CH486435A - Process for the preparation of benzenesulfonylureas - Google Patents
Process for the preparation of benzenesulfonylureasInfo
- Publication number
- CH486435A CH486435A CH937669A CH937669A CH486435A CH 486435 A CH486435 A CH 486435A CH 937669 A CH937669 A CH 937669A CH 937669 A CH937669 A CH 937669A CH 486435 A CH486435 A CH 486435A
- Authority
- CH
- Switzerland
- Prior art keywords
- carbon atoms
- alkyl
- formula
- benzenesulfonylureas
- benzenesulfonyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- -1 cyclohexenylmethyl Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 3
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- PVMBGVAQRSHDBB-UHFFFAOYSA-N benzenesulfonylthiourea Chemical compound NC(=S)NS(=O)(=O)C1=CC=CC=C1 PVMBGVAQRSHDBB-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 239000008280 blood Substances 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical class NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000474 mercury oxide Inorganic materials 0.000 description 1
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
-
- 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
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Verfahren zur Herstellung von Benzolsulfonylharnstoffen Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Benzolsulfonylharnstoffen der Formel
EMI0001.0000
in welcher bedeuten: R a) Alkyl, Alkenyl mit 2 bis 8 Kohlenstoffatomen, b) Phenylalkyl mit 1 bis 4 Alkylkohlenstoffatomen, c) Cyclohexylalkyl mit 1 bis 4 Alkylkohlenstoff atomen, d) Endoalkylencyclohexyl, Endoalkylencyclohexenyl, Endoalkylencyclohexylmethyl oder Endoalkylencyclo- hexenylmethyl mit 1 bis 2 Endoalkylen-Kohlenstoff- atomen, e) Alkylcyclohexyl oder Alkoxycyclohexyl mit 1 bis 4 Alkylkohlenstoffatomen, f) Cycloalkyl mit 5 bis 8 Kohlenstoffatomen, g) Cyclohexenyl, Cyclohexenylmethyl, Z, Z' Wasserstoff, Halogen,
Alkyl oder Alkoxy mit 1 bis 4 Kohlenstoffatomen, X einen gesättigten oder ungesättigten Kohlenwasser stoffrest mit 2 Kohlenstoffatomen, Y eine Alkylkette mit 1 bis 3 Kohlenstoffatomen sowie Salze der genannten Benzolsulfonylharnstoffe.
Die Alkylreste können dabei jeweils gerad- oder ver- zweigtkettig sein.
R kann beispielsweise bedeuten: Äthyl, Propyl, Isopropyl, Butyl, Isobutyl, sek.-Butyl, geradkettiges oder verzweigtes Amyl (Pentyl), Hexyl, Heptyl oder Octyl; die den genannten Kohlenwasserstoffresten entsprechenden Reste mit einer äthylenischen Doppelbindung, wie Allyl oder Crotyl. Weiterhin kommen als R in Frage: Benzyl, a-Phenyläthyl, B-Phenyläthyl, a-, B- αder g-Phenyl- propyl oder Phenylbutyle.
Besonders bevorzugt sind im Sinne der Erfindung solche Verbindungen, die als R einen cycloaliphatischen, gegebenenfalls mit Alkyl bzw. Alkoxy substituierten oder über Alkylen an das Stickstoffatom gebundenen Kohlenwasserstoffrest enthalten. Als solche Reste seien beispielsweise genannt: Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Methylcyclohexyl, Äthylcyclohexyl, Propyl- und Iso- propylcyclohexyl, Methoxycyclohexyl, Äthoxycyclohexyl, Propoxy- und Isopropoxycyclohexyl, wobei die Alkyl- bzw. Alkoxygruppen vorzugsweise in 4-Stellung, und zwar sowohl in cis- als auch in trans-Position vorliegen kön nen, Cyclohexylmethyl, α
- oder B-Cyclohexyläthyl, Endo- methylencyclohexyl (2,2,1-Bicycloheptyl), Endoäthylen- cyclohexyl (2,2,2-Bicyclooctyl), Endomethylencyclohexe- nyl, Endoäthylencyclohexenyl, Endomethylencyclohexyl- methyl, Endoäthylencyclohexylmethyl, Endomethylen- cyclohexenylmethyl oder Endoäthylencyclohexenyl- methyl.
