JP2002543127A - Methods for treating abnormal cell proliferation in the brain - Google Patents

Abstract

  (57) [Summary] The present invention relates to a method of treating abnormal cell proliferation in the brain by administering a compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof; wherein R is a hydrogen atom or Represents an acetyl, alkoxyacetyl or alkyl group; ₁Is a benzoyl group or a group R_Two-O-CO- (wherein, R_TwoRepresents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclic group) and Ar represents an aryl group. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to a compound of the general formula (I):

[0002]

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[0003] A method for treating abnormal cell proliferation in the brain by administering a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof.

The compounds of the general formula (I) exhibit a significant inhibitory activity on the abnormal growth of malignant and non-malignant cells of the brain. The compounds of formula (I) also have therapeutic properties that allow for the treatment of conditions associated with abnormal cell proliferation. The compounds of the formula (I) exhibit such properties, especially in the brain, due to their longer residence time in the brain compared to other tissues and / or organs. As used in this application, the term “treatment” refers to both reducing cell proliferation and preventing cell proliferation.

As used in this application, the term “abnormal cell proliferation in the brain” refers to brain tumors and brain metastases that occur in the development of cancer in the brain or other tissues.

In the general formula (I), Ar represents an aryl group, R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl group, and R ₁ represents a benzoyl group or a carbon atom having R ₂ of −1 to 8 carbon atoms. Linear or branched alkyl groups containing atoms, alkenyl groups containing 2 to 8 carbon atoms, alkynyl groups containing 2 to 8 carbon atoms, 3
A cycloalkyl group containing from 4 to 6 carbon atoms; a cycloalkenyl group containing from 4 to 6 carbon atoms or a bicycloalkyl group containing from 7 to 11 carbon atoms, these groups being halogen Atoms and hydroxyl groups, alkyloxy groups containing 1-4 carbon atoms, dialkylamino groups wherein each alkyl moiety contains 1-4 carbon atoms, piperidino group, morpholino group, 1-piperazinyl group (4
An alkyl group containing from 1 to 4 carbon atoms in the
A cycloalkyl group containing 3 to 6 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, a phenyl group, A group in which a cyano group, a carboxy group or an alkyl moiety is optionally substituted by one or more substituents selected from an alkyloxycarbonyl group containing 1 to 4 carbon atoms; A phenyl group optionally substituted with one or more atoms or groups selected from an alkyl group containing carbon atoms or an alkyloxy group containing 1 to 4 carbon atoms, or-1 to 4 carbon atoms Saturated or unsaturated 4- or 6-membered nitrogen-containing hetero optionally substituted by one or more alkyl groups containing Ikuriru group, a group R ₂ -O-CO- representing a cycloalkyl, cycloalkenyl or bicycloalkyl radicals may be optionally substituted by one or more alkyl groups containing 1 to 4 carbon atoms Things are understood.

Preferably Ar is a halogen atom (fluorine, chlorine, bromine or iodine) and alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl Optionally, one or more atoms or groups selected from acylamino, aroylamino, akoxycarbonylamino, amino, alkylamino, dialkylamino, carboxy, akoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl groups. Represents a substituted phenyl or α- or β-naphthyl group, wherein the alkyl and alkyl portions of the alkyl group and other groups contain 1-4 carbon atoms, and The alkenyl and alkynyl groups contain 2 to 8 carbon atoms and the aryl group represents phenyl or an α- or β-naphthyl group, or Ar is the same or different and is selected from nitrogen, oxygen or sulfur atoms A halogen atom (fluorine, chlorine, bromine or iodine) and an alkyl group containing 1 to 4 carbon atoms, an aryl group containing 6 to 10 carbon atoms, containing 1 or more atoms, 1
An alkoxy group containing 4 to 4 carbon atoms, an aryloxy group containing 6 to 10 carbon atoms, an amino group, an alkylamino group containing 1 to 4 carbon atoms,
A dialkylamino group in which each alkyl moiety contains 1 to 4 carbon atoms, an acylamino group in which the acyl moiety contains 1 to 4 carbon atoms, an alkoxycarbonylamino group containing 1 to 4 carbon atoms, 1 Acyl groups containing 4 carbon atoms,
An aryl carbonyl group having 6 to 10 carbon atoms, a cyano group, a carboxy group, a carbamoyl group, an alkyl carbamoyl group having an alkyl moiety containing 1 to 4 carbon atoms, 5-membered aromatic optionally substituted with one or more substituents, the same or different, wherein the dialkylcarbamoyl group containing 1 carbon atom or the alkoxy moiety is an alkoxycarbonyl group containing 1 to 4 carbon atoms Represents a group heterocyclic group.

More particularly, Ar is represented by the same or different atoms or groups selected from halogen atoms and alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl groups. Represents a phenyl, 2- or 3-thienyl or 2- or 3-furyl group substituted by

[0009] Even more particularly, Ar is selected from a chlorine or fluorine atom, or an alkyl (methyl), alkoxy (methoxy), dialkylamino (diethylamino),
Acylamino (acetylamino) or alkoxycarbonylamino (tert-
Butoxycarbonylamino) or a phenyl group optionally substituted by a 2- or 3-thienyl or a 2- or 3-furyl group.

[0010] Even more particularly interesting are compounds of general formula (I) in which Ar represents a phenyl group and R ₁ represents a benzoyl or tert-butoxycarbonyl group.

According to the present invention, the taxoid of the general formula (I) has the general formula:

[0012]

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Wherein Ar and R ₁ are as defined above, and R ₃ and R _{4 which} are the same or different are a hydrogen atom, or an alkyl group containing 1-4 carbon atoms, or an alkyl moiety An aralkyl group containing 1 to 4 carbon atoms and representing an phenyl optionally substituted by one or more alkoxy groups containing 1 to 4 carbon atoms, or preferably 1 to 4 R ₃ represents an aryl group representing phenyl optionally substituted by one or more alkoxy groups containing 1 to 4 carbon atoms, or R ₃ represents an alkoxy group containing 1 to 4 carbon atoms, or trichloromethyl, represents a phenyl group substituted by a trihalomethyl group such as trihalomethyl group or trichloromethyl methyl, and R ₄ is table a hydrogen atom Or, alternatively R ₃ and R ₄ together with the carbon atoms to which they are attached, to 7-membered ring to form 4, and G ₁ represents a hydrogen atom or an acetyl, alkoxy acetyl or alkyl or hydroxyalkyl, Which represents a protecting group, the procedure being carried out according to the meaning of R ₃ and R ₄ in the following manner: 1) R ₃ contains a hydrogen atom or from 1 to 4 carbon atoms When R ₄ represents a hydrogen atom and represents an alkoxy group, or an optionally substituted aryl group, the product of general formula (II) has the general formula:

[0014]

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Wherein Ar, R ₁ and G ₁ are as defined above, wherein the G ₁ group is treated in an acidic medium to obtain the product of which is optionally replaced by a hydrogen atom.

The deprotection of the side chain of the product of the general formula (II) can also be carried out by using an inorganic acid (hydrochloric acid or sulfuric acid) or an organic acid (acetic acid, methanesulfonic acid, trifluoromethanesulfonic acid or p-type) used alone or in a mixture. -Toluenesulfonic acid), this procedure involves an alcohol (methanol, ethanol or isopropanol),
Ethers (tetrahydrofuran, diisopropyl ether or methyl t-butyl ether), esters (ethyl acetate, isopropyl acetate or n-butyl acetate),
Organic solvent selected from aliphatic hydrocarbons (pentane, hexane or heptane), halogenated aliphatic hydrocarbons (dichloromethane or 1,2-dichloroethane), aromatic hydrocarbons (benzene, toluene or xylene) and nitrile (acetonitrile) In a temperature of between -10 ° C and 60 ° C, preferably between 15 and 30 ° C.
The acids can be used in catalytic or stoichiometric amounts or in excess.

The deprotection is carried out, for example, in an acetonitrile-water mixture or in 2,3-dichloro-water.
It can also be carried out under oxidizing conditions using ammonium cerium (IV) in -5,6-dicyano-1,4-benzoquinone.

Deprotection can also be carried out under reducing conditions, for example by hydrogenolysis in the presence of a catalyst.

When G ₁ represents a protecting group, the replacement of the 2,2,2-trichloroethoxycarbonyl or 2- (2-triclomethylpropoxy) carbonyl group by a hydrogen atom may employ zinc optionally combined with copper. In an aliphatic alcohol containing 1 to 3 carbon atoms at a temperature between 20 and 60 ° C. in the presence of acetic acid or by means of an inorganic or organic acid such as hydrochloric acid or acetic acid in solution. Or in an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate, preferably in the presence of zinc, optionally in combination with copper, or, when G ₁ represents an alkoxycarbonyl group, a hydrogen atom Is optionally carried out by treatment in an alkaline medium or by the action of zinc halide under conditions which do not affect the rest of the molecule. Generally, the alkali treatment is performed at a temperature around 20 ° C. by the action of ammonia in the aqueous-alcoholic medium. In general, treatment with zinc halide, and preferably with zinc iodide, is carried out in methanol at a temperature around 20 ° C. 2) the same or different R ₃ and R ₄ contain 1 to 4 alkyl groups containing carbon atoms or an alkyl moiety having 1 to 4 carbon atoms, and the aryl moiety is preferably optionally substituted R ₃ represents a trihalomethyl group or a phenyl group substituted by a trihalomethyl group, and R ₄ represents a hydrogen atom, or R ₃ and R ₄ represent When forming a 4- to 7-membered ring with the carbon atom to which it is attached, the product of general formula (II) is converted to a compound of general formula:

[0020]

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Wherein Ar and G ₁ are as defined above, which is converted to the product of benzoyl chloride or a general formula: R ₂ —O—CO—X (V) wherein R ₂ is X is as defined above, and X represents a halogen atom (fluorine or chlorine) or a residue —OR ₂ or —O—CO—OR _2, and is treated with a reactive derivative of the general formula (III ) Wherein Ar, R ₁ and G ₁ are as defined above, wherein the G ₁ group is replaced by a hydrogen atom if necessary.

