WO1996023779A1 - Derives ethers - Google Patents

Derives ethers Download PDF

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Publication number
WO1996023779A1
WO1996023779A1 PCT/JP1996/000207 JP9600207W WO9623779A1 WO 1996023779 A1 WO1996023779 A1 WO 1996023779A1 JP 9600207 W JP9600207 W JP 9600207W WO 9623779 A1 WO9623779 A1 WO 9623779A1
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group
groups
compound according
salt
compound
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PCT/JP1996/000207
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English (en)
Japanese (ja)
Inventor
Hirofumi Terasawa
Tsunehiko Soga
Kouichi Uoto
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Daiichi Pharmaceutical Co., Ltd.
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Priority to AU45482/96A priority Critical patent/AU4548296A/en
Publication of WO1996023779A1 publication Critical patent/WO1996023779A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a novel taxol derivative having an antitumor fistula action.
  • Taxol is a natural product represented by the following chemical structural formula, and can be obtained in trace amounts from the roots of western yew.
  • Taxol is known to have antitumor activity, and its mechanism of action is based on the inhibitory effect of microtubule depolymerization on cell division. Its clinical application as a carcinoma drug is expected.
  • taxol was only available in trace amounts from nature.
  • a taxol precursor represented by the following formula which can be obtained in relatively large amounts from yew vegetables, etc., is 10-0-0-deacetylbaccatin III.
  • Taxotere A taxol derivative semi-synthesized by using as a raw material has begun to be reported (Japanese Unexamined Patent Publication (Kokai) No. 03-5705725).
  • a compound having a structure represented by the following formula (Taxotere) is attracting attention as a compound having an antitumor activity equal to or higher than that of Taxol, and is currently being developed as an antitumor fistula.
  • taxol and taxotere derivatives are promising anti-tumor pain agents, clinical trials have shown that they have low efficacy against gastrointestinal cancers, especially colorectal cancer. Is desired. Also, taxol and Taxotere derivatives are also known to have low water solubility, Disclosure of the invention
  • the present invention provides a compound represented by the general formula (I)
  • R 1 is a phenyl group
  • the phenyl group may have, as a substituent, one or more groups selected from the group consisting of a halogen atom, an alkyl group and an alkoxyl group.
  • R 2 is an alkyl, alkenyl, alkynyl, cycloalkyl or alkoxyl group (These alkyl, alkenyl, alkynyl, cycloalkyl and alkoxyl groups include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an alkoxycarbonyl group, The substituent may have one or more groups selected from the group consisting of an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group. , Alkenyl, alkynyl, cycloalkyl and alkoxyl groups.)
  • R 3 represents a hydroxyl group, a hydrogen atom or a halogen atom.
  • R 3 may form the following partial structure together with the methyl group bonded to the 8-position.
  • R is an alkyl, alkenyl, or alkynyl group
  • alkyl groups, alkenyl groups and alkynyl groups include carboxyl groups, alkoxyl groups, aryloxy groups, alkoxycarbonyl groups, aryloxy groups, cyano groups, hydroxyl groups, amino groups, alkylamino groups, acyl groups, and acyl groups. It may have, as a substituent, one or more groups selected from the group consisting of a lumino group, an acyloxy group, an alkoxycarbonylamino group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an aryl group and a heterocyclic group.
  • the substituent may be substituted at any position of the alkyl group, alkenyl group and alkynyl group, and the aryl group and the double-ring group are further substituted with a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, or an alkoxy group.
  • Carbonyl group Consists of a phenyloxycarbonyl group, a cyano group, a hydroxyl group, an amino group, an alkylamino group, an aminoalkyl group, an acyl group, an acylamino group, an acyloxy group, an alkoxycarbonylamino group, an alkylthio group, an alkylsulfinyl group, and an alkylsulfonyl group May have one or more substituents selected from the group No. The substituent may be substituted at any position of the aryl group and the complex group. )
  • R 5 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
  • R 6 represents a hydrogen atom, a hydroxyl group, a halogen atom or an alkyl group.
  • R 7 is an alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heterocyclic group
  • alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, and heterocyclic groups include halogen atoms, hydroxyl groups, carboxyl groups, alkyl groups, alkoxyl groups, aryloxy groups, phenyl groups, amino groups, and alkylamino groups.
  • Group may have, as a substituent, one or more groups selected from the group consisting of aminoalkyl, alkylaminoalkyl, alkoxycarbonyl, aryloxycarbonyl, acyl, acylamino and acyloxy.
  • the substitution position of the substituent may be any of the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group and heterocyclic group.
  • R B is an alkyl group, aryl group or alkoxyl group
  • alkyl groups, aryl groups or alkoxyl groups include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, a phenyl group, an amino group, an alkylamino group, an aminoalkyl group, and an alkylaminoalkyl group. And may have one or more groups selected from the group consisting of an alkyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, an acylamino group and an acyloxy group as a substituent. May be the position of L of the alkyl group, aryl group and alkoxyl group, or a shift position.
  • C 2 -C 6 alkenyl group means an alkenyl group having 2 to 6 carbon atoms I do.
