MXPA94001623A - Taxan derivatives in c9 and pharmaceutical compositions that contain them - Google Patents

Abstract

The present invention relates to a taxane having the formula (3) characterized in that X1 is -OX6, -SX7, or -NX8X9; X2 is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; and X4 are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11; R1 is hydroxy, protected hydroxy or together with R14 forms a carbonate, R2 is hydroxy or -OCOR31, R4a is hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, or -OCOR30, R7a is hydrogen, halogen, or -OR28; hydrogen, α-hydroxy, hydroxy-protected or acyloxy, R10 is hydrogen or together with R10a forms an oxo, R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms a

Description

"DERIVATIVES OF TAXANO IN C9 AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM" Inventors: ROBERT A. HOLTON, American, domiciled at 2035 East Paul Dirac Drive, 109 Herb Morgan Building, Tallahassee, Florida 32310, E.U.A .; KI-BYUNG CHAI, Korean, domiciled at 2035 East Paul Dirac Drive, 109 Herb Morgan Building, Tallahassee, Florida 32310, E.U.A. and YUKIO SUZUKI, Japanese, domiciled at 2035 East Paul Diras Drive, 109 Herb Morgan Building, Tallahassee, Florida 32310, E.U.A.

Causaire: FLORIDA STATE UNIVERSITY, entity of the State of Florida, E.U.A. domiciled at 2035 East Paul Dirac Drive, 109 Herb Morgan Building, Tallahassee, Florida 32310, E.U.A.

SUMMARY OF THE INVENTION Taxane derivatives are described, which have alternative substituents on C9.

BACKGROUND OF THE INVENTION The present invention relates to novel taxanes which have utility as antileukemic and antitumor agents. The taxane family of terpenes, of which taxol is a member, has attracted considerable interest both in the biological field and in the chemical field. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor inhibitory activity. Taxol has a 2'R, 3'S configuration and the following structural formula: where Ac is acetyl. Due to this promising activity, taxol is currently undergoing clinical trials in both France and the United States.

Colin et al. Reported in US Pat. No. 4,814,470 that the taxol derivatives having the structural formula (2) shown below have a significantly higher activity than that of taxol (1). (2) R 'represents hydrogen or acetyl and one of R "and R' * 'represents hydroxy and the other represents tert-butoxycarbamylamin and their stereoisomeric forms, and mixtures thereof The compound of the formula (2) in which R '' is hydroxy, R '' 'is ter-butoxycarbonylamino having the 2'R, 3'S configuration, is commonly referred to as a taxotere.Although taxol and taxotere are promising chemotherapeutic agents, these are not universally active. , a need remains for additional chemotherapeutic agents.

