DE1518878A1 - Benzenesulfonylureas and process for their preparation - Google Patents

Description

1518879

FARBWERKE HOECHST AG. formerly Master Lucius & Brüning

File number: P 15 18 8? 8.0 - Fw ^ 903

Date:

Benzenesulfonylureas and process for their preparation

The present invention relates to benzenesulfonylureas the formula

CO-X-Y-phenylene-SO -XH-CO-NH-R ι *

in Λ / elcher mean:

R is hydrogen, lower alkyl or lower phenylalkyl,

R ¹ (a) alkyl, alkenyl or mercaptoalkyl with 2-8 carbon atoms,

(b) alkoxyalkyl, alkyl mercaptoalkyl or alkylsulfinylalkyl with 4 - 8 carbon atoms, of which at least 2 the alkylene part of the Alkoxyalkyl, alkyimercaptoalkyl or alkylsulfinylalkyl belong to

(c) lower phenylalkyl, phenylcyclopropyl,

(d) lower cyclohexylalkyl, cycloheptylmethyl, Cycloheptylethyl or Cyclooctylnie thyl,

(e) endoalkylene cyclohexyl, endoalkylene cyclohexenyl, endoalkylene cyclohexylmethyl or endoalkylene

New ^

909809/0572 Original inspect ^

Cyclohexenylmethyl has 1 - 2 endoalkylene carbons stoffatcKien,

(f) lower alkylcyclohexyl, lower «alkoxycyclohexyl,

Cycloalkyl with 5 - 8 carbon atoms, (h) cyclohexyl, cyclohexenylmethyl,

(i) a heterocyclic ring with k - 5 carbon atoms and one oxygen or sulfur atom and up to two ethylenic double bonds or

(k) a heterocyclic ring bonded to the nitrogen atom via a methylene radical: with k - 5 carbon atoms and one oxygen or sulfur atom and up to two ethylenic double bonds;

Y is a hydrocarbon chain with 1 - h carbon atoms,

Z alkyl with k - 5 carbon atoms, alkoxy with ^ - 5 carbon atoms, cycloalkoxy with 5-6 carbon atoms, cyclohexyl, lower alkyl mercapto, lower alkylsulphinyl, lower alkylsulphonyl, phenylsulphonyl, phenyl, lower phenylalkyl, lower acyl, benzoyl, trifluorinethyl, hydroxy, lower acyloxy, benzyloxy, carboxy, lower carbalkoxy, nitrile, carbamyl, lower alkyl carbamyl, lower dialkyl cjcrbaciyl or nitro,

Z ^{1 is} hydrogen or - if Z is hydroxy or carboxy, lower alkyl, lower alkoxy or halogen,

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and salts of the benzenesulfonylureas mentioned, with compounds the formula

VcO-NH-Y ° - / "" "\ -

SO-NH-CO-NH-R

in the

Z ° alkyl, cycloalkyl, alkoxy, cycloalkoxy rait 4-5 Carbon atoms; Alkylmercapto, alkylsulfinyl, Lower alkyl alkylsulfonyl; Phenyl, Benzyl, benzyloxy, lower alkanoyl; Aroylj trifluoromethyl; a.Hydroxy-, acyloxy-, carboxy-, carbalkoxy-, nitrile or optionally through lower alkyl radicals substituted carbamyl group j

Z '° hydrogen or - if Z ° = hydroxy or carboxy as well Halogen, lower alkyl or lower alkoxy,

Y is a straight or branched hydrocarbon radical with 1-3 carbon atoms, and

R is a saturated or unsaturated, optionally branched alkyl radical with 2-8 carbon atoms, an alkyl radical with h - 8 carbon atoms interrupted by oxygen or sulfur, a benzyl, phenylethyl, cyclohexylmethyl, cyclohexylethyl radical, one with methyl, ethyl, propyl, isopropyl, Methoxyl, ethoxyl, propoxyl or isopropoxyl substituted cyclohexyl radical, a cycloalkyl radical with 5-8 carbon atoms or a saturated or unsaturated cycloalkyl or cycloalkylmethyl radical with h - 5 ring carbon atoms containing in the ring oxygen or sulfur atoms ""

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mean, and their salts are excluded.