  • alkyl group may be linear or branched, and preferably have 1 to 6 carbon atoms (in the case of alkenyl and alkynyl groups) from 6 carbon atoms.
  • alkoxyl group means a group in which an alkyl group is bonded to the group —0—, and may be a group in which the alkyl group is substituted by a phenyl group (which may have a substituent). Specific examples include benzyloxy, phenethyloxy, p-methoxybenzyloxy and the like.
  • the alkyl moiety preferably has 1 to 6 carbon atoms.
  • alkoxycarbonyl group means a group in which an alkyl group is bonded to an oxygen atom of the group CO 0—, which is substituted by a phenyl group (which may have a substituent).
  • a phenyl group which may have a substituent.
  • Such examples include benzyloxycarbonyl, phenethyloxycarbonyl, p-methoxybenzyloxycarbonyl and the like.
  • the alkyl moiety preferably has 1 to 6 carbon atoms.
  • aryl group means a monovalent group obtained by removing one hydrogen atom from the nucleus of an aromatic hydrocarbon, and includes, for example, phenyl, tolyl, bifXnilyl, naphthyl and the like.
  • the bonding position of the amino group in the “aminoalkyl group” may be any position of the alkyl group.
  • the alkyl group preferably has 1 to 6 carbon atoms.
  • Alkylamino group refers to an amino group substituted with one alkyl group or an amino group substituted with two alkyl groups (the two alkyl groups may be the same or different). Means Further, the alkyl group preferably has 1 to 6 carbon atoms. C
  • the “acyl group” means a carbonyl group (—CO—) to which a hydrogen atom, an alkyl group or an aryl group is bonded, for example, formyl, acetyl , Propanol, benzoyl and the like.
  • the alkyl group to be bonded is preferably one having 1 to 6 carbon atoms, and the aryl group to be bonded is preferably a phenyl group.
  • Heterocyclic group refers to a monocyclic or bicyclic ring containing one or more atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as constituent atoms of a ring structure. Means a substituent derived from a saturated or unsaturated heterocyclic compound, These heterocyclic groups may be bonded at any position.
  • Monocyclic compound groups include, for example, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, virazolidine, oxazole, thiazole, oxazine diazole, thiadiazole, Substituents derived from monocyclic compounds such as pyridin, dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, virazine, piperazine, dioxane, pyran, and morpholine.
  • bicyclic heterocyclic group examples include substituents derived from a bicyclic heterocyclic compound such as benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, and chroman.
  • alkyl group and the “alkoxyl group” as substituents of the phenyl group of R 1 preferably have 1 to 3 carbon atoms.
  • the number of substituents of the phenyl group of R 1 is preferably 1 or 2, and
  • the substitution position is preferably a meta position.
  • R ′ is preferably a fluorine group, a chlorine atom, a phenyl group in which one or two methyl groups or methoxy groups have been substituted at the meta position, or an unsubstituted phenyl group.
  • R 2 is preferably an alkyl group, an alkoxyl group or a cycloalkyl group
  • alkyl group for R 2 , a C, to C 6 alkyl group is preferable, and a methyl group and an ethyl group are particularly preferable. A propyl group is preferred.
  • the “alkoxyl group” for R 2 is preferably a C 1, to C 6 alkoxyl group, and particularly preferably a methoxy group or an ethoxy group.
  • cycloalkyl group for R 2 , a C 3 -C 6 cycloalkyl group is preferred, and a cyclopropyl group is particularly preferred.
  • R 2 is particularly preferably a methyl group, an ethyl group, a propyl group, a methoxy group, an ethoxyquin group or a cyclopropyl group.
  • halogen atom a fluorine atom is preferable.
  • R 3 is preferably a hydrogen atom or a hydroxyl group.
  • R 4 is preferably an alkenyl group or an alkyl group.
  • the alkyl group is a carboxyl group, an alkoxyl group, an aryloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a cyano group, a hydroxyl group, an amino group, an alkylamino group, an acyl group, an acylamino group, an acyloxy group, an alkoxycarbonyl group.
  • the aryl group and the heterocyclic group may have one or more substituents selected from the group consisting of an amino group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an aryl group and a heterocyclic group.
  • the group further includes a carboxyl group, an alkyl group, an alkoxyl group, an aryloxy group, an alkoxycarbonyl group, an aryloxycarbonyl group, a cyano group, a hydroxyl group, an amino group, an alkylamino group, an acyl group, an unamino group, an alkoxy group, and an alkoxy group.
  • alkyl group for R, C, -C 6 alkyl group is preferable, especially methylcarbamoyl group, Echiru group, a propyl group.
  • alkenyl group for R 4 , a C 3 -C 6 alkenyl group is preferred. An aryl group is particularly preferred.
  • an alkylamino group or a heterocyclic group is preferable.
  • Alkyl moiety of the alkylamino group is preferably -C 3 Arukinore group or a dialkyl kill substituted. (In the case of dialkyl substitution, the two alkyl groups may be the same or different.)
  • a group derived from pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine is particularly preferable.
  • ⁇ is C, ⁇ C 3 al Kill groups are preferred.
