UA71604C2 - C-21 modified epothilones - Google Patents

Abstract

The invention is concerned with epothilones in which the thiazole substituent has been modified, with methods for their preparation and with antifungal or therapeutic agents which contain these epothilones.

Description

Description of the invention

Epothilones are macrocyclic lactones that have useful antifungal and cytotoxic 2 properties. their action, as in the case of TaxoluF, is based on the stabilization of microtubules, resulting in the inhibition, in particular, of cancer and other rapidly dividing cells. Typical epothilones contain a methylthiazolyl side chain, a 12,13-double bond (C, Y), a 12,13-epoxide (A, B) and a proton (A, C) or a methyl group (B, 0) at 0-12 ; see, for example: (Review Apdem. Spet. 1998, 110, 89-92 and 2120-2153;

Neuroscience 1998, 48, 2485-2488. 10 | i - o, t 1 o i vc "7 |. Z ov 15 what o it

Epothilon A, Academy of Sciences

V, V - Me 20 i "/ i "i r z on 5 . se 25 o Ge; SHY is) o

Epothilon S, K: N

Ov - Me « 30 The essence of the invention of Fr

The present invention relates to a compound having the general formula ii | (Se)

In -

II he 35 c. i-NI M. tu i, i. For her " " . And 40 - s pe

P-O is a C, C double bond or epoxide; . and о represents ой, -й4 or -А

K is selected from the group consisting of H, alkyl, and substituted alkyl; -th V! selected from the group consisting of

And 7 with shi

F v--6 v vo U bosheto R o F), KY - with fo» khm s ;

GT"

E" represents

M, what about S! selected from the group consisting of H, halogen, CM, alkyl and substituted alkyl; ime) C2 is selected from the group consisting of H, alkyl and substituted alkyl;

He is selected from the group consisting of iso, 5, and M27; for Ge is selected from the group consisting of H, alkyl, substituted alkyl, 077,

M2279, 720, 77502 and optionally substituted glycosyl; and

C is selected from the group consisting of halogen, Mz, MC5, ZN, CM, MC, M(7c) and heteroaryl;

CO is selected from the group consisting of H, alkyl, substituted alkyl, C3, O79, 875 and M2526: 65 C is C7" or M;

o selected from the group consisting of H, halogen, alkyl, substituted alkyl, 0719, 87719. We!02 11; c is selected from the group consisting of О, 5, -МН-МН- and -М-М-,

CO is M or C7 12;

WITH!! selected from the group consisting of H M, substituted NoM, alkyl, substituted alkyl, aryl, and substituted aryl; 71,76 79771 independently selected from the group such as H, alkyl, substituted alkyl, acyl and substituted acyl; 72 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle; 0 73,75, 78 1 219 independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl and substituted aryl; 77 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl and heterocycle; 7" selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, 078, 5781 M7879: 72 selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl, provided that when B! is b--c 9

AND

C, 82 o3 and 07 cannot simultaneously have the following values: 5! and 052 - H, 53-01 07- H or 720 -0O, where 72 is an alkyl group.

In addition, the invention relates to a compound having the general formula Ia Ga v sv a ooo o o o. ia o sn o ! " where the symbols have the following meanings:

P-O is a C, C double bond or epoxide; | "in)

K is an H atom or a methyl group; with with! is an H atom, an alkyl group, a substituted alkyl group or a halogen atom; c2 is an H atom, an alkyl group, or a substituted alkyl group: -- c is an O atom, a 5 atom, or a M group, where 7! is an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and

C" represents an H atom, an alkyl group or a substituted alkyl group, a 072 group, a M2273 group, a 770-0 group, a 77502 group, or an optionally substituted glycosyl group, "where 72 is an H atom, an alkyl group, a substituted alkyl group, an aryl a substituted aryl 70 group or a heterocyclic group, 8 c 73 is an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl :c" group, and 77 is an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group group or 415 heterocyclic group, -1 provided that 57,52,03 and 07 cannot simultaneously have the following values: 5 and 52 - H atom, C tatomoO and 07. - and H atom or 72C-0, where 72 - alkyl group.

In addition, the invention relates to a compound having the general formula 165

F! 5 5 R so spa a d) t» c, 1 55 where the symbols have the following meanings:

P-O is a C,C double bond or epoxide;

K is an H atom or a methyl group; oh c! is an H atom, an alkyl group, a substituted alkyl group or a halogen atom; where c2 is an H atom, an alkyl group or a substituted alkyl group, i

OZ is a halogen atom, a Mz group, a MOZ group, a ZN group, a CM group, a MC group, or a heterocyclic group. In addition, the invention relates to a compound having the general formula Pa a yav 00 V-t vyt o. for Ma 15 where the symbols have the following meanings:

P-O is a C,C double bond or epoxide;

K is an H atom or a methyl group; 5 is an H atom, an alkyl group, a substituted alkyl group, or C3, 0277, 879, or a M2275 group, where 75 is an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group, and 75 is an H atom, an alkyl group or a substituted alkyl group; c" is a C7" group or an M atom, where 7" is H or a halogen atom, an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group or 078, 578 or a M7979 group, where 78 is an H atom, an alkyl group , a substituted alkyl group, an acyl group or a substituted acyl group, and 73 is an H atom or an alkyl group, and o8 is an H atom or a halogen atom, an alkyl group or 0779, 5719 or Group M7!9711 where 719 is an H atom, an alkyl group , a substituted alkyl group, an acyl group, a substituted acyl group, an aryl group, a substituted aryl group, and 7! is an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group.

In addition, the invention relates to a compound having the general formula:

P-O is a C,C double bond or epoxide; C 30 K is an H atom or a methyl group, av 5 is an H atom, an alkyl group, a substituted alkyl group or CE3, 0277, 879 or a M2275 group, where CO 75 is an H atom, an alkyl group, a substituted alkyl group, acyl group or a substituted acyl group and 75 represents an H atom, an alkyl group or a substituted alkyl group, and -- 35 С? represents the O atom or the 5 atom, or the -MAM- group. Cha

In addition, the invention relates to a compound having the general formula PI 5 in vego-4 M 4 « 40: 9 - with its 15 : z» where the symbols have the following meanings:

P-O is C, C is a double bond or epoxide, 415 K is an H atom or a methyl group; -1 819 represents an M atom or a C7 72 group, where 72 is an H atom or a halogen atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group.

He») In addition, the invention relates to a compound having the general formula IM

Their! Mr. SHY - A

ЧТ» mecha 07 in No. 6 where the symbols have the following meanings:

HF) P-O is a C,C double bond or epoxide; yuyu K is a hydrogen atom or a methyl group and

WITH! represents a group H»M, a substituted group NoM, an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group. 60 In addition, the invention relates to an antifungal agent containing or consisting of a compound of the present invention in addition to an optional carrier, diluent or additive.

In addition, the invention relates to a therapeutic agent for the treatment of tumor diseases and the prevention of the development of a pathological condition, containing or consisting of a compound of the present invention in addition to an optional carrier, diluent or additive. 65 Detailed description of the invention

Terminology

The following are definitions of various terms used in this specification. These definitions are valid throughout the text of the description, unless their limitations are introduced in the special requirements both individually and in groups.

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

The term "alkyl" refers, but not necessarily, to substituted straight or branched chain saturated hydrocarbon groups containing from 1 to 20 carbon atoms, preferably from 1 to 7 carbon atoms. The term "lower alkyl" refers to, but is not limited to, substituted alkyl groups containing from 1 to 4 carbon atoms. 70 The term "substituted alkyl" refers to an alkyl group having, for example, one to four substituents, such as halogen, trifluoromethyl, trifluoromethoxy, shydroxy, alkoxy. cycloalkyloxy, heterocyclooxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylamino, cycloalkylamino, heterocycloamino, disubstituted amines in which 2 amino substituents are selected from alkyl, aryl, or aralkyl, alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoyl, substituted amino arylamino, substituted aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio, cycloalkylthio, heterocyclothio, alkylthio, arylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g., 5OMN»o), substituted sulfonamido, nitro, cyano, carboxy, carbamyl (e.g. , SOMN"), substituted carbamyl (e.g., alkyl SOMN, aryl SOMN, aralkyl SOMN, or cases where there are two substituents on nitrogen selected from alkyl, aryl, or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino, and heterocycles such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl, etc.

If, as noted above, the substituent is additionally substituted, then with halogen, alkyl, alkoxy, aryl or aralkyl.

The term "acyl" refers to a radical formed, usually from an acid with the removal of a hydroxyl. Examples here include acetyl (CHzZCO-), benzoyl (CeHbCO-) and phenylsulfonyl (CeHzO»-). high school

The term "substituted acyl" refers to a substituted acyl group in which the radical, usually formed from an acid by removal of a hydroxyl, is substituted with, for example, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, and heterocycle. .

The term "ring system" refers, but not necessarily, to a substituted ring system containing from one to three rings and at least one carbon-carbon double bond in at least one ring. Examples of such ring systems include, but are not limited to, aryl or a partially or fully unsaturated heterocyclic ring system that may, but not necessarily, be substituted. at

The term "aryl" refers to such monocyclic or bicyclic aromatic hydrocarbon groups having He from 6 to 12 carbon atoms in the ring, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may, but not necessarily, be substituted. --

The term "substituted aryl" refers to an aryl group having, for example, one to four substituents, such as alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy. cycloalkyloxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylamino, aralkylamino, cycloalkylamino, heterocycloamino, dialkylamino, alkanoylamino, thiol, alkylthio, cycloalkylthio, heterocyclothio, ureido, nitro, cyano, carboxy. carboxyalkyl. carbamil alkoxycarbonyl, alkylthiono, arylthiono. alkylsulfonyl. sulfonamido, aryloxy, etc. The substituent may be further substituted with halogen, hydroxy, alkyl, aluoxy, aryl, substituted aryl, substituted alkyl, or aralkyl. And and I

And the term "aralkyl" refers to an aryl group bonded directly through an alkyl group, such as a benzyl.

The terms "substituted alkene" and "substituted alkenyl" refer to a residue having a carbon-carbon double

A BOND which may be part of a ring system with at least one lower alkyl or -I substituted lower alkyl substituent. Other substituents have the values given for substituted alkyl.

The term "cycloalkyl" refers to, but is not limited to, substituted saturated cyclic hydrocarbon ring systems containing, as a rule, from 1 to 3 rings and from 3 to 7 carbon atoms in each ring, which may, in addition, be condensed with an unsaturated C3-C7 carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and o-adamantyl. Substituents can be one or more of the above-mentioned alkyl groups or one or more of the groups mentioned above as alkyl substituents.

The terms "heterocycle", "heterocyclic" and "heterocyclo" refer, but not necessarily, to a substituted, unsaturated, partially or fully saturated aromatic or non-aromatic cyclic group, which is, for example, a 4-7 membered monocyclic, 7-11 membered bicyclic or 10-15 membered tricyclic ring system having at least one heteroatom in at least one carbon-containing ring. Each ring of a heterocyclic (F) group containing a heteroatom may have 1, 2, or C heteroatoms selected from nitrogen, oxygen, or sulfur atoms, where the nitrogen and sulfur heteroatoms may, but need not, be oxidized, and the nitrogen heteroatoms may , but also not necessarily, to be quaternized to form a quaternary basis. Heterocyclic groups can be attached to any heteroatom or carbon atom.

Monocyclic heterocyclic groups can be pyrrolidinyl. pyrrolyl indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl. isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl. isothiazolidinyl. furil tetrahydrofuryl, thienyl, oxadiazolyl piperidinyl. piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl. 2-oxopyrrolidinyl, 65 2-oxazepinyl, azepinyl, 4-pyleridonyl. pyridyl, M-oxopyridyl. pyrazinyl, pyrimidinyl. pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl sulfone, morpholinyl, thiomorpholinyl,

thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl, dioxanil, isothiazolidinyl, thietanyl, thiiranyl, triazinyl, and triazolyl, etc.

Examples of bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl. quinolinyl-M-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such as furo|2,3-s|pyridinyl, furo3,1-in |pyridinyl) or furo|2,3-B|Ipyridinyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, benzotriazolyl, 70 benzpyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl. dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, purinyl, pyridopyridyl, quinazolinyl, tetrahydroquinolinyl, thienofuryl, thienopyridyl, tinothienyl, etc.

Examples of substituents on the terms "heterocycle", "heterocyclic" and "heterocyclo" include one or more of the alkyl or substituted alkyl groups specified above, or one or more of the groups specified above /5 AND alkyl or substituted alkyl substituents. It also includes such small heterocycles as epoxides and aziridines.

The term "alkanoyl" refers to -C(O)-alkyl,

The term "substituted alkanoyl" refers to -C(O)-substituted alkyl.

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

The term "substituted aroyl" refers to -C(O)-substituted aryl.

The term "trialkylsilyl" refers to -Zi(alkyl)z.

The term "aryldialkylsilyl" refers to -Zi(alkyl)(aryl).

The term "diarylalkylsilyl" refers to -Zi(aryl)»(alkyl).

The term "heteroatoms" includes oxygen, sulfur and nitrogen. high school

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

Compounds described by formulas I-IM can form salts with alkali metals such as sodium, i) potassium, lithium, with alkaline earth metals such as calcium and magnesium, with organic bases such as dicyclohexylamine and tributylamine, with pyridine and amino acids such as arginine, lysine, etc. Such salts can be obtained, for example, by replacing the protons of carboxylic acids, if they contain the carboxylic "E

From an acid, to compounds described by formulas I-IM, to the desired ion in the medium in which the salt precipitates, or in an aqueous medium with subsequent evaporation. It is well understood by a person skilled in the art that other salts may also be formed. "at

Compounds having formulas I-IM. form salts with various organic and inorganic acids.

These salts contain such salts, which are formed with the help of hydrogen chloride, hydrogen bromide, -- methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluene sulfonic acid, as well as, for example, nitrates, phosphates, borates, tartrates, citrates, succinates, benzoates, ascorbates, salicylates, etc. Such salts are formed by reacting compounds according to the formulas I-IM 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 can also be formed ("internal salts"); they also fall within the definition c of the term "salts" as used herein. . The invention also covers prodrugs and solvates of compounds described by formulas I-IM. Under the term and? "prodrugs" in this description mean compounds with which, when they are administered to a patient, chemical transformations occur through metabolic or chemical processes with the formation of compounds according to the formulas !I-IM, their salts and/or derivatives. For example, compounds according to formulas I-IM can form a molecule of complex ester of carboxylic acid -I. Carboxylic acid esters are usually formed by esterification of certain carboxylic acid functional groups located on an open ring structure (or structures). - According to this invention, the best solvates of the compounds described by formulas I1-IM are hydrates.

A wide variety of forms of prodrugs are well known in the art. As examples, we can cite the following sources where the above-mentioned pro-drug derivatives are described: o a) Oezidp oyi Rgodgydv, N. Vypadaaga (eaiiug), Eivemieg (1985); i» r) Mebtosdvz ip Epgutoiiodu, K. Uuidaeg ei ai.. (eaiogv). Asadetis Rgezv, Moi. 42. 309-396 (1985); c) A Tehirook oi Ogyd Oezidp apa Oemeiortepi.

Kgozdaaga-I agzep apa N. Vypadaaga (ediugvg), Sparieg 5. "Oevidp apa Arriisavyop oi Rgodgydv," 113-191 (1991); 4) N. Vypddaaga, Admapsed Ogyd Oeiiimegu Kemigyemuv, 8, 1-38 (1992); f) N. Vypdodaaga, . Oi Riagt. Zsiepsev 77, 285 (1988): i

F) 7) M. KakKeua ei aiI., Spet. Rpagt. howl 32,692 (1984). ka Compounds according to this invention can exist in the form of various optical, geometric and stereoisomers. Although the compounds given in this description are defined for one optical orientation, it is assumed that the invention covers all isomers and their mixtures.

