BE564006A - - Google Patents

Description

       

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   The present intention relates to novel disulfamyl-aniline compounds having the following general structural formula:
 EMI1.1
 R2 Rl - ## 1 r I R3 #### FL4. SO2 N R4 '-I, lso 2 R5 / and their non-toxic salts, in which formula, is a halogen such as chlorine, bromine or fluorine, a lower alkyl radical advantageously containing 1 to 5 carbon atoms, a radical lower alkoxy also advantageously containing 1 to 5 carbon atoms in its alkyl part, a nitro group or an amino group, R2 is hydrogen or a lower alkyl radical advantageously containing 1 to 5 carbon atoms, R3 is hydrogen, a lower alkyl radical advantageously containing 1 to 5 carbon atonies,

   a lower alkanoyl radical, preferably a straight or branched chain alkanoyl radical containing 1 to 12 carbon atoms, such as one of formyl, acetyl, caproyl, capryl, lauroyl and the like, a radical mononuclear aroyl, such as a bonzoyl radical or a mononuclear aryl-lower alkanoyl radical advantageously containing 1 to 3 carbon atoms in the alkanoyl part, such as one of the radicals phenylacetyl, phenylpropionyl, cinnamoyl and the like, and N R4 is an unsubstituted or substituted amino radical, R4

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 and R5 being, if they are substituted,

   identical or different radicals chosen respectively from alkyl radicals with a straight or branched chain and advantageously comprising 'from 1 to 6 carbon atoms, the alkanoyl radicals preferably having from 1 to 3 carbon atoms, N R4 R5 possibly R represents a heterocyclic ring such as a 5- or 6-membered ring, such as one of 1-pyrrolidyl, 1-piperidyl, 4-morpholinyl and the like.



   The novel compounds according to the present invention constitute useful chemotherapeutic agents, primarily because of their diuretic and / or natri-uetic properties. These compounds can be administered in therapeutic doses in ordinary vehicles or excipients, for example in the form of tablets, these compounds being effective both by the oral route and by injection. Since the compounds according to the present invention are also easily soluble in dilute alkaline medium and in solutions of polyethylene glycol, injectable solutions can be prepared by dissolving the desired compound in the chosen medium, to which preservatives or preservatives can be added, if desired.



   The new compounds according to the present invention can also be used for the preparation of new compounds of benzothiadiazine 1,1-dioxide, which also have diuretic and / or natriuretic properties.



   The disulfamylaniline derivatives according to the present invention can be prepared by a number of methods. Two processes, which have been found to be particularly suitable for the preparation of these compounds, can be illustrated as follows:

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 R2 1 N ¯ R3 R1: O¯N..R3 4- .. S02N / R R4 NSO2 z R "0, R5 III 1. Ammonia or amine 2. Acid chloride or anhydride R2 R2 v 1 R 1.01SO13ii R 1 S0Gl 2.N c (Cl,,. S0201 i C1S02 II Acid anhydride or chloride << R2 R2 t - N - R3 -N.R3 .. R3 ammonia R 1 N..R3 p4! I ..

   SO 2 Cl or R4% i% ..SO 2 N ¯ Rr; I amine 4 NSO. ./ "cis amine R4 \ NS02 IV R 5 /
Some disulfonyl (II) chlorides are known and those which have not been described in the literature can be readily prepared by chlorosulfonation of the selected aniline compound (I), preferably in the presence of an alkali metal halide. , such as sodium, potassium or lithium chloride. For all practical purposes, one can use

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 sodium chloride, because this compound is easy to
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 to obtain and is pnu expensive, 1;, ridis that in its presence the reaction ion progresses in a very uniform manner.

   Since the reaction between these ingredients is generally very vigorous, it is preferred to add the aniline derivative to the chlorosulfonic acid, drop by drop, citing and cooling.
 EMI4.2
 health. When all of the aniline derivative has been added, the alkali metal chloride is added in small fractions, so as to allow moderate evolution of hydrogen chloride. After that, the mixture is heated to a temperature between 100 and 200 C, preferably in an oil bath.



   The disulfonyl (II) chloride thus obtained can then be converted to the disulfamyl derivative (III) by treatment with ammonia or with a primary or secondary amine, by well-known methods. If desired, after the reaction
 EMI4.3
 tion with the onipc or with a pY'i! 11Gire or secondary amine, the resulting product can be reacted with the agent.
 EMI4.4
 the desired acylation, preferably in a steam bath, so as to form the corresponding acylated aniline compound. The acylating agent can be any of the agents described later for this use.



