Taxane, pharmaceutical composition based on thereof and method for inhibition of tumor growth

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

 

Background of the invention

This invention is directed to new taxanes that have exceptional utility as anticancer agents.

Taxonomy a number of terpenes, the members of which are baccatin III and Taxol, is the object of attention both in biology and in chemistry. The Taxol is used as a chemotherapeutic agent in cancer treatment and has a broad spectrum of inhibitory tumor activity. Taxol has the 2'R, 3'S configuration and the following structural formula:

where AC is acetyl.

Colin with TCS. in U.S. patent 4814470 indicate that some analogs of Taxol have activity, much higher than the activity of Taxol. One of these analogues, often called docetaxel, has the following structural formula:

Although Taxol and docetaxel useful as chemotherapeutic agents, there are limitations to their effectiveness, including limited activity against some types of cancer and toxicity in relation to the subjects with the introduction of various doses. Accordingly there is a need for additional chemotherapeutic agents with increased efficacy and less toxicity.

Brief description of the invention

About what hachami of the present invention are taxanes, different from most of Taxol and docetaxel in relation to efficiency as anticancer agents and in terms of toxicity. In General these taxanes have carbonate substituent in position(10), hydroxyl substituent in position(7) and a set of side chain substituents in positions(2), (9), (14) and(13).

In short, this invention is directed to taxonomy composition, as such, to pharmaceutical compositions comprising Texan and a pharmaceutically acceptable carrier and methods of introduction.

Other objects and distinctive features of the present invention will be explained separately and separately highlighted next.

A detailed description of the preferred variants of the invention

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

where

R2is alloctype;

R7is a hydroxy-group;

R9is keto, hydroxy - or alloctype;

R10is carbonate;

R14hydrido - or hydroxy-group;

X3is substituted or unsubstituted alkyl, alkenyl, quinil, phenyl or heterocycle, where the alkyl comprises at least two carbon atoms;

X5is-SOH10, -COOH10the Li-CONHX 10;

X10is hydrocarbon, substituted hydrocarbon or heterocycle;

AC is acetyl; and

R7, R9, R10independently of one another have the stereochemical configuration of alpha or beta.

In one embodiment, R2a complex air (R2aC(O)O-), a carbamate (R2aR2bNC(O)O-), carbonate (R2aOC(O)O -), or THIOCARBAMATE (R2aSC(O)O-), where R2aand R2bindependently of one another are hydrogen, hydrocarbon, substituted hydrocarbon or heterocycle. In a preferred embodiment, R2a complex air (R2aC(O)O-), where R2ais an aryl or heteroaromatic group. In another preferred embodiment, R2a complex air (R2aC(O)O-), where R2ais substituted or unsubstituted phenyl, fullam, tanila or pyridium. In one particularly preferred embodiment, R2is benzyloxypropionic.

If R9in one embodiment of the present invention is geography, in other embodiments, R9may have the stereochemical configuration of the alpha or beta, preferably stereochemical configuration of the beta, and can be, for example, αor β-hydroxy or αor β-acyloxy. For example, if R9is alloctype, this may be an ester (R9aC(O)O-), to Ramat (R 9aR9bNC(O)O-), carbonate (R9aOC(O)O -), or THIOCARBAMATE (R9aSC(O)O-), where R9aand R9bindependently of one another are hydrogen, hydrocarbon, substituted hydrocarbon or heterocycle. If R9a complex air (R9aC(O)O-), R9ais substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic group. Even more preferably, R9an ether (R9aC(O)O-), where R9ais substituted or unsubstituted phenyl, substituted or unsubstituted fullam, substituted or unsubstituted tanila or substituted or unsubstituted pyridium. In one embodiment, R9is (R9aC(O)O-), where R9ais stands, ethyl, propylene (a straight, branched or cyclic), bootrom (a straight, branched or cyclic), Pentium (a straight, branched or cyclic) or hexyl (a straight, branched or cyclic). In another embodiment, R9is (R9aC(O)O-), where R9ais replaced by stands, substituted ethyl, substituted by propylene (a straight, branched or cyclic), substituted by bootrom (a straight, branched or cyclic), substituted Pentium (a straight, branched or cyclic) or substituted, gexi the Ohm (direct, branched or cyclic), where the substituent(s) selected(s) from the group consisting of heterocycle, alkoxy, alkenone, alkyloxy, aryloxy, hydroxy, protected hydroxy, geograpy, alloctype, nitro, amino, aminogroup, Colnago, catalogo, acatalog, ester or ether fragments, but not phosphorus-containing fragments.

In one embodiment, R10is R10aOCOO-, where R10arepresents (i) a substituted or unsubstituted With1-C8alkyl (straight, branched or cyclic), such as methyl, 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 a heterocycle, such as furyl, thienyl or pyridyl. Substituents can be hydrocarbon or any of the substituents containing a heteroatom defined anywhere in the text to be substituted hydrocarbide. In a preferred embodiment, R10ais stands, ethyl, a straight, branched or cyclic propylene, straight, branched or cycle the definition bootrom, straight, branched or cyclic hexyl, straight or branched propanolol, Isobutanol, fullam or Tienam. In another embodiment, R10ais substituted by ethyl, substituted by propylene (a straight, branched or cyclic), substituted by propanolol (straight or branched)substituted by Isobutanol, replaced by fullam or substituted by tanila, where the substituent(s) selected(s) from the group consisting of heterocycle, alkoxy, alkenone, alkyloxy, aryloxy, hydroxy, protected hydroxy, geograpy, alloctype, nitro, amino, aminogroup, Colnago, catalogo, acatalog, ester or ether fragments, but not phosphorus-containing fragments.

Examples of the substituents X3include substituted or unsubstituted With2-C8alkyl, substituted or unsubstituted With2-C8alkenyl, substituted or unsubstituted With2-C8quinil, substituted or unsubstituted heteroaromatic group containing 5 or 6 atoms in the ring, and substituted or unsubstituted phenyl. Preferred substituents X3include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutyl, furyl, thienyl and pyridyl.

Examples of the substituents X5include-MOR10, -COOH10or CONHX10where X10is C is displaced or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic group. Preferred examples of the substituents X5include-MOR10, -COOH10or CONHX10where X10is (i) substituted or unsubstituted With1-C8the alkyl, 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-C8the quinil, such as, substituted or unsubstituted ethinyl, PROPYNYL (straight or branched), butynyl (straight or branched), pentenyl (straight or branched) or hexenyl (straight or branched); (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic group such as furyl, thienyl or pyridyl, where the substituent(s) selected(s) from the group consisting of heterocycle, alkoxy, alkenone, alkyloxy, aryloxy, hydroxy, protected what about hydroxy, ketogroup, alloctype, nitro, amino, aminogroup, Colnago, catalogo, acatalog, ester or ether fragments, but not phosphorus-containing fragments.

In one embodiment of the invention taxanes of the present invention corresponds to the structure (2):

where

R7is a hydroxy-group;

R10is carbonate;

X3is substituted or unsubstituted alkyl, alkenyl, quinil or heterocycle, where the alkyl comprises at least two carbon atoms;

X5is-SOH10, -COOH10or CONHX10; and

X10is hydrocarbon, substituted hydrocarbon or heterocycle.

For example, in this preferred embodiment, in which taxon corresponds to the structure (2), R10may be R10aOCOO-, where R10ais substituted or unsubstituted stands, ethyl, propylene, bootrom, Pentium or hexyl, more preferably substituted or unsubstituted stands, ethyl or propylene, more preferably substituted or unsubstituted stands, ethyl, and most preferably unsubstituted stands or ethyl. When R10aselected from the above, in one embodiment, X3selected from substituted or unsubstituted alkyl, alkenyl, phenyl or CGU is erotica, more preferably from substituted or unsubstituted, alkenyl, phenyl or heterocycle, more preferably from substituted or unsubstituted phenyl or heterocycle, and most preferably from substituted or unsubstituted heterocycle, such as furyl, thienyl or pyridyl. When R10aand X3selected from the above, in one embodiment, X5choose from SOKH10where X10is a phenyl, alkyl or heterocycle, more preferably a phenyl. Alternatively, when R10Aand X3selected from the above, in one embodiment, X5choose from SOKH10where X10is a phenyl, alkyl or heterocycle, more preferably a phenyl, or X5is COOH10where X10is alkyl, preferably tert-bootrom. Among the most preferred options are taxanes corresponding to the structure 2 in which (i) X5is COOH10where X10is tert-bootrom or X5is-SOH10where X10is phenyl, (ii) X3is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocycle, more preferably a substituted or unsubstituted Isobutanol, phenyl, fullam, tanila or pyridium, even more preferably unsubstituted Isobutanol, fullam, tie the sludge or pyridium, and (iii) R10ais unsubstituted stands, ethyl or propylene, more preferably - stands or ethyl.

Among the preferred options are taxanes corresponding to the structure 1 or 2, where R10is an R10aOCOO-, where R10ais stands. In the specified case X3preferably is cycloalkyl, Isobutanol or heterocycle, more preferably a heterocycle, more preferably fullam, tanila or pyridium; a X5preferred is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl. In one alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-b is oxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is a hydroxy-group, and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is hydro what syrupy and R 14is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is alloctype and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9- alloctype and R14- gidrogrupp. In each of the alternatives of this embodiment in the case, if Texan has the structure 1, R7and R10each may have the stereochemical configuration beta, R7and R10each may have the stereochemical configuration of alpha, R7may have the stereochemical configuration of alpha, whereas R10has the stereochemical configuration beta or R7may have the stereochemical configuration beta, whereas R10has the stereochemical configuration is a function of alpha.

Also among preferred embodiment variants of the invention are taxanes corresponding to the structure 1 or 2, where R10is an R10aOCOO-, where R10ais ethyl. In the specified case X3preferably is cycloalkyl, Isobutanol, phenyl, substituted phenyl such as p-nitrophenyl, or heterocycle, more preferably a heterocycle, more preferably fullam, tanila or pyridium; a X5preferred is benzoyl, alkoxy-carbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm. In one alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-what ethoxycarbonyl; R2is benzoyl, R9is catography and R14is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is a hydroxy-group, and R14is a hydroxy-group. In another alternative embodiment of this variant X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is a hydroxy-group, and R14is gidrogrupp. In the other is an alternative version of this embodiment X 3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is alloctype and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, r9is alloctype and R14is gidrogrupp. In each of the alternatives of this embodiment in the case, if Texan has the structure 1, R7and R10each may have the stereochemical configuration beta, R7and R10each may have the stereochemical configuration of alpha, R7may have the stereochemical configuration of alpha, whereas R10has the stereochemical configuration beta or R7may have the stereochemical configuration beta, whereas R10has the stereochemical configuration of the alpha.

