Taxaide, methods for their preparation, intermediate compounds and pharmaceutical composition

 

(57) Abstract:

Describes the new taxoid General formula (I) in which R is a hydrogen atom or acetyl or alkoxyalkyl radical, R1is benzoline radical R2-O-CO-in which R2is an alkyl radical, straight or branched, containing 1 to 8 carbon atoms, and Ar is a phenyl radical or heterocyclic aromatic radical having 5 units and containing one or more sulfur atoms. New products show significant inhibitory activity against abnormal cell proliferation and possess therapeutic properties, which allows to treat patients with pathological conditions associated with abnormal cell proliferation. Also describes the method of production thereof, intermediate compounds and pharmaceutical composition based on compounds of the formula (I). 6 C. and 30 C.p. f-crystals.

The invention relates to new taxoids General formula

< / BR>
their receiving and containing pharmaceutical compositions.

In the General formula (I) Ar is an aryl radical, R is a hydrogen atom or acetyl, alkoxyalkyl or Ala is tsya:

is an alkyl radical with a straight or branched chain containing 1-8 carbon atoms, alkenyl radical containing 2 to 8 carbon atoms, alkynylaryl radical containing 3-8 carbon atoms, cycloalkenyl radical containing 3 to 6 carbon atoms, cycloalkenyl radical containing 4-6 carbon atoms, and bicycloalkyl radical containing 7 to 11 carbon atoms, these radicals possibly substituted by one or more substituents selected among halogen atoms and hydroxyl, CNS, containing 1-4 carbon atoms, dialkylamino, each alkyl portion of which contains 1-4 carbon atoms, piperidino, morpholino, piperazinil-1 (possibly substituted in position 4 alkyl radical containing 1-4 carbon atoms, or phenylalkyl radical, the alkyl part of which contains 1-4 carbon atoms), cycloalkyl containing 3-6 carbon atoms, cycloalkenyl containing 4-6 carbon atoms, phenyl, cyano, carboxyl or alkoxycarbonyl, the alkyl portion of which contains 1-4 carbon atoms, radicals,

or phenyl radical, possibly substituted by one or more atoms or radicals selected from halogen atoms and alkyl radikalyazaryazisi radical, saturated or unsaturated, containing 4-6 links and possibly substituted by one or more alkyl radicals containing 1-4 carbon atom,

provided that cycloalkyl, cycloalkenyl and bicycloalkyl radicals can be substituted by one or more alkyl radicals containing 1-4 carbon atoms.

Preferably Ar is phenyl or - or-nafcillin radical, possibly substituted by one or more atoms or radicals selected from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, etkinlik, aryl, arylalkyl, alkoxy, alkylthio, aryloxy, aaltio, hydroxyl oxyalkylene, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl, amino, alkylamino, dialkylamino, carboxyl, alkoxycarbonyl, karamolegos, dialkylanilines, cyano, nitro and triptorelin radicals, provided that the alkyl radicals and alkyl portions of other radicals contain 1-4 carbon atoms, alkeline and alkyline radicals contain 2 to 8 carbon atoms) and aryl radicals are phenyl or - or-naftiliaki radicals, or Ar is a heterocyclic aromatic radicaltheme nitrogen, oxygen or sulfur, possibly substituted by one or more substituents, the same or different, selected among halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals containing 1-4 carbon atoms, aryl radicals containing 6 to 10 carbon atoms, alkoxyalkyl containing 1-4 carbon atoms, aryloxyalkyl containing 6-10 carbon atoms, amino, acylaminoalkyl containing 1-4 carbon atoms, dialkylaminoalkyl, each alkyl portion of which contains 1-4 carbon atoms, acylaminoalkyl, acyl part of which contains 1-4 carbon atoms, alkoxycarbonylmethyl containing 1-4 carbon atoms, acyl radicals, containing 1-4 carbon atoms, arylcarboxylic radicals, the aryl portion contains 6-10 carbon atoms, cyano, carboxyl, karamolegos, alkylcarboxylic, the alkyl portion of which contains 1-4 carbon atoms, dialkylanilines, each alkyl portion of which contains 1-4 carbon atoms, or alkoxycarbonyl, CNS portion of which contains 1-4 carbon atoms, radicals.

More specifically, Ar is phenyl, 2 - or 3-thienyl, 2 - or 3-FullName radical, possibly substituted by one or more of the LASS="ptx2">

More specifically, Ar is a phenyl radical, possibly substituted by a chlorine atom or fluorine, or alkyl radical (methyl), alkoxy (methoxy), dialkylamino (dimethylamino) acylamino (acetylamino) or alkoxycarbonyl (tert. -butoxycarbonylamino) or 2 - or 3-thienyl or 2 - or 3-FullName radical.

Especially interesting are the products of General formula (I) in which Ar is a phenyl radical and R1is benzoline or tert.butoxycarbonyl radical.

C. J. Med, Chem., 34, 992-998 (1991) described taxaide, which differ from the products of General formula (I) nature of the substituent in position 7 and which does not have the properties to be active against resistant tumor cells.

According to the present invention taxaide products of General formula (I) can be obtained from a product of General formula (II):

< / BR>
in which Ar and R1have the previously indicated meanings, and R3and R4identical or different, are hydrogen atom or alkyl radical containing 1-4 carbon atoms, or Uralkali radical, the alkyl part of which contains 1-4 carbon atoms and the aryl part is preferably phenyl radical,inim radical, preferably being a phenyl radical, possibly substituted by one or more CNS radicals containing 1-4 carbon atoms, or R3is CNS radical containing 1-4 carbon atoms, or trihalomethyl radical, such as trichlorethylene, or phenyl radical, substituted trihalomethyl radical, such as trichlorethylene, and R4is a hydrogen atom, and R3and R4form together with the carbon atom to which they are attached, the loop having 4-7 links, and G1is a hydrogen atom or acetyl, alkoxyalkyl or alkyl radical or a group protecting the hydroxyl function, working, depending on the values of R3and R4as follows:

1) if R3is a hydrogen atom or CNS radical containing 1-4 carbon atoms, or aryl radical, possibly substituted, and R4is a hydrogen atom, the product of General formula (II) is treated in an acidic medium to obtain a product of General formula:

< / BR>
in which Ar, R1and G1have these values, if necessary, radical G1replaced by a hydrogen atom.

Removing protection from Boko is a, sulfuric acid) or organic acids (acetic acid, methanesulfonate acid, triftormetilfullerenov acid, p-toluensulfonate acid), used individually or in mixtures, when working in an organic solvent, selected from among alcohols (methanol, ethanol, isopropanol), ethers (tetrahydrofuran, diisopropyl ether, methyl tert.butyl ether), esters (ethyl acetate, isopropylacetate, n-butyl acetate), aliphatic hydrocarbons (pentane, hexane, heptane), halogenated aliphatic hydrocarbons (dichloromethane, 1,2-dichloroethane), aromatic hydrocarbons (benzene, toluene, xylenes) and NITRILES (acetonitrile), at a temperature between -10oand 60oC, preferably between 15oand 30oC. the Acid may be used in catalytic quantities, the stoichiometric amount or in excess.

Removing protection can also be performed in an oxidizing conditions using, for example, ammonium nitrate and cerium IV in a mixture of acetonitrile-water or 2,3-dichloro-5,6-dicyano-benzoquinone-1.4 in the water.

Removing protection may also be performed in reducing conditions, for example, by hydrogenolysis in the presence of a catalyst.

If G1oand 60oC, or with mineral or organic acids, such as hydrochloric acid or acetic acid, in solution in an aliphatic alcohol containing 1-3 carbon atoms, or complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly associated with copper, or if G1is alkoxycarbonyl radical, its possible replacement by a hydrogen atom is carried out when processing in an alkaline medium or by the action of zinc halide under conditions which do not affect the rest of the molecule. Typically, the alkaline treatment is carried out under the action of ammonia in aqueous-alcoholic medium at a temperature of about 20oC. it is Usually a zinc halide, preferably the iodide of zinc, is carried out in methanol at a temperature of about 20oC.

