MXPA06008999A - C10 cyclopentyl ester substituted taxanes - Google Patents

Abstract

A taxane having a cyclopentyl ester substituent at C10, a keto substituent at C9, a hydroxy substituent at C2, a 2-thienyl substituent at C3'and an isopropoxycarbamate substituent at C3'.

Description

TAXANES REPLACED WITH CIC OPENT STERES OR IN CIO FIELD OF THE INVENTION The present invention is directed to new taxanes possessing utility as antineoplastic agents. BACKGROUND OF THE INVENTION The terpene family of taxanes, to which baccatin III and taxol belong, also commonly referred to as paclitaxel, has been the subject of considerable interest in both the biological and chemical areas. Taxol itself is used as an antineoplastic chemotherapeutic agent and has a broad tumor inhibitory activity. Taxol has a 2'R, 3'S configuration and the following structural formula: AcO where Ac is acetyl and Bz is benzoyl. Colin et al. reported in the Patent of the States No. 4,814,470 that certain paclitaxel analogues possess significantly greater activity than taxol. One of these analogues, which is commonly known as docetaxel (Taxotere®), has the following formula Ref .: 174644 structural While taxol and docetaxel are useful as chemotherapeutic agents, there are limits to their actual efficacy, including their limited efficacy against certain types of cancer and the side effects in patients when administered in various doses. Consequently, the need to obtain other antineoplastic chemotherapeutic agents that have greater efficacy and lower toxicity persists. SUMMARY OF THE INVENTION Therefore, among the various aspects of the present invention is to provide taxanes, which compared with taxol and docetaxel in terms of their efficacy as antineoplastic agents and their toxicity, show a favorable result. In general, these taxanes possess a cyclopentyl ester substituent on CIO, a keto substituent on C9, a hydroxyl substituent on C7, a thienyl substituent on C3 'and an isopropoxycarbamate substituent on C3'. Therefore, in summary, the present invention is directed towards the taxanes themselves, to prodrugs thereof, to pharmaceutical preparations comprising taxanes or prodrugs and a vehicle approved for pharmaceutical use, to the methods of treatment and administration methods, as well as towards methods of preparation of medicines that include taxanes or prodrugs. Other objects and features of this invention will be apparent in part and in part to be pointed out below. BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the curves of the median tumor growth in mice treated with compound 9091 relative to compound 3071 in the Panc-1 study (oral doses q4dX4). Figure 2 shows the curves of the median tumor growth in mice treated with compound 9091 relative to compound 3071 in study HT29 (oral doses q4dX4). Figure 3 shows the curves of the median tumor growth in mice treated with compound 9091 in the HT29 study (single oral dose of 60 mg / kg). Figure 4 shows the median curves of tumor growth in mice treated with compound 9091 in the Panc-1 study (single oral doses of 60 mg / kg and 120 mg / kg). Figure 5 shows the curves of the median tumor growth in mice treated with IV dose of compound 9091 in the HT29 study. Figure 6 shows the median group of tumor growth curves in mice treated with vehicles or with IV doses q4d x 4 of compound 9091 in 5% E-95% 1-20, 5% ET in physiological saline and 5% EC in physiological serum in the HT2S study; (E-ethanol; I-Intralipid; T-tween; C-cremophor; for example, 5% EC in physiological saline is 5% ethanol and 5% cremophor in physiological saline). Figure 7 shows the curves of the median tumor growth in mice treated with IV dose of compound 9091 in the Panc-1 study. DETAILED DESCRIPTION OF THE INVENTION The taxane of the present invention has the following chemical structure: (I) wherein X3 is thienyl, Ac is acetyl and the hydroxy substituent on C7 and the cyclopentylcarbonyloxy substituent on CIO independently have an alpha or beta stereochemical configuration. In a modality, X3 is 2-thienyl. In one embodiment of choice, X3 is 2-thienyl and the hydroxyl substituent on C7 and the cyclopentylcarbonyloxy substituent on CIO both have the beta stereochemical configuration. The compounds of the present invention are more active against cancer than the taxanes that are conventionally used for certain types of tumors, including sensitive and paclitaxel-resistant tumor lines. The compounds of the present invention are reasonably well tolerated whether they are administered orally or intravenously and can be effective in a single or multiple dose - with improved toxicity profiles. The compounds of the present invention are also effective with vehicles other than cremophor. The taxanes of the present invention can be obtained by treating a β-lactam with an alkoxide having the tetracyclic taxane core and a C 13 metal oxide substituent to form compounds having a β-amido ester substituent at C 13 (as it was described in more detail in Holton US Pat. No. 5,466,834), followed by removal of the hydroxyl protecting groups. The β-lactam has the following structural formula (1): where P2 is a protective group of the hydroxyl, X3 is thienyl and X5 is isopropoxycarbonyl and the alkoxide has the structural formula (2): wherein M is a metal or ammonium, P7 is a protecting group of the hydroxyl and RIO is cyclopentylcarbonyloxy. The alkoxide of the structural formula (2) can be prepared from lOdesacetylbaccatin III (or a derivative thereof) by selective protection of the hydroxyl group of C7 and then the esterification of the hydroxy group of CIO followed by treatment with a metal amide. In one embodiment of the present invention, the C7 hydroxyl group of 10-desacetylbaccatin III is selectively protected with a silyl group as described, for example in Denis, et. to the. (? 7. Am. Chem. Soc, 1988, 110, 5917). In general, silylating agents can be used alone or in combination with a catalytic amount of a base, such as an alkali metal base. Alternatively, the CIO hydroxyl group of a taxane can be acylated selectively in the absence of a base, as described, for example in Holton et al., PCT patent application WO 99/09021. Acylating agents that can be used for the selective acylation of the C CO hydroxyl group of a taxane include substituted or unsubstituted alkyl or aryl anhydrides. Although the acylation of the CIO hydroxyl group of the taxane can be developed at an adequate rate with many of the acylating agents, it has been observed that the reaction rate can be increased if a Lewis acid is included in the reaction mixture. The Lewis acids of choice include zinc chloride, stannic chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride and ytterbium trichloride. When the acylating agent is an anhydride, zinc chloride or cerium trichloride are preferred. In general, processes for the preparation and resolution of β-lactam as a starting material are well known in the area. For example, ß-lactam can be prepared as described in Holton, U.S. Patent No. 5,430,160 (col 9, lines 2-50) or Holton, U.S. Patent No. 6,649,632 ( col 7, line 45 - col 8, line 60), both are incorporated here in their entirety by this reference. The resultant enantiomer mixtures of β-lactams can be resolved by stereoselective hydrolysis by a lipase or an enzyme as described, for example, in Patel, U.S. Patent No. 5,879,929 (Col. 16, line 1 -col. 18, line 27) or Patel, U.S. Patent No. 5,567,614 or a liver homogenate as described, for example, in Holton, U.S. Patent No. 6,548,293 (Col. 30-61). By way of example, U.S. Patent No. 6,649,632 describes the preparation of a β-lactam with a furyl substituent at the C 4 position of the β-lactam. With modifications obvious to persons with experience in the area, a β-lactam with a thienyl substituent at the C 4 position of the β-lactam can be prepared as is. illustrated in these prior patents and as described in more detail in Example 1. The compounds of the present invention can be provided in the form of a pre-drug. In general, a pharmaceutically acceptable derivative or prodrug is any salt, ester, salt of an ester or other derivative of a pharmaceutically acceptable compound of this invention which, when administered to a recipient, is capable of of generating, directly or indirectly, a compound of this invention or a metabolite with inhibitory action or a residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when said compounds are administered to a patient (for example, by allowing an orally administered compound to be absorbed more easily in the blood) or that increase the arrival of the original compound in a biological compartment (for example, the brain or the lymphatic system) with respect to the original compound. Pharmaceutically acceptable pre-drugs include, but are not limited to, the taxanes of the present invention derivatized with one or more of the following groups: phosphates, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, methoxymethyl, methylpyridinium mesylate, bicarbonate, salts of onium, phosphonooxymethyl carbonate, cinnamate, amino acids, benzoyl, acyl, thioaryl, based on polyethylene glycol, bonded by esters, polyalkylene oxide, dextran, polyvinyl alcohols, carbohydrate-based polymers, oligopeptides, polyglutamic acid, polyamino acids, onium salts of aza arenos halogenated in 2, very polar amino sugars and the like. Suitable positions in the taxane molecule of the present invention for predrug formation include, among others, positions C2 'and C7. Various forms of pre-drugs are well known in the area. About examples of such prodrug derivatives, see: (a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et. to the. (Acamedic Press, 1985); (b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H. Bundgaard, p. 113191 (1991); (c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); (d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and (e) N. Kakeya, et al., Chem Phar Bull, 32, 692 (1984). The taxanes of the present invention are useful for inhibiting the development of tumors in mammals, including humans, and are preferably administered in the form of a pharmaceutical preparation which includes an amount of a compound of the present invention effective as an antineoplastic agent, in combination with at least one vehicle approved for pharmaceutical or pharmacological use. The vehicle, also known in the area as excipient, auxiliary, adjuvant or diluent, can be any pharmaceutically inert substance, which gives the preparation the appropriate consistency or shape without diminishing the therapeutic efficacy of the antineoplastic compound. The vehicle is "approved for pharmaceutical or pharmacological use" if it does not produce adverse reactions, allergies or other unwanted reactions when administered to mammals or humans in an appropriate manner. The pharmaceutical preparations of the present invention containing the antineoplastic compound can be formulated in conventional manner. The appropriate formulation depends on the chosen route of administration. The preparations of the invention can be formulated for any route of administration, as long as the tissue on which the drug is to act is accessible in that way. Suitable routes of administration include, but are not limited to, the following: oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal or intrasternal); topical (nasal, transcutaneous, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intrddermal, aural, intramammary, buccal, orthotopic, endotracheal, intralesional, percutaneous, endoscopic, transmucosal, sublingual and intestinal. The vehicles approved for pharmaceutical use which are used in the preparations of the present invention are well known to those who work in the area and are selected on the basis of a number of factors: in particular, the antineoplastic compound used, its concentration, stability and presumed bioavailability; the disease, disorder or condition that will be treated with the preparation, the patient, their age, size and general condition and the route of administration. Those who have knowledge in the subject can easily determine the right vehicles. (consult, for example, J.G.Nairn in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, whose index of matters is added in this as reference).

