C7-ester-substituted taxanes as anti-tumor agents

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

 

BACKGROUND of the INVENTION

This invention relates to new similarly to taxanes that have exceptional fitment as anticancer agents.

Takanawa group of terpenes, the members of which are baccatin III and Taxol, is of considerable interest both biological and chemical kind. The Taxol is used as an anti-cancer chemotherapeutic agent and has a broad spectrum of inhibitory tumor activity. Taxol has the 2'R,3'S configuration and represented by the following structural formula:

where Ac represents acetyl.

Colin and others described in the patent US 4814470 that some analogs of Taxol are much more active than Taxol. One of these analogues, commonly called docetaxel, has the following structural formula:

Although Taxol and docetaxel can be used as chemotherapeutic agents, there are limitations to their effectiveness, including limited effectiveness against certain types of cancer and toxicity to the subject with the introduction of various doses. Accordingly, there remains a need for additional chemotherapeutic agents with improved efficacy and less toxicity.

The INVENTION

Among the objects of the data of the invention, therefore, there taxanes, which have advantages in comparison with Taxol and docetaxel effectiveness as anticancer agents and toxicity. Usually these taxanes contain ester Deputy, other than formate, acetate and heterothermy acetate, in position C-7, hydroxysultaine in position With a-10 and the number of C-3'-substituents.

Briefly, the invention therefore relates to taxanomy composition, as such, to pharmaceutical compositions containing Texan and a pharmaceutically acceptable carrier, and to methods of introduction.

Other objects and characteristics of this invention will be partially cleared and partially noted below.

A DETAILED DESCRIPTION of the PREFERRED EMBODIMENTS

In one of the embodiments of the present invention taxanes according to this invention corresponds to the structure (1):

where

R2represents acyloxy;

R7is an R7aCOO-;

R7arepresents hydrocarbon, substituted hydrocarbon or heterocycle where specified hydrocarbon or substituted hydrocarbon contain carbon atoms in the alpha and beta positions relative to the carbon Deputy who is R7a;

R9is a keto, hydroxy or acyloxy;

R10 represents hydroxy;

R14represents hydrido or hydroxy;

X3represents a substituted or unsubstituted alkyl, alkenyl, quinil, phenyl or heterocycle;

X5is a-MOR10, -COOH10or CONHX10;

X10represents hydrocarbon, substituted hydrocarbon or heterocycle;

Ac represents acetyl;

R7, R9and R10independently from each other are alpha or beta stereochemical configuration.

In one embodiment R2is an ester (R2aC(O)O-), carbamate (R2aR2bNC(O)O-), carbonate (R2aOC(O)O-) or THIOCARBAMATE (R2aSC(O)O-), where R2aand R2bindependently of one another denote hydrogen, hydrocarbon, substituted hydrocarbon or heterocycle. In the preferred embodiment R2is an ester (R2aC(O)O-), where R2arepresents an aryl or heteroaromatic group. In another preferred embodiment R2is an ester (R2aC(O)O-), where R2arepresents a substituted or unsubstituted phenyl, furyl, thienyl or pyridyl. In one particular preferred embodiment R2represents a benzoyloxy.

In one embodiment R7is an R7aCOO-, where R7arepresents (i) substituted sludge is unsubstituted With 2-C8alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl or hexyl; (ii) substituted or unsubstituted With2-C8alkenyl (a straight, branched or cyclic), such as ethynyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted With2-C8quinil (straight or branched), such as ethinyl, PROPYNYL, butynyl, pentenyl or hexenyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic radical, such as furyl, thienyl or pyridyl. Substituents can be hydrocarbon or any containing heteroatom substituents specified hereinafter for substituted hydrocarbide. In the preferred embodiment R7arepresents an ethyl, a straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic pentyl, straight, branched or cyclic hexyl, straight or branched propenyl, Isobutanol, furyl or thienyl. In another embodiment R7arepresents a substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched)substituted Isobutanol, substituted furyl or substituted thienyl, where the substituent(s) selected(s) from the group comprising heterocycle, Alcock and, alkenone, alkyloxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether group, but not phosphorus-containing group.

If R9is a keto in one of the embodiments of the present invention, in other embodiments, R9may be alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, αor β-hydroxy - or αor β-acyloxy. For example, if R9represents acyloxy, this may be an ester (R9aC(O)O-), carbamate (R9aR9bNC(O)O-), carbonate (R9aOS(O)O-) or THIOCARBAMATE (R9aSC(O)O-), where R9aand R9bindependently of one another denote hydrogen, hydrocarbon, substituted hydrocarbon or heterocycle. If R9is an ester (R9aC(O)O-), R9arepresents a substituted or unsubstituted alkyl, substituted or unsubstituted of alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic radical. Even more preferably, R9is an ester (R9aC(O)O-), where R9arepresents a substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl or zamesheny or n is substituted pyridyl. In one of the embodiments, R9represents (R9aC(O)O-), where R9arepresents methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (a straight, branched or cyclic) or hexyl (a straight, branched or cyclic). In another embodiment R9represents (R9aC(O)O-), where R9arepresents a substituted methyl, substituted ethyl, substituted propyl (straight, branched or cyclic), substituted butyl (straight, branched or cyclic), substituted pentyl (a straight, branched or cyclic) or substituted hexyl (a straight, branched or cyclic), where the substituent(s) selected(s) from the group comprising heterocycle, alkoxy, alkenone, alkyloxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether group, but not phosphorus-containing group.

Examples of the substituents X3are substituted or unsubstituted With2-C8alkali, substituted or unsubstituted With2-C8alkenyl, substituted or unsubstituted from C2to C8alkinyl, substituted or unsubstituted heteroaromatic radicals containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Examples prefer is lnyh substituents X 3are substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutyl, furyl, thienyl and pyridyl.

Examples of the substituents X5is-SOH10, -COOH10or CONHX10where X10represents a substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic radical. Examples of preferred substituents X3is-SOH10, -COOH10or CONHX10where X10represents (i) substituted or unsubstituted C1-C8alkyl, such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (a straight, branched or cyclic) or hexyl (a straight, branched or cyclic); (ii) substituted or unsubstituted With2-C8alkenyl, such as substituted or unsubstituted ethynyl, propenyl (a straight, branched or cyclic), butenyl (a straight, branched or cyclic), pentenyl (a straight, branched or cyclic) or hexenyl (a straight, branched or cyclic); (iii) substituted or unsubstituted With2-C8quinil, such as substituted or unsubstituted ethinyl, PROPYNYL (straight or branched), butynyl (straight or branched), pentenyl (straight or branched) or hexyne is l (straight or branched); (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic radical, such as furyl, thienyl or pyridyl, where the substituent(s) selected(s) from the group comprising heterocycle, alkoxy, alkenone, alkyloxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether group, but not phosphorus-containing group.

In one of preferred embodiments of the taxanes according to this invention correspond to the following structural formula (2):

where

R7is an R7aCOO-;

R10represents hydroxy;

X3represents a substituted or unsubstituted alkyl, alkenyl, quinil or heterocycle;

X5is a-MOR10, -COOH10or CONHX10;

X10represents hydrocarbon, substituted hydrocarbon or heterocycle;

R7arepresents hydrocarbon, substituted hydrocarbon or heterocycle where these hydrocarbon or substituted hydrocarbon contain carbon atoms in the alpha and beta positions relative to the carbon, Deputy which is Ra;

Bz represents a benzoyl;

Ac represents acetyl.

For example, in this preferred embodiment, to what PR taxon corresponds to the structure (2), R7amay be substituted or unsubstituted ethyl, propylene or bootrom, more preferably substituted or unsubstituted ethyl or propylene, more preferably substituted or unsubstituted ethyl, and more preferably unsubstituted ethyl. If R7aselected from among the above, one of the incarnations of X3selected from substituted or unsubstituted Akilov, alkenyl, phenyl or heterocycle, more preferably substituted or unsubstituted alkenyl, phenyl or heterocycle, even more preferably substituted or unsubstituted phenyl or heterocycle and even more preferably heterocycle, such as furyl, thienyl or pyridyl. If R7aand X3selected from among the above, one of the incarnations of X5selected from SOKH10where X10represents a phenyl, alkyl or heterocycle, more preferably phenyl. Alternatively, if R7aand X3selected from among the above, one of the incarnations of X5selected from SOKH10where X10represents a phenyl, alkyl or heterocycle, more preferably phenyl, or X5means COOH10where X10represents alkyl, preferably tert-butyl. Therefore, among the more preferred embodiments presented taxanes corresponding to the structure 2 in which (i) X5before the hat is-COOH 10where X10represents tert-butyl, or X5is a-MOR10where X10represents phenyl, (ii) X3represents a substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocycle, more preferably substituted or unsubstituted isobutyl, phenyl, furyl, thienyl or pyridyl, more preferably unsubstituted isobutyl, furyl, thienyl or pyridyl, and (iii) R7arepresents unsubstituted ethyl or propyl, more preferably ethyl.

Among the preferred embodiments, therefore, presents taxanes corresponding to structure 1 or 2, where R7is an R7aCOO-, where R7arepresents ethyl. In a specific embodiment X3preferably represents cycloalkyl, isobutyl, phenyl, substituted phenyl, such as para-nitrophenyl, or heterocycle, more preferably heterocycle, even more preferably furyl, thienyl or pyridyl; and X5preferably represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines more before occhialino benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is a keto and R14represents hydrido. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is a keto and R14represents hydrido. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is a keto and R14represents hydroxy. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxy arbonyl; R2represents benzoyl, R9represents hydroxy and R14represents hydroxy. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9represents hydroxy and R14represents hydrido. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9represents acyloxy and R14represents hydroxy. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is allocs and R 14represents hydrido. In each of the alternatives specified embodiment, where Texan has the structure 1, each of R7and R10can have the beta stereochemical configuration, each of R7and R10may have an alpha stereochemical configuration, R7may have an alpha stereochemical configuration, whereas R10have the beta stereochemical configuration or R7can have the beta stereochemical configuration, whereas R10has alpha stereochemical configuration.

Also among preferred embodiments presented taxanes corresponding to structure 1 or 2, where R7is an R7aCOO-, where R7arepresents propyl. In this embodiment X3represents preferably cycloalkyl, isobutyl, phenyl, substituted phenyl, such as para-nitrophenyl, or heterocycle, more preferably heterocycle, even more preferably furyl, thienyl or pyridyl; and X5represents preferably benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl. In one alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferred is entrusted benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is a keto and R14represents hydrido. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is a keto and R14represents hydrido. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9is a keto and R14represents hydroxy. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxy arbonyl; R2represents benzoyl, R9represents hydroxy and R14represents hydroxy. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9represents hydroxy and R14represents hydrido. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9represents acyloxy and R14represents hydroxy. In another alternative of the specified embodiment X3represents heterocycle; X5represents benzoyl, alkoxycarbonyl or heterocyclicamines, more preferably benzoyl, tert-butoxycarbonyl or tert-aryloxyalkyl, even more preferably tert-butoxycarbonyl; R2represents benzoyl, R9represents acyloxy R 14represents hydrido. In each of the alternatives specified embodiment, where Texan has the structure 1, each of R7and R10can have the beta stereochemical configuration, each of R7and R10may have an alpha stereochemical configuration, R7may have an alpha stereochemical configuration, whereas R10have the beta stereochemical configuration or R7can have the beta stereochemical configuration, whereas R10has alpha stereochemical configuration.

Taxanes General formula 1 can be obtained by processing β-lactam-alcoholate having Aksenovo tetracyclic nucleus and a metal oxide substituent at position C-13, to obtain the compounds having β-amidoamines Deputy in position C-13 (as described more fully in Holton patent US 5466834), with the subsequent removal hydroxyamino group.

β-Lactam has the following structural formula (3):

where P2represents hydroxyamino group and X3and X5such as defined above; and anion has the structural formula (4):

where M is a metal or ammonium, R10represents hydroxyamino group, and R2, R9, R7and R10such as defined by the above.

