BE548145A - - Google Patents

Description

       

   <Desc / Clms Page number 1>
 
 EMI1.1
 



  It is known that certain compounds of the class of J. mil1obenzenesulfomides lower the sugar content of sclng in experimental animals, patg-xer [irle in chin. Thus, for example, para "'l: 3.mirlQ (, enzèn (-sulf.mido-isopropylth, odiaol causes a moderate decrease in the blood sugar content in dogs for 4 to 6 hours) (compare Jean la Barre and Jean Reuse, Arch.nëerland.physiol. 2e (19iF7) pé1CO 473) 'We know, on the other hand, doo roprosentants due benzonesulfonyluruos, 1 COMIlO la 1% -bé> nzénesuLòny.lu;, ùe, la ly '-benrul-

 <Desc / Clms Page number 2>

 
 EMI2.1
 nesulfonyl-N '-phenylurea, benznesulfonyl-11,111-diethylur6e, as well as N-p-toluonasulfonylurea, N-p-toluenesulfonyl-N'-phenylurea (compare Chem.Rev. Vol. 50, pages 28/29).

   These substances have not so far acquired an important industri.
 EMI2.2
 le.On know plir patent ci 'njfriuc by le.One knows from the United States patentrJ.p.253 and from the French patent 993,465 other products of the series of sulfonylureas.



   The present invention relates to the preparation of sulfonylureas corresponding to the general formula
 EMI2.3
 R - SO -: N1I .. CO - NH - 11. in which the symbol R is a phenyl residue carrying option -
 EMI2.4
 Or, as substituents, 1 or 2 alkyl or alooxy radicals, of which the alkyl group is preferably of low molecular weight, or halogen atoms, or else an aliphatic or cycloaliphatic hydrocarbon residue of at least 3 carbon atoms. carbon, containing at least 2 carbon atoms and R1 an aliphatic or cycloaliphatic hydrocarbon residue / as well as the preparation of their salts.



   The symbol R can for example represent the following residues: phéylic, methylphenylic, in particular para-methylphenyl, ethylphenyl, propylphenyl, tibutylphenyl.
 EMI2.5
 lic, pentylphenyl and hexylphenyl. The tsxKt subuants can be both straight chain and branched; apart from the para position, the substituent can also occupy other places on the phenyl residue, in particular the position
 EMI2.6
 meta. On the other hand, the chlorophenyl and bromophenyl residues can be considered as the residues R).

   For example, the bisubstituted phenyl residues may also be indicated, such as the d3.a1coyl-, dialkoxy- or alkyl-alco: y -phenyl residues. It is also possible to choose phenyl residues containing at the same time a group
 EMI2.7
 alkyl or alkoxylic and a halogen atom, for example the methyl-chlorophenyl residue. The substituents can be found at any position on the bernic nucleus.

 <Desc / Clms Page number 3>

 



   Furthermore, the symbol R can represent the propyl, butyl, pentyl, hexyl, cyclohexyl and cycloalkyl-alooyl residues, like the hexahydrobenxyl residue, If they are aliphatic residues, these can be both straight chain and branched .



   The symbol R1 can for example represent the methyl, ethyl, propyl, allyl, butyl, butylene, pentyl, hexyl, cyclohexyl or hexahydrobenzyl residue.



  Again, if they are aliphatic in nature, the residues can be straight chain or branched.



   As preparation processes, it is possible to envisage those generally used for obtaining sulfonylureas, for example the following methods:
Benzene sulfonylisocyanates, optionally aloylated or alkoxylated, can be reacted with a primary butylamine or with another alkyl-, alkenyl; cyclocalcoyl; or cycloal- of at least 2 carbon atoms coyl- primary alkyl- amine / but it is also possible, conversely, to obtain the desired sulfonylureas by reaction between butyl isocyanate or a corresponding isocyanate and benzenesulamides, optionally alkylated or alkoxylated, usefully in the form of their salts.

   Instead of isocyanates, it is also possible to start from compounds converted into isooyanates during the reaction, for example azides such as the azide of valerianic acid.



  Another process for obtaining these new compounds consists in using urethanes, instead of isocyanates, and it is possible to use any esters of carbamic acid, such as methyl, ethyl, propyl, butyl or aryl esters.



  For example, benzene-sulfonyl-urethanes or alkylated or alkoxylated compounds can be reacted on the benzene ring with butylamine or another primary amine, or, conversely, alooyl-urethanes with the corresponding benzene-sulfonamides, usefully in the form of their salts. We can also

 <Desc / Clms Page number 4>

 advantageously use carbamyl halides. New sulfonylureas are thus formed, for example, from
 EMI4.1
 butyloabamyl chloride and optionally alkylated or alkoxylated benzene-sulfonamides, or from benzene-sulfone-carbamyl chloride, and for example from butylamine or from another primary amine.

   Another possibility of synthesis oonsiste starting from the benzene-sulphonyl-ureas unsubstituted on the group NH2 and
 EMI4.2
 to convert them into benzene-sulfoethyl-alkyl-ureas by alkylation, for example by butylation, optionally using butylami-
 EMI4.3
 born. The alkyl ureas can also be reacted with benzene sulfonamides. Instead of alkyl ureas, it is also possible to use the corresponding isourea ethers, suitably in the form of their salts, to react these with benzene sulfonyl chlorides, then to convert the products obtained into sulfonylureas. sought by hydrolysis in medium
 EMI4.4
 acid. Instead of corresponding alkyl ureas or isourea ethers, further corresponding derivatives can be employed.



   In other methods of synthesizing the new compounds, the corresponding thioureas from which the sulfur is removed in the conventional manner are first prepared, or else N-benzenesulfonyl-N'-alkyl- guanidines, for example by reaction of benzene-sulfonyl-cyanamides with a butylamine or another primary amine, then the guanidines obtained are hydrolyzed. In all cases, the components can be replaced
 EMI4.5
 , posed benzenesulfony, iques unsubstituted by the alcoyl or alkoxylated corresidants compounds.

   Instead of a butylamine, it is also possible to choose alkyl, alkenyl; cycloalcoyl-ou cycloalaoyi- 1 les 001; '(' 058 tes (b rrardèm -lue 1-e remainders in Ib product of reaction: tion contie> i.t3! .t 's 2 atcnls cb C ao: rt .. As the alkyl residues may occur once or twice as substituents on the phenyl group, optionally via an oxygen bond, low molecular weight residues are preferably envisioned. residues having 1 to 3 carbon atoms, but it is also possible to choose residues having

 <Desc / Clms Page number 5>

 of up to 6 carbon atoms and more. With the higher rents, the effectiveness of the products obtained generally decreases a lot.

   Instead of benzene-sulfonyl compounds, which may be alkylated or alkoxylated, it is also possible to use aromatic compounds in which the phenyl residue bears as substituents one or two halogen atoms, preferably chlorine or bromine, or else a halogen and an alkyl or alkoxylic residue. The individual methods of obtaining the desired sulfonylureas are, for the halogen-substituted benzene-sulfonyl compounds, the same as those described above.



   The primary amines chosen for this synthesis preferably have saturated or unsaturated aliphatic or cycloaliphatic hydrocarbon residues having from 3 to 6 carbon atoms. However, here too it is possible to choose residues of higher molecular weight, while observing, however, that for residues with more than 12 carbon atoms, the efficiency of the products obtained is generally reduced.



   In the above discussion always envisaged as starting substances for benzene-sulfonyl compounds, but it is also possible, according to the invention, to start from aliphatic and cycloaliphatic sulfonyl compounds, with less than 3 carbon atoms. Here too, the desired sulfonylureas can be obtained by the general methods for preparing sulfonylureas, for example by the methods indicated in detail above.



   The reaction conditions can be varied within wide limits and adapted to each case. One can for example carry out the reactions in the presence of solvents, at room temperature or hot. The following methods are particularly suitable:
1) - Reaction of compounds of general formula R - SO2NH2, in which R has the meaning already indicated, usefully in the form of the corresponding aloalias salts, with

 <Desc / Clms Page number 6>

 isocyanates of general formula R1 - NCO, working in the presence of a solvent, for example nitrobenzene or acetone, at room temperature or under heat.



     2) - Reaction of benzene-sulfonyl-carbamic esters of general formula R - SO2 - NH - C00 - R2, R corresponding to the definition already indicated and R2 denoting any hydrocarbon residue, preferably lower, with amines of formula R1 NH2, in equivalent amounts. It is good in this case to use a glycol monolalkyl ether as the solvent, and it is advantageous to carry out the reaction between 100 and 140. In this procedure, the ratio of the compounds participating in the reaction to the solvent may be of importance. Amounts of solvent representing 55 and 65% of the total amount of the reaction mixture are preferably used.



   In order to obtain the present products in the purest possible state, it is useful to carry out as complete a separation as possible of the benzene sulfonamides serving as starting substances or formed during the reaction, which can advantageously be done. carried out by taking up the products formed in ammonia diluted in the ratio of 1 part by volume of ammonia to 20 to 30 parts by volume of water, sulfonamides generally being poorly soluble at room temperature in this medium.



     As regards the starting substances which can be used in this process, these are very often compounds mentioned in the literature. Examples include benzene sulfonylurea, 4-methylbenzene sulfonylurea, 4-ethylbenzene sulfonylurea, 4-n-propylbenzene sulfonylurea, 4-isopropylbenzene-sulfonamide, 4- n-butylbenzene-sulfonamide, 4- isobutylbenzenesulphonamide, 4methyloxybenzenesulphonamide, 4-ethoxybenzenesulphonamide.

   It is also possible to use isocyanates or the corresponding carbamic esters, among which one can indicate, for example, the isocyanates of benzene-sulfonyl, 4- @ ethylbenzene-sulfonyl,

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 4-ethoxybenzene-sulfonyl, 4-methylbenzene-sulfonyl-carba-
 EMI7.1
 ethyl mate, 4-6thoxybonzene-sulfonyl-carb% Methyl Late, etc. Instead of these compounds substituted in position 4 of the benzene ring, it is also possible to use the corresponding compounds substituted in position 2, or in particular in position 3.



   In addition, as starting substances, the
 EMI7.2
 nalogenobenzene-sulfonyl-isocyanates, the halogen atom possibly being found anywhere in the benzene ring; correspondingly substituted benzenesulfonamides; correspondingly substituted benzenesulfonyl urethanes in which the urethane component has a low weight alkyl residue
 EMI7.3
 molecular ', re, for example a methyl, ethyl, prapyl or butyl residue, in particular an ethyl residue or an aryl residue; correspondingly substituted benzene-sulfonylureas or benzene-sulfonyl halides.