The preparations are preferably formulated as tablets, dispersible powders, capsules, gelatin capsules, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, pills, dragees, tablets and any other pharmaceutical form that can be administered orally. . The techniques and preparations for the manufacture of pharmaceutical forms for oral use in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker &Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976). The preparations for oral administration of. The invention contains the compound of the invention in an amount that is effective as an antineoplastic, in a vehicle approved for pharmaceutical use. Suitable excipients for solid dosage forms include sugars, starches and other conventional substances, such as lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, gum tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate and stearic acid. In addition, said solid dosage forms may or may not be coated by conventional techniques; for example, to delay disintegration and absorption. The antineoplastic compounds of the present invention can also be formulated preferably for parenteral administration, ie to be injected intravenously, intraarterially, subcutaneously, rectally, intramuscularly, intraorbitally, intracapsularly, intradermally, intraperitoneally or intrasternally. The preparations for parenteral administration of the invention contain a compound of the invention in an amount which is effective as an antineoplastic, in a vehicle approved for pharmaceutical use. The pharmaceutical forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other presentation that can be administered by this route. Techniques and preparations for the manufacture of pharmaceutical forms for parenteral administration are known in the medium. Suitable carriers which are used to prepare liquid dosage forms for oral or parenteral administration include non-aqueous polar solvents, approved for pharmaceutical use such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water , saline solutions, dextrose solutions (for example, DW5), electrolyte solutions or any other aqueous liquid, approved for pharmaceutical use. Pharmaceutically suitable non-aqueous polar solvents include, among others, alcohols (eg, α-glycerol formal, β-glycerol formal, 1,3-butylene glycol, aliphatic or aromatic alcohols of 2-30 carbon atoms as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol or stearyl alcohol, fatty acid esters with fatty alcohols such as polyalkylene glycols (for example, polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (for example, dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N- (β-hydroxyethyl) -lactamide, N, N-dimethylacetamide amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone or polyvinylpyrrolidone); esters (for example, l-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate , dimethylsulfoxide (DMSO), glycerin esters such as citrates or mono, di, or triglyceryl tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters with sorbitan, esters of fatty acids with PEG derivatives, glyceryl monostearate, glyceride esters such as mono, di or triglycerides, esters of fatty acids such as isopropyl myristate, fatty acid esters with PEG derivatives, such as PEG hydroxyoleate and PEG hydroxystearate, N-methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such as poly (oleate) 2-4 poly (ethoxylate) 30-60 sorbitol, poly (oxyethylene) monooleate 15-20, mono 12-hydroxies poly (oxyethylene) 15-20 and poly (oxyethylene) 15-20 poly ricinoleate granules, polyoxyethylene sorbitan esters such as polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate and Polysorbate® 20 , 40, 60 or 80 of ICI Americas, Wilmington, DE, polyvinylpyrrolidone, fatty acid esters with modified alkyleneoxy such as hydrogenated castor oil and polyoxyethylated castor oils (for example, Cremophor® EL solution or Cremophor® RH40 solution ), esters of fatty acids with saccharides (ie, the condensation product of a monosaccharide (eg, pentoses such as ribose, ribulose, arabinose, xylose, lixose and xylulose, hexose such as glucose, fructose, galactose, mannose and sorbose, triose) , tetroses, heptoses and octoses), a disaccharide (for example, sucrose, maltose, lactose and trehalose) or an oligosaccharide or a mixture thereof with acid (s) or (s) C4"-C22 (for example, saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid and unsaturated fatty acids such as palmitoleic acid, oleic acid, edaidic acid, acid erucic and linoleic acid), or steroid esters); alkyl, aryl or cyclic ethers having 230 carbon atoms (for example, diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol ether and polyethylene glycol); Ketones of 3-30 carbon atoms (for example, acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons of 430 carbon atoms (eg, benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylene sulfone, tetramethylene sulfoxide, toluene, dimethylsulfoxide (DMSO) or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin (for example, mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed hydrocarbons of aliphatic or aromatic base and refined paraffin oil, vegetable oils such as flax oil, of tong, safflower, soya, castor, cotton, peanut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, peach and peanut and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm whale, cod liver, halibut liver, squalene, squalane and shark liver oil, oleic oils and polyoxyethylated castor oil); alkyl or aryl halides of 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzine; trola ina; omega-3 polyunsaturated fatty acids (eg, alpha-linolenic acid, icosapentaenoic acid, docosapentaenoic acid or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate, sodium oleate or sorbitan monooleate. Other solvents approved for pharmaceutical use which can be used in this invention are well known to those working in the area, and are identified in The Chemotherapy Source Book (Williams &Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, DC, and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., Eds., 3d ed.) (Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman &Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., Eds.,) (Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), AJ Spiegel et al., And Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, NA 10, p. 917-927 (1963). The solvents of choice are those that are known to stabilize antineoplastic compounds, such as triglyceride-rich oils, such as safflower oil, oil. soybeans or mixtures thereof, and modified fatty acid alkylenoxy fatty acids such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (for example, Cremophor® EL solution or Cremophor® RH 40 solution). Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc, Stockholm, Sweden), Nutralipid® emulsion (McGaw, Irvine, California), 20% Liposyn® II emulsion (an emulsified 20% fat solution containing 100 mg of safflower oil, 100 mg of soybean oil, 12 mg of egg phosphatide and 25 mg of glycerin per ml of solution, Abbott Laboratories, Chicago, Illinois), 20% Liposyn® III emulsion (an emulsified solution of 20% fat containing 100 mg of safflower oil, 100 mg of soybean oil, 12 mg of egg phosphatide and 25 mg of glycerin per ml of solution, Abbott Laboratories, Chicago, Illinois), natural or synthetic derivatives of glycerol containing the docosahexaenoyl group at levels that are between 25% and 100% by weight based on the total content of Dhasco® fatty acids (from Martek Biosciences Corp., Columbia, MD), DHA Maguro® (from Daito Enterprises, Los Angeles , CA), Soyacal®, and Travemulsion®. The solvent of choice used to dissolve the antineoplastic compound to prepare solutions, emulsions, and the like is ethanol. Components of minor importance can be included in the preparations of the invention for a variety of purposes well known in the pharmaceutical industry. These compounds will mostly impart properties to increase retention of the antineoplastic compound at the site of administration, protect the stability of the preparation, control the pH, facilitate the processing of the antineoplastic compound in pharmaceutical and other similar formulations. Preferably, each of these compounds individually represents less than about 15% of the total weight of the preparation; it is better if it represents less than about 5% of the total weight, and even better if it is less than about 0.5% of the total weight of the preparation. Some components, such as fillers and diluents can constitute up to 90% by weight of the total preparation, as is known in the formulation area. Such additives include cryoprotective agents to prevent reprecipitation of taxane, surfactants, humectants or emulsifiers (eg, lecithin, polysorbate-80, pluronic 60, polyoxyethylene stearate), preservatives (e.g., ethyl p-hydroxybenzoate), antimicrobial preservatives. (for example, benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), pH adjusting agents or buffering agents (eg, acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (for example, glycerin), thickeners (for example, aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropyl cellulose, tristearin, cetyl wax esters, polyethylene glycol), dyes, pigments, auxiliary agents of flowability, non-volatile silicones (eg, cyclomethicone), clays (eg, bentonite), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (eg, sugars such as lactose, sucrose, mannitol or sorbitol, cellulose) , or calcium phosphate), diluents (e.g., water, physiological saline, electrolyte solutions), binders (e.g., starches such as corn starch, tri-starch) go, rice starch or potato starch, gelatin,. Adjuvant gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sugars, polymers, gum arabic), disintegrating agents (for example, corn starch, wheat starch, rice starch, potato starch or carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (eg, silica, talc, stearic acid or its salts such as magnesium stearate or polyethylene glycol), coating agents (eg example, concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol or titanium dioxide) and antioxidants (eg, sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols and thiophenols).

