CH516543A - Antidiabetic sulphonyl ureas and sulphonyl - Google Patents

Antidiabetic sulphonyl ureas and sulphonyl

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Publication number
CH516543A
CH516543A CH1344770A CH1344770A CH516543A CH 516543 A CH516543 A CH 516543A CH 1344770 A CH1344770 A CH 1344770A CH 1344770 A CH1344770 A CH 1344770A CH 516543 A CH516543 A CH 516543A
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Switzerland
Prior art keywords
benzenesulfonyl
group
aminoethyl
acetyl
urea
Prior art date
Application number
CH1344770A
Other languages
German (de)
Inventor
Nat Winter Werner Dr Rer
Erich Dr Techn Fauland
Stach Kurt Ing Dr
Nat Schmidt Felix Helmut D Rer
Walter Dr Aumueller
Original Assignee
Boehringer Mannheim Gmbh
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Publication date
Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority claimed from CH367568A external-priority patent/CH516535A/en
Publication of CH516543A publication Critical patent/CH516543A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/38—[b, e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/02—Seven-membered rings
    • C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D337/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
    • C07D337/16—Eight-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Sulphonyl ureas and -semicarbazides of (I) X = -O or -S, satd. or unsatd., straight- or branched alkylene group (C1 - C3); oxymethylene, thiamethylene, thiaethylene, opt. alkylated or acylated iminomethylene, opt. alkylated carboximido or a valency bond. R1 = H, halogen, alkyl, alkoxy or CF3; Y = satd. or unsatd., straight- or branched alkylene (C1 - C6) which may contain an N- or -O atom; Z = straight- or branched alkylene (C1 - C4); R2 = satd. or unsatd., straight- or branched alkyl- or cycloalkyl residue opt. interrupted by S or O or containing an endoalkylene group, opt. substd. aryl or aralkyl residue or opt. substd., satd. or unsatd. alkylene imino residue (C3 - C7) which may contain an endoalkylene group (I) have anti-diabetic activity.

Description

  

  
 



  Verfahren zur Herstellung von neuen antidiabetisch wirksamen Sulfonylharnstoffen bzw. -semicarbaziden
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen antidiabetisch wirksamen Sulfonyl-harnstoffen bzw. -semicarbaziden der Formel I
EMI1.1     
 worin X ein Sauerstoff- bzw. Schwefelatom, eine aliphatische
Kohlenwasserstoffgruppe mit 1 bis 3 Kohlenstoff atomen, die Oxymethylen-, Thiomethylen-, Thioäthy lengruppe, eine gegebenenfalls alkylierte bzw.

   acylier te Iminomethylen- oder gegebenenfalls alkylierte
Carboximidogruppe oder einen Valenzstrich, R1 Wasserstoff, Halogen oder eine Alkyl-, Alkoxy- oder
Trifluormethylgruppe, V eine geradkettige oder verzweigte aliphatische Koh lenwasserstoffgruppe mit 1 bis 5 Kohlenstoffatomen oder einen Valenzstrich, Y eine Methylengruppe oder ein Stickstoffatom, Z eine geradkettige oder verzweigte Alkylengruppe mit
1 bis 4 Kohlenstoffatomen, R2 einen aliphatischen oder cycloaliphatischen Kohlen wasserstoffrest, der auch durch Sauerstoff- oder
Schwefelatome unterbrochen sein bzw.

   eine Endo alkylengruppe enthalten kann, einen gegebenenfalls substituierten Aryl- oder Aralkyl-Rest oder einen ge gebenenfalls substituierten, ganz oder teilweise ge sättigten Alkyleniminorest mit 3 bis 7 Kohlenstoffato men, der auch eine Endoalkylengruppe enthalten kann, bedeuten, das dadurch gekennzeichnet ist, dass man Benzolsulfonyl-Derivate der Formel II
EMI1.2     
 mit einem reaktionsfähigen Derivat einer Säure der Formel III
Q-OH III worin Q den Rest
EMI1.3     
 bedeutet, umsetzt.



