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    • 专利摘要:

    公开号:SU910118A3
    申请号:SU782626797
    申请日:1978-06-14
    公开日:1982-02-28
    发明作者:Станек Ярослав
    申请人:Циба-Гейги Аг (Фирма)；
    IPC主号:
    专利说明:

    where Rj, R2,% are as defined above, sodium nitrite in the presence of a mineral acid. The reaction is preferably carried out at a low temperature, e.g., from 10 to 30 ° C. The starting materials used in this process are also new. They can be prepared by known methods from the corresponding unsubstituted in the 6-position glucofuranose, for example, by reacting to yield reactive esters, for example alkansulfokislotamn, arylsulfonic acids or galogenvodorodnrmi acids, then to oxides and reducing these oxides to 6-deoxy-6aminoglyukofuranozy, which is then condense with a suitable NR derivative. - carbamic acid, for example, with the corresponding isocyanate 6-deoxy-6-GZ-.N, -ureido.) glucofuranose. The novel compounds of general formula J may exist as pure oC or fb isomers or as isomeric mixtures. The latter can be divided by their physico-chemical difference into their constituent parts by known methods into pure isomers, for example, by chromatographic separation, thin-layer chromatography or by some other separation method. New compounds have valuable pharmacological properties, and they show particularly good effect in various types of transplant tumors and leukemias, as well as partially in those induced by the virus leukemia x. The compounds are effective at doses of 25,500 mg / kg I, p, and have a strong inhibitory effect on tumor growth in menia, for example, with Ehr ich-Asc hites-Karzinom or with Hardinq-Passey MeEarom, as well as in rats with Joshida Aschites-Sarcom . Similar doses prolong life compared with control samples of mice, for example, with leukemia 1210 or Rauscher leukemia. So, when using ethyl-6-deoxy-3, 5-di-0-methyl-6 - (. 3-mvtil-3-nitro zoo-ureido) - -D-glucofuranoside at a dosage of 50-250 mg / kg. P. The 80-100% growth retardation of these tumors and the prolongation of life in L 1210 leukemia reach approximately 60%, as well as in the case of oral administration to mice with Rauscher leukemia reach approximately 100%. The compatibility of the new connections is good. In the case of normal animals after a three-week oral administration of drugs, no macroscopic organ changes are observed. Example 1. A solution of 60.7 g of ethyl-3,5-di-0-methyl-6-deoxy-6- (3-methyl-ureido)) - glucofuranoside in 500 ml of water, cooled to 0 ° C, and 15 ml of acetic acid Mix 15 mnn dropwise with a solution of 15.8 g of sodium nitrite in 80 ml of water, stir for 1 hour at the same temperature and leave to stand for 16 hours at room temperature. The crystallized product is filtered off with suction, washed with a small amount of ice water and dried. The mother liquor is extracted with chloroform, the organic phase is dried over magnesium sulfate and the solvent is distilled off. The residue is purified through a chromathophic column with silica gel with methylene chloride - ethyl acetate (85:15), the crystalline product is combined with the first crystallisate and is recrystallized from ether-petroleum ether. Etcs | 3, 3-di-0-methyl-6-deoxy-6 - (3-Methylnitrosoureido-J-D-glucofuranoside melts at 90 ° C; fi-f0.45 on a thin-layer silica gel plate. Methylene chloride-methanol (15: 1), .0 43 t I (chloroform. С G, 465). The starting material can be prepared as follows: A solution of 207 g of 3,5-di-O-methyl-1,2 isopropylidene-o -glucofuranose 600 ml of absolute pyridine is mixed with 67 ml of methanesulfonic acid chloride and stirred for 45 minutes with stirring and external cooling and left to stand for 4 hours at room temperature. 50 ml of water are added and the main amount of pyridine is evaporated after another 15 minutes The residue is taken up in ether, the ethereal solution is washed with water, ice-cooled 2N, hydrochloric acid, water, saturated sodium hydrogen carbonate solution and water, dried over magnesium sulfate and the solvent is distilled off. The oily residue is 3,5-di-O-methyl5 1,2-0-isopropylidene-6-0-mesyl-g -: Glucofuranose with a value of 35 on a thin-layer silica gel solvent in the methylene chloride-ethyl ether system (85 :15). 