DE2104955A1 - Cytostatic sulphonyloxyethylamino-sugar - alcohols - Google Patents

Abstract

Cytostatic sulphonyloxyethylamino-sugar alcohols. Title cpds. are formula: CH2 - NHCH2CH2 - O - SO2 - R - Z (CHOH)n 2 HX CH2 - NHCH2CH2 - O - SO2 - R - Z (where n is 1-4; R is aryl, aralkyl or cycloalkyl opt. substd. by 1 or more Z, where Z is H, halogen, Me, OMe or nitro; X is an anion).

Description

PROCESS FOR THE PRODUCTION OF 2-SULFONYLOXYETHYLAMINO DERIVATIVES The invention relates to new 2-sulfonyloxyethylamino derivatives fn patent specification no.

are alkanesulfonyloxy-ethylamino derivatives of alkanes or oxyalkanes where the Alkån- and Osyalkanverbindungen from 3 to 6 carbon atoms containing alkane chains or oxyalkane chains exist, therein one or two carbon atoms substituted with the group R-SO2-O-CH2-CH2-NH- are and in the Formula R denotes an alkyl radical with 1 to 3 carbon atoms. These connections have a cytostatic effect.

It has been found that the 2-sulfonyloxyethylamino derivatives of the general formula I. - where n is 1, 2, 3 or 4, R is an aryl, aralkyl or cycloalkyl group which is not substituted or is substituted by one or more Z groups; Z represents a hydrogen or halogen atom, a methyl, methoxy or nitro group; 1 means a therapeutically applicable inorganic or organic acid residue - have a favorable cytostatic effect, especially the tetritol or rexite derivatives, e.g. the derivatives of erythritol, threitol, mannitol, dulcitol, sorbitol, etc.

According to the invention, the 2-sulfonyloxy-thylamino derivatives of the general Formula I prepared in such a way that on the two terminal carbon atoms of the sugar alcohol containing 3 to 6 carbon atoms is the 2-sulfonyloxythylamino group of the general formula II Z-R-SO2-OCH2-CH2-NH- (II) - where the meaning of R and Z is the specified - is formed.

The preparation of the compounds 1 or the formation of the groups with the general formula II can be done in such a way that the diet limino sugar alcohol Derivative with an unsubstituted or substituted l-, ralkyl- or cycloalkylsulfonic acid is reacted.

The preparation of the compounds I can also be carried out in the way be carried out that the di- (2-haloethylamino) sugar alcohol derivative with the salt of an unsubstituted or substituted aryl, aralkyl or cycloalkylsulfonic acid, is expediently brought into reaction with its heavy metal salt. In response is a polar solvent as a solvent, expediently acetonitrile and as Heavy metal salt e.g. the silver or lead sulfonate used.

The preparation of the 2-sulfonyloxyäthylamino derivatives can also be carried out in take place in such a way that the groups of the general formula (II) on such sugar alcohol derivatives are formed whose hydroxyl groups partially or wholly with protective groups, Are advantageously protected with acetal or acyl groups, then the protective Groups removed in a known manner.

The biological activity of the compounds according to the invention of general formula (I) is determined by the test results [toxicity (LD50), Tumor growth inhibiting effect (x) or prolongation of the lifespan (xx>, more therapeutic Index (TIi.p. = LD50 / ED0), effect the blood count (+)] illustrates. The examined Compounds are: Ä 1,4-Di- (2-BenzolsulfonyloxySthylamino) -1,4-dide30syerythritol-dibenzenesulfonate, B 1,4-di- (2-p-chlorobenzenesulfonyloxyethylamino) -1,4-dideoxyerythritol-di-p -chlorobenzenesulfonate, C 1,4-di- [2-p-nitrobenzenesulfonyloxyethylamino) -1,4-dideoxyerythritol di-p-nitrobenzenesulfonate, D 1,4-di- (2-benzilsulfonyloxyäthylamino) -1,4-dideoxy erythritol dibenzilsulfonate, E 1,4-di- (2-cyclohexylsulfonyloxyethylamino) -1,4-dideoxy erythritol dicyclohexylsulfonate.

Signs of the LD50 mg / kg TIi p on the Yoshida effect on the compound Blood count + i.v. s.c.

