DE1029819B - Process for the production of orally applicable, blood sugar lowering benzenesulfonyl urethanes - Google Patents
Process for the production of orally applicable, blood sugar lowering benzenesulfonyl urethanesInfo
- Publication number
- DE1029819B DE1029819B DEN12853A DEN0012853A DE1029819B DE 1029819 B DE1029819 B DE 1029819B DE N12853 A DEN12853 A DE N12853A DE N0012853 A DEN0012853 A DE N0012853A DE 1029819 B DE1029819 B DE 1029819B
- Authority
- DE
- Germany
- Prior art keywords
- methyl
- benzenesulfonyl
- urethanes
- blood sugar
- production
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- C07C311/53—X and Y not being nitrogen atoms, e.g. N-sulfonylcarbamic acid
Description
Verfahren zur Herstellung von oral anwendbaren, den Blutzucker senkenden Benzolsulfonyl-urethanen Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von oral anwendbaren, den Blutzucker senkenden Benzolsulfonyl-urethanen, die in der p-Stellung zur Sulfonamid-Gruppe keine freie Amino-Gruppe enthalten. Das Fehlen der o-ständigen freien Amino-Gruppe bietet den Vorteil, daß die betreffenden Produkte auch bei längerer unterschwelliger Verabreichung keine Sulfonamid-Resistenz gegenüber Erregern hervorrufen können.Process for the production of orally applicable, blood sugar lowering Benzenesulfonyl urethanes The present invention relates to a process for the preparation of orally applicable, blood sugar lowering benzenesulfonyl urethanes, which are used in the p-position to the sulfonamide group contain no free amino group. The missing the o-free amino group has the advantage that the products in question no sulfonamide resistance even with prolonged subliminal administration Cause pathogens.
Es sind bereits oral anwendbare, den Blutzucker senkende Substanzen bekannt, die in der p-Stellung zur Sulfonamid-Gruppe keine freie Amino-Gruppe enthalten. Von ihnen wird der Nl-(p-Toluolsulfonyl)-N2 n-butylharnstoff klinisch verwendet.They are already orally applicable, blood sugar lowering substances known which contain no free amino group in the p-position to the sulfonamide group. Of them, the Nl- (p-toluenesulfonyl) -N2 n-butylurea is used clinically.
Es wurde nun gefunden, daß die Benzolsulfonylurethane der Formel worin R Methyl oder Äthyl bedeutet und X für eine Alkoxygruppe mit einem niederen Alkylrest steht, nach oraler Gabe ebenfalls die Blutzuckerkonzentration senken, jedoch eine vergleichsweise geringe Toxizität besitzen. So beträgt die LD50 beim Ni (p=roluolsulfonyl)-N2 nbutylharnstoff 0,75 g/kg, beim p-Methoxybenzolsulfonylcarbamidsäuremetliylester dagegen 1,3 g/kg. Der Blutzucker ist nach peroralen Gaben von 500 mg/kg beim Ni (p-Toluolsulfonyl)-Nz n-butylharnstoff nach 5 Stunden von 100 °/o auf 82 °/o, beim p-Methoxybenzolsulfonylcarbamidsäuremethylester dagegen von 10001/0 auf 760/ o gesunken.It has now been found that the benzenesulfonyl urethanes of the formula where R is methyl or ethyl and X is an alkoxy group with a lower alkyl radical, after oral administration likewise lower the blood sugar concentration, but have a comparatively low toxicity. For example, the LD50 for Ni (p = roluenesulfonyl) -N2 n-butylurea is 0.75 g / kg, whereas for methyl p-methoxybenzenesulfonylcarbamic acid it is 1.3 g / kg. The blood sugar after oral administration of 500 mg / kg with Ni (p-toluenesulphonyl) -Nz n-butylurea is from 100% to 82% after 5 hours, with p-methoxybenzenesulphonylcarbamic acid methyl ester from 10001/0 to 760 / o sunk.
Die genannten Benzolsulfonylurethane lassen sich nach an sich dem Fachmann bekannten Methoden folgendermaßen herstellen: 1. durch Umsetzung eines entsprechend substituierten Benzolsulfonamids mit einem Clllorkohlensäuremethyl-oder -äthylester.The benzenesulfonyl urethanes mentioned can be according to the Manufacture methods known to those skilled in the art as follows: 1. By implementing a appropriately substituted benzenesulfonamides with a methyl carbonic acid or ethyl ester.
2. durch Umsetzung eines entsprechend substituierten Benzolsulfonylharnstoffes mit Methyl- oder Äthylalkohol unter Abspaltung von Ammoniak, oder 3. durch Umesterung eines entsprechend substituierten Benzolsulfonylurethans, in dem die Carbonsäuregruppe mit einem höheren Alkohol verestert ist, mit Methyl-oder Äthylalkohol.2. by reacting an appropriately substituted benzenesulfonylurea with methyl or ethyl alcohol with elimination of ammonia, or 3. by transesterification an appropriately substituted benzenesulfonyl urethane in which the carboxylic acid group is esterified with a higher alcohol, with methyl or ethyl alcohol.