240 g of this product is dissolved in 1700 ml of N, N - dimethylformamide, mixed with 142 g of sodium acetate and 170 ml of water and stirred at 110 ° C for 3 hours. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in ether, washed with water, dried over magnesium sulphate and the solvent is distilled off. 6-acetyl-6-deoxy3, 5-di-O-methyl-1,2-0-isopropylidene-oi.-D-glucofuranose is obtained in the form of a yellowish mixture with the value R.rO 61 on a thin-layer silica gel plate in the methylene chloride system ethyl ether (85:15), optical rotation oi 3. 57 tl (chloroform, s 1.9 5). A solution of 193 g of this compound in 3500 ml 1 and. alcoholic hydrochloric acid solution is left to stand for 18 hours at room temperature. Immediately thereafter, the main amount of solvent was evaporated with a water jet pump, the residue was taken up in ether and the solution was washed with water, saturated sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated to dryness. The resulting mixture of isomers is separated by chromatography on a silica gel with a mixture of methylene chloride - ethyl acetate (85:15). Ethyl-6-acetyl-6deoxy-3, 5-di-O-methyl-oL- 2) -glucofuranoside has a value of R 0.32 on a thin-layer silica gel plate in the methylene chloride-ethyl ether system (85:15) and 56 tl optical rotation (chloroform, with 0.89). The corresponding glucofuranoside in the same system has the value of Rr 1 1. 21.9 g of ethyl-6-acetyl-6-deoxy3, 5-di-O-methyl-ci-3) -glucofuranoside in 200 ml of ethanol in the presence of 2 g 5% - Palladium on carbon is reduced by hydrogen. After the catalyst is filtered off and the solvent (alcohol) is distilled off by distillation, ethyl 6-amino-6-deoxy-3,5-d-O-methyl-oL-D-glucofuranoside is obtained as a yellowish oil. A solution of 74.9 g of this oil in 550 ml of ethanol is mixed with a solution of 18.5 g of methyl isocyanate in 60 methylene chloride in drops for 1 h and the reaction mixture is evaporated to dryness. The ethyl-6-deoxy-3, 5-di-0-methyl-6 (3-methyl-ureido) -glucofuranoside obtained is crystallized from ethyl ether-ether. M.p. 144 ° C, o / | f 57 ± 1 (chloroform, c 1, 1.134) and the value of R 0.22 on silica gel in the methylene chloride system 1 methanol (15: 1). PR and measures 2. A solution of 33.4 g of 3,5-di-0-methyl-6-deoxy-1,2-isopropylidene-6- (3-methylureido) -o (.- T) -glucofuranose in 280 ml water cooled to 0-5 ° C and 8.0 ml of glacial acetic acid are mixed for 30 minutes with a solution of 8.3 g of sodium nitrite in 40 ml of water dropwise. The reaction mixture is stirred for 1 hour at 0-5 ° C and 18 hours at room temperature. Directly thereafter, the solution is extracted with chloroform, the organic phase is washed with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on 1200 g of silica gel with methylene chloride-ethyl ether (85:15). The fractions with a R.J value of 0.41, with 6-deoxy-5-di-0-methyl-1, 2-isopropylidene-6- (3-methyl-3-nitrosoureido) -oi-D-glucofuranic acid, dried to dryness; aL -49 ± 1 (chloroform, c 1,127). The starting material used is prepared as follows. 60.0 and 6-acetyl-6-deoxy-3,5-di-methyl-1, 2-0-isopropylidene-o.-1) glucofuranose is dissolved in 600 ml of ethanol and in the presence of 5% palladium on carbon reduced by hydrogen. After separating the catalyst and distilling off the solvent, 6-amino-6-deoxy-3, 5-di-O-methyl-1,2 0 isopropylidene-dL-D-glucofuranose is obtained as a colorless oil, 33.2 g of this product is dissolved in 250 ml of ethanol are mixed with a solution of 8.4 ml of methyl isocyanate in 25 ml of methyl eschoride with dropwise over 30 minutes while stirring. Stirring is continued for another 60 minutes, after which the reaction mixture is evaporated to dryness and the residue is crystallized from acetone. Thus obtained 6-deoxy-3,5di-O-methyl-1, 2-0-isopropylidene-6- (3-methylureido) - o / - 1) -glucofuranose with an RP value of 0.45 on silica gel II 2O -7 4- 1 In the system, acetone and OL-Q x i (chloroform, melts from 1.987 at 66-69 p. 7 Example 3. Solution of 52.4 g of et11l-6-deoxan-3, 5-di-0-methyl -6- {3methylureido) - -D-glucofuranoside in 420 ml of water, cooled to, and a solution of 24.5% acetic acid with