CH507954A - Hypoglycaemic sulphanilamide derivs. - Google Patents

Abstract

(A) Cpds. of general formula (I) R' = (1-5C)alkyl or (is not >7C) cycloalkyl or cycloalkenyl (B) Acid addn. salts of I. Oral and parenteral hypoglycaemics. Dose 100-500 mg/d. BrCN (10.6 g.) was added to N'-(2-butylamino-ethyl)-N4-acetylsulphanilamide (31.3 g.) in 2N-NaOH (100 ml), stirred 30 mins. at 20-30 deg., filtered, and recryst. from D.M.F., giving N-acetyl-I, m.p.243-4 deg. This (33.8 g.) was heated 1 h. at 80 deg. in 2N-HCl (100 ml), cooled to 20 deg., basified with 2N-NaOH, filtered, washed, and recryst. from EtOH, giving I, m.p.179-181 deg.

Description

       

  
 



  Process for the preparation of new derivatives of sulfanilamide
The present invention relates to a process for the preparation of new derivatives of sulfanilamide.



   Compounds of the general formula I
EMI1.1
 in which R1 denotes an alkyl group with at most 5 carbon atoms, or a cycloalkyl or cycloalkenyl group with at most 7 carbon atoms, and their addition salts with inorganic or organic acids have not yet become known.



   As has now been found, these compounds have valuable pharmacological properties, in particular 1-sulfanilyl-2-imino-3-butyl, 1-sulfanilyl-2-imino-3-tert.butyl- and 1-sulfanilyl-2 -imino-3-cyclohexyl-imidazolidine have hypoglycemic effects when administered perorally or parenterally, which characterize them as being suitable for the treatment of diabetes. The hypoglycemic effect is demonstrated in standard tests on warm-blooded animals, e.g. in rabbits and rats.



   In the compounds of general formula I, R1 can be used as lower alkyl groups e.g. the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, isopentyl, 2,2-dimethyl-propyl, 1-methyl-butyl , 1-ethyl-propyl, 1, 2-dimethyl-propyl group.

  Furthermore, R1 can be, for example: as the cycloalkyl group, the cyclopropyl, cyclopropylmethyl, 2-cyclopropyl-ethyl, 3-cyclopropyl-propyl, cyclobutyl, cyclobutylmethyl, 2-cyclobutyl-ethyl, 3-cyclobutylpropyl, cyclopentyl, 1-methyl-cyclopentyl-, 2-methyl-cyclopentyl-, 3-methyl-cyclopentyl-, 1-ethyl-cyclopentyl-, 2-ethyl-cyclopentyl-, 3-ethyl-cyclopentyl-, cyclopentylmethyl-, 2-methyl-cyclopentylmethyl -, 3-methyl-cyclopentylmethyl-, cyclohexyl-, 1-methyl-cyclohexyl-, 2-methyl-cyclohexyl-, 3-methyl-cyclohexyl-, 4-methyl-cyclohexyl-,

   Cyclohexylmethyl or the cycloheptyl group and, as the cycloalkenyl group, the 2-cyclopenten-1-yl, 2-methyl-2-cy clopenten-1 -yl, 3-methyl-2-cyclopenten-1-yl, 2-ethyl-2 -cyclopenten-1-yl-, 3-ethyl-2-cyclopenten- 1 -yl-, 3-cyclo penten- 1 -yl-, 2-methyl-3-cyclopenten- 1 -yl-, 3-methyl-3 - cyclopenten- 1 -yl-, 2-ethyl-3 -cyclopenten- 1 -yl-, 3-ethyl -3 -cyclopenten- 1 -yl-, 2-cyclohexen-1 -yl-, l-methyl-2-cy- clohexen-1-yl-, 2-methyl-2-cyclohexen-1 -yl-, 3-methyl-2 -cyclohexen- 1 -yl-, 4-methyl-2-cyclohexen-1 -yl-, 3-cyclohexene 1-yl-,

   1 -Methyl-3-cyclohexen-1-yl-, 2-methyl-3-cyclohexen-1-yl-, 3-methyl-3-cyclohexen-1-yl-, 4-methyl-3-cyclohexen-1- yl-, 2- or 3-cyclopenten-1-ylmethyl-, 2-, 3 or 4-cyclohexen-1-ylmethyl-, 2-cyclohepten-1-yl-, 3-cyclohepten-1-yl- or the 4-cyclohepten-1-yl group.



   According to the inventive method, compounds of general formula I are prepared by adding a reactive ester of a compound of general formula II
EMI1.2
 in which X denotes a radical which can be converted into the free amino group by hydrolysis, reduction or reductive cleavage, with an amine of the general formula III
R1 - NH (III) in which R, which has the meaning given under formula I, condenses and cyclizes, if necessary hydrolyzes, reduces or reductively cleaves the reaction product to convert the radical X into the free amino group and optionally cleaves the compound obtained with an inorganic or organic one Acid converted into an addition salt.



