CH512452A - Hypoglycaemic benzenesulphonylureas - Google Patents
Hypoglycaemic benzenesulphonylureasInfo
- Publication number
- CH512452A CH512452A CH33771A CH33771A CH512452A CH 512452 A CH512452 A CH 512452A CH 33771 A CH33771 A CH 33771A CH 33771 A CH33771 A CH 33771A CH 512452 A CH512452 A CH 512452A
- Authority
- CH
- Switzerland
- Prior art keywords
- cyclopentyl
- alkoxy
- alkyl
- bicyclo
- halogen
- Prior art date
Links
- 230000002218 hypoglycaemic effect Effects 0.000 title 1
- -1 norcaran-7-yl Chemical group 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 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 claims abstract description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 5
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 5
- 235000013877 carbamide Nutrition 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 150000002542 isoureas Chemical class 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- ZFLIKDUSUDBGCD-UHFFFAOYSA-N parabanic acid Chemical class O=C1NC(=O)C(=O)N1 ZFLIKDUSUDBGCD-UHFFFAOYSA-N 0.000 claims description 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002071 phenylalkoxy group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 235000019253 formic acid Nutrition 0.000 claims 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 abstract 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 239000001273 butane Substances 0.000 abstract 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 abstract 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 abstract 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 abstract 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 abstract 1
- 125000001400 nonyl 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])C([H])([H])[H] 0.000 abstract 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 abstract 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 abstract 1
- 125000003003 spiro group Chemical group 0.000 abstract 1
- 125000001544 thienyl group Chemical group 0.000 abstract 1
- 239000008280 blood Substances 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000004202 carbamide Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 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
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000694 effects Effects 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
- 239000000155 melt Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 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
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 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
- 150000007524 organic acids Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- QXKXDIKCIPXUPL-UHFFFAOYSA-N sulfanylidenemercury Chemical compound [Hg]=S QXKXDIKCIPXUPL-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
Classifications
-
- 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Benzenesulphonylureas and their suitable salts. - (I) R1 = 4, 7-endomethyleneperhydroindan-5-yl opt. 6-Cl, 4, 7-endomethyleneperhydroindan-2-yl, 2, 6-endomethylenecycloheptyl, 4, 4-Me2-DELTA2-cyclohexenyl, DELTA2-cyclopentenyl/heptenyl/octenyl, norcaran-7-yl, bicyclo (5.1.0) octyl (8)/(6.1.0) nonyl (9)/(4.2.0) octyl (7), 2, 5-endocyclobutylene (1, 2) cyclohexyl, Me/3, 3-Me2/3-Et/3-t-Bu/2-Cl-cyclopentyl, DELTA2-cyclopentenylmethyl, bicyclo-(2.1.1) pentyl (2), spiro (2-cyclopropane/butane/pentanepent yl), cyclopropryl/butyl, 5-Me-DELTA2-cyclohexenyl, bicyclo (3.1.0) hexyl; - X = Ph, opt. substd. by Z and Z' where Z = H, halogen, alkyl, alkoxy, alkenoxy, alkoxyalkoxy, phenalkoxy, acyl, PhCH2, CF3, OH and Z' = CN, NO2, H, halogen, alkyl, alkoxy, alkoxyalkoxy, OH; thienyl opt. mono/disubstd. by alkyl, alkoxy, alkoxyalkoxy, alkenoxy, phenalkoxy, halogen; Y = CH2CH2, CH2CHMe or CHMe. CH2.
Description
Verfahren zur Herstellung von Benzolsulfonylharnstoffen Gegenstand der Erfindung ist ein Verfahren zur Her stellung von Benzolsulfonylharnstoffen der Formel
EMI0001.0003
die als Substanz oder in Form ihrer Salze blutzucker- senkende Eigenschaften besitzen und sich durch eine starke und langanhaltende Senkung des Blutzuckerspie gels auszeichnen.
