WO1998000419A1

WO1998000419A1 - Ortho-ester analogs of paclitaxel

Info

Publication number: WO1998000419A1
Application number: PCT/US1997/010586
Authority: WO
Inventors: John F. Kadow; Qiufen Xue; James G. Tarrant; Shu-Hui Chen
Original assignee: Bristol-Myers Squibb Company
Priority date: 1996-07-02
Filing date: 1997-06-17
Publication date: 1998-01-08
Also published as: AU3572397A

Abstract

The present invention concerns novel ortho-ester containing paclitaxel derivatives, their use as antitumor agents, and pharmaceutical compositions containing the novel compounds.

Description

ORTHO-ESTER ANALOGS OF PACLITAXEL

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.

Background Art

Taxol® (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It has recently been approved for the treatment of refractory advanced ovarian cancer and breast cancer; and studies involving other cancers have shown promising results. The results of paclitaxel clinical studies are reviewed by numerous authors, such as by Rowinsky and Donehower in "The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics," Pharmac. Ther.. 52:35-84, 1991; by Spencer and Faulds in "Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer," Drugs . 48 (5) 794-847, 1994; by K.C. Nicolaou et al. in "Chemistry and Biology of Taxol," Angew. Chem.. Int. Ed. Engl.. 33: 15-44, 1994; by F.A. Holmes, A.P. Kudelka, J.J. Kavanaugh, M. H. Huber, J. A. Ajani, V. Valero in the book "Taxane Anticancer Agents Basic Science and Current Status" edited by Gunda I. Georg, Thomas T. Chen, Iwao Ojima, and Dolotrai M. Vyas, 1995, American Chemical Society, Washington, DC, 31-57; by Susan G. Arbuck and Barbara Blaylock in the book "TAXOL^® Science and Applications" edited by Matthew Suffness, 1995, CRC Press Inc. , Boca Raton, Florida, 379-416; and also in the references cited therein. Recently, a semi-synthetic analog of paclitaxel named Taxotere® (docetaxel) has also been found to have good antitumor activity in animal models. Taxotere® is also currently undergoing clinical trials in Europe and the United States. The structures of paclitaxel and docetaxel are shown below along with the conventional numbering system of taxane molecules; such numbering system is also employed in this application.

Taxol®: R = Ph; R' = acetyl

Taxotere®: R = t-butoxy; R' = hydrogen

Novel taxanes that retain the cytoxicity and tubulin stabilization properties of paclitaxel and docetaxel are of great commercial and clinical importance, and are the subject of this patent application.

SUMMARY OF THE INVENTION

The present invention relates to ortho-ester taxane derivatives having the formula (I), or pharmaceutically acceptable salts thereof:

l r wherein p is 0 or 1; X is NH or O; R or R are independently hydrogen, hydroxyl, -OC(0)C₁.₈alkyl, -OC(0)OCι-₈ alkyl, OCH₂SCH₃, OCH₃, or

OCH₂OCH₃ provided that R¹ is in the ^β (up) position and R^1' is in the α

1 1' 2 2'

(down) position, and that at least one of R or R is hydrogen; R or R are independently hydrogen, hydroxyl, -OC(0)Cι_₈alkyl, -OC(0)OC₁.₈ alkyl, OCH2SCH3, OCH3, or OCH2OCH3 provided R² is in the β position and R^2'

2 2' 1 is in the α position; and that at least one of R or R is hydrogen; or R and

2 1' 2' 3

R form a double bond and R or R are hydrogen; R is d.₆ alkyl, C₃.₆

4 cycloalkyl or Ci.₆ O-alkyl; R is Cι_₈ alkyl, Cι.₈ O-alkyl, aryl, substituted aryl,

5 -OCH₂Ph, C3.8 cycloalkyl or heteroaryl; R is C₂.₆ alkyl, C₂.₆ alkenyl, C₃.₇

6 cycloalkyl, aryl, substituted aryl, or heteroaryl; R is hydrogen, hydroxyl or

7 C₁-₈ alkanoxy; R is aryl, substituted aryl, or heteroaryl provided R⁷ can be

8 either in the α or β position; R is -8 alkyl, C₁-₈ alkanoyl, or -CH2OCH3; and R⁹ is methyl, hydroxymethyl, or R⁹ and R¹ together can form a cyclopropane ring with the proviso that when these substituents are cyclopropane ring than R¹ is hydrogen.

Another aspect of the present invention provides a method for inhibiting tumor in a mammalian host which comprises administering to said mammalian host an antitumor effective amount of a compound of the formula (I).

Yet another aspect of the present invention provides a pharmaceutical composition (formulation) which comprises an antitumor effective amount of a compound of the formula (I) and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

In the present application, the numbers in the subscript after the symbol "C" define the number of carbon atoms a particular group can contain. For example, "C1-8 alkyl" means a straight or branched saturated carbon chain having from one to eight carbon atoms; examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl, isopentyl, n-hexyl, n-heptyl, and n-octyl. "C1-8 alkylene" means C1-8 alkyl with two points of attachment; examples include methylene, ethylene, and propylene. "C2-8 alkenyl" means a straight or branched carbon chain having at least one carbon-carbon double bond, and having from two to eight carbon atoms; examples include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, and hexenyl. "C2-8 alkenediyl" refers to C2-8 alkenyl with two points of attachment; examples include ethylene-l,2-diyl (vinylene), 2-methyl-2- butene-l,4-dinyl, 2-hexene-l,6-diyl, and the like groups. "C2-8 alkynyl" means a straight or branched carbon chain having at least one carbon-carbon triple bond, and from two to eight carbon atoms; examples include ethynyl, propynyl, butynyl, and hexynyl. "Cι-8 alkanoyl" refers to groups such as formyl, acetyl, propanoyl, hexanoyl, etc.

"Aryl" means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and naphthyl. "Substituted aryl" means aryl substituted with at least one group selected from C1-8 alkanoyloxy, hydroxyl, halogen, C1-8 alkyl, trifluoromethyl, Ci-β alkoxy (alkyloxy), aryl,

C2-8 alkenyl, O-β alkanoyl, nitro, amino, and amido.

"Halogen" means fluorine, chlorine, bromine, and iodine.

"Methylthiomethyl" (also abbreviated as MTM) refers to the group

"Heteroaryl" means a five- or six-membered aromatic ring containing at least one and up to four non-carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, and like rings.

As used herein, hydroxyl protecting groups are moieties which can be employed to block or protect the hydroxyl function and they are well known to those skilled in the art. Preferably, said groups are those which can be removed by methods which result in no appreciable destruction to the remaining portion of the molecule. Examples of such readily removable hydroxyl protecting groups include chloroacetyl, me tho xy me thyl , 2, 2, 2 - t richl o roethy oxy me thy l , 2 ,2,2- trichloroethyloxycarbonyl, tetrahydropyranyl, tetrahydrofuranyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, triCi -6 alkylsilyl, triphenylsilyl, and the like. Preferred protecting groups for the 2'-hydroxyl group of paclitaxel and a derivative thereof are triethylsilyl, 2,2,2-trichloroethyloxycarbonyl and benzyloxycarbonyl. Additional examples of hydroxyl protecting groups may be found in standard reference works such as Greene and Wuts, Protective Groups in Organic Synthesis. 2d Ed., 1991, John Wiley & Sons, and McOmie, Protective Groups in Organic Chemistry. 1975, Plenum Press. Methods for introducing and removing protecting groups are also found in such textbooks.

"Taxane" denotes moieties containing the twenty carbon taxane core framework represented by the structural formula shown below with the absolute configuration.

The numbering system shown above is one used in conventional taxane nomenclature, and is followed throughout the application. For example, the notation Cl refers to the carbon atom labeled as "1"; C5-C20 oxetane refers to an oxetane ring formed by the carbon atoms labeled as 4, 5 and 20 with an oxygen atom.

The synthesis of a compound of formula (I) can be accomplished by a wide variety of methods. The synthetic descriptions and specific examples that follow are only intended for the purpose of illustration, and are not to be construed as limiting in any manner ways to make compounds of the present invention by any other methods.

For example, a compound of formula (I) can be prepared by a process of Scheme I or an obvious variant thereof. In Scheme I, a compound of formula (II) is treated phenoxyacetic acid in the presence of 1,3-dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine (DMAP) to provide a compound of formula (III) (Step a). Subsequently a compound of formula (III) is treated with a strong base and quenched with an alkylating or acylating reagent to give a compound of formula (IV) (Step b). In Step b, the preferred reagents for preparing ethers are various alkyl trifluoro-methanesulfonates (triflates), some of which are available commercially while others can be readily prepared by anyone skilled in the art using conventional organic chemistry technique.