   Das erfindungsgemässe Verfahren kann durchgeführt werden, indem man beispielsweise die Verbindungen der Formel II mit den entsprechenden Säurehalogeniden oder  deren reaktionsfähigen Derivaten, vorzugsweise in Gegenwart eines Säureakceptors, umsetzt.



   Das erfindungsgemässe Verfahren wird anhand des nachstehenden Beispiels näher erläutert.



   Beispiel 3-[4-(ss-Xanthen-9-yl-carboxamidoäthyl)-benzolsulfonyl]  -cyclohexylharnstoff
Man suspendiert 6,5 g 3-[4-(ss-Aminoäthyl)-benzolsulfonyl]-1-cyclohexylharnstoff (Fp. 211 bis 212 C) in 75 ml   Pyridin,    versetzt mit 5 g   Xanthen-9-carbonsäure-    chlorid und   lässt    48 Stunden bei Raumtemperatur stehen. Danach wird das Lösungsmittel im Vakuum abdestilliert, der Rückstand mit verdünnter Salzsäure digeriert, abgesaugt und mit Wasser gewaschen. Zur Reinigung löst man das erhaltene Rohprodukt in 0,2n Natronlauge und fällt mit verdünnter Salzsäure. Ausbeute: 8,6 g   (81%    d.Th.); Fp. 218 bis   220 C    (nach Umkristallisation aus Methanol).



   In analoger Weise erhält man den 3-{4-(ss-10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl-carboxamido äthyl)-benzolsulfonyl}-1-cyclohexylharnstoff, Fp. 202 bis   203 C.   



   Aus 4-[4-(ss-Aminoäthyl)-benzolsulfonyl]-1,1-(3-methylpentamethylen)-semicarbazid (Fp. 210 bis 212 C) und   6,11      -Dihydrodibenz[b,e]-thiepin-      11 -yl-acetylchlorid    erhält man in analoger Weise das 4-{4-(ss-6,11-Dihydrodibenz [b,e]-thiepin-11-yl-acetylamino thyl)-benzolsulfonyl}-1.1 -(3-methylpentamethylen)-semicarbazid, Fp. 222 bis   223 C.   



   Weiter erhält man in analoger Weise die folgenden Verbindungen: 3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl]-1 -(4-methyl-cyclohexyl)-harnstoff, Fp. 198 bis 199 C; 4-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1,1-(3,3-dimethyl-pentamethylen)-semicarbazid, Fp. 163 bis   164 C;    4-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1,1-(3-methyl-pentamethylen)-semicarbazid, Fp. 132 bis   133 C;    4-{4-(ss-6,11-Dihydro-dibenz[b,e]-oxepin-11-yliden-acetyl -aminoäthyl)-benzolsyulfonyl}-1,1-(3,3-dimethyl-pentamethylen)-semicarbazid, Fp. 183 bis   184 C;    3-{4-(ss-6,11-Dihydro-dibenz[b,e]-oxepin-11-yliden-acetyl-aminoäthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl) -harnstoff, Fp. 216 bis 217 C ;

   3-{4-(ss-6,11-dihydro-dibenz[b,e]-oxepin-11-yl-acetyl -aminoäthyl)-benzolsulfonyl}-1-(4-methylcyclohexyl) -harnstoff, Fp. 186 bis   187 C;    4-{4-(ss-6,11-Dihydro-dibenz[b,e]-oxepin-11-yl-acetyl-aminoäthyl)-benzolsulfonyl}-1,1-(3,3-dimethyl-pentamethylen)-semicarbazid, Fp. 202 bis   203 C;    3-[4-(ssXanthen-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-(4-methyl-cyclohexyl)-harnstoff.

