MC654A1 - Benzene sulfonyl ureas and their preparation - Google Patents

Description

PATENT FOR INVENTION

Benzene-suifonyl-ureas and their preparation.

Company known as: FARBWERKE HOECHST AKTIENGESELLSCHAFT VORMALS MEISTER LUCIUS & BRUNING

The present invention relates to benzenesulfonyl ureas conforming to the formula I

X-CO-N-Y- phenylene - S02 - NH - CO - NH - R1 (I)

R

5 and the salts formed by these benzene-suifonyl-ureas.

In the previous formula:

R denotes a low molecular weight alkyl group,

10

R

1

a low molecular weight phenyl-alkyl group or, preferably, hydrogen,

refers to:

(a) an hydroxyl group bearing two substituents selected from the set comprised the methyl group and alkoxy groups containing 1 or 2 carbon atoms,

15

(b) a chloro-cyclohexyl group,

\

"

I

* '

- 2 -

(c) a spiro[5.5]undecyl-(3) group of formula—

O A.

(d) an exo-tricycloL3.2.1.0 ' octane group of formula

(e) a 4-methylcyclohexenyl group,

(f) a dimethyl-cyclohexyl or 4,4-diethyl-cyclohexyl group,

X designates:

(a) a phenyl remainder bearing in any positions the following substituents Z and Z', identical or different from each other;

Z denotes hydrogen, a halogen atom, a low molecular weight alkyl group, an alkenyl group, alkoxy, alkenoxy, halogeno-alkoxy, alkoxy-alkoxy, phenyl-alkoxy or phenyl-alkyl, cyclo-alkoxy, phenyl, phenoxy, low molecular weight acyl, benzoyl, trifluoromethyl, hydroxy, low molecular weight acyloxy, -CN, -NO2?

Z' denotes hydrogen, a halogen atom, a low molecular weight alkyl group, an alkoxy, alkoxy-alkoxy, acyloxy or hydroxy group,

(b) a naphthyl residue which may carry one or two substitutes taken from the set comprising the halogens,

low molecular weight alkyl groups, low molecular weight alkoxy groups, and the hydroxyl group,

(c) a tetrahydronaphthyl or indanyl residue,

30 (d) a thiophenyl residue which may bear one or two

substituents selected from the set including low molecular weight alkyl groups, phenyl-alkyl, alkoxy, alkoxy-alkoxy, alkenoxy, phenyl-alkoxy, aryl groups and halogens,

(e) a tetramethylene-threnyl or trimethylene-threnyl residue,

the definition of X given in (a) being preferred, and X denotes a hydrocarbon chain containing from 1 to 3

carbon atoms, preferably the -C^-CH-,- group.

In the definitions given above and below, 'low molecular weight alkyl' means in all cases an alkyl group containing 1 to 4 carbon atoms in a straight or branched chain. 'Low molecular weight acyl' means an acyl residue (organic acid residue) containing up to 4 carbon atoms, preferably an alkanoyl residue with a straight or branched chain of corresponding chain length.

to designate, for example, a methyl, ethyl, propyl, butyl, benzyl, or p-phenylethyl group. Compounds in which R designates a hydrogen atom are preferred.

The remainder designated by X in formula I will be chosen, for example, from the following groups:

According to the definitions given above, R can

Cl

Br

CH.

'3

- 4 -

15

20

10

0ch20ch3

p-

och-,

p-

0c2h5

/ w

0ch2ch20ch3

25

ch3

0-

/ W

0ch2-</ v

30

7 \W/ \

"W-

coch3 no2

cf.

^ho=ho2hoo (^)^o'

ç OH

^h2do

"HOO

-b -&

it

OH

\ç OH

\

HO(HO)

"hoo,

^HOO O^H

200H

it

OH

"HOO

&

HO

ç OH

it

OH

"HOOOO HO.

^HO

TO TO

^HS00.

"hoo

ÇHS00

\ //

•*has

'HOO.

eH003H03H0Q

sh0=h03hd0

'HOO

TO

TO

TO

(")AH0

*4

to to to w /.

to

Oh, ch7

3/3

S'

ch3 h3c

(/ \

Cl

G

! I

^DCHj

OC2H5 OG^H^Cn)

/

0ch2ch=ch2

he 'I

"S'

0ch20ch3

oce2-//_n^

-s oh, j)gr3 /oc2h5

ch.

H-zO

3

OCHgCHgOGH^

- 8 -

Examples of bridge-forming group T include the following groups:

-ch2-, -ch2-ch2-, -ch-, -ch2-ch2-ch2-,

ch3

5 -ch - 0h2-, -ch2-ch-,

ch5 CH3

lajjréférence given to those which link the benzene ring to the carbonamido group by 2 carbon atoms.

Among the E residues, we will mention, among others, the following 10: 2,3-chlorocyclohexyl, 4-chlorocyclohexyl,

3-Methoxy-4-Methylcyclohexyl, 3-Ethoxy-4-Methylcyclohexyl,

3-methyl-4-methoxy-cyclohexyl, 4-methoxy-2-methyl-cyclohexyl,

4—methyl-/^-cyclohexenyl.

The phenylene residue, designated in the present formula as "phenylene," is preferably unsubstituted, but it may also bear one or two substituents chosen from among the halogens, lower alkyl groups, and lower alkoxy groups. It may have the two remaining parts of the molecule in the ortho, meta, or para positions relative to each other, with the para position being preferred.

The present invention also relates to a process for preparing the benzene-suifonyl-ureas described above, a process which implements the methods set out below.

a) Amines bearing the substituent y are reacted

25 R, or their salts, with benzene-suifonyl isocyanates, benzene-suifonyl-carbamic acid esters, benzene-suifonyl-thiocarbamic acid esters, benzene-sulfonyl-carbamic acid halides, benzene-suifonyl-

ureas, benzene-suifonyl-semicarbazides or benzene-tallow onyl-semicarbazones bearing the substituent

X-CO-ÏT-Y-

I

E

b) Benzenesulfonamides of formula are reacted

X-CO-IT-Y-phenylene - S 02 - NH2 E

or their salts, with isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas bearing the R substituent.

c) Benzene-suifonyl-iso-urea ethers, benzene-suifonyl-iso-thio-urea ethers, benzene-suifonyl-iso-urea esters, benzene-suifonyl-nyl-parabanic acids or benzene-suifonyl-amidines of halogeno-formic acids are hydrolyzed.

d) In benzene-suifonyl-thioureas bearing corresponding substituents, the sulfur atom is replaced by an oxygen atom.

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

f) benzene-suifonyl-ureas or corresponding benzene-tallow enyl-ureas are oxidized.

g) In benzene-suifonyl-ureas of formula m-Y-phenylene-SO2-NH-CO-NH-E1 i d-

E

we introduce the remainder X - CO -

by acylation in one or more reaction phases.

- 10 -

h) 011 reacts benzene-suifo-nyl halides bearing corresponding substituents with ureas bearing the R substituent.

i) In thio-amido-alkyl-benzene-sulfonyl-ureas or thio-amidoalkyl-benzene-sulfonyl-thio-ureas bearing corresponding substituents, the sulfur atom or atoms are replaced by one or more oxygen atoms.

j) In the case where R denotes hydrogen ion atom, compounds of formula are hydrolyzed

X-C=N-Y- phenylene - SO9NHC0NH-R^

i £-

ii

or their parabanic acid derivatives, or compounds

formula

X-C«N-Y-phenylene-S09NH-C =N-R1

I t

U U

formulas in which IJ denotes u in each case:

lower -O-alkyl groups, lower -S-alkyl groups or a halogen atom, preferably chlorine.

s]

k) In the case where R does not designate the methyl-cyclohexenyl group, hydrogen from the corresponding benzene-suifonyl-ureas containing unsaturated bonds in the molecule is used, and where appropriate, the reaction products are treated with alkaline agents to induce the formation of salts.

It may happen, in particular cases, depending on the nature of the starting materials, especially those of member X, that one or another of the processes mentioned is unsuitable for the preparation of some of the compounds represented by the general formula, or at least necessitates measures for the protection of active groups. Such cases, which are relatively rare, will be easily recognized by the expert, and there will be no difficulty in choosing among the synthesis methods.

- 11 -

described, to find one that leads to the desired result in such cases.

Instead of benzene-suifonyl isocyanates, one can also use reaction products of ben-

5 zene-sulfonyls with acid arnides, such as caprolactam or butyrolactam, or with weakly basic amines, such as carbazoles.

Benzene-suifonyl-carbamic acid esters or benzene-suifonyl-thiocarbamic acid esters can have a low molecular weight alkyl group or a phenyl group in their alcoholic component. The same applies to the starting compounds; they can be devoid of a substituent on the side of the urea molecule opposite the sulfonyl group, or they can have one or, better yet, two. Since these substituents are eliminated during the reaction with amines, their character can be varied within wide limits. In addition to benzene-tallow onyl ureas bearing alkyl, aryl, acylic, or heterocyclic substituents, bis-(benzene-suifonyl)-ureas can also be used, possibly bearing yet another substituent on one of the nitrogen atoms, for example, a methyl group. For example, these bis-(benzenesulfonyl)-ureas or ii-benzenesulfonyl-N'-acyl-ureas can be treated with amines of formula E and the resulting salts heated to high temperatures, particularly above 100°C. It is also possible to start from ureas that meet

1

carbamic esters bearing the E substituent or the corresponding thiocarbamic esters.

As suitable halides of carbamic acids, 15 in the first place, chlorides.

Benzene-suifonyl-ureas used as materials

- 12 -

to the formula R-Hi-CG-NHg or ureas which have one or, better, two substituents on the free nitrogen atom and to react them with benzene-suifonamides bearing the substituent

X-CO-ÏJ-Y-

i

R

Suitable starting materials include, for example, U'-acetyl- or N1-nitro-ureas substituted at the N atom by R1, N'-N'-diphenyl-ureas (in which the two phenyl residues may also bear substituents or be linked to each other, either directly or by a bridge such as -CH^-, -NH-, -O- or -S—), N-methyl-1T'-phenyl- or U'-N'-dicyclohexyl-ureas as well as corresponding carbamoyl-imidazoles or carbamoyl-triazoles, and finally ureas corresponding to the formula R^-HH-CO-KH-R1.

The hydrolysis of benzene-suifonyl-parabanic acids, benzene-suifonyl-isourea ethers, benzene-tallow-onyl-isothiourea ethers, benzene-suifonyl-isourea esters, or benzene-suifonyl-amidines of halogenoformic acids, mentioned as starting substances, is carried out readily 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-suifonyl-thioureas 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, according to known methods.

- 13 -

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 benzenesulfonylureas by appropriate measures, for example by saponification or by water fixation.

Benzenesulfonyl ureas bearing corresponding substituents and containing an unsaturated bond in the molecule, for example 10 X-C0-HK-CH=CH-phenylene-SO2-NH-C0-NH-R1

can be converted into benzene-sulfonyl-ureas according to the invention by hydrogenation, for example with molecular hydrogen in the presence of a known hydrogenation catalyst.

The acylation of amino-alkylbenzenesulfonyl ureas can be carried out either in one step, for example by reaction with 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-alkylbenzenesulfonyl ureas with 2-methoxybenzoyl chloride and the subsequent introduction of a halogen atom into the benzene ring of the benzamido group.

The replacement of the sulfur atom(s) in thio-amido-alkyl-benzene-sulfonyl-ureas or thio-amido-alkyl-benzene-sulfonyl-thioureas, carrying corresponding substituents, by one or more oxygen atoms can be done, for example, with the help of oxidizing agents, such as hydrogen peroxide, sodium peroxide and other peroxide compounds.

Instead of thio-amido-alkyl-benzene-suifonyl-ureas, one can also desulfurize to amido-alkyl-benzene-suifonyl-ureas ethers or esters of thio-amido-alkyl-benzene-sulfonyl-isothio-ureas or thio-amido-alkyl-benzene-sulfonyl• iso-ureas, thio-amido-alkyl-benzene-sulfonyl-parabanic acids or thio-amido-alkyl-benzene-sulfonyl-amidines of haloeno-formic acids, by treatment with oxidation agents in an acidic or alkaline medium with simultaneous hydrolytic release of the sulfonyl-urea group.

Instead of thio-amido-alkyl-benzene-sulfonyl-thioureas, it is also possible to convert compounds corresponding to the formula into amido-alkyl-benzene-sulfonyl-ureas

- 15 -

X-0 =N-Ï-^^)- S 02 -NHCSNH-B.

ii

in which U has the meaning mentioned above, by treatment with oxidizing agents in an acidic or alkaline medium with simultaneous desulfurization and hydrolysis.

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

As the Applicant found, benzenesulfonylureas of formula I and their salts are characterized by a powerful hypoglycemic activity and, above all, of long duration.

To establish the hypoglycemic action of the benzenesulfonylureas described above, these substances are administered, for example in the form of their sodium salts, at a dose of 10 mg/kg to normally fed rabbits, via the buccal route, and blood glucose is measured for a fairly long time, by the classic Hagedorn-Jensen method using an auto-analyzer.