   It is also possible to start from: dihalogenobenzene-sulfonyl-isocyanates, the halogen atoms being in any position on the benzene ring; substituted benzene sulfonamides
 EMI7.4
 correspondingly killed; correspondingly disubstituted benzene sulfonyl urethanes, the urethane component of which has a lower alkyl residue, for example methyl, ethyl, propyl or butyl, in particular ethyl, or an aryl residue; benzenesulfonylureas, halo-
 EMI7.5
 benzene sulfonyl genides, benzene sulfonyldi-carbamyl halides, / correspondingly substituted.



  It is also possible to use starting substances) dimethylbenzenesulphonyl compounds in the form of chlorides, amides, isocyanates, carbamyl halides, carbon esters and ureas, or the corresponding dimethoxy-benzenesulphonyl compounds or methyl-chlorobenzene derivatives,
 EMI7.6
 methoxy-chlorobenzene and methoxy-methylbenzne sulfonyls.

 <Desc / Clms Page number 8>

 
 EMI8.1
 .9. instead of the methyl residue, we can also have a res-ce
 EMI8.2
 ethyl, propyl, butyl, or even higher alkyl residues.



  Let us also mention, as starting substances, the alkyl-,
 EMI8.3
 cycloalkyl- or cycloalkylalkyl-sulfonylamides or-sulfonyl-isocyanates, which may bear as anleoyl residues for example
 EMI8.4
 the propyl, butyl- (1), butyl- (2), 2-methylpro- residue
 EMI8.5
 pylic- (1), pentylic- (2), pentylic- (3), 3-methylbutyl- (1),
 EMI8.6
 2-methylbutyl- (1), hexyl- (1), hexyl- (2), 4-methylpen-
 EMI8.7
 tylic- (2), 2-ethylbutyl- (1), heptyl- (1), hepty-lique- () heptyl- (4), 2,4-dimethyl-pentyl- (1),, -dimethylpentylic- (3 ), OCtYIIC- (1>, octyl- <2>, and n-dodecyl, such as
 EMI8.8
 cycloalkyl residues, for example cyclohexyl residues
 EMI8.9
 and cycloheptyl and, as cycloalkyl-alkyl radicals, for example the cyclohexβmethyl and cyclohexylethyl radicals;

   alkyl-, cycloalkyl-, or OY010alcoYl-alkyl-sulfonyl-urethanes,
 EMI8.10
 in which the urethane component has a lower alkyl residue, for example methyl, ethyl, propyl or butyl, and in particular ethyl, or else an aryl residue; lesalco-
 EMI8.11
 yl-, cycloalkyl- or cycloalkyl-alkyl-sulfonyl-ureas; alkyl-, cycloalkyl or cycloy-alkayl-alkyl-sulfonyl halides,
 EMI8.12
 correspondingly substituted.



  To react with the preceding compounds, one can
 EMI8.13
 choose the following primary amines: as alkylamines, for example methyl> / ethylo / n-PrOPY1, / ÎsoPropylemine, normal butylamine, isobutylamine, secundo-butylamine, tertio-nutylamine, pentylamine- (l), peqtylaiuine- (2>, pentylamine- (3), -methyl-.but ... ylamin- (1), 2-methyl-but / ylamlne ... (1), s2 -dim, ethylpropyl, amins -. (1), 3-.inëthylàutylamina- (), hexylamines, like hexylamine- (1) and 2-methylpent.ylanine- (1j, heptylemines, like hePtylamine - (1) and heptylamine- (4), odylamines, such as ootyl.amine- (1).



  Let us mention, of other prtJ aomue aloenylamines by

 <Desc / Clms Page number 9>

 example allylamine and orotylamine, as cycloalkylamine, oyclohexylamine and cyclopentylamine, and, as cycloalkyl-alkylamine, cyclohexyl-methylamine and cyclohexyl-ethylamine,
Instead of these amines) it is also possible to use, to react with benzene sulfonamides or benzene sulfonyl halides, or with alkyl; correspondingly substituted cycloalkyl- or cycloalkyl-alkyl-sulfonamides or sulfonyl halides, the corresponding isocyanates, urethanes, carbamyl halides, ureas and iso-ureas, and which can be prepared from the amines in question.



   If we start to obtain the desired sulfonylureas from the corresponding thioureas, for example from N-4-methyl or N-4-methyoxybenzene-sulfonyl-N'-alkyl, alkenyl, cycloalkyl, hydrocarbon residues containing in mons 2 carbon atoms or-cycloalkyl-alkyl-thioureas, / to remove sulfur, heavy metal oxides or their salts, for example compounds of lead, copper or silver, can be used, in aqueous or alcoholic solution.



   The desired sulfonylureas can also be obtained by hydrolysis, with the aid of acids or diluted alkaline lyes, of the guanidines of corresponding constitution.



   As shown in animal experiments and clinical trials, the products of the invention cause a sharp decrease in blood sugar. They can be used as such or in the form of salts, or in the presence of substances which lead to the formation of salts. To form salts, it is possible, for example, to use ammonia, alkaline agents, such as alkali metal or aloalino-earth hydroxides, alkaline carbonates or bioarbonates, and, on the other hand, physiological organic bases. compatible. These compounds are used, among other things, to obtain preparations which can be administered orally and which induce a reduction in blood sugar, in the treatment of diabetes.



   The effect on blood sugar level can be shown

 <Desc / Clms Page number 10>

 for example on the mouse, the rat, the guinea pig, the rabbit, the cat and the dog. By applying, for example to rabbits normally fed the compounds of the structure claimed in a single dose of on average 400 mg / kg, for example in alkaline bicarbonate solution or in the form of alkali salts, a rapid decrease is observed. the blood sugar level reaching, in about 3 to 4 hours, a maximum of about 30 to 40% of the initial value.



   Blood sugar values can be determined by hourly analyzes according to the Hagedorn-Jensen method. The decrease in blood sugar is determined by comparison with the values found in control animals maintained under the same conditions, but not treated.



   The following table shows the effectiveness of the products of the invention.

 <Desc / Clms Page number 11>

 
 EMI11.1
 



  .'13ïJllJ '1
 EMI11.2
 
<tb>
<tb> Substance <SEP> under <SEP> form <SEP> of <SEP> salt <SEP> sodium <SEP> Maximum <SEP> reduction <SEP> of
<tb> blood <SEP> sugar <SEP> <SEP> level
<tb> at <SEP> the <SEP> rabbit <SEP> for <SEP> 400
<tb> mg / kg <SEP> by <SEP> route <SEP> or * lē¯¯¯
<tb>
 
 EMI11.3
 N- (4-methyl-benzenesulfonyl)
 EMI11.4
 
<tb>
<tb> -N'-n-butylurea <SEP> 45 <SEP>%
<tb> N- (4-n-propyl-benzenesulfonyl)
<tb> -N'-n- <SEP> butylurea <SEP> 30 <SEP>%
<tb> N- (4-methoxy-benzenesulfonyl)
<tb> -N'-isobutylurea <SEP> 30 <SEP>%
<tb>
 
 EMI11.5
 N- (3-methyl-b enz ene sptl f onyl) -N'-n-butylurea 40) 1 N- benzene-sulfonyl-Ntrisobutylurea 40 N- (4-methyl-benzenesulfonyl)
 EMI11.6
 
<tb>
<tb>.-N'-tert.-butylurea <SEP> 30 <SEP>%
<tb> N- (4-ethyl-benzenesulfonyl)

  
<tb>
 
 EMI11.7
 -111-cyclohaxylurea 30
 EMI11.8
 
<tb>
<tb> N- (4-methyl-benzenesulfonyl)
<tb> -N'-n-propylurea <SEP> 40 <SEP>%
<tb> N- (4-methyl-benzenesulfonyl)
<tb> -N'-hexylurea <SEP> 33
<tb> N- (4-methyl-benzenesulfonyl)
<tb> -N'-allylurée <SEP> 45 <SEP>%
<tb> N- (4-chloro-benzenesulfonyl)
<tb> -N'-n-butylurea <SEP> 30 <SEP>% <SEP>
<tb> N- (3-chloro-benzenesulfonyl)
<tb> -N'-n-butylurea <SEP> 50 <SEP>%
<tb>
 
 EMI11.9
 N-Cyclohexane-sulfonyl-NI-n-butylurea 40% N-oylcohexanesulfonyl.-N'-cyclohexylurea 30 b N-butanesulfonyl-N'-n-butylurea 33 N-cyclohexanosulfonyl-NI-cyclohexyl-aethylur6e 30%
 EMI11.10
 
<tb>
<tb> N- (3,4-dimethoxy-benzenesulfonyl)
<tb> -N'-hexylurea <SEP> 50 <SEP>% <SEP>
<tb> N- (2,4-dimethylbenzenesulfonyl)
<tb> -N'-cyclohexylurea <SEP> 30 <SEP>% <SEP>
<tb>
 
 EMI11.11
 N- (3-chlora-4-methylbenzenesulfonyl)

   
 EMI11.12
 
<tb>
<tb> -N'-lsobutylurea <SEP> 30 <SEP>%
<tb>
 
Testing the compounds on dogs offers the advantage that the resorption conditions in the stomach and intestines are much the same as in humans, and that the blood sugar level shows individual fluctuations.
 EMI11.13
 less than in rabbits.

   Very reproducible values are obtained in dogs, even at low doses, with sulfonylureas.
 EMI11.14
 free, administering the compounds to fasting dogs in one

 <Desc / Clms Page number 12>

 single dose of 100 mg / kg, and by determining the blood sugar content at certain periods, the decreases indicated by the following table are observed:
TABLE 2
 EMI12.1
 
<tb>
<tb> Substance <SEP> Lowering <SEP> of <SEP> the <SEP> content <SEP> in
<tb> sugar <SEP> of <SEP> blood <SEP> in <SEP> the <SEP> dog
<tb> in <SEP>%
<tb> N- (4-methylbenzenesulfonyl) <SEP> 30 <SEP>% <SEP> after <SEP> 1 <SEP> hour
<tb> -N'-n-butylurea <SEP> 30 <SEP>% <SEP> "<SEP> 24 <SEP>"
<tb> 22 <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> 8 <SEP>% <SEP> "<SEP> 72-96
<tb>
 
 EMI12.2
 .

