WO1996006852A1 - Nouveau derive du taxol - Google Patents

Nouveau derive du taxol Download PDF

Info

Publication number
WO1996006852A1
WO1996006852A1 PCT/JP1995/001684 JP9501684W WO9606852A1 WO 1996006852 A1 WO1996006852 A1 WO 1996006852A1 JP 9501684 W JP9501684 W JP 9501684W WO 9606852 A1 WO9606852 A1 WO 9606852A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
taxol
water
added
mixture
Prior art date
Application number
PCT/JP1995/001684
Other languages
English (en)
Japanese (ja)
Inventor
Morihiro Mitsukuchi
Hisaya Wada
Yoshinori Sekiguchi
Chihiro Yokoo
Katsuo Hatayama
Original Assignee
Taisho Pharmaceutical Co., Ltd.
Institute Of Materia Medica Chinese Academy Of Medical Sciences
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co., Ltd., Institute Of Materia Medica Chinese Academy Of Medical Sciences filed Critical Taisho Pharmaceutical Co., Ltd.
Priority to AU32651/95A priority Critical patent/AU3265195A/en
Publication of WO1996006852A1 publication Critical patent/WO1996006852A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present invention relates to a novel taxol derivative having antitumor activity.
  • Yuxol is an antitumor diterbene compound isolated from the bark of Pacific yew. Taxol binds to tubulin, promotes its polymerization, stabilizes the formed microtubules, thereby inhibiting microtubule depolymerization, and as a result, the spindle force during cell division does not function normally It has a novel mechanism of action in which cell division is inhibited. It has also been reported in clinical practice that it has excellent anticancer effects on ovarian cancer and breast cancer.
  • taxol Since taxol is very insoluble in water, it is dissolved in a mixture of polyoxyethylene castor oil (Cremophor EL), a solubilizing agent, and 50Z50 (v / v) of ethanol. At present, injections prepared by diluting 10-fold are administered intravenously by intravenous drip.
  • Cremophor EL polyoxyethylene castor oil
  • 50Z50 v / v
  • hypersensitivity reactions due to bronchospasm, rash, hypotension, anaphylaxis, etc.
  • corticosteroids histamine H I antagonists and histamine H 2 antagonists has been performed.
  • hydroxyl group at the 2'-position or 7-position of taxol is esterified with a substituent having a water-soluble functional group such as carboxylate, quaternary ammonium salt, quaternary pyridinium salt, sulfonate and phosphate.
  • the present invention relates to a taxol derivative having improved water solubility by bonding or acetanol bonding.
  • water-soluble taxol derivatives are water-soluble taxol prodrugs in which a water-soluble substituent introduced into the hydroxyl group at the 2'-position or 7-position of taxol is hydrolyzed in vivo to produce taxol. It is oriented.
  • US Pat. No. 5,424,073 discloses a study on taxol ribosome formulations.
  • This 7-xylosyltaxol has a microtubule depolymerization inhibitory activity equivalent to that of oxol [Proc. Natl. Acad. Sci. USA, 81, 4090, 1984] and It has been reported to have in Vitro antitumor activity [Pharm. Res., 10, 521, 1993]. Also, Taki W
  • An object of the present invention is to introduce a novel water-soluble hexol derivative different from the conventional water-soluble prodrug derivative, that is, a highly polar amino sugar into the hydroxyl group at the 7-position of taxol by an organic synthetic chemistry technique, and then add a salt.
  • a novel water-soluble hexol derivative different from the conventional water-soluble prodrug derivative that is, a highly polar amino sugar into the hydroxyl group at the 7-position of taxol by an organic synthetic chemistry technique
  • the compounds of the present invention have the formula
  • R represents a hydrogen atom or a methyl group.
  • the medically acceptable acid addition salts include, for example, acetate, propionic acid Salt, butyrate, lactate, maleate, fumarate, tartrate, citrate, stearate, succinate, ethylsuccinate, benzoate, salicylate, methansulfonate, ethanesulfone Acid salt, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfonate, camphorsulfonate, radium sulfate, malate, aspartate, glutamate, adipate, cysteine salt , Lactobionate, glucuronate, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, oxalate, picrate.
  • the method for producing the compound of the present invention represented by the formula (II) is as shown in the following production schemes (I) and (II).