Direction strength in mice sarcoma A 50 100 lymphoid strong B 45 15 mixed strong C 32 18 lymphoid medium D 37 33 lymphoid medium E 88 35 lymphoid moderate + The effect on the blood count was unique in rats administered LD50 / 5 5 i.p. Dose checked, direction and strength of effect on that Blood counts mean the percentage reduction expressed in absolute numbers the number of lymphocytes and granulocytes (strong effect: 70 to 90% reduction, moderate effect: 50 to 70% reduction).

Sign rat tumors mouse tumors of the compound Walkerx Guerinx Shayxx Ehrlichxx NK / Lyxx Sarc.-180x sc. Carc. sc. chloro- asc.carc. asc.

carc. leuko.

A -92 -43 + 36 + 52 + 54 -42 B -99 0 +400 +280 +100 0 C -99 -42 + 60 +105 + 80 0 D -98 -48 + 17 +186 + 38 -38 E -96 0 0 + 56 + 73 -15 x bass of tumor inhibition in% »xx measure of the extension of the service life, expressed in%.

The doses used were 5 x LD50 / 20 or 5 x LD50 / 10 i.p. administered.

The compounds of the invention can be in the form of powder ampoules or coated tablets can be adjusted.

The daily dose of the compounds is generally 0.02 to 0.2 G.

Example 1 14.88 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxyerythritol dihydrobromide (Acta Chim. Hung. 19, 295 / L959 /) with the solution of 47.7 g of silver benzene sulfonate boiled in 220 ml of anhydrous acetonitrile with stirring for 45 hours. The cooled down The reaction mixture is filtered and the isolated salt is mixed with 300 ml of acetonitrile washed.

The salt is removed from the suction filter with 400 ml of boiling, eluted anhydrous methanol; The methanolic filtrates are combined with Treated hydrogen sulfide, clarified with charcoal, then in a vacuum at 40 ° C lt Concentrated bath temperature. After adding 120 ml of ether this will turn into crystal needles separating product isolated (yield 17.8 g, 74 * of theory) and from a methanol Ether mixture (10 ml - 20 ml / g) recrystallized. In this way it becomes 16.7 g (69.5% of theory) 1,4-di- (2-benzenesulfonyloxyethylamino) -1,4-dideoxyerythritol dibenzenesulfonate obtained, m.p. 163 to 164 ° C (with decomposition) Production of the silver salt of Sulphonic acid: The corresponding sulphonic cure chloride is treated with anhydrous methanol (6 ml / g) boiled (6 to 10 hours) until the development of methyl chloride is noticeable is. Then the solvent is driven off in vacuo and the sulfonic acid obtained is dissolved in water (3 to 8 ml / g), then by adding the equivalent Amount of silver carbonate neutralized with stirring. The salt solution is clarified with charcoal, filtered clear - if necessary concentrated in vacuo - by adding isopropanol or acetone, the product is precipitated in crystalline form, filtered off with suction, with ether washed, dried in vacuo, protected from light. If necessary, add the salt for cleaning in wanser-free acetonitrile (5 to 6 ml / g) dissolved, a clear filtrate is prepared, this is evaporated to dryness in vacuo, or After concentrating, the salt is made by adding isopropanol, acetone or ether pleases. In this way, the silver salt of the desired sulfonic acid becomes 90% strength Yield gained.

Example 2 9.92 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxyerythritol dihydrobromide are with the solution of 33.5 g of silver ptoluenesulfonate in 300 ml of anhydrous acetonitrile Cooked for 21 hours. The cooled mixture is filtered and the salt mixture is washed in portions with acetonitrile, then on the suction filter in several Portions eluted with 500 ml of boiling methanol. The combined solutions become treated with hydrogen sulfide, clarified with charcoal and filtered warm. That I Crystalline product separating from the solution during cooling is suctioned off, washed with acetonitrile: yield 12.1 g, melting point 181 to 183 ° C. The mother liquor is evaporated to dryness in vacuo at a bath temperature of 40 ° C, the residue becomes Stirred with 100 ml of acetonitrile and the crystalline product which separates out is isolated: 4.3 g. The crude product (15.4 g, 69.5 ffi of theory) from anhydrous ethanol (95 ml / g) recrystallizing, 14.1 g of 1,4-di- (2-p-tosyloxyethylamino) -1,4-dideoxyerythritol di-p-tosylate are obtained obtained, m.p. 183 to 184 ° C (under decomposition) *.

