MC633A1 - Benzene-sulfonyl-ureas and their preparation - Google Patents

Description

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CASE: Fw 4936 B PATENT OF INVENTION

Benzene-sulfonyl-ureas and their preparation.

Company known as: MRBWERKE HOECHST AETIENGES^LLSCHAFT VOmiAlS JkJEIS!3E LÏÏCIUS & BRTOING-

-o-o-o-o-o-o-

The present invention relates to benzenesulfonyl ureas having the formula X

(t) - 00 - N - T -phenylene- SO2 - WH - 00 - ÏÏH -OZ

as well as their salts.

In the previous formula:

R denotes hydrogen, a low-weight alkyl group

10 molecular or a low molecular weight p-benyl-alkyl group,

R^ denotes

(a) an alkyl, alkenyl or mercapto-alkyl group containing 2 to 8 carbon atoms, 15 (b) an alkoxy-alkyl, alkyithi-o-alky or alkyl-

sulfinyl-alkyl containing 4 to 8 carbon atoms, of which at least 2 belong to the alkylene portion,

- 2 -

(c) a low molecular weight phenyl-alkyl group, or phenyl-cyclopropyl,

(d) a low molecular weight cyclohexyl alkyl group, a cycloheptyl-methyl, cycloheptyl-ethyl or cyclo-octyl-

5-methyl,

(e) an endoalkylene-cyclohexyl, endoalkylene-cycloliexenyl, endoalkylene-cyclohexyl-methyl or endo-alkylene-cyclohexenyl-methyl group containing 1 or 2 carbon atoms in the endoalkylene portion,

10 (f) a low molecular weight alkyl-cyclohexyl group or a low molecular weight alkoxy-cyclohexyl group,

(g) a cycloalkyl group of 5 to 8 carbon atoms,

(h) a cyclohexenyl or cyclohexenyl-methyl group,

(i) a heterocyclic nucleus containing 4 or 5 carbon atoms and one oxygen or sulfur atom and up to 2 ethylenic double bonds, or

(k) a heterocyclic nucleus linked to the nitrogen atom by a methylene residue, containing 4 or 5 carbon atoms and one oxygen or sulfur atom and up to 2 ethylenic bonds, 20 Y denotes a hydrocarbon chain containing 1 to 4

carbon atoms,

Z denotes a remnant of aliphatic hydrocarbon, saturated or unsaturated, containing 5 or 6 carbon atoms, or a phenyl group possibly bearing, as substituents, a low molecular weight alkyl group, an alkoxy group

with a low molecular weight, a -CF^ group or a chlorine, bromine or fluorine atom,

Z denotes a halogen atom, a low-weight alkyl group

• a low molecular weight alooxy group, such as the -Cl^ group or the -IK^ group, or even

30 when Z represents a phenyl group, substituted or not

a hydrogen atom, with the S substituent preferably occupying position 4 or 5.

In this description, the term "low molecular weight alkyl" always refers to an alkyl group containing 1 to 4 carbon atoms, in a straight or branched chain.

According to the definitions given above, R can designate, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, α- or γ-phenylethyl, α-, β- or γ-phenylpropyl group. Compounds in which R designates a methyl or benzyl group, and especially those in which R designates hydrogen, are the most suitable.

R^l can designate, for example, an ethyl, propyl, isopropyl, butyl, isobutyl, sec group. butyl, amyl (pentyl) straight-chain or branched-chain, hexyl, heptyl, or octyl, a mono-olefin residue corresponding to any of the hydrocarbon residues mentioned, for example, the allyl or cro-tyl group; an alkyl group containing 2 to 8 carbon atoms and bearing a mercapto group, for example, the β-mercaptoethyl group or higher mercaptoalkyl groups. R^ may also designate, for example, a β-methoxypropyl, β-methoxyn-butyl, β-ethoxyethyl, β-ethoxypropyl, β-ethoxybutyl, or higher alkoxyethyl, alkoxypropyl, or alkoxybutyl groups, and the corresponding groups that contain a sulfur atom or the -SO- member instead of an oxygen atom. In addition, R^ may designate, for example, the benzyl, α-phenylethyl, p-phenyl-ethyl, a-, j3- or X-phenyl-propyl or phenyl-butyl groups.

For the present invention, compounds containing, as a substituent R, a cycloaliphatic hydrocarbon residue that may bear alkyl or alkoxy groups or that may be bonded to the nitrogen atom are particularly appreciated.

by an alkylene group. Among such remnants, we will mention, for example, the cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, propylcyclohexyl and isopropylcyclohexyl groups, methoxycyclohexyl, ethoxycyclohexyl, propoxycyclohexyl and isopropoxycyclohexyl groups, the alkyl or alkoxy groups being able to be in position 2, 3 or, preferably, in position 4, and this with both the cis and trans configurations. In addition, we will mention the cyclohexyl-methyl, α- or β-cyclohexyl- groups

ethyl, cyclohexyl-propyls, endo-methylene-/(i.e. bicyclo/5.2.1_7heptyl), endoethylene-cyclohexyl (i.e. bicyclo/5.2.27octyl), endomethylene-cyclohexenyl, endoethylene-cyclohexenyl, endomethylene-cyclohexylmethyl, endoethylene-cyclohexylmethyl, endomethylene-cyclohexenylmethyl or endoethylene-cyclohexenylmethyl, oc- or p-phenyl-cyclopropyl with the cis or trans configuration.

