Method of obtaining derivatives of vinblastin or their epimers

专利摘要:
The method of obtaining vinblastine derivatives of the general formula: R R3 OR sh.o OR where R is a methoxy group; R is acetyl; R-oC-ethyl, or -ethyl; I - -oxy group, or a hydrogen atom; R is a linear C-St-alkyl, or isopropyl, isobutyl, cyclohexyl, allyl, benzyl, or their epimers, characterized in that the compound of the general formula "OR CH 2 O (CO.CO 00 OR with where R, R2,; R3 and R have the indicated values, and R has any of the values of SAE R, in addition, which is desirable for the final product, is subjected to a 30-50-fold excess of alcohol of the general formula ROH, where R is the specified values, at pH 3, then set for the reaction mixture The pH 7 and the obtained product or its epimers are purified, followed by purification if desired.
公开号:SU1138033A3
申请号:SU813320102
申请日:1981-08-17
公开日:1985-01-30
发明作者:Данчи Лайош；Кеве Тибор；Фекете Дьердь；Дежери Эстер；Герег Шандор；Ач. Тибор；Сантаи Чаба；Сабо Лайош；Хонти Каталин；Экхардт Шандор；Хинди Иван；Керпель-Фрониуш Шандор；Релле Жужанна；Шугар Янош
申请人:Рихтер Гедеон Ведьесети Дьяр Рт (Инопредприятие)；
IPC主号:

专利说明:

1 The invention relates to a process for the preparation of novel chemical compounds that are α-vinblas-derivatives, namely compounds of the general formula. R3 (1) H СООСНз where R is a methoxy group; R is acetyl; R3 is ethyl or ethyl; R is an I -oxy group or a hydrogen atom; R is a linear C, —C —Appsch1, or isopropyl, isobutyl, hexyl, allyl, benzyl cycle, or their epimers, which possess cytostatic activity. A natural alkaloid is known: blastin wines, which are obtained by treating a water-alcohol solution of Vinca rosea plant raw material - an acid with subsequent extraction of vinblastine by extraction and chromatography. A method of cleaving an ether linkage under the influence of acidic agents, for example, anhydrogen or chlorohydride 2) acid is known. The purpose of the invention is to obtain new vinblastine derivatives exhibiting cytostatic action. The objective is achieved in that, according to the method for producing iinblastin compounds, the compound of the general form is -S W I V OR2 "HDCORI 32 where R, R, R and R have the indicated meanings; R has any of the values of R, in addition, which is desirable for the final product, is reacted with 30 to 50-fold excess of the general formula alcohol where R is isopropyl or isobutyl, at pH 3, then the pH of the reaction mixture is adjusted to 7 and the resulting product or its zimers isolated followed by, if desired, purification. Example 1. N-Desmethyl-L- (methoxymethyl) -vinblastin. 1.0 g (1.1 mmol) of vinblastine sulfate is dissolved in a mixture of 240 ml of absolute dichloromethane-free alcohol, 8.0 ml of methanol and 25 ml of glacial acetic acid and the resulting solution is cooled to -55 ° C. A solution of 0. 0. 5 g (5.0 mmol) of chromium trioxide in 40 ml of acetic anhydride is added to a solution of vinblastine for 5 minutes in a stream of dry nitrogen with vigorous stirring. At the same time it is necessary to ensure that the temperature of the mixture does not rise above -55 ° C. The course of the oxidation is monitored by thin layer chromatography (adsorbent: aluminum foil for thin layer chromatography — silica gel 60 F254 Art. 5554; mobile phase: a mixture of diethyl ether, ethanol, benzene and distilamine in a ratio of 10: 0.5: 0.5: 0.5 ). The oxidation generally ends after 2030 minutes. After completion of the reaction, while cooling, 190 ml of a concentrated aqueous ammonia solution and 200 g of ice are added to the reaction mixture. The temperature of the mixture rises to O-10 ° C. After that, the cooling is stopped and the mixture is vigorously stirred, the pH of which is 8.5–9, for 10 minutes. The phases are separated and the extraction is carried out three times with 30 ml of dichloromethane. The extracts were washed four times with 25 ml of a diluted 1: 1 solution of ammonia and then twice with 30 ml of water, dried over magnesium sulfate, filtered, and the filtrate was evaporated in vacuo. The result is 0.85 g of crude product, 0.3 g of which is subjected to column chromatography
ke, filled with alumina activity P-III, using dichloromethane as eluent. 6 ml fractions were collected and analyzed by thin layer chromatography (adsorbent: aluminum foil for thin layer chromatography — silica gel Art. 5554; mobile phase: a mixture of dichloromethane and methanol in a ratio of 5: 0.4; iodine vapor or UV light with wavelength 254 nm).
The fractions containing the same and the same alkaloid are combined and separately evaporated. The target compound is contained in fractions 6-25. The result is H-desmethyl-H- (methoxymethyl) -vinblast (64% chromatographic purity), melting at 205-2 ° C (ethanol). K1 +23 (, chloroform).
Mass spectrometry t / e: 840 (M 100%), 810, 809, 781, 751, 681, 651, 650, 601, 499, 355, 282, 243, 241, 154, 149.
Example 2. S-Desmuetch1-N- (isobutoxymethyl) -vinblastin.