   As a variant, the disulfonyl (II) chloride can be acylated with the aid of an organic acid chloride or anhydride, the acid being advantageously chosen from alkanol acids.
 EMI4.5
 lower ones, such as: acetic, propiolic, caproic, capric, stearic and anyl acids, or among the aryl mononuclear acids IIIonogrboxylic :; or aryl mononuclear lower alkanoic acids, such as benzolques, phenylacetic, phenylpropionic, cillnamic and analogous acids C3tt, the reaction pVOgF> jss13 very uniform on heating moderately a steam bath, so that one obtains 14-acyl-diulfonyl (IV) chloride.



  The acylated compound (IV) can then 8trM converted to an amide

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 corresponding by treatment with ammonia or with a primary or secondary amine, by the process described above for the conversion of disulfonyl chloride (compound II) -in.disulfamyl compound (compound III).



   The desired salt of the disulfamylaniline compounds of the present invention, wherein R4 or R5 denote hydrogen, can be advantageously prepared by dissolving the selected compound in an aqueous or alcoholic solution of a metal hydroxide. alkaline and, if desired, isolating the salt by evaporating the solvent.



  Any common alkali metal salt, such as sodium, potassium, lithium, or the like can be prepared by this method or by other methods known to organic chemists.



   The preparation of the compounds according to the invention is described in more detail in the following examples. It should be noted, however, that these examples only constitute illustrations of the compounds coming within the scope of the invention and of the processes which can be used for their preparation, these examples should not be considered as limiting the invention to particular compounds or to particular methods described therein.



   EXAMPLE 1. - 5-Chloro-2.4-disulfamylaniline. -
M-Chloroaniline (64g, 0.5mol) was added dropwise with stirring to 375ml of chlorosulfonic acid in a 3 liter round bottom three-necked flask cooled in an ice bath. Sodium chloride (350 g) was added in portions over a period of 1 to 2 hours and the mixture was then gradually heated in an oil bath to 150 C. After 3 hours of heating. to 150-160 0, the flask was cooled strongly in ice-cream and its contents were treated with 1 liter of cold water.

   The product was extracted with ether and the former

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 The milk was washed with water and dried over sodium sulfate. After removing the ether on a steam bath, the 5-chloraniline-2,4-disulfonyl chloride, which can be crystallized from a mixture of benzene-hexane (PF 130- 132 C) was cooled in an ice bath. and treated with 150 ml of 28% ammonium hydroxide in a 2 liter Erlenme --- er flask. The mixture was heated on a steam bath for 1 hour and cooled and the product was collected on a filter, washed with water and dried.

   After crystallization from dilute alcohol, 5-chloro-2,4-disulfamylaniline was obtained as colorless needles; P.F.: 251-252 C.
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  Analysis for 6HaCIN} 04S2: Calculated: 0 = 25.22%; Hx2.82% 1; PI = 11 '71 ô Found: C = $ 25.1; I = 2, $ l; ô; N = 14.68% EXF1-TPLE 2.- 6- <Cihlsro-JZ,! - disulfamylaniline.-
O-Chloroacetanilide (15.2 g) was added portionwise to 120 mL of chlorosulfonic acid at room temperature, after which 100 g of sodium chloride was added portionwise over one hour. The mixture was then gradually heated to 150 C in an oil bath over half an hour, and then kept at 150 C for two hours. After intense cooling in an ice bath, the reaction mixture was treated with 500 ml of ice water and the product was taken up in ether, washed with water and dried over sodium sulfate.

   After removal of the ether by evaporation on a steam bath, the residual disulfonyl chloride was cooled in an ice bath and treated with 50 ml of 28% ammonium hydroxide. The ammoniacal solution was heated in a steam bath for 1 hour, then cooled, after which the product was collected.

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 on a filter. By crystallization from dilute alcohol, 6-chloro-2,4-disulfamylaniline was obtained in the form
 EMI7.1
 colorless needles; P.F .; 212..21. vs.



  Analysis for C6H $ C1N30 * SZ: Calculated: G = 25.22 $ S; H = $ 2; N = 14.71% Found: 0 = 25.52%; ff = 275; N, 14.59%.