Application

The compounds of the present invention are stabilizing agents for microtubules. Thus, they are suitable for the treatment of a variety of cancers and other proliferative diseases, including, without limitation, such as 65 - carcinoma and, including, bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, neck, thyroid gland 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 (Noadakipv), non-Hodgkins lymphoma, hairy cell lymphoma and Burkitt lymphoma; - hematopoietic spinal tumors, including acute and chronic myelopoietic leukemia and promyelocytic leukemia; - tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; - other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma; 70 - tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and neuroma; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyosarcoma and osteogenic sarcoma; and other tumors, including melanoma, xenodermal chromatoblast, keratoacanthoma, seminoma, follicular thyroid tumor, and teratocarcinoma.

The compounds of the present invention also inhibit the development of blood vessels, thus influencing the growth of tumors and providing treatment of tumors and related diseases. Such anti-angiogenic properties of the compounds described by formulas I-IM are also useful in the treatment of other diseases responsive to anti-angiogenic agents, including, but not limited to, some forms of retinal vascular blindness, arthritis , especially inflammatory arthritis, multiple sclerosis, restenosis and psoriasis.

The compounds of this invention stimulate or inhibit apoptosis, a physiological process of cell death critical for normal development and homeostasis.

Alteration of apoptosis pathways contributes to the pathogenesis of various human diseases. Compounds described by formulas I-IM as apoptosis modulators are useful in the treatment of various human diseases with abnormalities in apoptosis, including, but not limited to, cancerous and precancerous lesions, such as immune-dependent diseases, viral infections, skeletal muscle degeneration ulcer system and kidney diseases.

The compounds of the present invention can also be used to treat other diseases other than i) cancer or proliferative. Such diseases include, but are not limited to, viral infections such as herpes virus, poxvirus, Epstein-Barr virus, Sindbis virus, and adenovirus; autoimmune diseases such as systemic lupus erythematosus, immune glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases and autoimmune diabetes; neurodegenerative diseases such as Alzheimer's disease, HIV-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy and cerebral Ge degeneration; AIDS; bone marrow leukocytosis; aplastic anemia; ischemic injuries associated with myocardial infarction; -- reperfusion injuries; restenosis: arrhythmia; i- atherosclerosis; liver diseases caused by toxins or alcohol; hematological diseases such as chronic anemia and aplastic anemia; degenerative diseases of the musculoskeletal system such as osteoporosis and arthritis; aspirin-sensitive rhinosinusitis; cystic fibrosis; multiple sclerosis; kidney diseases; and cancer pain.

Thus, the present invention provides a method of treating patients, mainly mammals and, in particular, "humans" in need of treatment for any of the above diseases, especially cancer or other proliferative diseases, which includes the step of administering to the patient at least of one compound per . formulas of !I-IM, taken in an amount effective for treatment. Along with the proposed compounds, other therapeutic agents can also be used in the proposed method, for example, those described below. In the method of the present invention, another therapeutic agent (or agents) may be administered before, simultaneously with, or after the administration of the compound (or compounds) of the present invention. -I An effective amount of the compound according to the invention can be determined by a person skilled in the art, and includes approximate dosage amounts for humans in the range of 0.05 to 200 mg/kg/day, which can be administered in the form of single or separate doses, the number of which is from 1 to 4 times a day. It is better if the compounds are introduced in the amount of no

Ge» more than 100Omg/kg/day in one dose or in divided 2-4 doses. It is clear that the level and frequency of the 5th dose defined here can be changed for a specific patient and depend on various factors, including the activity of a specific compound, metabolic stability and duration of action of this compound, gender, age, body weight, and general health. , the patient's gender and diet, the method and time of administration, the degree of secretion, the combination of drugs and the severity of a particular disease. This invention is intended for the treatment, mainly, of animals and especially mammals - humans and domestic animals, in particular, dogs, cats, etc., which are prone to the above-mentioned diseases.

The present invention also provides a pharmaceutical composition containing at least one of the following compounds

F) formulas of I-IM capable of treating cancer and other proliferative diseases and taken in an effective amount for this purpose, and a pharmaceutically acceptable carrier or diluent. Compositions according to the present invention may contain other therapeutic agents, as described below, and may include conventional solid or liquid solvents or diluents, as well as pharmaceutical additives of a type appropriate to the desired route of administration of the drug (e.g., excipients, binders, preservatives, stabilizers, flavorings, etc.) in accordance with the technology known to specialists in this field or accepted for pharmaceutical practice.

The compounds described by formulas I-IMM can be administered to the patient in any suitable way, 65 for example, orally, in the form of tablets, capsules, granules or powders; under the tongue; buccally; parenterally and, in particular, subcutaneously, intravenously, intramuscularly, or by parenteral administration or infusion

(for example, in the form of sterile injected aqueous or non-aqueous solutions or suspensions); through the nose and, in particular, by inhalation spraying; locally in the form of creams or ointments, or rectally in the form of suppositories; dosed preparations containing non-toxic, pharmaceutically acceptable solvents or diluents. Compounds according to this invention can be administered, for example, in a form suitable for their immediate or prolonged release. Immediate or prolonged release can be achieved by means of suitable pharmaceutical compositions comprising the compounds of the present invention or, especially in the case of prolonged release, by the use of devices such as subcutaneous capillary tubes or osmotic pumps. The compounds of the present invention can also be administered in a liposomal manner. For example, the active substance can be part of a tablet, capsule, solution or suspension containing approximately 5 to 500 mg per dosage unit of a compound or a mixture of compounds according to formulas I-I, or used by local application (from 0.01 to 595 (wt.) of compounds according to one of the formulas I-II from one to five times a day).

The compounds may be formulated in a conventional manner with a physiologically acceptable diluent or carrier, filler, binder, preservative, stabilizer, flavoring agent, etc., or with a carrier for topical application. The compounds described by formulas 1-IM can also be included in such compositions as sterile solutions or suspensions for parenteral administration. Approximately from 0.1 to 500 mg of the compound according to one of the formulas

IM can be combined with a physiologically acceptable carrier-solvent, carrier, filler, preservative, binder, stabilizer, etc. in a single dose in accordance with generally accepted pharmaceutical practice. The amount of active substance in these compositions or compositions is, as a rule, such that the appropriate dosage is provided in the specified range.

Examples of compositions for oral administration include suspensions that may contain, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose for viscosity, and sweetening or flavoring agents well known in the art. industries; and tablets that are readily disintegrating and may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose, or other art-known fillers, binders, thickeners, disintegrants, thinners, and lubricants. As examples of the used forms of the proposed i) compounds, pressed or freeze-dried tablets can be mentioned. Examples of such compositions include compositions in which the compounds of the present invention are administered with rapidly soluble diluents such as mannitol, lactose, sucrose and/or cyclodextrins. High molecular weight excipients such as cellulose (amisei!) or polyethylene glycol (RES) can also be included in such formulations. In order to ensure adhesion to the mucous membrane, such formulations may also include excipients such as hydroxypropyl cellulose (HPO), o hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose (CSMS), maleic He anhydride copolymer (eg, Sapige?), and agents to regulate secretion drug, such as a polyacrylic copolymer (eg, Sagroro! 934). In order to facilitate the production and use of compositions in them --

Зз5 Lubricants, lubricating oils, flavorings, dyes and stabilizers can also be added. Cha

As examples of aerosol compositions for administration through the nose or for inhalation, physiological solutions can be named, the composition of which may include benzyl alcohol or other suitable preservatives, absorption promoters to increase bioactivity and/or other solubilizing or dispersing agents known in this field.

Examples of compositions for parenteral administration include injectable solutions or suspensions that may contain suitable, non-toxic, parenterally acceptable diluents or solvents such as cremophor, mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or others suitable dispersing, wetting or suspending agents, including synthetic mono- or diglycerides and fatty;" acids, including oleic acid.

Compositions for rectal administration can be in the form of suppositories, which can include,

For example, a suitable non-irritating excipient such as cocoa butter, synthetic esters of glycerol-I or polyethylene glycols, which are solid at normal temperature, but become liquid and/or dissolve in the rectal cavity, releasing the drug. - Compositions for local use include, for example, appropriate carriers for local use

Ge" application, such as Riaziirase (mineral oil in the form of a gel with polyethylene). Compositions according to the present invention can be applied locally, to a given place on the body, for example, in the treatment of plaques associated with psoriasis. At the same time, they can be in the form of a cream or ointment. Compounds of the present invention can be administered both separately and in combination with other antitumor and cytotoxic agents and drugs used in the treatment of cancer and other proliferative disorders. Especially effective are combinations of antitumor and cytotoxic medicinal agents, in which the second constituent medicinal product acts in a different way or at a different phase of the cell cycle, for example, the 3rd phase, than the compounds described by formulas I-IM and exert their effects on c 5- M-phase. Typical (F) classes of such antitumor and cytotoxic agents are, but are not limited to, for example, alkylating agents such as nitrogen-containing mustards, alkylsulfonates, nitrosoureas, ethyleneimines, and triazenes; antimetabolites such as folate antagonists, purine analogs, and pyrimidine analogs; antibiotics such as anthracyclines, bleomycins, for Mitomycin, dactinomycin and plicamycin; enzymes, type I-asparaginase; farnesyl protein transferase inhibitors; hormonal agents, such as glucocorticoids, estrogens and anti-estrogens, androgens and anti-androgens, progestins and luteinizing hormone-releasing hormone antagonists, octreotide acetate; microtubule-destroying agents such as ectinascidins or their analogs and derivatives; microcapsule-stabilizing agents such as paclitaxel (TachoI!F), docetaxel (Tachoieget), and epothilones A-E or their analogs or derivatives; 65 products isolated from plants, such as vincaalkaloids, epipodophyllotoxins, taxanes; and topoisomerase inhibitors, prenylprotein transfer inhibitors basics; and various dissolving agents such as hydroxyurea, procarbazine, mitotane,

hexamethylmelamine, coordination complexes of platinum such as cisplatin or carboplatin; and other agents used as antitumor and cytotoxic agents, such as biological reaction modifiers, growth factors; immunomodulators and monoclonal antibodies. The compounds of the present invention may also be used in conjunction with radiation therapy.

Typical examples of such classes of antitumor and cytotoxic agents include, but are not limited to, mechlorethamine hydrochloride, cyclophosphamide, chlorambucil, melphalan, ifosfamide, busulfan, carmustine, lomustine, semustine, streptozocin, thiotep, dacarbozine, methotrexate, thioguanine, mercaptopurine, fludarabine. pentastatin, cladribine, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, 70 idarubicin. bleomycin sulfate, mitomycin C, oactinomycin OO, safracins, satramycins, quinocarcins, discodermolidines. vincristine, vinblastine, vinorelbin tartrate. etoposide, teniposide, paclitaxel, tamoxifen, estramustine, estramustine sodium phosphate, flutamide, buserillin, leuprolide, pteridines, dinesins, levamisole, aflacon, interferon, interleukins, aldesleukin, filgrastim, sagramostin, rituximab, BSO, tretinoin, irinotecan hydrochloride, betamethasone, gemcitabine hydrochloride, altretamine and topoteka, as well as their analogues and derivatives.

Preferred members of these classes include, but are not limited to, laclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, metopterin. mitomycin C, ecteinascidin 743, porphyromycin, 5-fluorouracil, b-mercaptopurine, gemcitabine, cytosinarabinoside, podophyllotoxin or derivatives of podophyllotoxin such as etoposide, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, leuorosidine, vindesine and leurosine.

Examples of typical antitumor and other cytotoxic agents are the epothilone derivatives described in the patent

Germany M 4138042.8; UMO 97/19086, UMO 98/22461, MO 98/25929, MO 98/38192, MO 99/01124, UMO 99/02224,

MO 99/02514, MO 99/03848, MO 99/07692, MO 99/27890, MO 99/28324, MO 99/43653, MO 99/54330, MO 99/54318, UMO 99/54319, MO 99/65913, MO 99/67252, MO 99/67253, and MO 00/00485; inhibitors of cyclin-dependent kinase - in UUO 99/24416; and inhibitors of prenylprotein transferase - in MO 97/30992 and MO 98/54966. high school

Combinations according to this invention can also be composed or administered together with other therapeutic agents used due to their exceptional effectiveness in the therapeutic treatment of i) the above-mentioned diseases. For example, the compounds of the present invention can be combined with agents such as antiemetics and anti-nausea, anti-allergy and anti-nausea antihistamines. The above-mentioned therapeutic agents, in the case of their use in combinations with the compounds according to the present invention, can be used in the quantities indicated in the therapeutic guide of the Russian Federation of Russian Federations of the Russian Federation of the Republic of Kazakhstan (ROC) or determined by a specialist. Ge

General methods of obtaining (A) Epothilone derivatives described by formulas 1-PI --

This invention is aimed at obtaining epothilone derivatives Ia, IB, Pa, Pr and IP, in which the hydrogen atoms of the methyl group C-21 are partially or completely replaced by other groups with E! until 2! BC can be hydrogen or methyl, P-O is C, C is a double bond or an epoxide.

The general formula below shows the epothilone residue containing the -CH- group at position 17" (carbon atom C17), and the formulas Ia, Ir, Pa, Pr, and PI refer to compounds containing the specified epothilone residue 70 plus one of the substituents shown in combination with the designations of these compounds а, ИБ, Па, ПБ and ПИ. - a .- s v khz» moe o. and about him G.Sh

And

She «v 8 sms 5 5 - -, o chu (o) iv Ma sh y ,; : zov ro, iz" y y tlo" and ts a Mar

GF) e" .

and name)

C - H, halogen, CM, alkyl, substituted alkyl; in C2 - H, alkyl, substituted alkyl; 63-0.5, M2; 01 - H, alkyl, substituted alkyl, 072, M2273, 72-00, 7780", optionally substituted glycosyl; k c5 - halogen, Mz, MOZ, ZN, CM, MC, M(2 c, heteroaryl; c o - H, alkyl, substituted alkyl, CEz, 079, 875, M2275; c'-c27, M;

о8 - H, halogen, alkyl, substituted alkyl, 079, 5779, mi!"9211; в9- 0, 8, -МН-МН-,-М-М-; sto M, sya"; still HNM, substituted HNM, alkyl, substituted alkyl, aryl, substituted aryl; 71 E H, alkyl, substituted alkyl, acyl, substituted acyl; 72 E H, alkyl, substituted alkyl, aryl, substituted aryl, heterocycle; 73 E H, alkyl, substituted alkyl, acyl , substituted acyl, aryl, substituted aryl; 70 77 « alkyl, substituted alkyl, aryl, substituted aryl, heterocycle; 75 H, alkyl, substituted alkyl, acyl-, substituted acyl, aryl, substituted aryl; 75 - H, alkyl, substituted alkyl, acyl, substituted acyl; 7" H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, 079, 578, M27879: 78 - H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl; 73 E H, alkyl, substituted alkyl, acyl, substituted acyl; 770 - H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl; 77 H, alkyl, substituted alkyl, acyl, substituted acyl; 712 H, halogen, alkyl, substituted alkyl, aryl, substituted aryl.

Compounds of the present invention may be prepared from the compounds and according to the general techniques shown in Schemes 1 through 8. All substituents have the meanings defined in the schemes or given above.

