Substituted taxanes as antitumour agents

Abstract: A taxane derivative of the formula wherein R₁ and R₃ are independently selected from the group comprising phenyl, naphthalene, C₆H₅CHCH-, and provided, however, R₁ and R₃ are not both phenyl; Q is CH₃-, (CH₃)₃C-, CH₃O-, Cl, Br, F, NO₂, Z is -OT₁, T₁ is hydrogen, hydroxyl protecting group, or -COT₂, T₂ is H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl or monocylic aryl, Ac is acetyl, and E₁ and E₂ are independently selected from hydrogen and functional groups which increase the water solubility of the taxane derivative are useful as antitumor agents.

Description: BACKGROUND OF THE INVENTION The present invention is directed to novel taxanes which have utility as antileukemia and antitumor agents. The taxane family of terpenes, of which taxol is a member, has attracted considerable interest in both the biological and chemical arts. Taxol is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol has a 2'R, 3'S configuration and the following structural formula: wherein Ac is acetyl. Because of this promising activity, taxol is currently undergoing clinical trials in both France and the United States. Colin et al. reported in U.S. Patent No. 4,814,470 that taxol derivatives having structural formula (2) below, have an activity significantly greater than that of taxol (1) . R' represents hydrogen or acetyl and one of R" and R''' represents hydroxy and the other represents tert-butoxycarbonylamino and their stereoisomeric forms, and mixtures thereof. The compound of formula (2) in which R' is hydrogen, R" is hydroxy, and R"' is tert-butoxycarbonylamino having the 2'R, 3'S configuration is commonly referred to as taxotere. Georg et al., Bioorganic & Medicinal Chemistry Letters, Vol. 2, No. 4, pages 295 to 298 (1992), published according to the publishers on 31 March 1992, teach a compound of the formula: wherein Ar 1 is p -chlorophenyl, Ar 2 is phenyl, and R 1 and R 2 are both H and also a compound of the same formula wherein Ar 1 is phenyl, Ar 2 is p -chlorophenyl, and R 1 and R 2 are both H. Monsarrat et al, Drug Metabolism and Disposition, Vol. 18, No. 6, pages 895 to 901 (1990), disclose as a metabolite of taxol in rat bile the compound of the formula: wherein R 1 is Although taxol and taxotere are promising chemotherapeutic agents, they are not universally effective. Accordingly, a need remains for additional chemotherapeutic agents. SUMMARY OF THE INVENTION Among the objects of the present invention, therefore, is the provision of novel taxane derivatives which are valuable antileukemia and antitumor agents. Briefly, therefore, the present invention is directed to taxane derivatives of the formula: wherein: R 1 and R 3 are independently selected from the group consisting of phenyl, naphthyl, and provided that R 1 and R 3 are not both phenyl; Q is CH 3 -, (CH 3 ) 3 C-, CH 3 O-, or NO 2 ; Z is -OAc; Ac is acetyl; and E 1 and E 2 are hydrogen. The invention further provides taxane derivatives of the formula: wherein: R 1 and R 3 are independently selected from the group consisting of phenyl, naphthyl, C 6 H 5 CHCH-, provided that R 1 and R 3 are not both phenyl; Q is CH 3 -, (CH 3 ) 3 C-, CH 3 O-, Cl, Br, F, or NO 2 ; Z is -OT 1 ; T 1 is hydrogen, hydroxyl protecting group, or -COT 2 ; T 2 is H, C 1 -C 6 alkyl, up to C 6 alkenyl, up to C 6 alkynyl or monocyclic aryl; Ac is acetyl; and E 1 and E 2 are independently selected from hydrogen and -COGCOR 1 ; provided that, when R 1 and R 2 are independently selected from the group consisting of phenyl, naphthyl and and when Z is -OAc, E 1 and E 2 are not both hydrogen and that when Z is -OH and E 1 and E 2 are both hydrogen, R 3 is not phenyl; and wherein: G is ethylene, propylene, -CH=CH-, 1,2-cyclo-hexylene, or 1,2-phenylene; R 1 = OH base, NR 2 R 3 , OR 3 , SR 3 , OCH 2 CONR 4 R 5 , or OH; R 2 = hydrogen or methyl; R 3 = (CH 2 ) n NR 6 R 7 or (CH 2 ) n N ⊕ R 6 R 7 R 8 X ⊖ ; n = 1 to 3; R 4 = hydrogen or lower alkyl containing 1 to 4 carbons; R 5 = hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CH 2 CO 2 H, or dimethylaminoethyl; R 6 and R 7 = independently selected from lower alkyl containing 1 or 2 carbons or benzyl, or R 6 and R 7 together with the nitrogen atom of NR 6 R 7 forms one of the following rings R 8 = lower alkyl containing 1 