SK181799A3 - Epothilone derivatives - Google Patents

Abstract

Epothilone derivates of formula (V), where meaning of substituent is described in description. It is described pharmaceutical composition included epothilone derivate and pharmaceutically acceptable carrier too and use of epothilone derivates for treating cancer.

Description

Technical field

The present invention relates to epothilone derivatives, to processes for the preparation of these derivatives and to intermediates for their preparation.

BACKGROUND OF THE INVENTION

Epothilones are macrolide compounds that find use in the pharmaceutical field. For example, epothilones A and B have been found to have the following structure:

I Epothilone A R = H

II Epothilone B R = Me show a stabilizing effect on microtubules, similar to TAXOL, and therefore cytotoxic activity against rapidly malignant cells, such as tumor cells or other cellular hyperproliferative diseases, see Angew. Chem. Int. Ed. Enol. 13/14. 35 (1996).

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula V

PV-1817-99, 51 / Ts / I 22.1.2001 wherein Q is selected from the group consisting of

G is selected from the group consisting of alkyl, substituted alkyl, substituted or unsubstituted aryl, heterocyclo,

Bra Bu 12 7 «o'y ^R, ^ NX

RL4

W is O or NR ₁₅ ;

X is O or H, H;

Y is selected from the group consisting of oxygen; hydrogen, OR ₁₆ ; ORv, OR, β; NORi ₈ ; a hydrogen atom, NORw; a hydrogen atom, NR 20 R 21; H, H; or CHR22; OR 17 OR 17 may be a cyclic ketal;

Z 1 and Z 2 are selected from the group consisting of CH ₂ , oxygen, NR ₂₃ , sulfur or SO ₂ , with only one Z 1 or Z ₂ being a heteroatom;

B 1 and B ₂ are selected from the group consisting of OR ₂₄ or OCOR 25 or O 2 -CNR ₂₆ R ₂₇ if Bi is hydrogen and Y is OH, H may then form a six membered ketal or acetal ring;

D is selected from the group consisting of NR 28 R 29. NR ₃₀ COR ₃ and the saturated heterocycle;

R 11, R 21, F 21, R ₄₁ , R 5, R 8, R ₇ , R 13, R ₁₄ , R 18, R 19, R ₂₀ , R 21, R 21, R 26 and R 27 are selected from the group consisting of hydrogen, alkyl, substituted alkyl or aryl and when R 1 and R _{2 are} alkyl, they may be joined to form cycloalkyl; if R ₃ and R _{4 are} alkyl, they may be joined to form cycloalkyl;

R9, Rw. Ri6. R 17, R 24, R 25 and R ₃₁ are selected from the group consisting of an atom

PV-1817-99, 51 / Ts / I 22.1.2001 hydrogen, alkyl, substituted alkyl;

Ra, R11, R12, R281, R30, R32, R33 and R310 are selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, or heterocyclo;

R 15, R 23 and R ₂ 9 are selected from hydrogen, alkyl, substituted alkyl, aryf, substituted aryl, cycloalkyl, heterocyclo, R ₃₂ C = O, R33SO2, hydroxy, O-alkyl or O-substituted alkoxy;

and any salts, solvates and hydrates thereof.

condition

This invention does not encompass compounds of formula V wherein

W and X are both oxygen atoms;

R _{1 (} R ₂ and R ₇ are hydrogen atoms;

R ₃ , R ₄ and R _e are methyl; and

R ₈ is hydrogen or methyl; and

Z 1 and Z ₂ are CH ₂ ; and

G is 1-methyl-2- (substituted-4-thiazolyl) ethenyl;

Q has the same meaning as above.

DETAILED DESCRIPTION OF THE INVENTION

The following are definitions of various terms used to describe the present invention. These definitions apply to terms as used throughout this specification, except as limited in specific cases, either individually or as part of a larger group.

The term "alkyl" refers to a linear or branched chain of unsubstituted hydrocarbon groups having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. The expression "lower alkyl" refers to unsubstituted alkyl groups containing 1 to 4 carbon atoms.

PV-1817-99, 51 / Tš / I 22 1.2001 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The term "substituted alkyl" refers to an alkyl group substituted with, for example, one to four substituents such as halogen, trifluoromethyl, trifluoromethoxyhydroxy, alkoxy, cycloalkoxy heterocycloxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, aralkylaminocycloalkylamino-, heterocycloamino, disubstituted amines in which the 2 amine substituents are selected from alkyl, aryl or arylalkyl, alkanoylaminoaroylamino, arylalkanoylamino, substituted alkanoylamino, heterocyclo, alkyltiono- aryltiono-, arylalkyltionoskupinou, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, sulfonamido (e.g. SO2NH2), substituted sulfonamido, nitro, cyano carboxy, carbamyl (e.g. _CONH2), substituted carbamyl (e.g., CONH-alkyl, CONH-aryl, CONH-arylalkyl or cases in which there are two substituents on the nitrogen atom selected from alkyl, aryl or aralkyl), alkoxycarbonyl, aryl, substituted aryl, guanidino and heterocyclo groups such as indolyl, imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like. If it is stated above that the substituent is further substituted, it will be halogen, alkyl, *

alkoxy, aryl or aralkyl.

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

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring moiety, such as phenyl, naphthyl, biphenyl and diphenyl groups, each of which may be substituted.

The term "aralkyl" refers to an aryl group directly bound to an alkyl group such as benzyl.

The term "substituted aryl" refers to an aryl group substituted with, for example, one to four substituents such as alkyl, substituted alkyl, halogen, trifluoromethoxy, trifluoromethyl, hydroxy, alkoxy, cycloalkoxy, heterocyclooxy, alkanoyl, alkanoyloxy, amino, alkylaminoaralkylamino, cycloalkylamino-, heterocycloamino-dialkylaminoalkanoylamino, thio-, alkylthio-, cycloalkythio-, heterocyclotio-, ureido-, nitro-,

PV-1817-99, 51 / Ts / I 22.1.2001

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cyano, carboxy, carboxyalkyl, carbamyl, alkoxycarbonyl, alkylthiono-, arylthio, alkylsulfonyl, sulfonamido, aryloxy, and the like. The substituent may be further substituted by halogen, hydroxy, alkyl, alkoxy, aryl, substituted aryl, substituted alkyl or aralkyl.

The term "cycloalkyl" refers to optionally substituted, saturated hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 ring carbon atoms, which may be further fused with an unsaturated carbocyclic ring containing 3 to 7 carbon atoms. Exemplary groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and adamantyl. Exemplary substituents include one or more alkyl groups as mentioned above, or one or more groups described above as alkyl substituents.

The terms "heterocycle", "heterocyclic" and "heterocyclo" refer to an optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic ring group, which is, for example, a 4- to 7-membered bicyclic, 7- to 11-membered bicyclic or 10 a up to 15-membered tricyclic ring system having at least one heteroatom in at least one ring containing carbon atoms. Each heteroatom-containing heterocyclic group ring may have 1, 2 or 3 heteroatoms selected from nitrogen, oxygen, and sulfur atoms, wherein the nitrogen and sulfur heteroatoms may be further quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, thiothiazolidinyl, thiothiazolidinyl, thiothiazolidinyl, thiothiazolidinyl, thiothiazolidinyl, thiothiazolidinyl, thiazolyl, , 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxazepinyl, azepinyl, 4-piperidonyl, pyridyl, N-oxopyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyranylsulfone, morpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl dioxolane and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl, tietanyl, thiiranyl, triazinyl and triazolyl and the like.

PV-1817-99, 51 / Tä / I 22 01.2001 ··· ··········

Exemplary bicyclic heterocyclic groups include benzothiazolyl, benzoxazolyl, benzthienyl, quinuclidinyl, quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzpyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, pyrrolinyl, quinolinyl, quinoxalinyl, quinoxalinyl, quinoxalinyl 2,3-c] pyridyl, furo [3,1-b] pyridyl or furo [2,3-b] pyridyl), dihydroisoindolyl, dihydroquinazolinyl (such as 3,4-dihydro-4-oxoquinazolinyl), benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl , benzotriazolyl, benzopyrazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranylsulfone, dihydrobenzopyranylsulfone, indolinyl, isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl, piperonyl, thienyl, thienolopyridinyl, quinopyridyl, quinopyridyl, quinopyridyl, quinopyridyl, quinopyridyl, quinopyridyl, quinopyridyl, quinopyridyl;

Exemplary substituents include one or more alkyl groups as described above, or one or more groups described above as alkyl substituents. They also include smaller heterocycles such as epoxides and aziridines.

The term "heteroatom" includes oxygen, sulfur and nitrogen.

The compounds of formula V may form salts with alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium or magnesium, with organic bases such as dicyclohexylamine, tributylamine, pyridine and amino acids such as arginine, lysine and the like. Such salts can be obtained, for example, by exchanging the carboxylic acid protons in the compounds of formula V, if they contain the carboxylic acid, with the desired ion, in a salt-precipitating medium or in an aqueous medium followed by evaporation. Other salts may also be formed as known to those skilled in the art.

The compounds of formula V form salts with various organic and inorganic acids. Such salts include those formed with hydrochloric, hydrobromic, methanesulfonic acid, hydroxyethanesulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, and various other acids (e.g., nitrates, phosphates, borates, tartrates, tartrates). , citrates, succinates, benzoates, ascorbates, salicylates and the like). Such salts are formed by reacting a compound of formula V with an equivalent amount of an acid in the environment in which it is formed

PV-1817-99, 51 / Ts / I 22.1.2001

• · • · ·· · • · • · • • · ·· • · • · · · • 9 · • • ···· · · ·· ··· ·· ·

the salt precipitates or in an aqueous medium with subsequent evaporation.

In addition, zwitterions ("inner salts") are formed.

The compounds of formula V may also take the form of a prodrug. Any compound that is converted in vivo to provide a bioactive agent (i.e., a compound of Formula V) is a prodrug within the scope and spirit of the invention.

For example, compounds of Formula V may form an ester group of a carboxylate. The carboxylate esters are conveniently formed by esterifying any of the carboxylic acid functionalities found on the disclosed ring structure (s).

Various forms of prodrugs are well known in the art. For examples of such precursor derivatives, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier) (1985) and Methods in Enzymology, 42, 309-396, edited by K. Widder et al. (Academic Press) (1985);

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

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

d) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1998);

e) N. Kakeya et al., Chem. Phar. Bull., 32, 692 (1984).

It is further understood that solvates (e.g., hydrates) of the compounds of Formula V are within the scope of this invention. Methods of solvation are generally known in the art.

Use and utility

Compounds of formula V are microtubule stabilizing agents. Thus, they can be used in the treatment of various cancers or other diseases associated with abnormal proliferation, including but not limited to:

- cancers, including bladder, breast, colon, kidney,

PV-1817-99, 51 / TS / I 22 1.2001

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liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma;

haematopoietic tumors of lymphoid origin, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma and Burkett's lymphoma;

- haematopoietic tumors of myeloid origin, including acute and chronic myelogenous leukemia and promyelocytic leukemia;

tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma;

- other tumors, including melanoma, testicular tumor, teratocarcinoma, neuroblastoma and glioma;

tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannoma;

tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma and osteosarcoma;

- other tumors, including melanoma, xenoderma pigmentosum, keratoactantoma, testicular tumor, thyroid cancer and teratocarcinoma

Compounds of formula V may also prevent tumor angiogenesis, thereby affecting excessive malignancy of cells. These anti-angiogenic properties of the compounds of formula (V) may be useful in the treatment of certain forms of blindness associated with vascular supply of retina, arthritis, particularly inflammatory arthritis, multiple sclerosis, restinosis and psoriasis.

Compounds of formula V may induce or suppress apoptosis, a physiological cell death event critical to routine development and homeostasis. The alternation of apoptotic pathways contributes to the emergence and development of disease changes in various diseases in humans. Compounds of formula V, as apoptosis modulators, will be useful in the treatment of a variety of diseases in humans with apoptosis abnormalities, including cancer (particularly follicular lymphomas, p53 mutation cancers, hormone-dependent breast, ovary gland and ovarian cancer, pre-cancerous lesions, such as but not limited to familial adenomatous polyposis, viral infections (including herpesvirus, smallpox, Epstein-Barr virus, Sindbis virus and

PV-l 817-99, 51 / Tš / I 22.1.2001 ···········

999 9 9 9 99 • Adenovirus, but not limited to, adenovirus, autoimmune diseases ( including, but not limited to, systemic lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease and autoimmune diabetes, neurodegenerative diseases (including Alzheimer's disease, dementia associated with AIDS, Parkinson's disease, Parkinson's mucosa, but not limited to atrophy of the back muscles and degeneration of the cerebellum), AIDS, myelodysplastic syndromes, aplastic anemia, myocardial infarction associated with ischemic injury, stroke and reperfusion injury, arrhythmia, atherosclerosis, hepatic disease or disease (including, but not limited to, chronic anemia and aplastic anemia), degenera musculoskeletal disorders (including, but not limited to, osteoporosis and arthritis), aspirin sensitivity rinosinusitis, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

The compounds of the invention are also useful in combination with known anticancer and cytostatic agents and drugs, including radiation. When prepared in solid dosages, such combination formulations of the compounds of this invention are utilized within the dosage ranges described below and other pharmaceutically active agents within the recommended dosage ranges. The compounds of formula (V) may be used sequentially with known anticancer and cytostatic agents and drugs, including radiation, unless the combination is inappropriate. Particularly effective are combinations of cytostatic drugs in which the second drug acts at a different stage of the cell cycle, e.g. in the S-phase, as the present compounds of formula V, which exert their effect in the G ₂ -M phase. E.g. thymidilate synthase inhibitors, DNA crosslinking agents, topoisomerase I and II inhibitors, DNA alkylating agents, ribonucleoside reductase inhibitors, cytotoxic factors, e.g. TNF-α or growth factor inhibitors, e.g. HER2 receptor MAB. The present compounds may exist in multiple optical,

P V-1817-99, 51 / Tš / I 22.1.2001

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geometric isomers and stereoisomers. All such isomers and mixtures thereof are within the scope of the invention.