For example, a dose of 10 mg/kg of N-[4-((3-<^2-methoxy-5-fluoro-benzamido^> -ethyl)-benzene-25sulfonyl]-N'-(3,4-dimethyl-cyclohexyl)-urea causes a 45% decrease in blood glucose after 3 hours, which, after 24 hours, is still 44% and only falls back to zero after 48 hours. Similarly, a dose of 10 mg of N-[4-((3-<^2-methoxy-5-chloro-benzamido^> -ethyl)-30benzenesulfonyl]-11''-(2,4-dimethyl-cyclohexyl)-urea causes

"after 3 hours a decrease in blood glucose of 31%, which after 24 hours rises to 39% and a dose of 10 mg/kg of ir-[4-((3-<^2-methoxy-5-chlorobenzamido]>-ethyl)-benzenesulfonyl]-N'-(4—methyl-A^-cyclohexenyl)-urea causes after 3 hours a decrease in blood glucose of 22%, which after 24 hours still rises to 19%, while the known E-[4-methyl-benzenesulfonyl]-N'-butyl-urea, administered to the rabbit at a dose of less than 25 mg/kg, no longer causes a decrease in blood glucose.

The powerful activity of the described benzenesulfonyl ureas is manifested with particular clarity when the dose is reduced. When N-[4-(|3-<2-n-propoxy-benzamido^>-ethyl)-benzenesulfonyl]-N'-(4.4-dimethyl-cyclohexyl)-urea is administered at a dose of 0.02 mg/kg, F-[4-((3-<^2-nethoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-W-(3 •4— dimethyl-cyclohexyl)-urea at a dose of 0.01 mg/kg and N-[4-(|3-<^2-methoxy-5-fluorobenzamido-ethyl)-benzene-tallow onyl]-N'-(4.4-dimethyl-cyclohexyl)-urea at a dose of 0.008 mg/kg to the rabbit, a pronounced decrease in blood glucose is still observed.

Furthermore, it was found that a dose of 10 mg/kg of H-[4-(|3-<^2-ethoxy-5-fluorobenzamidb> -ethyl)-benzene-tallow onyl] -N1-(4-chloro-cyclohexyl)-urea causes a 39% drop in blood glucose after 3 hours, which after 24 hours is still 28%, after 48 hours still 16%, and only falls back to zero after 72 hours; A dose of 10 mg/kg of N-[4-(p-2-ethoxy-5-fluorobenzamidoethyl)benzenesulfonyl]-F'-(3-methoxy-4-methylcyclohexyl)urea causes a 32% decrease in blood glucose after 3 hours, which is still 21% after 24 hours and only falls back to zero after 48 hours. Similarly, a dose

- 17 -

10 mg of N-[4-((3- <2-methoxy-5-chlorobenzamido>-ethyl)-p. causes benzene-tallow onyl]-N'-(4-chlorocyclohexyl)-urea/after

A 25% drop in blood glucose levels within 3 hours, which after

After 24 hours it rises to 53% and after 4-8 hours to 25%.

5 A dose of 10 milligrams of N-[N-( (3-< 2-methoxy-5-chloro-

N-[4-((3-<2-methoxy-5-chlorobenzamido<sup>-ethyl)-benzene-tallow onyl]-N'-(3-niethoxy-4-methylcyclohexyl)-urea causes a 21% decrease in blood glucose after 3 hours, which rises to 23% after 24 hours and to 17% after 48 hours. A 10 mg dose of N-[4-((3-<2-methoxy-5-chlorobenzamido<sup>-ethyl)-benzene-tallow onyl]-N'-(3-niethoxy-4-methylcyclohexyl)-urea causes a 25% decrease in blood glucose after 3 hours.

which after 24 hours still amounts to 25% and after 48 hours still to 12%.

15 If N-[4-((3~<C2-methoxy-benzamido> -

ethyl)-benzenesulfonyl]-N,-(4-chloro-cyclohexyl)-urea at a dose of 0.04 mg/kg, the T-[4-(p-<2-methoxy-5-chlorobenzamido^>-ethyl.)-benzenesulfonyl]-W'-(2-chloro-cyclohexyl)-urea at a dose of 0.04 mg/kg, the N-[4-(3-<C2-methoxy-5-chloro-benzamido> -20 ethyl)-benzenesulfonyl]-N'-(4-chloro-cyclohexyl)-urea at a dose of 0.02 mg/kg, the ]i-[4-(p-<2-methoxy-^-chlorobenzamido^>-ethyl)-benzenesulfonyl]-N'-(3-iaethoxy-4-methyl-cyclohexyl)-urea at a dose of 0.1 mg/kg, the N-[4-(|3-<2-methoxy-5-methyl-benzamido>-ethyl)-benzene-sulfonyl]-N'-(spiro <5-5> undecyl-3)-25 urea at a dose of 0.06 mg/kg or fI-[4-((B-<2-methoxy-5-methyl-benzamido>-ethyl)-benzene-suifonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea at a dose of 0.01 mg/kg in rabbits, a pronounced decrease in blood glucose is still observed.

Regarding the toxicity of the compounds, we arrive at values that are of the same order of magnitude as those provided by benzenesulfonyl ureas such as the

- 18 -

N-[4-meth.yl-benzene-tallow onyl]-N'-n~butyl-urea and N-[4-methyl-benzene-sulfonyl-J-tf'-cyclohexyl-urea, whose LD^q by oral route are respectively 2.5 and 4.8 g/kg.

The products obtained according to the present invention therefore possess a very strong hypoglycemic activity and, at the same time, are extremely well tolerated.

The benzenesulfonylureas described are preferably intended for use in the manufacture of hypoglycemic preparations for oral administration in the treatment of diabetes mellitus, and can be administered as is, in the form of their 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.

As medicinal preparations, tablets 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, will be preferred.

A preparation, for example a tablet or a powder, containing the benzene-suifonyl-urea described as the active ingredient, with or without the additives mentioned, will preferably be presented in a dosed form, adapted to the efficacy of the active substance and the desired effect. The dose will, for example, be approximately 0.5 to 100 mg per unit, preferably 2 to 10 mg; however, it may be lower or higher, and in that case, it may be divided or multiplied before administration.

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

It is understood that the present invention does not relate to the described substances when used therapeutically.

19 -

EXAMPLE 1:

N-[4--(|3-<l2-meth.oxy-5-chlorobenzamido>-ethyl)-benzene-tallow onyl] -IT ' - ( 3 -methoxy-4—meth thy 1 - c yc 1 ohexy 1 ) -urea e.

4.2 g of N-[4—(p-(2-meth.oxy-5-5 chlorobenzamido)-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point: 189-191°0) is suspended in 50 ml of dioxanne, and after adding 2 g of 3-methoxy-4-methyl-cyclohexyl-amine acetate (a substance that melts at 134-136°C and is obtained by hydrogenation of the nucleus of 3-methoxy-4-methyl-aniline in the presence of 100000 at 260°C and under 250 atmospheres of Hg) dissolved in 50 ml of dioxanne, the whole is heated for 1 hour at 110°C, the methanol formed during the reaction being driven off by distillation. After cooling, a little water is added: the N-[4-((3-<£2~methoxy-5-chlorobenzamido>-ethyl)-benzene-tallow onyl]-15 K',-(3-methoxy-4-methyl-cyclohexyl)-urea that has formed precipitates in crystalline form and is recrystallized in methanol; melting point 179-181°0.

Similarly, we obtain:

20 from H-[4~(|3-<3-trifluoromethyl-benzamido>~ethyl)-benzene-

sulfonyl-methyl-urethane (melting point 178-180°C):

the l-[4~(f3-43-trifluoromethyl~benzamido>-ethyl)-benzene~ sulfonyl]-ïT!-(3-methoxy-4--methyl-cyclohexyl)-urea with a melting point of 159-161°C (recrystallized in methanol);

25

from N-[4~(|3-^3«4—dichloro-benzamido>-ethyl)-benzene-sulfonyl 3—methyl —nrôthan© (melting point of 198—200^0"):

N-[4--((3-(3.4—dichloro-benzamido)*--ethyl)-benzene-tallow onyl]-N'-(3-methoxy-zl—methyl-cyclohexyl)-urea with a melting point of 190-191°0 (recrystallized in methanol);

- 20 -

from N~[4^3-^3-benzyloxy-thiophene-carbonamido)>—ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 163-164°C):

N-[4-( (3-(3-benzyloxy-thiophene-2-carboitami4e»>-ethyl)-benzene-tallow onyl]-N '-(3-meth.oxy-4-methyl-cyclohexyl )-urea 5 with a melting point of 177-178°C (recrystallized in methanol);

from N-[4-((3-^3-ethoxy-thiophene-2-carbonamido)-ethyl)-benzenesulfonyl]-methylurethane (melting point 163-165°C): 10 the N-[4-(|3-^3-ethoxy-thiophene-2-carbonamido-ethyl)-

benzene-sulfony 1]-N1-(3-methoxy-4-methy1-cyc1ohexy1)-urea has a melting point of 154–156 °C (recrystallized in methanol);

from N-[4-((3-^2-methoxy-benzamido>-ethyl)-benzene-15 sulfonyl]-methyl-urethane (melting point 174°-176°C):

the ïf-[4— (p-<^2-met;ho3cy-benzamido'>'-ethyl)-benzene-sulfonyl]-]?1-{3—methoxy-4-methyl-cyclohexyl)-urea with a melting point of 184-185°0 (recrystallized in methanol);

20 from N-[4—((3-^2-methoxy-4-chloro-benzamido).-ethyl)-

benzene-suifonyl-methyl-urethane (melting point 178-180°C):

N-[4-((3-.(2-methoxy-4-chloro-benzamido^-ethyl)-benzene-suifonyl]-N1-(3-methoxy-4-methyl-cyclohexyl)-urea with a melting point of 191-193°C (recrystallized in methanol);

25

from N-[4-(j3-{2-methoxy-5-methyl-benzamido^>-ethyl)-benzene--sulfonylj-methyl'l-urethane (melting point 175-177°C):

N-[4-((3-^-methoxy-^-methylbenzamido^-ethyl)-benzenesuifonyl]-N'-(3-methoxy-4-methylcyclohexyl)-urea with a melting point of 177-179°C (recrystallized in a mixture of methanol and dimethylformamide);

- 21 -

from N-[4-((3-2-methoxy-5-bromobenzamido-ethyl)-benzenesulfonyl]-methylurethane (melting point 197-199°C):

N- [4-( (3-{2-methoxy-5-bromobenzamido^-ethyl) -benzene-suifonyl] -N ' -(3-methoxy-4-methyl-cyclohexyl)-urea with a melting point of 181~183°C (recrystallized in a mixture of methanol and dimethyl-formamide);

from ÏT-[4-((3-,<i3»5-dimethyl-benzamido>-ethyl)-benzene-sulfonyl-D-methyl-urethane (melting point 223-225°C):

the H"-[4— ((3-^3 ♦ 5-dimethyl-benzamido^—ethyl)-benzene-10 sulfonyl]-N'-(3-rmethoxy-4-methyl-cyclohexyl)-urea with a melting point of 181-183°C (recrystallized in methanol);

from H-[4-(|3-<-2-allyloxy~5-ch.loro-"benzamido)-- ethyl)-benzenesulfonyl]-methyl-urethane (melting point 167-169°C); 15 the ÏT-[4~(j3~<2-allyloxy-5-chlorobenzamido^-ethyl)-

benzene-suifonylJ-N'-(3-methoxy-4-methyl-cyclohexyl)-urea with a melting point of 146-148°C (recrystallized in methanol);

from ET-[4-(|3-^2-ethoxy-5-fluoro-benzamido>-ethyl)-benzene-20 suifonyl]-methyl-urethane (melting point 193-195°C):

N-[4-(p-42-ethoxy-5-fluoro-"benzamido)>-ethyl)-benzenesulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea with a melting point of 173-174-°C (recrystallized in methanol);

25 from K-[4-(3~(2-ethoxy-4-trifluor^methyl-benzamido)> -

ethyl)-benzene-suifonyl]-methyl-urethane (melting point of 166-168°C):

N-[4-(p-^2-ethoxy-4-trifluoromethyl-benzamido)- -ethyl)-benzene-sulfonyl]-ÏT' -(3-methoxy-4-methyl-cyclohexyl) -urea 30 with a melting point of 171-173°0 (recrystallized in methanol);

- 22 -

from N-[4-((3-tetraline-(2)-carbamido)-ethyl]~benzene-suifonyl-methyl-urethane (melting point 176°0):

N-[4-(0-tetraline-(2)-carbamidoethyl)benzene-tallow onyl]-IT'-(3-ethoxy-4-diethyl-cyclohexyl)-urea with a melting point of 138°C (recrystallized in a mixture of methanol and water);

EXAMPLE 2:

N-[4~ ( 2-methoxy-5-methyl-benzamido")-ethyl)-benzene-tallow onyl]-N'-(3~ethoxy-4~methyl-cyclohexyl)-urea.

Four grams of N-[4-(p-2-methoxy-5-methylbenzamidoethyl)benzenesulfonyl]-methylurethane, with a melting point of 175-177 °C, are suspended in 75 ml of dioxane, and 1.7 g of 3-ethoxy-4-methylcyclohexylamine (boiling point 80 °C at a pressure of 10 mmHg, obtained by hydrogenation of the nucleus of 3-ethoxy-4-methylaniline in the presence of CO2O at 260 °C under a pressure of 250 atmospheres of Hg) are added. The mixture is heated for 1 hour at 110 °C. Next, we precipitate with water the ÏT-[4~(p-^2-methoxy-5-methyl-benzamido^»-ethyl)-benzene-sulfonyl]-W-(3-ethoxy-4—methyl-cyclohexyl)-urea.