Finally, heterocycles containing, besides 4 or 5 carbon atoms, 1 oxygen or sulfur atom and up to 2 double bonds, and which can be linked to the neighboring nitrogen atom by a methylene group, are also suitable as R^ residues.

Examples of such heterocycles include the following:

/ cyclohexy]^'

As examples for the bridge-forming group Y

The following groups will be mentioned

- 5 -

-CH2- -CH2-CH2- -CE(CH5)- -CH2-CH2-CH2

-CH(CH5)-CH2- -CH2-CH(CH5)- -C(CH5)2-

-CH2-0H2-CH2-CH2- -CH(CH3)-CH2-CH2- -CH2-CH(CH,)-CH2-

5 -CH2-CH2-0H(CH5)-, -CH(OH5)-OH(OH5)- -C(OH5)2-CH2-

CH2-C(CH5)2- -CH(02H5)- -C(CH5)(G2H5)-

Among which the following groups are preferred:

-CH2-CH2- -CH(CH5)-CH2- and -CH^CHCCH^)-.

10 The phenylene residue designated in the formula by "pheny-

The "lene-" is preferably devoid of a substituent, but it may also bear one or more substituents chosen from the set comprising halogens, lower alkyl groups, and lower alkoxy groups. It may carry the remaining parts of the molecule in the ortho, meta, or para position, the para position being preferable.

The present invention also relates to a process for preparing the benzenesulfonyl ureas described above, a process which employs known methods for the synthesis of 20 compounds of this type. For example, the methods described below are used.

(a) Amines bearing the R^ substituent are reacted,

or their salts, with benzene-suifonyl isocyanates, benzene-suifonyl-carbamic acid esters, acid esters,

of the

25 benzene-sulfonyl-thiatearbamics, benzene-sulfonyl-ureas,/benzene-tallow onyl-semi-carbazides or benzene-sulfonyl-

carbazones bearing the X substituent

- GO - AND - Y 30 \ R

(b) Benzenesulfonamides of formula or their salts are reacted with isocyanates, carbamic acid esters, thicibarbamic acid esters, carbamic acid halides or ureas bearing the substituent E^.

benzene-tallow ethers, onyl-iso-thicûs-ureas, benzene-tallow onyl-parabanic acids or benzene-sulfonyl amidines of halogeno-formic acids, bearing corresponding substituents.

(d) Water is fixed onto carbodi-imides bearing corresponding substituents.

(e) In benzenesulfonylthioureas bearing corresponding substituents, the sulfur atom is replaced by an oxygen atom.

(f) In benzenesulfonylureas of formula MH-Y-phenylene-SO2-lîH-CO-KH-E1

E

The remainder is introduced by acylation in one or more reaction phases.

If necessary, the products obtained according to one or the other of the preceding methods are treated with alkaline agents in order to convert them into salts.

x

OZ

(c) Benzene sulfonyl isourea ethers, benzene sulfonyl isourea esters, are hydrolyzed

It can happen, in particular cases, depending on the

nature of group X

OZ

that one or another of the processes mentioned may not be suitable for the preparation of some of the compounds represented by the general formula. Such cases, which are relatively rare, will be easily recognized by the expert, and there will be no difficulty in finding one among the methods described that leads to the desired result.

Instead of benzene-suifonyl isocyanates, one can also use reaction products of benzene-tallow isocyanates with acid amides, such as caprolactam or butyrolactam, or with weakly basic amines, such as carbazoles.

Benzene-suifonyl-carbamic or benzene-suifonyl-thiobarbamic acid esters may contain, in their alcoholic component, an alkyl group, an aryl group, or a heterocyclic ring. Since this group is eliminated during the reaction, its chemical composition has no influence on the character of the final product, and therefore it can be varied within wide limits. The same applies to carbamic esters bearing the R substituent or the corresponding thiocarbamic esters.

Chlorides are suitable as halides of carbamic acids in the first place.