Starting from unprotected 3,7-hydroxy or, for example, TM5-protected epothilones A-C (1), 21-hydroxyepothilones (4) can be synthesized from M-oxides (2), the preparation of which is described in MUO 98/38192 and included into this scheme as part of a chain (scheme 1). M-oxides (2) interact with halogen anhydrides of acids and strong bases, mainly halogen anhydrides of p-toluenesulfonic acid and 2,b-lutidine, with the formation of 21-halogenepothilones (3). Deoxygenation of epoxides (4) according to known methods allows obtaining (8) 21-hydroxyepotylones C and O (5).

Alternatively, compounds (4) and (5) can be synthesized by biotransformation (21-hydroxylation) of epothilones A-O using, for example, strains Zohapdisht seiyshiozit as described in MO "g zo 98/22461, or strain 15847 Asiipotusez vzr ., as described in PCT/O599/27954 (incorporated herein by reference), as part of a chain. 3,7-OH protected or unprotected epothilone 3, 4, 5 (scheme 1) (see, for example, UMO 97/19086) is further used to obtain derivatives of structural formulas of type I-I. Ge

Scheme 1 «- | eh! m. 4 o'clock p.m

In: sho A o) s ts shk do i sia ; - and?" 2 о 3 о о о о но о о о о о о о о но о о о о о о о о о о о о о о о но о о о о о о о о о о о о

Scheme 2 can be illustrated as follows (detached epothilone residue, including the group -CH-

T" in position 17, means that this part of the molecule was not included in the reaction process according to the illustration).

F) ko bo b5

І V yuyu | A Ves A t- neoye yana; at. 5. 48 o ono r (» o 5. x z vie z. 70 -, -y, - -a, b V'z apkyl, acyp ХX x Halogen BB» apkip, acyl (substituted) apkip 7 He Mi, Meo -5, ЗН, СМ, (substituted) arylsulfonyl and (substituted) glycosyl Me, hai sh hetsv |ya 15. pn 5. xM- 1,

M

It's paradise |» and 20 I-Kv in the 5th century. on a, schu a,

M: t M

IN! - alkyl, acyl 41 B, B" i alkyl, acy 12, A c alkyl a) Compounds C and 7 can be obtained from compounds 4 or 5 by i) activation, for example, with the help of TozNai/pyridine, followed by i) by nucleophilic substitution of halide anions (compound 3) by Mz, МАС-5, СМ, MC or ЗН anions (compound 7) on OH; Mama is used, for example, to introduce M» and АЯ9СМ, for example, for (8) introduction of an isonitrile group.

B) Compound 6 can be obtained from compound 4 or 5, compound 8 - from compound Z or 7 (X - 5H), and compound 10 - from compound 9 by reacting the starting compound with the reagent according to the formula K "Na! in the presence of a base, where B! "And may, but not necessarily, be substituted by alkyl, acyl, optionally substituted arylsulfonyl, or optionally substituted glycosyl in the case of obtaining compound (6) and by alkyl or acyl in the case of obtaining compounds (8) or ( 10). If compound 9 interacts with reagents according to the formula B Na! and "Na (dev'iv2- (o alkyl or acyl), then compound 11 is obtained, and if compound 9 interacts with reagents according to the formulas B "Nai, "- vnai and EZNa! (where B", B2 and BZ are alkyl), then compound 12 is obtained.

From c) Compound 9 can be obtained from compound 7 at X - Mz by ii) reduction, for example, with the help of No» ii- and a Lindlar catalyst (Ipaiag sagaiuzO/EUN or ii) with phosphines, for example, PMez, and then with aqueous MH "with.

Scheme Z

Scheme C can be illustrated as follows (the detached epothilone residue, which includes the -CH- group in position 17 means that this part of the molecule does not participate in this reaction process). - o

Io 5 no 5 t wo a. du nad, ch i F " » 1 y o pn o 2 y y (v 45 . -i mno V p v Y i. chay she -. -, A, - 1o(R-a ny) vva" Du 1

F |» o "7 and voskno 8 i Y i" a - he Mu - I what

In 2 a on o o on o 10(P-ah ss) zirnat ss) 59 a) Compound 2 can be obtained by bringing compound 1 into interaction with an oxygenating agent,

HF) such as M-chloroperbenzoic acid. 7 B) and c) Compound 4 can be obtained by reacting compound 2 with (B) an addition system containing, for example, (5) (СЕ3СО)20/2,6-lutidine, and then (c) СНЗОН/ MNzvod a) Compound 7 can be obtained by reacting compound 4 with diphenylphosphoryl azide 60 and (ORPA)U/diazabicycloundecene (OB). f) Compound 9 (P-O - epoxide) can be obtained by reduction of compound 7 with phosphine, for example,

RME»z, and then MN» water.

Compound 10 with P-O - epoxide can be obtained by reacting compound 9 with (IVOCO)2O/MEI. 9) Compound 10 with P-O - C-C double bond can be obtained by reduction of compound 10 with P-O - epoxide using M/CI/nVig and.

P") Compound 9 (P-O - double bond) can be obtained by deprotection of compound 10 with P-O - C-C double bond, and K - IVNOSO, using trifluoroacetic acid (TEA),

Scheme 4

Scheme 4 can be illustrated as follows (the cleaved epothilone residue, which contains a -CH- group in position 17 means that this part of the molecule does not participate in this reaction process). 5 in and 5 with and. in 9 zno r |v z 5. - cha, - |v tah) t o ono tTrRagsgs) - a) Compound 6 can be obtained from compound 4 by acylation in the presence of p-tosyl chloride/base

Khaniga (Nipid bavze).

B) Compound 7 with unchanged epoxide can be obtained from compound b by substitution with

Cyanide, for example KSM/18-crown-6. c) Compound 7, with Р-О - С-С double bond can be obtained from compound 7, with Р-О - epoxide by i) reduction with UMUSIv/H-Via and. 4) Compound 7 with an unchanged epoxide can be obtained from compound b by substitution with imidazole in the presence of a base, for example, K»CO»z. Scheme 5

Scheme 5 can be illustrated as follows (the cleaved epothilone residue containing the -CH- group at position 17 means that this part of the molecule does not participate in this reaction process). Ge yah o, ch- ti -a "in it- 10,44 v'.kazN, Al 9 2 m of 14 23 I | paradise « I- in She MA in I c) s nada, ch ha zvovuvinAzhiddnyai 3 45 yah lzhilyava g" TM ly 22s Ot Alkil, Ar ry | a x 5-X and

On Sun: Fri. sha |» 18 8. Azhii and |»

F a, a. o -c ("v | 250 20 ven piy FI VV" dyd 17 ve, Azhid a i" a) Compound 13 can be obtained by oxidizing compound 4 or 5 using, for example, MpO".

B) Compound 14 can be obtained by reacting compound 13 with CHOM." c) Compound 15 can be obtained by subjecting compound 13 to the Wittig reaction (MUiNscha). a) Compound 16 can be obtained by treating compound 13 with a reaction system containing CgCl 2 and CHnNa!z.

F) e) Compound 17 can be obtained by reaction of compound 16 with Vy and KNai (K - H, alkyl or ka acyl).

I) Compound 18 can be obtained by reacting compound 13 with CH oMo for 18 (K - H on the Substituents C21) or with Me-ZOSNK for 18 (K - H, alkyl). 9) Compound 19 can be obtained by reaction of compound 13 with E"MoNai| or B? (B2 - alkyl).

P) Compound 20 can be obtained by oxidizing compound 19 using, for example, MnO.

І) Compound 21 can be obtained by reaction of compound 20 with K"Manai! or Bi (B! - alkyl).

K) Compounds 22a, 226b and 22c can be obtained by reaction of compound 13 with NoMK, where K - 65 ОВ, ав! - hydrogen, alkyl or aryl for compound 22a; Kk - M(B2)», K - hydrogen, alkyl or acyl for compound 226 and

K is alkyl or aryl for compound 22c.

I) Compound 23 can be obtained by reaction of compound 13 with a source of SM, for example, HSM. t) Compounds 10 and 11 can be obtained by reductive amination of compound 13 using

NMA" and, for example, MaBvNzsmM, where B and B? - H, alkyl.

Scheme 6

Scheme 6 can be illustrated as follows (the cleaved epothilone residue containing the -CH- group in position 17 means that this part of the molecule does not participate in this reaction process). on, n - 13

V. o. 3-4, 24 I ra o o - 25 28 Ve N, Aled Ar e ken|e ku S, --

Gu M Y 26 V» ley 23 Ge! a) Compound 24 can be obtained by oxidizing compound 13 with, for example, АЯ2О in a THF/water solution (at a THF:water ratio of, for example, 9:1).

B) Compound 25 can be obtained by methylation of compound 24 using, for example, CH 2 Mo in ethyl acetate. "- c) Compound 26 can be obtained by reacting compound 25 with an excess of KE Man! or Vi m (B! - alkyl). 4) Compound 27 can be obtained by acylation of compound 26 with B "Na! (82 - acyl) in the presence of a base, for example, OMAR. e) Compound 28 can be obtained by applying the first reaction of the activation of the carboxyl group in " 24 with, for example, the system ethyl chloroformate/MEIz and the second reaction with v'MNo (B! - hydrogen, alkyl or ШШШЖ3 with aryl) in T/F. c U) Compound 29 can be obtained by dehydrogenation of compound 28 (K - hydrogen) using for example, "» ROSIZMEVB.

Scheme 7

Scheme 7 can be illustrated as follows (the cleaved epothilone residue containing the -CH- group in -I position 17 means that this part of the molecule does not participate in this reaction process). - (22) at 50 s"

F) ime) 60 b5 o 5. ol, 18,24 with I

He ate wild" at 5:00 a.m

In yes, prnu 20 va» Alkyl -a 31 jaZa sa vu) pyasya, G 5. 6, and also 34 vemovnnnnka in

YAMA "Alkil, Arip vus M 35 32 nya 5.

IN

S a » 96 ov 7 vk. vd "Ya, tyu 33 vn 38 ze, Alkip, Acyl 5. VZ Alkyl, Acyp "Ya, and Zoya dlkyl, shchi a) Compound 31 (BZ - acyl) can be obtained by reaction of compound 19 or 21 with an activated carbon derivative acids, for example ESONAai (Z - CO) in the presence of a base. high school

B) Compound 20 can be obtained by oxidizing compound 19 (B - hydrogen, BK? - alkyl) using, (o) for example, MpO". c) Compound 34 can be obtained by condensation of compound 20 with noMmAZ (83 - hydrogen, alkyl, aryl OB or MEV", where B and B" - alkyl, aryl). "E 4) Compound 35 can be obtained by reaction of compound 34 (23 - alkyl, aryl) with E/MoNai! or about

VZC (B and 82 - alkyl). e) Compound 32 can be obtained by reaction of compound 20 (VK2 - CEz) with i) NeMOrtTozv and its) NMz ise) (liquid). "-

TU) Compound 36 can be obtained by subjecting compound 20 to a reductive amination reaction.

From 9) Compound 38 can be obtained by alkylation or acylation of compound 35 using V Nai! (B? - - alkyl or acyl) in the presence of a base.

P) Compound 33 can be obtained by oxidizing compound 32 using, for example, A920.

І) Compound 37 can be obtained by alkylation or acylation of compound 36 using V ZNai! (VZ « di - alkyl or acyl) in the presence of a base. with (B) Derivatives of epothilone IM with i

AND

. at. - in in " - ov

Fo te N g g -i M o ono - In addition, the invention is directed to obtaining derivatives of epothilone IM, which are described by the formula IM, where the symbols used have the following meanings:

Ge) P-O is a C, C double bond or epoxide; o 50 K is an H atom or a methyl group; and

CO! is a NOM group, a substituted NOM group, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group.

Preparation and rearrangement of M-acylepotylon-M-oxides

Preparation of epothilone-H-oxides (2), where P-O is an epoxide, and their rearrangement into 21-acyloxyepothilone of the following formula 6 is described in MO 98/38192, the full text of which is incorporated into this description as a reference. o and o 5 visas » and yu KI,

In | heaven and sleep 60 9.

Co ono 6 in - alkyl, acyl, (substituted) alkyl, (substituted) arylsulfonyl, (substituted) glucosyl. b5

Scheme 8

AND

70 with ts, with ma, o, -.77-,

Z and I Where and in | -, 7 4

Scheme 8 can be illustrated as follows (the cleaved epothilone residue containing the -CH- group in position 17 means that this part of the molecule does not participate in this reaction process):

Here, P-O is an epoxide or SS double bond, K is hydrogen or a methyl group. a) Compounds C and b can be obtained by reacting compound 2 with K 18051 in the presence of a base (B! - optionally substituted alkyl or optionally substituted aryl).

B) Compounds 6 and Ma/yu can be obtained by reacting compound 2 with an activated carboxylic acid derivative, for example, carboxylic acid anhydride. c) Compound 4 can be obtained by the reaction of the compound IMa/u with the nucleophile MiN or Mi". c

Ethers 6 are used as intermediate products to obtain a large number of epothilones, which are subsequently modified by Ge) at the C-21 position.

If 2 reacts, for example, with acetic anhydride, a new, unexpected intermediate compound IM can be formed in a short reaction period, while M is completely transformed into compound b during a long reaction time. If the reaction is stopped at a certain moment, the IM compound can be isolated by the chromatographic C method in the form of two diastereoisomers Ma and Mr. aw!

Compounds of the IM type have not been previously described, and their structure can apparently be established on the basis of their spectroscopic data and subsequent reactions. at

For preparative purposes, their reaction with nucleophiles is especially important, which leads to the formation of C-21 "- substituted epothilones b, where M is, for example, carbon, nitrogen, oxygen, sulfur and halogen

With a substitute. -

Examples

Below, for the purpose of illustration, which is not of a limiting nature, some examples of practical implementation of this invention are given. "

Example 1 - 70 Conversion of epothilone B to epothilone E with 9. and o». ;z» oi -oi gr o . a bno Y (a I o - 175 () 1.98 g (3.9 b0 mmol) of epothilone B was placed in an argon atmosphere and dissolved in bOml of dry CH Si". 0.720 g of tSRVA (4.17 mmol, 1.07 equivalent). - The mixture was stirred at 25"7C for 5.5 hours. Then the reaction mass was quenched with bbOml of MansSo»z b and extracted with 3x/5ml of SNCl3. The organic phase was washed with 10O0ml of water, then 7Oml of 595 Ma»ZOz (aq.) and 70ml of 5% brine. The organic phase was dried over Ma»5O). The crude reaction product was subjected to chromatography on o silica gel and elution of 295 Meon in SNCl3 with a yield of 0.97 bg of M-oxide (4895) in the form of a white fluffy solid

T" substances. (i) In a hermetic tube filled with argon, 0.976 bg of M-oxide (1.8 bmmol) dissolved in ZbBml of dry СНоСи», 2,6b-lutidine (1.7 Bml, 14.88 mmol, 8 equivalents) and (СЕ 3С20 )20 (1.84 ml, 13.02 mmol, 7 equivalents). The tube was sealed and kept at 70°C for 25 minutes. After this, the mixture was allowed to cool, the solvent was removed under a stream of argon, and then it was concentrated under vacuum until (F) several milliliters of dark yellow solution remained. The reaction medium was diluted 25 ml of SNZON and

GI added 2.9 ml of 2895th MNAON (aqueous). The mixture was heated at 457°C for 20 min and cooled to room temperature. The crude product was concentrated in a rotary evaporator and subjected to chromatography eluting with silica gel 495 with a solution of SNZON in SNCI3, obtaining 0.815 g of epothilone E (8496) as a product.