Also among the preferred options of the incarnation from which retene are taxanes, corresponding to the structure 1 or 2, where R10is an R10aOCOO-, where R10ais propylene. In the specified case X3preferably is cycloalkyl, Isobutanol, phenyl, substituted phenyl such as p-nitrophenyl, or heterocycle, more preferably a heterocycle, more preferably fullam, tanila or pyridium; a X5preferred is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm. In one alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14 is gidrogrupp. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is catography and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is a hydroxy-group, and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is a hydroxy-group, and R14is gidrogrupp. In another alternative of this embodiment X3is GE what eroticka; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is alloctype and R14is a hydroxy-group. In another alternative of this embodiment X3is heterocycle; X5is benzoyl, alkoxycarbonyl or heterocyclisation, more preferably a benzoyl, tert-butoxycarbonyl or tert-meloxicalm, even more preferably tert-butoxycarbonyl; R2is benzoyl, R9is alloctype and R14is gidrogrupp. In each of the alternatives of this embodiment in the case, if Texan has the structure 1, R7and R10each may have the stereochemical configuration beta, R7and R10each may have the stereochemical configuration of alpha, R7may have the stereochemical configuration of alpha, whereas R10has the stereochemical configuration of the beta, or R7may have the stereochemical configuration beta, whereas R10has the stereochemical configuration of the alpha.

Taxanes having the General formula 1 can be obtained by processing β-lactam, Alcock the home, having taxonomie tetracyclic nucleus and the metal oxide zamestitel at C-13 to form compounds having β-aminoclonazepam Deputy With(13), which is more fully described in U.S. patent 5466834 issued to Holton, with the subsequent removal of the protection of the hydroxy-group.

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

where P2is hydroxyamino group, and X3and X5defined above, and the alkoxide has the structural formula (4):

where M represents a metal or ammonium, P7is hydroxyamino group, a R10defined above.

The alkoxide can be obtained from 10-deacetylbaccatin III selective formation of carbonate C-10 hydroxyl groups, and then protecting the C-7 hydroxy-group (as more fully described in Holton et al., the PCT application WO 99/09021), followed by treatment with Amida metal. Alleluya agents that can be used for the selective acylation of C(10) hydroxyl group taxane include dimethyldicarbonate, diethylcarbamyl, di-tert-BUTYLCARBAMATE, dibenzyldithiocarbamate and the like. Although the acylation With(10) hydroxyl group taxane occurs with sufficient speed with many allerease agents, it was found that the reaction rate can be increased with the introduction of reaktsionnuyu mixture of Lewis acids. The preferred Lewis acid include zinc chloride, tin chloride, trichloride cerium chloride shallow, trichloride lanthanum, trichloride of dysprosium and trichloride ytterbium. Zinc chloride and cerium chloride are particularly preferable if allermuir agent is dicarbonate.

Derivatives of 10-deacetylbaccatin III with alternative substituents at C(2), (9) and(14), and methods for their production are known in the art. Taxonomie derivative having allacciamento other than benzoyloxy With(2)can be obtained, for example, as described in U.S. patent 5728725, issued with Holton al., or in U.S. patent 6002023 issued to Kingston with TCS. Taxanes having acyloxy or hydroxysultaine With (9) instead of ketogroup can be obtained, for example, as described in U.S. patent 6011056, issued with Holton al., or in U.S. patent 5352806 issued gunawardana with TCS. Taxanes having a beta hydroxysultaine With(14), can be obtained from natural 14-hydroxy-10-deacetylbaccatin III.

Methods of obtaining and allocating the original β-lactam in General well known. For example, β-lactam can be obtained, as described in U.S. patent 5430160 issued to Holton, and the resulting enantiomeric mixture β-lactams can be divided stereoselective hydrolysis using a lipase or f is of rment, as described, for example, in U.S. patent 5879929, issued to Patel, in U.S. patent 5567614, issued to Patel, or homogenizate liver, as described, for example, in patent application PCT 00/41204. In the preferred embodiment, when β-lactam is substituted With(4) fullam, β-lactam can be obtained, as shown in the following reaction scheme:

Stage And

where AC denotes acetyl, NEt3means triethylamine, CAN indicates nitrate cerium-ammonium (NCA)and p-TsOH denotes p-toluensulfonate acid. Separation using bovine liver can be performed, for example, the Association of enantiomeric mixtures β-lactams suspension bovine liver (obtained, for example, by adding 20 g of frozen bovine liver in the mixer and the subsequent addition of a buffer with pH 8 to a final volume of 1 l).

The compounds of formula 1 of this invention are useful for inhibiting tumor growth in mammals, including humans, and is preferably introduced in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the present invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier. The carrier, also referred to in this field as excipient, filler, excipient, adjuvant, or diluent, is any substance which is pharmaceutically inert, gives the composition a suitable consistency or form and does not reduce therapeutic efficacy of antitumor compounds. The media is a "pharmaceutically or pharmacologically acceptable"if he does not give adverse, allergic or other untoward reactions when administered to a mammal or human, if necessary.

Pharmaceutical compositions containing anti-tumor compounds of this invention can be made by any of the conventional ways. The right way to build depends on the selected route of administration. The composition of the invention can be formulated for any route of administration, if the target tissue is available in this way. Suitable routes of administration include, but are not limited to these, oral, parenteral (e.g. intravenous, vnutriarterialno, subcutaneous, rectal, subcutaneous, intramuscular, vnutrioblastnoe, vnutricapsulino, intraspinal, intraperitoneal or vnutrigrudne), local (nasal, intradermal, intraocular), introduction into the bladder, intrathecal, internal, pulmonary, WinUtilities, intracavitary, vaginal, transurethral, intradermal, ear, introduction to the mammary glands is, buccal, orthotopic, intratracheal, oral administration of pathology, percutaneous, endoscopic, introduction through the mucosa, sublingual and putting in the introduction.

Pharmaceutically acceptable carriers for use in the compositions of this invention are well known to the average person skilled in the art and are selected based on a number of factors: the specific antitumor substance, its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the patient's age, weight and General condition; the route of administration. Suitable carrier materials can be easily determined by the average person skilled in the art (see, for example, J.G.Nairn, in: Remington''s Pharmaceutical Sciences (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp.1492-1517, the content of which is incorporated by reference).

Preferably the compositions are in the form of tablets, designerwear powders, pills, capsules, gelatin capsules, dripping, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, tablets, pills, candies or any other dosage forms that can be administered orally. Methods and compositions for the preparation of oral dosage forms used in this invention, described below is the links: 7 Modern Pharmaceutics, Chapter 9 and 10 (Banker &Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction of Pharmaceutical Dosage Forms 2ndEdition (1976).

Compositions of the present invention for oral administration include an effective amount of the compounds of the present invention and a pharmaceutically acceptable carrier. Suitable carrier materials for solid dosage forms include sugars, starches and other common compounds, including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium salt of saccharin, magnesium carbonate, tragant, microcrystalline cellulose, colloidal silicon dioxide, sodium salt croscarmellose, talc, magnesium stearate and stearic acid. Further, such solid dosage forms may not be covered or coated by known techniques; for example, to delay disintegration and absorption.

Antitumor compounds of this invention also preferably are prepared for parenteral administration, for example, are prepared for intravenous, intraarterial, subcutaneous, rectal, intramuscular, lower eyelid, vnutrikoronarnogo, intraspinal, intraperitoneal or intrasternal ways BB is Denia. The composition of this invention for parenteral administration include an effective antitumor amount of antitumor compounds in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions, or any other dosage form, which may be introduced parenterally. Methods and compositions for the preparation of parenteral dosage forms known in the art.

Suitable carrier materials used in the preparation of liquid dosage forms for oral or parenteral administration include non-aqueous 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 are not limited to these, alcohols (for example, α-glycerolphosphate, β-glycerolphosphate, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms, such as methanol, ethanol, propanol, isopropanol, butanol, tertbutanol, hexanol, octanol, ailinger, Ben is silt alcohol, glycerin, glycol, hexyleneglycol, tetrahydrofurfuryl alcohol, lauric alcohol, cetyl alcohol or stearyl alcohol; esters of fatty acids and fatty alcohols such as polyalkylene glycols (e.g., polypropylenglycol, polyethylene glycol), sorbitan, sucrose or cholesterol; amides (for example, dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(β-hydroxyethyl)lactamide, amides (N,N-dimethylacetamide, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidine); esters (for example, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, acetate esters, such as monoacetin, diacetin and triacetin, 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 and sorbitan, esters PEG-based fatty acids, glycerylmonostearate, glycerine esters, such as mono-, di - or triglycerides, esters of fatty acids, such as isopropylmyristate, esters PEG-based fatty acids, such as PEG-hydroxyoleic and PEG-hydroxystearate, N-methylpyrrolidinone, pluronic 60, complex oleic polyesters of policies is inserbia, such as poly(ethoxylated)30-60sorbitol(oleate)2-4, poly(oksietilenom)15-20monooleate, poly(oksietilenom)15-20mono-hydroxystearate and poly(oksietilenom)15-20monoricinoleate, esters of polyoxyethylenesorbitan, such as polyoxyethylene sorbitan monooleate, polyoxyethylenesorbitan, polyoxyethylenesorbitan, polyoxyethylenesorbitan, Polysorbate® 20, 40, 60 or 80 production of ICI Americas, Wilmington, DE, polyvinylpyrrolidone, alkilalkoksimyetilfosfinov esters of fatty acids, such as gidrirovannoe castor oil polyoxyl 40 and polyoxyethylene castor oil (for example, a solution of Cremophor® EL or Cremophor solution® RH 40), esters of fatty acid saccharide (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose lyxose, xylulose, hexoses, such as glucose, fructose, galactose, mannose and sorbose, trios, tetras, Gatos and octos), disaccharide (e.g. sucrose, maltose, lactose and trehalose), or oligosaccharide, or their mixtures with fatty(s) acid(s)4-C22(for example, saturated fatty acids such as Caprylic acid, hexanoic acid, lauriola acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such to the to palmitoleic acid, oleic acid, elaidic, erucic, linoleic acid)), or steroid esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimetridazole, monotropy ether of diethylene glycol); glycoluril (simple ester of polyethylene glycol and tetrahydrofurfuryl alcohol); ketones having 3-30 carbon atoms (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms (for example, benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolan, tetramethylarsonium, tetramethylsilane, toluene, dimethylsulfoxide (DMSO) or tetramethylsilane); oils of mineral, plant, animal, natural or synthetic origin (e.g., mineral oils such as aliphatic or paraffinic hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, Tung, safflower, soybean, castor, cottonseed, peanut oil, rapeseed, coconut, palm, olive, corn oil from corn germ, sesame, peach oil and oil of groundnuts and glycerides, such as mono-, di - or triglycerides, animal oils such as fish oil, seal oil, spermaceti, fat of cod liver oil, fat from the liver, halibut, squalene, squalane and oil from shark liver, oleic oils and polyoxyethylene castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen Deputy; methylene chloride; monoethanolamine; gasoline fraction oil; trolamine; omega-3 polyunsaturated fatty acids (for example, alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid); compound polyglycolide esters of 12-hydroxystearate acid and polyethylene glycol (Solutol® HS-15 production BASF, Ludwigshafen, Germany); polyoxyethyleneglycol; sodium laurate; sodium oleate or servicemanual.

