DE1568626A1 - Benzenesulfonyl ureas and process for their preparation - Google Patents

Description

PAKBWiMiKE hCKCiiST AG, in front alii Keistcr Lucius C-. Pruning

File number: P 15 68 626.? - Fw 5229

Date: . July 22, 19o9 - Dr Li/ö3.

Benzene sull'onyl-urnüt of fe and procedure :: u your ! lere Ire} l unr:

The invention relates to Benzolsulfonyl-urn.'3toi.'fü the formula

■ CQ-lftl-CH ^ -üHjp ^ Jr "SOg-ÜH-CO-i ^ i-R OR

those as a substance or in Γογπί their salts Eißenschartoii own and the eich by a strong and compensate for a long-lasting decrease in blood sugar levels.

In the formula mean

R methyl or.-Ithyl,

X hydrogen; Fluorine, chlorine or bromine, above ^ usr.v / eise ohlo

Methyl or kethoxy;
r ' ¹ endociethylenecyclohexyl, enaomethylenecyclohe: -: enyl, 2ndo

ethylene cyclohexyl, endoethylene cyclohexenyl

The substituent X is located in A-- or preferably 5-position to the carbonanide group.

In the definitions above and below, no alkyl or lower alkenyl always stands for such n ± t 1 carbon atoms in a straight or twisted chain.

009810/1726

According to the definitions given above, harm Ii mean, for example: methyl, ethyl, pro _; . = yl, isopropyl, butyl, isobutyl, t ^ r'z. Lutyl, allyl.

R can in particular mean: 2,5-L ^: ridoKethy ± er.cvcloi! Exonyi, 2,5-endomethylene cyclohexy! , 2,5-Endoaeth3.rlGr.icycJ.ohoxyl, 2,5-i.ndoaethyleiic ,, -: '. Iohexenyl.

The invention also relates to a process for:. * Production the fjCnamed lionzoloulfonyl-urinntoffo. The procedure is characterized in that nan

a) with the group

uenzenesulfonylisccyanate substituted in p-3tellunr, -carbai.iinsäureester, -thiolcarbarjinsllureestcr, -ureas, -semicarbazide or -semicarbazones i:> it R -substituted Converts amines or their salts,

b) Benzolsulfonanide der I'orir.el

V CO-N-CH ₀ -CH ₀
\ / j 2 2

or their salts with R -substituted isocyanates, Carbaic acid esters, thiolcarbanine lure esters, carbamic acid halides or converts ureas

c) appropriately substituted benzoisulfonyl isourea ethers, -isourea ester, -isothioureaether, -pära-

■> '' ■ - ■■; - - ϊ

009810/1726 ßAD OFUGINAL

^; ■ .. ■■. - 3 .- ■

bansruren or haloenaneic acid amidines hydrolyzed,

d) adds water to appropriately substituted carbodiimides,

e) in 'correspondingly substituted benzenesulfonyl-thioureas the .Schulfelatom exchanged for an oxygen atom ,

f) corresponding benzenesulfonylureas in the molecule unsaturated bonds contain hydrogenated,

s) inbenenolsulfonyl ureas of the formula

by acylation, if necessary in stages, the P.est

introduces

and the seaction products optionally with salt formation treated with alkaline coats.

The mentioned BenzOlsulfonyl-carbaiHinsaureestGr bzv /. thiolcarbamic acid ester can be an alkyl radical or an aryl radical or a heterocyclic group in the alcohol component Hest exhibit. Because this residue is split off during the reaction its chemical constitution has no influence on the ghar acter of the end product and can therefore be varied within "wide limits. The same applies to the R -substituted carbamic acid ester or the corresponding thi oil carbamic acid ester. "" '

0 09810/1726

As Carbaininsüurchalogenide see in harvest line the Chlorides.

The lenzenesulfonyl ureas which are suitable as starting materials for the process can be unsubstituted or monosubstituted, in particular doubly substituted, on the side of the urea molecule facing away from the oulfonyl group. Since these substituents are split off in the reaction with amines, their character can be varied within wide limits , which on one of the stickstoffatoi; .o another substituent, z. Yy. Methyl, can carry, use. For example, Kan can treat such ice (benzenesulfonyl) ureas or II-benzenesulfonyl-II'-acylureas with amines R -IUIp and heat the salts obtained to elevated temperatures, in particular those above 100.degree.