BRIEF DESCRIPTION OF THE INVENTION Therefore, among the objects of the present invention is the provision of novel taxane derivatives, which are antileukemic and antitumor agents, valuable. Therefore, in summary, the present invention relates to taxane derivatives at C9. In a preferred embodiment, the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula: where is -OX 6! -SX -N? Q? Q; X "is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; X and X independently are hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X5 is -C0X1Qf -C00X10, -C0SX1 (), -C0NXgX1O 'or -S02Xn' X, is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, protective group for hydroxy, or a functional group that increases the solubility in water of the taxane derivative; X_ is alkyl, alkenyl, alkynyl, aryl, heteroaryl or protecting group for sulfhydryl; Xfi is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or alkyl, alkenyl, alkynyl, aryl or heteroaryl substituted with heteroatoms; Xq is a protective group for amino; X.n is alkyl, alkenyl, alkynyl, aryl, heteroaryl or alkyl, alkenyl, alkynyl, aryl or heteroaryl substituted with heteroatoms; X .. is alkyl, alkenyl, alkynyl, aryl, heteroaryl, -OX,? or -NX_X ,,; X ... is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R, is hydrogen, hydroxy, protected hydroxy or together with R., forms a carbonate; R2 is hydrogen, hydroxy, -0C0R ~,, or together with R "¿a to an oxo: R2a eS hidrd8eno ° together with R2 forms an oxo; R ^ is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R3-.cl and the carbon atoms to which they are attached, forms an oxetane ring; R is hydrogen, alkyl, alkenyl, alkyloyl, aryl, heteroaryl, cyano, hydroxy, -0C0R "or, or together with R, forms an oxo, oxirane or methylene; Roc is hydrogen or together with R5ca forms an oxo; R? is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R_ forms an oxo, or together with R, and the carbon atoms to which they are attached form an oxetane ring; Rfi is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6, to an oxo; RA is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R, forms an oxo; R7 is hydrogen or together with R-, forms an oxo, R7 is hydrogen, halogen, protected hydroxy, -0R2ft > or together with R7 forms an oxo; Rg is hydrogen; Rg is hydrogen, hydroxy, protected hydroxy or acyloxy; RJQ is hydrogen or together with RiQa f ° r to an oxo, R1f) is hydrogen, -OCOR ^ Q, hydroxy, or protected hydroxy, or together with R, forms an oxo; R., is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R, forms a carbonate; R,, is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R2ft is hydrogen, acyl, hydroxy, protective group for hydroxy or a functional group that increases the solubility of the taxane derivative; and ^ 29 '^ 10 and ^ 31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl. Other objects and characteristics of this invention will be partly apparent and partly indicated later.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES As used herein, "Ar" means aryl; "Fen" means phenyl; "Ac" means acetyl; "Et" means ethyl; "R" means alkyl unless otherwise defined; "Bu" means butyl; "Pr" means propyl; "TES" means trilethylsilyl; "TMS" means trimethylsilyl; "TPAP" means tetrapropylammonium perrhoate; "DMAP" means p-dimethyl-aminopyridine; "DMF" means dimethylformamide; "LDA" means lithium diisopropylamide; "LHMDS" means lithium hexamethyldisilazide; "LAH" means aluminum lithium hydride; "Red-Al" means bis (2-methoxyethoxy) aluminum sodium hydride; "AIBN" means azo- (bis) -isobutyronitrile; "10-DAB" means 10-desacetylbacca-tina III: FAR means 2-chloro-l, 1,2-trif luorotriethylamine; "protected hydroxy" means -OR, wherein R is a protective group by hydroxy; "protecting group for sulfhydryl" includes, but is not limited to, hemitium acetals such as 1-ethoxyethyl and methoxymethyl, thioesteres or thiocar bonatos; "protecting group for amino" includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or terbutylcarbamate; and "protective group for hydroxy" includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxy-benzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, ahydroxypyrapyl, tetrahydrothiopyranilic, and trialkyl silyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether, and t-butyldimethylsilyl ether; esters such as benzollic, acetyl, phenylacetyl, formyl, mono-, di- and trihaloacetyl such as chloroacetyl, dichloro-acetyl, trichloroacetic, trifluoroacetyl tr; and carbonates, including, but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted by one or more halogen atoms such as carbonates of 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopenyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more alkoxies of 1 to 6 carbon atoms, or nitros. Other protecting groups for hydroxyl, for sulfhydryl and for amine, can be found in "Protective Groups in Organic Synthesis" by TW Greene, John Wiley and Sons, 1981. The alkyl groups described herein, either alone or with the various substituents defined herein, are preferably lower alkyl containing from one to six carbon atoms in the main chain and up to 15 carbon atoms. These can be straight chain, branched or cyclic, substituted, and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like. The alkenyl groups described in the pree, either alone or with the various. Substituents defined herein, are preferably lower alkenyl containing from two to six carbon atoms in the main chain and up to 15 carbon atoms. These may be straight or branched chain, substituted, which include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. The alkynyl groups described herein, either alone or with the various substituents defined herein, are preferably lower alkynyl containing from two to six carbon atoms in the main chain and up to 15 carbon atoms. These can be straight or branched chain, substituted and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The aryl portions described herein, either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the most preferred aryl. The heteroaryl moieties described herein, either alone or with various substituents, contain from 5 to 15 carbon atoms and include, furyl, thienyl, pyridyl and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino and amido. The acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups. Substituents of the substituted alkyl, alkenyl, alkynyl, aryl and heteroaryl groups and the moieties described herein may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and / or may contain nitrogen, oxygen, sulfur, halogens and include, example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chlorine or fluorine, nitro, amino and keto. In accordance with the present invention, it has been found that the compounds corresponding to structural formula 3 # show remarkable properties in vitro, and are antileukemic and antitumor agents, valuable. Its biological activity has been determined in vitro, using tubulin assays according to the method of Parness et al., J. Cell Biology, 91: 479-487 (1981) and in cancer cell lines, human, and is comparable to that exhibited by taxol and taxotere. In a preferred embodiment of the present invention, the taxane has a structure corresponding to the taxol or taxotere, except for the substituents on C9, Rg, which is hydrogen and Rg, which is hydrogen, hydroxy or acyloxy (such as acetoxy). That is, 2 is hydrogen, R2 is benzoyloxy, R ,, and R ,, are hydrogen, RQ is hydrogen, R, n is hydroxy or acetoxy, R is hydrogen, R-, is hydroxy, R, is hydrogen, R- . and R, and the carbons to which they are attached form an oxetane ring, R4, a is acetoxy, R, 1 is hydroxy, X, 1 is -OH, X "2 is hydrogen, X is phenyl, X is hydrogen, X is -COX X is phenyl or t-butoxy and the taxane It has the configuration 2'R, 3'S. In other embodiments of the present invention, the taxane has a structure that differs from that of the taxol or taxdret with respect to the C9 substituent and at least one other substituent. For example, R_ may be hydroxy or -OCOR ,,, wherein R, is hydrogen, alkyl or selected from the group comprising and Z is alkyl, hydroxy, alkoxy, halogen or trifluoromethyl. R4, a can be hydroxy or acyloxy (other than acetoxy) R-, can be hydrogen and Ry can be acetoxy or another acyloxy or halogen, R, Q and R-n can be hydrogen or together they form an oxo; X ~ can be selected from isobutenyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclohexyl, furyl, thienyl, pyridyl or substituted derivatives thereof, Xr can be -C0X. «Or -C00X, 0 and X "Q can be selected from furyl, thienyl, furyl or thienyl substituted with alkyl, pyridyl, tert-, iso- or n-butyl, ethyl, iso- 0 n-propyl, cyclopropyl, cyclohexyl, allyl, crotyl, 1,3-diethoxy-2-propyl, 2-methoxyethyl, amyl, neopentyl, FenCH20-, -NFen2, -NHnPr, -NHFen, and NHEt. The taxanes having the general formula 3, can be obtained by reacting a ^ -lactam with alkoxides having the tricyclic or tetra-cyclic taxane core and a metal oxide in C-13, substituent, to form compounds having an ester / 9-amido substituent on C-13. The β-lactams have the following general formula: where X, - X, - are as defined above. The fJ-lactams can be prepared from readily available materials, as illustrated in Schemes A and B, below: It is A Scheme B reagents: (a) triethylamine, CH-Cl-, 25 ° C, 18 h; (b) 4 equivalents of ceric ammonium nitrate, CH-CN, -10 ° C, 10 min; (c) KOH, THF, H.O, 0 ° C, 30 min, or pyroli-dine, pyridine, 25 ° C, 3h, (d) TESC1, pyridine, 25 ° C, 30 min. or 2-methoxypropentoluenesulfonic acid (cat.), THF, 2h; (e) n-butyllithium, THF, -78 ° C, 30 min; and an acyl chloride or chloroformate (X, - = -COX .., »), sulfonyl chloride (X5 = -C0SX1Q) or isocyanate (X5 = -C0NXgX1 ()) (f) lithium diisopropylamide, THF -78 ° C at -50 ° C; (g) lithium hexamethyldisilazide, THF -78 ° C at 0 ° C; (h) THF, -78 ° C to 25 ° C, 12 h. The initial materials are easily available. In scheme A, the oxy acetoxyacetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, is cyclocondensated with imines prepared from aldehydes and p-methoxyaniline, to give the 1-p-methoxyphenyl- 3- acyloxy-4-ar-ylazetidin-2-ones. The p-methoxyphenyl group can be easily removed through oxidation with ceric ammonium nitrate, and the acyloxy group can be hydrolyzed under normal conditions, familiar to those skilled in the art to provide 3-hydroxy-4-arylazetidin-2. -onas. In Scheme B, ethyl-β-triethylsilyloxyacetate is prepared from glycolic acid. In Schemes A and B, X, it is preferentially "O ^? X" is a hydroxy protecting group.Protective groups such as 2-methoxy-propyl ("MOP"), 1-ethoxyethyl (" EE "), but a variety of other normal protecting groups, such as the triethylsilyl group or other trialkyl (or aryl) silyl groups can be used.As mentioned above, the additional hydroxy protecting groups and the synthesis of the They can be found in "Protective groups in Organic Synthesis" by TW Greene, John Wiley &Sons, 1981. Racemic [3-lactams can be resolved in pure enantiomers, before protection by recrystallization of the esters. -methoxy-2- (tri-fluoromethyl) -phenylacetic agents, however, the reaction described below, in which it is attached to the side chain of the ji-amido ester, has the advantage of being highly diastereoselective, thus allowing the use of a racemic mixture of side chain ecursor. Alkoxides having the tricyclic or tetracyclic taxane core and a C-13 metal oxide or ammonium oxide substituent have the following structural formula: where R, 1 - R, 14, a are as previously defined and M comprises ammonium or is a metal optionally selected from the group comprising Group IA, Group IIA and transition metals, preferably Li, Mg, Na, K or Ti. More preferably, the alkoxide has the tetracyclic taxane core and corresponds to the structural formula: wherein M, R2, R4a > Ry, Rya, Rg, Rga, R1Q, and R SOn as defined below. The alkoxides can be prepared by reacting an alcohol having a taxane nucleus and a C-13 hydroxyl group, with an organometallic compound in a suitable solvent. Most preferably, the alcohol is a protected baccatine III, in particular, 7-0-triethylsilyl-baccatine III (obtainable as described by Greene, and co-workers in JACS 110: 5917 (1988) or by another route) or 7,10-bis-O-triethylsilyl-baccatine III. As reported in Greene et al., 10-desacetyl-baccatine III is converted to 7-0-triethylsilyl-10-desacetyl-baccatine III, according to the following reaction scheme: OCOCjH, 1 . C C8HS} 3S I C I, C, H5N 2. CHaC0C l, C5H5N (4) a, R = H b, R = COCH3 Under which it is reported that they are carefully optimized conditions, 10-desacetyl-baccatine III is reacted with 20 equivalents of (C ^ H, -), -SiCl at 23 ° C under an argon atmosphere for 20 hours, in the presence of 50 ml of pyridine / mmol of 10-deacetyl-baccatin III to provide 7-triethylsilyl-10-deacetylbaccatine III (4a) as a reaction product in a yield of 84-86% after purification . The reaction product can then be optionally acetylated with 5 equivalents of CH ~ C0C1 and 25 mL of pyridine / mmol of 4a at 0 ° C under an argon atmosphere for 48 hours to provide an 86% yield of 7-0-triethylsilyl -baccatine III (4b). Greene and collaborator in JACS 110, 5917 in 5918 (1988). The 7-protected baccatine III (4b) is reacted with an organometallic compound such as LHMDS in a solvent such as tetrahydrofuran (THF), to form 13-0-lithium-7-0-triethylsilyl-baccatine III metal alkoxide , as shown in the following reaction scheme: I aH93 j LHMDS THF I C CJHJJ J As shown in the following reaction scheme, 13-0-lithium-7-0-triethylsilyl-baccatine III reacts with one. { J-lactam, in which X. is preferentially "" 0Xfi, (Xfi is a protective group for hydroxy) and X2 ~ ^ c are as previously defined, to provide an intermediate in which the hydroxyl groups are protected in C-7 and C-2 '. The protecting groups are then hydrolyzed under mild conditions, so as not to alter the ester bond or the taxane substituents.

