Modified c-21-epothilones

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

 

The level of technology

Epothilone are macrocyclic lactones, with useful antifungal and cytotoxic properties. Their action, as in the case of TaxolRbased on stabilizing microcannulas, resulting in inhibited, particularly cancer and other rapidly dividing cells. Typical epothilone contain methylthiazolidine side chain, 12,13-double bond (C, D), 12,13-epoxide (a, b) and proton (a, C) or metal group (b, D) on C-12; see, for example, Review Angew. Chem. 1998, 110, 89-92 and 2120-2153, and Heterocycles 1998, 48, 2485-2488.

Epothilone A, R=H

In, R=Me

Epothilone S, R=H

D, R=Me

The invention

The present invention relates to a compound having a General formula I

where P-Q is a double bond or an epoxide;

G represents a

R is selected from the group comprising N and C1-6alkyl;

R1selected from the group consisting of

G1represents N;

G2represents N;

G3selected from the group comprising O, S and NZ1;

G4selected from the group including H, C1-6alkyl, substituted C1-6alkyl, OZ2, Z2C=O and Z4SO2;

G5selected from the group comprising halogen, N3, CN, NC, heteroaryl containing N or O, and heterocycle;

G6selected from the group including H, C1-6alkyl, and OZ5where Z5selected from the group comprising N and C1-6alkyl;

G9represents About;

Z1selected from the group of H, C1-6alkyl, substituted C1-6alkyl, acyl and substituted acyl;

Z2selected from the same group as C1-6alkyl, substituted C1-6alkyl, aryl;

Z4selected from the group comprising aryl and substituted aryl;

provided that when R1represents a

or

G1, G2, G3and G4cannot simultaneously have the following values:

G1and G2- N, G3"Oh and G4- N or Z2C=O, where Z2=H or alkyl group, and when G1and G2- H, G5may not be halogen;

where substituted C1-6alkyl represents a C1-6alkyl having from one to four substituents selected from hydroxy, alkoxy, oxo, alkanoyl, aryl, aryloxy, alkanoyloxy, amino, C1-6alkylamino, disubstituted amines in which two aminosalicylates selected from C1-6the alkyl);

substituted aryl represents phenyl or naphthyl having from one to four batch is of Italy, selected from C1-6of alkyl, and

substituted acyl represents an acyl group, in which the radical derived from an acid by removal of hydroxyl, substituted C1-6by alkyl, substituted C1-6the alkyl.

In addition, the invention relates to a compound having a General formula I

where R is an atom H or a metal group,

G1represents the atom N.

In addition, the invention relates to compounds having the General formula Ib

where R is an atom H or a methyl group,

G1is an atom of N,

G2represents the atom N.

In addition, the invention relates to a compound having the General formula

In addition, the invention relates to a compound having the General formula IIb

where R is an atom H or a methyl group;

G6represents the atom N.

In addition, the invention relates to a compound having General formula IV

where R is an atom H or a metal group,

P-Q is a double bond or an epoxide,

G11represents a C1-6alkyl.

Additionally, the invention relates to FA the pharmaceutical composition, inhibiting the growth of cells containing or consisting of compounds in accordance with the invention, in addition to the optional carrier, diluent or additive.

A detailed description of the invention

Definition

The following are the values of the various definitions used in the description of the present invention. These values are applicable to the definitions as they are used throughout the present description, if not entered any restrictions in special requirements or individually, or as part of a large group.

The definition of "pharmaceutically active agent" or "pharmaceutically active epothilone" refers to epothilone, which is pharmacologically active in the treatment of cancer or other diseases listed in the description.

The definition of "alkyl" refers to optionally substituted straight or branched chain saturated hydrocarbon groups containing from 1 to 6 carbon atoms. The expression "lower alkyl" refers to optionally substituted alkyl groups comprising from 1 to 4 carbon atoms.

The definition of "substituted alkyl" refers to alkyl group having, for example, from one to four substituents, such as halogen, trifluoromethyl, triptoreline, hydroxy, alkoxy, cycloalkane, heterocyclic, oxo, alkanoyl, aryloxy, alkanoyloxy, and the Ino, alkylamino, arylamino, aralkylamines, cyclooctylamine, heterocyclimamines, disubstituted amines in which two aminosalicylates selected from alkyl, aryl or aralkyl, alkanolamine, aroylamino, alcanolamines, replaced alkanolamine, replaced arylamino, replaced alcanolamines, thiol, alkylthio, aaltio, Uralkali, cycloalkylation, heterocycly, alkylthio, Aristion, aracytine, alkylsulfonyl, arylsulfonyl, Arakishvili, sulfonamide (e.g., SO2NH2), replaced sulfonamide, nitro, cyano, carboxy, carbamyl (for example, CONH2), substituted carbamyl (for example, CONH-alkyl, CONH-aryl, CONH-aralkyl or cases where there are two substituents on the nitrogen selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocycles, such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. Where, as noted above, if the Deputy optionally substituted, with the help of halogen, alkyl, alkoxy, aryl or aralkyl.

The term "acyl" refers to a radical formed usually of acid while removing hydroxyl. Examples include acetyl (CH3The CO-), benzoyl (C6H5CO-and phenylsulfonyl (C6H5SO2-).

The definition of "substituted acyl" refers to substituted acyl is the group, in which the radical is typically formed from an acid by removal of hydroxyl, substituted, for example, alkyl, substituted alkyl, cycloalkyl, replaced by cycloalkyl the aryl, substituted aryl, aralkyl, replaced by aralkyl and heterocyclyl.

The definition of "ring system" refers to an optionally substituted ring system containing one to three rings and at least one carbon-carbon double bond in at least one ring. Examples of ring systems include, but are not limited to such values as aryl or partially or fully unsaturated heterocyclic ring system, which may be optionally substituted.

The definition of "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring, such as phenyl, naftalina, biphenylene and diphenylene groups, each of which may be optionally substituted.

The definition of "substituted aryl" refers to aryl group having, for example, from one to four substituents such as alkyl, substituted alkyl, halogen, triptoreline, trifluoromethyl, hydroxy, alkoxy, cycloalkane, heterocyclics, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamines, cyclooctylamine, heterocyclimamines, dialkylamino, alkanolamine, thiol, and is kiltie, cycloalkylation, heterocycly, ureido, nitro, cyano, carboxy, carboxylic, carbamic, alkoxycarbonyl, alkylthio, Aristion, alkylsulfonyl, sulfonamide, aryloxy and the like. The Deputy may be optionally substituted with halogen, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.

The definition of "aralkyl" refers to an aryl group linked directly through an alkyl group, such as benzyl.

The definition of "substituted alkene" and "substituted alkenyl" refers to the residue having a carbon-carbon double bond, which may be part of a ring system with at least one Deputy, which is lower alkyl or substituted lower alkyl. Other substituents have the meanings that are given for substituted alkyl.

The definition of "cycloalkyl" refers to optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbon atoms in each ring, which may be, in addition, with unsaturated condensed With3-C7carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and substituted. Examples of the substituents include one or bol is e alkyl groups, as described above, or one or more groups described above as alkyl substituents.

The definition of "heterocycle", "heterocyclic" and "heterocycle" refers to optionally substituted, unsaturated, partially saturated or fully saturated, aromatic or nonaromatic cyclic group, for example, which is a 4-7-membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered tricyclic ring system, which has at least one heteroatom in at least one carbon-containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, sulfur atoms, where the heteroatoms nitrogen and sulfur may be optionally oxidized and the nitrogen heteroatoms can be optionally Quaternary,with the formation of Quaternary base.

Heterocyclic group may be attached at any heteroatom or carbon atom.

Examples of monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolines, imidazoles, imidazolines, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, diazolidinyl, isothiazolin, isothiazolinones, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxazepines, azepine, 4-piperidinyl, pyridyl, N-oxopyridine, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl sulfon, morpholinyl, thiomorpholine, dimorpholinyldiethyl, thiomorpholine sulfon, 1,3-dioxolane and tetrahydro-1,1-DIOXOLANYL, dioxane, isothiazolinones, titanyl, thiiranes, triazinyl and triazolyl, and the like.

Examples of bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothiazyl, hinokitiol, chinoline, chinoline-N-oxide, tetrahydroisoquinoline, ethenolysis, benzimidazolyl, benzopyranyl, indolizinyl, benzofuran, chromones, coumarinyl, cinnoline, honokalani, indazoles, pyrrolopyridine, properidine (such as furo[2,3-C]pyridinyl, furo[3,1-b]pyridinyl] or furo[2,3-b]pyridinyl), dihydroisoquinolyl, dihydroquinazolines (such as 3,4-dihydro-4-oxo-hintline), benzisothiazole, benzisoxazole, benzodiazines, benzofurazanyl, benzothiophenes, benzotriazolyl, benzimidazolyl, dihydrobenzofuran, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, indolinyl, isopropanol, isoindolines, naphthyridine, phthalazine, piperonyl, purinol, iridoviridae, hintline, tetrahydroquinoline, thieno uril, cyanopyridyl, theNational and the like.

Examples of substituents for the definitions of "heterocycle," "heterocyclic," and "heterocycle include one or more alkyl or substituted alkyl group as described above, or one or more groups described above as alkyl or substituted alkyl substituents. They also have a small heterocycles, such as epoxides and aziridines.

The definition of "alkanoyl" refers to-C(O)-alkyl.

The definition of "substituted alkanoyl" refers to-C(O)-substituted to the alkyl.

The definition of "aroyl" refers to-C(O)-aryl.

The definition of "substituted aroyl" refers to-C(O)-substituted with the aryl.

The definition of "trialkylsilyl" refers to a-Si(alkyl)3.

The definition of "kildalkey" refers to a-Si(alkyl)2(aryl).

The definition of "diaryl alkylsilane" refers to a-Si(aryl)2(alkyl).

The term "heteroatoms" will include oxygen, sulfur and nitrogen.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

Compounds having formulas I through IV, may form salts with alkali metals such as sodium, potassium, lithium, with alkaline earth metals such as calcium and magnesium, with organic bases, such as dicyclohexylamine and tributylamine, pyridine and amino acids such as arginine, lysine and the like. With such and can be obtained, for example, by replacing the protons of carboxylic acids, if they contain carboxylic acid, the compounds having formulas I through IV, the desired ion in a medium in which the salt precipitates or in an aqueous medium followed by evaporation. As is well-known specialist in this field, can be formed and other salts.

Compounds having formulas I through IV, form salts with various organic and inorganic acids. These salts include salts, which are formed by means of hydrogen chloride, hydrogen bromide, methanesulfonate, hydroxyethanesulfonic, sulfuric acid, acetic acid, triperoxonane acid, maleic acid, benzosulfimide, toluenesulfonic acid and other acids (such as nitrates, phosphates, borates, tartratami, citrates, succinate, benzoate, ascorbate, salicylates and the like). Such salts are formed by the interaction of compounds having formulas I through IV, with an equivalent amount of acid in the medium in which the salt precipitates or in an aqueous medium followed by evaporation.

In addition, zwitterions ("inner salts ") may be formed and are included in the definition of the salt used in the description.

Prodrugs and the solvate of the compounds having formulas I to IV are also included in the invention. The definition of the prodrug, as it is used in the description, means a compound that with the introduction of his patient, undergoes chemical conversion by metabolic or chemical processes to form compounds having formulas I through IV, salt and/or solvate. For example, the compounds of formulas I through IV can form a molecule of ester carboxylic acid. Esters of carboxylic acids are usually formed by the esterification of any functional groups carboxylic acid located on the open(s) ring(s) structure(s). The preferred solvate of the compounds having formulas I to IV are hydrates.

Various forms of prodrugs are well known in the prior art. Examples of such proletarienne derivatives disclosed in the following links:

a) Design of Prodrugs, H. Bundgaard (editor), Elsevier (1985);

b) Methods in Enzymology, K. Widder et al. (tors). Academic Press, Vol. 42, 309-396 (1985);

c) A Textbook of Drug Design and Development, Krosgaard-Larsen and H.Bundgaard (etors), Chapter 5, "Design and Application of Prodrugs," 113-191(1991);

d) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

e) H.Bundgaard, J. of Pharm. Sciences, 77, 285 (1988), and

f) N.Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984).