The alcoholate (4) can be obtained from 10-deacetylbaccatin III (or its derivative) by selective protection of the C-10 hydroxyl group and then esterification of the C-7 hydroxyl group followed by treatment with Amida metal. In one of the embodiments of the present invention With(10) hydroxyl group of 10-deacetylbaccatin III selective silyl protecting group, using, for example, silylated or bisyllabic as cilleruelo agent. Preferred similitudine agents are three(hydrocarbon)silyl-cryptomelane and bis-three(hydrocarbon)-silentaffiliate (hydrocarbonate, substituted or unsubstituted alkyl or aryl), such as N,O-bis(trimethylsilyl)triptorelin, N,O-bis-(triethylsilyl)-triptorelin, N-methyl-N-triethylcitrate and N,O-bis(tert-butyldimethylsilyl)triptorelin. Similitude agents may be used either individually or in combination with a catalytic amount of base such as the base of an alkali metal. As catalysts in General preferred amides of alkali metals such as lithium amide, and, in particular, hexamethyldisilazide lithium. The solvent for the selective reaction of sililirovanie is preferably an ethereal solvent such as tetrahydrofuran. Alternatively, however, may be COI is used other solvents, such as a simple ester or dimethoxyethane. The temperature at which carry out selective similarobama in position With(10), are not restricted to narrow limits. Usually, however, it is carried out at 0°C or higher.

Selective esterification With(7) hydroxyl group protected status(10) taxane can be done using various conventional alleluya agents, including, but not limited to, derivatives of substituted and unsubstituted carboxylic acids, such as halogenoacetyl carboxylic acids, anhydrides, dicarbonate, isocyanates and halogenfrei. For example, C(7) hydroxyl group of 10-reserved 10-deacetylbaccatin III can be selectively alkylated by dibenzylammonium, dialliltiokarbamidom, 2,2,2-trichlorethylphosphate, benzylchloride or other conventional allerease agents. Usually acylation With(7) hydroxy-group With(10) protected taxane more efficiently and more selectively than With(7) acylation 7,10-dihydroxylation, such as 10-DAB; in other words, if C(10) hydroxyl group is protected, there is a significant difference in the reactivity of the remaining(7), (13) and(1) hydroxyl groups. The above acylation reaction can be carried out in the presence or in the absence of amine base.

Derivatives of 10-deacetylbaccatin III, with alternate Deputy is in position(2), With(9) and(14), and methods for their production are known from modern technology. Derivatives taxane with acyloxy substituents other than benzoyloxy With(2)can be obtained, for example, as described Holton and others in the US patent No. 5728725 or Kingston and others in the US patent No. 6002023. Taxanes having acyloxy or hydroxysultaine With(9) instead of keto, can be obtained, for example, as described Holton and others in the US patent No. 6011056 or Gunawardana, etc., in US patent No. 5352806. Taxanes having a beta hydroxysultaine With(14), can be obtained from natural 14-hydroxy-10-deacetylbaccatin III.

Methods of obtaining and separating the source β-lactams are generally well known. For example, β-lactam can be obtained as described Holton in US patent No. 5430160, and the resulting enantiomeric mixture β-lactams can be separated by using stereoselective hydrolysis using a lipase or an enzyme as described, for example, Patel in US patent No. 5879929, Patel in US patent No. 5567614, or liver homogenate, as described, for example, in patent application PCT No. 00/41204. In the preferred embodiment, in which β-lactam substituted fullam in C(4)-position β-lactam can be obtained, as shown in the following reaction scheme:

where Ac represents acetyl, NEt3represents triethylamine, CAN is ARYAMAN initrt and p-TsOH is a pair-toluensulfonate acid. The dissolution of bovine liver can be produced, for example, by combining a mixture of enantiomeric β-lactams suspension bovine liver (obtained, for example, by placing 20 g of frozen bovine liver in the mixer and then adding a buffer solution with a pH of 8 to obtain a total volume of 1 l).

The compounds of formula 1 according to this invention can be used to inhibit the growth of tumors in mammals, including humans, and is preferably introduced in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound according to this invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier. The media, also known in the technique as excipient, solvent, auxiliary connection, additive or diluent, is any compound that is pharmaceutically inert, gives a suitable consistency or form of the composition and does not reduce therapeutic efficacy of antitumor compounds. The media is a "pharmaceutically or pharmacologically acceptable"if it does not cause any adverse, allergic or other adverse reactions when administered to a mammal or a human as assigned.

Pharmaceutical compositions containing anticancer compounds by Dan the WMD to the invention, can be prepared in any convenient way. The corresponding ready preparative form depends on the choice of route of administration. The composition of the invention can be prepared for any route of administration, provided that the target tissue is available by the specified path. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g. intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or vnutrigrudne), local (nasal, intradermal, intraocular), intravesical, intrathecal, enteral, pulmonary, WinUtilities, intracavitary, vaginal, transurethral, intradermal, ear, intramammary, buccal, orthotopic, intratracheal, intranidus, percutaneous, endoscopic, through the mucosa, sublingual and intestinal introduction.

Pharmaceutically acceptable carriers for use in the compositions of this invention are well known to specialists in this field and is chosen based on a number of factors: the specific antitumor compound and its concentration, stability and intended bioavailability; the disease, disorder or condition under the action of the composition; the subject, its age, size and about the General condition and route of administration. Suitable carrier materials can be easily determined in the usual experts in this field (see, for example, J.G.Nairn, Remington''s Pharmaceutical Science (A.Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), s-1517, the contents of which are incorporated herein by reference).

The composition is preferably prepared in the form of tablets, dispersible powders, pills, capsules, gelatin pads, tires, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, tablets, pills, cakes or any other dosage forms that can be administered orally. Methods and compositions for the manufacture of oral dosage forms that can be used in this invention are described in the following references: 7 Modern Pharmaceutics, parts 9 and 10 (Banker &Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd edition (1976).

The composition of the invention for oral administration containing an effective antitumor amount of a compound according to the invention in a pharmaceutically acceptable carrier. Suitable carrier materials for solid dosage forms include sugars, starches and other substances, including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, Arabic gum, corn starch, potato grahm is l, saccharinate, sodium, magnesium carbonate, tragakant, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate and stearic acid. Further, these dosage forms can be uncoated or coated by known methods, for example, to delay disintegration and absorption.

Antitumor compounds of this invention also preferably introduced in the formulations for parenteral administration, for example, introduced into the preparations for injection by intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or nutrigrain ways. The composition according to the invention for parenteral administration containing an effective antitumor amount of the antitumor substance in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration are solutions, suspensions, dispersions, emulsions, or any other dosage forms that can be injected parenterally. Technology and composition for the manufacture of parenteral dosage forms are known from modern technology.

Suitable carriers used in the manufacturing of liquid dosage forms for oral or parenteral is doing, are nonaqueous, pharmaceutically acceptable polar solvents, such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and their mixtures, as well as water, salt solutions, solutions of dextrose (for example, DW5), solutions of electrolytes or any other water pharmaceutically acceptable liquid.

Suitable non-aqueous pharmaceutically acceptable polar solvents include, but or not limited to, alcohols (for example, α-formate, glycerol β-formate, glycerol, 1,3-butyleneglycol, aliphatic or aromatic alcohols containing 2-30 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, hexanol, octanol, amiloride, benzyl alcohol, glycerol, glycol, hexyleneglycol, tetrahydrofuranyl alcohol, lauric alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters and fatty alcohols, such as polyalkylene glycols (for example, polypropylenglycol, polyethylene glycol), sorbitol, sucrose, and cholesterol); amides (for example, dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethyl-ndimethylacetamide-amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidone); esters (for example, 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetates, such as monoacetate glycerol diacetate of glycerol, treats the tat glycerin, aliphatic or aromatic esters, such as ethylcaproic or octanoate, alkyllead, benzyl benzoate, benzoylacetate, dimethylsulfoxide (DMSO), esters of glycerol, such as mono-, di - or triglyceriderich or tartratami, ethylbenzoic, ethyl acetate, ethylcarbonate, ethyllactate, etiloleat, esters of fatty acids with sorbitan esters of fatty acids with PEG, glycerol monostearate, glycerol esters of (glycerides), such as mono-, di - or triglycerides, fatty acid esters, such as isopropylmyristate, esters of fatty acids with PEG, such as PEG and hydroxyoleic hydroxystearate PEG, N-methylpyrrolidinone, pluronic 60 (pluronic 60), polyester polyoxyethylenesorbitan with oleic acid, such as poly(oleate)2-4poly(ethoxylated)30-60sorbitol, monooleate poly (oxyethylene)15-20mono-12-hydroxystearate poly (oxyethylene)15-20and monoricinoleate poly (oxyethylene)15-20, esters of polyoxyethylene-sorbitan, such as monooleate polyoxyethylene-sorbitol, monopalmitate polyoxyethylene-sorbitol, monolaurate polyoxyethylene-sorbitol, monostearate polyoxyethylene-sorbitol and Polisorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, alkilalkoksimyetilfosfinov esters of fatty acids, such as polyoxyl 40 gidrirovannoe castor oil and polyoxyethylene castor oil (for example, Cremophor® EL or Cremophor solution® RH 40), sugars fatty acids (i.e., the condensation products of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose, xylulose, hexose, such as glucose, fructose, galactose, mannose and sorbose, TRIZ, tetrose, heptose and actoz), disaccharide (e.g. sucrose, maltose, lactose and trehalose) or oligosaccharide, or a mixture thereof with4-C22fatty acid(s) (e.g., saturated fatty acids such as Caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)) or steroid esters); alkalemia, arrowie or cyclic ethers containing 2 to 30 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimetridazole, monotropy ether of diethylene glycol); plicopurpura (ether glycol and tetrahydrofurfuryl alcohol); ketones containing 3-30 carbon atoms (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons containing 4-30 carbon atoms (for example, benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-DoD is Kahn, n-hexane, sulfolan, tetramethylarsonium, tetramethylsilane, toluene, dimethylsulfoxide (DMSO) or tetramethylsilane); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or waxy hydrocarbons, aromatic hydrocarbons, mixed aliphatic-aromatic hydrocarbons, and purified paraffin oil, vegetable oils such as linseed, Tung, safflower, soybean, castor, cottonseed, peanut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, peach and peanut butter and glycerides, such as mono-, di - or triglycerides, animal oils such as fish oil, pironet, spermaceti, fat, cod-liver, haliver, squalane, squalene and shark liver oil, oleic acid and polyoxyethylene castor oil); alkyl or aryl halides containing 1-30 carbon atoms and possibly more than one halogen substituent; methylene chloride; monoethanolamine; petroleum gas; trolamine; omega-3 polyunsaturated fatty acids (for example, alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid); polyglycidyl ester 12-hydroxystearate acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, GE is mania); polyoxyethyleneglycol; sodium laurate; sodium oleate; or monooleate sorbitan.

Other pharmaceutically acceptable solvents for use in the invention are well known to specialists in this area and is listed in The Chemotherapy Sourse Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipiets (American Pharmaceutical Association, Washington D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics (G.Banker and others, eds., 3 ed.) (Marcel Dekker, Inc. New York, new York, 1995), The Pharmacological Basis of Therapeutics (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms (H.Lieberman and others, eds.) (Marcel Dekker, Inc., New York, new York, 1980), Remington''s Pharmaceutical Sciences (A.Gennaro, ed., 19-ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19 (National Publishing, Philadelphia, PA, 2000), A.J.Spiegel and others, and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, volume 52, No. 10, pp. 917-927 (1963).

Preferred solvents are those, which are known to stabilize antineoplastic agents, such as oils rich in triglycerides, for example sunflower oil, soybean oil or a mixture thereof, and esters alkilalkoksimyetilfosfinov fatty acids, such as polyoxyl 40 gidrirovannoe castor oil and polyoxyethylene castor oil (for example, a solution of Cremophor® EL or Cremophor solution® RH 40). Commercially available triglycerides are emulsified soybean oil Intralipid® (Kabi-Pharmacia Inc., Stockholm, Sweden), emulsion Nutralipid® (McGaw, Irvine, CA), 20%emulsion Lyposyn® II (20%fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbot Laboratories, Chicago, Illinois), 2%emulsion (Liposyn® III (2%fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml solution; Abbot Laboratories, Chicago, Illinois), natural or synthetic derivatives, glycerol, containing docosahexaenoyl group level between 25% and 100% by weight calculated on the total content of fatty acids (Dhasco® (from Martek Biosciences Corp., Columbia, MD), DHA Maguro® (Daito Enterprises, Los Angeles, CA), Soyacalr® and Travemulsion®. Ethanol is the preferred solvent for use in dissolving antitumor substances with obtaining solutions, emulsions and the like.