C1D THF C2D HF, pyridine, CH, CN Both the conversion of the alcohol to the alkoxide and the final synthesis of the taxane derivative can take place in the same reaction vessel. Preferably, the 3-lactam is added to the reaction vessel after the formation of the alkoxide therein. The compounds of the formula 3 of the present invention are useful for inhibiting tumor growth in animals, including humans, and are preferably administered in the form of a pharmaceutical composition, comprising an effective anti-tumor amount of the compound of the present invention. invention, in combination with a pharmaceutically acceptable carrier or diluent. The antitumor compositions herein may be constituted in any suitable manner, suitable for the intended use; for example, oral, parenteral or topical administration. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration. The diluent or carrier components should not be such as to diminish the therapeutic effects of the antitumor compounds. Dosage forms suitable for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs. Diluents and inert carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose and talc. The tablets may also contain granulation and disintegration agents, such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc.

The tablets may be uncoated or they may be coated by known techniques; for example, to delay disintegration and absorption. Inert diluents and carriers that can be used in the capsules include, for example, calcium carbonate, calcium phosphate and kaolin. Suspensions, syrups and elixirs may contain conventional excipients, for example, methylcellulose, tragacanth, sodium alginate; wetting agents, such as polyoxyethylene lecithin and stearate; and preservatives, for example ethyl p-hydroxybenzoate. Suitable dosage forms for parenteral administration include solutions, suspensions, dispersions, emulsions and the like. These can also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in a sterile injectable medium immediately before use. These may contain suspension or dispersing agents, known in the art. The solubility in water of the compounds of the formula (3) can be improved by modifying the substituents on C2 'and / or on C7. For example, the solubility in water can be increased if X, is -OX, i o and Rya is independently hydrogen or -C0GC0R, where: G is ethylene, propylene, -CH = CH-, 1,2-cyclohexylene, or 1,2-phenylene; .1 = base OH, NR2R3, OR3, SR3, 0CH2C0NR4R5 or OH; R = hydrogen or methyl; R3 = (CH) nNR6R7 or (CH) nN + R6R7R8 x "n = 1 to 3; 4 R = hydrogen or lower alkyl containing 1 to 4 carbon atoms; R = hydrogen, lower alkyl containing 1; to 4 carbon atoms, benzyl, hydroxyethyl, CH2C02H, or dimethylaminoeti? r 7 R and R * independently selected from lower alkyl containing 1 or 2 carbon atoms or benzyl, or R and R together with the nitrogen atom of NR R forms one of the following rings lower alkyl containing 1 or 2 carbon atoms or benzyl; X = halide; and base = NH3, (H0C2H4) 3N, N (CH3) 3 > CH. »N (C ^ OH) 2, NH2 (CH2) 6NH2, N-methylglucamine, NaOH, or KOH. The preparation of the compounds in which X. or X? is -C0GC0R is disclosed in U.S. Patent No. 4,942,184 issued to Haugwitz, which is incorporated herein by reference. Alternatively, the solubility may be increased when X. is "OX, - and X-- is a radical having the formula -COCX-CHX or -C0X-CHX-CHX-S020-M, wherein X is hydrogen, alkyl or aryl and M is hydrogen, alkali metal or an ammonium group, as described in U.S. Patent No. 5,059,699 to Kingston et al. (incorporated herein by reference.) Taxanes having alternative substituents on C9, can be prepared by selectively reducing the C9 keto substituent to produce the corresponding C9-hydroxy derivative at C9 The reducing agent is preferably a borohydride and, more preferably, tetrabutylammonium borohydride (BuiNBH) or triacetoxyborohydride. is illustrated in Reaction Scheme 1, the reaction of baccatine III with Bu.NBH, in methylene chloride, produces 9-deoxo-9 (J-hydroxybaccatine III 5. After the hydroxy group in C7 is protected with the triethylsilyl protective group, for example, an ac Suitable side-chain can be linked to the 7-proteido-9/5-hydroxy 6 derivative, as described elsewhere herein. The removal of the remaining protecting groups thus produces 9- (3-hydroxy-deoxo-taxol or another 9/3-tetracyclic hi-droxitaxane having a C13 side chain.

REACTION SCHEME 1 Alternatively, the C13 hydroxy group of the 7-protected-9,3-hydroxy derivative can be protected with trimethylsilyl or another protecting group, which can be selectively removed relative to the protective group for C7 hydroxy, as it is illustrated in Reaction Scheme 2, to facilitate the selective, additional manipulation of the various taxane substituents. For example, the reaction of the 7,13-protected-93-hydroxy derivative with KH causes the acetate group to migrate from CIO to C9 and the hydroxy group migrates from C9 to CIO, to thereby produce the derivative of C9. -deacetyl 8. The protection of the hydroxy group in CIO of the derivative 10-desacetyl 8 with triethylsilyl, produces the derivative 9. The selective removal of the protective group for hydroxy in C13, of the derivative 9, produces the derivative 10, to which it can be attached a side chain, suitable, as described above.

REACTION SCHEME 2 8 HF pyridine 10 As shown in Reaction Scheme 3, the 10-oxo derivative 11 can be provided by the oxidation of the 10-desacetyl derivative 9. Then, the protective group for C13 hydroxy can be removed in the form selective, followed by the joining of a side chain as described above, to produce 9-acetoxy-10-oxo-taxol or other tetracyclic 9-acetoxy-10-oxotaxane, having a C13 side chain. Alternatively, the acetate group at C9 can be removed selectively by reducing the 10-oxo derivative 11, with a reducing agent such as samarium diiodide, to produce the 9-deoxo-10-oxo derivative. , from which the protective group for C13 hydroxy can be selectively removed, followed by the attachment of a side chain as described above to produce 9-deoxo-10-oxo-taxol or other 9-deoxo-10 -tetracyclicoxotaxanes, which have a side chain at C13.

REACTION SCHEME 3 REACTION SCHEME 3 (continued) 1 2 Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to produce pentaol 13. The hydroxyl groups in C7 and in CIO of tetraol 13, can then be selectively protected with triethylsilyl or another protecting group to produce triol 14, to which a side chain at C13 can be attached, as described above or, alternatively, after further modification of the tetracyclic substituents.