Compounds according to the invention can exist in the form of various optical, geometric and stereoisomers. Because the connections presented in the description defined for the same optical orientation, it is understood that all isomers and mixtures thereof are included in the present invention.

<> The application and use

Compounds according to the invention are stabilizing agents for microanalyses. Thus, they are suitable for the treatment of various cancers and other related diseases, disorders, including, but not limited to, the following:

carcinoma, including carcinoma of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, neck, thyroid and skin; including squamous cell carcinoma;

hematopoietic tumors of lymphoid origin, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, b-cell sarcoma, T-cell sarcoma, (Hodgkins) lymphoma Hodgkins, Alimta Hodgkins, hair lymphoma cells and Burkitt's lymphoma;

hematopoietic bone marrow tumors, including acute and chronic Malopolskie leukemia and promyelocyte leukemia;

tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

other tumors, including melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma;

tumors of the Central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and neuromas;

tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma, osteogenic sarcoma;

other tumors, including chalk the WMD, centernary chromatoplate, keratoakantoma, seminoma, follicular tumors of the thyroid gland and teratocarcinoma.

Compounds of the present invention also inhibit the development of blood vessels, thus, affecting the growth of tumors and providing treatment of tumors and associated with tumor diseases. Such antiangiogenic properties of the compounds having formulas I through IV are also useful in the treatment of other diseases that respond to the action antiangiogenic means, including, but not limited to, certain forms of blindness related to retinal vascularization, arthritis, especially inflammatory arthritis, multiple sclerosis, restenosis and psoriasis.

Compounds according to the invention stimulate or inhibit apoptosis, a physiological process of cell death, is critical for normal development and homeostasis.

Changing pathways of apoptosis contributes to the pathogenesis of various human diseases. Compounds having formulas I through IV, as modulators of apoptosis, will be useful in the treatment of various human diseases with abnormalities in apoptosis, including, but not limited to, cancer and precancerous damage immunogenicity disease, viral infection, degeneration of the skeletal-muscular system and kidney disease.

Compounds according to the invention can also use the be used to treat other diseases, non-cancerous or proliferative. Such diseases include, but are not limited to, viral infections type of herpes virus, se-virus, virus, Epstein-Barr virus Sindbis and adenovirus; autoimmune diseases like systemic lupus erythematosus, eritematoso, immune glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes mellitus;

neurodegenerative diseases such as Alzheimer's, HIV-related dementia, Parkinson's Disease, amyotrophic lateral sclerosis, pigmentose of pigmentosa, spinal muscular atrophy and cerebellar degeneration; AIDS;

leukocytosis bone marrow; aplastic anemia; ischemic injury associated with myocardial infarction; reperfusion injury; restenosis; arrhythmia;

atherosclerosis; caused by a toxin or alcohol liver disease; hematologic disease type chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis; multiple sclerosis; kidney disease; cancer pain.

The present invention thus provides a method of treating a patient, preferably a mammalian animal, and especially the people who need treatment of any of the above mentioned ill the deposits, especially cancer or other proliferative diseases including stage injection to a patient in need this, at least one compound having the formula I to IV, taken in an amount effective for treatment. Other therapeutic agents, such as those described below, can be used in conjunction with the proposed connections in the proposed method. In the method according to the present invention, such other therapeutic agent(s) may be administered before, simultaneously with or after administration of the compound(s) according to the invention.

An effective amount of the compounds according to the invention can be determined by the person skilled in the art, and includes exemplary dosage amounts for a human, comprising from about 0.05 to 200 mg/kg/day, which can be administered in one dose or in the form of individual separate doses, the number of which is from 1 to 4 times a day. Preferably the compound is administered at a dose less than 100 mg/kg/day, single dose or in divided doses 2 to 4. It is clear that a certain dosage level and frequency of dosage for any particular patient may be changed and will depend on various factors, including the activity of the specific compound, the metabolic stability and length of action of that compound, race, age, weight of the body, General health, sex and diet of the patient, method and time of administration, the degree of selection, combination of drugs and the severity of the particular disease. Preferred patients for treatment include animals, most preferred genus of mammals such as human and domestic animal type dogs, cats, etc. subject to the above-mentioned diseases.

The current invention also provides a pharmaceutical composition comprising at least one of the compounds having formulas I through IV, capable of treating cancer and other proliferative diseases, taken effective for this number, and pharmaceutically acceptable carrier or diluent. The compositions of the present invention may contain other therapeutic agents as described below, and may be composed, for example, using conventional solid or liquid solvents or diluents, as well as pharmaceutical additives of a type that corresponds to the way the desired administration (for example, fillers, binders, preservatives, stabilizers, fragrances and so on) according to techniques known to experts in this field or to accepted pharmaceutical practice.

Compounds having formulas I to IV, can be introduced in any suitable manner, for example orally in the form of tablets, capsules, granules or powders; sublingual; buccal; parenteral, namely, subcutaneously, intravenously, intramuscularly, or epigastric introduction, or by infusion (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasal, namely, by inhalation spray; topically, in the form of creams or ointments; rectally in the form of suppositories; in dosage forms containing non-toxic, pharmaceutically acceptable solvents or thinners. Compounds in accordance with the present invention may, for example, be administered in a form suitable for immediate or prolonged discharge. Immediate or prolonged isolation can be achieved by means of suitable pharmaceutical compositions, comprising compounds of the present invention, or, especially in the case of prolonged separation, by use of devices such as subcutaneous capillary or osmotic pumps. Compounds of the present invention can also be administered liposomal. For example, the active substance may be used in the composition of the tablet, capsule, solution or suspension containing from about 5 to about 500 mg per unit of dosage of a compound or mixture of compounds having formulas I to II, or in the case of local application (from 0.01 to 5% by weight is soedineniya, having the formula I-II, using from one to five times a day). Connections can be arranged in a conventional way with a physiologically acceptable diluent or carrier, excipient, binder, preservative, stabilizer, perfume, etc. or with a carrier for topical application. Compounds having formulas I-IV may also be included in such compositions, as sterile solutions or suspensions for parenteral administration. From about 0.1 to 500 mg of the compounds having formula I-IV may be combined with a physiologically acceptable carrier solvent, carrier, filler, preservative, binder, stabilizer, etc. in a unit dosage according to accepted pharmaceutical practice. The amount of active substance in these compositions or the compositions preferably such that this produces the appropriate dosage in the indicated range.

Examples of compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for imparting volume, alginic acid or sodium alginate as suspenzirutego agent, methylcellulose to impart viscosity and sweeteners or flavors, known in this area; immediately decaying tablets which may contain, for example, microcrystallites the Yu cellulose, the dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, thickening agents, disintegrating agents, diluents and lubricants known in this area. Molded tablets, compressed tablets or freeze dried tablets are examples of forms that can be used. Examples of compositions include those compositions in which compounds of the present invention is injected rapidly soluble diluents such as mannitol, lactose, sucrose and/or cyclodextrins. In such compositions can be entered high eccipienti type cellulose (avicel) or polyethylene glycol (PEG). Such compositions may also include excipient to create adhesion to the mucosa, such as hydroxypropylcellulose (LDCs), hypromellose (receiver array), sodium carboxymethyl cellulose (SCMC), a copolymer of maleic anhydride (e.g., Gantrez), and agents for controlling the discharge, such as polyacrylic copolymer (e.g., Carbopol 934). Grease, lubricating oils, fragrances, dyes and stabilizers may also be added for ease of manufacture and use.

Examples of compositions for nasal aerosol or inhalation include physiological solutions, which may contain, for example, benzyl alcohol or other suitable preservatives, polotical the e promoters to increase the bioactivity and/or other solubilizing or dispersing agents, known in this field.

Examples of compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents such as cremophor, mannitol, 1,3-butanediol, water, ringer's solution, isotonic sodium chloride or other suitable dispersing or wetting, or suspiciouse agents, including synthetic mono - or diglycerides, and fatty acids, including oleic acid.

Examples of compositions for rectal injection include candles, which can contain, for example, suitable non-irritating excipient type of cocoa butter, synthetic esters of glycerol or polyethylene glycols, which are solid at ordinary temperature but liquid and/or dissolve in the rectal cavity, with the release of the drug.

Examples of compositions for topical application include carriers for topical application such as Plastibase (mineral oil in the form of a gel with polyethylene). For example, the composition of the invention can be applied topically for the treatment of plaque associated with psoriasis, and in this case they can be made in the form of a cream or ointment.

Compounds according to the invention can be administered alone or in combination with other protivoop what elymi and cytotoxic agents and drugs useful in the treatment of cancer or other proliferative diseases. Particularly useful combinations of antitumor and cytotoxic drugs, in which the selected second drug is effective excellent way or another phase of the cell cycle, such as S-phase than the compounds having formulas I through IV, which have their impact on G2-M-phase. Examples of classes of such antitumor and cytotoxic agents include, but are not limited to alkylating agents of the type of nitrogen mustards, alkyl sulphonates, nitrosamine, ethylenimine and triazine; antimetabolites type volitich antagonists, purine analogues, and pyrimidine analogues; antibiotics such anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; the enzyme L-asparaginase; inhibitors farnesyl-protein transferase; hormonal agents type of glucocorticoids, estrogens/antiestrogens, androgens/anti-androgens, progestins, and luteinizing hormone - releasing hormone antagonists, octreotide acetate; microcannulae destructive agents of type ecteinascidins or their analogs and derivatives; microcapsular-the stabilizing agents of the type paclitaxol (Taxol®), docetaxel (Taxotere®), and epothilones A-F or their analogues or derivatives; products extracted from plants of the type winkalk is oidov, epipodophyllotoxins, taxan; and topoisomerase inhibitors; inhibitors prenylation transferase; and various agents of the type hydroxyurea, procarbazine, mitotane, hexamethylmelamine, coordination complexes of platinum type cisplatin or carboplatin; and other media used as anticancer and cytotoxic agents as biological modifiers reactions, growth factors; immune modulators and monoclonal antibodies. Compounds of the present invention can also be used in combination with radiation therapy.

Typical examples of such classes of anticancer and cytotoxic agents include, but are not limited to, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustin, lomustin, semustine, streptozocin, thiotepa, dacarbazine, methotrexate, tioguanin, mercaptopurine, fludarabine, pentostatin, cladribine, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, idarubitsin, bleomycin sulfate, mitomycin C, actinomycin D, saracini, tetramycin, chinacartimes, discodermolide, vincristine, vinblastine, vinorelbine tartrate, etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine sodium phosphate, flutamide, buserelin, leuprolide, pteridine, dizisini, levamisol, flacon, interferon, interleukins, aldesleukin, pilger is Tim, sargramostim, rituximab, BCG, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabine hydrochloride, altretamine and topotecan, as well as any analogues and derivatives.

Preferred members of these classes include, but are not limited to, paclitaxel, this drug called cisplatin, carboplatin, doxorubicin, karminomitsin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin or derivatives podofillotoksina type etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, lemuroidea, vindesine and Laurasia.

Examples of anticancer and other cytotoxic agents include the following: derivative epothilone described in German patent No. 4138042.8; WO 97/19086, WO 98/22461, WO 98/25929, WO 98/38192, WO 99/01124, WO 99/02224, WO 99/02514, WO 99/03848, WO 99/07692, WO 99/27890, WO 99/28324, WO 99/43653, WO 99/54330, WO 99/54318, WO 99/54319, WO 99/65913, WO 99/67252, WO 99/67253 and WO 00/00485; inhibitors of cyclin-dependent kinase - WO 99/24416; inhibitors prenyl-protein transfers in WO 97/30992 and WO 98/54966.

The combination in accordance with the present invention may also be composed or put together with other therapeutic tools that are selected for their exceptional usefulness in carrying out therapeutic treatment of these diseases. For example, soy is inane in accordance with the present invention can be combined with the means, to prevent nausea, allergies and gastric irritation, type antiemetics and H1and H2antihistamine drugs.

The above-mentioned therapeutic agents, when they are used in combination with the compounds of the present invention may be used in quantities that are listed in the Physicians’ Desk Reference (PDR) or may be determined by the expert in this field.

General methods of obtaining

(A) Derivatives epothilone having formulas I through III

The present invention is directed to deriving epothilone Ia, Ib, IIA, IIb and III, in which the hydrogen atoms of the C-21 methyl group substituted partially or completely by other groups with G1G11. R may be hydrogen or stands, P-Q is a C, C double bond or an epoxide.