  EXAMPLE 3.- 5-Br omo-l.-disulfamylaniline. -
M-Bromoaniline (86 g, 0.5 mole) was added dropwise over 1 hour to 375 ml of chlorosulfonic acid cooled in an ice bath. Sodium chloride (350g) was added in portions over 2 hours and the mixture was then heated in an oil bath at 150 ° C for 3 hours. After intense cooling in an ice bath, the reaction mixture was treated with 1 liter of ice water. The product was taken up in ether, washed with water and dried. After removing the solvent on a steam bath, the residue was cooled in an ice bath and treated with 150 ml of 28% ammonium hydroxide.

   After the initial vigorous reaction had ceased, the mixture was warmed in the value bath for 1 hour, then cooled, after which the precipitate was collected on a filter. By crystallization in dilute alcohol, 5-
 EMI7.2
 bmo-R4.-disulfamylanilinP in the form of colorless needles; M.p. 265-267 C,
Analysis for C6H8BrN3O4S2;
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 Calculated: C = 21.2it; H = 2 tl ,. ; N = 1273;, 0 Found: C = 22.0% Cb; ü = 2.72; N, 12.72.

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  EXEI \ IPLE 1, .. - 2, l-li sulf :, m.yl-5methY, lanil.ne. -
By replacing the m-bromoaniline used in Example 3 with an equimolecular amount of m-toluidine (53.5 g) and by substantially following the procedure described in Example 3, 2,4-disulf & myl was obtained. - 5-methylaniline in the form of colorless needles; P.F .:
 EMI8.2
 21i.6-2ia.7 C.



  Analysis for C7H11N3z: Calculated: C = 31.69; H = the $ 1 ;; r = $ 15 Ir; â Found: C = $ 31.5 ;; H = 3.97%; N = 15, $ 4.



  EXF.T4IPLF 5: 4-Chloro-2.5-disulfsmylFniline.-
By replacing the m-bromoaniline employed in Example 3 with an equimolecular amount of 5-amino acid
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 no-2-chloroben ne-sulfonic acid and by substantially following the procedure described in Example 3, Q-chloro-2,5-disulfamylaniline was obtained in the form of colorless needles, m.p. 289-290 C
Analysis for C6H8C1N3O4S2;
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 Calculated: C = 25.22%; H = $ 2 ;; N = 14.71% Found: C = 25 r 51 ;; H = 2, ES; fl; N = 1.58 ExEi, 11.1.6 - 2 yl-Disulfamyl-5-methoxyaniline. -.



   Chlorosulfonic acid (150 mL) was added dropwise over 30 minutes with stirring to 24.6 g (0.2 mole) of ice bath cooled m-anisidine.



  When the addition of chlorosulfonic acid was complete, 140 g of sodium chloride was added in portions over one hour. The mixture was heated for 2 hours in a steam bath, then for 3 hours in an oil bath (150-160 C), after which the mixture was cooled.

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 strongly in an ice bath and treated with 500 ml of ice water. The product was taken up in ether, washed with water, dried and removed from the solvent by evaporation on a steam bath.

   The residue was cooled in an ice bath and treated with 100 ml of 28% ammonium hydroxide, The precipitate was collected on a filter, washed with water and recrystallized from water, so that 2,4-disulfamyl-5-methoxyaniline was obtained in the form of colorless needles; P.F.: 252-253 C.



   Analysis for C7H11N3O5S2;
 EMI9.1
 Calculated: 0 = 29.69%; H = 3, .j; N = li., 94 ;, 'Found: C = 30.12 <<; H = 1.09 ;; N, 14.93%.



  EXENPLB 7. - 2,1-Disulfamyl-5-nitroaniline.-
To a solution of 27.6 g of m-nitroaniline in 150 ml of chlorosulfonic acid was added portionwise 140 g of sodium chloride with stirring over the course of one hour. After heating at 160 ° C for 2 hours, the reaction mixture was cooled in ice and treated with 1500 ml of ice water, after which the product was extracted with ether. The ethereal extract was dried over anhydrous sodium sulfate, filtered and evaporated to dryness on a steam bath. The residue was cooled in an ice bath and treated with 100 ml of 28% ammonium hydroxide. After heating in a steam bath for one hour, the reaction mixture was cooled and the solid was obtained. collected on a filter.

   By recrystallization from water, there was obtained
 EMI9.2
 2, γ-disulflamyl-5-nitro-nnilino suüs colorless needle; M.P.: 260-262 0.



   Analysis for C6H8N4O6S2;
 EMI9.3
 Calculated: 0 = 24.32 /; It = 2, 72 ;; N = 1.91 Found: 0 = 24.53%; II = z'1 ;; Pd = 19.11 ,.