The product of general formula (IV) is a product of general formula (II) (where Ar, R ₁ and G ₁ are as defined above, and the same or different R ₃ and R ₄ are alkyl, Represents an aralkyl or aryl group, or R ₃ and R ₄ together with the carbon atom to which they are attached form a 4- to 7-membered ring), an inorganic acid (hydrochloric acid or sulfuric acid) or an organic acid (Formic acid), optionally in an alcohol having 1 to 3 carbon atoms (methanol, ethanol or isopropanol), from 0 to 50
Obtained by treatment at a temperature between ° C. Preferably formic acid is used at a temperature around 20 ° C.

Formula (IV) with benzoyl chloride or a reactive derivative of formula (V)
Acylation of the product is carried out in an inert organic solvent selected from esters such as ethyl acetate, isopropyl acetate or n-butyl acetate and halogenated aliphatic hydrocarbons such as dichloromethane or 1,2-dichloroethane. In the presence of an inorganic base such as sodium bicarbonate or an organic base such as triethylamine. The reaction is carried out at a temperature between 0 and 50 ° C, preferably around 20 ° C.

When the group G ₁ represents a protecting group, its replacement by a hydrogen atom takes place under the conditions described above.

The product of general formula (II) can be obtained according to one of the following methods: 1) General formula:

[0026]

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Wherein G ₁ is as defined above, wherein the general formula of the product:

[0028]

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Wherein Ar, R ₁ , R ₃ and R ₄ are as defined above, by esterification with an acid or a derivative of this acid.

The esterification with an acid of the general formula (VII) is carried out in the presence of a condensing agent (carbodiimide, reactive carbonate) and an activator (aminopyridine) in the presence of an organic solvent (ether, ester, ketone, nitrile, aliphatic). (Hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at temperatures between -10 and 90 ° C.

The esterification can also be carried out using an acid of the general formula (VII) in the anhydrous state, this procedure being carried out in the presence of an activator (aminopyridine) in an organic solvent (ether, ester). , Ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at temperatures between 0 and 90 ° C.

The esterification can also be carried out using an acid of the general formula (VII) in the halogenated or anhydrous state, optionally containing an in situ prepared aliphatic or aromatic acid, using a base (3
In the presence of an organic solvent (ether, ether).
(Esters, ketones, nitriles, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons or aromatic hydrocarbons) at temperatures between 0 and 80 ° C.

The acid of the general formula (VII) has the general formula:

[0034]

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Wherein Ar, R ₁ , R ₃ and R ₄ are as defined above, and R ₅ represents alkyl containing 1-4 carbon atoms optionally substituted with a phenyl group; Can be obtained by saponification of an ester of

In general, saponification is an inorganic base (alkali metal hydroxide, carbonate or bicarbonate)
In an aqueous-alcoholic medium (methanol-water) at a temperature between 10 and 40 ° C.

The ester of the general formula (VIII) has the general formula:

[0038]

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Wherein R ₃ and R ₄ are as defined above, in the form of a dialkyl acetal or an enol alkyl ether,
General formula:

[0040]

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Where Ar, R ₁ and R ₅ are as defined above, can be obtained by acting on an ester of the following procedure, in an inert organic solvent (aromatic hydrocarbon): It is carried out at a temperature between 0 and the boiling temperature of the reaction mixture in the presence of a strong inorganic acid (sulfuric acid) or an organic acid (optionally p-toluenesulfonic acid in the form of a pyridinium salt).

The ester of the general formula (X) is a product of the general formula (V),

[0043]

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Wherein Ar and R ₅ are as defined above, which can be obtained by the action on an ester of an inorganic or organic base in an organic solvent (ester, halogenated aliphatic hydrocarbon). From 0 in the presence of
Perform at a temperature between 50 ° C.

The product of general formula (XI) is converted to a compound of general formula (XI) with hydrogen in the presence of a catalyst such as palladium on carbon:

[0046]

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Wherein Ar and R ₅ are as defined above, which can be obtained by reduction of the azide, which is carried out in an organic solvent (ester).

The product of general formula (XII) can be obtained by boiling the reaction mixture in an aqueous-organic medium (water-tetrahydrofuran) from 20 ° C. in the presence of zinc chloride or an alkali metal (sodium, potassium or lithium) azide. An azide such as trimethylsilyl azide at a temperature between the temperatures, optionally with an in situ prepared general formula:

[0049]

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Wherein Ar and R ₅ are as defined above, which can be obtained by acting on an epoxide of

The epoxides of the general formula (XIII) can be prepared in situ in certain places by the general formula:

[0052]

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Wherein Ar is as defined above, Hal represents a halogen atom, preferably a bromine atom, and the same or different R ₆ and R ₇ are halogen atoms or 1 to 1
Represents an alkyl or phenyl group containing 4 carbon atoms, at least one of which is an alkyl or phenyl group, in an inert organic solvent such as tetrahydrofuran between -80 ° C and 25 ° C. At a temperature of, can be obtained by dehydrohalogenation with an alkali-metal alcoholate prepared in situ by the site.

The product of general formula (XIV) has the general formula: Ar-CHO (XV) wherein Ar is as defined above, wherein the aldehyde of the general formula is previously anionized:

[0055]

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In the formula, Hal, R ₆ and R ₇ can be obtained by acting on a halide as defined above.

In general, this procedure involves the tertiary process in an inert organic solvent selected from ethers (ethyl ether) and halogenated aliphatic hydrocarbons (methylene chloride) at a temperature between −80 ° C. and 25 ° C. The reaction is performed in the presence of an amine (triethylamine) and an enolizing reagent (di-n-butylboron triflate).

The product of general formula (XVI) is obtained by reacting a halide of haloacetic acid, preferably bromoacetic bromide, with the corresponding oxazolidinone.

The product of general formula (XI) has the general formula:

[0060]

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Wherein Ar and R ₅ are as defined above, and Ph represents an optionally substituted phenyl group, which can be obtained by hydrogenolysis of the product

Generally, the hydrocracking is carried out with hydrogen in the presence of a catalyst. More specifically, 1
Palladium on carbon containing 1010% by weight of palladium or palladium dihydroxide containing 20% by weight of palladium is used as catalyst.

The hydrocracking is carried out in an organic solvent or a mixture of organic solvents. This procedure is advantageously carried out in acetic acid, optionally in combination with an aliphatic alcohol containing 1 to 4 carbon atoms, such as an acetic acid-methanol mixture, at a temperature between 20 and 80 ° C.

The hydrogen required for hydrocracking can also be provided by chemical reactions or by compounds that liberate hydrogen by thermal decomposition (ammonium formate). This procedure is 1 to 50
It is advantageous to work at a hydrogen pressure between bars.

The product of general formula (XVII) has the general formula:

[0066]

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Where Ar and Ph are as defined above, can be obtained by hydrolysis or alcoholysis of the product of

The alcoholysis is carried out with an alcohol of the formula R ₅ —OH, where R ₅ is as defined above, and it is particularly advantageous to carry out this procedure in an acidic medium.

The alcoholysis is preferably carried out with methanol in the presence of a strong inorganic acid such as hydrochloric acid at a temperature near the reflux temperature of the reaction mixture.

The product of general formula (XVIII) has the general formula:

[0071]

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Wherein Ar and Ph are as defined above, and R ₈ represents an alkyl, phenylalkyl or phenyl group, followed by saponification of an ester of the general formula (XVIII), followed by a 3R, 4S diastereomer of general formula (XVIII) It can be obtained by separation of the mer from other diastereomers.

In general, the saponification is carried out with an inorganic or organic base such as ammonium hydroxide, lithium hydroxide, sodium hydroxide or potassium hydroxide, in a suitable solvent such as methanol-water or tetrahydrofuran-water mixture. It is carried out at a temperature between 10 ° C and 20 ° C.

The separation of the 3R, 4S diastereomer can be performed by a selective crystallization method from a suitable organic solvent such as ethyl acetate.

The product of general formula (XIX) has the general formula:

[0076]

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Wherein Ar and Ph are as defined above, wherein the general formula of the imine is:

[0078]

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Wherein R ₈ is as defined above, and Y represents a halogen atom such as a bromine or chlorine atom, which can be obtained by cycloaddition onto an acid halide.

In general, the reaction is carried out at a temperature between 0 and 50 ° C., in the presence of a base selected from aliphatic tertiary amines (triethylamine) or pyridine, optionally aliphatic hydrocarbons which may be halogenated. (Methylene chloride or chloroform) and an aromatic hydrocarbon (benzene, toluene or xylene).

The product of the general formula (XX) can be obtained from M. Furukawa et al., Chem. Phar. Bull., 25 (1), 181-18.
4 (1977).

The products of the general formula (VI) are represented by the general formulas of alkali metal halides (sodium iodide or potassium fluoride) or alkali metal azides (sodium azide) or quaternary ammonium salts or alkali metal phosphates :

[0083]

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Wherein G ₁ is as defined above, which can be obtained by the action of on the baccatin III or 10-deacetylbaccatin III derivative.

In general, the reaction is carried out with an ether (tetrahydrofuran, diisopropyl ether,
The reaction is carried out in an organic solvent alone or in a mixture selected from methyl t-butyl ether) at a temperature between 20 ° C. and the boiling temperature of the reaction mixture.

The products of formula (XXII) in which G ₁ represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl group can be obtained from anhydrides or baccatin III or 10 trifluoromethanesulfonic acid derivatives such as N-phenyltrifluoromethanesulfonimide. - can be obtained by action on deacetylbaccatin III derivatives, which is extracted according to known methods from the European yew (yew leaves) (Taxus baccata) , optionally can be protected with 10-position, G ₁ is alkoxy In order to obtain the product of the general formula (XXII) which is an acetyl or alkyl group, the 7-position protected 10-
It may be necessary to treat the deacetylbaccatin III, preferably with a silylated group, with an alkoxyacetic acid halide or with an alkyl halide.