After recrystallization in methanol the crystals melt at 172-174°C.

Similarly, we obtain:

from N-[4~([3-<3-chlorobenzamido)>-ethyl)-benzenesulfonyl]-methylurethane (melting point 173-175°C):

the F-[4-(p-/3-chlorobenzamido)-ethyl)-benzene-tallow onyl3-ïï"' -(3-ethoxy-4-methyl-cyclûhexyl)-urea with a melting point of 178-180°C;

from N-[4(p-<(3-methoxy-thiophene-2-carbonamido>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 226-228°C):

N-[4-(3~(3-methoxy-thiophene-2-carbonamidd) -ethyl)-benzene-sulfonyl]-N1-(3-ethoxy-4-methyl-cyclohexyl)-urea with a melting point of 157-159°C (recrystallized in methanol);

from N-[4-(p-(£2-methoxy-benzamido)>-ethyl)-benzene-tallow onyl]~methyl-urethane (melting point 174-176°C):

N-[4-(p-^2-methoxy~benzamido)>-ethyl)-benzene-10 sulfonyl]-lT,-(3-ethoxy-4-methyl-cyclohexyl)-urea with a melting point of 168-169°C (recrystallized in methanol);

from N-[4-(3-(2-n-butoxybenzamido-ethyl)benzenesulfonyl]-methylurethane (melting point 160-162°C): 15 the E-[4-(3-<2-n-butoxybenzamido-ethyl)benzene-

tallow onyl3-N'-(3-ethoxy-4-methyl-cyclohexyl)-urea with a melting point of 140-142°0 (recrystallized in methanol);

from ÎT-C4-(3-α,2-methoxy-5-chlorobenzamido)~ethyl)-20 "benzenesulfonyl]-methylurethane (melting point 189-191°C):

N-[4-(p-^2-methoxy-5-chlorobenzamido).-ethyl)-benzene-sulfonyl]-N'-(3-ethoxy-4-methyl-cyclohexyl)-urea with a melting point of 173-175°C (recrystallized in methanol);

25 from N-[4-(3-<2-methoxy-5-benzamido>-ethyl)-benzene-tallow onyl]-methyl-urethane (melting point 197-199°C):

the F-[4-(3-{2-methoxy-5-bromo-benzamido>~ethyl)-benzene-sulfonyl]-N'-(3-ethoxy-4-methyl-cyclohexyl)-urea with a melting point of 178-180°C (recrystallized in methanol);

from N~[A~(P-<2.5-dimethylbenzamide>-et]2yl)-benzenesulfonyl]-methylurea (melting point 223-225°C):

N- [4~ ( 3-<J • 5-dimethyl-benzamido>-ethyl ) -benzene-sulfonyl]-îT,-(3-ethoxy-4~methyl-cyclohexyl)-urea with a melting point of 190-192°C (recrystallized in methanol);

from IJ-[4--(0-<t?~ethoxy-5--a.cetyl-benzamido>-ethyl}-benzene~ suifonyl]-methyl-urethane (melting point 164-166°C):

the IF-[4~ (3-<J-ethoxy-5-acetyl-benzamido>-ethyl)-benzene-suifonyl]-N' -(3-ethoxy-4~methyl-cyclohexyl)-urea with a melting point of 155-157°C (recrystallized in methanol);

from (p-<3-chlorobenzamido>-ethyl)-benzenesulfonyl]-

Methyl urethane (melting point 173-175°C):

N-[4—(p-<J-chlorobenzamido>-ethyl)-benzenesulfonyl]-■ ïr,-(spiroC5»53undecyl-3)-urea with a melting point of 211-212°C (recrystallized in a mixture of methanol and dimethyl-formamide);

from N-[4~(|3-<5-methoxy-thiophene-2-carbonamido>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 226-228°C):

E-[4--(p-<3-methoxy-thiophene-2-carbonamido>-ethyl)-benzene-sulfonyl]-N'-(spiro[5'33undecyl-3)-urea with a melting point of 182-183°C (recrystallized in methanol);

from N-C4--(|3-<2-methoxy-5-methyl-benzamide>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 175-177°C):

the F-[4— (p-<^-methoxy-5 -methyl-benzamido>-ethyl)-benzene-sulfonyl]N'-(spiro[5*5]undecyl-3)-urea with a melting point of 172-173°C (recrystallized in methanol);

- 25 -

from F-[4-(p-<2-methoxy-5-bromobenzamido>-ethyl)-benzenesulfonyl]-methylurethane (melting point 197-199°C):

the F-[4-((3-<$-metho:xy-5-bromobenzam.id^>-ethyl)-benzene-sulfonyl]-F'-(spiro[5.53undecyl-3)-urea with a melting point of 194-196°0 (recrystallized in a mixture of methanol and dimethyl-formamide);

from H-[4~((3-<2-phenoxybenzamide-ethyl)benzenesulfonyl]methylurethane (melting point 167-169°C):

the F-[4— (P-<^-phenoxy-benzamido>-ethyl)-benzene-sulfonyl]-F'-(spiro[5.53undecyl-3)-urea with a melting point of 166-167°C (recrystallized in methanol);

from F-[4-(p-<g!-methoxy-4--chlorobenzamido>-ethyl)-benzene-sulfonyllmethyl-urethane (melting point 178-180°C):

N-[4~(p-<ê-metho:xy-4--chloro"benzamidS>-ethyl)-benzenesulfonyl]-N'-(spiro[5«53undecyl-3)-urea with a melting point of 213-215°C (recrystallized in a mixture of methanol and dimethyl-formamide;

from ÏT-[4-(|B-<^-methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl]-methylurethane (melting point 175-177°C):

the F-[4-(p~<^-methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl]-N1-(3-methyl-4-methoxycyclohexyl)-urea e with a melting point of 110-112°C (recrystallized in methanol);

from F-£4~(p-<2-methoxy-5~bromobenzamid$>-ethyl)-benzene-tallow onyl]-methyl-urethane (melting point 197-199°C):

N-[4~((3-<£Î-methoxy-5-bromobenzamido^-ethyl)-'bcn z èn e-sulf onyl ] -F ' •- (3-methyl-4~methoxy-cyclohexyl ) -urea e

- 26 -

10

Mistletoe melts at 113°C by undergoing decomposition (recrystallized in methanol);

from N-[4-(j3-<2-methoxy-5-chlorobenzamid^>-ethyl)-benzene-tallow onyl]-methyl-urethane (melting point 189-191°C):

N-[4-(3-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(3-methyl-4-methoxy-cyclohexyl)-urea with a melting point of 112-114°C (decomposition) (recrystallized in methanol);

from N-[4-((3-<3-clllorc)benzamidô>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 173-175°C):

the N- [4-( 3-<J-chlorobenzamidS>-ethyl ) -benzene-tallow onyl ] N'-(3-methyl-4-methoxy-cyclohexyl)-urea with a melting point of 166-168°C (recrystallized in methanol);

EXAMPLE 3:

F' [4-({3-<J-methoxymethoxy-thiopliene~2-car'bonarnido>-ethyl-benzene-sulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea e.

5g of 4-((3-<S-methoxymethoxy-thiophene-2-^0 oa.x'1 *S+?hyl ) -Ixsiiaèxio aulfona.mj.de (melting point 160—

162°'G) in 7 ml of 2N sodium hydroxide solution and 50 ml of acetone, and at a temperature of 0-5°C, 2.4 g of 3-methoxy-4-methylcyclohexyl isocyanate (boiling point 90°C under a pressure of 10 mm of mercury) is added dropwise. The mixture is stirred for 2 hours, diluted with water, and removed by filtration.

The undissolved matter is removed, and the filtrate is acidified with dilute hydrochloric acid. The N-[4-((3-<3-methoxymethoxy-thiophene-2-carbonamid3>-ethyl)-benzene-suifonyl]-W-(3-methoxy-4-methyl-cyclohexyl)-urea separates into crystalline form 30 melts, after recrystallization in methanol, at 125-127°C.

- 27 -

Similarly, we obtain:

from 4-(|3-<J~chlorobenzamido>-ethyl)-benzenesulfonamide (melting point 225-226°C):

N-[4-(chlorobenzamido-ethyl)-benzene-5 sulfonyl]-N,~(3-niethoxy-4-ineth.yl-cyclohexyl)-urea with a melting point of 209-210°0 (recrystallized in a mixture of methanol and dimethyl-formamide);

from 4-((3-<!3>~II1©ethyl-benzamido>-ethyl)-benzene-sulfonamide 10 (melting point 197-199°0):

N-[4-(p-methylbenzamid-ethyl)benzenesulfonyl]-N-(3-methoxy-4-methylcyclohexyl)-urea with a melting point of 167-169°C (recrystallized in methanol);

15 from 4-((B-<3.4-tetramethylene-thiophene-2-carbonamido-ethyl)-benzene-sulfonamide (melting point 173-1740C):

the N- [4- ( (3-<5.4-te stranded ethylene-thiophene-2-carbonamide 5> ethyl)benzene-sulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea with a melting point of 187-188°C (recrystallized in 20 methanol);

from 4-((3-<2-methoxy-5-phenyl-benzamido>-ethyl)-benzene-sulfonamide (melting point 213-214°C):

the N-[4-(|B-<^-methoxy-5-phenyl-benzamidd>-ethyl)-25 benzene-sulfonyl]-N,-(3-methoxy-4-methyl-cyclohexyl)-urea of a bridge df3 fusion do 1;i-3-145°C (rocx-istallized in methanol);

from 4-(jB-C^-phenoxy-benzamidô>-ethyl)-benzene-tallow onamide (melting point 187-188°C):

30

- 28 -

N-[4-(|3-<$-phenoxy-benzalïiido>-ethyl)-benzene-sulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea has a melting point of 170-172°C (after recrystallization in methanol)

from 4-((3-<£-methoxy-5-acetyl-benzamid3>-ethyl)-benzene-sulfonamide (melting point 206-208°C):

E-[4-(j3-<^-methoxy-5-acetyl-benzamidc>>-ethyl)-benzene-suifony1]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea with a melting point of 174-176°C (recrystallized in a mixture of methanol and dimethyl-formamide).

EXK JPliE 4:

N-[4-(P-<^2-methoxy-5-chlorobenzamido^>-ethyl)-benzene-tallow o-nylD-I'T1 -(spiro-[5.5]-undecyl-3)-urea.

A mixture of 10.5 g of N-[4-(j3-<^2-methoxy-5-chlorobenzamido^5-ethyl)~ is heated under reflux for 5 hours.

benzene-sulfonyl urea, 300 ml of toluene.

30 ml of glycol-monomethyl ether, 1.65 g of glacial acetic acid, and 4.2 g of spiro-[5.53-undecyl-(3)-amine (boiling point 120-122°C at a pressure of 10 mm of mercury). The mixture is then concentrated under vacuum, the residue is treated with alcohol, and the resulting crystals of μJ-μ-(μ3-μ2-methoxy-5-chlorobenzamidoμ-ethyl)benzenesulfonyl]-μT'-(spiro-[5-53-undecyl-3)-urea are recrystallized in methanol. (Melting point 190°C).

Similarly, we obtain:

from N-[4-(p-<j2-methoxy-benzamido^>-ethyl)-benzene-sulfonylk-urea (melting point 183-185°C)

5l-[4-(;3-<^2-methoxy-benzamido^>-ethyl)-benzene-tallow onyl]~ïï' -(spiro-[5»5]-undecyl-3)-urea with a melting point of 207-209°C ■ (recrystallized in a mixture of methanol and dimethylformamide).

- 29 -

Example 5:

U- [/]._( p_ <^2-methoxy-5-chl or obenzamido^>-ethyl) -"benzene-sulfonyl]-H'-(3-methoxy-4-methyl-cyclohexyl)-urea .

Heat 3.9 g of the sodium salt of 4-(3-2-methoxy-5-chlorobenzainidoethyl)benzenesulfonamide and 6.7 g of N.N-diphenyl-N'-O-methoxy-1-methylcyclohexyl)urea (melting point 125-126°C) in 100 ml of dimethylformamide for 4-5 minutes at 110°C. Allow to cool, pour into water and add 1% ammonia. We filter, we acidify the filtrate and purify the precipitate again over ammonia and hydrochloric acid. The N-[4-(,3-<^2-methoxy-5-chlorobenzamido^> -ethyl) -benzene-sulfonyl] -I'I' - (3-methoxy-4--methyl-cyclohexyl)-urea which is obtained in crystalline form, after being recrystallized in methanol, melts at 179-181°C.

Example 6:

N-[4-( |3-<^2-methoxy-5-chlorobenzamido^>-ethyl)-benzene-sulf o~ nyl ] -N ' - ( 3-methoxy-4--methyl- cyc 1 ohexyl ) -ure e e .

8.2 g of 20 F-[4-(3-acetamidoethyl)benzenesulfonyl]-(3-methoxy-4-methylcyclohexyl)urea (melting point 151-153°C) is heated for 2 hours under reflux with a solution of 1.6 g of sodium hydroxide in 30 ml of water. The mixture is allowed to cool to room temperature, and 20 ml of acetone and 1.2 g of glacial acetic acid are added, along with 25 to 4.1 g of 2-methoxy-5-chlorobenzyl chloride in portions. The mixture is then stirred for another 2 hours at room temperature.

