• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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  • 优先权
    • 专利摘要:
    Acyl derivatives of 2-aminobenzothiazole and alkylated analogs thereof as antitumor agents.
    公开号:SU1681728A3
    申请号:SU894614242
    申请日:1989-05-23
    公开日:1991-09-30
    发明作者:Франц Джозеф Флири Антон；Кохрен Шнур Родни
    申请人:Пфайзер Инк. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to methods for producing biologically active chemical compounds, namely, derivatives of M- (benzthiazolyl-2) amides of benzoic or thiazole-4-carboxylic acid, which have antitumor activity and can be
    used to treat various cancers in mammals.
    The purpose of the invention is to obtain new M- (benzthiazolyl-2) amides of carboxylic acids, which possess a new type of biological effect in this range of compounds.
    Example 1. Preparation of 4-guanidino M- (b-nitrobenzothiazol-2-yl) benzamide hydrochloride.
    To a stirred cold (-5 ° C) solution of 1.07 g of 4-guanidinobenzoic acid hydrochloride and 740 mg of 1-hydroxybenzotriazole in 8 ml of dimethylformamide, 1.12 g of dicyclohexylcarbodiimide are added in one portion. After 2 hours, 950 mg of b-nitro-2-aminobenzothiazole is added at 0 ° C and the reaction mixture is stirred at room temperature for 2 hours. The mixture is filtered and the filtrate is applied to 35 g of the ion exchange resin SS5E (form). The column is washed with water (200 ml) and a sufficient amount of methane until the washing liquid becomes colorless. After the second wash with water / methanol, the product is eluted from the column using a 0.05 M solution of hydrochloric acid in methanol. The fractions containing the product are combined, concentrated to dryness and recrystallized from methanol. T. pl. 311-329 ° C.
    Example 2 Preparation of 4-guanidino M- (6-nitrobenzothiazol-2-yl) benzamide hydrochloride.
    A solution of M-hydroxysuccinimide ester of 4-guanidine benzoic acid (44.51 g), 31, Zgb-nitro-2-aminobenzothiazole and 3.13 g of hydroquinone in 200 ml of M-methyl-2-pyrrolidone is stirred in a dark inert atmosphere at 175 ° C 90 min. The reaction mixture is cooled to room temperature, diluted with 300 ml of methanol and filtered. The filtrate is combined with 500 g of the CC50 ion exchange resin (Form H4) and the pH is adjusted to a neutral state by the addition of 10-20 ml of pyridine. The resins are washed several times with methanol, poured into a glass column and washed with methanol until the washes are colorless. The main product was eluted with a 0.01 M solution of hydrochloric acid in methanol. The fractions containing the product are combined and concentrated in vacuo until a precipitate forms. The product is filtered off, dehydrated and 22.5 g of a substance identical to that obtained in Example 1 are obtained.
    Example 3, Preparation of 4-guanidino M- (6-nitrobenzothiazol-2-yl) benzamide hydrochloride.
    A saturated solution of 25 g of 4-guanidine benzoic acid N-oxysuccinimide ester hydrochloride and 31.2 g of b-nitro-2-aminobenzothiazole in dimethylformamide is stirred at 120 ° C for 72 hours. The reaction mixture is cooled to room temperature, filtered and the solid is washed small.
    the amount of dimethyl sulfoxide and methanol.
    The original filtrate and washings were combined, concentrated in vacuo to 100 ml, and introduced into a column 55 mm in diameter, filled to 22 inches with CC50 ion exchange resin (form), filled in methanol. The column was eluted with methanol until the washing liquid became colorless. Then, a 0.01 M solution of the hydrochloride in methanol is used to elute the desired product. Neutral pH fractions are collected, concentrated under vacuum and recrystallized from methanol using a Soxhlet extractor. 5.2 g of product, identical to that obtained in Example 1, are obtained.
    Example 4. Starting from the corresponding 2-aminobenzothiazole and p-guanidinebenzoic acid ester and using the procedure of Example 2, the compounds shown in Table 2 are obtained. one.