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 EXAMPLE 8. -
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 5-Amino - ', l..disulfa, lanilin ^ A solution of 3 g of 2,1-disulfamyl-5-nitroaniline, obtained as described in Example 7, in 150 ml of ethanol was stirred. with hydrogen in the presence of 250 mg of platinum oxide until the end of hydrogen absorption (4 hours). The catalyst was filtered off and the alcoholic solution was concentrated to dryness in vacuo. The residue was recrystallized from
 EMI10.2
 some water.

   5-Amino-2, γ-disulflamylaniline was obtained as pale yellow needles; P.F .: 245-246 c, (dec.)
Analysis for C6H10N4O4S2;
 EMI10.3
 Calculated: 0 = 27.06%; H = 3.7c; ô; ir = 21.0 .; Found: 0 = 27.37%; F'¯ = 3.95 >>; N, 21.06; ".



  EXPLE 9 ....



  5-Chloro - ?, 1-disulfanylacetnilida. 5-chloroaniline-2.4-disulfonyl chloride (3.8 g) prepared as described in Example 1, was dissolved in 10 ml of acetic anhydride and after being left for 1/2 hour at room temperature, the solution was cooled in ice and the product was collected on a filter. After crystallization from a mixture of benzene and hexane, chloride was obtained.
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 of 5-chloro-acetanilide-2, @ - disulflonyl which, after separation by filtration, was added in fractions to 50 ml
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 Liquid, after which the ammonia was allowed to evaporate at room temperature. The residue was dissolved in 10 ml of water, acidified with 5 ml of concentrated hydrochloric acid and the crystalline product was collected.
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 on a fliter.

   Ppr recrystnll: 1s [tion of the water, 1, .. '5-crtloro-, 1H-.aisul.Ca.rnyl-Ûcét; on xlide: in the form of colorless needles ; P.F .: 261-262 c (dec.).

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  Analysis for C6H10C1PT055 ?: Calculated: C = z9.31ô; H = 3.0%; Td = 12, $ z; Found: 0 = 29.49; H = 3.5 ;; TT = 1Z, $ 5ja EXAMPLE 10 N-Benzoyl-5-chloro-2, @ - disulfanlylaniline A solution of 6.6 g of 5-chloroaniline- ^ 1 * -disulfonyl chloride prepared as described. in Example 1, in 10 ml of benzoyl chloride was left at room temperature for 17 hours.

   The crystalline product was collected, washed with a small amount of benzene and crystallized from a mixture of benzene and hexane, so that N-benzoyl-5 chloride was obtained.
 EMI11.2
 -chloroaniline-2,% - cii.si; ù- ±, Sii;. S '-' U8 forms colorless needles; M.P .: 171-173 C (dec.). The disulfonyl chloride thus obtained (7.4 g) was added to an excess of liquid ammonia (50-75 ml) and allowed to evnporate to dryness at room temperature; The residue was crystallized from dilute alcohol, so that N-benzoyl 5-chloro-2,4-disulfamylaniline was obtained; M.P .: 266 C (dec.).
 EMI11.3
 



  Analysis for c13rOClR304S2: analysis for 13 l-1 .. 3 4S, '-: Calculated: C = I * 0'GS;:; H =), 10 ;; '; IT = $ 10.7; Found: 0 = 39.96; T3--3.7; N = 10.6; EIZi'0i: ± Il.¯ N-But: rry1-5-chl.oroz, l, ... d 1; 1f1Tty1aI1111.T1t '..-
A solution of 5.4 g of 5-chloroaniline-2,4-disulfonyl chloride, prepared as described in Example 1 in a mixture of 10 ml of butyric anhydride and 10 ml of benzene was allowed to stand. at room temperature for 1 hour. After cooling in an ice bath, the ciiatalline product was collected and crystallized from a mixture of benzene and hexane, so
 EMI11.4
 that N-butyryl-5-chloroaniline-2,4-disulfonyl chloride was obtained in the form of colorless needles; P.F ..

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 121-122 C.

   The disulfonyl chloride thus obtained (9.9 g) c was added in fractions to an excess of liquid ammonia (100 ml), then the mixture was allowed to evaporate to dryness at room temperature. was treated with water and the product was collected on a filter.
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  By recrystallization of picool ::: queux, N-butyl-5-chlaro-2, @ - disi; lft> iaylaniline was obtained.