X stellt einen gesättigten oder ungesättigten Kohlen wasserstoffrest mit 2 C-Atomen dar, welcher durch zwei Phenylreste substituiert ist, die ihrerseits Substi- tuenten, wie Fluor, Chlor, Brom, niederes Alkyl oder niederes Alkoxy tragen können. Die Phenylreste kön- nen sich am gleichen Kohlenstoffatom oder an verschie denen Kohlenstoffatomen des Restes X befinden.
Die mit Y bezeichnete Alkylkette kann geradkettig oder verzweigt sein. Die Herstellung der genannten Benzolsulfonylharn- stoffe erfolgt erfindungsgemäss, indem man Benzolsul- fonylisoharnstoffäther der Formel 11
EMI0002.0004
worin R, Niederalkyl bedeutet, oder einen Benzolsulfonylisothioharnstoffäther der Formel 111
EMI0002.0005
oder Benzolsulfonylparabansäuren der Formel IV
EMI0002.0006
hydrolysiert und die Verfahrensprodukte gegebenenfalls zur Salzbildung mit alkalischen Mitteln behandelt.
Je nach der Natur der Glieder X und R wird es sich in einzelnen Fällen bei der Durchführung des Verfahrens als notwendig erweisen, Vorkehrungen zum Schutz aktiver Gruppen zu treffen. Derartige, verhältnismässig selten auftretende Fälle können vom Fachmann un schwer erkannt werden, und es bereitet keine Schwierig keiten, in solchen Fällen die entsprechenden Massnahmen zu treffen.
Die Ausführungsformen des Verfahrens gemäss der Erfindung können im allgemeinen hinsichtlich der Reak tionsbedingungen weitgehend variiert und den jeweiligen Verhältnissen angepasst werden. Beispielswaise können die Umsetzungen unter Ver wendung von Lösungsmitteln bei Zimmertemperatur oder bei erhöhter Temperatur durchgeführt werden.
Als Beispiele für den Bestandteil der Verbindungen der Formeln 11 bis IV X-C O- kommen in Betracht.
EMI0002.0018
EMI0003.0000
Die nach dem Verfahren gemäss der Erfindung er- hältliichen Benzolsulfonylharnstoffderivate stellen wert volle Arzneimittel dar, die sich durch eine starke und vor allem lang anhaltende blutzuckersenkende Wirkung aus zeichnen. Ihre blutzuckersenkende Wirkung konnte z. B. am Kaninchen dadurch festgestellt werden, dass man die Verfahrensprodukte in Dosen von 10 mg/kg verfütterte und den Blutzuckerwert nach der bekannten Methode von Hagedorn-Jensen über eine längere Zeitdauer be stimmte.
So wurde beispielsweise ermittelt, dass der N-[4-(B-{B,B-Diphenylpropionamido}-äthyl)- benzolsulfonyl]-N'-n-butylharnstoff nach 3 Stunden eine Blutzuckersenkung von 26 und der N-[4-(B-{B,B-Diphenylpropionamido}-äthyl) benzolsulfonyl]-N'-(4-methyl-cyclohexyl)- harnstoff eine solche von 32 5.," bewirkt. Vergleicht man damit den als orales Antidiabetikum bekannten N-(4-Methyl- benzolsulfonyl)-N'-butylharnstoff, so stellt man fest, dass bei der angegebenen Dosierung von 10 mg, kg am Kaninchen keine Blutzuckersenkung mehr erfolgt.
Erst bei Dosen von 25 mg; kg und mehr ist eine Blutzucker- reaktion zu beobachten.
Die starke \'Wirksamkeit der Verfahrensprodukte wird besonders deutlich, wenn man die Dosis verringert. Ver abreicht man den N-[4-(B-{B,B-Diphenylpropionamido}-äthyl) benzolsulfonyl]-N'-(4-methyl-cyclohexyl)- harnstoff in einer Dosierung von 0,4 mg/kg am Kaninchen, so ist immer noch eine deutliche Blutzuckersenkung fest zustellen.