The compounds of the invention may be formulated with pharmaceutical excipients or solvents for oral, intravenous or subcutaneous administration. The pharmaceutical compositions may be formulated in conventional manner using solid or liquid excipients, diluents, and adjuncts suitable for the desired mode of administration. Orally, the compounds may be administered in the form of tablets, capsules, powders and the like. The compounds are administered in dosages ranging from 0.05 to 200 mg.kg ^-1 per day, preferably less than 100 mg.kg ^-1 per day in a single dose or divided into 2-4 doses.

Preferred compounds

Particularly preferred compounds of formula V are those in which:

X is an oxygen atom,

Y is an oxygen atom,

Z 1 and Z ₂ are CH ₂ and groups

W is NRis.

Method of preparation

Compounds of formula V are prepared according to the following schemes:

PV-1817-99, 51 / TS / I 22 1.2001

Scheme 1

· · · · · · • · · 9 • · • • • · · • · 99 • · · · • · • • 9 9 • • · • · • • · • 9 9 • • · • · • • 9 • ···· · · · · · · · · · · · ·

xv χνι χνιι

V (Q is ethylene)

V (Q is an oxirane group) wherein R ₃₁ R ₄ , R ₅ , R ₆ , R e and R 15 have the same meanings as above and

Pi is an oxygen protecting group.

PV-1817-99, 51 / Tš / l 22.1.2001

• · • ·· • ··· · · • · · • ·· • · • · • • · • • • • • ···· · · · · · · · · · · · ·

Compounds of formula V wherein W is NR 15 and X is an oxygen atom may be prepared according to Scheme 1. A compound of formula XII wherein P 1 is an oxygen protecting group such as tert-butyldimethylsilyl may be prepared from a compound of formula VI known by by methods (ie Nicolaou KC et al., Angew. Chem. Int. Ed. Engl., 36, 166-168 (1997)). The aldol reaction of a compound of formula XII and a compound of formula XIV provides a compound of formula XIII. The compound of formula XIV can be prepared by known methods (ie Schinzer D. et al., Eur. Chem. Chron., 1, 7-10 (1996)). The aldehyde of formula XVIII can be prepared from a compound of formula XV according to Scheme 1 or by known methods (ie Taylor RE et al., Tetrahedron Lett., 38, 2061-2064 (1997)). A compound of formula XIX can be prepared from a compound of formula XVIII by treatment with an amine using dehydration conditions such as a catalytic amount of p-toluenesulfonic acid and azeotropic removal of water. A compound of formula XX can be prepared from a compound of formula XIX by treatment with an allylating agent, such as allylmagnesium bromide. A compound of formula XXI can be prepared from compounds of formulas XIII and XX, by reaction with conventional amide bonding agents (ie, DCC, BOP, EDC / HOBT, PyBrOP). A compound of formula XXII can be prepared from a compound of formula XXI by ring closure reaction using either Grubbs (RuCl ₂ (= CHphenyl) (PCY ₃ ) 2, see Grubbs RH et al., Angew. Chem. Int. Ed. Engl. , 34, 2039 (1995) or a Schrock catalyst (see Schrock RR et al., J. Am. Chem. Soc., 112, 3875 (1990)) Removal of a protecting group in a compound of formula XXI using, for example, when Pi is a tert-butyldimethylsilyl group, hydrogen fluoride in acetonitrile or tetra-butylammonium fluoride in THF provides a compound of formula V wherein Q is an ethylene group, W is NR ₁₅ , X is oxygen and R ₃ , R ₄ , R ₅ and R ₆ have the same meaning as above . regioselective epoxidation of the compound of formula V where Q is an ethylene group using dimethyldioxirane provides a compound of formula V where Q is an oxirane group, W is NR _{5 R} X is O, and R ₃₁ R 4, R and R _{1 s} are same meaning as above.

PV-1817-99, 51 / Ts / I 22.1.2001

Scheme 2

· · • · • · · • ··· ·· • · • · • • · • • • • • · • · • • ···· · · · · · · ·

··· *

Alternatively, a compound of formula VIII can be prepared by reacting a compound of formula XXIII with magnesium and an acid chloride (R 5 CH 2 COCI) to give a compound of formula XXIV (see, for example, Heathcock C. et al., J. Org. Chem., 55, 1114-1117 ( 1990)) and subsequent ozonolysis to give a compound of formula VIII as shown in Scheme 2.

Scheme 3

The compound of formula XIV may optionally be prepared according to the scheme

3. Reaction of a compound of formula XXV and pseudoephedrine provides a compound of formula XXVI. A compound of formula XXVII can be prepared from a compound of formula XXVI by alkylation with a pentenyl halide such as 5-bromo-pentene according to the method of Meyers (ie, Meyers A. et al., J. Am. Chem. Soc., 116, 9361 and 9362 (1994)). )). A compound of formula XXVIII can be prepared from a compound of formula XXVII by reaction with a reducing agent such as lithium pyrrolidinylborohydride. Oxidation of a compound of formula XXVIII using, for example, pyridinium chlorochromate, provides a compound of formula XIV. Direct conversion of a compound of formula XXVII to a compound of formula XVI may be achieved with a reducing agent such as lithium triethoxyaluminium hydride.

PV-1817-99, 51 / Tš / I 22 Jan 2001

Scheme 4

• 9 • · • 99 • 999 · · • • · • • 9 9 9 9 9 9 • • • • • 9 9 • • 9 9 9 ···· 99 · · · · · 99 9

Alternatively, the compound of formula XX can be prepared from allylglicin as shown in Scheme 4. The nitrogen atom in allylglicin can be protected by methods known in the art to provide a compound of formula XXIX wherein P ₂ is a suitable nitrogen protecting group such as tert- butoxycarbonyl. Alternatively, if R ₂₉ is not a hydrogen atom, the compound of formula XXX can be prepared from a compound of formula XXIX by alkylation with an alkyl halide in the presence of a base such as sodium hydride. A compound of formula XXXI can be prepared from a compound of formula XXX using Ν, Ο-dimethylhydroxylamine and conventional coupling agents such as EDCI and HOBT. A compound of formula XXXII can be prepared from a hydroxamate of formula XXXI by treatment with an organometallic reagent such as an alkyl or aryl magnesium halide. Wittig olefination of a compound of formula XXXII provides a compound of formula XXXIII (Wittig reagent is prepared as described by Danishefsky SE et al., J. Org. Chem., 61: 7998-7999 (1996)). Removal of the nitrogen protecting group in the compound of formula XXXIII by methods known in the art provides a compound of formula XX.

P V-1817-99, 51 / Tš / I 22.1.2001

Scheme 5

· · · · · · • · · • • · • • • · · • • • · • · · · • • • • • • • • · • • • • • • ···· · · · · • ·· · · · · ·

NR ₁₅ P ₂ a

RiiCHžPOPte

V (Q is ethylene)

V (Q is oxirane group)

A compound of formula V where W is NR _51, X is O, and G is a set 1,2disubstituovaný olefin can be prepared as shown in Scheme 5. A compound of formula XXXV may be prepared by the Wittig olefination of a compound of formula XXXII. The compound of formula XXXIV can be prepared by methods known in the art. The compound of formula XXXVI can be prepared by removing the nitrogen protecting group in the compound of formula XXXV using known methods. The compound of formula XXXVII can be prepared by the condensation reaction of a compound of formula XXXVI and a compound of formula XIII using conventional coupling reagents such as EDCI and HOBT. A compound of formula XXXVIII can be prepared from a compound of formula XXXVII by the methods described in Scheme 1 for the preparation of a compound of formula XXII. Using these methods (steps o and p), a compound of formula XXXVIII can be converted to compounds of formula V wherein W is NR ₁₅₁ X is an oxygen atom and G is a 1,2-disubstituted olefin.

PV-1817-99, 51 ZTšfl 22 1.2001

Scheme 6

· · • · • ·· • ··· • · 9 • · • • · • · • · • · • • • • • • · • 9 • • · ···· · · · · 999 · · • ·

V (Q is ethylene)

V (Q is oxirane group)

A compound of formula V wherein W and X are oxygen atoms and G is a 1,2-disubstituted olefin can be prepared according to Scheme 6. A compound of formula XXXX can be prepared from a compound of formula XXXIX by treatment with an allylating agent such as allylmagnesium bromide. The enantiomerically pure compound of formula XXXX can be prepared using chiral reagents (see, for example, Taylor RE et al., Tetrahedron Lett. 38, 2061-2064 (1997), Nicolaou KC et al., Angew Chem. Int. Ed. Engl., 36). Keck, G. et al., J. Am. Chem. Soc., 115, 8467 (1993), 1997, 166-168. A compound of formula XXXXI can be prepared from compounds of formulas XXXX and XIII using known esterification methods such as DCC and DMAP. A compound of formula XXXXII can be prepared from a compound of formula XXXXI by a ring-closing olefin exchange reaction as described in Scheme 1 for the preparation of a compound of formula XXII. Compounds of formula V wherein W and X are oxygen atoms and G is a 1,2-disubstituted olefin can be prepared from a compound of formula XXXXII by deprotection (if Q is an ethylene group) and, if desired, epoxidation (if (Q is an oxirane group) as described above.

P V-1817-99,51 TS / I 22.1.2001

Scheme 7

• · • · • ·· • ··· ·· • • • • • · · • · · • • · • • • • • • • · • • • • • • ···· · · · · · · · · · · · ·

V (Q is ethylene)

V (Q is oxirane group)

A compound of formula V wherein W and X are oxygen atoms and G is alkyl, aryl, heteroaryl, bicycloaryl or bicycloheteroaryl may be prepared as shown in Scheme 7. A compound of formula XXXXIV may be prepared by allylating a compound of formula XXXXIII, wherein G is alkyl, substituted alkyl, aryl, heteroaryl, bicycloaryl or bicycloheteroaryl, by reaction with an allylating agent such as allyl magnesium bromide. A compound of formula XXXXV can be prepared from a compound of formula XXXXIV by esterification with a compound of formula XIII using, for example, DCC or DMAP. The compound of formula XXXXVI can be prepared from compound XXXXV by ring closure as described above. Following the methods described in Scheme 1 above, a compound of formula XXXXVI can be converted to a compound of formula V by deprotection followed by epoxidation.

P V-1817-99, 51 ITill 22.1.2001

Scheme 8

· · · · · · • ·· · • · • • · ·· · · • · • · · · • • • ♦ · • • · • · • • · · · • • e • · • · · • ···· · · · · ··· ·· · · ·

βγΗ.

O XXXXIII

NR15 XXXXVII

V (Q is an ethylene group) V (Q is an oxirane group)

A compound of formula V wherein W is NR ₁₅₁ X is an oxygen atom and G is alkyl, aryl, heteroaryl, bicycloaryl or bicycloheteroaryl can be prepared as shown in Scheme 8. A compound of formula XXXXVII can be prepared by reacting a compound of formula XXXXIII wherein G is alkyl, substituted alkyl, aryl, heteroaryl, bicycloaryl or bicycloheteroaryl, and an amine under dehydration conditions. The compound of formula XXXXVIII can be prepared from compound XXXXVII by treatment with an allylating agent such as allylmagnesium bromide. A compound of formula XXXXIX can be prepared from a compound of formula XXXXVIII and a compound of formula XIII by conventional amide bond coupling methods using, for example, EDCI or HOBT. The compound of formula L can be prepared from the compound of formula XXXXIX by ring closure as described above. Following the methods described in Scheme 1 above, a compound of formula L can be converted to compounds of formulas

In deprotection and subsequent epoxidation.