Subsequently a compound of formula (IV) is treated with a sterically hindered amine base to give a compound of formula V (Step c) The preferred amine base is tert-butyl amine.

Subsequently a compound of formula (V) is treated with a strong base and the resulting alkoxide is quenched with a β-lactam of formula (VI) to afford a compound of formula (VII) (Step d). The preparation of β- lactams of formula (VI) have been described in the chemical literature and in various patents.

Subsequently a compound of formula (VII) is deprotected according to the appropriate protocol obtained from the literature to afford a compound of formula (I) (Step e). All symbols used in connection with Scheme I are as defined earlier.

The syntheses of methylthiomethyl derivatives of formula (II) or other starting materials are described in detail in our European patent application 604,910 Al published July 6, 1994 which is herein incorporated by reference in its entirety. Other starting materials not specifically described in 604,910 Al are reported elsewhere or can be readily obtained by anyone skilled in the art using conventional organic chemistry technique. SCHEME I

π

Step a

in

Stepb

Stepc

V

Stepd

VII

Stepe

By now there are many publications reporting the introduction of a wide variety of groups onto a taxane core. By using these well established methods or obvious variants thereof, the starting taxanes of formula VII, or hydroxyl protected analogues thereof, can be readily made. For example, for transforming C4-acetoxy into other functional groups see, S. H. Chen et al., /. Organic Chemistry, 59, pp 6156- 6158 (1994) and PCT application WO 94/14787 published July 7, 1994; for converting C2-benzoyloxy to other groups see, S.H. Chen et al, Bioorganic and Medicinal Chemistry Letters, Vol. 4, No. 3, pp 479-482 (1994); K.C. Nicolaou et al., /. Am. Chem. Soc, 1995, 117, 2409 and European Patent Application 617,034 Al published September 28, 1994; for modifying C10- acetyloxy see, K.V. Rao et al., /. Med. Chem., 38, pp 3411-3414 (1995), J. Kant et al., Tetrahedron Letters, Vol. 35, No. 31, pp 5543-5546 (1994); and U.S. Patent No. 5,294,637 issued March 15, 1994; for making CIO and/or C7 unsubstituted (deoxy) derivatives see, European Patent Application 590,267A2 published April 6, 1994 and PCT application WO 93/06093 published April 1, 1993; for making C-10 epi hydroxyl or acyloxy compounds see PCT application WO 96/03394; for making C-10 deoxy-C- 10 alkyl analogs see PCT application WO95/33740; for making 7β,8β- methano, 6α,7α-dihydroxyl and 6,7-olefinic groups see, R. A. Johnson, Tetrahedron Letters, Vol. 35, No 43, pp 7893-7896 (1994), U.S. Patent No. 5,254,580 issued October 19, 1993, and European Patent Application 600,517A1 published June 8, 1994; for making C7/C6 oxirane see, X. Liang and G.I. Kingston, Tetrahedron Letters, Vol. 36, No. 17, pp 2901-2904 (1995); for making C7-epi-fluoro see, G. Roth et al, Tetrahedron Letters, Vol 36, pp 1609-1612 (1995); for forming C7 esters and carbonates see, U.S. Patent No. 5,272,171 issued December 21, 1993 and S. H. Chen et al., Tetrahedron, 49, No. 14, pp 2805-2828 (1993); for 9a- and 9b-hydroxyl taxanes see, L. L. Klein, Tetrahedron Letters, Vol 34, No 13, pp 2047-2050 (1993), PCT application WO 94/08984 published April 28, 1994, U.S. Patent No. 5,352,806 issued October 4, 1994, PCT application WO 94/20485 published September 15, 1994, and G.I. Georg et. al. . Tetrahedron Letters, Vol 36, No 11, pp 1783-1786 (1995).

Compounds of formula (I) of the instant invention are effective tumor inhibiting agents, and thus are useful in human and /or veterinary medicine. Thus, another aspect of the instant invention concerns a method for inhibiting human and /or other mammalian tumors which comprises administering to a tumor bearing host an antitumor effective amount of a compound of formula (I).

Compounds of formula (I) of the present invention may be used in a manner similar to that of paclitaxel; therefore, an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering a compound of the present invention. The dosage, mode and schedule of administration for compounds of this invention are not particularly restricted, and will vary with the particular compound employed. Thus a compound of the present invention may be administered via any suitable route of administration, preferably parenterally; the dosage may be, for example, in the range of about 1 to about 100 mg/kg of body weight, or about 20 to about 500 mg/m^. The actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of tumor being treated. Many factors that modify the action of the drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.

The present invention also provides pharmaceutical compositions (formulations) containing an antitumor effective amount of a compound of formula (I) in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants. Examples of formulating paclitaxel or derivatives thereof may be found in, for example, United States Patents Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compounds of this invention. For example, compounds of the present invention may be formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms. They may also be manufactured in the form of sterile solid compositions, for example, freeze dried and, if desired, combined with other pharmaceutically acceptable excipients. Such solid compositions can be reconstituted with sterile water, physiological saline, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like, or some other sterile injectable medium immediately before use for parenteral administration.

Typical of pharmaceutically acceptable carriers are, for example, mannitol, urea, dextrans, lactose, potato and maize starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, ethyl cellulose, poly(vinylpyrrolidone), calcium carbonate, ethyl oleate, isopropyl myristate, benzyl benzoate, sodium carbonate, gelatin, potassium carbonate, silicic acid. The pharmaceutical preparation may also contain nontoxic auxiliary substances such as emulsifying, preserving, wetting agents, and the like as for example, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene monostearate, glyceryl tripalmitate, dioctyl sodium sulfosuccinate, and the like.

DESCRIPTION OF SPECIFIC EMBODIMENTS

The specific examples that follow illustrate the syntheses of representative compounds of the instant invention and their starting materials, and are not to be construed as limiting the invention in sphere or scope. The methods may be adapted to variations in order to produce compounds embraced by this invention but not specifically disclosed. Further, variations of the methods to produce the same compounds in somewhat different manner will also be evident to one skilled in the art.

In the following experimental procedures, all temperatures are understood to be in Centigrade (C) when not specified. The nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (δ) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs or br s), broad doublet (bd or br d), broad triplet (bt or br t), broad quartet (bq or br q), singlet (s), multiplet (m), doublet (d), quartet (q), triplet (t), doublet of doublets (dd), doublet of triplets (dt), and doublet of quartets (dq). The solvents employed for taking NMR spectra are acetone-d₆ (deuterated acetone). DMSO-d₆ (perdeuterodimethylsulfoxide), D₂0 (deuterated water), CDC1₃ (deuterochloroform) and other conven-tional deuterated solvents. The infrared (IR) spectral description include only absorption wave numbers (cm ¹) having functional group identification value.

Celite is a registered trademark of the Johns-Manville Products Corporation for diatomaceous earth.

The abbreviations used herein are conventional abbreviations widely employed in the art. Some of which are: MS (mass spectrometry); HRMS (high resolution mass spectrometry); Ac (acetyl); Ph (phenyl); v/v (volume/volume); ESI (electron spray ionization); FAB (fast atom bombardment); DCC (1,3-dicyclohexylcarbodiimide); DMAP (dimethylaminopyridine); DMF (N,N-dimethylformamide); min (minute(s)); h or hr(s) (hour(s)); BOC (t-butoxycarbonyl); Bn (benzyl); Bz (benzoyl); TES (triethylsilyl); DMSO (dimethylsulfoxide); NMO (N- methylmorpholine oxide); THF (tetrahydrofuran); LHMDS (lithium hexamethyldisilazane); TBAF (tetrabutylammonium fluoride).

Example 1. 13-Phenoxyacetyl-7-triethylsilyloxybaccatin III (formula Ilia).