  RXEnPLE 12.N-Ciproyl.-5-chloro-2,, 4-disulfem-vlaniline. 5-crloroiniline-21-disulfonyl chloride (5g), prepared as described in Example 1, a
 EMI12.3
 Was dissolved in 10 µl of n-cr anhydride produced with moderate heating in a steam bath, after which the solution was left at room temperature for 2 hours. The crystalline product formed was collected and recrystallized from hexane, so that chlorine was obtained.
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 re 'of iI-caproyl-5-chloroaniline-2, µ-disulionyl, in the form of colorless needles; P. F. 91-93 G. The disulfonyl chloride thus obtained (9.9 g) was added in portions to 50 ml of liquid ammonia.

   The solution was then allowed to evaporate to dryness at room temperature, the residual solid was treated with 50 ml of water and the product was collected on a filter.



  By recrystallization in aqueous alcohol, we obtained
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 I-caproyl-5-chloro-2,1i.-disulfamyl-aniline in the form of colorless needles; P.F .: 213-215 C.
EXAMPLE 13.-
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 , 1, ... Disulfamyl-.5-fluoro-N..phenyla cetYh, n3¯lin e. By replacing the m-chloroiniliiio in Example 1 with an equimolecular amount of m-fluoroaniline and substantially following the process described in Example 1, for the preparation of 5-chloroaniline-2,4-disulfnyl chloride, we prepared 5-fluoroaniline chloride- disulfonyl chloride
 EMI12.7
 j.4-disulfony <Lall; insi obtained 8 was dissolved in chloride-

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 of phenyl-acetyl and the solution was left at room temperature for 17 hours.

   The product was collected and washed with benzene so as to obtain sodium chloride.
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 5-Fluoro-No-phenylacetylaniline - ?, i + -disulfonyl, which after addition to an excess of liquid atllonic acid and evaporating to dryness at room temperature gave 2, -
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 disulfamyl-5-fluoro-N -phenylecétylé: niline.



  ECF, j \ 7PLf !: 14 ....



  5-Chlo ro -2, 1 + .- di- (N -in4t, byl sylfam 1 d auJl ine. -
5-Chloroaniline-2,4-disulfonyl chloride (6.6g), prepared as described in Example 1, was added portionwise to 40% aqueous methylamine (50ml). After heating on a steam bath for 1 hour, the reaction mixture was cooled and the crystalline solid was collected on a filter. By recrystalll. satation in aqueous alcohol, 5-chloro-
 EMI13.4
 2; -di -. (PT-methyl-sulfmnyl) anilina in the form of colorless needles; M.P .: 175.5-178 È.



  Analysis for CH1Cl1230S2: Calculated: C = 30, G21; H = 3, b ;; N13930 Found: C = 3 C f5: i N = 3 1 N = 13.347, P, XJ, -, 5-PLr, 15. ¯ 5-0hloro-2, .-- tif-rH -rrtéthy1su1fBmv1) -N .. .formyl-An: 1.line .A mixture of 5-chloro-2,4-di- (N-methyl-lsulfamyl) aniline (2, F3 g), prepared as described in Example 14 and ethyl orthoformate (4 mil) was heated at 110-130 ° C for one hour and then for a further 15 minutes 4130-150 ° C. By rch.lr4id.s; .ement a solid residue was obtained which was filtered off and recrystallized from aqueous alcohol, so as to form
 EMI13.5
 5-chloro-2, rr ... di- (Iv -mcthylsulfmyl) -N.-formyl-. rrilire, in the form of colorless platelets; M.P .: 192-195 C.

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  Analysis for CHIZC1N305S2: Calculated: c * 31.63il; H = 3.54 6; Nno Found: C = 31.99%; H = 36; N = 12.29 %% EXAMPLE 16. -
 EMI14.2
 5-Chloro-2,4-di- (N -ac ethylsulfamyl) acetanilide.A mixture of 5-chloro-2,4-disulfamylaniline (2.9 g) prepared as described in Example 1, and Acetic anhydride (10 ml) was treated with two drops of concentrated sulfuric acid. After one hour, the crystal mass was cooled in ice and the product was collected on a filter and washed with water. By recrystallization from alcohol, 5-
 EMI14.3
 Chloro-2, @ - di- (N-ecetylsulflemyl) acetanilide, in the form of colorless needles; P.F.: 222-224 C.
Analysis for C12H14C1N3O7S2;
 EMI14.4
 Calculated: C = 31.9914; H = 3.43%; rT = lo, 2.



  Found: CÇ31.91ja; H, 3.77%; N, 10.1.