or 2 carbons or benzyl; X ⊖ = halide; and base = NH 3 , (HOC 2 H 4 ) 3 N, N(CH 3 ) 3 , CH 3 N(C 2 H 4 OH) 2 , NH 2 (CH 2 ) 6 NH 2 , N-methylglucamine, NaOH, or KOH. Other objects and features of this invention will be in part apparent and in part pointed out hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In accordance with the present invention, it has been discovered that compounds having structural formulae (3a) and (3b) show remarkable properties, in vitro, and are valuable antileukemia and antitumor agents. Their 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 human cancer cell lines, and is comparable to that exhibited by taxol and taxotere. Taxane derivatives having formula (3a) or formula (3b) may be obtained by reacting a β-lactam with metal alkoxides having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a β-amido ester substituent at C-13. The β-lactams have the following structural formula: wherein R 1 and R 3 are as previously defined, and R 2 is a hydroxy protecting group, β-lactams (4) can be prepared from readily available starting materials, as is illustrated by the following reaction scheme: reagents (a) LDA, THF, -78°C to -50°C; (b) LHMDS, THF, -78°C to 0°C; (c) THF, -78°C to 25°C, (2h); and (d) triethylamine and an acyl chloride, where R 3 is, for example, (LDA is lithium diisopropylamide and LHMDS is lithium hexamethyldisilazane). The 3-hydroxyl protecting group shown in the above reaction scheme is -SiR 5 wherein R 5 is trialkyl or triaryl such as triethyl. The 3-hydroxyl may be protected with other standard protecting groups such as 1-ethoxy-ethyl, or 2,2,2-trichloroethoxymethyl. Additional hydroxy protecting groups and the synthesis thereof may be found in "Protective groups in Organic Synthesis" by T.W. Greene, John Wiley & Sons, 1981. The racemic β-lactams may be resolved into the pure enantiomers prior to protection by recrystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reaction described hereinbelow in which the β-amido ester side chain is attached has the advantage of being highly diastereoselective, thus permitting the use of a racemic mixture of side chain precursor. The metal alkoxides having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent have the following structural formula: wherein Z is -OT 1 ; T 1 is hydrogen, hydroxyl protecting group, or -COT 2 ; T 2 is H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl or monocylic aryl; T 3 is a hydroxy protecting group; and M is a metal, preferably selected from the group comprising Group IA, Group IIA and transition metals, and most preferably, Li, Mg, Na, K or Ti. The metal alkoxides are prepared by reacting an alcohol having the taxane tetracyclic nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Preferably, the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al. in JACS 110 : 5917 (1988) or by other routes) or 7,10-bis-O-triethylsilyl baccatin III. As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-O-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme: Under what is reported to be carefully optimized conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (C 2 H 5 ) 3 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-deacetyl baccatin III (7a) as a reaction product in 84-86% yield after purification. The reaction product may then optionally be acetylated with 5 equivalents of CH 3 COCl and 25 mL of pyridine/mmol of 7a at 0 °C under an argon atmosphere for 48 hours to provide 86% yield of 7-O-triethylsilyl baccatin III (7b) . Greene, et al. in JACS 110 , 5917 at 5918 (1988). The 7-O-triethylsilyl baccatin III (7b) is reacted with an organometallic compound such as n-butyllithium in a solvent such as tetrahydrofuran (THF), to form the metal alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III (8) as shown in the following reaction scheme: As shown in the following reaction scheme, 13-O-lithium-7-O-triethylsilyl baccatin III (8) reacts with β-lactam (4) in which R 2 is triethylsilyl to provide an intermediate in which the C-7 and C-2' hydroxyl groups are protected with a triethylsilyl group. The triethylsilyl groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents. wherein R 1 and R 3 are as previously defined, Ac is acetyl, TES is triethylsilyl and Ph is phenyl. Both the conversion of the alcohol to the metal alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel. Preferably, the β-lactam is added to the reaction vessel after formation therein of the metal alkoxide. The present invention also provides pharmaceutical compositions containing a compound of formula (3) in combination with one or more pharmaceutically acceptable, inert or physiologically active, diluents or adjuvants. These compositions may be presented in any form appropriate for the administration route envisaged. The parental route, and especially the intravenous route, is the preferential route for administration. The compositions according to the invention for parenteral administration may be aqueous or nonaqueous sterile solutions, suspensions or emulsions. Propylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be used as the solvent or the vehicle. These compositions may also contain adjuvants, especially wetting agents, emulsifiers or dispersants. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents into the composition, by irradiation or by heating. They may also be in the form of sterile solid compositions which may be dissolved or dispersed in sterile water or any other injectable sterile medium. The products of general formula (3) are more particularly used in the treatment of acute leukemias and solid tumors, at daily doses which are generally between 1 and 2 mg/kg by the intravenous (perfusion) route for an adult. The water solubility of compounds of formula (3) may be improved by modification of the C2' and/or C7 substituents to incorporate appropriate functional groups, E 1 and E 2 . For increased water solubility, E 1 and E 2 may independently be hydrogen and -COGCOR 1 wherein G is ethylene, propylene, CH=CH, 1,2-cyclohexane, or 1,2-phenylene, R 1 = OH base, NR 2 R 3 , OR 3 , SR 3 , OCH 2 CONR 4 R 5 , OH R 2 = hydrogen, methyl R 3 = (CH 2 ) n NR 6 R 7 ; (CH 2 ) n N ⊕ R 6 R 7 R 8 X ⊖ n = 1 to 3 R 4 = hydrogen, lower alkyl containing 1 to 4 carbons R 5 = hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CH 2 CO 2 H, dimethylaminoethyl R 6 R 7 = lower alkyl containing 1 or 2 carbons, benzyl or R 6 and R 7 together with the nitrogen atom of NR 6 R 7 form the following rings R 8 = lower alkyl containing 1 or 2 carbons, benzyl X ⊖ = halide base = NH 3 , (HOC 2 H 4 ) 3 N, N(CH 3 ) 3 , CH 3 N(C 2 H 4 OH) 2 , NH 2 (CH 2 ) 6 NH 2 , N-methylglucamine, NaOH, KOH. The preparation of compounds in which X 1 or X 2 is -COGCOR 1 is set forth in Hangwitz U.S. Patent 4,942,184. . The following examples illustrate the invention. EXAMPLE 1 wherein N p1 is Preparation of 3'-desphenyl-3'-(1-naphthyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 ml of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-benzoyl-3-triethylsilyloxy-4-(1-naphthyl)azetidin-2-one (620 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 325 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(1-naphthyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 325 mg (0.287 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give 166 mg (64%) of 3'-(1-naphthyl) taxol, which was recrystallized from methanol/water. m.p. 164-165 °C; [α] 25 NA -52.6° (c 0.005, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.11 (d, J = 7.1 Hz, 2H, benzoate ortho), 8.11 (m, 3H, aromatic), 7.91 (m, 3H, aromatic), 7.70 (m, 2H, aromatic), 7.63-7.46 (m, 7H, aromatic), 6.75 (d, J = 8.8 Hz, 1H, NH), 6.52 (dd, J = 8.8, 1.6 Hz, 1H, H3'), 6.27 (s, 1H, H10), 6.27 (dd, J = 9.1, 9.1 Hz, 1H, H13), 5.68 (d, J = 7.1 Hz, 1H, H2β), 4.85 (dd, J = 7.6, 2.2 Hz, 1H, H5), 4.97 (dd, J = 1.6 Hz, 1H, H2'), 4.39 (m, 1H, H7), 4.24 (d, J = 8.5 Hz, 1H, H20α), 4.17 (d, J = 8.5 Hz, 1H, H20β), 3.80 (d, J = 7.1 Hz, 1H, H3), 3.65 (br, 1H, 2'OH), 2.55 (m, 1H, H6α), 2.48 (br, 1H, 7OH), 2.41 (S, 3H, 4Ac), 2.38 (m, 1H, H14), 1.96 (s, 3H, 10Ac), 1.86 (m, 1H, H6β), 1.80 (br s, 3H, Me18), 1.76 (s, 1H, 1OH), 1.69 (s, 3H, Me19), 1.28 (s, 3H, Me17), 1.16 (s, 3H, Me16). EXAMPLE 2 wherein N p2 is Preparation of 3'-desphenyl-3'-(2-naphthyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-benzoyl-3-triethylsilyloxy-4-(2-naphthyl)azetidin-2-one (620 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(2-naphthyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.283 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 166 mg (64%) of 3'-desphenyl-3'-(2-naphthyl) taxol, which