JP2000510148A - 7-O-methoxymethyl paclitaxel - Google Patents

Abstract

  (57) [Summary] The present invention relates to a novel 7-O-methoxymethylpaclitaxel, its use as an anticancer agent, and pharmaceutical compositions containing the novel compound.

Description

DETAILED DESCRIPTION OF THE INVENTION                   7-O-methoxymethyl paclitaxel                               Technical field   The present invention relates to a novel anticancer compound, 7-O-methoxymethylpaclitaxel, It relates to pharmaceutical compositions and their use as anticancer agents.                               Background fields brevifolia) extracted from the bark of the yew (a yew genus native to the west coast of North America) Natural product. This compound is an excellent anticancer in in vivo animal models Has been shown to be active, and recent studies indicate that abnormal tubulin polymerization And a specific mechanism of action associated with mitosis. Recent ovarian cancer Is approved, and research on breast, colon and lung cancer is also promising The results are shown. Regarding the results of the clinical trial of paclitaxel, Rowinsky and Do nehower, The Clinical Pharmacology and Use of Antimicrotubule Agcn ts in Cancer Chcmotherapcutics "Pharmec.Ther.,52: 35-84, 1991 gives an overview Have been.   Recently, taxotere, a semi-synthetic analog of paclitaxel Is shown below, and its structure is the same as the conventional numbering system for taxane molecules. Are shown using This numbering system is also used in this specification. Have been used. Detailed description of the invention   The present invention relates to a novel compound having the structure of formula (I), 7-O-methoxymethylpaclitax Regarding the cell. Wherein Ph represents phenyl;       Ac represents acetyl; and       Bz represents -C (O) Ph.                       Typical examples of in vivo anticancer activity   William Rosc, Evaluation of Medison 109 Lung Carcinoma Model for Scree ning Antitumor Drugs,Cancer Treatment Reports, 65, No. 3-4 (1981) Balb / c x DBA / 2F₁Intraperitoneally in hybrid mice, M109 lung cal 0.5 ml of 2% (w / v) brei of sinoma was inoculated.   Mice were injected with various doses of test compound (I) 5 to 8 days after cancer transplantation by peritoneal injection. Received more dosing. Daily tracking of mice survival approximately 75-90 days after cancer transplantation did. One group of mice per experiment was untreated and used as a control group .   Compound-treated (T) median survival time of mice (C) Compared to Ann survival time. The ratio of the two values of the mice in each compound treatment group was set to 100. And expressed as a percentage (i.e.% T / C). % T / C value ≥125 Think of it as a cancer activity.   Compound (I) has a% T / C value of 192 at a dose of 50 mg / kg per injection. Met.   The compounds of formula (I) of the present invention are effective cancer suppressants and are therefore Useful in veterinary medicine. Thus, another aspect of the present invention is that of formula (I) Administering an effective anticancer activity of the compound to a host having cancer, comprising: And / or a method of inhibiting cancer in other mammals.   The compounds of formula (I) of the present invention may be used in a similar manner to paclitaxel: Thus, oncologists in the field of cancer therapy, without undue experimentation, Appropriate treatment protocols for administering the compounds of the present invention will be assured. Departure There is no particular limitation on the dosage, action and administration schedule of the disclosed compounds. like this The compounds of the present invention may be administered by any suitable route of administration, preferably Is administered parenterally; dosages may range, for example, from about 1 to 100 mg / kg body weight. Around or about 20-500mg / m^TwoMay be within the range. Dosage actually used Is the formulation of each composition, the route of administration, and the individual Varies by type. Drugs, including patient age, weight, gender, diet and physical condition The dosage can be determined taking into account many factors that alter the effect.   The present invention also provides an effective anticancer activity of a compound of formula (I) and a pharmaceutically acceptable dose of the compound. With more than one carrier, excipient, diluent or additive Pharmaceutical compositions (formulations) are provided.   Examples of the formulation of paclitaxel or a derivative thereof are described in, for example, U.S. Pat. And 4,814,470, and such processes are used to formulate the compounds of the present invention. An example may be used. For example, the compounds of the present invention can be used in tablets, pills, powder blends Products, capsules, injections, solutions, suppositories, emulsions, dispersions, food premixes and others May be in a suitable form. Also for example optionally other pharmaceutically acceptable excipients It may be a sterile solid composition such as freeze-dried mixed with a. like that The solid composition may be sterile water, physiological saline, or water and an organic solvent such as propylene. Glycol, ethanol, etc.) or other mixtures with sterile injectable media. It can be reconstituted immediately before use for oral administration.   