The following General formula demonstrates the remainder epothilone, including-CH=group 17 position (17 carbon atom), where the formula Ia, Ib, IIA, IIb and III are compounds containing the specified residue epothilone plus one of the substituents shown in combination with the notation of these compounds Ia, Ib, IIA, IIb and III.

G1=H, halogen, CN, alkyl, substituted alkyl;

G2=H, alkyl, substituted alkyl;

G3=O, S, NZ1

G4=H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C=O, Z4SO2, optionally substituted glycosyl;

G5=halogen, N3, NCS, SH, CN, NC, N(Z1)3+heteroaryl;

G6=H, alkyl, substituted alkyl, CF3, OZ5, SZ5, NZ5Z6;

G7=CZ7N;

G8=H, halogen, alkyl, substituted alkyl, OZ10, SZ10, NZ10Z11;

G9=O, S, -NH-NH-, -N=N-;

G10=N,CZ12;

G11=H2N is replaced with an H2N, alkyl, substituted alkyl, aryl, substituted aryl;

Z1=H, alkyl, substituted alkyl, acyl, substituted acyl;

Z2=H, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle;

Z3=H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl;

Z4=alkyl, substituted alkyl, aryl, substituted aryl, heterocycle;

Z5=H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl;

Z6=H, alkyl, substituted alkyl, acyl, substituted acyl;

Z7=H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, NZ8Z9;

Z8=H, alkyl, substituted alkyl, acyl, Zam is placed acyl, aryl, substituted aryl;

Z9=H, alkyl, substituted alkyl, acyl, substituted acyl;

Z10=H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl;

Z11=H, alkyl, substituted alkyl, acyl, substituted acyl;

Z12=H, halogen, alkyl, substituted alkyl, aryl, substituted aryl.

Compounds according to the invention can be derived from those compounds and in accordance with the General methods described in schemes 1 to 8. All substituents have the meanings given in the diagrams or the earlier.

On the basis of unprotected 3,7-hydroxy or, for example, the TMS-protected epothilone a-C (1), 21-hydroxyapatite (4) can be synthesized from N-oxides (2), the receipt of which is described in WO 98/38192 and included in this scheme as part of the chain (scheme 1). N-Oxides (2) interact with halides of acids and bases, preferably the halides, p-toluenesulfonic acid and 2,6-lutidine, with the formation of the 21-halogenation (3). Deoksigenirovanii epoxides (4) in accordance with known techniques leads to a 21-gidroxiapathitom C and D (5).

Alternatively, (4) and (5) can be synthesized by biotransformation (21-hydroxylation) epothilones A-D using, for example, Sorangium cellulosum strains, as described in WO 98/22461, or Actinomyces sp. strain 15847, as described in PCT/US99/27954, which included the us in the form of links as part of the chain. 3,7-HE secured or unsecured epothilone 3, 4, 5 (scheme 1) (see, for example, WO 97/19086) used to obtain the derivatives of structural type formulas I-III.

Scheme 2

Scheme 2 can be illustrated as follows (derived residue epothilone, including-CH=group at position 17 means that this part of the molecule was not included in the reaction process, in accordance with the illustration).

a) Compounds 3 and 7 can be obtained from compounds 4 or 5 by (i) activation, for example, using TosHal/pyridine followed ii) nucleophilic substitution of the halide anions (compound 3) N3- N=C=S, CN, NC or SH anions (compound 7) on IT; NaN3use, for example, for the introduction of N3and AgCN, for example, for the introduction of isonitrile group.

b) Compound 6 can be obtained from compounds 4 or 5, compound 8 from compound 3 or 7 (X=SH) and junction 10 of the compound (9) by reacting the parent compound with a reagent of formula R1Hal in the presence of a base, where R1may be optionally substituted by alkyl, acyl, optionally substituted arylsulfonyl or optionally substituted glikozidom in the case of obtaining the compound (6), the alkyl or acyl in the case of obtaining the compound (8) or (10). If the connection 9 mutual acts with reagents of the formula R 1Hal and R2al (R1and R2=alkyl or acyl), I get the connection 11, and if the connection 9 interacts with reagents of the formula R1Hal, R2Hal and R3Hal (R1, R2and R3=alkyl), I get the connection 12.

(C) Compound 9 can be obtained from compound 7 when X=N3by (i) recovery, for example, using H2and Lindlar catalyst (Lindlar catalyst)/EtOH or ii) phosphines, such as RME3and then the aqueous NH3.

Scheme 3

Scheme 3 can be illustrated as follows (derived residue epothilone, including-CH=group in position 17 means that this part of the molecule does not participate in the illustrated reaction process).

a) Compound 2 can be obtained by the reaction of compound 1 with agent oxygenlive, such as m-chloroperbenzoic acid.

b) and (C) Compound 4 can be obtained by the reaction of compound 2 with (b) alleluya system containing, for example (b) (CF3CO)2O/2,6-lutidine, and then (C) CH3HE/NH3(waters).

d) Compound 7 can be obtained by the reaction of compound 4 with diphenylphosphorylacetate (D)/databaseconnection (DBU).

e) Compound 9 (P-Q=epoxide) can be obtained by restoring the connection 7 a phosphine, for example, RME3and then NH3waters).

f) Connection 10 with P-Q=the epoxide can be obtained by interaction of the compound (9) with (t-BuOCO)2On/NEt3.

g) Connection 10 with P-Q=C=C double bond can be obtained by reduction of compound 10 with P-Q=the epoxide using WCl6/n-BuLi.

h) Compound 9 (P-Q=double bond) can be obtained by removing protection from the connection 10 with P-Q=C=C double bond and R1=t-BuOCO using triperoxonane acid (TFA).

Scheme 4

Scheme 4 can be illustrated as follows (derived residue epothilone, including-CH=group at position 17 means that this part of the molecule does not participate in the illustrated reaction process):

a) Compound 6 can be obtained from compound 4 by acylation in the presence of p-taillored/base Janiga (Hunig base).

b) Connection 7 with the same epoxide can be obtained from compound 6 by substitution with cyanide, for example KCN/18-crown-6.

c) Connection 7 with P-Q=C=C double bond can be obtained from compound 7 with P-Q=the epoxide by restoring using WCl6/n-BuLi.

d) Connection 7 with the same epoxide can be obtained from compound 6 by substitution with imidazole in the presence of a base, such as2CO3.

Scheme 5

Scheme 5 can be illustrated as follows (use the feudal remnant epothilone, includes-CH=group at position 17 means that this part of the molecule does not participate in the illustrated reaction process):

a) Connection 13 can be obtained by oxidation of compound 4 or 5 by using, for example, Mno2.

b) Compound 14 can be obtained by reacting compound 13 with CH2N2.

c) Compound 15 can be obtained by introducing a connection 13 into the reaction type of reaction, Wittig (Wittig).

d) Compound 16 can be obtained by processing the connection 13 of the reaction system containing rl2and l3.

e) Compound 17 can be obtained by reacting compound 16 with BuLi and RHal (R=H, alkyl or acyl).

f) Connection 18 can be obtained by reacting compound 13 with CH2N2for 18 (R=H C21 Deputy) or Me2SOCHR for 18 (R=H, alkyl).

g) Connection 19 can be obtained by reacting compound 13 with R2MgHal or R2Li (R2=alkyl).

h) Compound 20 can be obtained by oxidation of compounds 19, for example, using IGOs2.

i) Connection 21 can be obtained by reacting compound 20 with R1MgHal or R1Li (R1=alkyl).

k) Connections 22A, 22b or 22s can be obtained by reacting compound 13 with H2NR, where R=OR1and R1=hydrogen, alkyl or aryl for compound (22A); R=N(R2)2and R2=hydrogen, alkyl or acyl for compound (22b) and R=alkyl or aryl to connect 22p.

l) Compound 23 can be obtained by reacting compound 13 with a source of CN, such as HCN.

m) Compounds 10 and 11 can be obtained by reductive amination 13 using HNR1R2such as NaBH3CN, where R1and R2=H, alkyl.

Scheme 6

Scheme 6 can be illustrated as follows (derived residue epothilone, including-CH=group at position 17 means that this part of the molecule does not participate in the illustrated reaction process):

a) Connection 24 can be obtained by oxidation of compound 13 using, for example, Ag2O in THF/water (ratio of THF/water, for example, 9:1).

b) Compound 25 can be obtained by methylation of compound 24 using, for example, CH2N2in ethyl acetate.

c) Connection 26 can be obtained by reacting compound 25 with an excess of R1MgHal or R1Li (R1=alkyl).

d) Compound 27 can be obtained by acylation of compound 26 with R2Hal (R2=acyl) in the presence of a base, such as DMAP.

e) Connection 28 can be obtained by first activating the carboxyl group 24 using, for example, ethylchloride the/NEt 3and the second reaction with R1NH2(R1=hydrogen, alkyl or aryl) in THF.

f) Compound 29 can be obtained by dehydrogenation of compound 28 (R1=hydrogen) by using, for example, POCl3/NEt3.

Scheme 7

Scheme 7 can be illustrated as follows (derived residue epothilone, including-CH=group at position 17 means that this part of the molecule does not participate in the illustrated reaction process):

a) Compound 31 (R3=acyl) can be obtained by reacting compound 19 or 21 with activated derivatives of carboxylic acids, for example RCOHal (R3=RCO) in the presence of a base.

b) the Connection 20 can be obtained by oxidation of compound 19 (R1=hydrogen, R2=alkyl), for example, using IGOs2.

c) Connection 34 can be obtained by condensation of compound 20 with H2NR3(R3=hydrogen, alkyl, aryl or or NRR4with R and R4=alkyl, aryl).

d) Compound 35 can be obtained by reacting compound 34 (R3=alkyl, aryl) with R1MgHal or R2Li (R1and R2=alkyl).

e) Connection 32 can be obtained by reacting compound 20 (R2=CF3) i) H2NOpTos and (ii) NH3(Jew.).

f) Connection 36 can be obtained by introducing a connection 20 in Rea is of reductive amination.

g) Compound 38 can be obtained by alkylation or acylation of compound 35 with R5Hal (R5=alkyl or acyl) in the presence of a base.

h) Compound 33 can be obtained by oxidation of compound 32 using, for example, Ag2O.

i) Connection 37 can be obtained by alkylation or acylation of compound 36 with R3Hal (R3=alkyl or acyl) in the presence of a base.

(C) Derived epothilone IV

In addition, the invention is directed to deriving epothilone IV having the following formula IV, where the symbols have the following notation:

P-Q is a C, C double bond or an epoxide,

R is an atom H or a methyl group, and

G11is a group, H2N is replaced with an H2N group, alkyl group, substituted alkyl group, aryl group, substituted aryl group.

Obtaining and rearrangement of N-aceleration-N-oxide

Getting epothilone-N-oxide (2) (P-Q=epoxide) and their rearrangement in the 21st allocation the following formula 6 described in WO 98/38192, the full text of which is included in the description by reference.

6 R1=alkyl, acyl, (substituted) alkyl, (substituted) arylsulfonyl, (substituted) glucosyl

Scheme 8

Scheme 8 can be illustrated as follows (derived residue epothilone, including-CH=group at position 17 means that this part of the molecule does not participate in the illustrated reaction process).

P-Q represents a epoxide, or C With a double bond, R is hydrogen or methyl group.

a) Compounds 3 and 6 can be obtained by reacting compound 2 with R1SO2Cl in the presence of base (R1= optionally substituted alkyl or optionally substituted aryl).

b) Compounds 6 and IVa/b can be obtained by reacting compound 2 with the derived activated carboxylic acid such as a carboxylic acid anhydride.

c) Compound 4 can be obtained by reacting compounds IVa/b nucleophile NuH or Nu-.

Esters 6 are used as intermediates to obtain a large number epothilones, which further modify the position C-21.

For example, if 2 reacts, for example, with acetic anhydride, in a short period of time can produce unexpected new intermediate compound IV, while IV is completely transformed into the connection 6 through a long period of time. If the reaction to stop at a certain point in time, compound IV can be selected chromatographic two is diastereoisomers IVa and IVb.

Compounds of type IV have not been previously described. Their structure could clearly be established on the basis of spectroscopic data and subsequent reactions.