was recrystallized from methanol/water. m.p 164-165 °C; [α] 25 Na -52.6° (c 0.005, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.14 (d, J = 7.3 Hz, 2H, benzoate ortho), 7.96 (m, 1H, aromatic), 7.90 (m, 1H, aromatic), 7.85 (m, 2H, aromatic), 7.76 (m, 2H, aromatic), 7.60 (m, 3H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 2H, aromatic), 7.01 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.26 (dd, J = 9.2, 9.2 Hz, 1H, H13), 5.97 (dd, J = 8.8, 2.5 Hz, 1H, H3'), 5.68 (d, J = 7.1 Hz, 1H, H2β), 4.93 (m, 1H, H5), 4.92 (m, 1H. H2'), 4.39 (m, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20α), 4.20 (d, J = 8.5 Hz, 1H, H20β), 3.81 (d, J = 7.1 Hz, 1H, H3), 3.60 (d, J = 5 Hz, 1H, 2'OH), 2.48 (m, 1H, H6α), 2.45 (br, 1H, 7OH), 2.39 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.83 (m, 1H, H6β), 1.82 (br s, 3H, Me18), 1.68 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.24 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 3 Preparation of 3'-desphenyl-3'-(4-methoxyphenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-benzoyl-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (590 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.288 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 172 mg (68%) of 3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 174-176 °C; [α] 25 Na -48.86° (c 0.05, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.12 (d, J = 7.1 Hz, 2H, benzoate ortho ), 7.72 (m, 2H, aromatic), 7.59 (m, 1H, aromatic), 7.53-7.36 (m, 8H, aromatic), 6.96 (d, J = 8.8 Hz, 1H, NH), 6.90 (m, 2H, aromatic), 6.26 (s, 1H, H10), 6.21 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.70 (dd, J = 8.8, 2.7 Hz, 1H, H3'), 5.66 (d, J = 6.8 Hz, 1H, H2β), 4.93 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.74 (dd, J = 5.5, 2.7 Hz, 1H, H2'), 4.39 (m, 1H, H7), 4.29 (d, J = 8.8 Hz, 1H, H20α), 4.18 (d, J - 8.8 Hz, 1H, H20β), 3.78 (d, J = 6.3 Hz, 1H, H3), 3.78 (s, 3H, Ar OMe ), 3.67 (d, J = 5.5 Hz, 1H, 2'OH), 2.61 (m, 1H, H6α), 2.50 (d, J = 4.4 Hz, 1H, 7OH), 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.22 (s, 3H, 10Ac), 1.84 (m, 1H, H6β), 1.79 (br s, 3H, Me18), 1.79 (s, 1H, 1OH), 1.67 (s, 3H, Me19), 1.22 (s, 3H, Me17), 1.13 (s, 3H, Me16). EXAMPLE 4 Preparation of 3'-desphenyl-3'-(3,4-methylenedioxyphenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-benzoyl-3-triethylsilyloxy-4-(3,4-methylenedioxyphenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(3,4-methylenedioxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 113 mg of material which was purified by flash chromatography to give 165 mg (64%) of 3'-desphenyl-3'-(3,4-methylenedioxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 178-180 °C; [α] 25 Na -46.6° (c 0.005, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.14 (d, J = 7.2 Hz, 2H, benzoate ortho ), 7.72 (m, 2H, aromatic), 7.15 (m, 1H, aromatic), 7.50 (m, 2H, aromatic), 7.38 (m,2H, aromatic), 7.0 (m, 1H, aromatic), 6.94 (m, 2H, aromatic), 6.88 (d, J = 9.1 Hz, 1H, NH), 6.83 (m, 1H, aromatic), 6.28 (s, 1H, H10), 6.23 (dd, J = 9.1, 9.1 Hz, 1H, H13), 5.97 (s, 2H, methylene), 5.69 (dd, J = 9.1, 2.5 Hz, 1H, H3'), 5.68 (d, J = 6.9 Hz, 1H, H2β), 4.95 (dd, J = 9.6, 2.2 Hz, 1H, H5), 4.72 (dd, J = 2.5 Hz, 1H, H2'), 4.41 (m, 1H, H7), 4.31 (d, J = 8.4 Hz, 1H, H20α), 4.20 (d, J = 8.4 Hz, 1H, H20β), 3.81 (d, J = 6.9 Hz, 1H, H3), 3.60 (br, 1H, 2'OH), 2.56 (m, 1H, H6α), 2.43 (d, J = 4.1 Hz, 1H, 7OH), 2.39 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.24 (s, 3H, 10Ac), 1.88 (m, 1H, H6β), 1.82 (br s, 3H, Me18), 1.69 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.24 (s, 3H, Me17), 1.15 (s, 3H, Me16). EXAMPLE 5 Preparation of 3'-desphenyl-3'-(3,4-dimethoxyphenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-benzoyl-3-triethylsilyloxy-4-(3,4-dimethoxyphenyl)azetidin-2-one (630 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(3,4-dimethoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 330 mg (0.286 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give 175 mg (67%) of 3'-desphenyl-3'-(3,4-dimethoxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 165-167 °C; [α] 25 Na -42.0° (c 0.005, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.12 (d, J = 8.3 Hz, 2H, benzoate ortho ), 7.73 (d, J = 8.2 Hz, 2H, benzamide ortho ), 7.65-7.35 (m, 6H, aromatic), 