In the composition of the invention may include additional minor components for various purposes are well known in the pharmaceutical industry. These components are interesting from the point of view of the majority of attached properties, which improve the retention of antitumor substances in the introduction, increase stability, pH control, facilitate the introduction of antitumor substances in the finished pharmaceutical preparative Faure is s and such. Preferably each of these components separately is present in amount of less than 15 mass % of the total composition, more preferably less than 5 mass % and most preferably less than 0.5 mass % of the whole composition. Some components, such as fillers and diluents, can be up to 90 wt.% on the whole composition, as is well known ready for preparative forms. Such additives are agents that protect against freezing to prevent resultant deposition rates taxane, surfactant, wetting or emulsifying agents (e.g., lethicin, Polysorbate-80, Tween® 80, pluronic (pluronic) 60, polyoxyethylenated), preservatives (for example, ethyl-para-hydroxybenzoate), antimicrobial preservatives (e.g. benzyl alcohol, phenol, meta-cresol, chlorobutanol, sorbic acid, thimerosal (thimerosal) and paraben), agents to maintain pH or buferiruemoi agents (e.g., acids, bases, sodium acetate monolaurate sorbitan), agents to maintain osmoticnosti (for example, glycerin), thickeners (for example, aluminum monostearate, stereonova acid, cetyl alcohol, stearyl alcohol, guar gum, methylcellulose, hydroxypropylcellulose, tristearin, esters of cetyl wax, polyethylene glycol), podrachivala, dyes, liquid AIDS, nelet is Chiyo silicones (for example, cyclomethicone), clay (e.g. bentonite), adhesives, increasing the volume of agents, flavors, sweeteners, adsorbents, fillers (for example, sugars such as lactose, saccharose, mannitol or sorbitol, cellulose or calcium phosphate), diluents (e.g., water, saline solution or an electrolyte solution), binders (for example, starches such as corn starch, wheat starch, rice starch or potato starch, gelatin, resin tragant, methylcellulose, hypromellose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, Arabian gum), dezintegriruetsja agents (for example, starches such as corn starch, wheat starch, rice starch, potato starch or carboximetilkrahmal, transversely crosslinked polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium alginate, crosscarmellose sodium or crosspovidone), lubricants (for example, silica, talc, stearic acid or its salts, such as magnesium stearate, or polyethylene glycol), coating agents (for example, concentrated solutions of sugar, including gum Arabic, talc, polyvinylpyrrolidone, carboranyl, polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols and thiophenol).

In a preference for the equipment of the embodiment of the pharmaceutical composition of the invention contains at least one non-aqueous, pharmaceutically acceptable solvent and antitumor substance with a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being tied to a specific theory, argue that the solubility in alcohol antitumor substances can be directly attributed to its effectiveness. Antitumor substance may also be able to crystallization from a solution. In other words, the crystalline antitumor substance, such as substance 1393, can be dissolved in a solvent to obtain a solution and then recrystallized by evaporation of the solvent without the formation of amorphous antitumor substances. It is preferable that the antitumor substance had an ID50 value (i.e. the concentration of the drug giving 50%inhibition of the formation of a tumor, in at least 4, 5, 6, 7, 8, 9 or 10 times less than paclitaxel, as measured according to the Protocol described in the working examples.

The introduction of the dosage forms listed ways can be continuous or intermittent, depending, for example, on the physiological state of the patient, whether the purpose of the introduction of therapeutic or prophylactic, and other factors known to practitioners.

Dose and mode of administration of the pharmaceutical compositions of the image is to be placed can be easily identified as commonly used in the treatment of cancer. It is clear that doses of anticancer substances depend on age, sex, health and weight of the recipient, kind of competitive treatment, frequency of treatment and nature of the expected effect. For any method of introducing the actual quantity delivered antitumor substances, as well as the dosage required to achieve the described here: preemptive effect depends in particular on factors such as biocompatibility antitumor substances, violations that heal, the desired therapeutic dose, and other factors that are obvious to experts in this field. Dose entered the animal, particularly a human, in the context of this invention should be sufficient to achieve the desired therapeutic response in the animal over a reasonable period of time. Preferably an effective amount of an antitumor substance, administered orally or by other means, is any number that lead to the desired therapeutic response with the introduction of the specified path. Preferably the composition for oral administration is prepared so that a single dose of one or more oral ready preparative forms contain at least 20 mg antitumor substances on m2the surface area of the patient's body or at measures the 50, 100, 150, 200, 300, 400 or 500 mg antitumor substances on m2the surface area of the patient's body, where the average surface area of the body is equal to 1.8 m2. Preferably the unit dosage composition for oral administration contains from about 20 to about 600 mg of antitumor substances on m2the surface area of the patient's body, more preferably from about 25 to about 400 mg/m2even more preferably from about 40 to about 300 mg/m2and even more preferably from about 50 to about 200 mg/m2. Preferably the composition for parenteral administration is prepared in such a way that a single dose contains at least 20 mg antitumor substances on m2the surface area of the patient's body or at least 40, 50, 100, 150, 200, 300, 400 or 500 mg antitumor substances on m2the surface area of the patient's body. Preferably a single dose in one or more parenteral preparations contain from about 20 to about 500 mg of antitumor substances on m2the surface area of the body connection, more preferably from about 40 to about 400 mg/m2and even more preferably from about 60 to about 350 mg/m2. However, the dosage may vary depending on the dosage regimen which can be adjusted is, as needed to achieve the desired therapeutic effect. It should be noted that the limits of effective doses reported here do not propose to limit the invention and represent preferred dose limits. The most preferred dose should be assigned to the individual subject, as it understands and defines an ordinary person skilled in the art without ilichevo experimentation.

The concentration of the antitumor substance in the liquid pharmaceutical composition is preferably equal to between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg / ml, even more preferably between about 0.5 mg and about 5 mg / ml and most preferably between about 1.5 mg and about 4 mg per ml of Relatively low concentration is usually preferred because of the antitumor substance is most soluble in solutions with low concentrations. The concentration of anticancer substances in solid pharmaceutical composition for oral administration is preferably between about 5 masuimi % and about 50 mass%, based on the total weight of the composition, more preferably between about 8 mass % and about 40 mass%, and most preferably between about 10 mass % and about 30 mass is %.

In one of the incarnations solutions for oral administration are prepared by dissolving antitumor agents in any pharmaceutically acceptable solvent capable of dissolving substances (for example, ethanol or methylene chloride) to obtain the solution. An appropriate volume of media that is solution such as a solution of Cremophor® EL is added to the solution under stirring to obtain pharmaceutically acceptable solution for oral administration to a patient. If desired, these solutions can be formed with the support of minimum or free of ethanol, which is known to be state of the art, cause adverse physiological effect when injected into certain concentrations in ready oral formulation.

In another embodiment of powders or tablets for oral administration are prepared by dissolving antitumor agents in any pharmaceutically acceptable solvent capable of dissolving substances (e.g., ethanol or methylene chloride) to obtain the solution. The solvent may be capable of evaporation, if the solution is dried in vacuum. Before drying the solution may be subject to an additional media, such as a solution of Cremophor® EL. The resulting solution was dried in vacuum to obtain a glassy mass. Vitreous m is cel then mixed with a binder to form a powder. The powder can be mixed with filler or suitable tabletiruemye agents and processed to form tablets for oral administration to a patient. The powder can also be added to any liquid medium, as described above, to obtain a solution, emulsion, suspension or the like for oral administration.

Emulsion for parenteral administration can be obtained by dissolving antitumor agents in any pharmaceutically acceptable solvent capable of dissolving substances (e.g., ethanol or methylene chloride) to obtain the solution. To the solution under stirring add the appropriate volume of media, which is an emulsion, such as emulsion Liposyn® Liposyn II or® III, getting a pharmaceutically acceptable emulsions for parenteral administration to a patient. If desired, such emulsions can be prepared with the content of the minimum amount or free of ethanol or a solution of Cremophor®known state of the art, cause adverse physiological effect when introducing certain concentrations in parenteral ready formulation.

Solutions for parenteral administration can be obtained by dissolving antitumor agents in any pharmaceutically acceptable solvent capable of RA is the creation of a substance (for example, in ethanol or methylene chloride) to obtain the solution. To the solution under stirring add the appropriate volume of media, which is a solution such as a solution of Cremophor®pick pharmaceutically acceptable solution for parenteral administration to a patient. If desired, these solutions can be prepared with the content of the minimum amount or free of ethanol or a solution of Cremophor®known state of the art, cause adverse physiological effect when introducing certain concentrations in parenteral ready formulation.

If desired, the emulsions or solutions for oral or parenteral administration can be packaged in IV vials, vials or other suitable containers in concentrated form and razbavlennye any pharmaceutically acceptable liquid, such as saline, to obtain the acceptable concentration taxane before use, as it is known at the present level of technology.

Definition

The terms "hydrocarbon" and "hydrocarbon", as used here, describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These parts are alkyl, alkeline, alkyline and aryl radicals. These radicals include alkyl alkeneamine, alkyline and aryl radicals, substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenyl and alkylaryl. Unless otherwise specified, these radicals preferably contain from 1 to 20 carbon atoms.

"Substituted hydratability" radicals described herein are gidrolabilna radicals, substituted by at least one different from the carbon atom, including radicals in which the carbon atom in the chain is substituted by a heteroatom, such as nitrogen, oxygen, silicon, phosphorus, boron, sulfur, or halogen. These substituents include halogen, heterocycle, alkoxy, alkenone, alkyloxy, aryloxy-, hydroxy, substituted hydroxy, ketogroup, acyl, acyloxy-, nitro-, amino-, amido-, nitro-, ceanography, tirinya, Catalunya, acetylene, ester ether group.

The term "heteroatom" represents the atoms different from carbon and hydrogen.

"Heterosomata methyl" radicals mean here a methyl group in which the carbon atom is covalently bonded with at least one heteroatom and may, with hydrogen; the heteroatom is, for example, nitrogen atom, oxygen, silicon, phosphorus, boron, sulfur, or halogen. The heteroatom can be, in turn, replaced by other atoms to form heterocyclic radical, alkoxy, alkenoic and-, alkyloxy, aryloxy-, hydroxy, substituted hydroxy, hydroxy-, acyloxy-, nitro-, amino-, aminogroup, tylnej, katalinich acetylenic, ester or ether radicals.

"Heterosomata acetate radicals"described here are the acetate groups in which the carbon of a methyl group is covalently bonded with at least one heteroatom and may, with hydrogen; the heteroatom is, for example, nitrogen atom, oxygen, silicon, phosphorus, boron, sulfur, or halogen. The heteroatom can be, in turn, replaced by other atoms to form heterocyclic radical, alkoxy, alkenone, alkyloxy, aryloxy-, hydroxy, substituted hydroxy, hydroxy-, acyloxy-, nitro-, amino-, aminogroup, tylnej, katalinich, acetylenic, ester or ether radicals.

Unless otherwise specified herein described alkyl groups are preferably lower alkilani containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They can be linear or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like.

Unless otherwise specified herein described alkeneamine groups are preferably lower alkenylamine containing from two to eight carbon atoms in the principal chain and up to 20 atoms angle of the ode. They can be linear or branched and include ethynyl, propenyl, Isopropenyl, butenyl, Isobutanol, hexanol and the like.

Unless otherwise specified herein described alkyline groups are preferably lower akinyemi containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They can be straight or branched and include ethinyl, PROPYNYL, butynyl, Isobutanol, hexenyl and the like.

The terms "aryl" and "ar"as used here individually or as part of another group denote optionally substituted homozygotes aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbon cycle, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are more preferred Allami.

The terms "halogen" or "halogen", as used here, either individually or as part of another group refers to chlorine, bromine, fluorine and iodine.

The terms "heterocycle" or "heterocyclic", as used here, either individually or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic group containing ENISA least one heteroatom in at least one cycle, and preferably 5 or 6 atoms in each cycle. The heterocyclic group preferably contains 1 or 2 oxygen atoms, 1 or 2 sulfur atom and/or 1 to 4 nitrogen atoms in the cycle and may be associated with the remainder of the molecule through a carbon or heteroatom. Exemplary heterocycles are heteroaromatic compounds, such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, chinoline or ethenolysis and the like. Exemplary substituents are one or more of the following groups: hydrocarbon, substituted hydrocarbon, keto, hydroxy, substituted hydroxy-group, acyl, acyloxy-, alkoxy-, alkenone, alkyloxy, alloctype, halogen, amido, amino -, nitro-, ceanography, tirinya, Catalunya, acetylene, ester and ether groups.

The term "heteroaromatic"as used here individually or as part of another group, represents an optionally substituted aromatic group containing at least one heteroatom in at least one cycle, and preferably 5 or 6 atoms in each cycle. Heteroaromatic group preferably contains 1 or 2 oxygen atoms, 1 or 2 sulfur atom and/or 1 to 4 nitrogen atoms in the cycle and may be associated with the remainder of the molecule through a carbon or heteroatom. Approximate heteroaromatic groups are furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, chinoline or from indolinyl and the like. Exemplary substituents are one or more of the following groups: hydrocarbon, substituted hydrocarbon, keto, hydroxy, substituted hydroxy-group, acyl, acyloxy-, alkoxy-, alkenone, alkyloxy, alloctype, halogen, amido, amino -, nitro-, ceanography, tirinya, Catalunya, acetylene, ester and ether groups.