    Example 5. Preparation of 4-guanidinomethyl-M- (6-nitrobenzothiazol-2-yl) benzamide of methanol sulfate.
    A solution of 7.0 g of M-oxysuccinimide ester of 4-guanidinomethylbenzoic acid, 5.5 g of b-nitro-2-aminobenzothiazole and 700 mg of hydroquinone in 60 ml of G 1-methyl-2-pyrrolidone is stirred at 180 ° C in the dark in inert atmosphere 40 min. The reaction mixture is cooled to room temperature, diluted with 400 ml of methanol and stirred for 30 minutes. The solid is filtered off, the filtrate is concentrated to 100 ml in vacuo and introduced into a column containing ion exchange resin CC50 (form H). The resin is washed with methanol until the washes are colorless. Then the column material was eluted with a 0.01 M solution of methasulfonic acid in methanol. The fractions containing the product were combined, concentrated in vacuo, and the residue recrystallized from methanol using a Soxhlet extractor. Obtain 1.8 g of substance with so pl. 300 ° C.
    Example 6. Using the procedure of Example 5 and starting from the corresponding starting materials, the compounds listed in Table 2 are obtained. 2,
    Example 7. Preparation of 3-guanidino-methyl-M- (b-phenylbenzothiazol-2-yl) benzamide hydrochloride.
    A suspension of 5 g of N-oxysuccinimide ester of 3-guanidino-methylbenzoic acid, 8.8 g of 2-amino-6-phenylbenzothiazole and 500 mg of hydroquinone in 15 ml of M-methyl-2-pyrrolidone is stirred at 130 ° C in the dark in inert At 6 hours, the reaction mixture is cooled, diluted with 200 ml of methanol, added to 250 mg of ion exchange resin CC50 (form H4) and the pH adjusted to 5 with pyridine. The resins are rinsed with methanol until the wash liquid becomes colorless. The desired product is eluted with 0.01N hydrochloric acid in methanol. The fractions containing the product are combined and concentrated under vacuum. The residue was recrystallized from methanol and 2.2 g of product were obtained with mp. 180 ° C.
    Similarly, 3-guanidinomethyl. -M- (6-nitrobenzothiazol-2-yl) benzamide hydrochloride, m.p., 295-300 ° C. with decomposition is obtained.
    Example 8. Preparation of 2-guanidino M- (5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide.
    Suspension of 42.86 g of 2-amino-5-fluoro-benzothiazole hydrochloride, 66.95 g of hydrochloride of 2-guanidinothiazole-4-carboxylic acid N-oxysuccinimide ester and 100 mg of hydroquinone in 300 ml of M-methyl-2-pyrrolidone heated under stirring in the dark in an inert atmosphere at 125 ° C for 6 h. The reaction mixture is cooled to room temperature and diluted with 500 ml of 5% aqueous sodium bicarbonate solution. The resulting precipitate is filtered, washed with water (3 x 500 ml) and dehydrated . The crude product is recrystallized twice from pyridine and get 22.5 g of substance with so pl. 290-291 ° C. .
    Similarly, 2-guanidino-M- (5-chloro-6-methylbenzothiazol-2-yl) thiazole-4-carboxamide, m.p. 286-287 ° C with decomposition.
    Example 9. Preparation of 2-guanidino-M- (5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide hydrochloride.
    The procedure of Example 8 is repeated using 4.08 g of 2-amino-5-fluorobenzothiazole hydrochloride, 6.37 g of 2-guanidino-thiazole-4-carboxylic acid N-hydroxysuccinimide ester hydrochloride and 10 mg of hydroquinone in 30 ml of 11-methyl -2-pyrrolidone. After cooling, the reaction mixture was diluted with 1.5 liters of ether, causing an oily precipitate to form. The ether is decanted and the residual oil is dissolved in 100 ml of dimethyl sulphoxide and 50 ml of methanol. The solution is added slowly to 2.5 L of ether with stirring. The precipitate is filtered off and dried and 6.7 g of product are obtained. The sample is cleaned by rubbing into powder with methanol, so pl. 279-280 ° C.
    Example 10. Preparation of 2-guanidino-M- (5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide sodium salt.
