专利摘要:
Compounds which, in form of therapeutical compositions, exhibit antitumoral activity. …<??>These compounds are of the general formula I …<CHEM>… wherein R1 represents a hydrogen atom or a hydroxy or methoxy group, R2 represents a hydrogen atom or a hydroxy group, and each of R3 and R4 independently represents a hydrogen atom or a methyl group, with the proviso that R3 and R4 do not simultaneously represent hydrogen atoms and the pharmaceutically acceptable addition salts thereof, a process for producing said compounds and therapeutical composition containing same.
公开号:SU1017173A3
申请号:SU802943002
申请日:1980-07-03
公开日:1983-05-07
发明作者:Кассинелли Джузеппе;Френза Сальваторе;Клара Рипамонти Мария;Руджиэри Даниэла
申请人:Фармиталия Карло Эрба С.П.А. (Фирма);
IPC主号:
专利说明:

The high resonance of CBS shows the presence of absorption at 1.37 (S, CHj-C-S); 2.38 (4, CH, 3.55 t-S, C-4-OCH5); 4.02 s, two aromatic groups OGHj) 15.33. (Wide signal, C-7-NL and 5.43 f H wide signal,). A solution of the compound tW), 0.230 g (0.37 mmol) in a 0.25 M aqueous solution of sodium hydroxide 25 md1 is quenched in 30 minutes at room temperature and stirring. The resulting solution is diluted with water (30 ml, adjusted to pH 3 with a 0.25 M hydrochloric acid solution, and extracted with chloroform to remove contaminants. The aqueous phase is adjusted to pH 8.2 with a saturated aqueous solution sodium bicarbonate solution, extraction from chloroform (3x100 ml). The combined organic extracts are dried over anhydrous sodium sulfate, brought to a small volume and diluted to a pH of 4.5 with 0.5 M solution of hydrogen chloride in methanol. Adding Enough Petro This compound allows precipitating 4-O-methyl-11-deoxidounorubicin (II) in the form of its chloride-prenatal salt (0.200 g; 0.36 tful, 97.2% yield, mp 194-197 s (with decomposition); mass spectrum under conditions of field desorption, w / e 525 (), the spectrum of infrared radiation (KBf) shows the presence of absorption in values of 1710 ChcosGNe670, 1 $ 20 and 1590 cm (absorption band of the quinone). Visible part of the spectrum of ultraviolet radiation shows the presence maximum absorption at 227, 260, 284, 417 and 434CSii) by them (El 500, 330.173,., 167 and 146). . PRI and M e p 2. 4-O-Methyl-11-; - deoxyoxorubicin (.X) ffCE / 20291) A solution of compound 11 (.0.180 g, 0.34 mmol) in anhydrous methanol (2.5 ml) I anhydrous dioxane (6., 9 ml); and orthoformate ethyl ester (0, 18 ml) is treated with a 1.3 M solution of bromine in chloroform. After 2 hours, the resulting solution is poured into petroleum ether (18 ml) and diethyl flux. ether (36 ml). The precipitate is filtered off, washed with diethyl ether and dried under vacuum. The product thus obtained was dissolved in acetone (5.8 ml) and 0.25 M aqueous solution of hydrogen bromide (5.8 ml) was added. This reactive cMiscb was kept for overnight at room temperature, then 20% aqueous sodium formate solution (35 ml) was added to it. This solution is incubated for 24 hours at. The resulting mixture is extracted with chloroform to remove contaminants, and then adjusted to pH 7.5 seconds. using a saturated aqueous solution of sodium bicarbonate and extract with chloroform. The organic phase is flushed with water, dried over anhydrous sodium sulphate, dissolved in n-propanol and brought to a small volume. Adding 2.1N of a solution of hydrogen chloride in methanol and diethyl ether in a sufficient amount of dL to cause precipitation gives 0.135 g (0.23) yield of 67.6% 4-O-methyl-11-deoxyoxorubicin (Y) in the form of its hydrochloric resin; m.p. 189-19З C, mass spectrum, under field desorption conditions, In / e (N. The infrared radiation spectrum (KVU) shows the presence of absorption at values of 1725 (coSONaON), 1670, 1630 and 1590 CM (absorption bands of quinone). Visible A portion of the ultraviolet radiation spectrum in () indicates the presence of maximum absorption at -227, 25.9, 285 (5ti), 418 and 436 (Sfi) values (EH 673.424, 221, 177 n 151). Example 3. 4, 6-Di -O-methyl-11-deoxidaunorubicin (Vll) (FCE / 20302). Alkaline hydrolysis of 4, -di-O-methyl-11-deoxy-M-trifluoroacetyldounsfubiine (Y 0.180 g; 0.23 yulol), produced following the procedure described in the example 1, allows the preparation of 4, b-di-O-methyl-I-deoxy. Daunorubicin as its hydrochloride salt (Vli) (0.030 g; 0.05 mmol) (yield D8%), mp. 182 -185 ° C with decomposition} mass spectrum, under field desorption conditions, vr / e 539 (MV. Infrared spectrum Kv indicates the presence of absorption at 1710 (COCH) values of 1670 and 1590 cm (quinone absorption bands). A visible part of the spectrum ultraviolet radiation (c) shows the presence of maximum absorption at 223, 260 and 382 nm (, 326 and 109). The new compounds tested -i on Hela cells in relation to the effectiveness of cloning in laboratory conditions and in the treatment of P-388 ascites leukemia with a mouse compared to daunorubicin and doxorubicin. The data presented in table. 1, shows that 11-deoxy 4-0-methyl derivatives of daunorubicin IN) and daunorubicin (vi are less cytotoxic than their parent compounds - so, they are also less toxic in natural animals.