Die beschriebenen Benzolsulfonylharnstoffe sollen vorzugsweise zur Herstellung von oral verabreichbaren Präparaten mit blutzuckersenkender Wirksamkeit zur Behandlung des Diabetes mellitus dienen und können als solche oder in Form ihrer Salze bzw. in Gegenwart von Stoffen, die zu einer Salzbildung führen, appliziert wer den. Zur Salzbildung können beispielsweise herange zogen werden: Alkalische Mittel, wie Alkali- oder Erdalkali- hydroxyde, -carbonate oder -bicarbonate, aber auch organische Basen, insbesondere tertiäre Stickstoffbasen, vorausgesetzt, dass sie physiologisch verträglich sind.
Als medizinische Präparate kommen vorzugsweise Tabletten in Betracht, die neben den Verfahrenserzeug- nissen die üblichen Hilfs- und Trägerstoffe, wie Talkum, Stärke Milchzucker, Tragant oder Magnesiumstearat enthalten.
Ein Präparat, das die beschriebenen Benzolsulfonyl- harnstoffe als Wirkstoff enthält, z. B. eine Tablette oder ein Pulver mit oder ohne den genannten Zusätzen, ist zweckmässig in eine geeignete dosierte Form gebracht. Als Dosis ist dabei eine solche zu wählen, die der Wirk samkeit des verwendeten Benzolsulfonylharnstoffs und dem gewünschten Effekt angepasst ist. Zweckmässig be trägt die Dosierung je Einheit etwa 0,5 bis 100 mg, vor zugsweise 2 bis 10 mg, jedoch können auch erheblich darüber oder darunter liegende Dosierungseinheiten ver wendet werden, die gegebenenfalls vor Applikation zu teilen bzw.
zu vervielfachen sind. <I>Beispiel</I> N-[4-(B-{B,B-Diphenylpropionamido}-äthyl) benzolsulfonyl]-N'-(2,5-endomethylen-cyclohexyl- methyl)-harnstoff 2,9 g N-[4-(3-{B,B-Diphenylpropionamido}-äthyl) benzolsulfonyl]-N'-(2,5-endomethylen- cyclohexyl-methyl)-thioharnstoff (hergestellt durch Umsetzung von 4-[B-(B,B-Diphenyl- propionamido)-äthyl]-benzolsulfonamid und 2,5-Endo- methylen-cyclohexylsenföl, Schmelzpunkt l62-164' C) werden in 100 ml Methanol suspendiert.
Man fügt 0,1 g Kaliumcarbonat und 1,1g Quecksilberoxyd zu und rührt 4 Stunden bei 40 C.
Nach Abfiltrieren engt man ein. Der als zähes Harz erhaltene Rückstand von N-[4-(B-{B,B-Diphenylpropionamido}-äthyl) benzolsulfonyl]-N'-(2,5-endomethylencyclohexyl- methyl)-isoharnstoffmethyläther wird mit 250 ml konzentriertem HCl 30 Minuten auf dem Dampfbad erhitzt. Der gebildete kristalline Nieder schlag wird abgesaugt, mit Wasser gewaschen und aus Methanol umkristallisiert. Man erhält in guter Ausbeute den N-[4-(B-{B,B-Diphenylpropionanido}-äthyl) benzolsulfonyl]-N'-(2,5-endomethylencyclohexyl- methyl)-harnstoff vom Schmelzpunkt 191 bis 192 C.
