DE1157599B - Process for the preparation of sulfonylureas - Google Patents

Description

Process for the preparation of sulfonylureas It is already known that chemical compounds are able to reduce blood sugar levels when administered orally to lower. Vonkennel and Kimmig (Klinische Wochenschrift, 20 [1941], p. 2) have z. B. the 2-sulfanilamido-5-alkyl-1, 3,4-thiadiazoles described, their blood sugar lowering Effect Janbon et al. (Cf. Montpellier med., 21 [1942], p. 441; 22 [1942], P. 489) recognized.

Loubatières later reported on experiments specifically with 2-sulfanilamido-5-isopropyl- 1,3,4-thiadiazole in diabetics (cf. Sem. Hop. Paris, 32 [1956], p. 1). Both sulfanilamidoalkylthiadiazoles mentioned are sulfonamides with pronounced bacteriostatic effect.

Belong to the class of sulfonamides with chemotherapeutic activity also the N-sulfanilyl-N'-alkyl ureas, for example the N-sulfanilyl-N'-n-butyl urea, Franke and Fuchs about its blood sugar-lowering properties (cf.

German Medical Wochenschrift, 80 [1955], p. 1449) reports to have.

It is also known that representatives from the series of N-sulfonyl-N'-alkyl ureas, those compared to the above-mentioned compounds in place of the sulfanilyl radical contain differently substituted aromatic or aliphatic sulfonyl radicals, can be used as orally administrable antidiabetic agents (cf. Ehrhart, Naturwissenschaften, 43 [1956], p. 274). These compounds have no chemotherapeutic effects.

From the series of the N ', N'-disubstituted sulfonylureas are hitherto the N-benzenesulfonyl-N ', N'-diethyl urea (see patent specification No. 9688 of the Office for Inventions and Patents in the Soviet Occupation Zone of Germany) and some N-alkanesulfonyl-N ', N'-disubstituted ureas (cf. J. Org. Chem., 23 [1958], p. 925). However, these compounds only have one insignificant hypoglycemic effect.

Furthermore, it is from love. Ann. Chem., 596 [1955], p. 150, the preparation of N- (PMethylben2olsulfonyl) N ', N'-tetramethylene urea is known. The cited publication does not contain any information about any pharmacological, in particular blood sugar-lowering, properties of this compound. As has been established on the basis of extensive pharmacological comparative tests, the in Lieb. Ann. Chem., 596, p. 150, described N- (4-methylbenzenesulfonyl) -N ', N'-tetramethylene urea when administered orally to rabbits at a dose of 400 mg / kg, however, only a moderate lowering of the blood sugar level. The results obtained are compared in the table below with the corresponding values of the N- (4-methylbenzenesulfonyl) -N'-n -butylurea known under the symbol D 860. Dose blood sugar response in 0/0 Connection possible on rabbits after hours peros 1 2 4 6 N- (4-methyl- benzenesulfonyl) - N ', N'-tetra- methylene urinary fabric ....... 400 -25 -25 -25 -20 N- (4-methyl- benzenesulfonyl) - N'-n-butyl-urinary fabric (D 860) ... 400 -25 -40 -40 -40 It has now been found that sulfonylureas of the general formula where R is an alkyl group with 1 to 3 carbon atoms, R1 is a methyl group and R2 is the benzyl group or where R1 and R2 together with the nitrogen atom are the hexamethyleneimino radical and their salts are valuable drugs which, in the absence of chemotherapeutic activity, are characterized by valuable blood sugar-lowering properties.

The alkyl groups R are methyl, ethyl, n-propyl and isopropyl groups into consideration. The substituents can be in any position on the benzene nucleus are located.

The present invention relates to the preparation of the compounds of the formula given. A benzenesulfonamide is used, preferably in the form of its salt or in the presence of salt-forming substances, with an N, N-disubstituted carbamic acid halide or, conversely, a benzenesulfonyl-carbamic acid halide with an N, N-disubstituted amine of the general formula wherein R1 and R2 are as defined above, in the presence of acid-binding agents. Instead of the benzenesulfonyl-carbamic acid halides, it is also expedient to use benzenesulfonyl isocyanates or compounds which form sulfonyl isocyanates under the reaction conditions. Another possibility of synthesis consists in reacting a benzenesulfonyl carbamic acid ester with an N, N-disubstituted amine or, conversely, an N, N-disubstituted carbamic acid ester with sulfonamides in the presence of salt-forming agents.

One can also use a benzenesulfonylurea, a bis-benzenesulfonylurea or an N-benzenesulfonyl-N'-acylurea with an N, N-disubstituted amine or, conversely, a corresponding benzenesulfonamide with a compound which contains the remainder contains, react. The products of the process can also be obtained by reacting a corresponding N, N-disubstituted isourea ether, expediently in the form of a salt, with a sulfonic acid halide and hydrolytically converting the N, N-disubstituted sulfonylisourea ethers into the desired sulfonylureas. Finally, an N ', N'-disubstituted sulfonylthiourea can be prepared and the sulfur atom can be exchanged for an oxygen atom in this compound.