2) if R3and R4identical or different, are alkyl radicals containing 1-4 carbon atoms, or Uralkali radical, the alkyl part of which contains 1-4 carbon atoms and the aryl part is preferably phenyl what Yalom, substituted trihalomethyl radical, and R4is a hydrogen atom, or R3and R4form together with the carbon atom to which they are attached, the loop having 4-7 units, the product of General formula (II) into a product of General formula (IV):

< / BR>
in which Ar and G1have these values, which acelerou using benzoyl chloride or a reactive derivative of General formula:

R2-O-CO-X (V)

in which R2has the previously indicated meaning and X is a halogen atom (fluorine, chlorine) or a residue-O-R2or O-CO-O-R2in order to obtain a product of General formula (III) in which Ar, R1and G1have the previously indicated meanings, in which, if necessary, radical G1replaced by a hydrogen atom.

The products of General formula (IV) can be obtained by treatment of the product of General formula (II) in which Ar, R1and G1have these values, R3and R4identical or different, are alkyl, Uralkali or aryl radical, or R3and R4form together with the carbon atom to which they are attached, the loop having 4-7 units, mineral acid (hydrochloric acid, sulfuric acid) or organic kilomertre between 0oand 50oC. Preferably using formic acid at a temperature of about 20oC.

The acylation of the product of General formula (IV) by means of benzoyl chloride or a reactive derivative of General formula (V) is carried out in an inert organic solvent, selected from among esters, such as ethyl acetate, isopropylacetate or n-butyl acetate, and halogenated aliphatic hydrocarbons, such as dichloromethane or 1,2-dichloroethane, in the presence of a mineral base such as sodium bicarbonate, or organic bases such as triethylamine. The reaction is carried out at a temperature between 0 and 50oC, preferably about 20oC.

If the radical of G1is a protective group, its replacement by a hydrogen atom is carried out under the conditions described above.

The products of General formula (II) can be obtained by any of the following methods:

1) esterification of the product of General formula (VI):

< / BR>
in which G1has these values, using the acid of General formula:

< / BR>
in which Ar, R1, R3and R4have the previously indicated meanings, or a derivative of this acid.

The esterification with the acid of General formula (VII) can Ghent (aminopyridine) in an organic solvent (simple ether, ester, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between -10oC and 90oC.

The esterification can also be carried out using the acid of General formula (VII) in the form of anhydride when working in the presence of an activating agent (aminopyridine) in an organic solvent (simple ethers, esters, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature of between 0 and 90oC.

The esterification can also be carried out using the acid of General formula (VII) in the form of galodamadruga or anhydride with an aliphatic or aromatic acid, probably prepared in situ, in the presence of a base (tertiary aliphatic amine) in an organic solvent (ethers, esters, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons, aromatic hydrocarbons) at a temperature between 0 and 80oC.

The acid of General formula (VII) can be obtained by saponification of ester of the General formula:

< / BR>
in which Ar, R1, R3Yes, possibly substituted phenyl radical.

Generally, the saponification is carried out using a mineral base (hydroxide, carbonate, or bicarbonate of an alkali metal) in aqueous-alcoholic medium (methanol-water) at temperatures between 10 and 40oC.

Ester of General formula (VIII) can be charged under the action of a product of General formula

< / BR>
in which R3and R4have the previously indicated meanings, in the form of dialkylated or enol Olkiluoto simple ester to an ester of the General formula:

< / BR>
in which Ar, R1and R5have the previously indicated meanings, in an inert organic solvent (aromatic hydrocarbon) in the presence of a strong mineral acid (sulfuric acid) or organic acid (p-toluensulfonate acid, possibly in the form of a pyridinium salt) at a temperature between 0oC and the boiling temperature of the reaction mixture.

Ester of General formula (X) can be obtained by the action of a product of General formula (V) an ester of the General formula:

< / BR>
in which Ar and R5have these values, when working in an organic solvent (ester, halogenated aliphatic hydrocarbon) in the presence of mineral or org is Chen when restoring azide of General formula:

< / BR>
in which Ar and R5have the previously indicated meanings, with hydrogen in the presence of a catalyst such as palladium on coal, when working in an organic solvent (ester).

The product of General formula (XII) can be obtained by the action of azide, such as trimethylsilane, in the presence of zinc chloride or alkali metal azide (sodium, potassium, lithium) in an aqueous-organic medium (water-tetrahydrofuran) at a temperature between 20oC and the boiling temperature of the reaction mixture on the epoxide of General formula:

< / BR>
in which Ar and R5have mentioned previously, possibly prepared in situ.

The epoxide of General formula (XIII) can be obtained, possibly in situ, by dehydrohalogenation product of General formula:

< / BR>
in which Ar has the above meanings and Hal is a halogen atom, preferably a bromine atom, and R6and R7identical or different, are hydrogen atom or alkyl radical containing 1-4 carbon atoms, or phenyl radical, at least one of them is an alkyl radical or phenyl radical, with an alkali alkoxide, possibly obtained in situ, in an inert organic solvent, so the t can be obtained by the action of an aldehyde of General formula:

Ar-CHO (XV)

in which Ar has the previously indicated values on galoyanized General formula:

< / BR>
in which Hal, R6and R7have these values, pre-anonsirovanie.

Usually work in an inert organic solvent, selected from among ethers (ethyl ether) and halogenated aliphatic hydrocarbons (methylene chloride), at temperatures between -80oC and 25oC in the presence of tertiary amine (triethylamine) and agent enolizatsii (di-n-butalbital).

The product of General formula (XVI) can be obtained by the action of galodamadruga halodurans acid, preferably bromide bromoxynil acid, to the corresponding oxazolidinone.

The product of General formula (XI) can be obtained by hydrogenolysis of the product of General formula:

< / BR>
in which Ar and R5are these values and Ph is the phenyl radical, possibly substituted.

Typically, the hydrogenolysis is carried out using hydrogen in the presence of a catalyst. More specifically used as a catalyst palladium on coal containing 1-10 wt.% palladium, or digitoxin palladium with 20 wt.% palladium.

The hydrogenolysis is carried out in Horno in a mixture with aliphatic alcohol, containing 1-4 carbon atoms, such as a mixture of acetic acid-methanol, at temperatures between 20oC and 80oC.

The hydrogen required for the hydrogenolysis can be obtained from a compound that releases hydrogen by chemical reaction or thermal decomposition (ammonium formate). It is advantageous to work under hydrogen pressure between 1 and 50 bar.

The product of General formula (XVII) can be obtained by hydrolysis or alcoholysis product of General formula:

< / BR>
in which Ar and Ph have the above significance.

Especially advantageous to carry out the alcoholysis with an alcohol of formula R5-OH, in which R5has these values in the acidic environment.

Preferably carry out the alcoholysis with methanol in the presence of a strong mineral acid, such as hydrochloric acid, at a temperature of about the boiling temperature of the reaction mixture.

The product of General formula (XVIII) can be obtained by saponification of ester of the General formula:

< / BR>
in which Ar and Ph have the above significance and R8is alkyl, phenylalkyl or phenyl radical, followed by the separation of diastereoisomers 3R, 4S General formula (XVII) from other GeoStereo the ammonia, the lithium hydroxide, sodium hydroxide or potassium hydroxide, in a convenient solvent such as methanol-water or tetrahydrofuran-water, at a temperature between -10oC and 20oC.

The selection of diastereoisomer 3R, 4S can be carried out by selective crystallization in a suitable organic solvent, such as ethyl acetate.

The product of General formula (XIX) can be obtained by cycloaddition imine of General formula:

< / BR>
in which Ar and Ph have the above significance, to galodamadruga acid of General formula:

< / BR>
in which R8has the previously indicated meanings and Y is a halogen atom such as a bromine atom or chlorine.