    A solution of 3.36 g of the product from example 8 in 35 ml of dimethyl sulfoxide is treated with 540 mg of sodium methoxide in 5 ml of methanol. After stirring for 10 minutes, the solution is diluted with diethyl ether until a precipitate begins. After stirring for 30 minutes, the solid is filtered off, washed with a small amount of water, then ethanol and diethyl ether, dried, and a substance is obtained with m.p. 260 to 262 ° C.
    The sodium salt of the product of Example 9 is similarly formed using two equivalents of sodium methoxide per 1 mole of hydrochloride.
    Example 11. Using the procedure of example 9 and proceeding from the appropriate source, get listed in table. 3 compounds as indicated acid addition salts.
    Example 12. Using the procedure of example 10 and starting from the corresponding starting materials, the sodium salts of the compounds listed in Table 4 are obtained.
    Example 13. Using the procedure of Primer 8 and starting from the corresponding starting materials, the compounds listed in Table 2 are synthesized. five.
    Example 14. Preparation of 2-guanidino M- (3-methyl-6-nitrobenzothiazol-2-yl) thiazole-4-carboxamide and 2-guanidino-M-methyl-M- (6-nitrobenzothiazol-2-yl) thiazole-4-carboxamide.
    To a solution of 2.0 g of 2-guanidino-M- (6-nitrobenzothiazol-2-yl) thiazole-4-carboxamide sodium salt in 20 ml of M-methyl-2-pyrrolidone was added 739 ml of methyl iodide. After stirring for 72 hours, the mixture was poured into 100 ml of diethyl ether and filtered.
    The solid is triturated with 75 ml of dimethyl sulfoxide to obtain 1.01 g of the first of these compounds, mp. 350 ° C with decomposition, the Powder is diluted with methanol, the product is precipitated with diethyl ether and 215 mg of isomer is obtained, which is the second of these compounds, t. square 272-274 ° C.
    Example 15. Preparation of 2- (aminoethyl-thio) -M- (6-phenylbenzothiazol-2-yl) thiazole-4-carboxamide hydrochloride.
    A. 2- {Tert-butoxycarbonylaminoethyl-thio) -M- (6-phenylbenzothiazol-2-yl) thiazole-4-carboxamide.
    A stirred suspension of 3.8 g of N- oxysuccinimide ester of 2- (tert-butoxycarbonylaminoethyl) thiazole-4-carboxylic acid, 2.36 g of 2-amino-6-phenylbenzothiazole, and 200 mg of 4-dimethylaminopioidine in 60 ml of ethyl acetate is heated to
    reflux 15 h. The reaction mixture is cooled and concentrated to 10 ml. The precipitated product is filtered and recrystallized from ethyl acetate. Obtain 2.04 g of the product, so pl. 171-173 ° C.
    Similarly, 2- (tert-butoxycarbonylaminoethylthio) -M- (5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide is obtained, m.p. 198-199 ° C, and 2- {tert-butoxycarbonylaminoethylthio) -M- (3-methyl-5-fluorobenzothiazol -2-yl) thiazole-4-carboxamide, m.p. 204-205 ° C.
    B. 2- (Aminoethylthio) -M- (6-phenylbenzothiazol-2-yl) thiazole-4-carboxamide hydrochloride.
    A suspension of 2.04 g of the product obtained in Example 15A in 8 ml of trifluoroacetic acid is stirred overnight at room temperature. The solvent is removed in vacuo and the residue is suspended in 300 ml of ethyl acetate. The suspension is washed successively with 5% sodium bicarbonate solution (3x100 ml), water (2x100 ml) and brine (100 ml). The organic layer is dried over sodium sulfate and concentrated to dryness. The residue is dissolved in a small amount of a 0.1N methanolic hydrochloric acid solution, the precipitated solid is filtered off and the solution is dried, and 840 mg of compound with a m.p. 266-267 ° C.