0.5 g (0.55 mmol) of vinblastine sulfate is dissolved in a mixture of 120 ml of absolute dichloromethane, 3.7 ml of isobutanol and 12.5 ml of glacial acetic acid and the resulting solution is cooled to -55 ° C. To this solution: a solution of 0.25 g (0.5 mmol) of chromium trioxide in 40 ml of acetic anhydride, cooled to -55 ° C, is added. The reaction is monitored by thin layer chromatography (adsorbent: polymer film for thin layer chromatography — silica gel 60 F, Art. 5735, mobile phase: mixture of ether, ethanol, benzene and diethylamine in a ratio of 10: 0.5:: 0.5: 0 , 5) as described in example 1. The reaction ends after 140 minutes. The reaction mixture is treated further as described in example 1. 0.65 g of crude product is obtained, which is purified by chromatography on a column of silica gel 60 (Art. 9385) using dichloro ethane as solvent. Elution is carried out using dichloromethane. Collect fractions of 10 ml. In the first I330 ml of eluate there is no alkaloids and yes; Next, the elution continue to di
80334
chloromethane containing 3% methanol. The first 90 ml of the eluate obtained contains the desired compound, which is distilled off by distilling off the solvent. Yield 169 mg (35% of the theoretical yield) .i - IR (KBg): 3400 (NH, OH), 1730 (COjCH), 1605, 1220 (OAc). Mass spectrometry t / e: (M,
10 100%), 864, 851, 823, 810, 779, 751, 723, 651, 650, 514, 355, 346, 329, 154.
Example 3. L-Desmetsh1-H- (heptoxymethl) -vinblastin.
15 The process is carried out in the same manner as described in Example 2, nor is used as a reagent. 3.7 ml of 1-heptanol. The reaction lasts about 90 minutes. AT
20 By processing the reaction mixture, about 4 g of crude product is obtained, which is dissolved in 30 ml of dichloromethane and introduced into a column filled with silica gel 60. (Art.
5,9385). Elution is carried out with dichloromethane. Collect fractions of 10 ml. In the first 300 ml there is no alkaloid. Further, the elution is continued with dichlorome 3Q tane containing 3% methanol. AT
The first 120 ml of eluate obtained contains the desired product. Yield 21% of theoretical yield, so pl. 200-205 ° C (a mixture of acetone and ether). IR (KVg): 3450 (OH, N11), 1740
-one,
(CO.CH-), 1610, 1220 cm (OAc).
l j -
T / e mass spectrometry: (M, 100%), 906, 893, 865, 822, 810, 765, 751, 737, 651, 650, 649, 469, p 455, 355, 282, 154, 135, 122 .
Example 4. N-desmetip-N- (benzyloxymethyl) -vinblastin. Work in the same way as
5 is described in Example 2, with the difference that 4.3 ml of benzyl alcohol is used instead of isobutanol. The reaction is complete after 45 minutes. The result is 4 ml of raw
0 product as an oily liquid, which is obtained by preparative paper chromatography (adsorbent: silica gel mobile phase: a mixture of 100 ml of dichloromethane
5 and 8 ml of methanol). Output 75 mg (15% of theoretical yield), so pl. 215-218C (mixture of methylene chloride and ether).
S11
IR (KBr): 3400 (OH, NH), 1740 (CGjCHj), 1610, 1230 (OAc).
Mass spectrometry m / e; (M, 100%), 885, 857, 822, 810, 796, 799, 757, 751, 737, 651, 650, 649, 514, 355, 346, 329, 282, 154, 135.
Example 5. N-fle3MeTHn-N- (Metoxymethyl) -vinblastin.
5 g {5.5 mmol) vinblastine sulfate is dissolved in 150 ml of water. Vinblastine base was isolated in free form by adding to the solution a concentrated solution of ammonia (pH 8) and extraction was carried out four times with 50 ml of dichloromethane. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The result is 4 g of vinblastine base, which is dissolved in a mixture of 1000 ml of dichloromethane-free alcohol, 120 ml of acetic acid and 6 ml of methanol and the solution is cooled to. A solution of 2.5 g (25 mmol) of chromium trioxide in 470 ml of acetic anhydride, cooled to -55 ° C, is added to the resulting solution over about 5 minutes. The reaction mixture is stirred for 45 minutes at -55 ° C and then poured into a mixture of 940 ml of concentrated ammonia solution and 940 ml of ice water. At the same time it is necessary to ensure that the temperature does not rise above 30 ° C. The phases are then separated and the organic phase is shaken in a separatory funnel with 1 L of 1% ammonia solution. The organic phase is separated, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The resulting 3.8 g of crude product is purified by column chromatography. The column is filled with 230 g of alumina N-activity (Brockmann), which is moistened with benzene. The crude product is dissolved in 20 ml of a mixture of benzene and chloroform, taken in a ratio of 8: 2, and the resulting solution is added to the column. The elution is carried out with the same mixture (about (8 l). Collect fractions of 100 ml. The fractions containing the same substance are combined and evaporated (adsorbent: silica gel, mobile phase: a mixture of benzene, ethanol, diethylamine and diethyl ether in a ratio of 5 : 5: 5: 100). In result 36