REACTION SCHEME 4 REACTION SCHEME 4 (continued) 14 Taxanes having C9 and / or CIO acyloxy substituents, other than acetate, can be prepared using 10-DAB as an initial material, as illustrated in Reaction Scheme 5. The reaction of 10-DBA with the triethylsilyl chloride in pyridine, produces the 7-protected 10-DAB 15. The hydroxy substituent in CIO of the 7-protected 10-DBA 15, then can be easily acylated with any normal acylating agent, to produce the derivative 16, which has a new acyloxy substituent in CIO. Selective reduction of the C9 keto substituent of derivative 16, produces the 9-hydroxy derivative 17, to which a C13 side chain can be attached. Alternatively, the CIO and C9 groups may be caused to migrate as set forth in Reaction Scheme 2, above.

REACTION STRUCTURE 5 Taxanes having alternative esters in C2 and / or C4 can be prepared, using baccatine III and 10-DAB as starting materials. The C2 and / or C4 esters of baccatine III and 10-DAB can be selectively reduced to the corresponding alcohol (s), using reducing agents such as LAH or Red -Al, and the new esters, can then be replaced using the normal acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP or diiso-propylethylamine. Alternatively, the alcohols in C2 and / or in C4 can be converted to new esters in C2 and / or in C4, through the formation of the corresponding alkoxide, by treating the alcohol with a suitable base such as LDA, followed by by an acylating agent such as an acid chloride. The baccatine III and 10-DAB analogs having different substituents on C2 and / or C4 can be prepared as set forth in Reaction Schemes 6-10. To simplify the description, 10-DAB is used as the initial material. However, it should be understood that baccatine III derivatives or analogs can be produced using the same series of reactions (except for the protection of the hydroxy group in CIO) by simply replacing 10-DAB with baccatine III as the starting material. Baccatine III derivatives and 10-DAB analogs, which have different substituents on C9 and at least one other position, for example Cl, C2, C4, C7, CIO and C13, can then be prepared, 1 carry out any of the other reactions described herein, and some others that are within the level of one skilled in the art.

In Reaction Scheme 6, protected 10-DAB 3 is converted to triol 18 with aluminum lithium hydride. Triol 18 is then converted to the ester at corresponding C4, using C1 ~ C0 in pyridine, followed by a nucleophilic agent (eg, Grignard reagents or alkyllithium reagents).

Scheme 6 Deprotonation of triol 18 with LDA, followed by the introduction of an acid chloride, selectively gives the ester at C4. For example, when acetyl chloride was used, the triol 18 was converted to the 1,2-diol 4 as set forth in Reaction Scheme 7. The triol 18 can then be easily converted to the 1,2-car bonate 19. The acetylation of carbonate 19 under vigorous normal conditions, provides carbonate 21 as described in Reaction Scheme 8; the addition of alkyllithium or Grignard reagents to carbonate 19, provides the ester at C2, which has a hydroxyl group at C4, as set forth in Reaction Scheme 6.

Scheme 7 It's 8 As set forth in Reaction Scheme 9, other C4 substituents can be provided by reacting the carbonate 19 with an acid chloride and a tertiary amine, to produce the carbonate 22 which is then reacted with alkyl lithium or Grignard reagents to provide the 10-DAB derivatives, which have new substituents on C2.

It is a 9 2 3 2 2 Alternatively, baccatine III can be used as an initial material and can be reacted as shown in Reaction Scheme 10. After it is protected at C7 and at C13, baccatine III is reduced with LAH to produce 1 , 2, 4, 10-tetraol 24. The tetraol 24 is converted to the carbonate 25, using C12C0 and pyridine, and the carbonate 25 is acylated in CIO with an acid chloride and pyridine to produce the carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous normal conditions provides carbonate 27, which is then reacted with alkyl lithium to provide the baccatine III derivatives having new substituents on C2 and on CIO.

Scheme 10 Scheme 10 (continued) The 10-deacetoxy derivatives of baccatin III and the 10-deoxy derivatives of 10-DAB can be prepared by reacting baccatine III or 10-DAB (or its derivatives) with samarium diiodide. The reaction between the tetracyclic taxane having a leaving group in CIO and samarium diiodide, can be carried out at 0 ° C in a solvent such as tetrahydrofuran. Advantageously, the samarium diiodide selectively extracts the leaving group in CIO; the side chains - Al ¬ in C13 and other substituents in the tetracyclic nuclei, remain unchanged. Then, the keto substituent on C9 can be reduced to provide the corresponding 9-deoxo-9'3-hydroxy-10-desacetyloxy or 10-deoxy derivatives, as otherwise described herein. The taxanes substituted with dihydro in C7 and other substituted taxanes in C7 can be prepared as set forth in Reaction Schemes 11, 12 and 12a.

REACTION SCHEME 11 pBujSnH AIBN Ccat3 toluene (reflux) REACTION SCHEME 12 REACTION SCHEME 12a As shown in Reaction Scheme 12, Baccatine III can be converted to 7-fluoro-baccatine III by treatment with FAR at room temperature in THF solution. Other baccatine derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro-baccatin III can be prepared by treating baccatin III with raetanesulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydrochloride. The taxanes having C7 acyloxy substituents, can be prepared as set forth in Reaction Scheme 12a, the 7,13-protected-10-oxo derivative 11, is converted to its corresponding C13 alkoxide, by selectively removing the protective group at C13 and when replacing it with a metal such as lithium. The alkoxide is then reacted with one (5-lactam or other side chain precursor) The subsequent hydrolysis of the protecting group on C7, causes migration of the hydroxy substituent on C7 to CIO, migration of the oxo substituent on CIO to C9, and migration of the acyloxy substituent on C9 to C7. Naturally, a wide variety of tricyclic taxanes are occurring, and through manipulations analogous to those described herein, an appropriate side chain can bind to the C13 oxygen of these substances. Alternatively, as shown in Reaction Scheme 13, 7-C-triethylsilyl-baccatine m can be converted to a tricyclic taxane, through the action of Tachykon tetrafluaroborate ± Loxonium in methylene chloride solution. The diol product then reacts with the lead tetraacetate to provide the corresponding C4 ketone.

REACTION SCHEME 1 3 PbC OAc 34 Recently, a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) has been discovered in a needle extract of Tej o (C & EN, p 36-37, April 12, 1993). The derivatives of this hydroxylated taxane which have the various functional groups in C2, C4, etc. , described above, can also be prepared by the use of this hydroxylated taxane. In addition, the C14 hydroxy group together with the hydroxy group in Cl of the 10-DAB, can be converted to 1,2-carbonate as described in C & EN or can be converted to a variety of esters or other functional groups, as described otherwise in the present, with respect to substituents C2, 04, C9 and CIO. The following examples are provided to more fully illustrate the invention.

EXAMPLE 1 (67-3) Preparation of 10-desacetyl-9-deoxo-9 / e? -hydroxy-N-de-benzoyl-N- (t-butoxycarbonyl) -taxol.