Other pharmaceutically acceptable solvents for use in the invention are well known to the average person skilled in the art and defined in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics (G.Banker et al., 3rd ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms (H.Lieberman et al., eds.) (Marcel Dekker, Inc., New York, New York, 1980), Remington''s Pharmaceutical Sciences (A.Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulry 19, (National Publishing, Philadelphia, PA, 2000), A.J.Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, Jourlal of Pharmaceutical Science, Vol.52, No.10, pp.917-927 (1963).

Preferred solvents include, for whom it is established that they stabilize antitumor compounds, such as oils, enriched with triglycerides, for example, safflower oil, soybean oil and mixtures thereof, and alkilalkoksimyetilfosfinov esters of 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). Industrial output triglycerides include emulsified soybean oil Intralipid® (Kabi-Pharmacia Inc., Stockholm, Sweden), emulsion Nutralipid® II (McGraw, Irvine, California), 20% emulsion (Liposyn® (20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per 1 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 of glycerin in 1 ml of solution; Abbot Laboratories, Chicago, Illinois), natural or synthetic derivatives of glycerol, containing docosahexaenoyl group ranging from 25% to 100% (mass.) of the total content of fatty acids (Dhasco® (produced by Martek Biosciences Corp., Columbia, MD), DHA Maguro® (manufactured by Daito Enterprises, os Angeles, CA), Soyacol® and Travemulsion®. Ethanol is the preferred solvent when used for dissolution of antitumor compounds in obtaining solutions, emulsions and the like.

Auxiliary components may be included in the compositions in accordance with the invention for various purposes are well known in the pharmaceutical industry. These components are mainly to improve properties that enhance the retention of antitumor compounds in the injection site, maintain the stability of the composition, adjust pH, facilitate the transfer of antitumor compounds in pharmaceutical compositions and the like. Preferably, each of these components are present in amounts less than 15% (mass.) of the total weight of the composition, more preferably in quantities of less than 5% (mass.) of the total weight of the composition, and most preferably in amounts of less than 0.5% (mass.) of the total weight of the composition. Some components, such as fillers or diluents, can be up to 90% (mass.) of the total weight of the composition, which is well known in the technology of compositing. Such additives include cryoprotectants to prevent re-deposition taxane, surfactants, wetting or emulsifying agents (e.g. lecithin, Polysorbate-80, TWIN®80, pluronic is 60, politiestaat), preservatives (for example, ethyl-parahydroxybenzoate), antimicrobial preservatives (e.g. benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for regulating the pH or buffer agents (e.g., acids, bases, sodium acetate, sorbitanoleat), agents for regulating osmotic pressure (for example, glycerin), thickeners (for example, aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methylcellulose, hydroxypropylcellulose, tristearin, citylove wax esters, polyethylene glycol), pigments, dyes, fluidity modifiers, non-volatile silicones (for example, cyclomethicone), clay (e.g. bentonite), adhesives, agents, adds volume, flavors, sweeteners, adsorbents, fillers (for example, sugars such as lactose, saccharose, mannitol or sorbitol, cellulose or calcium phosphate), diluents (e.g., water, saline, solutions of electrolytes), binders (for example, starches such as maize starch, wheat starch, rice starch or potato starch, gelatin, tragant, methylcellulose, hypromellose, sodium salt carboxymethylcellulose, polyvinylpyrrolidone, sugars, polymers, acacia), dezintegriruetsja agents (e.g., starches, so the e as maize starch, wheat starch, rice starch, or potato starch, or karboksimetilirovaniya starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium alginate, sodium salt croscarmellose or crosspovidone), lubricants (for example, silicon dioxide, talc, stearic acid or its salts, such as magnesium stearate or polyethylene glycol), agents for coating (for example, concentrated solutions of sugar, including gum Arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide) and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols and thiophenol).

In a preferred embodiment, the pharmaceutical composition of the invention includes at least one non-aqueous pharmaceutically acceptable solvent and antitumor compound with a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml Regardless of the particular theory, it is assumed that the solubility of antitumor compounds in ethanol can be directly related to its effectiveness. Antitumor compound may also be able to crystallization from a solution. In other words, the crystalline antitumor compound, such as compound 1393, can be dissolved in the solvent with the coord is m solution, and then recrystallized by evaporation of the solvent without the formation of any amorphous antitumor compounds. Also preferably, the antitumor compound mattered ID50(that is, the concentration of drug causing 50% inhibition of the formation of the colony), at least in 4, 5, 6, 7, 8, 9 or 10 times less than for paclitaxel, when measured in accordance with methods described in the working examples.

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

Dosage and mode of administration of the pharmaceutical compositions of the invention can be easily determined by the average specialist in cancer treatment. It is clear that the dosage of anticancer compounds depends on age, sex, health and weight of the recipient, kind of concurrent treatment, if this is the place, frequency of treatment and the nature of the desired effect. For any method of introducing the actual number delivered anticancer compounds, as well as the mode of administration necessary to achieve favorable effects described here, also depends, in part, by such factors, the AK bioavailability of anticancer compounds disorder being treated, the desired therapeutic dose and other factors evident to the person skilled in the art. Dose, administered to an animal, particularly a human, in the context of this invention should be sufficient to achieve the desired therapeutic effect in the animal over a reasonable period of time. Preferably an effective amount of an antitumor compound, administered orally or by other means, is a quantity that can lead to the desired therapeutic effect by introduction of the specified path. Preferably compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of anticancer compounds on m2the body surface of the patient, or at least, 50, 100, 150, 200, 300, 400 or 500 mg of anticancer compounds on m2the body surface of the patient, if we assume that the average surface of the body of man is 1.8 m2. Preferably the unit dosage composition for oral administration contains from about 20 to 600 mg of anticancer compounds on m2the body surface of the patient, more preferably from about 25 to 400 mg/m2even more preferably from about 40 to 300 mg/m2and is more preferably from approximately 50 to 200 mg/m2. Preferably the composition for parenteral administration is prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of anticancer compounds on m2the body surface of the patient, or at least, 40, 50, 100, 150, 200, 300, 400 or 500 mg of anticancer compounds on m2the body surface of the patient. Preferably a single dose in one or more parenteral preparations contain from about 20 to 500 mg of anticancer compounds on m2the body surface of the patient, more preferably from about 40 to 400 mg/m2even more preferably from about 60 to 350 mg/m2. However, the dosage may vary depending on the destination, which may vary in the required direction to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided here is in no way limit the invention and represent preferred dose ranges. The most preferred dosage is chosen for each individual patient and is determined by the average person skilled in the art without any experiments.

The concentration of anticancer compounds in the liquid pharmaceutical composition of the local is seeking preferably between 0.01 mg and 10 mg/ml of the composition, more preferably between 0.1 mg and 7 mg/ml, even more preferably between 0.5 mg and 5 mg/ml and most preferably between 1.5 mg and 4 mg/ml of Relatively low concentrations in General are preferred because of the antitumor compound more soluble in solution at low concentrations. The concentration of anticancer compounds in a solid pharmaceutical composition for oral administration is preferably between approximately 5% (mass.) and 50% (mass.) of the total weight of the composition, more preferably between about 8% (mass.) and 40% (mass.) and most preferably between approximately 10% (mass.) and 30% (wt.)

In one embodiment, the solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. The appropriate volume of media, which solution such as a solution of Cremophor® EL, was added with stirring to the solution with formation of a pharmaceutically acceptable solution for oral administration to a patient. If required, these solutions can be designed to contain the minimum number, or does not contain ethanol, which is known in danniebelle equipment, showing adverse physiological effects when injected into certain concentrations in oral compositions.

In another embodiment, powders or tablets for oral administration obtained by dissolution of the antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. The optional solvent may be able to evaporation during drying of the solution in vacuum. Before drying the solution can be added additional media, such as a solution of Cremophor® EL. The resulting solution was dried in a vacuum with the formation of substances in the form of glass. This glass is then mixed with a binder to form a powder. The powder can be mixed with fillers or other generally accepted in the pelletizing agents and processed to obtain tablets for oral administration to a patient. The powder can also be added to any liquid medium, as described above, with formation of a solution, emulsion, suspension or the like for oral administration. Emulsion for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) OBR is reattaching the solution. Under stirring to the solution add the appropriate volume of media, which is an emulsion, such as Liposyn® Liposyn II or® III, with the formation of pharmaceutically acceptability emulsion for parenteral administration to a patient. If required, such emulsions can be prepared so that they contain the minimum number or does not contain ethanol or a solution of Cremophor®which, as is known in the art, have adverse physiological effects when injected into certain concentrations in parenteral formulations.

Solutions for parenteral administration can be obtained by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. Under stirring to the solution add an appropriate volume of media that is solution such as a solution of Cremophor®, with the formation of pharmaceutically acceptable solution for parenteral administration to a patient. If required, these solutions can be designed to contain the minimum number or does not contain ethanol or a solution of Cremophor®which, as is known in the art, have adverse physiological effects at rst the situation in certain concentrations in parenteral formulations.

If required, the above-described emulsions or solutions for oral or parenteral doing can be put up in packing for intravenous injection, ampoule or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, such as saline solution before applying to get a reasonable concentration taxane, as is known in the art.

Definition

The terms "hydrocarbon" and "hydrocarbon"used in this description represent organic compounds or radicals consisting exclusively of carbon atoms and hydrogen. These fragments include alkyl, alkeline, alkyline and aryl fragments. These fragments also include alkyl, alkeline, alkyline and aryl fragments replaced by other aliphatic or cyclic hydrocarbon groups such as alkaryl, alkenyl and alkylaryl. Unless otherwise specified, these fragments preferably comprise from 1 to 20 carbon atoms.

"Substituted gidrolabilna" fragments described above are hydratability fragments, substituted by at least one atom other than carbon, including fragments, in which the atom in the carbon chain substituted by a heteroatom, such as nitrogen, oxygen, silicon, f is the SFOR boron, sulfur, or a halogen atom. These substituents include halogen, heterocycle, alkoxygroup, allinoneruby, allinoneruby, alloctype, the hydroxy-group, a protected hydroxy-group, Citigroup, acyl group, alloctype, the nitro-group, amino group, aminogroup, cyano, Tilney group, ketals, acetals, esters and ethers.

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

Unless otherwise specified, alkeline group described above preferably are lower alkeneamine group containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They can have straight or branched chain, or be circular and include ethynyl, propenyl, Isopropenyl, butenyl, hexenyl and the like.

Unless otherwise specified, alkyline group described above preferably are lower alkyline group containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms is kind. They can have straight or branched chain, or be circular and include ethinyl, PROPYNYL, Isopropenyl, butenyl, hexenyl and the like.