Tata receive 2.1 g of the product. After recrystallization from 6 ml of ethanol, 1.5 g of purified product are obtained with the same physical constants as the product obtained by the method in accordance with Example 1.
Example 6. K-Desmethyl-N- (propoxymethyl) -vinblastin.
The operation is carried out in the same manner as described in Example 5, but instead of methanol, 4.5 ml of propanol is replaced. The result is 0.6 g of the title compound, melting at 200210 ° C, () 31.2 ° (c 1, chloroform).
Example 7. N-Desmethyl-N-, - (methoxymethyl) -vinblastin.
The operation is carried out in the same manner as described in Example 1, but vinblast dihydrochloride is used as the starting compound instead of vinblastine sulfate. The yield of the obtained product 28% of theoretical. Its physical constants are the same as the product obtained by the method in accordance with example 1.
Example 8. K-Desmethyl-N- (metroxymethyl) -vinblast,
Work in the same way as described in example 1, but instead of dichloromethane, chloroform, dichloroethane or
acetone. Output 40-50% of theoretical (depending on the nature of the solvent used). The physical characteristics of the obtained product are the same as the product obtained by the method in accordance with example 1.
Example 9. N-Desmethyl-N- (methoxymethyl) -20-deoxy-leurozidine.
60 mg (0.067 mmol) of 20-deoxy-leurozidine sulfate (obtained by catalytic hydrogenation of 3, 4-anhydrovinblastin in methanol in the presence of palladium on
coal as a catalyst and the subsequent preparation of sulphate) is dissolved in a mixture of 20 ml of absolute dichloromethane, 1.5 ml of glacial acetic acid and 0.5 ml of methanol. The solution is cooled to -55 ° C and mixed with a solution of 30 mg (0.3 Ymol) of chromium trioxide in 3.5 ml of acetic anhydride cooled to -55 ° C. The reaction was protected for 60 minutes, after which the reaction mixture was poured into a mixture of 12 ml of concentrated ammonia solution and 12 g of ice. After separation of the phases, the aqueous phase is shaken three times in a separatory funnel with 10 m of dichloromethane. The combined organic phases are washed twice with 10 ml of a diluted 1: 1 ammonia solution and then twice with water in 5 ml portions. After drying, the organic phase is evaporated. This gives 48 mg of the crude product, which is purified by column chromatography (silica gel adsorbent with a particle size of 0.0400,063 mm from Merck, Art. 9385, eluent: dichloromethane and then dichloromethane containing 3% methanol). The result is 18 mg (32% of theoretical yield) of the product, which is melted with decomposition at iBS-igo-c. (.) jj + 50 ° (c 1, chloroform). IR (KBr): 3400 (NH), 1720 (C02CH 1610, 1230 (AOc). 46 mg (22% of the theoretical yield of desmethyl-K-formyl-20-deoxy-L-lerozidine, mp 205-210 ° C (with decomposition), (") j5 + 54 ° (s 1, chloroform). Example 10. S-Desmethyl-K- (isobutyloxymethane 1) -vinblastin. 0.80 g obtained by the method according to Example 1, a crude product containing 65% N-desmethyl -H- (methoxymetch1) vinblastine is dissolved in a mixture of 50 ml of anhydrous dichloromethane and 2.4 ml (25 mmol) of zbutanol. The solution is cooled to 0 ° C and added to it with stirring anhydrous hydrochloric acid solution in ether until pH = 3 is reached. The reaction is monitored by thin-layer chromatography (adsorbent: aluminum; 1V foil for thin-layer chromate: decanter-silica gel 60 Fj; Art. 5554; mobile phase: ether mixture , ethanol, benzene and diethylamine in a ratio of 10: 0.5: 0.5: 0.5). After the end of the reaction, the mixture is poured into 2 ml of concentrated ammonia, the phases are separated and the aqueous phase is extracted three times with dichloromethane, a portion 5 ml each, Volume 3 of the diluted extracts are washed three times 3 ml of water, dried over magnesium sulfate, filtered and evaporated. The resulting 1.7 g of the product was dissolved in 25 ml of dichloromethane and chromatographed