In the above and the following definitions, "lower alkyl" always stands for one with 1-4 carbon atoms in a straight or branched chain. "Lower acyl" means an acyl radical (organic acid radical) with up to h carbon atoms, preferably a straight-chain or branched alkanoyl radical of a corresponding chain length.

| According to the definitions given above, R can mean, for example: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, CC- or ß-phenylethyl, OC- , ß- or ß-phenylpropyl. Compounds in which R is methyl or benzyl, and in particular those in which R is hydrogen, are preferred.

R ¹ can mean, for example: ethyl, propyl, isopropyl, butyl, isobutyl, sec. Butyl, straight-chain or branched amyl (pentyl), hexyl, heptyl or octyl; the radicals corresponding to the hydrocarbon radicals mentioned and having an ethylenic double bond: such as allyl or crotyl, furthermore those alkyls with 2-8 carbon atoms which still carry a mercapto group, such as β-mercaptoethyl or higher mercaptoalkyls ", furthermore (r 'can mean, for example: j -Methoxy-propyl, c / "- methoxy-n-butyl, ß-ethoxyethyl, / -ethoxypropyl, {/" - ethoxybutyl or higher alkyloxyethyl, -propyl or

-butyls and the corresponding groups that carry a sulfur atom or the -SO- member instead of the oxygen atom. Also suitable as R ^{1 are} : benzyl, C £ -phenylethyl, β-phenylethyl, C £ -, β- or J- phenylpropyl or -phenylbutyl.

For the purposes of the invention, particular preference is given to those compounds which, as R ^! a cycloaliphatic, given

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For the purposes of the invention, particular preference is given to those compounds which contain, as R *, a cycloaliphatic carbon radical, optionally substituted by alkyl or alkoxy or bonded to the nitrogen atom via alkylene. Examples of such radicals are: Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyj., Xthylcyclohexyl, propyl and Ieopropylcyclohexyl, methoxycyclohexyl, ethoxycyclohexyl, propoxy and isopropoxycyclohexyl, where the alkyl groups in 2-, 3- or isopropoxycyclohexyl, where the alkyl, 3- or isopropoxycyclohexyl, or 3- or 3- alkoxy groups preferably in the ^ position, both in cis and in trans position, cyclohexylinethyl, CC- or ß-cyclohexylethyl, cyclohexylpropyle, endomethylene cyclohexyl (2,2,1-tricycloheptyl), endoethylene cyclohexyl (2,2,2 -Tricyclooctyl), endomethylenecyclohexenyl, endoethylenecyclohexenyl, endomethylenecyclohexylraethyl, endoethylenecyclohexylmethyl, endomethylenecyclohexenylmethyl or endoäthylenecyclohexenylmethyl, OC- or ß-phenylcyclopropyl as well as in the cis-form.

Finally, heterocyclic rings are also ^{suitable as R 1} which, in addition to k - 5 carbon atoms, can also contain 1 oxygen or sulfur atom and up to 2 double bonds and can optionally be bonded to the adjacent nitrogen atom through a methylene group. Examples of such heterocyclic rings are:

-CH ₂

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Y represents a hydrocarbon radical with 1 to 1 h carbon atoms, which can be straight-chain or branched. Examples are -CH ₂ -, -CH ₂ -CH ₂ -, -CH (CH ₃ ) -, -CHg-CHg-CHg-, -CH (CH ₃ J-CH ₂ -, -CH ₂ - CH (CH ₃ ) -, -C (CH ₃ J ₂ -, -CH ₂ j ()

_{3 3 3}

-CH (CHj-CH ₂ -CH -, -CH ₂ -CH (CH ₃ ) -CH ₂ -, CH ₂₂ -CH (CH ₃ J-CH (CH ₃ ) -, -C (CH ₃ ) ₂ -CH ₂ -, -CH ₂ -C (CH ₃ ) ₂ -, -CH (C ₂ H ₅ ) -, -C (CH ₃ ) (C ₂ H ₅ ) -.