  • alkyl group substituted on carbon atoms which is a component of a ring of the heterocyclic group, c, to c 3 alkyl group is preferred, a methyl group is particularly preferable.
  • R 4 is most preferably an aryl group, a morpholinoethyl group, or a thiomorpholinoethyl group.
  • halogen atom a fluorine atom, a chlorine atom and a bromine atom are preferable.
  • alkyl group for R 5 and R 6 , a methyl group, an ethyl group, and a propyl group are preferable.
  • R 5 is preferably a halogen atom or a hydroxyl group, and among the halogen atoms, a fluorine atom is particularly preferred.
  • R 6 is preferably a halogen atom, a hydrogen atom or an alkyl group.
  • halogen atoms a fluorine atom is particularly preferred.
  • alkyl groups a methyl group is particularly preferred.
  • R 5 is a fluorine atom and R 6 is a combination of fluorine atom
  • R 5 is a hydroxyl group
  • those R e is a combination of hydrogen atoms
  • Oh Rui R 5 is a hydroxyl group
  • R 6 force A combination of butyl groups is exemplified.
  • R 7 is preferably an aryl group, a heterocyclic group, or an alkenyl group.
  • aryl group for R 7 , a phenyl group is preferable.
  • the heterocyclic group represented by R 7 is preferably a monocyclic heterocyclic group, and more preferably a monocyclic 5- or 6-membered heterocyclic group.
  • Examples thereof include pyrrole, furan, and thiophene. , Pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazonore, pyrazole, imidazolidin, virazolidine, oxazole, thiazole, oxaziazole, thiaziazol, pyridine, dihydropyridine, tetrahydridopyran, pyridine, pyridazine, pyridazine, pyridazine , Piperazine, dioxane, pyran, morpholine and the like.
  • heterocyclic groups represented by R 7 a monocyclic 5- or 6-membered heterocyclic group having a single oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure is particularly preferred.
  • Preferable examples include groups derived from pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyridine, dihydropyridine, tetrahydropyran, piperidine, pyran and the like.
  • a monocyclic 5- or 6-membered heterocyclic group which is an unsaturated heterocyclic group containing one oxygen atom, nitrogen atom or sulfur atom as a constituent atom of the ring structure Is the most preferable, and specifically, a group derived from furan, pyridine, or pyrrole is most preferable.
  • a 2-methyl-11-propenyl group, a phenyl group, a furyl group, a pyridyl group and a pyrrolyl group are particularly preferred.
  • R 8 is preferably an aryl group or an alkoxyl group.
  • aryl group for R 8 , a phenyl group is preferable.
  • alkoxyl group for R 8
  • a tertiary butoxy group is preferable.
  • R 8 is particularly preferably a phenyl group or a tertiary butoxy group.
  • R ' is Fuweniru group
  • R 2 is a methyl group, Echiru group, a propyl group, main butoxy group, Etokin group or a cyclopropyl group
  • R 3 force,' as compounds included in the present application a hydrogen atom or a hydroxyl group
  • IT is Ariru group , morpholinoethyl group or thiomorpholino ethyl Le group
  • R 5 is hydroxyl
  • R 7 is Fuweniru group, a furyl group or a 2-methyl-1 one propenyl group
  • R 8 is a tertiary butoxy The compound that is the group is most preferred.
  • the configuration at the 3′-position to which the substituent R 7 is bonded is preferably a configuration having the same configuration as that of natural taxol, which includes both configurations.
  • the taxonole derivative of the present invention may be in a free form, but may be in the form of an acid addition salt.
  • the acid addition salt include hydrochloride, sulfate, nitrate, hydrobromide, and hydrochloride.
  • Inorganic acid salts such as hydroperoxide and phosphate, or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate, etc.
  • Organic acid salts such as hydroperoxide and phosphate, or acetate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, maleate, fumarate, lactate, etc.
  • R 2 1 denotes a R 2 that is protected by R 2 and a protecting group (when R 2 is substituted with a hydroxyl group Ya Amino group).
  • R 31 represents a hydrogen atom, a halogen atom or a protected hydroxyl group.
  • X means a group which acts as a halogen atom such as iodine or bromine or a leaving group such as a methanesulfonyloxy group ⁇ p-toluenesulfonyloxy group.
  • R 51 represents a hydrogen atom, a protected hydroxyl group, a halogen atom or an alkyl group.
  • R 61 represents a hydrogen atom, a protected hydroxyl group, a halogen atom or an alkyl group o
  • R 71 means R 7 that is protected by R 7 and the protecting group (if R 7 is substituted with a hydroxyl group Ya Amino group).
  • R 81 means R 8 that is protected by R 8 and protecting group (if R 8 is substituted with a hydroxyl group Ya Amino group).
  • R 9 and R 111 each independently represent a hydrogen atom, an alkyl group, an aryl group, or the like, and it is preferable that both are a methyl group or that one is a p-methoxyphenyl group and the other is a hydrogen atom .