    Similarly, 2- (aminoethylthio) -1M- (5-fluorobenzothiol-2-yl) thiazole-4-carboxamide hydrochloride, m.p. 261-263 ° C with decomposition, and 2- (aminoethylthio) -Y- (3-methyl-5-fluorobenzothiazol-2-yl) thiazole-4-carboxamide hydrochloride, so pl. 267-277 ° C with decomposition.
    Example 16. Preparation of 2- (dimethylaminoethylamino) -M- (6-cyanobenzothiazol-2-yl) thiazole-4-carboxamide.
    2.19 g of 2-amino-b-cyanobenzothiazole was added to a suspension of 288 mg of oil-free sodium hydride in 20 ml of dry dimethylformamide. After stirring for 40 minutes, 1.52 g of ethyl 2- (dimethylaminoethylamino) thiazole-4-carboxylate is added to 3 ml of dry dimethylformamide and the reaction mixture is stirred for 24 hours. The reaction mixture is diluted with water (200 ml) and extracted with diethyl ether (3x250 ml). The aqueous layer was adjusted to pH 7 with 1N hydrochloric acid and the precipitated product was filtered. The solid is dissolved in 30% methanol / chloroform, dried over potassium carbonate and concentrated to dryness 2.56 g. The crude product is chromatographed on 300 g of silica gel using 5% methanol / chloroform.
    and 240 tubes. Tubes 148-240 are combined, concentrated, and 510 mg of the desired product is obtained with m.p. 201-203 ° C.
    Example 17. Preparation of 2- {dimethylaminoethylamino) -M- (6-phenylbenzothiazol-2-yl) thiazole-4-carboxamide.
    According to the procedure described in Example 16, 5.58 g of 2-amino-6-phenylbenzothiazole, 3.0 g of ethyl 2- (dimethylaminoethylamino) thiao sol-4-carboxylate and 592 mg of oil-free sodium hydride provide 2.89 g of the desired product after chromatography. This material was further purified by recrystallization from acetonitol, 2.22 g, m.p. 172-174 ° C.
    Example 18. Preparation of 2- {dimethyl-amino-ethylamino} -5-ethyl-M- (5,6-dichlorobenzothiazol-2-yl) thiazole-4-carboxamide.
    According to the procedure described in example 16,
    0 894 mg of 2-amino-5,6-dichlorobenzothiazole, 1.07 g of ethyl 2- (dimethylaminoethylamino) -5-ethyl thiazole-4-carboxylate and 108 mg of sodium hydride in 25 ml of dry tetrahydrofuran are refluxed for 16 h and are obtained after chromatography on silica gel 460 mg of the desired product with an mp. 199-201 ° C
    Example 19. Preparation of 2- {dimethyl-aminopropylamino) -5-ethyl-M- (5,6-dichlorobenzotisol-2-yl) thiazole-4-carboxamide.
    0 As in Example 18, 2-amino-5,6-dichlorobenzothiazole in the amount of 1.10 g, 1.43 g of ethyl 2- (dimethylaminopropylamino) -5-ethylthiazole-4-carboxylate and 144 mg of sodium hydride in 30 ml of dry furan tetrahydro5 provide 1.05 g of the target product with m. PL. 189-191 ° C.
    Example 20. Preparation of 2- {dimethyl-aminopropylamino) -5-ethyl-L- (6-cyanobenzothiazol-2-yl) thiazole-4-carboxamide.
    Analogously to example 16, sodium hydride in the amount of 673 mg 4.91 g of 2-amino-b-cyanobenzothiazole and 4.0 g of ethyl 2- (dimethylaminopropylamino) -5-ethyl thiazole-4-carboxylate in 65 ml of dry dimethylformamide After barely reacting at room temperature for 48 hours, 1.10 g of product with m.p. 159-161 ° C.
    Example 21. Preparation of 2- (piperidinoethylamino) -M- (6-cyanobenzothiazol-2-yl)
    0 thiazole-4-carboxamide.
    According to the procedure described in Example 16. 678 mg of sodium hydride, 4.95 g of 2-amino-b-cyanobenzothiazole and 4.0 g of ethyl 2- (piperidinoethylamino) thiazole-4-carboxylate in 65
    5 ml of dry dimethylformamide provide 2.0 g of product with m.p. 230-223 ° C.