The substance is extracted using a funnel, the residue is treated with a bicarbonate solution, dissolved, and precipitated again in a mixture of ammonia and dilute hydrochloric acid. The H-[4~(P-<^2-meth6xy-5-chlorobenzamido^>-ethyl)-benzene-

- 30 -

sulfonyl]-N'-(3-methoxy-4-methyl-cyclohexyl)-urea, after recrystallization in a mixture of methanol and dimethyl-formamide, melts at 179-180°C.

EZEI.-IPLE 7:

F-[4~(P-<^2~methoxy~5-chlorobenz starches-ethyl)-benzene-sil-fonyl]-ïT'~(4-chloro-cyclohexyl)-urea.

8.5 g of N-[4-(j3-<^2-methoxy-5-chlorobenzamido^>-ethyl)-benzenesulfonyl]-methylurethane (melting point 189-191°C) is suspended in 100 ml of dioxane, and 2.8 g of 4-chlorocyclohexylamine (boiling point 82-84°C at 7 mmHg) obtained by the reaction of 4-aminocyclohexanol with phosphorus pentachloride is added. The reaction mixture is heated for 1 hour at 110°C, whereby the methanol formed during the reaction is driven off by distillation; after cooling the substance, a little water is added, and the resulting 1T-[4-(j3~

2-rné thoxy-5-chlorobenz amido^>-ethyl )-benzene-sulfonyl ]-E1 - (4— chloro-cyclohexyl)-urea• After being recrystallized in a mixture of methanol and dimethylformamide it melts at 177-178°C.

Similarly, we obtain:

the ÏT-[4- 0-<^2-methoxy-3-chlorobenzamido^> -ethyl)-benzene-tallow onyl]-ÏT'-(2-chlorocyclohexyl)-urea- with a melting point of 194-195°G (recrystallized in a mixture of methanol and dimethylformamide;

from ten C4-0-<^3—chlorobenzainido^>—ethyl)—benzene-sulfate—fonyl]-methyl-urethane (melting point 173-175°C)

K-[4-((3~<^3-chlorobenzaBiido^>-ethyl)~benzene~ tallow onyl]-II1-2-chloro-cyclohexyl)-urea with a melting point of 179~180°C (recrystallization in methanol);

-31 -

from II-[4-(0-<^2-methoxy-benzamido^>-ethyl)~bcnzèri.e-sulfonyl]-methyl-urethane (melting point 174-176°C)

N-[4-(0-<^2-methoxy-benzamido^>-ethyl)-benzenesulfonyl]-i;r,-(4-chloro~cyclohe:xyl)-urea with a melting point of 137-158°C (recrystallized in methanol) and N-[4-(3-<C 2-methoxy-benzamido^>-ethyl)-benzenesulfonyl]-iP-(2-chloro-cyclohe:xyl)-urea with a melting point of 198-199°C (recrystallized in a mixture of methanol and dimethyl-formamide);

10 from E-[4-(|3-<^2—n-propoxy-benzamido^>-ethyl)-benzene-sulfonyll-methyl-urethane (melting point 159-161°C)

N-[4~(0-<^2-n-propoxy-benzamido^>-ethyl)-benzene-sulfonyl]-B"'-(2-chloro-cyclohexyl)-urea with a melting point of 100-102°C (recrystallized in methanol);

15 from the ïï—[4— ( 0-<^2-n-bT3tox:y"l>on7)nrnido^>-ethyl)-benzene-tallow onyl]-methyl.-urethane (melting point 160-162°C);

F-[4-(2-n-butoxy-benzamido-ethyl)-benzene-sulfonyl]-H1-(2-chloro-cyclohexyl)-urea with a melting point of 131-133°0 (recrystallized in methanol);

20 from the lT-[4-(|3-<^2-methoxy-4-c.chlorobenzamido^>~ethyl)-

benzenesulfonyl]~neWiyl--nrelliane (melting point 175-180°C):

the E~[4-( p-<^2-methoxy-/i -c.chlorobenzanido^>-ethyl)-benzenesulfony.13—lI'-(4-chloro-cyclohexyi'ï-a-un point do melting de 181-182°C (recrystall issëe dans du methanol);

25 from E"-[4-0-<^2-ethoxy-5-chlorobenzamido^>-ethyl)-

benzene-sulfonyl]-methyl-urethane (melting point 203-205°C);

- 32 -

N-[4-(0-<^2-ethoxy-5-chlorobenzamido^>-ethyl)-benzeno-sulfonyl]-N'-(2-chloro-cyclohexyl)-urea ion melting point of 162-164°C (recrystallized in methanol);

from F-[4-(l3-<^2-methoxy-5-bromo-benzamido^>--ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 197-199°C)-la 33-[4-( p-<^2-methoxy-5-bromobenzam.ido^>-ethyl)-benzene-sulfonyl]-ïT'-(4-chloro-cyclohexyl)-urea with a melting point of 180-182°C (recrystallized in methanol) and N-[4-(j3-<^2-iiiethoxy-5-bromobenzamido^>-ethyl)-benzene-sulfonyl]-IT,-(2-chloro-cyclohexyl)-'urea with a melting point of 198-199°C (recrystallized in a mixture of methanol and dimethylformamide);

from α-[4-(α3-2-ethoxy-5-fluorobenzamido]-ethyl)-benzenesulfonyl]-methyl-urethane (melting point 193-195°C): α-[4-(α3-2-ethoxy-5-fluorobenzamido]-ethyl)-benzenesulfonyl]-N,-(4-chloro-cyclohexyl)-urea with a melting point of 159-161°C (recrystallized in a mixture of methanol and dimethylformamide);

from ÎT-[4-(|B-<^2-methoxy-5-methylbenzamido^>-ethyl)-benzenesulfonyl]-netyl-urethane (melting point 175-177°C)»

the ÏT-[4-( 3-<^2-methoxy-5-methylbenzamido^>-ethyl)-benzenesulfonyl]-Kr'-(4-chloro-cyclohexyl)-urea with a melting point of 110-112°C (recrystallized in methanol) and the F-[4-(P-<^2-methoxy-5-methylbenzamido^>-ethyl)-benzenesulfonyl]-ïï'l-(2-chloro-cyclohexyl)-urea with a melting point of 206-207°C; (recrystallized in a mixture of methanol and dimethylformamide);

from the ïï'-/~4-0-<^2.5-dimethoxybenzamido^>-ethyl)-'benzenesulfonyl7-methylurethane (melting point 173-175°),'

the £r-/~4~( g-<^2.5-dimethoxybenzamido^>-ethyl )-benzene sulfonyl7-N'-(2-chloro-cyclohexyl)-urea with a melting point of 143-14-5°C (recrystallized in methanol);

from F~/~4-((3-<^3 • 5-α.imethylbenzamido^>-ethyl)-benzenesulfonyl7-methylurethane (melting point 223-225°C).'

the Nr/~4~ ( P-<C3 • 5-cLimethylbenzamido^>-ethyl ) -benzene-sulfonyl7-N'-(4-chloro-cyclohexyl)-urea with a melting point of 179-181°C (recrystallized in methanol) and the N-/~4-((3-<3« 5-d.imethylbenzamido^>-ethyl )-benzene-tallow ony^-N'-(2-chloro-cyclohexyl)-urea with a melting point of 202-204°0 (recrystallized in methanol);

from N-/~4--((3-<^2-phenoxybenzamido^>-ethyl)-benzene-sulfonyl7-methyl-urethane (melting point of 167-169°C);

the E-/~"4- ( (3-<^2-phenoxybenzamido^>-ethyl ) -benzene-sulfonyl7-F'-(2-chloro-cyclohexyl)-urea with a melting point of 147-149°C (recrystallized in methanol);

from 4-((3-<^3-methoxy-thiophene-2-carbonanido^>-ethyl)-bsnzene-sulfonyl-7-methyl-urethane (melting point 226-228°C)

the N-/—4-( (B-<^3-methoxy-thiophene-2-carbonamido^>-ethyl)-benzene~sulfonyl7-N'-(2-chloro-cyclohexyl)-urea with a melting point of 200-201°C (recrystallized in methanol);

from ÎT-/~4-(|3-benzamido-ethyl)-benzene-sulionyl7-methyl-urethane (melting point 185-187°C);

(p-benzamido-ethyl)-benzene-sulfonyl7-N'-

(2-chlorocyclohexyl)-urea with a melting point of 186-187°C (recrystallized in methanol); (\

- 34 -

from N-/~~4-(|3-<^3-methylbenzamido_^>-ethyl)-benzene-tallow onyl/-methyl-urethane (melting point 200-202°C)

the N-/~4-(|3-<^3-m®thy^benzamido^>-ethyl)~benzene-sulfonyl7-li^,-(2-chloro-cyclohexyl)-urea with a melting point of 179-181°0 (recrystallized in methanol);

from IT-/~4-(P-<^3-trifluoromethyl-benzamido^>-ethyl)-benzene-sulfonyl7-methyl-urethane (melting point 178-180CC);

N-/~~4-(3-<^3-trifluoromethyl-benzamido^>-ethyl)-benzene-suifony^-F1 -(2-chloro-cyclohexyl)-urea with a melting point of 177-179°C (recrystallized in methanol);

from N-/—4-((3-<j5-chlorobenzamido^>-ethyl)-benzene~ sulfonyl7-methyl-urethane (melting point 173-175°C)'

the rr-/~4- (p-3-<^chlorobenzamido^>-ethyl ) -benzene-sulf onyl7-îf'-(4-chloro-cyclohexyl)-urea with a melting point of 173-175°C (recrystallized in methanol);

from F-/-4-((3-<^3-methoxy-thiophene-2-carbonamido^>-ethyl)-benzene-suifonyl-7-methyl-urethane (melting point 226-228 °0):

N-/~4-(|3-<]3-methoxy-thiophene-2-carbonamido^-ethyl )-benzene-sulfony17-N'-(4-chloro-cyclohexyl)-urea with a melting point of 196-197°^ (recrystallized in a mixture of methanol and dimethylformamide);

from N-/--4-(|3-<^2-methoxy-5-chlorobenzamido^>~ethyl)-benzenesulfonyl-7-methylurethane (melting point 189-191°C)*

N-/~4-(P-<[2-methoxy-5-chlorobenzamido^:-ethyl)-benzene-sulfonyl7-N'-(3-chloro-cyclohexyl)-urea with a melting point of 144-146°C (recrystallized in a mixture of methanol and dimethylformamide);

from F-/~4-(~y-<^2-methoxy-5--chlorobenzamido^>~propyl-) benzene-sulfonyl-7-methyl-urethane (melting point 160°0)'

the F-/~4-()f-<^2-methoxy-5-chlorobenzamido^>-propyl)-benzene-sulfonyl7-F'-(2-chloro-cyclohexyl)-urea with a melting point of 93°C (decomposition) (recrystallized in a mixture of methanol and water);

from F-/*~4-(f3-<^2-methoxy-5-chlorobenzamido^>-propyl)-benzene-sulfonyl-7-inethyl-urethane (melting point 197°C)'

the F-/~~4-((3~<C2-methoxy-5-chlorobenzamido^>-propyl)• benzene-suifonyl7-F'-(2-chloro-cyclohexyl)-urea with a melting point of 78°C (decomposition) (recrystallized in a mixture of methanol and water);

from N-/~4-(@-<^3-chlorobenzamido^>-ethyl)-benzene~ sulfonyl7-methyl-urethane (melting point 173-175°C).'

the F-/-4-((3-<^3-chlorobenzamido^>-ethyl)-benzene-sulfonyl7-N*-(3-chloro-cyclohexyl)-urea with a melting point of 151~153°C (recrystallized in methanol);

from H-/-4-(0-<^2-methoxy-5-methylbenzamido^>-ethyl)-benzenesulfonyl-7-methylurethane (melting point 175-177 °C).'

the F-/~~4- ( (3-<^ 2-methoxy-5-methylbenzamido^>-ethyl ) -bens?',èrie-sulfonyl7-Fl-(3-chloro-cyclohexyl)-urea with a melting point of 1'i6-1480C (recrystallized in methanol);

from N-/~4-<^3~ethoxy-thiophùij.o--2-carbonfîni-i rio^-benzene-sulfonyl7-methyl-urethane (melting point 163-163°C);

F-/ 4-(p-<^3-ethoxy-thiophene-2-carbonamido^>-ethyl)-benzene-sulfonyl7-F!-(2-chloro-cyclohexyl)-urea with a melting point of 176-177°C (recrystallized in methanol):

- 36 -

from F-/~4-((3-<^2-allyloxy-5~chlorobenzamido^>-ethyl)-benzene-sulfonyl7-methyl-urethane (melting point 167-169°C);

U-/~"4-(P-<^ 2-allyloxy-5-chlorobenzamido^>- ethyl)-benzene-suifonyl7-N'-(2-chloro-cyclohexyl)-urea with a melting point of 145-147°C (recrystallized in methanol).