To a solution of 7-triethylsilyloxybaccatin III (2.0 g, 2.86 mmoles) in 30 mL of anhydrous toluene was added phenoxyacetc acid (1.37 g, 9.00 mmol, 3.0 equiv.), DCC (1.84 g, 8.92 mmol, 3.00 equiv.) and DMAP (0.62 g, 5.06 mmol, 1.7 equiv.). The mixture was stirred at 22°C for 24 h. After this time, the mixture was filtered through a pad of Celite®. The pad was washed with 110 mL of toluene. The toluene solution was concentrated in vacuo and the residue subjected to column chromatography on silica gel eluting with 70% hexanes/ethyl acetate to afford 2.50 g (100%) of the title compound as a white solid with the following physical properties: *H NMR (CDCI₃, 300 MHz) δ 8.03-8.00 (m, 2H), 7.58-7.53 (m, 1H), 7.45-7.40 (m, 2H), 7.31-7.25 (m, 2H), 7.00-6.97 (m, 1H), 6.92-6.90 (m, 2H), 6.39 (s, 1H), 6.19- 6.14 (m, 1H), 5.62 (d, J = 7.06 Hz, 1H), 4.91 (d, J = 8.14 Hz, 1H), 4.71 (s, 2H), 4.46-4.40 (d of d, J = 6.58 Hz, J = 10.00 Hz, 1H), 4.25 (d, J = 8.38 Hz, 1H), 4.17 (d, J = 8.38 Hz, 1H), 3.78 (d, J = 7.03 Hz, 1H), 2.60-2.40 (m, 1H), 2.33 (s, 1H), 2.23 (d, J = 8.99 Hz, 2H), 2.12 (s, 3H), 1.98 (s, 1H), 1.90-1.80 (m, 2H), 1.87 (s, 3H), 1.64 (s, 3H), 1.20-1.10 (m, 1H), 1.16 (s, 3H), 1.09 (s, 3H), 0.90-0.84 (m, 9H), 0.58-0.45 (m, 6H); ¹³C NMR (CDC1₃, 75.5 MHz) δ 201.58, 169.65, 169.09, 168.46, 166.83, 157.34, 139.87, 133.72, 133.56, 129.92, 129.60, 129.44, 129.12, 128.49, 122.04, 114.44, 84.03, 80.88, 78.74, 77.36, 76.94, 76.51, 76.31, 74.91, 74.64, 72.14, 70.76, 65.21, 58.36, 46.81, 43.01, 37.05, 35.44, 26.37, 22.21, 20.72, 20.66, 14.35, 14.21, 9.88, 6.62, 5.15, 5.08; MS (ESI): 852.4 ((M+NH₄)⁺, 62%); 835.4 ((M+H)⁺, 100%); 775.4 (25%), 417.3 (19%), 376.4 (32%), 131.2 (18%); HRMS (ESI) calcd for C₄₅H₅₈0₁₃SiNa: 857.3544; found: 857.3549.

Example 2. Compound with formula IVa.

To a solution of compound with formula Ilia (764 mg, 0.916 mmol) in 12 mL of anhydrous THF was added lithium bis(trimethyl-silyl)amide (1.0M solution in THF, 1.37 mL, 1.37 mmol, 1.5 equiv.) at -78°C in THF for 0.5 h. Methyl trifluoromethanesulfonate (0.15 mL, 1.37 mmol, 1.5 equiv.) was added to this solution. After 0.5 h, the reaction mixture was warmed to -40°C for 18 h. The reaction was quenched by addition of a saturated solution of NH₄C1 (8 mL), and the aqueous layer was extracted with ethyl acetate (3 x 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous Na₂S0₄, filtered and concentrated in vacuo. The crude product was then chromatographed on silica gel eluting with 70% hexanes/ethyl acetate to provide the compound with formula IVa (464 mg, 60% yield) as a white foam with the following physical properties: *H NMR (CDC1₃, 300 MHz) δ 7.53-7.52 (m, 2H), 7.36-7.23 (bm, 5H), 7.00-6.96 (m, 1H), 6.90-6.85 (m, 2H), 6.37 (s, 1H), 6.14-6.08 (m, 1H), 5.15 (d, J = 8.57 Hz, 1H), 4.73-4.54 (m, 4H), 4.41 (d of d J = 7.05 Hz, J = 9.68 Hz, 1H), 3.30 (d, J = 5.54 Hz, 1H), 3.09 (s, 3H), 2.61-2.53 (bm, 1H), 2.16 (s, 3H), 2.14 (s, 3H), 1.95-1.66 (bm, 4H), 1.84 (s, 3H), 1.77 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H), 0.93-0.89 (bm, 9H), 0.63-0.52 (bm, 6H); MS (ESI): 817.5 (100%), 757.6 (20%), 431.6, (35%).

Example 3. Compound with formula Va.

Compound with formula IVa (524 mg, 0.62 mmol) was dissolved in methanol (anhydrous, 12 mL) and treated with terf-butylamine (0.80 mL, 7.41 mmol) at 22°C for 22 h. The solvent was then removed in vacuo. The residue was chromatographed on silica gel eluting with 80% hexanes /ethyl acetate to afford 300 mg (74% yield) of compound with formula Va as a white foam with the following physical properties: NMR (CDC1₃, 300 MHz) δ 7.58-7.55 (m, 2H), 7.35-7.32 (m, 3H), 6.40 (s, 1H), 5.01 (d, J = 8.55 Hz, 1H), 4.71 (d, J = 8.67, 1H), 4.64 (d, J = 8.54 Hz, 1H), 4.45 (d of d, J = 7.04 Hz, J = 9.67 Hz, 1H), 4.27 (d, J = 5.73 Hz, 1H), 3.35 (d, J = 5.53 Hz, 1H), 3.11 (s, 3H), 2.70-2.50 (m, 1H), 2.15 (s, 3H), 2.12 (s, 3H), 2.10 (s, 3H), 1.95- 1.55 (bm, 5H), 1.76 (s, 3H), 1.26 (s, 3H), 1.10 (s, 3H), 0.93-0.88 (m, 9H), 0.61- 0.53 (m, 6H).

Example 4. Compound with formula Vila

A THF solution (5.5 mL) of compound with formula Va (197 mg, 0.276 mmol) was cooled to -40°C. Lithium bis(trimethylsilyl)amide ( 1.0M in THF, 0.41 mL, 0.414 mmol, 1.5 equiv.) was added to this solution followed by β-lactam of formula Via (210.2 mg, 0.552 mmol, 2.0 equiv.). The reaction mixture was stirred at 0°C for 18 h and the reaction quenched with 5 mL of a saturated solution of NH C1. The reaction mixture was extracted with ethyl acetate (3 x 15 mL) and washed with water and brine (10 mL each). The organic layer was dried over anhydrous Na₂S0 , filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 90%, 85% hexanes /ethyl acetate to afford compound with formula Vila (195 mg, 64% yield) as a white solid with the following physical properties: ^lH NMR (CDC1₃, 300 MHz) δ 7.65 (m, 2H), 7.55-7.23 (bm, 13H), 6.98 (d, J = 8.33 Hz, 1H), 6.39 (s, 1H), 6.06 (m, 1H), 5.44 (d of d, J = 2.56 Hz, J = 8.29 Hz, 1H), 5.01 (d, J = 9.23 Hz, 1H), 4.71 (d, J = 8.83 Hz, 1H), 4.63 (d, J = 8.76 Hz, 1H), 4.42 (d of d, J = 8.24 Hz, J = 10.33 Hz, 1H), 4.33 (d, J = 5.69 Hz, 1H), 3.33 (d, J = 5.39 Hz, 1H), 3.07 (s, 3H), 2.63-2.50 (m, 1H), 2.38 (s, 3H), 2.15 (s, 3H), 2.00-1.92 (bm, 2H), 1.91 (s, 3H), 1.77 (s, 3H), 1.26 (s, 3H), 1.21, (s, 3H), 0.93-0.86 (m, 9H), 0.77-0.70 (m, 9H), 0.60-0.52 (m, 6H), 0.45-0.31 (m, 6H); MS (ESI): 1094.6 ((M-H)^", 100%), 653.4 (100%), 180.0 (30%), 93.2 (20%); HRMS (ESI) calcd for C6θH8lNNa0₁ Si2: 1118.5093, found:

1118.5130.

Example 5. Compound with formula la.

