KR800000489B1 - Process for preparing benzenesulfonyl ureas - Google Patents

Abstract

Benzenesulfonyl ures and its salts(I; x = pyridyl, pyrimidinyl, quinolyl, benzothiazolyl, benzoxazolyl; R = C1-3 alkyl; R1 = C3-6 alkyl, C5-9 cycloalkenyl, cycloalkenyl, bicycloheptyl, bicycloheptenyl, adamantyl, benzyl), useful as hyperglycemic agent, were prepd. by oxidn. of benzenesulfinyl urea and benzenesulfenyl uresa. Thus, 3.4 g 4-(β-(N'-methyl-N'-pyridyl -ureidoethyl)-benzenesulfinic chloride and 1.7 g cyclohexyl urea were treaed at room temp. for 20 min in 20ml pyridine to give N-[4-(β-(N'-methyl-N'-pyridyl-ureidoethyl)-benzenesulfonyl urea.

Description

Method for preparing benzenesulfonyl-urea

The present invention relates to a method for preparing sulfonyl urea and salts of the following structural formula (I), which are strong and persistently lowering blood glucose concentrations as blood glucose reducing agents.

In the above formula

X represents a pyridyl, pyrimidinyl, quinolyl, benzthiazolyl or benzoxazolyl group, which groups may be substituted by one or two methyl groups and are connected with molecular moieties at positions adjacent to the nitrogen atom.

R is alkyl having 1 to 3 carbon atoms,

R ¹ is alkyl having 3 to 6 carbon atoms, cycloalkyl having 5 to 9 carbon atoms each, alkyl cycloalkyl, cycloalkylalkyl, cycloalkenyl or bicycloheptyl, bicycloheptenyl, nortricyclyl, ar Just kill or benzyl.

The compound of formula (I) is prepared by oxidation of a compound selected from the group consisting of the corresponding benzenesulfinyl urea and benzene sulfenyl urea and, if necessary, treatment with an alkalizing agent to form salts.

The reaction conditions for carrying out the present reaction are generally modified within a wide range and can be adopted in each case, for example, solvents may or may not be used and may be carried out at room temperature or at elevated temperatures.

Depending on the type of starting material, some of the previously described methods may produce only a small amount of sulfonyl urea or may be inadequate for its synthesis. In this relatively rare case the expert will never have difficulty in synthesizing the product to be obtained according to one of the other methods of the described recipe.

The hypoglycaemic action of benzenesulfonyl-urea described above is a Hagedorn-Jensen method or an automatic assay for a long time by administration as a free compound or in the form of sodium salt in a normal breeding rabbit at an amount of 10 mg / kg body weight. Measure and confirm by

The following table shows the hypoglycemic action of the compounds obtained according to the rod method.

[table]

Percentage of decrease in blood glucose levels in rabbits over time after the following compounds were administered to rabbits in an amount of 10 mg / kg

N- [4- (β-N'-methyl-N'-2-pyridylureido ethyl) -benzenesulfonyl] -N '-(4-methylcyclohexyl) -urea (Compound I)

N- [4- (β-N'-2-quinolyl-N'-methylureidoethyl) -benzenesulfonyl] -N'-cyclohexyl-urea (Compound II)

N- [4- (β-N'-2-quinolyl-N'-methylureidoethyl) -benzenesulfonyl] -N'-cyclopentyl-urea (Compound III)

Benzenesulfonyl-urea according to the present invention is preferably used for the preparation of pharmaceutical preparations suitable for oral administration to reduce blood glucose levels in the treatment of diabetes mellitus, in the form of the compound itself or physiologically tolerant salts or the production of such salts. Used in the presence of a substance causing Bases such as alkali or alkaline earth metals, hydroxides or alkali or alkaline earth metal carbonates or bicarbonates are used to make the salts.

The pharmaceutical preparations advantageously comprise, in addition to the compounds of the present invention, pharmaceutically toxic carrier materials such as talc, starch, lactose, tragacanth and magnesium stearate.

Pharmaceutical preparations containing the sulfonyl urea according to the invention as an active substance, for example, a substance or powder with or without carriers may be made in a suitable unit dosage form. The dosage chosen should depend on the activity of the sulfonyl-urea and the desired effect.

Unit doses correspond to 1 to 100 mg, with amounts of 5 to 20 mg being preferred but higher or lower amounts are generally used and, where necessary, divided or doubled prior to administration.

The sulfonyl-urea according to the present invention may be used alone or in combination with other oral antidiabetic agents in the treatment of diabetes mellitus. Such compounds include not only hypoglycemic sulfonyl-ureas but also compounds having other chemical compositions such as biguanides, especially phenylethyl-biguanide or difetyl-biguanide.

The following examples illustrate several of the various methods used for the synthesis of sulfonyl-ureas according to the present invention, but do not limit the object of the present invention.

EXAMPLE

N- [4- (β-N'-methyl-N'-2-pyridylureidoethyl) -benzenesulfonyl] -N'-cyclohexylurea

3.4 g of 4- (β-N'-methyl-N'-pyridyl-ureidoethyl) -benzenesulfinic acid chloride (4- (β-N'-methyl-N'-pyridyl-ureidoethyl)- Benzenesulfinic acid and thionyl chloride) are added to a solution containing 1.7 g of cyclohexylurea in 20 ml of pyridine and the mixture is left at room temperature for 20 minutes. The mixture is then poured into ice water and acidified with red acetic acid. The precipitate formed is treated with dilute ammonia, the insolubles are separated and dissolved in a small amount of dimethylformamide and an aqueous solution of permanganate is added to the resulting solution until the color of the permanganate remains. The mixture is decolorized with a small amount of sodium bisulfite, suction filtered the precipitated manganese dioxide and water and diluted acetic acid are added to the filtrate.

Precipitated N [4- (β-N'-methyl-N'-2-pyridyl-ureidoethyl) -benzenesulfonyl] -N'-cyclohexylurea is recrystallized from ethanol / DMF. Melting Point: 167-169 ℃

Claims (1)

A process for preparing the compound of formula (I) or a salt thereof, characterized by oxidizing a compound selected from benzenesulfinyl urea and benzenesulphenyl urea corresponding to the compound of formula (I).

In the above formula, X represents a pyridyl, pyrimidinyl, quinolyl, benzthiazolyl or benzoxazolyl group, which may be substituted by one or two methyl groups and connected to a molecular moiety at a position introduced to the nitrogen atom. . R is alkyl having 1 to 3 carbon atoms, R 1 is alkyl having 3 to 6 carbon atoms, cycloalkyl, alkyl cycloalkyl, cycloalkylalkyl, cycloalkenyl or bicycloheptyl, each having 5 to 9 carbon atoms, Bicycloheptenyl, nortricyclib, adamantyl or benzyl.