For preparative purposes especially important is their reaction with nucleophiles, leading to S-21 substituted epothilones 6; Nu=for example, carbon-, nitrogen-, oxygen-, sulfur - and halogensubstituted.

The following not limiting the scope of the invention examples serve as illustrations.

Example 1

Turning epothilone In epothilone F

(i) 1.98 g (3.90 mmol) epothilone In place in an atmosphere of argon and dissolved in 60 ml of dry CH2CL2. To this solution was added determined as 0.720 g msrv (4,17 mmol, 1.07 equivalent).

The mixture is stirred at 25°5.5 hours. Then the reaction mass is quenched with 60 ml of NaHCO3and extracted with 3×75 ml l3. The organic phase is washed with 100 ml of water, then 70 ml of 5% Na2SO3(waters) and 70 ml of brine. The organic phase is dried over Na2SO4. The crude reaction product chromatographic using silica gel and elution with 2% Meon in l3with the release of 0,976 g N-oxide (48%) as a white fluffy solid.

(ii) In a sealed tube filled with argon, add 0,976 g N-oxide (to 1.86 mmol), dissolved in 35 ml of dry CH2Cl2, 2,6-lutidine (1.73 ml, 14,88 mmol, 8 e is bivalents) and (CF 3CO)2(Of 1.84 ml, 13,02 mmol, 7 equivalents). The tube is sealed and heated at 70°25 minutes. The mixture is allowed to cool and the solvent is removed in a stream of argon, and then concentrated in vacuo before will remain a few milliliters of a dark yellow solution. The reaction was diluted with 25 ml of CH3HE added to 2.9 ml of 28% NH4OH (water). The mixture is heated to 45°20 min, then cooled to room temperature. The crude product is concentrated on a rotary evaporator and chromatographic using elution from silica gel using 4% CH3HE l3with the release of 0,815 g epothilone F (84%).

Example 2

Synthesis of 21-azido-epothilone 7

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (R=CH3, G1=G2=N, G5=N3in formula Ib)

To mix the solution epothilone F from the above example 1 (957 mg, to 1.83 mmol) of 20.0 ml of tetrahydrofuran at 0°in argon atmosphere add to 0.47 ml diphenylphosphinite (604 mg, 2,19 mmol, 1.2 equivalent). The mixture is stirred for approximately 3 minutes, and then add 1,8-diazabicyclo[5.4.0]undec-7-ene (0,27 ml, 278 mg and 1.83 mmol, 1 equivalent) and the mixture was stirred at 0°C. After 2 hours the mixture is heated to 25°C, after which lane is mesilat another 20 hours. Then the reaction mass is diluted with 150 ml ethyl acetate and washed with 50 ml of N2O. the Aqueous layer was extracted with 35 ml of ethyl acetate. The combined organic layers dried over Na2SO4and concentrate under vacuum. The crude product chromatographic using elution from silica gel with 50% ethyl acetate in hexane to obtain 913 mg (91%) 21 azido-epothilone In the form of a clear, colorless oil.

MS (ESI+):

549,3 (M+N)+;1H-NMR (300 MHz, CDCl3): δ=6,59 (broad s, 17-H),? 7.04 baby mortality (s, 19-H), 4,63 (s, 21-Hz); HRMS (DCI);27H40N4O6S:[M+] calculated 549,2747 found 549,2768.

Example 3

Synthesis of 21-amino-epothilone 9

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (R=CH3, G1=G2=G4=Z1=H, G3=NZ1in formula Ia)

The Lindlar catalyst in the amount of 18.0 mg suspended in 500 µl of ethanol in N2the atmosphere and saturate it. Then add to 15.9 mg (29,0 µmol) 21 azido-epothilone In example 2, above, dissolved in ethanole-methanol mixture. After stirring for 30 minutes at room temperature, the suspension is filtered through celite and washed with ethyl acetate. The solvent is removed from the organic phase and dry it in a high vacuum. Purification of the crude PR the product passes through the PSC (solvent: CH 2Cl2/methanol 90:10), you get to 12.3 mg (81%) 21-amino-epothilone In and 1 mg (6%) of adduct educt.

1H-NMR (300 MHz, Dl3): δ=return of 6.58 (broad s, 17H), 7,05 (s, N), 4,15 (C, 21 Hz); HRMS (DCI); C27H42N2O6S: [M+H+] calculated 522,2764 found 522,2772.

Example 4

Synthesis of 21-amino-epothilone 9 (alternative)

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To a stirred solution of 21 azido-epothilone In (example 2) (1,070 g 1,950 mmol) and 30.0 ml of tetrahydrofuran in an argon atmosphere add to 0.22 ml trimethylphosphine (0,163 g 2,145 mmol, 1.1 equivalent). Then add H2(5.5 ml) and the mixture was stirred at 25°C. After 3 hours azide decomposes and the resulting reaction mass add 3 ml of 28% aqueous NH4HE (waters) to complete the process of turning posteljina in Amin. After stirring at 25°C for 1 hour the reaction mixture, the solvents are removed under vacuum. Raw material chromatographic using elution from silica gel with 1% Et3N, 2.5% of CH3HE l3with the release of 924 mg (91%) 21-amino-epothilone In the form of a white solid. MS (ESI+):523,3 (M+H)+.

Example 5

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-Dimethylmethoxy)to rbony]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To a solution of 21-amino-epothilone In (126 mg, 0.24 mmol) in methanol (4.0 ml) is added triethylamine (67 μl, 0.48 mmol, 2 equivalent) and di-t-butylboronic (65 mg, 0.3 mmol, 1.25 equivalents). The reaction mixture is stirred for 2 hours. TLC shows no starting material. The reaction mixture was concentrated in vacuo and chromatographic on silica gel using 5% CH3HE l3as the eluent, to obtain 164 mg (100%) 21-amino-epothilone In the form of a white solid.

Example 6

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylmethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione

Anhydrous tetrahydrofuran (3.0 ml) is placed in a dried in a drying Cabinet flask in an argon atmosphere and cooled to -78°C. In a stream of argon to chilled tetrahydrofuran add WCl6(206 mg, 0.52 mmol, 2 equivalent), and then n-utility (0,650 ml, 1.6 M solution in hexane, 1.04 mmol, 4 equivalents). The reaction flask is removed from cooling to -78°With bath and stirred at ambient temperature for 15 minutes. Then the resulting reaction mass is placed in a bath at 0°and additionally stirred for 5 minutes before adding a solution of 21-amino-epothilone (dried via azeotropic distillation with toluene under vacuum overnight (164 mg, 0.26 mmol, 1 equivalent) in tetrahydrofuran (1.5 ml). The reaction is maintained at 0°With 45 minutes. TLC shows that the bulk of the source material entered into the reaction. The reaction is quenched with saturated aqueous NaHCO3(5 ml) and partitioned between saturated aqueous NaHCO3(25 ml) and CH2Cl2(50 ml). The aqueous phase is extracted three times with CH2Cl2. Combined organic layers dried over Na2SO4concentrate in vacuo and purify by chromatography on silica gel, first with 7% CH3HE l3and then the second time by elution from the column using 50% ethyl acetate in hexane to obtain 65 mg (41%) 21-N-BOC-amino-epothilone D. MS (ESI+): 605,3 (M+N)+; MS (ESD): 605,3 (M-N)-.

Example 7

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione

When 0°21-N-BOC-amino-epothilone D (98 mg, 0.16 mmol) is treated with pre-cooled solution of 10% triperoxonane acid in CH2CL2(4,0 ml). After 40 minutes the reaction mass, allow to warm to room temperature and after an additional 20 minutes add undiluted triperoxonane acid (0.6 ml). Even after 50 minutes, add the additional amount (0.5 ml) triperoxonane acids the. The reaction is terminated by 50% after 1.75 h, then the solvents removed in vacuo. The residue is transferred into ethyl acetate (50 ml), saturated aqueous NH4HE (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers dried over Na2SO4and then chromatographic, elwira with silica gel initially pure ethyl acetate, then 10% of CH3HE in ethyl acetate with 1% triperoxonane acid with getting to 16.8 mg (38%) of the desired 21-amino-epothilone D in the form of transparencies with 45 mg of 21-N-BOC-aminonaphthalene D. MS (ESI+): 506,3 (M+N)+; MS (ESI-):504,3 (M-N)-.

Examples of the synthesis of 21-acyloxy-epothilone shown in examples 8 through 10.

Example 8

Example:

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoate)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (R=G1=G2=N, G3=O, G4=Z2O, Z2=n-Bu in formula Ia)

To a solution of 20 mg (39 mmol) epothilone A-N-oxide in 100 μl of CH2CL2add 83,0 ál (419 mmol) of anhydride valerianic acid and 20.0 ml (172 mmol) of 2,6-lutidine. The reaction mass is stirred for 30 minutes at 75°C, the solvent is removed and dried in high vacuum. Purification of the crude product is carried out using preparative HPLC (Nucleosil 100, solvent: CH3CN/H2O 50:50)to give 9 mg (40%) epothilone-E-21-valerate.

1H-NMR (300 MHz, CDCI3); δ=6,60 (s, 17-H), 7,14 (s, 19-H), to 5.35 (s, 21-H2), 3,62 (t, 2’-H2), 1.6 to 1.7 (m, 3’-Hz), to 1.3-1.4 (m, 4’-H2), of 0.91 (t, 5’-H3). HRMS (EI);

C31H47NO8S: calculated 593,3022 found 593,3007.

Example 9

Example:[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione(R=G1=G2=H, G3=O, G4=Z2C=O, Z2=naphthyl in formula Ia)

Epothilone A-N-oxide, 21 mg (41 μmol) dissolved 80 ál of CH2Cl2and 10 ml (86 mmol) of 2,6-lutidine and add 82,0 ml (129 mmol) of a solution of 2-naphthylamide (300 mg/ml of CH2CL2). The reaction mixture is stirred for 10 minutes at 75°C. the Crude mixture was purified using preparative HPLC (Nucleosil 100, solvent: t-butyl methyl ether/hexane 1:2 with 1% methanol). Separation leads to 8 mg (29%) epothilone E-21 naphtholate.

1H-NMR (400 MHz, DI3); δ=6,64 (s, 17-H), 7,19 (s, 19-H), 5,67 (s, 21-Hz), of 8.09 (DD, 3’-H), of 7.96 (d, 4’-H), 7,89 (DD, 5’-H), 7,89 (DD, 6’-H), 7,58 (m, 7’-H), 7,58 (m, 8’-H), 8,67 (s, 9’-H); HRMS (DCI):37H45NO3S: [M+] calculated 663.2866 found 663.2877.

Example 10

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)atomic charges]methyl]-1-methyl-4-thiazolyl]ethynyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1,0]heptadecane-5,9-dione (R=G1=G2=H, G3/sup> =O, G4=Z3C=O, Z3=3’,6’-dioxaoctyl in formula Ia)

2-(2-Methoxyethoxy)acetic acid, 100 μl (880 mmol), dissolved in 1.6 ml of THF. Then add 137, 6mm ál (880,0 mmol) 2,4,6-trichlorobenzaldehyde and 135 μl (968 mmol) of triethylamine. The mixture is stirred for 1 hour at room temperature, during which the formed colorless precipitate. The reaction solution is centrifuged and add 120 μl of the upper layer to a solution of 23 mg (45 μmol) epothilone E in 400 μl of THF. Then add to 8.4 mg (46 μmol) dimethylaminopyridine and the mixture is stirred for 20 minutes at room temperature. Purification of the crude product carry out preparative HPLC (Nucleosil 100, solvent: t-butyl methyl ether/hexane 1:2+2% methanol). So allot of 14.7 mg (52%) 21-(3’,6’-dioxaheptyl)-epothilone E.

1H-NMR (300 MHz, DCI3): δ=6,60 (broad s, 17-H), 7,16 (S, 19-H), 5,42 (s, 21-H2), to 4.52 (s, 2’-H2), 3,74 (m, 3’-H2), to 3.58 (m, 4’-H2), 3,37 (s, 5’-H3); HRMS (DCI): C31H47NO10S: [M+H+] calculated 626,2999 found 626,2975.

Example 21 synthesis-allumination 10 are shown in the following example 11.