The benzene-suifonyl-ureas used as starting materials may be devoid of a substituent on the side of the urea molecule opposite the sulfonyl group, or they may

These compounds can be modified by adding one or, in particular, two substituents. Since these substituents are eliminated during the reaction with amines, their character can be varied within wide limits. In addition to benzenesulforiylureas bearing alkyl, aryl, acylic, or heterocyclic substituents, bis-(benzenesulfonyl)ureas or bis-(benzenesulfonyl)ureas bearing yet another substituent, for example, a methyl group, on one of the nitrogen atoms can also be used. These bis-(benzenesulfonyl)ureas or N-benzenesulfonyl-1T'-acylureas can, for example, be treated with cyclohexylamine or p-methylcyclohexylamine, and the resulting salts can be heated to high temperatures, particularly above 100°C.

It is also possible to start with ureas corresponding to the formula R^-NH-CO-NHg or with ureas that carry one or, in particular, two substituents on the free nitrogen atom and to react them with benzenesulfonamides carrying the substituent

OZ

Suitable starting materials include, for example, IT-cyclohexyl-urea or 11-(4-methyl-cyclohexyl)-urea, N'-acetyl-, N'-nitro-, N'-cyclohexyl-, N'-(4~methyl-cyclohexyl)-, N', N'-diphenyl- (in which the two phenyl residues may also bear substituents or be linked to each other either directly or by a bridge such as -CHg-, -MH-, -O- or -S-), N'-methyl-N'-phenyl-, and W, N'-di-cyclohexyl-ureas as well as cyclohexyl-carbamoyl-imidazoles or cyclohexyl-carbamoyl-triazoles bearing the Y substituent.

The hydrolysis of benzene-suifonyl-parabanic acids,

The hydrolysis of benzenesulfonyl isourecs ethers, benzene-tallow onyl isothioureas ethers, benzene-sulfonyl isourea esters or benzene-sulfonyl amidines of halogenated acids, mentioned as starting substances, is carried out satisfactorily in an alkaline medium; isourea ethers and isourea esters can also be successfully hydrolyzed in an acidic medium.

The replacement of the sulfur atom by an oxygen atom in benzene-sulfonyl-thiourecs bearing corresponding substituents can be done for example with the help of oxides or salts of heavy metals or by means of oxidizing agents, such as hydrogen peroxide, sodium peroxide or nitrous acid.

It is also possible to desulfurize thioureas by treatment with phosgene or phosphorus pentachloride. The amidines or carbodiimides of chloroformic acid obtained as intermediate products can be transformed into the desired benzenesulfonyl ureas by appropriate measures, for example by saponification or by the addition of water.

Iso-thiol^ired ethers behave like thio-ureas and can also be used as starting materials for desulfurization reactions.

The acylation of amino-ethylbenzenesulfonylureas can be carried out either in one step, for example by reaction with benzoic acid halides bearing corresponding substituents, or in several steps. To illustrate the many possibilities that exist for multi-stage acylation, we will mention the reaction of amino-ethylbenzenesulfonylurea with 2-alkoxybenzoyl or 2-aryloxybenzoyl chlorides and the subsequent introduction of a benzoyl peroxide atom.

- 10 -

halogen in the benzene ring of the benzamido group, or the introduction of a thio-benzoyl remainder bearing corresponding substituents and the conversion of the reaction product into the corresponding benzamide derivative.

The process of the invention is modified with regard to the reaction conditions and can be adapted to each particular case. For example, the reactions can be carried out in the absence or presence of solvents, at room temperature or at elevated temperature.

Starting materials are used compounds that contain a benzene residue bearing the group

ÔZ

As examples for the left-hand benzoyl part of this group, that is, for the component of formula

In general, the methods of execution can be varied widely.

X

X

The following groups should be mentioned:

- 11 -

// \Yco- /~VCo- fVco-

^-cv H.<q gh,

och-,

cl-y Vco-

w-o

Cl cf5^/ ^v-co-

h,c

■00-

ch3

Q-c°-

co

•o

Cl co-

(ch5)2 hc f\ 00-

5

' 0ch2ch2chc0h5)2

\ch2ch2ch(ch3)2

w co-

(ch2)4ch5

- 12 -

t>(CH2)5CH5

,c^-c0-

o-(gh2)4ch-

C2 H5Q

00-

0ch2ch2ch(ch,)2

oi^Q-°°-

^0CH2CH20H(CH3)2

10 Er-Q-co-

00-

6ch2ch2ch(ch5)2 h3o -och2ch2ch(ch3)2

O"co"

15 cl 0(ch2)4ch7

The benzene-sulfonyl-ureas which are the subject of the present invention are characterized by an intense hypoglycemic action and, above all, a long-lasting one.

