CH438302A - Process for the preparation of benzenesulfonyl semicarbazides - Google Patents
Process for the preparation of benzenesulfonyl semicarbazidesInfo
- Publication number
- CH438302A CH438302A CH1780966A CH1780966A CH438302A CH 438302 A CH438302 A CH 438302A CH 1780966 A CH1780966 A CH 1780966A CH 1780966 A CH1780966 A CH 1780966A CH 438302 A CH438302 A CH 438302A
- Authority
- CH
- Switzerland
- Prior art keywords
- preparation
- acids
- benzenesulfonyl
- carbon atoms
- substituted
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- LSNDGFYQJRXEAR-UHFFFAOYSA-N benzenesulfonamidourea Chemical class NC(=O)NNS(=O)(=O)C1=CC=CC=C1 LSNDGFYQJRXEAR-UHFFFAOYSA-N 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 239000002253 acid Substances 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- -1 3-ethylbenzenesulfonyl Chemical group 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000013078 crystal Substances 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
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ASRMWYDEZPXXBA-UHFFFAOYSA-N (sulfonylamino)urea Chemical class NC(=O)NN=S(=O)=O ASRMWYDEZPXXBA-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- KFPMLWUKHQMEBU-UHFFFAOYSA-N 3-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC(S(Cl)(=O)=O)=C1 KFPMLWUKHQMEBU-UHFFFAOYSA-N 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
- 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
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical class CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- GHDLZGOOOLEJKI-UHFFFAOYSA-N benzenesulfonylurea Chemical class NC(=O)NS(=O)(=O)C1=CC=CC=C1 GHDLZGOOOLEJKI-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- ZFLIKDUSUDBGCD-UHFFFAOYSA-N parabanic acid Chemical class O=C1NC(=O)C(=O)N1 ZFLIKDUSUDBGCD-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung von Benzolsulfonyl-semicarbaziden
Es ist bekannt, dass gewisse Benzolsulfonylharnstoff- Derivate blutzuckersenkende Eigenschaften aufweisen und als per os verabreichbare Antidiabetika geedgnet sind [vgl. z. B. Arzneimittelforschung, Band 8 (1958), Seiten 444-454].
Es wurde nun gefunden, dass Benzolsulfonyl-semi- carbazide der Formel
EMI1.1
worin X einen 1 bis 6 Kohlenstoffatome enthaltenden Alkylrest in ortho-oder meta-Stellung und Z-Z'-eine 5 Kohlenstoffatome enthaltende Alkylenkette, die gege benenfalls durch weitere niedsigmolekulare Alkylreste substituiert sein kann, bedeutet, und deren Salze blüt- zuckersenkende Eigenschaften besitzen.
Man erhält diese Verbindungen gemäss der Erfindung, indem man im Benzolkern entsprechend substitu- ierte l-Benzolsulfonyl-3-alkylleniminoparabansäuren hydrolytisch spaltet.
Die nach dem Verfahren gemäss der Erfindung er hältlichen Benzolsulfonyl-semicarbazide stellen wertrolle Arzneimittel dar, die & ich insbesondere durch eine gute blutzuckersenkende Wirksamkeit bei geringer r Toxizi tät auszeichnen.
Wie aus der folgenden Tabelle ersichtlich ist, tritt bereits nach peroraler Verabreichung von erfindungsgemäss dargestelltem 4- (3-Äthyl-benzolsulfonyl)-1, 1-pen- tamethylen-semicarbazid in Mengen von 100 mg/kg nach 6 Stunden eine 33% ige Blutzuckersenkung bei Kaninchen auf.