  • Examples of the acid for the acid catalyst include inorganic acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, and organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, and paratoluenesulfonic acid. .
  • the compound (2) and benzyloxycarbonyl chloride are mixed with an organic solvent such as 1,4-dioxane and water in the presence of a base such as sodium hydroxide, hydroxylammonium hydroxide or sodium hydroxide.
  • a base such as sodium hydroxide, hydroxylammonium hydroxide or sodium hydroxide.
  • a mixture of compound (3) —anomer) and compound (4) ⁇ -anomer) is obtained by reacting at ⁇ 10 to ⁇ 48 hours at room temperature. Both compounds can be separated by silica gel column chromatography.
  • Compound (5) is obtained by reacting compound (3) with 2,2,2-trichloromouth ethoxycarbonyl chloride in an organic solvent in the presence of a base at 0 to room temperature for about 1 to 24 hours.
  • compound (9) can be obtained from compound (4).
  • a mixture of compound (5) and compound (9) can be obtained from a mixture of compound (3) and compound (4).
  • Examples of the base used in the above reaction include organic bases such as pyridine, triethylamine, diisopyrupyramine, and 4-dimethylaminopyridine.
  • Examples of the organic solvent include halogen solvents such as chloroform, methylene chloride and 1,2-dichloroethane, and pyridine.
  • Examples of the organic solvent used in the above reaction include ethyl acetate, tetrahydrofuran, 1,4-dioxane, an alcoholic solvent such as methanol and ethanol, or a mixed solvent thereof.
  • a catalyst besides palladium-carbon Examples include palladium black, platinum oxide, Raney nickel, and barium palladium monosulfate.
  • the compound (6) is reacted with trichloroacetonitrile in an organic solvent in the presence of a base at room temperature for about 1 to 24 hours to give the compound (7) ( ⁇ -anomer) and the compound (8) (; ⁇ -anomer). Obtain the mixture of 1).
  • a mixture of compound (7) and compound (8) can be obtained from a mixture of compound (6) and its 9-anomer.
  • Compound (7) and compound (8) can be separated by silica gel column chromatography.
  • the most suitable organic solvents used in the above reaction include halogenated solvents such as methylene chloride, 1,2-dichloroethane and chloroform, and the bases include potassium carbonate, sodium hydride, 1,8- Diazabicyclo [5,4,0) -7-decene and cesium carbonate.
  • Examples of the organic solvent used in the above reaction include a halogen-based solvent such as methylene chloride, 1,2-dichloroethane, and chloroform, or a single or mixed solvent such as toluene, benzene, getyl ether, acetonitrile, and nitromethane.
  • Examples of the acid catalyst include trimethylsilyl trifluoromethanesulfonate, boron trifluoride dimethyl ether complex, silver trifluoromethanesulfonate, silver perchlorate, silver carbonate, mercury cyanide, mercury bromide, Examples include toluenesulfonic acid and camphorsulfonic acid.
  • Examples of the dehydrating agent include powdered molecular sieve 4A and anhydrous calcium sulfate.
  • the compound (11) is reacted with the zinc powder in an organic solvent in the presence or absence of an acid at 0 to room temperature for about 1 to 24 hours to give the compound of the present invention represented by the formula (II).
  • a compound (12) in which R is a hydrogen atom is obtained.
  • Examples of the organic solvent used in the above reaction include alcohol solvents such as methanol, ethanol, and propanol, and tetrahydrofuran, 1,4-dioxane, and ethyl acetate.
  • Examples of the acid include hydrochloric acid, sulfuric acid, and acetic acid.
  • Each target compound in the above reaction can be obtained by general isolation and purification methods, for example, extraction, chromatography, and recrystallization.
  • the pharmaceutically acceptable salts of the compounds of the present invention can be obtained by converting compound (12) or compound (13) into methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, methanol, ethanol, tert -Organic solvents such as butanol It can be obtained by adding an acid in or in a mixed solvent of water and these, and by an isolation or purification method such as chromatography, recrystallization, reprecipitation or lyophilization.
  • the effective dose of the compound of the present invention is 1 mg 500 mg, preferably 1 mg 30 Omg per lm 2 of adult daily Z body surface area. This dosage may be adjusted as appropriate according to the patient's age, weight and condition.