20 To establish the hypoglycemic action of the new benzene-suifonyl-ureas, these active substances to be studied are administered at a dose of 10 mgAg to the rabbit, orally, and blood glucose is measured for a certain time, by the classic Hagedorn-Jensen method or by means of an auto-analyzer.

i

25 This is how, for example, a dose of 10 mg/kg of

U-/î-(p-<^2-iso-amyloxy-5-methyl-henzamido> -ethyl)-benzene-sulfonylmethane-(4-methyl-cyclohexyl)-urea causes a 37% drop in blood glucose after 3 hours, which rises to 41% after 24 hours and only falls back to zero after

30 4-8 hours. Similarly, a 10 mg dose of N-^f-(j3- was found to

- 15 -

<2-phenoxybenzamido> -ethy^-benzenesulfonylT-N'-^-methylcyclohexyl)-urea causes a 25% decrease in blood glucose after 3 hours, which is still 25% after 24 hours, while the known H-(4-methylbenzenesulfonyl)-N,-butyl-5 urea, as long as it is not administered to the rabbit at a dose greater than 25 mg/kg, does not cause a decrease in blood glucose.

The powerful activity of the compounds, the subject of the invention, becomes particularly clear. When N->/Zf-(|3-<^2-phenoxy-5-methyl-benz zamido^>-ethyl)-benzene-sulfonyl7-N1-cyclohexyl-urea is administered at a dose of 0.05 mg/kg and N-/^f-((3-<C2-phenoxy-benzamido-ethyl)-benzene-sulfonyl/£-N'-cyclohexyl-urea at a dose of 0.06 mg/kg to the rabbit, a pronounced decrease in blood glucose is still observed.

Preferably, these are used in the manufacture of oral hypoglycemic preparations for the treatment of diabetes mellitus, and can be administered as is or in the form of salts, or in the presence of substances capable of generating salts. For salt formation, alkaline agents such as alkali or alkaline-earth hydroxides, carbonates, or bicarbonates may be used, for example.

25 prize-winning products containing, in addition to the products of the present invention, the usual adjuvants and excipients, such as talc,

starch, lactose, tragacanth gum or magnesium stearate.

30 powder, containing the benzene-sulfonyl-ureas described as

It is especially when the dose is further reduced that the

The described benzene-sulfonyl-ureas are intended

For medicinal preparations, com-

A preparation, for example a tablet or a

- 14 -

The active ingredient, with or without the aforementioned additives, should preferably be presented in a dosed form, adapted to the efficacy of the active substance and the desired effect. The dose may be, for example, approximately 0.5 to 100 mg per unit, preferably 52 to 10 mg, or lower or higher, and may be divided or multiplied before administration.

The following examples illustrate the present invention, without in any way limiting its scope:

EXAMPLE 1:

N-(f3-C2-phenoxybenzamidoethyl)-benzenesulfonamide (melting point 187-188°C, obtained from 2-phenoxybenzoic acid chloride and 4-((3-aminoethyl)benzenesulfonamide) in a mixture of 15-12.5 mL of sodium hydroxide solution and 50 mL of acetone; to this suspension, 3.3 g of cyclohexyl isocyanate are added dropwise at 0-5°C. The mixture is stirred for 3 hours at room temperature, the reaction mixture is diluted with water, the undissolved matter is removed by filtration, and 20 g of the filtrate is acidified with dilute hydrochloric acid. N-(f3-C2-phenoxybenzamidoethyl)-benzenesulfonamide cyclohexyl-urea which separates in crystalline form melts, after recrystallization in methanol, at 168-170°C.

sulfonyl7-N'-(4-methyl-cyclohexyl!)-urea (trans), melting point 186 - 188°C (recrystallized in methanol) and sulfonyl^-N'-hutyl-urea, melting point 138 - 140°C (recrystallized in methanol);

10

N-/5-((3-<C 2-phenoxy-benzamidq>-ethyl)-benzene-sulfonyl7-N1-cyclohexyl-urea.

9g of 4-(3- <^2-phenoxy-benza- are suspended

25

Similarly, we obtain:

N-benzene, N-benzene, and N-benzene.

- 15 -

from 4-((3-<^2-isoamyloxy-5-methyl-benzamido_^-ethyl)-benzenesulfonamide (melting point 152 - 155°C)

N-/4-((3-<C2-isoamyloxy-5-methyl-benzamido^> -ethyl)benzenesulfonyl-7-Nl-cyclohexyl-urea, melting point 163-164°C

the ÏT-^F- ( (3 - 2- i s oamyloxy-5-methyl-b en z amido^> - ethyl) benzene-sulfonyl7-N,-(4-methyl-cyclohexyl)-urea (trans), melting point 156 - 158°C (recrystallized in methanol);

from 4-(|3~<^ 2-isoamyloxy-5-chloro-benzamido^> -10 ethyl)-benzene-sulfonamide (melting point 147-148°C):

the F-/?-(|3-<^2-isoamyloxy-5-chloro-benzamido^>-ethyl) benzene-suifonyl7-N'-cyclohexyl-urea, melting point 173-174°C (recrystallized in methanol) and the ïï-^î-((3-<^2-isoamyloxy-5-chloro-benzamido]>-ethyl)-15 benzene-suifonyl7-N1 -(4-methyl-cyclohexyl)-urea (trans), melting point 165-166°C (recrystallized in methanol);

from 4-(f3-<C2-(4-methylphenoxy)benzamido> -ethyl)benzenesulfonamide (melting point 176 - 177°C):