The terms "aryl" or "Ar"as used alone or as part of another group denote optionally substituted homozygotes aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are preferred Allami.

The terms "halogen" or "halogen", used alone or as part of another group, denote chlorine, bromine, fluorine and iodine.

The terms "heterocycle" or "heterocyclic"as used alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic group having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atom and/or 1 to 4 nitrogen atoms in the ring and can be connected with the rest of the molecule through a carbon atom or heteroatom. Examples Goethe is of acyclov include heteroaromatic, such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, chinoline or ethenolysis and the like. Examples of the substituents include one or more of the following groups: hydrocarbon, substituted hydrocarbon, Citigroup, the hydroxy-group, a protected hydroxy-group, acyl, alloctype, alkoxygroup, allinoneruby, allinoneruby, alloctype, halogen, aminogroup, an amino group, a nitrogroup, cyano, thiol, ketals, acetals, esters and ethers.

The term "heteroaromatic"used alone or as part of another group, denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. Heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atom and/or 1 to 4 nitrogen atoms in the ring and can be connected with the rest of the molecule through a carbon atom or heteroatom. Examples of heteroaromatic compounds include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, chinoline or ethenolysis and the like. Examples of the substituents include one or more of the following groups: hydrocarbon, substituted hydrocarbon, Citigroup, the hydroxy-group, a protected hydroxy-group, acyl, alloctype, alkoxygroup, allinoneruby, is linuxhippy, alloctype, halogen, aminogroup, an amino group, a nitrogroup, cyano, thiol, ketals, acetals, esters and ethers.

The term "acyl"used alone or as part of another group, refers to a fragment obtained by removing the hydroxy-group of the group-COOH of an organic carboxylic acid, for example R(C)O-, where R is an R1, R1O-, R1R2N or R1S-, R1is hydrocarbon, heterogametes hydrocarbon or heterocycle, and R2is a hydrogen atom, hydrocarbon or substituted hydrocarbon.

The term "acyloxy", used alone or as part of another group, denotes an acyl group as described above attached via an oxygen linkage (-O-), for example, RC(O)O-, where R is defined in accordance with the term "acyl".

Unless otherwise specified, alkoxycarbonylmethyl described above, include a lower hydrocarbon, or substituted hydrocarbon, or substituted hydrocarbon fragments.

Unless otherwise specified, carbamoyloximes described above, are derived from carbamino acid in which one or both of the hydrogen atoms of an amino group optionally substituted hydrocarbonyl, substituted hydrocarbonyl or heterocyclic fragment.

The term "protective group of hydroxyl" or "hydroxy is safety group", used above, refers to a group capable of protecting a free hydroxyl group ("protected hydroxyl"), which, after the reaction, is used for protection, can be removed without changes to the rest of the molecule. A variety hydroxyamine groups and their syntheses can be found in "Protective Groups in Organic Synthesis" .W.Green, John Wiley and Sons, 1981 or in Fieser &Fieser. Examples hydroxyamine groups include methoxymethyl, 1-ethoxyethyl, benzoyloxymethyl, (β-trimethylsilyloxy)methyl, tetrahydropyranyl, 2,2,2-trichlorocyanuric, tert-butyl (diphenyl) silyl, trialkylsilyl, trichloromethylcarbnol and 2,2,2-trichloroacetyl.

Used abbreviations: "AC" means acetyl; "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "iPr" means isopropyl; "tBu" represents tert-butyl; "R" means lower alkyl, unless otherwise specified; "PY" represents pyridine or pyridyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "LAH" means socialogical; "10-DAB" means 10-deacetylbaccatin III; "aminosidine group" includes, but is not limited to these, carbamates, for example, 2,2,2-trichlorethylene or verbatiminput; "protected hydroxyl" means-OR, where R is hydroxyamino group; "tBuOCO" and "BOC" refers to tert-butoxy bonil; "tAmOCO" means tert-aryloxyalkyl; "PnCO" means phenylcarbinol; "2-FuCO" denotes 2-fullcarbon; "2-ThCO" denotes 2-thienylboronic; "2-Eng" denotes 2-pyridylcarbonyl; "3-Rus" means 3-pyridylcarbonyl; "4-Rus" means 4-pyridylcarbonyl; "C4H7WITH" means butylcarbamoyl; tC3H5CO" means the TRANS-propenylboronic; "EtOCO" means etoxycarbonyl; "iBueCO" means isobutylketone; "iBuCO" means isobutylketone; "iBuOCO" means isobutoxide; "iPrOCO" means isopropoxycarbonyl; "nPrOCO" denotes n-propylenecarbonate; "nPrCO" denotes n-propylboronic; "iBue" means Isobutanol; "THF" refers to tetrahydrofuran; "DMAP" refers to 4-dimethylaminopyridine; "LHMDS" means lithium hexamethyldisilazane.

The following examples illustrate the invention.

Example 1

10-Etoxycarbonyl-10-deazetil baccatin III. To the mixture 0,941 g (1,73 mmol) 10-deacetylbaccatin III and 0,043 g (0,17 mmol) CeCl3in 40 ml of THF at 25°With gain of 0.64 ml (4,32 mmol) diethylpyrocarbonate. After 3 hours regional mixture is diluted with 200 ml EtOAc, then washed three times with 5 ml saturated aqueous solution of NaHCO3and a saturated solution of salt. The organic extract is dried over Na2SO4and concentrated in vacuo. The crude tortoiseshell clear column flash chromatography on silica gel, using as eluent EtOAc/hexane, get 0,960 g (90%) 10-etoxycarbonyl-10-deazetil baccatin III in the form of solids.

7-Dimethylphenylsilane-10-etoxycarbonyl-10-deazetil baccatin. III. To a solution of 1.02 g (of 1.65 mmol) 10-etoxycarbonyl-10-deazetil baccatin III in 30 ml of THF at -10°C in nitrogen atmosphere are added dropwise 0,668 ml (4.00 mmol) of chlorodimethylvinylsilane and 2.48 ml (30,64 mmol) of pyridine. After 90 minutes the mixture is diluted with 200 ml of a mixture of ethyl acetate:hexane 1:1. The mixture was washed with 30 ml saturated aqueous Nestor sodium bicarbonate and separate the organic layer. The aqueous layer was extracted with 50 ml of a mixture of ethyl acetate:hexane 1:1, the combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo. The crude solid is purified column flash chromatography on silica gel, using as eluent 30% EtOAc/hexane, gain of 1.16 g (94%) 7-dimethylphenylsilane-10-etoxycarbonyl-10-deazetil baccatin III in the form of solids. Range1H NMR (400 MHz, CDCl3): 8,09 (DM, J=of 7.64 Hz, 2H, benzoate, o), to 7.59 (TT, J=7,54, 1,43 Hz, 1H, benzoate, p), EUR 7.57 (m, 2H, phenyl, o), 7,46 (t, J=rate of 7.54 Hz, 2H, benzoate, m), 7,37-7,33 (m, 3H, phenyl, m,p), 6,21 (s, 1H, H10), 5,63 (d, J=7,05 Hz, 1H, H2), 4,87-4,80 (m, 2H, H5 and H13), of 4.44 (DD, J=6,84, 10,37 Hz, 1H, H7), 4,27 (d, J=8,27 Hz, 1H, Na), 4,16 (KVM, J=7,00 Hz, 2H, CH3-CH2-), 4,13 (d, J=8,27 is C, 1H, 20b), 3,83 (d, J=7,05 Hz, 1H, H3), was 2.34 (DDD, J=6,84, 9,63, 14,66 Hz, 1H, Na), and 2.26 (d, J=7,65 Hz, 2H, H14a,b in), 2.25 (s, 3H, AC4), 2,03 (s, 3H, Me), to 1.98 (d, J=of 5.29 Hz, 1H, SN), or 1.77 (DDD, J=2,12, 10,37, 14,66 Hz, 1H, H6b), 1,73 (s, 1H, Me), 1,59 (s, 1H, ClOH), 1,32 (t, J=7,00 Hz, 3H, CH3-CH2-), 1,19 (s, 3H, Me), of 1.07 (s, 3H, Me), of 0.45 (s, 3H), PhMe2Si-), 0,35 (s, 3H), PhMe2Si-).

7-Dimethylphenylsilane-2'-O-triethylsilyl-3'-destiny-3'-(2-thienyl)-10-etoxycarbonyl-10-deazetil Taxotere. To a solution of 0,409 g (0,544 mmol) 7-dimethylphenylsilane-10-etoxycarbonyl-10-deazetil baccatin III 5.5 ml of THF at -45°C in an atmosphere of nitrogen was added 0,681 ml (0,681 mmol) of 1M solution of LHMDS in THF. After 1 hour slowly added a solution of MX 0.317 g (0,818 mmol) of CIS-N-benzoyl-3-triethylsilyl-4-(2-thienyl)azetidin-2-it's in 3 ml of THF. The mixture is heated to 0°and after 3 hours, add 10 ml of a saturated aqueous solution of sodium bicarbonate and the mixture extracted three times with 50 ml of ethyl acetate. The combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo. The crude product is purified column flash chromatography on silica gel, using as eluent 40% EtOAc/hexane, get 0,574 g (93%) 7-dimethylphenylsilane-2'-O-triethylsilyl-3'-destiny-3'-(2-thienyl)-10-etoxycarbonyl-10-deazetil of Taxotere in the form of solids.

3'-Destiny-3'-(2-t is enyl)-10-etoxycarbonyl-10-deazetil Taxotere. To a solution of 0,527 g (0,464 mmol) 7-dimethylphenylsilane-2'-O-triethylsilyl-3'-destiny-3'-(2-thienyl)-10-etoxycarbonyl-10-deazetil of Taxotere in 2 ml of CH3CN and 2 ml of pyridine at 0°add 0.5 ml of 30% HF in H2O. After 3 hours, add 20 ml of a saturated aqueous solution of sodium bicarbonate and the mixture extracted three times with 50 ml of ethyl acetate. The combined organic extracts washed with saturated salt solution, dried over Na2SO4and concentrated in vacuo. The crude product is purified column flash chromatography on silica gel, using as eluent 70% EtOAc/hexane, get 0,411 g (100%) 3'-destiny-3'-(2-thienyl)-10-etoxycarbonyl-10-deazetil of Taxotere in the form of solids. TPL-161°; [α]D25=-59,1 (1.0 CH2Cl2); Analysis, C44H55NO16S calculated: C, 59,65; N, of 6.26; found: C, 59,39; N, 6,34.

Spectrum data1H NMR (500 MHz, CDCl3) 3'-destiny-3'-(2-thienyl)-10-etoxycarbonyl-10-deazetil of Taxotere (500 MHz, CDCl3)

Example 2

Repeat the operations described in example 1, but other suitably protected β-lactam replace β-lactam of example 1 to obtain a series of compounds having the structural formula (13) and the combination of the substituents defined in the table below.