Typical pharmaceutically acceptable carriers include, for example, mannitol, Urea, dextran, lactose, potato and corn starch, steari Magnesium phosphate, talc, vegetable oil, polyalkylene glycol, ethylcellulo Ose, poly (vinylpyrrolidone), calcium carbonate, ethyl oleate, myris Isopropyl, formate, benzyl benzoate, sodium carbonate, gelatin, Potassium carbonate and silicic acid. Pharmaceutical preparations may also include, for example, emulsifying, preserving, wetting agents. Non-toxic auxiliary substances such as sorbitan monolaurate, trietano oleate Amine, polyoxyethylene monostearate, glyceryl tripalmitate And dioctyl sodium sulfosuccinate.   In the following experimental methods, all temperatures are in Celsius unless otherwise stated. Is shown. Nuclear magnetic resonance (NMR) is based on tetramethylsilane (TMS). m (parts per million) represented by the chemical shift (δ) means. Record for various shift values in proton NMR spectrum data The specific area listed corresponds to the number of hydrogen atoms of the individual functional groups in the molecule. Multiplicity Shift about The characteristics of broad single line (bs or brs), broad double line (bd or brd), broad triple line Doublet (bt or brt), Broad quadruple (bq or brq), Singlet (s), Multiplet (m), Doublet (d), quadruple (q), triplet (t), doublet doublet (dd), doublet triplet (dt) and doublet It is described as a quadruple line (dq) of the double line. The solvent used for NMR is acetone -d₆(Heavy acetone), DMSO-d₆(Deuterated dimethyl sulfoxide), D_TwoO (heavy water), CDCl_Three (Deuterochloroform) and others are conventional deuterated solvents. Infrared (IR) spectrum The description of the vector is based on the absorption wavelength (cm^-1) Only.   The compound of formula (I) is paclitaxel according to the following process scheme and method: Can be synthesized.   The following abbreviations have been used, and have the following meanings: “TES” is triethylsilyl, “TESCl” is triethylsilyl chloride It is. Synthesis of compounds of formula (I)  2'-O-TES paclitaxel (II)   Paclitaxel (8.1 g, 9.49 mmol) in 40 ml pyridine and 40 ml methylene chloride To the chloride solution at 0 ° C. was added TESCl (6.3 ml, 37.8 mmol). The solution Stir at 0 ° C for 1 hour, then dilute with ethyl acetate, wash with water and brine Was cleaned. Organic fraction_Four, And concentrate the residue. Chromatograph (3: 1 hexane / ethyl acetate, then 2: 1 and finally 1: 1 hexane / acetic acid Ethyl) treatment to give 9.34 g of 2'-O-TES paclitaxel (95%).   2'-O-TES-7-O-methylthiomethylpaclitaxel (III)   2'-O-TES-paclitaxel (15.0 g, 15.5 mmol) in 150 ml of anhydrous acetonitrile Dimethyl sulfide (11.4 ml, 154 mmol) and 0 ° C. Benzoyl peroxide (18.7 g, 77.3 mmol) was added. Solution at 30 ° C for 30 minutes Stir, then warm to room temperature and stir until the reaction is complete by TLC analysis . Saturated sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic Fraction MgSO_Four. , Filtered, concentrated and the residue was chromatographed on silica gel. Treated with 25% ethyl acetate / hexane, then 33% ethyl acetate / hexane. To give 15.14 g of product (95%).   Elemental analysis calculated value (C₅₅H₆₉NSiSO₁₄); C, 64.24; H, 6.76; N, 1.36.               Found C, 63.87; H, 6.70; N, 1.31.   FABMS (NOBA) M + Na C₅₅H₆₉NSiSO₁₄Calculated value as 1050                                                           Measured 1050   IR (KBr) 3442,1724,1242,1066cm^-1   7-O-methoxymethyl paclitaxel (I)   2'-O-TES-7-O-methylthiomethylpaclitaxel (10.48 g, 10.2 mmol ) In 100 ml of acetonitrile solution at 0 ° C. with 20.5 ml of 1N HCl (20.5 ml). mmol) was added. The solution is stirred at 0 ° C. for 1 hour, then with ethyl acetate Dilute and wash with water and saline. Organic fraction_FourDry in , Concentrated, 10.1 g (quantitative)¹1 H NMR-pure 7-methylthiomethyl paclitax I got a cell.   125 ml of 7-methylthiomethylpaclitaxel (6.54 g, 7.16 mmol) in anhydrous Tanol (CaH_TwoThe solution was distilled together with 1 g of total 4A sieve._Two(8 .2 g, 32.3 mmol) was added. The solution is stirred at room temperature for 1 hour, then in ethyl acetate Gently and the sieve was washed with ethyl acetate. Wash the solution twice with saturated sodium thiosulfate. Washed with brine, washed once with brine,_Four, And concentrated. The residue is purified by silica gel chromatography (40% ethyl acetate / hexane, then 50% ethyl acetate). Hexane), 660 mg of product (> 90% pure by HPLC) (10%) And 4.67 g of product (98.1% pure by HPLC) (72%). 98% pure (2.38 g) in a minimum amount of hot ethyl acetate and add hexane until turbid, then 0 ° C For 1.98 g of a white solid.   ESIMS M + H C₄₉H₅₆NO₁₅898 calculated as       Measured 898 IR (KBr) 3436,1724,1242,1106,1026cm^-1

────────────────────────────────────────────────── ─── Continuation of front page    (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, L U, MC, NL, PT, SE), OA (BF, BJ, CF) , CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, KE, LS, MW, S D, SZ, UG), EA (AM, AZ, BY, KG, KZ , MD, RU, TJ, TM), AL, AM, AT, AU , AZ, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, H U, IL, IS, JP, KE, KG, KP, KR, KZ , LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, R O, RU, SD, SE, SG, SI, SK, TJ, TM , TR, TT, UA, UG, UZ, VN

Claims (1)

Claims 1. 7-O-methoxymethyl paclitaxel having the following formula (I): Wherein Ph represents phenyl, Ac represents acetyl, and Bz represents -C (O) Ph. 2. A pharmaceutical composition comprising an effective amount of the compound of claim 1 as an anticancer agent and a pharmaceutically acceptable carrier. 3. A method for suppressing cancer growth in a mammalian host, comprising administering to the mammal host an amount of the compound of claim 1 that suppresses cancer growth.