In general, the reaction of the trifluoromethanesulfonic acid derivative is carried out in an inert organic solvent (optionally halogenated aliphatic or aromatic hydrocarbon), such as an aliphatic tertiary amine (triethylamine) or pyridine. The reaction is carried out at a temperature between -50 and + 20 ° C. in the presence of an organic base.

In general, the introduction of an alkoxyacetyl group is effected by the protected 10-deacetylbaccatin I
II is carried out by treatment with an alkoxyacetic acid halide, the procedure being carried out in a basic organic solvent such as pyridine at a temperature around 20 ° C.

In general, the introduction of an alkyl group is protected at the 10-position and metallized
The performed 10-deacetylbaccatin III is carried out, for example, with an alkali metal hydride (sodium hydride) or a metallic alkylide (butyllithium) using an alkyl halide. 2) General formula of alkali metal halide (sodium iodide or potassium fluoride) or alkali metal azide (sodium azide) or quaternary ammonium salt or alkali metal phosphate:

[0090]

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Wherein Ar, R ₁ , R ₃ , R ₄ and G ₁ are as defined above, depending on the effect on the product of

In general, the reaction is carried out in an organic solvent, alone or in a mixture selected from ether (tetrahydrofuran, diisopropyl ether or methyl t-butyl ether) and nitrile (acetonitrile), from 20 ° C. to the boiling temperature of the reaction mixture. Perform at a temperature between.

The product of general formula (XXIII) is a compound of the general formula: anhydride or a trifluoromethanesulfonic acid derivative such as N-phenyltrifluoromethanesulfonimide

[0094]

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Wherein Ar, R ₁ , R ₃ , R ₄ and G ₁ can be obtained by the action on taxoids as defined above.

In general, the reaction is carried out in an inert organic solvent (optionally halogenated aliphatic or aromatic hydrocarbon) in the presence of an organic base such as an aliphatic tertiary amine (triethylamine) or pyridine. At a temperature between -50 and + 20 ° C.

The taxoid of the general formula (XXIV) (wherein G ₁ represents a hydrogen atom or an acetyl group) has the general formula:

[0098]

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Wherein Ar, R ₁ , R ₃ , R ₄ are as defined above, and G ′ ₁ represents a hydroxy-protecting group, and G ′ ₂ is an acetyl, alkoxyacetyl or alkyl group or hydroxy group. - can be obtained by replacing the product, represents a protective group, a ₂ to hydrogen atom "G by _one and if 'protecting group G.

When the groups G ′ ₁ and G ′ ₂ represent a hydroxy-protecting group, they are preferably 2,2,
2-trichloroethoxycarbonyl or 2- (2-trichloromethylpropoxy) carbonyl group or trialkylsilyl, dialkylsilyl, alkyldiarylsilyl or triarylsilyl group, wherein the alkyl moiety contains 1 to 4 carbon atoms and, and the aryl moiety is preferably phenyl group, the more G _'2 is also possible to represent the alkoxy acetyl group.

When G ′ ₁ and G ′ ₂ represent 2,2,2-trichloroethoxycarbonyl or 2- (2-trichloromethylpropoxy) carbonyl, the replacement of the protecting group by a hydrogen atom is
Using zinc, optionally in combination with copper, in the presence of acetic acid at a temperature between 20 and 60 ° C. or with an inorganic or organic acid such as hydrochloric acid or acetic acid in solution
It is carried out in an aliphatic alcohol containing 1 to 3 carbon atoms or an aliphatic ester such as ethyl acetate, isopropyl acetate or n-butyl acetate, optionally in the presence of zinc in combination with copper.

When G ′ ₁ represents a silylated group and G ′ ₂ represents an acetyl, alkoxyacetyl or alkyl group, replacement of the protecting group G ′ _{1 by} a hydrogen atom can be carried out, for example, by adding gaseous hydrochloric acid in an ethanolic solution. Thus, the reaction can be carried out at a temperature around 0 ° C. without affecting the rest of the molecule.

When G ′ ₂ represents alkoxyacetyl, the optional replacement by a hydrogen atom is effected by treatment in an alkaline medium or by the action of zinc halide under conditions that do not affect the rest of the molecule. Generally, the alkali treatment is performed at a temperature around 20 ° C. by the action of ammonia in the aqueous-alcoholic medium. Generally zinc halide,
Preferably, treatment with zinc iodide is carried out in methanol at a temperature around 20 ° C.

The product of the general formula (XXV) is obtained under the conditions described in International Patent Application No. PCT / WO 9209589.

The derivatives of the general formula (I) have the general formula:

[0106]

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Wherein Ar and R ₁ are as defined above, and G ₃ is methoxymethyl,
1-ethoxyethyl, benzyloxymethyl, (β-trimethylsilyloxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxymethyl, 2,2,2-trichloroethoxycarbonyl or 2- (2-trichloromethylpropoxy) Carbonyl group,
Alternatively, a CH ₂ -PH group (where Ph is one or more of the same or different selected from a halogen atom and an alkyl group containing 1 to 4 carbon atoms or an alkoxy group containing 1 to 4 carbon atoms) Esterifying the product of the general formula (VI) with an acid of formula (I) or an activated derivative of this acid, which represents a hydroxy-protecting group selected from phenyl optionally substituted by atoms or groups. Can also be given by the general formula:

[0108]

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Wherein Ar, R ₁ , G ₁ and G ₃ are as defined above, followed by replacement of the protecting groups G ₁ , G ₂ and G ₃ by hydrogen atoms,
This gives the product of general formula (I).

The esterification can be carried out with an acid of the general formula (VII) under the conditions described above for the esterification of the product of the general formula (VI).

G₁And G_ThreeIs 2,2,2-trichloroethoxycarbonyl or 2- (2-trichloro
Methylpropoxy) carbonyl represents a protecting group G of the product of general formula (XXVII) ₁ And G_ThreeWith a hydrogen atom at a temperature between 30 and 60 ° C. in the presence of acetic acid.
Optionally by treatment with zinc in combination with copper or in solution
Or an aliphatic having 1 to 3 carbon atoms by an inorganic or organic acid such as acetic acid
Fats such as alcohol or ethyl acetate, isopropyl acetate or n-butyl acetate
It is carried out in an aliphatic ester in the presence of zinc, optionally in combination with copper. G_ThreeBut
When a lylating group or an acetal residue is represented, the protecting group G_ThreeIs, for example, 1-3
Aliphatic alcohols containing carbon atoms (methanol, ethanol, propanol
Acidic media such as hydrochloric acid in solution in aqueous or isopropanol) or aqueous fluoride.
Can be carried out in hydrofluoric acid by treatment at a temperature between 0 and 40 ° C .;_ThreeBut
When representing a tar residue, the protecting group G₁Is performed under the conditions described above. G_ThreeIs -CH_Two When -Ph is represented, substitution of this protecting group with a hydrogen atom can cause hydrogenolysis in the presence of a catalyst.
More can be done.

The acid of the general formula (XXVI) has the general formula:

[0113]

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Wherein Ar, R ₁ , R ₅ and G ₃ are as defined above, which can be obtained by saponification of an ester of

In general, the saponification is carried out at a temperature between 10 and 40 ° C. with an inorganic base (alkali metal hydroxide, carbonate or bicarbonate) in an aqueous-alcoholic medium (methanol-water).

The esters of general formula (XXVIII) can be prepared according to the customary methods for the preparation of ethers, and more particularly according to JN. DENIS et al., J. Org. Chem., 51 , 46-50 (1986). It can be obtained from the product of general formula (XI).

The product of general formula (I) obtained using the procedure according to the invention can be purified according to known methods such as crystallization or chromatography.

The products of general formula (I) have notable biological properties.

[0119] In vitro, using tubulin extracted measurement of biological activity from pig brain, MLShelanski et al., Proc.Natl.Acad.Sci.USA, method 70 .765-768 (1973) Performed by Experiments on depolymerization of microtubules to tubulin were performed as described by G. Chauviere et al.
, CRAcad. Sci., 293 , serie II, 501-503 (1981). In this experiment, the product of general formula (I) was shown to be at least as active as Taxol ™ and Taxotere ™.

In vivo, the products of general formula (I) are active in mice implanted with B16 melanoma at a dose of 1 to 10 mg / kg, as well as other liquid or solid tumors intraperitoneally. It was shown that.

This compound has anti-tumor properties, more particularly Taxol ™ and Taxotere ™
It has activity against tumors that are resistant to For example, such tumors
Includes colon tumors with elevated expression of the mdr1 gene (multidrug resistance gene). Multidrug resistance is a common term associated with resistance by tumors to various compounds having different structures and mechanisms of action. Taxoids are generally P388 / DOX, doxorubicin
It is known to be highly recognized by laboratory tumors such as the P388 murine leukemia cell line expressing mdr1 selected for (DOX) resistance. The compound of the present invention is P388 / DOX
Is difficult to recognize. More specifically, this compound is less recognizable by mdr1 than Taxotere ™.

In particular, compounds of the present invention include those of Example 1, Example 2 and Example 3,
Taxol ™ and Taxotere ™ were found to have better multidrug resistance properties. Even more surprisingly, the compound of Example 3 was found to have substantially better multidrug resistance properties than the compounds of Example 1 and Example 2.