  EXAMPLE 17.-, Chloro-2,4-di .- (1-piperid¯rlsulfonyl) aniline.-
A solution of 5-chloroaniline-2,4disulfonyl chloride (9.7 g), prepared as described in Example 1, in benzene (200 ml) was added dropwise over 10 minutes to piperidine. (50 ml).



  After heating on a steam bath for 3 hours, the mixture was cooled and washed successively with two 50 ml portions of water, with 1 portion of 50 ml of dilute hydrochloric acid and with a 50 ml portion of water. The benzene solution was dried over sodium sulfate and concentrated to dryness in vacuo.

   By recrystallization of the residue from ethanol, there was obtained
 EMI14.5
 5-chloro-2,1-di- (1-piperidylsulfonyl) aniline, in the form of colorless needles; P.F .: 162-164 C.
Analysis for C16H24C1N3O4S2;

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 EMI15.1
 Calculated: 0 = 45.75%; H = 5176lo; Nu Found: 0 = 46.04%; H = 5.67%; N = 100j, EXAMPLE 18- 5-Chloro-2.4-di- (NTN-dimethylsulfamvl) aniline.- A mixture of 5-chloroaniline -?, @ - chloride. disulfonyl (9.7 g), prepared as described in Example 1, and 25% aqueous dimethylamine (100 mL) was heated in a steam bath for 11/2 hours and baked.



  The product which separated was separated by filtration, then recrystallized from ethanol, so as to form 5-chloro-2,4-di- (N, N-dimethylsulfamyl) aniline in the form of colorless needles; M.p .: 182-182.5 C, Ahalyse for C10H16C1N3O4S2;
 EMI15.2
 Calculated: C = 35.14 :; H = H, 516; N = 12.29fo Found: C = 35.53%; H = @, $ 78; N, 12.30.



  Zh [Ei.iPL ± l.-, -Chl oro-.2, ... disulfamyl-N..inethylaniline ...



  By replacing the III-chloroaniline used in Example 1 by an equimolecular amount of N -methyl-m-chloroaniline and by substantially following the procedure described in Example 1, 5-chloro-2,4 was obtained. - disulfamyl-N-methyl-aniline.



   EXAMPLE 20. -
 EMI15.3
 -But 1-2 -di- 11-n-butt lsulfarn 1 -N N-lauro l-. rov lanil3 ... ne. - By replacing the m-chloroaniline used in
 EMI15.4
 Example 1 by a c; uanti.tWquimalécu7.aire of m-butyl-Npropyixniline and by substantially following the operating procedure described for the chlorosnlfonation of the derivative of an3.line described therein, 5-butyl chloride was obtained. N-propylaniiine-2 ,, .. disulfonyl. 5 g of the disulfonyl chloride thus bzz ohtenus was dissolved in 1 <uranyl chloride (10 ml) and the solution O; IjC; nl.1t;) was ohsur.r6n h: 4iËaTc: uvs bath of

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 steam. The reaction mixture was allowed to come back.
 EMI16.1
 At room temperature and solilized oroduJi, the form was collected on a filter.

   Acres crystallization from a mixture of benzene and hexane, there was obtained chloride of
 EMI16.2
 5-butyl r1, N-lauroylpropylantline-2I-disulfonyl chloride and disulfonyl chloride were added fractionally to n-butylamine (50 ml), after which it was heated for about 1 hour in a steam bath. After cooling to room temperature, the solid product was collected on a filter, washed with water and crystallized from a mixture of alcohol and water, whereby it was obtained.
 EMI16.3
 obtained 5-Butyl-2.4-di- (Il-n-butylsulf-iriyl) -N-Nlauroylpropylaniline.



  EXAMPLE 21. - 2a t, .- Di - (! 'D. Nn-butyl3tnrlsulfam., Rl ..5¯mëth, ylanilinp. By replacing the m-chloronniline used in Example 1 by an ecular quantity of m -toluidine and by substantially following the procedure described for the chlorosulfonation of the derivative of aniliaa described therein, 5-methylaniline chloride -?, @ - disuliony] .e. Five grar2ces of the disulfonyl chloride thus obtained were then obtained. Fractions were added to n-butylethyleniine and the mixture was heated for about 1 hour on a steam bath After cooling to room temperature the product was collected on a filter and washed with water.
 EMI16.4
 water, whereby 2,1.-di- (N, N-nbutylethylsulfamylj-5-m4thylniline was obtained.