  • hydroxyl- or amino-protecting group examples include silyl-based protecting groups such as triethylsilyl group and tert-butyldimethylsilyl group, 1-ethoxyshethyl group, 2,2,2-trichloromouth ethoxycarbonyl group, and benzyl group.
  • a compound represented by the formula (1) (hereinafter, referred to as compound (1), and compounds represented by other numbers as well) and a compound (2) are treated in a solvent in the presence of a base.
  • the compound (3) is obtained by selectively etherifying the hydroxyl group at the 10-position.
  • the solvent is preferably inert to the reaction, and examples thereof include tetrahydrofuran, N, N-dimethylformamide, and dimethylsulfoxide.
  • the base examples include normal butyl lithium and sodium hydride.
  • the compound (3) is condensed with the compound (4), the compound (5) or the compound (6) by various methods known in the art, and if necessary, further subjected to a conversion reaction to thereby give the compound. (7) can be obtained.
  • the condensation reaction using the compound (4) or (5) involves the activity of a carboxylic acid such as di (2-pyridyl) dicarbonate dicyclohexylcarposimid in the presence of a base catalyst such as 4-dimethylaminopyridine.
  • a carboxylic acid such as di (2-pyridyl) dicarbonate dicyclohexylcarposimid
  • a base catalyst such as 4-dimethylaminopyridine.
  • R 5 ′ and R 6 ′ are a combination of a hydrogen atom and a hydroxyl group.
  • the target compound in which R 3 is a hydrogen atom for example, after obtaining a compound (3) in which R 31 is a protected hydroxyl group, the protecting group is removed, and R 3 ′ is converted to a hydroxyl group.
  • the hydroxyl group is removed by a method known in the literature (for example, Journal of Organic Chemistry U. Org. Chem.), 58, 5028 (1993)), and a compound in which R 3 is a hydrogen atom ( After 3) is obtained, a condensation reaction with the compound (4), (5) or (6), conversion of the 10-position, if necessary, and deprotection may be carried out in the same manner as described above.
  • There is also a method of first synthesizing a compound (1) in which R 31 is a hydrogen atom converting the compound into a compound (3), performing a condensation reaction, and converting the 10-position to obtain a target product.
  • a target compound in which R 3 is a halogen atom for example, a compound in which R 3 is a fluorine atom
  • the protecting group is removed, R 3 'is converted to a hydroxyl group.
  • the compound (3) in which R 3 is a fluorine atom is obtained by treating with tetrahydrofuran, methylene chloride, ethyl ether, toluene, 1,1 dimethyloxetane or the like or a mixed solvent thereof with getylaminosulfur trifluoride.
  • the condensation reaction with the compound (4), (5) or (6), the conversion of the 10-position, if necessary, and the deprotection reaction may be carried out in the same manner as described above.
  • a compound having a R ′ force ⁇ substituted phenyl group can be obtained, for example, by subjecting the 2-position ester of the obtained compound (7) to a method described in the literature (Tetrahedron Letter,, 8931 (1994)). Is selectively hydrolyzed and then acylated.
  • the compound (1) which is a production raw material, can be synthesized from 10-0-deacetylbaccatin III, wherein R 1 is a fuundyl group, R Compounds in which the 2 ′ is a methyl group are known in the literature (eg, Journal of American Chemical Society (J.A. m. Chem. Soc.), 110, 5917 (1988))
  • the compound (1) in which R 2 is an alkyl group other than a methyl group can be produced as follows.
  • R represents a hydroxyl-protecting group, and is preferably a triethylsilyl group, a 2,2,2-trichloroethoxycarbonyl group, or a benzyl group.
  • R 1 and R 31 are the same as above.
  • compound (8) is oxidized (eg, treated with manganese dioxide in an inert solvent (eg, dioxane) at room temperature or under heating) to obtain compound (9).
  • an inert solvent eg, dioxane
  • the compound (9) is reacted with a base in a solvent inert to the reaction (such as tetrahydrofuran) at a reaction temperature of 100 ° C to 0 ° C, and then R 22 — Z (R 22 is an alkyl group And Z represents a halogen atom such as an iodine atom or a bromine atom, or a leaving group such as a methanesulfonyl group or a balatoluenesulfonyl group.) By reacting from C at room temperature, compound (10) is obtained.
  • a base in a solvent inert to the reaction temperature of 100 ° C to 0 ° C
  • R 22 — Z R 22 is an alkyl group And Z represents a halogen atom such as an iodine atom or a bromine atom, or a leaving group such as a methanesulfonyl group or a balatoluenesulfonyl group
  • Examples of the base used include lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, tert-butoxypotassium, and sodium hydride.
  • the amount may be 1 to 10 equivalents based on compound (9).
  • the compound (11) can be obtained by subjecting the obtained compound (10) to ⁇ reaction with a reducing agent (such as sodium borohydride) in a solvent (such as methanol-tetrahydrofuran) ⁇ .
  • a reducing agent such as sodium borohydride
  • a solvent such as methanol-tetrahydrofuran
  • the compound of the present invention can be used for the treatment of various cancers such as, for example, lung cancer, gastrointestinal cancer, ovarian cancer, uterine cancer, breast cancer, liver cancer, head and neck cancer, blood cancer, kidney cancer, Kogan tumor.