  Fp. 208 bis 210 C; 4-[4-(ss-Xanthen-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1,1-(3-methyl-pentamethylen)-semicarbazid, Fp. 128 bis   130 C;    3-{4-(ss-6,11-Dihydro-dibenz[b,e]-oxepin-11-yliden-2 -propionyl-aminoäthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 161 bis   163 C    (Kalium-Salz); 4-[4-(ss-Thiaxanthen-9-yl-acetyl-aminoäthyl)-benzolsulfo nyl]-1,1-(3,3-dimethyl-pentamethylen)-semicarbazid, Fp. 172 bis   174 C    (Z.) (Kalium-Salz); 3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-(bicyclo[2,2,1]heptyl-2)harnstoff, Fp. 191 bis 193 C; 3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -cyclooctyl-harnstoff, Fp. 192 bis 193 C; 3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-(adamentyl-1)-harnstoff, Fp. 201 bis 202ïC;

   3-[4-(ss-Fluoren-9-yl-acetyl-amino thyl)¯-benzolsulfonyl] -1-cycloheptyl-harnstoff, Fp. 178 bis 180 C; 3-{4-(ss-6,11-Dihydro-bidenz[b,e]-oxepin-11-yl-acetyl -aminoäthyl)-benzolsylfonyl}-1-cyclohexyl-harnstoff, Fp. 201 bis 202 C; 3-{4-(ss-6,11-Dihydro-dibenz[b,e]-oxepin-11-yl-acetyl -aminoäthyl)-benzolsulfonyl}-1-n-butyl-harnstoff, Fp. 154 bis 155 C; 3-[4-(ss-Fluoren-9-yliden-acetyl-aminoäthyl)-benzolsulfonyl[-1-cyclohexyl-harnstoff, Fp. 199 bis 200 C; 3-[4-(ss-Thiaxanthen-9-yl-acetyl-aminoäthyl)-benzolsulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 198 bis   199 C;    3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-(4-methoxy-cyclohexyl)-harnstoff, Fp. 196 bis 197 C; 4-[4-(ss-Thiaxanthen-9-yl-acetyl-aminoäthyl)-benzolsulfonyl]-1,1-(3-methyl-pentamethylen)-semicarbazid.

  Fp. 175 bis   176 C;    3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-(tetrahydro-thiapyranyl-4)-harnstoff, Fp. 221 bis 222 C; 3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl]-1 -(4,4-dimethyl-cyclohexyl)-harnstoff, Fp. 197 bis 198 C; 3-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-(ss-phenyl-äthyl)-harnstoff, Fp. 186 bis 187 C; 4-[4-(ss-Fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1,1-hexamethylen-semicarbazid, Fp. 110 bis 112 C;

   4-[4-(ss-Fluoren-9-yliden-acetyl-aminoäthyl)-benzolsulfonyl]-1,1-(3-methyl-pentamethylen)-semicarbazid, Fp 155 bis   156 C;       3-{4-(ss-6,11-Dihydro-dibenz[b,e]-thiepin-11-yliden -acetyl-aminoäthyl)-benzolsulfonyl]-1-(4-methyl-cyclo-    hexyl)-harnstoff, Fp. 189 bis   190 C;      4-{4-(ss-6,11-Dihydro-dibenz[b,e]-thiepin-11-yliden -acetyl-aminoäthyl)-benzolsulfonyl}-1,1-(3-methyl-1    methylen)-semicarbazid, Fp. 210 bis 211 C ;   3i[4-(Fluoren-9-yliden-acetyl-aminoäthyl)-benzolSulfo-    nyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 210 bis   212 C;    3-{4-ss-5H-Dibenzo[a,d]-cyclohepten-5-yl-acetyl-amino äthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl)-harnstoff.