A THF solution (8 mL) of compound with formula Vila (180 mg,

0.164 mmol) was cooled to -5°C and treated with TBAF (1.0M in THF, 0.36 mL, 0.362 mmol, 1.5 equiv.). The reaction mixture was allowed to stir for 18 h and was then diluted with ethyl acetate (20 mL) and washed with brine (10 mL). The organic layer was dried over anhydrous Na₂S0 , filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 70%, 50%, 40% hexanes /ethyl acetate to provide a compound with formula la (85 mg, 60% yield) as a white solid with the following physical properties: ^:H NMR (CDC1₃, 300 MHz) δ 7.72 (m, 2 H), 7.71-7.19 (m, 13H), 6.22 (s, 1H), 6.00 (m, 1H), 5.70 (d of d, J = 2.82 Hz, J = 8.89 Hz, 1H), 5.03 (d, J = 8.81 Hz, 1H), 4.70 (d, J = 8.50 Hz, 1H), 4.63-4.60 (m, 2H), 4.32 (m, 1H), 4.26 (d, J = 5.63 Hz, 1H), 3.99 (d, J = 3.90 Hz, 1H), 3.27 (d, J = 5.63 Hz, 1H), 3.07 (s, 3H), 2.68-2.57 (m, 1H), 2.26 (d, J = 4.08 Hz, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 1.98-1.54 (bm, 4 H), 1.78 (s, 3H), 1.58 (s, 3H), 1.23 (s, 3H), 1.21 (s, 3H); ¹³C NMR (CDC1₃, 75.5 MHz) δ 204.14, 171.19, 171.01, 170.74, 166.43, 142.91, 137.94, 137.40, 133.57, 132.43, 131.72, 128.94, 128.60, 128.50, 128.28, 128.07, 128.02, 127.06, 126.91, 125.95, 119.12, 86.84, 84.19, 80.96, 76.83, 76.51, 76.35, 73.75, 71.80, 70.95, 60.00, 54.76, 50.99, 42.84, 41.37, 36.50, 34.29, 26.13, 22.25, 20.72, 20.00, 15.45, 9.54; MS (ESI): 866.4 ((M-H)^", 50%), 539.4 (100%); HRMS (ESI): calcd for C4sH53NNaOι : 890.3364, found: 890.3349.

Example 6. Compound with formula Vllb.

A solution of compound with formula Va (300 mg, 0.419 mmol) in anhydrous THF (8.5 mL) was cooled to -40°C and treated with n - butyllithium (2.5M in hexanes, 0.20 mL, 0.503 mmol, 1.2 equiv.). After stirring for 15 min., the mixture was treated with a solution of β-lactam of formula VIb (237.5 mg, 0.629 mmol, 1.5 equiv.) in anhydrous THF (1 mL). After stirring for 15 min. at -40°C, the reaction vessel was transferred to a 0°C cooling bath and stirred for 6 h. The reaction was quenched by the addition of a saturated solution of NH₄C1 (5 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were dried over anhydrous Na₂S0₄, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 90% hexanes /ethyl acetate to provide compound with formula VII (330 mg, 72% yield) as a white solid with the following physical properties: ^JH NMR (CDC1₃, 300 MHz) δ 7.58-7.55 (m, 2H), 7.39- 7.19 (bm, 8H), 6.42 (s, 1H), 6.08 (m, 1H), 5.27 (d, J = 9.33 Hz, 1H), 5.05 (d, J = 8.11 Hz, IH), 4.74 (d, J = 8.59 Hz, IH), 4.66 (d, J = 8.65 Hz, IH), 4.45 (m, 2H), 4.35 (d, J = 5.68 Hz, IH), 3.36

(d, J = 5.45 Hz, IH), 3.10 (s, 3H), 2.60 (m, IH), 2.38 (s, 3H), 2.16 (s, 3H), 1.99- 1.75 (bm, 4H), 1.89 (s, 3H), 1.79 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H), 1.23 (s, 9H), 0.97-0.92 (bm, 9H), 0.75-0.70 (bm, 9H), 0.63-0.55 (bm, 6H), 0.43-0.25 (bm, 6H).

Example 7. Compound with formula lb.

A solution of the compound with formula Vllb (320.5 mg, 0.293 mmol) in 14.6 mL of anhydrous THF at -5 °C was treated with TBAF (1.0M in THF, 0.44 mL, 0.440 mmol, 1.5 equiv.). The solution was stirred for 60 min, and diluted with 100 mL of ethyl acetate. After warming to room temperature, the mixture was washed with 50 mL of brine, dried over anhydrous Na₂S0 , filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 75%-50% hexanes /ethyl acetate to provide compound with formula lb (144 mg, 80% yield) as a white solid with the following physical properties: ^αH NMR (CDC1₃, 300 MHz) δ 7.49-7.46 (m, 2H), 7.33-7.16 (m, 8H), 6.22 (s, IH), 5.94 (m, IH), 5.37 (d, J = 9.29 Hz, IH), 5.03 (d, J = 8.20 Hz, IH), 4.96 (d, J =8.54 Hz, IH), 4.57 (dd, J = 8.62 Hz, J = 21.19 Hz, 2H), 4.40 (s, IH), 4.32 (t, J = 7.59 Hz, IH), 4.22 (d, J = 5.57 Hz, IH), 3.65 (bs, IH), 3.23 (d, J = 5.50 Hz, IH), 3.02 (s, 3H), 2.62-2.51 (m, IH), 2.15 (s, 3H), 2.07 (s, 3H), 2.00-1.50 (bm, 3H), 1.97 (s, IH), 1.73 (s, 3H), 1.66 (s, 3H), 1.26 (s, 9H), 1.22 (s, 3H), 1.19(s, 3H); ¹³C NMR (CDC1₃, 75.5 MHz) δ 204.51, 170.972, 170.78, 155.12, 137.65, 129.09, 128.70, 128.20, 128.02, 126.95, 126.14, 119.30, 95.67, 87.03, 84.42, 81.01, 78.09, 76.55, 74.15, 72.03, 71.52, 60.18, 51.14, 42.92, 41.61, 36.59, 34.40, 28.25, 26.25, 22.43, 20.92, 20.53, 20.33, 15.67, 14.93, 13.86, 9.69; MS (ESI): 862.5((M-H)^", 100%), 787.1 (10%), 665.0 (18%) 570.4 (10%), 163.5 (18%), 83.2 (19%), 58.4 (70%); Example 8. Compound with formula Illb.

7-TES Baccatin III (2.0 g, 2.86 mmol) in anhydrous toluene (20 mL) was treated with trflns-cinnamic acid (1.35 g, 8.58 mmol, 3 equiv.), DCC (1.80 g, 8.58 mmol, 3 equiv.) and DMAP (0.36 g, 2.86 mmol, 1 equiv.) at room temperature for 15 h. The product mixture was filtered through Celite® and the organic layer was concentrated in vacuo. The residue was then chromatographed on silica eluting with 20%, 30% ethyl acetate /hexanes to afford 3.1 g (100% yield) of compound with formula Illb which exhibited the following physical properties: ^αH NMR (CDC1₃, 300 MHz) δ 8.05 (d, J = 7.89 Hz, 2H), 7.83 (d, J = 16.00 Hz, IH), 7.57 (m , 3 H), 7.46-7.35 (m, 8H), 6.50 (d, J = 16.07 Hz, IH), 6.47 (s, IH), 6.15 (m, IH), 5.67 (d, J = 6.93 Hz, IH), 4.95 (d, J = 9.01 Hz, IH), 4.47 (dd, J = 6.74 Hz, J = 12.27 Hz, IH), 4.27 (d, J = 8.37 Hz, IH), 4.15 (d, J = 8.42 Hz, IH), 3.85 (d, J = 7.11 Hz, IH), 2.61-2.35 (bm, 3H), 2.27 (s, 3H), 2.17 (s, 3H), 2.13 (s, 3H), 2.02 (s, IH), 2.32-1.75 (bm, 5H), 1.68 (s, 3H), 1.23 (s, 3H), 1.19 (s, 3H), 0.92 (m, 9H), 0.57 (m, 6H).

Example 9. Compound with formula IVb.

Compound with formula Illb (3.7 g, 4.46 mmol) was dissolved in anhydrous THF (60 mL) and cooled to -78°C. To this solution was added LHMDS (1.0M in THF, 5.35 mL, 5.35 mmol, 1.5 equiv.). After stirring for 0.5 h, methyltrifluoromethanesulfonate (0.61 mL, 5.35 mmol, 1.5 equiv.) was added to this solution and the resulting mixture was stirred at -78°C for about 4.5 h. The reaction was quenched with NH₄C1 and extracted with ethyl acetate. The organic layer was washed with brine and dried over M g S 0 . The crude product was concentrated in vacuo and chromatographed on silica eluting with 10%-20% ethyl acetate /hexanes to afford 3.04 g (81% yield) of compound with formula IVb which exhibited the following physical properties: ^αH NMR (CDC1₃, 300 MHz) δ 7.76 (d, J = 16.05 Hz, IH), 7.56-7.51 (m, 4H), 7.42-7.37 (m, 3H), 7.34-7.29 (m, 3H), 6.43 (s, IH), 6.40 (d, J = 16.56 Hz, IH), 6.08 (m, IH), 5.05 (d, J = 8.25 Hz, IH), 4.71 (d, J = 8.52 Hz, IH), 4.45 (dd, J = 7.13 Hz, J = 9.65 Hz, IH), 4.33 (d, J = 5.68 Hz, IH), 3.36 (d, J = 5.40 Hz, IH), 3.09 (s, 3H), 2.62 (m, IH), 2.16 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H), 2.05-1.72 (bm, 4H) 1.79 (s, 3H), 1.30 (s, 3H), 1.27 (s, 3H), 0.93 ( , 9H), 0.59 (m, 6H); MS (ESI): 813.6 (100%), 753.7 (55%), 427.4 (100%).