N-^-(p-<^2-(4-methyl-phenoxy)-benzamido^>-ethyl)-20 benzene-suifonyl7-N'-(4-methyl-cyclohexyl)-urea (trans), melting point 1$4-176°C (recrystallized in methanol^;

from 4-((3-<^2-phenoxy-4-chloro-benzamido]>-ethyl)-benzene-sulfonamide (melting point 191-192°C):

25 benzene-suifonyî7-N1-cyclohexyl-urea, melting point 168-169°C (recrystallized in methanol) and

5 (recrystallized in methanol) and IT-/4-((3-<C2-phenoxy-4-chloro-benzamido^>-ethyl)-

- 16 -

N-[4-(f3-<^2-phenoxy-4-chloro-benzamido^> -ethyl) -benzene-suifonyl]-N'-(4-methyl-cyclohexyl)-urea (trans), melting point 155 - 156°C (recrystallized in methanol);

from the 4-(p-<^2-(4-methyl-phenoxy)-4-chloro- link-

zamido^-ethyl)-benzene-suifonamide (melting point 189 - 190°0)

ethyl-

the N- [4- ( p - < 2-(4-methyl-phenoxy ) -4-chloro-b enz amidop» - ' benzene-sulfonylD-N'-cyclohexyl-urea, melting point 114-116°C (decomposition) (recrystallized in methanol);

N-[4-(|3-<^2-(4-methyl-phenoxy-)4-chloro-benzamidq]> -ethyl)-benzene-sulfonyl]-N'-butyl-urea, melting point 134-136°C (recrystallized in methanol) and N- [4-(P—<^2- (4-methyl-phenoxy-)-4-chloro-benzamidq]>

' i

ethyl)-benzene-sulfonyl]-N,-(4-methyl-cyclohexyl)-urea (trans), melting point 166 - 168°0 (recrystallized in methanol);

from 4-(p-2-phenoxy-5-chlorobenzamide)-ethyl)-benzenesulfonamide, (melting point 156-158°C):

N-[4-(P-<^2-phenoxy-5-chloro-benzamido]>-ethyl ^benzene-tallow onyl]-N'-cyclohexyl-urea, melting point 175-177°C (recrystallized in a mixture of methanol and diinethyl-formamide) and N-[4-(f3- <C2-phenoxy-5-chloro-benzamido>-ethy])-benzene-sulfonyl]-N,-(4-methyl-cyclohexyl)-pulled (trans), melting point 143-145°C (cecrystallized in methanol);

from 4-((3-<^2-phenoxy-5-nitro-benzamid<£> -ethyl)benzene-suifonamide (melting point 159-160 °G):

N-[4-(P-<5-phenoxy-5-nitro-benzamide]>-ethyl )-benzene-sulfonyl]-αβ-cyclohexyl-urea, melting point 134-136°C (recrystallized in methanol) and

- 17 -

N-[4-(f3-<C2-phenoxy-5-nitro-benzamido]>-ethyl)-benzene-sulfonyl]-N'-(4-methyl-cyclohexyl)-urea (trans)r melting point 167-169°C (in methanol);

from 4-(|3-<^2-n-amyloxy-5-chloro-benzamido^>-ethyl)-benzene-suifonamide (melting point 143-144°C):

N-[4-(p-<12-n-amyloxy-5-chloro-benzamido^>-ethyl)-benzene-sulfonyl]-N'-cyclohexyl-urea, melting point 169-170°C (recrystallized in a mixture of methanol and dimethyl--formamide) and N-[4-(p-<C2-n-amyloxy-5-chloro-benzamido^>~ethyl)-benzene-sulfonyl]-1Tl-(4-methyl-cyclohexyl)-urea (trans), melting point 168-170°C (recrystallized in a mixture of methanol and dimethyl--formamide).

Example 2:

N-[4-((3-<^2-phenoxy-5-methyl-benzamida>> -ethyl )-ben-

zene-sulfonyl]-N1-cyclohexyl-urea.

•»

954 g of methyl 1T-[4-(p-2-phenoxy-5-methylbenzamidoethyl)benzenesulfonyl]carbamate (melting point 165-167°C) is suspended in 150 ml of xylene, and 2 g of cyclohexylamine is added at 80°C. The mixture is then heated, with vigorous stirring, to 140°C and maintained at this temperature for one hour, during which time the methanol formed is removed by distillation. After cooling; The solvent is decanted and the oily residue is triturated with methanol. The crystals thus obtained constituting N-[4-(|3-<^2-phenoxy-5-methyl-benzamide9>—ethyl)-benzene-sulfonyl3-!!î,-cyclohexyl-urea are then recrystallized in methanol and melt at 129-131°C.