They were added dropwise to a solution of 7, 10- (bis) triethylsilyl-10-deacetyl-9-deoxo-9 / C7 -hi-droxy-baccatine III (95 mg, 0.123 mmol), in 1 mL of THF a -45 ° C, 0.250 mL of a 0.98M solution (TMS) 2 ~ NLi in THF. After 1 hour at -45 ° C, a solution of cis-1- (t-butoxycarbonyl) -3-triethylsilyloxy-4-phenylazetidin-2-one (137 mg, 0.37 mmol) in 1 L of solution was added dropwise. THF, to the mix. The solution was gradually heated to 0 ° C, for 6 hours before 1 mL of aqueous solution was added. The mixture was partitioned between aqueous, saturated NaHCO- and ethyl acetate. Evaporation of the organic layer gave a residue which was purified by flash chromatography, to give 127 mg of (2'R, 3'S) -2 ', 7, 10- (tris) triethylsilyl-10-deacetyl-9- deoxo-93-hydroxy-N-debenzoyl-N- (t-butoxycarbonyl) taxol and 8 mg of the isomer (2'S, 3'R). They were added to a solution of 90 mg of the greater compound obtained from the previous reaction, in 1.5 mL of acetonitrile and 2 mL of pyridine at 0 ° C, 0.8 mL of 48% aqueous HF. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 24 hours, and partitioned between aqueous, saturated sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 71 mg of the material, which was purified by flash chromatography, to give 58 mg (92%) of 10-desacetyl-9-deoxo-93-hydroxy-N-des -benzoyl-N- (t-butoxycarbonyl) -taxol, which was recrystallized with ethyl acetate / ether / hexane. p.f. 160-161 • C; [Ct] 25Mi -18 .75 • (c0.08, CHC1,).

NMR-1 ^ (CD.OD, 500 MHz) d 8.10 (d, J = 7.0 Hz, 2H, ortho-benzoate), 7.61 (m, 1H, for benzoate), 7.50 (m, 2H, meta benzoate), 7.41 (d, J = 8 .0 Ht, 2H, ortho phenyl), 7.36 (m, 2H, meta phenyl), 7.28 (m, 1H, For phenyl .6 6.18 ( ni, 1H, H13), 6.18 (d, J = 5.5 Hz, 1H, H2S), 5.18 (broad s, 1H, H3 '), 5.10 (d, J «5.5 Hz, 1H, H10), 4.99 ( d, J = 8.2 HZ, 1H, H5), 4.91 <d, J = 9.3 Hz, 1H, NH), 4.59 (broad s, 1H, H2 '), 4.51 (d, J = 5.5 Hz, 1H, H9 ), 4.22 (d, J - 8.0 Hz, 1H, H20a), 4.16 (d, J = 8.0 Hz, 1H, H20β), 3.86 (dd, J = 9.5, 7.5 Hz, 1H, H7), 3.13 (d, J = 5.5 Hz, 1H, H3), 2.48 (m, 1H, Hßa), 2.29 (m, 1H, H14a), 2.28 (s, 3H, 4AC), 2.19 (m, 1H, Hl4β), 1.85 (ddd, J = 15.1, 9.6, 1.4 Hz, 1H, H6β), 1.79 (3, 3H, Mel6), 1.78. { s, 3H, Mel?), 1.61 (s, 3H, Mel9H), 1.42 (s, 9H, t-Bu), EXAMPLE 2 i (70-2) Preparation of 3 '-des-3-enyl-3' - (2-thienyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9 (3-hydroxy-10-desacet) -taxol were added dropwise to a solution of 7, 10- (bis) -0-triethylsilyl-9-deoxo-9 / J-hydroxy-10-desa-cetyl-baccatine (III) (70.0 mg, 0.09 mmol ) in 1.0 mL of THF at -45 ° C, 0.10 mL of a 0.98 M solution of LiN (SiMe3) in hexane.After 0.5 hours at -45 ° C, a solution of cis-1- was added dropwise. t-butoxy-carbonyl-3-triethylsilyloxy-4- (2-thienyl) azetidin-2-one (103.8 mg 0.27 mmol) in 1.0 mL of THF, the mixture was heated to 0 ° C and maintained at room temperature. this temperature for 1 hour, before 1 mL of a 10% solution of AcOH in THF was added in. The mixture was divided between aqueous NaHCO., saturated and ethyl acetate / hexane, 60/40. Evaporation of the organic layer gave the residue which was purified by filtration through silica gel to give 97.4 mg of a mixture containing (2 'R, 3' S) -2 ', 7, 10- ( tris) -0-triethylsilyl-3 '-desphenyl-3' - (2-thienyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9 ^ 3 -hydroxy-10-desacetyl-taxol and a small amount of the isomer (2'S, 3'R). They were added to a solution of 97.4 mg (0.084 mmol) of the mixture obtained from the previous reaction in 13.5 mL of acetonitrile and 0.57 mL of pyridine at 0 ° C, 1.92 L of 48% aqueous HF. The mixture was stirred at 0 ° C for 3 hours. it was divided between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 69.4 mg of a material which was purified by chromatography with _.- * - ~ - instantaneous evaporation, to give 63.1 mg (89%) of 3'-desphenyl-3 '- (2-thienyl) -N-debenzoyl-N- (t-butoxycarbo-nili- g-deso or g) ^ -hydroxy-10-desacetyl taxol, which was recrystallized with methanol / water. p.f 146-148 «C; [a] 25Na-54.2 * (c 0.0026, CHC1.). 1 H-NMR (MβOH, 300 MHz) d 8.11 (d, J = 7.1 Hz, 2H, ortho-benzoate), 7.61 (m, 1H, for benzoate), 7.48 (m, 2H, meta-benzoate), 7.25 (dd, J = 5.4, 1.2 Hz, 1H, thienyl), 7.14 (d, J = 3.3 Hz, 1H, thienyl), 7.03 (dd, J = 5.4, 3.9 Hz, 1H, thienyl), 6.18. { m, 1H, H13), 6.18 (4 / J »5.5 Hz, 1H, H2), 5.23 (broad s, 1H, H3 '), 5.07 (d, J = 5.5 Hz, 1H, H10), 4.97 (d, J = 8.1 Hz, 1H, H5), 4.84 (d, J = 9.3 hz, 1H, NH), 4.52 (broad s, 1H, H2 '), 4.50 (d, J = 5.5 Hz, 1H, H9), 4.23 (d, J-8.1, 1H, H20a), 4.16 (d, J-8.1 Hz, 1H, H20), 3.92 (d, J = 9.4, 7.5 HZ, 1H, H7), 3.13 (d, J, 5.5 Hz , H3), 2.47 (m, 1H, H6a), 2.26 (tn, 1H, H14?), 2.27 (s, 3H, 4Ac), 2.16 (m, 1H, Hl4β), 1.84 (ddd, J-15.1, 9.4 , 1.2 Hz, H6β), 1.79 (s, 3H, Mel6), 1. 76 (9.3H, Ml18), 1.62 (S, 3H, Ml19) 1.39 (3, 9H, 3Me t-butoxy), 1.27 (8, 3H, Mel7).

EXAMPLE 3 (70-3) Preparation of 3 '-desphenyl-3' - (2-furyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9-hydroxy-10-desacetyl-taxol.

They were added dropwise to a solution of 7, 10- (bis) -0-triethylsilyl-9-deoxo-9S-hydroxy-10-desacetyl-baccatine (III) (70.0 m, 0.09 mmoles) in 1.0 mL of THF a -45 ° C, 0.10 mL of a 0.98 M solution of LiN (SiMe ^) 2 in hexane. After 0.5 hours at -45 ° C, a solution of cis-1-t-butoxy-carbonyl-3-triethylsilyloxy-4- (2-furyl) azetidin-2-one (99.5 mg, 0.27 mmol) was added dropwise. ) in 1.0 mL of THF, to the mixture. The solution was heated to 0 ° C and kept at this temperature for 1 hour, before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO ~ and 60/40 ethyl acetate / hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel, to give 94.3 mg of a mixture containing (2'R, 3'S) -2 ', 7, 10- (tris) - 0-triethylsilyl-3 '-des-phenyl-3' - (2-furyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9 / i? -hydroxy-10-desacetyl-taxol and a small amount of the isomer (2'S, 3'R). They were added to a solution of 94.3 mg (0.082 mmol) of the mixture obtained from the previous reaction in 13.5 mL of acetonitrile and 0.57 mL of pyridine at 0 ° C, 1.92 mL of 48% aqueous THF. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 13 hours, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 72.3 mg of material, which was purified by flash chromatography, to give 59.1 mg (89%) of 3'-desphenyl-3 '- (2-furyl) -N- Debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9 / * - hydroxy-10-desacetyl-taxol, which was recrystallized with methanol / water.