It is also possible to use ureas of the formula R ¹ -HH-CO-HH ₂

or of those ureas which are still mono- or, in particular, doubly substituted on the free nitrogen atom, to go out and this with

CO-NH-CH ₂ -CH ₂ -

to implement in p-3tellurig substituted benzenesulfonamides. Such starting materials come, for example, in embossed N-endomethylene-cyclohexyl or ii-endomethylene cyclohexenylurea, the corresponding IF-acetyl, i? ¹ -nitro-, N'-endo-

009810/172 6 '' "'

SAD ORJGiNAL

156B626

methyleiicyclohexyl-, 17'-endomethylenecycloheicenyl-, II ', 11' -diphenyl- (whereby the two phenyl radicals are also substituted and directly or also via a bridging link such as -CiIp-., -KH-, -0- or -S- vex -bond), N'-Hethyl-l] '-phenyl-, iv' ~, N '-Dicyclohexyl-urstofTe as well as R ¹ -sub:
azoles.

H -substituted cyclohexyl-carbar-ioyl-imidazoles or -tri-

The hydrolysis of the benzenesulfohyl-jjarabanic acids mentioned as starting materials, -isoureaether, -isothiourea- ether, -isournst of solid or -haloEenarneisensäureair.idine . Successful U: zv / square in alkaline I-iediun. Isourea j. "- ether and isourea esters can also be used in an acidic Hedium can be hydrolyzed with good success.

The replacement of the sulphurizer by an oxygen atom in the appropriately substituted benzenesulfonyl thioureas can be used in a well-known way, for example with the help of Oxides or salts of heavy rivets or by application of oxidizing agents, such as hydrogen peroxide, uranium peroxide or nitrous acid.

The Thio-urstofxe can also be desulfurized by grounding “Treatment with phosgene or phosphorus pentachloride, Als Intermediate obtained chloroformic acid amidines or; Carbodiimides can be removed by suitable measures such as saponification or by adding water to the benzene sulfonylureas.

Appropriately substituted benzenesulfonyl urea, the contain an unsaturated bond in the molecule, e.g. B.

00981071726 ■ -

BATH

can by hydrogenation, ζ. L. mix- i :: olel.ulare :: NassereΙοΓΓ, in the presence of a well-known Hydrioruri_Gka-ualj \ -; aLorc, in The revised LenzolsulfonyliiurnsuofiO transferred will.

The acylation of Aränoüthyl-benzoisulfonyl-hary'r / uof_en can onüv.'c-cicr in a · ::; ochritfc, e.g. L. by dissolving an appropriately substituted. As an example of the numerous. '! Possibilities of a step / iron acylation are the conversion of Aninoäöhylbenzenesulfonylurstofi'cr; with 2-I-ethoxy-benzoyl chloride and the subsequent introduction of a halogen atom into the lenzene nucleus of the 3enzamido group .

The embodiments of the method according to the invention can generally with regard to the reaction conditions largely varied and adapted to the respective conditions. For example, the conversions in Absence or presence of solvent oils, at room temperature or be carried out at an elevated temperature.

Depending on the character of the raw materials, one or the other other of the processes described in detail! 'all a desired individual benzenesulfonylurea only in deliver low yields or be unsuitable for its synthesis. In such cases it does not matter to the reporter Difficulties in synthesizing the desired product by any other of the routes described.

As starting materials one verv / ends those compounds that in p-position one with the group

009 810/1726 bad original

CO-KH-CiI ₂ -CH ₂ -

OR

contain substituted benzene nucleus, As an example of the component

this formula

sexen

in particular the following are mentioned

OCH ₅

CO-

GCH ₅

CO-

OCH,

CO-

OC ₂ H ₅ H ₇₁ C

GO-

H ₅ C

"\ -co-

CO-

OCH ₅

0098 107 1726 BAD. ORIGINAL

Q-CO-

H ₃ CO

CO-

CO-OCH ^ C ₂ H ₅ O

Q-CO-

CH

Cn) C ₃ II ₇ O

H ₇ CQ-CH-,

CO-OCH,

OCII ₃ H ₃ CO

CO-

1st floor _D H

C ₂ II ₅ O

CO-

C ₂ H ₅ O

OC. ^ H

'-CO-OCH

ii ₃ approx

CO OCH, ^ C

OCH-

CO-

CO-'OCH,

Cl

CO-Cl

00-

OC ₃ H ₇ (II)