PV-1817-99, 51 / TS / I 22 1.2001

Scheme 9

· · · · • · • · • • · • · · · • · • • · • · · • • · • · ··· · · · · ·

• · · · · · · · · · · · · · · · · · · · · · · · ·

Compound of Formula V wherein X is O, W is NR 15, and G is

and D is selected from the group consisting of NR 28 R 29, NR 30 COR 31 and a saturated heterocycle (ie piperidinyl, morpholinyl, piperazinyl, etc.), can be prepared as outlined in Scheme 9. A compound of formula L1 can be prepared from a compound of formula XXXII by reductive amination using a primary or secondary amine and a reducing agent such as sodium triacetoxyborohydride. Compounds of formulas LII, LIV and V can then be prepared by the methods described in Scheme 1 above.

PV-1817-99, 51 / Tš / I 22 Jan 2001

Scheme 10

• · · · ·· · · · • · • • · · · • · · • · · · • · • • · • • · • · · • • · · • • · • · • • · ···· • · · · • · · ·· ·

Alternatively, a compound of Formula V wherein X is O, W is O, or NR 15 and

G is

and D is selected from the group consisting of NR _{2 and} R 29, NR 30 COR 31 and a saturated heterocycle (ie piperidinyl, morpholinyl, piperazinyl etc.) can be prepared from a compound of formula V as shown in Scheme 10. A compound of formula V can be converted to a compound of formula LV by protecting hydroxyl groups with suitable protecting groups such as tert-butyldimethylsilyl. A compound of formula LVI can be prepared from a compound of formula LV by ozonolysis. Treatment of a compound of formula LVI with an amine and a reducing agent such as sodium triacetoxyborohydride provides a compound of formula LVVII. Removal of protecting groups from a compound of formula LVII, for example with hydrogen fluoride, provides a compound of formula V wherein X is O, W is NR _15, or O and

G is

9L2

PV-1817-99, 51 / Tš / l 22 1.2001

• .G is • · • · ·· ·

Scheme ·······································

Compound of Formula V wherein W is NR ₁₅ , X is O and ^R '3 (A)

R 14 can be prepared as outlined in Scheme 11. A compound of formula LVIII can be prepared from compounds of formula XXX by treatment with an amine and conventional amide bond condensing agents such as EDCI and HOBT. A compound of formula LX can be prepared from a compound of formula LVIII by removal of a nitrogen protecting group using, for example, trifluoroacetic acid when P _{2 is a} tert-butoxycarbonyl group, followed by condensation of compounds of formulas LIX and XIII using conventional amide bonding reagents such as EDCI and HOBT. The compound of formula LXI can be prepared from a compound of formula LX by ring closure. The compound of formula V can then be prepared from the compound of formula LXI by the methods described in Scheme 1 above.

P V-1817-99, 51 / Tš / I 22.1.2001

Scheme 12

• · • · • • ··· • · • · • · • • · • ·· · • · ·· • · · • • · · · • · · · · · · ·· ···

A compound of formula V wherein W is oxygen, X is oxygen and

G is

O ^{R 3} > A /

R 1h can be prepared as outlined in Scheme 12. A compound of Formula LXII can be prepared from zalylglycine by treatment with nitrous acid. A compound of formula LXIII can be prepared from a compound of formula LXII by treatment with an amine and conventional amide bond condensing agents such as EDCI and HOBT. A compound of formula LXIV can be prepared from compounds of formulas LXIII and XIII using conventional amide bond forming reagents such as EDCI and HOBT. The compound of formula LXV can be prepared from the compound of formula LXIV by ring closure reaction. The compound of formula V can then be prepared from the compound of formula LXV by the methods described in Scheme 1.

PV-1817-99, 51 / Tš / I 22.1.2001

Scheme 13

·· ·· • · · • ··· ·· · • · ·· • · · ·· · • · · • · · • · · • • · 23 ···· ·· ·· ··· • · · · ·

r ₈ R < > Olympics and A OH 0

A compound of formula V wherein G is a 1,2-disubstituted ethyl group can be prepared from a compound of formula V wherein G is a 1,2-disubstituted ethylene group by hydrogenation with a catalyst (palladium on carbon) as shown in Scheme 13 In addition, a compound of formula V wherein G is a 1,2-disubstituted cyclopropyl group can be prepared from a compound of formula V wherein G is a 1,2-disubstituted ethylene group by cyclopropanation with diiodomethane and a zinc-copper pair as shown in the scheme. 4th

Scheme 14

A compound of formula V wherein Z 1 is an oxygen atom can be prepared according to Scheme 14. A compound of formula LXVII can be prepared from a hydroxy ester of formula LXVI and 3-buten-1-yltrifluoromethanesulfonate (or

XII

PV-1817-99, 51 (Tš / I 22 January 2001 with 3-butenyl bromide and silver trifluoromethylsulfonate). The compound of formula LXVII may be reduced with a reducing agent such as diisobutylaluminium hydride to provide a compound of formula LXVIII. Alternatively, the compound of formula LXVIII can be obtained from the compound of formula LXVII by a two-step process comprising lithium borohydride reduction and pyridinium chlorochromate oxidation. This compound of formula LXVIII can be substituted with a compound of formula XIV from Scheme 1 to give a compound of formula LXIX. Further treatment of the compound of formula LXIX as described above provides a compound of formula V wherein Z 1 is an oxygen atom.

Scheme 15

Similarly, a compound of formula V wherein Z 1 is NR _{23 can be} prepared as outlined in Scheme 15. A compound of formula LXXI can be prepared from the α-aminoester of formula LXX and 3-buten-1-yl bromide. The compound of formula LXXI may be reduced with a reducing agent such as diisobutylaluminum hydride to provide a compound of formula LXXII. Alternatively, the compound of formula LXXII can be obtained from the compound of formula LXXI by a two-step process, which includes lithium borohydride reduction and pyridinium chlorochromate oxidation. This compound of formula LXXII may be substituted with a compound of formula XIV of Scheme 1 to give a compound of formula LXXIII. Further treatment of the compound of Formula LXXIII as described above gives a compound of Formula V wherein Z 1 is NR 23.

PV-1 817-99,51 / TS / I 22 1.2001

Scheme 16

• · · · ·· · • 0 · • · • • · ·· • · ·· • · · · • · · • · · • ··· · • · ·· ··· ·· ···

A compound of formula V wherein Z ₂ is an oxygen atom may be prepared as shown in Scheme 16. A compound of formula LXXV may be prepared from a β-hydroxyester of formula LXXIV and an allylating agent such as allyl bromide (or allyl bromide and silver trifluoromethylsulfonate). ). The compound of Formula LXXV can be reduced with a reducing agent such as diisobutylammonium hydride to provide a compound of Formula LXXVI. Alternatively, the compound of formula LXXVI can be obtained from the compound of formula LXXV by a two-step process that involves reduction with lithium borohydride a. oxidation of pyridinium chlorochromate. This compound of formula LXXVI may be substituted with a compound of formula XIV from Scheme 1 to give a compound of formula LXXVI I. Further treatment of the compound of formula LXXVII as described above provides a compound of formula V wherein Z ₂ is oxygen.

Scheme 17

Similarly, a compound of formula V wherein Z ₂ is NR _{23i can be} prepared according to Scheme 17. A compound of formula LXXIX can be prepared from βP V-1817-99,51 / Tä / I 22 1.2001

· · • · • ·· • ··· ·· • · • · • · · • · · • • • • · • · • • ···· · · · · · · · · ·

An aminoester of formula LXXVIII and an allylating agent such as allyl bromide. The compound of formula LXXIX can be reduced with a reducing agent such as diisobutylaluminum hydride to provide a compound of formula LXXX. Alternatively, the compound of formula LXXX can be obtained from the compound of formula LXXIX by a two-step process that involves reduction with lithium borohydride and oxidation with pyridinium chlorochromate. This compound of formula LXXX can be substituted with a compound of formula XIV of Scheme 1 to give a compound of formula LXXXI. Further treatment of the compound of Formula LXXXI as described above provides a compound of Formula V wherein Z ₂ is NR ₂₃ .

Scheme 18

A compound of formula V wherein W is oxygen or NR 18 and Y is H, H may be prepared as outlined in Scheme 18. A compound of formula V may be converted to a compound of formula LXXXII wherein P ₄ and P ₅ are hydroxyl protecting groups by treatment with an agent such as tert-butyldimethylsilyltrimethylsulfonate. The compound of formula LXXXIII can be prepared from a compound of formula by treatment with Lawesson's reagent. A compound of formula LXXXIV can be prepared from a compound of formula LXXXIII using a reducing agent such as tri-n-butyltin hydride when W is an oxygen atom or by treatment with methyl iodide and sodium borohydride when W is NR ₁₅ . Removal of protecting groups from a compound of formula LXXXIV using, for example, hydrogen fluoride, when P ₄ and P _{5 are} silyl groups, provides a compound of formula V wherein W is O or NR 15 and Y is H, H.

V-1817-99. 51 / Tš / I 22.1.2001

Scheme 19 ·······································

OP:

PV-1817-99, 51 / Tš / I 22 1.2001 ································

A compound of formula V wherein W and Y are oxygen atoms and R 1 is alkyl or substituted alkyl can be prepared according to Scheme 19. A compound of formula V can be protected to give a compound of formula LXXXV where P ₅ and P ₆ are protecting groups hydroxyl groups by treatment with an agent such as tert-butyldimethylsilyltrifluoromethanesulfonate. A compound of formula LXXXVI can be prepared from a compound of formula LXXXV by treatment with a reducing agent such as sodium borohydride. A compound of formula LXXXVI I can be prepared from a compound of formula LXXXVI by introducing a hydroxyl protecting group, wherein P? is, for example, pmethoxybenzyl, using p-methoxybenzyltrichloroacetimidate. Removal of the protecting groups P ₅ and P ₆ from a compound of formula LXXXXVII, using, for example, hydrogen fluoride in pyridine when P ₅ and P _{6 are} tert-butyldimethylsilyl groups, provides a compound of formula LXXXXVIII which can subsequently be selectively protected using for example tert-butyldimethylsilyl chloride. to form a compound of formula LXXXXIX where P ₈ is a t-butyldimethylsilyl group. A compound of formula C can be prepared from a compound of formula LXXXXIX by treatment with a base such as lithium diisopropylamide and subsequent treatment with an alkylating agent such as methyl iodide. A compound of formula C can be protected to give a compound of formula Cl wherein P ₉ is a hydroxyl protecting group by treatment with a reagent such as tert-butyldimethylsilyltrifluoromethanesulfonate. A compound of formula CII can be prepared from a compound of formula CI by removal of P ₇ by using, for example, DDQ when P ₇ is a p-methoxybenzyl group. A compound of formula V wherein W and Y are oxygen atoms and R 1 is alkyl or substituted alkyl may be prepared from a compound of formula Cl1 by oxidation using, for example, TPAP / NMO and subsequent deprotection using, for example, hydrogen fluoride when P ₈ and P ₉ silyl groups. This compound of formula V can be further oxidized with dimethyldioxirane according to Scheme 1 to give the corresponding epoxy compound of formula V.

P V-1817-99, 51 / Tš / I 22.1.2001

Scheme 20

· · • · • · · • · · · ·· · · · • · • • • • · · • • • • • • • · • • • • • ···· · · · · · · · • · • ·

V (W is oxirane group)

V (W is an ethylene group)

A compound of formula V wherein X is an oxygen atom and Q is an olefin can be prepared from a compound of formula V wherein X is an oxygen atom and Q is an oxirane ring by treatment with a reactive metallocene such as titanium, zirconocene or niobocene as is shown in Scheme 20 (see, for example, R. Schobert and U. Hohlein, Synlett, 465-466 (1990)).

V (W is an oxygen atom)

V (W is NR ₁₅ )

A compound of formula V wherein X is O and W is NR _5, wherein Rizia is H, may be prepared from a compound of formula V where both X and W are oxygen as shown in Scheme 21. A compound of formula ClII can be prepared from a compound of formula V wherein both X and W are oxygen atoms by forming a pi-allyl palladium complex using, for example, palladium-tetrakistriphenylphosphine and subsequent treatment with sodium azide (see, e.g.

OJ V-1817-99, 51 / Tšll 22.1.2001

· · • · • ·· • ··· • e • · • · • · · • ·· · • · ·· • · · • ··· · · · · · · · · ·· ···

for example: Murahashi S.-l. et al., J. Org. Chem., 54, 3292 (1989)). Subsequent reduction of a compound of formula III with a reducing agent such as triphenylphosphine provides a compound of formula CIV. A compound of formula V wherein X is O, and V is NR ₁₅₁ wherein R ₁₅ is H, can be prepared from a compound of formula CIV Macrolactamization using, for example diphenylphosphoryl azide or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP).