The administration of the pharmaceutical forms by these routes can be continuous or periodic, depending, for example, on the physiological state of the patient, on whether the purpose of the administration is therapeutic or prophylactic and other factors known and evaluated by an experienced physician. The dose and therapeutic guidelines of the pharmaceutical preparations of the invention can be determined without difficulty by those who perform in the area of cancer treatment. It is understood that the dose of the antineoplastic compounds will depend on the age, sex, health and weight of the recipient, the type of joint treatment, if any, the frequency of treatment and the nature of the desired effect. In any mode of administration, the actual amount of antineoplastic compound administered, as well as the administration schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antineoplastic compound, the disorder being trying, the desired therapeutic dose and other factors that will be evident to those with experience in the subject. The dose administered to an animal, in particular to a human being, in the context of the present invention, should be sufficient to produce the desired therapeutic response in the animal within a reasonable period. Preferably, the effective amount of the antineoplastic compound, whether administered orally or by any other route, is that amount which results in the desired therapeutic response when administered by that route. Preferably, preparations for oral administration are prepared such that a single dose in one or more oral preparations contains at least 20 mg of the antineoplastic compound per m2 of patient's body surface, or at least 50, 100, 150, 200, 300 , 400, or 500 mg of the antineoplastic compound per m2 of body surface of the patient, with the average body surface area for a human being 1.8 m2. Preferably, a single dose of a preparation for oral administration contains from about 20 to about 600 mg of the antineoplastic compound per m2 of body surface of the patient, better if it is from about 25 to about 400 mg / m2, even better if it is about 40. at about 300 mg / m2, and even better if it is from about 50 to about 200 mg / m2. Preferably, preparations for parenteral administration are made such that a single dose contains at least 20 mg of the antineoplastic compound per m2 of body surface of the patient, or at least 40, 50, 100, 150, 200, 300, 400, or 500 mg of the antineoplastic compound by 2 m of the patient's body surface. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antineoplastic compound per m2 of the patient's body surface, better if it is from about 40 to about 400 mg / m2, and even better if it is from about 60 to about 350 mg / m2. However, the dose may vary depending on the administration plan, which may be adapted as necessary to achieve the desired therapeutic effect. It should be noted that the effective dose ranges provided herein are not intended to limit the invention and represent the therapeutic margins of choice. As it is understood, the most appropriate dosage should be established for each individual and should be determined, without undue experimentation, by an expert in the field. The concentration of choice of the antineoplastic compound in a liquid pharmaceutical preparation is between about 0.01 mg and about 10 mg / ml of the preparation, better, if it is between about 0.1 mg and about 7 mg / ml, still better if it is between about 0.5 mg and approximately 5 mg / ml, and even better if it is between approximately 1.5 mg and approximately 4 mg / ml. In one embodiment of choice, the concentration of 9091 in this formulation is 2 to 4 mg / ml. In general, relatively low concentrations of the antineoplastic compound are preferred because it is more soluble in the solution at low concentrations. The concentration of choice of the antineoplastic compound in a solid pharmaceutical preparation for oral administration is between about 5% by weight and about 50% by weight with respect to the total weight of the preparation, even better if it is between about 8% by weight. weight and approximately 40% by weight, and even better if it is between approximately 10% by weight and approximately 30% by weight. In one embodiment, solutions for oral administration were prepared by dissolving the antineoplastic compound in a solvent approved for pharmaceutical use (eg, ethanol or polyethylene glycol), capable of dissolving the compound to obtain a solution. An appropriate volume of a surfactant vehicle such as the Cremophor® EL solution, polysorbate 80, Solutol HS15 or Vitamin E TPGS is added to the solution, while stirring, to obtain an acceptable pharmaceutical solution for oral administration. Preferably, the concentrations are about 5-10% by volume of ethanol with an equal volume of the surfactant and distilled water in the range of 80-90% by volume. For flavor purposes, the distilled water can be replaced with a diluted cherry or raspberry syrup, preferably about 10-30% syrup with the rest of water. In one embodiment of choice, the concentration of 9091 in this formulation is 2 to 4 mg / ml. If desired, such solutions can be formulated to be free of or contain a minimum amount of ethanol, which as is known to those working in the area, causes adverse physiological effects when administered in oral pharmaceutical formulations at certain concentrations. In another embodiment, powders or tablets for oral administration were prepared by dissolving the antineoplastic compound in a solvent approved for pharmaceutical use (for example ethanol or polyethylene glycol), capable of dissolving the compound to obtain a solution. The solvent may optionally be capable of evaporating when the solution is dried under vacuum. An additional vehicle such as Cremophor® EL can be added to the solution prior to drying. The resulting solution is dried under vacuum to obtain a crystal. The crystal is then mixed with a binder to form a powder. The powder can be mixed with filling agents or other conventional excipients for tabletting and then processed to obtain a tablet for oral administration. The powder can also be added to a liquid vehicle as described above to obtain a solution, emulsion, suspension or the like, for oral administration. Emulsions can be prepared for parenteral administration, by dissolving the antineoplastic compound in a solvent approved for pharmaceutical use (for example ethanol or polyethylene glycol), capable of dissolving the compound to obtain a solution. An appropriate volume of a vehicle which is an emulsion such as Liposyn® II or Liposyn® III or Intralipid® is added to the solution while stirring, to obtain a pharmaceutical emulsion suitable for oral administration. Preferably, the ethanol range is about 5-10% and the lipid emulsion range is about 90-95%. In one embodiment of choice, the concentration of 9091 in the administration solution is approximately 1 to 2 mg / ml. If desired, said emulsions can be formulated to be free of or contain minimal amounts of ethanol or Cremophor® solution, which as those skilled in the art know, cause adverse physiological effects when administered in parenteral pharmaceutical formulations, at certain concentrations. Solutions for parenteral administration can be prepared, dissolving the antineoplastic compound in a solvent approved for pharmaceutical use (for example ethanol or polyethylene glycol), capable of dissolving the compound to obtain a solution. An appropriate volume of a vehicle which is surfactant, such as Cremophor® solution, polysorbate 80 or Solutol HS15, is added to the preparation, while stirring, to form an acceptable pharmaceutical solution for parenteral administration to a patient. If desired, such solutions can be formulated to be free of or contain minimal amounts of ethanol or Cremophor® solution, which, as those skilled in the art know, in the area, cause adverse physiological effects when administered in parenteral pharmaceutical formulations, at certain concentrations. . Other suitable parenteral formulations include liposomes. Liposomes are spherical or spheroidal aggregates or aggregates of antipathetic compounds, including lipid compounds, usually in the form of one or more concentric layers, for example, monolayers or bilayers. Liposomes can be formulated with either ionic or non-ionic lipids. The -liposomes made from non-ionic lipids are also known as niosomes. Among the references on liposomes are: (a) Liposomes Second Edition: A Practical Approach, edited by V. Torchillin and V. Weissig, Oxford University Press, 2003; (b) M. Malmstein, Surfactants and Polymers in Drug Delivery, Marcel Dekker Inc., 2002; and (c) Muller et al. , Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs, Medpharm Scientific Publishers, 1998. If desired the solutions or emulsions described above for oral or parenteral administration can be packed in IV bags, vials or other conventional containers in concentrated or diluted forms with Any approved pharmaceutical use liquid, such as saline, to obtain an appropriate concentration of taxane, prior to use. The term "hydroxyl protecting group" and "hydroxy protecting group" as used herein, designates a group capable of protecting a free hydroxyl group ("protected hydroxyl") which upon completion of the reaction that gave rise to the protection, can be removed without altering the rest of the molecule. A wide range of hydroxyl protecting groups can be found and the synthesis thereof in Protective Groups in Organic Synthesis by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser The hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (ß-trimethylsilylethoxy) methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl (diphenyl) -silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2- trichloroethoxymethyl. As used herein, "Ac" means acetyl, "Bz" means benzoyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "LAH" means lithium aluminum hydride; "10-DAB" means 10-deacetylbaccatin III ";" THF "means tetrahydrofuran;" DMAP "means 4-dimethylamino pyridine;" LHMDS "means lithium hexamethyldisilazide;" TESC1"means triethylsilyl chloride;" cPtc-Cl "means chloride of cyclopentanecarbonyl; "DMF" means N, -dimethylformamide; "MOP" means 2-methoxypropene; "iProc" means N-isopropoxycarbonyl; "iProc-Cl" means isopropyl chloroformate; and "LDA" means lithium diisopropylamide.