Process for the preparation of benzenesulfonylureas The present invention relates to a process for the preparation of benzenesulfonylureas of the formula
EMI0001.0000
in which mean: R a) alkyl, alkenyl with 2 to 8 carbon atoms, b) phenylalkyl with 1 to 4 alkyl carbon atoms, c) cyclohexylalkyl with 1 to 4 alkyl carbon atoms, d) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, endoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1 bis-hexenylmethyl Endoalkylene carbon atoms, e) alkylcyclohexyl or alkoxycyclohexyl with 1 to 4 alkyl carbon atoms, f) cycloalkyl with 5 to 8 carbon atoms, g) cyclohexenyl, cyclohexenylmethyl, Z, Z 'hydrogen, halogen,
Alkyl or alkoxy with 1 to 4 carbon atoms, X a saturated or unsaturated hydrocarbon radical with 2 carbon atoms, Y an alkyl chain with 1 to 3 carbon atoms and salts of the benzenesulfonylureas mentioned.
The alkyl radicals can each be straight-chain or branched.
R can mean, for example: ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, straight-chain or branched amyl (pentyl), hexyl, heptyl or octyl; the radicals corresponding to the hydrocarbon radicals mentioned and having an ethylenic double bond, such as allyl or crotyl. Also possible as R are: benzyl, a-phenylethyl, B-phenylethyl, a-, B-α, g-phenylpropyl or phenylbutyl.
For the purposes of the invention, particular preference is given to those compounds which contain, as R, a cycloaliphatic hydrocarbon radical, optionally substituted by alkyl or alkoxy or bonded to the nitrogen atom via alkylene. Examples of such radicals are: cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, propyl and isopropylcyclohexyl, methoxycyclohexyl, ethoxycyclohexyl, propoxy and isopropoxycyclohexyl, preferably in the 4-alkoxy position, preferably in the 4-alkoxy position can be in both cis and trans positions, cyclohexylmethyl,?
- or B-Cyclohexylethyl, endomethylene cyclohexyl (2,2,1-bicycloheptyl), endoethylene cyclohexyl (2,2,2-bicyclooctyl), endomethylene cyclohexenyl, endoethylene cyclohexenyl, endomethylene cyclohexyl- orhexoethylene-cyclohexyl- methyl, endoethylene-cyclohexyl- methyl, endoethylene-cyclohexyl- methyl, endoäthylenecyclohexyl- methylen, endoäthylenecyclohexyl- methylen, endoäthylenecyclohexyl- methylen, endoäthylenecyclohexyl- methylen, endoäthylenecyclohexyl- methyl, endoäthylenecyclohexyl- methyl, endoethylenecyclohexyl- methylen, methyl.
X represents a saturated or unsaturated hydrocarbon radical with 2 carbon atoms, which is substituted by two phenyl radicals, which in turn can carry substituents such as fluorine, chlorine, bromine, lower alkyl or lower alkoxy. The phenyl radicals can be on the same carbon atom or on different carbon atoms of the X radical.
The alkyl chain denoted by Y can be straight-chain or branched. The benzenesulfonylureas mentioned are prepared according to the invention by adding benzenesulfonylisourea ethers of the formula II
EMI0002.0004
wherein R 1 is lower alkyl or a benzenesulfonylisothiourea ether of the formula III
EMI0002.0005
or benzenesulfonylparabanic acids of the formula IV
EMI0002.0006
hydrolyzed and the products of the process treated with alkaline agents to form salts.
Depending on the nature of members X and R, it will be necessary in individual cases to take precautions to protect active groups when carrying out the procedure. Such cases, which occur relatively rarely, are easy for the skilled person to recognize, and it is not difficult to take the appropriate measures in such cases.
The embodiments of the process according to the invention can generally be varied widely with regard to the reaction conditions and adapted to the particular circumstances. For example, the reactions can be carried out using solvents at room temperature or at elevated temperature.
Examples of the constituent of the compounds of the formulas II to IV X-C O- come into consideration.
EMI0002.0018
EMI0003.0000
The benzenesulfonylurea derivatives obtainable by the process according to the invention are valuable medicaments which are distinguished by a strong and, above all, long-lasting blood sugar-lowering effect. Their blood sugar lowering effect could be B. can be found in rabbits by feeding the process products in doses of 10 mg / kg and agreeing the blood sugar level according to the known method of Hagedorn-Jensen over a longer period of time.