P.f.144-146-C; [a] 25Na-54.0 »(c 0.0028, CHC1.).

NMR-H (MβOH, 300 MHz) 6 8.10 (d, J = 7.1 Hz, 2H, ortho-benzoate), 7.60 (, 1H, for benzoate), 7.51 (m, 2H, meta-benzoate), 7.40 (m, 1H, furyl), ß.37 (m, 1H, furyl), 6.34 (, 1H, furyl), 6.17 (, 1H, H13), 6.16 (d, J = 5.4 Hz, 1H, H2), 5.24 (broad s, 1H , H3 '), 5.11 (d, J = 5.5 Hz, 1H, H10), 4.86 (d, J = 8.1 Hz, 1H, H5), 4.83 (d, J »9.3 hz, 1H, NH), 4.50 (d , J-5.5 Hz, 1H, H9), 4.45 (broad s, 1H, H2 '), 4.21 (d, J = 8.1, 1H, H20O), 4.13 (d, J "8.1 Hz, 1H, H20β) , 3.92 (dd, J.9.4, 7.5 Hz, 1H, H7), 3.11 (d, J-5.5 Hz, H3), 2.46 (m, 1H, H6a), 2.24 (m, 1H, Hl4?), 2.21 ( s, 3H, 4Ac), 2.15 (, 1H, H14ß), 1.79 (ddd, J = 15.1, 9.4, 1.2 Hz, H6β), 1.77 (s, 3H, M «16), 1.73 (9, 3H, Mßl8) , 1.61 (3, 3H, Mel9), 1.37 (s, 9H, 3Mβ t-butoxy), 1.26 (9, 3H, M «17).

EXAMPLE 4 (70-4) Preparation of 3 '-desphenyl-3' ~ (isobutenyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9 f3-hydroxy-10-desacetyl-taxol.

They were added dropwise to a solution of 7, 10- (bis) -0-tristylsilyl-9-deoxo-93-hydroxy-10-desacetyl-baccatine (III) (70.0 mg, 0.09 mmol) in 1.0 mL of THF a -45 ° C, 0.10 mL of a 0.98 M solution of LiN (SiMe ~) 2 in hexane. After 0.5 hours at -45 ° C, a solution of cis-1- (t-butoxy-carbonyl) -3- (2-metho isopropyloxy) -4- (isobutenyl) -azetidin-2-one (84.5 mg, 0.27 mmol) in 1.0 was added dropwise. mL of THF, to the mixture. The solution was heated to 0 ° C and maintained at that temperature for 1 hour, before 1 mL of a 10% solution of AcOH of THF was added. The mixture was partitioned between saturated aqueous NaHCO- and ethyl acetate / hexane, 60/40. Evaporation of the organic layer gave a residue, which was purified by filtration through silica gel, to give 88.3 mg of a mixture containing (2 'R, 3' S) -2 ', 7, 10- ( tris) -0-triethylsilyl-3 '-desphenyl-3' - (isobutenyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-9 ^ -hydro i-10-desacetyl-taxol and a small amount of the isomer (2'S, 3'R). They were added to a solution of 88.3 mg (0.080 mmol) of the mixture obtained from the previous reaction, in 13.5 mL of acetonitrile and 0.55 mL of pyridine at 0 ° C, 1.90 mL of 48% aqueous HF. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 13 hours, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 67.2 mg of material which was purified by flash chromatography to give 52.7 mg (82%) of 3 '-desphenyl-3' - (isobutenyl) -N-debenzoyl- N- (-butoxycarboni1) -9-deoxo-9 (3-hydroxy-10-desacetyl-taxol, which was recrystallized with methanol / water. p.f.138-140 «C; [a. ^ h-55.2 »(c 0.0026, CHC1.). 1 H-NMR (MeOH, 300 MHz) d 8.11 (d, J = 7.1 Hz, 2H, ortho-benzoate), 7.61 (, 1H, for benzoate), 7.48 (m, 2H, meta-benzoate), 6.13 (, 1H, H13) ), 6.12 (m, 1H, H2), 5.21 (broad s, 1H, H3 '), 5.02 (d, J-5.3 Hz, 1H, H10), 4.93 (d, J * 8.1 Hz, 1H, H5), 4.85 (d, J-9.1 hz, 1H, NH), 4.84 (d, J = 8.5 Hz, 1H, MßjC-CH.-), 4.50 (broad s, 1H, H2 '), 4.50 (d, J = 5 Hz, 1H, H9), 4.22 (d, J-ß.l, 1H, H20Ct), 4.18 (d, J.8.1 Hz, 1H, H203), 3.89 (dd, J = 9.4, 7.5 Hz, 1H, H7), 3.12 (d, J.5.5 Hz, H3), 2.45 (m, iH, H6a), 2.31 (m, 1H, H14?), 2.29 (9, 3H, 4AO, 2.18 (m, 1H, H14ß) , 1.85 (ddd, J = 15.1, 9.4, 1.2 Hz, H6ß), 1.81 (9, 3H, M «16), 1.76 (3, 3H, Mßl8), 1.72 (9, 6H, 2Me of isobutenyl >, 1.61 {s, 3H, Mßl9), 1.39 (9, 9H, 3Me t-butoxy), 1.26 (9, 3H, M «17).

EXAMPLE 5 (74-3) Preparation of N-desbenzoyl-N- (t-butoxycarbonyl) -9-deoxo-10-desacetyl-10-keto-taxol.

They were added dropwise to a solution of 7-0-triethylsilyl-9-deoxo-10-desacetyl-10-keto baccatine (III) (30.0 mg, 0.047 mmol) in 0.5 mL of THF at -45 ° C, 0.05 mL of a 0.98 M solution of LiN (SiMe, ») 2 in hexane. After 0.5 hours at -45 ° C, a solution of cis-1-t-butoxycarbonyl-3-triethylsilyloxy-4-phenylazetidin-2-one (53.1 mg, 0.14 mmole) in 0.5 L of solution was added dropwise. THF, to the mix. The solution was heated to 0 ° C and kept at this temperature for 1 hour, before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO3 and ethyl acetate / hexane, 60/40. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 43.7 mg of a mixture containing (2'R, 3'S) -2I, 7- (bis) -0- triethylsilyl-N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-10-deacetoxy-10-keto taxol and a small amount of the isomer (2'S, 3'R). To a solution of 43.7 mg (0.042 mmol) of the mixture obtained from the above reaction were added in 4.0 mL of acetonitrile and 0.20 mL of pyridine at 0 ° C 0.50 mL of 48% aqueous HF. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 13 hours, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 33.2 mg of material which was purified by flash chromatography to give 24.1 mg (73%) of N-debenzoyl-N- (t-butoxycarbonyl) -9- deoxo-10-deacetoxy-10-keto taxol, which was recrystallized with methanol / water. p.f.162-165 «C; (c 0.0025, CHCl.).