(W is NR _1S )

A compound of formula V wherein X is O and W is NR ₅₁ wherein Rizia alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, O-alkyl, 0substituovaný alkyl, can be prepared from a compound of formula V where both X, W is oxygen atoms as shown in Scheme 22. A compound of formula CV can be prepared from a compound of formula V where both X and W are oxygen atoms by forming a pi-allyl palladium complex using, for example, palladium tetrakisphenylphosphine and subsequent treatment with a primary amine. A compound of formula V wherein X is O and W is NR ₁₅ , wherein R 15 is alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, hydroxyl, O-alkyl, O-substituted alkyl, can be prepared from a compound of general formula of formula V by macrolactamization using, for example, diphenylphosphoryl azide or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP). If R ₁₅ is a hydroxyl group, it may be necessary to remove a protecting group, such as tert-butyldimethylsilyl, from an intermediate wherein R ₁₅ is O-tert-butyldimethylsilyl.

P V-1817-99, 51 / Tš / I 22.1.2001

· · • · • • · • ··· • · • · · • ·· • · • · • • · • • • • • ···· • · • · · · · · · • · ·

In vitro monitoring of the biological activity of compounds of formula V was performed as follows:

In vitro polymerization of tubulin

Double-cycled calf tubulin was prepared according to the method of Williams and Lee (see Williams RC Jr. and Lee JC, Preparation in Tubulin from the Brain. Methods in Enzylology, 85, part D: 376-385 (1982)) and before use. kept in liquid nitrogen. Quantification of tubulin polymerization efficiency was achieved by the following modified procedure of Swindell et al. (see Swindell C.

S., Krauss NE, Horwitz SB and Ringel I., Biologically active taxol analogues with deleted A-ring side chain substituents and variable C-2 'configurations. J. Med. Chem., 34, 1176-1184 (1991)). These adjustments partially resulted in the expression of tubulin polymerization efficiency as an effective concentration for any given compound. In this method, various concentrations of compound in polymerization buffer (0.1 M MES, 1 mM EGTA, 0.5 mM MgCl ₂ , pH) are added to the tubulin at 37 ° C in a Beckman Model DU 7400 micro-flow cell. 6.6). Used microtubule protein final concentration of 1.0 mg.ml ^"1 and the concentration of the compound is usually 2.5, 5.0 and 10 μΜ. The default optical density change (OD) guideline, measured every 10 seconds, was calculated by the program incorporated into the instrument after the start and end times of the linear region including at least 3 time points were manually determined. Under these conditions, the linear deviations were typically <10 · ®, the slopes ranged from 0.03 to 0.002 absorbance units per minute and the highest absorbance was 0.15 absorbance units. The effective concentration (ECo.oi) is determined as an interpolated concentration capable of producing a slope of 0.01 OD.min ^-1 and is calculated according to the equation: EC0.01 = concentration / slope. ECo.oi values are expressed as the mean of the standard deviation obtained from three different concentrations. The EC _o , _o i values of the compounds of the invention fall within the range of 0.01 to 1000 μΜ.

Cytotoxicity (in vitro)

Cytotoxicity was determined on human colon carcinoma cells HCTPV-1817-99, 51 / Tä / l 22.1.2001 ··· ············· ·· ·· ·· ··· ·· ···

116 by MTS (3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -

2- (4-sulfenyl) -2H-tetrazolium, inert salt) as described by TL Riss et al. in Comparison of MTT, XTT, and a novel tetrazolium compound MTS for in vitro proliferation and chemosensitivity assys, Mol. Biol. Cell, 3, (Suppl.), 184a (1992). Cells were seeded, 4000 cells per well in a 96-well microfiltration plate and after 24 hours drug was added and serially diluted. The cells were incubated at 37 for 72 hours, at which time the tetrazolium stained, treated with MTS at a concentration of 333 pg.mľ ¹ (final concentration), in combination with the electron coupling agent phenazine methosulfate at 25 μΜ (final concentration). The dehydrogenase enzyme in living cells reduces MTS to a form that absorbs light at 492 nm, which can be determined spectrophotometrically. The greater the absorbance, the greater the number of viable cells. The results were expressed as IC _50l, which is the concentration of drug required to prevent cell malignancy (ie absorbance at 450 nm) in 50% of cells as compared to untreated reference cells. IC50 values for compounds of the invention fall within the range of 0.01 to 1000 μΜ.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

[4S- [4R *, 7S _L *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5 _I, 5,7,9-tetramethyl-16- [1-methyl-2- ( 2-Methyl-4-thiazolyl) ethenyl] -1-aza-13 (E) -cyclohexadecene-2,6-dione

A. N - [(2-Methyl) -1-propenyl] morpholine

To stirred morpholine (165.5 g, 1.9 mol) was added isobutyraldehyde (173 mL,

1.9 mol) at a rate that did not allow the reaction mixture to exceed 30 ° C. After

PV-1817-99, 51 / TS / I 22 Jan 2001 After complete addition, the reaction mixture was stirred at room temperature for 2 hours, then on a flask. gave a Dean-Stark adapter and heated to 160 ° C for 20 hours.

The reaction mixture was then cooled to room temperature and the flask was equipped with a vigreux column distillation apparatus. Distillation under high vacuum gave 135 g (50%) of Compound A as a clear colorless oil. MS (M + H, 142).

B. 2,2-Dimethyl-3-oxopentanal

To a stirred solution of propionyl chloride (44 mL, 0.50 mol) in ether (135 mL) at 0 ° C under nitrogen was added a solution of compound A (69 g, 0.50 mol) in ether (135 mL) at 0 ° C over 45 min. After complete addition, the mixture was stirred at reflux for 2 hours and then stirred at room temperature for 16 hours. The reaction mixture was filtered and the filter cake was washed with ether (50 mL). The volatiles were distilled off in vacuo. The residue was dissolved in H ₂ O (80 mL) and the solution was adjusted to pH 4. Ether was added and the biphasic mixture was stirred for 16 hours. The reaction mixture was poured into a separatory funnel, the layers were separated, and the aqueous layer was extracted with ether (5x100 mL). The combined organic phases were dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was distilled under high vacuum to give 10.4 g (16%) of Compound B as a clear colorless oil. MS (MH +, 127).

C. 4-tert-Butyldimethylsilyloxy-5,5-dimethyl-6-oxo-1-octene

To a solution of (-) - β-methoxydiisopinocamphenylborane (25.7 g, 81 mmol) in ether (80 mL) at 0 ° C under nitrogen atmosphere was added a 1.0 M solution of allyl magnesium bromide in ether (77 mL) over 1.5 h. , 77 mmol). The reaction mixture was stirred at 25 ° C for 1 hour and then evaporated in vacuo. The residue was extracted with pentane (2 x 150 mL) and the extracts were filtered through Celite under nitrogen. The combined extracts were then evaporated in vacuo to give B-allyldiisopropinocamphenylborane. This material was dissolved in ether (200 mL) and cooled to -100 ° C under nitrogen. A solution of compound B (11.42 g, 89 mmol) in ether (90 mmol) was then added over 1 h at -78 ° C. The reaction mixture was stirred for an additional 0.5 hour and then methanol (1.5 mL) was added. The reaction mixture was equilibrated to room temperature, treated with 3 N NaOH solution (32 mL) and 30% H ₂ O ₂ (64 mL), and then held at reflux 2.

PV-1817-99, 31 / Tš / I 22.1 2001 · · · · · · · · · · · · · · · · · · · · · · · · hours. The reaction mixture was cooled to room temperature, the layers were separated, and the organic phase was washed with H 2 O (500 mL). The combined aqueous washes were re-extracted with ether (2 x 100 mL). The combined organic extracts were washed with saturated aqueous NaCl (100 mL), dried (MgSO ₄ ), filtered and evaporated in vacuo. The residue was dissolved in CH 2 Cl 2 (250 mL), cooled to 0 ° C, and diisopropylethylamine (93 mL, 535 mmol) was added. To the stirred solution was then slowly added tert-butyldimethylsilyltrifluoromethanesulfonate (69 g, 260 mmol) such that the temperature did not rise above 10 ° C. After complete addition, the reaction mixture was poured into H ₂ O (650 mL), the layers were separated and the aqueous layer was washed with CH ₂ Cl ₂ (2x650 mL). The combined organics were dried (Na 2 SO 4), filtered and evaporated in vacuo. The residue was purified by flash chromatography eluting with hexanes followed by 10% EtOAc / hexanes to give 17.2 g (78%) of Compound C as a clear colorless oil. An enantiomeric difference of 94% was found by ¹ H NMR analysis of Mosher's alcohol ester. ¹³ C NMR (CDCl ₃ , 80 MHz) d 215.8, 136.1,

116.5, 52.8, 39.0, 31.9, 26.0, 22.4, 20.1, 18.1, 7.6, -3.6, -4.4.

D. 3-tert-Butyldimethylsiloxy-4,4-dimethyl-5-oxoheptanal

A solution of compound C (10.8 g, 38.0 mmol) in CH 2 Cl 2 was bubbled with O ₃ at -78 ° C until the solution became permanently blue (1 hour). O ₂ was then bubbled through for 15 minutes, followed by N ₂ bubbled for 30 minutes, after which time the solution remained clear. Then triphenylphosphine (10 g, 38 mmol) was added and the reaction mixture was warmed to -35 ° C and allowed to stand for 16 hours. The volatiles were evaporated in vacuo and the residue purified by flash chromatography eluting with 8% EtOAc / hexanes to afford 8.9 g (74%) of Compound D as a clear colorless oil. ¹ H NMR (CDCl ₃ , 300 MHz) d 9.75 (m, 1H), 4.53 (t, J = 4.8 Hz, 1H), 3.40-3.60 (m, 4H), 1.10 (s, 3H), 1.07 (s, 3H), 0.98 (t, J = 7.0 Hz, 3H), 0.83 (s, 9H), 0.07 (s, 3H) ), 0.04 (s, 3H).

E. 3-tert-Butyldimethylsiloxy-4,4-dimethyl-5-oxoheptanoic acid

To a solution of compound D (3.90 g, 13.6 mmol) in tert-butanol (75 mL) was added 2-methyl-2-butene (5.85 mL, 55.2 mmol) and then dropwise at room temperature.

P 9189 added sodium chlorite solution (4.61 g, 40.8 mmol) and monobasic sodium phosphate (2.81 g, 20.4 mmol) in H ₂ O (15 mL). The reaction mixture was stirred for 0.5 hour and then the solvents were removed in vacuo. H ₂ O (150 mL) was added to the residue, followed by extraction with EtOAc (3x150 mL). The combined organic extracts were dried (MgSO ₄ ), filtered and the volatiles removed in vacuo. The residue was purified by flash chromatography eluting with 20% EtOAc / hexanes / 1% AcOH to give 3.79 g (92%) of Compound E as a clear colorless viscous oil. MS (M + H, 303).

F. (R, R) -N- (2-Hydroxy-1-methyl-2-phenethyl) -N, 2- (S) -dimethyl-6-heptenamide

A suspension of LiCl (6.9 g, 0.16 mol) and preformed lithium diisopropylamide (Aldrich, 2.0 M solution in heptane / ethylbenzene / THF, 27.6 mL, 55 mmol) in additional THF (70 mL) was added at - 78 ° C was treated dropwise with a solution of (R, R) -N- (2-hydroxy-1-methyl-2-phenethyl) -N-methylpropionamide (6.0 g, 27 mmol, Meyers AG et al., J. Am. Chem. Soc., 116, 9361 (1994)) in THF (30 mL) for 10 minutes. The light yellow reaction mixture was stirred at -78 ° C (1 hour), 0 ° C (15 minutes) and 25 ° C (5 minutes) before being re-cooled to 0 ° C and treated with 5-bromine solution. -1-pentene (4.8 mL, 40 mmol) in THF (5 mL). The reaction mixture was stirred at 0 ° C (24 h), poured into saturated aqueous NH ₄ Cl (100 mL) and EtOAc (100 mL). The two phases were separated and the aqueous phase was further extracted with EtOAc (3 x 100 mL). The organic extracts were combined, washed with saturated aqueous NaCl (200 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO ₂ , 4.0x25 cm, 2% MeOH-CHCl ₃ ) gave compound F (6.9 g, 88%) as a yellow oil. MS (ESI +): 290 (M + H) ⁺ , MS (ESI +): 288.2 (MH) -.

G. (S) -2-Methyl-6-heptenol

A 250 mL round bottom flask was sequentially charged with pyrrolidine (2.6 mL, 30 mmol) and BH ₃ -THF complex (1.0 M in THF, 31 mL, 30 mmol) at 0 ° C. The borane-pyrrolidine complex was heated to 25 ° C (1 hour), cooled to 0 ° C, and treated dropwise with n-butyllithium (1.6 M in hexane, 19 mL, 30 mmol) over 30 minutes while which was carefully maintained at an internal temperature of 5.5 ° C. Reaction mixture

P V-1817-99, 51 / Tš / I 22.1.2001 · was stirred at 0 ° C for a further 30 minutes before a solution of compound F (3.0 g, 10 mmol) in THF (23 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at 25 ° C (6 hours) before the reaction was quenched by dropwise addition of aqueous 3 N HCl (25 mL). The reaction mixture was then poured into aqueous 1 N HCl (200 mL) and extracted with Et ₂ O (4x80 mL). The combined organics were washed with a 1: 1 mixture of saturated aqueous NaCl solution and 1 N aqueous HCl (2 x 150 mL) and evaporated in vacuo. Aqueous NaOH (1 N, 200 mL) was added to the residue and the suspension was stirred for 30 minutes. The mixture was extracted with Et ₂ O (3x100 mL) and the combined ether layers were washed with a 1: 1 mixture of saturated aqueous NaCl and 1 N NaOH (2x200 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO ₂ , 4.0x25 cm, gradient elution with 15-25% Et ₂ Opentane solution) gave compound G (1.26 g, 95%) as a colorless oil. [α] ²⁵ _D -11 (c 12, CH ₂ Cl ₂ ).