Usually the reaction is carried out at a temperature between 0oand 50oC in the presence of a base, selected from among tertiary aliphatic amines (triethylamine) or pyridine in an organic solvent, selected from among aliphatic hydrocarbons, possibly halogenated (methylene chloride, chloroform and aromatic hydrocarbons (benzene, toluene, xylenes).

The product of General formula (XX) can be obtained under conditions similar to those described M. Furukawa et coll., Chem. Pharm. Bull., 25 (1), 181-184 (1977).

The product of General formula (VI), mo is edema (sodium azide), or salts of Quaternary ammonium or phosphate of alkali metal derivative baccatin III or 10-deacetylbaccatin III of General formula:

< / BR>
in which G1has the previously indicated meaning.

Usually the reaction is carried out in an organic solvent, selected from among ethers (tetrahydrofuran, diisopropyl ether, methyl tert.butyl ether) and NITRILES (acetonitrile), alone or in a mixture, at a temperature between 20oC and the boiling temperature of the reaction mixture.

The product of General formula (XXII), in which G1is a hydrogen atom or acetyl, alkoxyalkyl or alkyl radical, can be obtained by the action of a derivative triftormetilfullerenov acid such as the anhydride or N-phenyltrichlorosilane, baccatin III or 10-deacetylbaccatin III, which can be extracted by known methods from the leaves Tissa (Taxus baccata), with possible subsequent protection in position 10, provided that to obtain a product of General formula (XXII), in which G1is alkoxyalkyl or alkyl radical, must be pre-treated with 10-deacetylbaccatin III, secured in position 7, preferably similarbank radical, halogen is analhooboy acid is carried out in an inert organic solvent (aliphatic hydrocarbon, possibly halogenated, aromatic hydrocarbons) in the presence of organic bases, such as tertiary aliphatic amine (triethylamine) or pyridine at temperatures between -50oC and +20oC.

Usually the introduction alkoxyamines grouping is performed during processing of protected 10-deacetylbaccatin halogenerator alkoxyalkyl acid, working mainly organic solvent, such as pyridine, at a temperature of about 20o.

Usually the introduction of the alkyl radical is carried out at a processing 10-deacetylbaccatin III, protected and metallizovannogo in position 10 using, for example, alkali hydride (sodium hydride) or altimetrical compounds (butyl lithium), haloalkyl.

2) under the action of alkali metal halide (sodium iodide, potassium fluoride or alkali metal azide (sodium azide), or salts of Quaternary ammonium or phosphate of an alkali metal on a product of General formula:

< / BR>
in which Ar, R1, R3, R4and G1have these values.

Usually the reaction is carried out in an organic solvent, selected from among ethers (tetrahydrofuran, diisopropyl ether, methyl tert.butyl is the ionic mixture.

The product of General formula (XXIII) can be obtained by the action of a derivative triftormetilfullerenov acid such as the anhydride or N-phenyltrichlorosilane) taxoid General formula:

< / BR>
in which Ar, R1, R3, R4and G1have these values.

Usually the reaction is carried out in an inert organic solvent (aliphatic hydrocarbons, possibly halogenated, aromatic hydrocarbons) in the presence of organic bases, such as tertiary aliphatic amine (triethylamine) or pyridine, at temperatures between -50oC and +20oC.

Taxoid General formula (XXIV), in which G1is a hydrogen atom or an acetyl radical, can be obtained from the product of General formula:

< / BR>
in which Ar, R1, R3and R4have these values, G'1is a group protecting the hydroxyl function, and G'2is acetyl, alkoxyalkyl or alkyl radical or a group protecting the hydroxyl function, when replacing the protective groups G'1and may G'2hydrogen atoms.

The radicals G'1and G'2if they are groups, sasysusie.exe)-carbonyl radicals or trialkylsilyl, dialkylacrylamide, alkyldiethanolamine or triarylamine radicals in which the alkyl portion contains 1-4 carbon atoms and the aryl portion preferably are phenyl radicals, G'2also , may be alkoxyalkyl radical.

When G'1and G'2are 2,2,2-trichlorocarbanilide or 2-/2-trichloromethylpyridine/-carbonyl radical, the replacement of the protective groups by hydrogen atoms is carried out under the action of zinc, possibly associated with copper, in the presence of acetic acid at a temperature between 20oC and 60oC, or with mineral or organic acids, such as hydrochloric acid or acetic acid, in solution in an aliphatic alcohol containing 1-3 carbon atoms, or complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly associated with copper.

When G'1is similarbank radical and G'2is acetyl, alkoxyalkyl or alkyl radical, the replacement of the protective groups G'1the hydrogen atom may be carried out, for example, by using gaseous hydrogen chloride in ethanol solution at temple G'2is alkoxyalkyl radical, its possible replacement by a hydrogen atom is carried out when processing in an alkaline medium or by the action of zinc halide under conditions which do not affect the rest of the molecule. Typically, the alkaline treatment is carried out under the action of ammonia in aqueous-alcoholic medium at a temperature of about 20oC. it is Usually a zinc halide, preferably the iodide of zinc, is carried out in methanol at a temperature of about 20oC.

The product of General formula (XXV) can be obtained under the conditions described in international application PCT/WO 92/09589.

New derivatives of General formula (I) can also be obtained by esterification of a product of General formula (VI) using the acid of General formula:

< / BR>
in which Ar and R1are these values and G3is a group protecting the hydroxyl function, chosen among methoxymethyl, 1-ethoxyethyl, benzoyloxymethyl, (trimethylsilyloxy)bromide, tetrahydropyranyl, 2,2,2-trichloroacetyl, 2,2,2-trichlorocarbanilide, 2-/2-trichloromethylpyridine/-carbonyl or CH2-Ph, where Ph is a phenyl radical, possibly substituted by one or more atoms or radicals, identical or difference is fishing, containing 1-4 carbon atoms, or an active derivative of this acid, to obtain a product of General formula:

< / BR>
in which Ar, R1, G1and G3have the previously indicated meanings, with subsequent replacement of the protective groups G1and G3hydrogen atoms to obtain a product of General formula (1).

The etherification can be carried out under the conditions previously described for the esterification product of General formula (VI), using the acid of General formula (VII).

The replacement of the protecting groups G1and G3the product of General formula (XXVII) with hydrogen atoms is carried out by treatment with zinc, it is possible with copper, in the presence of acetic acid at a temperature between 30oC and 60oC, or with mineral or organic acids, such as hydrochloric acid or acetic acid, in solution in an aliphatic alcohol containing 1-3 carbon atoms, or a complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly with copper, when G1and G3are 2,2,2-trichlorocarbanilide or 2-/2-trichloromethylpyridine/-carbonyl radical. Replacement of the protective groups G3if it is the silyl ridiculousthe in aliphatic alcohol, containing 1-3 carbon atoms (methanol, ethanol, isopropanol), or in aqueous hydrofluoric acid at a temperature between 0oC and 40oC, if it represents the balance acetal, replacement of the protective groups G1then carried out under the conditions described above. When G3is a group-CH-Ph, replacement of this group by a hydrogen atom can be increased by hydrogenolysis in the presence of a catalyst.

The acid of General formula (XXVI) can be obtained by saponification of ester of the General formula:

< / BR>
in which Ar, R1, R5and G3have these values.

Generally, the saponification is carried out using a mineral base (hydroxide, carbonate or bicarbonate of an alkali metal) in aqueous-alcoholic medium (methanol-water) at temperatures between 10oC and 40oC.

Ester of General formula (XXVIII) can be obtained by the usual methods of obtaining ethers, more particularly, to methods described by J-N. Denis et coll., J. Org. Chem., 51, 46-50 (1986), from the product of General formula (XI).