7.1-7.0 (m, 2H, aromatic), 6.94 (d, J = 8.8 Hz, 1H, NH), 6.88 (d, J = 8.3 Hz, 2H, aromatic), 6.27 (s, 1H, H10), 6.21 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.69 (m, 2H, H3, H2β), 4.94 (dd, Hz, J = 9.9, 2.2 Hz, 1H, H5), 4.77 (d, J = 2.8 Hz, 1H, H2'), 4.39 (dd, J = 11.0, 6.6 Hz, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20α), 4.19 (d, J = 8.5 Hz, 1H, H20β), 3.88 (s, 3H, ArO Me ), 3.87 (s, 3H, Ar OMe ), 3.80 (d, J = 7.1 Hz, 1H, H3), 3.59 (d, J = 4.4 Hz, 1H, 2'OH), 2.54 (m, 1H, H6α), 2.38 (s, 3H, 4Ac), 2.36 (m, 2H, H14α, H14β), 2.23 (s, 3H, 10Ac), 1.86 (m, 1H, H6β), 1.80 (br s, 3H, Me18), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 6 Preparation of 3'-desphenyl-3'-(4-nitrophenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-benzoyl-3-triethylsilyloxy-4-(4-nitrophenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 320 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl-3'-desphenyl-3'-(4-nitrophenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 320 mg (0.284 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 147 mg (57%) of 3'-desphenyl-3'-(4-nitrophenyl) taxol, which was recrystallized from methanol/water. m.p. 188-190 °C; [α] 25 Na -63.7° (c 0.01, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.26 (d, J = 8.8 Hz, 2H, benzoate ortho ), 8.20 (m, 2H, aromatic), 7.73 (m, 4H, aromatic), 7.60 (m, 1H, aromatic), 7.52 (m, 4H, aromatic), 7.41 (m, 1H, aromatic), 7.15 (d, J = 8.8 Hz, 1H, NH), 6.25 (s, 1H, H10), 6.26 (dd, J = 9.3, 9.3 Hz, 1H, H13), 5.93 (dd, J = 8.8, 2.8 Hz, 1H, H3'), 5.66 (d, J = 6.6 Hz, 1H, H2β), 4.94 (dd, J = 9.3, 1.7 Hz, 1H, H5), 4.82 (dd, J = 3.9, 2.8 Hz, 1H, H2'), 4.38 (m, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20α), 4.19 (d, J = 8.8 Hz, 1H, H20β), 3.86 (d, J = 3.9 Hz, 1H, 2'OH), 3.79 (d, J = 6.6 Hz, 1H, H3), 2.55 (m, 1H, H6α), 2.46 (d, J = 3.8 Hz, 1H, 7OH), 2.41 (s, 3H, 4Ac), 2.38 (m, 2H, H14), 2.23 (s, 3H, 10Ac), 1.82 (m, 1H, H6β), 1.80 (br s, 3H, Me18), 1.74 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.21 (s, 3H, Me17), 1.13 (s, 3H, Me16). EXAMPLE 7 Preparation of N -debenzoyl- N -(4-methylbenzoyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of (+) -cis -1-(4-methylbenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (203 mg, 0.513 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 386 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl- N -debenzoyl- N -(4-methylbenzoyl) taxol. To a solution of 386 mg of this crude product in 6 mL of acetonitrile and 0.3 mL of pyridine at 0 °C was added 0.9 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 283 mg of material which was purified by flash chromatography to give 240 mg (97%) of N -debenzoyl- N -(4-methylbenzoyl) taxol, which was recrystallized from methanol/water. m.p. 175-176.5 °C; [α] 25 Na -50.9° (c 0.00975, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J= 7.1 Hz, 2H, benzoate ortho ), 7.7-7.3 (m, 10H, aromatic), 7.19 (d, J = 7.7 Hz, 2H, benzoate meta ), 6.94 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.22 (dd, J= 9.3, 9.3 Hz, 1H, H13), 5.77 (dd, J = 9.3, 2.3 Hz, 1H, H3'), 5.67 (d, J= 7.2 Hz, 1H, H2b), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.78 (dd, J = 4.9, 2.8 Hz, 1H, H2'), 4.42 (m, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20a), 4.19 (d, J = 8.5 Hz, 1H, H20b), 3.79 (d, J = 7.2 Hz, 1H, H3), 3.60 (d, J = 4.9 Hz, 1H, 2'OH), 2.53 (m, 1H, H6a), 2.46 (d, J = 4.4 Hz, 1H, 7OH), 2.38 (s, 3H, 4Ac), 2.37 (s, 3H, Ar Me ), 2.31 (m, 2H, H14a, H14b), 2.23 (s, 3H, 10Ac), 1.87 (m, 1H, H6b), 1.78 (br s, 3H, Me18), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 8 Preparation of N -debenzoyl- N -(4-t-butylbenzoyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of (+)- cis -1-(4-t-butylbenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (226 mg, 0.515 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl- N -debenzoyl- N -(4-t-butylbenzoyl) taxol. To a solution of 330 mg (0.289 mmol) of this crude product in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 260 mg of material which was purified by flash chromatography to give 240 mg (92%) of N -debenzoyl- N -(4-t-butylbenzoyl) taxol, which was recrystallized from methanol/water. m.p. 171-173 °C; [α] 25 Na -49.1° (c 0.05, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho ), 7.76-7.25 (m, 12H, aromatic), 