on silica gel 60, Art. 9385). Elution was carried out with 120 ml of dichloromethane, and then with mixtures of methanol and dihpormethane with a methanol content of 1.2 and 4%. No alkaloid is contained in the first 290 ml of eluate. The next 300 ml of eluate contains N-desmethyl-H- (isobutoxymethyl) -vinblastin. The result is 416 mg of the product with the same physical characteristics as the product obtained by the method in accordance with example 2. Example 11, K-desmethyl-K- (heptoxymethyl) -vinblastin. Work in the same manner as described in example 10, with the difference that instead of isobutanol use 2.5 ml (17 mmol) of 1-heptanol. The reaction is controlled using thin layer chromatography, and a polymer film for thin layer chromatography coated with 60 Fog silica gel (Aft. 5735) is used as an adsorbent. The resulting crude product was purified by column chromatography as described in Example 10. The first 310 ml of eluate did not contain an alkaloid. The following 200 ml contain H-desmethyl-L- (heptoxymethyl) -vinblastin. Exit 350 mg. The physical characteristics of the obtained product are the same as those of the product obtained by the method in accordance with d by example 3. Example 12, H-Desmethyl-L- (benzyloxymethyl) -vinblastin. The operation is carried out in the same manner as described in Example 10, with the difference that 3.0 ml (.27 mmol) of benzyl alcohol is used as the starting reagent. The resulting crude product is purified by the method described in Example 10. No alkaloid is contained in the first 350 ml of eluate. The desired product is contained in the following 300 ml of eluate. Exit 320 mg. The physical characteristics of the obtained compound are the same as those obtained by the method in accordance with Example 4.
Example 13. L-Desmethyl-N- (isobutoxymethyl) -vinblastin.
O, 1 g of the crude product obtained by the method in accordance with Example 1, containing 65% S-desmethyl-S- (methoxymech1) -vinblastin, is dissolved in a mixture of 15 ml of dichloromethane and 30-50 mol of equivalents of isobutanol. Anhydrous solution of hydrochloric acid in ether is added to the solution at 0 ° C with stirring to pH 3. After completion of the reaction, the mixture is neutralized with potassium carbonate to pH 7, the precipitated salt is filtered, and the filtrate is evaporated, if necessary in vacuum, with using column chromatography as described in method 10. The result is the target product with 53% yield, the physical characteristics of which are the same as that of the product obtained by the method in accordance with example 2.
Using the appropriate starting materials, L-desmethyl-L- (isopropoxymetch1) -vinblastin is obtained in the same way. Output 35% of theoretical, so pl. 172-182С (with decomposition).
IR (KBr): 3400 (OH, NH), 1730 (COjCHj), 1610, 1220 cmHLOs). 1H-NMR (C DClj) 100 MHz: c 8, .1 (S, 1H, NH), 7.51 (t, 1H, C, jH), 7.2-7.03 (m, 3N, Cd, - C, -H), 6.70 (S, 1H, C9-H), 6.35 (S, 1H.) 5.85 (dd, 1H,). 5.38 (S, 1H, C „-H), 5.30 (d, 1H, C, 5-H), 4.75, 4.15 (2H, Hz, Na-CHj-O-), 4 , 0 OS, W,), 2.1 (S, ЗН, OCOCHj), 60 (12H, CH -groups
N-fle3MeTmT-N- (alyloxymethyl) -.-Vinblastine (yield 55% of theoretical), so pl. 205-210 ° С (with decomposition).
IR (KBr): 3300 (OH. NH), 1730 (COjCHj), 1610, cm (AOc).
N-De to serpentyl-N- (cyclohexylmethyl) -vinblastin.
Output 36% of theoretical, so pl. 175-180 ° C (with decomposition).
IR (KBr): 3400 (OH, NH), 1730 (COjCHj), 1610, 1230 cm (OAc).
Example 14. N-Desmethyl-N- (methoxymett) -vinblastin.
0.15 g (0.17 mmol) of N-desmethyl-N- (isobutoxymethyl) -vinblastine, prepared according to the method
with Example 2, dissolved in a mixture of 30 ml of dichloromethane and 1.5 ml of methanol. The solution is cooled to 0 ° C and its pH is set to 3 with an anhydrous solution of hydrochloric acid in ether. The reaction is controlled by thin layer chromatography (adsorbent silica gel 60, mobile phase: ether mixture,
About ethanol, diztile ether and benzene (20: 1: 1: 1). After completion of the reaction, the reaction mixture is neutralized with solid potassium carbonate, the solution is filtered and the filtrate
5 evaporated d vacuum. Output 14, the Physical characteristics of the obtained product are the same as the product obtained by the method in accordance with example 1.