The products of general formula (I) exhibit significant inhibitory activity with respect to abnormal cell proliferation and have therapeutic properties which enable the treatment of patients with conditions associated with abnormal cell proliferation. Medical conditions include, but are not limited to, muscle, bone or connective tissue, skin,
Abnormal cell proliferation of malignant and non-malignant cells of various tissues and / or organs including brain, lung, bladder, reproductive organs, lymph and kidney system, mammary gland or blood cells, liver, gastrointestinal tract, pancreas and thyroid or adrenal glands Including. Such conditions also include psoriasis, solid tumors, lung, bladder, ovary, breast, brain, prostate, colon, stomach, cancer of the kidney or testis, Kaposi's sarcoma, cholangiomas, choriomas, neuroblastomas, Wilms Includes tumors, Hodgkin's disease, melanoma, multiple myeloma, lymphocytic leukemia and acute or chronic granular lymphoma. The products of the present invention are particularly useful for the treatment of lung or bladder; more particularly lung cancer. The products of the invention can be used to prevent or delay the onset or recurrence of a condition, or to treat such a condition.

In particular, according to the present invention, the compounds of general formula (I), in particular the compounds of Example 3, are used for the treatment of brain cancer or brain or brain metastases, which are cancers of the brain or other tissues, in particular lung cancer, and furthermore It is particularly useful for treating abnormal cell growth in the brain (such as may occur in the development of non-small cell lung cancer).

In accordance with the present invention, it has been found that compounds of general formula (I), especially the compound of Example 3, are useful for treating non-small cell lung cancer that metastasizes to the brain.

According to a preferred object of the present invention, the compound of general formula (I), in particular the compound of Example 3, is used for the non-small cell lung cancer metastases to the brain as an IV infusion every 3 weeks for 1 hour. It has been found useful in treatment.

[0127] In accordance with a further preferred object of the present invention, compounds of formula (I), especially the compound of Example ^{3, 75mg / m 2 ~90mg /} m every 1 hour 3 weeks ² ranging dose IV - non metastasize to the brain as an infusion - useful for the treatment of small cell lung carcinoma; even more particularly to be a dose of 75 mg / m ² for patients a suitable dose is receiving radiation therapy in advance, and pre It can be 90 mg / m ^{2 for} patients who have not received radiation therapy.

This is because the compounds exhibit significant inhibitory activity on the abnormal growth of malignant and non-malignant cells of the brain. The compounds of the general formula (I) exhibit such properties, in particular in the brain, due to their longer residence time in the brain compared to other tissues and / or organs.

The compounds of the present invention can be administered to a patient in various forms adapted to the chosen route of administration, preferably by the parenteral or oral route. Parenteral administration includes intravenous, intraperitoneal, intramuscular or subcutaneous administration. Intraperitoneal, intravenous or oral administration is particularly preferred.

The present invention also comprises a pharmaceutical composition comprising at least one compound of general formula (I) in a quantity sufficient for the treatment of humans or domestic animals. The compositions can be prepared according to the usual methods using one or more pharmaceutically acceptable auxiliaries, carriers or excipients. Suitable carriers include diluents, sterile aqueous media and various non-toxic solvents. Preferably, the compositions are provided in the form of an aqueous solution or suspension of an injectable solution, which may include emulsifiers, colorants, preservatives or stabilizers.

The choice of adjuvant or excipient is dictated by the solubility and chemical properties of the product, the particular mode of administration and good pharmaceutical practice, all of which are known to those skilled in the art.

For parenteral administration, sterile aqueous or non-aqueous solutions or suspensions are used. For the preparation of non-aqueous solutions or suspensions, natural vegetable oils, such as olive oil or sesame oil, or injectable organic esters, such as paraffin oil or ethyl oleate, can be used. Aqueous sterile solutions can consist of a solution of a pharmaceutically acceptable salt in solution in water. Aqueous solutions are suitable for intravenous administration, as long as the pH is adjusted appropriately and isotonicity is achieved, for example, with a sufficient amount of sodium chloride or glucose. Sterilization can be accomplished by heating or by any other means that does not adversely affect the composition.

It is clearly understood that all products entering the compositions of the present invention should be pure and non-toxic in the amounts used.

The composition may contain at least 0.01% of the therapeutically active product. The amount of active product in the composition is such that a suitable dosage can be formulated. Preferably, the compositions are prepared so that a single dose contains from about 0.01 to 1000 mg of the active product for parenteral administration.

[0135] Therapeutic treatment can be concurrent with other therapeutic treatments, including anti-tumor agents, monoclonal antibodies, immunotherapy or radiation therapy or biological response modifiers. Response modifiers include, but are not limited to, interleukins, interferons (α, β or δ) and lymphokines and cytokines such as TNF. Other chemotherapeutic agents useful in the treatment of diseases caused by abnormal cell proliferation include, but are not limited to, alkylating agents such as nitrogen mustards such as mechlorethamine, cyclophosphamide, melphalan and chlorambucil , Alkyl sulfonates such as busulfan, carmustine,
Metabolism such as nitrosoureas such as lomustine, semustine and streptozocino, triazenes such as dacarbazine, folate homologs such as methotrexate, pyrimidine homologs such as fluorouracil and cytarabine, purine homologs such as mercaptopurine and thioguanine. Antagonists, vinca alkaloid-like natural products such as vinblastine, vincristine and vindesine, epipodophyllotoxins such as etoposide and teniposide, dactinomycin,
Antibiotics such as daunorubicin, doxorubicin, bleomycin, pyricamycin and mitomycin, enzymes such as L-asparaginase, coordination complexes of platinum such as cisplatin, substituted ureas such as hydroxyurea, methylhydrazines such as procarbazine Derivatives, corticosteroids such as mitotane and aminoglutethimide, hormones and antagonists such as corticosteroids such as prednisone, hydroxyprogesterone caproate, progestins such as methoxyprogesterone acetate and megesterol acetate, diethylstil Bestrol and estrogens such as ethinylestradiol, antiestrogens such as tamoxifen, and like testosterone propionate and fluoroxymesterone Including androgen.

The dose used to perform the methods of the invention is that dose that allows for prophylactic treatment or maximal therapeutic response. The dosage will vary with the mode of administration, the particular product chosen and the particular characteristics of the individual being treated. Generally, a dose is a therapeutically effective amount for treating a disorder caused by abnormal cell proliferation. The products of the present invention can be administered as often as necessary to achieve the desired therapeutic effect. Some patients may respond rapidly to relatively high or low doses and then require a low or zero maintenance dose. Generally, lower doses are used early in the treatment and higher doses are administered, if necessary, until the optimal effect is obtained. For other patients, it may be necessary to administer 1 to 8 and preferably 1 to 4 maintenance doses per day, depending on the physiological needs of the patient being considered. Also, certain patients may need to use only once or twice daily dosing.

For the purposes of the present invention, the compounds of general formula (I), and especially the compounds of Example (3), can preferably be administered as a 1- or 3-hour IV infusion every three weeks; Preferably, the compound of general formula (I) and especially the compound of Example (3) can be administered as a 1-hour IV infusion every three weeks; according to another purpose, the compound can be suitably administered weekly.

To select the most appropriate dosage, consideration should be given to the route of administration, the weight of the patient, the general health of the patient, the age and all factors which may affect the efficacy of the treatment.

[0139] In accordance with the present invention, the dose of the compound is generally parenteral administration the range of 50 to 150 mg / m ^2; preferably in the range of ^{75mg / m 2 ~90mg / m 2} . Even more specifically, a suitable dose can be 75 mg / m ^{2 for} patients who have previously received radiation therapy, and 90 mg / m ² for patients who have not received prior radiation therapy.

The present invention will be described in more detail with reference to the following Examples, which, however, do not limit the present invention.

[0141]

EXAMPLE 1 2.01 g of 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene-13α -Il (4S, 5R)-
A solution of 3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate (in 20 cm ³ of formic acid) was stirred at a temperature near 20 ° C. for 4 hours and then at 40 ° C. under reduced pressure It was concentrated to dryness under (0.27 kPa). The resulting foam was dissolved in 100 cm ³ of dichloromethane and the resulting solution was supplemented with 20 cm ³ of saturated aqueous sodium bicarbonate. The aqueous phase separated after standing and was extracted with 20 cm ³ of dichloromethane. The organic phases are pooled, dried over magnesium sulfate, filtered, and
It was concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 1.95 g of a white foam are obtained, which is purified by chromatography on 200 g of silica (0.063-0.2 mm) contained in a 7 cm diameter column and eluted with a dichloromethane-methanol mixture (98-2, by volume), And 30 cm ³ fractions were collected. Pool fractions containing only the desired product,
Then, the mixture was concentrated and dried under reduced pressure (0.27 kPa) at 40 ° C. for 2 hours. 1.57 g of 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (2R, 3S) -3-Amino-2-hydroxy-3-phenylpropionate was obtained as a white foam.