The term "acyl", as used here, either individually or as part of another group, represents a radical formed by removal of the hydroxy-group of the group-COOH of an organic carboxylic acid, e.g., RC(O)-, where R is an R1, R1O-, R1R2N or R1S-, R1represents hydrocarbon, heterothermy hydrocarbon or heterocycle, and R2represents hydrogen, hydrocarbon or substituted hydrocarbon.

The term "acyloxy", as used here, either individually or as part of another group, represents an acyl group as described above connected through an oxygen linkage (-O-), for example, RC(O)O-, where R is such as defined in connection with the term "acyl".

Unless otherwise specified, described here alkoxycarbonylmethyl contain lower hydrocarbon radical or substituted hydrocarbon radical or substituted hydrocarbon radical.

Unless otherwise specified, described here carbamoyloximes is the tsya derived carbamino acid, in which one or both hydrogen from an amine substituted hydrocarbon, substituted hydrocarbon or heterocyclic radical.

The term "hidroxizina group", as used here, means a group capable of protecting a free hydroxyl group ("protected hydroxyl"), which after the reaction, which was intended to protect, can be removed without damaging the remaining molecules. Options protective groups for hydroxyl group and the synthesis of them can be found in "Protective Groups in Organic Syntheses", T.W.Greene, John Wiley and Sons, 1981, or Fieser &Fieser. Exemplary protective groups for hydroxyl include methoxymethyl, 1-ethoxyethyl, benzoyloxymethyl, (beta-trimethylsilyloxy)methyl, tetrahydropyranyl, 2,2,2-trichlorocyanuric, tert-butyl(diphenyl)silyl, trialkylsilyl, trichloromethylcarbnol and 2,2,2-trichloroacetyl.

As used here, "Ac" represents acetyl; "Bz represents a benzoyl; "Et" represents ethyl; "Me" represents methyl; Ph represents phenyl; and "Pr" represents a propyl; "Bu" represents a butyl; "Am" is an amyl; "cpro" is cyclopropyl; "iPr" represents isopropyl; "tBu" and "t-Bu" means tert-butyl; R is a lower alkyl, unless otherwise specified; "Py" represents pyridine or pyridyl; "TES" is treat lilil; "TMS" represents trimethylsilyl; "LAH" is alumoweld lithium; "10-DAB" is a 10-deacetylbaccatin III; "protective group for the amino group" represents, but is not limited to, carbamates, for example 2,2,2-trichlorethylene or tert-BUTYLCARBAMATE; "protected hydroxy-group is a PR, where P is hydroxyamino group; "PhCO" is phenylcarbinol; "tBuOCO" and "Boc" means tert-butoxycarbonyl; "tAmOCO" represents tert-aryloxyalkyl; "2-FuCO" is a 2-fullcarbon; "2-ThCO" is a 2-thienylboronic; "2-PyCO" is a 2-pyridylcarbonyl; "3-PyCO" is a 3-pyridylcarbonyl; "4-PyCO" is a 4-pyridylcarbonyl; "C4H7WITH" is butylcarbamoyl; tC3H5WITH" is a TRANS-propenylboronic; "EtOCO" is a etoxycarbonyl; "ibueCO" is isobutylketone; "iBuCO" is isobutylketone; "iBuOCO" is isobutoxide; "iPrOCO" is isopropoxycarbonyl; "nPrOCO" represents n-propylenecarbonate; "nPrCO" means n-propylboronic; "ibue" is Isobutanol; "THF" is tetrahydrofuran (THF); "DMAP" is a 4-dimethylaminopyridine (DMAP); "LHMDS" is hexametric Sasanid lithium.

The following examples illustrate the invention.

Example 1

10-Triethylsilyl-10-deacetylbaccatin III.

To a solution of 1.0 g (of 1.84 mmol) 10-deacetylbaccatin III in 50 ml of THF at -10°C in an atmosphere of nitrogen was added 0,857 ml (was 2.76 mmol of 1.5 mol equiv.) N,O-(bis)-TES-trifurcated for 3 min. Then added 0,062 ml, 0.89 M solution in THF bis(trimethylsilyl)amide lithium (by 0.055 mmol, 0,03 mol. EQ.). After 10 min was added 0,038 ml (0,92 mmol to 0.5 mol. EQ.) methanol and after 5 min was further added 4 ml (by 0.055 mmol, 0,03 mol. EQ.) of acetic acid. The solution was diluted with 300 ml ethyl acetate and washed twice with 100 ml saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with 100 ml of ethyl acetate and the combined organic layers were washed with saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure. To the residue was added 100 ml of hexane and the solid product (1.23 g, 101%) was collected by filtrowanie. Recrystallization of the solid substance is dissolved in boiling ethyl acetate (20 ml 17 ml/g) and cooling to room temperature gave 1,132 g (94%) of a white solid product with TPL 242°; [α]D25- 60,4 (0.7, CHCl3);1H NMR (COCl3, 400 MHz) δ (ppm): 8,10 (2H, d, Jm=7.5 Hz, Bz-ortho), 7,60 (1H, t, Jm=7.5 Hz, Bz-pair), 7,47 (2H, t, Jo=7.5 Hz, Bz-meta), 5,64 (1H, d, J3=6,9 Hz, H2)of 5.26 (1H,s, N10), equal to 4.97 (1H, DD, J6β=2,2 Hz, J6α=9.9 Hz, H5), is 4.85 (1H, DD, J14α=8,9 Hz, J14β=8,9 Hz, H13), 4,30 (1H, d, J20β=8,5 Hz, H20α), to 4.23 (1H, DDD, J7OH=4.5 Hz, J6α=6,6 Hz, J6β=to 11.0 Hz, H7), is 4.15 (1H, d, J20α=8,5 HZ, H20β), of 4.00 (1H, d, J2=6.9 Hz, H3), 2,58 (1H, DDD, J7=6,6 Hz, J5=9.9 Hz, J6β=14,5 Hz, h6α), 2,28 was 2.25 (5H, m, 4Ac, H14α, H14β), 2,02 (3H, s, me), of 1.97 (1H, d, J7=4.5 Hz, NON), of 1.78 (1H, DDD, J7=11,0 Hz, J5=2,2 Hz, J6α=14,5 Hz, h6β), by 1.68 (3H, s, me), and 1.56 (1H, s, ON), 1,32 (1H, d, J13=8,8 Hz, ON), OF 1.18 (3H, s, me), 1,06 (3H, s, me), and 0.98 (N, t, JCH2(TES)=7,3 Hz, CH3(TES)), 0,65 (6N, DQC., JCH3(TES)=7,3 Hz, CH2(TES)).

10-Triethylsilyl-10-deacetyl-7-propionibacter III.

To a solution of 1.0 g (1,517 mmol) 10-triethylsilyl-10-deacetylbaccatin III and 37,0 mg (0,303 mmol) DMAP in 20 ml of dichloromethane at room temperature under nitrogen atmosphere was added 0,920 ml (11,381 mmol) of pyridine and 0,329 ml (3,794 mmol, 2,5 mol. EQ.) propionitrile in the specified order. The mixture was stirred at room temperature for 6 h, diluted with 350 ml of ethyl acetate and was extracted with 50 ml of 10%aqueous copper sulfate solution. The organic layer was washed with 50 ml saturated aqueous sodium bicarbonate solution, 50 ml of saturated salt solution, dried over sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in 75 ml of ethyl acetate, was added 100 mg of Norit A, the mixture was filtered through celite and concentrated PR is the reduced pressure, getting 1.13 g of material. Recrystallization from ethyl acetate/hexane (dissolved in 6.5 ml of boiling ethyl acetate, then was added 24 ml of hexane, was left to cool to room temperature and left to stand for 17 h) gave 787 mg (72,5%) of white crystalline solid. A second recrystallization (about 340 mg of material was dissolved in 2 ml of boiling ethyl acetate, then was added 10 ml of hexane, was left to cool to room temperature and left to stand for 17 h) give 181 mg (16.7%) of white crystalline solid. The total yield after recrystallization was of 89.2%, TPL 129°; [α]D25- 47,9 (from 1.0, CHCl3); NMR1H (COCl3, 300 MHz) δ (ppm): 8,10 (2H, d, Jm=7,4 Hz, Bz-ortho), 7,60 (1H, t, Jm=7,4 Hz, Bz-pair)of 7.48 (2H, DD, Jo=7,4 Hz, Jp=7,4 Hz, Bz-meta), 5,64 (1H, d, J3=7.4 Hz, H2), vs. 5.47 (1H, DD, J6α=7,4 Hz, J6β=the 10.1 Hz, H7), 5,28 (1H, s, H10), 4,94 (1H, d, J6α=9.4 Hz, H5), 4.80 to the 4.90 (1H, m, H13), or 4.31 (1H, d, J20β=8,1 Hz, H20α), to 4.16 (1H, d, J20α=8,l Hz, H20β), 4,06 (1H, d, J2=7.4 Hz, N3), to 2.55 (1H, DDD, J7=7,4 Hz, J5=9.4 Hz, J6β=14,8 HZ, h6α), of 2.28 (3H, 4Ac), 2,23 of-2.32 (4H, m, SN, H14α, H14β), 2,07 (3H, s, me), 2,02 (1H, d, J13=4,7 Hz, ON), 1,76-TO 1.87 (4H, m, 5 N6β, me), 1,60 (1H, s, ON), OF 1.17 (3H, s, me), of 1.09 (3H, t, J7CH2=7,4 Hz, SN3), was 1.04 (3H, s, me), 0,96 (N, t, JCH2(TES)=8.0 Hz, CH3(TES)), 0,52-0,62 (6N, m, CH2(TES)).

2'-O-MOR-3'-Desferal-3'-(2-furyl)-10-triethylsilyl-7-propionyl cater.

To a solution of 493 mg (0,690 mmol) 10-triethylsilyl-10-deacetyl-7-propionibacteria III in 4 ml of anhydrous THF in a nitrogen atmosphere at -45°With probalaly to 0.72 ml (to 0.72 mmol) of 1M solution of LiHMDS in THF. After 0.5 h was added a solution of 263 mg (0,814 mmol) of beta-lactam (pervertere dried as described above) in 2 ml of anhydrous THF. The mixture was heated to 0°and after 2 h was added 0.5 ml of saturated aqueous sodium bicarbonate solution. The mixture was diluted with 50 ml ethyl acetate and washed twice with 5 ml of saturated salt solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure, getting 742 mg (104%) of light yellow solid. The solid is recrystallized by dissolving it in 12 ml of a mixture 1:5 ethyl acetate and hexane boiling under reflux and then cooled to room temperature, receiving 627 mg (88%) of white crystalline substance. The process of evaporation of the mother liquor gave 96 mg of material which was recrystallized as described above from 2 ml of a mixture 1:5 acetylacetone and hexane, obtaining additional 46 mg (6%) of white crystalline solid. The total yield after recrystallization was 94%. The process of evaporation of the mother liquor gave 46 mg of material which was purified column chromatography on silica gel, giving an additional 20 mg (3%) of product with TPL 207-209°; [α]D/sub>  25- 30,0 (with 5.0, methanol);1H NMR (COCl3, 400 MHz) δ (ppm): 8,09-8,11 (m, 2H), 7,58-to 7.61 (m, 1H), 7,47-7,51 (m, 2H), 7,39 (d, J=0.8 Hz, 1H), 6,34 (DD, J=3.2, and 1.6 Hz, 1H), of 6.26 (d, J=3.2 Hz), 6,14 (DD, J=8,8, 8,8 Hz, 1H), 5,71 (d, J=6,8 Hz, 1H), vs. 5.47 (DD, J=10,0, 7.2 Hz, 1H), and 5.30 and 5.36 (m, 2H), 5,28 (s, 1H), 4.95 points (d, J=7,6 Hz, 1H), amounts to 4.76 (s, 1H), 4,33 (d, J=8.0 Hz, 1H), 4,19 (d, J=8,4 Hz, 1H), a 4.03 (d, J=6,8 Hz, 1H), and 2.83 (s, 3H), by 2.55 (DDD, J=17.2 in and 9.6 and 7.6, 1H), 2,50 (s, 3H), 2,20-2,40 (m, 2H), 2,28 (sq, J=7,6 Hz, 2H), 1,95 (s, 3H), of 1.84 (DDD, J=14,8, 10,8, 2 Hz), of 1.80 (s, 3H), 1,67 (s, 1H), 1.39 in (C, N), 1,32 (s, 3H), 1,21 (s, 3H), of 1.20 (s, 3H), 1,74 (s, 3H), of 1.09 (t, J=7,6 Hz, 3H), 0,93 is 0.99 (m, N), 0,50-0,65 (m, 6N).