EXAMPLE 8:

((3-<^2-methoxy^5-chlorobenzamidcT> -ethyl)-

benzenesulfonyl/'-N'-(4-chlorocyclohexyl)urea. \ during

4.26 g of N-(4-methoxy-5-chlorobenzamido-ethyl)benzenesulfonyl-7-methylurethane is heated for 90 minutes in a descending chiller with 2 g of 4-chlorocyclohexylamine acetate in 100 ml of dioxane. After the addition of water and recrystallization of the product obtained in a mixture of methanol and dimethylformamide, N-(4-methoxy-5-chlorobenzamido-ethylbenzenesulfonyl-7-N-(4-chlorocyclohexyl)urea with a melting point of 177-178°C is obtained in very good yield.

EXAMPLE 9:

N-/~4-(P-<^2-methoxy-5-chlorobenzamido^>-ethyl)-benzenesulfonyl7-N'-(2-chlorocyclohexyl)-urea. A mixture of 10.3 g of N-/~4-(|3-<^2-methoxy-5-chlorobenzamido^>-ethyl )-

benzene-sulfonyl-7-urea (point of

(melting point 171-173°C), 300 ml of toluene, 30 ml of glycol-monomethyl ether, 1.65 g of glacial acetic acid, and 3.3 g of 2-chlorocyclohexylamine. The mixture is concentrated under vacuum, and the residue is treated with alcohol. The 4-([3-<^2-methoxy-5-chlorobenzamido^>-ethyl-benzene-sulfonyl7-N'-(2-chloro-cyclohexyl)-urea obtained as the crude product, after being recrystallized in a mixture of methanol and dimethylformamide, melts at 194-195°C.

CL

- 37 -

EXAMPLE 10:

3.9 g of the sodium salt of 4-(p-2-methoxy-5-chlorobenzamido-ethylbenzenesulfonamide, 6.5 g of N.N-diphenyl-N'-(4-chlorocyclohexyl)urea (melting point 115-116°C) and 100 ml of DIVFA are heated for 45 minutes at 110°C. The mixture is allowed to cool, poured into water, and 1% ammonia is added. It is then filtered, the filtrate is acidified, and the resulting precipitate is purified again over a mixture of ammonia and hydrochloric acid.

After being recrystallized in a mixture of methanol and dimethylformamide, the K-/~4-((3-<^2-methoxy-5-chlorobenza-mido^>-ethyl)-benzene-sulfonyl7-N,-(4-chlorocyclohexyl)-urea precipitates in crystalline form and melts at 178-179°C.

EXAMPLE 11:

N-/7"4-( (3-<^2-methoxy-5-chlorobenzamido^> -benzene-tallow onyl7~N,-(4-chloro-cyclohexyl)-urea.

758 g of 1T-/~4-(3-acetamidoethyl)benzenesulfonyl7-N'-(4-chlorocyclohexyl)urea (melting point 151-153°C) is heated under reflux for 2 hours with 1.6 g of sodium hydroxide and 30 mL of water. The substance is cooled to room temperature, 20 mL of acetone and 1.2 g of glacial acetic acid are added, 4.1 g of 2-methoxy-5-chlorobenzoyl chloride are introduced in portions, and the mixture is stirred for another hour. The precipitate is squeezed out, mixed by stirring with a bicarbonate solution and recrystallized in a mixture of methanol and dimethyl-formamide. The melting point of the E-/~4-(|3-<^ 2-methoxy-5-chlorobenzamido^>-ethyl)-benzene-tallow onyl7-Er' -(4-chloro-cyclohexyl)-urea obtained is 178-179°C.

- 38 -

EXAMPLE 12:

ÎI-[4-(p~<^2-methoxy-4-chlorobenzamido^>-ethyl) -benzene-tallow onyl] -U'-(2-chloro-cyclohexyl)-urea.

Five grams of 4-(|3-<^2-methoxy-/)-chlorobenzamido^j-ethyl)-benzenesulfonamide (melting point 185-186°C) are dissolved in 7 ml of dinormal sodium hydroxide solution and 50 ml of acetone. At 0-5°C, 2.5 grams of 2-chlorocyclohexyl isocyanate are added dropwise while stirring. The mixture is stirred for 2 hours, then diluted with water and methanol. Undissolved material is removed by filtration, and the filtrate is acidified with dilute hydrochloric acid. M-[4- (p-<^2--methoxy-4-chlorobenzamido^>-ethyl)-benzene-sulfonyl[-N'-(2-chloro-cyclohexyl)-urea melts at 17^—176°C after being recrystallized in methanol.

Similarly, we obtain:

from 4-(p-4-chlorobenzamido-ethyl)-benzene-suifonamide (melting point 225-226°0):

the H-[4-(|3- 4-chlorobenzamido -ethyl)-benzene-sulfonyl]-ÏSr'-(2-chloro-cyclohexyl)-urea with a melting point of 180-181°C, (recrystallized in methanol);

from 4-((3-<^2-ethoxybenzamido^>-ethyl)~benzene-sulfonamide (melting point 148-150°C):

the N~[4-((B-<^2-ethoxybenzamido^>-ethyl)-benzene-sulfonylU-N,-(2-chloro-cyclohexyl)-urea with a melting point of 147-148°0, (re-stallized in methanol);

- 39 -

from 4-((3-<^3.5-dimethyl-thiophene-2-carbonamido^>-ethyl)-benzene-sulfonamide, (melting point 176-177°G).'

N-[4-((3-<^3-5-dimethyl-thiophene-2-carbonamido^>-ethyl)-benzene-suifonyl]-F'-(2-chloro-cyclohexyl)-urea with a melting point of 177-179°C, (recrystallized in methanol). EXAMPLE 13:

F-[4- ( p-<^2-methoxy-5-chlorobienzamido^5-ethyl)-benzene-sulfonyl]-F'-(4-chloro-cyclohexyl)-urea.

a) 2.3 S of 4-chlorocyclohexylparabanic acid (melting point 222-223°C) is suspended in 50 mL of benzene and the suspension is heated for two hours under reflux with 3.9 g of 4-(3-2-methoxy-5-chlorobenzamidoethyl)benzosulfone chloride and 1 g of triethylamine. The solvent is removed by decantation, the remaining oil is treated with water, and the insoluble residue is recrystallized from methanol. The melting point of 1-[4-(3-2-methoxy-5-chlorobenzamidoethyl)benzenesulfonyl]-3-(4-chlorocyclohexyl)parabanic acid is

at 179-181°C.

b) 0.9 g of the compound mentioned above is heated in a steam bath for 45 minutes in 5 ml of dioxane and 10 ml of normal sodium hydroxide solution. Water is added, the mixture is acidified, and then recrystallized in methanol. The resulting compound is F-[4-(j3-<^2-methoxy-5-chlorobenzamidcT^>-ethyl)-benzene-suifonyl]-F'-(4-chloro-cyclohexyl)-urea with a melting point of 179-181°C.

EXAMPLE 14:

F-[4-((3-<^2-methoxy-5-chlorobenzamido]]>-ethyl)-benzenesulfonyl-F'-2-chlorocyclohexyl-urea. a) 1 g of F-[4-(3-<^2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-F'-2-chlorocyclohexyl-thiourea (melting point 173-175°C) is dissolved in 100 ml of methanol

- 40 -

to which 10 ml of dioxane had been added. 1.1 g of mercury oxide is added and the mass is stirred for 3 hours at 50-60°C. After the mercury sulfide has been removed by filtration, the substance is concentrated under vacuum. The methyl ether of N-[4-(|3-<^2-niethoxy-5-chlorobenzanido^>='ethyl)-benzenesulfonyl-U1-2-chloro-cyclohexyl--iso-urea melts at 125-127°C after being recrystallized in dilute methanol*

b) 0.1 g of the product obtained according to a) is suspended in 2 ml of dioxane and 10 ml of concentrated hydrochloric acid. It is heated for 5 minutes in a steam bath, the mass is poured into water, the precipitate is removed by draining, and it is recrystallized in methanol.

N-[4-((3-<^2~methoxy-5-chlorobenzamido^:-ethyl)-benzenesulfonyl]-1T'-2-chloro-cyclohexyl-urea melts at 192-194°G„ EXAMPLE 15:

H-[4-(j3-<^2-methoxy-5-chlorobenzamido^>-ethyl)-benzenesulfonyl]-N'-2-chlorocyclohexyl-urea

0.5 g of N-[4-(3-2-methoxy-5-chlorobenzamido-ethyl)benzenesuifonyl]-N-2-chlorocyclohexylthiourea (melting point 173-175°C) is dissolved in 30 mL of dinormal sodium hydroxide solution, and 10 mL of 30% hydrogen peroxide is added. The solution is heated for 20 minutes in a steam bath, cooled, and acidified. A precipitate is obtained, which is drained and treated with highly dilute ammonia. After filtering, the filtrate is acidified. The resulting N-[4-(3-2-methoxy-5-chlorobenzamido-ethyl)benzenesuifonyl]-N-2-chlorocyclohexylthiourea melts at 192-194°C after recrystallization in r.ethanol

EXAMPLE 16;

N- [4-( |3-<^2-methoxy-3-chlorobenzamido^> -ethyl)-benzene-tallow onyl] -N ' -( exo-tricyclo- [3.2.1. 0^ * -octane-3-anti)-urea »

We dissolve 18.5' £ of 4-(3-<^2-methoxy-5-chloro-

benzamido(ethyl)benzenesulfonamide in 250 ml of dioxane,

Add 13.8 g of powdered potassium hydroxide and heat the mixture for 2 hours with reflux and stirring. Add drop by drop to

2 4

A solution of exo-tricyclo-C3.2.1.0 * ]-octane-3-antiisocyanate is dropped into benzene (obtained by thermal rearrangement of the corresponding acid azide), and stirring is continued for another 5.5 hours at boiling point. The cooled solution is poured into water, acidified, the precipitate is drained, and it is recrystallized twice in a mixture of dioxane and water. Melting point 188-190°C (decomposition).

The N-[4-(|3-<^2-methoxy-benzamido^>-ethyl)-benzene-sulfonyl]-H ' -( oxotricyclo- [3 • 2.1. 0^ *ZJ"] -octane-3-ant i) -urea obtained in a similar manner melts at 186-188°C.

The N-[4—(|3-<l2-niethoxy-5-methylbenzamido^5-ethyl)-

0 Ll benzene-sulfonyl]-N'-(oxotricyclo—L3.2.1.0. * ]-octane-3-anti)~urea obtained in a similar manner melts at 175-177°C (decomposition).

The N-[4-(3-<C4-chlorobenzamido-ethyl)-benzene-tallow onyl]-H'-(oxotricyclo-[3-2.1.02°]-octane-3-anti)-urea obtained in a similar manner melts at 202-204°C (decomposition). EXAMPLE 17:

N-[4—(p-benzamido-ethyl)-benzene-suifonyl]-N1-(4-methyl-/\^-c.Tclohexenyl-urea.

7.6 g of 4-((3-benzamidoethyl)benzenesuifonamide) is boiled with stirring in a reflux cooler.

- 42 -

in 150 ml of acetone with 5 S of potassium carbonate. 3.5 g of 4-methyl-cyclohexenyl isocyanate (boiling point 72-74°C at 12 mmHg, produced by the decomposition of 4-methylcyclohexenecarboxylic acid azide obtained by conventional means from 4-methylcyclohexenecarboxylic acid) are added. Stirring is continued for 8 hours at boiling point. The solvent is removed by evaporation, the residue is treated with water, filtered, and the filtrate is acidified. N-[4-(3-benzamidoethyl)benzenesuifonyl]-N'-(4-methyl-3-cyclohexenyl)urea is obtained by dewatering and recrystallized from dilute ethanol. It melts at 195-196°C.

Similarly, we obtain

from 4-(3-c^2-methoxy-5-chlorobenzamido^>-ethyl)-benzene-tallow onamide (melting point 214-216°C)'.

the N- [4-(jB-<^2-methoxy-5-chlorobenzamido^> -ethyl ) -benzene-tallow onyl] -N ' -(4-methyl-A3-cyclohexenyl)-urea has a melting point of 158-160°C;

from 4-({3-<^2-methoxy-benzamido^>-ethyl)-benzene-sulfonamide (melting point 178-180°C):

the F-[4-(p-<^2-methoxy-benzamido^>-ethyl)-benzene-sulfonyl]-N'-(4-methyl-A3-cyclohexenyl)-urea with a melting point of 173-175°C;

from 4-(3-<^3-chlorobenzamido^>-ethyl)-benzene-suifonamite (melting point 161-163°C);

the ÏT-[4-((3-<^3-chlorobenzamido^>-ethyl)-benzene-sulfonyl]-ÎT,-(4-methyl-A3-cyclohexenyl)-urea with a melting point of 147-149°C;

_ 43 -

from 4-(P-4-chlorobenzamido3-ethyl)-benzenesulfonamide (melting point 220-221 °C).

the N-[4-(p-<[4-chlorobenzamido]>~ethyl)~benzene-sulfonyl]'-I!J',-(4-methyl _A3-cyclohexenyl)~urea of a melting point of 201-203°C;

from 4-(|3-<^3-iDiethylbenzamido^>-ethyl)-benzene-tallow onamide (melting point 187-189°C);

the N-[4-(pr<^3-methylbenzamido^>-ethyl)-benzene-sulfonyl]-lT'-(4-methyl-A 3-cyclohexenyl)-urea with a melting point of 160-162°C;

from 4-(p-C2-methoxy-4-chlorobenzamido-ethyl)-benzene-sulfonamide (melting point 187-/188°C).