Example 11

Example: [1S-[1R*,3R*(E),7R*,10S-11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionamido)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

(R=H, G1=G2=N, G3=NZ1, Z1=N, G4=Z C=O, Z2=Et in the formula 1A)

The triethylamine, 70 μl (500 μmol), dissolved in 250 μl of absolute THF and then cooled to 0°using ice water. Then to this solution was added 53 ml (400 mmol) of methylchloroform. After about 5 minutes added dropwise 25 ál (334 mmol) of propionic acid and the mixture is stirred for additional 10-15 minutes. Then the reaction mass is then warmed to room temperature and the precipitate was separated by centrifugation. After that add 47 µl of the upper layer to a solution of 13 mg (26 mmol) of 11-amino-epothilone And 250 μl of absolute THF and 5.4 μl (from 39.0 mmol) of triethylamine. After 20 minutes, the crude reaction mixture was purified using preparative TLC (solvent: CH2Cl2/CH3IT is 90:10). So get to 11.2 mg (76%) 21-amino-epothilone And-propionamide.

1H-NMR (300 MHz, DCI3): δ=6,57 (broad s, 17-H), 7,07 (s, 19-H), 2,28 (kV, 2’-H2), 1,18(3-N3), of 6.29 (t, MN);

IR-MS (El): C29H44N2O7S: calculated 564,2869 found 564,2854.

Synthesis epothilones formula IV and 21-allocationof 6 described in examples 12 to 18, below.

Derivative 6 is described in DE 19907588.3 and they can be obtained, usually in several stages of 2, while the process described below corresponds to DE 19930111.5, both source information included in the description as references.

the example 12

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-[methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, N-oxide (formula IVa and IVb: R=H, G11=CH3)

102 mg (0.2 mmol) of compound 2 dissolved in 2 ml acetic anhydride and heated for 5 minutes to 75°C. Then the reaction medium was concentrated at 30°C/1 mbar before the formation of viscous oil and separated on silica gel Si 60 (solvent: hexane/methyl t-butyl ether/methanol 66:33:1); in addition to 65 mg (41%), elute 17 mg (11%) of each of the IVa and IVb.

IVa: colorless oil; DC:Rf=0,66 (dichloromethane/methanol 95:5); UV (CH3HE: λmax(ε)=203 (13800), 267 (13200), 315 nm (5000); [α]D21=185,1 (=0,94 in l3/Meon 1:1); IR (KBr): ν=3446, 2965, 2936, 2877, 1742, 1691 cm-1;1H-NMR (Dl3): δ=2,43 (DD, J=4,8, and 3.7 H-2A); 2,53 (DD, 14,8, 10,2, H-2b); 4,13 (m, 3-1); to 3.33 (d, J=6,4, 3-one); to 1.86 (dt, J=15,0, 7,8, 14-1a); of 2.08 (m, 14-Hb); of 5.39 (DD, J=7,8, 2,2, 15-H); 6,23 (broad, 17-H); 6,95 (s, 19-H); 5,18 (C, 21); 5,71 (with a wide, 21-Kb); and 2.26 (with a wide, 27-H3); 2,12 (s, CH3CO);13C-NMR (CDCl3); δ=73,4 (C-3); 52,8 (C-4); 151,5 (C-16); 116,0 (C-17); To 158.0 (C-18); To 88.7 (C-19); 166,9 (C-20); 107,2 (C-21); 20,7 (C-22); 170,2, 21,2 (acetyl); HPLC/ESI-MS (acetonitrile/0.02 M buffer of ammonium acetate, pH 7, pos. ions): m/e 569 [M+NH4].

IVb: colorless oil; DC:Rf=0,69 (conditions above); [α]D21=119,6 (C=1,1; l3/Meon 1:); 1H-NMR (Dl3): 1,90 (m, 14); of 2.09 (m, 14-Hb); 5,42 (DD, J=7,8, 2,2, 15-H); 6,92 (s, 19-H); of 2.23 (s, 27 H3); 2,10 (s, CH3CO);13C-NMR (Dl3): 150,8 (C-16); 116,5 (C-17); And 17.2 (C-27); 170,3, 21,0 (acetyl).

Example 13

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (6A, R=N, Nu=co3)

14 mg (25 µl) IVa or IVb (R = from example 12, above), heated in 1 ml of methanol for 30 minutes to 75°, concentrated under vacuum and separated with preparative HPLC (RP-18, CH3CN/H2O 1:1). Receive 2.5 mg (19%).

Rf(CH2Cl2/MeOH): 0,33.

1H-NMR (Dl3): δ=4,71 (s, 21-CH2), 3,49 (s, 21-och3);

13C-NMR (CDCl3): δ=59,1 (och3); 71,5 (C-21); 167,8 (C-20); DCI-MS (isobutane: m/z=524,2609 [m+H+], for C27H41NO7S calculated 524,2604.

Example 14

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

6.6 mg (11.7 mmol) of N-acetyl-21-methylene-epothilone And N-oxide are dissolved in 1.5 ml dichloromethane and treated to 11.1 mg (120 μmol) of phenol, dissolved in 300 μl of dichloromethane. After stirring the mixture at 75°within two hours, the solvent evaporated and the crude product was purified preparative TLC (solvent: CH2CL2/sub> /methanol 95:5) with the formation of 1.8 mg (30%) 21 phenoxy-epothilone Century

1H-NMR (400 MHz, CDCI3) Delta=6,59 (broad s, 17-H), 6,99 (s, 19-H), is 4.21 (s, 21-H2), 6.78, and 7,16 (DD, fragrance. H); HR-MS (DCI): C28H43NO7S, [M+H]+calculated 538,2839 found 538,2832.

Example 15

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-(2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (8, R=CH3, R1=C2H5)

20 mg of compound 2 (R=CH3) translate using acetic anhydride in a mixture of 6 (R1= acetyl) and IVa and IVb of example 12, above, and concentrate under vacuum before formation of the oil. The specified oil is dissolved in 100 μl of ethyl mercaptan and heated for 1 hour to 105°C. thereafter, the mixture is subjected to drying under vacuum and the dried residue was separated using preparative DC (silica gel, petroleum ether/ethyl acetate 1:1). Output 5 mg (25%). Rf(petroleum ether/ethyl acetate 1:1): 0,48.

1H-NMR (CDCI3): δ=3,98 (s, 21-CH2); 1,24, 2,60 (t, kV, 21-SC2H5) (, 21-och3); DCI-MS (isobutane): m/e=554.

Example 16

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

10 mg (19,7 µmol) epothilone E dissolved in a mixture of 100 μl of dichloromethane and 300 µl of diethyl ether and about abayat 54,6 mg (236 mmol) of silver oxide (1) and 47.6 μl (590 mmol) iodata. After stirring over night at room temperature the mixture is filtered through celite and evaporated to dryness. Purification of the crude product is carried out using preparative TLC (solvent: CH2CL2/methanol 95:5), which gives an 8.8 mg (of 83.4%) 21 ethoxy-epothilone A.

1H-NMR (400 MHz, CDCl3): δ = 6,60 (wide, 17-H), 7,11 (s, 19-H), and 4.75 (s, 21-H2), the 3.65 (q, 1’-H2), 1.27mm (t, 2’-H3); HR-MS (DCI): C28H43NO7S, [M+H+] calculated 538,2839 found 538,2832.

Example 17

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2’,3’,4’,6-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Epothilone E (50 mg, 98 μmol) and tetramethylrhodamine (46 μl, 383 mmol), dissolved in 200 ml of dry CH2Cl2add to the suspension triftoratsetata silver (101 mg, 393 mmol) and powdered molecular sieves 4Å (500 mg) in 2 ml dry CH2CL2. The mixture is stirred in an atmosphere of N21 hour at room temperature. Add β-D-acetobromogalactose (121 mg, 295 μmol)dissolved in 200 μl of dry CH2CL2. React the mixture was stirred at room temperature overnight, filtered through celite and concentrated. Purification using chromatography with reversed phase (CH3SP/N2About 48:52), and then on silica gel (CH2CL2/methanol 95:5) leads to alpha-glucoside (4.2 mg, 5%) and β-glucoside (5.6 mg, 6%) as colorless solids.

alpha-glucoside:

1H-NMR (300 MHz, CDCl3): δ = 6,58 (broad s, 17-H), 7,11 (s, 19-H), 4,82 (s, 21-Hz), 5,74 (l, 1’-H), to 4.38 (DDD, 2’-H), 5,19 (t, 3’-H), the 4.90 (DD, 4’-H), of 3.94 (dt, 5’-H), 4,20 (m, 6’-Hz); DCI-MS (120 eV, NH4+): 857 [M+NH4+].

beta-glucoside:

1H-NMR (400 MHz, CDCl3): δ = 6,59 (broad s, 17-H), 7,14 (s, 19-H), 4.92 in (d, 21), is 5.06 (d, 21-b), 4,69 (l, 1’-H)5,08 (t, 2’-H), 5,20 (t, 3’-H), 5,11 (t, 4’-H), 3,71 (m, 5’-H), 4,13 (DD, 6’-On), of 4.25 (DD, 6’-b);

DCI-MS (120 eV, NH4+): 857 [M+NH4+].

Example 18

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*1]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6’-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione

β-Glucoside, obtained above (4,8 mg, 5.8 mmol), dissolved in 50 μl DMSO. Add phosphate buffer (4 ml, 20 mm, pH=7) and the reaction mixture was exposed to ultrasound for 5 minutes. Add esterase pig liver (0.3 ml, Boehringer Mannheim) and continue stirring for another 3 hours. The mixture is extracted with ethyl acetate and the combined organic extracts are concentrated. Cleaning with XP is matography with reversed phase (CH 3CN/H2O 38:62) gives 1 mg (24%) glucoside.

1H-NMR (600 MHz, CDCl3): δ = 6,62 (broad s, 17-H), to 7.15 (s, 19-H), of 4.95 (d, 21), 5,14 (d, 21-b), a 4.53 (d, 1’-H), of 3.45 (DD, 2’-H), 3,57 (t, 3’-H), 3,42 (t, 4’-H), 3,50 (m, 5’-H), 4,30 (DD, 6’-On), 4,48 (DD, 6’-b), 2,12 (s, acetyl-Hs).

Synthesis of 21-sulfonyloxy-epothilone 6 shown in examples 19 and 20 below.

Example 19

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluensulfonate)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (R=Me, G1=G2=H, G3=O, G4=Z4SO2, Z4=p-toluyl in formula Ia)

To a stirred solution of 104 mg epothilone F (199 mmol, 1 equivalent) in 5 ml of CH2CL2when 0°in argon atmosphere add to 0.17 ml of N,N-diisopropylethylamine (993 μmol, 5 equivalents), and then 45 mg of p-toluensulfonate (238 mmol, 1.2 equivalent). The mixture is stirred at 25°With 47 hours, to allow the source material to completely react. The reaction mixture is poured into 40 ml of a saturated aqueous solution of NaHCO3. The aqueous layer was extracted with CH2CL2(3×50 ml). The combined organic layers dried over Na2SO4and concentrate under vacuum. Raw material chromatographic using 50% ethyl acetate in hexane, to yield 18 mg (16%) 21-chloro-epothilone and 85 In the g (63%) 21 tosyloxy-epothilone, in the form of a clear oil. MS (SI+): to 678.4 (M+H)+.

The reaction epothilone And p-toluensulfonate leads by analogy to the formation of 21 tosyloxy-epothilone A. Reaction epothilone A-N-oxide with p-toluensulfonate leads to the formation of a mixture of 21-tosyloxy-epothilone and 21-chloro-epothilone And who share chromatography.

21 Tosyloxy-epothilone And

1H-NMR (300 MHz, CDCI3): δequals 6.54 (broad s, 17-H), to 7.15 (s, 19-H), from 5.29 (s, 21-Hz), 7,82 (d, 2’,6’-H), 7,34 (DM, 3’,5-H), 2,44 (C, 7’-H3).

21-Chloro-epothilone And

1H-NMR (300 MHz, CDCI3): δ=6,59 (broad s, 17-H), 7,16 (s, 19-H), to 4.81 (s, 21-Hz); HRMS (DCI):26H38NO6S: [M+H*] calculated 528,2187 found 528,2154.