The specified processes can largely be used in their reaction conditions can be varied and adapted to the respective conditions. For example, can the reactions also using solvents at room temperature or be carried out at elevated temperature.

The sulfonylureas obtainable according to the invention are acidic Body that already are soluble in very dilute ammonia. From this fact makes use of the method according to the invention for the pure preparation of the compounds, by treating the reaction mixture with dilute ammonia and then eventually existing by-products are separated. For the pure display is still It is of great advantage that the products of the process which have been pre-cleaned in this way are treated Form crystalline ammonium salts with concentrated ammonia, which are stable and can be recrystallized from water.

In the starting materials used in the process according to the invention it is often a matter of compounds known from the literature. As starting materials are named for example: 4-methylbenzenesulfamide, 4-ethylbenzenesulfamide, 4-n-propylbenzenesulfamide and 4-isopropyl benzenesulfamide.

The corresponding sulfonyl isocyanates, such as 4-methylbenzenesulfonyl isocyanate, can also be used or 4-ethylbenzenesulfonyl isocyanate, sulfonyl carbamic acid halides or sulfonyl carbamic acid esters, which in the ester component is a low molecular weight alkyl radical, for example one Methyl, ethyl, propyl and butyl radicals, or containing an aryl radical, are used of which, for example, 4-methyl-benzenesulfonyl-carbamic acid methyl ester and methyl 4-isopropyl-benzenesulfonylcarbamate may be mentioned. Furthermore are to mention: appropriately substituted benzenesulfonylureas and their acyl derivatives, such as N-sulfonyl-N'-acyl ureas, e.g. B. N- [4-methylbenzenesulfonyl] -N'-acetyl urea, N- [4-ethylbenzenesulfonyl] -N'-acetylurea. There are also correspondingly substituted ones Benzolsulfonsäurehalogenide into consideration. Instead of such connections that are in the Benzene nucleus are substituted in the 4-position, the corresponding, in 2- or better substituted in the 3-position compounds used and with an N, N-disubstituted Amine of the formula given are reacted.

Instead of an N, N-disubstituted amine of the formula According to the process according to the invention, appropriate carbamic acid esters, carbamic acid halides, ureas and isourea ethers which can be prepared from this amine can also be used for the reaction with the correspondingly substituted benzenesulfonyl compounds.

If you want to represent the desired sulfonylureas from the corresponding sulfonylthioureas emanates, for example from N- (4-methylbenzenesulfonyl) -N '-methyl-N'-benzyl-thiourea or N- (4-methyl-benzenesulfonyl) -N', N'-hexamethylene thiourea, one can replace the sulfur stream with an oxygen atom salts or oxides of heavy metals, for example lead, copper or silver compounds or oxidizing agents, For example, use nitrous acid, hydrogen peroxide.

The products of the process show due to the lack of a p-position Amino group on the benzene nucleus does not have the (therapeutic for infectious diseases used) Sulphonamides have a comparable effect, so that even with one lasting several years Medication no generation of resistance is to be feared. Step for the same reason also side effects that can be traced back to a disturbance of the intestinal fiora, not on.

For a long-term therapeutic agent, it is also of great importance that the compounds used are not very toxic and well tolerated. These requirements are largely met by the new process products.

As can be seen from the results of comparative tests contained in the table below, the process products are superior to the known N - (4 - methyl - benzenesulfonyl) - N '- n - butyl urea. For example, N- (4-methylbenzenesulfonyl) -N'-methyl-N'-benzylurea and N- (4-methylbenzenesulfonyl) -N ', N'-hexamethylene urea have a lower blood sugar-lowering effect with about the same blood sugar-lowering effect Toxicity than the well-known N- (4-methylbenzenesulfonyl) -N '-n -butylurea. LDoper Dosage blood sugar reaction in ° / 0 os on the No connection mglkg on rabbits after hours mouse in per lot 1 2 3 4 ~ 5 6 g / kg 1 N- (4-methylbenzenesulfonyl) -N ', N'-hexa- methylene urea (sodium salt ...... 400 10 - 30 - 40 - 40 - 40 - 40 2.15 2 N- (4-methyl-benzenesulfonyl) -N'-methyl- N'-benzyl urea (ammonium salt) .. 400 -20 -40 -40 -40 -40 -45 2.25 3 N- (4-methyl-benzenesulfonyl) -N'-n-butyl- urea (sodium salt) .............. 400 -25 -40 -40 -40 -40 -40 1.80 The numerical values given in the table were determined by comparison with similarly kept, untreated control animals. The blood sugar values were determined according to the Hagedorn-Jensen method.