Example 2

Synthesis of 21-azidoepothilones 7

Example: 15-1A,ZKE),7K,1057,114К7,12К7,16571)-3-(2-(2--azidomethyl)-4-thiazolyl|-1-methylethenyl|-7,11-dihydroxy-8, 8,1 65 0,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione (К-СНу», с!-02-Н, в5-М3 in formula IB)

at,

M 5 | i - 4. zone |c) about it:

To a stirred solution of epothilone E from Example 1 (957 mg, 1.8 mmol) in 20.00 ml of tetrahydrofuran at a temperature of 0"C in an argon atmosphere, 0.47 ml of diphenylphosphoryl azide (b04 mg, 2.19 mmol, 1.2 equivalents) was added. The mixture was stirred for approximately After a few minutes, 1,8-diazabicyclo(5.4.FO)undec-7-ene (0.27ml, 278mg, 1.83mmol, 1 equivalent) was added to it and all this was stirred at 0"C. In 2 hours, the mixture was heated to 2572 and stirred for another 20 hours. Then the reaction mass was diluted with 150 ml of ethyl acetate and washed with 50 ml of Na.

The aqueous layer was extracted with 35 ml of ethyl acetate. The combined organic layers were dried over MA and concentrated in vacuo. The crude product was subjected to chromatography eluting from silica gel 5095 with ethyl acetate in hexane, obtaining as a product 91 µg (9195) of 21-azidoepothilone B in the form of a clear, colorless oil. and M5 mass spectroscopy (EBI"): 549.3 (MAN); 7H-NMR (300MGu, SOSI3): 5 - 6.59 (broad s, 17-H), 7.04 (s, 19-H) , 4.63 (c, 21-H»5);

НЕМ5 (ОСИ): Со7НаоМаОв5: IM" calculation: 549.2747; experiment: 549.2768.

Example C

Synthesis of 21-aminoepothilones 9

Example: (15-1A,ZKE),7K,1057,114K7,12K7,16571I-3-(2-(2-(aminomethyl)-4-thiazolyl|-1-methylethenyl|-7,11-dihydroxy-8, 8,1 0,12,16-pentamethyl-4,17-dioxabicyclo(/14.1.0)heptadecane-5,9-dione (B-CHu, 51-052-857-21-H, 53-M7! in formula

Ia) p

Lindlar's catalyst in the amount of 18.0 mg was suspended in 500 μl of ethanol in an atmosphere of NO and saturated it. at

Then 15.9 mg (29.00 μmol) of 21-azidoepothilone B from Example 2, dissolved in an ethanol-methanol mixture, was added. After stirring for 30 minutes at room temperature, the suspension was filtered through celite and washed with ethyl acetate. The solvent was removed from the organic phase and the residue was dried under high vacuum.

The crude product was purified through RDS (solvent: СНоSiO:methanol - 90:10) and as a result received 12.3 mg (8195) of "Ж 21-aminoepothilone B and mg (695) of the adduct (e.g. by 7H-NMR (Z00MHC, SOSI) z): 5 - 6.58 (broad c, 17-H), 7.05 (c, 19-H), 4.15 (c, 21-H");

НЕМ5 (ОСИ): Со7На2М2ОБ65: MAN calculation 522.2764, experiment 522.2772. i-th

Example 4 h

Synthesis of 21-aminoepothilones 9 (alternative) 15-1А,ЗКЕ),7К,105711К12К71657)-3-(2-(2-(aminomethyl)-4-thiazolyl|-1-methylethenyl|)-7,11-dihydroxy-8 ,8 - 210,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione in " nm 8 i o s (c) "" o ono " To a stirred solution of 21-azidoepothilone In (Example 2) (1.070 g, 1.950 mmol) 0.22 ml of trimethylphosphine (0.163 g, 2.145 mmol, 1.1 equivalent) was added to 30.0 ml of tetrahydrofuran in an argon atmosphere.

Next, HoO (5.5 ml) was added to the solution, and the mixture was stirred at 25 "С. According to the agreement, the azide completely decomposed, and to complete the process of converting phosphorylimine into an amine, 3 ml - 2890th aqueous MNAOH ( (water). After stirring the reaction mass at a temperature of 2573 for an hour, the solvents were removed under vacuum. The crude material was subjected to chromatography with elution from silica gel by

Ф with the help of 195 EM, 2.596 СНЗОН in СНСЯ3, obtaining 924 mg (9195) of 21-aminoepothilone B in the form of a white solid av) 50 substance.

M5 (EB8I"): 523.3 (MAN) s"

Example 5 15-71 WHY),7K1057,11K7,12K716571I-3-(2-(2-I(C0I1,1-dimethylethoxy)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

F) sunrise and |» yu AD, call Fr. 6 o o ono

To a solution of 21-aminoepothilone B (12 mg, 0.24 mmol) in methanol (4.0 mL) was added triethylamine

0.48 mmol, 2 equivalents) and di-i-butyl bicarbonate (b5 mg, 0.3 mmol, 1.25 equivalents). The reaction mixture was stirred for 2 hours. Thin-layer chromatography (TLC) showed the absence of starting material.

The reaction mixture was concentrated in a vacuum and subjected to chromatography on silica gel using 595 SNHZON in CHO as an eluent. As a result, 164 mg (100965) of 21-aminoepothilone B was obtained as a white solid.

Example 6

I45-I4k757,8K9K15ATE)I-16-(2-I2-IS(1,1-dimethylethoxy)carbonylI|amino|methyl-4-thiazolyl|-1-methylethenyl|-4,8-dihydroxy-5,5, 7,9,13-pentamethyl-1-oxa-13(7)-cyclohexadecene-2,6b-dione

Anhydrous tetrahydrofuran (3.00 ml) was placed in an oven-dried flask in an argon atmosphere and cooled to -78°C. In a stream of argon, M/Civ (206 bmg, 0.52 mmol, 2 equivalents) was added to the cooled tetrahydrofuran, and then n- butyllithium (0.65Oml, 1.6M solution in hexane, 1.04mmol, 4 equivalents).The reaction flask was removed from the cooling bath (-78"C) and its contents were stirred at an ambient temperature of 7/0 for 15 minutes. Then the resulting reaction mass was placed in a bath with a temperature of 0"C and further stirred for 5 minutes before adding a solution of 21-aminoepothilone B (dried by azeotropic distillation with toluene under vacuum overnight) (16b4mg, 0.2bmmol, 1 equivalent) in tetrahydrofuran (1.5 ml). The reaction lasted 45 minutes at 0"C. TI C showed that the main part of the starting material had reacted. The reaction was quenched with a saturated aqueous solution of MnSO (5 mL), and the product was partitioned between a saturated 7/5 aqueous solution of MnHsSO (25 mL) and SiOCl (50 mL).

The aqueous phase was extracted three times with СНоСи». The combined organic layers were dried over magnesium, concentrated in vacuo and purified by chromatography on silica gel first with 795 CH 2OH in CHCl 2 and then eluting a second time from a 5095 column with ethyl acetate in hexane. As a result, b5mg (4195) of 21-M-VOC-aminoepothilone O was obtained.

M5 (EBI"): 607.3 (MAN); M5 (E5I): 605.3 (M-H)-

Example 7

I45-I4k7,757,8K9A15KE)I)16-(2-(2-(aminomethyl)-4-thiazolyl|-1-methylethenyl)-4,8-dihydroxy-5,5,7,9,13-pentamethyl -1-oxa-13(2)-cyclohexadecene-2,6b-dione nm 5 and

AH "he about

Ge) o ono e "I

At a temperature of 0"C, 21-M-BOC-aminoepothilone O (98 mg, 0.1 bmmol.) was treated with a pre-cooled solution of 1095 trifluoroacetic acid in CH2Cl2 (4.0 ml). After 40 minutes, the reaction mass was allowed to warm to room temperature, and after another 20 minutes, undiluted trifluoroacetic acid (O0.bml) was added. After another 50 minutes, an additional amount (0.5 ml) of trifluoroacetic acid was added to the mixture. The reaction was completed at 5090 "- after 1.75 hours, after which the solvents were removed in vacuum. The residue was taken up in ethyl acetate (50ml) and saturated aqueous MNAOH (B50ml) and extracted with ethyl acetate (3x50ml). The combined organic layers were dried over

Ma»3O, and then subjected to chromatography eluting from silica gel first with pure ethyl acetate and then with 1090

SNZONH in ethyl acetate from 195 trifluoroacetic acid. As a result, 16b, mg (3890) of the target 21-aminoepothilone O was obtained in the form of a transparent film together with 45 mg of 21-M-VOC-aminoepothilone 0.

M5 (E8I"): 506.3 (MAN) M5 (E5IU: 504.3 (M-H)

Below, in Examples 8-10, the synthesis of 21-acyloxyepothilones 6 ne) c Example 8 "» Example: " 154-1A,ZKE), 7 1057,11К7,121К7.16577|-7,11-dihydroxy-8,8 . (В-01-02-Н, 33-0, 57-720-0, 77-н-Вы 395 in the formula Та) ate. 83.0 µl (419 mmoles) of valeric anhydride and 20.00 µl (172 mmoles) of 2,6-lutidine were added to a solution of 20 mg (30 mmoles) of epothilone A-M-oxide in 100 µl of CHClCl. The reaction mass was stirred for 30 minutes at 75°C, the solvent was removed, and the mass was dried under high vacuum. The resulting crude product was purified by

Ф with the help of preparative liquid chromatography with high resolution (NRI C) (Misieovii (ав) 50 100, solvent: СНУСМ:Н»О-50:50), obtaining Umg (4095) of epothilone-E-21-valerate.

I" 7H-NMR (300 MHz, SOSI3); 5 - 6.60 (c, 17-H), 7.14 (c, 19-H), 5.35 (c, 21-No), 3.62 (t, 2'-No), 1.6 -1.7 (m, 3-H"), 1.3-1.4 (m, 4-H"), 0.91 (t, 5-H3).

NAM (EI): Сз34НА7МОва: calculation 593.3022, experiment 593.3007.

Example 9

Example: (F) 5-1 AUZKCHE) AK 1057,11K7,12K716571I-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-Knaphthiloyloxy)

HI )methyl)-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1,0)heptadecane-5,9-dione (v-c!-02-H, 53-50, (7-2206-0, 72-Naphthyl in the formula Ia) 60 (Epothilon A)-M-oxide in the amount of 21 mg (41 μmole) was dissolved in 8 μl of CHCl and 1 μl (8 μmole) of 2,6-lutidine, and 82.0 μl (129 mmol) of a solution of 2- of naphthylloyl chloride (30 Омг/ml СН»еси»).

The reaction mixture was stirred for 10 minutes at 757C. The crude mixture was purified using a preparative

NRI C (Misieovii 100, solvent: ibutyl methyl ether/hexane with a ratio of 1:2 with 195 methanol).

Resolution gave dZmg (29965) epothilone-E-21-naphthoylate. 65 "H-NMR (400 MHz, SOCI3); 5 - 6.64 (s, 17-H), 7.19 (s, 19-H), 5.67 (s, 21-No), 8.09 ( dd, 3-H), 7.96 (d, 4-H), 7.89 (dd, 5-H), 7.89 (dd, 6-H), 7.58 (m, 7-H) .

Example 10

Example: 15-11, ZKE), 7 1057,11К7,124К7,165771|-7,11-dihydroxy-3-(2-(2-I(2-methoxyethoxy)acetyloxy|methyl|-1-methyl -4- thiazolyl|ethenyl)-8,8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione (k-o 1 -02-H, b3-0, b4-730- 0.73-3, 6'-dioxahexyl in the formula Ia) 2-(2-Methoxyethoxy)acetic acid, 100 μl (8800 mmol), was dissolved in 1.6 ml of THF. Then 137 µl (880 mmol) of 2,4,b-trichlorobenzoyl chloride and 135 µl (968 mmol) of triethylamine were added. The mixture was stirred for 70 hours. at room temperature, resulting in the formation of a colorless precipitate. The reaction solution was subjected to centrifugation, and 120 μl of the upper layer was added to a solution of 23 mg (45 μmol) of epothilone E in 400 μl of THF.

Then, 8.4 mg (4 bmcmol) of dimethylaminopyridine was added to the solution, and the mixture was stirred for 20 minutes at room temperature. The crude product was purified using preparative NRI C (Missieovzii 100, solvent:

I-butyl methyl ether hexane 1:2-295 methanol). In this way, 14.7 mg (52905) of 75. 21-(3,6'-dioxaheptanoyl)epothilone E were isolated. 7H-NMR (300MHC, SOCI3): 5 - 6.60 (broad s, 17-H), 7 .16 (5, 19-H), 5.42 (c, 21-H"), 4.52 (c, 2'-No), 3.74 (m, 3-H"), 3.58 ( m, 42-H"), 3.37 (s, 5-H");

НЕМ5 (ОСИ): Сз1НА7МО 05: (MAN calculation 626.2999, experiment 626.2975.

Below, in Example 11, an example of the synthesis of 21-acylaminoepothilones 10 is considered.

Example 11

Example: 15-11 ZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-(M-propionyl ino)methyl-4-thiazolyl|ethenylI-4,17-dioxabicyclo(14.1.0)heptadecane-5,9-dione, (B-H, 05'1-052-H, c53-MY!, 71-H, ov 8y-27s-0, 27-EKu formula Ia) see

Triethylamine in the amount of 7Oml (500μmole) was dissolved in 250μl of absolute THF and then cooled to 07C (o) with ice water. After that, 53 μl (400 μmole) of methyl chloroformate was added to the solution. After approximately 5 minutes, 25 μl (334 mmol) of propionic acid was added dropwise, and the mixture was stirred for an additional 10-15 minutes. Then the reaction mass was heated to room temperature, and the precipitate was separated by centrifugation. After this, 47 μl of the upper layer was added to a solution of 1 mg (2 bmmol) of 11-aminoepothilone A in 250 μl of absolute

THF and 5a4 μl (39.00 μmole) of triethylamine. After 20 minutes, the crude reaction mixture was purified with the help of (2 preparative TI C (solvent: SNCI"/SNZON 90:10). In this way, 11.2 mg (76905) of 21-amino-epothilone so were obtained

A-propionamide. 7H-NMR (300MGu, SOCI3): 5 - 6.57 (broad s, 17-H), 7.07 (s, 19-H), 2.28 (square, 2'-No), 1.18( 3-NH),6.29(T,MH); --

NA-M5 (EI): SooNdaM2O075: calculation 564.2869, experiment 564.2854. uh-

Below, in Examples 12-18, the synthesis of epothilones according to the formula IM and 21-acyloxyepothilones 6 is described.