N-[4-(p-<^2-methoxy-4-chlorobenzamido^>-ethyl)-benzene-sulfonyl]-N'-(4-methyl-Zi\3-cyclohexenyl)-urea has a melting point of 160-162°C;

from 4-(p-2.4-dichlorobenzamido-ethyl)-benzene-tallow onamide (melting point 162-164°C).

the N-[4-(p—£2..4-dichlorobenzamido^>-ethyl)-benzene-sulfonyl]-ïT'-(4-methyl-</^-cyclohexenyl)-urea with a melting point of 178-180°0;

from 4-(P-<^2-ethoxybenzamido^>-ethyl)-benzene-sulfonamide (melting point 148-150°C);

the N-[4-(P-<^2-ethoxy-benzamido^>-ethyl)—benzene-sulfonyl]-N,-(4-methyl-/^-cyclohexenyl)-urea with a melting point of 158-160°C;

- 44 -

from 4-(p-2-iso-amyloxy-benzamido-ethyl)-benzene-sulfonamide (melting point 148°C)

the N-[4-(f3-<^2-iso-amyloxy-benzamido^>-ethyl)-benzene-tallow onyl]-F'-(4-methyl-^^-cyclohexenyl)-urea with a melting point of 140-142°C;

from 4-(|3-<^2-allyloxy-benzamido^>-ethyl)-benzene-sulfonamide (melting point 129-130°C)I

the N-[4-(3-<^2-allyloxy-benzamido^> -ethyl)-benzene-sulf onyl]-N1-(4-methyl-/^ ^-cyclohexenyl)-urea of a melting point of 144-146°C;

from 4-({3-<^2-iso-amyloxy-5-chlorobenzamido^>-ethyl-benzene-sulfonamide (melting point 142-144°C)."

KT—C4—(p-<^2-iso-amyloxy-5-chlorobenzamido^>-ethyl)-benzene-tallowyl]-ET'-(4-methyl-yuy'-cyc 1 ohexenyl)-urea with a melting point of 124-126°C;

from 4-((3-<^3-fluorobenzamido^>-ethyl)-benzene-sulfonamide (melting point 218-219°C):

the N-[4-(|3-<^3-fluorobenzamido^>-ethylj!)-benzene-sulfonyl]-N'-(4-methyl-£\3-cyclohexenyl)-urea with a melting point of 188-190°C;

from 4-(3-<^3-chloro-4-methyl-benzamido^-ethyl)-benzene-sulfonamide (melting point 184-185°C):

ET-[4-((3-<^3-chloro-4-methylbenzamido^>-ethyl)-benzene-sulfonyl]-N'-(4-methyl-A3-cyclohexenyl)-urea has a melting point of 185-187°C;

I

- 45 -

from 4--(p-<^2.5-dimethylbenzamido^>-ethyl)-"benzenesulfonamide (melting point 139-14-1 °C):

ET-C4— ((3-<^2.5-dimethyl-benzamido^>-ethyl)-benzene-sulfonyl]-iP-(4~methyl- A3-cyclohexenyl)-urea with a melting point of 173-175°C;

from 4— ((3-naphthalene-2-carbonamidoethyl)-benzenesulfonamide (melting point 206-208°C)!

ET-[4— (3-<jiaphthalene-2-carbonamido^>-ethyl)-benzene-sulfonyl]-N' -(4—methyl--urea has a melting point of 180-182°C;

from 4— ((3-<^4—nitro-benzamido^>-ethyl)-benzene-sulfonamide (melting point 182-184-°C):

the N-[4~(|3-<^4—nitro-benzamido^>-ethyl)-"benzene-tallow onyl]-N'-(4—methyl- 3-cyclohexenyl)-urea with a melting point of 172-174-°C;

from 4— (j3-<^2-methoxy-5-iaethyl-benzamido^>-ethyl)-"benzene-sulfonamide (melting point 193-194-°C):

the N-[4~( 3-<^2-methoxy-5-methyl-"benzamido^> -ethyl)-benzene-tallow onyl] -N ' -(4—methyl-<A3-cyclohexenyl ) -urea e d ' a melting point of 14-9-151°G;

from 4— (p-<^2-ethoxy-5-niethyl-benzamido^>-ethyl)-benzene-sulfonamide (melting point 151-153°C)".

N-[4-(p-<^2-ethoxy-5-methyl-henzamido^>-ethyl)-benzenesulfonyl]-N'-(4-methyl-Al3~cyclohexenyl)-urea with a melting point of 158-159°0-

EXAMPLE 18:

N-*[4-({3-<£-methoxy-4-chlorobenzamidd>-ethyl)-benzene-sulfonyl] -N!~(4-methyl-A3-cyclohexenyl)-urea.

4.2 g of N-[4-(p-5 <2-methoxy-4-chlorobenzyl)-benzenesulfonyl-methylurethane (melting point 178-180°C)] is heated, with stirring, to 110°C with 4-methyl-13-cyclohexenylamine (boiling point 50°C at 10 mmHg; prepared from 4-methyl-13-cyclohexenyl isocyanate by hydrolysis with 10-50% acetic acid) in 50 mL of dioxane, whereupon the methanol formed during the reaction escapes by distillation. Most of the dioxane is evaporated under reduced pressure, and water is added to the residue. The precipitated product is drained and recrystallized in dilute ethanol. The N-[4-( (3-<^2-15 methoxy-4-chlorobenzamido^>-ethyl)-benzene-suifonyl]-N'-(4—

methyl-A3*-cyclohexenyl)-urea obtained melts at 160-162° C.

EXAMPLE Y):

N-[4-(p-<5-methoxy-5~chlorobenzamidc£>-ethyl)-benzenesulfonyl]-

2 4

N1- exotriclco[3.2.1.0 * 3-octane-3-anti-urea.

20. 18.5 g of 4-((3-<$-methoxy-5-chlorobenzamidS) are dissolved

ethyl)benzenesulfonamide in 250 ml of dioxane. 13.8 g of powdered potassium hydroxide are added, and the mixture is heated with stirring for 2 hours under reflux. A

2 4_

A solution of exo-tricycloC3.2.1.0 "J-octane-3-antiisocyanate 25" in benzene (prepared by thermal transposition of the corresponding acid azide) is heated for 5.5 hours at boiling point. The cooled solution is poured into water, acidified, the precipitate is drained, and it is recrystallized twice in a mixture of dioxane 30 and water. Melting point 188-190°C (decomposition).

- 47 -

EXAMPLE 20:

N-L4-( (3<j5-methoxy-5-chloro.§enzamidd>-ethyl)-benzene-sulfonyl3-

N'- 3.4-dimethylcyclohexyl)-urea.

5.7 g of N-L4-(j3-<J~methoxy-5- are suspended

chlorobenzamid-ethylbenzenesulfonyl-methylurethane (melting point 189-191°C) in 100 ml of dioxane and add

1.7 g of 3,4-dimethylcyclohexylamine (boiling point ■one

47°C under a pressure of 6 mm of mercury, acetate: melting point 114-115°C). The suspension is heated to 110°C while stirring for 90 minutes; the methanol formed during the reaction escapes by distillation. Upon the addition of a little water, the crystallized N-[4-(|3-<£-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyll-n,-(3,4-dimethyl-cyclohexyl)-urea, after being recrystallized in methanol, melts at 170-171°C. Similarly, the following are obtained:

N-L4-(p-methoxy-5-chlorobenzamid-ethyl)benzenesulfonyl-N'-(4,4-dimethylcyclohexyl)urea with a melting point of 177-178°C (recrystallized in methanol)

the N-[.4-( (3-<2-methoxy-5-chlorobenzamido>-ethyl)-benzene sulfonyl3-N'-(3.5-dimethyl-cyclohexyl)-urea with a melting point of 193° C (recrystallized in a mixture of methanol and dimethylformamide) and the n_[4—( p-<^-methoxy-5-chlorobenzamido<5>-ethyl ^"benzene-tallow onyl3-N'-(4.4-diethyl-cyclohexyl)-urea with a melting point of 174-175° C (recrystallized in methanol);

from N-[4-( p-<g~ethoxy-5~chlorobenzamidc>>-ethyl ^benzene-

tallow}-methyl-urethane (melting point 203-204° C):

the N-[4—p-<2-ethoxy-5~chlorobenzamid5>-ethyl)-

benzenesulfonyl]-N'-(4„4-diethylcyclohexyl)~urea with a melting point of 136-138°C (recrystallized in methanol);

from N-_/4-(p-<^2-allyloxy-5(chlorobenzainido3>-ethyl)-benzene-sulfonyl7-methyl--urethane (melting point 167 - 168°0):

- 48 -

N-4-(3-2-allyloxy-5-chlorobenzamido-ethyl)-benzenesulfonyl-7-N'-(3,4-diethylcyclohexyl)-urea with a melting point of 158-160°C (recrystallized in methanol) and N*-[4-(2-allyloxy-5-chlorobenzamido-ethyl)-T-

benzenesulfonyl]-N'-(4.4-dimethylcyclohexyl)-urea with a melting point of 156-158° C (recrystallized in methanol);

from N-[4-(|3-<^-methoxy-5-f luorobenzamido>-ethyl)-benzene-su.ifonyl]-methyl-urethane (melting point 171-173° C):

N-[4-(p-methoxy-5-fluorobenzamidoethyl)benzenesulfonyl]-N,-(2,4-dimethylcyclohexyl)-urea with a melting point of 175-176° C (recrystallized in methanol) °

N-[4-(p-methoxy-5-fluorobenzamid5-ethyl)benzenesulfonyl]-N'-(3,4-dimethylcyclohexyl)-urea with a melting point of 180-182°C (recrystallized in methanol); and N-[4-(p-methoxy-5-fluorobenzamid5-ethyl)benzenesulfonyl]-N'-(4,4-dimethylcyclohexyl)-urea with a melting point of 196-197°C (recrystallized in methanol);

from N-[4-((3-<2-ethoxy-5-fluorobenzamidc3>-ethyl)-benzenesulfonyl]-methylurethane (melting point 193-195° C).*

the N-[4-( f3<^2-ethoxy-5-f luorobenzamido5-ethyl)-benzene-sulfonyll-N'-(4.4.-dimethyl-cyclohexyl)-urea with a melting point of 167-168° C;

from N-[4-(p-methoxy-5-bromobenzamide-ethyl)benzenesulfonyl]methylurethane (melting point 197-199°C)

N-L4-(p-methoxy-5-bromobenzamido-ethyl)-benzenesulfonyl-N'-(2.4-dimethylcyclohexyl)-urea with a melting point of 204-205°C (recrystallized in a mixture of methanol and dimethylformamide);

N-l4-(p-<5-methoxy-5-bromobenzamidc5>-ethyl)-

_ 49 -

benzenesulfonyl]-N-(3.4-dimethylcyclohexyl)-urea with a melting point of 166-168° C (recrystallized in methanol) and N-[4-(p-<2-methoxy-5-bromobenzamidcî>-ethyl)-benzenesulfonyl}-N'-(3.5-dimethylcyclohexyl)-urea with a melting point of 202-204° C (recrystallized in a mixture of methanol and dimethylformamide);

from N-[4-(p-methoxy-5-methylbenzamide-ethyl)benzenesulfonyll-methylurethane (melting point 175-177°C)~

N-[4-(p-methoxy-5-methylbenzamid-ethyl)-benzenesulfonyl]-N,-(4.4-dimethylcyclohexyl)-urea with a melting point of 164-166° C (recrystallized in methanol);

h starting from N-[4-(p-<J.5-dimethoxy-benzamid§>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 175-175° C);

N-[4-(p-<£.5™'dimethoxy-benzamid5>-ethyl)-benzene-sulfonyll-N'-CS^-dimethyl-cyclohexylJ-urea with a melting point of 157-159° C (recrystallized in methanol);

N-[4-(p-<$.5-dimethoxy-benzamid^>-ethyl)-benzene-sulfonyl3-N'-(4.4.-dimethyl-cyclohexyl)-urea with a melting point of 132-134° C (recrystallized in methanol);

N-[4-(p-<^.5-dimethoxy-benzamidc?>-ethyl)-benzene-sulfonyl ]-N'-(4.4-diethyl-cyclohexyl)-urea with a melting point of 142-144° C (recrystallized in methanol);

from N-[4-(p-<£-ethoxy~5-acetyl-benzamir1c£>-ethyl)--benzer.e-sulfonyl]-methyl-urethane (melting point 164-166° C)'.

N-[4-(p-<$~ethoxy-5-acetyl-benzamidS>-ethyl)-benzene-sulf onyl}-N'-(4,4-dime thyl-cyclohexyl )-urea with a melting point of 138-140° C (recrystallized in r.othanol) ? .

from N-[4-((3-<2-methoxy-benzamido>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 174-176° C)-.