400 mg of 4-acetoxy-2α-benzoyloxy-5β maintained under an argon atmosphere
, 20-Epoxy-1β, 10β-dihydroxy-7β, 8β-methylene-9-oxo-19-nor-11-
Taxen-13α-yl (2R, 3S) -3-amino-2-hydroxy-3-phenylpropionate
Solution (1cm^ThreeIn dichloromethane), add 60 mg of sodium bicarbonate.
And then a solution of 0.16 g of di-tert-butyl dicarbonate (1 c
m^ThreeIn dichloromethane) was added dropwise. The resulting solution is stirred for 64 hours at a temperature around 20 ° C.
Stir and then 5cm^ThreeOf distilled water and 10cm^ThreeReplenish the mixture with dichloromethane
Was. 2 cm of organic phase^ThreeOf distilled water three times. Dry the organic phase over magnesium sulfate
Dry, filter, and then concentrate to dryness at 40 ° C. under reduced pressure (2.7 kPa). 317m
g of white foam was thus obtained, which was added to a 30 g column contained in a 3 cm diameter column.
Purified by chromatography on mosquitoes (0.063-0.2 mm), dichloromethane-methano
Elution with the mixture (95-5, by volume) and 5 cm^ThreeFractions were collected. Desired
The fractions containing only the desired product were pooled and at 40 ° C. for 2 hours under reduced pressure (0.27 kPa
) And concentrated to dryness. 161 mg of 4-acetoxy-2α-benzoyloxy-5β, 20-epo
Xy-1β, 10β-dihydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene
-13α-yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenyi
Lepropionate is thus obtained in the form of a white foam, the properties of which are as follows:
-Specific rotation: [α] D²⁰= -17 ° (c = 0.482; methanol)-Proton NMR spectrum: (400 MHz; CDCl_ThreeA temperature of 323 K;
Coupling constant J at δ ppm, in Hz): 1.21 (s, 3H: -CH _Three 16
Or 17); 1.28 (s, 3H: -CH _Three 16 or 17); 1.34 [s,
9H: -C (CH _Three)_Three]; 1.30 to 1.50 (mt, 1H:-H 7); 1.8
0 and 2.36 (2 mt, each 1H: -C of cyclopropaneH _Two-); 1.88
(S, 3H: -CH _Three 18); 2.13 [mt, 1H:-(CH)-H 6]; 2
.26 [dd, 1H, J = 15 to 8.5:-(CH)-H 14]; 2.35 (s
, 3H: -COCH _Three); 2.35 to 2.50 [mt, 2H:-(CH)-H 1
4 and-(CH)-H 6]; 3.21 (d, 1H, J = 4: -OH 2 ');
4.08 [d, 1H, J = 8:-(CH)-H 20]; 4.16 (d, 1H, J
= 7:-H 3); 4.18 (s, 1H, -OH 10); 4.31 [d, 1H, J
= 8:-(CH)-H 20]: 4.61 (dd, 1H, J = 4 and 2:-H 
2 '); 4.74 (d, 1H, J = 4:-H 5); 5.00 (s, 1H:-H 1
0); 5.26 (dd, 1H, J = 9 and 2:-H 3 '); 5.33 (d, 1
H, J = 9: -NH 3 '); 5.69 (d, 1H, J = 7:-H 2); 6.29
(D, 1H, J = 8.5:-H 13); 7.30 to 7.50 [mt, 5H: 3 '
C₆H_Five(-H From 2-H 6); 7.51 [t, 2H, J = 7.5: -OCOC ₆ H_Five(-H From 3H 5)]; 7.60 [t, 1H, J = 7.5: -OCOC₆H_Five (-H 4)]; 8.14 [d, 2H, J = 7.5: -OCOC₆H_Five(-H 2 and
AndH 6)].

4-Acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (4S, 5R) -3-tert
-Butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was prepared in the following manner: 2.5 g of 4-acetoxy-2α-benzoyloxy-5β, maintained under an argon atmosphere.
20-epoxy-1β, 10β-dihydroxy-9-oxo-7β-trifluoromethanesulfonate-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl- To a solution of 5-oxazolidine carboxylate (in 25 cm ³ of anhydrous acetonitrile and 3 cm ³ of anhydrous tetrahydrofuran) was added 2.5 g of sodium azide. The reaction mixture is stirred under an argon atmosphere at a temperature of
Heated for an hour, then cooled to a temperature near 20 ° C. and supplemented with 30 cm ³ of distilled water. The aqueous phase was separated by decanting and then extracted with 20 cm ³ of dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and then
The solution was concentrated to dryness under reduced pressure (0.27 kPa) at ℃. 2.44 g of a yellow foam were thus obtained, which were purified by chromatography on 300 g of silica (0.063-0.2 mm) contained in an 8 cm diameter column and a dichloromethane-ethyl acetate mixture (90-10, by volume) And a 60 cm ³ fraction was collected. Pool fractions 47-70, and 40
The mixture was concentrated to dryness under reduced pressure (0.27 kPa) at 2 ° C. for 2 hours. 2.01 g of 4-acetoxy-2α-
Benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-7β, 8β-methylene-
9-oxo-19-nor-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-
2,2-Dimethyl-4-phenyl-5-oxazolidine carboxylate was thus obtained in the form of a white foam.

4-Acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-9-oxo-7β-trifluoromethanesulfonate-11-taxen-13α-yl (4S,
5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was prepared in the following manner: 2.86 g of 4-acetoxy-2α-benzoyloxy maintained under an argon atmosphere -5β
, 20-Epoxy-1β, 7β, 10β-trihydroxy-9-oxo-11-taxen-13α-yl (
4S, 5R) in the -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidine carboxylate solution (anhydrous dichloromethane 29cm ^3), the powder of pyridine 0.955Cm ³ and 50mg Supplemented with activated 4% molecular sieves. The reaction mixture was cooled to a temperature of around -35 ° C., supplemented with trifluoromethanesulfonic anhydride 0.85 cm ^3, and stirred for 15 minutes at a temperature of around -5 ° C., and supplemented with distilled water 10 cm ^3. Filter through sintered glass with celite and wash the sintered glass three times with 10 cm ³ of a methanol-dichloromethane mixture (10-90, by volume), separate the aqueous phase after standing, and remove 10 cm ³ of water. Extracted twice with dichloromethane. The organic phases were pooled, dried over magnesium sulfate, filtered and then concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). 3.87 g of a white foam are obtained, which is purified by chromatography on 400 g of silica (0.063-0.2 mm) contained in a 10 cm diameter column, gradient of a dichloromethane-ethyl acetate mixture (97.5-2.5 to 90-10, (By volume) and a fraction of 80 cm ³ was collected. Fractions containing only the desired product were pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. for 2 hours. 3.0 g of 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-9-oxo-7β-trifluoromethanesulfonate-11-taxen-13α-yl (4S, 5R) -3-t
ert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was thus obtained in the form of a white foam.

4-Acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 7β, 10β-trihydroxy-9-oxo-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl
-2,2-Dimethyl-4-phenyl-5-oxazolidinecarboxylate was prepared in the following manner: 24.35 g of 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-9-oxo-7β
, 10β- [Bis (2,2,2-trichloroethoxy) carbonyloxy] -1β-hydroxy-11
-Taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate solution (130 cm ³ of ethyl acetate and 46.
(In a mixture of 5 cm ³ of acetic acid) was heated with stirring and under an atmosphere of argon to a temperature near 60 ° C., and then supplemented with 40 g of zinc powder. The reaction mixture is then 6
Stirred at 0 ° C. for 30 minutes and cooled to a temperature near 20 ° C. and filtered through sintered glass with celite. The sintered glass was washed with 100 cm ³ of a methanol-dichloromethane mixture (20-80, by volume); the filtrates were pooled and concentrated to dryness under reduced pressure (0.27 kPa) at a temperature around 40 ° C.

The residue was supplemented with 500 cm ³ of dichloromethane. The organic phase was washed twice with 50 cm ³ of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm ³ of distilled water. After standing, the aqueous phase was obtained and the pool was extracted twice with 30 cm ³ of dichloromethane. The organic phases were pooled, dried over magnesium sulfate, filtered and then concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). 19.7 g of a white foam are obtained, which is purified by chromatography on 800 g of silica (0.063-0.2 mm) contained in a 10 cm diameter column and a dichloromethane-methanol gradient (100-0 to 97-3, by volume) ) And 80 cm ³ fractions were collected. Fractions containing only the desired product were pooled and concentrated to dryness under reduced pressure (0.27 kPa) at 40 ° C. for 2 hours. 16.53g
4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 7β,
10β-Trihydroxy-9-oxo-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was formed.

4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-9-oxo-7β, 10β- [
Bis (2,2,2-trichloroethoxy) carbonyloxy] -1β-hydroxy-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5 -
Oxazolidine carboxylate was prepared according to the method described in PCT WO9209589, the disclosure of which is incorporated herein by reference. Example 2 550 mg of 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-
Hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (2R, 3S
) -3-Amino-2-hydroxy-3-phenylpropionate solution (45 cm ³ of distilled water)
45 cm ³ of saturated aqueous sodium hydrogen carbonate solution and then 0.096 at a temperature around 20 ° C.
cm ³ of benzoyl chloride was added dropwise. The resulting mixture is heated at a temperature around 20 ° C for 10
Stirred for minutes. After standing, the aqueous phase was extracted twice with 30 cm ³ of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and at 40 ° C. under reduced pressure (2.
7 kPa) and concentrated to dryness. 670 mg of a white foam were thus obtained, which were purified by chromatography under atmospheric pressure on 50 g of silica (0.063-0.2 mm) contained in a 2.5 cm diameter column and a methanol-dichloromethane mixture (1 -99 then
2.5-97.5, by volume) and 10 cm ³ fractions were collected. Fractions containing only the desired product were pooled and concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). 610 mg of a white foam were thus obtained. A 300 mg sample was purified by preparative chromatography on 12 thin-layer silica plates (Kieselgel 60F254, Merck; 0.25 mm thick) and eluted with a methanol-dichloromethane mixture (3-97, by volume). The zone corresponding to the main product is eluted with a methanol-dichloromethane mixture (10-90, by volume), and the solvent is then evaporated under reduced pressure (0.27 kPa) at a temperature around 40 ° C. to give 155.2 mg of 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19
-Nor-11-taxen-13α-yl (2R, 3S) -3-benzoylamino-2-hydroxy-3-phenyl-propionate was obtained in the form of a white foam, the properties of which were as follows: Optical rotation: [α] D ²⁰ = −30.5 ° (c = 0.391; methanol)-Proton NMR spectrum: (300 MHz; CDCl ₃ ; δ ppm, coupling constant J, Hz): 1.27 (s, 3H) : -C H ₃ 16 or 17);
1.30 (s, 3H: -C H 3 16 or 17); 1.40 (mt, 1H : - H
7); 1.62 and 2.25 (q and m, each 1H: C H ₂ cyclopropanecarboxylic
-); 1.85 (s, 3H : -C H 3 18); 1.96 (s, 1H: 1 of -O H)
; 2.05 and 2.48 (d and m, each IH: 6 -C of H ₂ -); 2.24 (
s, 3H: -COC H ₃ of 10); 2.28 and 2.50 (m, each IH: 14
Of _{-C H 2); 2.45 (s} , 3H: -COC H 3 of 4); 3.52 (d, 1H : 2
-O H) of '; 4.10 and 4.35 (d, respectively IH: 20 -C of H _2); 4.1
1 [d, 1H: - H 3); 4.77 ( broad d, 1H: - H 5) ; 4.82 (d
d, 1H: - H 2 ' ); 5.70 (d, 1H: 2 of - H); 5.84 (dd, 1
H: -H 3 '); 6.30 (broad t, 1H: -H 13); 6.36 (s, 1H:
- H 10); 7.00 (d , 1H: -CON H -); 7.35 from 8.30 (m,
15H: -C ₆ H ₅ in 3 ', -OCOC ₆ H ₅ and NHCOC ₆ H _5).