Example 10. Compound with formula Vllb.

Compound with formula IVb (3.0 g, 3.55 mmol) was dissolved in t-

BuOH (18ml) and THF (10 mL). (DHQ)₂PHAL (110.6 mg, 0.142 mmol, 4 mol%) and NMO (8 mL, 60% w/w in H₂0) were added to this solution and stirred at room temperature. K₂0s0 2H₂0 (26.1 mg, 0.071 mmol, 2 mol%) and H₂0 (9 mL) were then added and the mixture stirred for about 20 h. The reaction was quenched with Na₂S0₃ (9.0 g) and stirred for 1 h . The product mixture was filtered through Celite®, and the filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na₂S 0 , concentrated in vacuo and chromatographed on silica eluting with 40% ethyl acetate /hexanes to provide 1.23 g (39% yield) of compound with formula Vllb, which exhibited the following physical properties: *H NMR (CDC1₃, 300 MHz) δ 7.54-7.51 (m, 2H), 7.38-7.17 (m, 8H), 6.38 (s, IH), 6.03 (m, IH), 5.00-4.95 ( , 2H), 4.67 (d, J = 8.68 Hz, IH), 4.62 (d, J = 8.66 Hz, IH), 4.38 (m, IH), 4.31-4.27 (m, IH), 3.46 (d, J = 6.65 Hz, IH), 3.28 (d, J = 5.60 Hz, IH), 3.06 (s, 3H), 2.78 (d, J = 6.21 Hz, IH), 2.55 (m, IH), 2.15 (s, 3H), 2.01 (s, 3H), 1.93 (s, 3H), 1.93- 1.56 (bm, 4H), 1.77 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H), 0.90 (m, 9H), 0.56 (m, 6H); MS (ESI): 877.5 ((M-H)^", 100%), 654.6 (10%).

Example 11. Compound with formula VIIc.

Compound with formula Vllb (1.22 g, 1.39 mmol) was dissolved in anhydrous THF (28 mL) and cooled to 0°C. This solution was treated with imidazole (104 mg, 1.53 mmol, 1.10 equiv.) and TESC1 (0.26 mL, 1.53 mmol, 1.10 equiv.). After stirring for 3 h, the reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was concentrated in vacuo and chromatographed on silica, eluting with 10%- 20% ethyl acetate /hexanes to afford 459 mg (33% yield) of compound formula VIIc, which exhibited the following physical properties: ^]H NMR (CDC1₃, 300 MHz) δ 7.53-7.49 (m, 2H), 7.40-7.37 (m, 3H), 7.24-7.18 (m, 2H), 7.10-7.04 (m, 2H), 6.88-6.83 (m, IH), 6.37 (s, IH), 5.85 (m, IH), 4.97 ( d, J = 8.63 Hz, IH), 4.74 (m, IH), 4.67 ( d, J = 8.62 Hz, IH), 4.59 ( d, J = 8.55 Hz, IH), 4.39 (dd, J = 7.02 Hz, J = 9.54 Hz, IH), 4.26 ( d, J = 5.61 Hz, IH), 4.19 ( d, J = 5.94 Hz, IH), 3.23 ( d, J = 5.60 Hz, IH), 3.02 (s, 3H), 2.97 ( d, J = 4.01 Hz, IH), 2.56 (m, IH), 2.12 (s, 3H), 2.06 (s, 3H), 2.00 (s, IH), 1.86 (s, 3H), 1.73 (s, 3H), 1.60-1.36 (bm, 2H), 1.25 (s, 3H), 1.21 (s, 3H), 0.91-0.78 (bm, 18H), 0.58-0.45 (bm, 12H); MS (ESI): 991.0 ((M-H)^", 4%), 885.5 (10%), 653.4 (100%).

Example 12. Compound with formula Vlld.

Compound with formula VIIc (442 mg, 0.445 mmol) in DCM (9 mL) was treated with Hunigs base (0.12 mL, 0.668 mmol, 1.5 equiv.) followed by p-nitrophenylchloroformate (134.6 mg, 0.668 mmol, 1.5 equiv.) and DMAP (cat.) at 0°C. After stirring 1 h, the reaction was stirred at room temperature for about 2 h. The solvent was then removed in vacuo, and the residue was chromatographed on silica eluting with 20% ethyl acetate /hexanes to provide 529 mg (100% yield) of compound with formula Vlld which exhibited the following physical properties: *H NMR (CDC1₃, 300 MHz) δ 8.25-8.21 (m, 2H), 7.55-7.52 (m, 2H), 7.40-7.34 (m, 5H), 7.30-7.17 (m, 4H), 7.08-7.03 (m, IH), 6.30 (s, IH), 5.94 (d, J = 8.51 Hz, IH), 5.78 (m, IH), 5.02 (d, J = 8.51 Hz, IH), 4.72-4.59 (m, 3H), 4.41-4.36 (dd J = 7.06 Hz, J = 9.57 Hz, IH), 4.25 (d, J = 5.75 Hz, IH), 3.23 (d, J = 5.62 Hz, IH), 3.06 (s, 3H), 2.61 (m, IH), 2.28 (s, 3H), 2.11 (s, 3H), 1.95-1.26 (bm, 6H), 1.75 (s, 3H), 1.52 (s, 3H), 1.24 (s, 3H), 1.16 (s, 3H), 0.94-0.84 (bm, 18H), 0.60-0.52 (bm, 12H); MS (FAB): 1158 ((M-2H)⁺), 18%), 1126 (28%), 1066 (32%), 416 (62%), 221 (100%).

Example 13. Compound with formula Vile.

Compound with formula Vlld (496 mg, 0.428 mmol) was dissolved in anhydrous THF (8.5 mL) and treated with iso-propylamine at 0°C. After stirring 0.5 h, the reaction was stirred at room temperature for an additional 4 h. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with 20% ethyl acetate /hexanes to afford 430 mg (93% yield) of compound with formula Vile, which exhibited the following physical properties: ^αH NMR (CDC1₃, 300 MHz) δ 7.58-7.54 (m, 2H), 7.36-7.16 (m, 8H), 6.37 (s, IH), 5.87 (m, IH), 5.79 (d, J = 4.01 Hz, IH), 5.05 (d, J = 8.68 Hz, IH), 4.75 (d, J = 8.68 Hz, IH), 4.66 (d, J = 8.66 Hz, IH), 4.41-4.35 (m, 2H), 4.33 (d, J = 5.80 Hz, IH), 3.63 (m, IH), 3.31 (d, J = 5.61 Hz, IH), 3.11 (s, 3H), 2.55 (m, IH), 2.55 (s, 3H), 2.14 (s, 3H), 1.99-1.87 (m, 2H), 1.77 (s, 6H), 1.66-1.54 (m, 2H), 1.28 (s, 3H), 1.25 (s, 3H), 1.11 (d, J = 6.49 Hz, 3H), 1.07 (d, J = 6.59 Hz, 3H), 0.89-0.86 (bm, 9H), 0.61-0.51 (bm, 15H), 0.24-0.11 (bm, 6H); MS (ESI): 1136.8 ((M + NH₄ + Acn)\ 52%), 1095.6 ((M + NH₄)⁺, 18%), 1046.6 (70%), 986.6 (42%), 665.6 (100%).

Example 14. Compound with formula Ic.