Example 3 18.2 g of 1 1,4-diethylenimino-1,4-dideoxyerythritol dimesylate are dissolved in 18.2 ml (27 g) of 100% methanesulfonic acid and for 2.5 hours at 100 to 102 OC. The reaction becomes exothermic when it reaches 98 ° C, this is compensated by briefly suspending the heating or by air cooling. After the reaction has ended, the mixture is stirred with 135 ml of anhydrous methanol and quickly warmed up until completely dissolved, filtered through a glass filter and possibly cooled down quickly.

The precipitating crystalline product becomes after a short cooling isolated in ice water, with 2 x 8 ml of methanol and with 5 x 10 ml of anhydrous isopropanol washed, dried in vacuo at 40 ° C. 25.6 g (92% of theory) 1,4-di- (2-mesyloxyethylamino) -1,4-dideoxyerythritol dimesylate are obtained, M.p. 142 to 143 ° C.

Preparation of 1,4-diethylenimino-1,4-dideoxyerythritol dimesylate: The mixture of 100 g of methanesulfonic acid and 300 ml of water are stirred and Cooling at -5 to 0 00 86 g of powdered 1,4-diethylenimino-1,4-dideoxyerythritol (Acta Chim. Hung. 19, 295/1959 /) added. The solution is filtered through a glass filter filtered clear, then 3600 ml of isopropanol are added with stirring. That I Crystalline product which separates out is filtered off with suction, with isopropanol and with ether washed, dried in vacuo at 20 ° C. Yield 172.5 g (93% of theory), m.p. 217 up to 218 ° C (with decomposition).

The product can also be made from a mixture of water-acetone, water-acetonitrile as well as be crystallized from dimethylformamide.

Example 4 5.16 g of 1,4-diethylenimino-1,4-dideoxyerythritol di - p-tosylate (M.p. 2160, with decomposition) are mixed with the solution of 6 g of p-toluenesulfonesEwre boiled in 40 ml of nitromethane for 2 hours with stirring. That from the reaction mixture Crystalline product which separates out after cooling is filtered off with suction with nitromethane and washed with ether. Yield 6.2 g, m.p. 170 to 174 00. By concentrating the Mother liquor in vacuo is recovered a further 1.05 g. The crude product from ethanol Recrystallizing twice, 5.9 g of 1,4-di- (2-p-tosyloxyäthylamino) -1,4-dideoxyerythritol are obtained - di-p-tosylate, M.p. 183 to 184 00.

Example 5 4.96 g of 1,4-di- (2-bromoethylmino) -1,4-dideoxyerythrite dihydrobromide are with the solution of 17.7 g of silver-p- methoxybenzenesulfonate boiled in 180 ml of anhydrous acetonitrile with stirring for 64 hours. After completion the reaction, the cooled reaction mixture is filtered and the roller washed with copious amounts of acetonitrile.

Then on the funnel in portions with 500 ml of boiling anhydrous Methanol eluted, the combined solutions are treated with hydrogen sulfide, Clarified with charcoal and concentrated in vacuo at a bath temperature of 40 ° C. The exiting crystalline product is filtered off with suction, washed with ethanol. Yield 5.45 g (59% d.Th.), m.p. 170 to 172 ° C. The crude product is made from a methylcellosolve ether Mixture (4.5 ml - 30 ml / g) crystallizes, 5.25 g (56.9% of theory) 1,4-di- (2-p-methoxybenzenesulfonyloxyethylamino) -1,4-dideoxyerythritol are obtained di-p-methoxybenzenesulfonate, Mp. 171 to 172 ° C (with decomposition).

Example 6 3 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxyerythritol dihydrobromide are with the solution of 12.6 g of silver 3,4,5 - trimethoxybenzenesulfonate in 90 ml anhydrous acetonitrile boiled with stirring for 30 hours. The Salts which deposit the reaction mixture are filtered and washed with 70 ml of acetonitrile washed, The silver is obtained from the filtrate by treatment with hydrogen sulfide removed, it is clarified with charcoal and then at 40 ° C bath temperature in a vacuum evaporated to dryness. The residue is stirred with 3 × 20 ml of ether, the ether is decanted, the tookblrebene resin is in 3 x 50 ml hot, anhydrous Isopropanol is dissolved and the resin that separates out on cooling is used Solvent poured off from time to time. The product obtained in this way becomes rubbed again with ether, whereby it recrystallizes, then it is sucked off, washed with ether and dried over phosphorus pentoxide at 20 ° in vacuo. 6.25 g (70-5% of theory) 1,4-di- [2- (3,4,5-trimethoxybenzenesulfonyloxy) ethylamino] - 1,4-dideoxyerythritol di (3,4,5-trimethoxybenzenesulfonate) will recovered, m.p. 57-58 ° C (with decomposition); its dihydrochloride (m.p. 106-108 ° C with decomposition) is not hygroscopic.