Derivatives would be described in OE 19907588.3. They can be obtained, as a rule, in several stages of 2, while the method described below corresponds to JOE 19930111.5 (both of these sources are incorporated herein by reference). "

Example 12 shsh s Example: and 15-11, ZKE), 7 1057.11K7,124K7,165771I-3-(2-(3-acetyl-2,3-dihydro-2-methylene-4-thiazolyl)-1- (methylethenyl|-7,1 and? 1-dihydroxy-8,8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, M-oxide (Formula Ma (

ImMb: В-Н, в11-СНу)

Compound 2 in the amount of 102 mg (0.2 mmol) was dissolved in 2 ml of acetic anhydride and heated for 5 minutes at 75 °C. After that, the reaction medium was concentrated at 30 °C/1 mbar until a viscous oil was formed, and separated on silica gel 5 and 60 (solvent: hexane:methyl-i-butyl ether:methanol in a ratio of 66:33:1) and, in addition to bomg (4195) 6, 17 mg (1195) of each of Ma and Mr were eluted. (is) Ma: colorless oil; OS: - 0.66; (dichloromethane:methanol - 95:5); UV spectrum. (СНзЗОН): Khpakh(e)-203 (13800), (av) 50 267 (13200), Z15nm (5000); (in "185 (c-0.94 in SNSIZ:Meon-1:1); IR spectrum. (KVh): o-3446, 2965, 2936, 2877,

Y" 1742, 1691 cm"; "H-NMR (SOCI3): 5-2.43 (dd, U-14.8, 3.7 H-2a); 2.53 (dd, 14.8, 10.2, H-25); 4.13 (m, 3-H); 3.33 (d, 9-64, 3-OH); 1.86 (dt, 9U-15.0, 7.8, 14-Na); 2.08 (m, 14-HN); 5.39 (dd, 9U-7.8, 2.2, 15-H); 6.23 (s wide, 17-H); 6.95 (c, 19-H); 5.18 (c, 21-Na); 5.71 (s wide, 21-H); 2.26 (s wide, 27-Naz); 2.12 (c, 5th century); ISR-NMR (SRSIz); 5-73.4 (0-3); 52.8 (0-4); 151.5 (0-16); 116.0 (0-17); 158.0 (C-18); 88.7 (C-19); 166.9 (0-20); 107.2 (0-21); 20.7 (0-223; 170.2, 21.2 (acetyl); NRI C/EBI-M5: (acetonitrile/0.02M ammonium acetate buffer pH 7, positive ions): m/2 569 |MAMNO and . by IMB: colorless oil; OS: CI - 0.69 (conditions given above); Ha) 0 -1196 (c-1.1; SNSIz:Meon 1:1); "H-NMR (SOCI3): 1.90 (m, 14-Na); 2.09 (m, 14-Hb); 5.42 (dd, 9-7.8, 2.2, 15-H); 6 .92 (c, 19-H); 2.23 (c, 27-H3z); 2.10 (c, 60 CHzeo); ISR-NMR (SOCIz): 150.8 (C-16); 116.5 (C-17), 17.2 (C-27), 170.3, 21.0 (acetyl);

Example 13

Example: 15-11 ZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-3-(2-(2-(methoxymethyl)-4-thiazolyl|-1-methylethenyl|-8, в5 8 ,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione (ba, K-H, My-OSH»)

The compound Ma or IMB (K - the same as in example 12, see above) in the amount of 14 mg (25 μl) was heated in 1 ml of methanol for 30 minutes at 75"C, concentrated in a vacuum and separated using a preparative

NRGS (AR-18, SNZUSM:NJO-1:1). As a result, 2.5 mg (19965) of the target product was obtained. casNnosi"/mMeon):0.33. 7H-NMR (SOSIS): 5 - 4.71 (c, 21-CH"); 3.49 (c, 21-OSN.). 136-NMR (SOSI»z): 5 - 59.1 (OSN»); 71.5 (C-21); 167.8 (C-20).

OSI-M5 (isobutane: "/,-524.2609 (pt AN"Y, for Co7Nl1MO75 the calculation is 524.2604.

Example 14 15-11 ZKE), 7 1057,11К7,124К7,16577|-7,11-dihyroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-I(2-( phenoxime 70 ethyl)-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione b,bmg (11.7 μmol) M-acetyl-21-methylene-epothilone A M-oxide was dissolved in 1.5 mL of dichloromethane and treated with 11.1 mg (120 µmol) of phenol dissolved in 30 µM of dichloromethane. After stirring the mixture at 7570 for two hours, the solvents were evaporated, and the crude product was purified using preparative Ti!C (solvent: СНоСи:methanol - 95:5) with the formation of 1.8 mg (30905) of 21-phenoxy-epothilone B. 12 "H-NMR (400 MHz, SOCI5): delta - 6.59 (broad s, 17-H), 6.99 (s , 19-H), 4.21 (c, 21-H"), 6.78 and 7.16 (d, d, aroma. H).

NE-M5 (OSI): SovNaziMO, 8, (MANI calculation 538.2839, experiment 538.2832.

Example 15

Example: 15-11, ZKE), 7 1057,11K7,12K7,16571I-3-(2-(2-Ketylthio)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, К-СНу», В/-СоНв)

Compound 2 (K:CH") in the amount of 20 mg is converted into mixture 6 (27 - acetyl) with the help of acetic anhydride,

ЎМа and ЎМБ from the above Example 12 and concentrated under vacuum until the formation of oil. The oil is dissolved in 100 ml of ethyl mercaptan and heated for an hour. at a temperature of 10570. After that, the mixture is dried in a vacuum, and the dried residue is separated using preparative OS (silica gel, petroleum ether/ethyl acetate at 1:1). Output 5mg (25965).

CI (petroleum ether:ethyl acetate -1:1): 0.48. "H-NMR (SOSI»z): 5 - 3.98 (s, 21-CH"); 1.24, 2.60 (t, KV, 21-5SoNv) (s, 21-OSN"); " AND

OSI-M (isobutane): "/,-554. o

Example 16 15-11, ZKE), 7 1057,11K7,12K7,16571I-3-(2-(2-(ethoxymethyl)-4-thiazolyl|-1-methylethenyl/|-7,11-dihydroxy (Ce)) - 8,8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione - 10 mg (19.7 μmol) epothilone E was dissolved in a mixture of 100 μl of dichloromethane and 100 μl of diethyl ether and treated with 54, bmg (23bmmol) of silver (I) oxide and 47.bmcl (590mmol) of iodethane. After stirring - overnight at room temperature, the mixture was filtered through celite and evaporated to dryness. The crude product was purified using preparative TS (solvent: СНоСиометанол - 95: 5), and as a result 8.8 mg (83.4965) of 21-ethoxyepothilone A were obtained. . : SovNaziMO, 8, (MANI calculation 538.2839, experiment 538.2832.

From" Example 17 15-11AZKE), 7 1057,11К7124К7,16577)|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-(1-methyl-2-(2-(2,3,4 ,6-t etraacetyl-alpha-glucosyloxy)methyl-4-thiazolyl|ethenyl)|-4,17-dioxabicyclo|14,1.0)heptadecan-5,9-dione 15-11, ZKE), 7 1057,11K,12K7 ,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-(1-methyl-2-(2-K2,3,4,6 and -tetraacetyl-beta-glucosyloxy)methyl|- 4-thiazolyl|ethenyl/)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione - o n (22) vas 5 . he o t, Ai- - y eh ked a

I" and Fr. it

Epothilone E (5mg, 98µmole) and tetramethylurea (4bml, 383µmole), dissolved in 200ml of dry

СНоСИ", added silver trifluoromethanesulfonate suspension (101 mg, 39 Zmmol) and crushed into powder и и ; of molecular sieves 4A (500 mg) in 2 ml of dry CH 2 Si". The mixture was stirred in an atmosphere of Mo for 1 h. at (F) room temperature. Then B-O-acetobromoglucose (121 mg, 295 µmole) dissolved in 200 µl g of dry SNSI was added to it. The reaction mixture was stirred at room temperature overnight, filtered through celite and concentrated. The product was purified by reversed-phase chromatography (SNUSM:HNO-48:52), and then on silica gel (CHNOSiO:methanol - 95:5). As a result, alpha-glucoside (4.2mg, 590) and B-glucoside (5.bmg, 695) were obtained as colorless solids.

Alpha-glucoside: "H-NMR (ZO0MHC, SOCIz8): delta - 6.58 (broad s, 17-H), 7.11 (s, 19-H), 4.82 (s, 21-No), 5.74 (d, 1-H), 4.38 (ddd, 2-H), 5.19 (t, 3-H), 4.90 (dd, 4-H), 3.94 (dt, 5-H), 4.20 (m, 6-H»5). k k 65 OSI-M5 (120 eV, MNa): 857 |M-AMNYA).

Beta-glucoside:

TN-NMR (400 MHz, SOSIz): delta - 6.59 (broad c, 17-H), 7.14 (c, 19-H), 4.92 (d, 21-Na), 5.06 (d , 21-HB), 4.69 (d, 1-H), 5.08 (t, 2'-H), 5.20 (t, 3-H), 5.11 (t, 2-H) , 3.71 (m, 5-H), 4.13 (dd, 6-Na), 4.25 (dd, 6-HB). k k

OSI-M5 (120 eV, MNa): 857 |M-AMNYA).

Examples 15-11, ZKE), 7 1057,11К7,12К7,16571|-7.11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-(6'-acetyl - alpha-glucosyloxy)methyl-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione

B-Glucoside, obtained as described above, (4.8 mg, 5.8 µmole) was dissolved in 5 µM of ЮМ5О. Phosphate buffer (4 ml, 20 mM, pH 7) was added to the solution, and the reaction mixture was subjected to ultrasound treatment for 70 5 minutes. Pig liver esterase (0.3 ml, Voegipdeg Mapppeit) was then added to the mixture and mixed again.

According to After that, the mixture was extracted with ethyl acetate, and the combined organic extracts were concentrated. The concentrate was purified by reversed-phase chromatography (CH3SM:NO - 38:62), resulting in mg (2496) of glucoside. 1H-NMR (600 MHz, SOSIz): delta - 6.62 (broad c, 17-H), 7.15 (c, 19-H), 4.95 (d, 21-Na), 5.14 (d , t 21-NB), 4.53 (d, 1-H), 3.45 (dd, 2-H), 3.57 (t, 3-H), 3.42 (t, "4-H ), 3.50 (m, 5-H), 4.3O0(dd, 6-Na), 4.48 (dd, 6'-NB), 2.12 (s, acetyl-H»3).

Below, in Examples 19 and 20, the synthesis of 21-sulfonyloxy-epothilones 6 is described.

Example 19

Example: 15-11 ZKE), 7 1057,1K7,12K,1651711-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-Kp-toluene) (phenyloxy)methyl)-4-thiazolyl|ethenyl)|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione (B-Me, 51-02-H, 5350, 57-7 180", 27 -p-toluene in formula Ia) a, o o. o "ВХ o, 95 ra ! o y « o ono o

To a stirred solution of 104 mg of epothilone E (199 µmole, 1 equivalent) in bml of CHNSiO at a temperature of 0"C in an argon atmosphere, 0.17 ml of M,M-diisopropylethylamine (99 µmole, 5 equivalents) was added, and then 45 mg of p-toluenesulfonyl chloride ( 238 micromoles, 1.2 equivalents). The mixture was stirred at 257"C for 47 hours to ((zh7) ensure the opportunity for the starting material to fully react. The reaction mixture was poured into 40 ml of an aqueous solution of ManCO3 saturated with it. The aqueous layer was extracted with CHClCl (3x50ml). The combined organic layers were dried over NaCl5O) and concentrated in vacuo. The crude material was chromatographed using 5095 ethyl acetate in hexanes to give 18 mg (1695) of 21-chloro-epothilone B and 85 mg (6390 ) of 21-tosyloxy-epothilone B in the form of a transparent oil.

M5 (EBI"): 678.4 (MAN)". The reaction of epothilone A with p-toluenesulfonyl chloride similarly gives the formation of 21-tosyloxy-epothilone A. and The reaction of epothilone A-M-oxide with p-toluenesulfonyl chloride gives the formation of a mixture of 21-tosyloxy-epothilone A and "" 21-chloro-epothilone A, which are separated by chromatography. 21-Tosyloxy-epothilone A: 7H-NMR (300 MHz, SOCI3): 5 - 6.54 (broad c, 17-H), 7.15 (c, 19-H), 5.29 (c, 21-H ), 7.82 (d, 2,6-H), 7.34 -I (dm, 3,5-H), 2.44 (c, 7-H"). with 21-chloro-epothilone A: 7H-NMR (300 MHz, SOCI»z): 5 - 6.59 (broad c, 17-H), 7.16 (c, 19-H), 4.81 (c, 21-Na).

Me, NEM5 (OSI): SovNzamMOv8: (MAN calculation 528.2187, experiment 528.2154. with SHI Example 20 5-1 AUZAKCHE), AK 1057.11K7,12K7,16571I-3-(2-(2-(bromomethyl) )-4-thiazolyl|-1-methylethenyl-7,11-dihydroxy-8,;8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione 15-71 ZACHE),7AK1057,114K7,12K716571I-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 59 45mg (9UlImmol) of epothilone A was dissolved in vml of absolute THF in an atmosphere of Mo and cooled to minus

GF) 907C. Then 100 ml (40 bmmol) of tetramethylethylenediamine and 270 ml (40 bmmol) were added to the solution.

It is butyllithium in hexane. After ten minutes of stirring at minus 90°C, 21 µl of (40 bµmole) bromine was added to the solution. After 5 minutes of stirring, the reaction was quenched with 1 Oml of saturated ammonium chloride solution at minus 90°C. After that, the mixture was warmed to room temperature with continuous stirring and extracted with ethyl acetate. . The organic layer was dried over sodium sulfate and evaporated to dryness. Using preparative NRI/C, the residue was separated to give 2.bmg (5965) of 21-bromo-epothilone A and 2.1 mg (4.095) of 19-bromo-epothilone A. 7H-NMR (600 MGu, SOSIz): delta - 6.58 (s, 17-H), 7.17 (s, 19-H), 4.70 (s, 21-H"). k 65 NeE -M5 (OSI): SovNzaMO9Vg, (MAMNA) calculation 589.1916 "UVg, experiment 591.1903 "Vu,

Example 21

15-11 ZKE), 7 1057,11К7124К7,16577|-3-(2-(2-(cyanomethyl)-4-thiazolyl|-1-methylethenyl/|-7,11-dihydroxy-8,8,10,12 ,16-pentamethyl-4,17-duxabicyclo|14.1.0)heptadecane-5,9-dione and A from them - as sn o ono () With the help of Katad (Kaiada) reaction, epothilone B-M oxide is converted into epothilone HE. To a stirred 7/0 solution of 104 mg of epothilone P (199 micromoles of 5 equivalents) in 550 ml of СНоСН» at 0"С in an argon atmosphere was added

0.17 ml of n,n-diisopropylethylamine (0.993 mmol, 5 equivalents), and then additionally 0.045 g of p-toluenesulfonyl chloride (238 μmol, 1.2 equivalents). The mixture was stirred at 257C for 47 hours to ensure that the starting material (ZM) had the opportunity to fully react. Then the mixture was poured into 40 ml of a saturated aqueous solution of ManCO3. The aqueous layer was extracted using СНоСи» (333x5Oml). The combined 7/5 organic layers were dried over Na»5O; and concentrated in vacuo. The crude material was chromatographed using 5095 ethyl acetate in hexane to give 18 mg of C21 chloride (1695) and 85 mg of the desired tosylate (6390) as a clear oil. (ii) To the stirred solution, 84 mg of ZM from the previous experiment (124 μmol, 1 equivalent) in 3.50 ml

SNSI" in an atmosphere of argon at 25C added 40mg of KSM (6b20μmole, 5 equivalents) and ZZmg 18-crown-b (124μmole, 1 equivalent). The mixture was stirred at 257C for 15 hours, during which the starting material was fully reacted. The mixture was then loaded directly onto a silica gel column and chromatographed using ethyl acetate:hexanes (2:1) as eluent to afford 41 mg of the target nitrile (6190) as a colorless solid.