The following examples illustrate the invention. Example 1 Preparation of compound 9091 -DAB SET310 Protection and acylation of 10-DAB to SIT310. By the following procedure, the tandem protection of the C7 hydroxyl of 10-DAB with triethylsilyl chloride (TESC1) and the acylation of its hydroxyl in CIO with cyclopentanecarbonyl chloride (cPtc-Cl) produced SIT310. Preferably, the reaction is carried out in 6 ml of DMF per 1 g of 10-DAB as a clear solution (10-DAB is soluble in DMF up to ~ 5 μg at 22 ° C, but precipitates when cooled to 0-5. ° C). The addition of DMAP to the 10DAB solution in DMF at room temperature helps its solubility. Preferably, the anhydrous solvents and the reactors are under an inert nitrogen atmosphere. The water will consume triethylsilyl chloride with a 1: 2 molar ratio. In a 1-liter, 3-neck, externally jacketed, oven-dried flask equipped with magnetic stirring, with an internal temperature probe and an addition funnel under an inert nitrogen atmosphere, 10-DAB ( 54.46 g, 0.100 mol), DMAP (36.60 g, 0.300 'mol) and anhydrous DMF (330 ml). The mixture (0.3 M) was stirred to give a clear yellow clear solution at 22 ° C. The reaction mixture was cooled to an internal reactor temperature of 0-5 ° C with a circulation cooler. Protection of 7-TES: The addition funnel was charged with TESC1 (17.6 ml, 0.105 mol, 1.05 eq). When the internal temperature of the reactor was < 5 ° C, the addition of TESC1 drop by drop to control the exotherm and maintain the internal temperature of the reactor at < 5 ° C (time of addition of to 30 minutes). After the addition of 15 ml of TESC1, began to precipitate DMAP-HC1 salt. After the addition was complete, the reaction was stirred at a temperature between 0 and ° C for 2.5 hours. The follow-up by TLC (EtOAc: heptanes, 3: 1) showed a small amount of raw material (Rf = 0.20) compared to the product 7-TES-10-DAB (Rf = 0.65). The HNMR sampling of the reaction mixture showed that the amount of raw material was 2.5% of the product according to the integration of the proton resonance of carbinol in CÍO. Additional TESC1 (0.45 ml, 0.0027 mol) was added and the mixture was stirred between 0 and 5 ° C. After 2 hours, sampling by HNMR showed < 1% of initial 10-DAB, approximately 1.2% of the 7, 13-bisilylated secondary product (the reaction was stirred overnight without further changes). Formation of 10-cPtc: The addition funnel was charged with cyclopentanecarbonyl chloride (12.76 ml, 0.105 mol) and added to the reaction flask dropwise over a period of 30 minutes to control the exotherm and maintain the internal temperature of the reactor < 10 ° C. After the addition was complete, the mixture was stirred at 15-22 ° C for 12 hours. TLC monitoring of the reaction mixture showed a conversion of about 95% to the less polar product. The HNMR sampling of the reaction mixture showed that 4.5% of the intermediate 7-TES-10-DAB relative to the product remained according to the integration of the proton resonance of carbinol in CÍO. Additional cPtc-Cl (0.55 ml, 0.0045 mol) was added and the mixture was stirred for 4.5 hours. Tracking by TLC (EtOAc: heptanes, 1: 1) showed complete conversion to the product and purification was started. Purification: The reaction mixture was gradually poured into a 3 liter flask with rapid stirring containing 1.5 liters of ice water for 5 minutes to form a thick white precipitate. After stirring for 15 minutes, the precipitate was collected by vacuum filtration through a medium fried Büchner funnel. The filtered mass was carefully washed with pure water.

The water filtrate showed no product by TLC and was discarded. The filter cake was dissolved in ethyl acetate (300 ml) and collected in the vacuum filtration flask.

The funnel was washed with ethyl acetate (100 ml) -in the ethyl acetate filtrate. The filtrate was transferred to a 2 liter separatory funnel and washed with water (1x100 ml), a saturated solution of sodium bicarbonate (1x100 ml) and a saturated aqueous solution of sodium chloride (1x50 ml). The organic phase was dried over MgSO4 (30 g) for 1 hour. The MgSO4 was filtered and washed with ethyl acetate in the filtrate. The filtrate was concentrated in a rotavapor at 40 ° C to -100 ml. The remaining ethyl acetate was exchanged with acetonitrile (500 ml). The mixture was further concentrated until the formation of crystals was observed, leaving about 375 ml of acetonitrile in the evaporating flask. The concentration was stopped and 50 ml of acetonitrile was added to aid the agitation of the crystals. The solution was then cooled to -20 ° C for 1 hour while rotating on a rotary evaporator. The crystals were collected by vacuum filtration. The filtered pulp was washed with cold acetonitrile at -20 ° C (150 ml) and heptanes at room temperature (200 ml). The crystals were dried under high vacuum (<0.1 mmHg) at 22 ° C overnight to constant weight (59.90 g, 79.3%). Mp: 241-243 ° C, 97.5% purity by HPLC. KF: 0.96% w / w of water. The HNMR spectrum of the crystals coincides with the structure of SIT310. [] D20 = -43.5 (MeOH, 2.07). The acetonitrile filtrate was concentrated in a rotary evaporator to -100 ml to induce a second crystal formation.