NMR ^ H (CDC1, 300 MHz) d 8 .11 (d, J "7 .1 Hz, 2H, orthobenzoate.), 7.63 (m, 1H, for benzoate), 7.50 (m, 2H, meta benzoate), 7.40-7.29 (m, 5H, benzoate, phenyl), 6.11 (td, J.7.8, 1.0 Hz, 1H, H13), 5.94 (d, J = 6.4 Hz , 1H, H2), 5.52 (d, J = 9.8 Hz, 1H, H3 '), 5.27 (d, J-9.3 Hz, 1H, NH), 4.93 (dd, J = 8.8 Hz, 1H, H5), 4.64 (s broad, 1H, H2 '), 4.32 (d, J-8.3 Hz, 1H, H20CC), 4.18 (d, J-8.3 Hz, 1H, H20β), 3.88 (s broad, 1H, 2 '0H), 3.7l (m, 1H, H7), 3.11 (d, J = 5.1 Hz, 1H, H3), 3.10 (d, J-15.7 Hz, H9a), 2.88 (d, J-16.1, 1H, H9β), 2.54 (m, 1H, H6a), 2.44 (m, 1H, Hl4β), 2.29 (3, 3H, 4Ac), 2.26 (m, 1H, H14a), 2.02 (broad s, 1H, 7 OH), 1.88 (5, 1H, 1 OH), 1.80 (m, 1H, H6β), 1.65 (s, 3H, Mel8), 1.55 (9, 3H, Mßl6), 1.46 (s, 3H, Mßl9), 1.35 (3, 9H, 3Mβ t-butoxy), 1.29 (s, 3H, EXAMPLE 6 (74-4) Preparation of 3 '-desf-3' - (isobutenyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-10-deacetoxy-10-keto taxol.

They were added dropwise to a solution of 7-0-triethylsilyl-9-deoxo-10-deacetoxy-10-keto baccatine (III) (30.0 mg, 0.047 mmol) in 0.5 mL of THF at -45 ° C, 0.05 mL of a 0.98 M solution of LiN (SiMe3) 2 in hexane. After 0.5 hours at -45 ° C, a solution of cis-1-t-butoxycarbonyl-3- (2-methoxy-isopropyloxy) -4- (isobutenyl) -azetidin-2-one was added dropwise ( < +4.1 mg, 0.141 mmol) in 0.5 mL of THF, to the mixture. The solution was heated to 0 ° C and kept at that temperature for 1 hour, before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO and 60/40 ethyl acetate / hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel, to give 40.8 mg of a mixture containing (2 'R, 3' S) -2 '-0- (2-methoxy-isopropyl) -7-0-triethylsilyl-3' -desphenyl-3 '- (isobutenyl) -N-desbenzoyl-N- (t-butoxycarbonyl) -9-deoxo-10-desacetyl-10-keto taxol and a small amount of the isomer (2 »S, 3'R). They were added to a solution of 40.8 mg (0.043 mmol) of the mixture obtained from the previous reaction, in 4 mL of acetonitrile and 0.2 mL of pyridine at 0 ° C, 0.5 mL of 48% aqueous HF. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 13 hours and partitioned between aqueous and saturated sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 34.4 mg of material, which was purified by flash chromatography, to give 23.0 mg (70%) of 3 '-desphenyl-3' - (isobutenyl) -N-debenzoyl -N- (t-butoxycarbonyl) -9-deoxo-10-deacetoxy-10-keto taxol, which was recrystallized with methanol / water. p.f.149-153O; [al ^ a-dß.S »(c 0.0025, CHC1.

NMR ^ H (CDC1, 300 MHz) d 8.12 (d, J-7.2 Hz, 2H, orthobenzoate), 7.64 (m, 1H, for benzoate), 7.51 (m, 2H, meta benzoate), 6.12 (t, J-7.5 HZ, 1H, H1), 5.95 (d, J-6.2 Hz, 1H, H2), 5.30 (d, J-8.9 Hz, 1H, NK), 4.94 (d, J = 8.2 Hz, 1H, H5 ), 4.88 (d, J-8.9 Hz, 1H,, 4.79 (td, J-8.9, 2.4 HZ, 1H, H3 '), 4.34 (d, J-8.2 Hz, 1H, H20?), 4.27 (dd, J-5.5, 2.7 Hz, 1H, H2 '), 4.19 (d, J = 8.2 Hz, 1H, H203),, 3.73 (m, 1H, H7), 3.67 (broad s, 1H, 2'0H), 3.13 (d, J = 5.1 Hz, 1H, H3), 3.12 (d, J = 15.7 Hz, 1H, H9a), 2.90 (d, J-15.7 Hz, 1H, H9β), 2.55 (m, 1H, H6?) , 2.47 (m, 1H, H14β), 2.32 (3, 3H, 4AC), 2.28 (m, 1H, H14a), 2.04 (broad s, 1H, 7 OH, 1.88 (s, 1H, 1 OH), 1.82 ( m, 1H, H6β), 1.79 (3, 3H,, M «18), 1.76 (8, 6H, 2M« isobutenyl), 1.57 (s, 3H, M * 16), 1.47 (3, 3H, M « 19), 1.40 (3, 9H, 3M * t-butoxy) 1.30 (3, 3H, Mel7). (75-1) EXAMPLE 7 (75-1) Preparation of 3 '-desphenyl-3' - (2-thienyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-deoxo-10-deacetoxy-10-keto taxol. were added drop by drop to a solution of 7-0-triethylsilyl-9-deoxo-10-desacetoxy-10-keto baccatin (III) (25.0 mg, 0.039 mmol) in 0.5 mL of THF at -45 ° C, 0.05 mL of a 0.98 M solution of LiN (SiMe3) 2 in hexane. After 0.5 hours at -45 ° C, a solution of cis-lt-butoxycarbonyl-3-triethyl-silyloxy-4- (thienyl) azetidine-2-one (45.0 mg 0.117 mmol) in 0.5 mL was added dropwise. THF, to the mix. The solution was heated to 0 ° C and kept at this temperature for 1 hour, before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO3 and ethyl acetate / hexane, 60/40. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel, to give 36.2 mg of a mixture containing (2'R, 3'S) -2 ', 7- (bis) -0- triethyl silyl 3 -desfenil-3 - (2-thienyl) -N-debenzoyl-N- (t-butoxycarbonyl) -9-desoxo-10-desacetoxy-10-keto taxol and a small amount of the (2'S , 3 * R). They were added to a solution of 36.2 mg (0.035 mmol) of the mixture obtained from the previous reaction in 3.0 mL of acetonitrile and 0.15 mL of pyridine at 0 ° C, 0.45 mL of 48% aqueous HF. The mixture was stirred at 0 ° C for 3 hours, then at 25 ° C for 13 hours, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 29.4 mg of material, which was purified by flash chromatography, to give 24.3 mg (87%) of 3 '-desphenyl-3' - (2-thienyl) -N- deben-zoil-N- (t-butoxycarbonyl) -9-deoxo-10-deacetoxy-10-keto taxol, which was recrystallized with methanol / water. p.f..l63-169'C; [afta-54.2 '(c 0.0023, CHC1,). 1 H-NMR C ^ Cl, 300 MHz) 6 8.12 (d, J = 7.3 Hz, 2H, orthobenzoate), 7.64 (p, 1H, for benzoate), 7.51 (, 2H, meta benzoate), 7.26 (m , 1H, thienyl), 7.10 (d, J-3.4 Hz, 1H, thienyl), 6.99 (dd, J-5.1, 3.4 Hz, 1H, thienyl), 6.12 (td, J-6.1, 1.0 Hz, 1H, H13 ), 5.95 (d, J-5.9 Hz, 1H, H2), 5.50 (d, J = 4.4 Hz, 1H, NH), 5.42 (d, J = 9.8 Hz, 1H, H3 '), 4.94 (d, J) = 8.3 Hz, 1H, H5), 4.64 (dd, J-4.2, 2.0 Hz, 1H, 2 '), 4.33 (d, J-7.8 Hz, 1H, H20a), 4.18 (d, J-7.8 Hz, 1H , H20ß), 3.90 (broad s, 1H, 2'0H), 3.73 (m, 1H, H7), 3.11 (d, J.15.8 Hz, H9a), 3.09 (d, J-5.1 Hz, 1H, H3) , 2.90 (d, J-15.6 Hz, 1H, H9β), 2.54 (m, 1H, H6?), 2.45 < m, 1H, H14β), 2.31 (3, 3H, 4AC), 2.28 (m, 1H, Hl4a) "2.01 (broad s, 1H, 7 OH), 1.88 (3, 1H, 1H), 1.83 (m, 1H, H6β), 1.69 (S, 3H, Mel8), 1.56 (9, 3H, Mel6), 1.46 (s, 3H, Mel9), 1.40 (s, 9H, 3M "t-butoxy), 1.29 (9, 3H , Mel7).

