DE1570032B

DE1570032B - Sulphonylureas, process for their preparation and pharmaceuticals. Elimination from: 1214675

Info

Publication number: DE1570032B
Authority: DE
Inventors: Tsutomu; Suzue Seigo; Abe Yasuo; Tokio Irikura
Original assignee: Kyorin Pharmaceutical Co Ltd
Current assignee: Kyorin Pharmaceutical Co Ltd

Description

Beispiel 1
N-p-Chlorbcnzolsulfonyl-N'-morpholinharnstoffexample 1
Np-chlorobenzene sulfonyl-N'-morpholine urea

Eine Lösung von 26 g p-Chlorbenzolsulfonylcarbamidsäureäthylester in 120 ml Benzol wird mit 10 g N-Aminomorpholin versetzt. Unter schwacher Wärmeentwicklung wird eine homogene Lösung erhalten. Nach dem Abdestillieren des Benzols unter vermindertem Druck wird der Rückstand 4 Stunden auf 110 bis 130⁰C erhitzt. Nach dem Abkühlen wird das Produkt aus Methanol umkristallisiert. Ausbeute 25,5 g farblose Kristalle vom Schmelzpunkt 205 bis 208° C.
*) Generic, name für N-Biilyl-N'-(p-melhy1sulfonyl)-harns!olT. A solution of 26 g of ethyl p-chlorobenzenesulfonylcarbamate in 120 ml of benzene is mixed with 10 g of N-aminomorpholine. A homogeneous solution is obtained with a slight evolution of heat. After the benzene has been distilled off under reduced pressure, the residue is ^{heated to 110 to 130 °} C. for 4 hours. After cooling, the product is recrystallized from methanol. Yield 25.5 g of colorless crystals with a melting point of 205 to 208 ° C.
*) Generic, name for N-Biilyl-N '- (p-melhy1sulfonyl) -harns! OlT.

I 570 032
3 ⁴ I 570 032
3 ⁴

Example 2

N-p-Chlorbenzolsulfonyl-N'-l.ö-dimeihylmorpholinharnstolTN-p-chlorobenzenesulfonyl-N'-l.ö-dimethylmorpholine urine

Ein Gemisch aus 10 g N-Amino-^-dimethylmor- umgesetzt. Nach dem ^*^£«^η "£ ^S pholin, 20 g ρ - Chlorbenzolsulfonylcarbamidsäure- 5 werden 8 g Produkt in Form farbloser Kristalle äthylester und 50 ml Benzol wird gemäß Beispiel 1 erhalten. Schmelzpunkt 192 bis 195 C.A mixture of 10 g of N-amino - ^ - dimethylmor- implemented. After the ^ * ^ £ « ^η " £ ^ S pholine, 20 g of ρ-chlorobenzenesulfonylcarbamic acid, 8 g of product in the form of colorless crystals of ethyl ester and 50 ml of benzene are obtained according to Example 1. Melting point 192 to 195 C.

Hierzu 1 Blatt Zeichnungen1 sheet of drawings

Claims

Patent claims:

1. Sulphonylureas of the general formula

R ¹

SO ₁ -NH-CO-NH-NOI

R ²

in which R ¹ and R ^{2 are} either hydrogen atoms or methyl groups.

2. Process for the preparation of the sulfonylureas of the general formula I, characterized in that in a known manner ρ - ethyl chlorobenzenesulfonylcarbamic acid with an aminomorpholine of the general formula II

R ¹

H ₁ NN

II

R ²

in which R ¹ and R ^{2 have} the meaning given above, at temperatures of 100 to 140 "C.

3. Medicinal preparation consisting of a sulfonylureader general formula I and customary carriers and diluents.

3535

The invention relates to sulfonylureas in general Formula I.

R ¹

SO ₃ -NH-CO-NH-NOI

4545

R ²

in which R ¹ and R ^{2 are} either hydrogen atoms or methyl groups, and a process for their preparation, which is characterized in that ethyl p-Chlorbcnzenesulfonylcarbamidsäureät with an aminomorpholine of the general formula II

R¹ R ¹

H, N -N

II

R ²

5555

6060

in which R ¹ and R ² have the meaning given above, at temperatures of 100 to 140 ⁰ C. The desired product can be obtained by heating N-aminomorpholine or N-amino-2,6-dimethylmorpholine with the alkyl p-chlorobenzenesulfonylcarbate acid in the presence of either an organic solvent. such as benzene or acetone, or from water or in the absence of any solvent, the heat treatment being carried out ^{at 100 to 140 ° C.}

The compounds of general formula I are valuable antidiabetic agents. Your effect was with Tolbutamide *) compared.

The tests were carried out as follows:

Wistar rats that have not been fed for 24 hours were, one compound in each case in an amount of 300 mg / kg i.p. v. injected. The blood sugar v / were 1, 2, 4, 6 and 24 hours after administration of the test compound by enzymatic determination the blood glucose determined, the rats were fed after the first 6 hours to the To facilitate re-adjustment of the blood sugar level. The drop in blood sugar levels was always in Ratio to the blood sugar content of the control animals, which was set at 100, in milligram percent definitely. The values given are average values from a group of six test animals. The blood sugar values as a function of time were entered in a diagram.

The figure shows the effectiveness of N-p-chlorobenzenesulfonyl - 2,6 - dimethylmorpholine urea. And N - ρ - chlorobenzenesulfonyl - N '- morpholine urea.

As can be seen from the drawing, the morpholine compound according to Example 1 in the first Hour has a stronger effect than tolbutamide, but the duration of the effect is compared to tolbutamide a bit shorter. On the other hand is the 2,6-dimethylmorpholine compound according to Example 2 somewhat weaker in the effect than the morpholine compound according to Example 1, but stronger than tolbutamide. In terms of the duration of the hypoglycemic effect approaches The 2,6-dimethyl derivative is best suited to tolbutamide. The therapeutic progress lies in that the compounds of the invention during the first three hours after administration a have a stronger effect than tolbutamide.

The acute toxicity of tolbutamide is 2.5 g / kg, that of the compound according to Example I is above 20 g / kg * that of the compound according to Example 2 is above 2.5 g / kg, determined as LD ₅₀ on the mouse perorally.

The compounds of general formula I show in tests carried out on mice for more than 75 days who were offered 0.05% solutions of the sodium salt of the compounds for drinking, none chronic symptoms and no growth retardation. The number of erythrocytes and leukocytes in the test animals and a control group, the 0.05% aqueous saline solution for drinking was offered showed no differences.