0Example15. N-Desmethyl-N- (ethoxymethyl) -vinblastin.
Chilled to 0 ° C, a solution of 50 mg of N-desmetsh1-N- (alyloxymethyl) -vinblastin in 10 ml of anhydrous dichloro-
5 methane and 0.3 ml of ethanol are acidified with anhydrous hydrochloric acid in ether to pH 3. After 5 minutes, the solution is neutralized with solid potassium carbonate. Salt precipitate
0 filtered and the filtrate evaporated. The result is 46 mg of N-desmetsloksi-N- (ethoxymethyl) vinblastine, so pl. 235-238 ° C. (с6) + 30.5 ° (с 1, chloroform).
Example 16. N-Desmethyl-N- (propoxymethyl) -vinblastin.
To a solution of 100 mg of H-desmethyl-K- (heptoxymethyl) -vinblastin in 20 ml of anhydrous benzene is added
0 1 ml n-propyl alcohol. The solution is acidified with anhydrous hydrochloric acid in ether to pH 3 and after 5-10 minutes neutralized with solid potassium carbonate. After evaporation of the filtrate, 90 mg of N-desmethyl-N- (propoxymethyl) -vinblastin are obtained. The physical characteristics of the obtained compound are the same as for the product obtained by the method
0 in accordance with example 6.
The reaction also proceeds completely if diethyl ether, dioxane, acetone-OR ethyl acetate is used as a solvent.
-5 Example 17., H-Desmethyl-K- (allyloxymethyl) -vinblastin.
50. MG N-desmethyl-N- (methacimethyl) -vinblastin is dissolved in a mixture of 10 ml of anhydrous dichloromethane and 0.5 ml of allyl alcohol. The solution, cooled to 0 ° C, is acidified with anhydrous 50% ethereal boron trifluoride etherate solution to pH 3. After 5 minutes, the solution is neutralized with potassium carbonate, the salt precipitates are filtered out, and the filtrate is evaporated. As a result, 40 mg of N-desmetip-N- is obtained. (allyloxymethyl) -vinblastine with the same physical characteristics as the product obtained by the method according to example 13. The compounds of the general formula (1) are cytostatic. They are less poisonous than known compounds. The acute toxicity of the compounds was tested on male Swiss mice. Each group of experimental animals consisted of 6 smaller weights of 27-31 g. Of the tested compounds, physiological solution of sodium chloride was prepared for injection solutions, in which Tween 80 pots were added to the mash at the urine. The resulting solutions were administered intraperitoneally to the animals in doses from non-fatal outcome before causing 100% mortality. Below are the results of tests evaluated by the method of Lichfield and Wilcoxon (for comparison, the data obtained using the known compounds, vinblastine, vindecine and vincristine are also given)
(methoxymethyl1-vinblastine
(ethoxymetsh1) -vinblaskhin
(propoximet1) -vinblast
(isobutoxymethyl) -vinblast
(heptoximetsh1) -vinblast
(allyloxymethyl) -vinblast
(benzsh10ximethyl) -vinblast
(Cyclohexyloxymethyl) -vin. A side paralyzing effect is observed.
The proposed compounds are 15–25 times less toxic than vincristine and vindecine and 8–13 times less toxic.
us than vinblastine. Unlike vincristine and vindecine, in the case of the proposed compounds, up to
 no average lethal dose, no side paralyzing effects are observed.
The cytostatic activity of the proposed compounds was tested for tissue-100
-110
- 80
 60
- 60
45
70
 60 4.2 7.6 4.0
nevy cultures in various transplatirovanny tumors.
Test compounds were dissolved in cell cultures (Hela culture) in amounts from a threshold dose of µg / ml to an upper limit of 100 µg / ml. After 24 h, in vivo cultures were examined under a microscope. At the same time, the following results were obtained (taking into account the cells fixed in metaphase). Experiments were conducted under similar conditions with stained cell cultures, which made it possible to record more accurate differences. At the same time, the detected action can be divided into 5 stages. The first stage characterizes the dose of the minimal effect that increases the number of blocked mitosis. Some of these mitosis, for example, triple mitosis, degenerate or at their poles there are several separated chromosomes, anaphases in most cases disappear. At the second stage, there is a strong blocking of metaphases and normal