Examples of the Z and Z * substituents are in the $ frame of the definitions given above n-, iso- or tert-butyl as well as the corresponding A J.koxy groups, fluorine, chlorine, bromine, Iodine, Cycbhexyloxy, Cyclopentyloxy, Methyl-, Xthyl-, Propyi « or butyl mercapto, sulfinyl or sulfonyl with straight * chain or branched alkyl radicals, benzyl, phenylethyl, Phenylpropyl, acetyl, propionyl, butyryl, acetoxy, Propionyloxy, butyryloxy, carbomethoxy, carboethoxy, Carbopropoxy, methylcarbamyl, ethylcarbamyl, dimethyl or diethylcarbamyl.

The phenylene radical denoted by -phenylene- in the formula is preferably unsubstituted. But it can also be used several times with HeJLogen, lower alkyl or lower Alkoxy substituted. He can use the rest of the

Carry molecule in o-, m- or p-position to one another, with the p-position is preferred.

The production of said benzenesulfonylureas can take place according to methods which are generally used for the preparation of compounds of this class. So can man

(a) Amines of the formula R ¹ NH ₃ or, if appropriate, their salts with the substituents

CO-N - Y -

N -

ORIGINAL INSPECTED

carrying benzenesulfonyl isocyanates, carbamic acid esters, -thiocarbamic acid esters, -carbamine «convert acid halides or -ureas",

(b) the substituent

bearing benzenesulfonamides or their salts with R'-substituted isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or convert ureas,

(c) the substituent

carrying benzenesulfonyl chlorides with R'-substi * Uated ureas, isourea ethers. Isothiourea ethers or parabanic acids convert and the benzenesulf obtained in this way or in another way onylisourea father, -isothioureaether hydrolyzed or parabanic acids,

(d) in appropriately substituted benzenesulfonylthioureas replace the sulfur atom with an oxygen atom,

(e) oxidize appropriately substituted benzenesulfenyl or benzenesulphinyl ureas,

9098C8 / 0672

(f) in benzenesulfonylureas cerium formula

NY-phenylene - SO ₂ -NH-CO-NH-R ¹ .

the remainder by acylation in one or more reaction steps

CO -

introduce,

(g) in benzenesulfonylureas of the formula given above, in which Z is one by esterification . protected hydroxy or carboxy group or a hydroxy group protected by etherification or in the event that R = H, one by ethhalidine formation represents protected carboxy group in the o-position to the carbonamide group, this by Saponification or catalytic hydrogenation exposed

and the products of the process are optionally treated with alkaline agents to form salts.

Depending on the nature of the members Z, Z ¹ and R ', one or the other of the processes mentioned will in individual cases be unsuitable for the preparation of the individual compounds falling under the general formula or at least make precautions necessary to protect active groups. Such relatively rarely occurring cases can be appreciated by those skilled easily, and there is no difficulty in successfully applying another of the synthesis routes described in such cases. So it may be necessary, instead of Z-standing hydroxy groups by esterification or etherification at corresponds

909809 / 0S72

carboxyl groups stony due to esterification, or a carboxy group in o-position to the carbonamide group also by ring closure to the To protect phthalimide derivatives. The same applies to the Cases in which R 'represents a mercaptoalkyl group.

The mentioned benzenesulfonyl-carbamic acid esters or -thiocarbamic acid esters can have a lower alkyl radical or a phenyl radical in the alcohol component. The same applies to the R'-substituted carbamic acid esters or the corresponding mono thiocarbamic acid esters.

Carbamic acid halides are primarily suitable the chlorides.

The benzenesulfonylureas in question as starting materials for the process can be unsubstituted on the side of the urea molecule facing away from the sulfonyl group or substituted one or two times by preferably lower alkyl radicals or aryl radicals, the aryl radicals optionally being by a chemical bond or via a bridge member such as -CH-- , -NH-, -0- or -S- can be connected to one another. Instead of benzenesulfonylureas substituted in this way, corresponding 1ST ben ζ oil are also used if onyl-N'-acylureas, which ^{can also be alkylated or arylated on the N f} nitrogen atom, and bis (benzenesulfonyl) ureas' to use. For example, bis (benzenesulfonyl) ureas or N-benzenesulfonyl-N'-acylureas of this type can be treated with amines R NH ".