Br

00-

0098 10/1726 BAD ORIGINAL

⁰¹ v_ / ^co ~ οι - / _ Λ-σο-

(DCH (CH ^) ₂ OGH _5. ^Νϋσ 2 ^Π 5

Cl _ / y. CO-

OCn ₂ CH = CH ₂

The blood sugar-reducing effect of the described Eennol As a result, sulfonyl urine derivatives could be solid (. 'esttillfc to be sold in doses of 10 nig / kg "'in rabbitons feed and the blood sugar level according to the known Hagedorn-Jensen method or with an auto analyzer determined over a longer period of time.

For example, it was determined that 10 mg / kr of the N-_f "4- (ß- <2-ketho;: y - $ - bromobenzanido) ethyl) -benzenesulfonyl J N ^l - (2 ₁ 5-endomethylene cyclohexyl) -ureas after 3 hours cause a blood sugar senloing of 35 ^ j after 24 hours of 26 j ^ and after 48 hours of 18 ^c , 6 .

It was also determined that 10 mg / kg of the Ν - / "4- (β- <2-methoxy-5 ^w clilor-benzamido> -ethyl) -benzenesulfonyl_7-ii '- (2.5-01 ¹ ClOnIe ethylene cyclohexyl) - harnst of fs after 3 hours lower blood sugar u © 32 £>, after 24 hours at 43 c "after 48 hours at 28 ° J>, and even after 72 hours in order. 14 ^c £, while the known ΙΪ- (4 -i: ethyl-benzenesulfonyl) -N'-butyl-urea at a dose of less than 25 mg / kg in rabbits no longer causes a lowering of the blood sugar level *

. . - ■ - '■ JC

BAD QBIGtNAL

00981071728

- ίο -

The strong effectiveness of the described Lcy urinstolTc is particularly clear, v; enn:.: To the i; on.ir; v.'oi · ter decreased. One submits the \\ - £ ^l \ - (£ - <2-Kefch o; -: i ~ - 5-broir.-bensar: iido>-ätli,> l) -bc :: zolsuliOnyl JW '- (2, 5-endo-ethylene-cyclohi: xyl) -urea in a dosage of C, 1 ms / kü odi.T den ü- £ ~ i \ ~ (ß- (2 - ;. eL-i: c: -: y-5 -chlor-bonaariido> ethyl) -benzolDuiron, yl_7- .. '- (^, ^ - enuoi.iGthj-iencycloiiO.-yi) -harneborf in a dosage of ü, u6 me / k ^; oö.er den

sulf onyl _7-i! '- (2,5-endoi: .eüh one. Dosierun :; from ü, C & nz still a clear i-Juü

lenc; -clohcxvl) -urea Γ i "6 an KanincLen, :: o is ir. crcenl-un ^ rc-stzuotollen.

Further information on the blood sugar lowering 'Jirksex.keii; the following table shows the connections:

TABEL

K 10 means blood sugar lowering effectiveness ara rabbits in percent with peroral application of 10 mg of substance per kg test animal.

substance

K 10 after 1 3

24 hours

- (β- (2-I] ethoxy-benzaraido> -äthyl) -benzenesulfonyl_7-N '- (2,5-endomethylene cyclohexyl) urea 13

22 25 2?

N- / "4- (ß- <2-Hethoxy-4-chlorobenzamido) -ethyl) -benzenesulfonyl_7-1, '- (2,5-endomethylene-cyclohexyl) -urea 21 27 28

0 0 9810/1726

BAD ÖFUG / NAL

1-10 after 3; -6- ' ·

met] iylen-cycloliexyl) rii3.rnst; orf -:. 25 21 .. 16.15-

-öyclohexyi ^ -liaFiistoff "- ..""10 26 - " 23 ' aOiGuIxOXIyI _- Z-H' - (2,3-eii

. 26 28 $ 0

ätliylj-bensolsulfonyl _7-K ^r - ( _: 2 _r 5 _ς

Eietliylen-cyelohexylv-liarnstoxf '-' 23 * 2? 22 9-

Raethylene-GyclGliexyD-Liarstoff; m 22 22 8

ethyl) -benzolsrtlfonyl_7- »N '- ^ 2 _: 5-c
methylen- £ 5-cyclohexenyl>-liai'iistbi ^v f ■ '"-19 20.-v ^ - 26