    Example 22. Preparation of 2-aminomethyl-M- (6-n-butylbenzothiazol-2-yl) thiazole-4-carboxamide hydrobromide.
    A. (4-ethoxycarbonylthiazol-2-yl) benzamide.
    A solution of 19.02 g of benzoyl thiourea and 19.12 g of ethyl bromopyruvate in 300 ml of ethanol is heated to reflux for 2 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate (1 L) and 20% aqueous sodium carbonate (400 ml ). The organic layer is separated, washed successively with 20% aqueous sodium carbonate (3x400 ml), water (2x400 ml) and brine (2x400 ml) and dried over sodium sulfate. The solution is concentrated to about 50 ml, the precipitated solid is filtered off, dried, and 20.16 g of substance are obtained with a mp. 14b-147 ° C.
    B. 2-Aminoethylthiazole-4-carboxylic acid hydrochloride.
    The product from example 22A (19.16 g) is added to 25 ml of concentrated hydrochloric acid and heated at reflux for 2 hours. The reaction mixture is cooled, the product is filtered, dried and 11.8 g of product are obtained with m, pl. 281-282 ° C.
    B.2- (tert-butoxycarbonylaminomethyl) thiazole-4-carboxylic acid,
    In a cooled (10 ° C) solution of 2.5 g of the product from Example 22B in .25 ml of dioxane, 10 ml of 3N are added. an aqueous solution of sodium hydroxide and the solution is stirred .30 min at 10 ° C. Tert-butoxycarboxylic anhydride (3.27 g) is added to the reaction mixture, and the mixture is stirred for 6 hours. The mixture is heated to room temperature and the solvent is removed in vacuo. The residue is dissolved in 200 ml of water and then extracted with ethyl acetate (4x400 ml). The organic layer is discarded and the aqueous is acidified to pH 2 with citric acid. The aqueous layer was extracted with ethyl acetate (4 x 300 ml), the extracts were combined and extracted with water (2 x 100 ml) and brine (1 x 150 ml). Ethyl acetate is dried over sodium sulfate and concentrated to 25 ml. The product is filtered off, dehydrated and 2.9 g of product are obtained with a mp. 185 ° C.
    G. Succinimido-2- (tert-butoxycarbonylaminomethyl) thiazole-4-carboxylate.
    To a solution of 1.75 g of the product from Example 22B in 10 ml of tetrahydrofuran was added 940 mg of 11-hydroxysuccinimide and the solution was cooled to 10 ° C in an ice bath. Dicyclohexylcarbodiimide (1.67 g) is added to the reaction mixture, and then it is stirred for 16 hours under nitrogen. The solid is filtered off and the solvent is removed in vacuo. The residue is placed at 800
    ml of ethyl acetate and washed with 10% citric acid solution (3 x 150 ml), water (1 x 100 ml) and brine (1 x 100 ml). The organic phase is dried over sulfate.
    sodium and concentrate to 25 ml. The product is filtered, recrystallized from ethyl acetate, 2.12 g, so pl. 171 ° C.
    D. 2- (Tert-butoxycarbonylaminomethyl) -Y- (6-n-butylbenzothiazol-2-yl) thiazole 0 4-carboboxyamide.
    A mixture of 4.82 g of 2-amino-6-n-butylbenzothiazole, 7.1 g of the product from example 22G and 250 mg of 4-dimethylaminopyridine in 75 ml of ethyl acetate is heated at a temperature of 5 hours for 15 hours. The mixture is cooled to room temperature and diluted with 1 L of ethyl acetate. The organic solution is washed with 10% citric acid solution (3x200 ml), water (1 x 200 ml), saturated
    Sodium bicarbonate solution (3x200 ml), water (1x200 ml) and brine (1x200 ml). The organic phase is dried over sodium sulfate and concentrated to 30 ml. When cooled, a solid is formed, which is filtered, dehydrated
    and obtain 6.1 g of product, t, mp, 143-144 ° C.
    E, 2-Aminomethyl-L- (6-butylbenzothiazol2-yl) thiazole-4-carboxamide hydrobromide.