Zeit in Stunden 1 2 3 4 5 6 Blutzucker senkung in % 0-27-28-28-27-33
Auch das in gleicher Weise in Mengen von 400 mg/kg applizierte 4-(2-Methyl-benzolsulfonyl)-1, 1-pentamethy- len-semicarbazid zeichnet sich durch eine sehr gute blut- zuckersenkende Wirkung aus :
Zeit in Stunden 1 2 3 4 5 6
Blutzucker senkung in %-14-20-23-28-31-36
Die Verfahrensprodukte'sollen vorzugsweise zur HerstellungvonoralverabreichbarenPräparatenmithy- poglykämischer Wirkung zur Behandlung des Diabetes mellitus dienen, wobei die Sulfonylsemicarbazide sowohl als solche oder in Form ihrer Salze mit Basen oder Säu- ren oder in Gegenwart von Stoffen, die zu einer Salz bildung fiihren, verwendet werden können. Zur Salzbildung können beispielsweise herangezogen werden :
Alkalische Mittel, wie Alkali-oder Erdalkalihydroxyde, -carbonate,-bicarbonate sowie physiologisch verträgliche organische Basen; ferner Säuren, wie Chlorwasserstoffsäure, Bromwasserstoffsäure, Schwefelsäure und Amidosulfonsäure.
Als medazinische Präparate kommen vorzugsweise Tabletten in Betracht, die neben den in Mengen von 0, 05 bis 0, 5 g pro VerabreichungseinheX enthaltenen Verfahrenserzeugnissen die üblichen Hilfs-und Träger- stoffe, wie Talkum, Stärke, Milchzucker, Tragant, Magnesiumstearat, enthalten.
Beispiel
4-(3-Methyl-benzols, ulfonyl)-l, 1-pentamethylen- semicarbazid a) 19, 7 g Pentamethyleniminoparabansäure (hergestellt durch Umsetzung von 1, l-Pentamethylensemicar- bazid und Oxalylchlorid, Schmp. 136-138 C) werden in 250 ml Benzol suspendiert und mit 10 g Triäthyl- amin versetzt. Es tritt Lösung ein. Dann gibt man 19 g 3-Methyl-benzolsulfochlorid zu und erhitzt 2 Stunden unter Rückfluss zum Sieden. Die ausgeschiedenen Kristalle werden nach längerem Stehen abgesaugt, mit Wasser gewaschen und getrocknet.
Die l- (3-Methyl-benzol- sulfonyl)-3-pentamethyleniminoparabansäure schmilzt bei 193-195 C. b) 3, 5 g des rohen Parabansäurederivates werden mit 80 ml In Natronlauge auf dem Dampfbad erhitzt. Nach kurzer Zeit tritt Lösung ein, dann scheiden sich Kristalle ab. Man saugt das Natriumsalz ab, wäscht mit Azeton, löst in Wasser und fällt durch Ansäuern mit Essigsäure. Das 4-(3-Methyl-benzolsulfonyl)-l, l-penba- methylen-semicarbazid schmilzt nach Umkristallisieren aus Methanol bei 156-158 C.
Process for the preparation of benzenesulfonyl semicarbazides
It is known that certain benzenesulfonylurea derivatives have blood sugar-lowering properties and are suitable as antidiabetic agents that can be administered orally [cf. z. B. Pharmaceutical Research, Volume 8 (1958), pages 444-454].
It has now been found that benzenesulfonyl-semicarbazide of the formula
EMI1.1
wherein X is an alkyl radical containing 1 to 6 carbon atoms in the ortho or meta position and Z-Z 'is an alkylene chain containing 5 carbon atoms, which may optionally be substituted by further low molecular weight alkyl radicals, and the salts thereof have blood sugar-lowering properties.
These compounds according to the invention are obtained by hydrolytically cleaving l-benzenesulfonyl-3-alkylleniminoparabanic acids which are correspondingly substituted in the benzene nucleus.
The benzenesulfonyl-semicarbazides obtainable according to the method according to the invention are valuable drugs which, in particular, are characterized by good blood-sugar-lowering effectiveness with low toxicity.
As can be seen from the following table, after oral administration of 4- (3-ethylbenzenesulfonyl) -1, 1-pentamethylene semicarbazide in amounts of 100 mg / kg after 6 hours, a 33% decrease in blood sugar occurs in rabbits.
Time in hours 1 2 3 4 5 6 Blood sugar drop in% 0-27-28-28-27-33
The 4- (2-methyl-benzenesulfonyl) -1, 1-pentamethylene-semicarbazide applied in the same way in amounts of 400 mg / kg is characterized by a very good blood-sugar-lowering effect:
Time in hours 1 2 3 4 5 6
Blood sugar reduction in% -14-20-23-28-31-36
The products of the process should preferably be used for the production of orally administrable preparations with hypoglycemic activity for the treatment of diabetes mellitus, it being possible to use the sulfonyl semicarbazides either as such or in the form of their salts with bases or acids or in the presence of substances which lead to salt formation . For example, the following can be used for salt formation:
Alkaline agents, such as alkali or alkaline earth hydroxides, carbonates, bicarbonates and physiologically compatible organic bases; also acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid and sulfamic acid.
Tablets which, in addition to the process products contained in quantities of 0.05 to 0.5 g per administration unit, contain the usual auxiliaries and carriers such as talc, starch, lactose, tragacanth, magnesium stearate are preferred medicinal products.
example
4- (3-methyl-benzenes, sulfonyl) -1, 1-pentamethylene semicarbazide a) 19.7 g of pentamethyleneiminoparabanic acid (prepared by reacting 1,1-pentamethylene semicarbazide and oxalyl chloride, melting point 136-138 C) are in Suspended 250 ml of benzene and mixed with 10 g of triethylamine. Solution occurs. 19 g of 3-methylbenzenesulphonyl chloride are then added and the mixture is refluxed for 2 hours. The precipitated crystals are filtered off with suction after long standing, washed with water and dried.
The 1- (3-methylbenzenesulfonyl) -3-pentamethyleneiminoparabanic acid melts at 193-195 ° C. b) 3.5 g of the crude parabanic acid derivative are heated with 80 ml of sodium hydroxide solution on the steam bath. After a short time, solution occurs, then crystals separate out. The sodium salt is filtered off with suction, washed with acetone, dissolved in water and precipitated by acidification with acetic acid. The 4- (3-methyl-benzenesulfonyl) -l, l-penba-methylene-semicarbazide melts after recrystallization from methanol at 156-158 C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF0035064 | 1961-10-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH438302A true CH438302A (en) | 1967-06-30 |
Family
ID=7095838
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1164362A CH427794A (en) | 1961-10-05 | 1962-10-03 | Process for the preparation of benzenesulfonylsemicarbazides |
| CH1780966A CH438302A (en) | 1961-10-05 | 1962-10-03 | Process for the preparation of benzenesulfonyl semicarbazides |
| CH1781066A CH438303A (en) | 1961-10-05 | 1962-10-03 | Process for the preparation of benzenesulfonyl semicarbazides |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1164362A CH427794A (en) | 1961-10-05 | 1962-10-03 | Process for the preparation of benzenesulfonylsemicarbazides |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1781066A CH438303A (en) | 1961-10-05 | 1962-10-03 | Process for the preparation of benzenesulfonyl semicarbazides |
Country Status (3)
| Country | Link |
|---|---|
| CH (3) | CH427794A (en) |
| DK (7) | DK102798C (en) |
| GB (1) | GB980116A (en) |
-
1962
- 1962-09-28 DK DK329663A patent/DK102798C/en active
- 1962-09-28 DK DK330063A patent/DK102742C/en active
- 1962-09-28 DK DK422562A patent/DK102740C/en active
- 1962-09-28 DK DK329963A patent/DK102800C/en active
- 1962-09-28 DK DK329863A patent/DK103019C/en active
- 1962-09-28 DK DK329763A patent/DK102799C/en active
- 1962-09-28 DK DK329563A patent/DK102797C/en active
- 1962-10-03 CH CH1164362A patent/CH427794A/en unknown
- 1962-10-03 CH CH1780966A patent/CH438302A/en unknown
- 1962-10-03 CH CH1781066A patent/CH438303A/en unknown
- 1962-10-04 GB GB3757862A patent/GB980116A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK102800C (en) | 1965-10-11 |
| DK103019C (en) | 1965-11-08 |
| CH427794A (en) | 1967-01-15 |
| DK102740C (en) | 1965-10-04 |
| DK102798C (en) | 1965-10-11 |
| DK102799C (en) | 1965-10-11 |
| CH438303A (en) | 1967-06-30 |
| GB980116A (en) | 1965-01-13 |
| DK102742C (en) | 1965-10-04 |
| DK102797C (en) | 1965-10-11 |
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