The salts obtained are at ei ^ elevated temperatures, in particular heated to those above 100 ° C.

909809/0672

It is also possible to use ureas of the formula R -NH-CO-NH or acylated ureas of the formula

R -NH-CO-NH-acyl j wherein acyl is a preferably low molecular weight aliphatic or aromatic acid residue or the nitro group, or of phenylureas of the formula R ^ NH-CO-NH-C ^ H- or of diphenylureas of the formula R -NH -CO-N (CgH,.) ^ Where the phenyl radicals are substituted as well as directly or via a bridge member such as -CH _? -, -NH-, -0- or -S- can be connected to one another, or starting from Ν, Ν-disubstituted ureas of the formula R -NH-CO-NH-R and these with

to implement substituted benzenesulfonamides,

The replacement of the sulfur atom with an oxygen atom in the appropriately substituted benzenesulfonyl thioureas can for example with the help of oxides or salts of heavy metals or by using Oxidizing agents such as hydrogen peroxide, sodium peroxide, or nitrous acid. The thioureas can also be desulfurized by treatment

ι
with phosgene or phosphorus pentachloride. As an intermediate stage

obtained chloroformic acid amidines or carbodiimides can converted into the benzenesulfonylureas by leveled measures such as saponification or the addition of water will. Isothiourea ethers behave in the desulfurization like thioureas, they can accordingly serve as starting materials for this reaction in the same way as these.

909809/0572

The use of phthalimide compounds where Z = carboxyl in the o-position to the carbonamide group is fundamental possible for all reaction types. The splitting of the phthalimide residue can take place through alkali, it occurs but generally already in the reaction or in the work-up of the reaction products. When using Esters or benzyl ethers can subsequently be split into the free compounds.

Likewise, the protection of a hydroxyl or carboxy group as Z and the subsequent cleavage of the protective group can be carried out in all of the types of reaction mentioned. In the case where Z is a hydroxy group, suitable protective groups are acyl groups, in particular lower alkanoyl and benzoyl groups, and hydrocarbon radicals, namely benzyl., Which can be split off by saponification or catalytic hydrogenation. In the event that Z is a carboxy group, an esterification with alcohols, namely lower aliphatic alcohols or benzyl alcohol, and subsequent cleavage by saponification can be used for protection. In cases where connections. are desired, contain as Z or carbalkoxy, acyloxy or Benz3 ^'r loxy, of course, has to remain under a saponification.

The embodiments of the method according to the invention can generally with regard to the reaction conditions largely varied and adapted to the respective conditions. For example, the implementations under Use of solvents, can be carried out at room temperature or at elevated temperature.

90 9 8 09/0572

On the one hand, such compounds are used as starting materials, the one with the group

CON - Y

contain substituted benzene radical. As examples of the component

CO -

this formula can be considered:

CH,

'CH-CH ₂ -

v ^ -CO- ·, CH -C-f V -CO-,

CH,

-CO-,

CO

H> -O- ξ V -CO-, CH S- / \ V -CO-

ί ~ \

-CO-,

C \ -

co 3

CH ₃ -SO ₂ - & \ -co-

■ co-,

\. ΓΛ

-CO-,

C \ ■ -co- f \ -co-

co-,

CH ₂

-co-,

.909809 / 0572

f ~ \

CH ₂ -O- {>

CO-

-CH ₂ -O

H ₂ -O-

, CH ₃ CO- / \ -CO, CF ₃ - ^

-CO-, ·

CO 1

.CO-,

CO-, HO- - AA-CO-

CO-, CI

VS -co-,

CF,

OH OH

CH

CH ₂ -CH

CO-,

) HO-,

OCOCH

CO-,

COOH

CO-, HOOC-f ^v > -CO-,

COOH

CO-,

COOC ₀ K 2

CO-, 2 CO

^ C ON

CK,

CH,

N) -CO-,

-CO-

The benzenesulfonylurea derivatives obtainable by the process according to the invention are valuable medicaments.