   N- (4-iùethyl-benzenesulfonyl) 47% 1 1 hour -N'-isobutylurea 47 I "24"
 EMI12.3
 
<tb>
<tb> 20 <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> 10 <SEP>% <SEP> "<SEP> 72 <SEP>"
<tb> 0 <SEP>% <SEP> "<SEP> 96 <SEP>"
<tb> N-benzenesulfonyl-N'-n-butylurea <SEP> 25 <SEP>% <SEP> "<SEP> 1 <SEP>"
<tb> 25 <SEP>% <SEP> "<SEP> 24 <SEP>"
<tb> 16 <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> 0 <SEP>% <SEP> "<SEP> 72 <SEP>"
<tb> N- (4-ethyl-benzenesulfonyl) <SEP> 25 <SEP>, <SEP> 1 <SEP> hour
<tb> -N'-n-butylurea <SEP> 30 <SEP>% <SEP> "<SEP> 2 <SEP>"
<tb> 33 <SEP>% <SEP> 3 <SEP> "
<tb> 27 <SEP>% <SEP> "<SEP> 24 <SEP>"
<tb> O <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> N- (4-methoxy-benzenesulfonyl) <SEP> 20 <SEP>% <SEP> 2 <SEP> "
<tb> -N'-n-butylurea <SEP> 4 <SEP>% <SEP> "<SEP> 24
<tb> O <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb>
 
 EMI12.4
 N- (3-methyl-benzenesulfonyl)

   48 joz "3"
 EMI12.5
 
<tb>
<tb> -N'-isobutylurea <SEP> 30 <SEP> "<SEP> 6 <SEP>"
<tb>
 
 EMI12.6
 14 '"z4 tut
 EMI12.7
 
<tb>
<tb> O <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> N- (4-methyl-benzenesulfonyl) <SEP> 39 <SEP>% <SEP> 1 <SEP> "
<tb>
 
 EMI12.8
 -Nt.cyc1ohexy1urea 43 I damn 24
 EMI12.9
 
<tb>
<tb> 10 <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb>
 
 EMI12.10
 0% if f 2 "N- (4-methyl-benzenesulfonyl) 32 I t! 1" -Nt -a11y1urea 34 / ""
 EMI12.11
 
<tb>
<tb> 34 <SEP>% <SEP> "<SEP> 24 <SEP>"
<tb> 10 <SEP> the <SEP> "<SEP> 48 <SEP>"
<tb>
 
 EMI12.12
 o j tt 9:,;

   "N - (4-methyl-benzenesu1fony1) 40 I" 1 "-N cyclopentylurea 40 '",> 4 "
 EMI12.13
 
<tb>
<tb> 25 <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> O <SEP>% <SEP> "<SEP> 72 <SEP>"
<tb>
 
 EMI12.14
 N- (4-methyl-benzenesulfonyl) 30 '"1" -Nt-he: x: y urea 35; "" 6H
 EMI12.15
 
<tb>
<tb> 16 <SEP>% <SEP> "<SEP> 24 <SEP>"
<tb> 10 <SEP>% <SEP> "<SEP> 72 <SEP>"
<tb>
 
 EMI12.16
 0 '/ "± \ 1;

     

 <Desc / Clms Page number 13>

 
 EMI13.1
 
<tb>
<tb> Substanoe <SEP> Lowering <SEP> of <SEP> the <SEP> content <SEP> in
<tb> sugar <SEP> of <SEP> blood <SEP> in <SEP> the <SEP> dog
<tb> ¯¯¯ <SEP> in <SEP>%
<tb> N- (4-chloro-benzenesulfonyl) <SEP> 27 <SEP>% <SEP> after <SEP> 1 <SEP> hour
<tb>
 
 EMI13.2
 -N '-n ... butylurea 40 lU "3 il 40 ti It
 EMI13.3
 
<tb>
<tb> 32 <SEP>% <SEP> "<SEP> 48 <SEP>"
<tb> 15 <SEP>% <SEP> "<SEP> 72 <SEP>"
<tb>) <SEP>% <SEP> "<SEP> 96 <SEP>"
<tb> N-cyclohexylsulfonyl-N'-n- <SEP> 35 <SEP>%
<tb> butylurea <SEP> e <SEP> 40 <SEP>% <SEP> 5 <SEP> "
<tb> 0 <SEP>% <SEP> "<SEP> 24 <SEP>"
<tb>
 
 EMI13.4
 N-butanesulfonyl N'-n-butylurea 27 1 ",

   6 "10 ô" '24 "
 EMI13.5
 
<tb>
<tb> O <SEP>% <SEP> 48 <SEP> "
<tb>
 
The above values are determined by comparison with the values found on control animals maintained under the same conditions, but not treated. It has been recognized that single doses, for example 5 mg / kg of N- (4-methyl-benzenesulfonyl) -
 EMI13.6
 N'-nbutylurea already produced a 30% decrease in blood sugar levels for 48 hours.



   Clinical trials on a large number of patients have fully confirmed the efficacy of these products, for example N- (4-methylbenzenesulfonyl) -N'-n-butylurea and N- (4- methyl-benzenesulfonyl) - N'-isobutylurea. The first compound, for example, lowers blood sugar levels in healthy men by an average of 20 to 40 mg%. In certain diabetics, a decrease, for example of approximately 300 mg% over the normal value of approximately 120 mg%, can be observed. The products of the invention have been tested as antidiabetics in mild and severe cases of diheteucrate. Impressive improvements in nutrient exchange are often noted, particularly in stenic-adipose elderly subjects.

   Acute glycosuria and hyperglycemia are largely normalized, and painful polydipsia and polyuria disappear. The effect of the preparations is sometimes felt from the first day, usually between the second and the 5th day. Regression of glycosuria is always accompanied

 <Desc / Clms Page number 14>

 
 EMI14.1
 of a perceptible decrease in the level of J iJuci> ;; cJ: c renal threshold relative to glucouo could not be increased. At,:.> ..: treat, we must absolutely obsorvo. 1 ..i: af,: 1 ï ...,;. . severe normal for diabetics. According to 1 <,; 1 "::, <111.'1 ',', current rhiments, these compounds are effective in the r.:I '1;,'; '::; forms of diabetes, but not, however, in all; :: 1 1;:, r,.; Of this disease.
 EMI14.2
 



  In many patients successfully treated I81l ';,' nt a fairly long duration with the compounds of the invention, 1 (;; 3 nutrient exchanges remain compensated for a while, even after interruption of treatment, and can be stabilized if necessary by reapplication Insulin resistance has not been observed so far. Treatment with these compounds can be switched back to insulin treatment at any time. hemogram or picture of blood, liver function and urine condition, no pathological changes are observed. Treatment with a combination of insulin and the present products can also be carried out. insulin and improved assimilation is obtained.

   We have to
 EMI14.3
 in this case watch the patients very carefully, C: 'l' '1'. edition of the effects ac: r: r6! t the danger of a shock by 11 read:! ',,,:! :: r :. , We can assay these products according to the following lines (t - ;. r'h ,; f ": ',;: <, taking as an example N - (-. Methylke; é4:., 1t-L- , a =.



  N '- (n-butyl urea.



  To quickly obtain a blood sugar level of "; ' ..;>,,; sufficiently high, we give the first day z; to 5 ca of this # ..... carefully controlling the assimilation. The second:;, zc t, i,,, reduces the dose to 1.5 or 2 g, and the following days or: à., .. daily 1 to 1.5 g. In individual cases, one can, .. close to the sugar level of the bran4; and of the urinü, di'ld \ 11 "1- ¯, the dose or over.press it complete: tclltll1t. Bu rai.on of 7 ': t ¯ .; a: "along the pr'puration, one can u1 1? li ùuwr 1. <as; quot, i.Üi, <"; in a single hay, Des dosed Plus Ólov, '\ t'S do not have PHS or; ,, ¯ more lnioortunt effect.

 <Desc / Clms Page number 15>

 



   The products which are the subject of the invention are generally distinguished in that they are extremely well supported. Their acute toxicity (on the mouse or the rat) is, orally, as shown in the following table, from 1 to several g / kg for the lethal dose 50 (LD50).



   TABLE III
 EMI15.1
 
<tb>
<tb> Substance <SEP> LD50 <SEP> for <SEP> the <SEP> mouse <SEP> by <SEP> oral <SEP> application, <SEP> in <SEP> g / kg <SEP> of <SEP> weight
<tb>
 
 EMI15.2
 N- (3-methyl-bonzenesulfonyl)
 EMI15.3
 
<tb>
<tb> -N'-isobutylurea <SEP> 4.5 <SEP> g
<tb> N- (4-methylbenzenesulfonyl)
<tb> -N'-n-butylurea <SEP> 2.5 <SEP> g
<tb> (4 <SEP> g <SEP> at <SEP> the <SEP> rat)
<tb> N- <SEP> (4-methylbenzenesulfonyl)
<tb> -N'-isobutylurea <SEP> 4 <SEP> g
<tb> N- (4-methyl-benzenesulfonyl)
<tb> -N-tert.-butylurea <SEP> 6 <SEP> g
<tb> N- (4-methylbenzenesulfonyl)
<tb>
 
 EMI15.4
 -N 'tpropylurea 5 g N- (4methyl-benzenesulfonyl)
 EMI15.5
 
<tb>
<tb> -N'-hexylurea <SEP> 6 <SEP> g
<tb> N- (4-methyl-benzenesulfonyl)
<tb>
 
 EMI15.6
 -Nt-oyc2.ohezylurea 4.8 g nN- (4- / pr'opyl-benzenesulfonyl) N'-n-butylurea 4.5 g N- (4-isopropyl-benzenesulfonyl)

   -N'-n-butylurea 5 g N-cyclohexanesulfonyl-NI-a-butylurea 2 g (SOU5forne sodium salt) N-cyclohexanesulfonyl-NI-cyclohexylurea 4.5 g
 EMI15.7
 
<tb>
<tb> N- (3-methyl-butanesulfonyl)
<tb> -N'-n-butylurea <SEP> 6.5 <SEP> g <SEP>
<tb>
 
Tests with sulfur-labeled N- (4-methyl-benzenesulfonyl) -N'-n-butylurea showed that the passage of these compounds from the stomach and intestine into the blood was very rapid. Passage through the urine is also relatively rapid.
 EMI15.8
 of and practically quantitative. There is no detectable enrichment in the individual organs, which can be attributed to the good compatibility of these compounds.