   Suitable reactive esters of a hydroxy compound of the general formula II are e.g. Halides, in particular chlorides or bromides, or sulfonic acid esters, in particular a benzenesulfonic acid ester which is substituted by the radical X in the para position. The condensation is preferably carried out in a solvent.



   Alkanols, e.g. Butanol, ethereal liquids, e.g. Dioxane, diethylene glycol monomethyl ether, carboxamides such as N, N-dimethylformamide. or sulfoxides such as dimethyl sulfoxide can be used.



   It is advantageous to carry out the reaction in the presence of an acid-binding agent. Suitable acid-binding agents are preferably excess bases of the general formula III.



   The subsequent conversion of the group X of the reaction product into the free amino group, which converts it into a compound of the general formula I, is carried out, depending on the nature of the group X, by hydrolysis, reduction or reductive cleavage.



   X radicals which can be converted into the free amino group by hydrolysis are, for example, acylamino radicals, e.g. the acetamido group. Furthermore, such radicals are lower alkoxy carbonylamino radicals, e.g. the ethoxycarbonylamino group. Aryloxycarbonylamino radicals, such as the phenoxycarbonylamino radical, or arylmethoxycarbonylamino radicals, such as the benzyloxycarbonylamino radical, or radicals of corresponding thiocarbonic acid derivatives.



  Further examples are substituted methylene amino radicals, e.g. the benzylideneamino or the p-dimethylamino-benzylideneamino group. The hydrolysis to liberate the amino group can be carried out in an acidic medium, e.g.



  in methanolic hydrochloric acid, or in dilute aqueous hydrochloric acid or sulfuric acid or, if X is embodied by an alkoxycarbonylamino radical.



  also under mild alkaline conditions, e.g. by means of 1-n or 2-n sodium hydroxide solution.



   An example of a radical X which can be converted into the amino group by reduction is the nitro group and examples of such radicals which lead to the amino group by reductive cleavage are the phenylazo or p -dimethylaminophenylazo groups. The reduction of these residues can generally be catalytic, e.g. by means of hydrogen in the presence of Raney nickel, palladium or platinum carbon, in an inert solvent such as e.g.



  Ethanol. In addition to these, other customary reduction processes can also be used, for example the reduction of nitro groups or the reductive cleavage of azo groups using iron in acetic acid or hydrochloric acid.



   The reactive esters of the hydroxyl compounds of the general formula II, the symbol X of which corresponds to the groups listed after formula II, are used as starting materials for this process. Such connections are made, for example, as follows:
The starting point is aziridine and this is reacted with cyanogen bromide in ether to form N- (2-bromo-ethyl) cyanamide; this cyanamide is condensed in acetone with a benzenesulfonyl chloride, which is substituted in the para position by the radical X ', in the presence of dilute sodium hydroxide solution with elimination of hydrogen chloride to give a corresponding N- (2-bromo-ethyl) -N-cyanobenzene sulfonamide .



   The compounds of general formula I obtained by the process according to the invention are then, if desired, converted into their salts with inorganic and organic acids. These salts are produced e.g. by reacting the compounds of general formula I with the equivalent amount of an acid in a suitable aqueous, organic or organic solvent, such as e.g.



  Methanol, ethanol, diethyl ether, chloroform or methylene chloride.



   For use as medicinal substances, their pharmaceutically acceptable salts with acids can be used instead of the free compounds of the general formula I. Suitable addition salts are e.g. Salts with hydrochloric acid, hydrobromic acid, sulfuric acid. Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, P-hydroxyethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phen¯lesetic acid. Almond acid and erbonic acid.



   The following examples explain the preparation of the new compounds of general formula I and of hitherto not described intermediates in more detail, but are by no means the only embodiment of the same. The temperatures are given in degrees Celsius.



   Example I a) 34.6 g of N1- (2-bromo-ethyl) -Nl-cyano-N4-acetyl-sulfanilamide are dissolved in 500 ml of ethanol and 7.3 g of butylamine and refluxed for 17 hours. The reaction mixture is evaporated and the residue is taken up in chloroform and 2N hydrochloric acid. The acidic, aqueous extract is treated with conc. Sodium hydroxide solution made alkaline. The crude product precipitates: it is filtered off and purified by recrystallization from ethanol and acetone. The 4 '- (2-imino-3-butyl-imidazolidin-l-ylsulfonyl) acetanilide obtained melts at 249-2510.



   b) 33.8 g of the acetanilide obtained according to a) are heated to 800 for one hour with 100 ml of 2N hydrochloric acid.



  The reaction mixture is then cooled to 20 and made alkaline with 2N sodium hydroxide solution. The precipitated, crude base is filtered off, washed with water and recrystallized from ethanol. The l-sulfanilyl-2-imino-3-butyl-imidazolidine obtained melts at 179 to 181.



   The sulfanilamide that was assumed. can be made as follows:
A solution of 4.3 g of aziridine in 20 ml of ether is added dropwise within 30 minutes at 0 to a solution of 10.6 g of cyanogen bromide in 30 ml of ether. The suspension obtained is evaporated in vacuo at a bath temperature below 400. The residue is slurried in 60 ml of water and the suspension is treated with a solution of 25 g of N4-acetyl-sulfanilyl chloride in 190 ml of acetone.