  • the compound of the present invention can be administered as various injections such as intravenous injection, intramuscular injection and subcutaneous injection, or by various methods such as oral administration and transdermal administration.
  • intravenous administration by an aqueous preparation and oral administration are preferred.
  • Aqueous preparations can be prepared by forming acid addition products with pharmacologically acceptable acids or by preparing alkali metal salts such as sodium.
  • oral administration it may be in a free form or in a salt form.
  • an appropriate preparation is selected according to the administration method, and the preparation can be prepared by various commonly used preparation methods.
  • examples of oral preparations include tablets, powders, granules, capsules, solutions, syrups, elixirs, oily or aqueous suspensions, and the like.
  • stabilizers, preservatives, solubilizing agents, etc. can be used in the preparation.
  • a solution that may contain these adjuvants may be stored in a container, and then freeze-dried or the like to form a solid preparation for use at the time of use.
  • Liquid preparations include solutions, suspensions, emulsions, and the like.When preparing these preparations, suspending agents, emulsifiers, and the like can also be used as additives.
  • the compound of the present invention can be used for the treatment of cancer in mammals, especially in humans. When administered to humans, it is preferably administered once a day and repeated at appropriate intervals.
  • the dose is preferably in the range of about 0.5 mg to 50 mg, preferably about 1 mg to 2 Omg, per lm 2 of the body surface area.
  • Step 1 10—0—aryl-10-deacetyl-7—0—triethylsilyl paccatin I I I
  • Step 2 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -10-0-aryl-10-decetyl- 7-0 — Triethylsilyl paccatin III
  • Step 3 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3--3-phenylpropionyl] -10-0-aryl-10-deacetylbacca Tin III 45.5 mg of the compound obtained in Step 2 above was dissolved in 2 ml of acetonitrile and -10. Cooled to C. Next, 0.035 ml of 12N hydrochloric acid aqueous solution was added dropwise, and the mixture was stirred for 1 hour. An aqueous saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous sodium sulfate.
  • Step 1 13-0-[(2R, 3S) -3- (tert-butynecarbonylamino) -3-fuunyl-2- (triethylsilyloxy) propionyl] -10-deacetyl-10-O-formylmethy Le-7—0—Triethylsilyl paccatin III
  • Step 2 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -10-deacetyl-10-O- (2-morpholinoethyl) -7-0—triethylsilylpaccatin III
  • Step 3 13—0 _ [(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-hydroxypropionyl] -10-deacetyl-10-O- (2-morpholinoethyl )
  • Power force III 91.6 mg of the compound obtained in the above step 2 was dissolved in 4 ml of acetonitrile, 0.20 ml of pyridine and 0.60 ml of a 48% aqueous hydrogen fluoride solution were added under ice cooling, and the mixture was reacted at 0 for 2 hours and at room temperature overnight. The reaction solution was ice-cooled and made weakly alkaline with a saturated aqueous solution of sodium bicarbonate.
  • Step 1 4,10-dideacetyl-4-0-propionyl-10-0- (2,2,2-trichloroethoxycarbonyl-7-7-0-triethylsilylpaccatin ⁇ 1
  • Step 2 4, 10-dideacetyl-4-10-propionyl-7-0-triethylsilylbaccatin III
  • Step 4 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propioni -]-4,10-dideacetyl-4-1-0-propionyl-7-0-triethylsilylpaccatin ⁇ ⁇ 50 mg of the compound obtained in step 3 above and (3R, 4S) -l-tert-butoxycarbonyl _4_ (2-Furyl) -3- (triisopropylsilyloxy) azetidin-2-one 43 rog was dissolved in 2 ml of tetrahydrofuran and cooled to -78 ° C.
  • Step 5 13— 0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisobrovirsilyloxy) propionyl] -4,10— Didacetyl -10-0 —formylmethyl -4-1-O-propionyl -7—0 _triethylsilyl baccatin III
  • Step 6 13-0-[( 2R, 3S) -3- (terbutoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-10- ⁇ - (2- Morpholinoethyl) -4-0-propionyl -7-0-triethylsilyl puckachi N III
  • Step 7 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3_ (2-furyl) -2-hydroxypropionyl] -4,10-dideacetyl-10-O- (2-morpholinole
  • Step 1 4-0-Butanoyl-4,10-dideacetyl -10-0- (2,2,2-trichloroethoxycarbonyl) -7-0-Triethylsilylpaccatin ⁇
  • Step 2 4-0—Butanoyl-4,10-dideacetyl-7-7-0—Triethylsilylpackatin III
  • Step 4 10—O—aryl-13-0 _ [(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl]- 4_0—butanol-4,10-dideacetyl-7—0—triethylsilylpaccatin III
  • Step 5 13-0-[( 2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4-O-butanoyl-4,10-di Deacetyl-10-O-formylmethyl-7-0-triethylsilylpaccatin III
  • the compound obtained in the above Step 4 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid. .