6.98 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.77 (dd, J = 8.8, 2.7 Hz, 1H, H3'), 5.67 (d, J = 6.6 Hz, 1H, H2β), 4.94 (dd, J = 9.3, 1.2 Hz, 1H, H5), 4.78 (dd, J = 4.4, 2.7 Hz, 1H, H2'), 4.38 (m, 1H, H7), 4.29 (d, J = 8.2 Hz, 1H, H20α), 4.20 (d, J = 8.2 Hz, 1H, H20β), 3.79 (d, J = 6.6 Hz, 1H, H3), 3.65 (d, J = 4.4 Hz, 1H, 2'OH), 2.57 (m, 1H, H6α), 2.48 (d, J = 4.1 Hz, 1H, 70H), 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.22 (s, 3H, 10Ac), 1.85 (m, 1H, H6β), 1.79 (br s, 3H, Me18), 1.68 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.29 (s, 9H, Ar t Bu ), 1.23 (s, 3H, Me17), 1.13 (s, 3H, Me16). EXAMPLE 9 Preparation of N -debenzoyl- N -(4-methoxybenzoyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.285 mmol) in 2 mL of THF at -45 °C was added dropwise 0.175 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of (+)-cis-1-(4-methoxybenzoyl)-3-triethylsilyloxy-4-phenylazetidin-2-one (211 mg, 0.513 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 2 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 406 mg of crude (2'R,3'S)-2',7-(bis)triethylsilyl- N -debenzoyl- N -(4-methoxybenzoyl) taxol. To a solution of 406 mg (0.112 mmol) of this crude product in 12 mL of acetonitrile and 0.6 mL of pyridine at 0 °C was added 1.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 308 mg of material which was purified by flash chromatography to give 236 mg (94%) of N -debenzoyl- N -(4-methoxybenzoyl) taxol, which was recrystallized from methanol/water. m.p. 174.5-176 °C; [α] 25 Na -49.5° (c 0.0084, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho ), 7.75-7.3 (m, 10H, aromatic),6.90 (d, J =8.2 Hz, 1H, NH), 6.88 (d, J = 7.1 Hz, 2H, benzoate meta ), 6.27 (s, 1H, H10), 6.22 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.76 (dd, J = 8.8, 2.7 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.78 (d, J = 2.7 Hz, 1H, H2'), 4.40 (dd, J = 11.0, 7.1 Hz, 1H, H7), 4.30 (d, J = 8.5 Hz, 1H, H20α), 4.19 (d, J= 8.5 Hz, 1H, H20β), 3.82 (s, 3H, OMe), 3.79 (d, J = 7.1 Hz, 1H, H3), 2.55 (m, 1H, H6α),2.38 (s, 3H, 4Ac), 2.30 (m, 2H, H14α, H14β), 2.23 (s, 3H, 10Ac), 1.87 (m, 1H, H6β), 1.78 (br s, 3H, Me18), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 10 Preparation of N -debenzoyl- N -(4-chlorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-(4 -chlorobenzoyl ) -3 -triethylsilyloxy -4-(4-fluorophenyl)azetidin-2-one (630 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl- N -debenzoyl- N -(4-chlorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 330 mg (0.283 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 250 mg of material which was purified by flash chromatography to give 166 mg (65%) of N -debenzoyl- N -(4-chlorobenzoyl)-3'-desphenyl-3'-(4-fluorophenyl) taxol, which was recrystallized from methanol/water. m.p. 178-179 °C; [α] 25 Na -51.9° (c 0.01, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho ), 7.64 (m, 3H, aromatic), 7.49 (m, 4H, aromatic), 7.36 (m, 2H, aromatic), 7.10 (m, 2H, aromatic), 6.97 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.76 (dd, J = 8.8, 2.2 Hz, 1H, H3'), 5.67 (d, J = 7.2 Hz, 1H, H2β), 4.94 (dd, J = 9.3, 2.2 Hz, 1H, H5), 4.75 (dd, J = 4.4, 2.2 Hz, 1H, H2'), 4.39 (ddd, J = 11.0, 6.6, 3.9 Hz, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20α), 4.19 (d, J = 8.8 Hz, 1H, H20β), 3.79 (d, J = 7.2 Hz, 1H, H3), 3.60 (d, J = 4.4 Hz, 1H, 2'OH), 2.54 (m, 1H, H6α), 2.47 (d, J = 3.9 Hz, 1H, 7OH), 2.38 (s, 3H, 4Ac), 2.30 (m, 2H, H14), 2.28 (s, 3H, 10Ac), 1.87 (m, 1H, H6β), 1.78 (br s, 3H, Me18), 1.78 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 11 Preparation of N -debenzoyl- N -(4-methylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-(4-methylbenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (610 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 325 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl- N -debenzoyl- N -(4-methylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 325 mg (0.289 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 265 mg of material which was purified by flash chromatography to give 165 mg (64%) of N -debenzoyl- N -(4-methylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 173-174 °C; [α] 25 Na -50.2° (c 0.01, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.61 (m, 3H, aromatic), 7.51 (m, 2H, aromatic), 7.40 (m, 2H, aromatic), 7.19 (m, 2H, aromatic), 6.93 (m, 2H, aromatic), 6.86 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.70 (dd, J = 8.8, 2.8 Hz, 1H, H3'), 5.66 (d, J = 7.2 Hz, 1H, H2β), 4.94 (dd, J = 9.9, 2.2 Hz, 1H, H5), 4.74 (dd, J = 5.5, 2.8 Hz, 1H, H2'), 4.40 (ddd, J = 11.0, 6.5, 3.8 Hz, 1H, H7), 4.30 (d, J = 8.8 Hz, 1H, H20α), 4.19 (d, J = 8.8 Hz, 1H, H20β), 3.79 (d, J = 7.2 Hz, 1H, H3), 3.78 (s, 3H, Ar OMe ), 3.63 (d, J = 5.5 Hz, 1H, 2'OH), 2.54 (m, 1H, H6α), 2.46 (d, J = 3.8 Hz, 1H, 7OH), 2.38 (s, 3H, Ar Me ), 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.23 (s, 3H, 10Ac), 1.88 (m, 1H, H6β), 1.80 (br s, 3H, Me18), 1.80 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 12 Preparation of N -debenzoyl- N -(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-(4-t-butylbenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (670 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 340 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl- N -debenzoyl- N -(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 340 mg (0.291 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 275 mg of material which was purified by flash chromatography to give 188 mg (70%) of N -debenzoyl- N -(4-t-butylbenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 184-185 °C; [α] 25 Na -50.4° (c 0.01, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho ), 7.53 (m, 9H, aromatic), 6.92 (m, 2H, aromatic), 6.38 (d, J = 8.8 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.21 (dd, J= 8.8, 8.8 Hz, 1H, H13), 5.72 (dd, J = 8.8, 2.8 Hz, 1H, H3'), 5.67 (d, J = 7.1 Hz, 1H, H2β), 4.95 (dd, J = 9.8, 2.2 Hz, 1H, H5), 4.74 (dd, J = 5.5, 2.8 Hz, 1H, H2'), 4.40 (ddd, J = 11.0, 6.6, 3.8 Hz, 1H, H7), 4.30 (d, J = 8.4 Hz, 1H, H20α), 4.19 (d, J = 8.4 Hz, 1H, H20β), 3.80 (d, J = 7.1 Hz, 1H, H3), 3.79 (s, 3H, Ar OMe ), 3.63 (d, J = 5.5 Hz, 1H, 2'OH), 2.54 (m, 1H, H6α), 2.46 (d, J = 3.8 Hz, 1H, 7OH), 2.38 (s, 3H, 4Ac), 2.32 (m, 2H, H14), 2.23 (s, 3H, 10Ac), 1.87 (ddd, J = 11.0, 14.7, 2.2 Hz, 1H, H6β), 1.81 (br s, 3H, Me18), 1.80 (s, 1H, 1OH), 1.68 (s, 3H, Me19), 1.30 (s, 9H, Ar t Bu ), 1.23 (s, 3H, Me17), 1.14 (s, 3H, Me16). EXAMPLE 13 Preparation of N -debenzoyl -N -(4-methoxybenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol. To a solution of 7-triethylsilyl baccatin III (200 mg, 0.286 mmol)) in 2 mL of THF at -45 °C was added dropwise 0.174 mL of a 1.63M solution of nBuLi in hexane. After 0.5 h at -45 °C, a solution of cis -1-(4-methoxybenzoyl)-3-triethylsilyloxy-4-(4-methoxyphenyl)azetidin-2-one (630 mg, 1.43 mmol) in 2 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO 3 and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 330 mg of a mixture containing (2'R,3'S)-2',7-(bis)triethylsilyl -N -debenzoyl -N -(4-methoxybenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol and a small amount of the (2'S,3'R) isomer. To a solution of 330 mg (0.289 mmol) of the mixture obtained from the previous reaction in 18 mL of acetonitrile and 0.93 mL of pyridine at 0 °C was added 2.8 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 255 mg of material which was purified by flash chromatography to give 183 mg (70%) of N -debenzoyl- N -(4-methoxybenzoyl)-3'-desphenyl-3'-(4-methoxyphenyl) taxol, which was recrystallized from methanol/water. m.p. 174-175 °C; [α] 25 Na -50.6° (c 0.01, CHCl 3 ). 1 H NMR (CDCl 3 , 300 MHz) δ 8.13 (d, J = 7.1 Hz, 2H, benzoate ortho), 7.69 (d, J = 8.8 Hz, 2H, benzamide ortho ), 7.62 (m, 1H, aromatic), 7.51 (m, 2H, aromatic), 7.39 (m, 2H, aromatic), 6.90 (m, 4H, aromatic), 6.82 (d, J = 8.2 Hz, 1H, NH), 6.27 (s, 1H, H10), 6.20 (dd, J = 8.8, 8.8 Hz, 1H, H13), 5.69 (dd, J = 8.2, 2.7 Hz, 1H, H3'), 5.67 (d, J = 6.6 Hz, 1H, H2β), 4.95 (dd, J = 7.7, 1.6 Hz, 1H, H5), 4.73 (dd, J = 5.5, 2.7 Hz, 1H, H2'), 4.40 (ddd, J = 11.0, 6.6, 4.4 Hz, 1H, H7), 4.30 (d, J = 8.24 Hz, 1H, H20α), 4.19 (d, J = 8.24 Hz, 1H, H20β), 3.81 (s, 3H, Ar OMe ), 3.80 (d, J = 6.6 Hz, 1H, H3), 3.78 (s, 3H, Ar OMe ), 3.71 (d, J = 5.5 Hz, 1H, 2'OH), 2.54 (ddd, J = 7.7, 14.3, 6.6 Hz, 1H, H6α), 2.47 (d, J = 4.4 Hz, 1H, 7OH), 2.37 (s, 3H, 4Ac), 2.31 (m, 2H, H14), 2.23 (s, 3H, 10Ac), 1.89 (ddd, J = 11.0, 14.3, 1.6 Hz, 1H, H6β), 1.79 (br s, 3H, Me18), 1.69 (s, 1H, 1OH), 1.67 (s, 3H, Me19), 1.23 (s, 3H, Me17), 1.13 (s, 3H, Me16). EXAMPLE 14 Tubulin binding assays were performed