DE1670319A1 - 2-Benzosulfonamido-pyrimidines and process for the preparation thereof - Google Patents

Description

2-Benzenesulfonamido-pyrimidines and process for the preparation thereof.

Ai) of the Belgian patent 664 178 is known that # 2- [4- (ß-benzoylaminoethyl) -benzenesulfonamido] -5- (hexahydrobenzyl) -pyrimidine has a blood sugar lowering effect. It has now surprisingly been found that the blood sugar lowering effect is due to certain substituents on the benzoylamino group can be increased several times.

The present invention accordingly relates to 2-benzenesulfonamido-pyrimidines of the general formula I which lower blood sugar in which A is a phenyl radical which is substituted one or two times by halogen, lower alkoxy and methyl groups, or a thienyl radical substituted by a methoxy group, the alkali metal, alkaline earth and. Ammonium salts and processes for making the same.

The present invention also relates to the use of 2-benzenesulfonamido-pyrimidines of formula I for the production of drugs with an antidiabetic effect.

2-Benzenesulfonamido-pyrimidines of the general formula Ia are particularly effective in which X1 denotes hydrogen, a halogen atom or the methyl radical and X2 denotes a lower alkoxy group and, in the event that X1 denotes a halogen atom or the methyl radical, also denotes hydrogen.

The manufacturing process according to the invention is characterized in that either a) substances of the general formula II in which A has the meaning given above and n is the number 0, 1 or 2, with 2-amino-5-hexahydrobenzylpyrimidine of the formula III converts, optionally being subsequently oxidized to the sulfonamide, or b) benzenesulfonylguanidines of the general formula IV in which A has the meaning given above, with substances of the general formula V in which Y and Y 'represent hydrogen or alkoxy groups, or their functional derivatives are reacted, whereupon the pyrimidines, which may be hydroxylated in the 4- and 6-positions, are converted into the halogen compounds and reductive dehalogenation into the pyrimidines unsubstituted in the and 6-positions, or c) the compound of the formula VI reacts with the reactive derivative of an acid of the formula A-CO-OH, where A has the meaning given above, or d) benzenesulfonamides of the general formula VII m the A has the meaning above, with a pyrimidine ferivate of the general formula VIII in which Z denotes a reactive ester group or a low molecular weight trialkylamino group, or e) sulfonic acids of the general formula IX in which A has the meaning given above, reacts with 2-acetylamino-5-hexahydrobenzyl-pyrimidine and, if desired, then converted into the alkali, alkaline earth or ammonium salts in the usual manner.

The implementation of the compounds II and III is expedient in one inert solvent in the presence of a base, preferably pyridine or trimethylamine, carried out. But you can search with a molar excess of the aminopyrimidine work to trap the hydrogen chloride formed in the reaction. the subsequent oxidation of the sulfenamides or sulfinamides takes place in the usual way, z. B. by treatment with hydrogen peroxide, potassium permanganate or nitric acid.

The output connection. Use benzenesulfonylguanidine IV can e.g. B. by melting the appropriate benzenesulfonamides with guanidine carbonate can be obtained. The condensation according to the invention with the β-dicarbonyl compounds V can e.g. B. be carried out by means of alkali alcoholate in alcohol. The.-dicarbonyl compounds are here in free form or as functional derivatives, e.g. B. acetals, 'used ; but they can also in the "one-pot process" according to Vilsmeier from aldehyde acetals, Acid chloride and dialkyl formane: id are produced. If you use the Dialdehydes correspondingly substituted malonic esters or malonic ester aldehydes or their functional ones Derivatives must then be those in the 4- and / or 6-position of the pyrimidine ring located hydroxyl groups with the help of an inorganic acid chloride by chlorine be replaced, which then z. B. can easily be removed again reductively with zinc dust leaves.

The acylation of the compound VI is carried out in the usual way, so z. B. by reaction with the corresponding acid halides or anhydrides, preferably in the presence of an acid acceptor, or by treatment with reactive ones Esterr ..