H. (S) -2-Methyl-6-heptenal

A solution of compound G (0.24 g, 1.9 mmol) in CH ₂ Cl ₂ (6 mL) was treated with pyridinium chlorochromate (0.61 g, 2.8 mmol) and the reaction mixture was stirred at 25 ° C for 5 hours . The resulting dark brown viscous suspension was passed through a silica gel-Celite column (Celite 1.0x1 cm on top of SiO ₂ , 1.0x5 cm, eluting with 50 mL of CH ₂ Cl ₂ ). The solvent was evaporated in vacuo to give crude compound H (0.15 g, 63%) as a colorless oil that was sufficiently pure to be used in subsequent reactions. ¹ H NMR (300 MHz, CD ₂ Cl ₂ ): d 9.62 (s, 1H), 5.88-5.68 (m, 1H), 5.13-4.92 (m, 2H), 2 37-2.24 (m, 1H). 2.15 to 2.05 (m, 2H), 1.62 to 1.78 (m, 1H), 1.51 to 1.32 (m, 3H), 1.07 (d, 3H, J = 7) , 0 Hz).

I (3 S, 6 R ₁ 7 S, 8 S) -3-t-butyldimethylsilyloxy-4 _I 4 ₁ 8 ₁ 6-tetramethyl-7-hydroxy-5-oxo-12-Tridecenoic

To a previously prepared solution of LDA (Aldrich, 2.0 M solution in heptane / ethylbenzene / THF, 3.8 mL, 7.6 mmol) in additional THF (25 mL) at -78 ° C was added dropwise over 3 minutes a solution of compound E (1.0 g, 3.4 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -78 ° C (10 minutes), warmed to -40 ° C (20 minutes)

PV-1817-99, 51 / Ts / I 22.12001

· · • · • • · • ··· ·· · • · ·· • · · ·· · • · · · • · · ···· • · ·· ··· • · · · ·

and re-cooled to -78 ° C before compound H (0.56 g, 4.4 mmol) in THF (5 mL) was added. The reaction mixture was warmed to -40 ° C, stirred for 1 hour, and diluted with saturated aqueous NH ₄ Cl (50 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (4x50 mL). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO 2.5x20 ₂₁ cm, gradient elution with 2-5% MeOH-CHCl ₃₎ followed by separation by HPLC (YMC S-10 ODS, 30x500 mm column, eluting with MeOH flow rate of 20 ml min ^-1) to give the title the syn-aldol product, compound I (0.60 g, 43%) and the undesired diastereoisomer (0.32 g, 22%) together with the starting compound E (about 10%).

MS (ESP): 879.3 (2M + Na) ⁺ , 451.2 (M + Na) ⁺ , 429.2 (M + H) ⁺ , MS (ESP) 427.3 (MH) -.

Stereochemistry was confirmed by direct comparison of ¹³ C NMR and ¹ H NMR of the following ester derivative (used in the synthesis of epothilone C) with the same intermediate previously described by KC Nicolaou et al. in Angew. Chem. Int. Ed. Engl., 36, 166 (1997).

J. (S) -2- [N- [tert -Butyloxy] carbonyl] amino] -4-pentenoic acid

A solution of L-2-amino-4-pentenoic acid (NovaBiochem, 3.0 g, 26 mmol) in THF-H ₂ O (1: 1, 200 mL) at 0 ° C was treated sequentially with NaHCO ₃ (6.6 g, 78 mmol) and di-tert-butyl dicarbonate (10.4 g, 1.8 mmol). The reaction mixture was warmed to 25 ° C and stirred for 16 hours. The pH of the mixture was adjusted to pH 4 by carefully adding saturated aqueous citric acid solution at 0 ° C and extracted with EtOAc (4x50 mL). The combined organic layers were washed with saturated aqueous NaCl (75 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO ₂ , 4.0x6 cm, gradient elution with 5 to 10% MeOH-CHCl ₃ ) gave compound J (5.5 g, 99%) as a colorless oil. MS (ESI +): 429.3 (2M-H) -,

214.1 (M-H) ’.

K. (S) -2- [N ² - [(tert -Butyloxy) carbonyl] amino] -N-methoxy-N-methyl-4-pentenamide

A solution of compound J (2.9 g, 13 mmol) in CHCl ₃ (55 mL) at 0 ° C was treated sequentially with Ν, Ο-dimethylhydroxylamine hydrochloride (1.4 g, 15 mmol), 1PV-1817-99, 51]. T / I 22 1.2001 hydroxybenzotriazole (2.0 g, 15 mmol), 4-methylmorpholine (4.4 mL, 40 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.4 g, 18 mmol). The reaction mixture was slowly warmed to 25 ° C, stirred for 16 hours, and diluted with H ₂ O (100 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (3x75 mL). The combined organic phases were washed with 5% aqueous HCl (100 mL), saturated aqueous NaHCO ₃ (100 mL), saturated aqueous NaCl (100 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO ₂ , 3.0x20 cm, gradient elution 25 to 50% EtOAc-hexane) afforded compound K (2.5 g, 71%) as a colorless oil. MS (ESI +): 258.9 (M + H) ⁺ , 202.9 (M-isobutylene), 158.9 (MBOC), MS (ESI +): 257.2 (MH) -.

L. (S) -3- [N - [(tert-Butyloxy) carbonyl] amino] -5-hexen-2-one

A solution of compound K (2.5 g, 1.0 mmol) in THF (65 mL) at 0 ° C was treated with methylmagnesium bromide (3.0 M solution in Et ₂ O, 8.1 mL, 2.4 mmol). The reaction mixture was stirred at 0 ° C (2.5 hours) and carefully poured into saturated aqueous NH ₄ Cl solution (100 mL). The two layers were separated and the aqueous phase was extracted with EtOAc (3x75 mL). The combined organic extracts were washed with saturated aqueous NH ₄ Cl (75 mL), H ₂ O (75 mL), saturated aqueous NaCl (75 mL), dried (MgSO ₄ ) and evaporated in vacuo. Flash chromatography (SiO ₂ , 3.0x20 cm, gradient elution with 10-25% EtOAc-hexane) gave (S) -2- [N - [(tert-butyloxy) carbonyl] amino] -5-hexene-2- One (2.2 g, 67%) as a colorless oil. MS (ESI +): 213.9 (M + H) ⁺ , 157.9 (M-isobutylene), 113.9 (M-BOC), MS (ESI +): 212.2 (MH) -.

M. (S) -4- [3- [N - [(tert-Butyloxy) carbonyl] amino] -2-methyl-1 (E), 5-hexadienyl] -2-methylthiazole

A solution of 2-methyl-4-thiazolylmethyldiphenylphosphine oxide (2.5 g, 8.0 mmol, Danishefsky et al., J. Org. Chem., 61, 7998 (1996)) in THF (38 mL) at -78 ° C treated dropwise over 5 minutes with n-butyllithium (1.6 M in hexane, 5.2 mL, 8.4 mmol). The resulting bright orange mixture was stirred for 15 minutes at -78 ° C and treated with a solution of compound L (0.81 g, 3.8 mmol) in THF (5 mL). After 10 minutes at -78 ° C, the cooling bath was removed and the reaction mixture was allowed to warm to 25 ° C (2 ° C).

PV-1817-99, 51 / Tš / I 22.1.2001 ··· · · · · ··· · ··· · · · · · hours). The mixture was poured into saturated aqueous NH ₄ Cl (50 mL) and the two layers were separated. The aqueous phase was extracted with Et ₂ O (3x50 mL) and the combined organic extracts were washed sequentially with H ₂ O (75 mL), saturated aqueous NaHCO ₃ (75 mL), saturated aqueous NaCl (75 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO _2, 4.0x30 cm, gradient elution with 10-20% EtOAc-hexane) afforded compound M (0.23 g, 18%) as a colorless oil along with the restored starting ketone (20-30%). MS (ESI +): 309.1 (M + H) +, 253.0 (M-isobutylene), MS (ESI +): 307.3 (MH) -.

N. (S) -4- (3-Amino-2-methyl-1 (E), 5-hexadienyl) -2-methylthiazole

Compound M (0.15 g, 0.49 mmol) was treated with 4.0 N HCl in 1,4-dioxane (5 mL) at 0 ° C under argon. The volatiles were evaporated in vacuo and the resulting white foam was dissolved in cold saturated NaHCO ₃ (3 mL). This solution was extracted with EtOAc (4 x 10 mL) and the combined EtOAc portions were dried (Na ₂ SO ₄ ) and evaporated in vacuo. Flash chromatography (SiO ₂ , 1.0x5 cm, 5 to 10% MeOH-CHCl ₃ gradient elution) afforded compound N (88 mg, 88%) as a colorless oil. MS (ESI +): 209.0 (M + H) ⁺ , MS (ESI +): 207.2 (MH) -.

O. (3S, 6R, 7S, 8S) -N- (S) - [1- (2-Methyl-4-thiazolyl) -2-methyl-1 (E) -5-hexadien-3-yl] -3 -fercbutyldimetylsiloxy 4,4,6,8-tetramethyl-7-hydroxy-5-oxo-12-tridecenamide

A solution of compound M (88 mg, 0.42 mmol) in DMF (1.3 mL) was treated sequentially with compound I (0.15 g, 0.35 mmol), 1-hydroxybenzotriazole (49 mg, 0) at 0 ° C. , 36 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.10 g, 0.52 mmol). The reaction mixture was slowly warmed to 25 ° C, stirred for 15 hours, and diluted with H ₂ O (3 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the combined organic phases were washed with 5% aqueous HCl (10 mL), saturated aqueous NaHCO ₃ (10 mL), saturated aqueous NaCl (10 mL), dried (Na ₂ SO _4). ) and evaporated in vacuo. Flash chromatography (SiO ₂ 1.5x20 cm, 2.5% MeOH-CHCl ₃ ) gave compound O (0.17 g, 77%) as a white foam. MS (ESI +): 619.3 (M + H) ⁺ .

PV-1 817-99, 51 / Ts / I 22.1.2001

· · · · · · • · · • · • • • • · • • • · • · · · • • • • • e • · • • • • · ···· · · · · · · · · · · ·

A. [4S- [4R *, 7S *, 8R *, 9R * _I, 15R * (E)]] - 4-t-butyldimethylsilyloxy-8-hydroxy-5,5,7,9tetrametyl-16- [1-methyl -2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13 (E) -cyclohexadecene-

2,6-dione

A solution of compound O (17 mg, 27 mmol) in degassed benzene (8.0 mL) was treated with Grubb's catalyst [bis (tricyclohexylphosphine) benzylidene-ruthenium dichloride, Strem Chemicals, 11 mg, 14 mmol) under argon. The reaction mixture was stirred at 25 ° C for 15 hours and re-treated with additional catalyst (5.0 mg, 4.5 mmol). After an additional 7 hours, the benzene was evaporated in vacuo and the black viscous residue was passed through a pad of silica gel (1.0x3 cm) eluting with Et ₂ O (25 mL). The eluent was evaporated in vacuo to give a separable 5: 1 (E / Z) geometric isomer mixture. PTLC (SiO ₂ , 1 mm plate, 2 eluting with 1: 1: 1 hexane-toluene-ethyl acetate) gave the E-isomer of compound P (5.1 mg, 34%) and the corresponding zizomer (1.0 g, 6.7%) . For compound P: MS (ESI +): 1181.7 (2M + H) +, 591.4 (M + H) +. For the Z-isomer: MS (ESI ⁺ ): 1181.5 (2M + H) ⁺ , 613.2 (2M + Na) ⁺ , 591.2 (M + H) ⁺ , MS (ESI +): 589.3 ( MH).