  • Step 6 13— 0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4-0— Butanoyl-4,10-didecyl -10-O- (2-morpholinoethyl) -7-0—Triethylsilyl paccatin I II
  • Step 7 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2-hydroxyhydrionyl] -4-dibutanoyl-4,10-dideacetyl -10-0- (2-morpholinoethyl) -paccatin ⁇
  • Step 1 13-0-[(23S) -3- (tert-butoxycarbonylamino) -3- (2-furyl)- 2- (triisopropylsilyloxy) propionyl] -4,10-dideacetyl-10-O- [2- (N, N-getylamino) ethyl] -4-0-propionyl-7-7-0-triethylrunlylp Kachin III
  • Step 1 13—O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4, 10-dideacetyl-4-1-0-propionyl-10-O- (2-thiomorpholinoethyl) -7-0-triethylsilylbactin III
  • Step 1 10-0-aryl-13-0-[(2R, 3S) -N- (tert-butynecarbonyl) -2,3-N, 0-isopropylidene-3-phenylphenyliserinyl] -10-deacetyl -7—0— Triethylilrilpackachin ⁇ ⁇
  • Step 2 13-0-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O-isobutypyridene-3-phenylisocerinyl] -10-deacetyl-10 -O-Formylmethyl -7-0-Triethylsilyl baccatin III
  • Step 1 The compound obtained in the above Step 1 was reacted in the same manner as in Step 1 of Example 2 to obtain the title compound as a colorless amorphous solid.
  • Step 3 13-0-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, 0-isopyridene-3-pyranylisoselinyl] -10-deacetyl-10 -0-(2-piperidinoethyl) -7-0—triethylsilylpaccatin III
  • Step 1 13-0-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, 0-isopyridene 3-pyranylisoselinyl] -10-deacetyl-10 -O- [2- (N-pyrrolidino) ethyl] -7-0-triethylsilylpaccatin ⁇
  • Step 2 13—0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3- phenylpropionyl] -10-deacetyl-10-O- [2- (N —Virolizino) ethyl] Paccatin III
  • Step 3 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butynecarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10- Decetyl -7-Doxypaccatin III
  • the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 4 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butynecarbonylamino) -2-hydroxy-3--3-phenylpropionyl] -10-deacetyl-7 Deoxypaccachin 1 1 1 1
  • Step 1 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3_fuunylpropionyl] -10-deacetyl-7- Deoxy -10-O- (2-morpholinoethyl) paccatin III
  • Step 3 of Example 9 The compound obtained in Step 3 of Example 9 was reacted in the same manner as in Step 1 of Example 2 and then reacted in the same manner as in Step 2 of Example 2 to obtain the title compound.
  • Step 2 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -10-deacetyl-7-deoxy-10-O_ ( 2-Morpholinethyl) Paccatin III
  • Step 1 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -4,10- Didacetyl -4-0- propionyl -7- 0- triethylsilyl paccatin III
  • Step 2 13-0 _ [(2R, 3S) -3- (tert-butoxycarbonylamino) -3-phenyl-2- (triethylsilyloxy) propionyl] -4,10-didecetyl-4-0- Propionyl -10-0- (2-thiomorpholinoethyl) -7-0-triethylsilylpaccatin III
  • the compound obtained in the above step 1 was reacted in the same manner as in the step 1 of the example 2.
  • the reaction was carried out using thiomorpholine in place of morpholine 2 to give the title compound as a colorless amorphous solid.
  • Step 3 13-0-[(2R.3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -4,10-dideacetyl-4-4-0-propionyl- 10-O- (2-thiomorpholinoethyl) paccatin 111
  • Step 1 10-0-aryl-10-deacetyl-13-0- (2,2,2-trichloromouth ethoxycarbonyl) -7-0-triethylsilylpaccatin ⁇
  • Step 1 The compound obtained in the above Step 1 was reacted in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiomorpholine instead of morpholine to give the title compound as a colorless amorphous solid As obtained.
  • Step 3 10-Deacetyl -10-O- (2-thiomorpholinoethyl)-7-0- Triethylsi Lilpacchin III
  • Step 1 10-0-aryl-13_0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl]- 10- Dasechi Le -7- 0- Triethylsilyl paccatin III
  • Step 2 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (terbutyldimethylsilyloxy) -3-phenylpropionyl] -10 -Dessic Rubaccatin III
  • Step 3 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10- Deacetyl-7- 0- Trifluoromethanesulfonyl baccatin III
  • Step 4 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butynecarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-7-deoxy-7,8; 9-methanobaccatin III
  • Step 5 13-0-[(2R, 3S) -3- (tert-butynecarbonylamino) -2- (tert-butyldimethylsilyloxy) _3-phenylpropionyl] -10-deacetyl-7- Deoxy- ⁇ , ⁇ -methano-10- ⁇ - (2-thiomorpholinoethyl) paccatin III
  • Step 4 The compound obtained in the above Step 4 was reversed in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiomorpholine instead of morpholine to convert the title compound to a colorless amorphous substance. Obtained as a crystalline solid.