using compounds from the previous Examples substantially as set forth in Parness et al., J. Cell Biology 91: 479-487 (1981) and compared to taxol and taxotere. The results are presented in Table 1. Tubulin Assay Compound Init. Peak Rel. Rate Example 1 0 0 2 0 0 3 59 87 4 53 85 5 11 26 6 114 105 7 107 110 8 67 85 9 95 99 10 109 92 11 77 96 12 24 44 13 51 81 Taxol 100 98 Taxotere 100 ― EXAMPLE 34 IC 50 data were obtained in vitro on a human cancer cell line (HCT 116) which is available from the National Cancer Institute, and a multidrug resistant cell line (HCT/VM46), which is resistant to a variety of hydrophobic agents, including taxol. Cytotoxicity was assessed in HCT116 and HCT VM46 human colon carcinoma cells by XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide assay (Scudiero 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). Cells were plated at 4000 cells/well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted. The cells were incubated at 37°C for 72 hours at which time the tetrazolium dye, XTT, was added. A dehydrogenase enzyme in live cells reduces the XTT to a form that absorbs light at 450 nm which can be quantitated spectrophotometrically. The greater the absorbance the greater the number of live cells. The results are expressed as an IC 50 which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450 nm) to 50% of that of untreated control cells. The results are presented in Table 2. Lower numbers indicate greater activity. IC 50 Compound HCT 116 HCT VM46 Example 1 .385 2.58 2 .084 1.89 3 .005 0.469 4 .021 1.7 5 .303 >7.8 6 .014 2.6 7 .005 0.442 8 .006 0.651 9 .004 0.973 Taxol 0.004 0.536 Taxotere 0.007 0.246 In view of the above, it will be seen that the several objects of the invention are achieved.

Claims: A taxane derivative of the formula wherein: R 1 and R 3 are independently selected from the group consisting of phenyl, naphthyl, and provided that R 1 and R 3 are not both phenyl; Q is CH 3 -, (CH 3 ) 3 C-, CH 3 O-, or NO 2 ; Z is -OAc; Ac is acetyl; and E 1 and E 2 are hydrogen. A taxane derivative of the formula wherein: R 1 and R 3 are independently selected from the group consisting of phenyl, naphthyl, C 6 H 5 CHCH-, provided that R 1 and R 3 are not both phenyl; Q is CH 3 -, (CH 3 ) 3 C-, CH 3 O-, Cl, Br, F, or NO 2 ; Z is -OT 1 ; T 1 is hydrogen, hydroxyl protecting group, or -COT 2 ; T 2 is H, C 1 -C 6 alkyl, up to C 6 alkenyl, up to C 6 alkynyl or monocyclic aryl; Ac is acetyl; and E 1 and E 2 are independently selected from hydrogen and -COGCOR 1 ; provided that, when R 1 and R 3 are independently selected from the group consisting of phenyl, naphthyl and and when Z is -OAc, E 1 and E 2 are not both hydrogen and that when Z is -OH and E 1 and E 2 are both hydrogen, R 3 is not phenyl; and wherein: G is ethylene, propylene, -CH=CH-, 1,2-cyclo-hexylene, or 1,2-phenylene; R 1 = OH base, NR 2 R 3 , OR 3 , SR 3 , OCH 2 CONR 4 R 5 , or OH; R 2 = hydrogen or methyl; R 3 = (CH 2 ) n NR 6 R 7 or (CH 2 ) n N ⊕ R 6 R 7 R 8 X ⊖ ; n = 1 to 3; R 4 = hydrogen or lower alkyl containing 1 to 4 carbons; R 5 = hydrogen, lower alkyl containing 1 to 4 carbons, benzyl, hydroxyethyl, CH 2 CO 2 H, or dimethylaminoethyl; R 6 and R 7 = independently selected from lower alkyl containing 1 or 2 carbons or benzyl, or R 6 and R 7 together with the nitrogen atom of NR 6 R 7 forms one of the following rings R 8 = lower alkyl containing 1 or 2 carbons or benzyl; X ⊖ = halide; and base = NH 3 , (HOC 2 H 4 ) 3 N, N(CH 3 ) 3 , CH 3 N(C 2 H 4 OH) 2 , NH 2 (CH 2 ) 6 NH 2 , N-methylglucamine, NaOH, or KOH. A taxane derivative according to claim 1 or claim 2, wherein R 1 is phenyl. A taxane derivative according to claim 1, wherein R 3 is phenyl. A taxane derivative according to any one of claims 1 to 4, wherein the taxane has the 2'R, 3'S configuration. A pharmaceutical composition which contains a taxane derivative according to any one of claims 1 to 5 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.

Inventors: BIEDIGER RONALD J, HOLTON ROBERT A, KIM SEOKCHAN, NADIZADEH HOSSAIN, BIEDIGER, RONALD J., HOLTON, ROBERT A., KIM, SEOKCHAN, NADIZADEH, HOSSAIN
Applicants: UNIV FLORIDA STATE, FLORIDA STATE UNIVERSITY
Application year: 1992
Main classification: C07D305
IPC codes: A61K31, C07D305, A61P35, C07D407, C07F7, C07D409, C07D405, C07D205