For example, it was found that the N- [4- (B- {B, B-diphenylpropionamido} -ethyl) -benzenesulfonyl] -N'-n-butylurea reduced blood sugar by 26 after 3 hours and the N- [4- ( B- {B, B-diphenylpropionamido} -ethyl) benzenesulfonyl] -N '- (4-methyl-cyclohexyl) -urea causes a rate of 32 5. "If one compares this with the N- (4- Methylbenzenesulfonyl) -N'-butylurea, it is found that at the stated dosage of 10 mg, kg in rabbits there is no longer any lowering of blood sugar.
Only at doses of 25 mg; kg and more, a blood sugar reaction can be observed.
The strong \ 'effectiveness of the process products becomes particularly clear when the dose is reduced. If the N- [4- (B- {B, B-diphenylpropionamido} -ethyl) benzenesulfonyl] -N '- (4-methyl-cyclohexyl) urea is administered in a dosage of 0.4 mg / kg in rabbits, a significant drop in blood sugar can still be seen.
The benzenesulfonylureas described should preferably be used for the production of orally administrable preparations with blood sugar-lowering effectiveness for the treatment of diabetes mellitus and can be administered as such or in the form of their salts or in the presence of substances that lead to salt formation. For salt formation, for example, the following can be used: Alkaline agents such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, but also organic bases, especially tertiary nitrogen bases, provided that they are physiologically compatible.
Tablets which, in addition to the products of the process, contain the usual auxiliaries and carriers, such as talc, starch, lactose, tragacanth or magnesium stearate, are preferably used as medical preparations.
A preparation that contains the benzenesulfonyl ureas described as an active ingredient, z. B. a tablet or a powder with or without the additives mentioned is expediently brought into a suitable dosed form. The dose to be selected is one that is adapted to the effectiveness of the benzenesulfonylurea used and the desired effect. The dosage per unit is expediently about 0.5 to 100 mg, preferably 2 to 10 mg, but dosage units that are considerably higher or lower can also be used, which if necessary have to be divided or taken before administration.
are to be multiplied. <I> Example </I> N- [4- (B- {B, B-diphenylpropionamido} -ethyl) benzenesulfonyl] -N '- (2,5-endomethylene-cyclohexyl-methyl) -urea 2.9 g N - [4- (3- {B, B-Diphenylpropionamido} -ethyl) benzenesulfonyl] -N '- (2,5-endomethylene-cyclohexyl-methyl) -thiourea (produced by reacting 4- [B- (B, B -Diphenyl-propionamido) -ethyl] -benzenesulfonamide and 2,5-endomethylene-cyclohexyl mustard oil, melting point 162-164 ° C.) are suspended in 100 ml of methanol.
0.1 g of potassium carbonate and 1.1 g of mercury oxide are added and the mixture is stirred at 40 ° C. for 4 hours.
After filtering off, it is concentrated. The residue of N- [4- (B- {B, B-diphenylpropionamido} -ethyl) benzenesulfonyl] -N '- (2,5-endomethylenecyclohexylmethyl) -isourea methyl ether obtained as a viscous resin is mixed with 250 ml of concentrated HCl for 30 minutes heated on the steam bath. The crystalline precipitate formed is filtered off with suction, washed with water and recrystallized from methanol. The N- [4- (B- {B, B-diphenylpropionanido} -ethyl) benzenesulfonyl] -N '- (2,5-endomethylenecyclohexylmethyl) urea with a melting point of 191 to 192 ° C. is obtained in good yield.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF0045611 | 1965-03-24 | ||
| CH1735366 | 1966-03-21 | ||
| CH405566A CH468357A (en) | 1965-03-24 | 1966-03-21 | Process for the preparation of benzenesulfonylureas |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH486435A true CH486435A (en) | 1970-02-28 |
Family
ID=27174685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH937669A CH486435A (en) | 1965-03-24 | 1966-03-21 | Process for the preparation of benzenesulfonylureas |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH486435A (en) |
-
1966
- 1966-03-21 CH CH937669A patent/CH486435A/en not_active IP Right Cessation
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