S1T302 S? T304 Tandem protection and N-acylation, conversion from SIT302 to SIT304. By the following procedure, the tandem protection of the hydroxyl of SIT302 with 2-methoxypropene (MOP) and the introduction of the N-isopropoxycarbonyl group (iProc) using isopropyl chloroformate (iProc-Cl) produced SIT304. Preferably, the following reactions take place under anhydrous conditions and solvents and under inert nitrogen atmospheres. Glassware and equipment should be washed with triethylamine base and carefully dried. The MOP polymerizes easily in the presence of minimum amounts of acid at temperatures > 0 ° C. SIT302 will precipitate at -25 ° C at a concentration of < 15 ml THF / g.

MOP protections: SIT302 (36.0 g, 0.213 mol) and THF (540 ml) were charged in a 2-liter ball flask with magnetic stirring under nitrogen, equipped with a 0.5-liter addition funnel and a low temperature probe. to produce a clear yellow clear solution. The solution was cooled to -25 ° C then loaded with pTsOH monohydrate (1.8 g, 9.4 mmol). The addition funnel was charged with MOP (23.5 ml, 0.245 mol). After the reactor temperature reached -25 ° C, MOP was added drop by drop at a rate that controlled the exotherm and maintained the reactor temperature < -20 ° C (15 minutes). After the addition was complete, the follow-up TLC, eluted with 2: 1 ethyl acetate: hexanes showed that -15% SIT302 remained (Rf = 0.2). Additional MOP (5 ml, 0.052 mol) was added dropwise over 5 minutes to complete the conversion to SIT302 protected with less polar MOP (Rf = 0.5). The ketal formation reaction was stopped with triethylamine (108 ml, 0.775 mol) at -25 ° C. N-Acylation: After stopping the protection reaction with MOP, DMAP (3.24 g, 0.0265 mol) was added to the reaction flask and warmed to room temperature. The addition funnel was dried under a stream of nitrogen and charged with iProc-Cl (245 ml, 1.0 M in toluene, 0.245 mol). After the reactor temperature reached 22 ° C, the chloroformate addition was started drop by drop to control the exotherm and keep the reactor temperature below 28 ° C. The addition was completed in 30 minutes and yielded a white precipitate of triethylammonium chloride. After stirring at room temperature for 1 hour, the follow-up TLC, eluted with ethyl acetate-hexanes 1: 1 showed a conversion of -90% and remained 10% of the MOP-SIT302. Additional iProc-Cl (40 mL, 0.04 mol) was added to the reaction. After stirring for 2.5 hours at 22 ° C, TLC showed complete conversion to the less polar product and purification was started. Purification: The reaction mixture was added to a 1: 1 mixture of saturated sodium bicarbonate and saturated aqueous sodium chloride solution (300 ml) and stirred vigorously for 10 minutes. The mixture was then transferred to a 2-liter separatory funnel and the phases allowed to separate. The lower aqueous phase was emptied and discarded. The organic phase was washed twice with a saturated aqueous solution of sodium chloride (2x100 ml) and dried over MgSO 4 (15 g) for 1 hour with stirring. The MgSO4 was filtered and the filtered slurry was washed with ethyl acetate to ensure complete product recovery (TLC). The filtrate was transferred to 3 liters by evaporation and concentrated in a rotary evaporator under vacuum at 40 ° C until an oil was obtained and the solvents toluene and THF were removed. The viscous oil was dissolved in ethyl acetate (500 ml) in the rotavapor evaporation flask and heptanes (1500 ml) were added to the evaporation flask for 10 minutes with good agitation. The clear solution was further concentrated in vacuo. After approximately 350 ml of the solvent mixture had been removed, the formation of crystals began and the concentration was stopped in vacuo. The mixture was cooled with continuous rotation for 1 hour at 22 ° C, then 1 hour at 0 ° C. The crystals were collected by vacuum filtration and the filtered pulp was washed with cold heptanes (150 ml). The product was dried under high vacuum (0.1 mm Hg) at room temperature until constant weight (51.52 g; 0.157 mol; 73.7%). The filtrate was concentrated to a volume of about 200 ml to induce a second crystallization. After cooling to 0 ° C for 1 hour, the second crystal formation was collected by vacuum filtration and washed with heptanes (-50 ml) and dried to constant weight (10.25 g, 0.031 mol, 14.7%). After the TLC verification of the two crystal formations showed that they were of similar purity, they were combined (61.52 g, 88.4%). Mp: 74-75 ° C, 99.4% purity by CLAR. KF: 1.48% p / p of water. The HNMR spectrum of the crystals coincides with the structure of SIT304. [a] D20 = + 3.6 (MeOH, 0.93). It was stored in a flask washed with triethylamine base under nitrogen at < -20 ° C.

S1T304 Conversion of SIT310 to SIT312 by coupling with lithium alkoxide Using the following procedure, SIT310 and SIT304 were coupled to produce SIT312. The reactions are sensitive to moisture.

Preferably, the reactions are carried out under an inert nitrogen atmosphere and with reactors and anhydrous solvents. The lithium diisopropylamide base (LDA) should be prepared immediately before each use. Preparation of LDA: Diisopropylamine (13.1 ml, 92.98 mmol) and THF (26 ml) were charged in a 250 ml ball flask, dried under nitrogen, equipped with magnetic stirring and with an internal temperature probe. The mixture was cooled to -45 ° C and a freshly titrated nBuLi solution (54 ml, 1.62 M, 85.83 mmol) was added dropwise to control the exotherm and maintain reactor temperature < -40 ° C. After the addition was completed within 30 minutes, the temperature of the cooling bath was raised to 0-5 ° C before use. Coupling reaction: In a 1 liter ball flask oven dried, under nitrogen, equipped with magnetic stirring and with an internal temperature probe were charged SIT310 (54.0 g, 71.525 mmol), SIT304 (28.1 g, 85.83 mmol) and THF (325 mL, 0.22 M). The mixture was cooled to -45 ° C. The addition funnel was loaded with freshly prepared LDA and added to the reaction flask drop by drop for 30 minutes to control the exotherm and maintain the reactor internal temperature < -40 ° C. After the addition, the reactor temperature was raised to -20 ° C and maintained while stirring for 1.5 hours. The follow-up of the reaction by TLC (EtOAc: Hept / l: 3) showed -10% SIT31 (Rf = 0.25,) -90% of the SIT312 product and none of the initial SIT304. More was added SIT304 (2.8 g, 8.56 mmol) solid to the reaction mixture. After stirring for 1.5 hours at -20 ° C, TLC showed a complete reaction and purification was started. Purification: To the reaction flask at -20 ° C a 1: 1 mixture of saturated sodium bicarbonate and saturated aqueous sodium chloride solution (100 ml) was added to stop the reaction. The reaction flask was heated to room temperature and its contents transferred to a separatory funnel. Ethyl acetate (200 ml) was added to help separate the phases. The aqueous phase was emptied and discarded. The organic phase was washed once more with saturated aqueous sodium chloride solution (50 ml) and dried over MgSO 4 (30 g). The MgSO4 was filtered and the filtered slurry was washed with ethyl acetate (100 ml) within the filtrate. The filtrate was concentrated in a vacuum rotary evaporator to a volume of approximately 150 ml. The remaining solvent was exchanged with isopropanol (500 ml). After further concentration to an approximate volume of 350-400 ml, crystal formation began and the concentration was stopped. The mixture was cooled to-0 ° C with stirring for 1 hour. The crystals were collected by vacuum filtration and washed with isopropanol (200 ml) previously cooled to 0 ° C and dried to constant weight (73158 g, 6810 mmol, 9510%) under high vacuum (011 mmHg). The HNMR spectrum of the crystals coincides with the structure of SIT312. Mp: 137-140 ° C, purity by CLAR 95.4%. It was unstable in the conditions of preparation for CLAR and lost protection 2 '-MOP during the analysis (0.83%).