Example 3

The methods described in example 1 or elsewhere in this text, can be obtained from the following specific taxanes having structural formula 14, where R10defined above, including R10representing R10aOCOO-, and R10arepresents (i) a substituted or unsubstituted alkyl, C1-C8such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl or hexyl; (ii) substituted or unsubstituted of alkenyl3-C8such as propenyl or a straight, branched or cyclic butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted quinil3-C8such as PROPYNYL or a straight, branched or cyclic butenyl, pentenyl or hexenyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic group, such as pyridyl. Substituents can be substituted hydrocarbide defined elsewhere in this text. For example, R10may be R10aOCO-, where R10arepresents methyl, ethyl or a linear, branched or cyclic propyl.

X5sub> 3R10
tBuOCO2-furylRaOCOO-
tBuOCO3-furylRaOCOO-
tBuOCO2-thienylRaOCOO-
tBuOCO3-thienylRaOCOO-
tBuOCO2-pyridylRaOCOO-
tBuOCO3-pyridylRaOCOO-
tBuOCO4-pyridylRaOCOO-
tBuOCOIsobutanolRaOCOO-
tBuOCOisopropylRaOCOO-
tBuOCOcyclopropylRaOCOO-
tBuOCOcyclobutylRaOCOO-
tBuOCOcyclopentylRaOCOO-
tBuOCOphenylRaOCOO-
benzoyl2-furylRaOCOO-
benzoyl3-furylRaOCOO-
benzoyl2-thienylRaOCOO-
benzoyl3-thienylRaOCOO-
baseoil2-pyridylRaOCOO-
benzoyl 3-pyridylRaOCOO-
benzoyl4-pyridylRaOCOO-
benzoylIsobutanolRaOCOO-
benzoylisopropylRaOCOO-
benzoylcyclopropylRaOCOO-
benzoylcyclobutylRaOCOO-

benzoylcyclopentylRaOCOO-
benzoylphenylRaOCOO-
2-FuCO-2-furylRaOCOO-
2-FuCO-3-furylRaOCOO-
2-FuCO-2-thienylRaOCOO-
2-FuCO-3-thienylRaOCOO-
2-FuCO-2-pyridylRaOCOO-
2-FuCO-3-pyridylRaOCOO-
2-FuCO-4-pyridylRaOCOO-
2-FuCO-IsobutanolRaOCOO-
2-FuCO-isopropylRaOCOO-
2-FuCO-cyclopropyl.RaOCOO-
2-FCO- cyclobutylRaOCOO-
2-FuCO-cyclopentylRaOCOO-
2-FuCO-phenylRaOCOO-
2-ThCO-2-furylRaOCOO-
2-ThCO-3-furylRaOCOO-
2-ThCO-2-thienylRaOCOO-
2-ThCO-3-thienylRaOCOO-
2-ThCO-2-pyridylRaOCOO-
2-ThCO-3-pyridylRaOCOO-
2-ThCO-4-pyridylRaOCOO-
2-ThCO-IsobutanolRaOCOO-
2-ThCO-isopropylRaOCOO-
2-ThCO-cyclopropylRaOCOO-
2-ThCO-cyclobutylRaOCOO-
2-ThCO-cyclopentylRaOCOO-
2-ThCO-phenylRaOCOO-
2-PyCO-2-furylRaOCOO-
2-PyCO-3-furylRaOCOO-
2-PyCO-2-thienylRaOCOO-
2-PyCO- 3-thienylRaOCOO-
2-PyCO-2-pyridylRaOCOO-
2-PyCO-3-pyridylRaOCOO-

2-Rus-4-pyridylRaOCOO-
2-Rus-IsobutanolRaOCOO-
2-Rus-isopropylRaOCOO-
2-Rus-cyclopropylRaOCOO-
2-Rus-cyclobutylRaOCOO-
2-Rus-cyclopentylRaOCOO-
2-Rus-phenylRaOCOO-
3-Rus-2-furylRaOCOO-
3-Rus-3-furylRaOCOO-
3-Rus-2-thienylRaOCOO-
3-Rus-3-thienylRaOCOO-
3-Rus-2-pyridylRaOCOO-
3-Rus-3-pyridylRaOCOO-
3-Rus-4-pyridylRaOCOO-
3-Rus-IsobutanolRaOCOO-
3-the uso- isopropylRaOCOO-
3-Rus-cyclopropylRaOCOO-
3-Rus-cyclobutylRaOCOO-
3-Rus-cyclopentylRaOCOO-
3-Rus-phenylRaOCOO-
4-Rus-2-furylRaOCOO-
4-Rus-3-furylRaOCOO-
4-Rus-2-thienylRaOCOO-
4-Rus-3-thienylRaOCOO-
4-Rus-2-pyridylRaOCOO-
4-Rus-3-pyridylRaOCOO-
4-Rus-4-pyridylRaOCOO-
4-Rus-IsobutanolRaOCOO-
4-Rus-isopropylRaOCOO-
4-Rus-cyclopropylRaOCOO-
4-Rus-cyclobutylRaOCOO-
4-Rus-cyclopentylRaOCOO-
4-Rus-phenylRaOCOO-
With4H7WITH-2-furyl RaOCOO-

With4H7WITH-3-furylRaOCOO-
With4H7WITH-2-thienylRaOCOO-
With4H7WITH-3-thienylRaOCOO-
With4H7WITH-2-pyridylRaOCOO-
With4H7WITH-3-pyridylRaOCOO-
With4H7WITH-4-pyridylRaOCOO-
With4H7WITH-IsobutanolRaOCOO-
With4H7WITH-isopropylRaOCOO-
With4H7WITH-cyclopropylRaOCOO-
With4H7WITH-cyclobutylRaOCOO-
With4H7WITH-cyclopentylRaOCOO-
With4H7WITH-phenylRaOCOO-
EtOCO-2-furylRaOCOO-
EtOCO-3-furylRaOCOO-
EtOCO-2-thienylRaOCOO-
EtOCO-3-thienylRaOCOO-
EtOCO-2-pyridylRaOCOO-
EtOCO-3-pyridylRaOCOO-
EtOCO-4-pyridylRaOCOO-
EtOCO-IsobutanolRaOCOO-
EtOCO-isopropylRaOCOO-
EtOCO-cyclopropylRaOCOO-
EtOCO-cyclobutylRaOCOO-
EtOCO-cyclopentylRaOCOO-
EtOCO-phenylRaOCOO-
iBueCO2-furylRaOCOO-
iBueCO-3-furylRaOCOO-
iBueCO-2-thienylRaOCOO-
iBueCO-3-thienylRaOCOO-
iBueCO-2-pyridylRaOCOO-
iBueCO-3-pyridylRaOCOO-
iBueCO-4-pyridylRaOCOO-
iBueCO-IsobutanolRaOCOO-

iBueCO-isopro the Il RaOCOO-
iBueCO-cyclopropylRaOCOO-
iBueCO-cyclobutylRaOCOO-
iBueCO-cyclopentylRaOCOO-
iBueCO-phenylRaOCOO-
iBuCO-2-furylRaOCOO-
iBuCO-3-furylRaOCOO-
iBuCO-2-thienylRaOCOO-
iBuCO-3-thienylRaOCOO-
iBuCO-2-pyridylRaOCOO-
iBuCO-3-pyridylRaOCOO-
iBuCO-4-pyridylRaOCOO-
iBuCO-IsobutanolRaOCOO-
iBuCO-isopropylRaOCOO-
iBuCO-cyclopropylRaOCOO-
iBuCO-cyclobutylRaOCOO-
iBuCO-cyclopentylRaOCOO-
iBuCO-phenylRaOCOO-
iBuOCO-2-furylRaOCOO-
iBuOCO-3-furyl RaOCOO-
iBuOCO-2-thienylRaOCOO-
iBuOCO-3-thienylRaOCOO-
iBuOCO-2-pyridylRaOCOO-
iBuOCO-3-pyridylRaOCOO-
iBuOCO-4-pyridylRaOCOO-
iBuOCO-IsobutanolRaOCOO-
iBuOCO-isopropylRaOCOO-
iBuOCO-cyclopropylRaOCOO-
iBuOCO-cyclobutylRaOCOO-
iBuOCO-cyclopentylRaOCOO-
iBuOCO-phenylRaOCOO-
iPrOCO-2-furylRaOCOO-
iPrOCO-3-furylRaOCOO-
iPrOCO-2-thienylRaOCOO-

iPrOCO-
iPrOCO-3-thienylRaOCOO-
iPrOCO-2-pyridylRaOCOO-
iPrOCO-3-pyridylRaOCOO-
iPrOCO-4-pyridylRaOCOO-
IsobutanolRaOCOO-
iPrOCO-isopropylRaOCOO-
iPrOCO-cyclopropylRaOCOO-
iPrOCO-cyclobutylRaOCOO-
iPrOCO-cyclopentylRaOCOO-
iPrOCO-phenylRaOCOO-
nPrOCO-2-furylRaOCOO-
nPrOCO-3-furylRaOCOO-
nPrOCO-2-thienylRaOCOO-
nPrOCO-3-thienylRaOCOO-
nPrOCO-2-pyridylRaOCOO-
nPrOCO-3-pyridylRaOCOO-
nPrOCO-4-pyridylRaOCOO-
nPrOCO-IsobutanolRaOCOO-
nPrOCO-isopropylRaOCOO-
nPrOCO-cyclopropylRaOCOO-
nPrOCO-cyclobutylRaOCOO-
nPrOCO-cyclopentylRaOCOO-
nPrOCO-phenylRaOCOO-
nPrCO-2-furylRaOCOO-
nPrCO-3-furylRaOCOO-
nPrCO-2-thienylRaOCOO-
nPrCO-3-thienylRaOCOO-
nPrCO-2-pyridylRaOCOO-
nPrCO-3-pyridylRaOCOO-
nPrCO-4-pyridylRaOCOO-
nPrCO-IsobutanolRaOCOO-
nPrCO-isopropylRaOCOO-
nPrCO-cyclopropylRaOCOO-
nPrCO-cyclobutylRaOCOO-

nPrCO-cyclopentylRaOCOO-
nPrCO-phenylRaOCOO-
tBuOCOcyclopentylEtOCOO-
baseoil3-furylEtOCOO-
benzoyl3-thienylEtOCOO-
benzoyl2-pyridylEtOCOO-
benzoyl3-pyridylEtOCOO-
benzoyl4-pyridylEtOCOO-/td>
benzoylIsobutanolEtOCOO-
benzoylisopropylEtOCOO-
benzoylcyclopropylEtOCOO-
benzoylcyclobutylEtOCOO-
benzoylcyclopentylEtOCOO-
benzoylphenylEtOCOO-
2-FuCO-3-furylEtOCOO-
2-FuCO-3-thienylEtOCOO-
2-FuCO-2-pyridylEtOCOO-
2-FuCO-3-pyridylEtOCOO-
2-FuCO-4-pyridylEtOCOO-
2-FuCO-IsobutanolEtOCOO-
2-FuCO-isopropylEtOCOO-
2-FuCO-cyclopropylEtOCOO-
2-FuCO-cyclobutylEtOCOO-
2-FuCO-cyclopentylEtOCOO-
2-FuCO-phenylEtOCOO-
2-ThCO-3-furylEtOCOO-
2-ThCO-3-thienylEtOCOO-
2-ThCO-2-pyridylEtOCOO-
2-ThCO-3-pyridyl EtOCOO-
2-ThCO-4-pyridylEtOCOO-
2-ThCO-IsobutanolEtOCOO-
2-ThCO-isopropylEtOCOO-
2-ThCO-cyclopropylEtOCOO-
2-ThCO-cyclobutylEtOCOO-