äi3liyl) -benzalsulfonyl_7 - ^ * ^I - (2,5-öndo --... - - -. ■■, - - -. ■ '. i) J ^! . Λ0 : 32-25 '

len-cyeloliexyl) -liarnea 26 19 2? 29

0 0 98 1 07 17 2B3. - - - · ^:

BATH ORIGINAL

The benzenesulfonyl ureas described should preferably for the production of orally pre-dispensable preparations With blood sugar-lowering effectiveness for treatment of diabetes mellitus and can serve as such or in ΐοηη their üalts or in the presence of substances, which lead to the formation of salt, have been applied. To the Particularly suitable for salt formation are alkaline agents such as alkali or lurodalkali hydroxides, carbonates and bicarbonates.

Tablets are preferably used as medical preparations, each of which, in addition to the products of the process, contains the common auxiliary and carrier substances such as talc, starch, Contain lactose, tragacanth or magnesium, stoarate.

A preparation containing the benzenesulfonylureas described as active ingredient, e.g. B. a tablet or a powder with oier without the additives mentioned is expediently brought into a suitably dosed form. The dose to be chosen is one which is adapted to the effectiveness of the benzenesulfojiviurea used and the desired effect. Advantageously, the dosage per unit of about 0.5 to 1GO mg, preferably 2 to 10 mg, but can also significantly above or below Dosierungseiniieiten be used to divide the BZV optionally \ ^r or application /. are to be multiplied.

example 1

~ (ß- <2-IIethox.y-5-chloro-benzamido> -äth7 / l) -benzenesulfonyl IV - (2, ^ -enaoraethylene cyclohexyl; -urea .... '

4.2 g N- / ~ 'l ~ (ß- <2-Iiethoxy-5-chlor-benzamidd> -äthyl) -benzene! - sulfonyl_7-methyl urethane (melting point 189 - 191 ° C)

009810/1726 bad oracW

^{; ; : J} 1568826

suspended in 100 ml of dioxane and "after adding 1.2 g of 2,5-SndornGthylenecyclohexylamine heated to 110 ° G for 1 hour. On cooling, crystallized; the formed I - ^ /" 4- (ß- <2-Iiethoxy-5- chlor-benaaEiido> -äthyi) -benzolsuiroiiyl J- N ¹ - (2 ^ -endomethylene-cyclohexyl) -urea, which after recrystallization from! -ethanol melts at 187-189 ° C.

In an analogous way one obtains

from the K- / "4 ~ (β- (2-kethoxy-4 ~ chloro-benaaniido). -ethyl) -benzenesulfonyl-7-methyl urethane (Israel point 1? 8 -18 ° C)

den l's ^r - / 7 ^ - (ß- (2Wiethoxy - '' l - chlorobenzamido) -ethyl) -benzenesulfonylj -li '- (2,5-endomethylene-cyelohexyl) -urea with a melting point of 203 - 205 ° C ( from methanol);

from the N - / "4-Cß- (2-iLthoxy - 5-chloro-benzaiiiido) -ethyl) -benzenesuifonyl_7-methyiurethane (melting point 203-205 ^ό " C)

the N ^ / "4- (ß- <2-ethoxy-5-chloi.« benzaniido> - ethyl) -benzenesulfonyi _, 7-Ν * - (2,5-endome thyiencyclohexyl) urea from melting point 158-160 ° C (from methanol);

from the N- / ~ ^ - (ß- <2-Hethoxy-5-bromo-ben2amid.o> '- ethyl) - benzenesulfonyl_7-methyl urethane (Melting point 197 - 199 ° C)

the ri - / "4- (ß-i2-methoxy-5-bromo-benzamido) -ethyi) -benzolsulfonyl JT-ti '- (2,5-endoiae ethylene cyclohexyl) -urea of melting point ^{171-172 σ} C (from ethanol / Dimethylformamide) j

from the BT- / ~ 4- (ß- <2- methoxy-5-methyl-benzamido> -ethyl) -benzene sulfonyl J ^ -methyl urethane (melting point 175 - 177 °

den K - / "4- (ß - (2-l> iethoxy-5-methyl-fc € maaffiido> -a1 ^ l·l- ^ sulf onyl_J-N '- (2,5-endomethylene-C7clohexyl> -harns-tαff