Tandem checkout and conversion from SIT312 to 9091.

By the following procedure, the tandem removal of MOP and TES protective groups from SIT312 under acidic conditions yielded 9091. SIT312 (70.0 g, 64.67 mmol) and THF (350 mL, 0.185 M) were added to a 1 liter beaker , with outer jacket, equipped with magnetic stirring, an internal temperature probe and an addition funnel. The mixture was cooled to 0 ° C with a circulation bath. The addition funnel was charged with formic acid (96%, 175 ml, 4.45 mol). The formic acid was added dropwise for 30 minutes to control the exotherm and keep the reactor temperature at <10 ° C. After the addition of formic acid was complete, the addition funnel was charged with 1.0 M HCl (87.5 ml, 87.5 mmol). The addition of the HCl was carried out dropwise for 15 minutes, to control the exotherm and maintain the reactor temperature at < 10 ° C. TLC of the reaction mixture (EtOAc: Hept 1: 1) after the addition showed an immediate loss of the MOP protecting group to produce a more polar product (Rf = 0.65) compared to SIT312 (Rf = 0.7). The mixture was stirred between 8 and 10 ° C. After 9 hours, the TLC showed a conversion > 95% to a more polar product together with approximately 2-3% by-product (Rf = 0.55) and -1% of the intermediate with Rf = 0.65 and purification was initiated. Purification: The reaction was diluted with ethyl acetate (1 liter) and transferred to a 3 liter separatory funnel and washed, twice with water (2x500 ml) and twice with saturated sodium bicarbonate (2x100 ml). The pH of the organic phase was checked to be 8 and washed twice with saturated aqueous sodium chloride solution. (2x100 ml). The monitoring of the aqueous phase showed no product by TLC analysis. The organic phase was dried over Na2SO4 (100 g) for 1 hour. The Na2SO4 was filtered by gravity with Whatman No. 1 filter paper and the filter cake was washed with ethyl acetate to ensure complete recovery of the product. The filtrate was concentrated with a vacuum rotary evaporator to produce a foam (65.59 g).

The HNMR spectra of the foam confirmed the structure of the 9091 together with triethylsilylated by-products. Recrystallization: The foam was dissolved in ethyl acetate (280 ml) and heated to 50 ° C with stirring. Heptanes (455 ml) were added gradually over 15 minutes to maintain a clear solution. The mixture was gradually cooled to room temperature. After 1 hour at 22 ° C, seed crystals were introduced and crystal formation occurred within 5 minutes. The mixture was cooled in a water bath at 0 ° C for 1 hour before collecting the crystals by vacuum filtration and the filtered slurry was washed with a cold mixture at 0 ° C of EtOAc: heptanes 1: 4 (200 ml) . After drying at room temperature for 3 hours and under high vacuum (<0.1 mmHg), 57.23 g (expected yield 57.23 g) of a white powder were obtained. The analysis by CLAR showed 96.8% of purity and 1.2% of an impurity by relative integration of areas. The white powder was redissolved in ethyl acetate (225 ml) at 50 ° C. While stirring gently, heptanes (320 ml) were gradually added to maintain a clear solution. After the addition was complete, the mixture was cooled to 22 ° C and spontaneous crystal formation occurred within 5 minutes. After 10 hours at 22 ° C, the mixture was cooled to 0 ° C. After 1 hour at 0 ° C, the crystals were collected by vacuum filtration and the filtered slurry was washed with a cold mixture at 0 ° C of EtOAc: heptanes 1: 4 (200 ml). The HPLC analysis of the crystals showed a purity of 98.5%. The white powder was dried at 50 ° C and under high vacuum (0.1 mmHg) for 2 days until constant weight (40.58 g, 45.3 mmol, 70.0%). Mp: 159-161 ° C, 98.5% purity by HPLC. The XHNMR and 13CNMR spectra coincided with the structure of 9091. [a] D20 = -43.1 (MeOH, 0.91). The mother liquor from the first recrystallization was concentrated to give 15.0 g of a waxy material. It was triturated with heptanes (200 ml) to give approximately 7 g of a free flowing powder. The powder was purified by flash chromatography, on a column of silica gel eluted with ethyl acetate: heptanes 1: 1. The collection of the fractions containing 9091 and the concentration with a vacuum rotary evaporator gave 5.84 g of 9091. The pooling of the fractions containing the impurity provided 0.55 g of a white solid with an HNMR spectrum that matches 9091-7-formate . The mother liquor concentration of the second recrystallization gave 4.50 g of material. It was combined with 5.84 g of 9091 purified by chromatography of the first mother liquor to give 10.34 g (17.8%).

Data of ^? NMR of compound 9091 (CDC13) CHEMICAL DISPLACEMENTS OF H and 1"3, C of compound 9091 Example 2 Measurement of in vitro cytotoxicity by the cell colony formation assay. 400 cells were seeded (HCT 116 human colon carcinoma obtained from the American Type Culture Collection, Manassas, VA) in 60 mm Petri dishes containing 2.7 ml culture medium (modified Mc Coy 5a medium, containing 10 ml). % of bovine fetal serum, 100 units / ml of penicillin and 100 g / ml of streptomycin). The cells were incubated in a culture oven with C02 at 37 ° C for 5 hours for adhesion to the base of the Petri dishes. The compound of the present invention was prepared fresh in a medium at a concentration ten times greater than the final concentration and then 0.3 ml of this concentrated solution was added to the 2.7 ml of medium in the plate. After, the cells were incubated with drugs at 37 ° C for 72 hours. At the end of the incubation period, the culture media containing the drugs were decanted, the plates were washed with 4 ml of Hank's Balanced Salt Solution (HBSS) and 5 ml of fresh medium was added, after which the plates were returned to the stove for the formation of colonies. After 7 days of incubation the colonies were counted with a colony counter. Cell survival was calculated and the IC50 value (the concentration of drug causing a 50% inhibition) in colony formation was determined for each compound tested. Identical assays were performed using VM46 (strain of human colon carcinoma HCT116 resistant obtained from Dr. Li-Xi of California Pacific Medical Center, CA). Evaluations with DLD-1 (human resistant colon carcinoma obtained from the American Type Culture Collection, Manassas, VA) were performed in a similar manner using an MTT assay (3- (4,5-dimethythiazole-2-bromide). il) -2,5-diphenyltetrazolium).