Example 22 ch 45-75, 15ACE)1I-16-(2-(2-(cyanomethyl)-4-thiazolyl|-1-methylethenyl|-4,8-dihydroxy-5,5,7,9,13-pentamethyl) -1-oxa-13 (72) i) -cyclohexadecene-2,6-dione

Mo With 4 people:

M y , he o (av) o ono Ge)

Anhydrous tetrahydrofuran (5.00 ml) was placed in an argon atmosphere in a carefully dried flask and cooled to -78°C. MUSI was added to the cooled tetrahydrofuran under a stream of argon; (30Omg, 0.75 bmmol, 2 equivalents), -- and then n-butyllithium (0.946 bml, 1.6 M solution in hexane, 1.51 mmol, 4 equivalents). The reaction flask was removed from the bath cooled to -787C, and its contents were stirred at room temperature for 15 minutes. The reaction flask was then placed in the bath at 0"C, and the mixture was stirred for an additional 5 minutes. In a separate flask, 21-cyanoepothilone B (72 mg, 0.135 mmol), previously dried by azeotropic distillation in a vacuum with toluene, was cooled with ice to 0 °C, and a bright green solution of tungsten reagent (2.12 ml) was added to it. The reaction was maintained at a temperature of 0°C for 20 minutes. Thin-layer chromatography - c (TS) showed the disappearance of the starting material. After that, the reaction was quenched with a saturated aqueous solution of MnSO (10 mL), and the mixture was partitioned between a saturated aqueous solution of MnSO (20 mL) and ethyl acetate (50 mL). The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed water (25ml) and brine (15ml) and then, before being concentrated in vacuo, dried over Ma»5O). 0. - M5 (EBI"): 516.3 (MAN).

Example 23 b» 15-11, ZKE), 7 1057,11K7,12K,16571I-7,11-dihydroxy-3-(2-(2-(1H-imidazol-1-ylmethyl)-4-thiazolyl|-1 -me o 50 tylethenyl)|-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione

T» Tk, there is o, - I | And he is 55: oh oh oh it

Imidazole (4.8mg, 71μmol, 8 equivalents) and K»CO3 (12.Zmg, 0.089Omole) were added to a stirred solution of bmg 21-tosyloxy-epothilone B (8.bmmol, 1 equivalent) in 1.Oml o dimethylformamide under an argon atmosphere , 10 equivalents). 60 The mixture was stirred at 257C for 5 hours. The solvent was removed in vacuo, and the reaction mixture was chromatographed on silica gel, using as an eluent 195 ЕІ3M, 396 СНЗОН in ХО», and as a result, 1.4 mg (2796) of 21-imidazolinepotylone B was obtained in the form of a clear oil.

M5 (EBI"): 574.4 (MAN).

Below, in Examples 24 and 25, an example of the synthesis of epothilone-20-carbaldehydes 13 is considered. Because Example 24

Example: 15-11, ZKE), 7 1057,11K7,12K7,16571I-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. (59-H, (39-0O in formula IB)

Epothilon E in the amount of 58 mg (114 micromoles) was dissolved in 1 ml of SiOCl. At intervals of 10 minutes, 295 mg (3.4 mmol) of manganese dioxide was added to the solution three times, and the mixture was stirred at room temperature. After 40 minutes, the manganese dioxide was filtered off and washed with methanol. The combined organic phases were evaporated to dryness, and the crude product was purified using preparative NRI C (Misieovzi! 100, solvent: ibutyl methyl ether/hexane with 395 methanol). As a result, 36 mg (6295) of epothilone A-20-carbaldehyde was obtained. 7H-NMR (400 MGu, SOSIZz): delta - 6.67 (s, 17-H), 7.53 (s, 19-H), 9.98 (d, 21-H);

НЕМ5 (OS): СовНз7 MO: MAN calculation 508.2369, experiment 508, 2367.

Example 25 15-11, ZKE), 7 1057,11К7,12К7,16571|-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 19 Ok I o 5 I o E

Hek s; WRITE

Epothilone E (180 mg, 344 micromoles, 1 equivalent) was dissolved in SNCl in an argon atmosphere. Manganese dioxide (9O0Omg, 10.Zmmol, 30 equivalents) was added to the solution, and the reaction mixture was stirred at 257C for 2 hours. Then an additional amount of manganese dioxide (40 Ωg, 4.bOmole, 13.4 equivalents) was introduced and the reaction mixture was stirred for another 2 hours. The mixture was filtered through celite, washed with CHCl 2 , and then concentrated in vacuo. The crude material was subjected to silica gel chromatography eluting with 5095 ethyl acetate in 29% hexane. As a result, 92 mg (51905) of 21-formyl-epothilone B was obtained as a colorless solid. Gee)

E8I-M5: 522.3 (MAN)".

Below, in Example 26, the synthesis of 21-alkylidenepothilones 15 is considered. Example 78 « report: 15-1A,ZKE), 7 1057,11K7,12K7,16571I-3-(2-(2-ethenyl-4-thiazolyl)-1 -methylethenyl|-7,11-dihydroxy-8,8,10,12- (ав) tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione (В-Н, 59-08-727 -H, 057-077 in formula Ia) so

17 mg of methyl phosphoric bromide was treated with 5 mg of methyl instandylide (ipziapa-uiia) (Rika) and suspended in 500 μl of absolute THF. The mixture was placed in an ultrasonic bath for 2-3 minutes and then stirred at room temperature. When the reaction solution acquired a bright yellow color, the suspension was added dropwise to a solution of 15.2 mg (ZOμmole) of A-aldehyde in 1000 μl of absolute THF. In 1 hour, the mixture was diluted with water and extracted three times with dichloromethane. The organic phase was evaporated and dried under high vacuum. The crude mixture was separated using preparative NRI C (Misieosi! 100, solvent: I-butyl methyl ethertexane 1:214-195 methanol). The result was isolated 1.7 mg (1195) of 20-vinyl-epothilone A. "" NA-NMR (400 MHz, SOSIsh): 5 - 6.59 (broad s, 17-H), 7.04 (s, 19-H), 6 ... 506,2589. ," Below, in Example 27, the synthesis of 21-imino-epothilones 22 is considered.

Example 27

Example: - I 15-11, ZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-3-(2-(2-(methoxyimino)-4-thiazolyl|-1-methylethenyl|-8 , with 8,10,12-tetramethyl-4,17-dioxabicyclo(/14.1.0)heptadecane-5,9-dione, (B-O9-H, c'/-M, 058-079, 710-Me in formula

Pa) (o) Pyridine in the amount of 1Ocl (124µmol) and 1133µl (54µmol) of a solution of O-methylhydroxyammonium chloride (4Omg/ml) at 50 was added to a solution of 25mg (49µmol) of epothilone A-21-aldehyde in 200µl of methanol. After stirring the reaction mass for 1 hour at room temperature, the solvent was removed, and the residue was transferred to

I" ethyl acetate. The organic phase was extracted once with water and dried with (Ma»5O). The crude product was purified using preparative NRI C (Misieovzi! 100, solvent: ibutyl methyl ether: hexane 1:2 with 190 methanol). As a result, Umg (3690) (21E) and 7 mg (27905) (212 )-21-(M-methoxyimino)-epothilone A were obtained. (21E)-isomer

He) 7H-NMR (Z00MGu, SOSI»z): 5 - 6.61 (broad c, 17-H), 7.12 (c, 19-H), 8.22 (c, 21-H), 4 ,01 (c, 1-Hv), (212)-isomer o 7H-NMR (300MGu, SOCI3): 5 - 6.65 (broad c, 17-H), 7.36 (broad c, 19-H) , 7.86 (D.21-H), 4.15 (c1--H3). in НЕМ5 (ОСИ): Со7НаоМ2О75: MAN calculation 537.2634, experiment 537.2637.

Example 28 154-1AM,ZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-Kphenylmethyl) imino|methyl)-4-thiazolyl|ethenyl)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione

Epothilon A-21-aldehyde (19 mg, Zvmkmoley) was dissolved in 1 ml of dry SNCI. Crushed molecular sieves 4 A and benzylamine (4.5 mg, 41 μmol) were added to the solution. The reaction mixture was stirred at room temperature for 45 minutes, filtered through celite and concentrated. The concentrate was purified on silica gel

(CHNSiO/methanol 95:5), resulting in 21-benzylimino-epothilone A (1Omg, 45965). 7H-NMR (Z00MGu, SOSI»5): delta - 6.62 (broad c, 17-H), 7.21 (c, 19-H), 8.46 (c, 21-H), 4.87 (d, 1-No).

Example 29

Example: 15-11, ZKE), 7 1057,11К7,12К7,165771|-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 (c5-Me, b9-o in the formula Che) and 20-(21,22-epoxyethyl)-epothilone A (87 -Н, 82, 65-СН.-О in formula IB)

Epothilone A-21-aldehyde (Example 28) in the amount of 10 mg (200 μmole) was dissolved in 200 μl of CH»oSi» and an excess of diazomethane was added to the solution. The mixture was then stirred at room temperature. After 15 minutes, the reaction mass was subjected to evaporation, and then separated using preparative TIS (silica gel 60, solvent:

СНоSiO:methanol 95:5). As a result, 4.5 mg (4495) of 21-acetyl-epothilone A and 1.mg (1995) of 20-epoxytyl-epothilone A were obtained. 15-11 ZKE), 7 1057,11К7,124К7,16577|-3-(2- (2-acetyl-4-thiazolyl)-1-ethylethenyl)|-7,11-dihydroxy-8,8,10, 12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione 7Н -NMR (Z00MGu, SOSIz): 5 - 6.62 (broad c, 17-H), 7.45 (c, 19-H), 2.71 (c, 1-Na). 154-1AZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-oxiranyl-4-thiazolyl)ethenyl |-4,17-dioxabicyclo|14.1.O)heptadecane-5,9-dione: 7"H-NMR (300 MHz, SOCI8): 5 - 6.58 (broad s, 17-H), 7.09 (s , 19-H), 4.22 (t, 21-H), 3.00 (m, 1-Na), 3.23 (dd, 1-HB).

Example 30 15-71 WHY),7K1057,11K7,12K716571I-7,11-dihydroxy-3-(2-(2-(2-iodethenyl)-4-thiazolyl|-1-methylethenyl)-8,8,10, 12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione c

Iodomethyltriphenylphosphonium iodide in the amount of 26mg (49μmoles) was suspended in one ml of absolute THF, 49μl (49μmoles) of a solution of sodium hexamethyldisilazane in THF was added to the suspension. After stirring for one minute at room temperature, the mixture was cooled to minus 78°C, and 14 μl (in 10 μmole) of NMRA was added to it, and then - a solution of 20 mg (40 μmole) of epothilone A-21-aldehyde in 0.2 ml of absolute THF. at the same temperature, the reaction mixture was stirred for 30 minutes and then the reaction was quenched with 1Tml of saturated ammonium chloride solution. After heating to room temperature, the reaction mixture (a) was extracted with ethyl acetate, the organic layer was separated, dried with sodium sulfate and evaporated to dryness. were separated using preparative NRIS, resulting in 8.4 mg (34965) (207)-iodovinyl and 2 mg (895) (20OE)-iodovinyl analog. --

E-isomer m 7H-NMR (600 MGu, SOSI»z): delta - 6.56 (s, 17-H), 7.07 (s, 19-H), 7.53 (d, 21-H), 7.39 (d, 1"-H). 2-isomer 7H-NMR (300MGu, SOSI33): delta - 6.63 (broad c, 17-H), 7.21 (c, 19-H), 7 .82 (dd, 21-H), 7.03 (d, 1"-No). "

Ne-M5 (OSI): Co7NzvOv851I, (MAN calculation 632.1543, experiment 632.1593.

Example 31 - p 15-11, ZKE), 7 1057,11К7,124К7,16577|-3-(2-(2-ethynyl-4-thiazolyl)-1-methylethenyl)|-7,11-dihydroxy-8, 8,10 and ,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione is» Diisopropylamine in the amount of 18.5 μl (131 μmol), dissolved in 04 ml of absolute THF, processed at minus 107C 7Omcl ( 105 μmole) of n-butyllithium in hexane. After one hour, 17 mg (27 µmole) of (207)-iodvinyl derivative in 0.5 ml of absolute THF was added to the solution at a temperature of 0"C. After one hour of stirring at - and 0"C, the reaction was quenched with 2 ml of saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate, the organic phase was evaporated to dryness and separated using preparative NRI C. The product yield was 2.4 mg (3696). (2) TN-NMR (400MHz, SOSIz): delta - 6.60 (broad c, 17-H), 7.15 (c, 19-H), 3.46 (c, 21-H). ("in") 20 Nai-M5 (OSI): So7NaiMO 5, IMeMNa) calculation 521.2685, experiment 521.2696.

T» Below, in Examples 32 to 36, an example of the synthesis of 21-alkylamino-epothilones 10 and 11 is considered.

Example 32 15-11, ZKE), 7 1057,11K7,124K7,16577|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-Kmethyl) mino)methyl-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione (Ф) НМ in рако - А, ; he o chi bo o ono

A 2.0 M solution of methylamine (0.1 bml, 0.32 bmmol, 10 equivalents) was added to a stirred solution of epothilone B-21-aldehyde (17 mg, 0.03 mmol) in 2.0 ml of SNHSM in an argon atmosphere at 0"C. After 15 min. Bmg MavnasmM (0.098 mmol, 3 equivalents) was added to the solution and stirred at 0"C for 30 minutes. Then acetic acid was added dropwise until the pH of the solution reached approximately 7. After that, the solution was stirred for an additional 2 hours, and 20 ml of 2895 MNAOH aqueous solution (water) was added to it. The mixture was stirred for 5 minutes, then extracted with 75 bml of ethyl acetate. The organic layer was dried over Na2O and concentrated in vacuo. The crude material was subjected to chromatography on silica gel with elution of 195 EBM, 2956 Meon in SNFOSY5. As a result, 8 mg (4795) of 21-H-methylamino-epothilone B was obtained in the form of an opaque oil.

M5 (EBI"): 537.4 (MAN)"

Example 33 15-11, ZKE), 7 1057,11K7,124K7,16577|-3-(2-I2-((2-(dimethylamino)ethyl|amino|methyl|)-4-thiazolyl|-1-methyl ethenyl )-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione zd u o,

NM Z i o h o ono y

M,M-dimethylethylenediamine (31 μl, 0.288 mmol, 10 equivalents) was added to a stirred solution of epothilone B-21-aldehyde (15 mg, 0.029 mmol) in 2.0 ml of CHZSM in an argon atmosphere at 257"C. After 10 minutes, 5 mg was added

MmavnzoM (0.08 bmmol, 3 equivalents), and the mixture was stirred at 257°C for 30 minutes. Then, AsOHN was added dropwise until the pH reached about 7. After that, the mixture was stirred for another 2 hours, and 20 ml of 2895 was added to it. of an aqueous solution of MNAOH (water). The mixture was stirred for 5 minutes and then extracted with 75 ml of ethyl acetate. The organic layer was dried over NaCl5O and concentrated in vacuo. The crude material was subjected to chromatography on silica gel with an elution of 195 ЕІ33M, 595 MeonN in СНІІІ»z. B as a result, 5.8 mg (34965) of 21-2-M,M-dimethylaminoethyl)amino-epothilone B was obtained in the form of a transparent oil.

M5 (E8I"): 594.5 (MAN) 7. p

Example 34 o 15-11, ZKE), 7 1057,11K7124K7,16577|-3-(2-(2-Kdimetalamino)methyl|-4-thiazolyl|-1-methylethenyl)-7,11-dihydroxy-8, 8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione -MK in p" : "I vne o

Gee! and o ono Ge)

An aqueous solution of formaldehyde (00004 ml of a 3790 aqueous solution, 0.1817 mmol, 5 equivalents) and 7 mg of Mmavn zscmM 3o (0.1089 mmol, Z equivalents). in.