- ■■ - [ from melting point 191-193 ° C- C from methanol / dimethyl-

Q 09 S ta / Mti ^: ~ "■■ '■■'" BAD ORIGINAL

from the: .- / * 4- (ß- (2,5-üin! cthoxy-benzainiäo> -äthylJ -benzenesulforiyl_ / -niethylurethar. (ochnielz point 173 ~ 1? 5 ° C)

the i; - / ~ 4- (ß- (2,5-DiEiethoxy-benzai: .ido) -utyl) -benzenesulfony! _7-K ¹ - (2 _v 5-endoniethylGncj ₎ -clolie :: _< >'l)-harnsi; Off vom Schmolz - "point 163 -165 ° C (from methanol) -; ·" .. ".." .

from your N- / ~ 4- (ß- <2-I.ethöxy-benzarnido) -ätr.y 1) -bsnzolsitlfonyl ^: J- iaet: ylurethan (melting point 174 - 176 C) ". ■ ·

den N - / "4- (ß <2-i: othoxy-bc-nzar.: Luo> -äthyl) -bur.zolsuli ^> onyl_7-H ^l - (2,5-endoi.iethylenecyclohe :: yl) -liarnstofi 'from CchniGlzpunkt 197-1 ^: 98 ^Ql Ö' (from methanol);

from the H - / "4- (β- <2-i; etho; -: y-5-fluoro-benzane: ido) -ethyl) -benzenesulfonyl_7-methyl urethane (oil melting point 171 - 173 ° G)

the N - / "4- (β- <2-methoxy-5-fluoro-benzamido) -lithyl) -benzenesulfonyl JW '- (2, ^ -endoraethylene-cycloh;: yl) -liarnea of melting point 206-207 ° G (from KethanolZDiroethylformamide).

Example 2

N- _l 4 "4- (ß- (2-Hethoxy-5-fluoro-benzamido) -ethyl) -benzenesulfon.yl_7 -Ii '- (2, ^ - endornethyienc.yclohexyl) -urea f

6 g 4- (ß- <2-methoxy-5-fluoro-benzamido) -ethyl) -benzenesulfonamide (Schnelz-Öünkt 167-169 ° C) are dissolved in 8.5 ml 2 ή sodium hydroxide solution and 50 ml acetone and at 0 - 5 ° C dropwise with 2.5 S 2.5-2ndomethylene cyclohexyl isocyanate added. Ilan. Leave to stir for 3 hours, water and methanol are added, undissolved material is filtered off and the piltrate is acidified with dilute hydrochloric acid. The precipitated I7- / ~ 4- (β- (2-methoxy ~ 5-fluoro-benzainido) -ethyl) -benzenesulfonyl J-Yi '- (2,5-endomethylene-cyclohexyl) -urea melts after recrystallization from i -Iethanol / DimethylformaEid at 206 - 207 ° C ".

0 0 9810/1726

BAD OFUGfNAL

Example 3,,

N- / ~ 4- (ß- {2-i cL-ho ::. Y - ^ - chlor-bensanido) -p-tliyl) -bcTi ^ ol-

2 GI - 'Z ~ ^z l (ß <second-Hcihp: - y-5-cl ^"t--Lor _bcnza. Ido) -ütii;>' l) - bcnzolsulf onyl_7-r! '- (2, 5-endoirietkylenecyclohexyl) -thiourea (prepared from 4- (ß- <2-Iietiiox;r-5-chloi'-bGnaaiaiGo)-iL'chyl) -benDolsulfonar.id and 2, i; -

by lioclien in Acelcii in Gegciiv.'Q.rt of K carbonat ur.tc, for several hours:, 15 & - 160 ° C, (from dilute methanol)) v / ground in approx ml of dioxane dissolved. After adding 5 nil 35 pigments / ash hydroxide, the mixture is heated. About 20 minutes into the water bath. Kacli the cold one süuei't. \ / x> \ "erhtlt a crystalline filling, .the UAN sucks, in about 1 # Issen ijp.:::onialc dissolves and after i'iltration by acidification ausfi'llt again. Ler thus obtained crude Z £ ^l \ - (ß- <2-i-X'thoxy -> - cl: lor-bcnzariido) -ethyl) -benzenesulioiiyl JU '- (2,5-cndomethylon-cyclohexyl) -urstoi'i "closes after recrystallization from methanol 186 - 188 ° C.