909809/0572

if

iaittel, which is characterized by a strong and above all long distinguish lasting blood sugar lowering effect.

The 'strong effectiveness of the process products is determined when fed to rabbits in a dose of 10mg / kg per os and the blood sugar according to the known Hagedorn-Jensen method or with an autoanalyzer determined over a longer period of time.

For example, it was determined that the N- ^ T- (β- ^ 2-n-Anylox3 ⁱ -benzamido ^ »ethyl) -benzoisulfonylJ-N '- (2,5-endorcethylene-cyclohexylmethyl) ~ urea 3 hours causes a blood sugar drop of $ 27, which after 6 hours is h2 <ft and after Zh hours is still 1b <p .

The benzenesulfonylureas described should be preferred for the production of orally administrable preparations with blood sugar lowering effectiveness for the treatment of Diabetes mellitus and can serve as such or in the form of their salts or in the presence of substances that contribute to lead to salt formation. For salt formation can be used, for example: Alkaline Agents such as alkali or alkaline earth hydrosides, carbonates or bicarbonates, but also organic bases, especially tertiary nitrogen bases, provided that they are physiological are compatible.

Tablets are preferably used as medical preparations Consider, besides the procedural products, the usual ones Auxiliaries and carriers such as talc, starch, lactose, Tragacanth or. Contains magnesium stearate.

A preparation containing the described benzenesulfonylureas contains as an active ingredient, e.g. a tablet or a powder

909809/0572

with or without the additives mentioned, is expediently brought into a suitable metered form. As a dose is To choose one that takes into account the effectiveness of the benzenesulfonylurea used and the desired one Effect is adjusted. The dosage per unit is expediently about 0.5 to 100 mg, preferably 2 to 10 mg, however, dosage units which are considerably above or below this can also be used, if necessary to be divided or multiplied prior to application »

example 1

Ν- / ζ "- (ß - ^ - trifluoromethylbenzamido ^ -ethyl) -benzenesulfonyl ^ - N ^f - (2,5-endomethylene-cyclohexylmethyl) -urea

3 g of N - ^^ - * (ß- ^ 3-Trifluormethylbenzamidq ^ -äthyl) -benzolsulfonyl7_methylurethan (melting point 178 - 180 ° C) are suspended in 50 ml of xylene and treated at 80 ° C with 1 g of 2,5-Bndomethylenecyclohexylmethylamiti- . The mixture is then heated to \ ho C and kept at this temperature for 1 hour, the methanol formed in the reaction being distilled off. The crude product precipitating from the cooled reaction mixture is purified by reprecipitation with dilute ammonia / hydrochloric acid. After recirculation from methanol, the melting point of Ts-Jß- (ß- ^ 3-trifluoromethylbenzamido ^ -ethyl) -benzenesulfonyl7_N '- (2,5-endomethylene-cyclohexylmethyl) urea is 174 - 176 ^P C ^.:

In an analogous way one obtains

from the N- ^ T- (ß- ^ 2-n-Butoxybenzamido ^ -äthyl) -benzenesulfonyly-methyl urethane (M.p. 160-162 C)

the T $ - / h ~ (ß ^ 2 ~ n-Butoxybenzamido ^> - ethyl) -benzolsulf onyl N '- (2, 5-endomethylene-cyclohexylmeth3'l) urea of melting »1 ^ 7 - 1'19 ⁰ C (from methanol),

9Ö9809 / 0572

from the N - ^ - (B- (2-n-amyloxybenzamido ^ räthyl) -benzenesulfonylj-methyl urethane (M.p. 160 - 162 ° C)

the Nj / ΣΓ- (ß- <£ -n-amyloxybenzamido ^ -ethyl) -benzenesulfonylj / -N ¹ - (2,5-endomethylene-cyclohexylmethyl) -urea of melting point 117-119 ° C (from methanol).