   Research phar.-
 EMI15.9
 macological changes, especially with regard to glycogen in muscles and liver, have shown that the lowering of the blood sugar level by the present products is not

 <Desc / Clms Page number 16>

 symptom of a toxic action, and the compatibility in the duration test is also very good, as it has been recognized.
 EMI16.1
 qioUrionnG be by an application of 100 mg / kg, for example, of N- (4-iB3thyl-benzenesulfonyl) -N'-n-butylurea, for several times on animals.



   Clinical experiments carried out on numerous patients have confirmed the good compatibility of these compounds,
 EMI16.2
 for example N- (4-methyl-benzenesulfonYl) -,: - n-butyl-oll -isobutylurea.



   With respect to compounds of similar constitution of the sulfanilyl series, the compounds of the invention are distinguished, on the one hand, by their better stability to oxidative influences.
 EMI16.3
 external, corme the oxygen of the air, which is a.jgntaùg¯u + for their conservation and their handling. On the other hand, unlike sulfanilyl compounds, they do not have bacteriostatic activity, which is particularly important.
 EMI16.4
 



  The compounds of the invention do not exert the known secondary ectiens of the sulfonamides on the blood (suStCO3 e Heinz), nor on the thyroid, and the digestion determined by the bacterial flora of the l2E is not observed. 'i2 = oe ,.



  EXELIPLE 1, ¯ N-4-methYl-benzenesulfonyl-Nf-n-butylurse.



  In a suspension of 03 j .3 i- = iétj, j; rj;, <g ;;,;.; Z ,,, = ¯ sodium in 120 om3 of dry nitrobenzene, is introduced,. ordinary peeling and stirring, 50 g, # scc; ,: ;; ## do i,:, i, l ... n;, ¯, mal, then heat for 7 hours at 10011.,; p, j; rr.i..ment, one dilutes the aid of chloride of: llétl1ylèn.0 or; j;: cjt, .td "6thyle, the mixture forming a slurry 6pn.iE::':c,; ,,;, ,,, ¯ ,, ¯ trifuge the sodium salt of sulf'onylurl for, ¯, c. T¯i, ià ,,,, in 500 to 600 cm3 of water at 500 the residue ci, 1n-t; , iiiy.j. # organic solvents and decolorized with black @ ni @@ l.

   We

 <Desc / Clms Page number 17>

 dissolved in dilute ammonia (approximately 1:20) in an equivalent quantity @@ - the precipitate formed by aoi / fication with the aid of dilute hydrochloric acid, treated again with animal charcoal and again precipitated by dilute hydrochloric acid. We obtain
 EMI17.1
 , thus pure N-4-methylbenzenesulfonyl-N'-n-butylurea on analysis, with a yield of 70 to 80% of what theory indicates.



   Melting point 125-127, with decomposition.



   By reacting other 4-alkylbenzenesulfonamides or their alkali salts, for example 4-ethyl, 4-n-propyl, 4- 'isopropyl or 4-n-butyl-benzene-sulfonylurea, or 4-alkoxy -
 EMI17.2
 benzenesulfonamides, such as 4-ethoxybenzenesulfonylurea, together with normal butyl isocyanate, the homologues of 3-4-methyl-benzene-sulfonyl..N-n-butylurea are obtained in the same way. The properties of these compounds and the yields with which they are obtained are identical.
 EMI17.3
 



  By reaction between 2-methylbenzenesultamide and normal butyl isQ cyanate, N-2methylbenzene-sulfonyl-N'-n-butylurea, melting at 160-161 ° h instead of 2- is similarly obtained. methylbenzene sulfonamide, it is also possible to start from other benzene sulfonamides substituted with alkyl radicals.
 EMI17.4
 or alkoxylic c '-. uy.j. than s / inferior.
 EMI17.5
 



  100 g of N-4-methylbenzene-sulfonyl-Nt-n-butylur6a are dissolved, while heating slightly, in 370 CM3 of normal caustic soda lye, then the clear colorless solution is concentrated (pH 8.5-9.5) at 50-60 under reduced pressure. The residue, which is at first only partially solid, crystallizes completely after standing for a while. It is triturated with acetone, filtered off, washed with acetone and dried at 100. We get 90
 EMI17.6
 to 1.00 g of sodium salt of N-4-methyl-benzene-sulfonyl ruz. butylurea (83-92% of theory).

   Melting point 130-133. By cooling its aqueous solution to 20%, this
 EMI17.7
 sodium salt crystallizes in tetrahydrate, melting at 41-43.

 <Desc / Clms Page number 18>

 EXAMPLE 2:
 EMI18.1
 N-benzene-sulfonyl-N'-n-butylurea.



   Stirred for 1 hour at 56 63 g of benzene sulfonylurea, 120 g of finely ground potassium carbonate and 600 cm3 of dry acetone, then 40 g of isocyanate is slowly poured in dropwise, at reflux and with stirring. of normal butyl.



  Heat for 6 more hours at 50-55, the acé is completely evaporated. tone, the residue is dissolved in water, treated with animal charcoal and acidified with dilute hydrochloric acid. The already very pure sulfonylurea is dissolved in the equivalent amount of dilute ammonia (approximately 1:20), again treated with animal charcoal, and precipitated with dilute hydrochloric acid. In this way, pure N-benzenesulfonyl-N'-n-butylurea is obtained on analysis with a yield of 70 to 80% of what theory indicates. Melting point 129-131.



   We obtain in a similar way, from benzene-sul-
 EMI18.2
 famide and isobutyl isocyanate, N-benzenesulfonyl-N'4 isobutylurea melting at 132-133. EXAMPLE 3:
 EMI18.3
 N-4-methylb enzene-sulfonyl-N'-n-butylurea e.



   60 g of 4-methylbenzenesulphonyl isocyanate are dissolved in 30 cm3 of anhydrous absolute dioxane, then 22 g of normal butylamine dissolved in 50 anise of dioxane are slowly poured in at room temperature with stirring.



  When the addition is complete, the mixture is stirred for a further 1 hour at 80 m, then part of the dioxane is evaporated off and the sulfonylurea is precipitated by adding water. By dissolving in dilute ammonia treated
 EMI18.4
 ment to animal black and precipitation with 7 i. dzlue hydrochloric acid, one obtains with a good yield the:; - 4-méth.ylben = tna-sul fonyl-N'-n-hutylurea melting at 125-127.

 <Desc / Clms Page number 19>

 
 EMI19.1
 



  EXmPLE 4: T1 -methylbzene-sulfonyl-N'-n-butylurea.



   97 g of ethyl N-4-methylbenzene-sulfonyl-carbamate are dissolved in 130 cm3 of glycol-monomethyl ether, melting point 84-
 EMI19.2
 850 (prepared by reacting 4-methylbenzene-sulfamide with ethyl ohloroformate in the presence of potassium carbonate), the solution of 29 g of normal butylamine is added, then the mixture is boiled under reflux for 20 hours. The residue obtained after distillation of the glycol-monomethyl ether is crystallized, by triturating it with water, it is filtered off, it is dissolved in dilute ammonia (1:20), the solution is decolorized with animal charcoal, and the sulfonylurea is precipitated with dilute hydrochloric acid.

   After recrystallization from 50% ethanol, N-4-methyl-benzene-sulfonyl-N'-n-butylurea, pure on analysis and melting at 125-127, is obtained with a good yield.
 EMI19.3
 



  N., iiPT: 5: N-4-thylbenzene-sulfonyl-N'-n-butylurea.



  56 g of 4 -, 6ylbenzenesulfonamide (melting point 110) are suspended in 100 cm3 of acetone, and dissolved with 200 cm3 of an aqueous sodium hydroxide solution containing 12 g of sodium hydroxide. 33 g of normal butyl isocyanate are then poured in dropwise, with stirring, while cooling to about 10 and, after the addition is complete, the mixture is further stirred for 1 hour. After dilution with water, the mixture is filtered off to separate out a slight insoluble material, the clear filtrate is sucked through a layer of charcoal and slowly acidified, with stirring to 3, with 2- hydrochloric acid. not. The precipitate which is initially only partly semi-solid soon becomes crystalline.

   The crude product is filtered off with suction, washed with water, taken up in dilute ammonia (1:25), treated with animal charcoal and again acidified, with stirring, with acid.

 <Desc / Clms Page number 20>

 
 EMI20.1
 hydrochloric acid 2-n. We separate by cssorij; e ln ;; ultc> ii% 1.ai>?,; <a'i-i # 1 pure white precipitated, washed with water and leaked] ': Ju.rl :: tallize in ethanol ù 70, j. We thus obtain bvf3c a voucher. yield N-4-ethylbonzene-sulfonyl-Td'-n-butylurf.e melting at 100-102.
 EMI20.2
 



  We obtain in a similar way, by making r.3 & gir 1: <4-ethylbenzene-sulfonylurea (fusionµ10), in the sodium salt state, with isohutyl isocyanate, N-4-ethylbenzene-sulfonyl-11 '- isobutylurea melting at 144-146.



  EXAMPLE 6: N-4-n-propylbenzene-sulfonyl-N'-n-butylurea.



   By reaction in 30% acetone between 4-n-propylbenzenesulfonamide (melting 108-110), in the sodium salt form, and normal butyl isocyanate, one obtains, by the fashion
 EMI20.3
 procedure of Example 5, N-4-n-propylbenzene-sulfonyl-2'-n-butylurea melting at 104-105, with a good yield.



   Analogously obtained from the sodium salt of 4-isopropyl-benzenesulfamide and butyl -sulfonyl isocyanate
 EMI20.4
 normal, N-4-isopropylbenzeneN'-n-butylurea melting at 135- 137
 EMI20.5
 XX & .ÈL% 7 N-4-methoxybenzene-sulfonyl-N '-n-butylurea.