4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (2R, 3S) 3-Amino-2-hydroxy-3-phenylpropionate is a 4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-dihydroxy-7β, 8β-methylene-9-
Prepared by performing under the conditions described in Example 1 for the preparation of oxo-19-nor-11-taxen-13α-yl (2R, 3S) -3-amino-2-hydroxy-3-phenylpropionate. That is, 1.6 g of 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 2
0-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene-
Starting from 13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate, 1.14 g of 4α, 10β-diacetoxy-2
α-Benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl was obtained as a white foam.

4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (4S, 5R) -3-te
rt-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate is 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 10β-
Dihydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (4S,
Prepared under the conditions described in Example 1 for the preparation of 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate. Ie
2.2 g of 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-9-oxo-7β-trifluoromethanesulfonate-11-taxen-13α-yl (4S, 5R) -3-tert Starting from -butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate, 1.62 g of 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19
-Nor-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was obtained as a white foam.

4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydro
Xy-9-oxo-7β-trifluoromethanesulfonate-11-taxen-13α-yl (4
(S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidine
Carboxylate is 4α-acetoxy-2α-benzoyloxy-5β, 20-epoxy-
1β, 10β-dihydroxy-9-oxo-7β-trifluoromethanesulfonate-19-no
Ru-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4
The preparation of -phenyl-5-oxazolidine carboxylate is described in Example 1
Prepared under the following conditions. That is, 2.4 g of 4α, 10β-diacetoxy-2α-benzoyl
Xy-5β, 20-epoxy-1β, 7β-dihydroxy-9-oxo-11-taxen-13α-yl
(4S, 5R) -3-tert-butoxycarbonyl-2,2-dimethyl-4-phenyl-5-oxazolidy
Starting from carboxylate, 2.46 g of 4α, 10β-diacetoxy-2α-benzo
Iloxy-5β, 20-epoxy-1β-hydroxy-9-oxo-7β-trifluorometa
Sulfonate-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl-2,
2-dimethyl-4-phenyl-5-oxazolidinecarboxylate was obtained as a white foam
. 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β, 7β-di
Hydroxy-9-oxo-11-taxen-13α-yl (4S, 5R) -3-tert-butoxycarbonyl
2,2-dimethyl-4-phenyl-5-oxazolidine carboxylate is an international application
No. PCT WO9209589, prepared under the conditions described in this specification, the disclosure of which is incorporated by reference.
This is incorporated herein by reference.Example 3 550 mg of 4α, 10β-diacetoxy-2α-benzoyl maintained under an argon atmosphere
Oxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-
11-taxen-13α-yl (2R, 3S) -3-amino-2-hydroxy-3-phenylpropione
Solution (1cm^ThreeIn dichloromethane), 76 cm^ThreeSodium bicarbonate and next
197 mg of di-tert-butyl dicarbonate solution (1 cm^ThreeThe jig
(In dichloromethane) was added dropwise. The resulting solution was stirred at a temperature around 20 ° C for 15 hours,
And then 5cm^ThreeOf distilled water and 10cm^ThreeWas replenished. water
Sex phase 5cm^ThreeExtracted with dichloromethane. The combined organic phase is magnesium sulfate
Dried over, filtered and concentrated to dryness at 40 ° C. under reduced pressure (2.7 kPa). 780m
g of white foam is thus obtained, which is contained in a 50 g column contained in a 2.5 cm diameter column.
On silica (0.063-0.2 mm) under atmospheric pressure by chromatography.
Elution with a mixture of ethanol and dichloromethane (1-99 then 2.5-97.5, depending on volume)
And then 10cm^ThreeFractions were collected. Pool fractions containing only the desired product,
Then, the mixture was concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. 660 mg of white in this way
A foam was obtained. A 300 mg sample is transferred to 12 thin silica plates (Kieselgel 60F
254, purified by preparative chromatography on Merck (0.25 mm thick).
, Eluting with a methanol-dichloromethane mixture (4-96, by volume). Master student
The zone corresponding to the product is the methanol-dichloromethane mixture (10-90, depending on volume).
And evaporate the solvent under reduced pressure (0.27 kPa) at a temperature around 40 ° C.
159.7 mg of 4α, 10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxide
Xy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene-13α-
Yl (2R, 3S) -3-tert-butoxycarbonylamino-2-hydroxy-3-phenyl-pro
The pionate was obtained in the form of a white foam, the properties of which were as follows: Specific rotation: [α] D²⁰= -34 ° (c = 0.564; methanol)-Proton NMR spectrum: (400 MHz; CDCl_Three; Cup at δ ppm
Ring constant J, Hz): 1.28 (s, 3H: -CH _Three 16 or 17); 1.
30 [s, 9H: -C (CH _Three)_Three]; 1.38 (mt, 1H:-H 7); 1.6
0 (s, 3H; -CH _Three 16 or 17); 1.68 and 2.25 (t and m
, Each 1H; C of cyclopropaneH _Two-); 1.85 (s, 3H: -CH _Three 18)
2.10 and 2.45 (d and td, each 1H: -C of 6;H _Two-); 2.23
(-COC of (s, 3H: 10)H _Three); 2.22 and 2.40 (m, each 1H: 1).
4-CH _Two-); 2.40 (-COC of s.3H: 4)H _Three); 3.28 (d, 1H
: -O of 2 'H); 4.05 and 4.22 (d, each 1H: -C of 20).H _Two);
4.10 (d, 1H:-H 3); 4.62 (wide s, 1H:-H 2 '); 4.7
3 (d, 1H:-H 5); 5.29 (wide d, 1H:-H 3 '); 5.37 (
d, 1H: -CONH−); 5.67 (−, of 1H: 2)H); 6.28 (wide
t, 1H:-H 13); 6.33 (s, 1H:-H 10); 7.30 to 7.4
5 (mt, 5H: -C of 3 '₆H_Five); 7.51 [t, 2H: -OCOC₆H_Five(-
H 3 and-H 5)]; 7.61 [t, 1H: -OCOC₆H_Five(-H 4)];
8.17 [d, 2H: -OCOC₆H_Five(-H 2 and-H 6)].Example 4 100 mg of 10-day cooled to a temperature near -78 ° C and maintained under an argon atmosphere.
Solution of acetylbaccatin III (3 cm^ThreeOf tetrahydrofuran and 0.05cm^ThreePiri
0.09cm^ThreeOf trifluoro-methanesulfonic anhydride was added dropwise. Temperature
Slowly raise the temperature to around 0 ° C. for about one hour, and then
Temperature to around 20 ° C. After 2 hours at a temperature around 20 ° C, 200 mg of tet iodide
Rabutylammonium was added, and the solution was heated at the boiling temperature of the solvent for 15 hours.
After cooling to a temperature around 20 ° C, 10cm^ThreeOf ethyl acetate and then 1 cm^ThreeOf distilled water
added. After separation after settling, the organic phase was dried over magnesium sulfate, filtered.
, And concentrated to dryness under reduced pressure (2.7 kPa) at 40 ° C. This is 116mg of yellow oil
30 g of silica (0.063-0.2 m) contained in a 2.5 cm diameter column.
m), purify by chromatography under atmospheric pressure, ethyl acetate-dichlorometh
Elution was performed with a mixture of tans with an elution gradient of 0-100 to 80-20 (by volume). Place
Fractions containing the desired product are pooled and concentrated at 40 ° C. under reduced pressure (0.27 kPa)
To dryness. Thus 10.3 mg of 10-deacetyl-7β, 8β-methylene-19-norva
Caccin III was obtained in the form of a white foam, the properties of which were as follows:-Proton NMR spectrum: (400 MHz; CDCl_Three; Cup at δ ppm
Ring constant J, in Hz): 1.14 (s, 3H: -C of 16 or 17)H _Three); 1
.42 (mt, 1H:-of 7)H); 1.76 and 2.31 (t and m, each 1
H, C of cyclopropaneH _Two); 2.07 (s, 3H; -C of 18)H _Three); 2.15
And 2.50 (wide d and td, each 1H: 6 CH _Two−); 2.30 (s,
-COC of 3H: 4H _Three); 2.28 and 2.35 (m, each 1H: -C of 14
H _Two); 4.11 and 4.37 (d, each 1H: -C of 20).H _Two); 4.28 (d
, 1H: 3-H 3); 4.79 (-d of 1H: 5)H); 4.88 (wide t,
1H:-of 13H); 5.09 (s, 1H: 10-H); 5.66 (d, 1H:
2-H); 7.51 [t, 2H: -OCOC₆H_Five(-Of 3 and 5H)]; 7.
61 [t, 1H: -OCOC₆H_Five(4-H)]; 8.17 [d, 2H: -OC
OC₆H_Five(-Of 2 and 6H)].¹³ C NMR spectrum: (100 MHz; CDCl_ThreeAt δ ppm; unbound;
s = singlet, d = doublet; t = triplet; q = quartet: 15 (q, C18); 1
6.5 (t, C19); 20 and 27 (q, C16 and C17); 22.5 (
q, -COCH_Three); 26.5 (t, C6); 33 (d, C7); 35 (s, C8).
); 39 (d, C3); 39.5 (t, C14); 43 (s, C15);
d, C13); 76 (t, C20); 76.2 (d, C10); 79.5 (s, C
1); 80 (s, C4); 81 (d, C2); 85 (d, C5); 129 (d,
C2: -OCOC₆H_Five); 130 (s, -OCOC)₆H_FiveCl); 130.5 (
d, -OCOC₆H_FiveC3); 134 (d, -OCOC)₆H_FiveC4); 136 (
s, C11); 143 (s, C12); 168 (s, -OCOC₆H_Five); 171
(S, -COCH_Three); 210 (s, C9).Example 5 Breast C / 16 adenocarcinoma was implanted into C3H / HeN female mice. After at least 7 days, 4α, 10
β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β,
8β-methylene-9-oxo-19-nor-11-taxen-13α-yl (2R, 3S) -3-tert-butoxy
Cycarbonylamino-2-hydroxy-3-phenyl-propionate (“Compound A”
) By intravenous injection at 0.4 or 0.5 ml / infusion for 15 seconds, 9.5, 15.4, 24
Groups of female mice were administered at doses of .8, 40 or 60.5 mg / kg. Weight and transplant
Days were recorded for each mouse. Blood and tissue samples were given at 2,5,
Collected at 15, 30 and 45 minutes and at 1, 4, 14, 24 and 48 hours. Plasma is
Blood samples were separated at 4 ° C. and frozen immediately. Tissue and tumor weight
And immediately frozen (-20 ° C).