In der Formel bedeuten: R1 4,7-Endomethylen-perhydroindan-5-yl
EMI0001.0009
das in 6-Stellung durch Chlor substituiert sein kann, 4,7-Endomethylen-perhydroindan-2-yl
EMI0001.0013
2,6-Endomethylen-cycloheptyl, 4,4-Dimethy1-42-cyclohexenyl, O2-Cyclopentenyl, A2-Cycloheptenyl, A2-Cycloocte- nyl, Norcaran-7-yl,
EMI0001.0021
Bicyclo 15,1,
0] octyl-(8)
EMI0001.0025
Bicyclo <B>[</B>6,1,0] nonyl-(9)
EMI0001.0028
Bicyclo t4,2,0] octyl-(7)
EMI0001.0032
2,5-Endo-cyclobutylen-(1,2)-cyclohexyl
EMI0001.0034
Methyl-cyclopentyl, 3,3-Dimethyl-cyclopentyl-, 3-Äthyl-cyclopentyl, 3-tert.-Butyl-cyclopentyl, 2-Chlor-cyclopentyl, A2-Cyclopentenyl-methyl,
Bicyclo [2,1,1] hexyl- (2)
EMI0001.0044
Spiro-(2-cyclopropan-cyclopentyl)
EMI0002.0001
Spiro-(2-cyclobutan-cyclopentyl)
EMI0002.0003
Spiro-(2-cyclopentan-cyclopentyl)
EMI0002.0005
Cyclopropyl, Cyclobutyl, 5-Methyl-A2-cyclohexenyl, Bicyclo 13,1,0] hexyl
EMI0002.0012
X (a) einen Phenylrest,
der an beliebigen Stellen die folgenden Substituenten Z und Z' trägt, wobei Z und Z' gleich oder verschieden sein können, Z Wasserstoff, Halogen; Alkyl, Alkoxy, Alken- oxy, Alkoxy-alkoxy, Phenalkoxy oder Acyl mit 1 bis 4 Kohlenstoffatomen in der Alkyl- gruppe; Benzoyl: Trifluormethyl; Hydroxy; Z' -CN;
-N02; Wasserstoff; Halogen; Alkyl, Alkoxy oder Alkoxy-alkoxy mit 1 bis 4 Kohlenstoffato- men in der Alkylgruppe oder Hydroxy, (b) einen Thiophenrest, der gegebenenfalls ein- oder zweifach durch Alkyl, Alkoxy, Alkoxyalkoxy,
Alkenoxy oder Phenylalkoxy mit 1 bis 4 Koh- lenstoffatomen in der Alkylgruppe oder Halo gen substituiert sein kann, wobei die unter (a) genannte Bedeutung von X bevorzugt ist, Y eine der Gruppierung
EMI0002.0050
Acyl bedeutet einen organischen Säurerest,
vorzugs weise einen geradkettigen oder verzweigten Alkanoyl- rest mit 1 bis 4 Kohlenstoffatomen in der Alkylgruppe.
Als Glied X in der obigen Formel in Frage kommen de Ringsysteme sind beispielsweise folgende:
EMI0002.0058
EMI0003.0000
EMI0004.0000
Das erfindungsgemässe Verfahren ist dadurch ge kennzeichnet, dass man entsprechend substituierte Ben- zolsulfonylisoharnstoffäther, -isothiohamstoffäther, -iso- harnstoffester,
-parabansäuren oder -halogenameisen- säureamidine oder Verbindungen der Formel
EMI0005.0010
oder deren Parabansäurederivate oder Verbindungen der Formel
EMI0005.0012
wobei U jeweils eine der Gruppen -O- Alkyl mit 1 bis 4 Kohlenstoffatomen in der Alkylgruppe, -S- Alkyl mit 1 bis 4 Kohlenstoffatomen in der Alkylgruppe oder Ha logen (vorzugsweise Chlor) bedeutet,
hydrolysiert und die Reaktionsprodukte gegebenenfalls zur Salzbildung mit alkalischen Mitteln behandelt.