example

nyl_7-K '- (2,5-endoKethylene-c: y clohe :: yl) -ur3tof f

a) 1 g ΐΐ- / ~ 4- (β- (2 ~ I-: ethoxy-5-chlorobensacido> -ethyl) -benzoisulfonyl_Z-H '- (2,5-endoraethylene-cyclohexyl) -thiourea (vei- gl · Eeispiel 3) is dissolved in 50 nl Methaiiol IIact ■ addition of 0.5 g Quecksilberoxr / d and _something; .Kaliumcarbonat erh.ix.zt ntan stirring 4 hours at 50 - 60 ,, ^, C... It is filtered, concentrated and crystallized from thinned

0 0 9 810/172 6

Dor go obtained iT- £ ~ 4- (ß- <2-I.ethoxy-i) -chlorobcnaar.iido> -ethyl) -ben2ol. ':. uiroriyl JW ' - (L ³ , ^ -eridornctbylcncyclohexyl) -ifjourea- : .iethylütlier melts at 118 120 ° C.

0.1 β of the ^{i J roduktü.'j obtained according to J} V a) are heated in 2 ml of dioxane and 1-0 ml of concentrated jaizcilurc for 20 minutes on the steam bath. The product obtained after pouring into water is acidified and made from dilute . ethanol u;.: crystallized. The melting point of the N- / ~ 4- (β- <2-Lcthoxy-5-Cjilor-benzane: ido> -ethyl) -bcnzo: ^t - -Ii '- (2,5-endomethylene-c, yciLohexyl ) -harnctof i.'s

1Ü6 - 188 ° C.

The same product is obtained by alkaline saponification of the Isoharnstofi'-Uthors prepared according to 4 a) 1-hour heating with 2N sodium hydroxide solution on the steam bath. "..

example

nyl J-W '- (2,3-ondorrict?: Ylen-cyclohexyl) urea

a) 0.5 ε endomethylene cyclohexyl parabanic acid (melting point 11 - 113 ° C from dilute methanol) v / earth in 30 ml Dissolved benzene; raan gives 0.4 g of trimethylamine and 1.5 g 4- (β- <2-Iiet :: oxy-5-chloro-bfcnzainido> -ethyl) -bonzenesulfonic acid chloride and heated to boiling under reflux for 2 1/2 hours. It is concentrated in vacuo, added. the residue obtained is ir.it water and triturated. the Substance crystallizes after standing for some time. It is filtered off with suction, washed with water and made from ethanol / dioxane

0098 10/1726 BAD

recrystallized. The Λ- £ '\ - (ß- <2-l..otho; -: y-5-chloro-bc \ nzamiao.> -Ύ uhyl) -bonzoisulfonyl _7-3- (2,5- & ndoniethylen- cycloiiexyl) parabanic acid melts at 227 229 ° C. *

b) The product obtained according to 5 &) is in a little üio :: an and 2n sodium hydroxide solution and the solution for 4-5 minutes on the Steam bath heated. Wake up to a cold, diluted uan r.; It \ / aoser and siluerb an. The Erlialbone r.iedernchiy. :: from

sulfonyl_7_ _r i ^l - (2,5-endOi..eühylon-cyclohe :: yl) -har-irjtoi'f schiiiilst after recrystallization from ethanol · / 'varser at 186 -. 1B8 ° G.