Example 3 Evaluation of oral efficacy of 9091 [0070] The efficacy of 9091 against a pancreatic human pancreatic tumor xenograft Panc-1, obtained from the Collection was evaluated American Type Crop, Manassas, FSUM 10607.2 PATE? T VA. The tumor used for this study was maintained in nude 3 nude mice. A tumor fragment (1 mm) was implanted s.c. on the right flank of each test mouse. The tumors were verified twice a week and then 3 daily as their volume reached 200-400 mm with 3 an average of 250-300 mm. On day 1 of the study, the animals were distributed into treatment groups with sizes of were distributed in treatment groups with tumor sizes of 171.5 - 320.0 mm3 and group average - tumor size of 212.6 - 216.0 mm3. The tumor size, in mm3, was calculated by the following formula: Tumor volume = w SJ 2 where w = width and 1 = length in mm of the tumor. The tumor weight was calculated with the assumption that 1 mg is equivalent to 1 mm3 of the tumor. The mice were distributed in groups with six mice per group - and treated according to the protocol of tables IA and IB. All treatments were administered orally, once a day (qd x 1). Groups 2 and 3 received compound 9091 to 120 and 60 mg / kg respectively. In all groups, the volume of administration of 0.6 ml / 20 g of mouse was calculated to scale according to the body mass of each animal. Each animal was euthanized when its neoplasm reached the size of the predetermined criterion (1200 mm3). The time elapsed until the determined criterion (TTE) for each mouse was calculated according to the following equation: TTE = loggia (view of the detetromated criterion) - b where TTE is expressed in days, the volume of the determined criterion is expressed in mm3, b is the ordinate at the origin and m is the slope of the line obtained by linear regression of a set of logarithmic data of tumor growth. The data set consists of the first observation that exceeds the volume of the study criterion and the three consecutive observations immediately preceding the point at which the determined criterion volume is reached. Animals that do not meet the criteria are assigned a TTE value equal to the last day of the study (59 days). Animals classified as TR deaths (related to treatment) or NTRM deaths (metastases not related to treatment) are assigned a TTE value equal to the day of death. Animals classified as NTR deaths (not related to treatment) are excluded from TTE calculations. The effectiveness of the treatment was determined according to the tumor growth retardation (PDD), which is defined as the increase in the mean TTE for a treatment group compared to the control group: TGD = T - C, expressed in days , or as a percentage of the average TTE of the control group:% TGD = TC slOO where: T = median TTE for a treatment group and C = median TTE for control group 1. The treatment can cause a partial remission (PR) or a complete remission (CR) of the tumor in an animal. In a PR response, the tumor volume is 50% or less of its volume at day 1 for three consecutive measurements during the course of the study, and equal to or greater than 13.5 mm3 for one or more of these three measurements. In a CR response, the tumor volume is less than 13.5 mm3 for three consecutive measurements during the course of the study. An animal with a CR response at the end of a study is also classified as a long-term tumor-free survivor (LTTFS). With respect to toxicity, the animals were weighed daily on days 1-5, then twice a week until the end of the study. The mice were examined frequently to detect overt signs of any adverse side effects related to the drug. The NCI defines the acceptable toxicity for the maximum tolerated dose (MTD) of a drug for cancer in mice as an average body mass loss (BW) of the group less than 20% during the test and no more than one death due to toxicity between ten animals treated. The "log rank" test was used to analyze the significance of the difference between the TTE values of a group treated with the drug and the control group treated with the vehicle. The "log rank" test analyzes the data for all animals except the NTR deaths. Bilateral statistical analyzes were performed at P = 0.05. The median curves of tumor growth in the group show the median tumor volume (MTV) as a function of time. In cases where an animal was removed from the study due to tumor size or death TR, the final tumor volume recorded for the animal was included with the data used to calculate the median volume at subsequent time points. When more than one death occurred in a treatment group, the tumor growth curve for that group was truncated at the time of the second death. Groups 2 and 3 received compound 9091 to 120 and 60 mg / kg respectively. Groups 2 and 3 experienced 212% TGD and a very significant antineoplastic activity (P <; 0.001). The MTV for six mice in each group were 56 and 148 mm3, respectively. In group 2, 9091 produced three PR responses and three LTTFS responses. In group 3, 9091 produced five PR and one LTTFS responses. Compound 9091 yielded 100% survival and six regression responses at both doses, at 120 and 60 mg / kg: these treatments produced three and one LTTFS and caused average body mass losses of 10.7% and 5.5%, respectively.

The data can be found in tables 1A and IB below: Summary of responses to treatment for the Pane-1 Table study TTE - time elapsed up to the determined criterion (days), 1200 mg TC - Difference between TTE (days) of the treated group with respect to the control group,% TGD = [(TC) / C] n - number of mice 5% EC - 5% Ethanol + 5% Cremophor Table IB CR - Non-palpable tumor for three consecutive measurements during the PR study - Remission of the tumor at 50% of the initial size for three consecutive measurements during the LTTES study - Survivors without long-term tumor, animals classified as CR at the end of a study The test log rank is equivalent to the Mantel-Haenszel test; ns = not significant, * - p < 0.05; ** - p < 0.01; *** - p < 0.001; compared to group 1 TR - Death related to NTR treatment - Death not related to treatment Example 4 Evaluation of efficacy 9091 IV The anticancer activity of 9091 was evaluated against a pancreatic human pancreatic tumor xenograft Panc-1. Pancreatic human pancreatic carcinomas were maintained in nude nude mice. A tumor fragment (1 mm3) was implanted s.c. on the flank, right of each test mouse. The tumors were verified twice a week and then daily as their size reached 200-400 mm3 with an average of 250-300 mm3. On day 1 of the study, the animals were distributed in groups of six mice with tumor sizes of 171.5 - 486.0 mm3 and a group average of tumor size of 269.7 - 275.0 mm3. The mice were distributed in groups with six mice each and treated according to the protocol of Tables 2A and 2B. All treatments were administered intravenously. Control group 1 mice received 5% ethanol and 95% Liposyn II vehicle, once on day 1 (qd x 1). Group 2 received 9091 in a dose of 20 mg / kg every two days x 5. Group 3 received 9091 in a dose of 30 mg / kg q4d x 4. Groups 4 and 5 received 9091 qd x 1 in a dose of 120 and 60 mg / kg, respectively. The administration volumes were 0.5 ml / 20 g of body mass for administration regimens qd x 1 and 0.3 ml / 20g of body mass for administration plans qod x 5 or q4d x 4. The volumes of administration were regulated to Scale according to the body mass of each animal. The vehicle was administered to the mice of group 1 in a single dose on day 1 (qd x 1). Tumors in five of the six mice treated with the vehicle grew at the criterion volume of 1200 mm3, with an average TTE of 15.8 days. No referral responses were recorded. The presence of a survivor at 56 days indicates a potential background level of a somewhat unsatisfactory tumor graft per group. Group 2 received 9091 in a dose of 20 mg / kg qod x 5. Group 3 received 9091 in a dose of 30 mg / kg q4d x 4. Groups 4 and 5 received 9091 qd x 1 in a dose of 120 and 60 mg / kg respectively. Five TR deaths were recorded in group 2, which could not be evaluated with respect to treatment efficacy. Two mice of group 4 died from NTR causes. Groups 3-5 experienced 254% TGD each. This result is very significant in groups 3 and 5 (P < 0.01), and significant in group 4 (P < 0.05). In groups 3-5 no tumor reached the criterion volume; MTV for six mice was 40, 58 and 126 mm3, respectively. In group 3, five PR responses and one LTTFS were recorded. In each of groups 4 and 5, six PR responses were recorded. 9091 reached its highest efficacy in the 30 mg / kg q4d x 4 regimen. This treatment provided five PR responses and one LTTFS, while causing a maximum loss of average body mass in the -13% group. Single doses at 120 and 60 mS./kg produced six PR responses each, while causing a loss of average body mass in the group of -8% and -5%, respectively. Each of these three treatments with 9091 produced six survivors at the end of the MTV study of 40, 58 and 126 mm3, respectively. Table 2: Summary of the treatment responses for the Panc-1 study Table 2A TTE - time elapsed up to the determined criterion (days), 1200 mg T-C - Difference between TTE (days) of the treated group with respect to the control group,% TGD = [(T-C) / C] n - number of mice CR - Tumor not palpable for three consecutive measurements during the PR study - Tumor regression at = 50% of the initial size for three consecutive measurements during the LTTES study - Survivors without long-term tumor, animals classified as CR at the end of a study log rank test is equivalent to the Mantel-Haenszel test; ns = not significant, * - p < 0.05; ** - p < 0.01; *** - p < 0.001; compared with group 1 TR - Death related to NTR treatment - Death not related to NTR treatment - Death not related to treatment Example 5 Study of efficacy for 9091 in xenograft HT29 Following oral and intravenous administration regimens similar to those of xenograft with Panc -1 described in examples 3 and 4, compound 9091 was also evaluated in the xenograft with HT29 (human colon carcinoma obtained from the American Type Culture Collection, Manassas, VA). The results are summarized in tables 3 and 4. Table 3:. Protocol design for the HT29 study with the compound 9091 Table 3B: Summary of response to treatment for study HT29 with compound 9091 n - number of mice 5% EC - 5% Ethanol + 5% Cremophor Table 4A: Protocol design for the HT29 study with compound 9091 (IV) Table 4B: Summary of response to treatment for study HT29 with compound 9091 In figures 1-7 the graphic results of the evaluation of compound 9091 with mouse xenografts are presented. EXAMPLE 6 Evaluation of In Vitro Toxicity in Rats The toxicity was evaluated in Sprague-Dawley rats of 250-300 g and three rats were used per dose group. One study consisted of three dose groups of the test compound (ie 3 mg / kg, 9 mg / kg and 12 mg / kg for intravenous administration, 15 mg / kg, 30 mg / kg and 40 mg / kg) and a control group. The animals were observed and clinical chemistry data were collected on days 4 and 10. On day 11 the rats were euthanized and the nerves were removed and fixed after euthanasia for further examination. Each rat was assigned the score described below and assigned a final toxicity score that incorporates all the parameters. A dead rat is assigned a score of zero. Table 5 below provides the criteria used to determine how each toxicity parameter contributes to the score. Most parameters provide a positive value with respect to the possible total score of 130. For body mass, white blood cell count and platelet depletion, recovery is taken into account. If the parameter does not show a recovery, then a value of -5 is subtracted from the total. The total score is divided by 13 to place it on a scale of 0 to 10. For the neurotoxicity score, a -10 indicates that degenerative axon lesions were observed, while 0 indicates no lesions. Table 5. Criteria for toxicity score in rats Maximum assigned score (each rat) = 130; Group score = average of 3 rats / 13; Prom = average of 3 weight groups Prom = (S (dose x group)) / 24 control AST - Aspartate aminotrasferase (AST); ALT - Alanine aminotransferase; PTL - Platelets; BUN - Blood urea nitrogen WBC - white blood cells Table 6 shows a sample of the data for a toxicity study in rats with oral administration of compound 9091.