Similarly, we obtain 11-[4-(P-<^2-phenoxy-5-methyl-benzamidd>-ethyl)-benzene-sulfonyl]-N'-(4-ethyl-cyclohexyl)-urea (trans), point of

- 18 -

melting point 153 - 154°C (recrystallized in methanol).

EXAMPLE 3:

N- [4- ( p-<C phenox^-benzamidq>-ethyl ) -benzene-suifonyl]-

N'-cyclohexyl-urea.

7.4 g of N,N-diphenyl-IT-cyclohexyl-urea is heated for 7 hours in an oil bath at 100°C with 10.5 g of the sodium salt of 4-(p-C2-phenoxybenzamide-ethyl)-benzenesulfonyl in 25 mL of dimethylformamide. Water and sodium hydroxide solution are added to the cooled solution, and the diphenylamine formed is extracted with ether. The aqueous solution is filtered and acidified with dilute hydrochloric acid. The reaction product is extracted using a pump and recrystallized from methanol. The IT-[4-(p-C2-phenyloxybenzamide-ethyl)-benzenesulfonyl]-N'-cyclohexyl-urea melts at 168–170°C.

EXAMPLE 4 s

N-[4-(p-<^2-phenoxybenzamido> -ethyl)-benzenesulfonyl]-N'-cyclohexylurea a) 2 g of N-[4-(p-<12-phenoxybenzamido> -

ethyl)-benzene-silfonyl]-N'-cyclohexyl-thio-urea (prepared compound-

Benzene is prepared from 4-(p-2-phenoxybenzamidoethyl)sulfonamide and cyclohexyl isothiocyanate by boiling in acetone in the presence of potassium carbonate. It recrystallizes in a mixture of methanol and dioxane and melts at 148-150°C in a mixture of 40 mL of dioxane and 40 mL of 2N NaOH. One g of mercury oxide is added, and the mixture is stirred for 4 hours at approximately 60°C. After cooling, the mercury sulfide formed is removed by suction with a funnel, the filtrate is diluted with water, and acidified. A crystalline precipitate is obtained, constituting N-[4-(0-<C2-phenoxybenzamide>-ethylbenzenesulfonyl]-N'-cyclohexyl urea, which is extracted using a funnel, washed with water, and recrystallized.

in methanol. The substance melts at 168-170°C.

b) We add, in agit-.\nt, 2 g of N-[4-(p-<2-phenoxy-

benzamidQ>-ethyr)-benzenesulfonyl]-N'-cyclohexyl-thiourea

to 40 ml of 2N NaOH. To the suspension obtained from the sodium salt of the sulfonyl-thiourea formed, 10 ml of 35% hydrogen peroxide is added, and the mixture is heated for 30 minutes over a

/we acidify/

Steam bath. The precipitate of N-[4-(p-<2-phenoxybenzamido]>-ethyl)-benzien-sulfonyl]-ir,-cyclohexyl-urea is cooled with dilute hydrochloric acid and separated by spinning. After washing with water, the substance is recrystallized in methanol. Melting point 168–170°C.

EXAMPLE 5:

N-[4-(p-<C2-phenoxybenzamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl urea a) 5.4 g of N-[4-(p-<C2-phenoxybenzamido>-ethyl)-benzenesulfonyl]-N'-cyclohexyl thiourea are dissolved in 250 ml of methanol. 2.16 g of mercury oxide and a spatula tip of potassium carbonate are added, and the mixture is heated to

1* Boil gently while stirring, after 4 hours

•fi--'

removes the mercury sulfide formed by wringing with a trumpet and the filtrate is concentrated.

The resulting residue, constituting the methyl ether of N-[4-(O-<^2-phenoxybenzamido>-ethyl)benzenesulfonyl]-N'-cyclohexyl isourea, crystallizes when left to stand overnight. After recrystallization in dilute methanol, the substance melts at 92-94°C.

b) 1 g of N-[4-(g-<^-phenoxybenzamido> -ethyl)-benzenesulfonyl]-N'-cyclohexyl- methyl ether is dissolved

urea obtained according to a) in a mixture of 20 ml of dioxane and 30 ml of 2N FaOH. It is heated for 4 hours at 90°C, while

- 20 -

After stirring, the mixture is poured into water and acidified. The resulting precipitate, constituting N-[4-((3-<^2-phenoxy-benzamido^>-eth.yl)-benzene-sulfonyl]-lîl-cyclohexyl-urea, melts at 168-170°C after recrystallization in methanol.