New products of General formula (I), obtained by carrying out methods according to the invention can be purified by known methods such as crystallization and chromium

In vitro, the degree of biological activity was evaluated on tubulinea extract brain pigs according to the method of M. L. Shelanski et coll., Proc. Natl. Acad. Sci. USA, 70, 765-769 (1973). The study of the depolymerization microcannulas in tubulin carried out by the method of G. Chauviere et coll., C. R. Acad. Sci., 293, series II, 501-503 (1981). In this study, the products of General formula (1) was at least as active as Taxol and Taxotere.

In vivo, the products of General formula (I) has been active in mice inoculated with melanoma B16 in doses between 1 and 10 mg/kg intraperitoneal introduction, as well as against other solid and liquid tumors.

New products have antitumor properties and, more specifically, activity against tumors that are resistant to Taxolor Taxotere. Such tumors are tumors of the colon, which have increased expression of the mdr gene 1 (gene multiple drug resistance). Multiple drug resistance is a common term referring to the resistance of the tumor to the products of different patterns and with different mechanisms of action. Taxaide, as it is known, can be interpreted experimental tumors such as R/DOH, cell Lin is ugena, what new products of the present invention, representing the products of examples 1, 2 and 3 have multiple resistance to drugs, and better than Taxoland Taxotere. In addition, it was unexpectedly discovered that the product of example 3 has the properties of multiple drug resistance, better than the products of examples 1 and 2.

The following examples illustrate the present invention.

Example 1.

The solution for 2.01 g of 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S,5R/-oxazolidinecarboxylate-4-acetoxy-2,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il 20 cm3formic acid is stirred for 4 hours at a temperature of about 20oC, then concentrated to dryness under reduced pressure (to 0.27 kPa) at 40oC. the resulting foam is dissolved in 100 cm3dichloromethane and the solution obtained is supplemented 20 cm3saturated aqueous sodium bicarbonate solution. The aqueous phase is separated by decantation and extracted with 20 cm3dichloromethane. Combine the organic phases, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Gain of 1.95 g of a white foam which is purified by chromatography on 200 volume), collect fractions at 30 cm3. Combine the fractions containing only the desired product, and concentrate them under reduced pressure (to 0.27 kPa) to dryness at 40oC for 2 hours. So get of 1.57 g of 3-amino-2-hydroxy-3-phenyl-(2R,3S)-propionate-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il in the form of a white foam.

To a solution of 400 mg of 3-amino-2-hydroxy-3-phenyl-(2R,3S)-propionate-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il 1 cm3dichloromethane, maintained in an argon atmosphere, was added 60 mg of sodium bicarbonate, then dropwise at a temperature of about 20oC, a solution of 0.16 g of di-tert.-BUTYLCARBAMATE 1 cm3dichloromethane. The resulting solution was stirred for 64 hours at a temperature of about 20oC, then add a mixture of 5 cm3distilled water and 10 cm3dichloromethane. The organic phase is washed with 3 times 2 cm3of distilled water. The organic phase is dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Thus obtain 317 mg of a white foam which is purified by chromatography on 30 g of silica (0,063-0.2 mm) in column diametral target product, are combined and concentrated to dryness under reduced pressure (to 0.27 kPa) at 40oC for 2 hours. Thus obtain 161 mg of 3-tert.butoxycarbonylamino-2-hydroxy-3-phenyl-/2R,3S/-propionate-4-acetoxy-2,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il in the form of a white foam, which has the following characteristics:

specific rotation: []2D0= -17o(C = 0,482, methanol);

- proton NMR spectrum (400 MHz, CDCl3), the temperature of 323 K, MRP, constants combination J in Hz): to 1.21 (s, 3H: 16 or 17), of 1.28 (s, 3H: 16 or 17), of 1.34 (s, 9H,- C(CH3)3), 1,30 - 1,50 (MT, 1H: 7), 1,80 - 2,36 (2MT, 1H each: -cyclopropane), a 1.88 (s, 3H: 18), 2,13 (MT, 1H: -(CH) 6), and 2.26 (DD, 1H, J = 15 and 8.5: -(CH) 14), to 2.35 (s, 3H: ), 2,35 - 2,50 (MT, 2H: -(CH) 14 -(CH) 6), 3,21 (d, 1H, J = 4: 2'), 4,08 (d, 1H, J = 8: -(CH) 20), 4,16 (d, 1H, J = 7: 3), 4,18 (s, 1H, 10), or 4.31 (d, 1H, J = 8; -(CH) 20), br4.61 (DD, 1H, J = 4 and 2: 2'), 4,74 (d, 1H, J = 4: 5),

to 5.00 (s, 1H: 10), of 5.26 (DD, 1H, J = 9 and 2: 3'), 5,33 (d, 1H, J = 9: 3'), 5,69 (d, 1H, J = 7: 2), of 6.26 (d, 1H, J= 8,5: 13), 7,30 - 7,50 (MT, 5H: -C6H53'(-H 2 ), 7,51 (t, 2H, J = 7,5: -OCOC6H5( 3 and 5)), 7,60 (t, 1H, J = 7,5: - OCOC6H5( 4)), to 8.14 (d, 2H, J = 7,5: -OCOC6H5( 2 and 6)).

3-Tert. -butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R/-oxazolidinecarboxylate-acetoxy-2-benzoyloxy-5,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il can be obtained sladowski-2-benzoyloxy-5,20-epoxy-1,10-deoxy-9-oxo-7-triftorbyenzola-11-taxen-13-Il 25 cm3anhydrous acetonitrile and 3 cm3anhydrous tetrahydrofuran, maintained in an argon atmosphere, was added 2.5 g of sodium azide. The reaction mixture is heated for 2 hours under stirring in an argon atmosphere at a temperature of approximately 80oC, then cooled to a temperature of about 20oC and add 30 cm3of distilled water. The aqueous phase is separated by decantation, and then extracted with 20 cm3dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. are Thus obtained of 2.44 g of a yellow foam which is purified by chromatography on 300 g of silica (0,063-0.2 mm) in a column with a diameter of 8 cm, elute with a mixture of dichloromethylsilane (90-10 by volume), collecting fractions of 60 cm3. Faction 47-70 are combined and concentrated to dryness under reduced pressure (to 0.27 kPa) at 40oC for 2 hours. So get a 2.01 g of 3-tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-(4S, 5R)-oxazolidinecarboxylate-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il in the form of a white foam.

3-Tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R/-oxazolidin-carboxylate-4-acetoxy methodology:

To a solution of 2.86 g of 3-tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R)-oxazolidinecarboxylate-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,7,10-trioxi-9-oxo-11-taxen-13-Il 29 cm3anhydrous dichloromethane, maintained in an argon atmosphere, are added 0,955 cm3pyridine and 50 mg of molecular sieves 4 in the form of activated powder. The reaction mixture is cooled to a temperature of about -35oC, slowly add 0,85 cm3anhydride triftormetilfullerenov acid, is stirred at a temperature of about -5oC for 15 minutes and add 10 cm3of distilled water. After filtration through sintered glass with telicom, and washing the sintered glass 3 times 10 cm3a mixture of methanol-dichloromethane (10-90 by volume) to separate the aqueous phase by decantation and extracted with 2 times 10 cm3dichloromethane. Combine the organic phases, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Get a 3.87 g of a white foam which is purified by chromatography on a column of silica (400 g) (0,063-0.2 mm) in column 10 cm in diameter, elute with a gradient of dichloromethane-ethyl acetate (from a 97.5-2.5 to 90-10 by volume), collecting fractions of 80 cm3. Combine faction is Uchenie 2 hours. Thus obtain 3.0 g of 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R)-oxazolidinecarboxylate 4-acetoxy-2-benzoyloxy-5,20-dihydroxy-1,10-deoxy-9-oxa-7-triftorbyenzola-11-taxen-13-Il in the form of a white foam.