The mixture was stirred for 20 minutes, and acetic acid (1 drop) was added to it, after which it was stirred for another 40 minutes. The crude reaction mixture was loaded directly onto a column with silica gel and eluted with 195 EBM, 196 SNHZON in SNH3, obtaining 2.5 mg (1295) of 21-M,M-dimethylamino-epothilone B.

M5(E5I7):551, (МН). WITH

Example 35 with 15-71 ZACHE),7K1057,11K7,12K716571I-3-(2-(2-((bis-(2-methoxyethyl)amino|methyl|-4-thiazolyl|-1-methyleth) : z» nil| -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, where 8 compounds

AD on - o M. o | oh it

Bis-(2-methoxyethyl)amine (1µl, 0.13 mmol, 10 equivalents) was added to a stirred solution of aldehyde (b.8 mg, 0.01 mmol) in 2.0 ml of CH 3SM in an argon atmosphere at 0 (av). After 15 minutes, 2.5 mg was added

T» Mmavzem (0.039 mmol, 3 equivalents), and the mixture was stirred at 07C for 30 minutes. Then acetic acid was added dropwise to it until the pH value of the solution reached approximately 7. After that, the mixture was stirred for an additional 2 hours and 10 ml of 2895th aqueous solution of MNAOH (water) was added. Then the mixture was stirred for 5 minutes and extracted with 75 ml of ethyl acetate. The organic layer was dried over NaCl2O and concentrated in vacuo.

The crude material was chromatographed on silica gel eluting with 195 ЕЖ3M, 1906 СНЗОН in СНЖЖ3, obtaining (Ф) 5.bmg (67965) of 21-(bis-2-methoxyethyl)amino-epothilone B in the form of an oil. ka M5 (E8I"): 639.5 (MAN) 7.

Example 36 in 15-11, ZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2- K4-methyl (1-piperazinyl)methyl)-4-thiazolyl|ethenyl)|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione b5 x

М со 5 з х-у З и ОН (c) su o ono 70 To a stirred solution of aldehyde (11 mg, 0.0211 mmol) in 1.00 ml of CH 33CH in an argon atmosphere, 1-methylpiperazine (21 mg, 0.2109 mmol, 10 equivalents) was added ) and Mavn zsM (4 mg, 0.063 Zmmol, C equivalents). The mixture was stirred for 20 minutes. Then acetic acid was added dropwise to it until the pH value of the solution reached approximately 7, and the mixture was stirred for another 2 hours. After that, 1 Oml of the 2890th aqueous solution of MNAOH (water) was added to it, and the mixture was extracted with СНоСи» (2x75 ml). The organic layer was dried over (5 Ma»2ZO) and concentrated in vacuo. The crude material was chromatographed on silica gel eluting with 1956 EBM, 5906 MeonN in CHCl3 to give 10.7 mg of (8495) 21-(M-methylpiperazine)amino-elothilone B as a white foamy oil.

M5 (EBI"): 606.4 (MAN). 60 Example 37 20 Example: 5-1 AUZACHE), AK 1057.11K7.12K7.16571)-4-(2-(7,11-dihydroxy-8,8 ,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyl|14.1.0)heptadecan-3-yl)-1-propenyl|-2-thiazolecarboxylic acid (055-075, 75-Н, ( 39-O in formula IB).

Methyl ether 5-1 AUZACHE), AK 1057,11К7,12К7,16571)-4-(2-(7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17- dioxabit He!25 iklo|14.1.0)heptadecan-3-yl)-1-propenyl|-2-thiazolecarboxylic acid (595-077, 72-Me, 59-00 in formula IB). at

Epothilone A-21-aldehyde in the amount of 8.00mg (1bmmol) was dissolved in 300ml of a mixture of THF/water (9:1) and 24.0mg (194mmol) of silver (I) oxide was added. The reaction mixture was stirred for 12 hours at room temperature.

The solvent was then removed, and the residue was taken up in ethyl acetate. Evaporation of the solvent gave an unstable carboxylic acid, which was characterized by NRI C/E5BI-M5; delay time - 13.8 minutes; "/,-522 - 30 (М-Н) (KR-18 silica gel, SNZSM (10MM MNASAS buffer gradient from 10:90 to 45:55). According to the best "is version of the invention, the organic phase was not evaporated, but washed twice 0.190 hydrochloric acid and once with water, and then treated with an excess of diazomethane. The mixture was then stirred for 10 minutes at room temperature. After removal of the solvent, the crude product was purified using preparative NRI C "-(Misieovii 100, solvent: ibutyl methyl ether/hexane 1 :2 with 195 methanol). As a result, 2.5 mg (3090) of epothilone A-21-carboxylic acid methyl ester 35 was obtained. - 7H-NMR (400 Mg, SOCI3): 5 - 6.73 (broad s, 17-H) , 7.42 (c, 19-H), 4.00 (c, 1"-H5).

NeM5 (OSI): C37NzoMOv28: |MANA calculation 537.2396, experiment 537.2408.

Example 38 « 20 Biological characteristics of epothilone derivatives -v

Cytostatic activity. Derivatives of epothilone inhibit the growth of mammalian cell cultures, as well as cell lines resistant to other cyclostatic agents.

Growth inhibition of transformed mouse and human carcinoma cells, as well as leukemia cell lines.

Growth inhibition of the following cell lines is measured on microtiter plates: 1929 (OM ACC 2), -1 mouse connective tissue fibroblasts; KV-3.1 (OM ACC 158), human neck carcinoma; KV-MI (О5М ACC 149), human cervical carcinoma resistant to many drugs; PO-3 (ATSS SK 1435), human prostate adenocarcinoma; ZK-OM-3 (ATSS NTV-77), human ovarian adenocarcinoma; A-549 (05MM ACC 107), lung carcinoma

Fu man; K-562 (АТСС СС -243), chronic myelogenous leukemia of man; 0О-937 (OM ACC 5), human histotic lymphoma. Cell lines were obtained from YUOZM (German Collection of Microorganisms and Cell Culture Lines), (av) Vgaspzspugeid, Segtapu, or ATSS (American Collection of Type Cultures), KoskmiPe, MO, O.5.A.

Aliquots of suspended cells (50,000/ml) were exposed to serially diluted inhibitor. As a growth parameter, MTT recovery was measured by 3-(4,5-dimethylthiazol-2-yl|-2,5-diphenyltetrazolium bromide) or, in the case of leukemia cells, MUZT-1 (Voepgipdeg MappNeit, szegtapu) after an incubation period of 5 days. The obtained values were compared with control cells to which only the solvent methanol was added

Both values were taken as 10095. IC500 (concentration causing 5095 growth inhibition) was derived from (F) inhibition curves (percentage of MTT recovery depending on inhibitor concentration). with 50 ihleryulv 00001 o || 80 000101111100000000000 sq vpoAooarsaldotymrya 7010 vpoAooarbaldedtdvyayun 12001011 iavidoveyrya 0000511 dvo 0oamnyuvyuVI 10184053 30955 20-vinyl-epo A (15) Z Z Z OA 1 13.5) (0-9)

btzmdovyuvt 3331 05 (05, 05:1...04111

Ftamnyuvuviv! 11110604. 15001181

Claims (30)