3'-Destiny-3'-(2-furyl)-7-propionibacter (1393)

To a solution of 206 mg (0,199 mmol) of 2'-O-MOR-3'-destiny-3'-(2-furyl)-10-triethylsilyl-7-propionylcarnitine in 1.7 ml of pyridine and 5.4 ml of acetonitrile at 0°added to 0.80 ml (2.0 mmol) of an aqueous solution containing 49% HF. The mixture was heated to room temperature for 14 h and then diluted with 20 ml ethyl acetate and washed three times with 2 ml of saturated aqueous sodium bicarbonate and then 8 ml of a saturated salt solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure, getting 170 mg (100%) of a white solid. The crude product was led with 2 ml of solvent (CH2Cl2:hexane=1:1,7), getting 155 mg (90,5%) of white crystals. Concentration of the mother liquor under reduced pressure gave 15 mg of material, kotoryjrazrabatyvaet using 0.2 ml mixture of 1:1.7 methylene chloride and hexane, receiving an additional 11 mg (7,5%) of white crystals. The total yield from the recrystallization was 98%, TPL 150-152°; [α]D25- 27,0 (with 5.0, methanol; analysis: calculated for C44H55NO16·0.5 H2O: C, 61,18; N, 6.48 IN. Found: C, 61,40; N. of 6.65.1H NMR (CDCCl3, 500 MHz) d (ppm): 8,11 (d, J=7.5 Hz, 2H), to 7.61 (DD, J=7,5, 7.5 Hz, 1H), 7,50 (DD, J=8,0, 7.5 Hz, 2H), 7,41 (d, J=1.0 Hz, 1H), 6,38 (dd, J=3,0, 2.0 Hz, 1H), 6,33 (d, J=3.5 Hz), to 6.22 (DD, J=a 9.5, 9.5 Hz, 1H), 5,69 (d, J=7,0 Hz, 1 H), 5,49 (DD, J=11,0, 7.5 Hz, 1 H), was 5.35 (d, J=9.5 Hz, 1 H), 5,33 (d, J=1.5 Hz, 1H), 5.25-inch (d, J=9.5 Hz, 1H), 4,94 (d, J=8.5 Hz, 1H), 4,71 (DD, J=5,5, 2.0 Hz, 1H), 4,33 (d, J=8.5 Hz, 1H), is 4.21 (d, J=8.5 Hz, 1H), 4,01 (d, J=6,5 Hz, 1H), 3,97 (d, J=1.5 Hz, 1H), 3,30 (d, J=5.5 Hz, 1H), 2,54 (DDD, J=16.5, and a 9.5, 7,0, 1H), 2,41 (s, 3H), 2,37 (DD, J=to 15.0, 9.0 Hz, 1H), 2,30 (DD, J=17,5, 9.5 Hz, 1H), 2,25 (sq, J=7.5 Hz, 2H), 1,96 (s, 3H), of 1.93 (DDD, J=14.5 m, 11,0, 2,5 Hz), of 1.85(s, 3H), 1,64 (s, 1H), 1,36 (s, N), of 1.23 (s, 3H), 1,10 (t, J=7.5 Hz, 3H).

Example 2

The procedure of example 1 was repeated, but other suitable protected β-lactams have been replaced by β-lactam of example 1 to obtain a series of compounds having the structural formula (13) and the combination of the substituents listed in the following table 1.

Table 1
ConnectionX5X3R7
1351tBuOCO-ibueEtCOO-
1364tBuOCO-2-pyridylEtCOO-
1372tBuOCO-3-pyridylEtCOO-
1386tBuOCO-4-pyridylEtCOO-
1393tBuOCO-2-furylEtCOO-
1401tBuOCO-3-furylEtCOO-
1418tBuOCO-2-thienylEtCOO-
1424tBuOCO-3-thienylEtCOO-
1434tBuOCO-isopropylEtCOO-
1447tBuOCO-cyclobutylEtCOO-
1458tBuOCO-phenylEtCOO-
30692-FuCO-2-thienylEtCOO-
3082iPrOCO-2-thienylEtCOO-
3171nPrCO-2-furylEtCOO-
3196iBuOCO-2-furylEtCOO-
3232iBuOCO-2-thienylEtCOO-
3327nPrCO-2-thienylEtCOO-
3388PhCO-3-tie the Il EtCOO-
3444iPrOCO-2-furylEtCOO-
34792-ThCO-2-thienylEtCOO-
3555C4H7CO-2-thienylEtCOO-
3560Tc3H5CO-2-thienylEtCOO-
3611EtOCO-2-furylEtCOO-
36292-FuCO-2-furylEtCOO-
36322-ThCO-2-furylEtCOO-
3708tC3HCO-2-furylEtCOO-
3713C4H7CO-2-furylEtCOO-
4017PhCO-2-furylEtCOO-
4044EtOCO-2-thienylEtCOO-
41063-FuCO-2-thienylEtCOO-
4135IprOCO-2-thienylPrCOO-
4175PhCO-2-thienylPrCOO-
42192-FuCO-2-thienylPrCOO-
4256tBuOCO-2-Tien the l PrCOO-
4283ibueCO-2-thienylPrCOO-
4290ibuOCO-2-thienylPrCOO-
4312ibueCO-2-thienylEtCOO-
43882-ThCO-2-thienylPrCOO-
4394tBuOCO-3-furylPrCOO-
4406tBuOCO-IsobutanolPrCOO-
4446tBuOCO-3-thienylPrCOO-
4499tBuOCO-2-furylPrCOO-
4544iBuOCO-3-thienylEtCOO-
4600iBuOCO-3-thienylPrCOO-
4616iBuOCO-2-furylPrCOO-
4737tC3H5CO-2-furylPrCOO-
4757tC3H5WITH-2-thienylPrCOO-
6171ibueOCO-2-furylEtCOO-
6131ibueOCO-2-furyliBuCOO-
5989ibueOCO-2-furyl iPrCOO-
6141ibueOCO-2-furylnBuCOO-
6181ibueOCO-2-furylnPrCOO-
6040ibuOCO-2-furylibueCOO-
6121iPrCO-2-furyliPrCOO-
6424tAmOCO-2-furylEtCOO-
6212tAmOCO-2-furylEtCOO-
6282tAmOCO-2-furyliBuCOO-
6252tAmOCO-2-furyliPrCOO-
6343tAmOCO-2-furylnBuCOO-
6272tAmOCO-2-furylnPrCOO-
6202tC3H5WITH-2-furyliPrCOO-
44542-ThCO-2-thienylnPrCOO-
4414PhCO-2-thienylnPrCOO-
6333tBuOCO-2-thienyliPrCOO-
6686tBuOCO-2-thienyltC3H5Soo-
6363tBuOCO-2 tiasoEtCOO-
4787iBuOCO-3-furylEtCOO-
4828iBuOCO-3-furylnPrCOO-
4898tC3H5WITH-3-furylEtCOO-
4939 milestC3H5WITH-3-furylnPrCOO-
5020tC3H5WITH-3-thienylEtCOO-
5030tC3H5WITH-3-thienylnPrCOO-
5191iBuOCO-cproEtCOO-
5202iBuOCO-cpronPrCOO-
5070tBuOCO-cproEtCOO-
5080tBuOCO-cpronPrCOO-
5121iBuOCO-ibueEtCOO-
5131iBuOCO-ibuenPrCOO-

Example 3

Following the procedure described in example 1 and elsewhere in the description, can be obtained specific taxanes having structural formula 14, where: R7as defined earlier, including R7is an R7aCOO - and R7arepresents (i) substituted or unsubstituted C2-C8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl or hexyl; (ii) substituted or unsubstituted C2-C8alkenyl (a straight, branched or cyclic), such as ethynyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2-C8quinil (straight or branched), tackle as ethinyl, PROPYNYL, butynyl, pentenyl or hexenyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heterocycle, such as furyl, thienyl or pyridyl. Substituents can be hydrocarbon or any containing heteroatom substituents selected from the group consisting of heterocycle, alkoxy, alkenone, alkyloxy, aryloxy-, hydroxy, protected hydroxy, keto -, acyloxy-, nitro-, amino-, aminogroup, Tilney, Catalinas, acetaldol, ester and simple ester groups, but not phosphorus-containing radicals (see table 2).