3-Tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R)-oxazolidinecarboxylate 4-acetoxy-benzoyloxy-5,20-epoxy-1,7,10-trioxi-9-oxo-11-taxen-13-Il can be obtained in the following way:

The solution 24,35 g of 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S,5R/-oxazolidinecarboxylate 4-acetoxy-2-benzoyloxy-5,20-epoxy-9-oxo-7,10-bis-/2,2,2-trichloroethane/carbonyloxy-1-Il in a mixture of 130 cm3ethyl acetate and 46.5 cm3acetic acid is heated under stirring in an argon atmosphere to a temperature of about 60oC, then add 40 g of zinc powder. Then the reaction mixture is stirred for 30 minutes at 60oC, and then cooled to a temperature of about 20oC and filtered through a filter made of sintered glass with telicom. The filter of sintered glass is washed with 100 cm3a mixture of methanol-dichloromethane (20-80 volume); the filtrates are combined and then concentrated to dryness under reduced pressure (to 0.27 kPa) at a temperature of approximately 40oC.

The residue is treated with 500 cm3UP>3of distilled water. Obtained by decantation and the combined aqueous phase is extracted with 2 times 30 cm3dichloromethane. The combined organic phases, dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Gain of 19.7 g of a white foam which is purified by chromatography on 800 g of silica (0,063-0.2 mm) in column 10 cm in diameter, elute with a gradient of dichloromethane-methanol (from 100-0 to 97-3 by volume), collecting fractions of 80 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (to 0.27 kPa) at 40oC for 2 hours. So get 16,53 g of 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R)-oxazolidinecarboxylate-4-acetoxy-2-benzoyloxy-5,20-epoxy-1,7,10-trioxi-9-oxo-11-taxen-13-Il in the form of a white foam.

3-Tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R/-oxazolidinecarboxylate-acetoxy-2-benzoyloxy-5,20-epoxy-9-oxo-7,10-bis-(2,2,2-trichloroethane)carbonyloxy-1-yl can be obtained according to the method described in international application PCT/WO 9209589.

Example 2.

To a solution of 550 mg of 3-amino-2-hydroxy-3-phenyl-/2R,3S/-propionate 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-7,8-methylene-9-the saturated aqueous sodium bicarbonate solution, then added dropwise at a temperature of about 20oC 0,096 cm3of benzoyl chloride. The resulting mixture was stirred for 10 minutes at a temperature of about 20oC. After decanting, the aqueous phase is extracted with 2 times 30 cm3ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Thus obtain 670 mg of a white foam which is purified by chromatography at atmospheric pressure on 50 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter, elute with a mixture of methanol-dichloromethane (1-99, then a 2.5 to 97.5 by volume), collecting fractions of 10 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Thus obtain 610 mg of a white foam. A sample (300 mg) is purified by preparative chromatography on 12 plates with a thin layer of silica (Kieselgel 60F254, Merck, 0.25 mm thick), elute with a mixture of methanol-dichloromethane (3-97 by volume). After elution of the zone corresponding to the main product, a mixture of methanol-dichloromethane (10-90 by volume), followed by evaporation of the solvents under reduced pressure (to 0.27 kPa) at a temperature of approximately 40oC get 155, 2mm mg 3-taxen-13-Il in the form of a white foam, which has the following characteristics:

specific rotation []2D030.5 pero(C = 0,491; methanol);

- proton NMR spectrum: (300 MHz, CDCl3in MRP, the constant combination J in Hz):

of 1.27 (s, 3H: 16 or 17), of 1.30 (s, 3H: 16 or 17), to 1.40 (MT, 1H: ), 1,62 2.25 (m, 1H each:

cyclopropane), of 1.85 (s, 3H: 18), 1,96 (-s, 1H: 1), 2,05 and 2.48 (d and m, 1H each: 6), 2,24 (s, 3H: 10), 2,28, and of 2.50 (m, 1H each: 14), of 2.45 (s, 3H: 4), 3,52 (d, 1H, 2'), 4,10 and 4.35 (d, 1H each: 20), 4,11 (d, 1H: 3), 4,77 (d broad, 1H: 5), 45,82 (DD, 1H: 2'), 5,70 (d, 1H: 2), of 5.84 (DD, 1H: 3'), 6,30 (t, broad, 1H: 13), 6,36 (s, 1H: 10), of 7.00 (d, 1H: ), 7,35 - 8,30 (m, 15H: 3').

3-Amino-2-hydroxy-3-phenyl-/2R,3S/-propionate,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il can be obtained by the method of example 1 to obtain 3-amino-2-hydroxy-3-phenyl-(2R,3S)-propionate-acetoxy-2-benzoyloxy-5,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il. So, from 1.6 g of 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-(4S,5R)-oxazolidinecarboxylate-diacetoxy-benzoyloxy-5,20-epoxy-1-hydroxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il get to 1.14 g of 3-amino-2-hydroxy-3-phenyl-(2R,3S)-propionate,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il in the form of a white foam.

3-Tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-(4S, at to be obtained in terms described in example 1 to obtain 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S,5R/-oxazolidinecarboxylate 4-acetoxy-2-benzoyloxy-5,20-epoxy-1,10-deoxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il. So, from 2.2 g of 3-tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5- /4S,5R/-oxazolidinecarboxylate 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9-oxo-7-triftorbyenzola-11-taxen-13-Il gain of 1.62 g of tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S,5R/-oxazolidinecarboxylate 4,10-diacetoxy-2-benzoyloxy--5,20-epoxy-1-hydroxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il in the form of a white foam.

3-Tert. butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S, 5R)-oxazolidinecarboxylate 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9-oxo-7-triftorbyenzola-11-taxen-13-Il can be obtained under the conditions described in example 1 to obtain 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5/4S,5R/-oxazolidinecarboxylate-

benzoyloxy-5,20-epoxy-1,10-deoxy-9-oxo-7-triftorbyenzola-19-nor-11-taxen-13 diacetoxy-2-benzoyloxy-5,20-epoxy-1,7-deoxy-9-oxo-11-taxen-13-Il gain of 2.46 g of 3-tert.butoxycarbonyl-2,2-dimethyl-4-phenyl-5-/4S,5R/-oxazolidinecarboxylate 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-9-oxo-7-triftorbyenzola-11-taxen-13-Il in the form of a white foam.

C-1,7-deoxy-9-oxo-11-taxen-13-Il can be obtained in terms described in the international patent application PCT/ WO 9209589.

Example 3

To a solution of 550 mg of 3-amino-2-hydroxy-3-phenyl-/2R,3S/-propionate 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il 1 cm3dichloromethane, maintained in an argon atmosphere, was added 76 mg of sodium bicarbonate, then dropwise at a temperature of about 20oC a solution of 197 mg bi-tert.BUTYLCARBAMATE 1 cm3dichloromethane. The resulting solution is stirred for 15 hours at a temperature of about 20oC, then add a mixture of 5 cm3distilled water and 10 cm3dichloromethane. The aqueous phase is extracted with 5 cm3dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Thus obtain 780 mg of a white foam which is purified by chromatography at atmospheric pressure on 50 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter, elwira a mixture of methanol-dichloromethane (1-99, then a 2.5 to 97.5 by volume), collecting fractions of 10 cm3. Combine the fractions containing only the desired product, and concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Thus obtain 660 mg of the white is (Kieselgel 60F254, Merck, 0.25 mm thick), elute with a mixture of methanol-dichloromethane (4-96 by volume). After elution of the zone corresponding to the main product, a mixture of methanol-dichloromethane (10-90 by volume) and subsequent evaporation of the solvents under reduced pressure (to 0.27 kPa) at a temperature of approximately 40oC get 159,7 mg of 3-tert.butoxycarbonylamino-2-hydroxy-3-phenyl-/2R,3S/-propionate 4,10-diacetoxy-2-benzoyloxy-5,20-epoxy-1-hydroxy-7,8-methylene-9-oxo-19-nor-11-taxen-13-Il in the form of a white foam, which has the following characteristics:

specific rotation: []2D0= -34 (C = 0,564, methanol);