The formula of the invention 1. A compound with the general formula Y Y P 11 | сн С Шик 14 с к-т 15 7 ры 1 З 5 - І ИН о он о 1 where Р-О is a C, C double bond or epoxide; с С represents Ге) о 1 Ви и M « or (ав) о , со - - U. with, I. . - K is selected from the group consisting of H, alkyl and substituted alkyl; IN! selected from the group consisting of Ф-с3.. 05 in h x - s se seschb o 0 dno 03 V i: - Ge»! -6 stI1 (ав) и» B2 represents an ion, - o shcha o o ko 1 sh. and 2, and and c" is selected from the group consisting of H, halogen, CM, alkyl and substituted alkyl; in C2 is selected from the group consisting of H, alkyl and substituted alkyl; He is selected from the group consisting of iso, 5 and M27; C is selected from the group consisting of H, alkyl, substituted alkyl, 07 2, M2273, 72-00, 7.550" and optionally substituted glycosyl; and c5 is selected from the group consisting of halogen, Mz . C" represents C7" or M; o selected from the group consisting of H, halogen, alkyl, substituted alkyl, 0719, 87719. We!02 11; CO is selected from the group consisting of О, 5, -МН-МН- and -М-М-, СО is M or С7 12; WITH!! selected from the group consisting of H M, substituted NoM, alkyl, substituted alkyl, aryl, and substituted aryl; 71,75 797211 independently selected from the group such as H, alkyl, substituted alkyl, acyl and substituted acyl; 70 72 selected from the group such as H, alkyl, substituted alkyl, aryl, substituted aryl and heterocycle; 73.75, 78 1 219 independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl and substituted aryl; 77 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl and heterocycle; 7" selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, 75 078, 58781M7879: and 72 selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl , provided that when B is - c 2. i 7 c c, 82, 63 | 07 cannot simultaneously have the following values: c c!i6c2-H, oZ0i07- H or 72C - O, where 72 is an alkyl group. at 2. The compound according to claim 1, which has the general formula Ia I h 5 Z c-- az | P - o - (Se) se M DE M si o i- Ta (8 OH o « e p smoly yad . t P-O is a C, C double bond or an epoxide; c K is an H atom or a methyl group; :z» c! represents an H atom, an alkyl group, a substituted alkyl group or a halogen atom; C2 represents an H atom, an alkyl group or a substituted alkyl group; o represents an atom 0, an atom 5 or a group M7 ", where 7 ! is an H atom, an alkyl group, a substituted alkyl -I group, an acyl group, or a substituted acyl group, and C" is an H atom, an alkyl group, or a substituted alkyl group, Group 072, Group M7273, Group 770-0, Group 2505 or an optionally substituted glycosyl group, b» where 72 is an H atom, an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl o 50 group or a heterocyclic group, 73 is an H atom, an alkyl group, a substituted alkyl group, an acyl group or substituted acyl T" group, and 77 represents an alkyl group, a substituted alkyl group, an aryl group, a substituted aryl group, or a heterocyclic in the group, 59, provided that C, 02, 03 | 07 cannot simultaneously have the following values: З! and 52 is the H atom, OZ atomO is - (F; H atom or 72C-0, where 72 is an alkyl group. ka 3. The compound according to claim 2, in which OZ is atom 0. 4. Compound according to claim 2, in which OZ is atom 5. vo 5. The compound according to claim 2, in which OZ is M7 7. 6. The compound according to claim 1, which has the general formula IB b5 77 lk ton yu o o On o "t where 15 P-O is a C, C double bond or an epoxide; K is an H atom or a methyl group; c! is an H atom, an alkyl group, a substituted alkyl group or a halogen atom, c2 represents an H atom, an alkyl group, or a substituted alkyl group, and 20 C represents a halogen atom, a M3 group, an MC5 group, a 3H group, a CM group, a MC group, or a heterocyclic group. 7. The compound according to claim 6, in which 9 is the M group. 8. The compound according to claim 6, in which C? is a group of MC5. 9, Compound according to claim 6, in which C? is a 5H group. 10, Compound according to claim 6, in which C? is a SM group. p. 25 11. The compound according to claim 6, in which C? is a group of MS. at 12. The compound according to claim 6, in which C? is a heterocyclic group. 13. The compound according to claim 1, which has the general formula Ia KE « 30 | o o 5 rn s NI o what t 35: m. se Z ; Ца « ю (о; он (о; Z s where Р-О is C, C is a double bond or an epoxide; "" K is an H atom or a methyl group; is an H atom, an alkyl group, a substituted alkyl group or CEz, 0277, 879 or group M2275, where 75 is an H atom, an alkyl group, a substituted alkyl group, an acyl group or a substituted acyl group, and - 75 is an H atom, an alkyl group or a substituted alkyl group; c" is a C7" group or an M atom, where F7" is H or a halogen atom, an alkyl group, a substituted alkyl group, an aryl group or a substituted HeSho aryl group or 078, 578 or a M7979 group, where І»78 is an H atom or an alkyl a substituted alkyl group, an acyl group, or a substituted acyl group, and 73 is an H atom, an alkyl group, or a substituted alkyl group, and o8 is an H atom or a halogen atom, an alkyl group, a substituted alkyl group, or 07 79, 85710, or an o group M279211, where 719 is an H atom, an alkyl group, a substituted alkyl group, an acyl group, substituted by an acyl o group, an aryl group or a substituted aryl group, and 7! is an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group. 14. The compound according to claim 1, which has the general formula Pr: b5 Ккс сроны Уур ОН ю о ,Цё (6) Он о where 15 Р-О is a C, C double bond or epoxide; K represents an H atom or a methyl group, o represents an H atom, an alkyl group, a substituted alkyl group or CEz, 077, 872 or a M7279 group, where 75 represents an H atom, an alkyl group, a substituted alkyl group, an acyl group, or a substituted acyl group and 20 75 represents an H atom, an alkyl group or a substituted alkyl group; and C is an O atom or a 5 atom or a -MAM- group. 15. The compound according to claim 14, in which OZ is atom 0. 16. The compound according to claim 1, which has the general formula PI E sh 25 | o -- - b7- o cho sen h 30 y : o (o) (Se) t «- 35 s On o ! where P-O is C, C is a double bond or epoxide, K is an H atom or a methyl group; CO represents an M atom or a C27 2 group, where « 772 is an H atom or a halogen atom, an alkyl group, a substituted alkyl group, an aryl group, or a substituted aryl group. . 17. The compound according to claim 16, in which 579 is an M atom. 18. The compound according to claim 16, in which 519 is the group C7 2, 19. The compound, according to claim 1, which has the general formula ИМ Е з - р ре, зттю о и р Шче Он І» ВК Я то щ TE (о; Он о ! Ф) where Р-О represents С , C double bond or epoxide; K represents an H atom or a methyl group and 6o С! represents a group H»M, a substituted group NoM, an alkyl group, a substituted alkyl group, an aryl group or a substituted aryl group. 20. A compound selected from the group consisting of: 15-11, ZKE), 7 1057,11К7,12К7,165771|-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; bo 154-1A,ZKE),7К1057,11К7, 12K7,16571|-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; 15-71 ZACHE),7K1057,11K7,12K716571I-3-(2-(2-I(C0I1,1-dimethylethoxy)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; I45-I4k757,8K9K15ATE)I-16-(2-I2-IS(1,1-dimethylethoxy)carbonylI|amino|methyl-4-thiazolyl|-1-methyletheneil|-4,8-dihydroxy-5,5, 7,9,13-pentamethyl-1-oxa-13(2)-cyclohexadecene-2,b-dione; I45-I4k7,757,8K9A15KE)I-16-(2-(2-(aminomethyl)-4-thiazolyl) |-1-methylethenyl|)|-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(7)-cyclohexadecene-2,b-dione; 15-11, ZKE) . 4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, 15-11, ZKE), 7 1057,11K7,12K7,16571I-7,11-dihydroxy-8,8,10,12-tetramethyl- 3-11-methyl-2-(2-Naphthoyloxy)methyl|-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, 15-11 ZKE), 7 1057, 11K7,127,16571I-7,11-dihydroxy-3-(2-(2-(I(2-methoxyethoxy)acetyloxy|methyl|)|-1-m ethyl-4-thiazolyl|ethenyl)-8,8, 10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, 15-11, ZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-8,8 ,10,12-tetramethyl-3-|/1-methyl-2-(2-(M-propion ylamino )methyl)-4-thiazolyl|ethenyl)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, 15-11, ZKE), 7 1057,11К7,124К7,16571|-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) of heptadecane-5,9-dione, M-oxide, 15-11, ZKE), 7 1057,11K7124K7,165771|-7,11-dihydroxy-3-(2-(2-(methoxymethyl)-4-thiazolyl |-1-methylethenyl 1-8,8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, 15-11, ZKE), 7 1057,11К7,124К7,1657 :71|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-|1-methyl-2-(2-(phenoxy methyl)-4-thiazolyl|ethenyl|-4,17- dioxabicyclo|14.1.0)heptadecan-5,9-dione, 15-11 ZKE), 7 1057.11К7,124К7,16577)|-3-(2-(2-Ketylthio)methyl|)-4-thiazolyl|- 1-methylethenyl|-7,11-dihydro xy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, sch 15-11, ZKE), 7 1057,11K7,12K7,16571I-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, (8) 15-11AZKE), 7 1 057,11К7124К7,165771|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-(1-methyl-2-(2-(2,3,4,6-tetraacetyl-alpha-glucosyloxy) )methyl-4-thiazolyl|ethenyl)|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione, 154-11AZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy- 8,8,10,12-tetramethyl-3-(1-methyl-2-(2-(2,9 2, "g zo b-tetraacetyl-beta-glucosyloxy)methyl|)-4-thiazolyl|ethenyl/) |-4,17-dioxabicyclo|14.1.0)heptadecan-5,9-dione, 15-11, ZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12 -tetramethyl-3-/1-methyl-2-(2-(6'-acetyl o -alpha-glucosyloxy)methyl-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9 -dione; Ge 15-11, ZKE), 7 1057,11К7124К7,165771|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-|1-methyl-2-(2-Cap-toluene olsulfonyloxy )methyl)-4-thiazolyl|ethenyl()-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; -- 5-1 AUZAKCHE), AK 1057,11K7,12K7,16571I-3-(2-(2-(bromomethyl)-4-thiazolyl|-1-methylethenyl-7,11-dihydroxy-8 y-,;8 ,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-71 ZACHE),7AK1057,114K7,12K716571I-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; 15-11 ZKE), 7 1057,11К7124К7,16577|-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; with И45-И4к7,757,8К9А15КЕ)И-16-(2-(2-(cyanomethyl)-4- thiazolyl (1-methylethenyl)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(7)-cyclohexadecene-2,b-dione; and? 15-11 , ZKE), 7 1057,11K7,12K,16571I-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; 15-11, ZKE), 7 1057,11К7,124К7,16577|-3-(2-(2-formyl-4-thiazolyl)-1-methylethenyl|-7,11-dihydroxy-8,8,10-I ,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5.9-dione; 15-11, ZKE), 7 1057,11К7,124К7,16577|-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; He» 15-1A,ZKE), 7 1057,11К7,124К7,16571|-3-(2-(2-ethenyl-4-thiazolyl)-1-methylethenyl|-7,11-dihydroxy-8,8,10 ,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; o 15-11 ZKE), 7 1057,11K7,124K7,165771|-7,11-dihydroxy-3-(2-(2-(methoxyimino)-4-thiazolyl|-1-methylethenyl)» 1-8,8 . 8,10,12-tetramethyl-3-/1-methyl-2-(2-Icphenylmethyl)imino|methyl)-4-thiazolyl|ethenyl1-4,17-dioxabicyclo|14.1.0)heptadecane-5,9- Dion; 15-11, ZKE), 7 1057,11К7,124К7,16577|-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; (F) 154-1AZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-oxiranyl-4 ka) -thiazolyl)ethenyl)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-71 ZACHE),7K1057,11K7,12K716571I-7,11-dihydroxy-3-(2-(2-(2-iodethenyl)-4-thiazolyl|-1-methylethenyl) in -8,8,10,12 -tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11К7,124К7,16577|-3-(2-(2-ethynyl-4-thiazolyl)-1-methylethenyl)|-7,11-dihydroxy-8,8,10 , 12-tetramethyl-4,17-dioxabicyclo|14.1.0Y heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11K7,124K7,16577|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-Kmethylamino) methyl-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 65 15-11, ZKE), 7 1057,11K7,124K7,16577|-3-(2-I2-((2-(dimethylamino)ethyl|amino|methyl|)-4-thiazolyl|-1-methyl ethenyl) -7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11K7124K7,16577|-3-(2-(2-Kdimetalamino)methyl|-4-thiazolyl|-1-methylethenyl)-7,11-dihydroxy-8,8,10 ,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-71 ZACHE),7K1057,11K7,12K716571I-3-(2-(2-((bis-(2-methoxyethyl)amino|methyl|-4-thiazolyl|-1-methylethene nil|-7,11-dihydroxy -8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11К7,124К7,16577|-7, 11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-K4-methyl-1-piperazinyl)methyl|)-4-thiazolyl|ethenyl)-4, 17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11К7,124К7,16577)-4-(2-(7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-diox) abicyclo|14.1.0)heptadecan-3-yl)-1-propenyl)|-2-thiazolecarboxylic acid; 70 methyl ether 5-1 AUZACHE), AK 1057,11К7,12К7,16571)-4-(2-(7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17 -dioxabic acid|14.1.0)heptadecan-3-yl)-1-propenyl)|-2-thiazolecarboxylic acid and their pharmaceutically acceptable salts, solvates and hydrates. 21. The method of obtaining a compound according to formula 9, which corresponds to the general formula Ia, where C and 52 are H, C atoms 75. Z is a group M7, 17 and 7 are atoms H, g E P- 595 her "- E-H, CH, z (8) - ek M shti on Vsch GOYU o o o ono Z ch zo which consists of because the compound having the formula 4 or 5, E | "in) 9. F o r - m. M to on o "A shi s (9) ON o y;" E « -I shi | p - M dO shen F E o 50 Ho c» o On o Z is first activated, and then subjected to nucleophilic substitution to obtain a compound having the formula 7, F) ime) 60 b5 Ko E R - 259 - her a58- E-N, SN, y o hi | in M tya m On 70: (o (o; ОН o 719 tX-Ma,MeS-8, 8H, SM, MS), after which the obtained compound having the formula 7 is subjected to reduction with the formation of the compound having the formula 9, where P-O is CH-C or CH...C, where ... C-C is a single bond with an epoxy O-bridge, K is a hydrogen atom or a methyl group and Haemu, 22. The method according to claim 21, which differs in that the activation is carried out using ToznNai| (Na!I-Si, Vg or I) and pyridine, and nucleophilic substitution with the help of Mam z, or (ii) activation and nucleophilic substitution is carried out with the help of diazabicycloundecene (OB) and diphenylphosphoryl azide (ORPA). 23. The method according to claim 21, which is characterized by the fact that the reduction is carried out (i) by hydrogenation in the presence of a Lindlar catalyst or (it) with the help of phosphine. at 24. A pharmaceutical composition that contains as an active ingredient at least one compound selected from the group consisting of a compound of the general formula according to claim 1, a compound of the formula Ia according to claim 2, a compound of the formula II according to claim 6, a compound of the formula Ia according to claim 13, compounds formula II6 according to claim 14, compounds of formula PI according to claim 16, compounds of formula IM according to claim 19 and their pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, excipients C 3o or diluents. (av) 25. Pharmaceutical composition according to claim 24, which contains as an active ingredient at least one compound that is an antitumor or cytotoxic agent. and 26. Pharmaceutical composition according to claim 25, which contains an antitumor or cytotoxic agent selected from the group consisting of 15-11, ZKE), 7 1057,11К7,12К7,165771|-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 ; 154-1A,ZKE),7К1057,11К7,12К7,16571|-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; « du 15-71 ZACHE),7K1057,11K7,12K716571I-3-(2-(2-I(C0I1,1-dimethylethoxy)carbonyl|amino|methyl)-4-thiazolyl|- with 1-methylethenyl)-7, 11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; c I45-I4k7757,8K9K15AE)1I-16-(2-2-Х1,1-dimethylethoxy)carbonyl|amino|methyl-4-thiazolyl|-1-methylethene; z» yl|-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13(2)-cyclohexadecene-2,b-dione; I45-I4k7757,8K9K15KE)I-16-(2-(2-(aminomethyl)-4-thiazolyl|-1-methylethenyl|)|-4,8-dihydroxy-5,5,7,9,13-pentamethyl -1-oxa-13(2)-cyclohexadecene-2,b-dione; - 75 15-11, ZKE), 7 1057,11К7,124К7,165771|-7,11-dihydroxy-8,8,10,12 -tetramethyl-3-|1-methyl-2-(2-Cpentanoyloxy)methyl)-4-thiazolyl|ethenyl)|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; - 15-1AZKE), 7 1057,11K7,12K7,16571I-7,11-dihydroxy-8,8,10,12-tetramethyl-3-11-methyl-2-(2-Knaphtoylobsi)methyl)-4 -thiazolyl|ethenyl)|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11 ZKE), 7 1057,11K7,127,16571I-7,11-dihydroxy-3-(2-(2-(I(2-methoxyethoxy)acetyloxy|methyl|)|-1-m (ав) 50 ethyl-4-thiazolyl|ethenyl)-8,8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; HT» 15-11, ZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-|/1-methyl-2-(2-(М -propionylamino)methyl)-4-thiazolyl|ethenyl)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11 ZKE), 7 1057,11K7,12K7,16571I-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, M-oxide; 15-11, ZKE), 7 1057,11К7124К7,165771|-7,11-dihydroxy-3-(2-(2-(methoxymethyl)-4-thiazolyl|-1-methylethenyl HF) 1-8,8,10 ,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 7 15-11, ZKE), 7 1057,11К7,124К7,1657:71|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-|1-methyl-2-(2- (phenoxy methyl)-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11 ZKE), 7 1057,11К7,124К7,16577)|-3-(2-(2-Ketylthio)methyl|)-4-thiazolyl|-1-methylethenyl|-7,11-dihydro boxi-8 ,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11K7,12K7,16571I-3-(2-(2-(ethoxymethyl)-4-thiazolyl|-1-methylethenyl/|-7,11-dihydroxy-8,8,10 ,12-tetramethyl-4,17-dioxabicyclo|14.1.O)heptadecan-5, 9-dione; 15-11AZKE), 7 1057,11К7124К7,165771|-7,11-dihydroxy-8,8,10,12- Tetramethyl-3-(1-methyl-2-(2-(2,3,4,6-tetraacetyl-alpha-glucosyloxy)methyl-4-thiazolyl|ethenyl)|-4,17-dioxabicyclo|14.1.0) heptadecane-5,9-dione; bo 154-11AZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-(1-methyl-2-(2-(2,9 2, b-tetraacetyl-beta-glucosyloxy)methyl|)-4-thiazolyl|ethenyl/)|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-(6'-acetyl) -alpha-glucosyloxy)methyl-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11К7124К7,165771|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-|1-methyl-2-(2-Cap-toluene olsulfonyloxy) methyl)-4-thiazolyl|ethenyl()-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 5-1 AUZAKCHE), AK 1057,11K7,12K7,16571I-3-(2-(2-(bromomethyl)-4-thiazolyl|-1-methylethenyl-7,11-dihydroxy-8,;8,10,12 -tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-71 ZACHE),7AK1057,114K7,12K716571I-3-(2-(5-bromo-2-methyl-4-thiazolyl) )-1-methylethenyl-7,11-dihydroxy-70 8,8,10,12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11 ZKE), 7 1057,11К7124К7,16577|-3-(2-(2-(cyanomethyl)-4-thiazolyl|-1-methylethenyl/|-7,11-dihydroxy-8,8,10,12 ,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecan-5,9-dione; I45-I4Kk7757,8K9K15KE)1I-16-(2-(2-(cyanomethyl)-4-thiazolyl|-1- methylethenyl)|-4,8-dihydroxy-5,5,7,9,13-pentamethyl-1-oxa-13 (2)-cyclohexadecene-2,b-dione; 15-11, ZKE), 7 1057, 11K7,12K,16571I-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; 15-11, ZKE), 7 1057,11К7,124К7,16577|-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; 15-11, ZKE), 7 1057,11К7,124К7,16577|-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; 15-1A,ZKE), 7 1057,11К7,124К7,16571|-3-(2-(2-ethenyl-4-thiazolyl)-1-methylethenyl|-7,11-dihydroxy-8,8,10 ,12 -tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11 ZKE), 7 1057,11К7,124К7,165771|-7,11-dihydroxy-3-(2-(2-(methoxyimino)-4-thiazolyl|-1-methylethenyl 1-8,8,10, 12-tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; sch 154-1AM,ZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8, 10,12-tetramethyl-3-(1-methyl-2-(2-I-phenylmethyl)imino|methyl)-4-thiazolyl|ethenyl1-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; i) 15-11, ZKE), 7 1057,11К7,124К7,16577|-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; 154-1AZKE), 7 1057,11К7,12К7,16571|-7,11-dihydroxy-8,8,10,12-tetramethyl-3-/1-methyl-2-(2-oxiranyl-4"g zo - thiazolyl)ethenyl)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-71 ZACHE),7K1057,11K7,12K716571I-7,11-dihydroxy-3-(2-(2-(2-iodethenyl)-4-thiazolyl|-1-methylethenyl) o -8,8,10,12 -tetramethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; He 15-1A,ZKE), 7 1057,11К7,124К7,16571|-3-(2-(2-ethenyl-4-thiazolyl)-1-methylethenyl|-7,11-dihydroxy-8,8,10 , 12-tetramethyl-4,17-dioxabicyclo|14.1.0Y of heptadecan-5,9-dione; -- 15-11, ZKE), 7 1057,11К7,124К7,16577|-7,11-dihydroxy-8,8, 10,12,16-pentamethyl-3-(1-methyl-2-(2-Kmethylimino)methyl-4-thiazolyl|ethenyl|-4,17-dioxabicyclo|14.1.0)heptadecane-5,9- Dion; 15-11, ZKE), 7 1057,11K7,124K7,16577|-3-(2-I2-((2-(dimethylamino)ethyl|amino|methyl|)-4-thiazolyl|-1-methyl ethenyl)- 7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11K7124K7,16577|-3-(2-I(2-Kdimethylamino)methyl)-4-thiazolyl|-1-methylethenyl|-7,11-di" hydroxy-8,8 ,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; with p 15-71 ZACHE),7K1057,11K7,12K716571I-3-(2-(2-((bis-(2-methoxyethyl)amino|methyl|-4-thiazolyl|-1-methyleth. nil|-7, 11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; i? 15-11, ZKE), 7 1057,11К7,124К7, 16577|-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-(1-methyl-2-(2-K4-methyl-1-piperazinyl)methyl|)-4-thiazolyl| ethenyl)-4,17-dioxabicyclo|14.1.0)heptadecane-5,9-dione; 15-11, ZKE), 7 1057,11К7,124К7,16577)-4-(2-(7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-diox) -I abicyclo|14.1.0)heptadecan-3-yl)-1-propenyl)|-2-thiazolecarboxylic acid; methyl ether - 5-1 AUZACHE), AK 1057,11К7,12К7,16571)-4-(2-(7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17 -dioxabit He» iclo|14.1.0)heptadecan-3-yl)-1-propenyl)|-2-thiazolecarboxylic acid and their pharmaceutically acceptable salts, solvates and hydrates. at 27. Pharmaceutical composition according to claim 24 for the treatment of cancer and other proliferative diseases. her" 28. Pharmaceutical composition according to claim 24 for inhibiting the development of blood vessels. 29. Pharmaceutical composition according to claim 24 for inducing apoptosis. 30. A pharmaceutical composition for the treatment of cancer and other diseases according to claim 27 simultaneously or sequentially with another therapeutic agent suitable for the treatment of cancer and other proliferative diseases. F) Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuits", 2004, M 12, 15.12.2004. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 60 b5