td align="left"> 2-PyCO- 4-pyridyltd align="left"> EtCOO-
Table 2
X5X3R7
tBuOCO-2-furylRaCOO-
tBuOCO-3-furylRaCOO-
tBuOCO-2-thienylRaCOO-
tBuOCO- 3-thienylRaCOO-
tBuOCO-2-pyridylRaCOO-
tBuOCO-3-pyridylRaCOO-
tBuOCO-4-pyridylRaCOO-
tBuOCO-IsobutanolRaCOO-
tBuOCO-isopropylRaCOO-
tBuOCO-cyclopropylRaCOO-
tBuOCO-cyclobutylRaCOO-
tBuOCO-cyclopentylRaCOO-
tBuOCO-phenylRaCOO-
benzoyl2-furylRaCOO-
benzoyl3-furylRaCOO-
benzoyl2-thienylRaCOO-
benzoyl3-thienylRaCOO-
benzoyl2-pyridylRaCOO-
benzoyl3-pyridylRaCOO-
benzoyl4-pyridylRaCOO-
benzoylIsobutanolRaCOO-
benzoylisopropylRa COO-
benzoylcyclopropylRaCOO-
benzoylcyclobutylRaCOO-
benzoylcyclopentylRaCOO-
benzoylphenylRaCOO-
2-FuCO-2-furylRaCOO-
2-FuCO-3-furylRaCOO-
2-FuCO-2-thienylRaCOO-
2-FuCO-3-thienylRaCOO-
2-FuCO-2-pyridylRaCOO-
2-FuCO-3-pyridylRaCOO-
2-FuCO-4-pyridylRaCOO-
2-FuCO-IsobutanolRaCOO-
2-FuCO-isopropylRaCOO-
2-FuCO-cyclopropylRaCOO-
2-FuCO-cyclobutylRaCOO-
2-FuCO-cyclopentylRaCOO-
2-FuCO-phenylRaCOO-
2-ThCO-2-furylRaCOO-
2-ThCO-3-furylRa COO-
2-ThCO-2-thienylRaCOO-
2-ThCO-3-thienylRaCOO-
2-ThCO-2-pyridylRaCOO-
2-ThCO-3-pyridylRaCOO-
2-ThCO-4-pyridylRaCOO-
2-ThCO-IsobutanolRaCOO-
2-ThCO-isopropylRaCOO-
2-ThCO-cyclopropylRaCOO-
2-ThCO-cyclobutylRaCOO-
2-ThCO-cyclopentylRaCOO-
2-ThCO-phenylRaCOO-
2-PyCO-2-furylRaCOO-
2-PyCO-3-furylRaCOO-
2-PyCO-2-thienylRaCOO-
2-PyCO-3-thienylRaCOO-
2-PyCO-2-pyridylRaCOO-
2-PyCO-3-pyridylRaCOO-
2-PyCO-4-pyridylRaCOO-
2-PyCO-IsobutanolRaCOO-
isopropylRaCOO-
2-PyCO-cyclopropylRaCOO-
2-PyCO-cyclobutylRaCOO-
2-PyCO-cyclopentylRaCOO-
2-PyCO-phenylRaCOO-
3-Rus-2-furylRaCOO-
3-PyCO-3-furylRaCOO-
3-PyCO-2-thienylRaCOO-
3-PyCO-3-thienylRaCOO-
3-PyCO-2-pyridylRaCOO-
3-Rus-3-pyridylRaCOO-
3-Rus-4-pyridylRaCOO-
3-Rus-IsobutanolRaCOO-
3-Rus-isopropylRaCOO-
3-Rus-cyclopropylRaCOO-
3-Rus-cyclobutylRaCOO-
3-Rus-cyclopentylRaCOO-
3-Rus-phenylRaCOO-
4-Rus-2-furylRaCOO-
4-Rus-3-furylRaCOO-
4-Rus-2-thienylRaCOO-
4-Rus-3-thienylRaCOO-
4-Rus-2-pyridylRaCOO-
4-Rus-3-pyridylRaCOO-
4-Rus-4-pyridylRaCOO-
4-Rus-IsobutanolRaCOO-
4-Rus-isopropylRaCOO-
4-Rus-cyclopropylRaCOO-
4-Rus-cyclobutylRaCOO-
4-Rus-cyclopentylRaCOO-
4-Rus-phenylRaCOO-
With4H7WITH-2-furylRaCOO-
With4H7WITH-3-furylRaCOO-
With4H7WITH-2-thienylRaCOO-
With4H7WITH-3-thienylRaCOO-
With4H7WITH-2-pyridylRaCOO-
With4H7WITH-RaCOO-
With4H7WITH-4-pyridylRaCOO-
With4H7WITH-IsobutanolRaCOO-
With4H7WITH-isopropylRaCOO-
With4H7WITH-cyclopropylRaCOO-
With4H7WITH-cyclobutylRaCOO-
With4H7WITH-cyclopentylRaCOO-
With4H7WITH-phenylRaCOO-
EtOCO-2-furylRaCOO-
EtOCO-3-furylRaCOO-
EtOCO-2-thienylRaCOO-
EtOCO-3-thienylRaCOO-
EtOCO-2-pyridylRaCOO-
EtOCO-3-pyridylRaCOO-
EtOCO-4-pyridylRaCOO-
EtOCO-IsobutanolRaCOO-
EtOCO-isopropylRaCOO-
EtOCO-cyclopropylRaCOO-/td>
EtOCO-cyclobutylRaCOO-
EtOCO-cyclopentylRaCOO-
EtOCO-phenylRaCOO-
ibueCO-2-furylRaCOO-
ibueCO-3-furylRaCOO-
ibueCO-2-thienylRaCOO-
ibueCO-3-thienylRaCOO-
ibueCO-2-pyridylRaCOO-
ibueCO-3-pyridylRaCOO-
ibueCO-4-pyridylRaCOO-
ibueCO-IsobutanolRaCOO-
ibueCO-isopropylRaCOO-
ibueCO-cyclopropylRaCOO-
ibueCO-cyclobutylRaCOO-
ibueCO-cyclopentylRaCOO-
ibueCO-phenylRaCOO-
iBuCO-2-furylRaCOO-
iBuCO-3-furylRaCOO-
iBuCO-2-thienylRaCOO-
iBuC- 3-thienylRaCOO-
iBuCO-2-pyridylRaCOO-
iBuCO-3-pyridylRaCOO-
iBuCO-4-pyridylRaCOO-
iBuCO-IsobutanolRaCOO-
iBuCO-isopropylRaCOO-
iBuCO-cyclopropylRaCOO-
iBuCO-cyclobutylRaCOO-
iBuCO-cyclopentylRaCOO-
iBuCO-phenylRaCOO-
iBuOCO-2-furylRaCOO-
iBuOCO-3-furylRaCOO-
iBuOCO-2-thienylRaCOO-
iBuOCO-3-thienylRaCOO-
iBuOCO-2-pyridylRaCOO-
iBuOCO-3-pyridylRaCOO-
iBuOCO-4-pyridylRaCOO-
iBuOCO-IsobutanolRaCOO-
iBuOCO-isopropylRaCOO-
iBuOCO-the CEC is aproper RaCOO-
iBuOCO-cyclobutylRaCOO-
iBuOCO-cyclopentylRaCOO-
iBuOCO-phenylRaCOO-
iPrOCO-2-furylRaCOO-
iPrOCO-3-furylRaCOO-
iPrOCO-2-thienylRaCOO-
iPrOCO-3-thienylRaCOO-
iPrOCO-2-pyridylRaCOO-
iPrOCO-3-pyridylRaCOO-
iPrOCO-4-pyridylRaCOO-
iPrOCO-IsobutanolRaCOO-
iPrOCO-isopropylRaCOO-
iPrOCO-cyclopropylRaCOO-
iPrOCO-cyclobutylRaCOO-
iPrOCO-cyclopentylRaCOO-
iPrOCO-phenylRaCOO-
nPrOCO-2-furylRaCOO-
nPrOCO-3-furylRaCOO-
nPrOCO-2-thienylRa/sub> COO-
nPrOCO-3-thienylRaCOO-
nPrOCO-2-pyridylRaCOO-
nPrOCO-3-pyridylRaCOO-
nPrOCO-4-pyridylRaCOO-
nPrOCO-IsobutanolRaCOO-
nPrOCO-isopropylRaCOO-
nPrOCO-cyclopropylRaCOO-
nPrOCO-cyclobutylRaCOO-
nPrOCO-cyclopentylRaCOO-
nPrOCO-phenylRaCOO-
nPrCO-2-furylRaCOO-
nPrCO-3-furylRaCOO-
nPrCO-2-thienylRaCOO-
nPrCO-3-thienylRaCOO-
nPrCO-2-pyridylRaCOO-
nPrCO-3-pyridylRaCOO-
nPrCO-4-pyridylRaCOO-
nPrCO-IsobutanolRaCOO-
nPrCO-isopropylRaCOO-
nPrCO-cyclopropylRaCOO-
nPrCO-cyclobutylRaCOO-
nPrCO-cyclopentylRaCOO-
nPrCO-phenylRaCOO-
tBuOCO-cyclopentylEtCOO-
benzoyl3-furylEtCOO-
benzoyl2-thienylEtCOO-
benzoyl2-pyridylEtCOO-
benzoyl3-pyridylEtCOO-
benzoyl4-pyridylEtCOO-
benzoylIsobutanolEtCOO-
benzoylisopropylEtCOO-
benzoylcyclopropylEtCOO-
benzoylcyclobutylEtCOO-
benzoylcyclopentylEtCOO-
benzoylphenylEtCOO-
2-FuCO-3-furylEtCOO-
2-FuCO-3-thienylEtCOO-
2-FuCO-2-pyridylEtCOO-
2-FuCO-3-pyridylEtCOO-
2-FuCO-EtCOO-
2-FuCO-IsobutanolEtCOO-
2-FuCO-isopropylEtCOO-
2-FuCO-cyclopropylEtCOO-
2-FuCO-cyclobutylEtCOO-
2-FuCO-cyclopentylEtCOO-
2-FuCO-phenylEtCOO-
2-ThCO-3-furylEtCOO-
2-ThCO-3-thienylEtCOO-
2-ThCO-2-pyridylEtCOO-
2-ThCO-3-pyridylEtCOO-
2-ThCO-4-pyridylEtCOO-
2-ThCO-IsobutanolEtCOO-
2-ThCO-isopropylEtCOO-
2-ThCO-cyclopropylEtCOO-
2-ThCO-cyclobutylEtCOO-
2-ThCO-cyclopentylEtCOO-
2-ThCO-phenylEtCOO-
2-PyCO-2-furylEtCOO-
2-PyCO-3-furylEtCOO-
2-PyCO-2-thienylEtCOO-
2-PyCO-3-thienyl EtCOO-
2-PyCO-2-pyridylEtCOO-
2-PyCO-3-pyridylEtCOO-
2-PyCO-4-pyridylEtCOO-
2-PyCO-IsobutanolEtCOO-
2-PyCO-isopropylEtCOO-
2-PyCO-cyclopropylEtCOO-
2-PyCO-cyclobutylEtCOO-
2-PyCO-cyclopentylEtCOO-
2-PyCO-phenylEtCOO-
3-Rus-2-furylEtCOO-
3-PyCO-3-foripEtCOO-
3-PyCO-3-thienylEtCOO-
3-PyCO-2-pyridylEtCOO-
3-PyCO-3-pyridylEtCOO-
3-PyCO-4-pyridylEtCOO-
3-PyCO-IsobutanolEtCOO-
3-PyCO-isopropylEtCOO-
3-PyCO-cyclopropylEtCOO-
3-PyCO-cyclobutylEtCOO-
3-PyCO-cyclopentylEtCOO-
3-PyCO-phenylEtCOO-
4-PyCO-2-furylEtCOO-
4-PyCO-3-furylEtCOO-
4-PyCO-2-thienylEtCOO-
4-PyCO-3-thienylEtCOO-
4-PyCO-2-pyridylEtCOO-
4-PyCO-3-pyridylEtCOO-
4-PyCO-4-pyridylEtCOO-
4-PyCO-IsobutanolEtCOO-
4-PyCO-isopropylEtCOO-
4-PyCO-cyclopropylEtCOO-
4-PyCO-cyclobutylEtCOO-
4-PyCO-cyclopentylEtCOO-
4-PyCO-phenylEtCOO-
With4H7WITH-3-furylEtCOO-
With4H7WITH-3-thienylEtCOO-
With4H7WITH-2-pyridylEtCOO-
With4H7WITH-3-pyridylEtCOO-
With4H7WITH-4-pyridylEtCOO-
With4H7WITH-IsobutanolEtCOO-
With4H7WITH-isopropyl EtCOO-
With4H7WITH-cyclopropylEtCOO-
With4H7WITH-cyclobutylEtCOO-
With4H7WITH-cyclopentylEtCOO-
With4H7WITH-phenylEtCOO-
EtOCO-3-furylEtCOO-
EtOCO-3-thienylEtCOO-
EtOCO-2-pyridylEtCOO-
EtOCO-3-pyridylEtCOO-
EtOCO-4-pyridylEtCOO-
EtOCO-IsobutanolEtCOO-
EtOCO-isopropylEtCOO-
EtOCO-cyclopropylEtCOO-
EtOCO-cyclobutylEtCOO-
EtOCO-cyclopentylEtCOO-
EtOCO-phenylEtCOO-
ibueCO-2-furylEtCOO-
ibueCO-3-furylEtCOO-
ibueCO-2-thienylEtCOO-
ibueCO-3-thienylEtCOO-
ibueCO-2-pyridylEtCOO-
ibeCO- 3-pyridylEtCOO-
ibueCO-4-pyridylEtCOO-
ibueCO-IsobutanolEtCOO-
ibueCO-isopropylEtCOO-
ibueCO-cyclopropylEtCOO-
ibueCO-cyclobutylEtCOO-
ibueCO-cyclopentylEtCOO-
ibueCO-phenylEtCOO-
iBuCO-2-furylEtCOO-
iBuCO-3-furylEtCOO-
iBuCO-2-thienylEtCOO-
iBuCO-3-thienylEtCOO-
iBuCO-2-pyridylEtCOO-
iBuCO-3-pyridylEtCOO-
iBuCO-4-pyridylEtCOO-
iBuCO-IsobutanolEtCOO-
iBuCO-isopropylEtCOO-
iBuCO-cyclopropylEtCOO-
iBuCO-cyclobutylEtCOO-
iBuCO-cyclopentylEtCOO-
iBuCO-phenylEtCOO-
iBuOCO-2-pyridyl
iBuOCO-3-pyridylEtCOO-
iBuOCO-4-pyridylEtCOO-
iBuOCO-IsobutanolEtCOO-
iBuOCO-isopropylEtCOO-
iBuOCO-cyclobutylEtCOO-
iBuOCO-cyclopentylEtCOO-
iBuOCO-phenylEtCOO-
iPrOCO-3-furylEtCOO-
iPrOCO-3-thienylEtCOO-
iPrOCO-2-pyridylEtCOO-
iPrOCO-3-pyridylEtCOO-
iPrOCO-4-pyridylEtCOO-
iPrOCO-IsobutanolEtCOO-
iPrOCO-isopropylEtCOO-
iPrOCO-cyclopropylEtCOO-
iPrOCO-cyclobutylEtCOO-
iPrOCO-cyclopentylEtCOO-
iPrOCO-phenylEtCOO-
nPrOCO-2-furylEtCOO-
nPrOCO-3-furylEtCOO-
nPrOCO-2-thienylEtCOO-
3-thienylEtCOO-
nPrOCO-2-pyridylEtCOO-
nPrOCO-3-pyridylEtCOO-
nPrOCO-4-pyridylEtCOO-
nPrOCO-IsobutanolEtCOO-
nPrOCO-isopropylEtCOO-
nPrOCO-cyclopropylEtCOO-
nPrOCO-cyclobutylEtCOO-
nPrOCO-cyclopentylEtCOO-
nPrOCO-phenylEtCOO-
nPrCO-3-furylEtCOO-
nPrCO-3-thienylEtCOO-
nPrCO-2-pyridylEtCOO-
nPrCO-3-pyridylEtCOO-
nPrCO-4-pyridylEtCOO-
nPrCO-IsobutanolEtCOO-
nPrCO-isopropylEtCOO-
nPrCO-cyclopropylEtCOO-
nPrCO-cyclobutylEtCOO-
nPrCO-cyclopentylEtCOO-
nPrCO-phenylEtCOO-

Example 4

Following IU the ode, described in example 1 and elsewhere in the description, can be obtained specific taxanes having structural formula 15 where R10represents hydroxy and R7in each series (i.e. each of series "A" through "K") such as previously defined, including R7is an R7aCOO - and R7arepresents (i) substituted or unsubstituted, preferably unsubstituted, With2-C8alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C2-C8alkenyl (a straight, branched or cyclic), such as ethynyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, With2-C8quinil (straight or branched), such as ethinyl, PROPYNYL, butynyl, pentenyl or hexenyl; (iv) substituted or unsubstituted, preferably unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted heteroaromatic radical, such as furyl, thienyl or pyridyl.