2-ThCO-cyclopentylEtOCOO-
2-ThCO-phenylEtOCOO-
2-PyCO-2-furylEtOCOO-
2-PyCO-3-furylEtOCOO-
2-PyCO-3-thienylEtOCOO-
2-PyCO-2-pyridylEtOCOO-
2-PyCO-3-pyridylEtOCOO-
2-PyCO-4-pyridylEtOCOO-
2-PyCO-IsobutanolEtOCOO-
2-PyCO-isopropylEtOCOO-
2-PyCO-cyclopropylEtOCOO-
2-PyCO-cyclobutylEtOCOO-
2-PyCO-cyclopentylEtOCOO-
2-PyCO-phenylEtOCOO-
3-PyCO-2-furylEtOCOO-
3-PyCO-3-furylEtOCOO-
3-PyCO-3-thienylEtOCOO-
3-PyCO-2-pyridylEtOCOO-
3-PyCO-3-pyridylEtOCOO-
3-PyCO-4-pyridylEtOCOO-
3-PyCO-IsobutanolEtOCOO-
3-PyCO-isopropylEtOCOO-
3-PyCO-cyclopropylEtOCOO-
3-PyCO-cyclobutylEtOCOO-
3-PyCO-cyclopentylEtOCOO-
3-PyCO-phenylEtOCOO-
4-PyCO-2-furylEtOCOO-
4-PyCO-3-furylEtOCOO-
4-PyCO-3-thienylEtOCOO-
4-PyCO-2-pyridylEtOCOO-
4-PyCO-3-pyridylEtOCOO-
4-PyCO-4-pyridylEtOCOO-
4-PyCO-IsobutanolEtOCOO-
4-PyCO-isopropylEtOCOO-

4-Rus-cyclopropylEtOCOO-
Ruso- cyclobutylEtOCOO-
4-Rus-cyclopentylEtOCOO-
4-Rus-phenylEtOCOO-
With4H7WITH-3-furylEtOCOO-
With4H7WITH-3-thienylEtOCOO-
With4H7WITH-2-pyridylEtOCOO-
With4H7WITH-3-pyridylEtOCOO-
With4H7WITH-4-pyridylEtOCOO-
With4H7WITH-IsobutanolEtOCOO-
With4H7WITH-isopropylEtOCOO-
With4H7WITH-cyclopropylEtOCOO-
With4H7WITH-cyclobutylEtOCOO-
With4H7WITH-cyclopentylEtOCOO-
With4H7WITH-phenylEtOCOO-
EtOCO-3-furylEtOCOO-
EtOCO-3-thienylEtOCOO-
EtOCO-2-pyridylEtOCOO-
EtOCO-3-pyridylEtOCOO-
EtOCO-4-PI is ideal EtOCOO-
EtOCO-IsobutanolEtOCOO-
EtOCO-isopropylEtOCOO-
EtOCO-cyclopropylEtOCOO-
EtOCO-cyclobutylEtOCOO-
EtOCO-cyclopentylEtOCOO-
EtOCO-phenylEtOCOO-
iBueCO-2-furylEtOCOO-
iBueCO-3-furylEtOCOO-
iBueCO-2-thienylEtOCOO-
iBueCO-3-thienylEtOCOO-
iBueCO-2-pyridylEtOCOO-
iBueCO-3-pyridylEtOCOO-
iBueCO-4-pyridylEtOCOO-
iBueCO-IsobutanolEtOCOO-

td align="left"> 2-pyridyl
iBueCO-isopropylEtOCOO-
iBueCO-cyclopropylEtOCOO-
iBueCO-cyclobutylEtOCOO-
iBueCO-cyclopentylEtOCOO-
iBueCO-phenylEtOCOO-
iBuCO-2-furylEtOCOO-
iBuCO-3-furylEtOCOO-
iBuCO-2-thienylEtOCOO-
iBuCO-3-thienylEtOCOO-
iBuCO-2-pyridylEtOCOO-
IBuCO-3-pyridylEtOCOO-
iBuCO-4-pyridylEtOCOO-
iBuCO-IsobutanolEtOCOO-
iBuCO-isopropylEtOCOO-
iBuCO-cyclopropylEtOCOO-
iBuCO-cyclobutylEtOCOO-
iBuCO-cyclopentylEtOCOO-
iBuCO-phenylEtOCOO-
iBuOCO-2-pyridylEtOCOO-
iBuOCO-3-pyridylEtOCOO-
iBuOCO-4-pyridylEtOCOO-
iBuOCO-isopropylEtOCOO-
iBuOCO-cyclobutylEtOCOO-
iBuOCO-cyclopentylEtOCOO-
iBuOCO-phenylEtOCOO-
iPrOCO-3-furylEtOCOO-
iPrOCO-3-thienylEtOCOO-
iPrOCO-EtOCOO-
iPrOCO-3-pyridylEtOCOO-
iPrOCO-4-pyridylEtOCOO-
iPrOCO-IsobutanolEtOCOO-
iPrOCO-isopropylEtOCOO-
iPrOCO-cyclopropylEtOCOO-
iPrOCO-cyclobutylEtOCOO-

EtOCOO-
iPrOCO-cyclopentylEtOCOO-
iPrOCO-phenylEtOCOO-
nPrOCO-2-furylEtOCOO-
nPrOCO-3-furylEtOCOO-
nPrOCO-2-thienylEtOCOO-
nPrOCO-3-thienylEtOCOO-
nPrOCO-2-pyridylEtOCOO-
nPrOCO-3-pyridylEtOCOO-
nPrOCO-4-pyridylEtOCOO-
nPrOCO-IsobutanolEtOCOO-
nPrOCO-isopropylEtOCOO-
nPrOCO-cyclopropylEtOCOO-
nPrOCO-cyclobutylEtOCOO-
nPrOCO-cyclopentyl
nPrOCO-phenylEtOCOO-
nPrCO-3-furylEtOCOO-
nPrCO-3-thienylEtOCOO-
nPrCO-2-pyridylEtOCOO-
nPrCO-3-pyridylEtOCOO-
nPrCO-4-pyridylEtOCOO-
nPrCO-IsobutanolEtOCOO-
nPrCO-isopropylEtOCOO-
nPrCO-cyclopropylEtOCOO-
nPrCO-cyclobutylEtOCOO-
nPrCO-cyclopentylEtOCOO-
nPrCO-phenylEtOCOO-
tBuOCOcyclopropylMeOCOO-
tBuOCOcyclopentylMeOCOO-
benzoyl2-furylMeOCOO-
benzoyl3-furylMeOCOO-
benzoyl2-thienylMeOCOO-
benzoyl3-thienylMeOCOO-
benzoyl2-pyridylMeOCOO-
benzoyl3-pyridylMeOCOO-

benzoyl4-pyridylMeooo-
benzoylIsobutanolMeooo-
benzoylisopropylMeooo-
benzoylcyclopropylMeooo-
benzoylcyclobutylMeooo-
benzoylcyclopentylMeooo-
benzoylphenylMeooo-
2-FuCO-2-furylMeooo-
2-FuCO-3-furylMeooo-
2-FuCO-2-thienylMeooo-
2-FuCO-3-thienylMeooo-
2-FuCO-2-pyridylMeooo-
2-FuCO-3-pyridylMeooo-
2-FuCO-4-pyridylMeooo-
2-FuCO-IsobutanolMeooo-
2-FuCO-isopropylMeooo-
2-FuCO-cyclopropylMeooo-
2-FuCO-cyclobutylMeooo-
2-FuCO-cyclopentylMeooo-
2-FuCO-phenyl/td> Meooo-
2-ThCO-2-furylMeooo-
2-ThCO-3-furylMeooo-
2-ThCO-2-thienylMeooo-
2-ThCO-3-thienylMeooo-
2-ThCO-2-pyridylMeooo-
2-ThCO-3-pyridylMeooo-
2-ThCO-4-pyridylMeooo-
2-ThCO-IsobutanolMeooo-
2-ThCO-isopropylMeooo-
2-ThCO-cyclopropylMeooo-
2-ThCO-cyclobutylMeooo-
2-ThCO-cyclopentylMeooo-
2-ThCO-phenylMeooo-
2-PyCO-2-furylMeooo-

2-Rus-3-furylMeooo-
2-Rus-2-thienylMeooo-
2-Rus-3-thienylMeooo-
2-Rus-2-pyridylMeooo-
2-Rus-3-pyridylMeooo-
2-Rus-4-pyridylMeooo-
2-Rus-IsobutanolMeooo-
2-Rus-isopropylMeooo-
2-Rus-cyclopropylMeooo-
2-Rus-cyclobutylMeooo-
2-Rus-cyclopentylMeooo-
2-Rus-phenylMeooo-
3-Rus-2-furylMeooo-
3-Rus-3-furylMeooo-
3-Rus-2-thienylMeooo-
3-Rus-3-thienylMeooo-
3-Rus-2-pyridylMeooo-
3-Rus-3-pyridylMeooo-
3-Rus-4-pyridylMeooo-
3-Rus-IsobutanolMeooo-
3-Rus-isopropylMeooo-
3-Rus-cyclopropylMeooo-
3-Rus-cyclobutylMeooo-
3-Rus-cyclopentylMeooo-
3-Rus is- phenylMeooo-
4-Rus-2-furylMeooo-
4-Rus-3-furylMeooo-
4-Rus-2-thienylMeooo-
4-Rus-3-thienylMeooo-
4-Rus-2-pyridylMeooo-
4-Rus-3-pyridylMeooo-
4-Rus-4-pyridylMeooo-
4-Rus-IsobutanolMeooo-
4-Rus-isopropylMeooo-