Je nach der Natur der Ausgangsmaterialien insbe sondere des Gliedes X wird in einzelnen Fällen das eine oder andere der genannten Verfahren für die Herstellung der unter die allgemeine Formel fallenden individuellen Verbindungen ungeeignet sein, oder zumindest Vorkeh rungen zum Schutz aktiver Gruppen notwendig machen. Derartige verhältnismässig selten auftretende Fälle kön nen vom Fachmann unschwer erkannt werden, und es bereitet keine Schwierigkeiten, in solchen Fällen die ent sprechenden Massnahmen zu ergreifen.
Die Hydrolyse der als Ausgangsstoffe genannten Benzolsulfonylparabansäuren, -isoharnstoffäther, -iso- thioharnstoffäther, -isoharnstoffester oder -halogenamei- sensäureamide erfolgt zweckmässig in alkalischem Medium. Isoharnstoffäther und Isoharnstoffester kön nen auch in einem sauren Medium mit gutem Erfolg hy- drolysiert werden.
Die Ausführungsformen des Verfahrens gemäss der Erfindung können im allgemeinen hinsichtlich der Re aktionsbedingungen weitgehend variiert und den jewei ligen Verhältnissen angepasst werden. Beispielsweise kön nen die Umsetzungen in Abwesenheit oder Anwesenheit von Lösungsmitteln, bei Zimmertemperatur oder bei erhöhter Temperatur durchgeführt werden.
Die blutzuckersenkende Wirkung der beschriebenen Benzolsulfonylharnstoffderivate konnte dadurch festge stellt werden, dass man sie, z.B. in Form des Natrium salzes, in Dosen von 10 mg/kg an normal ernährte Ka ninchen verfütterte und den Blutzuckerwert nach der bekannten Methode von Hagedorn Jensen oder mit einem Autoanalyzer über eine längere Zeitdauer ermit telte.
So wurde beispielsweise ermittelt, dass 10 mg/kg N- -[4 - (ss - < 2 = Methoxy-5-methyl-benzamido>-äthyl) - benzol- sulfonyl]-N'- (4,7-endomethylen-perhydroindanyl-5)-harn- stoff nach 3 Stunden eine Blutzuckersenkung von 24% bewirkt. Gleichermassen bewirken 10 mg N-[4-(ss- < 2- -Methoxy-5-chlorbenzamido> - äthyl) - benzolsulfonyl]-N'- -(4,
7-endomethylen-perhydroindanyl-5)-harnstoff nach 6 Stunden eine Blutzuckersenkung von 23%, während der bekannte N-[4-Methyl-benzolsulfonyl]-N'-butylharnstoff bei einer Dosierung von weniger als 25 mg/kg am Ka- ninchen keine Senkung des Blutzuckerspiegels mehr hervorruft.
Ferner wurde ermittelt, dass 10 mg N-[4-(ss- < 2-Meth- oxy-benzamido>-äthyl)-benzolsulfonyl] - N'- (4,7-endome- thylen-perhydroindanyl-5)-harnstoff nach 3 Stunden eine Blutzuckersenkung von 40% bewirken.
Die Verfahrensprodukte besitzen somit eine sehr starke blutzuckersenkende Wirksamkeit bei einer ausser- ordentlich guten Verträglichkeit.
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 werden. Zur Salzbildung können beispielsweise alkali sche Mittel wie Alkali- oder Erdalkalihydroxyde, -car- bonate oder -bicarbonate herangezogen werden.
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 die genannten Zusätze, ist zweckmässig in eine geeignet dosierte Form gebracht. Als Dosis ist dabei eine solche zu wählen, die der Wirksam keit des verwendeten Benzolsulfonylharnstoffs und dem gewünschten Effekt angepasst ist.
Zweckmässig beträgt die Dosierung je Einheit etwa 0,5 bis 100 mg, vorzugs weise 2 bis 10 mg, jedoch können auch erheblich dar über oder darunter liegende Dosierungseinheiten verwen det werden, die gegebenenfalls vor Applikation zu tei len bzw. zu vervielfachen sind.