N-[4-( {3-<JJ-methoxy-benzamid&>-ethyl)-benzene-sulfonyl]-N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 197-199° C (recrystallized in a mixture of methanol and dimethylformamide);

N-C4-(p-<2-methoxy-benzamido>-ethyl)-benzene-sulfonyl]-N'-(3.4-dimethyl-cyclohexyl)-urea with a melting point of 169-171° C (recrystallized in methanol);

N-4-(3-methoxybenzamido-ethyl)benzenesulfonyl-N'-(3.5-dimethylcyclohexyl)urea with a melting point of 179-181°C (recrystallized in methanol) and N-4-(4-methoxybenzamido-ethyl)benzenesulfonyl-N'-(4.4-dimethylcyclohexyl)urea with a melting point of 188-189°C (recrystallized in a mixture of methanol and dimethylformamide);

from N-[4-(p-<£-propoxy-benzamidc£)-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 159-161° C)',

N-[4-(p-<£-propoxy-benzamid9? -ethyl)-benzene-sulfonyl]-N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 183-184° C recrystallized in methanol);

from N-L4-( (3-<$-methylbenzamid^;-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 200-202° C)'.

N-[4-(p-<3-methylbenzamido>-ethyl)-benzenesulfonyl]-N'-^4.4-dimethylcyclohexyl)-urea with a melting point of 170-172° C (recrystallized in methanol);

from N-[4-(p-<^-chlorobenzamidB>-ethyl)-benzene-

- 51 -

sulfonyll-methyl-urethane (melting point 173-175° C).

N-[4-(p-chlorobenzamidethyl)benzenesulfonyl]-N'-(3,4-dimethylcyclohexyl)urea with a melting point of 163-165°C (recrystallized in methanol); ^ N-[4-(p-chlorobenzamidethyl)benzene-

sulfonyl]-N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 168-169° C (recrystallized in methanol) and N-C4-( f3-<^-chlorobenzamidcî>-ethyl)-benzene-sulfonyl]-N'-(4.4-diethyl-cyclohexyl)-urea with a melting point of 175-176° C (recrystallized in methanol);

from N-[4-(p-<^.5-dimethyl-benzamid5>-ethyl)-benzene-sulfonyl]-methyl-urethane (melting point 223-225° C)"

N-[4-(p~<^05-dimethyl~benzamicfè>-ethyl)-benzene-15 suifonyll-N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 194-195° C (recrystallized in methanol);

from N-[4-(p-<S-ethoxy-thiophene-2-carbonamid-ethyl)-benzenesulfonyl]-methylurethane (melting point 163-165°C); 20 the N-L 4~(p-<3~ethoxy-thiophene-2-carbonamid-ethyl)-

kenzene-sulf ony l]-N'~-(4.4-dime thyl--cyclohexyl)-urea with a melting point of 181-183° C (recrystallized in methanol);

from N-[4-(p-<5.4-tetramethylene-thiophene-2-carbonamid§>-25 (ethyl)-benzene-sulfcnyl]-methyl-urethane (melting point

194-196° C):

N- 4-(p-<^.4-tetramethylene-thiaphene-2-carbonamido>-ethyl)-benzene-sulfonyl]-N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 186-187° C (recrystallized in methanol);

- 52 -

EXAMPLE 21:

N-/^-(P<C2-methoxy~benzamido^ -ethyl ^benzene-tallow onyl_7-ÎT' -(4.4-diethyl-cyclohexyl)-urea.

6 g of 4-2-methoxybenzamido(ethyl)benzenesulfonamide (melting point 178-180°C) is dissolved in 9 mL of dinormal sodium hydroxide solution and 40 mL of acetone. While stirring at 0-5°C, 3.3 g of 4,4-diethylcyclohexyl isocyanate (boiling point 108-110°C at 10 mmHg) obtained by the reaction of 4,4-diethylcyclohexylamine (boiling point 95-97°C at 11 mmHg, hydrochloride: melting point 243°C with phosgene) is added dropwise. The mixture is stirred for another 2-3 hours at room temperature. The solution is then diluted with water and methanol, and the undissolved material is removed. by filtration and the filtrate is acidified with dilute hydrochloric acid. The N-/ 4-((3-<C2-methoxy-benzamido^>-ethyl)-benzene-sulfonyl_7-N'-(4.4-diethyl-cyclohexyl)-urea obtained in crystalline form, after recrystallization in methanol melts at 186-187°C.

Similarly, we obtain:

from 4-(p-2-n-butoxybenzamido-ethyl)benzenesulfonamide (melting point 151-152°C)

N-/~4- (|3<^2-n-butoxy-benzamido ^>-ethyl ) -benzene-sulfonyl_7-N'~(2.4-dimethyl-cyclohexyl)-urea with a melting point of 190-191°C; (recrystallized in a mixture of methanol and dimethyl-formamide);

from 4-((3-<^2-methoxy-5--methylbenzamido>-ethyl-benzene-sulfonamide (melting point 197-198°C)

F-/~4-(|3-<^2-methoxy-5-methylbenzamido^>-ethyl)-benzenesulfonyl_7~N"'-(2.4-dimethylcyclohexyl)-urea with a melting point of 191-192°C (recrystallized in a methanol mixture)

and dimethylformamide); and N-/~4-((3-<|>-methoxy-5-Eiethylbenzamido^>-ethyl)-benzene-tallow onyl_7-N'-0.5-dimethyl-cyclohexyl)-urea with a melting point of 203-204°C (recrystallized in a mixture of methanol and dimethylformamide);

from 4-(f3-<^2-methoxy-4-chlorobenzamido^>-ethyl^benzene-sulfonamide (melting point 187-188°C)

the N-/~4-((3- <12-methoxy-4-chlorobenzamido^>-ethyl)-benzene-

suifonyl_7-N'-^2.4-dimethyl-cyclohexyl)-urea from a point of

✓

melting point of 186-188°C (recrystallized in methanol) and N-/~4- (@-<^2-methoxy-'4-chlorobenzamido^>-ethyl)-benzene-sulfonyl_7-Wf-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 201-203°C (recrystallized in methanol);

from 4-((3-<^2-ethoxy-5-chlorobenzamido^>-ethyl)-benzene-sulfonamide (melting point 168-170°C)

N-/~4~(P-<^2-ethoxy-5-chlorobenzamido^>-ethyl)-benzene-sulfonyl_7-K''-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 195~196°C (recrystallized in methanol);

from 4-(P-<^2-ethoxy-5-acetylbenzamido^>-ethyl)-benzene-sulfonamide (melting point 197-198°C);

the ïf-/*"4-(p-<^2-ethoxy-5-acetyl-benzamido^>-ethyl)-benzene-sulfonyl_7-N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 168-169°C (recrystallized in methanol);

from 4-(|3-<^2-(3-methoxyethoxy-benzamido_~^>-ethyl)-benzene-sulfonamide (melting point 128-130°C)t N-/~4-(f3-<^2-|3-methoxyethoxy-benzamido^> -ethyl ^benzene-tallow onyl_7-N' -(2.4-dimethyl-cyclohexyl)-urea with a melting point of 164-165°C (recrystallized in methanol) and ÎT-/~4-((3-<^2-(3-methoxyethoxy-benzamido^> -ethyl)-benzene-sulfonyl_7-K'1-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 190-191°C (recrystallized in methanol);

5

10

15

20

25

from 4-(p-<"2-|3-methoxyethoxy-5~chlorobenzamidcr> -ethyl)--benzenesulfonamide (melting point 161-162°C):

the N"-/~4-((3-<C2-(3-methoxyethoxy-5-chlorobenzamido^>-ethyl)-benzene-tallow onyl_7-ÏT'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 163~164°C (recrystallized in methanol);

from 4-(2-methoxybenzamidomethyl')-benzenesulfonamide (melting point 190-191°C):

ET-/~4- (2-methoxy-benzamido-methyl)-benzene-suifonyl_/~ N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 210-211°C (recrystallized in methanol);

from 4-(|3-<^2-phenoxybenzamido^>-ethyl)benzenesulfonamide (melting point 187-188°C):

the N-/""4-(f3-<^2-phenoxy-benzamido_> -ethyl)-benzene-sulfonyl_7-N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 167-168°C (recrystallized in methanol) and the ÏT-/~4- ( (3- < 2-phenoxy-benzamido> -ethyl)-benzene-sulfonyl7-N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 148-150°C (recrystallized in methanol);

from 4-((3-<C3-methylbenzamidoJ> -ethyl)-benzenesulfona~

Mide (melting point 187-189°C):

N-/~4-(f3-<3-methylbenzamido> -ethyl)-benzene-sulfonyl7-N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 178-180°C (recrystallized in methanol);

from 4-((3-<^-methyl-3-methylbenzamido^>-ethyl)-benzene-sulfonamide (melting point 146°0):

the ÎT-/~4-(p-<N-methyl-3-methylbenzamido> -ethyl)-benzene~ sulfonyl_7-N'-(4.4-diethyl-cyclohexyl)-urea with a melting point of 141-142°C (recrystallized in methanol);

from 4-([3-<0«5-dimethyl-benzamido^> -ethyl)-benzene-sulfonamide (melting point 194-196°C):

N-/~4-(p-<^3»5-àiI&ethyl--benzamido^> -ethyl)-benzene-

- 55 -

sulfonyl_7-N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 202-204°C (recrystallized in methanol);

from 4- (|3-<.3-trifluoromethyl-benzamido^>-ethyl-benzene-sulfonamide (melting point 145-14-7°C):

N-/~4-(p-<^3-trifluoromethyl-benzamido>-ethyl)-benzene-5 sulfonyl_7-N,-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 185-187°0 (recrystallized in methanol) and N-/[""4-((B-<^ 3-trifluoromethyl-benzamido"> -ethyl)-benzene-sulfonyl 7-F'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 169-170°C (recrystallized in methanol);

10 from 4-(P-<T3-methoxy-thiophene-2 -carbonamide->-ethyl )-

benzene-sulfonamide (melting point 201-203°0);

the H-/~4-(|3-<[3-iiiethoxy-thiophene-2-carbonamido^>-ethyl)-benzene-sulfonyl7-Nl-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 175-176°C (recrystallized in methanol);

15 from 4-(|3-<3-ethoxy-thiophene-2-carbonamido^>-ethyl)-

benzenesulfonamide (melting point 177-179°C):

$T-/~4-((3-<T3-ethoxy-thiophene-2-carbonamido_^>-ethyl)-benzene-sulfonyl_7-N1-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 168-169°C (recrystallized in methanol);

20 from 4-((3-<3-benzyloxythiophene-2-carbonamido]>-ethyl)-

benzenesulfonamide (melting point 196-198°C):

N-/~4-(f3-<^3-"benzyloxythiophene-2-carbonamido"^> -ethyl)-benzenesulfonyl_/-N ' - (4,4-dimethyl-cyclohexyl ) --urea with a melting point of 181-182°C (recrystallized in a

25 mixture of methanol and dimethyl formamide);

EXAMPLE 22:

N-/~4-((3-<" 2-methoxy-5-chlorobenzamido^>-ethyl)-

benzene-suifonyl_7-N'-(2.4-dimethyl-cyclohexyl)-urea.

8.2 g of E-/4-(|3--<2~) are suspended.

30 methoxy-5-chlorobenzamido (ethylbenzenesulfonyl-7-urea)

- 56 -

(melting point 171-173°C) in 150 ml of dioxane and after the addition of 3.75 g of 2,4-dimethylcyclohexylamine acetate, the suspension is heated for 1 hour under reflux. The solvent is removed by distillation under reduced pressure, and water is added to the residue. The crystals of N-[4-(p-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(2,4-dimethylcyclohexyl)-urea are recrystallized in a mixture of methanol and dimethylformamide; they melt at 200-201°C. EXAMPLE 23:

N-[4-( (3-<T2-methoxy-5-chlorohenzamido^> -ethyl)-benzene-tallow onyl]-N'-(4.4-dimethyl-cyclohexyl)-urea e.

a) 5.6 g of 4,4-dimethylcyclohexylparabanic acid (melting point 182-183°C) (obtained by the reaction of 4,4-dimethylcyclohexylurea with oxalyl chloride) is heated for 90 minutes with a constant flow, along with 9.7 g of 4-(3-β2-methoxy-5-chlorobenzamido-ethyl)benzene sulfochloride and 2.5 g of triethylamine in 100 mL of benzene. The undissolved material is removed by hot filtration, and the crystals obtained are boiled with methanol after cooling the filtrate. After recrystallization in a mixture of methanol, dimethylformamide, and water, the acid 1-[4-(β2-methoxy-5-chlorobenzamido-ethyl)benzene-sulfochloride onyl]-3-(4,4-dimethyl-cyclohexyl)-parabanic melts at 196-197°C.

b) 0.5 g of parabanic acid obtained as described above is heated in 5 ml of dioxane and 10 ml of sodium hydroxide solution for 45 minutes in a steam bath. After cooling, water is added, the mixture is acidified, and the N-[4-(|B-<^2-methoxy-5-chlorobenzamidoJ>-ethyl)-benzenesulfonyl]-N'-(4„4-dimethyl-cyclohexyl)-urea is recrystallized in methanol (melting point 177-178°0).

- 57 -

EXAMPLE 24:

N- [4-( |3-<2-methoxy-5-chlorobenzamid§>-ethyl)-benzene-sulfonyl]-F'-(4.4-dimethyl-cyclohexyl)-urea.

1) Dissolve 2.9 g 5 of F-[4-(|3-<^2-methoxy-5-chlorobenzamido> -ethyl)-benzenesulfonyl]-F'-(4.4-dimethyl-cyclohexyl)-thio-urea (prepared by reaction of 4-C(3- <C 2-methoxy-5-chlorobenzamido> -ethyl]-benzenesulfonamide with cyclohexyl senevol in a mixture of dioxane and acetone in the presence of potassium carbonate) melting point 175-177°C (decomposition).