  • the compound of the present invention thus obtained can be used as an injection or as a known additive such as an excipient, a disintegrant, a binder, a lubricant, an antioxidant, a coating agent, a coloring agent, Hashimi Bridge Oral preparations such as granules, powders, capsules, tablets, dry syrups, and liquid preparations can be prepared by mixing odorants, surfactants, plasticizers, and the like in a conventional manner. These additives can be used in general. Industrial applicability
  • the compound of the present invention exhibits excellent antitumor activity, and has been found to have improved water solubility and reduced toxicity compared to taxol, and is useful as an antitumor agent.
  • the extract was washed with saturated saline and water, and dried over anhydrous magnesium sulfate.
  • reaction mixture was added with 100 ml of ethyl acetate, washed sequentially with a 5% aqueous hydrochloric acid solution and saturated saline, and dried over anhydrous magnesium sulfate.
  • the reaction mixture was added with 100 ml of ethyl acetate, washed sequentially with a 5% aqueous hydrochloric acid solution and saturated saline, and dried over anhydrous magnesium sulfate.
  • the solvent is obtained by evaporation under reduced pressure.
  • reaction solution was diluted with 180 ml of ethyl acetate, washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • reaction solution was diluted with ethyl acetate, washed with water and saturated saline, and then dried over anhydrous magnesium sulfate.
  • reaction solution was filtered to remove insolubles, and the filtrate was added to a saturated aqueous solution of sodium hydrogen carbonate, extracted with methylene chloride, and dried over anhydrous magnesium sulfate.
  • the reaction solution was diluted with methylene chloride, the insolubles were separated by filtration, and the organic layer was separated.
  • the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution.
  • medium 100 1 dimethylsulfoxide final concentration 0.5%) was added, and the cells were cultured in the same manner. After completion of the culture, the medium was removed, the cells were measured for absorbance was dissolved in 150 1 of dimethyl sulfoxide to obtain the ratio of the absorbance of the present invention compounds to the absorbance of the control group, 50% growth inhibitory concentration (IC 5. ) was calculated.
  • a 10% homogenate solution of B16 melanoma tumor mass passaged in female C57B LZ6 mice was prepared by adding Hank's balanced salt solution, and 0.5 ml of the solution was intraperitoneally injected into female BDF1 mice. Transplanted.
  • the compound of the present invention and taxol were intraperitoneally administered once a day for 5 consecutive days from the day after the tumor cell transplantation.
  • Compound (12) and taxol were dissolved in a solvent consisting of 50% polyoxyethylene castor oil and 50% ethanol, and diluted with physiological saline immediately before administration. That is, physiological saline containing 5% of polyoxyethylene castor oil and 5% of ethanol was used as a solvent for administration. Taxol formed a precipitate in a short time, whereas compound (12) was clear for a long time (over 24 hours).
  • Compound (14) was administered by dissolving in distilled water for injection before use.
  • the control group received distilled water for injection, and the vehicle control group received only saline containing 5% of polyoxetylene castor oil and 5% of ethanol.
  • the control group used 12 mice, and the vehicle control group and drug administration group used 6 mice per group.
  • Median survival time of control group The median survival time of the control group was 23.3 days, and the median survival time of the solvent control group was 22.3 days.
  • Table 2 shows the survival rate and weight change of compound (12), compound (14) and taxol.
  • Compound (12) exhibited a life-promoting effect that was equivalent to or slightly weaker than taxol.
  • Compound (14) showed comparable survival benefit and taxol, since toxicity was seen in 3 Omg / k g dose weight loss and early death was observed by administration in taxol, toxic or Gensa is It is thought that it is.
  • Test example 3 Measure the resolution to 7k
  • Table 3 shows the solubility of compound (14) and taxol in water.
  • Taxol 0, 0 2 6 1