Example Zx

N ~ / 5 "- (β- <2-nitrobenzamido > ethyl) -benzenesulfonyl7-N '- (Jf-methylcyclohexylJ-urea (trans)

3 ^, 9 g of 4- (3-nitrobenzamido ß ^ ^ ethyl) ~ benzenesulfonamide (m.p., 205-207 ° C) are dissolved in 50 ml of 2N sodium hydroxide solution and 100 ml of acetone and at 0 - 5. C dropwise with '. \ k g trans - ^ - Methyicyclohexylisocyanat added. The mixture is stirred for 3 hours, diluted with water, filtered and the piltrate is acidified with dilute hydrochloric acid. The N- / £ - (β «0-nitrobenzamido ^ ~ ethyl) 'benzenesulfonylT'-N ¹ - (^ - methylcyclohexyl) urea is purified by recrystallization from methanol / dimethylformamide and melts at; 200 - 202 ° C.

Example 3 *

N ~ 2? * "" (Β-2-isobutoxy-benzemidoethyl) -benzenesulfonyl7-N '- (2,5-endome ethylene-cyclohexylraethyl) -harnetoff

27 e N- / f - {ß-2-Isobutoxy-benzamidoethyl) -ben8oleuli * onyl7 «N ♦" (2, ^ -endotnethylen-cyclohexylmethyl) -thiourea (m.p. 15 ^ - 156 ° C, made from * f «(Ss-2 ~ xeobutoxy-benjEamidoethyl) -beniEoleulfonamid and 2,5-endomethylene-cyclohexylmethyl mustard oil) are dissolved in about 500 ml 1 η sodium hydroxide solution and with « about

BATH ORIGINAL

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50 ml 35% Hydrogen peroxide added.
The batch is heated on the steam bath for 30 minutes,
filtered, cooled and acidified. The precipitate is acidified, washed with water and extracted from methanol
recrystallized. The obtained N - / ^ - (ß-2-Isobutoxybenzamidoethyl) -benzenesulfonyly ^ -N · - (2,5-endome thylenecyclohexylmethyl) -urea melts at 12 ^ - 126 ° C.

αηάαηο / λ cτ

Claims (1)