 

  4.5 g of sodium hydroxide in 10 ml of water are then added dropwise over the course of 10 minutes and the resulting mixture is refluxed for 30 minutes. After cooling, the crude product crystallizes out. It is filtered off.



  When diluted with water, the filtrate gives a further amount of crude product, which is separated off and combined with the first fraction. The two fractions are recrystallized from methanol, after which the N1- (2-bromo-ethyl) -N1-cyano-N4-acetylsulfanilamide melts at 177-1790.



   Example 2
Analogously to Example 1, starting from 34.6 g of N1 - (2 - bromo-ethyl) - N1 - cyano-N4-acetyl-sulfanilamide in 500 ml of ethanol: a) with 31.0 g of methylamine the 4 '- (2- Imino-3-methyl-imidazolidin-1-ylsulfonyl) -acetanilide of melting point 266 to 2670, which hydrolyzes according to Example 1 b) to l-sulfanilyl-2-imino-3-methyl-imidazolidine of melting point 209-2110 becomes; b) with 45.0 g of ethylamine the 4 '- (2-imino-3-ethyl-imide azolidin-l-ylsulfonyl) -acetanilide of melting point 267-2690, which according to example 1 b) for 1-sulfanilyl-2- imino-3-ethyl-imidazolidine with a melting point of 171-1720 is hydrolyzed;

   c) with 59.0 g of propylamine the 4 '- (2-imino-3-propyl-imidazolidine-l -ylsulfonyl) -acetanilide of melting point 253 to 2550, which according to Example 1 b) to 1-sulfanilyl-2-imino- 3-propyl-imidazolidine with a melting point of 164-1660 is hydrolyzed; d) with 59.0 g of isopropylamine the 4 '- (2-imino-3-iso propyl-imidazolidin-1 -ylsulfonyl) -acetanilide of mp.



     253-2540, which is hydrolyzed according to Example 1 b) to 1-sulfanilyl -2-imino-3-isopropyl-imidazolidine with a melting point of 183-1840; e) with 730 g of isobutylamine the 4 '- (2-imino-3-isobutyl-imidazolidine-1 -ylsulfonyl) -acetanilide of melting point 264 to 2650, which according to Example 1 b) to 1-sulfanilyl-2-imino-3 -isobutyl-imidazolidine with a melting point of 146-1470 is hydrolyzed; f) with 73.0 g of sec-butylamine 4 '- (2-imino-3-sec.bu tyl-imidazolidin- 1 -ylsulfonyl) acetanilide of melting point 265 to 2660, which according to Example 1 b) for Sulfanilyl-2-imino-3-sec-butyl-imidazolidine with a melting point of 173-173.50 is hydrolyzed;

   g) with 73.0 g of tert-butylamine the 4 '- (2-imino-3-tert-butyl-imidazolidin-1 -ylsulfonyl) acetanilide with a melting point of 245 to 2470, which according to Example 1 b) becomes 1-sulfanilyl -2-imino-3-tert-butyl-imidazolidine with a melting point of 187-1890 is hydrolyzed; h) with 87.0 g of pentylamine the 4 '- (2-imino-3-pentyl-imidazolidin-1 -ylsulfonyl) -acetanilide with a melting point of 248 to 2500, which according to Example 1 b) becomes the l-sulfanilyl-2-imino -3-pentyl-imidazolidine with a melting point of 167-1680 is hydrolyzed; i) with 85.0 g of cyclopentylamine the 4 '- (2-imino-3-cy elopentyl-imidazolidin-1-ysulfonyl) -acetanilide of mp.

 

     261-2630, which according to Example 1 b) is hydrolyzed to 1-sulfanilyl -2-imino-3-cyclopentyl-imidazolidine of melting point 192 to 1930, and j) with 99.0 g of cyclohexylamine the 4 '- (2-imino- 3-cy clohexyl-imidazolidin-1 -ylsulfonyl) -acetanilide of mp.



  283-2840, which according to Example 1 b) is hydrolyzed to 1-sulfanilyl -2-imino-3-cyclohexyl-imidazolidine with a melting point of 178-1790.


    

Claims (1)

PATENT CLAIM Process for the preparation of new derivatives of sulfanilamide of the general formula I. EMI3.1 in which R7 is an alkyl group with at most 5 carbon atoms, or a cycloalkyl or cycloalkenyl group with at most 7 carbon atoms, and its addition salts with inorganic or organic acids, characterized in that a reactive ester of a compound of the general formula II EMI3.2 in which X denotes a radical which can be converted into the free amino group by hydrolysis, reduction or reductive cleavage, with an amine of the general formula III R, -NH (III) in which R7 has the meaning given under formula I, condenses and cyclizes, if necessary the reaction product is hydrolyzed to convert the radical X into the free amino group, reduces or reductively cleaves and, if appropriate, converts the compound obtained into an addition salt with an inorganic or organic acid.