The blood sugar-lowering effect of the process products can be also in lower doses as well as on other experimental animals, for example show experimentally on guinea pigs, dogs and cats.

The new process products are proportionate in their free form hardly soluble in water.

It is therefore appropriate to use them in the form of their salts, which in general are more soluble to use.

For example, the following can be used for salt formation: ammonia, Alkali or alkaline earth hydroxides, carbonates or bicarbonates, also physiological compatible organic bases. The reaction with ammonia is particularly advantageous suitable for the production of the corresponding crystalline ammonia salts.

The compounds can be used as such or in the form of antidiabetic effective preparations can be used in therapy. For the production of such Such auxiliaries and carriers can be used for antidiabetic preparations which do not change the active ingredients and which also decay quickly of the tablets or coated tablets. In particular, there are neutral fabrics, such as different ones Starches, lactose, talc, tragacanth and magnesium stearate can be considered.

Example 1 N- (4-methyl-benzenesulfonyl) -N'-methyl-N'-benzylurea 91.6 g of p-toluenesulfonyl-carbamic acid methyl ester and 48.4 g of N-methyl-N-benzylamine are mixed together and heated to 130 ° C in an oil bath for 90 minutes. the after recording the response tion mixture obtained in ethyl acetate solution is repeated several times shaken with dilute ammonia, the ammoniacal solutions with charcoal clarified and acidified with hydrochloric acid. The deposited semi-solid precipitate is rubbed with excess ammonia (about 1: 1) and sucked off the resulting crystals. After recrystallization from water, the ammonium salt of N- (4-methylbenzenesulfonyl) -N'-methyl-N'-benzylurea is obtained, that after recrystallization from water between 131 and 137 "C blurred and below Decomposition melts.

Example 2 N- (4-methyl-benzenesulfonyl) -N ', N'-hexamethylene urea 50 g of N- (4-methylbenzenesulfonyl) -N'-acetylurea (produced by reaction of 4-methylbenzenesulfonylurea and acetic anhydride in the presence of concentrated Sulfuric acid as a catalyst) are mixed with 20g of hexamethyleneimine and 11/2 Hours heated to 130 to 140 ° C. The reaction product is taken up in ethyl acetate and the resulting solution shaken several times with about 10% aqueous ammonia. The combined ammomacal solutions are clarified with charcoal and then added cooling with concentrated sodium hydroxide solution. The precipitated crystallized Precipitate is filtered off with suction, dried and boiled with about 1 liter of acetone. The emerging Solution of the sodium salt of the desired sulfonylurea is added dropwise neutralized by concentrated sulfuric acid and filtered hot. After cooling down the filtrate is mixed with ether and the deposited precipitate after Wash with ether dried. The N- (4-methylbenzenesulfonyl) -N ', N'-hexamethylene urea is obtained in the form of its sodium salt with a melting point of 258 to 261 "C.

Claims (1)

PATENT CLAIM: Process for the preparation of sulfonylureas of the formula in which R is an alkyl group with 1 to 3 carbon atoms, R is a methyl group and R is the benzyl group or in which R, and R2 together with the nitrogen atom denote the hexamethyleneimino radical and salts thereof, characterized in that a corresponding benzenesulfonyl isocyanate or a compound which reacts under the reaction conditions like a sulfonyl isocyanate, e.g. B. a corresponding benzenesulfonylcarbamic acid halide, in the presence of acid-binding agents with an N, N-disubstituted amine of the formula in which R, and R2 have the meaning mentioned above, reacts or treats a corresponding benzenesulfonamide, preferably in the form of an alkali metal salt or in the presence of salt-forming substances, with an N, N-disubstituted carbamic acid halide, or that a corresponding benzenesulfonyl-carbamic acid ester is treated with an N, N-disubstituted amine or, conversely, an N, N-disubstituted carbamic acid ester with a corresponding benzenesulfonamide in the presence of salt-forming agents to react, or that a corresponding benzenesulfonylurea, bis-benzenesulfonylurea or N-benzenesulfonyl-N'-acyl- urea with an N, N-disubstituted amine or, conversely, a corresponding benzenesulfonamide with a compound which represents the remainder of the formula contains, reacts, or that a corresponding N ', N'-disubstituted isourea ether, advantageously in the form of its salts, is reacted with a corresponding benzenesulfonic acid halide and the N', N'-disubstituted benzenesulfonyl isourea ether obtained is hydrolyzed, or that a corresponding N ', N'-disubstituted benzenesulfonylthiourea and in these compounds the sulfur atom is exchanged for an oxygen atom in the usual way. ~~~~~~~~ Publications taken into consideration: German Auslegeschrift No. 1 003 716; Liebigs Annalen der Chemie, 596 (1955), p. 150.