Compound with formula Vile (11.4 mg., 0.0106 mmol.) was dissolved in anhydrous THF (0.5 mL) and cooled to -10°C. To this solution was added TBAF (1M solution in THF, 26.5 μL, 0.0265 mmol). After stirring at -10°C-0°C for about 1.5 h, the solvent was removed in vacuo and the residue was chromatographed on silica eluting with 50%, 60% ethyl acetate/ hexanes to afford 5 mg (56% yield) of compound with formula Ic which exhibited the following physical properties: *H NMR (CDC1₃, 300 MHz) δ 7.54-7.49 (m, 2H), 7.37-7.32 (m, 3H), 7.27-7.25 (m, 4H), 7.18-7.14 (m, IH), 6.27 (s, IH), 6.02-5.96 (m. IH), 5.89 (d, J = 3.55 Hz, IH), 5.09 (d, J = 8.18 Hz, IH), 5.04 (d, J = 8.86 Hz, IH), 4.71 (d, J = 8.71 Hz, IH), 4.62 (d, J = 8.69 Hz, IH), 4.42-4.35 (m, 2H), 4.29 (d, J = 5.59 Hz, IH), 3.60 (m, IH), 3.28 (d, J = 5.54 Hz, IH), 3.05 (s, 3H), 2.30 (m, 2H), 2.22 (s, 3H), 2.20 (s, 3H), 2.02 (s, IH), 1.93 (dd, J = 10.56 Hz, J = 14.89 Hz, IH), 1.80 (s, 3H), 1.78 (s, 3H), 1.64- 1.54 (m, 2H), 1.29 (s, 3H), 1.23 (s, 3H), 1.07 (d, J = 2.20 Hz, 3H), 1.05 (d, J = 2.11 Hz, 3H).

Example 15. Compound with formula IIIc.

7-TES baccatin (5 g, 7.14 mmol) was dissolved in anhydrous toluene (70 mL). This solution was treated with 3-(2-furyl)acrylic acid (2.96 g, 21.4 mmol, 3.0 equiv.), DCC (4.4 g, 21.4 mmol, 3.0 equiv.) and DMAP (0.87 g, 7.14 mmol, 1.0 equiv.) at room temperature for about 20 h. The product mixture was filtered through Celite® and the organic layer was concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 20%, 30% ethyl acetate /hexanes to provide 5.63 g (96% yield) of compound with formula IIIc which exhibited the following physical properties: H NMR (CDC1₃, 300 MHz) δ 8.02 (m, 2H), 7.57-7.50 (m, 3H), 7.44-7.38 (m, 2H), 6.67 (d, J = 3.36 Hz, IH), 6.49-6.47 (dd, J = 1.65 Hz, J = 3.32 Hz, IH), 6.45 (s, IH), 6.36 (d, J = 15.70 Hz, IH), 6.11 (m, IH), 5.64 (d, J = 7.04 Hz, IH), 4.93 (d, J = 8.47 Hz, IH), 4.50-4.44 (dd, J = 6.67 Hz, J = 10.38 Hz, IH), 4.25 (d, J = 8.33 Hz, IH), 4.12 (d, J = 8.33 Hz, IH), 3.83 (d, J = 6.98 Hz, IH), 2.50 (m, IH), 2.34-2.10 (bm, 2H), 2.28 (s, 3H), 2.14 (s, 3H), 2.08 (s, 3H), 1.99 (s, IH), 1.90-1.70 (bm, 2H), 1.66 (s, 3H), 1.20 (s, 3H), 1.15 (s, 3H), 0.89 (m, 9H), 0.54 (m, 6H).

Example 16. Compound with formula Illd.

Compound with formula IIIc (2.33 g, 2.84 mmol) was dissolved in

CH₃CN (35 mL) and THF (8.0 mL). 6N HC1 (1.42 mL, 3 equiv.) was added to this solution and the reaction was stirred at 0°C for about 20 h. The solvent was partially removed in vacuo. The residue was diluted with ethyl acetate and washed with sodium bicarbonate and brine. The organic layer was dried, concentrated in vacuo and chromatographed on silica gel eluting with 30%- 0% ethyl acetate/hexanes to afford 1.48 g (74% yield) of compound with formula Hid, which exhibited the following physical properties: ^αH NMR (CDC1₃, 300 MHz) δ 8.02 (m, 2H), 7.59-7.51 (m, 3H), 7.46-7.41 (m, 2H), 6.68 (d, J = 3.42 Hz, IH), 6.50 (dd, J = 1.81 Hz, J = 3.28 Hz, IH), 6.35 (d, J =15.76 Hz, IH), 6.31 (s, IH), 6.16 (m, IH), 5.64 (d, J = 7.01 Hz, IH), 4.96 (d, J = 7.92 Hz, IH), 4.44 (dd, J = 6.69 Hz, J =10.80 Hz, IH), 4.27 (d, J =8.38 Hz, IH), 4.15 (d, J =8.38 Hz, IH), 3.83 (d, J = 7.00 Hz, IH), 2.58-2.50 (m, IH), 2.42-2.18 (bm, 2H), 2.29 (s, 3H), 2.23 (s, 3H), 2.04 (s, IH), 1.96 (s, 3H), 1.91-1.81 (bm, 2H), 1.66 (s, 3H), 1.22 (s, 3H), 1.12 (s, 3H).

Example 17. Compound with formula IVc.

Compound with formula Hid (1.7 g, 2.41 mmol) was dissolved in anhydrous THF (34 mL) and cooled to -78°C. To this solution was added

LHMDS (1M solution in THF, 4.82 mL, 4.82 mmol, 2 equiv.). After stirring

0.5 h, methyl trifluoromethanesulfonate (0.55 mL, 4.82 mmol, 2 equiv.) was added to this solution, and the reaction was stirred at -78°C for 0.5 h, then warmed to -40°C for about 5 h. The reaction was quenched with NH C1 and the aqueous layer was extracted with ethyl acetate (3 x 50 mL).

The combined organic layers were dried, concentrated in vacuo and chromatographed on silica eluting with 30%, 40% ethyl acetate/hexanes to provide 1.48g (84% yield) of compound with formula IVc, which exhibited the following physical properties: *H NMR (CDC1₃, 300 MHz) δ 7.56-7.48 (m, 4H), 7.34-7.32 (m, 3H), 6.68 (d, J = 3.38 Hz, IH), 6.48 (dd, J = 1.74 Hz, J =

3.34 Hz, IH), 6.46 (s, IH), 6.30 (d, J = 15.70 Hz, IH), 6.10 (m, IH), 5.12 (d, J =

8.79 Hz, IH), 4.73 (d, J = 8.68 Hz, IH), 4.65 (d, J = 8.66 Hz, IH), 4.30 (d, J = 5.58 Hz, IH), 3.93 (dd, J = 7.07 Hz, J = 9.48 Hz, IH), 3.39-3.36 (m, IH), 3.38 (s, 3H), 3.10 (s, 3H), 2.85-2.80 (m, IH), 2.20 (s, 3H), 2.12 (s, 3H), 2.02-1.68 (bm, 3H), 2.00 (s, 3H), 1.84 (s, 3H), 1.30 (s, 6H).

Example 18. Compound with formula Vllf.

Compound with formula IVc (2.2 g, 3.0 mmol) was dissolved in t- BuOH (16 mL). (DHQ)₂PHAL (93.5 mg, 0.12 mmol, 0.04 equiv.) and NMO (4 mL, 60% w/w in H₂0) were added to this solution and stirred at room temperature. K₂Os0₄ 2H₂0 (22.1 mg, 0.06 mmol, 0.02 equiv.) and H₂0 (7 mL) were added later. After stirring for about 20 h, the reaction was quenched with a saturated aqueous solution of Na₂S0₃ and stirred for 1 h. The product mixture was filtered through Celite®, and the filtrate was diluted with ethyl acetate and washed with brine. The organic layer was dried, concentrated in vacuo and chromatographed on silica, eluting with 40% ethyl acetate/hexanes) to provide 639 mg (28% yield) of compound with formula Vllf, which exhibited the following physical properties: ^lH NMR (CDC1₃, 300 MHz) δ 7.55-7.51 (m, 2H), 7.36-7.34 (m, 3H), 7.25 (m, IH), 6.41 (s, IH), 6.35 (d, J = 3.28 Hz, IH), 6.27 (dd, J = 1.84 Hz, J = 3.18 Hz, IH), 6.09 (m, IH), 5.04 (d, J = 8.60 Hz, IH), 4.99 (dd, J = 3.19 Hz, J = 7.96 Hz, IH), 4.70 (d, J = 8.66 Hz, IH), 4.62 (d, J = 8.64 Hz, IH), 4.47 (dd, J = 3.22 Hz, J = 5.60 Hz, IH), 4.26 (d, J = 5.70 Hz, IH), 3.85 (dd, J = 7.15 Hz, J = 9.48 Hz, IH), 3.73 (d, J = 5.63 Hz, IH), 3.35-3.32 (m, IH), 3.34 (s, 3H), 3.07 (s, 3H), 2.89 (d, J = 7.94 Hz, IH), 2.77 (m, IH), 2.19 (s, 3H), 2.12 (s, 3H), 1.97-1.60 (bm, 3H), 1.93 (s, 3H), 1.82 (s, 3H), 1.27 (s, 3H), 1.26 (s, 3H).