  EKEi PL 22.- -Pro ox - .. '. -di-. -xror holin lsulfonrl -rT-but l: nil3.ne By replacing the rn-chloroaniline used in example 1 by an a, ur.nt 3 i: é eciu3.! nol 'cul i re of m-prop: ": YN-but% 3.einiline and following substantially the procedure described therein for the chlorosulfonation of the aniline derivative ', 5-propo; y-tl-butjrlaniline-2, @ - disulfonyl chloride was obtained. After separation by filtration, 5 g of

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 The disulfonyl chloride thus obtained was added in portions to morpholine (50 ml) and the mixture was heated for about 1 hour on a steam bath.

   After cooling to room temperature, the solid product was collected on a filter, washed with water and crystallized from a mixture of alcohol and water, followed by removal.
 EMI17.1
 5-propoxy-2,4-di- (4-rnorpholinylsulfonyl) -N-butylaniline was obtained.



  EXAMPLE 23.-
 EMI17.2
 2,% - Di- (N, t'-dinethylsulfamvl) -5-Propoxv-N-cinnamoYlaniline,
By replacing the m-chloroaniline used in Example 1 by a molecular amount of m-propoxyaniline and by substantially following the procedure described therein for the chlorosulfonation of the aniline derivative, 5-propoxyaniline-2 chloride is obtained, 4-disulfonyl. Five grams of the disulfonyl chloride thus obtained was dissolved in cinnamoyl chloride (10 ml) and the solution was heated briefly on a steam bath. The reaction mixture was then allowed to cool to room temperature and the solid product thus formed was collected on a filter.

   After crystallization from a mixture of benzene and hexane, bn obtained
 EMI17.3
 5-Propoxy-Pd-cinnamoylaniline-2I-dis.tl.fo-nyl chloride. After separation by filtration, this chloride was added in portions to 25% aqueous dimethylamine (50 ml) and heated for about 1 hour in a steam bath. After cooling to room temperature,
 EMI17.4
 the solid product at 4, received (-111.i on a filter and washed with water, so that 21-di- (N, N -dimethylsul f8myl) -5- was obtained. propoxy-N -cinnfJmoyl '> Q \ llne.



  EXAMPLE 25 ...



  Sodium salt of -chloro- -disulfam lan9.linca. 5-thloro-2,4-disulfamylaniline obtained as described in Example 1 is dissolved in alcoholic sodium hydroxide (2equivalents) and the O.-

 <Desc / Clms Page number 18>

 vant is then evaporated in vacuo, so that we obtain
 EMI18.1
 the sodium salt of 5-c: chloro-N-disulfamylaniline.



  EXE1PY: 1 .g5 .. :: ...



  Tablets tablets containing 0.5 active ingredient.
 EMI18.2
 
<tb>
<tb>, <SEP> Ingredients <SEP> Quantity
<tb> ¯¯¯¯¯¯¯¯ <SEP> grams
<tb> 5-Chloro-2,4-disulfamylaniline <SEP> 500.0
<tb>
 
 EMI18.3
 Dtrgiidon box 12-1 / 2, 100 cc 1¯2.5
 EMI18.4
 
<tb>
<tb> Total <SEP> 512.5
<tb> Starch <SEP> from <SEP> but <SEP> U.S.P. <SEP> 25.0
<tb> Magnesium <SEP> <SEP> stearate <SEP> 5.5
<tb> Total <SEP> 543.0
<tb>
 
 EMI18.5
 The 5-chloro-2,1-disulfamylaniline is granulated with the starch paste and the still wet granulated mass is passed through a No. 14 sieve, dried at 45 C for 20 hours and then passed through a sieve three times. n 14. The starch is then passed through a n 90 filter cloth and added to the granulated product, after which all the ingredients are thoroughly mixed.

   The magnesium stearate is then passed through a No. 90 cloth and added to the mixture. After mixing, the granulated mass is compressed into tablets using a 14/32 "flat punch beveled and having a thickness of 0.205 ¯ 0.005". There are thus obtained 1,000 tablets each weighing 0.543 g and having a hardness of 6 kg measured by the tablet hardness meter of the Monsanto Chemical Company, and a disintegration time of 5 minutes measured using the American Pharmacopoeia Tablet Disintegrator (15th Edition, page 937).