The starting compound VIII is, in particular, 2-halo-5-hexahydrobenzyl-pyrimidire. in question; this can e.g. B. by reacting 2-hydroxy-5-hexahydrobenzyl-pyrimidine be obtained with an excess of phosphorus oxychloride. The inventive Condensation with the benzenesulfonamides VII is preferred in Presence of a base such as potassium carbonate instead.

Instead of 2-halopyrimidine, the corresponding 2-trialkylammonio-pyrimidine salt can also be used with sulfonamides VII with exit of trialkylamine to benzenesulfonamido-pyrimidines I implemented.

The conversion of the sulfonic acids IX with 2-acetylamino-5-hexahydrobenzylpyrimidine is carried out according to the Freudenberg method by heating in absolute methanol, the split off acetyl radical being captured by the solvent and in the form of the methyl ester is distilled off.

Mixed for the production of antidiabetic drugs the 2-benzenesulfonamido-pyrimidines of the formula I according to the invention are fixed with or liquid carriers and then brings them into the desired shape (e.g. tablets, capsules, coated tablets, syrups, solutions, suspensions). examples for Solid carriers are milk sugar, mannitol, starch, talc, methyl cellulose, magnesium stearate and gelatine, to which color or flavoring agents can be added, if desired. Liquid carriers for injection purposes are preferably mixed with suitable additives made isotonic such as glucose or polyoxyethylene and filled in sterile ampoules.

The new substances and the method according to the invention for production these are explained in more detail using the following examples.

For example 1 1 2- [p- (β-2-methoxy-5-chloro-benzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine 0.01 mol of 2- [p- (ß-aminoethyl) -benzenesulfonamido] -5-hexahydrobenzylpyrimidine (m.p. 260 ° Z.), obtained from p- (ß-Äthoxycarbamidoäthyl) -benzenesulfochloride with 2-amino-5-hexahydrobenzyl-pyrimidine and t subsequent saponification, are added to 16 ml of absolute pyridine and with 0.012 mol of 2-methoxy-5-chloro-benzoyl chloride were added.

The reaction mixture is left to stand over yacht and then heated 1 Sti; nde to 60. The cooled solution is poured onto ice, neutralized and the precipitated substance is sucked off. Then you dissolve the product in strong dilute sodium hydroxide solution, filtered through charcoal and falls with the addition of concentrated Sodium hydroxide solution from the sodium salt. The sodium salt is then dissolved in water and precipitated again with concentrated sodium hydroxide solution. Eventually it becomes the sodium salt redissolved in lasser and then precipitated the sulfonamide with dilute hydrochloric acid. Finally, it is recrystallized once from ethanol; Mp 181-183 ° C.

The following compounds were prepared in an analogous manner: 2- [p- (β-2-ethoxy-5-chlorobenzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine ; Mp. 168-170 ° C. (after recrystallization from isopropanol).

2- [p- (β-2-methoxy-5-fluorobenzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine ; Mp. 167-168 ° C. (after recrystallization from isopropanol).

2- (p- (β-2-methoxy-5-bromobenzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine ; Mp. 182-183 ° C (after recrystallization from isopropanol).

2- [p- (β-2-methoxy-5-methylbenzoylamino-ethyl) -benzenesulfonamido] -5-nexahydrobenzyl-pyrimidine ; Mp. 150-152 ° C (after recrystallization from isopropanol).

2- [p- (β-2-methoxybenzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine ; Mp 162-163 ° C (after recrystallization from ethanol).

2- [p- (β-3-Calor-benzoylamino-ethyl) -benzenesulfonamido] -5-hexahydroxyxyl-pyrimidine ; M.p. 157-159 ° C. After recrystallization from ethanol, the compound contains 1 mol Crystal water.

2- [g- (α-3-methoxythenoyl- (2) -amino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine ; Mp. 170-172 ° C (after recrystallization from isopropanol).

B e i a p i e 1 2 2- [p- (β-2-ethoxy-5-chloro-benzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine 3.74 g of 2- [p - (@ - Aminoethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine are dissolved in 10 ml of 1N sodium hydroxide solution and diluted with a little water. Anacillia will end under R: their a solution of 2.2 g of 2-ethoxy-5-chlorobenzoyl chloride (melting point 60-64 °) slowly added dropwise in 5 ml of methylene chloride and the geniach after 1 hour at room temperature touched. The precipitated sus-stand is then filtered off with a little methylene chloride washed in dilute sodium hydroxide solution and by adding dilute hydrochloric acid fallen again. The melting point is after recrystallization from isopropanol at 168-170 °.