  Fp. 174 bis 175 C; 3-{4-(ss-12H-6,7-Dihydro-dibenz[b,e]-thiocin-12-yl-acetyl -aminoäthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl) -harnstoff, Fp. 184 bis   186 C    3-[4-(ss-Carbazol-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1-cyclohexyl-harnstoff, Fp. 196 bis 198 C; 3-[4-(ss-Carbazol-9-yl-acetyl-aminoäthyl)-benzolsulfonyl]1-(4-methyl-cyclohexyl)-harnstoff, Fp. 198 bis 200 C; 4-[4-(ss-Carbazol-9-yl-acetyl-aminoäthyl)-benzolsulfonyl] -1,1-(3-methyl-pentamethylen)-semicarbazid, Fp. 154 bis 156 C;    3-[4-#ss-(ss-Carbazol-9-yl-propionyl-amino)-äthyl > -benzol-    sulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 206 bis 208 C; 

   3-{4-(ss-5H-10,11-Dihydro-dibenzo[a,d]cyclohepten-5 -yliden-acetyl-aminoäthyl)-benzolsulfonyl}-1-(4-methyl -cyclohexyl)-harnstoff, Fp. 194 bis   195 C;    3-{4-(ss-5H-10,11-Dihydro-dibenzo[a,d]cyclohepten-5-yl -acetyl-aminoäthyl)-benzolsulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 204 bis   206 C;    4-{4-(ss-6,11-Dihydro-dibenz[b,e]thiepin-11-yl-acetyl -aminoäthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl) -harnstoff, Fp. 153 bis 155 C; 4-{4-(ss-6,11-Dihydro-dibenz[b,e]thiepin-11-yl-acetyl   -aminoäthyl)-benzolsulfonyl}-1,1-(3,3-dimethyl-pentamethylen)-semicarbazid, Fp. 226 bis 228 C;

   4-{4-(ss-6,11-Dihydro-dibenz[b,c]oxopin-11-yl-acctyl -aminoäthyl)-benzolsulfonyl}-1,1-(3-methyl-pentamethylen)-semicarbazid, Fp. 198 bis   200 C;    3-[4-(ss-Fluoren-9-yl-carboxamido-äthyl)-benzolsulfonyl] -1-cyclohexyl-harnstoff, Fp. 207 bis 208 C; 3-[4-(ss-Fluoren-9-yl-carboxamido-äthyl)-benzolsulfonyl] -1-(4-methyl-cyclohexyl)-harnstoff, Fp. 224 bis 226 C; 4-[4-(ss-Fluoren-9-yl-carboxamido-äthyl)-benzolsulfonyl] -1,1-(3-methyl-pentamethylen)-semicarbazid, Fp. 172 bis   173 C;    3-[4-(ss-Fluoren-9-yl-propionyl-aminoäthyl)-benzolsulfonyl]-1-cyclohexyl-harnstoff, Fp. 207 bis 208 C; 3-[4-(ss-Fluoren-9-yl-propionyl-aminoäthyl)-benzolsulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff. Fp. 210 bis   212 C;    4-[4-(ss-Fluoren-9-yl-propionyl-aminoäthyl)-benzolsulfo nyl]-1,1-(3,3-dimethyl-pentamethylen)-semicarbazid.



  Fp. 156 bis   158 C;    3-{4-(ss-2-Methoxy-6,11-dihydro-dibenz[b,e]oxepin-11-yl -acetyl-aminoäthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 172 bis   174 C;    3-{4-(ss-2-Methyl-6,11-dihydro-dibenz[b,e]oxepin-11-yl -acetylaminoäthyl)-benzolsulfonyl}-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 179 bis   180 C;    3-{4-(ss-2-Chloro-6,11-dihydro-dibenz[b,e]oxepin-11-yl -acetyl-aminoäthyl)-benzolsulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 210 bis   212 C,    3-[4-(ss-3-Methyl-fluoren-9-yl-acetyl-aminoäthyl)-benzolsulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 202 bis   203 C    3-[4-(ss-3-Methoxy-fluoren-9-yl-acetyl-aminoäthyl) -benzolsulfonyl]-1-(4-methyl-cyclohexyl)-harnstoff, Fp. 168 bis 169éC; 

   3-[4-(ss-2-Chlor-fluoren-9-yl-acetyl-aminoäthyl)-benzol sulfonyl]-1-(4-methylcyclohexyl)-harnstoff, Fp. 218 bis   220 C;    3-[4-(ss-Fluoren-9-yl-acetaminoäthyl)-benzolsulfonyl] -cyclohexylharnstoff, Fp. 204 bis 205 C. 