4-Rus-cyclopropylMeooo-
4-Rus-cyclobutylMeooo-
4-Rus-cyclopentylMeooo-
4-Rus-phenylMeooo-
With4H7WITH-2-furylMeooo-
With4H7WITH-3-furylMeooo-
With4H7WITH-2-thienylMeooo-
With4H7WITH-3-thienylMeooo-
With4sub> 7WITH-2-pyridylMeooo-
With4H7WITH-3-pyridylMeooo-
With4H7WITH-4-pyridylMeooo-
With4H7WITH-IsobutanolMeooo-
With4H7WITH-isopropylMeooo-
With4H7WITH-cyclopropylMeooo-
With4H7WITH-cyclobutylMeooo-
With4H7WITH-cyclopentylMeooo-
With4H7WITH-phenylMeooo-
EtOCO-2-furylMeooo-
EtOCO-3-furylMeooo-
EtOCO-2-thienylMeooo-
EtOCO-3-thienylMeooo-
EtOCO-2-pyridylMeooo-
EtOCO-3-pyridylMeooo-
EtOCO-4-pyridylMeooo-
EtOCO-IsobutanolMeooo-
EtOCO-isopropylMeooo-
EtOCO- cyclopropylMeooo-
EtOCO-cyclobutylMeooo-
EtOCO-cyclopentylMeooo-
EtOCO-phenylMeooo-
iBueCO-2-furylMeooo-
iBueCO-3-furylMeooo-
iBueCO-2-thienylMeooo-
iBueCO-3-thienylMeooo-

iBueCO-2-pyridylMeooo-
iBueCO-3-pyridylMeooo-
iBueCO-4-pyridylMeooo-
iBueCO-IsobutanolMeooo-
iBueCO-isopropylMeooo-
iBueCO-cyclopropylMeooo-
iBueCO-cyclobutylMeooo-
iBueCO-cyclopentylMeooo-
iBueCO-phenylMeooo-
iBuCO-2-furylMeooo-
iBuCO-3-furylMeooo-
iBuCO-2-thienylMEO is OO
iBuCO-3-thienylMeooo-
iBuCO-2-pyridylMeooo-
iBuCO-3-pyridylMeooo-
iBuCO-4-pyridylMeooo-
iBuCO-IsobutanolMeooo-
iBuCO-isopropylMeooo-
iBuCO-cyclopropylMeooo-
iBuCO-cyclobutylMeooo-
iBuCO-cyclopentylMeooo-
iBuCO-phenylMEOOO-
iBuOCO-2-furylMeooo-
iBuOCO-3-furylMeooo-
iBuOCO-2-thienylMeooo-
iBuOCO-3-thienylMeooo-
iBuOCO-2-pyridylMeooo-
iBuOCO-3-pyridylMeooo-
iBuOCO-4-pyridylMeooo-
iBuOCO-Isobutanolmeooo-
iBuOCO-isopropylMeooo-
iBuOCO-cyclopropylMEOOO-
iBuOCO-cyclobutylMeooo-
iBuOCO-cyclopentylMeooo-

iBuOCO-phenylMeooo-
iPrOCO-2-furylMeooo-
iPrOCO-3-furylMeooo-
iPrOCO-2-thienylMeooo-
iPrOCO-3-thienylMeooo-
iPrOCO-2-pyridylMeooo-
iPrOCO-3-pyridylMeooo-
iPrOCO-4-pyridylMeooo-
iPrOCO-IsobutanolMeooo-
iPrOCO-isopropylMeooo-
iPrOCO-cyclopropylMeooo-
iPrOCO-cyclobutylMeooo-
iPrOCO-cyclopentylMeooo-
iPrOCO-phenylMeooo-
nPrOCO-2-furylMeooo-
nPrOCO-3-furylMeooo-
nPrOCO-2-thienylMeooo-
nPrOCO-3-thienyl Meooo-
nPrOCO-2-pyridylMeooo-
nPrOCO-3-pyridylMeooo-
nPrOCO-4-pyridylMeooo-
nPrOCO-IsobutanolMeooo-
nPrOCO-isopropylMeooo-
nPrOCO-cyclopropylMeooo-
nPrOCO-cyclobutylMeooo-
nPrOCO-cyclopentylMeooo-
nPrOCO-phenylMeooo-
nPrCO-2-furylMeooo-
nPrCO-3-furylMeooo-
nPrCO-2-thienylMeooo-
nPrCO-3-thienylMeooo-
nPrCO-2-pyridylMeooo-
nPrCO-3-pyridylMeooo-
nPrOCO-4-pyridylMeooo-

nPrCO-IsobutanolMeooo-
nPrCO-isopropylMeooo-
nPrCO-cyclopropylMeooo-
nPrCO-cyclobutylMeooo-
nPrCO-cyclopentylMeooo-
nPrCO-phenylMeooo-

Example 4

The methods described in example 1 or elsewhere in this text, can be obtained from the following specific taxanes having structural formula 15, where in each series (i.e. series with "A" through "K") R7represents a hydroxy-group, a R10defined above, including R10representing R10aOCOO-, and R10a,represents (i) substituted or unsubstituted, preferably unsubstituted, alkyl With2-C8(a straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, alkenyl C2-C8(a straight, branched or cyclic), such as ethynyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, quinil C2-C8(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 group such as furyl, tie the sludge or pyridyl.

The "a" series of compounds X10different from that specified above. Preferably, the heterocycle is substituted or unsubstituted furyl, thienyl or pyridyl, X10is substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), a R7and R10each have the stereochemical configuration of the beta.

In the "B" series of compounds X10and R2adiffer from those defined above. Preferably, the heterocycle is 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, a R7and R10each have the stereochemical configuration of the beta.

In "C" series of compounds X10and R9adiffer from those defined above. Preferably, the heterocycle is 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, a R7, R 9and R10each have the stereochemical configuration of the beta.

In "D" and "E" series of compounds X10different from that specified above. Preferably, the heterocycle is 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 R7, R9(only D-series) and R10each have the stereochemical configuration of the beta.

In the "F" series of compounds X10, R2aand R9adiffer from those defined above. Preferably, the heterocycle is 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 R7, R9and R10each have the stereochemical configuration of the beta.

In the "G" series of compounds X10and R2adiffer from those defined above. Preferably, the heterocycle is substituted or unsubstituted furyl, thienyl or pyridyl, X10preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl (e.g. tert-butyl), Ra preferably represents a substituted or unsubstituted furyl, thienyl, pyridyl, phenyl or lower alkyl, a R7, R9and R10each have the stereochemical configuration of the beta.

In the "H" series of compounds X10different from that specified above. Preferably, the heterocycle is 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, a R7and R10each have the stereochemical configuration of the beta.

In the "I" series of compounds X10and R2adiffer from those defined above. Preferably, the heterocycle is 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, a R7and R10each have the stereochemical configuration of the beta.

In "J" series of compounds X10and R2adiffer from those defined above. Preferably, the heterocycle is substituted sludge is 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, a R7, R9and R10each have the stereochemical configuration of the beta.

In the "To" series of compounds X10, R2aand R9adiffer from those defined above. Preferably, the heterocycle is 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, a R7, R9and R10each have the stereochemical configuration of the beta.

Any of the substituents X3X5, R2, R9and R10can be hydrocarbonate or any of the substituents containing a heteroatom selected from the group consisting of heterocycle, alkoxygroup, allinoneruby, allinoneruby, alloctype, hydroxy-group-protected hydroxy-group, geograpy, alloctype, nitro, amino, aminogroup, Colnago, catalogo, acatalog,ester or ether fragments, but not phosphorus-containing fragments.

Example 5

Cytotoxicity in vitro, measured in the formation of a colony of cells

Four hundred cells (NSC) placed in Petri dishes 60 mm in diameter, containing 2.7 ml of medium (modified medium McCoy's 5A containing 10% fetal calf serum (FBS) and 100 u/ml penicillin and 100 g/ml streptomycin). Cells incubated in the incubator with CO2at 37°C for 5 hours before sticking to the bottom of the Petri dish. Of the compounds mentioned in example 2, prepare a fresh solution in an environment with a concentration ten times the final concentration, and then 0.3 ml of this initial solution is added to 2.7 ml of medium in a Cup. Cells incubated with drugs for 72 hours at 37°C. At the end of the incubation decanted the medium containing the drug, cups washed with 4 ml of balance salt solution hack (HBSR), add 5 ml of fresh medium, and the Cup returned to the incubator for the formation of colonies. Count colonies of cells and for each tested compound determine the value of ID50(the concentration of drug that causes the 50% inhibition of the formation of the colony).

Example 6

Preparation of solutions for oral administration

Solution 1: the antitumor compound 1771 dissolved in ethanol to form a solution containing 145 mg of compound in 1 ml solution. To the solution under stirring was added an equal volume of a solution of Cremophor® EL with the formation of a solution containing 72,5 mg connection 1771 in 1 ml solution. This solution was diluted with 9 mass parts of saline solution with the formation of pharmaceutically acceptable for administration to a patient of a solution.

Solution 2: antitumor compound 1781 dissolved in ethanol to form a solution containing 98 mg of compound in 1 ml solution. To the solution under stirring was added an equal volume of a solution of Cremophor® EL with the formation of a solution containing 49 mg of compound 1781 in 1 ml solution. This solution was diluted with 9 mass parts of saline solution with the formation of pharmaceutically acceptable for administration to a patient of a solution.

1. Taxon having the formula

where

R2is alloctype;

R7is a hydroxy-group;

R9is geography;

R10is carbonate;

X3is2-C6the alkyl, C2-C6alkenyl,3-C6cycloalkyl, phenyl, optionally substituted by a nitro-group, or a 5-6-membered heteroaromatic group containing heteroatoms selected from O, N or S;

X5is-C(O)X10or-C(O)OH10; where

X10is2-C6the alkyl, C2-C6alkenyl,3-C6cycloalkyl, phenyl, fullam, pyridium, or Tienam;

Ac is acetyl.

2. Texan according to claim 1, where R10is R10AOS(O)O -, and R10ais1-C6the alkyl.

3. Texan according to claim 2, where X3represents furyl, thienyl, pyridyl,2-C6alkyl or C2-C6alkenyl.

4. Texan according to claim 2, where X5represents-C(O)X10and X10is phenyl or X5represents-C(O)OH10and X10is tert-bootrom.