Example 20

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(methyl bromide)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-Bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

45 mg (91 μmol) epothilone And dissolved in 8 ml of absolute THF in an atmosphere of N2and cooled to minus 90°C. Then add 61 μl (406 mmol) of tetramethylethylenediamine and 270 μl (406 mmol) of t-utility in hexane. After ten minutes of stirring at minus 90°add 21 µl (406 mmol) of bromine. After 5 minutes of stirring the reaction quenched with the aid of the rd 10 ml of saturated solution of ammonium chloride at minus 90° C. the mixture is Then warmed to room temperature with continued stirring and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated to dryness. Separation using preparative HPLC gives 2.6 mg (5%) of 21-bromo-epothilone and 2.1 mg (4,0%) 19-bromo-epothilone A.

1H-NMR (600 MHz, DCl3): δ = 6,58 (s, 17-H), 7,17 (s, 19-H), 4,70 (s, 21-H2). HR-MS (DCI):26H38NO6SBr, [M+NH4+] calc. 589,191679Br found 591,190379Br.

Example 21

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

(i) using the reaction Qatada (Katada) epothilone B-N-oxide was transferred to epothilone F. To a stirred solution of 104 mg epothilone F (199 mmol, 5 equivalents) d 5.0 ml of CH2CH2when 0°in argon atmosphere add to 0.17 ml of n,n-diisopropylethylamine (0,993 mmol, 5 equivalents)and then further 0,045 g p-toluensulfonate (238 mmol, 1.2 equivalent). The mixture is stirred at 25°With 47 hours, to allow the source material (SM) to fully react. The mixture is then poured into 40 ml of a saturated aqueous solution Panso3. The aqueous layer was extracted with CH2Cl2(3×50 ml). The combined organic layers dried over Na2SO and concentrated in vacuo. Raw material chromatographic using 50% ethyl acetate in hexane to yield 18 mg C21 chloride (16%) and 85 mg of the desired tosilata (63%) as a clear oil.

(ii) To a stirred solution of 84 mg of SM from previous experience (124 mmol, 1 equivalent) of 3.50 ml of CH2Cl2in an argon atmosphere at 25°add 40 mg of KCN (620 μmol, 5 equivalents) and 33 mg of 18-crown-6 (124 mmol, 1 equivalent). Mixture is allowed to mix at 25°15 hours for which the source material is completely reacted. The mixture is then directly loaded into a column of silica gel and chromatographic using 2:1 ethyl acetate : hexane as eluent, which allows to obtain 41 mg of the desired nitrile (61%) as a colourless solid.

Example 22

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13 (Z)-cyclohexadien-2,6-dione

Anhydrous tetrahydrofuran (5.0 ml) is placed in a thoroughly dried flask in an argon atmosphere and cooled to -78°C. Add to chilled tetrahydrofuran in a stream of argon WCl6(300 mg, 0,756 mmol, 2 equivalent), and then n-utility (0,946 ml, 1.6 M solution in hexane and 1.51 mmol, 4 equivalents). The reaction flask is removed from cooling to -78°With bath and stirred at room temperature for 15 minutes. ZAT is m the reaction flask is placed in a bath at 0° C and stirred for an additional 5 minutes. In a separate flask 21-cyano-epothilone In (72 mg, is 0.135 mmol), previously dried via azeotropic distillation in vacuo with toluene, cooled with ice to 0°and add a bright green solution of tungsten reagent (2,12 ml). Reaction support at 0°20 minutes. TLC shows the disappearance of the starting material. Then the reaction quenched with saturated aqueous NaHCO3(10 ml) and partitioned between saturated aqueous Panso3(20 ml) and ethyl acetate (50 ml). The aqueous phase is extracted three times with ethyl acetate. The combined organic layers washed with water (25 ml) and brine (15 ml)and dried over Na2SO4before concentrating in vacuo. The crude material is purified using chromatography on silica gel with 40% ethyl acetate in hexane to obtain 43 mg (61%) 21-cyano-epothilone D. MS (ESI+): 516,3 (M+N)+.

Example 23

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(1H-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To a stirred solution of 6 mg 21 tosyloxy-epothilone In (8.9 mmol, 1 equivalent) in 1.0 ml of dimethylformamide in an argon atmosphere add imidazole (4.8 mg, 71 μmol, 8 equivalents) and K2CO3(12.3 mg, 0,0890 mmol, 10 equivalent is). Mixture is allowed to mix at 25°5 hours. The solvent is removed in vacuum and the reaction mixture chromatographic on silica gel using 1% Et3N, 3% SN3HE l3as eluent, which allows to obtain 1.4 mg (27%) 21-imidazolidinone In the form of a clear oil. MS (ESI+): 574,4 (M+N)+.

Example of synthesis epothilone-20-carbaldehyde 13 in the following examples 24 and 25.

Example 24

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (G6=N, G9=O in formula IIb)

Epothilone E 58 mg (114 μmol) dissolved in 1 ml of CH2CL2. At intervals of 10 minutes, three times add 295 mg (3.4 mmol) of manganese dioxide and the mixture is stirred at room temperature. After 40 minutes of manganese dioxide is filtered off and washed with methanol. The combined organic phases are evaporated to dryness and the crude product purified using preparative HPLC (Nucleosil 100, solvent: t-butyl methyl ether/hexane with 3% methanol. Thus obtain 36 mg (62%) epothilone And-20-carbaldehyde.

1H-NMR (400 MHz, DCI3): δ = 6,67 (s, 17-H), 7,53 (s, 19-H), 9,98 (d, 21-H); HRMS (DCI): C26H37NO7S: [M+H+] calculated 508,2369 found 508,2367.

Example 25

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-di is hydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Epothilone F (180 mg, 344 μmol, 1 equivalent) was dissolved in CH2CL2in an argon atmosphere. Add manganese dioxide (900 mg, or 10.3 mmol, 30 equivalents) and the reaction stirred at 25°2 hours. Enter the additional amount of manganese dioxide (400 mg, 4,60 mmol, 13.4 equivalent) and the reaction stirred for further 2 hours. The mixture is filtered through Celite, washed with CH2CL2and then concentrated in vacuo. Raw material chromatographic, elwira with silica gel using 50% ethyl acetate in hexane, to provide 92 mg (51%) 21-formyl-epothilone In the form of a colorless solid. ESI-MS: 522,3 (M+N)+.

Synthesis of 21-alkalinization 15 shown in example 26, which follows.

Example 26

Example: [1S[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (R=H, G6=G8=Z7=H, G7=CZ7in formula IIA)

Methyl-instantised (instand-ylid) (Fluka), 50 mg, treated with 17 mg of methylphosphinico and suspended in 500 μl of absolute THF. The mixture is placed in an ultrasonic bath for 2-3 minutes and then stirred at room temperature. When the reaction solution becomes bright yellow color, the suspension is added dropwise to a solution of 15.2 mg (30 mmol) And the aldehyde in 100 ál of absolute the GF. After 1 hour the mixture is diluted with water and extracted three times with dichloromethane. The organic phase is evaporated and dried in high vacuum. The separation of the crude mixture is carried out using preparative HPLC (Nucleosil 100, solvent: t-butyl methyl ether/hexane 1:2+1% methanol). Thus emit 1.7 mg (11%) 20-vinyl-epothilone A.

1H-NMR (400 MHz, CDCl3): δ=6,59 (broad s, 17-H), (? 7.04 baby mortality (s, 19-H)6,86 (DD, 21-H), equal to 6.05 (d, I’-b), of 5.55 (d, 1’); HRMS (DCI): C27H39NO6S: [M+H+] calculated 506,2576 found 506,2589.

Synthesis of 21-imino-epothilone 22 in the following example.

Example 27

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (R=G6=N, G7=N, G8=OZ10, Z10=Me in formula IIA)

Pyridine, 10 ml (124 mmol), and 113 μl (54 μmol) of a solution of O-methylhydroxylamine (40 mg/ml) are added to a solution of 25 mg (49 μmol) epothilone And-21-aldehyde in 200 μl of methanol. After stirring the reaction mixture for 1 hour at room temperature the solvent is removed and the residue is transferred into ethyl acetate. The organic phase is extracted once with water and dried with Na2SO4. Purification of the crude product is carried out using preparative HPLC (Nucleosil 100, solvent: t-butyl methyl ether, ether/hexane 1:2 with 1% methanol is). Thus obtain 9 mg (36%) (A)and 7 mg (27%) (21Z)-21-(N-methoxyimino)-epothilone A.

(E)-isomer

1H-NMR (300 MHz, CDCl3): δ=6,61 (broad s, 17-H), 7,12 (s, 19-H), by 8.22 (s, 21-H), to 4.01 (s, I’-HS).

(21Z)-isomer

1H-NMR (300 MHz, CDCl3): δ=of 6.65 (broad s, 17-H), was 7.36 (broad s, 19-H), 7,86 (d, 21-H), 4,15 (s, 1’-H3). HRMS (DCI): C27H40N2O7S: [M+H+] calculated 537,2634 found 537,2637.

Example 28

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

Epothilone And-21-aldehyde (19 mg, 38 μmol) dissolved in 1 ml dry CH2CL2. Add crushed molecular sieves 4 Å and benzylamine (4.5 mg, 41 μmol). The reaction mixture was stirred at room temperature for 45 minutes, filtered through Celite and concentrated. Purification on silica gel (CH2CL2/methanol 95:5) gives 21 benzylamino-epothilone A (10 mg, 45%).

1H-NMR (300 MHz, DI3): δ = 6,62 (broad s, 17-H), 7,21 (s, 19-H), 8,46 (s, 21-H), to 4.87 (d, I’-H2).

Example 29

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione (G6=Me, G9=O in formula IIb) and 20(21,22-epoxyethyl)-epothilone And (G1=H; G2, G5=CH2"Oh in formula Ib)

Epothilone And-21-aldehyde (example 28), 10 mg (20 μmol), dissolved in 200 μl of CH2CL2and add excess diazomethane, then the mixture is stirred at room temperature. After 15 minutes the reaction mass is evaporated and separated using preparative TLC (silica gel 60, solvent: CH2CL2/methanol 95:5). So get 4.5 mg (44%) 21-acetyl-epothilone and 1.9 mg (19%) 20-epoxyethyl-epothilone A.

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

1H-NMR (300 MHz, CDCI3): δ=6,62 (broad s, 17-H), 7,45 (s, 19-H), 2,71 (s, I’-Hs).

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

1H-NMR (300 MHz, CDCl3): δ=return of 6.58 (broad s, 17-H), to 7.09 (s, 19-H), 4,22 (t, 21-H)of 3.00 (m, I’-On), 3,23 (DD, I’-b).

Example 30

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-itatani)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

26 mg (49 μmol) of iodocyclization suspended in 1 ml of absolute THF, add 49 ál (49 μmol) of a solution hexamethyldisilazane sodium in THF. After stirring for one minute at room temperature the mixture is cooled to minus 78°and add 14 ál (80 μmol) of NMRA, and then a solution of 20 mg (40 MK is ol) epothilone And the 21-aldehyde in 0.2 ml of absolute THF. At the same temperature, the reaction mixture is stirred for 30 minutes and then quenched with 1 ml of saturated solution of ammonium chloride. After heating to room temperature the reaction mixture was extracted with ethyl acetate, the organic layer separated, dried with sodium sulfate and evaporated to dryness. Separation is achieved using preparative HPLC, giving an 8.4 mg (34%) (20Z)-iodine and 2 mg (8%) (20E)-izvinjavamo equivalent.

E-Isomer

1H-NMR (600 MHz, CDCl3): δ = 6,56 (s, 17-H), 7,07 (s, 19-H), 7,53 (d, 21-H), 7,39 (l, I’-H).

Z-Isomer

1H-NMR (300 MHz, DI3): δ = 6,63 (broad s, 17-H), 7,21 (s, 19-H), 7,82 (DD, 21-H), 7,03 (l, I’-H2); HR-MS (DCI):27H38NO6SI, [M+H+] calculated 632,1543 found 632,1593.

Example 31

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethinyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

of 18.5 ál (131 mmol) of Diisopropylamine dissolved in 0.4 ml of absolute THF, is treated with minus 10°With 70 μl (105 μmol) n-utility in hexane. After one hour at 0°to the solution was added 17 mg (27 μmol) (20Z)-odinochnogo derived in 0.5 ml of absolute THF. After one hour stirring at 0°the reaction is quenched with 2 ml saturated solution of ammonium chloride. The reaction mixture was extracted with ethyl acetate, the organic phase is evaporated of Dosh and shared by preparative HPLC. Output 2.4 mg (36%).