  
 



  Process for the production of new antidiabetic sulfonylureas or -semicarbazides
The present invention relates to a process for the preparation of new anti-diabetic sulfonyl ureas or semicarbazides of the formula I.
EMI1.1
 where X is an oxygen or sulfur atom, an aliphatic one
Hydrocarbon group with 1 to 3 carbon atoms, the oxymethylene, thiomethylene, thioethylene group, an optionally alkylated or

   acylated iminomethylene or optionally alkylated
Carboximido group or a valence stroke, R1 is hydrogen, halogen or an alkyl, alkoxy or
Trifluoromethyl group, V is a straight-chain or branched aliphatic hydrocarbon group with 1 to 5 carbon atoms or a valence line, Y is a methylene group or a nitrogen atom, Z is a straight-chain or branched alkylene group
1 to 4 carbon atoms, R2 is an aliphatic or cycloaliphatic carbon hydrogen radical, which is also through oxygen or
Sulfur atoms be interrupted or

   may contain an endo alkylene group, an optionally substituted aryl or aralkyl radical or an optionally substituted, fully or partially saturated alkylenimino radical with 3 to 7 carbon atoms, which may also contain an endoalkylene group, which is characterized in that one Benzenesulfonyl derivatives of the formula II
EMI1.2
 with a reactive derivative of an acid of the formula III
Q-OH III where Q is the remainder
EMI1.3
 means, implements.



   The process according to the invention can be carried out by reacting, for example, the compounds of the formula II with the corresponding acid halides or their reactive derivatives, preferably in the presence of an acid acceptor.



   The method according to the invention is explained in more detail using the following example.



   Example 3- [4- (ss-Xanthen-9-yl-carboxamidoethyl) -benzenesulfonyl] -cyclohexylurea
6.5 g of 3- [4- (β-aminoethyl) benzenesulfonyl] -1-cyclohexylurea (melting point 211 to 212 ° C.) are suspended in 75 ml of pyridine, 5 g of xanthene-9-carboxylic acid chloride are added and 48 Stand at room temperature for hours. The solvent is then distilled off in vacuo, the residue is digested with dilute hydrochloric acid, filtered off with suction and washed with water. For purification, the crude product obtained is dissolved in 0.2N sodium hydroxide solution and precipitated with dilute hydrochloric acid. Yield: 8.6 g (81% of theory); Mp. 218 to 220 ° C. (after recrystallization from methanol).



   The 3- {4- (ss-10,11-dihydro-5H-dibenzo [a, d] -cyclohepten-5-yl-carboxamido ethyl) -benzenesulfonyl} -1-cyclohexylurea is obtained in an analogous manner, melting point 202 bis 203 C.



   From 4- [4- (ss-aminoethyl) -benzenesulfonyl] -1,1- (3-methylpentamethylene) -semicarbazide (melting point 210 to 212 C) and 6,11 -dihydrodibenz [b, e] -thiepin- 11 - yl-acetyl chloride, 4- {4- (ss-6,11-dihydrodibenz [b, e] -thiepin-11-yl-acetylamino-methyl) -benzenesulfonyl} -1.1 - (3-methylpentamethylene) -semicarbazide is obtained in an analogous manner , M.p. 222-223 C.