TROUBLESHOOTING and at the maximum allowable dose showed the presence of antitumor activity, comparable to this activity in the starting compounds
Influenced (e on the efficiency of Hela cell cloning in laboratory conditions
(tab. 2). Of particular interest is compound (Vt), which is characterized by a wide range of active and. non-toxic doses ..
That b-faces
Note: Hela cells were exposed to drugs for 24 hours and then plated onto plates. The number of colonies was determined 5 days later.
Antitumor Activity in the Treatment of P-388 Ascitic Leukemia in Mice
I Ta blitz 2
权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING ANTHRACYCLINGGLYCOSIDES of the general formula
I
And <1 ( P in the presence of silver oxide, the thus obtained 4-0-methyl-11-deoxy-H-trifluoroacetyldaunorubicin is separated from the simultaneously formed 4-b-di-0-methylt11-deoxy-lAtrifluoroacetyldaunorubicin by chromatography on a column of silica gel using a gradient mixture of chloroform solution with methanol, • removed separately from each compound N-protecting trifluoroacetyl group by a mild alkaline hydrolysis to give the free; IR ^ -H glycoside base), which is isolated by treating the solution chl hydrogen sulfide in methanol; d, hydrochloric, if or if necessary, is reacted with bromine in chloroform, and the corresponding 14-bromine: derivative is hydrolyzed at room temperature with a solution of sodium formate to obtain the derivative / doxorubicin of the general formula (1). ( R ^ -OH /, which is also isolated in the form of a hydrochloride salt.
ngl) "" where R <is hydrogen or hydroxyl; th 2 and Rj, -. independently hydrogen or methyl, provided that й th and Rg are not simultaneously hydrogen,>
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引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题

US4039663A|1975-03-19|1977-08-02|Societa' Farmaceutici Italia S.P.A.|Daunomycins, process for their uses and intermediates|
GB1550879A|1976-12-22|1979-08-22|Farmaceutici Italia|Antitumour glycosides|
GB1573037A|1977-05-05|1980-08-13|Farmaceutici Italia|Anthracyclines|
BE864336A|1977-05-05|1978-06-16|Farmaceutici Italia|NEW ANTHRACYCLINE DERIVATIVES|
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BE883759A|1979-06-16|1980-10-01|Erba Farmitalia|ANTHRACYCLINE GLYCOSIDES|JPS6259719B2|1980-04-26|1987-12-12|Biseibutsu Kagaku Kenkyukai|
NL8300150A|1982-01-26|1983-08-16|Erba Farmitalia|DAUNORUBICINE AND DOXORUBICINE ANALOGA, THEIR PREPARATION AND APPLICATION.|
GB8708927D0|1987-04-14|1987-05-20|Erba Farmitalia|Chiral synthesis of anthracyclines|
US5177091A|1990-12-06|1993-01-05|Ciba-Geigy Corporation|Use of carbazones as novel active ingredients in medicaments|
AU658175B2|1991-04-12|1995-04-06|Novartis Ag|Use of 2-iminothiazolidin-4-one derivatives as novel pharmaceutical active ingredients|
PL380561A1|2006-09-05|2008-03-17|Szeja Wiesław Prochem Szeja|The manner of receipt of anrhcycline derivatives|
US8357785B2|2008-01-08|2013-01-22|Solux Corporation|Method of aralkylation of 4′-hydroxyl group of anthracylins|
CN104151376B|2014-06-23|2017-02-08|天津药物研究院新药评价有限公司|Anti-tumor medicament as well as synthetic method and application thereof|
法律状态:
优先权:
申请号 | 申请日 | 专利标题
GB7923225|1979-07-04|
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