    

Claims (1)

EMI19.1 Rr ,, VE, NDICA.TI ON S. - 1.-Derivatives of disulfamylaniline chosen from the group comprising the compounds having the following general structural formula: EMI19.2 R2 t ¯ R3 R 1 ¯ 3 Y - so 2N "ll R R5 '-" - and their non-toxic alkali metal salts, in which formula R1 denotes a halogen, a lower alkyl radical, a lower alkoxy radical or an amino radical , R2 denotes hydrogen or a lower alkyl radical, R3 denotes hydrogen, a lower alkyl radical, a lower alkanoyl radical, a mononu- EMI19.3 key or a lower mononuclear aryl7alkanoyl radical, while R and R5 denote respectively hydrogen, a lower alkanoyl radical, a lower alkyl radical or lower alkyl radicals linked so as to form, with the nitrogen atom to which they are attached, a 1-piperidyl, 4-morpholinyl or 1-pyrrolidyl heterocyclic ring. 2. - A disulfamylaniline compound having the following general structural formula: EMI19.4 - NII2 Ha 1 NH2 'HzNS02 - - SO2NHz in which Hal is a halogen radical. <Desc / Clms Page number 20> EMI20.1 3.- 5-Cliloro-2.-disulfamylsnil: tne. 4. - 6-Chloro '? .- disulf <^: ylGnilina. 5.- A compound of 4isuifamylaniiine having the following general structural formula: EMI20.2 H - N - Ac Ha 1 H2RS0z - - S02NII2 in which Hal is halogen and Ac is lower alkyl radical. EMI20.3 6.- N-Caproyl-5-chloro-2,4-disulfamylpniline. 7.- A process for preparing a disulfamyleniline compound, in which an aminobenzene-disulfonyl chloride having the general structural formula is reacted EMI20.4 following: R2 NH f5: R 1 ÇJ '- SO:, C, 1% / -SO .- .. C1 C1S02 in which R1 denotes a halogen, a lower alkyl radical, a lower alkoxy radical or a May- and 2 radical EMI20.5 no-; JR2 denotes hidro6: ne or a radical; 'lower lcoyls, with 1an.oni.ac or with an amine, of a substance to form the corresponding 6minobenzne-disul.ronchlide, which can be fpÍ ; :: 'o ensuibe rcaii.-' with a k) logn1.1, re of organic acid or with an atiyd'ride of acid or ..:; :: nique, so :( '0' l ... form a disulf [J'lJylDuiline of structural form EMI20.6 general following: nR. 1 f '-SCLN (' i, - lSO ') - 2 ") R51 2 z1' <Desc / Clms Page number 21> EMI21.1 in which R1 and R2 have the significance indicated above ,. R3 denotes hydrogen "a lower alkyl radical,. A. Lower alkyl radical,; a mononuclear aroyl radical or a mononuclear alkyl-alkanoyl 'rsdi'cal' inî: Liéur, t'1n: li's qu? R and R5 denote respectively of l1hy'clrone "an αiconoyl radical in: feri'8ur ,. a lower al.coyl radi.cal, or lower ol-coyie radi'caux connected so as to. form with the atom of a zobe to which they are attached a. ring Yterocycliqup 1¯-pipér.id.yle ,, 4-morRholi'nyle or 1-pyrr.olitl fle.¯ 8 ..- Eroçêdé to prepare- a compound of d'sulfamyl-.¯aniline in which a raminoienzene-disulfon chloride is reacted having; the general structure formula EMI21.2 next rr i 1 <bzz R 'CIP, i 1 * 16b - "> Ti. C1SQ? '' EMI21.3 in the case of R 'denotes halogen, a lower alkyl radical, an a7: infrared oxy or. a radical amt ---% t'If. :) e; R2. desigpe of I.thydra4ene or \ 11];), alkyl radical (i! 1! .r ': eieur)! 3v, ec an orzanic acid chloride olu with an organic anhydride, so e. forming the corresponding 1,1-acyl derivative, which is then chiuf ± 6 ave of ammoniac C or with a 1 ;; nine; so as to train. EMI21.4 a disulfamylaniline of formula of the following general structure EMI21.5 nz t Ri 0 ... N n3) 1 - R4. 5 'HSO 2 14 \ R5 .R5 / <Desc / Clms Page number 22> d: -. m which R1 and R2 have 1. meaning indicated above, R3 denotes HYDROGEN, a LOWER alkyl radical, a lower alkanoyl radical, a mononuclear aroyl radical or a mononuclear aryl-lower alkanoyl radical, while R4 and R respectively denote hydrogen, an interior alkanoyl radical, a lower alkyl radical or lower alkyl radicals linked so as to form with the nitrogen atom to which they are attached a 1-piperidyl, 4-morpholinyl or 1-pyrrolidyl heterucyclic ring.