DE965400C - Process for the preparation of benzenesulfonylureas - Google Patents

Description

ISSUED JUNE 6, 1957

F 18339 IVb / 12

It has been found that compounds of the general formula
R,

- SO, - NH-CO - NH-

wherein R is hydrogen or a low molecular weight Alkyl radical or alkoxy radical represents a significant and long-lasting lowering of the blood sugar level cause.

The subject of the present invention is the preparation of such compounds in per se Usually takes place by optionally alkylated or alkoxylated benzenesulfonyl isocyanates Reacts with cyclohexylamine. But you can also do the desired in reverse reaction Obtain urea derivatives by optionally alkylating N-cyclohexyl isocyanate or alkoxylated benzenesulfonic acid amides to implement. Instead of Isocyanates also include those compounds which, in the course of the reaction, turn into isocyanates pass over. Another way of producing the new compounds is that urethanes are used instead of isocyanates. For example, one can use benzenesulfonyl urethanes or derivatives alkylated or alkoxylated in the benzene nucleus with cyclohexylamine or vice versa Reaction of N-cyclohexyl urethanes with corresponding

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convert the benzenesulfamides. Also carbamic acid rehalides can be used. This is how the new sulfonylureas are created, for example from N-cyclohexylcarbamic acid chloride and optionally alkylated or alkoxylated benzenesulfamides or from benzenesulfonylcarbamic acid chloride and cyclohexylamine.

According to a further embodiment of the method according to the invention one can from in the ίο amino group unsubstituted benzenesulfonylureas go out and alkylate them in a known manner or by reaction with cyclohexylamine Convert into benzenesulfonylcyclohexylureas. One can also use N-cyclohexylurea go out and react this with benzenesulfamides. Instead of the urea derivatives one can also use isourea ethers, expediently in the form of corresponding salts, these with benzenesulfonic acid halides bring the products to reaction and then convert the products thus obtained into the desired compounds by acid hydrolysis convict.

Further possibilities for the synthesis of the new products are that "one first after known methods produces the corresponding thioureas and desulfurizes them, or in them, that one N-benzenesulfonyl-N'-cyclohexylguanidine in a known manner, e.g. B. by reacting benzenesulfonylcyanamides' with cyclohexylamine, produces and hydrolyzes the guanidines obtained. In all cases, benzenesulfonyl compounds can be used in place of alkyl or alkoxylbenzenesulfonyl compounds are also used.

The specified processes can vary widely in their reaction conditions and the be adapted to the respective conditions. For example, the implementations can be made using of solvents at room temperature or at elevated temperature.

The compounds obtainable by the process according to the invention are valuable medicinal agents which are characterized in particular by their excellent blood sugar-lowering effectiveness. They are very well tolerated with low toxicity. In pharmacological and clinical Tests have shown that the compounds reduce blood sugar levels in both healthy and are able to sustainably reduce in diabetic individuals. It is of particular importance that the Blood sugar level is kept very low for a long time after application of the process products and only then very slowly returns to the norm. Another advantage is that the connections can be given in the form of orally administrable preparations.

The compounds mentioned can be used as such or in the form of their salts or in the presence of Substances that lead to a salt formation are used. For salt formation, for example ammonia, alkaline agents such as alkali or alkaline earth hydroxides are used, Alkali carbonates or bicarbonates, and also physiologically compatible organic bases.

Example ι

N- (4-methyl-benzenesulfonyl) -N'-cyclohexyl- ^6s urea

33 S cyclohexylamine and 81 g of N-4-methylbenzenesulfonyl-ethyl urethane with a melting point of 84 to 85 ° - (represented by the reaction of 4-methylbenzenesulfamide with ethyl chloroformate in the presence of potassium carbonate) are heated to iio ° in 150 ecm of methylglycol for 18 hours. The reaction mixture is stirred into soda solution while still warm and then cooled. The undissolved portion is suctioned off and the mother liquor carefully acidified in the cold. The deposited precipitate is dissolved in dilute ammonia, filtered and reprecipitated with acetic acid. The N- (4-methylbenzenesulfony ^ -N'-cyclohexylurea obtained in this way in good yield is filtered off with suction, washed well with water, dissolved in ethyl alcohol in the heat and precipitated by adding water. Melting point 170 ^° .

The process can also be modified in such a way that instead of methylglycol aromatic hydrocarbons, such as xylene, toluene, mono- and dichlorobenzene, are used. For work-up the reaction mixture is extracted with sodium carbonate solution or dilute ammonia, and the alkaline solutions are acidified with acetic acid.

However, it may also enable the N- (4-benzenesulfonyl) -äthylurethan with the equivalent amount of cyclohexylamine and the mixture heated in an oil bath for about 1 hour at 120 to 130 ^0, where subtracting the ethyl alcohol formed in the reaction under reduced pressure. The crude urea obtained on cooling is processed further in the usual way.