5. Texan according to claim 2, where R2is benzoyloxy.

6. Texan according to claim 5, where X3represents furyl, thienyl, pyridyl,2-C6alkyl or C2-C6alkenyl.

7. Texan according to claim 5, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

8. Texan according to claim 2, where X 3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

9. Texan according to claim 1, where R10is R10AOS(O)O -, and R10ais2-C6alkyl.

10. Texan according to claim 9, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

11. Texan according to claim 9, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

12. Texan according to claim 9, where R14is hydrogen.

13. Texan indicated in paragraph 12, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

14. Texan indicated in paragraph 12, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

15. Texan according to claim 9, where R2is benzyloxypropionic.

16. Texan indicated in paragraph 15, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

17. Texan indicated in paragraph 15, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X 10is tert-bootrom.

18. Texan according to claim 9, where R2is benzyloxypropionic.

19. Texan on p, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

20. Texan on p, where X3represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

21. Texan according to claim 1, where R10is R10aOC(O)O -, and R10arepresents methyl or ethyl.

22. Texan on item 21, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

23. Texan on item 21, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

24. Texan on item 21, where R2is benzyloxypropionic.

25. Texan on point 24, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

26. Texan on point 24, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

27. Texan on item 21, where X5represents-C(O)OH10and X10the two who is tert-bootrom.

28. Texan on item 27, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

29. Texan according to claim 2, where X3is furyl or thienyl.

30. Texan on clause 29, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

31. Texan on clause 29, where X3represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

32. Texan according to claim 2, where R10Arepresents methyl or ethyl.

33. Texan on p, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

34. Texan on p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl./p>

35. Texan on p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

36. Texan on p, where X3is furyl or thienyl.

37. Texan on p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

38. Texan on p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

39. Texan on p, where X3is2-C6cycloalkyl.

40. Texan in 39, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5is-COOH10and X10is2-C6the alkyl or C2-C6alkenyl.

41. Texan in 39, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is t the em-bootrom.

42. Texan according to claim 2, where X3is furyl or thienyl, R10ais ethyl, and X5represents-C(O)OH10and X10is tert-bootrom.

43. Texan according to claim 2, where X3is 2-furyl or 2-thienyl, R10ais ethyl, and X5represents-C(O)OH10and X10is tert-bootrom.

44. Texan according to claim 2, where X3is isobutyl and X5represents-C(O)OH10and X10is tert-bootrom.

45. Texan according to claim 2, where X3is3-C6cycloalkyl, R10ais stands or ethyl, and X5represents-C(O)OH10and X10is tert-bootrom.

46. Taxon having the formula:

where

R2is benzyloxypropionic;

R7is a hydroxy-group;

R10is R10AOS(O)O-;

X3is3-C6cycloalkyl,2-C6the alkyl, C2-C6alkenyl, phenyl, optionally substituted by a nitro-group, or a 5-6-membered heteroaromatic group containing heteroatoms selected from O, N or S;

X5is-C(O)X10or-C(O)OH10;

X10is2-C6the alkyl, C2-C6alkenyl,3-C6cycloalkyl, phenyl is m, fullam, pyridium, or Tienam;

R10ais2-C6by alkyl; and

Ac is acetyl.

47. Texan on p.46, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

48. Texan on p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

49. Texan on p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

50. Texan on p.46, where X3is furyl or thienyl.

51. Texan according to item 50, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium or2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

52. Texan according to item 50, where X5represents-C(O)X10and X10is phenyl, or X5 represents-C(O)OH10and X10is tert-bootrom.

53. Texan on p.46, where X3represents phenyl.

54. Texan according to item 53, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium or2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

55. Texan according to item 53, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

56. Texan on p.46, where X3is Isobutanol.

57. Texan on p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

58. Texan on p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

59. Texan on p.46, where R10arepresents ethyl.

60. Texan on p, where X3represents 2-furyl, furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

61. Texan on p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium or2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

62. Texan on p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

63. Texan on p, where X3is furyl or thienyl.

64. Texan on p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium or2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

65. Texan on p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

66. Texan on p, where X5represents-C(O)OH10and X10is tert-bootrom.

67. The pharmaceutical is a mini-composition, with antitumor activity, containing taxon according to claim 1 and one or more pharmaceutically acceptable, inert or physiologically active diluents or adjuvants.

68. The pharmaceutical composition according p, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

69. The pharmaceutical composition according p, where X5represents-C(O)X10and X10is phenyl, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

70. The pharmaceutical composition according p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

71. The pharmaceutical composition according p, where R10Ais stands, ethyl or propylene.

72. The pharmaceutical composition according p, where X3represents 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

73. The pharmaceutical composition according to item 72, where X5represents-C(O)X10and X10is Fe the sludge, 2-fullam, 3-fullam, 2-tanila, 3-tanila, 2-pyridium, 3-pyridium, 4-pyridium,2-C6the alkyl or C2-C6alkenyl, or X5represents-C(O)OH10and X10is2-C6the alkyl or C2-C6alkenyl.

74. The pharmaceutical composition according to item 72, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

75. The pharmaceutical composition according p, where X3is furyl or thienyl, R10ais stands or ethyl, and X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

76. The pharmaceutical composition according p, where X3represents furyl, R10ais stands or ethyl, and X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

77. The pharmaceutical composition according p, where X3is thienyl, R10ais stands or ethyl, and X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

78. The pharmaceutical composition according p, where X3is Isobutanol, R1a is stands or ethyl, a X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

79. The pharmaceutical composition according p, where X3is 2-furyl or 2-thienyl, R10ais stands, X5represents-C(O)OH10and X10is tert-bootrom.

80. The pharmaceutical composition according p, where X3represents 2-furyl, R10ais ethyl, X5represents-C(O)OH10and X10is tert-bootrom.

81. The pharmaceutical composition according p, where X3is 2-thienyl, R10ais ethyl, X5represents-C(O)OH10and X10is tert-bootrom.

82. Pharmaceutical composition having antitumor activity, containing taxon in clause 29 and one or more pharmaceutically acceptable, inert or physiologically active diluents or adjuvants.

83. Composition for oral administration having antitumor activity, containing taxon according to claim 1 and at least one pharmaceutically acceptable carrier.

84. The composition according to p, where R10is R10aOC(O)O -, and R10ais1-C6alkyl.

85. The composition according to p, where X3represents phenyl, Isobutanol, 2-furyl, 3-furyl, 2-thienyl, 3-year is nil, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2-C6alkyl or C2-C6alkenyl.

86. The composition according to p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

87. The composition according to p, where R10ais stands, ethyl or propylene.

88. The pharmaceutical composition according p, where X3is Isobutanol, R10ais stands or ethyl, X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

89. The pharmaceutical composition according p, where X3is 2-furyl or 2-thienyl, R10ais ethyl, X5represents-C(O)OH10and X10is tert-bootrom.

90. Pharmaceutical composition having antitumor activity, containing Texan on 57 and at least one pharmaceutically acceptable carrier.

91. Method of inhibiting tumor growth in a mammal, comprising oral administration of a therapeutically effective amount of a composition containing taxon according to claim 1 and at least one pharmaceutically acceptable carrier.

92. The method according to p, where R10is R10aOC(O)O -, and R10ais1-C6alkyl.

93. The method according to p, where X3 represents phenyl, Isobutanol, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-C6alkyl or C2-C6alkenyl.

94. The method according to p, where X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

95. The method according to p, where R10arepresents methyl, ethyl or propyl.

96. The method according to p, where X3is Isobutanol, R10ais stands or ethyl, X5represents-C(O)X10and X10is phenyl, or X5represents-C(O)OH10and X10is tert-bootrom.

97. The method according to p, where X3is 2-furyl or 2-thienyl, R10ais ethyl, X5represents-C(O)OH10and X10is tert-bootrom.

98. Method of inhibiting tumor growth in a mammal, comprising oral administration of a therapeutically effective amount of a composition containing Texan on 57 and at least one pharmaceutically acceptable carrier.



 

Same patents:

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: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.

EFFECT: improved preparing method.

8 cl, 8 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to derivatives of N-desacetylthiocolchicine and 10-desacetylbaccatin III of the formula (I):

wherein R and n have values given in description. These compounds are valuable antitumor medicinal agents. Also, invention relates to a pharmaceutical composition based on compounds of the formula (I) and possessing an anti-proliferative activity. Invention provides preparing new derivatives of 10-desacetylbaccatin III possessing a valuable pharmaceutical effect.

EFFECT: valuable medicinal property of compounds.

5 cl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new semi-synthetic taxanes of the formula (1):

wherein R and R1 can be similar or different and represent hydrogen atom (H), (C1-C18)-acyl group, benzoyl group; R2 and R3 represent hydrogen atom (H) or R2 and R3 in common form carbonate or thiocarbonate residue; R4 represents benzoyl group optionally substituted at meta-position; R' represents hydrogen atom (H) or (C1-C4)-alkyl; R'' represents (C1-C4)-alkyl or phenyl; R''' represents tert.-butoxy-group under condition that R and R1 both can't represent hydrogen atom (H). Also, invention relates to a pharmaceutical composition based on compounds of the formula (1) eliciting an anti-tumor, anti-angiogenic and anti-arthrosis effect. Invention provides preparing new compounds eliciting cytotoxicity comparable with cytotoxicity of other taxanes but showing reduced systemic toxicity that can be administrated by intravenous and oral routes.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

6 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

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

SUBSTANCE: invention relates to new derivative of taxane of the formula (I):

that elicits strong antitumor effect. Also, invention relates to intermediates substances, a method for preparing compound of the formula (I), a method for preparing 1,14-β-hydroxy-1,14-carbonate-baccatin III-derivatives substituted with isoserine residue at position 3 and to pharmaceutical composition based on compounds of the formula (I). Invention provides preparing new derivative of taxane that elicits higher activity and reduced toxicity as compared with paclitaxel.

EFFECT: improved preparing method, enhanced and valuable medicinal properties of compound.

10 cl, 7 tbl, 6 ex

The invention relates to new S-4 carbonate-bearing similarly to taxanes of formula 1 and their pharmaceutical salts:

where R denotes phenyl, isopropyl or tert.butyl; R1denotes-C(O)RZin which RZmeans (CH3)3CO-, (CH3)3CLO2-, CH3(CH2)3Oh, cyclobutyl, cyclohexyloxy or 2-furyl and R2denotes CH3C(O)O-, and also to pharmaceutical compositions based on them and their use as protophobic agents to treat diseases of humans and animals

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to a new method of acylation of the hydroxyl group taxane, including processing taxane allermuir agent selected from the group consisting of anhydrides, dicarbonate, thiodicarb and isocyanate in the reaction mixture containing less than one equivalent of base for each equivalent taxane, preferably 1:1-1:100, with the formation of the C(10) acylated taxane

The invention relates to a new method of obtaining Taxol, its analogs and their intermediates, including the stage of protection of the hydroxy-group at C-7 position 9-dihydro-13-deacetylbaccatin III a suitable protecting group; oxidation of the hydroxy-group in position C-9; and attaching a suitable side chain at position C-13

FIELD: organic chemistry, biochemistry, pharmacy.

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

wherein R1 represents the following groups:

wherein * means the addition point; R4 means fluorine, chlorine, bromine atom, -CF3, -N=C, -CH3, -OCF3 or -CH2OH; R5 means chlorine, bromine atom or -OCH3; R6 means -CH3 or chlorine atom; R7 means -CH3 or chlorine atom; R8 means -CH3, fluorine, chlorine atom or -CF3; R2 represents pyridyl or group:

or ; R3 represents hydrogen or fluorine atom, and their tautomers, E-isomers or Z-isomers, racemates, enantiomers and salts also that are inhibitors of activity of tyrosine kinase KDR and FLT. Also, invention describes medicinal agents comprising the claimed compounds and designated for treatment of diseases associated with inhibition of activity of kinase KDR and FLT.

EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

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