- proton NMR spectrum (400 MHz, CDCl3in MRP, the constants of the combination of J in Hz): 1.28 (in s, 3H: 16 or 17), of 1.30 (s, 9H: ), to 1.38 (MT, 1H: 7), to 1.60 (s, 3H: 16 or 17) 1,68 and 2.25 (t and m, 1H each: cyclopropane), of 1.85 (s, 3H: 18), of 2.10 and 2.45 (d and TD, 1H each: 6), of 2.23 (s, 3H: 10), 2.22 and 2.40 a (m, 1H each: 14), is 2.40 (s, 3H: 4), or 3.28 (d, 1H, 2'), 4,05 and 4,22 (d, 1H each: 20), 4,10 (d, 1H: 3), to 4.62 (broad, 1H: 2'), to 4.73 (d, 1H: ), from 5.29 (d broad, 1H: 3'), lower than the 5.37 (d, 1H: ), 5,67 (d, 1H: 2), 6,28 (t, broad, 1H: 13), 6,33 (s, 1H: 10), 7,30 was 7.45 (MT, 5H: -C6H53'), 7,51 (t, 2H: -OCOC6H5( 3 and 5)), to 7.61 (t, 1H: -OCOC6H54)), 8,17 (d, 2H: -OCOC6H5( 2 and 6)).

Example 4

To a solution of 100 mg of 10-deacetylbaccatin III in a mixture of 2 cm3of tetrahydrofuran and 0.05 cm3anhydride triftormetilfullerenov acid. Allow the mixture is slowly heated to a temperature of about 0oC for about an hour, then to a temperature of about 20oC, about an hour. After 2 hours at a temperature of about 20oC add 200 mg of tetrabutylammonium iodide, then the solution is heated at the boiling temperature of the solvent for 15 hours. After cooling to a temperature of about 20oC add 10 cm3ethyl acetate, then 1 cm3of distilled water. After decanting, the organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. Thus obtain 116 mg of a yellow oil which is purified by chromatography at atmospheric pressure on 30 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter, elwira a mixture of ethyl acetate-dichloromethane gradient elution from 0-100 to 80-20 by volume. Combine the fractions containing the desired product, and concentrate their dryness under reduced pressure (to 0.27 kPa) at 40oC. Thus get to 10.3 mg 10-desacetyl-7,8-methylene-19-nor-baccatin III in the form of a white foam, which has the following characteristics:

- proton NMR spectrum: (400 MHz, CDCl3, MRP, to the d, wide, etc., 1H each: 6), 2,30 (-s, 3H: -COCH34), 2,28, and to 2.35 (m, 1H each: 14), 4,11 and 4,37 (d, 1H each: 20), 4,28 (d, 1H: 3), 4,79 (d, 1H, 5), 4,88 (t, broad, 1H: 13), 5,09 (s, 1H: 10), to 5.66 (d, 1H: 2), 7,51 (t, 2H: -OCOC6H53 and 5//, to 7.61 /t, 1H: -OCOC6H54//, 8,17 /d, 2H: -OCOC6H52 and 6//.

-13C-NMR spectrum (100 MHz, CDCl3in MRP, unsplit, s = singlet, d = doublet, t - triplet, K - quadruplet): 15 (K, C18), 16,5 (t, C19), 20 and 27 (K, C16 and C17), 22,5 (K ), 26,5 (t, C6), 33 (d, C7), 35 (C, C8), 39 (d, C3), 39,5 (t, C14), 43 (s, C15), 68 (d, C13), 76 (t, C20), 76,2 (d, C10) and 79.5 (s, C1), 80 (C, C4), 81 (d, C2), 85 (d, C5), 129 (d, C2: -OCOC6H5), 130 (C, C1-OCOC6H5), 130,5 (d, C3-OCOC6H5), 134 (d, C4 from OCOC6H5), 136 (s, C11), 143 (s, C12), 168 (C ), 171 (C , 210 (C, C9).

Example 5.

To a solution of 1.2 g of 4-acetoxy-2-alpha-benzoyloxy-beta, 20-epoxy-1-hydroxy-beta-methoxyethoxy-beta-Cryptor - methansulfonate-9-oxo-11-taxen-13-yl (2R, 3S)-3-tertbutoxycarbonyl-2-hydroxy-(3-thienyl)propionate in a mixture of 15 ml of anhydrous acetonitrile and 1.5 ml of anhydrous THF in an argon atmosphere add 0.6 g of powdered molecular sieves (4 ) and 1.8 g of sodium chloride. The reaction mixture is stirred at 20oC 30 min, then heated at the boiling temperature of the solvent for 2 hours, After cooling the Filter is washed twice with 20 ml of dichloromethane, the filtrates are combined, washed twice with 20 ml water, dried over sodium sulfate, filtered and concentrated at 40oC and reduced pressure (2.7 kPa). Get 925 mg of a white amorphous solid substances that cleanse chromatography on 100 g of silica gel (0,063-0.2 mm) column with a diameter of 3 cm, elwira a mixture of dichloromethane: methanol (99:10 vol.), collect fractions of 25 ml Fractions 16 and 26 combine, concentrate to dryness under reduced pressure (2.7 kPa) and 40oC for 16 h In the result 217 mg of 4-acetoxy-alpha-benzoyloxy-beta, 20-epoxy-1-hydroxy-beta-methoxyethoxy-beta, 8 beta-methylene-9-oxo-19-nor-11-taxen--13-yl (2R, 3S)-3-tertbutoxycarbonyl-2-hydroxy-(3-thienyl)propionate in the form of a solid white amorphous substance, with the following physicochemical characteristics:

beats. optical rotation: []2D0= -28 (C = 0,37; methanol),

1H NMR spectrum (400 MHz, CDCl3, d in ppm, constant spin-spin interaction J in Hz); 1,25 (s, 3H: - CH3); of 1.27 (s, 3H: - CH3); to 1.31 (s, N: C(CH3)3);

of 1.40 (m, 1H: H 7); 1,69, 2,20-2,25 (2m, 1H each: - CH219); of 1.84 (m, 1H: HE 1);

of 1.87 (s, 3H: - CH3); 2,11, 2,35-2,50 (respectively: ush.d, J= 16, +m, 1H, CH26); 2,20-of 2.50 (m, 2H: CH214), is 2.37 (s, 3H: COCH3); 3,30 (the>
About); to 4.62 (m, 1H: H 2'); 4.72 in (m, 1H: H 5); 5,20 (d, J= 10, IH: CONH); of 5.34 (m, IH: H 3'); of 5.68 (d, J= 7, 1H: H 2); 6,26 (ush.t, J = 9, 1H: H 13); 6,41 (c, 1H; H-10); 7,10 (d, J = 4, H-4 thienyl); 7,28 (m, 1H: H-2 thienyl); 7,37 (DD, J= 4 and 3.5, 1H, H-5 thienyl); 7,51 (t, J =7,5, 2H : OCOC6H5H-meta); to 7.61 (t, J= 7,5, 1H: OCOC6H5H-pair); 8,15 (d, J = 7,5, 2H: OCOC6H5H-ortho).

Example 6.