Table 6. Sample entries in rat toxicity scores; oral administration study The scores resulting from a complete study of the oral and two intravenous administration regimens in rats are summarized in Table 7 below and compared to a previously described analog, compound 3071. The structure of compound 3071 can be found in the 9. Table 7. Toxicity scores of studies performed on rats of compound 9091 (relative to 3071) Example 7 In vivo efficacy test in mouse xenograft studies To simplify the interpretation of xenograft studies in mice, an efficacy score was derived from the xenograft studies in mice already described in the examples 4 and 5. Score = 10 * (T dl - T dn) / TWdl, where TWdl = tumor weight on day 1 TWDn = minimum tumor weight after day 10. So the best score for a complete remission would be 10 The results for compound 9091 are summarized in Tables 8a and 8b and compared with the values for Analogs 3071 and 3102.

Table 8A: Efficacy of 9091 with respect to 3071 in mouse xenograft studies of single oral dose at 60 and 120 mg / kg Table 8B. Efficacy of 9091 compared to 3102 in single-dose IV xenograft studies in mice Example 9 Data on toxicity and comparative efficacy Table 9 presents additional efficacy data from cell proliferation studies as well as rat toxicity study scores for comparable compounds corresponding to the formula All the compounds shown in table 9, except compound 9091, appear in PCT publication WO01 / 57032 Table 9 Comparative summary of toxicity data The results of the studies described above indicate that compound 9091 belongs to a class of agents effective against various tumor lines. When compared to the analogs, compound 9091 demonstrates a better toxicity profile in rats when administered intravenously. Although it has a better toxicity profile in studies with rats in oral doses, compound 9091 is more effective than compound 3071 in single oral dose xenograft studies, and compound 9091 is much more effective than compound 3102 (another analogue) in single IV dose xenograft studies at doses of 60 mg / kg and 120 mg / kg. Therefore, compound 9091 has the potential of an effective and safe antineoplastic agent for oral and IV administration. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (36)

R E I V I N D I C A I N N E S Having described the invention as above, the content of the following claims is claimed as property:

1. A taxane that has the structure: characterized in that X3 is thienyl, Ac is acetyl and Bz is benzoyl.

2. The taxane according to claim 1, characterized in that it has the structure:

3. The taxane according to claim 1, characterized in that the C7 hydroxyl substituent and the cyclopentylcarbonyloxy substituent in CIO have the beta stereochemistry configuration.

4. A pharmaceutical composition, characterized in that it contains the taxane according to any of claims 1 to 3, and at least one vehicle approved for pharmaceutical use.

5. The composition according to claim 4, characterized in that the taxane concentration is between 0.01 mg / ml and 10 mg / ml.

The composition according to claim 4, characterized in that the composition is in a single dose unit for an oral administration form and the dose unit contains at least 20 mg of taxane per 2 of the surface area of the patient's body .

7. The composition in accordance with the claim 6, characterized in that the dosage unit form contains between 25 mg and 400 mg of taxane per m2 of the surface area of the patient's body.

8. The composition in accordance with the claim 7, characterized in that the dosage unit form of taxane is between about 50 mg / m2 and about 200 mg / m2. of the surface area of the patient's body.

9. The composition according to claim 4, characterized in that the composition is a dosage unit form for parenteral administration and the dose unit form of taxane contains at least 20 mg / m2 of the surface area of the patient's body. .

10. The composition in accordance with the claim 9, characterized in that the dosage form unit contains between about 40 mg and about 400 mg of taxane per m2 of the surface area of the patient's body.

11. The composition in accordance with the claim 10, characterized in that the dosage unit form of taxane contains between about 60 mg and about 350 mg per m2 area of the patient's body surface.

12. The composition according to claim 4, characterized in that the composition comprises up to about 10% ethanol.

13. The composition in accordance with the claim 12, characterized in that the composition is for oral administration.

14. The composition in accordance with the claim 13, characterized in that the composition is in the form of an oral solution.

15. The composition in accordance with the claim 14, characterized in that the composition comprises at least about 90% distilled water.

16. The composition in accordance with the claim 15, characterized in that the composition comprises less than about 10% surfactant.

The composition according to claim 16, characterized in that the surfactant is polysorbate 80, polyethoxylated castor oil or a combination thereof.

18. The composition according to claim 12, characterized in that the composition is for parenteral administration.

19. The composition according to claim 18, characterized in that the composition is in the form of an emulsion.

The composition according to claim 19, characterized in that it is prepared by a combination of ethanol solution and a fat emulsion.

21. The composition according to claim 20 ', characterized in that the fat emulsion contains about 10% to 20% fat.

22. The composition according to claim 18, characterized in that the composition is a solution.

23. The composition in accordance with the claim 22, characterized in that the composition comprises at least about 85% salt.

24. The composition in accordance with the claim 23, characterized in that the composition comprises less than about 10% surfactant.

25. The composition according to claim 24, characterized in that the surfactant is polysorbate 80, polyethoxylated castor, or a combination thereof.

26. A method for inhibiting tumor growth in mammals, characterized in that it consists in the administration of a therapeutic effective amount, of a pharmaceutical preparation containing the taxane according to claim 1 and at least one approved vehicle for pharmaceutical use.

27. The method according to claim 26, characterized in that the pharmaceutical composition is administered orally.

28. The method according to claim 26, characterized in that the pharmaceutical composition is administered parenterally.

29. The method according to claim 28, characterized in that the mammal is pretreated with dexamethasone, diphenyldramine, or another agent that minimizes the adverse reactions of the administration of the pharmaceutical composition and the pharmaceutical composition comprising a surfactant.

30. The method according to claim 29, characterized in that the surfactant is polysorbate 80, polyethoxylated caster oil, or a combination thereof.

31. The method according to claim 26, characterized in that the tumor is breast, lung, pancreas, colon, ovarian or prostate carcinoma.

32. The method according to claim 31, characterized in that the tumor is Panc-1 pancreatic adenocarcinoma or colon carcinoma HT-29.

33. The method according to claim 26, characterized in that the tumor is resistant to paclitaxel.

34. The method according to claim 33, characterized in that the tumor is a carcinoma of the human colon.

35. The method according to claim 34, characterized in that the tumor is a carcinoma of the human colon VM46.

36. The method according to claim 34, characterized in that the tumor is a carcinoma of the human colon DLD-1.