Q. [4S- [4R *, 7S _L *, 8R *, 9R * _L 15R * (E)]] - 4,8-Dihydroxy-5,5,7,9-tetramethyl-16- [1-methyl-2 - (2-Methyl-4-thiazolyl) ethenyl] -1-aza-13 (E) -cyclohexadecene-2,6-dione

To a 3.55 cm ³ vial filled with a solution of compound P (2.3 g, 3.9 mmol) in CH ₂ Cl ₂ (0.4 mL) at 0 ° C was added trifluoroacetic acid (0.1 mL). The reaction mixture was sealed under argon and stirred at 0 ° C. After 4 hours the volatiles were removed at 0 ° C with a constant flow of argon. To the residue was added saturated aqueous NaHCO ₃ (1 mL) and EtOAc (1 mL), and the two layers were separated. The aqueous phase was extracted with EtOAc (4 x 1 mL) and the combined ethyl acetate layers were dried (Na ₂ SO ₄ ) and evaporated in vacuo. PTLC (SiO ₂ 20x10x0.025 cm, eluting with 5% MeOH-CHCl ₃ ) gave [4S- [4R *, 7S *, 8R ', 9R *, 15R * (E)]] - 4,8-dihydroxy-5 5,7,9tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13 (E) -cyclohexadecene-2,6-dione (1.3 mg, 68% ) in the form of a white film. MS (ESI): 953.5 (2M + H) ⁺ , 477.3 (M + H) ⁺ , MS (ESI +): 475.5 (MH) -.

Example 2

P V-1817-99, 51 / TS / I 22 1.2001

· · • · • ·· • ··· · · • • • • • · · ·· • · • · • ·· • F • e · · · · · · · · · · · 1 · · ·

The following compounds can be prepared according to the above-described reaction schemes:

[1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3 - [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,13,17-trioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R] * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl)] -4-thiazolyl) ethenyl] -4,13,17-trioxabicyclo [14.1.0] heptadecane-5,9-dione, [4S- [4R * 7S *, 8R *, 9R *, 15R * (E)]] -4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1,10-dioxa-13-cyclohexadecene-2 6-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9-tetramethyl-16- [1- methyl-2 (2-methyl-4-thiazolyl) ethenyl] -1,10-dioxa-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S] *, 11R *, 12R *. 16S *]] - 7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,14,17-trioxabicyclo [14.1.0] Heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R * 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy -8,8,10,12tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,14,17-trioxabicyclo [14.1.0] heptadecane-5,9-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2- -methyl-4-thiazolyl) ethenyl] -1,11-dioxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R *, 1 SR, 4'-dihydroxy] -S.S-g-tetramethyl-6- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1,11-dioxa-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1- methyl 2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R] *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl ] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11] R *, 12R *, 16S *]] - 7,11-dihydroxy-3,8,8,10,12,16-hexamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] - 4,17-dioxabicyclo [14.1.0] 5,9-dione,

PV-1817-99, 51 / Tš / I 22 1.2001 • 999 9 99

9

9999 99 99999 9 9 9 i: ·· ·· [1 S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S * ]] - 7,11-Dihydroxy-3,8,8,10,12-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] heptadecan-5,9-dione, [4S44R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9,13,16-hexamethyl-16 - [1 methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-oxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R] * (E)]] - 4,8-Dihydroxy-5,5,7,9,16-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-oxa-13 -cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *]. 16S *]] - 7,11-Dihydroxy-6,8,8,10,12,16-hexamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [ 14.1.0] Heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *]. 12R *, 16S *]] - 7,11-Dihydroxy-6,8,8,10,12-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] 5,9-dione, [4S- [4R *, 7S *, 8R *, 9R * _l 15R * (E)]] - 4,8-dihydroxy-5,5,7,9 -tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E)] ), 7R *, 10S *, 11R *, 12R *. 16S *]] - 7,11-dihydroxy-4,8,8,10,12,16-hexamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17- oxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *]. 16S *]] - 7,11-Dihydroxy-4,8,8,10,12-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [ 14.1.0] Heptadecane-5,9-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-1,5,5,7, 9,13-hexamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R] *, 9R *, 15R * (E)]] - 4,8-dihydroxy-1,5,5,7,9-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] - 1-aza-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *]. 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -13-aza-4,17- dioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7.11 -dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -13-aza-4,17-dioxabicyclo [14.1.0] PV-1817- 99, 51 / Tš / I 22.1 2001 ················ 43 heptadecan-5,9-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R] * (E)]] - 4,8-Dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -10-aza-1- oxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R * _I, 15R * (E)]] - 4 _l 8-dihydroxy-5,5,7,9- tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -10-aza-1-oxa-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R] * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2 methyl-4-thiazolyl) ethenyl] -14-aza-4,17-dioxa-bicyclo [14.1.0] hepta decane-5,9-dione, [1S- [1R *, 3R * (E), 7R * 10S *, 11R *, 12R *]. 16S *]] - 7,11-Dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -14-aza-4,17-dioxabicyclo [ 14.1.0] Heptadecane-5,9-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9, 13-Pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -11-aza-1-oxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *] , 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9-tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -11-aza-1-oxa-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *] -N-phenyl-7,11-dihydroxy-

8,8,10,12,1 6-Pentamethyl-5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptadecane-3-carboxamide, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - N-phenyl-7,11-dihydroxy-8,8,10,12-tetramethyl-5,9-dioxo-4,17-dioxabicyclo [14.1. O] heptadecane-3-carboxamide, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - N-phenyl-4,8-dihydroxy-5,5,7,9, 13-pentamethyl

2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - N-Phenyl-4,8- dihydroxy-5,5,7,9-tetramethyl-2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide, [1S- [1R *, 3R * (E), 7R *, 10S *, 11] R *, 12R *. 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) cyclopropyl] -4,17-dioxabicyclo [14.1. O] heptadecan-5,9-dione and [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *]. 16S * j] -7,11-dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) cyclopropyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione.

PV-1817-99,51 / TS / I 22 1.2001

99 ···························· 9 9 9 9 ·

9999 99 99,999 99 ·

Example 3

[1S- [1R *, 3R * (E), 7R * 10S *, 11R *, 12R *]. 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-

3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [14.1.0] heptadecane-5.9dione.

A. (3S, 6R, 7S, 8S, 12R, 13S, 15S) -15-Azido-12,13-epoxy-4,4,6,8,12,16-hexamethyl-7-hydroxy-17- (2- methyl-4-thiazolyl) -5-oxo-16-heptadecenoic

A solution of epothilone B (0.35 g, 0.69 mmol) in degassed THF (4.5 mL) was treated with a catalytic amount (80 mg, 69 mmol) of tetrakis (triphenylphosphine) palladium (0) and the suspension was stirred under argon at 25 ° C for 30 minutes. The resulting bright yellow homogeneous solution was all treated at once with a solution of sodium azide (54 mg, 0.83 mmol) in degassed H ₂ O (2.2 mL). The reaction mixture was heated to 45 ° C for 1 hour, diluted with H ₂ O (5 mL) and extracted with EtOAc (4x75 mL). The organic extracts were washed with saturated aqueous NaCl (15 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (SiO ₂ , 3.0x15 cm, 95: 5.0: 0.5 CHCl ₃ -MeOH-AcOH) to give compound A (0.23 g, 61%) as a colorless oil. MS (ESI ⁺ ), 551 (M + H) ⁺ , MS (ESI +), 549 (MH) -.

B. (3S, 6R, 7S, 8S, 12R, 13S, 15S) -15-Amino-12,13-epoxy-4,4,6,8,12,16-hexamethyl-7-hydroxy-17- (2- methyl-4-thiazolyl) -5-oxo-16-heptadecenoic

A solution of compound A (0.23 g, 0.42 mmol) in THF (4.0 mL) at 25 ° C was treated with H ₂ O (23 mL, 1.25 mmol) and on a polymer saturated with triphenylphosphine (Aldrich, polystyrene crosslinked with 2% DVB, 0.28 g, 0.84 mmol). The resulting suspension was stirred at 25 ° C under argon atmosphere (32 hours), filtered through Celite and evaporated in vacuo. The residue was purified by flash chromatography (SiO ₂ 1.5x10 cm, gradient elution from 95: 5.0: 0, 5 to 90: 10: 1.0 CHCl ₃ -MeOH-AcOH) to afford compound B (96 mg, 44%) as a colorless oil. MS (ESI ⁺ ): 525.2

PV-1817-99, 51 / TS / I 22 1.2001

· · e · • ·· • ··· • 4 : with • · · • ·· • · • · • · ···· · · · · · · · · · · ·

(M + H) +, MS (ESI +): 523.4 (M-H) -.

Alternatively, absolute EtOH was added to a 25 mL round bottom flask charged with compound A (0.26 g, 0.47 mmol) and PtO ₂ (0.13 g, 50%) under argon. The resulting black mixture was stirred under a H ₂ atmosphere for 10 minutes, after which time the system was purged with N ₂ and another portion of PtO ₂ (65 mg, 25% by weight) was added. Once again, the reaction mixture was stirred under a H ₂ atmosphere for 10 hours. The system was then purged with N ₂ and the reaction mixture was filtered through a pad of Celite eluting with CH ₂ Cl ₂ (3 x 25 mL). The solvents were evaporated in vacuo and the residue was purified as above to give compound B (0.19 g, 75%).

Alternatively, a solution of compound A (20 mg, 36 mmol) in THF (0.4 mL) under argon was treated with triphenylphosphine (19 mg, 73 mmol). The reaction mixture was heated to 45 ° C, stirred for 14 hours and cooled to 25 ° C. The resulting iminophosphorane was treated with ammonium hydroxide (28%, 0.1 mL) and the reaction mixture was heated once more to 45 ° C. After 4 hours, the volatiles were removed in vacuo and the residue was purified as above to give compound B (13 mg, 70%).

C. [1S- [1R *, 3R * (E), 7R * 10S *]. 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4 aza-17-oxabicyclo [14.1.0] 5,9-dione.

A solution of compound B (0.33 g, 0.63 mmol) in degassed DMF (250 mL) was treated with solid NaHCO ₃ (0.42 g, 5.0 mmol) and diphenylphosphorylazide (0.54) at 0 ° C under argon. ml, 2.5 mmol). The resulting suspension was stirred at 4 ° C for 24 hours, diluted at 0 ° C with phosphate buffer (250 mL, pH 7) and extracted with EtOAc (5x100 mL). The organic extracts were washed with 10% aqueous LiCl solution (2 x 125 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was first purified by flash chromatography (SiO ₂ , 2.0x10 cm, gradient elution 2 to 5% MeOH-CHCl ₃ ) and then purified using Chromatotron (2 mm SiO ₂₁ GF rotor, gradient elution 2 to 5% MeOH-CHCl ₃ ) to give the title compound (0.13 g, 40%) as a colorless oil.

¹ H NMR (CDCl ₃₁ 400 MHz): δ 6.98 (s, 1 H, 6.71 (d, 1 H, NH, J = 8.1 Hz), 6.56 (s, 1H), 4.69 to 4.62 (m, 1H), 4.18 to 4.12 (m, 1H), 4.01 to 3.96 (m, 1H), 3.86 (s, 1H),

PV-1817-99, 51 / Tä / I 22.1. 2001

· · • · • • 9 9 999 9 · 9 9 9 · 9 99 9 99 9 · 9 9 9 99 9 • 9 9 9 9 9 š é 9 ···· 99 99 999 99 999

3.38 to 3.34 (m, 1H), 2.82 (dd, 1H, J = 5.6, 6.0 Hz), 2.71 (s, 3H), 2.58 (s, 1H) 1.43 (dd, h, J = 9.0, 14.5 Hz), 3.34 (dd, 1H, J = 3.0, 14.5 Hz), 2.14 (s, 3H) , 2.05-1.92 (m, 2H), 1.82-1.41 (multiplet series, 7H), 1.35 (s, 3H), 1.28 (s, 3H), 1.18 ( d, 3H, J = 6.8 Hz), 1.14 (s, 3H), 1.00 (d, 3H, J = 6.8 Hz); MS (ESI ⁺ ), 507.2 (M + H) ^&lt; ^{+ &gt};; MS (ESI +):

505.4 (Μ-H) ’.

Example 4

A method of reducing the epothilone oxirane ring and epothilone analogs

Chopped pieces of magnesium chips (24 mg, 1.0 mmol) were placed in a two-necked flask. The flask was flame dried in vacuo and cooled under argon. Bis (cyclopentadienyl) titanium dichloride (250 mg, 1.0 mmol) was added followed by anhydrous THF (5 mL). The stirred suspension was degassed under high vacuum and the flask was refilled with argon. The red suspension darkened, passing to a uniformly dark green after 1.5 hours as almost all of the magnesium metal had been consumed. An aliquot (3.5 mL, 0.70 mmol, 3.5 eq) was taken and cooled under argon to -78 ° C. To this solution was added epothilone A (99 mg, 0.20 mmol, 1.0 eq). The reaction mixture was warmed to room temperature and stirred for 15 minutes. The volatiles were evaporated in vacuo and the residue was chromatographed twice on silica (25 g) using 35% EtOAc / hexanes as the carrier liquid to give 76 mg (80%) of epothilone C as a light yellow viscous oil.