An aqueous solution of 0.7 g of sodium nitrite is added, and 15 mL of 5 times normal acetic acid is added dropwise while stirring at +5°C. After continuing to stir for another 2.5 hours, the acetone is removed by distillation. The residue is dissolved in dilute sodium hydroxide, the solution is clarified with bone black, and acidified. A crystalline precipitate is obtained, constituting F-[4-(f3~<"2-methoxy-5-chlorobenzamido^>-ethyl)-benzenesulfonyl]-F'-(4,4-dimethyl-cyclohexyl)-urea, which is extracted using a funnel and recrystallized in dilute methanol. The substance melts at 174-176°C.

2° a) 5138 S of F-[4-((3-<2-methoxy-5-chlorobenzamido-ethyl)benzenesulfonyl]-N'-(4,4-dimethylcyclohexyl)thiourea is dissolved in 5 ml of dioxane and 250 ml of 25 methanol. 2.16 g of mercury oxide is added and the mixture is stirred for 4 hours at 60°C. The mercury sulfide that has formed is removed by filtration, the filtrate is concentrated to half its original concentration, and water is added. After allowing the mixture to stand overnight, a crystalline precipitate is obtained, which is then extracted using a funnel and recrystallized.

- 58 -

in dilute methanol. The methyl ether of B-[4-(|3-<C2-methoxy-5-chlorobenzamido>-ethyl)-benzenesuifonyl]-N'-(4.4-dimethylcyclohexyl)-isourea thus obtained melts at 149-15'10C;-

b) 0.5 g of isourea ether obtained as described in 2 a) is dissolved in 5 ml of dioxane. After adding 20 ml of 2N sodium hydroxide solution, the solution is heated for 45 minutes in a steam bath. Acidification yields a crystalline precipitate constituting N-[4-(3-<^2 -methoxy-5-chlorobenzamid(i> -ethyl)-benzenesulfonyl]-N'-

(4,4-Dimethylcyclohexyl urea with a melting point of 174-176°C after recrystallization in dilute methanol. Example 25:

N- [4-(|B-bBnzamido-ethyl) -benzene-tallow onyl] -N' -( 4.4-diethyl-cyclohesyl)-urea.

a) 6.4 g of the sodium salt of 4-(3-benzamidoethyl)benzenesulfonamide and 7.2 g of methyl ester of 4-[(3-benzamidoethylbenzenesulfonyl]carbamic acid] are thoroughly mixed. The substance is introduced into a 300 mL Erlenmeyer flask so that it covers the bottom of the flask. The flask is then placed in an oil bath preheated to 250°C.

After a few minutes the mass begins to clump together and after another 5 minutes it solidifies again.

The reaction mass is allowed to cool, the cake is treated with approximately 1% aqueous ammonia, filtered, and the filtrate is acidified with dinormal hydrochloric acid. A crystalline precipitate is obtained, constituting N.N'-di-4-[p-(benzamidoethyl)benzenesulfonyl]urea, which is dissolved again in dilute ammonia and precipitated again by acidification with hydrochloric acid. After dewatering with a funnel and crystallization, the substance melts at 204°C with decomposition.

-59 -

b) 3.17 g of the bis-urea obtained as described in a) is suspended in 100 ml of dioxane. While stirring, 0.78 g of 4,4-diethylcyclohexylamine is added and salt formation is observed.

Next, the substance is heated to boiling point while stirring. After a few minutes, the suspension has changed into a clear solution.

It is concentrated under reduced pressure, the residue is treated with approximately 1% ammonia and filtered. Acidification of the filtrate yields a crystalline precipitate of N-[4-(p-benzamidoethyl)benzenesulfonyl]-N1-(4,4-diethylcyclohexyl)urea*. After recrystallization in methanol, the substance melts at 199-201°C.

EXAMPLE 26:

N-[4-(- <^-methoxy~5-bromobenzamido> -propyl)-benzene-sulfonyl]-U'-(4.4-dimethyl-cyclohexyl)-urea e.

9 S of sodium salt of 4-(α-2-methoxy-5-bromobenzamide-propyl)benzenesulfonamide and 16 g of U.N-diphenyl-N'-(4,4-dimethylcyclohexyl)urea are heated in 30 mL of dimethylformamide at 100°C for 7 hours. The mixture is allowed to cool, water and an alkali are added, and the resulting diphenylamine is extracted with ether. The aqueous phase is treated with bone black, and the filtrate is acidified. The suifonylurea is recrystallized from a mixture of methanol and water. It melts at 192°C.

Similarly, we obtain:

N-[4-(Y - <2-methoxy-5-bromobenzamidc£> -propyl)-

benzene-sulfonyl]-N'-(2,4-dimethyl-cyclohexy1)-urea with a melting point of 184°C (recrystallized in a mixture of methanol and water),

- 60 -

N~[4-('|3-<^2-methoxy-5-chlorobenzamidcî> -propyl)-benzenesulfonyl]-N'-(4.4-dimethyl-cyclohexyl)-urea with a melting point of 153°C (recrystallized in a mixture of methanol and water),

N-[4-((3- <2-methoxy-5-chlorobenzamido> -propyl)-benzenesulfonyllrN'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 181°C; (recrystallized in a mixture of methanol and water),

N-[4-((3-naphth- <^l > -amido-ethyl)-benzene-sulfonyl]--N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 216°C (recrystallized in a mixture of methanol and water) and F-[4--(|3-tetraline-carb~<2 '^> -amido-ethyl)-benzene-sulfonyl]-N'-(2.4-dimethyl-cyclohexyl)-urea with a melting point of 167°C (recrystallized in a mixture of methanol and water).

EXAMPLE 27:

N-[4-((3- <2-methoxy-5-chlorobenzamido> -a-methyl-ethyl)-benzene-suifonyl]-N'-(4.4-diethyl-cyclohexyl)~urea.

9.6 g of 4-( (3-<^2-methoxy-5-chloro-

benzamido-α-methylethylbenzenesulfonamide is dissolved in 250 ml of dioxane. 6.9 g of finely powdered potassium hydroxide is added, and the mixture is heated to a boil for 2 hours, stirring continuously. While continuing to stir, the remaining potassium hydroxide is added dropwise.

4.5 g of 4,4-diethylcyclohexyl isocyanate. The [material] is heated during [time period].

It is left to stand and stirred for another 8 hours, then poured into water and acidified. The resulting crystalline precipitate is extracted with a trumpet and dried. It is dissolved in dimethyl-formamide, methanol is added, and a crystallization product is obtained, constituting N-[4-((3-<2-methoxy-5-chlorobenzamido> -a-methyl)-ethyl-benzene-sulfonyl]-iP-(4.4-diethyl-cyclohexyl)-urea with a melting point of 161-163°0.

Claims (1)

SUMMARY The present invention includes in particular: 1) As novel industrial products, benzenesulfonyl ureas conforming to the formula I X-CO-N-Y- phenylene - S02 - NH - CO - NH - R1 (Z) I R in which R denotes a low molecular weight alkyl group, a low molecular weight phenyl-alkyl group or, from (a) a cyclohexyl group bearing two substituents chosen from the set comprising the methyl group and alkoxy groups containing 1 or 2 carbon atoms, (b) a chloro-cyclohexyl group, (e) a 4-methylcyclohexenyl group, (f) a dimethyl-cyclohexyl or 4,4-diethyl-cyclohexyl group, X designates (a) a phenyl remainder bearing in any positions the following substituents Z and Z', identical or different from each other; Z denotes hydrogen, a halogen atom, a low molecular weight alkyl group, an alkenyl group, alkyl alkenoxy, halogen-alkoxy, alkoxy-alkoxy, phenyl-alkoxy or phenyl-alkyl, cyclo-alkoxy, phenyl, phenoxy, acyl, preferably hydrogen, R"*" denotes: (c) a spiro group [5.5] u (d) an exo-tricyclo group 9 10 - 62 - low molecular weight, benzoyl, trifluoromethyl, hydroxy, low molecular weight acyloxy, -CN, -NO^, 2' denotes hydrogen, a halogen atom, a low molecular weight alkyl group, an alkoxy group, alkoxy-alkoxy, acyloxy or hydroxy, (b) a naphthyl residue which may bear one or two substituents taken from the set comprising halogens, low molecular weight alkyl groups, low molecular weight alkoxy groups and the hydroxyl group (c) a tetrahydronaphthyl or indanyl residue, (d) a thiophenyl remainder which may bear one or two substituents selected from the set comprising low molecular weight alkyl groups, phenyl-alkyl groups, alkoxy, alkoxy-alkoxy, alkenoxy, phenyl- 15 alkoxy, aryl and halogen compounds, (e) a tetramethylene-thenyl or trimethylene-thenyl residue, the definition of X given under (a) being preferred, and Y denotes a hydrocarbon chain containing 1 to 3 (aoy and their salts) 20 ^ carbon atoms, preferably the -C^-CFi^-*/ group 2°) The following varieties of benzenesulfonyl- specified under 1°; a)' N-[4-(p-<2-methoxy-5-fluoro-benzamido^>-ethyl)- benzene-sulfonyl]-N'-(4.4Tdimethyl-cyclohexyl)-urea; 25 b) N-L4-(p-<^2-methoxy-5-chloro-benzamido^>-ethyl)~ benzene-suifonyl]-N'-(3.4-dimethyl-cyclchexyl)-urea; c) N-[4-( {3- <l2-methoxy-5-chloro-benzamido^>-ethyl)-benzene-sulfonyl]-N'-(4-chloro—cyclohexyl)-urea; d) the N-[4-(p-<^2-methoxy-5-chloro-benzamido^>-ethyl)-30 benzene-tallow onyl] -N ' - ( 3-methoxy-4-methyl-c~yelohexyl)-urea. - 63 - 3°) A process for preparing the benzenesulfonylureas specified in 1° and 2°, according to which a) amines bearing the substituent are reacted -] R, or their salts, with benzene-suifonyl isocyanates, 5 of the esters of benzene-suifonyl-carbamic acids, of the esters of benzene-suifonyl-thiocarbamic acids, of the halides of benzene-tallow onyl-carbamic acids, of benzene-rrhalf onyl-ureas, of benzene-suifonyl-semicarbazides or of benzene-sulfonyl-semicarbazones bearing the substituent 10 X - 00 - N - Y - i R b) Benzenesulfonamides of formula are reacted X-CO-N-Y- phenylene - SO2 - NH2 R 15 or their salts, with isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas bearing the R substituent; c) Hydrolysis of benzene-suifonyl-iso-urea ethers, benzene-suifonyl-iso-thio-urea ethers, esters 20 of benzene-suifonyl-iso-ureas, benzene-suifonyl-parabanic acids or benzene-suifonyl-amidines of halo-formic acids; - And- - d) in benzene-suifonyl-thioureas bearing corresponding substituents the sulfur atom is replaced by an oxygen atom; e) water is fixed onto carbodi-imides bearing 5 of the corresponding substituents; f) benzene-suifinyl-ureas or corresponding benzene-tallow enyl-ureas are oxidized; g) in benzenesulfonylureas of formula HN-Y-phenylene-SO2-NH-CO-NH-E1 10th we introduce the rest X - CO - by acylation in one or more reaction phases; h) Benzene-sulfonyl halides 15 bearing corresponding substituents are reacted with ureas bearing the substituent E. (i) in thio-amido-alkyl-benzene-sulfonyl-ureas or thio-amido-alkyl-benzene-sulfonyl-thioureas bearing corresponding substituents, the atom or 20 sulfur atoms per -one or more oxygen atoms; j) where E represents a hydrogen atom, compounds of formula are hydrolyzed X-C=N-Y-phenylene-SO2NHC0NH-E1 ù 25 or their parabanic acid derivatives, or compounds of formula Xr-C =N-Y-phenyl ene-S0~NH-C =N-E1 i \ U U formulas in which U denotes in each case one of the lower -O-alkyl groups, lower -S-alkyl groups, or an atom 3D halogen, preferably chlorine; f - 65 - if k) in the case where R does not designate the methyl-cyclohexenyl group, we hydrogen the corresponding "benzene-sulfonyl-ureas" containing in the molecule unsaturated bonds, and where appropriate we treat the reaction products with 5 alkaline agents to obtain the salts. 4°) A process for preparing pharmaceutical compositions having hypoglycemic activity, administrable by the oral route in the treatment of diabetes mellitus, a process in which one of the benzenesulfonyl ureas specified under 10 1)+) is put as the active substance, where appropriate with adjuvants and excipients customary in pharmacy, in the form of suitable dosing units. 5°) Pharmaceutical compositions having hypoglycemic activity, administrable by the oral route in the treatment of diabetes mellitus and containing one of the benzene-sulfonyl-ureas specified under 1°) or one of their salts, as active substance, and the usual adjuvants and excipients in pharmacy. 6°) Method for lowering blood glucose in the treatment of diabetes mellitus, a method in which an effective quantity of one of the ureas specified under 1) or one of their salts is administered to the patient orally. +) or one of their salts. O R î A L in JUL. pages _____ containing References - - ^ o i 1 o t i i ——.— r"*c£ rsyo null J C Ù R A U "Industrial Property Consulting, 28 Princess Churchill Blvd., 28 montç.çarw «"ar prowj ri * -ors 4a r mvu/MJzsc /Ç^ ;