In the compounds of series "A" X10represents the rest as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10represents samewe the data or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), and each of R7and R10have the beta stereochemical configuration.

In the compounds of series "b" X10and R2amean otherwise as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents furyl, substituted or unsubstituted thienyl, pyridyl, phenyl or lower alkyl and each of R7and R10have the beta stereochemical configuration.

In the compounds of series "C" X10and R9ameans as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R9apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7, R9and R10have the beta stereochemical configuration.

In the compounds of series "D" and "E" X10represents as defined here. Preferably heterocy the lo represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl pyridyl, phenyl or lower alkyl (e.g. tert-butyl), and each of R7, R9(only for D series) and R10have the beta stereochemical configuration.

In the compounds of series "F" X10, R2aand R9ameans as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7, R9and R10have the beta stereochemical configuration.

In the compounds of series "G" X10and R2ameans as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7, R9and R10have beta-Stere the chemical configuration.

In the compounds of series "H" X10represents as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7and R10have the beta stereochemical configuration.

In the compounds of series "I" X10and R2ameans as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7and R10have the beta stereochemical configuration.

In the connections series "J" X10and R2ameans as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, Tien is l, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7, R9and R10have the beta stereochemical configuration.

In the connections series "To" X10, R2aand R9ameans as defined here. Preferably heterocycle represents a substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), R2apreferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl and each of R7, R9and R10have the beta stereochemical configuration.

Any substituents in each of the X3, X5, R2, R7and R9can be hydrocarbon or any containing heteroatom Deputy selected from the group consisting of heterocycle, alkoxy, alkenone, alkyloxy, aryloxy-, hydroxy, protected hydroxy, keto -, acyloxy-, nitro-, amino-, aminogroup, Tilney, Catalinas, acetaldol, ester and simple ester groups, but not phosphorus-containing radicals.

td align="right" namest="c0" nameend="c6"> Table 3 td align="center"> possibly substituted

With2-C8alkenyl I8
SeriesX5X3R7R2R9Rl4
A1-COOH10heterocycleR7aCOO-C6H5COO-OH
A2-COX10heterocycleR7aCOO-C6H5COO-OH
A3-CONHX10heterocycleR7aCOO-C6H5COO-OH
A4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OH
A5-COX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OH
A6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OH
A7-COOH10 possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OH
A8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OH
A9-CONHX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OH
A10-COOH10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OH
A11-COX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OH
A12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OH
B1-COOH10heterocycleR7aCOO-R2aCOO-OH
B2-COX10heterocycleR7aCOO-R2aCOO-OH
B3-CONHX10heterocycleR7aCOO-R2aCOO-OH
B4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OH
B5-COX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OH
B6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OH
V7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OH
B8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OH
B9-CONHX10R7aCOO-R2aCOO-OH
10-COOH10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OH
B11-COX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OH
B12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OH
C1-COOH10heterocycleR7aCOO-C6H5COO-R9AcOO-H
C2-COX10heterocycleR7aCOO-C6H5COO-R9aCOO-H
C3-CONHX10heterocycleR7aCOO-C6H5COO-R9aCOO-H
C4-COOH10perhaps samewe the hydrated

With2-C8alkyl
R7aCOO-C6H5COO-R9aCOO-H
C5-COX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-R9aCOO-H
C6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-R9aCOO-H
C7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-R9aCOO-H
C8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-R9aCOO-H
C9-CONHX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-R9aCOO-H
C10-COOH10possibly substituted

With2-C8quinil
R 7aCOO-C6H5COO-R9aCOO-H
C11-COX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-R9aCOO-H
C12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-R9aCOO-H
D1-COOH10heterocycleR7aCOO-C6H5COO-OHH
D2-COX10heterocycleR7aCOO-C6H5COO-OHH
D3-CONHX10heterocycleR7aCOO-C6H5COO-OHH
D4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OHH
D5-COX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OHH
D6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OHH
D7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OHH
D8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OHH
D9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHH
D10-COOH10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHH
D11-COX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHH
D12 -CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHH
E1-COOH10heterocycleR7aCOO-C6H5COO-OHH
E2-COX10heterocycleR7aCOO-C6H5COO-OOH
E3-CONHX10heterocycleR7aCOO-C6H5COO-OOH
E4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-CeHgCOO-OOH
E5-COX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OOH
E6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OOH
E7-COOH10perhaps alseny

With2-C8alkenyl
R7aCOO-C6H5COO-OOH
E8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OOH
E-CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OOH
E10-COOH10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OOH
E11-COX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OOH
E12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OOH
F1-COOH10heterocycleR7aCOO-R2aCOO-R9aCOO-H
F2-COX10heterocycleR7aCOO-R2aCOO-R9aCOO-H
F3-CONHX10heterocycleR7aCOO-R2aCOO-R9aCOO-H
F4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-R9aCOO-H
F5-COX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-R9aCOO-H
F6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-R9aCOO-H
F7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-R9aCOO-H
F8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-R9aCOO- H
F9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-H
F10-COOH10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-H
F11-COX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-H
F12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-H
G1-COOH10heterocycleR7aCOO-R2aCOO-OHH
G2-COX10heterocycleR7aCOO-R2aCOO-OHH
G3-CONHX10heterocycleR7aCOO-R2aCOO-OHH
G4 -COOH10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OHH
G5-COX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OHH
G6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OHH
G7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OHH
G8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OHH
G9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHH
G10-COOH10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OH H
G11-COX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHH
G12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHH
H1-COOH10heterocycleR7aCOO-C6H5COO-OHOH
H2-COX10heterocycleR7aCOO-C6H5COO-OHOH
H3-CONHX10heterocycleR7aCOO-C6H5COO-OHOH
N4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OHOH
H5-COX10possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OHOH
N6possibly substituted

With2-C8alkyl
R7aCOO-C6H5COO-OHOH
H7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OHOH
N8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-C6H5COO-OHOH
H9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHOH
N10-COOH10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHOH
H11-COX10possibly substituted

With2-C8quinil
R7aCOO-C6H5COO-OHOH
H12-CONHX10possibly substituted

With2-C8quinil
R 7aCOO-C6H5COO-OHOH
I1-COOH10heterocycleR7aCOO-R2aCOO-OOH
I2-COX10heterocycleR7aCOO-R2aCOO-OOH
I3-CONHX10heterocycleR7aCOO-R2aCOO-OOH
I4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OOH
I5-COX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OOH
I6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OOH
I7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OOH
-COX10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OOH
I9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OOH
I10-COOH10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OOH
I11-COX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OOH
I12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OOH
J1-COOH10heterocycleR7aCOO-R2aCOO-HEOH
J2-COX10heterocycleR7aCOO-R2aCOO-HEOH
J3-CONHX10 heterocycleR7aCOO-R2aCOO-HEOH
J4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-HEOH
J5-COX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OHOH
J6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-OHOH
J7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OHOH
J8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-OHOH
J9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHOH
J10-COOH10 possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHOH
J11-COX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHOH
J12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-OHOH
K1-COOH10heterocycleR7aCOO-R2aCOO-R9aCOO-OH
K2-COX10heterocycleR7aCOO-R2aCOO-R9aCOO-OH
K3-CONHX10heterocycleR7aCOO-R2aCOO-R9aCOO-OH
Q4-COOH10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-R9aCOO-OH
C5-COX10possibly substituted

With2 -C8alkyl
R7aCOO-R2aCOO-R9aCOO-OH
K6-CONHX10possibly substituted

With2-C8alkyl
R7aCOO-R2aCOO-R9aCOO-OH
K7-COOH10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-R9aCOO-OH
K8-COX10possibly substituted

With2-C8alkenyl
R7aCOO-R2aCOO-R9aCOO-OH
K9-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-OH
K10-COOH10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-OH
C-COX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R 9aCOO-OH
K12-CONHX10possibly substituted

With2-C8quinil
R7aCOO-R2aCOO-R9aCOO-OH

Example 5

Cytotoxicity in vitro, measured the breakdown of the education of the colony of cells

Four hundred cells (NSC) were placed in 60 mm Petri dishes containing 2.7 ml of medium (modified environment McCoy''s 5a containing 10% embryonic bovine serum and 100 units/ml penicillin and 100 g/ml streptomycin). Cells were incubated in an incubator with CO2at 37°5 h to precipitate to the bottom of the Petri dish. Compounds identified in example 2 were freshly prepared in an environment with a ten-fold of the final concentration, and then 0.3 ml of the specified main solution was added to 2.7 ml of medium in a Cup. Cells are then incubated with the drug for 72 h at 37°C. after the incubation containing medicine Wednesday decantation, the Cup was washed with 4 ml of saline solution Hank's Balance (HBSS), was added 5 ml of fresh medium and cups were returned to the incubator for the formation of colonies. Colonies of cells cheated using count colonies after 7 days of incubation. It has been estimated survival of cells and for each compound were determined ID50 values (concentration of drug that provides 50%inhib the of the education of the colony) (see table 4).

Table 4
ConnectionIN VITRO ID 50 (nm) HCT116
Taxol2,1
docetaxel0,6
1351<1
1364<10
137226,1
1386<1
1393<1
1401<1
1418<1
1424<1
1434<10
1447<10
1458<10
3069<1
3082<1
3171<1
3196<10
3232<1
3327<10
3388<10
3444<1
3479<1
3555<10
3560<1
3611<1
3629<1
3632<1
3708<1
3713<10
4017<10
4044<1
4106<10
4135<1
4175<10
421929.0
4256<1
4283<1
4290<10
4312<1
4388<1
4394<1
4406<1
4446<1
4499<1
4544<10
4600<10
4616<1
4737<1
4757<1
6171<10
6131<1
5989<10
6141<1
6181<1
6040<10
6121<10
642421,7
6212<1
6282<10
6252<1
6343<10
6272<1
6202<1
4454<1
4414<1
6333<1
6686<1
6363<10
4787<10
4828<10
4898<1
4939 miles<1
5020<1
5030<1
5191<10
5202<10
5070<10
5080<1
512121,1
5131<10

Example 6

Preparation of solutions for oral administration

Solution 1: the Antitumor compound 1393 was dissolved in ethanol to obtain a solution containing 140 mg of the substance per ml of solution. To the solution under stirring was added an equal volume of a solution of Cremophor® EL obtaining a solution containing 70 mg of the substance 1393 in ml. of This solution was diluted using 9 parts by weight saline solution to obtain pharmaceutically acceptable solution for administration to a patient.

Solution 2: Antitumor compound 1458 was dissolved in ethanol to obtain a solution containing 310 mg substances is and ml. To the solution under stirring was added an equal volume of a solution of Cremophor® EL obtaining a solution containing 155 mg of the substance 1458 in ml. of This solution was diluted using 9 parts by weight saline solution to obtain pharmaceutically acceptable solution for administration to a patient.

Solution 3: Antitumor compound 1351 was dissolved in ethanol to obtain a solution containing 145 mg substance per ml of solution. To the solution under stirring was added an equal volume of a solution of Cremophor® EL obtaining a solution containing 72,5 mg connection 1351 in ml. of This solution was diluted using 9 parts by weight saline solution to obtain pharmaceutically acceptable solution for administration to a patient.

Solution 4: the Antitumor compound 4017 was dissolved in ethanol to obtain a solution containing 214 mg of the substance per ml of solution. To the solution under stirring was added an equal volume of a solution of Cremophor® EL obtaining a solution containing 107 mg of the compound on 4017 ml of This solution was diluted using 9 parts by weight saline solution to obtain pharmaceutically acceptable solution for administration to a patient.

Solution 5: the Antitumor compound 1393 was dissolved in 100%ethanol, then mixed with an equal volume of a solution of Cremophor® EL obtaining a solution containing 70 gaedikeia 1393 on ml This solution was diluted using 9 parts by weight of D%W (aqueous solution containing 5% by weight on the amount of dextrose) or 0.9%saline to obtain pharmaceutically acceptable solution for administration to a patient.

Example 7

Preparation of a suspension containing the compound 1393, for oral administration

Oral composition antitumor compounds 1393 were prepared by suspendirovanie 25 mg of the substance 1393 in the form of fine powder in 1 ml of media containing 1% carboxymethylcellulose (CMC) in deionized water.