Example 7 9.92 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxyerythritol dihydrobromide are with the solution of 36 g of silver p - chlorobenzenesulfonate in 200 ml of anhydrous Acetonitrile boiled with stirring for 70 hours. Which after cooling off Salts separating out the mixture are filtered and washed with 200 ml of acetonitrile. Elute from the suction filter with 1600 ml of hot methanol added in portions, the combined methanolic filtrates are treated with hydrogen sulfide, Clarified with charcoal, then evaporated to dryness in vacuo at a bath temperature of 40 ° C. The crystalline residue is stirred with a little ethanol, filtered and washed with ether washed. 15.4 g (82% of theory) of product with a melting point of 183 to 185 are obtained 00. The crude product crystallizing from a dimethyl sulfoxide-isopropanol mixture, 1,4-di- (2-p-chlorobenzenesulfonyloxyethylamino) -1,4-dideoxyerythritol di-p-chlorobenzenesulfonate is obtained, M.p. 189 to 190 ° C (with decomposition).

Example 8 4.96 g of 1,4-di- (2-bromoethyramino) -14-dideoxyerythritol dihydrobromide are with the solution of 28.2 g of silver p-nitrobenzenesulfonate in 100 ml of anhydrous Acetonitrile boiled for 10 hours with stirring. The cooled mixture is filtered, the silver bromide is washed in portions with 300 ml of acetonitrile. The filtrate is treated with hydrogen sulfide, clarified with charcoal and in a vacuum at 40 ° C Bath temperature evaporated to dryness. The syrupy residue (20 g) is with Stir 200 ml of anhydrous isopropanol, which recrystallizes on cooling Product is filtered off with suction, washed with isopropanol: 6.2 g (63% of theory) are obtained. with a melting point of 176 to 1790 0e The crude product is on the filter with 3 x 8 ml ice water, 6 x 10 ml. Acetonitrile, stirred, washed. One wins 3.4 g (30.9% of theory) of crystalline 1,4-di- (2-p-nitrobenzenesulfonyloxy-ethylamino) -l , 4-dideoxyerythritol di-p-nitrobenzenesulfonate, m.p. 184 to 185 ° C (with decomposition).

J3eipiel 9 4.96 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxy-D.L -threit-dihydrobromide are with the solution of 28.2 g of silver p-nitrobenzenesulfonate in 100 ml of anhydrous Acetonitrile boiled for 10 hours with stirring. The reaction mixture according to the example 8 processing, 5.1 g (51.9 of theory) 1,4-di- (2-p-nitrobenzenesulfonyloxyethylamino) -1,4-dideoxy-D.L-thret-di-p-nitrobenzenesulfonate are obtained, M.p. 176 to 178 0 (with decomposition).

Example 10 4.96 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxyerythritol dihydrobromide are with the solution of 16> 8 g of silver benzilsulfonate in 160 ml of anhydrous Acetonitrile boiled for 18 hours with stirring. The from the reaction mixture after The salts which precipitate out on cooling are filtered off with suction and mixed with 250 ml of acetonitrile washed in portions.

From the suction filter, 1 x 250 ml and 2 x 100 ml are anhydrous Methanol eluted hot. The combined methanolic solutions are treated by freed from silver with hydrogen sulfide, clarified with charcoal and in a vacuum 40 ° G bath temperature concentrated. The crystalline that separates out when it cools down Product is filtered off with suction, washed with Isolt propanol and with ether, one wins 5.9 g (68.5% of theory) of product, m.p. 187 to 189 00. The crude product is made from methylcellosolve (7 ml / g) or recrystallized from a dimethyl sulfoxide-isopropanol mixture (4 ml - 12 ml / g), 5.3 g (61.7% of theory) 1,4-di- (2-benzilsulfonyloxyäthylamino) -1,4-dideoxyerythritol dibenzilsulfonate are obtained, M.p. 189.5 ° C (with decomposition).