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé hydrosoluble du taxol, représenté par la formule générale (I) et différent du type promédicament conventionnel de composés. Dans cette formule générale (I), 'R' représente hydrogène ou méthyle. L'hydrosolubilité a été accrue par introduction d'une unité de sucre aminé hautement polaire dans le groupe 7-hydroxy du taxol selon un procédé chimique de synthèse organique suivi de formation de sel. Par comparaison avec le taxol proprement dit, ce dérivé présente une excellente activité antitumorale, une meilleure hydrosolubilité et une toxicité réduite.
PCT/JP1995/001684 1994-08-26 1995-08-25 Nouveau derive du taxol WO1996006852A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32651/95A AU3265195A (en) 1994-08-26 1995-08-25 Novel taxol derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP20167994 1994-08-26
JP6/201679 1994-08-26

Publications (1)

Publication Number Publication Date
WO1996006852A1 true WO1996006852A1 (fr) 1996-03-07

Family

ID=16445110

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001684 WO1996006852A1 (fr) 1994-08-26 1995-08-25 Nouveau derive du taxol

Country Status (2)

Country Link
AU (1) AU3265195A (fr)
WO (1) WO1996006852A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104693252A (zh) * 2013-12-05 2015-06-10 中国科学院上海药物研究所 糖苷化紫杉烷类化合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6032799A (ja) * 1983-07-29 1985-02-19 Microbial Chem Res Found 新規４′−デメチル−４−エピポドフィロトキシン誘導体
JPH0678758A (ja) * 1992-04-07 1994-03-22 E R Squibb & Sons Inc カルス細胞の誘導およびタキサン類の製造
JPH0710858A (ja) * 1993-06-25 1995-01-13 Taisho Pharmaceut Co Ltd 新規タキソール誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6032799A (ja) * 1983-07-29 1985-02-19 Microbial Chem Res Found 新規４′−デメチル−４−エピポドフィロトキシン誘導体
JPH0678758A (ja) * 1992-04-07 1994-03-22 E R Squibb & Sons Inc カルス細胞の誘導およびタキサン類の製造
JPH0710858A (ja) * 1993-06-25 1995-01-13 Taisho Pharmaceut Co Ltd 新規タキソール誘導体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOMED. CHROMATOGR., 1993, Vol. 7, No. 2, MACHIDA M., TANKA S., NAKAMORI K., "Simultaneous Determination of NK611, a Novel Water-Soluble Derivative of Etoposide and Its Metabolite (DeNK611) in Dog Plasma", pages 82 and 85. *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104693252A (zh) * 2013-12-05 2015-06-10 中国科学院上海药物研究所 糖苷化紫杉烷类化合物及其制备方法

Also Published As

Publication number Publication date
AU3265195A (en) 1996-03-22

Similar Documents

Publication Publication Date Title
EP3260463B1 (fr) Dérivé d'acide chénodésoxycholique deutéré et composition pharmaceutique comprenant un composé à base de celui-ci
EP2947070B1 (fr) Dérivé de promédicament d'ubénimex à cibles multiples et procédé de préparation et utilisation correspondants
CN101289482B (zh) 藤黄酸苷衍生物和类似物及其制备方法和用途
WO2012073217A1 (fr) Procédé pour la préparation de dérivés de la morpholinyle anthracycline
NZ550665A (en) Novel water-soluble prodrugs of camptothecin derivatives
CN103702670A (zh) 苷前体药物类似物的合成和应用
CN113698401A (zh) β-榄香烯大环衍生物及其制备方法和应用
WO2012175002A1 (fr) Dérivé, procédé de préparation et utilisation de la 10-méthoxycamptothécine
CA2849114C (fr) Analogues de l'acide sialique
CN101805383B (zh) 异胡豆苷内酰胺类衍生物及制备和用途
KR20090104002A (ko) 매크롤라이드계 화합물의 고체, 그의 제조 방법 및 그의 의약 조성물
EP1938823A1 (fr) Agent de prevention ou de traitement du cancer du pancreas, du cancer de l'ovaire ou du cancer du foie contenant un promedicament innovant soluble dans l'eau
EP1935879B1 (fr) Dérivé de cycloalcène substitué
WO1996006852A1 (fr) Nouveau derive du taxol
WO1998031392A1 (fr) Medicaments nephrotropiques
JP4621588B2 (ja) 新規化合物カプラゼンとカプラゼン誘導体、ならびに新規化合物カプラゾールとカプラゾール誘導体
EP1968971B1 (fr) Dérivés de dioxolanne pour le traitement du cancer
HU202548B (en) Process for producing epipodophyllotoxin-glycoside-4'-acyl derivatives and pharmaceutical compositions comprising such compounds
CN109369667B (zh) 2，3，6-三脱氧糖基去甲表鬼臼毒素化合物及其制备方法和用途
CN110922450B (zh) Psma激活式抗肿瘤前药cpt-x及其制备方法和应用
CN115536696B (zh) Enpp1抑制剂
JP2005511550A (ja) エトポシドおよび類似体の誘導体、ならびにそれを含有する医薬組成物
KR101881115B1 (ko) 신규 2-치환된 테트라하이드로피란 또는 2-치환된 테트라하이드로퓨란 유도체 화합물, 이의 제조방법 및 이의 용도
EP1758904B1 (fr) Derives de flavopereirine pour le traitement du cancer
JPH08113589A (ja) 新規タキソール誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA CN KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase