US3812185A - Benzenesulfonyl ureas - Google Patents

Benzenesulfonyl ureas Download PDF

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US3812185A
US3812185A US00041161A US4116170A US3812185A US 3812185 A US3812185 A US 3812185A US 00041161 A US00041161 A US 00041161A US 4116170 A US4116170 A US 4116170A US 3812185 A US3812185 A US 3812185A
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Prior art keywords
benzenesulfonyl
ethyl
urea
melting point
methoxy
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H Weber
R Weyer
W Aumueller
K Muth
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Hoechst AG
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Hoechst AG
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Priority claimed from DE1966F0049329 external-priority patent/DE1252201B/en
Priority claimed from DE1967F0052152 external-priority patent/DE1618402B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/59—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D333/70—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/18—Systems containing only non-condensed rings with a ring being at least seven-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/50—Spiro compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
    • C07C2603/66—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing five-membered rings

Definitions

  • A stands for hydrogen, halogen or lower alkyl of 1-4 carbon atoms and B stands for hydrogen or lower alkoxy of 1-4 carbon atoms
  • Y is a hydrocarbon chain of 1-3 carbon atoms or a physiologically tolerable salt thereof.
  • the present invention relates to benzenesulfonyl-ureas corresponding to the formula which as such or in the form of their physiologically tolerable salts particularly their alkali or alkaline earth metal salts, show hypoglycemic properties and are characterized by a strong and long lasting hypoglycemic action.
  • A stands for hydrogen, halogen, trifiuoromethyl, phenoxy, lower alkyl or lower alkoxy both having 1-4 carbon atoms
  • A stands for hydrogen, halogen or lower alkyl of l-4 carbon atoms and B stands for hydrogen or lower alkoxy of 1-4 carbon atoms
  • Y is a hydrocarbon chain of 1-3 carbon atoms or a physiologically tolerable salt thereof.
  • halogen may represent fluorine, chlorine, bromine or iodine; chlorine and bromine being preferred; lower-alkyl or lower alkoxy may represent methyl, ethyl, propyl, isopropyl, n-butyl, tert.-butyl or methoxy, ethoxy, propoxy, isopropoxy, tert.-butoxy, respectively methyl and methoxy being preferred.
  • Ring systems representing the member X in the above mentioned formula are, for eample, the following:
  • the phenylene group mentioned in the formula by is preferably unsubstituted. It may, however, likewise be monoor polysubstituted by halogen, lower alkyl or lower alkoxy. It may carry the remaining parts of the molecule in ortho-, metaor para-position to each other, the paraposition being preferred.
  • the products of the present invention may be prepared by methods well known in the benzene-sulfonyl-urea and, for example by reacting a benzene-sulfonyl-isocyanate, -carbamic acid ester, -thiol-carbamic acid ester, -carbamic acid halide or -urea substituted by the group with a R -substituted amine.
  • reaction products are treated with alkaline agents, if the formation of the salts is desired.
  • one or the other method for the preparation of certain individual compounds corresponding to the general formula may be unsuitable in some cases, or, at least require measures for the protection of active groups. Such cases which do not occur very often can easily be recognized by the expert and there will be no difiiculty in applying in these cases another method of synthesis.
  • the forms of realizing the process of the invention may, in general, vary within wide limits and can be adapted to each individual case.
  • the reactions can be carried out with the use of solvents either at room temperature or at an elevated temperature.
  • hypoglycemic action of the benzene-sulfonyl-urea derivatives described above could be determined by feeding them to rabbits for example in the form of sodium salt in doses of 10 mg./kg. and determining the blood sugar value according to the known method by Hagedorn- Jensen or by means of an autoanalyzer over a prolonged period of time.
  • N-[4-(fi- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfony1]-N'-(4,7 endomethylene-perhydro-indanyl-S)-urea provoke after 6 hours a lowering of the blood sugar of 23%
  • the known N-[4-methyl-benzenesulfonyl]- N'-butyl-urea has no blood sugar lowering effect when administered to rabbits in a dose of less than 25 mg./kg.
  • the values are within the same range as those of benzenesulfonylureas, for example N- [4-methyl-benzenesulfonyl] -N'-nbutyl urea and N-[4-methyl-benzenesulfonyl]-N-cyclohexyl-urea the LD of which amounts to 2.5 or 4.8 grams/kg. respectively, with oral application.
  • the products of the present invention have a very strong blood sugar lowering action and are extraordinarily well tolerated.
  • the benzenesulfonyl-ureas of the present invention are preferably used for the manufacture of orally administrable pharmaceutical preparations having blood sugar lowering action for the treatment of diabetes mellitus and may be used as such or in the form of their physiologically tolerable salts or in the presence of substances which cause such salt formation.
  • physiologically tolerable salts there may be used, for example, alkaline agents such as alkali metal hydroxides or alkaline earth metal hydroxides or alkali metal or alkaline earth metal carbonates or bicarbonates, these agents are commonly used in the pharmaceutical industry to form physiologically tolerable salts.
  • the pharmaceutical preparations are advantageously in the form of tablets and the pharmaceutically suitable carrier may be, for example, talc, starch, lactose, tragacanth or magnesium stearate.
  • a pharmaceutical preparation for example a tablet or a powder, containing a benzenesulfonyl-urea of the invention or a physiologically tolerated salt thereof as the active substance, with or without one of the aforementioned carriers, is advantageously brought into a suitable unit dosage form.
  • the dose chosen should comply with the activity of the benzenesulfonyl-urea or of the physiologically tolerated salt thereof used and the desired effect.
  • the dosage per unit amounts to about 0.5 to mg., preferably 2 to 10 mg., but considerably higher or lower dosage units may also be used, which, if desired, are divided or multiplied prior to their administration.
  • the xylene was removed by distillation under reduced pressure, whereby the N-[4-(fl- 2-methoxy 5 chlorobenzamido -ethyl)- benzenesnlfonyl] -N'-(4,7-endomethylene perhydro-indanyl-5)-urea that had formed precipitated. It was recrystallized from methanol. Melting point 196198 C.
  • N [4 8-benzamido-ethyl -benzenesulfonyl]- methyl urethane melting point 177-179 C.: the N- [4-(3 benzamido ethyD-benzenesulfonyl]-N'-(4,7- endomethylene-perhydro-indanyl-5)-urea, melting point 218-220 C. (decomposition);
  • N [4-(B- 3-trifluoromethyl-benzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 178- 180" C.): the N-[4-([3- 3-trifluoromethyl-benzamido ethyl)-benzenesulfonyl1-N 4,7 endomethylene-perhydro-indan-2-yl)-urea, melting point l75l77 C. (from methanol);
  • N [4-(B- 3-chlorobenzamido -ethyl)-benzenesulfonyl]-methylurethane melting point 173-175 C.
  • N- [4- p 2 methoxy benzamido -ethyl)-benzenesulfonyl]-methyl-urethane melting point 174-176 C.
  • N [4- (13- 2-methoxy-benzamido -ethyl)-benzenesulfonyl] N 4,7-endomethylene-perhydro-indan- 2-yl)-urea melting point 187-189 C.
  • N [4 (fl- 3-methylbenzamido -ethyl)-benzenesulfonyl]-methylurethane melting point ZOO-202 C.: the N [4 (1 3-methyl-benzamido ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan-2- yl)-urea, melting point -177 C. (from methanol);
  • N [4- B- Z-methoxy-5-methylbenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 175- 177 C.); the N [4 (p- 2-methoxy-5-methylbenzamido -ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 204- 206 C.
  • N [4 S- 2 methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl]methyl-urethane: the N-[4-(B- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfonyl] N [spiro (2 cyelobutane)-cyclopentyl]- urea, melting point 176-178 C.
  • N [4 (p- 2-methoxy 5 methyl-benzamido ethyl)-benzenesulfonyl]-methyl-urethane: the N-[4-(fi- 2-methoxy 5 methyl-benzamido -ethyl-benzenesulfonyl] N [spiro (2 cyclobutane)-cyclopentyl]- urea, melting point 174 C.
  • N [4 ( ⁇ 8- 2-methoxy-benzamido -ethyl)-benzenesulfonyl]-methyl-urethane the N [4 B- 2-methoxy benzamido ethyl) benzenesulfonyl] N'- [spiro (2 cyclopropane)-cyclopentyl]-urea, melting point 165 C. (from methanol/water);
  • N-[4-(;8- 2-methoxy 5 chlorobenzamid ethyl)- benzenesulfonyl] -methyl-urethane the N [4 8- 2- methoxy chlorobenzamido ethyl) benzenesulfonylJ-methyl-urethane; the N [4 (fl- 2-methoxy-5- chlorobenzamido -ethyl)-benzenesulfonyl] N (bicyclo-[3,1,0]-hexyl(6))-urea, melting point 175-177 C. (from methanol);
  • N-[4-(;8- 2 methoxy 5 bromobenzamido ethyl)-benzenesulfonyl] -methylurethane (melting point 197199 C.): the N-[4-(,3- 2-methoxy 5 bromobenzamido -ethyl) benzenesulfonyl] N (spiro- 5.5 -undecyl- 3 urea, melting point 194196 (from methanol/dimethylformamide) from N-[4-(,8- 2-phenoxybenzamido -ethyl) benzenesulfonyH-methyl urethane (melting point 167169 C.): the N-[4-(fi- 2 phenoxybenzamido ethyl)- benzenesulfonyl]-N'-(spiro- 5.5 undecyl 3 urea, melting point 166-167 C. (from methanol);
  • the reaction mixture was heated for 2 hours to the boiling temperature, during which time the methanol that had formed during the reaction was distilled off; after removal by distillation of the xylene under reduced pressure, the residue was treated with strongly diluted sodium hydroxide solution. Undissolved matter was fil- 9 tered off and the filtrate was acidified.
  • the N-[4-'(p- 2- methoxy-5-chlorobenzamido -ethyl) benzenesulfonyfl- N'-(4,7-endomethylene-6-chloro-perhydro indanyl 5)- urea thus formed was filtered off with suction and recrystallized from aqueous dioxane. The substance was found to melt at 189-191 C.;
  • N-[4-(,3- 5-chlorothiophene 2 carbonamido ethyl)-benzenesulfonyl]-methylurethane melting point 174-176 C.
  • the N-[4-(13 5- chlorothiophene 2- carbonamido ethyl) benzenesulfonyl] N (4,7- endomethylene-perhydro-indanyl 5) urea, melting point (from methanol/dirnethylformamide); 190- EXAMPLE 5 N-[4- fi- 2-methoxy 5 chlorobenzamido ethyl)- benzenesulfonyl]-N-(exo-tricyclo [3,2,1,0 ]-octane- 3-anti)-urea N-[4-(;3- 2-methoxy benzamido ethyl)-benzene-sulfonyl] N (oxotricyclo [3,2,1,
  • a benzenesulfonyl-urea corresponding to the formula A stands for hydrogen, halogen, trifiuoromethyl,
  • phenoxy, lower alkyl or lower alkoxy both having 20 1-4 carbon atoms A stands for hydrogen, halogen or lower alkyl of 1-4 carbon atoms and Y is a saturated hydrocarbon chain of 1-3 carbon atoms or a salt thereof of a pharmaceutically acceptable base.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

BENZENESULFONYL-UREAS HAVING HYPOGLYCEMIC ACTIVITIES CORRESPONDING TO THE FORMULA

1-(R1-NH-CO-NH-SO2-),4-(X-CO-NH-Y-)BENZENE

WHEREIN R1 IS (A) NOCRARAN-7-YL, BICYCLO- 3,1,0!-HEXYL, BICYCLO- 5, 1,0!-OCTYL, OR BICYCLO- 6,1,0!-NONYL; (B) 4,7-ENDOMETHYLENE - PERHYDROINDAN-5-YL; 4,7ENDOMETHYLENE-6-CHLORO-PERHYROINDAN-5-YL; 4,7ENDOMETHYLENE-PERHYDROINDAN - 2 YL; 2,6-ENDOMETHYLENECYCLOHEPTYL; 2,5-ENDOCYCLOBUTYLENE-1,2CYCLOHEXYL; EXO-TRICYCLO-(3,2,1,02,4)-OCTANYL; (C) SPIRO-(2-CYCLOPROPANE) - CYCLOPETYL; SPIRO-(2CYCLOBUTANE)-CYCLOPENTYL; SPIRO-(2-CYCLOPETANE)CYCLOPENTYL; SPIRO-(2-CYLOHEXANE)-CYCLOPENTYL; OR SPIRO-(5,5)-UNDECYL-3; X IS

A,A1-PHENYL OR 3-B,5-A1-THIEN-2-YL

IN WHICH A STANDS FOR HYDROGEN, HALOGEN, RIFLUOROMETHYL, PHENOXY, LOWER ALKYL OR LOWER ALKOXY BOTH HAVING 1-4 CARBON ATOMS, A1 STANDS FOR HYDROGEN, HALOGEN OR LOWER ALKYL OF 1-4 CARBON ATOMS AND B STANDS FOR HYDROGEN OR LOWER ALKOXY HOF 1-4 CARBON ATOMS Y IS A HYDROCARBON CHAIN OF 1-3 CARBON ATOMS OR A PHYSIOLOGICALLY TOLERABLE SALT THEREOF.

Description

United States Patent 3,812,185 BENZENESULFONYL UREAS Helmut Weber, Frankfurt am Main, Walter Aumiiller and Karl Muth, Kelkheim, Taunus, and Rndi Weyer, Frankfurt am Main, Germany, assignors to Farbwerke Hoechst Aktiengesellschaft vormals Meister Lucius & Bruning, Frankfurt am Main, Germany No Drawing. Continuation-impart of applications Ser. No. 641,146, May 25, 1967, and Ser. No. 749,609, Aug. 2, 1968, both now abandoned. This application May 25, 1970, Ser. No. 41,161 Claims priority, application Germany, May 28, 1966, F 49,329; Apr. 18, 1967, F 52,152 Int. Cl. C07c 127/00 US. Cl. 260-553 DA 10 Claims ABSTRACT OF THE DISCLOSURE Benzenesulfonyl-ureas having hypoglycemic activities corresponding to the formula wherein R is (a) norcaran-7-yl, bicyclo-[3,1,0]-hexyl, bicycle-[5,
1,0]-octyl, or bicyclo-[6,1,0]-nonyl;
(b) 4,7-endomethylene perhydroindan-S-yl; 4,7- endomethylene-6-chloro-perhydroindan-S-yl; 4,7- endomethylene-perhydroindan 2 yl; 2,6-endomethylenecycloheptyl; 2,5-endocyclobutylene-1,2- cyclohexyl; exo-tricyclo-(3,2,l,0 )-octanyl;
(c) spiro-(Z-cyclopropane) cyclopentyl; spiro-(2- cyclobutane)-cyclopentyl; spiro-(2-cyclopentane)- cyclopentyl; spiro- (2-cyclohexane)-cyclopentyl; or spiro-(5,5)-undecyl-3;
Xis
All 8 in which A stands for hydrogen, halogen, trifluoromethyl, phenoxy, lower alkyl or lower alkoxy both having 14 carbon atoms,
A stands for hydrogen, halogen or lower alkyl of 1-4 carbon atoms and B stands for hydrogen or lower alkoxy of 1-4 carbon atoms Y is a hydrocarbon chain of 1-3 carbon atoms or a physiologically tolerable salt thereof.
This application is a continuation-in-part of application Ser. No. 641,146 filed May 25, 1967 and Ser. No. 749,609 filed Aug. 2, 1968, both of which are now abandoned.
The present invention relates to benzenesulfonyl-ureas corresponding to the formula which as such or in the form of their physiologically tolerable salts particularly their alkali or alkaline earth metal salts, show hypoglycemic properties and are characterized by a strong and long lasting hypoglycemic action. In the formula:
R is
(a) norcaran-7-yl, bicyclo-[3,1,0]-hexyl,
, 3,812,185 Patented May 21, 1974 ice (b) 4,7-endomethylene perhydroindan-S-yl; 4,7- endomethylene-6-chloro-perhydroindan-5-yl; 4,7- endomethylene perhydroindan-Z-yl; 2,6-endomethylenecycloheptyl; 2,5-endocyclobutylene-1,2- cyclohexyl; exo-tricyclo-(Il,2,1,O )-octanyl;
(c) spiro-(2-cyclopropane) cyclopentyl; spiro-(Z- cyclobutane)-cyclopentyl; spiro-(2-cyclopentane)- cyclopentyl; spiro-(Z-cyclohexane)-cyclopentyl; or spiro- (5,5 -undecyl-3;
X is
ll l in which A stands for hydrogen, halogen, trifiuoromethyl, phenoxy, lower alkyl or lower alkoxy both having 1-4 carbon atoms,
A stands for hydrogen, halogen or lower alkyl of l-4 carbon atoms and B stands for hydrogen or lower alkoxy of 1-4 carbon atoms Y is a hydrocarbon chain of 1-3 carbon atoms or a physiologically tolerable salt thereof.
According to the above mentioned definitions, halogen may represent fluorine, chlorine, bromine or iodine; chlorine and bromine being preferred; lower-alkyl or lower alkoxy may represent methyl, ethyl, propyl, isopropyl, n-butyl, tert.-butyl or methoxy, ethoxy, propoxy, isopropoxy, tert.-butoxy, respectively methyl and methoxy being preferred.
Ring systems representing the member X in the above mentioned formula are, for eample, the following:
(LOH; J) CzHs i 3 70 ;CHgCH(CH3)i (iCI-I 20 E;
on, on,
3 H3 CH3 CH3 HEDGE; 0CH3 C i s 1 s s OCH; 0 02H: Hi OHl l 0 s s As examples for the bridge member Y there are mentioned:
those binding the benzene nucleus with the carbonamido group over 2 carbon atoms are preferred.
The phenylene group mentioned in the formula by is preferably unsubstituted. It may, however, likewise be monoor polysubstituted by halogen, lower alkyl or lower alkoxy. It may carry the remaining parts of the molecule in ortho-, metaor para-position to each other, the paraposition being preferred.
The products of the present invention may be prepared by methods well known in the benzene-sulfonyl-urea and, for example by reacting a benzene-sulfonyl-isocyanate, -carbamic acid ester, -thiol-carbamic acid ester, -carbamic acid halide or -urea substituted by the group with a R -substituted amine.
The reaction products are treated with alkaline agents, if the formation of the salts is desired.
According to the nature of the starting substances in particular of the member X one or the other method for the preparation of certain individual compounds corresponding to the general formula may be unsuitable in some cases, or, at least require measures for the protection of active groups. Such cases which do not occur very often can easily be recognized by the expert and there will be no difiiculty in applying in these cases another method of synthesis.
As regards the reaction conditions, the forms of realizing the process of the invention may, in general, vary within wide limits and can be adapted to each individual case. For example, the reactions can be carried out with the use of solvents either at room temperature or at an elevated temperature.
The hypoglycemic action of the benzene-sulfonyl-urea derivatives described above could be determined by feeding them to rabbits for example in the form of sodium salt in doses of 10 mg./kg. and determining the blood sugar value according to the known method by Hagedorn- Jensen or by means of an autoanalyzer over a prolonged period of time.
Thus we have found, for example, that 10 mg./kg. of N [4-( 3- 2-methoxy-5-methyl-benzamido -ethyl)-benzenesulfonyl] -N'-(4,7-endomethylene perhydro-indanyl- 5)-urea provoke after 3 hours a lowering of the blood sugar of 24%. In the same manner, 10 mg. of N-[4-(fi- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfony1]-N'-(4,7 endomethylene-perhydro-indanyl-S)-urea provoke after 6 hours a lowering of the blood sugar of 23%, whereas the known N-[4-methyl-benzenesulfonyl]- N'-butyl-urea has no blood sugar lowering effect when administered to rabbits in a dose of less than 25 mg./kg.
Furthermore, we have found that 10 mg. of N-[4-(B- 2 methoxy-benzamido ethyl)-benzenesulfonyl] -N'- (4,7-cndomethylene perhydro indanyl-5)-urea provoke after 3 hours a lowering of the blood sugar of 40%.
In the same manner 10 mg./kg. of N-[4-(B- 2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonyl] -N- (exo-tricyclo [3,2,1,0 octane-3-anti)-urea provoke after 3 hours a lowering of the blood sugar of 21% which, after 24 hours amounts to 23% and after 48 hours still to 17%. When N-[4-(fl- 2 methoxy 5 methyl-benzamido -ethyl)-benzenesulfonyl] N (spiro- 5,5 -undecyl- 3 -urea is administered to rabbits in a dose of 0.06 mg./kg., a distinct lowering of the blood sugar can still be observed.
As regards the toxicity of the compounds the values are within the same range as those of benzenesulfonylureas, for example N- [4-methyl-benzenesulfonyl] -N'-nbutyl urea and N-[4-methyl-benzenesulfonyl]-N-cyclohexyl-urea the LD of which amounts to 2.5 or 4.8 grams/kg. respectively, with oral application.
Hence, the products of the present invention have a very strong blood sugar lowering action and are extraordinarily well tolerated.
The benzenesulfonyl-ureas of the present invention are preferably used for the manufacture of orally administrable pharmaceutical preparations having blood sugar lowering action for the treatment of diabetes mellitus and may be used as such or in the form of their physiologically tolerable salts or in the presence of substances which cause such salt formation. For the formation of salts, there may be used, for example, alkaline agents such as alkali metal hydroxides or alkaline earth metal hydroxides or alkali metal or alkaline earth metal carbonates or bicarbonates, these agents are commonly used in the pharmaceutical industry to form physiologically tolerable salts.
The present invention, therefore, also provides phar-= maceutical preparations which comprise a benzenesulfonyl-urea of the above general formula or a physiologically tolerated salt thereof, in admixture or conjunction with a pharmaceutical suitable carrier.
The pharmaceutical preparations are advantageously in the form of tablets and the pharmaceutically suitable carrier may be, for example, talc, starch, lactose, tragacanth or magnesium stearate.
A pharmaceutical preparation, for example a tablet or a powder, containing a benzenesulfonyl-urea of the invention or a physiologically tolerated salt thereof as the active substance, with or without one of the aforementioned carriers, is advantageously brought into a suitable unit dosage form. The dose chosen should comply with the activity of the benzenesulfonyl-urea or of the physiologically tolerated salt thereof used and the desired effect. Advantageously, the dosage per unit amounts to about 0.5 to mg., preferably 2 to 10 mg., but considerably higher or lower dosage units may also be used, which, if desired, are divided or multiplied prior to their administration.
The following examples illustrate the invention but they are not intended to limit it thereto:
EXAMPLE 1 N-[4-(fl- 2methoxy 5 chlorobenzamido -ethyl)-benzenesulfonyl]-N-(4,7-endomethylene perhydro-indanyl-S -urea 8.5 g. of N-[4-(fi- 2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonyl]-methyl-urethane (melting point 189191 C.) were suspended in 100 ml. of xylene and after addition of 3.3 g. of 5-amino-4,7-endomethyleneperhydro-indan (boilinb point: 96-98 C./8 mm.) (obtained by hydrogenation of dicyclopentadiene-bis-nitrosochloride/Raney nickel, 100 C. and hydrogen under a pressure of 100 atmospheres) dissolved in 50 ml. of xylene, the whole was heated for about 2 hours to 130 C., during which time the methanol which formed during the reaction was separated by distillation. The xylene was removed by distillation under reduced pressure, whereby the N-[4-(fl- 2-methoxy 5 chlorobenzamido -ethyl)- benzenesnlfonyl] -N'-(4,7-endomethylene perhydro-indanyl-5)-urea that had formed precipitated. It was recrystallized from methanol. Melting point 196198 C.
In analogous manner there were obtained:
from N-[4-(fi- 2-chlorobenzamido -ethyl) benzenesulfonyH-methyl-urethane (melting point: 212-215 C.): the N- [4-( fl- 4-chlorobenzamido -ethyl) -benzenesulfonyl]-N-(4,7-endomethylene perhydro indany1-5)- urea, melting point 206-208" C. (from methanol/dioxane);
from N-[4-(p- 2-methoxybenzamido -ethyl) benzenesulfonyl]-methyl urethane (melting point l74176 C.): the N-[4-(;3- 2-methoxybenzamido -ethyl)-benzenesulfonyl]-N-(4,7-endomethylene perhydro-indanyl-5))-urea, melting point 195-197 C. (from methanol from N-[4-(5- 2-methoxy-5-methylbenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 175 177 C.): the N- [4-(,8- 2-methoxy-5-methylbenzamido -ethyl)-benzenesulfonyl] -N-(4,7 endomethylene-perhydro-indanyl-S)-urea, melting point: 208210 C. (from dilute dioxane);
from N [4 8-benzamido-ethyl -benzenesulfonyl]- methyl urethane (melting point 177-179 C.): the N- [4-(3 benzamido ethyD-benzenesulfonyl]-N'-(4,7- endomethylene-perhydro-indanyl-5)-urea, melting point 218-220 C. (decomposition);
from N [4-(B- 3-trifluoromethyl-benzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 178- 180" C.): the N-[4-([3- 3-trifluoromethyl-benzamido ethyl)-benzenesulfonyl1-N 4,7 endomethylene-perhydro-indan-2-yl)-urea, melting point l75l77 C. (from methanol);
from N [4-(B- 3-chlorobenzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 173-175 C.): the N-[4-(,8- 3-chlorobenzamido -ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan-2-yl)- urea, melting point 191-192 C. (from methanol); the N [4 (fit- 3 chlorobenzamido ethyl)-benzenesulfonyl]-N-(2,6-endomethylene-cycloheptyl)-urea, melting point 186-187 C. (from methanol); the N-[4-(;9- 3 chlorobenzamido -ethyl) benzenesulfonyl]-N- [spiro (2 cyelopentane) cyclopentyl1-urea, melting point 192-193 C.;
from N-[4-(fl- 3-methoxythiophene 2 carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 226-228" C.): the N-[4-(f3- 3-methoxythiophene-2- carbonamido ethyl) benzenesulfonyl] N (4,7- endomethylene-perhydro-indan 2 yl) urea, melting point 199-200" C. (from methanol/dimethylformamide);
from N- [4- p 2 methoxy benzamido -ethyl)-benzenesulfonyl]-methyl-urethane (melting point 174-176 C.) the N [4- (13- 2-methoxy-benzamido -ethyl)-benzenesulfonyl] N 4,7-endomethylene-perhydro-indan- 2-yl)-urea, melting point 187-189 C. (from methanol/ dimethylformamide); the N-[4-(B- 2-methoxy-benzamido -ethyl)-benzenesulfony1] N (2,6-endomethylene-cycloheptyl)-urea, melting point -172" C. (from methanol); the N [4 (p 2 methoxy-benzamido -ethyl)-benzenesulfonyl] N [spiro-(Z-cyclopentane)-cyclopentyl]-urea, melting point 171172 C.;
from N [4 (fl- 3-methylbenzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point ZOO-202 C.): the N [4 (1 3-methyl-benzamido ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan-2- yl)-urea, melting point -177 C. (from methanol);
from N-[4-03- Z-methoxy-S-chloro-benzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 189- 191 C.): the N [4 ([3- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 177- 179 C. (from methanol); the N-[4-(B- 2-methoxy-5- chlorobenzamido -ethyl)-benzenesulfonyl] N (2,6- endomethylene cycloheptyl) urea, melting point 140 142 C. (from methanol);
from N [4- B- Z-methoxy-5-methylbenzamido -ethyl)- =benzenesulfonyl]-methylurethane (melting point 175- 177 C.); the N [4 (p- 2-methoxy-5-methylbenzamido -ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 204- 206 C. (from methanol/dimethylformamide); the N- [4 (5 2 methoxy-S-methylbenzamido -ethyl)- benzenesulfonyl] N (2,6 endomethylene cycloheptyl)-urea, melting point 189-191" C. (from methanol/dimethylformamide) from N [4 (B 2 methoxy 5 bromobenzamido ethyl) -benzenesulfonyl] -methylurethane (melting point 197-199 C.): the N-[4-(B- 2-methoxy-5-bromobenzamido -ethyl)-benzenesulfonyl] N (4,7-endomethylene-perhydro-indan 2 yl)-urea, melting point 178- C. (from methanol); the N-[4-(fi- 2-methoxy-5- bromobenzamido -ethyl)-benzenesulfonyl] N (2,6- endomethylene-cycloheptyl)-urea, melting point 170- 172 C. (from methanol);
from N [4 (fi- 2-ethoxy-S-chlorobenzamido ethyl)- benzenesulfonyl]-methylurethane (melting point 203- 205 C.); the N [4 (,3- 2-ethoxy 5' chlorobenzamido -ethyl) -benzenesulfonyl] N (2,6-endomethylene-cycloheptyl) -urea, melting point 172174 C. (from methanol);
from N [4 B- 3,5-dimethyl-benzamido -ethyl)-benzenesulfonyl]-methylurethane (melting point 223-225 C.): the N [4 (fl- 3,5-dimethyl-benzamido ethyl)- benzenesulfonyl] N (4,7 endomethylene-perhydroindan-2-yl)-urea, melting point 190192 C. (from methanol);
from N [4 S- 2 methoxy 5 chlorobenzamido ethyl)-benzenesulfonyl]methyl-urethane: the N-[4-(B- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfonyl] N [spiro (2 cyelobutane)-cyclopentyl]- urea, melting point 176-178 C. (from methanol/dimethylformamide/ water); the N-[4-(;3- 2-methoxy-5- chlorobenzamido -ethyl)-benzenesulfonyl] -N [spiro- (Z-cyclopropane)-cyclopentyl]-urea, melting point 167 C. (from methanol/ dimethylformamide/ water) the N- [4 (13 2 methoxy 5 chlorobenzamido -ethyl)- benzenesulfonyl] N bicyclo [5,1,0] octyl (8)- urea, melting point 150 C. (decomposition) (from methanol/ dimethylformamide/ water); the N- [4- S- 2- methoxy 5 chlorobenzamido ethyD-benzenesulfonyl] N [spiro-(2 cyclopentane) cyclopentyl]- urea, melting point 166168 C.; the N-[4-(,8- 2-methoxy 5 chlorobenzamido -ethyl)-benzenesulfony1]- N-[2,5-endocyclobutylene (1,2) cyclohexyll-urea, melting point 60 C.;
from N [4 (p- 2-methoxy 5 methyl-benzamido ethyl)-benzenesulfonyl]-methyl-urethane: the N-[4-(fi- 2-methoxy 5 methyl-benzamido -ethyl-benzenesulfonyl] N [spiro (2 cyclobutane)-cyclopentyl]- urea, melting point 174 C. (from methanol/dimethylformamide/water; the N-[4-(ti- 2-methoxy-5-methylbenzamido -ethy1)-benzene sulfonyl] N -[spiro-(2- cyclopropane)-cyclopentyl]-urea, melting point 188 C. (from methanol/dimethylformamide/water); the N- [4- (;8- 2-methoxy 5 methyl-benzamido -ethyl)-benzenesulfonyl] N [spiro (2 cyclopentane)-cyclopentyl]-urea, melting point 201-203 C.;
from N [4 (fit- 3 chlorobenzamido -ethyl)-benzene sulfonyl]-methyl-urethane; the N- [4- (,B- 3-chlorobenzamido ethyl)-benzenesulfonyl] N [spiro- 2-cyclobutane -cyclopentyl]urea, melting point 192 C. (from methanol/ dimethylformamide/ water); the N-[4- (fit- 3 chlorobenzamido ethyl)-benzenesulfonyl]- N- [spiro- 2-cyclopropane cyclopentyl]-urea, melting point 187 C. (from methanol/dimethylformamide/ water);
from N [4 (}8- 2-methoxy-benzamido -ethyl)-benzenesulfonyl]-methyl-urethane: the N [4 B- 2-methoxy benzamido ethyl) benzenesulfonyl] N'- [spiro (2 cyclopropane)-cyclopentyl]-urea, melting point 165 C. (from methanol/water);
from N-[4-(;8- 2-methoxy 5 chlorobenzamid ethyl)- benzenesulfonyl] -methyl-urethane: the N [4 8- 2- methoxy chlorobenzamido ethyl) benzenesulfonylJ-methyl-urethane; the N [4 (fl- 2-methoxy-5- chlorobenzamido -ethyl)-benzenesulfonyl] N (bicyclo-[3,1,0]-hexyl(6))-urea, melting point 175-177 C. (from methanol);
from N-[4-(B- 3-chlorobenzamido ethyl) benzenesulfonyl]-methyl-urethane, (melting point 173-175 C): the N-[4-(B- 3 chlorobenzamido ethyl)- benzenesulfonyl]-N'-(spiro- 5.5 undecyl 3 urea, melting point 211-212 C. (from methanol/ dimethylformamide) from N-[4-(ti- 3-methoxythiophene-2 carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 226228 C): the N-[4-(fi- 3 methoxythiophene 2- carbonamido -ethyl)-benzenesulfonyl] N (spiro- 5.5 -undecyl- 3 )-urea, melting point 182183 C. (from methanol);
from N-[4-(B- 2-methoxy-5-methylbenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 175- 177 C.): the N-[4-(B- 2-methoxy 5 methylbenzamido -ethyl)-benzenesulfonyl]-N' (spiro 5.5 undecyl 3 urea (melting point 172-173 C.) (from methanol);
from N-[4-(;8- 2 methoxy 5 bromobenzamido ethyl)-benzenesulfonyl] -methylurethane (melting point 197199 C.): the N-[4-(,3- 2-methoxy 5 bromobenzamido -ethyl) benzenesulfonyl] N (spiro- 5.5 -undecyl- 3 urea, melting point 194196 (from methanol/dimethylformamide) from N-[4-(,8- 2-phenoxybenzamido -ethyl) benzenesulfonyH-methyl urethane (melting point 167169 C.): the N-[4-(fi- 2 phenoxybenzamido ethyl)- benzenesulfonyl]-N'-(spiro- 5.5 undecyl 3 urea, melting point 166-167 C. (from methanol);
from N- [4- (B- 2-methoxy-4-chlorobenzamido -ethyl benzenesulfonyl]-methylurethane melting point 178- 180 C.): the N-[4-(fi- 2 methoxy 4 chlorobenzamido -ethyl)-benzenesulfonyl]-N' (spiro 5.5 undecyl- 3 )-urea, melting point 213-215 C. (from methanol/dimethylformamide) In analogous manner, there were obtained:
N-[4-(B-Z-methoxy-S-chloro-benzamido-ethyl) benzenesulfonyl-N'-[spiro (2 cyclohexane) cyclopentyl]- urea, melting point 152-153 Cs,
N-[4-([3-2-methoxy-S-methyl-benzamido-ethyl) benzenesulfonyl-N' [spiro (2 cyclohexane) cyclopentyl]- urea, melting point 198199 C.;
Fit
N- [4- (13-2-methoxy-benzamido-ethyl) benzenesulfonyl]- N'-[spiro-(Z-cyclohexane)-cyclopentyl] urea, melting point 188-189 C.;
N-[4-(13-3-chloro-benzamido-ethyl) benzene sulfonyl]- N'-[spiro-(2-cyclohexane)-cyclopentyl] urea, melting point 188-190 C.
EXAMPLE 2 N-[4-(}3- 2-methoxy 5 chlorobenzamido ethyl)- benzenesulfonyl]-N-(4,7 endomethylene perhydroindanyl-S -urea A mixture of 10.3 g. of N-[4-(5- 2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonyl] urea, 300 ml. of toluene, 30 ml. of glycol-monomethyl ether, 1.65 g. of glacial acetic acid and 4.2 g. of 4,7 endomethyleneperhydro-indanyl-S-amine was heated for 5 hours under reflux. The whole was then concentrated under reduced pressure the residue was treated with alcohol and the crystals obtained, constituting the N-[4-(p- 2-methoxy- 5-chlorobenzamido -ethyl)-benzensulfony1] N (4,7- endomethylene-perhydro-indanyl-S)-urea, were recrystallized from methanol. Melting point 196-198 C.
In analogous manner, there were obtained:
the N-[4-(;8- 2-methoxy-5 chlorobenzamido ethyl)- benzenesulfonyl]-N'-bicyclo-('6,1,0)-nonyl (9) urea, melting point C. (from methanol/dimethylformamide/ water) the N-[4-(;Ei- 2-methoxy-S-chlorobenzamido ethyl)- benzenesulfonyl]-N'-(spiro- 5,5 undecyl 3 urea, melting point C. (from methanol) and from the N-[4-(;3- 2-methoxy-benzamido -ethyl) benzenesulfonyl]-urea, (melting point 183185 C.): the N-[4-(p- 2-methoxy-benzamido ethyl) benzenesulfonyl]-N-(spiro- 5,5 undecyl 3 urea, melting point 207-209 C. (from methanol/dimethylformamide).
EXAMPLE 3 N-[4-(fl- 2-methoxy 5 chlorobenzamido ethyl)- benzenesulfonyl]-N'-(4,7 endomethylene perhydroindanyl-S -urea 8.2 g. of N-[4-(fl-acetamidoethyl) benzenesulfonyl]- N'-(4,7-endomethylene-perhydro-indanyl-S) urea were heated for 2 hours under reflux with a solution of 1.6 g. of sodium hydroxide in 30 ml. of water. The whole was allowed to cool to room temperature, combined with 20 ml. of acetone and 1.3 g. of glacial acetic acid and then, 4.1 g. of 2-methoxy-5-chlorobenzoyl chloride were added portionwise. After having stirred for 2 hours at room temperature the whole was suction-filtered, the precipitate was treated with bicarbonate solution and then dissolved and reprecipitated from dilute mixture of ammonia and hydrochloric acid. The N-[4- 2-methoxy-5-chlorobenzamido -ethylbenzenesulfonyl]-N'-(4,7 endomethyleneperhydro-indanyl-5) urea thus obtained was found to melt, after recrystallization from a mixture of methanol and dimethylformamide, at 196198 C.
EXAMPLE 4 N-[4-(/3- 2-methoxy 5 chlorobenzamido ethyl)- benzenesulfonyl]-N'-(4,7-endomethylene 6 chloroperhydro-ind anyl-S -urea 78 g. of N-[4-(B- 2-methoxy-5-chlorobenzamido ethyl) benzenesulfonyl] methylurethane (melting point 189-191 C.) were suspended in 50 ml. of xylene and combined with 2.7 g. of 4,7-endomethylene 6 chloroperhydro-indanyl-S-amine (boiling point 134-138 C./8 mm.). The reaction mixture was heated for 2 hours to the boiling temperature, during which time the methanol that had formed during the reaction was distilled off; after removal by distillation of the xylene under reduced pressure, the residue was treated with strongly diluted sodium hydroxide solution. Undissolved matter was fil- 9 tered off and the filtrate was acidified. The N-[4-'(p- 2- methoxy-5-chlorobenzamido -ethyl) benzenesulfonyfl- N'-(4,7-endomethylene-6-chloro-perhydro indanyl 5)- urea thus formed was filtered off with suction and recrystallized from aqueous dioxane. The substance was found to melt at 189-191 C.;
In analogous manner, there were obtained:
from N-[4-(fl 3-methoxythiophene 2 carbonamido ethyl) -benzenesulfonyl]-methylurethane (melting point 226-228" C.): the N-[4-(,3- 3-methoxythiophene-2- carbonamido -ethyl) benzenesulfonyl] N (4,7- endomethylene perhydro-indanyl 5) urea, melting point 163-165 C. (from methanol);
from N-[4-(,3- 5-chlorothiophene 2 carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 174-176 C.) the N-[4-(13 5- chlorothiophene 2- carbonamido ethyl) benzenesulfonyl] N (4,7- endomethylene-perhydro-indanyl 5) urea, melting point (from methanol/dirnethylformamide); 190- EXAMPLE 5 N-[4- fi- 2-methoxy 5 chlorobenzamido ethyl)- benzenesulfonyl]-N-(exo-tricyclo [3,2,1,0 ]-octane- 3-anti)-urea N-[4-(;3- 2-methoxy benzamido ethyl)-benzene-sulfonyl] N (oxotricyclo [3,2,1,0 ]-octane-3-anti)- urea, melting point 186-188 C.;
N- [4- (fl- 2-methoxy 5 methylbenzamido -ethyl)-benzenesulfonyl] N (oxotricyclo-[3,2,1,0 ]-octane-3- anti)-urea, melting point 175-177 C. (decomposition);
N [4-( fl- 4 chloro benzamido -ethyl)-benzene-sulfonyl]-N (oxo-tricyclo-[3,2,-1, ]-octane-3-anti)-urea, melting point 202-204" C. (decomposition).
EXAMPLE 6 N-[4 (fi- 2 methoxy chlorobenzamido -ethyl)- benzenesulfonyH-N' (4,7 endomethylene-perhydroindanyl-S -urea 5 g. of 4-(B- 2 methoxy 5 chlorobenzamido ethyl)-benzenesulfonamide were dissolved in 7 ml. of binormal sodium hydroxide solution and 50 ml. of acetone and to this solution, there were added dropwise, while stirring and at 0-5 C., 2.7 g. of 4,7-endomethyleneperhydro-indanyl-S-isocyanate. The whole was stirred for 3 hours, diluted with water and methanol, undissolved matter was filtered ofl? and the filtrate was acidified with dilute hydrochloric acid. The N-[4-(/3- 2-methoxy-5- chlorobenzamido -ethyl)-benzenesulfonyl] N (4,7- endomethylene-perhydro-indanyl-S)-urea that had precipitated was found to melt, after recrystallization from methanol, at 196-198 C.
In analogous manner, there were obtained: from 4-( S- 3,4-dichlorobenzamido -ethyl)-benzenesulfonamide (melting point 171-172 C.).
Furthermore, there were prepared in a manner analogous to that of Example 6: the N-[4-(B- 2-methoxy 5 chlorobenzamido -ethylbenzenesulfonyl]-N'-norcaran-7-yl-urea, melting point 158 C. (from methanol/water);
from 4-(fl- 2-methoxy 5 methylbenzamido -ethyl)- benzenesulfonamide (melting point 197 C); the N- [4 (B- 2-methoxy 5 methylbenzamido -ethyl-benzenesulfonyl]-N'-norcaran-7-yl-urea, melting point 183' C. (from methanol/ water);
from 4-(fl- 4 chlorobenzamido -ethyl)benzenesulfonamide (melting point 225 C.) the N-[4-(B- 4-chlorobenzamido ethyl) benzenesulfonyl]-N-norcaran-7- yl-urea, melting point 137 C. (from methanol/water).
EXAMPLE 7 N [4 (fi- 2-methoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl]-N 4,7 endomethylene-perhydroindanyl-S -urea 1 g. of N-[4-(,9- 2-methoxy-5-chlorobenzamido ethyl)-benzenesulfonyl]-N' (4,7-endomethylene-perhydro-indanyl-5)-thiourea (melting point 137-l39 C.) was dissolved in ml. of methanol which had been combined with 10 ml. of dioxane. 1.1 g. of mercury oxide was added and the whole was stirred for three hours at 50-60" C. After removal of the mercury sulfide by filtration, the whole was concentrated under reduced pressure. The N-[4 (ti- 2 methoxy 5 chlorobenzamido ethyl)-benzene-sulfonyl]-N' (4,7-endomethylene-perhydro-indanyl-5)-isourea methyl ether thus obtained was suspended in 20 ml. of dioxane and 100 ml. of concentrated hydrochloric acid. The whole was heated for 10 minutes on the steam bath, poured into water, the precipitate was filtered oif with suction and recrystallized from methanol.
The N-[4 (fi- Z-methoxy-S-chlorobenzamido ethyl)-benzenesulfonyl]-N (4,7 endomethylene-perhydro-indanyl-5)-urea was found to melt at 196-198 C.
EXAMPLE 8 N [4 (fl- 2-methoxy-5-chlorobenzamido -ethy1)- benzenesulfonyH-N' (4,7 endomethylene-perhydro indanyl-S -urea 1 g. of N-[4- 2-methoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl]-N (4,7 endomethylene-perhydroindanyl-5)-thio-urea (melting point 137-139 C.) were suspended in 20 ml. of binormal sodium hydroxide solution and combined with 5 ml. of hydrogen peroxide having a strength of 5%.
The whole was heated for 15 minutes on the steam bath, cooled and acidified. A precipitate was obtained which was filtered oil? with suction and washed with water. The N- [4 (18- 2-methoxy-5-chlorobenzamido -ethyl)-benzenesulfonyl]-N-(4,7-endomethylene-perhydro-indanyl 5)- urea thus obtained was found to melt, after recrystallization from a mixture of methanol and dioxane, at 196- 198 C.
EXAMPLE 9 N [4 (pi- 3 methoxy 5 chloro-thiophene 2- carbonamido -ethyl)-benzenesulfonyl] N (4,7- endomethylene-perhydro-ind anyl-S -urea 6.48 g. of N-[4-(fi- 3-rnethoxy-5-chloro-thiophene-2- carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 189-19l C.) together with 2.26 g. of 5- amino-4,7-endomethylene-perhydro-indan and 300 ml. of dioxane were heated for 1 hour to the boiling temperature under reflux. After removal of the solvent by distillation under reduced pressure, the residue obtained was treated with strongly diluted ammonia, filtered and the filtrate was acidified. The precipitate obtained was filtered off with suction and recrystallized from methanol. The N- [4- (fl- 3-methoxy-S-chlorothiophen-Z-carbonamido ethyl)-benzenesulfonyl]-N' (4,7 endomethylene-perhydro-indanyl-5)-urea thus obtained. was found to melt at 181-183 C.
In analogous manner, there was obtained:
from N-[4-(;3- 5-chloro-thiophene 2 carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 174-176 C.): the N [4 (B- 5-chloro-thiophene-2- carbonamido ethyl) benzenesulfonyl] N (4,7- endomethylene-perhydro-indanyl-5)-urea, melting point 190-l92 C. (from methanol/water).
We claim:
1. A benzenesulfonyl-urea corresponding to the formula A stands for hydrogen, halogen, trifiuoromethyl,
phenoxy, lower alkyl or lower alkoxy both having 20 1-4 carbon atoms, A stands for hydrogen, halogen or lower alkyl of 1-4 carbon atoms and Y is a saturated hydrocarbon chain of 1-3 carbon atoms or a salt thereof of a pharmaceutically acceptable base.
2. The compound of claim 1 wherein X is CH: 3. The compound of claim 1 wherein X is 4. The compound of claim 1 wherein Y is CH CH 5. The compound of claim 1 wherein 3 is -Q- 6. The compound of claim 1 wherein X is phenyl which is substituted in 2-positiou by lower alkoxy.
7. The compound of claim 1 wherein X is phenyl which is substituted in 2-position by lower alkoxy and in 4- or 5- position by halogen, lower alkyl or alkoxy.
8. The compound of claim 1 wherein X is phenyl which is substituted in 2-position by methoxy and in 4- or 5- position by halogen, methyl or methoxy.
9. The compound of claim 1 wherein X is phenyl which is substituted in 2-position by methoxy and in 4- or 5- position by chlorine.
10. The compound of claim 1, wherein X is Z-methoxy- S-methyl-phenyl, Y is --CH -CH and R is 2,6-endomethylene-cycloheptyl.
References Cited UNITED STATES PATENTS 3,426,067 2/ 1969 Weber et a1 260553 DA 3,183,260 5/1965 Loev 260553 D 3,454,635 7/1969 Wc'ber et al 260553 DA BERNARD HELFIN, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US. Cl. X.R.
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US3998968A (en) * 1974-03-21 1976-12-21 Hoechst Aktiengesellschaft Benzenesulfonyl ureas and process for their manufacture

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3998968A (en) * 1974-03-21 1976-12-21 Hoechst Aktiengesellschaft Benzenesulfonyl ureas and process for their manufacture

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