Patent claims: Ο Benzenesulfonylureas of the formula ^ ■ - ^ w CO-NY-phenylene-SOo-NH-CO-NH-R ¹ ι ^A in which mean: R is hydrogen, lower alkyl or lower phenylalkyl, R ¹ (a) alkyl, alkenyl or mercaptoalkyl with 2 - 8 carbon atoms, (b) alkoxyalkyl, alkyl mercaptoalkyl or alkylsulfinylalkyl with 4-8 carbon atoms, of which at least 2 are the alkylene part of the Alkoxyalkyl, alkylmercaptoalkyl or alkylsulfinylalkyl belong to (c) lower phenylalkyl, phenylcyclopropylii (d) lower cyclohexylalkyl, cycloheptylmethyl _r cycloheptylethyl or cyclooctylmethyl, (e) endoalkylenecyclohexyl, 'endoalkylenecyclohexenyl, Endoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1-2 endoalkylene carbon atoms . t. (f) lower alkylcyclohexyl, lower alkoxycyclohexyl » ι% \. ** _t ^ tm t <n i **> _m * m »4» mm 908801/0172 (β) Cycloalkyl with 5 - 8 carbon atoms, (h) Cyclohöxenyi »Cyclohexenylmethyl, (t) a heterocyclic ring with k - 5 carbon atoms and one oxygen or sulfur atom and up to two ethylenic double bonds or (k) one via a methylene radical to the nitrogen atom bonded heterocyclic ring with 4-5 carbon atoms and one oxygen or Sulfur atom and up to two ethylenic double bonds j Y is a hydrocarbon chain with 1 to k carbon atoms! Z alkyl with h - 5 carbon atoms, alkoxy with k - 5 carbon atoms, cycloalkoxy with 5-6 carbon atoms, cyclohexyl, lower alkyl mercapto, lower alkyl sulfinyl, lower alkylsulfonyl, phenylsulfonyl, phenyl, lower phenylalkyl, lower acyl, benzoyl, trifluoromethyl, hydroxy, lower Acyloxy, benzyloxy, lower alkylcarbamyl, lower dialkylcarbamyl or nitro, Z ^{1 is} hydrogen or - if Z is hydroxy or carboxy, lower alkyl, lower alkoxy or halogen, and salts of the benzenesulfonylureas mentioned, where Compounds of the formula 909809/0672 CO-NH-Y ⁰ ~ f \ -SO- ^ NH-CO-NH-R ⁰ ti in the Z ° alkyl, cycloalkyl, alkoxy, cycloalkoxy with 4-5 carbon atomsι alkylmereapto, alkylsulfinyl, alkylsulfonyl with a lower alkyl radical | Phenyl, benzyl, benzyloxy, lower alkanoyl, aroyl; Trifluoromethyl; a hydroxy, acyloxy, carboxy, carbaikoxy, nitrile or a carbamyl group which is optionally substituted by lower alkyl radicals; / Z ^fO hydrogen or - if Z ° - hydroxy or carboxy - also halogen, lower alkyl or lower alkoxy, Y °. a straight or branched hydrocarbon radical with 1-3 carbon atoms, and R ° a saturated or unsaturated, optionally branched alkyl radical with 2-8 carbon atoms, one interrupted by oxygen or sulfur "Alkyl radical with 4-8 carbon atoms, a benzyl, Phenylethyl, cyclohexylmethyl-iCJrclohexylethylrest, one by methyl, xthyl, propyl, isopropyl, methoxyl, üthoxy, propoxyl, or isopropoxyl substituted cyclohexyl radical or an oxygen or oxygen radical A saturated or unsaturated cycloalkyl or cycloalkylmethyl radical containing sulfur atoms 4-5 Ring-C-Afomen mean and their salts are excluded. ι • ■ 2 «Process for the manufacture of benzenesulfonyl urea according to claim 1, characterized in that one 90980S / 0572 a) Amines of the formula R ¹ NH or optionally ddren salts with the sulfo substituents carrying benzenesulfonyl isocyanates, carbaric acid esters » - thiocarbamic acid stars, carbamic acid halides or «converts ureas» " b) the substituent carrying benzenesulfonamides or their salts with R'-substituted isocyanates, carbamic acid esters ^ thi ocarbaininsäurees system, carbamic acid halides or ureas, '^; c) the substituent _f f carrying benzenesulfonyl chlorides with R'-substituted ureas "Isoharnstoffäthern, Isothloharnstoffäthei ii * _f or implement Parabaneäuren and Benzolsulfonylisoharnstoffäther thus obtained or by other means, or -isothioharnetoffäther -parabansäuren lysed hydro ~ d) in appropriately substituted benzenesulfonylthiolarine 808809/0672 n replace the sulfur atom with an oxygen atom !: j ' a) appropriately substituted benzenesulfenyl «or
sulfonylureas oxidized> t) in benzene sulfßHJlurstof fan. the * formula ^ N-T-phenylene-SOg-NH-CO-KH-R * by acylation in one or more reactions ^ «- steps:! ic.n reads ² N _introduces; in BenzolsLiIforiy! ureas of the formula given above, in which Z represents a hydroxyl carboxyl group protected by esterification or a hydroxyl group protected by hydroxyl group or in the event that R s H is a carbouy group which is protected by phthalimide formation and is o-position to the carbon dioxide group, these are exposed by saponification or catalytic hydrogenation. 3CHJ3Ö9 / 0572 3 · Process for the production of blood sugar-lowering effective »for the oral treatment of diabetes mellitus suitable pharmaceutical preparations, characterized in that that one Benzolsulfonylurstöffe in claim 1 given formula or its non-toxic salts, if applicable in a mixture with pharmaceutically customary excipients in a pharmaceutically suitable form of administration brings * 4 »Blood-reducing effective, for aralen treatment pharmaceutical preparations suitable for diabetes mellitus » characterized by a content of one in the claim defined benzenesulfonylurea or its salt. 909809/0672