mitosis is practically absent. The chromosomes are located in a looser tangle. The proportion of cells in the interphase is insignificant. In the third stage, the chromosomes are clustered (coalesced) as a dense mass in the center of the cell. This condition can be characterized as pycnimito or sharo, va metaphase. In the fourth stage, the effect of the compounds on the cells in the interphase is manifested in the fact that there are already a relatively small number of blocked cells, since they are no longer able to enter mitosis. The cytoplasm of cells in the interphase expands, its margins become vague, fucked, the cells often take on an elongated, fibroblastic form. At the fifth stage, the cytoplasm is filled with a finely contoured structure, and the cells in the interphase clearly die as a result of the treatment. These five stages can be easily distinguished from each other. The most active are heptoxy and allyloxy derivatives. Already at a dose of 0.001 µg / ml, these compounds cause a strong blocking of metaphase, picnimitosis appears at a dose of 0.1 µg / ml, and the effect on the cells / that are in the interphase appears at a dose of 1-10 µg / ml. The action of the isobutoxy and cyclohexyloxy derivatives is an order of magnitude lower: with a minimum dose of 0.001 µg / ml, normal mitoses still occur. The benzyloxy derivative has the lowest activity. At the minimum dose, it has a weak blocking effect, there is still some amount of generated mitosis, but there are no anaphases, however. At a dose of 0.01 µg / ml, moderate blocking; strong blocking and pycnomitosis appear only at a dose of 1 µg / ml. The effect of the proposed compounds on intraperitoneally transplanted tumors (leukemia P 388 and Ascites Lymphoma W / Ly). Leukemi P 388 was maintained in mice (BDF-hybrids). Each of the experiments was performed on 6 animals, which were intraperitoneally transplanted with 10 tumor cells. The treatment was started 24 hours after transplantation, for which the animals were administered intrabraniline compounds daily. The weight and condition of the experimental animals was monitored daily. The life expectancy of the treated patients was increased in
percent of life span of control animals.
The results are shown in Table. one.
From the data table. 1, it can be seen that the proposed compounds make it possible to significantly prolong the life of mice affected by leukemia.
Similar experiments were carried out using H-desmatyl-H- (methoxymethyl) -20-deoxy-leurozidine. In addition to the dosage, the duration of treatment also varied (see Table 2).
Experimental mice (Swiss-H / Riop, unrelated breeding) were transplanted intraperitoneally 5x10 ascites tumor cells. Each of the experiments was performed on 10 mice. Treatment was started 24 hours after transplantation. Test compounds vovO-Desmethyl-K- (heptoxymethyl) -vinblastin
N-Desmethyl-Y- (benzyloxymethyl) -vinblastin
K-Desmethyl-N- (isobutoxymethyl) -vinblastine
K-Desmethyl-Y- (methoxymetsh1) -vinblastine
Dili daily for 5 days. The average life span of the smaller of the control group was 15.7 days. The effectiveness of the compounds is manifested in an increase in the lifespan of the experimental animals, which follows from Table. 3
The proposed compounds are; development of tumor
strains R 388 and W / Ly doses
4–8 mg / kg. At the same time, their inhibitory effect is the same as in the case of the known diindole alkaloids. The proposed compounds, however, are significantly less toxic than the known analogous structures.
In the treatment of humans, the proposed compounds should be administered as intravenous injections or infusions.
,Table 1
122
12.7
10.3 178 10.5 18.7 155 16.8 171 19.0
11.1 17.7 163 182
10.5 19.2 172 10.9 205 20.2
17
N-Desmethyl-H- (propoxymethyl) With this prdibali
Y-Desmethyl-Y- (methoxymetsh1) -20-leurozidin
1138033
18 Continued table. 1 concentration of the compound had a toxic effect: and animals not infected with a tumor. Table 2
N-desmethyl-y- (heptoxnmethyl) -vinblastine, 5x6,0, intraperitoneally
N-Dés fetil-N- (isoboxymethyl) -vinblastin, 5x4.0
N-Desmethyl-H- (allyloxymethyl) -vinblastin, 5x4.0
N-Desmethyl-N- (cyclohexyloxymethyl) -vinblastine, 5x4.0
Table j
3/10 7/10 6/10 3/10