EXAMPLE 8 The taxanes 67-3, 70-2, 70-3, 70-4, 75-1, 74-4, and 74-3 of Examples 1-7 were evaluated in the vitro cytotoxicity activity against cells. of human colon carcinoma, HCT-116. Cytotoxicity was estimated in cells of human colon carcinoma HCT116 by the XTT assay (hydroxide 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) -5- [(phenyl-amino) carbo-nil] -2H-tetrazolium) (Scudieron et al., "Evaluation of a soluble tetrazolium / formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines", Cancer Res. 48: 4827-4833, 1988). The cells were placed in 96-well micro-titre plates, at a ratio of 4000 cells / well, and 24 hours later the drugs were added and serially diluted. The cells were incubated at 37 ° C for 72 hours, at which time the tetrazolium dye, XTT, was added. An enzyme dehydrogenase in living cells reduces the XTT to a form that absorbs light at 450 nm, which can be quantified in a spectrophotometric manner. The greater the absorbance, the greater the number of living cells. The results are expressed as a CI-, 0? which is the concentration of drug required to inhibit cell proliferation (ie the absorbance at 450 nm) at 50% of that of untreated control cells. All compounds have a CI- ^ less than 0.1, indicating that all are cytotoxic active.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, property is claimed as contained in the following:

Claims (9)

1. A taxane derivative that has the formula ' characterized in that: X, is ~ 0Xfi, -SX7, or -NXgXgj X2 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; X and X are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl; X5 is -C0X1Q, -C00X1Q, -C0SX10 > -C0NXgX1 () or -S02Xn; X is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, protective group for hydroxy, or a functional group that increases the water solubility of the taxane derivative; X is alkyl, alkenyl, alkynyl, aryl, heteroaryl or protecting group for sulfhydryl; Xo is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl or alkyl, alkenyl, alkynyl, aryl or heteroaryl substituted with heteroatom; Xq is a protective group for amino; X, 0 is alkyl, alkenyl, alkynyl, aryl, heteroaryl or alkyl, alkenyl, alkynyl, aryl or heteroaryl substituted with heteroatom; X .. is alkyl, alkenyl, alkynyl, aryl, heteroaryl, ~ 0X10 or -NXgX ,,; X1 is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R. is hydrogen, hydroxy, protected hydroxy or together with R., forms a carbonate; R2 is hydrogen, hydroxy, -0C0R-. , or together with R2a form oxo; R2 is hydrogen or together with R2 forms an oxo; R, is hydrogen, together with R, forms an oxo, oxirane or methylene, or together with R? and the carbon atoms to which they are attached form an oxetane ring; R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -0C0R3 (), or together with R ^ forms an oxo, oxirane or methylene, R5 is hydrogen or together with R? Forms an oxo; R-. is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R .. forms an oxo, or together with R, and the carbon atoms to which they are attached form an oxetane ring; R 1 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R 6, to an oxo; Rft Ocl is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with Rfi forms an oxo; R7 is hydrogen or together with R-, forms an oxo, R7 / Cl is hydrogen, halogen, protected hydroxy, -0R2fi, or together with R-, forms an oxo; R "is hydrogen; RQya is hydrogen, hydroxy, protected hydroxy or acyloxy; R.0 is hydrogen or together with R., »forms an oxo, R10 is hydrogen, -0C0R2g, hydroxy, or protected hydroxy, or together with R.,» forms an oxo; Rjt, is hydrogen, alkyl, alkenyl, alkynyl, aryl or heteroaryl; R ,, is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R ^ forms a carbonate; R2g is hydrogen, acyl, protecting group for hydroxy or a functional group that increases the solubility of the taxane derivative; and R2q, R3n and R-. they are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl.
2. 2. The taxane derivative according to claim 1, characterized in that X31 is selected from the group consisting of: and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.
3. 3. The taxane derivative according to claim 2, characterized in that Z is methyl or methoxy.
4. 4. The taxane derivative according to claim 2, characterized in that Rga is hydrogen.
5. The taxane derivative according to claim 1, characterized in that R 9, »a is hydroxy
6. 6. The taxane derivative according to claim 1, characterized in that R L (9a is acetoxy.
7. 7. The taxane derivative according to claim 1, characterized in that R., and R., are hydrogens, R.0 is hydrogen, R.Q is hydroxy or acetoxy, RQ is hydrogen or hydroxy, R-, is hydrogen, R-7, a is hydroxy, R5c is hydrogen, R5ca and J R4. and 'the carbohydrates to which they are attached form an oxetane ring, R4, a is acetoxy, R a is hydrogen, R 2"is benzoyloxy, R. is hydroxy, X. is -OH, X2 is hydrogen , X »is phenyl, X, is hydrogen, Xr is -C0X.,», Xlf. is phenyl or t-butoxy and the taxane has the 2'R, 3'S configuration.
8. 8. The taxane derivative according to claim 1, characterized in that R.it. and R.14.a are hydrogens, R.Q is hydrogen, R.Q is hydroxy or acetoxy, Rga is hydrogen, hydroxy or acetoxy, R is hydrogen, R_ is hydroxy, R-. is hydrogen, Rg and R, and the carbons to which they are attached form an oxetane ring, R is acetoxy, R is hydroxy, X is -OH, X2 is hydrogen, X is alkyl or alkenyl, X, is hydrogen, X. is -COX. , X10 is phenyl, ter-, iso- or n-butoxy, ethoxy, iso- or n-propoxy, cyclohexyloxy, allyloxy, cytyloxy, 1,3-diethoxy-2-propoxy, 2-methoxyethoxy, amyloxy, neopentyloxy, FenCH20-, NFen2 > -NHnPr, -NHFen, and NHEt.
9. 9. A pharmaceutical composition, characterized in that it contains a taxane derivative according to claim 1 and one or more diluents or adjuvants, pharmacologically acceptable, inert or physiologically active. In testimony of which I sign the present in this City of Mexico, D.F., on March 3, 1994. By: FLORIDA STATE ÜNIVERSITY Attorney