Example 8

Preparation of tablets containing compound 1393, for oral administration

Antitumor compound 1393 (100 mg) was dissolved in methylene chloride (2 ml) was added a solution of Cremophor® EL (100 mg). The methylene chloride was evaporated in vacuum to obtain a glassy mass. To a glassy mass was added microcrystalline cellulose (600 mg) and stirred to obtain a powder, which can be processed into tablet form.

Example 9

The preparation of the emulsion containing the compound 1393 for parenteral administration

Emulsion 1: Antitumor compound 1393 was dissolved in 100% ethanol to obtain a solution containing 40 ml of connection 1393 per ml of solution. The solution is then diluted with 19 parts by weight of Liposyn® III (20%) with stirring to obtain an emulsion with the containing a series of 2 mg of compound 1393 per ml, for parenteral administration.

Emulsion 2: Antitumor compound 1393 was dissolved in 100% ethanol to obtain a solution containing 40 ml of connection 1393 per ml of solution. The solution is then diluted with 19 parts by weight of Liposyn® III (2%) with stirring to obtain an emulsion containing 2 mg of the compound 1393 per ml, for parenteral administration.

Emulsion 3: Antitumor compound 1393 was dissolved in 100% ethanol to obtain a solution containing mg of compound 1393 per ml of solution. The solution is then diluted with 9 parts by weight of Liposyn® III (2%) with stirring to obtain an emulsion containing 4 mg of compound 1393 per ml, for parenteral administration.

Example 10

Preparation of solutions containing the compound 1393, for parenteral administration

Solution 1: the Antitumor compound 1393 was dissolved in 100% ethanol to obtain a solution containing 140 mg of compound 1393 per ml of solution. The solution is then diluted with stirring with an equal volume of a solution of Cremophor® EL and then diluted with 9 parts by weight of normal saline to obtain a solution containing 7 mg of compound 1393 per ml of solution for parenteral administration.

Solution 2: Antitumor compound 1393 was dissolved in 100% ethanol to obtain a solution containing 140 mg of compound 1393 per ml of solution. The solution is then diluted with premesis the NII equal volume of a solution of Cremophor® EL and then diluted with 4 parts by weight of normal saline to obtain a solution containing 11.7 mg of the compound 1393 per ml of solution for parenteral administration.

Solution 3: Antitumor compound 1393 was dissolved in 100% ethanol to obtain a solution containing 140 mg of compound 1393 per ml of solution. The solution is then diluted with stirring with an equal volume of a solution of Cremophor® EL and then diluted 2,33 parts by weight of normal saline to obtain a solution containing 16.2 mg of the compound 1393 per ml of solution for parenteral administration.

1. Taxon having the formula

where R2represents a benzoyloxy;

R7is an R7aCOO-;

R10represents hydroxy;

X3represents a C1-8alkyl, C2-8alkenyl,2-8quinil or 5 - or 6-membered heteroaryl group containing a heteroatom selected from O, N and S;

X5is a-MOR10where X10represents a C1-8alkyl, C2-8alkenyl, phenyl or 5 - or 6-membered heteroaryl group containing a heteroatom selected from O, N and S;

or represents-COOH10where X10represents a C1-8alkyl or C2-8alkenyl;

R7a represents a C1-20alkyl or C2-20alkenyl;

AC represents acetyl.

2. Texan according to claim 1, where X3represents a C1-C8alkyl, C2-C8alkenyl,2-C8quinil, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

3. Texan according to claim 2, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

4. Texan according to claim 2, where X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

5. Texan according to claim 1, where X3represents a furyl or thienyl.

6. Texan according to claim 5, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

7. Texan according to claim 5, where X5is a-MOR10/sub> and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

8. Texan according to claim 2, where X3is cycloalkyl.

9. Taxon of claim 8, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

10. Taxon of claim 8, where X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

11. Texan according to claim 2, where X3represents isobutyl.

12. Texan according to claim 11, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

13. Texan according to claim 11, where X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10PR is dstanley a tert-butyl.

14. Texan according to claim 1, where R7arepresents ethyl or propyl.

15. Texan at 14, where X3represents a C1-C8alkyl, C2-C8alkenyl, C2-C8quinil, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl.

16. Texan indicated in paragraph 15, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

17. Texan indicated in paragraph 15, where X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

18. Texan at 14, where X3represents a furyl or thienyl.

19. Texan on p, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

20. Texan on p, where X5is a-MOR10and X10presented yet a phenyl, or X5represents-COOH10and X10represents tert-butyl.

21. Texan at 14, where X3is cycloalkyl.

22. Texan on item 21, where X5is a-MOR10and X10represents a C2-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

23. Texan on item 21, where X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

24. Texan at 14, where X3represents isobutyl.

25. Texan on point 24, where X5is a-MOR10and X10represents a C1-C8alkyl, C2-C8alkenyl, phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, or X5represents-COOH10and X10represents a C1-C8alkyl or C2-C8alkenyl.

26. Texan on point 24, where X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

27. T is Xan according to claim 1, where X3represents a furyl or thienyl, R7arepresents ethyl and X5is a-MOR10where X10represents phenyl, or X5represents-COOH10where X10represents tert-butyl.

28. Texan according to claim 1, where X3represents furyl, R7arepresents ethyl, and X5is a-MOR10where X10represents phenyl, or X5represents-COOH10where X10represents tert-butyl.

29. Texan according to claim 1, where X3is thienyl, R7arepresents ethyl, and X5is a-MOR10where X10represents phenyl, or X5represents-COOH10where X10represents tert-butyl.

30. Texan according to claim 1, where X3represents isobutyl, R7arepresents ethyl and X5is a-MOR10where X10represents phenyl, or X5represents-COOH10where X10represents tert-butyl.

31. Texan according to claim 1, where X3represents a C1-C8alkyl, R7arepresents ethyl, and X5is a-MOR10where X10represents phenyl, or X5represents-COOH1010represents tert-butyl.

32. Texan according to claim 1, where X3represents a 2-furyl or 2-thienyl, R7arepresents ethyl, X5represents-COOH10and X10represents tert-butyl.

33. Texan according to claim 1, where X3represents 2-furyl, R7arepresents ethyl, X5represents-COOH10and X10represents tert-butyl.

34. Texan according to claim 1, where X3is a 2-thienyl, R7arepresents ethyl, X5represents-COOH10and X10represents tert-butyl.

35. Texan according to claim 1, where X3represents isobutyl, X5represents-COOH10and X10represents tert-butyl.

36. Method of inhibiting the growth of tumors in mammals, this method is oral administration of a therapeutically effective amount of a pharmaceutical composition containing taxon according to claim 1 and at least one pharmaceutically acceptable carrier.

37. The method according to p, where X3represents phenyl, Isobutanol, furyl or thienyl, R7arepresents ethyl, X5is a-MOR10and X10represents phenyl, or X5represents-COOH10and X10represents tert-butyl.

38. Pharmaceutical composition having antitumor activity, containing taxon according to claim 1 and at least one pharmaceutically acceptable carrier.

39. Pharmaceutical composition containing taxon according to claim 5 and at least one pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to derivatives of taxane of the general formula (I):

wherein R2 means acyloxy-group; R7 means hydroxy-group; R9 means keto-group; R10 means carbonate; R14 means hydrogen atom; X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted optionally with nitro-group or 5-6-membered heteroaromatic group comprising heteroatoms taken among oxygen (O), nitrogen (N) or sulfur (S) atoms; X5 means -C(O)X10, -C(O)OX10 or -CONHX10 wherein X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl, furyl, pyridyl or thienyl; Ac means acetyl. Also, invention describes a pharmaceutical composition based on taxanes and a method for inhibition of a tumor growth.

EFFECT: improved inhibiting method, valuable medicinal properties of compounds.

98 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to novel trifluoromethylpyrrole carboxamides of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl; R2 means (C1-C4)-alkyl, (C1-C4)-halogenalkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, cyano-group or (C1-C6)-alkylcarbonyl; A means the group of the formula:

, or wherein R3 means (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C2-C6)-alkenyl, (C3-C7)-cycloalkyl, (C1-C4)-alkyl-(C3-C7)-cycloalkyl, (C4-C7)-cycloalkenyl, (C1-C4)-alkyl-(C4-C7)-cycloalkenyl, phenyl, naphthyl or phenoxy-group, or substituted phenyl, or substituted phenoxy-group wherein substituted represent 1-3 groups taken independently among an order comprising halogen atom, (C1-C4)_alkyl, (C1-C4)-alkoxy-, cyano-group, (C1-C4)-alkylcarbonyl, (C1-C4)-halogenalkyl, (C1-C4)-halogenalkoxy-, methylenedioxy-, difluoromethylenedioxy-group or phenyl; R4 means hydrogen, halogen atom or (C1-C4)-alkyl; each among R5, R6 and R7 means (C1-C6)-alkyl. Compounds of the formula (I) are used for control of phytopathogen organisms or for prophylaxis in damaging cultured plants by these organisms.

EFFECT: valuable properties of compounds.

10 cl, 3 tbl, 1 sch, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new taxanes of the general formula (I)

wherein R2 means benzoyloxy-group; R7 means hydroxyl (OH); R9 means keto-group; R10 means R10aCOO-; R10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl or 5-6-membered heteroaromatic group wherein heteroatom represents oxygen atom (O), sulfur atom (S) or nitrogen atom (N); R14 means hydrogen atom (H); X3 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl substituted possibly with nitro-group (-NO2), 5-6-membered heteroaromatic group wherein heteroatom represents O, S or N; X5 means -COX10, -COOX10; X10 means (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heteroaromatic group wherein heteroatom represents O, S, N; Ac means acetyl. Compounds of the formula (I) elicit antitumor activity.

EFFECT: valuable medicinal properties of compounds.

68 cl, 1 tbl, 6 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention relates to substituted thienocycloalk(ene)ylamino-1,3,5-triazines of the general formula (I): wherein R1 means hydrogen atom; R2 means hydrogen atom, formyl or alkylcarbonyl, group N(R1R2) denoting dialkylaminoalkylideneamine; R3 means unsubstituted or halogen-substituted alkyl; Z means one of the following thienocycloalkyl groups: and wherein A1, A2 and A3 mean alkylene. Also, invention describes a method for synthesis of indicated compounds and intermediate compounds used in the synthesis. Compounds can be used as herbicides.

EFFECT: improved method for synthesis, valuable agricultural properties of compounds.

8 cl, 4 tbl, 5 ex

New compounds // 2261245

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes derivatives of 2-amino-1,3,5-triaziene of the formula (I): wherein R1 means phenyl or alkyl with from 1 to 6 carbon atoms that can be substituted with one or some radicals taken among halogen atom and cyano-group; R2 means unsubstituted cyclopropyl, cyclobutyl or cyclopentyl groups or substituted that with radical taken among halogen atom and alkyl with from 1 to 4 carbon atoms, or furyl, or tetrahydrofuryl; R3 means radical of the formula -N(B1-D1)(B2-D2); R4 means radical of the formula -B3-D3; A1 means direct alkylene with 1-5 carbon atoms or direct alkenylene with 2-5 carbon atoms; A2 means a direct bond or direct alkylene with 1-4 carbon atoms; B1, B2 and B3 mean a direct bond; D1, D2 and D3 mean hydrogen atom; (X)n means a number of X substitutes wherein X means independently halogen atom, nitro-group or unsubstituted alkyl with 1-6 carbon atoms or substituted that with one or some radicals taken among halogen atom and alkoxy-group with 1-6 carbon atoms; n = 0, 1 or 2 and wherein the total sum of carbon atoms in radicals A1 and A2-R2 is at least 6 carbon atoms. Also, invention describes the herbicide agent containing compound of the formula (I) and additives used usually for plants protection and a method for control of hazard plants and using the effective dose of compound of the formula (I) for treatment of plants or planting surface. Invention provides preparing effective herbicides.

EFFECT: valuable properties of compounds.

7 cl, 45 tbl, 4 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

The invention relates to new chemical compounds of the heterocyclic series, with pronounced anticalcium activity, which may find application in medical practice in the treatment and prevention of cardiovascular diseases and represent derivatives of 2-N-1-benzopyran-2-it General formula I

where R and R1have the meanings indicated in the claims

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to the field of chemistry of heterocyclic compounds and relates, in particular, a new chemical compound 2-isopropyl-4-[(furyl-2)metalinox] methylene-1,3-dioxolane exhibiting the properties of activator germination of wheat seeds and increases the resistance of seedlings to water stress

The invention relates to new compounds of the class of cetomacrogol and semisolids, potential intermediates in obtaining new macrolide and asamenew antibiotics, as well as the way they are received and intermediate compounds for their production

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

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