  • Step 6 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-fuunylpropionyl] -10-deacetyl-7-deoxy-7; 5, 85- methano-10-O- (2-thiomorpholinoethyl) paccatin III
  • Step 1 10-O-aryl-4,10-dideacetyl-4-0-propionylbaccatin III
  • the compound obtained in Step 3 of Example 3 is reacted in the same manner as in Step 7 of Example 3 to give the compound. Obtained as a colorless amorphous solid.
  • Step 3 10-0-aryl-7-dexoxy-4,10-dideacetyl-4-0-propionyl paccatin I I I
  • Step 4 10-0-aryl-13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilylloquine) -3-phenylpropionyl]- 7-deoxy-4,10-dideacetyl-4-0-propionylbaccatin III
  • Step 5 13-O-[(2R, 3S) -3- (tert-butynecarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -7-deoxy_ 4, 10-dideacetyl-4- 0-propionyl -10- 0- (2-thiomoriholinoethyl) paccatin 111
  • Step 4 The compound obtained in Step 4 above was reacted in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 by using thiomorpholine instead of morpholine to convert the title compound to a non-colored amorphous Obtained as a solid.
  • Step 6 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-phenylpropionyl] -7-deokin-4,10-dideacetyl-4 0-propionyl-10- 0- (2-thiomorpholinoethyl) paccatin III
  • Step 1 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2-furyl) -2- (triisopropylsilyloxy) propionyl] -4,10- Didacetyl -4- 0-propionyl-10-O- [2- (thiomorpholino-1-oxide) ethyl] -7-0-triethylsilylpaccatin III
  • Step 2 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -3- (2_furyl) -2-hydroxypropionyl] -4,10-dideacetyl-4-0- Propionyl-10-O- [2- (thiomorpholino-1-oxide) ethyl] paccatin III
  • the obtained residue was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 4 10-0-aryl- 13-0-[(2R, 3S) -3- (tert-butynecarbonylamino)-
  • Step 5 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2- (tert-butyldimethylsilyloxy) -3-phenylpropionyl] -10-deacetyl-7- Deoxy-7-na-fluoro-10-O- (2-thiomorpholinoethyl) paccatin III
  • Step 4 The compound obtained in the above Step 4 was reacted in the same manner as in Step 1 of Example 2, and then reacted in the same manner as in Step 2 of Example 2 using thiomorpholine instead of morpholine to give the title compound as a colorless amorphous solid. As obtained.
  • Step 6 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy
  • Step 1 10-0-aryl-4,10-dideacetyl-4-0-propionyl-13-0- (2,2,2-trichloroethoxycarbonyl) -7-0-triethylsilylpaccatin III
  • the compound obtained in Step 3 of Example 3 was reacted in the same manner as in Step 1 of Example 13 to give the title compound as a colorless amorphous solid.
  • Step 2 4,10- Didacetyl -4- 0-propionyl -10-O- (2-thiomorpholinoethyl) -13- 0- (2,2,2-trichloromouth ethoxycarbonyl) -7-0- triethylsilyl paccatin III
  • Step 3 4, 10-dideacetyl-4-0-propionyl-10-0- (2_thiomorpholinoethyl) -7-0-tritylsilylpaccatin III
  • the compound obtained in the above Step 2 was reacted in the same manner as in Step 3 of Example 13 to give the title compound as a colorless amorphous solid.
  • Step 4 13-0-[(2,3-threo) -3- (tert-butoxycarbonylamino) -5-methyl-2- (triethylsilyloxy) -4-hexenyl] -4,10 -Didecyl-4-O-propionyl-10-O- (2-thiomorpholinoethyl) _7-0- Triethylsilyl paccatin III
  • Step 5 13-O-[(2S, 3R) -3- (tert-butoxycarbonylamino) -2-hidequin-5-methyl-4-hexenyl] -4,10-dideacetyl-4 0-propionyl -10-O -(2-thiomorpholinoethyl) pacchinin 111 and 13-O-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-5-methyl-4-hexenyl] -4 , 10-Dideacetyl-4-0-propionyl-10-O- (2-thiomorpholinoethyl) paccatin III
  • Step 1 10-0-aryl-13-0- [3-61 "butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -4,10-dideacetyl-4 -0- propionyl -7- 0- triethylsilylpaccatin III (isomer ⁇ , isomer ⁇ )
  • reaction solution was diluted with ethyl acetate, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 2 13-0- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -4,10-dideacetyl-4-O-propionyl-10- O- (2-thiomorpholinoethyl) -7-0- Triethylsilylpaccatin 111 (isomer A, isomer B)
  • Step 3 13-0- [3- (tert-butoxycarbonylamino) -2,2-difluoro-3- (2-furyl) propionyl] -4,10-dideacetyl-4-0-propionyl- 10-O- (2-thiomorpholinoethyl) paccatin III (isomer A, isomer B)
  • Step 1 10-Deacetyl -10-O- (2-pyridylmethyl) -7-0- Triethylsilylbaccatin II 1
  • Step 2 13-0-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, 0- (4-methoxybenzylidene) -3-phenylisoselinyl]- 10-Decetyl -10-O- (2-pyridylmethyl) -7-0-Triethylsilylpaccatin III
  • Step 3 13-0-[(2R, 3S) -N- (tert-butynecarbonyl) -2,3-N, 0- (4-methoxybenzylidene) -3-phenylisoselinyl] -10- deacetyl-10- 0- (2-pyridylmethyl)
  • Step 4 13-0-[(2R, 3S) -3- (tert-butoxycarbonylamino) -2-hydroxy-3-fuunylpropionyl] -10-deacetyl -10-0- (2-pyridylmethyl ) Packa Chin III
  • Step 1 10-Deacetyl -10-0- (3-pyridylmethyl) -7-0-Triethylsilylbaccatin 1 1 1
  • the title compound was obtained as a colorless amorphous solid by reacting in the same manner as in Step 1 of Example 20 using 3-pyridylmethylbumidamide bromide instead of 2-pyridylmethylbumidamide bromide. .