BeisoxqI 6

(2 _% ^ -endomethylerq-c.yclohexen- (^) -yl) -urea

5 Q 4- (ß- <2-IIethoxy-bensaniido> -äthyl) -benzolsuifonaniid (SchEielzpunkt 178-180 ° C) are dissolved in 7.5 ml of 2N sodium hydroxide solution and 50 ml of acetone and 2.1 g of 2.5 -Endoniethylen-cyclohexen- (3) -yl-isocyanat at ^0-5 ° C. added dropwise. After 2 hours, it is diluted with water and methanol, the solution is filtered and acidified with 2N hydrochloric acid. The precipitate is filtered off with suction, after recrystallization from methanol one obtains the. N- / ~ 4- (β- <2-Ilethoxy-ben araido) -ethyl) -benaolsulfonyl J7-N '- (2,5-endOEiethylenecyclohexen- (3rd) - yl) -urea "from the melting point 189-190 ° C.

In. analogous way one obtains the

- (ß- <2-kethoxy-benzamido> -ethyl) -benzenesulfonyl J-II '(2,5-endoäthylenecyclohexen- (3) -yl) -urea, melting point

0 0 9810/1726. "FiSAD OWQINAL

184 - 186 ° G also methanol.

ii_ / ~ 4_ (ß_ <2 - :; othoxy-ben3a!:. ido) -i; t; hyl) -ocn ^ oiGuiL ^> o .: _J i J- Γ. ' - (2, ^ - endDäthylcncyclohexyi; -harneüo-'i ", Schrnoisjunl: t 183 - 185 ° 'J from methanol.

Aue 4- (ß- <2 -:. C tiio :: y - ^ - c: ilor-beiizar; .i
a ::. id, oci! r.eJ.:; yani: b 214 - 216 ° G.

NZ "4- (ß- <2 -.". Eoiio;: y-5-ciilor-ben;: air.ido> -äfchyl) -:> o: ^ oir; u L v, ..., J / · Ii '- (2,5-eiido: .. ot3: yi''- nc _f yclobe :: cri-0) -yl _< ) -; iarns1; ofi', \ lz \ v. ·. lzpuiikt 174 - 1 '/ C ° G from Ketli £ tnol / iJiEBühyiror ::. ar.ia.

W- £ 4- (ß- <2-I.othoxy-i? -Chlcr-b-iizäLiido> -ethyl) -b; .nzolsu ^. ^T 'O: "- _t . 1 J- II' - (2,5-endoäthylencyclohe>: Gii-C5) -yl) -hc.rnntorf, ;; oh:;. Cl :: - point 164 G from ι, ethanol.

- (ß- <2-i.ethoxy -> - chlor-bcnzs £: ido> -Lthyl) -bonzolculTony 1 J li '- (2,5-ondoäthylenecyciohexyl; -urstoiT, 3chi.; elzpunkt 148 150 ⁰ from methanol.

From 4- (ß- (2-i-.ethoxy-5-iaethyl-benzamido> -ethyi; -benzenesuironamide , Closing point 197 - 198 ° C.

N- / ~ 4- (β- <2-liethoxy-5-ynethylbenzainido> -ethyl) -benzenesulx'onyl_7-N '- (2,5-endoraethylene-cyclohexen- (3) -yl) urine eoff, melting point 180 - 182 ° C from !! ethanol.

Yl- £ ^ - (β- <2-kethoxy-> - methyl-benzamido> -ethyl) -benzenesulfonyl J-Yi '- (2,5-endoäthylenecyclohexen- (3) -yl) -urea, melting point 187-189 ° C from methanol.

009810/1726

-üthyl) -borii; olsulfo

_7 ~ N '- (2, S-endoäthylenecyclohexyl) urea, melting point 191- - 196 ° C from I-ethanol / DiiaethyliOrinamid.

From 4- (ß- (2-I-: othoxy-5-t> roia-benscunido) -ät :: yl) -benzolsullOn anid, üete: ice point 124 - 125 ° C.

nyl _7-i <'- (2, ^ -endomethylene cyclolioxen- (3) -ylO-liarnstorf, Melting point 1? 2 - .174 ° C from 1-ethanol ...

IT- / "4- (ß- <2-Keuh-axy ^ 5-trcri-b-enz'ar.i.ao> -Lltli-yl) -bonaolsulfonyl_7-K '- (2,5-endoäthylenecycloheryl) -liarnstcf Γ, melting point 181 - 183 ° C from methanol.