   Stirred for 1 hour at 50-60, 72 g of 4-methoxybenzene sulfonamide, 120 g of finely ground potassium carbonate
 EMI20.6
 and 800 cc of acetone, then 40 g of normal butyl isocyanate is slowly drip under reflux and with stirring, the mixture is further heated for 6 hours at 50-55 and the mixture is completely evaporated. acetone. The residue is dissolved in water, treated with animal charcoal and acidified with dilute hydrochloric acid. The sulfonylurea, which is at first only semi-solid, became
 EMI20.7
 crystalline after leaving it for several hours at 0, It is wrung out, it is diffused: 10ut Cblln l'Q! t'l () ninque dilu, (1, from where or In rL'nrcipite ;, and we read ftdt Tccrlntl11li :: JOr dnns of] '.t1] (\ 1101:', ::, ...

 <Desc / Clms Page number 21>

 Yield 70-75% of theory.

   Melting point 118-119.
 EMI21.1
 



  , Li, 11.1J..lCJJ3'J 8: N-4-methylbenzene-sulfonyl-hT'-isobutylurfe.



   4.62 g of ethyl N-4-methylbenzene-sulfonyl-carbamate are reacted by the method of example with 20.5 g of isohutylamine in glycol-monomethyl ether as solvent, then the mixture obtained is treated. as in Example 4. N-4-methylbenzene-sulfonyl-N'-isobutylurea, melting point 169-170, is obtained with a good yield.



   To prepare the sodium salt, 30 g of this compound are stirred with 160 cm3 of aqueous sodium hydroxide solution (containing 4 g of caustic soda), for a few minutes, the solution is filtered and concentrated under reduced pressure. With good regulation, a crystalline salt of N-4- sodium salt is obtained.
 EMI21.2
 methylbenzene-sulfonyl-1'-isobutylurea, which is filtered off and washed with acetone. After drying, this compound melts at 199 -?, 00 '.



   Potassium salt prepared in a similar fashion melts at 200-201. Solutions of these two salts in water are not colored by phenolphthalein.



   The ammonium salt crystallizes after standing for a while in its solution obtained by dissolving the compound in an excess of concentrated ammonia, EXAMPLE 9:
 EMI21.3
 N-4-methylbenzene-sulfonyl-ll-sec.-butylurea.



  A solution of 55 g of methyl N-4-methyl-4-methyl-sulfonyl-carbamate, 115 g of glycol monomethyl ether and 20 g of secondary bu tylamine is heated for 4.5 hours at reflux boiling. The mixture is concentrated under reduced pressure, the still hot residue is added with water and dissolved with the addition of concentrated aqueous ammonia. The solution is clarified over charcoal and hydrochloric acid is added with stirring until acidic reaction in the Conge indicator. We obtain
 EMI21.4
 a crystalline precipitate of N - methylbcnz¯ne-Nulfonyl-1T -seaundo-

 <Desc / Clms Page number 22>

 
 EMI22.1
 butylurea, which is purified by dissolving in a; #monieque (1:20) andrecipitation with dilute hydrochloric acid.

   48 g are collected; the melting point is 128-130, after recrystallization from aqueous ethanol. @ EXAMPLE 10:
 EMI22.2
 N-4-methoxybenzene-sulfonyl-N'-isobutylurea.



    38 g of 4-methoxybenzenesulfonamide, 60 g of finely ground potassium carbonate and 400 am 3 of acetone are stirred for 1 hour at 50-55, then the mixture is slowly poured in, with stirring and at reflux, 22 g of isobutyl isocyanate.



  The mixture is heated for a further 4 hours at 50, the acetone is completely evaporated off, the residue is dissolved in water, the residue is treated with animal charcoal and acidified with 2-n hydrochloric acid. The precipitated sulfonylurea is taken up in dilute ammonia (1:25), again treated with animal charcoal and reprecipitated with dilute hydrochloric acid. After recrystallization from 400 cm3 of ethanol
 EMI22.3
 at 50%, N-4-methoxybenzene-sulfonyl-N'-isobutylurea is obtained in an amount of 50 g (87% of theory). Melting point 141-142.



    EXAMPLE 11:
 EMI22.4
 N-3-methylbenzene-sulfonyl-NI-isobutylurea.



   85.5 g of 3-methylbenzenesulfonamide are suspended in 167 cm3 of acetone, then 333 om3 of an aqueous sodium hydroxide solution (containing 20 g of caustic soda) is added. Slowly drip, 10.50 g of isocyanate
 EMI22.5
 of isobutyl, without prejudice to possible crystallization of the sodium salt of toluenesulfamide. After stirring for 1 to 2 hours, filtered with animal charcoal and the filtrate is acidified with dilute hydrochloric acid while stirring. N-3-methylbenzene-sulfonylN'-isobutylurea crystals are obtained with a good yield, which are purified by dissolving them in 1 liter of dilute ammonia (1:20) and precipitating again by

 <Desc / Clms Page number 23>

 hydrochloric acid.

   After recrystallization from alcoholisepropyl, the product obtained melts at 105-106.



   One obtains in a similar way with 3-methylbenzene-
 EMI23.1
 sulfonylurea and standard butyl isocyanate, N-3-: ac: thylbenzene sulfonyl-N'-n-butylurea melting at 108-109. EXAMPLE 12
 EMI23.2
 N-4-mbthylbenzene-sulfonyl-N'-tertio-but ;, 7ux: e.



  65.7 g of 4-methylbenzene-sulfonyl isocyanate are dissolved in 500 cm3 of benzene, then 24.3 g of tertiary butylamine are slowly poured in dropwise, with stirring.
 EMI23.3
 constantly. The temperature is around 40. The solution is further heated for 1 hour at boiling under reflux, then concentrated. The residue is dissolved in dilute ammonia in the ratio of 1 to 20. It is filtered, if necessary, with the addition of water. animal black and, by slow acidification with dilute hydrochloric acid, crystals of N-4-methylbenzene-sulfonyl-N'-tertio-butylurea are obtained with a good yield, which, after draining, washing with water and drying, melt at 166-167. After recrystallization from methanol, the substance melts at 167-168.



  EXAMPLE 13:
N-4-methylbenzene-sulfonyl-N'-isobutylurea.



   One incorporates an excess of isobutylamine, upon cooling
 EMI23.4
 sant, 5 g of N-4-methylbenzene-sulfonyl-carbemyl chloride (prepared by passing dry hydrochloric gas through 4-methyl-benzene-sulfonyl-isocyanate; mp 95-96 with decomposition). The mixture is diluted with water, filtered to separate a slight fluffy precipitate and the filtered, oristallizable acetic acid is added until acidic reaction. A crystalline precipitate of N-4-methylben is obtained in a very good yield.
 EMI23.5
 zene-sultonyl-NI-inobutylur6e, which melts at 169-170.



  EXAMPLE 14: N-4-methylbnzene-sulfonyl-N'-cyolohexylurea. 18 hours are heated at 1.10, dens 150 cm3 of methyl

 <Desc / Clms Page number 24>

 
 EMI24.1
 glycol, 33 g of oyolohexylamine, and 81 g of lI-4-methylbenzenesulfonyl-ethylurethane, melting at 84-85 (prepared by reacting 4-methylbenzene-sulfonamide with ethyl chlorofortnate in the presence of potassium carbonate). The reaction mixture, while still hot, is introduced into a solution of sodium carbonate, then it is cooled. The insoluble part is separated out and the solution is carefully acidified in the cold.

   The precipitate formed is dissolved in dilute ammonia, filtered and pre-
 EMI24.2
 cipitates again with acetic acid. The N-4-methylbenzene-sulfonyl-N'-cyolohexylurea obtained is filtered off with a good yield, it is washed well with water, it is dissolved hot in ethanol, and it is precipitated by adding water. Melting point 170.



  EXAMPLE 15: N-4-methylbenzene-sulfonyl-N'-cyolohexylurea.



   17.1 g of para-toluene sulfonamide and 30 g of finely ground potassium carbonate are suspended in 250 cn of dry acetone, then stirred well for 1 hour at reflux. Is poured slowly, dropwise, into the mixture, with stirring, 12.5 g of cyclohexyl isocyanate. After boiling for 6 hours at reflux, the acetone is dissolved and the residue is dissolved in water. The insoluble matter is separated by suction, then the filtrate is acidified with hydrochloric acid with caution. As indicated in Example 14, it is dissolved and reprecipitated in
 EMI24.3
 dilute ammonia N-4-methyl-benzene-sulfonyl-N'-cyclohexyl-urea, precipitated with a good yield in the already very pure state, then it is recrystallized from a mixture of ethanol and water .



  It melts at 170.



  EXAMPLE 16:
 EMI24.4
 "YlbéesUlfonyl-11'-cyclohexylurea.



  40 g of 4-ethylbcnzene-sulfomxde (melting 1100) are suspended in 150 cm3 of tacetene, and dissolved with 105 cm3 of 3-n sodium hydroxide solution. We let run drop by drop, with stirring and in 30 minutes, to about 100,: 32 g of is0cy, iiiute of

 <Desc / Clms Page number 25>

 cyolohexyl and, the addition is complete, the mixture is stirred for a further 2.5 hours. The mixture is diluted with 2 liters of water and acidified with 2-n hydrochloric acid. The precipitate is filtered off with suction and then extracted 3 times with two and a half liters of dilute ammonia (1:75) each time. The ammoniacal extracts are combined, filtered and acidified with 2-n hydrochloric acid.

   To further purify the precipitated crude sulphonylurea, it is taken up in 3 liters of dilute ammonia (1:75), a slight insoluble material is separated by filtration, treated with animal charcoal, filtered again and acidified with hydrochloric acid. 2-n. The white crystals are recrystallized from 800 cm3 of 50% ethanol and obtained.
 EMI25.1
 holds N-4-ethylbenzene-sulfonyl-NI-cycloi. -cylurea with a good yield. Melting point 159-160.5 *.



    EXAMPLE 17 N-4-methylbenzene-sulfonyl-N'-allylurea.



   The mixture is boiled for 4.5 hours at reflux in 55 g of glycol monomethyl ether) 7.8 g of allyleminaet 28.7 g of methyl N-4-methylbenzene-sulfonyl-carbamate (prepared
 EMI25.2
 by reaction of 4-methylbenzene.rsulfamide with methyl chloroformate in the presence of potassium carbonate). The mixture is concentrated under reduced pressure, the still hot residue is added with water and dissolved by adding ammonia.



  The slightly colored solution is decolorized with animal charcoal and, after filtration, dilute hydrochloric acid is added until an acid reaction with the Congo indicator, with good stirring. A crystalline precipitate of N-4-methylbenzene-sulfonyl-N'-allylurea is obtained in good yield, which is purified by dissolution in dilute ammonia. (1:20) and precipitation with dilute hydrochloric acid. After recrystallization from diluted ethanol, the substance melts at 141-143.