Example 2
N- (4-methylbenzenesulfonyl) -N'-cyclohexyl-

urea

17.1 g of p-toluenesulfamide and 30 g of finely ground potassium carbonate are suspended in 250 ml of dry acetone and stirred well under reflux for 1 hour. 12.5 g of cyclohexyl isocyanate are slowly added dropwise to the reaction mixture with stirring. After refluxing for 6 hours, the acetone is distilled off and the residue is dissolved in water. The undissolved material is filtered off with suction and the filtrate is carefully acidified with hydrochloric acid. The N- (4-methyl-benzenesulfonyl) -N'-cyclohexylurea, which has already precipitated in very pure form and in good yield, is reprecipitated from dilute ammonia according to the instructions given in Example 1 and finally recrystallized from a mixture of ethyl alcohol and water. Melting point 170 ⁰ .

Example 3
N- (4-ethylbenzenesulfonyl) -N'-cyclohexyl-

urea

40 g of 4-ethylbenzenesulfamide, melting point rio ° are suspended in 150 ecm acetone and

brought into solution with 105 ecm 2 η sodium hydroxide solution. 32 g of cyclohexyl isocyanate are then added dropwise with stirring add within 30 minutes at about 10 ° and stir after all the isocyanate has been added, another 2V2 hours after. The reaction mixture is diluted with 2 liters of water and with 2N HCl acidified. The precipitate obtained is filtered off with suction and extracted twice with diluted 2V21 each time Ammonia (1:75). The ammoniacal extracts are combined, filtered and with 2 η-hydrochloric acid acidified. The precipitated crude sulfonylurea is taken up in 3 l of diluted ammonia (1: 75) for further purification, of A little undissolved material was filtered off, treated with animal charcoal, filtered again and acidified with 2η hydrochloric acid. The white crystals obtained are recrystallized from 800 ecm 50% ethanol, with the N- (4-ethylbenzenesulfonyl) -N'-cyclohexylurea is obtained in good yield. Melting point 159 to 16o.5 °.

Example 4

N- (3-methoxy-benzenesulfonyl) -N'-cyclohexylurea

ng m-methoxy-benzenesulfamide are in 20 ecm Suspended acetone and diluted with 45 ecm of a dilute sodium hydroxide solution containing 2.3 g of caustic soda Poured over, with solution entering. 7.3 g of cyclohexyl isocyanate are then added at 10 ° slowly added dropwise. For quantitative conversion, the mixture is subsequently stirred for 1 hour. It is filtered and acidified the filtrate with dilute hydrochloric acid. The precipitated N- (3-methoxy-benzenesulfonyl) -N'-cyclohexylurea is suctioned off and redissolved after drying from diisopropyl ether. Melting point 140 to 142 '.

Example 5
N-benzenesulfonyl-N'-cyclohexyl urea

39.2 g of benzenesulfamide are suspended in 84 ecm of acetone. The suspension is mixed with 168 ecm of sodium hydroxide solution with a content of 10 g Caustic soda and slowly dripped into the clear solution obtained at about 10 ° 31 g of cyclohexyl isocyanate.

After the reaction solution has been stirred for a further 1 hour , it is filtered and the crude N-benzenesulforiyl-N'-cyclohexylurea is precipitated with dilute hydrochloric acid the end. After standing overnight, the urea is suctioned off and washed with water and recrystallized from methanol. The pure N-benzenesulfonyl-N'-

cyclohexylurea with a melting point of 190 to 192 ⁰ .

In an analogous manner from 42.7 g of m-toluene-cyclohexyl isocyanate and the N - (3 - methyl - benzenesulfonyl) - N'-cyclohexylurea of melting point 141-142 ^0th

Claims (1)

PATENT CLAIM: Process for the preparation of new benzenesulfonylureas of the general formula SO ₂ -NH-CO-NH where R stands for hydrogen or a low molecular weight alkyl radical or alkoxy radical, characterized in that optionally alkylated or alkoxylated benzenesulfonyl isocyanates with cyclohexylamine or N-cyclohexyl isocyanate or those compounds which convert into N-cyclohexyl isocyanate in the course of the reaction with those of the above form Converts sulfonic acid amides; or that optionally alkylated or alkoxylated benzenesulfonyl urethanes are reacted with cyclohexylamine or N-cyclohexyl urethanes with optionally alkylated or alkoxylated benzenesulfamides; or that cyclohexylcarbamic acid halides are reacted with optionally alkylated or alkoxylated benzenesulfamides or the corresponding benzenesulfonylcarbamic acid halides with cyclohexylamine; or that optionally alkylated or alkoxylated benzenesulfonylureas which _{are unsubstituted in the NH 2} group are converted into the corresponding cyclohexyl compounds by alkylation or by reaction with cyclohexylamine; or that N-cyclohexylurea is reacted with optionally alkylated or alkoxylated benzenesulfamides; or that isourea ethers, expediently in the form of their salts, are reacted with optionally alkylated or alkoxylated benzenesulfonic acid halides and the products thus obtained are then hydrolyzed under acidic conditions; or that one first prepares the corresponding thioureas and desulfurizes them; or that optionally alkylated or alkoxylated N-benzenesulfonyl-N'-cyclohexylguanidines are prepared and these are hydrolyzed. © 609 738/372 12.55 (709 532/285 5. 57)