Example 6:

N-[4-(j3-<^2-phenoxybenzamido^>-ethyl)-benzenesulfonyl3

-N'-cyclohexyl-urea a) 9.9 g of 4-(p- <^2-phenoxy-benzamido^>-ethyl)-benzenesulfonanide is suspended in 30 ml of ethanol at

s\q 98%. A solution of 2.43 g of potassium cyanate in 5 ml of water is added to this suspension and the whole is heated to

Boiling under reflux for two and a half hours. After about 30 minutes, a clear solution is obtained, from which

/leave alone/

separate from the crystals. After letting the mixture rest overnight, a large quantity of ammonia (V/O) is added to the crystalline magma, causing almost complete dissolution. The mixture is filtered with bone char and acidified. The resulting precipitate, constituting ΔT;-[4—(α3-β2-phenoxybenzamidoβ-ethyl)benzenesulfonyl]urea, is separated by pressing and recrystallized in dilute methanol. The dry substance melts at 155–157°C.

b) 4.39 g of the N-[4-(p-<^2-pheno-oxy-benzamido>-ethyl)-benzene-sulfonyl]-urea obtained according to a) are suspended

in 40 ml of dioxane, and add another 40 ml of dimethylformamide and 1 g of cyclohexylamine. Heat for approximately

25 4 hours at 1' reflux boiling, pour everything into a large quantity of 1% ammonia and acidify the resulting solution with hydrochloric acid.

The precipitate, constituting crude N-[4-(p-<^2~phenoxy-benzamido^>-ethyl)-benzene-sulfonyl]-Nl-cyclohexyl-urea, is drained and recrystallized in methanol. Melting point 168 - 170°C.

& ••se

- 21 -

EXAMPLE 7:

N- [4- (Y-<^2-phenoxy-5-nitro-benzamide-propy ])-benzene-

sulfonyl]-IT1-cyclohexyl-urea

16 g of N-[4-(γ-acetamidopropyl)-benzene-5-sulfonyl]-N'-cyclohexyl urea is heated with 100 mL of 10% NaOH for 3 hours at 120°C. After cooling, the clear filtrate is acidified, filtered, and neutralized by the addition of sodium bicarbonate. The precipitated N-[4-(γ-aminopropyl)benzene-5-sulfonyl]-N'-cyclohexyl urea is recrystallized in aqueous methanol. The substance melts at 188°C.

10 g of the sul-fonyl-urea thus obtained is shaken for 12 hours at 35-40°C with 6.6 g of 2-chloro-5-nitro-benzoyl chloride and 5 g of pyridine in 80 ml of chloroform.

After the chloroform has been removed under reduced pressure, the residue is dissolved in a 1% aqueous solution of sodium carbonate, the solution is shaken with ether, and acidified with hydrochloric acid. The resulting N-[4-(-<^2-chloro-5-nitro-benzamido]>-propyl)-benzene-sulfonyl]-N'-cyclohexyl-urea is then recrystallized in methanol; it melts at 176°0'.

Five grams of this sulfonyl urea are dissolved in 70 ml of glycol monomethyl ether, 3.7 g of sodium phenolate are added, and the mixture is heated for 30 minutes at 125°C. After cooling, the mixture is poured into slightly acidified ice water (25°C) with hydrochloric acid. The precipitate is extracted with 1% ammonia, acidified again, and recrystallized in ethanol. N-[4-"3f'-<^2-phenoxy-5-nitro-benzamido>-propyl)-benzenesulfonyl]-N'-cyclohexyl urea melts at 90–92°C.

- 22 -

EXAMPLE 8:

N[4- (p-<^2-phenoxybenzamido]>-eth;}7l)-benzenesulfonyl]-

N'-(2,5-endomethylene-cyclohexyl-methyl)-urea

In 100 ml of 2N NaOH, 6 g of U_ [4-(p-3-2-phenoxybenzamidoethyl)benzenesulfonyl]-(2,5-endomethylenecyclohexylmethyl)thiourea are suspended. This compound melts at 183-185°C after being recrystallized in dilute methanol and is prepared by boiling 4-(p-2-phenoxybenzamidoethyl)benzenesulfonamide with 2,5-endomethylenecyclohexylmethyl isothiocyanate in dioxane for several hours, in the presence of potassium carbonate. 10 ml of 35% hydrogen peroxide is added, and the mixture is heated for 30 minutes in a steam bath. After cooling, the crystalline magma is acidified, drained, washed with water, and resuspended in ethyl acetate. After separating an aqueous layer, diisopropyl ether is added. The precipitated paste is separated by decantation from the ethyl acetate and diisopropyl ether mixture and recrystallized in methanol. N-[4-(p-<[2-phenoxybenzamido]>-ethyl)-benzenesulfonyl]-N,-(2,5-endomethylenecyclohexylmethyl)-urea melts at 138-140°C.

EXAMPLE 9:

N- [4-(P-<^2-phenoxy-benzamiçLo^>-ethyl)-benzene-sulfonyl]

-N'-cyclohexyl-urea

54-S of N-[4-(p-2-phenoxybenzamidoethyl)benzenesulfonyl]-N'-cyclohexylthiourea is dissolved in 60 mL of methanol. An excess of methyl iodide is added, and the mixture is heated for 45 minutes at reflux boiling. It is then concentrated under reduced pressure. The residue constituting the methyl ether of N-[4-(p-2-phenoxybenzamidoethyl)benzenesulfonyl]isothiourea is dissolved in methanol.