Example 5

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

A. Acid (SS.GRJS.eS, 12R, 13S, 15S) -15-azido-3,7-dihydroxy-12,13-epoxyPV-1817-99,51

·· • · • · · • ··· · · • · • · • · · • ·· • · • · • · · • ···· · · · · · · · · · ·· ·

4,4,6,8,16-pentamethyl-17- (2-methyl-4-thiazolyl) -5-oxo-16 (E) -heptadecénová

To a solution of epothilone A (4.97 g, 10.1 mmol, 1.0 eq) in degassed THF (100 mL) at room temperature was added tetrakis (triphenylphosphine) palladium (0) (1.17 g, 1.01) mmol, 0.10 eq) and stirred for 30 minutes under argon. To this reaction mixture was added sodium azide (0.980 g, 15.1 mmol, 1.5 eq) followed by degassed water (10 mL). The reaction mixture was heated at 45 ° C for 1 hour, cooled to room temperature, diluted with ethyl acetate (300 mL) and further diluted with water (150 mL). The aqueous layers were extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine (150 mL), dried (sodium sulfate), filtered and evaporated in vacuo. The oily residue was purified by flash chromatography on silica gel (eluting with 0 to 5% methanol / chloroform with 0.1% acetic acid) to give compound A (1.84 g, 34.0% yield) as a glassy solid. MS (ESI +): 537 (M + H) +, MS (ESI +): 535 (M-H) -.

B. (3S, 6R, 7S, 8S, 12R, 13S, 15S) -15-Amino-3,7-dihydroxy-12,13-epoxy-

4,4,6,8,16-pentamethyl-17- (2-methyl-4-thiazolyl) -5-oxo-16 (E) -heptadecénová

To a solution of compound A (1.85 g, 3.44 mmol, 1.0 eq) in absolute ethanol (137 mL) was added platinum oxide (0.980 g, 4.30 mmol, 1.25 eq). The reaction mixture was stirred vigorously at room temperature under a hydrogen balloon for 16 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The oily residue was purified by preparative HPLC (YMC S-15 ODS 50x500 mm column, 45 min / gradient elution, 0 to 100% B, 50 mL min ^-1 , retention time 17 min, A = 0.1% acetic acid / 5 % acetonitrile / 95% water, B = 0.1% acetic acid / 5% water / 95% acetonitrile). The appropriate fractions were evaporated in vacuo and the residue was lyophilized with an aqueous solution of acetonitrile to afford compound B (1.33 g, 76.0% yield) as a colorless solid. MS (ESI +): 511 (M + H) ⁺ , MS (ESI +): 509 (MH) -.

C. [1S- [1R *, 3R * (E), 7R *, 10S *]. 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza -17-oxabicyclo [14.1] octeptadecane-5,9-dione

Compound B (0.860 g, 1.68 mmol, 1.0 eq) was dissolved in anhydrous DMF

PV-1817-99, 51 / Tä / I 22.1.2001 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (0.00250 Μ, 672 mL) and degassed for 1 hour at room temperature. The solution was cooled to 0 ° C and anhydrous sodium bicarbonate (1.13 g, 13.4 mmol, 4.0 eq.) And diphenylphosphoryl azide (1.85 g, 6.72 mmol, 8.0 eq.) Were added under an argon atmosphere. .). The reaction mixture was kept under argon at 4 ° C and stirred for 16 hours. Then, the reaction mixture was cooled to -60 ° C and pH 7 phosphate buffer (400 mL) was added slowly to quench the reaction. The temperature was kept below -30 ° C. The mixture was allowed to warm slowly to room temperature and extracted with ethyl acetate (1 liter). The aqueous layer was washed with ethyl acetate (4x300 mL). The organic extracts were combined, washed with 10% LiCl solution (500 mL), dried (sodium sulfate), filtered and evaporated in vacuo. The oily residue was purified by preparative HPLC (YMC S-15 ODS 50x500 mm column, 45 min / gradient elution, 0 to 100% B, 50 mL min ^-1 , retention time = 35 min, A = 5% acetonitrile / 95% water B = 5% water / 95% acetonitrile). The appropriate fractions were evaporated in vacuo and the residue was lyophilized with an aqueous solution of acetonitrile to give the title compound (0.220 g, 26.0% yield) as a colorless solid. MS (ESI +): 493 (M + H) ⁺ , MS (ESI +): 491 (MH) -.

Example 6

[4S- [4R *, 7S *, 8R *, 9R * 15R * (E)]] - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2 ( 2-methyl-4-thiazolyl) ethenyl] -1-aza-13 (Z) -cyclohexadecene-2,6-dione

Tungsten chloride (0.19 g, 0.49 mmol, 0.5 eq) was dissolved in THF (5.0 mL) and the solution was cooled to -78 ° C. A solution of n-butyllithium in hexane (1.6 M, 0.63 mL, 1.0 mmol, 1.0 eq) was added in one portion and the reaction mixture was allowed to warm to room temperature over 20 minutes (while warming to room temperature dark green). A 0.1 M solution of the tungsten reagent thus prepared (0.79 mL, 0.079 mmol, 2.0 mmol) was added to 4C (0.020 g, 0.039 mmol, 1.0 eq) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then quenched with saturated NaHCO ₃ solution (2.0 mL). This solution was diluted with water (10 mL)

P V-1817-99, 51 / Ts / I 22 1.2001

· · • · • ·· • ··· ·· • · • · • ·· • • · • · • · • • · • ···· · · · · · · · · · ·· ·

and the solution was extracted with CH 2 Cl 2 (4x20 mL). The combined organic extracts were dried (Na ₂ SO 4), filtered and evaporated in vacuo. The inorganics were removed by passing the residue through a pad of silica gel (eluting with 19/1 CHCl3 / MeOH). The eluent was evaporated in vacuo. The residue was purified by PHPLC (YMC S-5 ODS, 30-100% B, A = 5% aq CH ₃ CN, B = 95% aqueous CH ₃ CN, 3 ml min ^-1, 220 nm, 30 min gradient elution) and the appropriate fractions were evaporated in vacuo. The sticky solid was lyophilized from aqueous acetonitrile to give the title compound (4.3 mg, 29%) as a white solid. TLC: Rf = 0.57 (9/1 CHCl3 / MeOH, UV visible), HRMS: (M + H) +, calc 491.29436, found 491.2934.

Example 7

[1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl3 - [1-Methyl-2- (2-hydroxymethyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [14.1.0] heptadecane-5,9-dione

A. N-Oxide [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10, 12,16pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1,0] heptadecane-5,9-dione

A solution of epothilone B (2.0 g, 3.9 mmol) in CH ₂ Cl ₂ (30 mL) was treated at 25 ° C for 2 h under argon with 3-chloroperoxybenzoic acid (1.0 g,

5.9 mmol). An additional 0.5 g (3.0 mmol) of 3-chloroperoxybenzoic acid was added and the reaction mixture was stirred for 2 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with saturated

PV-1817-99, 51 / Tš / I 22 1.2001 aqueous NaHCO ₃ solution (75 ml), 5% aqueous Na ₂ SO _{3 solution} (75 ml), H ₂ O (75 ml), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (SiO ₂ 4.5x30 cm, gradient elution with 2 to 10% MeOHCHCl ₃ ) to give compound A (1.04 g, 50%) as a white solid. MS (ESI ⁺ ), 524.3 (M + H) ^&lt; ^{+ &gt};; MS (ESI +): 522.5 (MH) -.

· · • · • ·· • ··· · · • · · • • · • • · • • • • • • • • • • • · • • • • • 9 ···· • · · · · · · · · • 44

B. [1S- [1R *, 3R * (E), 7R *, 10S *]. 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-hydroxymethyl-4-thiazolyl) ethenyl] -4 , 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione [epothilone F]

To a solution of compound A (0.46 g, 0.88 mmol) in CH ₂ Cl ₂ (10 mL) in a resealable tube was added 2,6-lutidine (0.82 mL, 7.0 mmol) under argon and trifluoroacetic anhydride (0.87 mL, 6.2 mmol). The reaction vessel was sealed under argon, heated to 75 ° C (12 minutes), cooled to 25 ° C, and the volatiles were removed under a constant stream of N ₂ . The reaction tube was then connected to the high vacuum pump for 15 minutes. The resulting residue was dissolved in MeOH (10 mL) and treated with ammonium hydroxide (28-30% NH ₄ in H ₂ O, 1 mL). The mixture was heated to 45 ° C (10 minutes) and the volatiles were evaporated in vacuo. The crude reaction mixture was purified by HPLC (YMC S-15 ODS 30x500 mm column, 50% acetonitrile-water solution, isocratic conditions, flow rate 20 ml.min ^-1 , retention time 28 minutes). The appropriate fractions were evaporated in vacuo and the residue was lyophilized from aqueous acetonitrile to give compound B (0.22 g, 48%) as a white solid. MS (ESI ⁺ ): 524.3 (M + H) ⁺ , 1047.6 (2M + H) ⁺ , MS (ESI +): 522.5 (MH) -

C. Acid (SS, 6R, 6S, 12R, 13S, 15S) -15-azido-3,7-dihydroxy-12,13-epoxyPV-1817-99, 51 / T / 1 22.1.2001

e · • · • ·· • ··· · · • · · • · · • • · • • • • • • • • • • • · • • • • • • ···· · · · · · · · • e • e ·

4,4,6,8,12,16-hexamethyl-17- (2-hydroxymethyl-4-thiazolyl) -5-oxo-16 (E) heptadecenoic

A solution of compound B (0.18 g, 0.34 mmol) in degassed THF (3.0 mL) was treated with a catalytic amount (40 mg, 3.4.10 ^-2 mmol) of tetrakis (triphenylphosphine) palladium (0) and the mixture was stirred was stirred under argon at 25 ° C for 30 minutes. The resulting bright yellow homogeneous solution was all treated at once with a solution of sodium azide (27 mg, 0.41 mmol) in degassed H ₂ O (1.5 mmol). The reaction mixture was heated to 45 ° C for 1 hour, diluted with H ₂ O (5 mL) and extracted with EtOAc (4x10 mL). The organic extracts were washed with saturated aqueous NaCl (15 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (SiO _2, 2.5 x 15 cm, gradient elution 95: 5.0: 0.5 CHCl ₃ -MeOH-AcOH) to give compound C (39 mg, 20%) as a colorless oil. MS (ESI ⁺ ): 567.4 (M + H) ⁺ , 1136.6 (2M + H) ⁺ , MS (ESI +): 565.5 (MH) +, 1131.8 (Μ-H) -.

D. (SS, 6RJS.eS, 12R, 13S, 15S) -15-amino-3,7-dihydroxy-12,13-epoxy-

4,4,6,8,12,16-hexamethyl-17- (2-hydroxymethyl-4-thiazolyl) -5-oxo-16 (E) heptadecenoic

To a 10 mL round bottom flask charged with compound C (40 mg, 71 mmol) and PtO ₂ (12 mg, 30%) was added absolute ethanol (3 mL) under argon. The resulting black mixture was stirred under a hydrogen atmosphere for 10 hours. The system was purged with nitrogen and the reaction mixture was filtered through a nylon membrane (washed with 25 mL of MeOH). The solvents were evaporated in vacuo to give compound D (29 mg, 76%) as a foam that was sufficiently pure to be used in the next step. LCMS: 541.3 (M + H) &lt; ^{+ &gt};.

P V-1817-99, 51 / TS / I 22 1.2001

·· • · · · • ··· 99 9 99 • 99 9 9 · • 9 9 e 9 9 9 9 9 • • · 9 9 9 • 9 • ···· • e 99 999 99 999

E. [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *]. 16S *]] - 7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-hydroxymethyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [ 14.1,0] heptadecane-5,9-dione

A solution of compound D (29 mg, 54 mmol) in degassed DMF (21 mL) at 0 ° C under argon was treated with solid NaHCO ₃ (36 mg, 0.43 mmol) and diphenylphosphoryl azide (46 mL, 0.21 mmol). . The resulting suspension was stirred at 4 ° C for 19 hours, cooled to -40 ° C, diluted with 25 mL of phosphate buffer pH 7 (carefully added to keep the internal temperature below -30 ° C) and extracted with EtOAc (4x10 mL). ). The organic extracts were washed with cold 10% aqueous LiCl solution (25 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified using chromatotron (1 mm SiO ₂ , GF rotor, gradient elution with 2-5% MeOH-CHCl ₃ ) to give the title compound (9.1 mg, 34%) as a colorless oil. MS (ESI ⁺ ): 523.2 (M + H) ⁺ , MS (ESI +): 521.5 (MH) -.