<I>Beispiel 1</I> N-[4-(ss- < 2-Methoxy-5-chlor-benzamido>-äthyl)-benzol- sul fonyn-N'-(4,7-methano-perhydro-indanyl-5)-harnsto <I>f f</I> 1 g N- [4- (ss- < 2-Methoxy-5-chlor-benzamido>-äthyl)- -benzolsulfonyl] - N'- (4,7- methano - perhydro-indanyl-5)- -thioharnstoff (Schmelzpunkt 137 - 139 C) wird in 100 ml Methanol gelöst, dem man 10 ml Dioxan zugesetzt hat. Man gibt 1,1 g Quecksilberoxyd zu und rührt 3 Stunden bei 50 - 60 C.
Nach Abfiltrieren von Quecksilbersulfid wird im Vakuum eingeengt. Der so erhaltene N-[4-(ss- < 2- -Methoxy-5-chlor-benzamido>-äthyl)-benzolsulfonyl] - N'- -(4,7 - methano-perhyd ro-indanyl - 5) - isoharnstoffmethyl- äther wird in 20 ml Dioxan und 100 ml konz. Salzsäure suspendiert. Man erhitzt 10 Minuten auf dem Dampf bad, giesst in Wasser, saugt den Niederschlag ab und kristallisiert aus Methanol um.
Der erhaltene N-[4-(ss- < 2-Methoxy-5-chlor-benzami- do>-äthyl)-benzolsulfonyl] - N'- (4,7-methano-perhydro-in- danyl-5)-harnstoff schmilzt bei<B>196</B> -198 C. <I>Beispiel 2</I> N-[4-(ss- < 2-Methoxy-5-chlor-benzamido>-äthyl)-benzol- stdf onya-N'-(3-methylcyclo pentyl )-harnsto <I>f f</I> 4,9 g 1-(3-Methylcyclopentyl)-parabansäure werden in 200 ml Benzol suspendiert.
Dazu gibt man 2,5 g Tri- äthylamin und anschliessend 8,9 g 4-(ss- < 2-Methoxy-5- -chlor-benzamido>-äthyl)-benzolsulfochlorid. Das Ge misch wird 3 Stunden am Rückflusskühler erhitzt, heiss filtriert, das gekühlte Filtrat mit Petroläther versetzt, die abgeschiedene Substanz abgesaugt, mit 50 ml Dioxan und 100 ml In Natronlauge 30 Min. auf dem Dampfbad erhitzt, die Lösung filtriert und mit Wasser und Salz säure versetzt.
Der abgeschiedene N-[4-(ss- < 2-Methoxy-5 -chlor-benzamido>-äthyl)-benzolsulfonyl]-N'-(3-methylcy- clopentyl)-harnstoff wird aus Methanol umkristallisiert und schmilzt bei 156 - 158 C.
Process for the preparation of benzenesulfonylureas The invention relates to a process for the preparation of benzenesulfonylureas of the formula
EMI0001.0003
which, as a substance or in the form of their salts, have blood sugar-lowering properties and are characterized by a strong and long-lasting lowering of the blood sugar level.
In the formula: R1 denotes 4,7-endomethylene-perhydroindan-5-yl
EMI0001.0009
which can be substituted in the 6-position by chlorine, 4,7-endomethylene-perhydroindan-2-yl
EMI0001.0013
2,6-endomethylene-cycloheptyl, 4,4-dimethy1-42-cyclohexenyl, O2-cyclopentenyl, A2-cycloheptenyl, A2-cyclooctenyl, norcaran-7-yl,
EMI0001.0021
Bicyclo 15.1,
0] octyl- (8)
EMI0001.0025
Bicyclo <B> [</B> 6,1,0] nonyl- (9)
EMI0001.0028
Bicyclo t4,2,0] octyl- (7)
EMI0001.0032
2,5-endo-cyclobutylene- (1,2) -cyclohexyl
EMI0001.0034
Methyl-cyclopentyl, 3,3-dimethyl-cyclopentyl-, 3-ethyl-cyclopentyl, 3-tert-butyl-cyclopentyl, 2-chloro-cyclopentyl, A2-cyclopentenyl-methyl,
Bicyclo [2,1,1] hexyl- (2)
EMI0001.0044
Spiro- (2-cyclopropane-cyclopentyl)
EMI0002.0001
Spiro- (2-cyclobutane-cyclopentyl)
EMI0002.0003
Spiro- (2-cyclopentane-cyclopentyl)
EMI0002.0005
Cyclopropyl, cyclobutyl, 5-methyl-A2-cyclohexenyl, bicyclo 13,1,0] hexyl
EMI0002.0012
X (a) a phenyl radical,
which bears the following substituents Z and Z 'at any point, where Z and Z' can be identical or different, Z is hydrogen, halogen; Alkyl, alkoxy, alkenoxy, alkoxyalkoxy, phenalkoxy or acyl with 1 to 4 carbon atoms in the alkyl group; Benzoyl: trifluoromethyl; Hydroxy; Z '-CN;