   We obtain, by operating as above, from N-4-
 EMI25.3
 methylbenzene-sulfonyl-oarbamate of methyl propylamine normal, by boiling in glycolmonomethyl ether as solvent

 <Desc / Clms Page number 26>

 
 EMI26.1
 N-4-methylbenzene-sulfonyl-Id'-n-ropylurea mp 151-153 ".



  N-4-methyi-snlfonyl-N'-isopropylurea, melting point 141-14-3, is obtained in a similar manner with isoproiJy1aaiine, benzene.



  '., Cc3, LPh 18: N-4-methylbenzene-sulfonyl-N'-allylurea.



   65.7 g of 4-methylbenzenesulfonydisocyanate are dissolved in 300 om 3 of benzene, then 20.9 g of allylamine are run in dropwise, with stirring, at room temperature. The temperature rises slightly, and we obtain with a good yield
 EMI26.2
 'ment a precipitate of N-4-methylbenzene-sulfonyl-N'-allylurea, which is filtered off and recrystallized from dilute ethanol. The substance melts at 141-143. EXAMPLE 19:
 EMI26.3
 N.-4.-Methylbenzenesulfonyl N'-iso-arriylurea.



   Stirred for 1 hour, between 50 and 60, 51 g of 4-methylbenzenesulfonamide, 90 g of finely cased potassium carbonate and 560 cm3 of acetone, then allowed to flow slowly dropwise, at reflux and with stirring, 37 g of iso-amyl isocyanate; the mixture is heated for a further 6 hours at 50-55, and the acetone is completely evacuated. The residue is dissolved in water and, after treatment with animal charcoal, the mixture is acidified with dilute hydrochloric acid. The precipitated N-4-methylbenzene-sulfonyl-N'-iso-amylurea is separated by suction. It is dissolved in diluted ammonia and reprecipitated with dilute hydrochloric acid according to the indications of Example 17, then it is recrystallized in 1.2 liters of ethanol at 50 ...

   60 g are collected, ie 70. of what the theory indicates; the melting point is 142-144.
 EMI26.4
 



  Analogously prepared '4NethYlbenzene-SUlfOny1-N'-n-amylurea, melts at 103-105. EXAMPLE 20:
 EMI26.5
 N-4-meth.ylbenzene-subnyl..3; '¯t; clopentylurea.



  49.3 3 (0.1; nolccu3u; -, of 4methylbenzene-sulfonylisocyanate are dissolved in 250 ClIl; {1fe 'b./t>ne nbsolu, pujs are slowly poured coultn, at 20%; 1.5 g (0,: 5, .niàcn-

 <Desc / Clms Page number 27>

 le) cyclopentylamine, with stirring. Stir until the isocyanate smell is gone, cool and wring out the
 EMI27.1
 N-4-ethylbenzene-sulfonyl-N'-cyclopentylurea precipitated in good yield. To purify it, it is dissolved in dilute ammonia, the solution is decolorized with charcoal, and the compound is reprecipitated with dilute acid. After recrystallization from acetic nitrile, the substance melts at 169-170.



    EXAMPLE 21:
 EMI27.2
 N-4-methylbenzene-sulfonyl-N '-heptyl- (4) -urea.



   From 39.5 g (0.2 molecule) of 4-methylbenzene-sulfonyl isocyanate and 23 g (0.2 molecule) of 4-heptylamine, one obtains in the same way as in Example 20, with a good meeting
 EMI27.3
 -decement, the N-4-.m6t-ihyli-benzene-sulfonyl-NI-heptyl - (- I) -ur6e, melting at 147-149 after recrystallization from acetonitrile.



  EXLIPL3 22: N-4-r-ethylbenzene-sulfonyl-NI-cyclohexyl-methyl-ur6e.



   In a solution of 28.3 g (0.25 molecule) of cyclohexyl-methylamine in 200 cm3 of absolute benzene, slowly dripped, cooling and with vigorous agitation.
 EMI27.4
 tion, 49.3 g of 4-methylbenzenesulfonyl isocyanate, then boiled for 1 hour at reflux. Cooled, diluted with ether and the precipitate formed is filtered off. The N-4-methylbenzene-sulfonyl-N'-cyolohexyl-methyl-urea obtained in good yield is dissolved in dilute ammonia, the solution is clarified with charcoal, and acidified with again with dilute hydrochloric acid, with good agitation. The compound which has precipitated is filtered off, washed well with water and recrystallized from aoetonitrile.

   Melting point 178-179.
 EMI27.5
 



  EXKIPL111 33: N4-lT ethylbenzene-sulfonyl-N'-n-hex: ylurea.



  40 g of 4-methylbenzene-aulfonyl isocyanate are dissolved in 150 em3 of absolute benzene, then the mixture is poured slowly. drop by drop, 21 g of 1-arn, na-n-hoaczne, stirring constantly.

 <Desc / Clms Page number 28>

 



  The temperature rises to about 55. The solution is heated for a further 3 hours between 60 and 70, then concentrated under reduced pressure. The residue is dissolved in dilute ammonia (1:10), the insoluble material is filtered off, the filtrate is aspirated through a layer of charcoal and acidified with 2-n hydrochloric acid. The precipitate formed is dissolved in dilute ammonia (1:25), filtered, treated with charcoal, and slowly acidified again with 2-n hydrochloric acid. After recrystallization from methanol at 50%, the crystals
 EMI28.1
 of N-4-methylbenzene-sulfonyl-Ny-hexylurea, obtained in good yield, melt at 120-122.
 EMI28.2
 



  JS: XK.1PLE 24: N-4-ehlorobenzene-sglfonyl-NI-n-butylur6e.



   We suspend 95.5 of 4-chlorobenzene sulfonamide in 500 cm3 of acetone, and they are dissolved by adding a solution of 20 g of NaOH in 400 cm3 of water. The solution is cooled to + 10, then 49.5 g of normal butyl isocyanate is slowly poured in dropwise, with vigorous stirring. Stirring of the mixture is continued until the isocyanate odor has disappeared, then it is filtered off, approximately 2/3 of the solvent is distilled, diluted with water and carefully acidified with acetic acid while stirring. The precipitate, at first slightly pasty, becomes crystalline on standing in the cold.

   To purify the N-4-chlorobenzene-sulfonyl-N'-n-butylurea, thus obtained with a
 EMI28.3
 good yield, it is dissolved in dilute ammonia, the solution is clarified with charcoal and again acidified with dilute acetic acid. The precipitated N-4-ohlorobenzene-sulfonyl-u, -n-butylurea is filtered off with suction and washed with water. After recrystallization from dilute ethanol, it melts at 115-116.
 EMI28.4
 



  An analog of 3-ellorobenzenesulphonamide is obtained N-3-utll orobenzenesulphonyl-N '-n-butylurea, which melts at 111-112.

 <Desc / Clms Page number 29>

 
 EMI29.1
 



  EXa, ï'Lh 5: N¯4-chlorobenzne-sulfonyl-N'¯cyclohexylurea.



  50 g of fine potassium carbonate are introduced, sprayed into a solution of 5 g of 4-chlorobenzene-sulfa-miàe in 200 cm3 of dry acetone, then the suspension is boiled for 3 hours at reflux. We then add slowly, drop by drop
 EMI29.2
 drop, 16.5 g of cyclohexyl isocyanate, to: d0 and with stirring. Stirring is continued at the same temperature, until
 EMI29.3
 you can no longer detect the smell of isosyanete. After cooling, the mixture is filtered off, the precipitate is dissolved in water, the insoluble material is separated off by filtration and the solution is decolorized using
 EMI29.4
 of coal.

   The sulfonylurea is then carefully precipitated with the addition of acid, dissolved in dilute ammonia, the solution is clarified with charcoal and again acidified with acetic acid. The precipitated N-4-chlorobenzene-sulfonyl-N'cyclohexylurea is filtered off with a good yield, washed with water and then recrystallized from acetic nitrile.



  Melting point 158-1590.
 EMI29.5
 h :. '.: P. 6 N-4-bromobenzene-sulfonyl-N'-n-butylurea.



  To a solution of 47 g of 4-bromobenzenesulfonamide in 150 cm3 of acetone, a solution of 8 g of Naos in 75 cm3 of water is added, then the mixture is slowly dripped into the mixture, at 20 and with good stirring C. g of butyl isocyanate, normal. When the addition is complete, stirring is continued until the isocyanate odor is gone, then the reaction mixture is concentrated and the residue dissolved in water. The solution is clarified with charcoal and acidified with hydrochloric acid.

   To purify the sulfonylurea precipitated it was dissolved
 EMI29.6
 in dilute zrnonia, the solution is clarified with charcoal and again acidified with ilacido ± lcc5tic; ue..After draining and washing with water, recrystallized from 7'etlzrnol diluted with N -4-bromobenzene-sulfonyl-N'-n-butYlUrea obtained with a good

 <Desc / Clms Page number 30>

 yield. It melts at 126-127. EXAMPLE 27:
 EMI30.1
 N-cyclohexane-sulfonyl-N'-butyl- (7..j-urea.



   In a solution of 57 g of cyclohexane sulfonamide - in 700 cm3 of dry acetone, 120 g of powdered seo potassium carbonate are introduced, then the suspension is boiled for 2 hours under reflux with stirring. slowly, dropwise, 35 g of normal butyl isocyanate, to 50 and with stirring and stirring continued at the same temperature until the isocyanate odor has disappeared. The precipitate is filtered off, the solution is concentrated and the residue is dissolved in water with the precipitate. The insoluble material is filtered off, the solution is decolorized with charcoal and carefully acidified in the cold with hydrochloric acid. The precipitate is filtered off and dissolved in dilute ammonia.