To a solution of 0.4 g of 3-tert-butoxycarbonyl-2,2-dimethyl-4-(4-were)oxazolidin-5-(4S,5R)carboxylic acid in 10 ml of toluene was added 0,247 g N, N'-dicyclohexylcarbodiimide, 0,675 g of 4-acetoxy-alpha-benzoyloxy-beta, 20-epoxy-1,13-dihydroxy-9-oxo-beta, beta-bis(2,2,2-trichloroethane)carbonyloxy-11-taxen and 0.046 g of 4-dimethyl-aminopyridine. The reaction mass is heated at a temperature of approximately 80oC with stirring for 3 h, then cooled to a temperature of about 20oC, add a mixture of 20 ml of dichloromethane and 25 ml of saturated aqueous sodium bicarbonate solution. Separate the aqueous phase by decantation, which then extravert 15 ml of dichloromethane. The combined organic phases, dried over magnesium sulfate, filtered, concentrated to dryness, under reduced pressure (2.7 kPa) and 50oC. Obtain 1.1 g of the substance in air masses of yellow color, which is purified by chromatography on 40 g of silica (fracc. II 3 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. the result of 0.6 g of 4-acetoxy-2 alpha-benzoyloxy-beta, 20-epoxy-1-hydroxy-9-oxo-beta, beta-bis(2,2,2-trichloroethane)carbonyloxy-11-taxen-13 or TNF. Other chemotherapeutic agents useful for treatment of disorders caused by abnormal proliferation of cells, include, but are not limited to, alkylating agents such as nitrogen mustard, for example, mechlorethamine, cyclophosphamide, melphalan and chlorambucil, alkyl sulphonates, for example, busulfan, nitrosamine, for example, carmustin, lomustin, semustine and streptozocin, triazine, such as dacarbazine, antimetabolites, for example, analogs of folic acid, such as methotrexate, pyrimidine analogues, for example, fluorouracil and cytarabine, purine analogues, for example, mercaptopurine and tioguanin, natural products such as Vinca alkaloids, for example, vinblastine, vincristine and vindesine, epipodophyllotoxin, for example, etoposide and teniposide, antibiotics such as dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitomycin, enzymes such as L-asparaginase, various agents, for example, the coordination complexes of platinum, such as cisplatin, substituted urea, such as oxytocin, derivatives methylhydrazine, for example, the use of which, adrenocorticosteroid, for example, prednisone, progestins, for example, Caproic oksiprogesterona, acetate methoxyprogesterone and acetate megestrol, estrogens, for example, diethylstilbestrol and estrogens, antiestrogens, such as tamoxifen, androgens, such as testosterone propionate and fluoxymesterone.

The dose used to implement the methods according to the invention are such that they provide prophylactic treatment or therapeutic response. Doses vary depending on the form of the introduction of specifically selected product and the exact characteristics of the subject to be treated. Usual doses are such that they are therapeutically effective for the treatment of disorders caused by abnormal cell proliferation. The products according to the invention can also be entered as often as necessary to obtain the desired therapeutic response. Some patients are able to respond quickly to relatively high or low dose, then you may need to support very low or zero doses. Usually at the beginning of treatment using low dose and, if necessary, impose increasingly higher doses to obtain optimally 1-4 times, depending on the physiological needs of a particular patient. It is also possible that for some patients it will be necessary to use only two cycles per day.

For men dose usually be from 0.01 to 200 mg/kg When intraperitoneally way dose will typically be between 0.1 and 100 mg/kg, preferably between 0.5 and 50 mg/kg, and even more specifically, between 1 and 10 mg/kg by intravenous route doses are usually between 0.1 and 50 mg/kg, preferably between 0.1 and 5 mg/kg, and even more specifically, between 1 and 2 mg/kg Should be aware that when choosing the most appropriate dose take into account the route of administration, the weight of the patient, his overall health, his age and any factors that may affect the effectiveness of the treatment.

The following example illustrates a composition according to the invention.

Composition for injection

The active substance, mg - 40

Surfactant (Polysorbate), ml - 1

Example

Dissolve 40 mg of the product obtained in example 1 in a 1 cm3Emulphor ATE 620 and 1 cm3ethanol, then the solution was diluted with the addition of 18 cm3physiological serum.

The composition is administered by perfusion for 1 hour by weaksignal cells P-388 Leukemia

The active compounds according to the invention was investigated in vitro on cell lines of mouse P-388 Leukemia. Cell medium with density 3105cells/ml, was collected for 96 h in the presence of investigated compounds in different concentrations.

Cells were incubated for 16 h in the presence of 0.02% dye natural red, washed with water, then subjected to lysis by the action of sodium dodecyl sulfate (1%).

Cell growth was determined from the change in the inclusion of the dye in the cell mass by measuring the optical density (at wavelengths of 540 and 360 nm). Identified concentrations of compounds inhibiting cell growth by 50% (IC50). The results are summarized:

Example - P388 IC50< / BR>
1 - 0,03

2 - 0,03

Will complement. - 0,007

1. Taxaide General formula I

< / BR>
in which R is a hydrogen atom or acetyl or alkoxyalkyl radical;

R1is benzoline radical or the radical R2-O-CO-, in which R2is an alkyl radical, straight or branched, containing 1 to 8 carbon atoms;

Ar is a phenyl radical or heterocyclic aromatic radical having 5 units and containing one or more atoms of the CE is R1- benzoline radical or the radical R2-O-CO-, in which R2is tert-botulinum radical, and Ar is a phenyl radical.

3. Derived under item 1, wherein R is an acetyl radical, R1the radical R2-O-CO-, in which R2is tert-bootrom, and Ar is a phenyl radical.

4. Derived under item 1, wherein R is an acetyl radical, R1- benzoline radical and Ar is a phenyl radical.

5. Derived under item 1, wherein R is a hydrogen atom, R1the radical R2-O-CO-, in which R2is tert-botulinum radical, and Ar is a phenyl radical.

6. Derived under item 1, wherein R is a hydrogen atom, R1- benzoline radical and Ar is a phenyl radical.

7. The method of obtaining taxoid one from p. 1 - 6, characterized in that etherification product of General formula VI

< / BR>
in which C1is a hydrogen atom, or acetyl, alkoxyalkyl or alkyl radical, or a group protecting the hydroxyl function by using the acid of General formula VII

< / BR>
in which Ar and R1have the values specified in paras.1 - 6,

R3possibly substituted;

R4is a hydrogen atom,

in order to obtain a product of General formula II

< / BR>
in which Ar, R and R1have the values specified in paras.1 - 6;

R3, R4and C1have the meanings given above,

which is treated in an acidic medium to obtain a product of General formula III

< / BR>
in which Ar, R1and C1have these values,

then maybe replace the protecting group of the C1a hydrogen atom and produce the product.

8. The method according to p. 7, characterized in that the esterification is carried out with the help of the free acid, working in the presence of a condensing agent selected among carbodiimides and reactive carbonates and activerules agent selected among aminopyridine, in an organic solvent, selected from among ethers, ketones, esters, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between -10 and 90oC.

9. The method according to p. 7, wherein conducting the etherification using anhydride in the presence of an activating agent selected among aminopyridine, in an organic solvent, selected from among them, hydrocarbons and aromatic hydrocarbons, at 0 - 90oC.

10. The method according to p. 7, wherein conducting the etherification using galodamadruga or anhydride of an aliphatic or aromatic acid, probably prepared in Situ, working in the presence of a base, selected from among tertiary aliphatic amines in an organic solvent, selected from among ethers, esters, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons, at 0 - 80oC.

11. The method according to p. 7, wherein spend processing the acid with a mineral or organic acid at a temperature between -10 and 60oC.

12. The method according to p. 11, wherein the acid is chosen among hydrochloric, sulfuric, acetic, methanesulfonic, triftormetilfullerenov and p-toluensulfonate acids used individually or in mixtures.

13. The method according to A11, wherein the solvent is selected from alcohols, ethers, esters, halogenated aliphatic hydrocarbons, aromatic hydrocarbons and NITRILES.

14. The method according to p. 7, characterized in that the replacement of a hydrogen atom, a protective group G1if it Get in the processing of zinc, possibly associated with copper, in the presence of acetic acid at 30 - 80oC or with mineral or organic acids, such as hydrochloric or acetic acid, in solution in an aliphatic alcohol containing 1 to 3 carbon atoms, or a complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly in conjunction with copper, and if it is alkoxyalkyl radical, when processing in an alkaline medium with ammonia in aqueous-alcoholic medium at a temperature of about 20oC, or in the processing of zinc halide in methanol at a temperature of about 20oC.