Next, plasma and tissue samples were analyzed for Compound A concentration. Plasma was assayed by high pressure liquid chromatography and detected spectrophotometrically. For tissue, liver, heart, kidney, lung, spleen and tumor tissue samples were assayed by the first method, whereas for brain tissue, the second method was used. In the first method, 0.2 g of tissue was combined with 2 ml of sodium phosphate buffer 0.1 M (pH 7.0) and homogenized. The homogenate was centrifuged and 0.5 ml of the supernatant was injected on the chromatography column. In the second method, 10 μl of the standard solution was combined with 0.2 g of brain tissue. 2 ml of methanol / 5% perchloric acid (50/50) were added and the mixture was homogenized. The homogenate was centrifuged and 100 μl of the supernatant was injected on the chromatography column.

The kinetics of Compound A in plasma and tumor tissue was in the experimental range (9.5-60.5 mg / kg
). The maximum plasma concentrations observed (at 2 minutes) are linear with dose and are 14 ± 1, 21 ± 2, 35 ± 2, 51 ± 1 and 133 ± 30 μg / ml, respectively.
Was equal to The pharmacokinetics of Compound A in mice with breast cancer were similarly linear over the range of doses administered. The pharmacokinetic linearity and comparable kinetic profiles in mice with and without tumors are comparable to those in tissues (liver, heart,
The distribution of Compound A in kidney, lung, spleen, brain, tumor) was determined by a single intermediate dose of 40 mg / kg (
This made it possible to experiment with the highest non-toxic dose (HNTD) observed in mice).

After administering an intermediate dose of 40 mg / kg to mice bearing tumors (breast carcinoma), the kinetic profile of Compound A showed a rapid uptake of the drug. The drug concentration then dropped in two phases. Except for tumor and brain tissue, the first abrupt phase that occurred (while 0.033 hours after administration, 70% of the drug was present) was cleared in 1 hour. For the tissues tested, excluding tumor and brain tissue, a slower phase followed by an elimination half-life in the range of 1.6-7.5 hours followed. The reduction in this concentration is illustrated in Table 1, which reports the tissue concentration (AUC) curve and the area under the elimination half-life observed. The brain and plasma AUC in mice were similar at 4 hours, and the 0 to infinity AUC of Compound A in mouse brain tissue was 10 times that observed in plasma. These results are consistent with the longer half-life of Compound A in brain tissue (47.6 hours) compared to the half-life observed in other tissues (1.6-9.3 hours).

[0154]

[Table 1]

The concentration of Compound A in tissues and plasma (μg / g) is illustrated in the figures. Tissue and plasma concentration ratios at each time point after administration of the 40 mg / kg dose are shown in Table 3 (liver, heart, kidney, lung, spleen and tumor), Tables 4 and 5 (brain) and Table 6 (tumor- All doses). These data indicate that Compound A was rapidly distributed in all tissues sampled. The half-life of the distribution phase in each tissue sample is 0.
It was determined to be 29 hours, 0.05 hours in kidney, 0.34 hours in lung, 0.23 hours in spleen, 0.07 hours in brain, and 0.23 + 0.20 hours in tumor tissue. For heart tissue, the half-life of the distribution phase was not calculated from poor fitting.

The maximum concentrations of Compound A in the sampled tissues occurred at 0.033 hours (heart and kidney), 0.083 hours (liver, lung, spleen) and 0.25 hours (tumor and brain).
The percentage of dose recovered in the tissue sampled is reported in Table 2.

[0157]

[Table 2]

The percentage (concentration) of Compound A in the sampled tissues, except for tumor and brain tissue, dropped sharply in the first 2-3 hours after drug administration. In the kinetic sense, after sharp tissue uptake of Compound A, the concentration sloped over the course of the two phases: a rapid rate decrease, and then a gentle slope. See the drawings. Example 6 According to the method of the present invention, the safety and efficacy of the treatment can be performed on the patient according to the following protocol: Global Criteria: Get Full Informed Consent Before Starting Special Procedures-Tissue Chemical (adenocarcinoma,
Metastatic non-small cell lung cancer (large cell or squamous carcinoma)-objective progressive disease-brain metastases demonstrated by CT / MR scan-18 <age <70 years-at least 1
2 weeks life expectancy-0 to 1 ECOG status-sufficient organ function including: neutrophils> 2
× 10 ⁹ / liter; platelets> 100 × 10 ⁹ / liter; creatinine within the upper limit of normal.
If so, creatinine clearance must be> 60 ml / min; total bilirubin within the upper limit of normal and ALAT / ASAT / AP <2.5 of upper limit of standard
Times. -Patients enrolled in this trial must be treated and follow up at participating centers-Prior treatment: < 1 line chemotherapy for advanced disease; no prior radiation therapy for brain; Radiation therapy can be given to other sites (mediastinum, bones, lymph nodes ...) but is not strong ( < 20% of bone marrow area). -At least 4 weeks and 6 weeks apart if previously nitrosoureas or mitomycin C;
Prior anticancer (radio- or chemo-) therapy or surgery. -Recovery from toxic effects before treatment (alopecia of any grade, peripheral neuropathy, and neurologic according to NCICCTC)
Hearing grade 1). -Patients should be given corticosteroids in advance or at the same time to control symptoms, but should be given a stable dose at least 2 weeks before study entry. The presence of at least one extracranial two-dimensionally measurable lesion is not pre-irradiated. -The patient has been working for 5 days
Study drugs must be received within ys)-initial work up is completed within 3 weeks prior to patient enrollment. Non-Comprehensive Criteria: Women who are pregnant or lactating or may have children (eg, not having sufficient contraception). -A history of malignancy other than previously removed or therapeutically irradiated basal cell skin cancer or in situ cervical cancer. -Symptomatic brain metastases, excluding convulsions not controlled by adequate anticonvulsant therapy-motor impairment-peripheral neuropathy according to NCICCTC> grade 1 or neurological hearing> grade 1. -One or more chemotherapy lines for advanced disease. -Pulmonary fibrosis-Other serious illnesses and medical conditions: even if medically controlled, congestive heart failure or angina, history of myocardial infarction within one year of study enrollment, uncontrolled hypertension or Arrhythmias; important neurological or psychiatric disorders that impair the ability to obtain consent; active infections; peptic ulcers, unstable diabetes or other contraindications for corticosteroid use; superior vena cava syndrome. −
Co-treatment with other study drugs. -Participation in other clinical trials with any investigational drug within 30 days prior to patient enrollment-Concurrent treatment with any other anti-cancer therapy-Concurrent radiation therapy-
Pleural effusion or endocardial effusion requiring intervention (drainage, puncture). -Pre-treatment with taxanes (paclitaxel, docetaxil). -The compound of Example 3 is supplied as a single dose vial containing a total of 94.4 mg of the compound of Example 3 in a concentration of 40 mg / ml of the compound of Example 3 in 2.36 ml of polysorbate 80. The solvent of the compound of Example 3 was ethyl alcohol 95% / water (13: 8
7m / m) is supplied as a single dose in a 15ml glass vial. Premedication every 12 hours beginning on day 1 (-25 from IV-infusion of compound of Example 3)
And -13 hours before) and one hour before IV-infusion of the compound of Example 3 on day 1 and an equal dose of dexamethasone or other corticosteroid administered as 8 mg PO. · Advance for patients who received extracranial radiotherapy, giving a dose of 75 mg / m ² of the compound of Example 3 as IV- infusion 1 hour every 21 hours. For patients who have not received prior extracranial radiation therapy, the compound of Example 3 is given as a 1 hour IV-infusion every 21 hours at a dose of 90 mg / m ² . Treat the patient until extracranial injury shows disease progression or unacceptable toxicity or patient rejection. In the case of progression in brain metastases associated with objective responses in other extracranial positions, brain radiation is administered and treatment with the compound of Example 3 is continued. If the patient needs G-CFS (granulocyte colony stimulating factor) as secondary prevention,
Administer as a subcutaneous injection of G-CFS starting at days 2-5 of the treatment cycle, at the dose and schedule recommended by the manufacturer. Evaluation Criteria Efficacy: Eligible patients should have a minimum of 2 cycles of treatment including at least one follow-up tumor assessment unless "early progression" occurs (in this case, the patient is considered evaluated). Can be evaluated when receiving The antitumor activity of the brain is assessed using two parameters: CT / MR brain scan and clinical neurological assessment. All CT / MR
Scans will be reviewed by an external panel of one oncologist and one neuroradiologist. Extracranial activity will be assessed in a thorough study (see Chapter ...) Pharmacokinetics: Reversed-phase HPLC Safety: All starting at least one injection of the compound of Example 3 Of patients will be analyzed for safety. Adverse effects (toxicity), vital signs, physical diagnosis (ECOG
Progress and neurological testing), laboratory findings in hematology and serum chemistry are analyzed.