Beispiel p -;Methoxy-benzolsulfonyl-carbamidsäuremethylester 37,4 g (0,2 Mol) p-Methoxy-benzolsulfonamid, 28,5 g (0,3 Mol) Chlorkohlensäuremethylester, 8,0 g (0,2 Mol) Natriumhydroxyd, gelöst in 200 ccm Wasser, 200 ccm Aceton.Example p -; Methoxy-benzenesulfonyl-carbamic acid methyl ester 37.4 g (0.2 mol) of p-methoxy-benzenesulfonamide, 28.5 g (0.3 mol) of methyl chlorocarbonate, 8.0 g (0.2 mol) of sodium hydroxide dissolved in 200 cc of water, 200 cc of acetone.
Man löst das p-Methoxy-benzolsulfonamid in der Natronlauge, vermischt die Lösung mit dem Aceton und kühlt die Mischung auf 0 bis + 5°C ab. Unter Kühlung und Rühren gibt man zu der Lösung zwischen 0 und -f- 5°C tropfenweise den Chlorkohlensäuremethylester, wobei man durch gelegentliche Zugabe von konzentrierter Natronlauge den pH-Wert zwischen 11 und 11,5 hält. Nach der Zugabe des Chlorkohlensäureesters rührt man 30 Minuten im Eisbad und anschließend so lange bei Zimmertemperatur weiter, bis keine weitere Natronlauge mehr verbraucht wird. Man bringt mit Säure auf pH 6,5, dampft das Aceton ab, verdünnt mit 200 ccm Wasser und kühlt gut im Eisbad.The p-methoxy-benzenesulfonamide is dissolved in the sodium hydroxide solution, mixed the solution with the acetone and cools the mixture to 0 to + 5 ° C. Under cooling and stirring, the methyl chlorocarbonate is added dropwise to the solution between 0 and -f- 5 ° C, with the occasional addition of concentrated sodium hydroxide solution to adjust the pH holds between 11 and 11.5. After the addition of the chlorocarbonic acid ester, the mixture is stirred 30 minutes in an ice bath and then continue at room temperature until no more caustic soda is used. It is brought to pH 6.5 with acid, the acetone evaporates, diluted with 200 cc of water and cools well in an ice bath.
Das auskristallisierte, nicht umgesetzte p-Methoxybenzolsulfonamid wird abfiltriert und das Filtrat zweimal mit Aktivkohle behandelt. Nach dem Ansäuern erhält man 40,5 g des p-Methoxy-benzol-sulfonyl-carbamidsä_uremethvlesters.The unreacted p-methoxybenzenesulfonamide that crystallized out is filtered off and the filtrate is treated twice with activated charcoal. After acidification 40.5 g of p-methoxy-benzene-sulfonyl-carbamidsä_uremethvlesters are obtained.
Zur Reinigung löst man das Rohprodukt in 800 ccm Wasser unter Zugabe von Natronlauge, bringt mit Säure auf pH 6,5, behandelt zweimal mit Aktivkohle und fällt die Substanz durch Ansäuern.For cleaning, the crude product is dissolved in 800 ccm of water with the addition of sodium hydroxide solution, brought to pH 6.5 with acid, treated twice with activated charcoal and the substance falls through acidification.
Der p-Methoxybenzolsulfonyl-carbamidsäuremethylester bildet farblose Kristalle, die zwischen 125 und 128°C unter Zersetzung schmelzen.The methyl p-methoxybenzenesulfonyl carbamate forms colorless Crystals that melt between 125 and 128 ° C with decomposition.
Claims (1)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEN12853A DE1029819B (en) | 1956-10-18 | 1956-10-18 | Process for the production of orally applicable, blood sugar lowering benzenesulfonyl urethanes |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEN12853A DE1029819B (en) | 1956-10-18 | 1956-10-18 | Process for the production of orally applicable, blood sugar lowering benzenesulfonyl urethanes |
Publications (1)
Publication Number | Publication Date |
---|---|
DE1029819B true DE1029819B (en) | 1958-05-14 |
Family
ID=7339646
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DEN12853A Pending DE1029819B (en) | 1956-10-18 | 1956-10-18 | Process for the production of orally applicable, blood sugar lowering benzenesulfonyl urethanes |
Country Status (1)
Country | Link |
---|---|
DE (1) | DE1029819B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE845042C (en) * | 1950-07-14 | 1952-07-28 | Basf Ag | Process for the preparation of sulfonyl urethanes, ureas or carboxylic acid amides |
-
1956
- 1956-10-18 DE DEN12853A patent/DE1029819B/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE845042C (en) * | 1950-07-14 | 1952-07-28 | Basf Ag | Process for the preparation of sulfonyl urethanes, ureas or carboxylic acid amides |
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