stirring dropwise over 45 minutes is mixed with a solution of 25.4 g of sodium nitrite in 130 ml of water and for 18 h, stirred at the same temperature, and immediately after that extract chl roformom, F zu wash the organic with water, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel mixtures of methylene chloride - ethyl ether (85: 1 Fractions with ethyl 6-deoxy-3, 5-di-Omethyl-6- (3-methyl-3-nitrosoureido) P-D-glucofuranoside) with a value of f 15 combined oCf ± I (chloroform, c 1.85. The starting compound used can be obtained as follows: 24 g of ethyl 6-acetyl-6-deoxy-3,5di 0-methyl- | L-D-glucofuranoside) created in L40 ml of methanol and in the presence of 5% palladium on carbon is reduced by hydrogen. The catalysis is filtered off and the filtrate is evaporated to dryness. The resulting 6-amino derivative The solution can be immediately further reacted. A solution of 39.2 g of this compound in 330 ml of ethanol with stirring is added dropwise over 40 minutes to a solution of 10 ml of methyl isocyanate in 30 ml of methyl chloride and is left to stand for 16 hours at room temperature Immediately thereafter, the reaction mixture is evaporated to dryness and the residue is taken up in ethyl ether. The solution is filtered through activated charcoal and evaporated to dryness. To obtain) 1 part oil is ethyl 6-deoxy-3,5-di-0-methyl-6 (3-methylureido) - p -1) -glucofuranoside WITH the value of R.4P 0.10 on silica gel e in the system methylene chloride-methanol (13: 1). Example 4. Similarly, starting from the corresponding starting materials, the following compounds can be obtained: eth1-2-0-acetyl-6-deoxy-3,5-di-0-methyl-6- (3-methyl-3-nitrosoureido) - J) - glucofuranoside; ethyl 6 - (3-ethyl-3-nitrosoureido) -6-deoxy-3, 5-di-0-metsh-1-in-1E-glucofuranoside; Edyl-6-3-2-chloro ethyl-3-ni of roses sureido-6-deoxy-3,5-di-0-methyl-o-Dgl): cofuranoside; ethyl 6- (3-n-butyl-3-nitrosoureido) -6-deoxy-3, 5-di-0-methyl-a-β-D-glucofuranoside; ethyl 6-deoxy-5-0-methyl-6- (3-methyl-3-nitrosoureido) -c /. -D -gluck furanoside; Etyl-5-0-Etil-6-deoxy-6-f3-methyl-3-nitrosoureido) - 3-0-propyl-o (.- 1) -glucofuranoside; eth1-3-0-benzyl-6-deoxy-5-0-methyl-6- (3-me-tyl-3-nitrose oureido -o-D) glucofuranoside. PRI me R 9. A solution of 3.0 g of ethyl-6-amino-6-deoxy-3,3-di-O-methylglucofuranoside in 40 ml of chloroform, cooled to, mixed with a solution of 2.5 g of N -neutro-methylcarbamyl acetyl in 40 mp ether 10 min, added dropwise, and then the reaction mixture is stirred for 1 h in an ice bath and for 3 h at room temperature. The solution is half evaporated, washed with ice-cold 2 n. hydrochloric acid, water, saturated sodium bicarbonate solution and water, dried over magnesium sulphate and evaporated to dryness. The crystalline residue of ethyl 6-deoxy-3, 5-di-0-methyl-6 deoxy-6 (3-methyl-3-nitrosoureido) - o (- D-glucofuranoside is recrystallized from ether-petroleum ether. So pl. 90 C, 43 ± 10 ° (chloroform, s - 1,102). Formula of the invention. Method of producing NJ-glucofuranoside-6-yl-N-nitrosoureas of the general formula G CRg-yji-CQ-V.-, I14-0-CH O CO-BAT) O-RI where R. is alkyl of R 2. hydrogen, alkanoyl C - Gi and RT. together they represent alkylidene, C - R, - apyl, C, C, j, benzyl; RM is alkyl C /} - Cz; R - alkyl C - Cg - or chlorine apkyl C / (- CJ, about tl and h and s and with 9910P that the compound of general formula P CH2-NH-CO - NH-R5 R4 0-CH5 1 (0 h l (0-R4) -0-Ri N-i i 210 8 10 sodium nitrite in the presence of mineral acid. Sources of information taken into account in the examination 1. Weigand-Hilgetag. Methods of experiment in organic chemistry. M. , Himi, 1968, pp. 397.
    权利要求:
    Claims (1)
    [1]
    Formula
    Method zid-6-yl formula t of the invention for the preparation of glucofurano-nitrosourea with total r 4 -o
    0-r1
    0-R, alkyl C ^ - Cy;
    hydrogen, alkanoyl C 4 - C ^ 'where R. * V
    R4 and R-x together represent so-called alkylidene C ^ “
    R ^ is alkyl C ^ - C , benzyl;
    R ^ is alkyl C 4 - C 3 ;
    R $ is alkyl C Cd · or chlorine ap kil C ^ - C · *,
    CH 2 -NH-CO - NH-R 5 R4-0-cn ^ O-Rj or 2 with sodium nitrite in the presence of mineral acid.
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