Example 19. Compound with formula Vllg.

Compound with formula Vllf (593 mg, 0.772 mmol) was dissolved in anhydrous THF (15 mL) and cooled to 0°C. This solution was treated with imidazole (57.8 mg, 0.849 mmol, 1.1 equiv.) followed by TESCl (142.6 μL, 0.849 mmol, 1.1 equiv.). The reaction was stirred at 0°C for 2 h, and then diluted with ethyl acetate. The organic layer was concentrated in vacuo and chromatographed on silica eluting with 20%, 30% ethyl acetate/hexanes to provide 254 mg (37% yield) of compound with formula Vllg, which exhibited the following physical properties: *H NMR (CDC1₃, 300 MHz) δ 7.56-7.51 (m, 2H), 7.37-7.33 (m, 3H), 7.13 (d, J = 1.83 Hz, IH), 6.41 (s, IH), 6.26 (d, J = 3.25 Hz, IH), 6.13 (dd, J = 1.85 Hz, J = 3.26 Hz, IH), 6.03 (m, IH), 5.05 (d, J = 8.90 Hz, IH), 4.78 (dd, J = 5.35 Hz, J = 6.25 Hz, IH), 4.72 (d, J = 8.68 Hz, IH), 4.63 (d, J = 8.53 Hz, IH), 4.49 (d, J = 4.96 Hz, IH), 4.28 (d, J = 5.75 Hz, IH), 3.86 (m, IH), 3.35 (m, 4H), 3.06 (s, 3H), 2.89 (d, J = 6.73 Hz, IH), 2.79 (m, IH), 2.19 (s, 3H), 2.16 (s, 3H), 1.89 (s, 3H), 1.85 (s, 3H), 1.27 (s, 3H), 1.19 (s, 3H)

Example 20. Compound with formula Vllh.

Compound with formula Vllg (250 mg, 0.283 mmol) in DCM (6 mL) was treated with Hunigs base (74 μL, 0.425 mmol, 1.5 equiv.) followed by p-nitrophenylchloroformate (85.7 mg, 0.425 mmol, 1.5 equiv.) and DMAP (cat.) at 0°C. After stirring 3 h in the cold, the reaction was stirred at room temperature for 3 h. The solvent was then removed in vacuo and the residue was chromatographed on silica gel, eluting with 20%-30% ethyl acetate/hexanes to afford 225 mg of compound with formula Vllh (77% yield), which exhibited the following physical properties: ^aH NMR (CDC1₃, 300 MHz) δ 8.27-8.23 (d, J = 9.11 Hz, 2H), 7.56-7.52 (m, 2H), 7.42-7.30 (m, 5H), 7.18 (m, IH), 6.5023 (d, J = 3.25 Hz, IH), 6.35 (s, IH), 6.17 (d, J = 1.65 Hz, IH), 6.00 (m, IH), 5.08 (d, J = 9.22 Hz, IH), 4.79 (d, J = 9.36 Hz, IH), 4.73 (d, J = 8.63 Hz, IH), 4.63 (d, J = 8.38 Hz, IH), 4.26 (d, J = 5.74 Hz, IH), 3.84 (m, IH), 3.34- 3.29 (m, IH), 3.32 (s, 3H), 3.07 (s, 3H), 2.81 (m, IH), 2.31 (s, 3H), 2.15 (s, 3H), 2.03 (s, IH), 1.85-1.68 (bm, 3H), 1.83 (s, 3H), 1.56 (s, 3H), 1.24 (s, 6H), 0.87-0.79 (m, 9H), 0.58-0.45 (m, 6H); MS (FAB): 1047.8 ((M⁺) 10%), 955.8 (6%), 251.1 (42%), 224.1 (100%).

Example 21. Compound with formula Vlli.

Compound with formula Vllh (220 mg, 0.213 mmol) was dissolved in anhydrous THF (4.50 mL) and treated with zso-propylamine (36.2 μL,

0.426 mmol, 2.0 equiv.) at 0°C. After stirring 0.5 h, the reaction was stirred at room temperature for an additional 4 h. The solvent was removed in vacuo and the residue was chromatographed on silica eluting with 25%-

30% ethyl acetate/hexanes to afford 118 mg (58% yield) of compound with formula Vlli: ^αH NMR (CDC1₃, 300 MHz) δ 7.55-7.52 (m, 2H), 7.38-7.34 (m,

3H), 7.17 (d, J = 1.08 Hz, IH), 6.35 (d, J = 3.27 Hz, IH), 6.20 (dd, J = 1.85 Hz, J =

3.25 Hz, IH), 5.97 (d, J = 4.37 Hz, IH), 5.79 (m, IH), 5.04 (d, J = 8.56 Hz, IH),

4.95 (d, J = 7.74 Hz, IH), 4.71 (d, J = 8.59 Hz, IH), 4.62 (d, J = 8.69 Hz, IH), 4.54

(d, J = 4.34 Hz, IH), 4.27 (d, J = 5.64 Hz, IH), 4.09 (d, J = 7.16 Hz, IH), 3.85 (dd, J = 7.15 Hz, J = 9.48 Hz, IH), 3.78 (m, IH), 3.35-3.30 (m, IH), 3.32 (s, 3H), 3.06

(s, 3H), 2.76 (m, IH), 2.39 (s, 3H), 2.20 (s, 3H), 2.03 (s, IH), 1.95-1.60 (bm, 2H), 1.80 (s, 3H), 1.72 (s, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.11 (d, J = 6.49 Hz, 3H), 1.07 (d, J = 6.59 Hz, 3H), 0.88-0.60 (bm, 9H), 0.40-0.21 (bm, 6H).

Example 22. Compound with formula Ie.

Compound with formula Vlli (118 mg, 0.122 mmol) was dissolved in anhydrous THF (2.5 mL) and cooled to 0°C. To this solution was added TBAF (1M solution in THF, 0.18 mL, 0.183 mmol, 1.5 equiv.) and stirred for 2 h. The solvent was then removed in vacuo and the residue was chromatographed on silica gel eluting with 50% ethyl acetate/hexanes to afford 53 mg (51% yield) of compound with formula Ie, which exhibited the following physical properties: ^XH NMR (CDC1₃, 500 MHz) δ 7.54-7.52 (m, 2H), 7.37-7.34 (m, 3H), 7.17 (d, J = 1.00 Hz, IH), 6.40 (s, IH), 6.34 (d, J = 3.36 Hz, IH), 6.19 (dd, J = 1.80 Hz, J = 3.16 Hz, IH), 6.00 (m, IH), 5.96 (d, J = 4.23 Hz, IH), 5.04 (d, J = 8.85 Hz, IH), 4.96 (d, J = 7.75 Hz, IH), 4.70 (d, J = 8.68 Hz, IH), 4.62 (d, J = 8.64 Hz, IH), 4.54 (d, J = 4.24 Hz, IH), 4.27 (d, J = 3.41 Hz, IH), 3.85 (dd, J = 7.03 Hz, J = 9.64 Hz, IH), 3.65 (m, IH), 3.34-3.31 (m, IH), 3.32 (s, 3H), 3.06 (s, 3H), 2.75 (m, IH), 2.20 (s, 3H), 2.17 (s, 3H), 2.01 (s, IH), 1.89 (s, 3H), 1.87-1.72 (bm, 3H), 1.80 (s, 3H), 1.26 (s, 6H), 1.08 (d, J = 6.62 Hz, 3H), 1.06 (d, J = 6.60 Hz, 3H); ¹³C NMR (CDC1₃, 125.75 MHz) δ 203.05, 171.06, 170.93, 169.38, 154.00, 149.25, 142.68, 141.55, 137.64, 132.61, 128.84, 128.06, 126.08, 119.12, 110.49, 109.50, 87.00, 84.06, 81.08, 80.14, 76.74, 75.68, 72.61, 71.26, 69.59, 60.29, 58.48, 57.43, 50.97, 43.88, 43.23, 41.69, 34.22, 33.42, 25.87, 22.71, 22.18, 20.77, 20.41, 15.01, 14.10, 10.42; MS (ESI): 852.4 ((M-H)^", 10%), 613.4 (100%), 571.4 (80%), 194.2 (12%); HRMS (ESI): calcd for CuHssOiβNNa: 876.3418, found: 876.3411. Cytoxicity

The ortho-ester taxane derivatives possessed cytoxicity in vitro against human colon carcinoma cells HCT-116. Cytoxicity was assessed in HCT- 116 human colon carcinoma cells by XTT (2,3-bis(2-methoxy-4-nitro-5- sulpphenyl)-5[(phenylamino)carbonyl]2H-tetrazolium hydroxide) assay as reported in D.A. Scudiero, et. al., "Evaluation of soluble tetrazolium 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 4,000 cell /well in 96 well microtiter plates and 24 hours later drugs were added and serial diluted. The cells were incubated at 37° form 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 450nM which can be quantitated spectrophotometrically. The greater the absorbance the greater the number of live cells. The results are expressed as an IC₅₀, which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450nM) to 50% of that of untreated control cells. The IC₅₀ values for compounds evaluated in this assay are evaluated in Table I.