  • Step 2 13-0-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, 0- (4-methoxybenzylidene) -3-phenylisoselinyl] -10- Decetyl-10-O- (3-pyridylmethyl) -7-0- Triethylsilylpaccatin III
  • Step 1 The compound obtained in the above Step 1 was reacted in the same manner as in Step 2 of Example 20 to obtain the title compound as a colorless amorphous solid.
  • Step 3 13-0-[(2R, 3S) -N- (tert-butoxycarbonyl) -2,3-N, O- (4-methoxybenzylidene) -3-phenylisoselinyl]- 10-Deacetyl -10-O- (3-pyridylmethyl) paccatin ⁇

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  • Organic Chemistry (AREA)
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Abstract

Nouveaux dérivés du taxol à action antitumorale, de formule (I) dans laquelle: R1 représente phényle; R2 représente alkyle, alcényle, alcynyle, cycloalkyle ou alcoxy; R3 représente hydroxy, hydrogène ou halogéné; R4 représente alkyle, alcényle ou alcynyle; R5 représente hydrogéno, hydroxy, halogéné ou alkyle; R6 représente hydrogène, hydroxy, halogéno ou alkyle; R7 représente alkyle, alcényle, alcynyle, cycloalkyle, aryle ou hétérocycle; et R8 représente alkyle, aryle ou alcoxy.
PCT/JP1996/000207 1995-02-02 1996-02-01 Derives ethers WO1996023779A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515151B1 (en) 1992-12-23 2003-02-04 Bristol-Myers Squibb Company Method for the preparation of novel sidechain-bearing taxanes and intermediates thereof
EP1534674A2 (fr) * 2002-08-02 2005-06-01 Immunogen, Inc. Agents cytotoxiques renfermant des nouveaux taxanes puissants et utilisation therapeutique de ceux-ci
US6906040B2 (en) 2000-09-22 2005-06-14 Bristol-Myers Squibb Company Method for reducing toxicity of combined chemotherapies
US7390898B2 (en) 2002-08-02 2008-06-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
CN104650012A (zh) * 2013-11-22 2015-05-27 天士力控股集团有限公司 一种紫杉烷类化合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06157489A (ja) * 1992-10-01 1994-06-03 Bristol Myers Squibb Co デオキシタキソール類
JPH06179666A (ja) * 1992-07-01 1994-06-28 Bristol Myers Squibb Co フッソ化されたタキソール類

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06179666A (ja) * 1992-07-01 1994-06-28 Bristol Myers Squibb Co フッソ化されたタキソール類
JPH06157489A (ja) * 1992-10-01 1994-06-03 Bristol Myers Squibb Co デオキシタキソール類

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6515151B1 (en) 1992-12-23 2003-02-04 Bristol-Myers Squibb Company Method for the preparation of novel sidechain-bearing taxanes and intermediates thereof
US6906040B2 (en) 2000-09-22 2005-06-14 Bristol-Myers Squibb Company Method for reducing toxicity of combined chemotherapies
EP1534674A2 (fr) * 2002-08-02 2005-06-01 Immunogen, Inc. Agents cytotoxiques renfermant des nouveaux taxanes puissants et utilisation therapeutique de ceux-ci
EP1534674A4 (fr) * 2002-08-02 2007-11-28 Immunogen Inc Agents cytotoxiques renfermant des nouveaux taxanes puissants et utilisation therapeutique de ceux-ci
US7390898B2 (en) 2002-08-02 2008-06-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US7414073B2 (en) 2002-08-02 2008-08-19 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US7495114B2 (en) 2002-08-02 2009-02-24 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
CN104650012A (zh) * 2013-11-22 2015-05-27 天士力控股集团有限公司 一种紫杉烷类化合物
JP2016539186A (ja) * 2013-11-22 2016-12-15 ジアンスー タスリー ディイ ファーマスーティカル カンパニー リミテッドＪｉａｎｇｓｕ Ｔａｓｌｙ Ｄｉｙｉ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． タキサン化合物、その調製方法およびその使用
US10253007B2 (en) 2013-11-22 2019-04-09 Jiangsu Tasly Diyi Pharmaceutical Co., Ltd. Taxanes compounds, preparation method therefor, and uses thereof

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