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of formula (I) in solvents such as water, methanol, ethanol etc., preferably water and recrystallizing by using different crystallization techniques.
  • the present invention also envisages pharmaceutical compositions containing compounds of the formula (I) defined earlier, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates or their mixtures in combination with the usual pharmaceutically employed carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc.
  • compositions typically contain from 1 to 25 %, preferably 1 to 15 % by weight of active compound, the remainder of the composition may be pharmaceutically acceptable carriers, diluents or solvents and also contain other active ingredients.
  • the compounds of the formula (I) as defined above are clinically administered to mammals, including man, via either oral or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection. However, in circumstances where the patient cannot swallow the medication, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
  • the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight p ' er day administered singly or as a divided dose.
  • Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical coriipositions may, if desired, contain additional components such as', fiavourarits, sweeteners, excipients arid the like.
  • the compounds cari be corribined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions for example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or salts with base of the compounds, the injectable soluti ns prepared in this r ⁇ anner can then be administered intravenously, LTDraperit ⁇ neally, subcutaneously, i . or intrarriuscularly, with intrariiuscular administration being preferred in humans.
  • the invention is explained in detail in the examples given below which are provided by way of illustration only arid therefore should not be construed to limit the scope of the invention.
  • N-Isopropyl isocyanate was prepared by adding a solution of isopropyl amine(1.2 ml) and triethyl amine (1.87 ml) in toluene (10 ml) to a stirred solution of tri- phosgene (1.25 g) in 30 ml toluene and heated at 100°C for 1 h. The reaction mixture was cooled, to this a solution of 3,19-isopropylidene andrographolide (700 mg)(obtained in example 1) and triethyl amine (1.87 ml) in toluene (25 ml) was added. The contents were stirred for 48 h at room temperature. The reaction was monitored by TLC.
  • Step 2 To a solution of 14-[4'S,5'R-(N-t-butoxycarbonyl)-2',2'-dimethyl-4'-phenyl-5'- oxazolidine]carbonyl-3,l 9-isopropylidene andrographolide obtained in step 1, in acetic anhydride (50 ml) at 80°C, zinc chloride (500 mg) was added in 100 mg portions over a period of 30 min. Stirring continued for another 30 min. The reaction was monitored by TLC. After confirming the completion of the reaction, the reaction mixture was poured into water, extracted with dichloromethane, dried over Na 2 SO 4 and concentrated.
  • Example 17 3,19-Diacetyl-14-[4'S,5'R-(N-t-b ⁇ toxycarbonyl)-2',2'-dimethyl-4'- phenyl-5'-oxazolidine]carbonyl andrographolide
  • Step 2 14-[4'S,5'R-(N-t-butoxycarbony l)-2 ' ,2 ' -dimethyl-4 ' -phenyl-5 ' -oxazolidine] carbonyl andrographolide (1.65 g), which was used further without purification.
  • Step 2 14-[4'S,5'R-(N-t-butoxycarbonyl)-2',2'-dimethyl-4'-phenyl-5'-oxazolidine] carbonyl andrographolide (1.15 g) obtained above was refluxed in acetic andhydride (40 ml) for about 15 min. The reaction was monitored by TLC.
  • Step 3 14-(N-Boc-glycinyl)andrographolide (200 mg) (obtained in step 2) was refluxed in propionic anhydride (20 ml) for about 10 min. The reaction was monitored by TLC. After confirming the completion of the reaction, the reaction mixture was cooled, poured into water, extracted with dichloromethane. The organic layer was separated, dried over Na 2 SO 4 and concentrated.
  • 14-(N-Boc-glycinyl)andrographolide (300 mg) (obtained in example 20, step 2) was refluxed in acetic anhydride (15 ml) for about 15 min. The reaction was monitored by TLC. After confirming the completion of the reaction, the reaction mixture was cooled, poured into water, extracted with dichloromethane. The organic layer was separated, dried over Na 2 SO 4 and concentrated.
  • Step 1 A mixture of 3,19-isopropylidene andrographolide (500 mg), obtained in example 1, calcium sulphate (555 mg), silver oxide (500 mg) and ethyl iodide (5 ml) were stirred at room temperature for 18 h. The reaction was monitored by TLC. After confirming the completion of the reaction, the inorganic solids were filtered, washed with dichloromethane.
  • Step 1 A mixture of 3,19-isopropylidene andrographolide (500 mg) (obtained in example 1), calcium sulphate (500 mg), silver oxide (480 mg) and methyl iodide (1.5ml) were stirred at room temperature for 18h. The reaction was monitored by TLC. After confirming the completion of the reaction, the reaction mixture was diluted with dichloromethane, inorganic solids were filtered, washed with dichloromethane.
  • Step 2 14-O-methy 1-3,19-isopropylidene andrographolide (550 mg) obtained in step 1, was treated with 25 ml of methanolic HCl (25 ml methanol : 200 ⁇ l HCl) at room temperature for about 2-5 min. The reaction was monitored by TLC.
  • reaction mixture was diluted with dichloromethane, washed with saturated aq. NaHCO 3) followed by water and dried over Na 2 SO 4 .
  • Step 3 A mixture of 14-(3,4-dimethoxy)cinnamoyl andrographolide (650 mg) and acetic anhydride (10 ml) was refluxed for about 15 min. The reaction was monitored by TLC.
  • 3,14-Diacetyl-19-trityl andrographolide (800 mg) obtained in step 1 was treated with a mixture of formic acid and dichloromethane (1:1) 20 ml for 10 min at room temperature. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with aq. NaHC0 3 followed by water and dried over Na 2 SO 4 . The residue obtained after " removal of solvent was chromatographed over a column of silica gel (230-400 riiesh; using chlorform : acetone
  • Anti-cancer activity The compounds prepared in the present invention exhibited good in vitro anti- cancer activity towards various human tumor cell lines.
  • test compound was screened against a battery of cell lines representing eight different types of cancers.
  • 1X10 4 cells were seeded into each well of 96 well plate in lOO ⁇ L volume of RPMI 1640 medium containing antibiotics and 10% FCS.
  • test compounds were evaluated at five 10 fold dilutions ranging from 100 to 0.01 ⁇ M.
  • medium with vehicle was added to control wells and the plates were further incubated. After 48 h of incubation, plates were terminated by Sulforhodamine B method.
  • the optical density which is proportional to protein mass, is then read by automated spectrophotometric plate reader at a wavelength of 515 nm. Readings were transferred to a microcomputer and mean 50 % Growth Inhibition (GI50).
  • the compounds of the present invention showed anticaricer activity, which can be seen from the data given below:
  • mice Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition (NIN), India) and acidified water, ad libitum. The animals having more than 350 mg / dl blood sugar were used for testing. The number of animals in each group was 4.
  • Test compounds were suspended in chemophore/DMSO/H 2 O and administered to test group at a dose of 1 mg to 500 mg / kg through oral gavage daily for 6 days.
  • the control group received vehicle (dose 10 ml / kg).
  • the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
  • the random blood sugar and triglyceride levels were measured by collecting blood (100 ⁇ l) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma.
  • the plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-PO 4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, India) methods respectively.
  • Body weight of the animals were measured at the beginning and at the end of the study period.
  • mice Male Swiss albino mice (SAM) were obtained from NIN and housed in DRF animal house. All these animals were maintained under 12 hour light and dark cycle at 25 + 1 °C. Animals were given standard laboratory chow (NIN,
  • test compounds were administered orally to Swiss albino mice at 30 to 500 mg/kg/day dose for 6 days. Control mice were treated with vehicle
  • the blood samples were collected in fed state 1 hour after drag administration on 0 and 6 day of treatment.
  • the blood was collected from the retro-orbital sinus through heparinised capillary in EDTA containing tubes. After centrifugation, plasma sample was separated for triglyceride (Wieland, O. Methods of Enzymatic analysis. Bergermeyer, H. O., Ed., 1963. 211 - 214; Trinder, P. Ann. Clin. Biochem. 1969. 6 : 24 - 27).
  • Measurement of plasma triglyceride was done using commercial kits (Dr. Reddy's Diagnostic Division, India).
  • Human CD4+ T cell line PM-1 used in the assay was cultured in RPMI-1640 medium containing 10% Fetal bovine serum, 2g/L sodium bicarbonate, 100,000 units/L Pencillin-G arid 100 mg/L streptomycin. Healthy PM-1 cells were plated on the first day in a 96 well plate at 2* 10 6 cells per well. After 24 h HIV-l/MN was added to the culture and incubated for 2 h for infection. Cells were washed twice with PBS to remove the virus in the culture. Different concentrations of DRF compounds ranging from 10 "4 to 10 "8 M were added to the culture and incubated for 96 h.
  • the viability of cells was then assessed by standard MTT assay and the viral antigen P24 levels were estirriated by ELISA method. Based on the MTT assay values the P 24 antigen values were corrected. All the samples were tested in triplicates and the average was used for calculations. AZT was used as standard compound for comparision.
  • Human lymphocytes were isolated from whole blood by using Ficoll Hypaque Plus (Amersham). On day one, 1 million lymphocytes were seeded into each well of 96 well plate in 100 ⁇ L volume of RPMI 1640 medium ' containing 10%FCS and Phytohemagglutitin A at 1 ⁇ g/well concentration. Plates were incubated at 37°C in CO 2 incubator for 24 h. Test compounds at various concentrations were added to test wells and only medium with vehicle was added to control wells. After 48 h of incubation 0.5 mCi of tritiated thymidine was added to each well. After 24 h of thymidine addition the cells were harvested and the incorporated radioactivity was determined. Stimulation Index (SI) was calculated using the formula,
  • a ⁇ Average CPM of treated wells
  • a c Average CPM of control wells.

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Abstract

L'invention concerne des dérivés d'andrographolide, leurs stéréoisomères, leurs polymorphes, leurs sels pharmaceutiquement acceptables et leurs solvates pharmaceutiquement acceptables. Ces dérivés, représentés par la formule générale (I), sont utiles pour le traitement des maladies suivantes: cancer, HSV, VIH, psoriasis, resténose, athérosclerose et autres affections cardiovasculaires. Ils sont également utiles comme agents antiviraux, antipaludiques, antibactériens, hépatoprotecteurs, immunomodulateurs, et aussi pour le traitement des troubles du métabolisme.
PCT/IB2001/000748 2000-05-05 2001-05-03 Composes anticancereux, procede de fabrication, et compositions pharmaceutiques renfermant ces composes WO2001085710A1 (fr)

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JP2008519066A (ja) * 2004-11-08 2008-06-05 コーネル リサーチ ファンデーション インコーポレーティッド ウイルス感染症を処置するためのアンドログラフォライド（ａｎｄｒｏｇｒａｐｈｏｌｉｄｅ）誘導体
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CN102716122A (zh) * 2012-07-03 2012-10-10 郑州大学 15-苄亚基-14-脱氧-11,12-脱氢穿心莲内酯衍生物在制备治疗糖尿病药物中的应用
CN103145665A (zh) * 2012-04-12 2013-06-12 江西青峰药业有限公司 17-氢-9-去氢-14，17-环-穿心莲内酯-19-硫酸酯化物、制备方法及其制备药物用途
CN103224492A (zh) * 2013-04-15 2013-07-31 南京工业大学 14-芳基醚穿心莲內酯衍生物及其制备方法和应用
CN104119251A (zh) * 2013-04-24 2014-10-29 江西青峰药业有限公司 9-去氢-穿心莲内酯-17-磺酸-16-羧酸或其盐、制备方法及其制备药物用途
CN104119253A (zh) * 2013-04-24 2014-10-29 江西青峰药业有限公司 一种穿心莲内酯衍生物的药物组合物及其制备方法与用途
WO2016065264A1 (fr) * 2014-10-24 2016-04-28 Biogen Ma Inc. Dérivés de diterpénoïdes et leurs procédés d'utilisation
CN106432153A (zh) * 2016-10-13 2017-02-22 四川理工学院 一类含硫穿心莲内酯衍生物、其药物组合物、合成方法、在制备治疗前列腺癌药物中的应用
CN108084122A (zh) * 2018-01-30 2018-05-29 北海开元生物科技有限公司 一种高纯度穿心莲内酯的提取方法
CN108129468A (zh) * 2018-01-29 2018-06-08 四川理工学院 一类阿司匹林衍生物及其制法和应用
CN108904446A (zh) * 2018-06-11 2018-11-30 中山大学 一种动脉斑块微环境响应的载药纳米胶束的制备方法及应用
CN109568265A (zh) * 2017-09-28 2019-04-05 神威药业集团有限公司 一种穿心莲内酯纳米混悬剂
CN113173896A (zh) * 2021-04-14 2021-07-27 张洪胜 一种抗氧化活性的阿魏酸衍生物及其制备方法

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US7794753B2 (en) 2003-03-31 2010-09-14 Council Of Scientific And Industrial Research Synergistic hepatoprotective composition and a method thereof
WO2004087127A1 (fr) * 2003-03-31 2004-10-14 Council Of Scientific And Industrial Research Composition hepatoprotectrice synergique et methode correspondante
JP2008519066A (ja) * 2004-11-08 2008-06-05 コーネル リサーチ ファンデーション インコーポレーティッド ウイルス感染症を処置するためのアンドログラフォライド（ａｎｄｒｏｇｒａｐｈｏｌｉｄｅ）誘導体
US8445533B2 (en) 2004-11-08 2013-05-21 Cornell Research Foundation, Inc. Andrographolide derivatives to treat viral infections
CN103145665B (zh) * 2012-04-12 2014-12-31 江西青峰药业有限公司 17-氢-9-去氢-14,17-环-穿心莲内酯-19-硫酸酯化物、制备方法及其制备药物用途
CN103145665A (zh) * 2012-04-12 2013-06-12 江西青峰药业有限公司 17-氢-9-去氢-14，17-环-穿心莲内酯-19-硫酸酯化物、制备方法及其制备药物用途
CN102716122A (zh) * 2012-07-03 2012-10-10 郑州大学 15-苄亚基-14-脱氧-11,12-脱氢穿心莲内酯衍生物在制备治疗糖尿病药物中的应用
CN102716122B (zh) * 2012-07-03 2014-06-25 郑州大学 15-苄亚基-14-脱氧-11,12-脱氢穿心莲内酯衍生物在制备治疗糖尿病药物中的应用
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CN104119251A (zh) * 2013-04-24 2014-10-29 江西青峰药业有限公司 9-去氢-穿心莲内酯-17-磺酸-16-羧酸或其盐、制备方法及其制备药物用途
CN104119251B (zh) * 2013-04-24 2015-12-09 江西青峰药业有限公司 9-去氢-穿心莲内酯-17-磺酸-16-羧酸或其盐、制备方法及其制备药物用途
WO2016065264A1 (fr) * 2014-10-24 2016-04-28 Biogen Ma Inc. Dérivés de diterpénoïdes et leurs procédés d'utilisation
CN106432153A (zh) * 2016-10-13 2017-02-22 四川理工学院 一类含硫穿心莲内酯衍生物、其药物组合物、合成方法、在制备治疗前列腺癌药物中的应用
CN109568265A (zh) * 2017-09-28 2019-04-05 神威药业集团有限公司 一种穿心莲内酯纳米混悬剂
CN109568265B (zh) * 2017-09-28 2021-09-28 神威药业集团有限公司 一种穿心莲内酯纳米混悬剂
CN108129468A (zh) * 2018-01-29 2018-06-08 四川理工学院 一类阿司匹林衍生物及其制法和应用
CN108129468B (zh) * 2018-01-29 2020-09-29 四川理工学院 一类阿司匹林衍生物及其制法和应用
CN108084122B (zh) * 2018-01-30 2021-05-07 北海开元生物科技有限公司 一种高纯度穿心莲内酯的提取方法
CN108084122A (zh) * 2018-01-30 2018-05-29 北海开元生物科技有限公司 一种高纯度穿心莲内酯的提取方法
CN108904446A (zh) * 2018-06-11 2018-11-30 中山大学 一种动脉斑块微环境响应的载药纳米胶束的制备方法及应用
CN108904446B (zh) * 2018-06-11 2021-05-11 中山大学 一种动脉斑块微环境响应的载药纳米胶束的制备方法及应用
CN113173896A (zh) * 2021-04-14 2021-07-27 张洪胜 一种抗氧化活性的阿魏酸衍生物及其制备方法

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