权利要求:
Claims (1)
[1]
A method of obtaining vinblastine derivatives of the general formula where R * is a methoxy group;
R ² is acetyl;
R ^{3 is} ° C-ethyl, or ft-ethyl;
R is an oxy group or atom ₍₁ hydrogen;
R ¹ is linear C _x -C ₇ -alkyl, or isopropyl, isobutyl, cyclohexyl, allyl, benzyl, or their epimers, characterized in that the compound of the general formations R *, except that which is desired
specifically for the final product, they are reacted with a 30-50-fold excess of alcohol of the general formula
R * OH where R * has the indicated values, at pH 3, then the pH of the reaction mixture is adjusted to pH 7 and the resulting product or its epimers are integrated, followed by purification if desired.

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SU1053757A3|1983-11-07|Process for preparing vinblastine derivatives

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US4279915A|1981-07-21|Method of treatment using new leurosine derivatives

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Umarov et al.1970|Alkaloids ofThalictrum flavum

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EP0207336B1|1991-01-02|Nitro derivatives of vinblastine-type bis-indoles, a process for preparing same and pharmaceutical compositions containing them

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Brown et al.1959|426. Experiments towards the synthesis of corrins. Part V. Base-catalysed aldol-type reactions of Δ 1-pyrroline 1-oxides

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EP0205168B1|1990-12-12|Furfuryl derivatives of vinblastine-type bis-indoles, a process for preparing same and pharmaceutical compositions containing them

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KR860001862B1|1986-10-24|Process for the preparation of dialkanoyloxybenzylidene dialkanoate

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Chaykovsky et al.1970|Transformation products of 2-| benzophenone

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US3968113A|1976-07-06|Conversion of leurosine to vincathicine

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AU675334B2|1997-01-30|Sterol compound

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EP0284337A1|1988-09-28|New indole alkaloid compositions and their methods of use

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US4025522A|1977-05-24|Conversion of leurosine to vincathicine

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EP0205169B1|1990-09-26|Bis-indole derivatives, process for preparing same and pharmaceutical compositions containing them

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Yuldashev et al.1966|The absolute configuration of majoridine

同族专利:

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公开号 | 公开日

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IT1138155B|1986-09-17|

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ATA358781A|1984-05-15|

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FR2492385A1|1982-04-23|

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CH648321A5|1985-03-15|

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US4490378A|1984-12-25|

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US4410459A|1983-10-18|

---

GB2086884A|1982-05-19|

---

IL63594D0|1981-11-30|

---

AT376679B|1984-12-27|

---

FR2492385B1|1985-08-02|

---

SE8104878L|1982-04-23|

---

ES8300778A1|1982-12-01|

---

ES505311A0|1982-12-01|

---

CA1182450A|1985-02-12|

---

DE3132475A1|1982-06-24|

---

IT8123541D0|1981-08-17|

---

SE442117B|1985-12-02|

---

DE3132475C2|1991-04-11|

---

JPS5772993A|1982-05-07|

---

NL8103843A|1982-05-17|

---

JPH0161119B2|1989-12-27|

---

HU181746B|1983-11-28|

---

BE889990A|1982-02-17|

---

GB2086884B|1984-07-25|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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---

US4075214A|1976-05-17|1978-02-21|Eli Lilly And Company|Preparation of leurosidine and novel leurosidine 4'-ethers and esters|

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US4143041A|1977-01-19|1979-03-06|Eli Lilly And Company|4'-Deoxyvincristine and related compounds|

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HU178706B|1979-04-23|1982-06-28|Richter Gedeon Vegyeszet|Process for preparing bis-indole alkaloids and acid addition salts thereof|

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JPS56128642A|1980-03-15|1981-10-08|Kubota Ltd|Production of frozen mold|HU198074B|1985-06-12|1989-07-28|Richter Gedeon Vegyeszet|Process for producing new bis-indole derivatives and pharmaceutical compositions comprising these compounds|

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HU193318B|1985-06-12|1987-09-28|Richter Gedeon Vegyeszet|Process for producing new bis- indol derivatives|

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JPH0747233B2|1987-09-14|1995-05-24|古河電気工業株式会社|Solder deposition composition and solder deposition method|

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US5095109A|1989-06-08|1992-03-10|University Of Vermont|Novel alkaloids|

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US5938163A|1997-10-20|1999-08-17|Eastman Kodak Company|Articulating touchscreen interface|

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US20130178618A1|2012-01-10|2013-07-11|William Allen Boulanger|Novel pharmaceutical intermediates and methods for preparing the same|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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HU802563A|HU181746B|1980-10-22|1980-10-22|Process for preparing vinblastine and leurosidine derivatives|

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