1H-NMR (400 MHz, CDCI3): δ = 6,60 (broad s, 17-H), to 7.15 (s, 19-H), 3.46 in (s, 21-H); HR-MS (DCI): C27H37NO6S, [M+NH4+] calc. 521,2685 found 521,2696.

Examples of syntheses 21 alkylamino-epothilone 10 and 11 shown in examples 32 to 36 below.

Example 32

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To mix the solution epothilone In-21-aldehyde (17 mg, 0,033 mmol) in 2.0 ml of CH3SN in an argon atmosphere at 0°add 2.0 M solution of methylamine (0.16 ml, 0,326 mmol, 10 equivalents). After 15 minutes add 6 mg of NaBH3CN (0,098 mmol, 3 equivalents), the mixture is allowed to mix at 0°With 30 minutes. Then added dropwise acetic acid until the pH value of the solution reaches a value of approximately 7. The mixture is then stirred for an additional 2 hours and add 20 ml of 28% aqueous solution of NH4OH(water.), the mixture is stirred for 5 minutes and then extracted with 75 ml of ethyl acetate. The organic layer is dried over Na2SO4and concentrate under vacuum. The crude material is then chromatographic using silica gel, elwira 1% Et3N, 2% Meon in l3with the release of 8 mg (47%) 21-N-methylamino-epothilone In the form of an opaque oil. MS (ESI+): 537,4 (M+is)*.

Example 33

[1S-[1R*,3R* (E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To mix the solution epothilone In-21-aldehyde (15 mg, 0,029 mmol) in 2.0 ml of CH3CN in an argon atmosphere at 25°add N,N-dimethylethylenediamine (31 μl, in 0.288 mmol, 10 equivalents). After 10 minutes add 5 mg N3JV (0,086 mmol, 3 equivalents) and the mixture is allowed to mix at 25°With 30 minutes. Then added dropwise Asón, until the pH reaches about 7. After that, the mixture is stirred an additional 2 hours, add 20 ml of 28% aqueous solution of NH4HE(water.). The mixture is stirred for 5 minutes and then extracted with 75 ml of ethyl acetate. The organic layer is dried over Na2SO4and concentrate under vacuum. The crude material is then chromatographic using silica gel and elution with 1% Et3N, 5% Meon in SNS3the output of 5.8 mg (34%) 21-(2-N,N-dimethylaminoethyl)aminopurine In the form of a clear oil. MS (ESI+): of 594.5 (M+N)+.

Example 34

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To a stirred solution of amine (19 mg, 0,0363 mmol) in 1 ml of CH 3JV in the atmosphere of argon is added an aqueous solution of formaldehyde (0.04 ml 37%aqueous solution, 0,1817 mmol, 5 equivalents) and 7 mg of NaBH3CN (0,1089 mmol, 3 equivalents). Mixture is allowed to mix for 20 minutes. Add acetic acid (1 drop), after which it is stirred an additional 40 minutes. The crude reaction mixture was applied directly to a column of silica gel and alumroot 1% Et3N, 1% CH3HE l3with the release of 2.5 mg (12%) 21-N,N-dimethylamino-epothilone C. MS (ESI+): 551,4 (M+N)+.

Example 35

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To a stirred solution of aldehyde (6,8 mg of 0.013 mmol) in 2.0 ml of CH3SN in an argon atmosphere at 0°add bis(2-methoxyethyl)amine (19 μl, 0,130 mmol, 10 equivalents). After 15 minutes, add 2.5 mg of NaBH3CN (0,039 mmol, 3 equivalents) and the mixture is allowed to mix at 0°With 30 minutes. Then added dropwise acetic acid until the pH value of the solution reaches about 7. The mixture is then stirred for an additional 2 hours, add 10 ml of 28% aqueous solution of NH4HE(water.). The mixture is stirred for 5 minutes and then extracted with 75 ml of ethyl acetate. The organic layer is dried over Na2SO4and Kon is intronaut under vacuum. The crude material is then chromatographic using silica gel and elwira 1% Et3N, 1% CH3HE SMS3the output of 5.6 mg (67%) 21-(bis-2-methoxyethyl)amino-epothilone In the form of oil. MS (ESI*): 639,5 (M+N)+.

Example 36

[1S-[1R*,3R*(E),7R*,10S*,11S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinil)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione

To a stirred solution of the aldehyde (11 mg, 0,0211 mmol) in 1.0 ml of CH3JV in argon atmosphere was added 1-methylpiperazine (21 mg, 0,2109 mmol, 10 equivalents) and Na3SN (4 mg, 0,0633 mmol, 3 equivalents). Mixture is allowed to mix for 20 minutes. Then added dropwise acetic acid until the pH value of the solution is about 7. The mixture is then stirred for an additional 2 hours, add 10 ml of 28%aqueous NH4HE(water.). The mixture is extracted with CH2Cl2(2×75 ml). The organic layer is dried over Na2SO4and concentrate under vacuum. Raw material chromatographic using silica gel and elution with 1% Et3N, 5% Meon in SNS3the output of 10.7 mg (84%) 21-(N-methylpiperazin)amino-epothilone In the form of a white foamy oil. MS (SI+): 606,4 (M+N)+.

Example 37

Example: [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]GE is tadenan-3-yl)-1-propenyl]-2-diazocarbonyl acid (G 6=OZ5, Z5=H, G9=O in formula IIb)

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-diazocarbonyl acid methyl ester (G6=OZ5, Z5=Me, G9=O in formula IIb)

Epothilone And-21-aldehyde, 8.0 mg (16 μmol) was dissolved in 300 μl of a mixture of THF/water (9:1) and add 24,0 mg (194 mmol) of silver oxide (I). The reaction mixture was stirred for 12 hours at room temperature. Then the solvent is removed and the residue is transferred into ethyl acetate. Evaporation of solvent gives an unstable carboxylic acid, which was characterized using HPLC/ESI-MS: delay time of 13.8 min; m/z = 522 (M-N)-(RP-18 silica gel, CH3CH (10 mm NH4OAc buffer gradient from 10:90 to 45:55). Preferably the organic phase is evaporated and washed twice with 0.1% hydrochloric acid, once with water and then treated with excess diazomethane. The mixture is stirred for 10 minutes at room temperature. After removal of solvent the crude product is purified using preparative HPLC (Nucleosil 100, solvent: t-butyl methyl ether/hexane 1:2 with 1% methanol), thus receive 2.5 mg (30%) epothilone And-21-carboxylic acid methyl ester.

1H-NMR (400 MHz, CDCI3): δ=6.73 x (broad s, 17-H), 7,42 (s, 19-H), 4.00 points (C, I’-Hs); HRMS (DCI): C27H39NO8S: [M+H*] calculated 537,2396, who were 537,2408.

Example 38

Biological characteristics of derivatives epothilone

Cytotoxic activity

Derivatives epothilone inhibit the growth of mammalian cell cultures, and cell lines that are resistant to other cilastatin.

Inhibition of growth of the transformed cell carcinoma mouse and human and lakeline cell lines.

The growth inhibition, the following cell lines measured in microtiter tablets: L929 (DSM ACC 2), the fibroblasts of the connective tissue of the mouse; KV-3.1 (DSM ACC 158), carcinoma of the neck of the person; KB-V1 (DSM ACC 149), cervical carcinoma human, resistant to many drugs; PC-3 (ATCC CRL 1435), adenocarcinoma of the prostate of a man; SK-OV-3 (ATCC HTB-77), of human ovarian adenocarcinoma; A-549 (DSM ACC 107), human lung carcinoma; K-562 (ATCC CCL-243), chronic myelogenous leukemia man; U-937 (DSM ACC 5), historically lymphoma person. Cell line derived from DSM (Collection of mikroorganizmov and lines and cell cultures, Germany), Braunschweig, Germany, or ATCC (culture Collection of the American type), Rockville, MD, USA.

Aliquots of suspended cells (50000/ml) exposed to serially diluted inhibitor. As a parameter of growth measure recovery bromide MTT 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium or, in the case of leukemia cells, WST-1 (Boehringer Mannheim, Germany) after incubation the aqueous period of 5 days. The obtained values are compared with control cells, which were added only the solvent is methanol. These values were taken as 100%. IC50(concentration that causes 50% growth inhibition) was derived from inhibition curves (percent recovery MTT depending on the concentration of the inhibitor).

Example 39

The characteristic of toxicity derived epothilone

Were conducted preclinical testing connection

in phase 1 trials (29 patients), it was found that the medicinal substance is portable in doses up to 50 mg/m2.

1. The compound having a General formula I

where P-Q is a C-double bond or an epoxide;

G represents

R is selected from the group comprising H and C1-6alkyl;

R1selected from the group consisting of

G1represents N;

G2represents N;

G3selected from the group comprising O, S and NZ1;

G4selected from the group including H, C1-6alkyl, substituted C1-6alkyl, OZ2, Z2C=O and Z4SO2;

G5selected from the group which Lucaya halogen, N3, CN, NC, heteroaryl containing N or O, and heterocycle;

G6selected from the group including H, C1-6alkyl and OZ5where Z5selected from the group comprising N and C1-6alkyl;

G9represents O;

Z1selected from the group of H, C1-6alkyl, substituted C1-6alkyl, acyl and substituted acyl;

Z2selected from the same group as C1-6alkyl, substituted C1-6alkyl, aryl;

Z4selected from the group comprising aryl and substituted aryl,

provided that when R1represents a

G1, G2, G3and G4cannot simultaneously have the following values: G1and G2-N, G3"Oh and G4-N or Z2C=O, where Z2=H or alkyl group and, when G1and G2- N, G5may not be halogen;

where substituted C1-6alkyl represents a C1-6alkyl having from one to four substituents selected from hydroxy, alkoxy, oxo, alkanoyl, aryl, aryloxy, alkanoyloxy, amino, C1-6alkylamino, disubstituted amines in which two aminosalicylates selected from C1-6the alkyl);

substituted aryl represents phenyl or naphthyl having from one to four substituents selected from C1-6and the Qila; and

substituted acyl represents an acyl group, in which the radical derived from an acid by removal of hydroxyl, substituted C1-6by alkyl, substituted C1-6the alkyl.

2. The compound according to claim 1, having a General formula I

where R is an atom H or a methyl group,

G1represents the atom N.

3. The compound according to claim 2, in which G3is an atom of O.

4. The compound according to claim 2, in which G3is the atom S.

5. The compound according to claim 2, in which G3represents NZ1.

6. The compound according to claim 1, having the General formula Ib

where R is an atom H or a methyl group,

G1is an atom of N,

G2represents the atom N.

7. The connection according to claim 6, in which G5is N3group.

8. The connection according to claim 6, in which G5is the CN-group.

9. The connection according to claim 6, in which G5is the NC-group.

10. The connection according to claim 6, in which G5represents a heterocyclic group.

11. The compound having the formula

12. The compound according to claim 1, having the General formula IIb

where R is an atom N Il is a methyl group;

G6represents the atom N.

13. The compound having General formula IV

where R is an atom H or a methyl group,

P-Q is a C-double bond or an epoxide;

G11represents a C1-6alkyl.

14. A compound selected from the group consisting of

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecan-5, 9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecan-5, 9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-Dimethylmethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylmethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methyl-ethynyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione;

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-Dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoate)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)atomic charges]methyl]-1-methyl-4-thiazolyl]ethynyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionamido)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione,N-oxide;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethynyl]-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-is hydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2’,3’,4’,6’-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6’-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluensulfonate)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(methyl bromide)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1,0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[4S-[4R*,7R*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(IH-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentane the Il-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-itatani)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*.12R*,16S*]]-3-[2-(2-Ethinyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl] ethynyl]-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxa icicle[14.1.0]heptadecane-5,9-dione;

(1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

(1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinil)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-diazocarbonyl acid;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-diazocarbonyl acid methyl ester,

and their pharmaceutically acceptable salts, solvate and hydrate.