/

0.5 g of sodium methylate is added and the mixture is heated for 2 hours under reflux at boiling point. The mixture is then poured into water and acidified with acetic acid. A crystalline precipitate is obtained, constituting N-[4—(P-<T2-phenoxy-benzamido]>-5 ethyl)-benzene-sulfonyl]-N'-cyclohexyl-urea, which is drained and dried. The substance melts at 168–170°C after recrystallization in methanol.

Claims (20)

- 24 - SUMMARY The invention includes, in particular: 1°) A process for preparing benzene-suifonyl-ureas conforming to the formula 5 X CO-N-Y-phenylene-SOg-WH-CO-NH-R^ R *oz in which R denotes hydrogen, a low molecular weight alkyl group, or a low molecular weight phenyl-alkyl group; R^l designates (a) an alkyl, alkenyl or mercapto-alkyl group containing 2 to 8 carbon atoms, 15 (h) an alkoxy-alkyl, alkylthio-alkyl or alkyl- sulfinyl-alkyl containing 4 to 8 carbon atoms, of which at least 2 belong to the alkylene portion, (c) a low molecular weight phenylalkyl group or a phenyl-cyclopropyl group, 20 (d) a low molecular weight cyclohexyl-alkyl group, a cycloheptyl-methyl, cycloheptyl-ethyl or cyclo-octyl-methyl group, (e) an endoalkylene-cyclohexyl, endoalkylene-cyclohexenyl, endoalkylene-cyclohexyl-methyl or 25 endoalkylene-cyclohexenyl-methyl containing 1 or 2 carbon atoms in the endoalkylene portion, (f) a low molecular weight alkyl-cyclohexyl group or a low molecular weight alkoxy-cyclohexyl group,- - 25 - 10Y Z 15X 20 25 (g) a cycloalkyl group containing 5 to 8 carbon atoms, (h) a cyclohexenyl or cyclohexenyl-methyl group, (i) a heterocyclic nucleus containing 4 or 5 carbon atoms and one oxygen or sulfur atom and up to 2 ethylenic double bonds, or (k) a heterocyclic nucleus linked to the nitrogen atom by a methylene residue and containing 4 or 5 carbon atoms, one oxygen or sulfur atom, and up to 2 ethylenic double bonds, denotes1 a hydrocarbon chain - containing from 1 to 4 carbon atoms, denotes a remnant of aliphatic hydrocarbon, saturated or unsaturated, containing 5 or 6 carbon atoms, or a phenyl group possibly bearing, as substituents, a low molecular weight alkyl group, a low molecular weight alkoxy group, a CF^ group or a chlorine, bromine or fluorine atom; denotes a halogen atom, a low molecular weight alkyl group, a low molecular weight alkoxy group, the -CF3 group or the -NO2 group, or, when Z represents a phenyl group or a phenyl group substituted in the manner described, a hydrogen atom, and their salts, the process according to which; a) Amino acids bearing the substituent, or their salts, are reacted with benzene-suifonyl isocyanates, benzene-sulfonyl-carbamic acid esters, benzene-sulfonyl-thiolcarbamic acid esters, benzene-sulfonyl-ureas, benzene-suifonyl-semicarbazides or benzene-sulfonyl semicarbazones bearing the substituent X - 26 - 5 or b) <bn reacts benzenesulfonamides of formula X CO-N-Y—phenylene-SC>2-NH2 10 or their salts, with isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas bearing the substituent or c) hydrolysis of benzene-suifonyl-iso-15 urea ethers, benzene-suifonyl-iso-urea esters, benzene-suifonyl-iso-thiol-urea ethers, benzene-sulfonyl parabanic acids or benzene-suifonyl-amidines of haloformic acids ureas, bearing corresponding substituents or, d) water is fixed onto carbodiimides bearing the corresponding substituents, or e) in benzenesulfonylthioureas bearing the corresponding substituents, the sulfur atom is replaced by an oxygen atom, or f) in benzenesulfonylureas of formula 25 R we introduce the rest X \ OZ - 27 - by acylation in one or more reaction phases, and where appropriate, the products obtained are treated with alkaline agents to obtain the salts. 2°) A process for preparing 5 pharmaceutical compositions having hypoglycemic activity, administrable by the oral route in the treatment of diabetes mellitus, a process according to which one of the benzene-suifonyl-ureas specified under 1)r is put as the active substance, where appropriate with adjuvants and excipients customary in pharmacy, in a form of 10 suitable dosage. ORIGINAL in pages cor the K" "• Pcnvoss ■ striped naked! José CURAtl Industrial Property Consultant 28, Princess Charlotte Blvd., 28 MONTE-CARLO Fsr procurotîo?1! de