-N02; Hydrogen; Halogen; Alkyl, alkoxy or alkoxyalkoxy with 1 to 4 carbon atoms in the alkyl group or hydroxy, (b) a thiophene radical, which is optionally substituted once or twice by alkyl, alkoxy, alkoxyalkoxy,
Alkenoxy or phenylalkoxy can be substituted with 1 to 4 carbon atoms in the alkyl group or halogen, the meaning of X mentioned under (a) being preferred, Y being one of the groupings
EMI0002.0050
Acyl means an organic acid residue,
preferably a straight-chain or branched alkanoyl radical with 1 to 4 carbon atoms in the alkyl group.
The following ring systems can be considered as member X in the above formula:
EMI0002.0058
EMI0003.0000
EMI0004.0000
The process according to the invention is characterized in that correspondingly substituted benzene sulfonyl isourea ethers, isothiourea ethers, iso urea esters,
-parabanic acids or -halogenoformic acid amidines or compounds of the formula
EMI0005.0010
or their parabanic acid derivatives or compounds of the formula
EMI0005.0012
where U is one of the groups -O- alkyl with 1 to 4 carbon atoms in the alkyl group, -S- alkyl with 1 to 4 carbon atoms in the alkyl group or halogen (preferably chlorine),
hydrolyzed and the reaction products, if necessary, treated with alkaline agents to form salts.
Depending on the nature of the starting materials, in particular the member X, one or the other of the processes mentioned will be unsuitable for the preparation of the individual compounds falling under the general formula, or at least precautions will be necessary to protect active groups. Such cases, which occur relatively rarely, can easily be recognized by a person skilled in the art, and there are no difficulties in taking the appropriate measures in such cases.
The hydrolysis of the benzenesulfonylparabanic acids, benzenesulfonylparabanic acids, isourea ethers, isothiourea ethers, isourea esters or haloformic acid amides mentioned as starting materials is expediently carried out in an alkaline medium. Isourea ethers and isourea esters can also be hydrolyzed with good success in an acidic medium.
The embodiments of the method according to the invention can generally be varied widely with regard to the reaction conditions and adapted to the respective ratios. For example, the reactions can be carried out in the absence or presence of solvents, at room temperature or at elevated temperature.
The blood sugar-lowering effect of the benzenesulfonylurea derivatives described could be determined by using them, e.g. in the form of sodium salt, fed in doses of 10 mg / kg to normally nourished rabbits and determined the blood sugar value over a longer period of time using the well-known method of Hagedorn Jensen or with an autoanalyzer.
For example, it was determined that 10 mg / kg of N- - [4 - (ss - <2 = methoxy-5-methyl-benzamido> -ethyl) -benzenesulfonyl] -N'- (4,7-endomethylene-perhydroindanyl -5) urea causes a blood sugar drop of 24% after 3 hours. 10 mg of N- [4- (ss- <2- -Methoxy-5-chlorobenzamido> - ethyl) - benzenesulfonyl] -N'- (4,
7-endomethylene-perhydroindanyl-5) urea resulted in a 23% reduction in blood sugar after 6 hours, while the well-known N- [4-methylbenzenesulfonyl] -N'-butylurea at a dose of less than 25 mg / kg in rabbits no longer causes a decrease in blood sugar levels.