Example 8

O OH O [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1- methyl-2- (2-hydroxymethyl-4-thiazolyl) ethenyl] -1-aza-13 (Z) -cyclohexadecene-2,6-dione

P V-18 J 7-99, 51 / Tš / I 22.1

· · • · • ·· • ··· • • · · • • • · · • · · • · • · • ·· • • 9 9 • • • • · • ···· 99 · · · · · · · · · ·

A. [1S- [1R *, 3R * (E), 7R *, 10S *]. 11R *, 12R *. 16S *]] - 7,11-Dihydroxy-8,8,10,12,16pentamethyl-3- [1-methyl-2- (2-tert-butyldiphenylsilyloxymethyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [ 14.1,0] heptadecane-5,9-dione

A solution of 7E (6.8 mg, 13 mmol) in CH 2 Cl 2 (0.5 mL) was treated with triethylamine (2.7 mL, 20 mmol), 4-N, N-dimethylaminopyridine (0.2 mL) at 0 ° C under argon. mg, 1.3 mmol) and tert-butyldiphenylsilyl chloride (3.7 mL, 14 mmol). The reaction mixture was gradually heated at 25 ° C (1 hour), cooled to 0 ° C, quenched with saturated aqueous NaHCO ₃ solution (1 mL), and extracted with EtOAc (4x2 mL). The combined organic extracts were washed with brine (5 mL), dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by flash chromatography (SiO ₂ , 1.0x5 cm, gradient elution with 2 to 5% MeOH-CHCl ₃ ) to give compound A (7.0 mg, 71%) as a colorless oil. MS (ESI +): 761.5 (M + H) ⁺ , MS (ESI +): 759.7 (MH) -.

B. [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl2] - (2-hydroxymethyl-4-thiazolyl) ethenyl] -1-aza-13 (Z) -cyclohexadecene-2,6-dione

A solution of tungsten trichloride (0.10 g, 0.25 mmol) in anhydrous THF was treated with n-BuLi (1.6 M in hexane, 0.32 mL, 0.50 mmol) at -78 ° C under argon. . The reaction mixture was heated at 25 ° C for 40 minutes and then recooled to 0 ° C. An aliquot (0.2 mL, 20 mmol) of the resulting dark green, homogeneous solution was added at 0 ° C under argon to a 3.55 cm ³ vial containing a Compound A (7.0 mg, 9.2 mmol). The reaction mixture was warmed to 25 ° C, stirred for 30 minutes, quenched with saturated aqueous NaHCO ₃ (0.5 mL) and extracted with EtOAc (4x1 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was purified by preparative TLC (SiO ₂ , 20x20x0.025 cm, eluting with 5% MeOH-CHCl ₃ ) to give an indivisible mixture of the silyl protected 13- (Z) -isomer

PV-1817-99, 51 / TS / I 22 1.2001

· · • · • · · • · · · · · • • · • ·· • · • · • · • • • • • • · • • • • · • · · · • · • · · · · · · • ·

Compound B and a small amount (<10%) of the minor 13 (E) -isomer, which was immediately deprotected in the next step.

A mixture of the silyl protected isomers of compound B (2.3 mg, 3.1 mmol) was treated with 0.3 mL of a buffered solution of HF-pyridine in THF (2: 1: 0.5 THF / pyridine / HF- solution at 25 ° C). pyridine from Aldrich Chemical Co.). After 1 hour, the mixture was neutralized with saturated aqueous NaHCO ₃ (0.5 mL) and extracted with EtOAc (4x1 mL). The combined organic extracts were washed with saturated aqueous NaHCO ₃ (1 mL), dried (Na ₂ SO ₄ ), and the volatiles removed in vacuo. The residue was purified by preparative TLC (SiO ₂ , 20x10x0.025 cm, eluting with 5% MeOH-CHCl ₃ ) to give the title compound 13 (Z) -isomer together with an inseparable amount (<10%) of the minor 13 (E) - isomer (0.96 mg, 20% for two steps) as a thin film. MS (ESI +): 507.3 (M + H) ⁺ , MS (ESI +): 505.6 (ΜΗ) -.

P V-1817-99, 51 TS / I 22.1.2001

Claims (6)

PATENT CLAIMS A compound of the general formula V wherein Q is selected from the group consisting of G is selected from the group consisting of alkyl, substituted alkyl, substituted or unsubstituted aryl, heterocyclo, W is O or NR ₁₅ ; X is O or H, H; Y is selected from the group consisting of O; H, OR ₁₆ ; OR _{17 71} OR ₁₇ ; NOR ₁₈ ; H, NOR _{1 S;} H, NR 20 R 21; H, H; or CHR22; ₇ ORi ORi ₇ may be a cyclic ketal; Z 1 and Z ₂ are selected from the group consisting of CH ₂₁ O, NR ₂₃ , S or SO ₂ , with only one Ζ _Ζ or Z ₂ being a heteroatom; Bi and _B2 are selected from OR ₂₄ or OCOR _25, or O ₂ CNR2 ₆ R @ 2 ₇₁ where Bi is H and Y is OH, H they can form a six-membered ring ketal or acetal; D is selected from the group consisting of NR 28 R 29, NR 30 COR 31 or saturated PV-1817-99, 51 / ls / I 22 1.2001 • · heterocycle; R, R ₂₁ R ₃₁ R 41 R, R, R ?, R 14 Ri3i, Rie, R19, R221 R26 R2O1 R2L 3 R 27 is selected from the group consisting of H, alkyl, substituted alkyl, or aryl and where the R 1 and R ₂ alkyls, may be joined to form cycloalkyl; if R ₃ and R ₄ alkyls, they may be joined to form cycloalkyl; R, R10, Rie, R 17, R 24, R 25 and R ₃ and selected from H, alkyl, substituted alkyl; Rs, R11, R12, R281, R30. R 32, R 33 and R ₃₀ are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl or heterocyclo; R 13, R ₂₃ and R ₂₉ are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R ₃₂ C = O, R ₃₃ SO ₂ , hydroxy, O-alkyl or O-substituted alkyl and its pharmaceutical acceptable salts and any hydrates, solvates or geometrical, optical and stereoisomers thereof, provided that compounds are excluded wherein: W and X are both oxygen atoms; R 1, R ₂ and R ₇ are hydrogen atoms; R ₃ , R ₄ and R ₆ are methyl; and R 8 is hydrogen or methyl; and Z 1 and Z ₂ are CH ₂ ; and G is 1-methyl-2- (substituted-4-thiazolyl) ethenyl; Q has the same meaning as above. The compound of claim 1, wherein Q is X is an oxygen atom PV-l 817-99, 51 / T5 / I 22 1.2001 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Y is an oxygen atom Z 1 and Z ₂ are CH ₂ and groups W is NR ₅ . 3. A compound selected from the group consisting of: [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *]. 16S *]] - 7,11-Dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,13,17-trioxabicyclo [ 14.1.0] Heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy -8,8,10,12tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,13,17-trioxabicyclo [14.1.0] heptadecane-5,9-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9,13-pentamethyl-16- [1-methyl-2- ( 2-methyl-4-thiazolyl) ethenyl] -1,10-dioxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] 4,8-dihydroxy-5,5,7,9-tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1,10-dioxa-13-cyclohexadecene-2,6 -dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12, 16pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,14,17-trioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R] *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- ( 2-methyl-4-thiazolyl) ethenyl] -4,14,17-trioxabicyclo [14.1.0] heptadecane-5,9-dione -dihydroxy-5S-g, 15-pentamethyl-1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1,11-dioxa-13-cyclohexadecene-2,6-dione, [4S- [4R * 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-5,5,7,9-tetramethyl-16- [1-methyl-2 (2-methyl-4)] -thiazolyl) ethenyl] -1,11-dioxa-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1. O] heptadecan-5,9-dione, [1S- [1R *, 3R * (E), 7R * 10S *, 11R *]. 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12 PV-1817-99, 51 / Ts / I 22.1.2001 Tetramets 1-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] heptadecane- 5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-3,8,8 , 10,12,16hexamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-3,8,8,10,12-pentamethyl-3- [1-methyl -2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione; -S-6-g-1S-hexamethyl-1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-oxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - _{4,8-dihydroxy-5,5,7,9-I,} 16-pentamethyl-16- [1-methyl-2- (2-methyl- 4-thiazolyl) ethenyl] -1-oxa-13-cyclohexadecene-2,6-dione _I [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S * ]] - 7,11-Dihydroxy-6,8,8,10,12,16-hexamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1. 0] heptadecan-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *] ] -7,11-Dihydroxy-6,8,8,10,12-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4,17-dioxabicyclo [14.1.0] heptadecane -5,9-dione, [4S- [4R *, 7S * _l * 8 R 9 R _{I l} * 15R * (E)]] - 4,8-dihydroxy-5,5,7,9-tetramethyl-16- [ 1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S] *, 11R *, 12R *. 16S *]] - 7,11-Dihydroxy-4,8,8,10,12,16-hexamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17- oxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7.11 dihydroxy-4,8,8,10,12pentametyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -4-aza-17-oxabicyclo [14.1.0] 5, 9-dione, [4S- [4R *, 7S *, 8R *, 9R * 15R * (E)]] - 4,8-dihydroxy-1,5,5,7,9,13-hexamethyl-16- [ 1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R * 15R * (E)] ]]] - 4,8-Dihydroxy-1,5,5,7,9-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -1-aza-13-cyclohexadecene- 2,6-dione, PV-1817-99, 51 / Ts / I 22.1.2001 ·· ·· ·· · · · • · · • · ·· • · · • ··· • e · • · ···· ·· ·· ··· ·· · [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - 4,8-dihydroxy-1,5,5,7,9-pentamethyl-16- [1 methyl-2] - (2-methyl-4-thiazolyl) ethenyl] -1-aza-13-cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *] . 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -13-aza-4 , 17-dioxabicyclo [14.1.0] heptadecane-5,9-dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8,10,12tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -13-aza-4,17-dioxabicyclo [14.1.0] heptadecane -5,9-dione, [4S- [4R *, 7S *, 8R *, 9R *, 1 SR-E] .mu.-dihydroxy-5'-g, 13-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -10-aza-1-oxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)] ]]] - 4,8-Dihydroxy-5,5 _L 7,9-tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -10-aza-1-oxa-13- cyclohexadecene-2,6-dione, [1S- [1R *, 3R * (E), 7R * 10S *, 11R *, 12R *, 16S *]] - 7,11-dihydroxy-8,8, 10,12,16pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -14-aza-4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione, [ 1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *. 16S *]] - 7,11-Dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -14-aza-4,17-dioxabicyclo [ 14.1.0] 5,9-dione, KS-KRVS-eR-R *, 1 SR-EJM-e-dihydroxy-S.SJ.g, 13-pentamethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -11- aza-1-oxa-13-cyclohexadecene-2,6-dione, [4S- [4R *, 7S *, 8R *, 9R * 15R * (E)]] - 4,8-dihydroxy-5,5,7 9-tetramethyl-16- [1-methyl-2- (2-methyl-4-thiazolyl) ethenyl] -11-aza-1-oxa-13-cyclohexadecene-2,6-dione, [1S- [1R] *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - N-phenyl-7,11-dihydroxy-8,8, 10,12,16-pentamethyl-5,9- dioxo-4,17-dioxabicyclo [14.1.0] heptadecane-3-carboxamide, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - N -phenyl-7,11-dihydroxy-8,8,10,12tetramethyl-5,9-dioxo-4,17-dioxabicyclo [14.1.0] heptadecane-3-carboxamide, [4S- [4R *, 7S *, 8R] *, 9R *, 15R * (E)]] - N-phenyl-4 _I 8-dihydroxy-5,5,7,9,13-pentamethyl 2,6-dioxo-1-oxa-13-cyclohexadecene-16-carboxamide, [4S- [4R *, 7S *, 8R *, 9R *, 15R * (E)]] - N-phenyl-4 _I 8- dihydroxy-5,5,7,9-tetramethyl-2,6PV-1817-99, 51 / TS / I 22.1.2001 ·· • · • ·· • ··· · · • · • · • · ·· • · • · • • · • • • ···· · · · · · · · • · • ··· dioxo-1-oxa-13-cyclohexadecene-16-carboxamide, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *, 16S *]] - 7.11 -dihydroxy-8,8,10,12,16pentamethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) cyclopropyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9- dione, [1S- [1R *, 3R * (E), 7R *, 10S *, 11R *, 12R *. 16S *]] - 7,11-Dihydroxy-8,8,10,12-tetramethyl-3- [1-methyl-2- (2-methyl-4-thiazolyl) cyclopropyl] -4,17-dioxabicyclo [14.1.0] heptadecane-5,9-dione, [4S- [4R *, 7S *, 8R *, 9R * _{l l} 15 R * (E)]] - 4,8-dihydroxy-5,5,7,9-pentamethyl 13 _l 16- [1-methyl-2- (2-hydroxymethyl-4-thiazolyl) ethenyl] -1-aza-13 (Z) -cyclohexadecene-2,6-dione, and pharmaceutically acceptable salts, solvates and hydrates thereof. A method of treating cancer in a patient, comprising administering to said patient an effective amount of a compound of claim 1. 5. A method of treating a hyperproliferative disorder in a patient comprising administering to said patient an effective amount of a compound of claim 1. A method of providing an anti-angiogenic effect in a patient in need of such treatment, comprising administering to said patient an effective amount of a compound of claim 1.