For example 3 2-p- (β-2-xethoxy-5-chlorobenzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrinidine 3.88 g of p- (3-2-methoxy-5-chlorobenzoylamino-ethyl) -benzenesulfochloride (melting point 106-109 °) become a solution of 1.9 g of 2-amino-5-hexahydrobenzyl-pyrimidine (melting point 142-143 °) given in 6 ml of absolute pyridine.

The mixture remains for two hours at room temperature, is heated for another two hours on the steam bath and after cooling in Poured water. The boiled-out product is dissolved in dilute sodium hydroxide solution, the solution treated with activated charcoal and the substance from the filtrate with dilute Hydrochloric acid precipitated. The extracted product is finally recrystallized from ethanol. Mp 181-183 °.

Example 4 2- [p- (β-methoxy-5-chloro-benzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine While cooling with ice, 10 g of phosgene are passed into a solution of 7.3 g of dimethylformamide in 25 ml of methylene chloride. 9.3 g of β-cyclohexylpropionaldehyde dimethylacetal are added to this (Bp 12: 103-106 °) and heated for 6 hours while flying back. After distilling off the Methylene chloride, the residue is taken up in 50 ml of methanol and treated with sodium methylate solution neutralized. Then 20.6 g of p- (β-2-methoxy-5-chlorobenzoylamino-ethyl) -benzenesulfonyl-guanidine (Mp. 220 °) and white. tere 1 g of a 30% sodium methylate solution was added. The reaction mixture is then refluxed for 10 hours. After that, that will Most of the methanol distilled off, the residue taken up in warm water The solution obtained in this way is filtered through activated charcoal and the 2- [p- (ß-methoxy-5-chloro-benzoylamino-ethyl) -benzenesulfonamido] -5-hexahydrobenzyl-pyrimidine precipitated by the addition of hydrochloric acid. For purification, it is recrystallized from ethanol ; Mp 181-183 °.

Claims (3)

Claims 1. 2-benzenesulfonamido-pyrimidines of the general formula in which A is a phenyl radical, one or two times through. Halogen, lower alkoxy and methyl groups, .. or a thienyl radical substituted by a methoxy group, as well as the alkali, alkaline earth and ammonium salts. 2. Use of 2-BenzoIsulfonamido-pyrimidinen according to # claim l for the production of drugs with an anti-diabetes effect. 3. Procedure for the preparation of blood sugar lowering 2-benzenesulfonamido -..'... - .'.'.-.- '''"pyrimidines of the general formula.; in. welcfier-A is a phenyl test which is mono- or disubstituted by halogen, lower alkoxy and methyl groups, or a thienyl radical substituted by a methoxy group, characterized in that a) substances of the general formula II in A the meaning given above. and n is the number 0, 1 or 2, with 2-amino-5-hexahydrobenzylpyrimidine of the formula III converts, with optionally subsequent oxidation to the sulfonamide, or r b) Benzolaulfonyl-guanidines of the general. in Formula IV tt, in which A has the meaning given above, with. Substances of the general formula V in which Y and Y 'represent hydrogen or alkoxy groups, or their functional derivatives are reacted, whereupon the pyrimidines, which may be hydroxylated in the 4- and / or 6-position, are then converted into the halogen compounds and reductive dehalogenation into the pyrimidines unsubstituted in the 4- and 6-positions transferred, or c) the compound of formula VI with the reactive derivative of an acid of the formula A-CO-OH, where A has the meaning given above, or d) benzene sulfonamides of the general formula VII in which A has the meaning given above, with a pyrimidine derivative of the general formula VIII in which ^ denotes a reactive eater group or a low molecular weight trialkylamino group, or e) sulfona acids of the general formula IX in the. A has the meaning given above, is reacted with 2-acetylamino-5-hexahydrobenzyl-pyrimidine, and, if desired, is then converted into the alkali, alkaline earth or ammonium salts in the usual manner.