It was also determined that 10 mg of N- [4- (ss- <2-methoxy-benzamido> -ethyl) -benzenesulfonyl] -N'- (4,7-endomethylene-perhydroindanyl-5) -urea after 3 hours cause a blood sugar drop of 40%.
The products of the process thus have a very strong blood sugar-lowering effectiveness with an extraordinarily good tolerance.
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 example, alkaline agents such as alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates can be used for salt formation.
Tablets which, in addition to the process products, contain the usual auxiliaries and carriers such as talc, starch, lactose, tragacanth or magnesium stearate are preferably used as medical preparations.
A preparation which contains the described benzenesulfonyl ureas as active ingredient, e.g. a tablet or a powder with or without the additives mentioned is expediently brought into a suitably 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 above or below this can also be used, which may have to be divided or multiplied before administration.
<I> Example 1 </I> N- [4- (ss- <2-methoxy-5-chloro-benzamido> -ethyl) -benzenesulfonyn-N '- (4,7-methano-perhydro-indanyl -5) urine <I> ff </I> 1 g N- [4- (ss- <2-methoxy-5-chlorobenzamido> -ethyl) - -benzenesulfonyl] - N'- (4,7- Methano - perhydro-indanyl-5) - -thiourea (melting point 137-139 ° C) is dissolved in 100 ml of methanol to which 10 ml of dioxane has been added. 1.1 g of mercury oxide are added and the mixture is stirred for 3 hours at 50 - 60 C.
After filtering off the mercury sulfide, it is concentrated in vacuo. The N- [4- (ss- <2-methoxy-5-chlorobenzamido> -ethyl) -benzenesulfonyl] -N'- (4,7-methano-perhydro-indanyl-5) -isoureamethyl obtained in this way - ether is concentrated in 20 ml of dioxane and 100 ml. Hydrochloric acid suspended. The mixture is heated on the steam bath for 10 minutes, poured into water, the precipitate is filtered off with suction and recrystallized from methanol.
The N- [4- (ss- <2-methoxy-5-chlorobenzamido> -ethyl) -benzenesulfonyl] - N'- (4,7-methano-perhydro-indanyl-5) -urea obtained Melts at <B> 196 </B> -198 C. <I> Example 2 </I> N- [4- (ss- <2-methoxy-5-chlorobenzamido> -ethyl) -benzene- stdfonya -N '- (3-methylcyclopentyl) urine <I> ff </I> 4.9 g of 1- (3-methylcyclopentyl) parabanic acid are suspended in 200 ml of benzene.
To this are added 2.5 g of triethylamine and then 8.9 g of 4- (ss- <2-methoxy-5- chlorobenzamido> -ethyl) benzene sulfochloride. The mixture is heated for 3 hours on a reflux condenser, filtered hot, petroleum ether is added to the cooled filtrate, the deposited substance is filtered off with suction, heated on the steam bath with 50 ml of dioxane and 100 ml of sodium hydroxide for 30 minutes, the solution is filtered and treated with water and salt acid added.
The deposited N- [4- (ss- <2-methoxy-5-chlorobenzamido> -ethyl) -benzenesulfonyl] -N '- (3-methylcyclopentyl) -urea is recrystallized from methanol and melts at 156-158 C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF0053202 | 1967-08-10 | ||
| CH1062168A CH506500A (en) | 1967-08-10 | 1968-07-16 | Hypoglycaemic benzenesulphonylureas |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH512452A true CH512452A (en) | 1971-09-15 |
Family
ID=25707003
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH34171A CH512453A (en) | 1967-08-10 | 1968-07-16 | Process for the preparation of new benzenesulfonylureas |
| CH33771A CH512452A (en) | 1967-08-10 | 1968-07-16 | Hypoglycaemic benzenesulphonylureas |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH34171A CH512453A (en) | 1967-08-10 | 1968-07-16 | Process for the preparation of new benzenesulfonylureas |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH512453A (en) |
-
1968
- 1968-07-16 CH CH34171A patent/CH512453A/en not_active IP Right Cessation
- 1968-07-16 CH CH33771A patent/CH512452A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH512453A (en) | 1971-09-15 |
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