Example 11 4.96 g of 1,4-di- (2-bromoethylamino) -1,4-dideoxver @ thrit dihydrobromide are with the solution of 16.3 g of silver - cyclohexyl sulfonate in 150 ml of anhydrous Acetonitrile boiled with stirring for 32 hours. After standing overnight was, the precipitating salts are sucked off and in portions of 200 ml Acetonitrile washed.

1 x 100 ml and 2 x 50 ml of anhydrous, eluted with hot methanol (the undissolved silver bromide is 7.35 g). The United methanolic solutions are treated with hydrogen sulfide, clarified with charcoal and concentrated to a volume of 25 ml at a bath temperature of 40 ° C. in vacuo. The Crystalline product which separates out cooling is filtered off with suction, washed with isopropanol: 6.7 g (81 * of theory) of product are obtained. This is repeated from methanol (5 ml / g) recrystallized, 5.7 g (69% of theory) 1,4-di- (2-cyclohe2yl-sulfonyloxyEthylamino) -1,4-dideoxyerithritol dicyclohexylsulfonate are obtained, M.p. 188 to 189 ° C. (with decomposition). The compound can also be made from ethanol a mixture of dimethylformamid.-acetone, or dimethylformalt mid-ethanol crystallized will.

Example 12 3.39 g of 1,6-di- (2-bromoethylamino) -1,6-dideoxyduleit - dihydrobromide are with the solution of 10 g of silver benzilsulfonate in 90 ml of anhydrous acetonitrile cooked with stirring for 20 hours. After the mixture has cooled down, the precipitated salts are suctioned off and washed with 3 × 20 ml of acetonitrile. Of the slide is eluted with 1 x 250 ml and 2 x 100 ml of anhydrous, hot methanol. The combined methanolic solutions are treated with hydrogen sulfide, Clarified with charcoal and evaporated to dryness in a vacuum. The crystalline residue is stirred with Isolt propanol, filtered off with suction, washed with isopropanol and with ether. The crude product (3.7 g, melting point 155 ° to 160 ° C.) is made from a mixture of dsmethylformamide and ether (3 ml - 50 ml / g) crystallized. 3.2 g (52.3% of theory) of 1,6-di- (2-benzilsulfonyloxyethylamino) -1,6-dideoxyduleit-dibenzilsulfonate are obtained, M.p. 160 nc (with decomposition).

Claims (3)

PATENT CLAIMS 1. Sulfonyloxy-ethylamino derivatives of the formula and their salts, in which n is 1, 2, 3 or 4, R is an atyl, aralkyl or cycloalkyl group which can optionally be substituted by one or more Z groups, Z is hydrogen or halogen, methyl, methoxy or a nitro group, x denotes a pharmaceutically usable inorganic or organic acid residue 2. Pharmaceutical preparations containing compounds of the formula I as active ingredients, or their salts in combination with customary auxiliaries and / or carriers. 3. Process for the preparation of 2-sulfonyloxy-ethylamino derivatives of the general formula I and their salts - where n is 1, 2, 3 or 4, R is an unsubstituted or an aryl, aralkyl or cycloalkyl group substituted by one or more Z groups; Z represents a hydrogen or halogen atom, a methyl, methoxy or nitro group; x denotes a pharmaceutically acceptable inorganic or organic acid residue - characterized in that the 2-sulfonyloxyethylamino group of the general formula ZR-SO2-OCH2-CH2-NH- (II) - where the meanings of Z and R are as given above -an the two terminal carbon atoms of a sugar alcohol having 3 to 6 carbon atoms is formed in such a way that a) the diethylenimino sugar alcohol derivative is treated with an aryl, aralkyl or cycloalkyleulfonic acid, or b) the di (2-haloethylamino) sugar alcohol derivative is treated with the heavy metal salt of a bryl, aralkyl or cycloalkylsulfonic acid reacts, or c) the groups of the general formula (II) are formed on such sugar alcohol derivatives, the hydroxyl groups of which are partially or completely protected with protective groups, advantageously with acetal or acyl groups, then the protective groups are removed in a manner known per se. 4 * The method according to claim 1, characterized in that it is e k e n nz e.i c fl n e t > ate the groups of the general formula (II) on a tetrite or on a hezite be formed.