   We clarify the
 EMI30.2
 solution with charcoal and carefully acidified with dilute acetic acid. The precipitated N-oyolohexane-sulfonyl-N'butyl- (1) -urea is filtered off with a good yield, it is washed well with water, then it is recrystallized from ethanol or from acetic nitrile. Melting point 135-136.
 EMI30.3
 



  N-cyclohexane-sulfonyl-N '-isobutylurea which melts at 167-1680 after recrystallization from methyl acetate is obtained in an analogous manner with isocyanate isonutyl.
 EMI30.4
 



  % X & GLE 28:. '1 cyclohxane-sulfonyl-N'-ëyelohexylurea .. According to the data-of-example 27, 17 g of cyclohexanesulfonylurea and 14 g of isooyanate'de'cyélohexyle in 300 cm3 of acetone as solvent are reacted. , and in the presence of 40 g of potassium carbonate. After recrystallization from nitrile
 EMI30.5
 acetic, N-cYOloheXane-sulfonYl-Nt-cyc10heXY1Urea, obtained with a good yield, melts at 150-151, One obtains in the same way, from 1 ti, .ocy: normal hexyl nate, the N- cycl, ohexane-sulfonyl-N -n-hexyl- (1) "I't> and

 <Desc / Clms Page number 31>

 which melts at 95-96 after recrystallization from diisopropyl ether.
 EMI31.1
 



  'Y: E'Lt 9: N-butane-su7.fonyl-1' -butyl- (1) -urQO.



   150 g of powdered dry potassium carbonate are introduced into a solution of 60 g of butane- (1) -sulfamide in 500 cm3 of dry acetone, then the mixture is boiled for 2 hours at reflux, with stirring. 44 g of butyl isocyanate normal to 50 normal and not stirring is then slowly poured in dropwise and the stirring of the mixture is continued at 50 until the isocyanate odor has disappeared. Diluted with 500 cm3 of di-isopropyl ether and cooled to 0. The precibian is wrung out well, dissolved in water, the aqueous alkaline solution is stirred with chloroform, the chloroform is separated off, and, after treatment with charcoal, the solution is carefully acidified in the cold. aqueous with hydrochloric acid.

   In order to purify the precipitated sulfonylurea with a good yield, it is dissolved in dilute ammonia, the solution is clarified with charcoal, the N-butane-sulfonyl-N'-butyl- (1) - urea is precipitated again with dilute acetic acid, drain and wash well with
 EMI31.2
 the water. After recrystallization from ui-isopropyl ether, the substance melts at 10.
 EMI31.3
 



  E .. "# ':. 1: PLE 30: I-cyclohexane-sulfanyl-Tt' -, so-amylu, rée.



   In a solution of 38 g of cyclohexanesulfonyl isocyanate (boiling point 88-94 under 0.5 mm), prepared from cyclohexanesulfonylurea and phosgene, in 150 cm3 of absolute benzene, poured slowly. dropwise 19 g of iso-amylamine, with stirring. After boiling for one hour at reflux, the benzene is distilled off, the residue is dissolved in
 EMI31.4
 the dilute monia, 011 clarifies the solution such as using charcoal, then hot acidification with hydrochloric acid. After cooling down; llt '! 1t, one wrung and one coiled with a little acetic acid

 <Desc / Clms Page number 32>

 
 EMI32.1
 diluted.

   The N-cyc10hûxnesulphonyl-NI-iso-amylur6e thus obtained is dried in vacuum over charcoal in good yield and recrystallized from methyl acetate. :: ± 11th bottom at 128-1290.
 EMI32.2
 



  We obtain in a similar way:
 EMI32.3
 a) from allylamine (13 g), N-cyclohexane-su1-
 EMI32.4
 fonyl-N'-allylurée, melting at 153-154,
 EMI32.5
 b) from cyclohexyl-methylemine (25 g), 1: -C7clohexane-sulfonyl-Nt-cyclohexyl-methyl-urea, melting point 141-155; c) from 2,4-dimethyl-pentyîe-r # ine- (S) (w5 g), N-cyclohexane-sulfonyl-Nt-Î 2. 4 -di. And ¯ y 1 -y, entyl- (3) - è ::: '' 3,
 EMI32.6
 melting at 165-166.
 EMI32.7
 



  '' 31: N-3-methyl-but ane-sulf ohy - N -but f l- (1) -, zre e.



  Dissolve or suspend in 300 c .; .. 5 dtsketone 30.2 g of 3-methylbutane- (1) -sulfar..de and 50 g of carbonate
 EMI32.8
 pulverized potassium; 24 g of butyl isocyanate are added
 EMI32.9
 normal, then boil the mixture for 3 hours at re'lüx, er
 EMI32.10
 stirring, until the odor of isocyanate is no longer detected.
 EMI32.11
 corn. The mixture is cooled, the precipitate is filtered off and washed with acetone. It is dissolved in water, the solution is clarified to 1 r;.; D of charcoal and carefully acidified with hydrochloric acid. The N-3-methYlbutane-sulfonYl'-butYl- (I) -u :: 'e t) 1 -:': 11 precipitated with a good yield is filtered off, washed / with water eà ,,,, After drying, it is recrystallized from diisopropyl ether.



  This substance melts at 120-121.



  , :: PLE 32: N-CyclohexY1: -meth8ne-su1fonyl-N '-b1' ty] -; 1) -urd.



  Boil for 5 hours at! ', Flux, in o.:.;it:':nt.



  40 g of the sodium salt of Y1 heXYl-methanesulramide and 26 of butylnormal isocyanate in 500 em3 of acetone. After re-
 EMI32.12
 cooling, draining, washing the precipitate with acetone and
 EMI32.13
 Dissolve it in ¯300 cn3 of water. We clarify the solution with acid

 <Desc / Clms Page number 33>

 
 EMI33.1
 charcoal, then hot acidified with 10 <1tic :: ue acid. The precipitated N-oyc1ohexyl-1Il6thnne -sulfanyl-N '-butyl- (1) -urea is filtered off with good yield, and washed with water. After recrystallization from methyl acetate, the substance melts at 126-127.
 EMI33.2
 s.f.rt 33: N- (4- = T1ethyl -3 - chlo rob enzene- sul ronyl) -N '- (n-but yl) -urea e.



  51 g of 4-methyl-3-h3.orobenzenesulfonamide are suspended in 80 cm3 of acetone, the suspension of .150 cm3 of sodium hydroxide containing 10 g of NaOH is added, then added dropwise, with stirring, 25 g of normal butyl isocyanate, keeping the temperature around 10. The solution is dispersed with charcoal, filtered and acidified with dilute acetic acid. We obtain with a good yield
 EMI33.3
 a crystalline precipitate of IJ- (4-methyl-3-ch10robenzene-sulfonyl) - N '- (n-butyl) -urea, which is recrystallized from dilute ethanol or from isopropyl alcohol. The substance melts at 145-146.



   In a similar fashion, from 105 g of 2-
 EMI33.4
 methyl-6-ohlorobenzene, esulfamide in 165 om3 of acetone and jazz cm3 of sodium hydroxide solution containing 20 g of NaOn, by reaction with 50 g of normal butylisocyanate, N- (3-m3thyl-6-ohlorobenzene -su. fonyl) -N '- (n-butyl) -urea which melts tri 134-155, FY: a; .T; 4: N- (4-methyl - chlorobenzc': nc-sulfanyl) -lt.-i sabutylurcsa . a) A suspension of 64 g of 4-methyl-α-chlorabFalzl.c: -çal't.fr3mide, the potassium carbonaceous O 13 and 600 cm3 of atone was heated for an hour, at 55, in 8 Bi as1. , then we let it flow slowly, drop to tS0utte, '17? (t of ethyl chAoformiKtc and. on 1,, ite for 4 haarns at 55. After r '.' l.'CV.Iü.l3C; .lCxli.p on <3e; a, ',, (1. ; precipitated and dissolved in 500 <# ;;; 5 of enu.

   Du i% jii;, = ecVdrci. \ L '(. Ide of black CAn: i.tlll, an j.ï' C;: l.J7i'l; r :, 011 fC; 1 ll C'7 .; ll'k L rv3., lr hydrochloric, le: -m.Gh1 - ulnorrb

 <Desc / Clms Page number 34>

 
 EMI34.1
 ethyl, first in the form of a gr1Ji ::; s0UX product, which soon crystallizes entirely. We wring it out and l1), '1e to l': 1., z. This substance melts at 85-87. b)} pcnd.é1nt 4 1: cures; # 1 7.'ébu113.t.on is boiled in .iL flux ,, 55.5 g of 4-methyl-3-ohlorobenzcne - 3ulfonyl-carbMate of ethyl obtained and dried with 16 g of isobutylamine in 107 g of Elyiomonomethyl ether. The mixture is concentrated under reduced pressure, and the still hot residue is dissolved in dilute ammonia.

   The solution is cleared with animal charcoal and a
 EMI34.2
 small amount of 4-methyl-3-ehlorobenzenesulfonyl, By acid fixation of the filtrate with dilute hydrochloric acid, we have ui, crystalline precipitate of N- (4-methyl-3-chlorobBnzene-sulfonyl) - N'-isobutylurea , which is wrung out and recrystallized in
 EMI34.3
 ethanol aqueous at 75. The substance melts at 15i-159.



  ..PZa 35: N - (. 4-dimethylbenzene-sulf'onyl) -1T'-cyclvhexylurea.



   29.5 g of 2.4-dimethylbenzenesulfonamide are suspended in 60 cm3 of acetone and a mixture is added to the suspension.
 EMI34.4
 Soda lye prepared with 7 g of IaQH and 130 cm3 of water. Into this solution of the sodium salt of 2,4-dim6thylbenzene-sulfide, one drip, with stirring, to the envies of
 EMI34.5
 15, 21.6 g of cyclohexylisocyanate, without precfcuring a transient precipitation. A slight insoluble matter is filtered off, the filtrate is clarified to animal charcoal and acidified with stirring with dilute hydrochloric acid.

   A crystalline precipitate is obtained which is filtered off and then taken up in 600
 EMI34.6
 cm3 of dilute ammonia (1 part by volume of a: TUnon3.rqua concentrated for 20 parts by volume of water); the insoluble constituents are separated by filtration. By acidifying the filtrate with dilute hydrochloric acid, one obtains, with a good roundness, the
 EMI34.7
 Id- (2.4-dimëthylbenzene-.sulfonyl) -N'-cyclohexyl¯ ra, which is drained and recrystallized from ethnnol. This substance melts at 183-185.

 <Desc / Clms Page number 35>

 
 EMI35.1
 



  L'G, .PL '36: N- (3.4-d¯imethoxybenzene-sulfonyl) -N'-isobutyluze.