    A mixture of 3.5 g of product from example 23D
    0 in 50 ml of 23% hydrogen bromide in acetic acid is heated to reflux temperature for 10 minutes. After stirring at room temperature overnight, the reaction mixture is diluted with 25 ml.
    5 of acetic acid and filtered, the solid is recrystallized from methanol and receive 723 mg of product, so pl. 255-257 ° C with decomposition.
    The antitumor activity of the target compounds of the method according to the invention, as well as their acid additive salts or additive salts with alkali metals, is studied in experiments on mice. The best known ones are used as controls.
    5 anticancer drugs; 5-fluorouracil and cis-platin, The test results are given in table. 6 and 7.
    To obtain the data given in Table. 6, the tumor is induced on the left for 0 days of the paw of adult female BDF-1 mice by subcutaneous administration of 8x105 cells (Sog phase) in 0.05 ml of vehicle. In all experiments, the day of tumor implantation is used as a starting point in time. Tumor sizes are measured using Vernier caliber (orthogonal diameters), and its weight is calculated using standard formulas. The dosage regimen used for each of the drugs is chosen optimally for any of the drugs and control samples when administered orally or intraperitoneally.
    To obtain the data given in Table. 7, a lung tumor is induced in adult female mice by intravenous injection of infection into the tail vein of 6x105 cells (log phase) in 0.05 ml of PPM1-1640 as carrier).
    In all experiments, the day of tumor implantation is considered the starting point in time. The dosage regimen used for each of the drugs is selected optimally for any of the drugs of the control samples. The increase in survival time is the ratio of the average survival time (for a group of animals treated) to the average survival time (UHV) for control groups of animals multiplied by 100% minus 100%.
    It is established that UHV for perceiving control animals is in the range of 16-20 days, mainly 17 days.
    The compounds of the invention may be administered as anti-tumor agents either orally or parenterally: orally in doses of 6-400 mg per kg of body weight per day, 1-200 mg per kg of body weight per day when administered parenterally, depending on the condition of the patient and specifically administered compound. These compounds can be administered in combination with pharmaceutically acceptable carriers in single and multiple doses.
    Thus, the compounds obtained by the proposed method are promising for the creation of antitumor preparations with low toxicity.
    权利要求:
    Claims (3)
    [1]
    Claims 1. Method for producing N- (benzthiazolyl-2) derivatives of benzoic or thiazole-4-carboxylic acid amides of general formula I
    fluorophenyl, cyano or hydroxy-Ci-Cs-alkyl;
    Y is hydrogen, methyl, methoxy, fluorine or chlorine;
    W is hydrogen or methoxy;
    or X and Y, together with the adjacent carbon atoms of the benzene ring to which they are attached, form another benzene ring;
    M - a group of general formula
    15
    -Sh-S-1Sh2
    II L NH
    where n 0 and the substituent is attached at position 4 of the phenyl radical or n 1 and the substituent is attached at position 3 or 4 of the phenyl radical, or M is a group of the general formula
    -N B, S R
    P
    where R2 is hydrogen or Ci-C3-alkyl;
    Рз - guanidino radical or radical of general formula
    -Q-iCH pK
    /
    R
    where Q is a simple chemical bond, -S- or -NH-;
    p - 1-3 is an integer; R4 and RS are hydrogen or Ci-Cz-alkyl or R4 and RS together with the nitrogen to which they are bound form a piperidine ring; characterized in that the acid derivative of general formula II
    UNPF
    where M has the indicated meanings, provided that in the case of the presence of a free amino group, it is in a protected form, it is reacted with 2-aminobenzothiazole of the general formula III
    S N-C-M
    where RI is hydrogen or methyl;
    X is hydrogen, Ci-Cs-alkyl, Ci-Cs-alkoxy, Ci-Cs-alkylthio; Ci-Cs-alkylsulfinyl, Ci-Cs-alkylsulfonyl, fluorine, chlorine, bromine, nitro, trifluoromethyl, carbamoyl, M, M-di (C1-Cz-alkyl) carbamoyl, phenyl,
    where X, Y and W have the indicated values, or with its salt with an alkali metal in a solvent inert under the reaction conditions until the reaction is complete, followed, if necessary, by removing the amino-protecting group and / or the resulting product, where RI is hydrogen. if necessary, subjected to methylation to obtain the target product, where RI is methyl.