Table I.

Cytotoxicity Assay IC₅₀ (nM) against

Compound HCT 116 Human colon tumor cell line¹ la 6.0

Ic 0.6

Ie 8.6

IVc >10.6

Vllf 23.4

¹Cytoxicity was determined after a 72 h exposure by XTT assay.

M109 Model

Balb/c x DBA/2 Fi hybrid mice were implanted intraperitoneally, as described by William Rose in Evaluation of Madison 109 Lung Carcinoma as a Model for Screening Antitumor Drugs, Cancer Treatment Reports. 65, No. 3-4 (1981), with 0.5 mL of a 2% (w/v) brei of M109 lung carcinoma. Mice were treated with compounds under study by receiving intraperitoneal injections of various doses on either days 1, 5 and 9 post- tumor implant or days 5 and 8 post-implant. Mice were followed daily for survival until approximately 75-90 days post-tumor implant. One group of mice per experiment remained untreated and served as the control group .

Median survival times of compound-treated (T) mice were compared to the median survival time of the control (C) mice. The ratio of the two values for each compound-treated group of mice was multiplied by 100 and expressed as a percentage (i.e. % T/C) in the following table for representative compounds. The in vivo antitumor data for some ortho-ester taxane derivatives are contained in Table II.

Table II.

% T/C (dose in mg/ kg /injection; schedule)

Compound la 130% (100 mg/kg/inj; days 5 & 8)

Ic 121% (100 mg/kg/inj; days 5 & 8)

Vllf 100% (200 mg/kg/inj; days 5 & 8)

Thus, another aspect of the instant invention concerns a method for inhibiting human and /or other mammalian tumors which comprises administering to a tumor bearing host an antitumor effective amount of a compound of formula I.

For treating a variety of tumors, the compound of formula I of the present invention may be used in a manner similar to that of paclitaxel, e.g. see Physician's Desk Reference, 49th Edition, Medical Economics, p 682, 1995. The dosage, mode and schedule of administration for the compound of this invention are not particularly restricted; an oncologist skilled in the art of cancer treatment will be able to ascertain, without undue experimentation, an appropriate treatment protocol for administering the compound of the present invention. Thus the compound of formula I may be administered via any suitable route of administration, parenterally or orally. Parenteral administration includes intravenous, intraperitoneal, intramuscular, and subcutaneous administration. The doses utilized to implement the methods in accordance with the invention are the ones that make it possible to administer prophylactic treatment or to evoke a maximal therapeutic response. The doses vary, depending on the type of administration, the particular product selected, and the personal characteristics of the subject to be treated. In general, the doses are the ones that are therapeutically effective for the treatment of disorders caused by abnormal cell proliferation. The products in accordance with the invention can be administered as often as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to relatively high or low doses, and then require mild maintenance or no maintenance dose at all. Via the iv route, the dosage may be, for example, in the range of about 20 to about 500 mg/m^ over 1 to 100 hours. Via the oral route, the dosage may be in the range of 5-1000 mg/kg/day of body weight. The actual dose used will vary according to the particular composition formulated, the route of administration, and the particular site, host and type of tumor being treated. Many factors that modify the action of the drug will be taken into account in determining the dosage including age, weight, sex, diet and the physical condition of the patient.

The present invention also provides pharmaceutical formulations (compositions) containing an antitumor effective amount of compound of formula I in combination with one or more pharmaceutically acceptable carriers, excipients, diluents or adjuvants. The compositions can be prepared in accordance with conventional methods. Examples of formulating paclitaxel or derivatives thereof may be found in, for example, United States Patents Nos. 4,960,790 and 4,814,470, and such examples may be followed to formulate the compound of this invention. For example, compound of formula I may be formulated in the form of tablets, pills, powder mixtures, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix, and in other suitable forms. It may also be manufactured in the form of sterile solid compositions, for example, freeze dried and, if desired, combined with other pharmaceutically acceptable excipients. Such solid compositions can be reconstituted with sterile water, physiological saline, or a mixture of water and an organic solvent, such as propylene glycol, ethanol, and the like, or some other sterile injectable medium immediately before use for parenteral administration.

Claims

What is claimed is:

1. A compound of formula (I); or a pharmaceutically acceptable salt thereof:

l r wherein p is 0 or 1; X is NH or O; R or R are independently hydrogen, hydroxyl, OC(0) .₈alkyl, OC(0)Od.₈ alkyl, OCH₂SCH₃, OCH₃, or OCH₂OC H₃ provided that R¹ is in the β position and R^1' is in the α

1 1 ' 2 2' position, and that at least one of R or R is hydrogen; R or R are independently hydrogen, hydroxyl, OC(0)C_x.₈alkyl, OC(0)Od-₈ alkyl,

OCH2SCH3, OCH3, or OCH2OCH3 provided R² is in the β position and R^2'

2 2^* 1 is in the α position; and that at least one of R or R is hydrogen; or R and

2 1' 2' 3 R form a double bond and R or R are hydrogen; R is Cι.₆ alkyl, C₃.₆

4 cycloalkyl or .₆ O-alkyl; R is Cι.₈ alkyl, .₈ O-alkyl, aryl, substituted aryl,

OCH₂Ph, C3-8 cycloalkyl or heteroaryl; R is C₂.₆ alkyl, C₂.₆ alkenyl, C₃.₇

6 cycloalkyl, aryl, substituted aryl, or heteroaryl; R is hydrogen, hydroxyl or

7 Ci-salkanoxy; R is aryl, substituted aryl, or heteroaryl provided R⁷ can be

8 either in the α or β position; R is Ci-₈ alkyl, Cι-₈ alkanoyl, or CH₂OCH₃; and R⁹ is methyl, hydroxymethyl, or R⁹ and R¹ together can form a cyclopropane ring with the proviso that when these substituents are cyclopropane ring than R^1' is hydrogen.

2. A compound of claim 1 wherein X is -NH.

8 3. A compound of claim 2 in which R⁷ is phenyl and R is methyl, acetyl or -CH2OCH₃ .

4. A compound of claim 3 in which R³ is methyl.

5. A compound of claim 4 in which R⁵ is phenyl.

6. A compound of claim 5 in which R⁶ is CH₃C(0)0-.

7. A compound of claim 6 in which R¹ is hydroxyl, OCH2SCH₃, OCH₃, or OCH₂0CH_3, provided R^1', R² andR^2' are each hydrogen and R⁹ is methyl.

8. A compound of claim 7 in which R⁴ is phenyl and p is 0, or R⁴ is t- butyl and p is 1. g

9. A compound of claim 2 in which R⁷ is phenyl, R is methyl, R³ is methyl, R⁵ is phenyl, R⁶ is CH₃C(0)0-, R¹ is hydroxyl, provided R¹', R² and R^2' are each hydrogen, R⁹ is methyl, and R⁴ is phenyl and p is 0, or R⁴ is t-butyl and p is 1.

10. The compound of claim 9 in which R⁴ is phenyl and p is 0.

11. The compound of claim 9 in which R⁴ is t-butyl and p is 1.

12. A compound of claim 2 in which R⁷ is phenyl, R is methyl, R³ is methyl, R⁵ is phenyl, R⁶ is CH₃C(0)0-, R¹ is OCH₂OCH₃, provided R^1', R² and R^2' are each hydrogen, R⁹ is methyl, and R⁴ is phenyl and p is 0, or R⁴ is t-butyl and p is 1.

13. A pharmaceutical composition which comprises an antitumor effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method for inhibiting tumor growth in a mammalian host which comprises administering to said mammal a tumor-growth inhibiting amount of a compound of a claim 1.