  27 g of 3,4-dimethoxybenzenesulfemide are suspended in 41 cm3 of acetone and dissolved in 82 cm3 of sodium hydroxide solution containing 5 g of NaOH. Approximately 12.4 g of isobutylisocyanate are slowly dripped in, the mixture is stirred for 30 minutes, filtered to separate a slight insoluble matter, and slowly acidified, with stirring, with water. dilute hydrochloric acid. We obtain a precipitate which we
 EMI35.2
 pxÉEipxiLZ purifies according to the prescriptions of exeraple 35 by dissolving it in dilute ammonia, then by acidifying with hydrochloric acid. After recrystallization from ethanol, the N- (3,4-dimethoxybenzene-sulfonyl) -N'-isobutylurea obtained in a good yield melts at 196.



     Analogously, by reacting 3,4-dimethoxybenzenesulfonamide with normal hexyl isocyanate, the
 EMI35.3
 N- (5.4-dinethoxybenzene-sulfonyl) -N'-n-hexylurea, which melts at 176-177.



    EXAMPLE 37: -N '
 EMI35.4
 N- (m-methoxybenzene-sultonyl) / - n-hexylurea. 14 g of m-methoxybenzene-sulfonamide are suspended
 EMI35.5
 in 25 cm3'dtacetone and 50 cm3 of a dilute sodium hydroxide solution containing 3 g of caustic soda are added. Then 9.5 g of normal hexyl isocyanate were slowly poured in at 10 with stirring, and the mixture was then stirred for a further 1 hour.



  After filtration, precipitated with dilute hydrochloric acid
 EMI35.6
 N- (m-methoxy-benzene-sulfonyl) -NI-n-hexylurea, in good yield. To purify it, it is dissolved in ether, filtered with charcoal and crystallized by evaporating the ether.
 EMI35.7
 The crystals are taken up in dilute ammonia (1: 0), filtered and precipitated with acetic acid cristH11i: HAb1è.



  After rfc: cistallization dhns l'i; orzcapc; nol, 1uroe 1 \ 'l1d: l 111- 11g o. H0ndc 'fJr: nt 8 L.

 <Desc / Clms Page number 36>

 EXAMPLE 38:
 EMI36.1
 N- (3-nethoxybenzene-sulfonyl) -ii'-cyclohexylurea.



   11 g of m-methoxybenzene-sulfemide are suspended in 25 cm3 of acetone, then dissolved by adding 45 cm3 of dilute sodium hydroxide solution containing 2.3 g of caustic soda. Then poured slowly dropwise, 10.7.3 g of cyclohexyl isocyanate. In order to have a quantitative reaction, the mixture is stirred for 1 hour. Filter and acidify the filtrate with dilute hydrochloric acid. The N- (3-methoxybenzene ..



    -N 'sulfonyl) / - cyclohexylurea precipitated and, after drying, it is recrystallized from diisopropyl ether. It melts at 140-142 EXAMPLE 39:
 EMI36.2
 N- (pentane-5-sulfonyl) -N'-hexyl- (1) -urea.



   Into a suspension of 38 g of the sodium salt of pentane-3-sulfonamide in 300 cm3 of acetone., Is poured slowly, dropwise, 40 and with stirring, 33 g of hexyl-1-isocyanate, then the mixture is boiled under reflux for 3 hours. Cooled, the precipitate is filtered off and the solution is concentrated.



  The solid residue is dissolved at the same time as the precipitate in 500 cm 3 of water, adding a little ammonia. The solution is clarified with charcoal, then it is acidified with acid
 EMI36.3
 hydrochloric. The N- (pentane-3-sulfonyl) -N'-hexyl- (1) - urea precipitated is filtered off with a good yield, washed with water, and,
 EMI36.4
 after drying, it is recrystallized from di-isopropyleths; it melts at 90-91. EXAMPLE 40:
 EMI36.5
 N- (dodecane: -I-sulfonyl) -NI-cyclohexylur6e.



   Boiled, 6 hours at reflux, in 350 cm3 of acetone, 38 g of sodium dodecane-1-sulfonamide and 20 g of cyclohexyl isocyanate, then cooled, diluted with 200 cm3 of di- ether. isopropyl, filtered off and the residue washed with diisopropyl ether. The hot residue is then dissolved in 400

 <Desc / Clms Page number 37>

 cm3 of water, the solution is clarified on charcoal and acidified with acetic acid. A first oily precipitate separates, but which solidifies on cooling. This precipitate is digested for a certain time with 1000 cm3 of dilute ammonia, clarified on charcoal and acidified with acid.
 EMI37.1
 acetic.

   The precipitated N- (dodecane-1-sulfonyl) -NI-cyclohexylur6 is filtered off, washed well with water and recrystallized from acetic nitrile. It is then obtained in the form of straws which melt at 118.



    EXAMPLE 41: N- (heptane-1-sulfonyl) -N'-hexyl- (1) -urea.



   In a solution of 36 g of heptane-1-sulfonamide in 500 cc of acetone and 400 cm3 of 0.5-n caustic soda lye, slowly dripped, at 10 and with stirring, 28
 EMI37.2
 g of hexyl-1-isocyanate. Stirred for 3 hours at room temperature, then boiled for 1 hour at reflux; the precipitate which first forms then returns for the most part to solution. The solution is diluted with 1 liter of water, acidified with acetic acid and cooled to 0. The precipitate formed is filtered off and washed well with water. To purify it, it is digested for some time in 2.5 liters of dilute ammonia, the solution is clarified on charcoal, then it is further acidified.
 EMI37.3
 cold calf by aca-tic acid.

   The 1VT- (heptane-1- -NI sulfonylj / -hexyl- (1) -urea precipitated is filtered off, washed well with water and, after drying), it is recrystallized from acetic nitrile. It melts at 103-104.


    

Claims (1)

ABSTRACT The present invention comprises in particular: A) As new industrial products :: and @@@@@@ EMI37.4 '.'i3:, <: u% 3CC'i:' i: '.' Y'.r% r ''. "C" 'r''r' :: ..; n'r.'i :; 're; â = 'k ë:, ..' i: 1 1) the compounds corresponding to the general formula R - SO 2 ¯ mi - Go - Nil - q1 <Desc / Clms Page number 38> in which the symbol R represents a phenyl residue, optionally carrying as substituents, 1 or 2 alkyl or alkoxylic radicals in which the alkyl group is preferably of low molecular weight, or halogen atoms, or else an aliphatic hydrocarbon residue or cycloaliphatic having at least 3 carbon atoms ,, and R an aliphatic hydrocarbon residue or of at least 2 dycloaliphatic darbon atoms /, as well as their salts. 2) The compounds corresponding to the appended formula 1, in which R4 represents a hydrogen atom or an alkyl, - or lower alkoxylic residue, and R1 an aliphatic or cycloaliphatic hydrocarbon residue having at least 3 carbon atoms, as well as the salts of these compounds. 3) The compounds corresponding to the appended formula 2, in which R5 denotes a lower alkyl residue, as well as the salts of these compounds. 4) The compounds corresponding to the appended formula 3, dar. which R5 has the meaning already indicated, and their salts. 5) The compounds corresponding to the appended formula 4, in which R5 has the meaning already indicated, and their salts. 6) The compounds corresponding to the attached formula 5, in which R5 has the meaning already indicated, and their salts. B) A process for the preparation of the compounds specified under A), according to which the methods generally used for the preparation of sulfonylureas are applied. C) Embodiments having the following particularities, taken separately or according to the various possible combinations: a) compounds of formula R - SO 2 - NH 2 are reacted suitably in the form of their alkali salts, with isocyanate of formula R1 - NCO R and R1 having the meanings already indicated; b) compounds of formula R - SO2 - NCO are reacted with amines of formula R1 - NH2, R and R1 corresponding to the definitions <Desc / Clms Page number 39> already indicated; makes r, 5; i = coinpog-és formulates SO2 - NH c) compounds of formula ..., -,;: NH - COO - R2 with amines of formula R1 - NH2, R te R1 having the meanings already indicated and R2 d4signnnt any hydrocarbon residue, preferably of low molecular weight; d) compounds of formula R - SO2 - NH2 are reacted with compounds of formula R1 - NH - COO - R2, R, R1 and R2 having the meanings already indicated; e) compounds of formula R - SO2 - NH - CO - Hal are reacted with compounds of formula R1 - NH2, R and R1 having the meanings already indicated; f) compounds of the formula R - SO2 - NH2, suitably in the form of their alkali salts, are reacted with compounds of the formula R1 - NH - CO - Hal, R and R1 having the meanings already indicated; g) compounds of formula R - SO2 - NH - CO - NH2 are reacted with alkylating agents, or cycloalkylating, for example with primary amines of formula R1 - NH2, R and R1 having the meanings already indicated; h) compounds of formula R - SO2 - NH2 are reacted with compounds of formula R1 - NH - CO - NH2, R and R1 having the meanings already indicated; @ i) compounds of formula R - SO2- Hal are reacted with isourea-ethers of formula R1 - NH - C = NH, R and R1 OR3 corresponding to the definitions already indicated,% denoting an aliphatic hydrocarbon residue and Hal a halogen atom, then the condensation products are hydrolyzed in an acid medium; j) the thiouroes of formula R - SO2 - NH - CS him - R1 are treated with sulfur-removing agents, R and R1 having the meanings already indicated; k) guanidines of formula are hydrolyzed in an acid medium <Desc / Clms Page number 40> EMI40.1 R - SO - 1a - G - fl 11 - tl, 1- and R having the combinations d4-802 - NH 4H - having the characteristics jà indicated; 1) the salts of the compounds of formula R - SO2 - NH - CO - NH - R1 are prepared by reacting alkaline agents, such as alkali metal or alkaline earth hydroxides, alkaline carbonates or organic bases, with sulfonylureas, R and R1 having the meanings already indicated; m) the compounds of formula R - SO2 - NH - CO - NH - R1 are prepared by reacting compounds of formula R - SO2 - NH - EMI40.2 COO - R in the presence of a solvent such as mono-alkyl ethers of glycol, and at temperatures of between 100 and 140, with amines of formula R1 - NH2, R, R1 and R having the meanings already indicated; n) the compounds of formula R - SO2 - NH - are prepared EMI40.3 CO - 1H - R1 by reacting compounds of formula R - SCS - NH2, usefully in the form of alkali salts, in the presence of a solvent such as nitrobenzene or acetone, at ordinary temperature or under heat , with compounds of formula R1 - NCO, R and R1 having the meanings already indicated.