15. The method of obtaining compounds having the formula 9

where P-Q - epoxide and R is methyl,

namely, the compound having the formula 4

first, activate, and then subjected to nucleophilic substitution with obtaining compounds having the formula 7,

after which the link is, having the formula 7, is subjected to recovery with the formation of compounds having the formula 9.

16. The method according to item 15, wherein the activation is carried out using TosHal (Tos - toluensulfonyl, Hal Is Cl, Br or I) and pyridine and nucleophilic substitution with NaNa3or activation and nucleophilic substitution is carried out with the help of databaseconnect and diphenylphosphoryl azide.

17. The method according to item 15, wherein the recovery is carried out by hydrogenation in the presence of Lindlar catalyst or by using phosphine.

18. Pharmaceutical composition having the property of inhibiting the growth of cells and containing as active ingredient at least one compound according to any one of claims 1 to 14 or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carrier, excipient or diluent.

19. The pharmaceutical composition according p, in which the active ingredient is selected from the group consisting of

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Azidomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-Dimethylmethoxy)carbonyl]amino]methyl]-4-thiazolyl]1-methylethenyl]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-Dimethylmethoxy)carbonyl]amino]methyl]-4-thiazolyl]-1-methyl-ethynyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione;

[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(Z)-cyclohexadien-2,6-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(pentanoate)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(naphthyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-[[(2-methoxyethoxy)atomic charges]methyl]-1-methyl-4-thiazolyl]ethynyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*:,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(N-propionamido)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-Acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, N-oxide;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxymethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,1216-pentamethyl-3-[1-methyl-2-[2-(phenoxymethyl)-4-thiazolyl]ethynyl]-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Ethylthio)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(Ethoxymethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(2’,3’,4’,6’-tetraacetyl-beta-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[(6’-acetyl-alpha-glucosyloxy)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(p-toluensulfonate)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(methyl bromide)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-bromo-2-methyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,1S*,11R*,12R*,16S*]]-3-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0] heptadecane-5,9-dione;

[4S-[4R*,7R*,8R*,9R*,15R*(E)]]-16-[2-[2-(Cyanomethyl)-4-thiazolyl]-1-methylethenyl]-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(2)-cyclohexadien-2,6-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(1H-imidazol-1-ylmethyl)-4-thiazolyl]-1-methylethenyl]-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Formyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethynyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(methoxyimino)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-[2-[[(phenylmethyl)imino]methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Acetyl-4-thiazolyl)-1-methylethenyl]-7,11-Dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12-tetramethyl-3-[1-methyl-2-(2-oxiranyl-4-thiazolyl)ethynyl]-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-3-[2-[2-(2-itatani)-4-thiazolyl]-1-methylethenyl]-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-Ethinyl-4-thiazolyl)-1-methylethenyl]-7,11-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(methylamino)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(Dimethylamino)ethyl]amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

(1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(Dimethylamino)methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[Bis(2-methoxyethyl)amino]methyl]-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3-[1-methyl-2-[2-[(4-methyl-1-piperazinil)methyl]-4-thiazolyl]ethynyl]-4,17-dioxabicyclo [14.1.0]heptadecane-5,9-dione;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-diazocarbonyl acid;

[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-Dihydroxy-8,8,10,12-Ter the methyl-5,9-dioxo-4,17-dioxabicyclo[14.1.0]heptadecan-3-yl)-1-propenyl]-2-diazocarbonyl acid methyl ester,

and their pharmaceutically acceptable salts, solvate and hydrate.

Priority over all claims except p. 15, set from 22.02.1999 and p. 15 from 01.07.1999 according to the correspondence of the applicant dated 13.05.2004.



 

Same patents:

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to 1-(3-heteroaromatic or prop-2-enyl)-4-benzylpiperidine formula (1), where X Is O, NR1, S, or CH2; Y is CH; Z is CH; Y and Z together may denote C= S; R1, R2and R3is hydrogen, R4- fluorine

The invention relates to novel polycyclic to dihydrothiazolo General formula (I), where Y is a simple bond; X is CH2; R1 is H, F, Cl, NO2, CN, COOH, (C1-C6)-alkyl, (C2-C6)-quinil, O-(C1-C6)-alkyl, and alkyl residues one, several or all of the hydrogen atoms may be replaced by fluorine; (CH2)n-phenyl, SO2-(C1-C6)-alkyl, and n = 0 and the phenyl residue up to twice may be substituted by F, Cl, CF3, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl; O-(CH2)n-phenyl, and n = 0 and phenyl cycle can be one - to twofold substituted by Cl, (C1-C6)-alkyl; 1 - or 2-naphthyl, 2 - or 3-thienyl; R1' is hydrogen; R2 is H, (C1-C6)-alkyl, R3 is hydrogen; R4 - (C1-C8)-alkyl, (C3-C7-cycloalkyl, (CH2)n-aryl, and n = 0-1, and aryl can be phenyl, 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2 - or 3-furyl, indol-3-yl, indol-5-yl, and aryl or heteroaryl residue up to twice may be substituted by F, Cl, HE, OCF3, O-(C1-C6)-alkyl, (C1-C6)-alkyl, 2-, 3-, 4-pyridium, pyrrol-1-yl, with peregrinae ring may be substituted CF3; and their physio is

The invention relates to new indole derivative of the formula I

< / BR>
in which R1is hydrogen, (NISS

The invention relates to a group of new compounds - heterocyclic derivatives of glycyl-beta-alanine General formula I

< / BR>
or pharmaceutically acceptable salt of this compound, where

< / BR>
is a 5-8-membered monocyclic heterocyclic, optionally unsaturated ring containing from 1 to 4 heteroatoms selected from the group comprising N and S, and1selected from the group comprising SN, SN2, N, NH, O and S, provided that

< / BR>
is not pyrrolidinium when V represents NH;

A represents a group of the formula

< / BR>
where Y1selected from the group comprising N-R2and R2means hydrogen; R2means hydrogen, R7when not with R2and R8mean hydrogen, alkyl, substituted alkoxy group, or R2together with R7form a 4 to 12-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted by one or more substituents selected from the group comprising hydroxy, C1-C10< / BR>
where R2together with R7form a 5-8-membered ring containing two nitrogen atom a heterocycle, R5means hydrogen, R8means alkyl, optionally substituted by alkoxygroup; or A signifies a group

< / BR>
where R2together with R7form a 5-8-membered ring containing 2 nitrogen atom a heterocycle, optionally substituted hydroxy-group; R8- alkyl, substituted alkoxygroup; V means-N(R6)-; R6is hydrogen; Y and Z denote hydrogen, t = 0, n and R = 1, 2; R means X-R3where X is-O-; R3is hydrogen, alkyl; R1selected from the group including aryl, alkyl, optionally substituted one or more times by halogen, alkyl, HE; monocyclic heterocycle; haloalkyl; R11means hydrogen, or a pharmaceutically acceptable salt of the compounds; pharmaceutical compositions having properties antagonistV3-integrin, as well as to a method of treating diseases mediatedV3-integrin in a mammal

The invention relates to new chemical compounds derived from anthra[2,1-d]isothiazol-3,6,11-trione General formula I, where a is the lowest alkylene, R1and R2(independent) - lower alkyl, or R1and R2together with the nitrogen atom form a six-membered saturated, a heterocycle, which may optionally contain a heteroatom such as oxygen atom, and their pharmaceutically acceptable salts

FIELD: medicine, oncology.

SUBSTANCE: the present innovation should be applied at adjuvant chemotherapy in case of tumors of central nervous system. Moreover, while carrying out lumbar puncture it is necessary to perform catheterization of subarachnoidal space. Moreover, one should daily sample liquor at the quantity of 10 ml to be incubated with chemopreparation in vitro for 30 min at 38 C. One should daily introduce chemopreparations upon autoliquor through catheter during the whole period of therapy course. The method enables to choose any mode and duration of endolumbar chemotherapy at its decreased toxicity.

EFFECT: higher efficiency of chemotherapy.

1 ex

Antitumor agent // 2253446

FIELD: drugs, medicine.

SUBSTANCE: invention relates to application of 2-METHYL-4-chlorophenoxyacetic acid tris-(2-hydroxyethyl)ammonia salt, which represents known microorganism living function stimulator, as antitumor agent and metastasis inhibitor. Present invention makes it possible to produce drugs for treatment cancers, in particular hepatoma, melanocytoma, lymphadenoma, etc.

EFFECT: new drug for cancer treatment.

2 tbl, 2 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: the suggested composition includes compounds of natural ethers in cancer of mammalian soft tissues (including, the man), for example, in case of diseases of mammary gland. Both dosage and frequency of introduction depending upon a certain symptomatics could be decreased up to the level at which it is necessary to maintain improved level. At weakening the symptoms up to desired level one should stop therapy immediately. At any relapse of disease symptoms patients could need periodic therapy upon lasting basis.

EFFECT: higher efficiency of application.

2 cl, 3 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: the present innovation includes polychemotherapy and radiation therapy. Moreover, polychemotherapy should be carried out by the following scheme: on the 1st and the 8th d of the first and the third courses it is necessary to introduce doxorubicin, cyclophosphan, vincristine, and since the 1st to the 14th d - procarbazine and prednisolone; moreover, on the 1st and the 8th d of the second and the fourth courses one should introduce doxorubicin, bleomycin, vinblastine, dacarbazine. The method enables to decrease the quantity of late therapeutic complications, improves the results of relapse-free, total tumor-specific survival rate and decreases the number of polychemotherapeutic cycles.

EFFECT: higher efficiency of therapy.

2 ex

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating oncological diseases. It is suggested to apply bisdioxopiperazine (previously known as cardioprotector) to either treat or prevent tissue lesions caused due to sporadic transudation of cytotoxic poison for topoisomerase II (represented by anthracyclines, etoposide, teniposide, mitoxantrone daunorubicin, doxorubicin, etc.), medicinal remedies and pharmaceutical set of the same indication. It is, also, suggested to apply the method to treat or prevent tissue lesions caused by sporadic transudation of topoisomerase II poison. BisdioxopiperazineICRF-187 has impact due to catalytic inhibiting topo II. Signs for possible transudation of topoisomerase II poison (of local toxicity) usually include the availability of acute pain, erythema, development of ulcerations in area of transudation; due to the action of ICRF-187 the quantity of wounds is reduced, or the development of side effects is not observed.

EFFECT: higher efficiency of therapy.

59 cl, 12 dwg, 13 ex, 10 tbl

FIELD: genetic engineering, in particular genes for cell cycle controlling point.

SUBSTANCE: polynucleotide encoding rad3 polypeptide ATR homologue is cloned into expression vector, having functionality in eucariotic cells. Polypeptide of rad3 polypeptide ATR homologue is obtained by cultivation of eucariotic cell culture, transformed by vector. Monoclonal antibody to rad3 polypeptide ATR homologue is obtained by hybridoma technologies. Polyclonal antibodies are obtained by inoculation of rad3 polypeptide ATR homologue in host animal. Polynucleotide presence in animal tissue sample is detected by contacting of this sample containing DNA or RNA with polynucleotide encoding rad3 polypeptide ATR homologue under hybridization conditions. Polypeptide in biological sample is detected by sample contact with monoclonal or polyclonal antibodies. Substances having anticancer activity are screened on the base of reduced activity of ATR polypeptide on substrate or reduced chelating of ATR homologue in presence of candidate substance. Present invention makes it possible to produce human or S.pombe rad3 polypeptide ATR homologue and is useful in investigation ATR role as gene for cell cycle controlling point in cell culture in vivo or in vitro.

EFFECT: new anticancer substances.

24 cl, 1 dwg

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: medicine.

SUBSTANCE: after keeping during pharmaceutically acceptable period oxaliplatinum is placed in transparent, colorless and residue-free solution at concentration of, at least, 7 mg/ml, and a solvent contains sufficient quantity of, at least, one hydroxylated derivative chosen among of 1.2-propandiol, glycerol, maltite, saccharose and inositol. The innovation describes the way to obtain such a preparation. The preparation is stable during pharmaceutically acceptable period of time, that is it remains transparent, colorless and free of any residue within the range of 2-30 C that could be available during its transportation, storage and/or any handling.

EFFECT: higher efficiency of application.

14 cl, 6 ex, 4 tbl

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

The invention relates to medicine, in particular to Oncology, and for the treatment of various cancers
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