   The following compounds are also obtained in an analogous manner: 3- [4- (ss-Fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1 - (4-methyl-cyclohexyl) -urea, melting point 198 to 199 ° C ; 4- [4- (ss-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3,3-dimethyl-pentamethylene) -semicarbazide, m.p. 163 to 164 C; 4- [4- (ss-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3-methyl-pentamethylene) -semicarbazide, m.p. 132 to 133 C; 4- {4- (ss-6,11-dihydro-dibenz [b, e] -oxepin-11-ylidene-acetyl-aminoethyl) -benzenesulfonyl} -1,1- (3,3-dimethyl-pentamethylene) -semicarbazide , M.p. 183 to 184 C; 3- {4- (ss-6,11-dihydro-dibenz [b, e] -oxepin-11-ylidene-acetyl-aminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, m.p. 216 to 217 C;

   3- {4- (ss-6,11-dihydro-dibenz [b, e] -oxepin-11-yl-acetyl-aminoethyl) -benzenesulfonyl} -1- (4-methylcyclohexyl) -urea, m.p. 186 to 187 C; 4- {4- (ss-6,11-dihydro-dibenz [b, e] -oxepin-11-yl-acetyl-aminoethyl) -benzenesulfonyl} -1,1- (3,3-dimethyl-pentamethylene) -semicarbazide , M.p. 202-203 C; 3- [4- (ssXanthen-9-yl-acetyl-aminoethyl) -benzenesulphonyl] -1- (4-methyl-cyclohexyl) -urea.

  M.p. 208 to 210 C; 4- [4- (ss-Xanthen-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3-methyl-pentamethylene) -semicarbazide, m.p. 128 to 130 ° C; 3- {4- (ss-6,11-dihydro-dibenz [b, e] -oxepin-11-yliden-2-propionyl-aminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, m.p. 161 to 163 C (potassium salt); 4- [4- (ss-Thiaxanthen-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3,3-dimethyl-pentamethylene) -semicarbazide, m.p. 172 to 174 C (Z.) ( Potassium salt); 3- [4- (ss-Fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (bicyclo [2.2.1] heptyl-2) urea, m.p. 191 to 193 C; 3- [4- (ss-Fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -cyclooctyl-urea, melting point 192 to 193 C; 3- [4- (ss-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (adamentyl-1) -urea, melting point 201 to 202 ° C;

   3- [4- (ss-Fluoren-9-yl-acetyl-aminothyl) ¯-benzenesulfonyl] -1-cycloheptyl-urea, m.p. 178 to 180 ° C; 3- {4- (ss-6,11-dihydro-bidenz [b, e] -oxepin-11-yl-acetyl-aminoethyl) -benzenesylfonyl} -1-cyclohexylurea, m.p. 201 to 202 C; 3- {4- (ss-6,11-dihydro-dibenz [b, e] -oxepin-11-yl-acetyl-aminoethyl) -benzenesulfonyl} -1-n-butyl-urea, m.p. 154-155 C; 3- [4- (ss-fluoren-9-ylidene-acetyl-aminoethyl) -benzenesulfonyl [-1-cyclohexyl-urea, melting point 199 to 200 ° C .; 3- [4- (ss-Thiaxanthen-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, melting point 198 to 199 C; 3- [4- (ss-Fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methoxycyclohexyl) -urea, m.p. 196 to 197 C; 4- [4- (ss-Thiaxanthen-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3-methyl-pentamethylene) -semicarbazide.

  M.p. 175 to 176 C; 3- [4- (ss-Fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (tetrahydro-thiapyranyl-4) -urea, m.p. 221 to 222 C; 3- [4- (ss-Fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1 - (4,4-dimethyl-cyclohexyl) -urea, m.p. 197 to 198 C; 3- [4- (ss-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (ss-phenyl-ethyl) -urea, melting point 186 to 187 C; 4- [4- (ss-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1-hexamethylene-semicarbazide, m.p. 110 to 112 C;

   4- [4- (ss-fluoren-9-ylidene-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3-methyl-pentamethylene) -semicarbazide, m.p. 155 to 156 C; 3- {4- (ss-6,11-dihydro-dibenz [b, e] -thiepin-11-ylidene-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, m.p. 189 to 190 C; 4- {4- (ss-6,11-dihydro-dibenz [b, e] -thiepin-11-ylidene-acetyl-aminoethyl) -benzenesulfonyl} -1,1- (3-methyl-1-methylene) -semicarbazide, Mp 210-211 C; 3i [4- (fluoren-9-ylidene-acetyl-aminoethyl) -benzene-sulfonyl] -1- (4-methyl-cyclohexyl) -urea, melting point 210 to 212 ° C; 3- {4-ss-5H-dibenzo [a, d] -cyclohepten-5-yl-acetyl-amino-ethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea.



  Mp 174-175 ° C; 3- {4- (ss-12H-6,7-dihydro-dibenz [b, e] -thiocin-12-yl-acetyl-aminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, m.p. 184 to 186 C 3- [4- (β-carbazol-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1-cyclohexylurea, melting point 196 to 198 C; 3- [4- (ß-carbazol-9-yl-acetyl-aminoethyl) -benzenesulfonyl] 1- (4-methyl-cyclohexyl) -urea, melting point 198 to 200 ° C; 4- [4- (ss-carbazol-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1,1- (3-methyl-pentamethylene) -semicarbazide, m.p. 154 to 156 C; 3- [4- # ss- (ss-carbazol-9-yl-propionyl-amino) -ethyl> -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, melting point 206 to 208 ° C;

   3- {4- (ss-5H-10,11-dihydro-dibenzo [a, d] cycloheptene-5-ylidene-acetyl-aminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, m.p. 194 to 195 C; 3- {4- (ss-5H-10,11-dihydro-dibenzo [a, d] cyclohepten-5-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, m.p. 204 to 206 C; 4- {4- (ss-6,11-dihydro-dibenz [b, e] thiepin-11-yl-acetyl-aminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, m.p. 153 bis 155 C; 4- {4- (ss-6,11-dihydro-dibenz [b, e] thiepin-11-yl-acetyl -aminoethyl) -benzenesulfonyl} -1,1- (3,3-dimethyl-pentamethylene) -semicarbazide, Mp 226-228 C;

   4- {4- (ss-6,11-dihydro-dibenz [b, c] oxopin-11-yl-acctyl-aminoethyl) -benzenesulfonyl} -1,1- (3-methyl-pentamethylene) -semicarbazide, m.p. 198 to 200 C; 3- [4- (ss-Fluoren-9-yl-carboxamido-ethyl) -benzenesulfonyl] -1-cyclohexyl-urea, m.p. 207 to 208 C; 3- [4- (ss-Fluoren-9-yl-carboxamido-ethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, m.p. 224 to 226 C; 4- [4- (ss-fluoren-9-yl-carboxamido-ethyl) -benzenesulfonyl] -1,1- (3-methyl-pentamethylene) -semicarbazide, m.p. 172 to 173 C; 3- [4- (ss-Fluoren-9-yl-propionyl-aminoethyl) -benzenesulfonyl] -1-cyclohexyl-urea, melting point 207 to 208 ° C; 3- [4- (ss-Fluoren-9-yl-propionyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea. M.p. 210 to 212 C; 4- [4- (ss-Fluoren-9-yl-propionyl-aminoethyl) -benzenesulfonyl] -1,1- (3,3-dimethyl-pentamethylene) -semicarbazide.



  M.p. 156 to 158 C; 3- {4- (ss-2-methoxy-6,11-dihydro-dibenz [b, e] oxepin-11-yl-acetyl-aminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, Mp 172-174 C; 3- {4- (ss-2-methyl-6,11-dihydro-dibenz [b, e] oxepin-11-yl-acetylaminoethyl) -benzenesulfonyl} -1- (4-methyl-cyclohexyl) -urea, m.p. 179 to 180 C; 3- {4- (ss-2-chloro-6,11-dihydro-dibenz [b, e] oxepin-11-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, M.p. 210 to 212 C, 3- [4- (ss-3-methyl-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, M.p. 202 to 203 C 3- [4- (ss-3-methoxy-fluoren-9-yl-acetyl-aminoethyl) -benzenesulfonyl] -1- (4-methyl-cyclohexyl) -urea, melting point 168 to 169 ° C;

   3- [4- (ss-2-chloro-fluoren-9-yl-acetyl-aminoethyl) -benzene sulfonyl] -1- (4-methylcyclohexyl) -urea, melting point 218 to 220 ° C; 3- [4- (ss-Fluoren-9-yl-acetaminoethyl) -benzenesulfonyl] -cyclohexylurea, m.p. 204 to 205 C.

Claims (1)

PATENTANSPRUCH PATENT CLAIM Verfahren zur Herstellung von neuen antidiabetisch wirksamen Sulfonyl-harnstoffen bzw. -semicarbaziden der Formel I EMI3.1 worin X ein Sauerstoff- bzw. Schwefelatom, eine aliphatische Kohlenwasserstoffgruppe mit 1 bis 3 Kohlenstoff atomen, die Oxymethylen-, Thiomethylen-, Thioäthy- lengruppe, Process for the preparation of new antidiabetic sulfonylureas or semicarbazides of the formula I. EMI3.1 where X is an oxygen or sulfur atom, an aliphatic one Hydrocarbon group with 1 to 3 carbon atoms, the oxymethylene, thiomethylene, thioethylene group, eine gegebenenfalls alkylierte Carboximi dogruppe oder einen Valenzstrich, R1 Wasserstoff, Halogen oder eine ALkyl-, Alkoxy- oder Trifluormethylgruppe, V eine geradkettige oder verzweigte aliphatische Koh lenwasserstoffgruppe mit 1 bis 5 Kohlenstoffatomen oder einen Valenzstrich, Y eine Methylengruppe oder ein Stickstoffatom, Z eine geradkettige oder verzweigte Alkylengruppe mit 1 bis 4 Kohlenstoffatomen, Re einen aliphatischen oder cycloaliphatischen Kohlen wasserstoffrest, der auch durch Sauerstoff- oder Schwefelatome unterbrochen sein bzw. an optionally alkylated carboximido group or a valence stroke, R1 is hydrogen, halogen or an alkyl, alkoxy or Trifluoromethyl group, V is a straight-chain or branched aliphatic hydrocarbon group with 1 to 5 carbon atoms or a valence line, Y is a methylene group or a nitrogen atom, Z is a straight-chain or branched alkylene group 1 to 4 carbon atoms, Re an aliphatic or cycloaliphatic carbon hydrogen radical, which is also through oxygen or Sulfur atoms be interrupted or eine Endo alkylengruppe enthalten kann, einen gegebenenfalls substituierten Aryl- oder Aralkyl-Rest oder einen ge gebenenfalls substituierten, ganz oder teilweise ge sättigten Alkyleniminorest mit 3 bis 7 Kohlenstoffato men, der auch eine Endoalkylengruppe enthalten kann, bedeuten, das dadurch gekennzeichnet ist, dass man Benzolsulfonyl-Derivate der Formel II EMI3.2 mit einem reaktionsfähigen Derivat einer Säure der Formel III Q - OH (III) worin Q den Rest EMI3.3 bedeutet, umsetzt. may contain an endo alkylene group, an optionally substituted aryl or aralkyl radical or an optionally substituted, fully or partially saturated alkylenimino radical with 3 to 7 carbon atoms, which may also contain an endoalkylene group, which is characterized in that one Benzenesulfonyl derivatives of the formula II EMI3.2 with a reactive derivative of an acid of the formula III Q - OH (III) wherein Q is the remainder EMI3.3 means, implements.
CH1344770A 1967-03-15 1968-03-13 Antidiabetic sulphonyl ureas and sulphonyl CH516543A (en)

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DEB0091627 1967-03-15
CH367568A CH516535A (en) 1967-03-15 1968-03-13 Process for the production of new antidiabetic sulfonylureas or -semicarbazides

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CH1344770A CH516543A (en) 1967-03-15 1968-03-13 Antidiabetic sulphonyl ureas and sulphonyl
CH1344570A CH516541A (en) 1967-03-15 1968-03-13 Process for the production of new antidiabetic sulfonyl ureas or semicarbazides

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