15. The method of obtaining compounds on p. 1, characterized in that etherification product of General formula VI

< / BR>
in which G1is a hydrogen atom or acetyl, alkoxyalkyl or alkyl radical or a group protecting the hydroxyl function by using the acid of General formula VII

< / BR>
in which Ar and R1have the values specified in paras.1 - 6;

R3and R4identical or different, are alkyl radicals containing 1 to 4 carbon atoms, or Uralkali radical, the alkyl part of which contains 1 to 4 carbon atoms, or ariline lydmetalis radical, and R4is a hydrogen atom, or R3and R4form together with the carbon atom to which they are attached, a cycle having 4 to 7 parts by obtaining after treatment in the acidic environment of the product of General formula IV

< / BR>
in which Ar has the values specified in paras.1 - 6;

G1matter mentioned previously,

which acelerou using benzoyl chloride or a reactive derivative of General formula V

R2-O-CO-X,

in which R2has the values specified in paras.1 - 6;

X is a halogen atom or a residue-O-R2or-O-CO-O-R2,

then, if necessary, replace the protecting group G1on the hydrogen atom and produce the product.

16. The method according to p. 15, wherein conducting the etherification with the help of the free acid, working in the presence of a condensing agent selected among carbodiimides and reactive carbonates, and the activating agent selected among aminopyridine, in an organic solvent, selected from among ethers, ketones, esters, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between 10 and 90oC.

17 is Ghent, selected among aminopyridine, in an organic solvent, selected from among ethers, esters, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons, at 0 - 90oC.

18. The method according to p. 15, characterized in that the esterification is carried out with the help of galodamadruga, or anhydride of an aliphatic or aromatic acid, probably prepared in situ, working in the presence of a base, selected from among tertiary aliphatic amines in an organic solvent, selected from among ethers, esters, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons, at 0 - 80oC.

19. The method according to p. 15, wherein spend processing the acid with a mineral or organic acid in an organic solvent at 0 - 50oC.

20. The method according to p. 19, characterized in that the acid selected from among hydrochloric, sulfuric and formic acids.

21. The method according to p. 19, wherein the solvent is selected from alcohols containing 1 to 3 carbon atoms.

22. The method according to p. 15, characterized in that acelerou the P CLASS="ptx2">

23. The method according to p. 22, wherein the inert organic solvent is selected among esters and halogenated aliphatic hydrocarbons.

24. The method according to one of paragraphs.21 to 23, characterized in that operate at 0 - 50oC.

25. The method according to p. 15, characterized in that the replacement of a hydrogen atom, a protective group G1if it is 2,2,2-trichlorocarbanilide radical or 2-/2-trichloromethylpyridine/-carbonyl radical, is performed during the processing of zinc, possibly in conjunction with copper, in the presence of acetic acid at 30 - 60oC or with mineral or organic acids, such as hydrochloric or acetic acid, in solution in an aliphatic alcohol containing 1 to 3 carbon atoms, or complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly in conjunction with copper, or when it is alkoxyalkyl radical, when processing in an alkaline medium with ammonia in aqueous-alcoholic medium at a temperature of about 20oC or in the processing of zinc halide in methanol at a temperature of about 20oC.

26. The method of obtaining compounds on p. 1, characterized in that etherification product total ban hydroxyl function,

using the acid of General formula XXVI

< / BR>
in which Ar and G1have the values specified in paras.1 - 6;

G3is a group protecting the hydroxyl function,

or active derivative of this acid, to obtain a product of General formula XXVII

< / BR>
in which Ar, R1, G1and G3have these values,

which replaces the protective groups R3and may G1on the hydrogen atom and produce the product.

27. The method according to p. 26, characterized in that conduct the esterification with the help of the free acid, working in the presence of a condensing agent selected among carbodiimides and reactive carbonates, and the activating agent selected among aminopyridine, in an organic solvent, selected from among ethers, ketones, esters, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons at a temperature between -10 and 90oC.

28. The method according to p. 26, characterized in that the etherification using the anhydride is carried out in the presence of an activating agent selected among aminopyridine, in an organic solvent, selected from among simple Dorogov and aromatic hydrocarbons, at 0 - 90oC.

29. The method according to p. 26, characterized in that the esterification is carried out with the help of galodamadruga or anhydride of an aliphatic or aromatic acid, probably prepared in situ, working in the presence of a base, selected from among tertiary aliphatic amines in an organic solvent, selected from among ethers, esters, ketones, NITRILES, aliphatic hydrocarbons, halogenated aliphatic hydrocarbons and aromatic hydrocarbons, at 0 - 80oC.

30. The method according to p. 26, characterized in that the replacement of the protective groups G1and G3hydrogen atoms spend in the processing of zinc, possibly associated with copper, in the presence of acetic acid at 30 - 60oC or with mineral or organic acids, such as hydrochloric or acetic acid, in solution in an aliphatic alcohol containing 1 to 3 carbon atoms, or complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly together with copper, when G1and G3are 2,2,2-trichlorocarbanilide radical or 2-(2-trichloromethylpyridine)-carbonyl radical or during treatment in an acidic environment, so anal, propanol, isopropanol) or an aqueous hydrofluoric acid, 0 - 40oC when G3is a silyl radical or a residue acetal, followed by replacement of the protecting groups G1in the processing of zinc, possibly together with copper in the presence of acetic acid at 30 - 60oC or with mineral or organic acids, such as hydrochloric or acetic acid, in solution in an aliphatic alcohol containing 1 to 3 carbon atoms or in an aliphatic alcohol containing 1 to 3 carbon atoms, or complex aliphatic ether, such as ethyl acetate, isopropylacetate or n-butyl acetate, in the presence of zinc, possibly together with copper, or when G1is alkoxyalkyl radical, when processing in an alkaline medium with ammonia in aqueous-alcoholic medium at a temperature of about 20oC or in the processing of zinc halide in methanol at a temperature of about 20oC.

31. The method according to p. 26, characterized in that, if G3is a radical-CH2-Ph, replacement group for the hydrogen atom is carried out by hydrogenolysis after replacement of the protecting groups G1in terms p. 30.

32. Taxaide General formula XXIII

< / BR>
in which W is hydrogen or a group< the, protecting the hydroxyl function;

Ar and R1have the values listed in one of the paragraphs. 1 - 6;

R3and R4have the meanings specified in paragraph 7 or 15.

33. Taxoid General formula VI

< / BR>
where G1have the above values.

34. Pharmaceutical composition having antitumor activity, characterized in that it contains an effective amount of at least one product in one of the paragraphs.1 - 6 together with one or more neutral pharmaceutically acceptable products.

35. The method according to p. 7, characterized in that the compound of formula II is obtained by reacting the halide or azide of an alkali metal, or Quaternary ammonium salt, or a phosphate of an alkali metal with the compound of the formula XXIII

< / BR>
in which Ar and R1have the values specified in paras.1 - 3;

G1, R3and R4have the meanings specified in paragraph 7 or 15,

and the compound obtained of the formula II

< / BR>
treated in an acidic medium to obtain the compounds of formula III under item 7, and then, if necessary, replace the protective group G1a hydrogen atom and produce the target product.

36. The method according to p. 35, characterized in that the compound of formula XXIII BR>G1'means a protective group hydroxypoly;

G2'- acetyl, alkoxyacetic or alkyl or a protective group hydroxypoly,

by replacement of the protective groups G1'and may G2'hydrogen atoms with obtaining the compounds of formula XXIII:

< / BR>
in which Ar, R1, R3, R4specified above;

G1is a hydrogen atom or acetyl,

with subsequent treatment of the obtained compound derived triftoratsetata to obtain the target product XXIII'< / BR>
< / BR>
where Ar, R1, R3, R4and G1have the specified values.

 

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