From 4- (ß- <2-iietho: cy-5-riuor-bcn ^ aiTido) -üthyl) -benzolsulToijaniid, ÖchraelsOunkt 16? - 169 ° C

Ij- / ~ 4- (ß- <2-IIcthoxy-5-i'luor-be; isair: ido> -äthyl) -bonzenesulfo- -l ·; ' - (2,5-eiidonetliylen-cyclol30xGn- (5) -yl) -J '! Ar-nGtofr,. kt 197 - 198 ° C from i-ethanol / dir.ethyirorr.ariid.

N-ZT4- (β- <2-Let> ioxy-5-iluor-bensanido> ~ Uthyl) -bonsolsulfonyl _7-N '- (2, J-endoäthylenecycloliexen- (5) -yl) .- urea, Sclirael ^ puiikt 190-192 ° C from methanol. .

From 4- (ß- (2-I-ethoxy-5-ethyl-bensainido> -ethyl) -benzenesulfone amld, Schmelzpuhk-b 193-195 ° C..

f- (ß_ <2-i: etlioxy'-5-ethyl ~ bensaiaido> _r ethyl) -benesolsulfonyl J-Yi * - (2,5-endoEethj-lencyclohexen -. (3) -yl) -urea, melting point 158 - 160 ° C from !! ethanol.

BATH 0 0 9810/1726

From ^L \ ~ (ß- <2-ethoxy-5-chlorobenzamido> -ethyl) -benzenesulfonamide, melting point 168 - 170 ° C.

~ (ß- <2-ethoxy-5-chlorobenzamido) -ethyl) -benzenesulfo nyl _7-H '- (2, ^ - endomethylene-cyclohexen-C ^ -yl) -urea, Melting point 171-173 ° C from methanol.

009 810/1726

Claims (1)

-3229 Claims 1.) Benzenesulfonyl ureas of the formula X - ■ '■' ■■ / CO-MH-CHp-CHp- ^ V -SQp-HH-CO-mi-R ¹ ' in the χ = hydrogen, fluorine, chlorine, bromine, methyl or methoxy R = methyl or ethyl and R = endomethylene hexyl, endomethylene cyclohexenyl, endoethylene cyclohexyl, or endoethylene cyclohexenyl mean and salts thereof * 2.) Process for the preparation of Benaolsulfonylureas according to claim 1 or their salts, characterized in that one a) with the group '- ■■ - ■■■ x .... .p * -v / Hp- benzenesulfonyl isocyanates substituted in the P position, -carbamic acid esters, -thiolcarbamic acid esters, -ureas, —Semicarbazide or -semicarbazone with Reacts R-substituted amines or their salts, New documents w. ? § ι Abs. Ζ ν .-. "T sefi s«. · - - -; -; es. V. 4. $>. Tw.i. 0 0 981 0/1726. BATHROOM ORIGINAL b) sulfonamides of the formula X \\ J- CO-ÜH-CH ₂ -C V) H or their salts r.it R -substituted isocyanates, carbamic acid esters ^ thiolcarbamic acid storn, CarbaininsKurchaloGeniden or ureas uiij c) appropriately substituted benzenesulfonyl isourea ethers, -isourea ester, -isothiourea ether, -parabansaui-eri or -halogenamgisensilureamidine hydrolyzed, d) to appropriately substituted carbodiimides Uasser camps, e) in appropriately substituted benzenesulfonyl thioureas replaces the sulfur atom with an oxygen atom, f) corresponding benzenesulfonyl ureas, which are im
Molecule containing unsaturated bonds, hydrogenated, g) in benzenesulfonyl iiarines of the formula by acylation, optionally in stages, the rest 009810/1726 introduces, and the reaction products, if appropriate, with alkaline ones Means treated, 5.) Process for the production of blood sugar lowering effective, suitable for oral treatment of diabetes rnellitUG pharmaceutical preparations, characterized in that that benzenesulfonylarneas the claim 1 given formula or its salts, if necessary in a mixture with pharmaceutically usual carrier substances, be brought into a pharmaceutically acceptable administration form. 4-.) Blood sugar-lowering effective, for the oral treatment of the Pharmaceutical preparations suitable for diabetes raellitus, characterized by a content of a benzenesulfonylurea defined in claim 1 or a salt of that. 0 0 9 8 1 0/1 7 2 6 bad original