    [2]
    2. A method according to claim 1, characterized in that its N-oxysuccinimidyl ester is derived as an acid derivative of the general formula II and dimethylformamide or L-methyl-2-pyrrolidone is used as the solvent inert under the reaction conditions.
    [3]
    3. The method according to claim 1, characterized in that, as a derivative of an acid of the general formula II, its lower alkyl ester, 2-aminobenzthiazole is taken, taken as its sodium salt, and the solvent inert under the reaction conditions methylformamide or acetonitrile.
    15168172816
    table 2
    go ™
    A. L with H CH-RTS-TCH BUT
    one
    6-CF, 6-Я04 4-СН, О 6-С1
    n
    6-F
    "-CHjO
    6-CH
    4-CH,
    4-CFj r
    6-CjHj.
    5-CHjS
    6-HOf
    5-CHjO
    6-C, Ng
    6-CH, (CH2
    A-SK,
    5-СЯ3
    5-KOi
    “- (
    -CB, S
    6-CN
    5-C6Hs
    5-CH, (CHt
    5- (CH,), C
    7-C "Hs
    6-CH, (CBz
    6-HO (CH.j)
    4-CH,
    4-CH,
    6,7-CH-CH
    6-p-FCsH4
    4-CH,
    6-CHj
    7-NOz
    5-Ct "fO
    4-CH3
    6- (CH,) 3C
    a 3
    acid
    Continuation of table 3
    yr
    Continued table. 3
    Optimized growth inhibition of subcutaneous adenocarcinoma Colon-38
    Table
    Optimized improvement in survival of Lewis-3 lung adenocarcinoma mice
    Connection example
    Dosage mg / kg / day
    9200 oral
    925 inb
    11 (Compound 43) 12.5 Int.
    11 (compound 39) 50 intramir.
    latin
    50 intrab 200 oral 50 intrab 200 oral
    200 oral .Ј 10 internal
    Table 6
    Increased survival time, X
    50.3 53.8 68.6 62.0 65.0 43.0 53.0 65.0 43.0 11, TG
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    同族专利:
    公开号 | 公开日
    ES2043012T3|1993-12-16|
    FI892498A0|1989-05-23|
    HUT51606A|1990-05-28|
    MX16158A|1993-06-01|
    CN1023700C|1994-02-09|
    PT90622B|1994-10-31|
    PL154875B1|1991-09-30|
    NZ229234A|1990-09-26|
    KR890017248A|1989-12-15|
    HU202507B|1991-03-28|
    NO172389C|1993-07-14|
    EP0343893B1|1992-08-05|
    NO892059L|1989-11-27|
    NO172389B|1993-04-05|
    DK249389A|1989-11-27|
    EP0343893A1|1989-11-29|
    DD283815A5|1990-10-24|
    GR3005844T3|1993-06-07|
    CN1037898A|1989-12-13|
    FI892498A|1989-11-25|
    IE891667L|1989-11-24|
    AU3509889A|1989-11-30|
    NO892059D0|1989-05-23|
    DK249389D0|1989-05-23|
    PL279613A1|1989-11-27|
    ZA893862B|1991-01-30|
    YU105989A|1990-08-31|
    AU601905B2|1990-09-20|
    YU47019B|1994-11-15|
    JPH0217181A|1990-01-22|
    DE68902358D1|1992-09-10|
    IL90337D0|1989-12-15|
    MY106035A|1995-03-31|
    DE68902358T2|1992-12-10|
    PT90622A|1989-11-30|
    KR910006864B1|1991-09-09|
    AT79114T|1992-08-15|
    CA1328871C|1994-04-26|
    JPH0678331B2|1994-10-05|
    MX173140B|1994-02-02|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US19803488A| true| 1988-05-24|1988-05-24|
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