Response speed, time to progression, and duration of response are endpoints of efficacy. State your quality of life. The criteria for the response are: ■ Complete response: Minimal 4 weeks, all radiographic and / or visible tumor loss; ■ Partial response: Minimal 4 weeks, all measurable damage A reduction of at least 50% in the sum of the vertical diameters of the products; ■ slight response: in the sum of the vertical diameters of the products of all measurable damage,
25% to 49% decrease; ■ Stable disease No more than 25% change in measurable lesion size; ■ Progressive disease: More than 25% increase in any measurable lesion, objective evidence ;
Alternatively; time to disease progression, progression-none, time to treatment failure and survival.

Although the invention has been described with reference to particular embodiments, many alternatives and modifications will be apparent to those skilled in the art from the foregoing description. Accordingly, the present invention is intended to embrace all such alternatives and modifications as fall within the spirit and scope of the appended claims.

[Procedural Amendment] Submission of translation of Article 34 Amendment

[Submission Date] July 10, 2001 (2001.1.710)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Contents of correction]

[Claims]

Embedded image Wherein R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl group, R ₁ represents a benzoyl or tert-butoxycarbonyl group, and Ar represents an aryl group, or a pharmaceutically acceptable compound thereof. Use of salts or hydrates.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 38/21 A61K 45/00 4C086 45/00 A61P 35/00 A61P 35/00 C07D 413/12 C07D 413 / 12 305/14 // C07D 305/14 A61K 37/66 Z (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU , MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K) E, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, A , AU, BA, BB, BG, BR, CA, CN, CR, CU, CZ, DM, DZ, EE, GD, GE, HR, HU, ID, IL, IN, IS, JP, KP, KR, LC, LK, LR, LT, LV, MA, MG, MK, MN, MX, NO, NZ, PL, RO, RU, SG, SI, SK, TR, TT, UA, UZ, VN, YU, ZA (72) Inventor Busanbar-Mirlon, Michel France-F-75013 Paris-Riubiille-Pian 6/8 F-term (reference) DA01 DA12 DA22 DA23 DA24 MA17 MA23 MA52 MA55 NA14 ZB262 4C085 AA14 CC23 EE03 4C086 AA01 AA02 AA03 BA02 BC69 GA02 GA09 MA01 MA04 MA17 MA23 MA52 MA55 NA14 ZB26

Claims (27)

[Claims] 1. A method for treating abnormal cell proliferation in the brain, comprising the step of providing a host in need thereof with an effective amount of formula (I) for the purpose of obtaining an improved residence time in the brain. ] Wherein R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl group; R ₁ represents a benzoyl group or R ₂ representing an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl or heterocyclyl group; Wherein Ar represents an aryl group, or a pharmaceutically acceptable salt or hydrate thereof, wherein R ₁ represents a group R ₂ —O—CO—; 2. R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl group; R ₁ represents a benzoyl group or a group R ₂ —O—CO—, wherein R ₂ represents 1 to 8 A linear or branched alkyl group containing carbon atoms, an alkenyl group containing 2 to 8 carbon atoms, an alkynyl group containing 3 to 8 carbon atoms,
A cycloalkyl group containing 3 to 6 carbon atoms, a cycloalkenyl group containing 4 to 6 carbon atoms or a bicycloalkyl group containing 7 to 10 carbon atoms, each of which is Is unsubstituted or a halogen atom and a hydroxy group, an alkoxy group containing 1 to 4 carbon atoms,
A dialkylamino group, a piperidino group, a morpholino group containing from 4 to 4 carbon atoms, an unsubstituted or alkyl group containing from 1 to 4 carbon atoms at the 4-position, or an alkyl moiety having from 1 to 4 carbon atoms A 1-piperazinyl group substituted by a phenylalkyl group containing 3 to 6 cycloalkyl groups containing from 6 to 6 carbon atoms;
A cycloalkenyl group having 6 carbon atoms, a phenyl group, a cyano group, a carboxy group and an alkoxycarbonyl group having an alkyl moiety containing 1 to 4 carbon atoms (where the cycloalkyl, cycloalkenyl or bicycloalkyl group is Unsubstituted or substituted by one or more substituents, which may be substituted with one or more alkyl groups containing 1 to 4 carbon atoms; Or an alkyl group containing 1-4 carbon atoms and 1
A phenyl group substituted by one or more identical or different groups selected from alkoxy groups containing from 4 to 4 carbon atoms; or one or more unsubstituted or one or more containing from 1 to 4 carbon atoms Represents a saturated or unsaturated 5- or 6-membered nitrogen-containing heterocyclyl group, which is substituted by an alkyl group; and Ar is unsubstituted or a halogen atom and alkyl, alkenyl,
Alkynyl, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino,
A phenyl or α- or β-naphthyl group substituted by one or more atoms or groups selected from amino, alkylamino, dialkylamino, carboxy, akoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl groups Wherein the alkyl group and the alkyl portion of the other group contain 1 to 4 carbon atoms, the alkenyl and alkynyl groups contain 2 to 8 carbon atoms, and the aryl group is phenyl or α- or represents a β-naphthyl group, or Ar is the same or different and contains one or more atoms selected from nitrogen, oxygen and sulfur atoms and is unsubstituted or
Alkyl groups containing 4 carbon atoms, aryl groups containing 6-10 carbon atoms, alkoxy groups containing 1-4 carbon atoms, aryloxy groups containing 6-10 carbon atoms An amino group, an alkylamino group containing 1 to 4 carbon atoms, a dialkylamino group in which each alkyl moiety contains 1 to 4 carbon atoms,
An acyl moiety has an acylamino group containing from 1 to 4 carbon atoms, an alkoxycarbonylamino group containing from 1 to 4 carbon atoms, an acyl group containing from 1 to 4 carbon atoms, and an aryl moiety having from 6 to 10 carbon atoms. Carbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl groups wherein the alkyl moiety contains 1 to 4 carbon atoms, each alkyl moiety contains 1 to 4 carbon atoms Represents a 5-membered aromatic heterocyclic group in which the dialkylcarbamoyl group and the alkoxy moiety are substituted with the same or different substituent (s) selected from an alkoxycarbonyl group containing 1 to 4 carbon atoms, The method of claim 1. 3. The method according to claim 1, wherein R represents a hydrogen atom or an acetyl, alkoxyacetyl or alkyl group, R ₁ represents a benzoyl or tert-butoxycarbonyl group, and Ar represents an aryl group. Method. 4. The method according to claim 1, wherein R represents an acetyl group, R ₁ represents a tert-butoxycarbonyl group, and Ar represents a phenyl group. 5. The method according to any of the preceding claims, wherein the abnormal cells are malignant cells. 6. The method according to any of the preceding claims, wherein the abnormal cells are non-malignant cells. 7. The method of any of the preceding claims, wherein the abnormal cell growth is a brain cancer. 8. The method of any of the preceding claims, wherein the abnormal cell growth is a cancer that metastasizes to the brain. 9. The method of claim 8, wherein the abnormal cell proliferation is a lung cancer that metastasizes to the brain. 10. The method of claim 9, wherein the abnormal cell proliferation is a non-small cell lung cancer that metastasizes to the brain. 11. The method according to any of the preceding claims, wherein the treatment is performed simultaneously with at least one other therapeutic treatment. 12. The method of claim 11, wherein the other therapeutic treatment comprises an anti-tumor agent, a monoclonal antibody, immunotherapy, radiation therapy or a biological response modifier. 13. The method of claim 12, wherein the response modifier comprises a lymphokine and a cytokine. 14. The method of claim 12, wherein the response modifier comprises an interleukin, an α, β or δ interferon and TNF. 15. The method according to any of the preceding claims, wherein the compound of formula (I) is administered parenterally or orally. 16. The method according to any of the preceding claims, wherein the compound of formula (I) is administered by intravenous, intraperitoneal, intramuscular, subcutaneous or oral administration. 17. The method according to any of the preceding claims, wherein the compound of formula (I) is administered in a composition comprising said compound and a pharmaceutically acceptable auxiliary, carrier or excipient. The described method. 18. The method according to claim 17, wherein the pharmaceutically acceptable auxiliary is a carrier comprising a diluent, a sterile aqueous medium or a non-toxic solvent. 19. The method of claim 17, wherein the pharmaceutical composition is in an aqueous solution, aqueous suspension, non-aqueous solution, non-aqueous suspension or injectable solution. 20. The pharmaceutical composition further comprising at least one emulsifier, a colorant,
20. The method of claim 19, comprising a preservative and a stabilizer. 21. The method according to any of the preceding claims, wherein the compound of formula (I) is administered as an hourly IV infusion every three weeks. 22. The method according to any of the preceding claims, wherein the compound of formula (I) is administered weekly. 23. compounds of formula (I) is administered at a dose ranging from 50 to 150 mg / m ^2, A method according to any one of the preceding claims. 24. The method according to claim 23, wherein the compound of formula (I) is administered at a dose ranging from 75 to 90 mg / m ² . 25. The method according to claim ² , wherein the compound of formula (I) is administered at a dose of 75 mg / m 2.
4. The method according to 4. 26. The method according to claim ² , wherein the compound of formula (I) is administered at a dose of 90 mg / m 2.
5. The method according to 5. 27. The compound of formula (I) is 4α-10β-diacetoxy-2α-benzoyloxy-5β, 20-epoxy-1β-hydroxy-7β, 8β-methylene-9-oxo-19-nor-11-taxene Any of the preceding claims, which is -13α-yl (2R, 3S) -3-tert-butoxy-carbonylamino-2-hydroxy-3-phenylpropionate or a pharmaceutically acceptable salt or hydrate thereof. The method described in Crab.