KR790001599B1 - Process for preparing sulfonyl ureas - Google Patents

Abstract

Sulfonylureas (I; R1 =H C1-6 alkyl, OR C3-8 cycloalkyl; R2= C1-6 alkyl C3-8 cycloalkyl ,or R1 and R2are forming heterocyclic compd. with nitrogen which is attached in R1 or R2 ; R3 = e.g., C1-8 alkyl C3-8 alkenyl-alkyl, or C5-8 cycloalkyl, or c7-10 endoalkylene-cycloalkyl), useful as antidiabetics, were prepd. by treating sulfonyl isocyanate (II) or sulfonylcarbamic acid derivs. (III; Z = halogen, alkoxy, aryloxy, alkylthio, amino, arylamino, l-imidazolyl, or trichloromethyl) with R3NH2

Description

Method for preparing sulfonylurea derivative

The present invention relates to a sulfonylurea derivative of formula (I) and a method for preparing a physiologically toxic salt thereof.

In the above structural formula

R ¹ is hydrogen or alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, R ² is alkyl having 1 to 6 carbon atoms or cycloalkyl having 3 to 8 carbon atoms, or R ¹ and R ² are bonded to nitrogen; Together form a heterocycle and R ³ may be substituted with alkyl of 1 to 8 carbon atoms, alkenyl-alkyl of 3 to 8 carbon atoms, or cycloalkyl of 5 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms (2 or 3 )-(Cyclopentene or cyclohexene) -1-yl, alkyl of 1 to 4 carbon atoms-cycloalkyl of 5 to 8 carbon atoms, endoalkylene-cycloalkyl of 7 to 10 carbon atoms, cycloalkyl of 3 to 8 carbon atoms- Alkyl of 1 to 4 carbon atoms, or cycloalkenyl-C 1 to 4 carbon atoms of 5 to 8 carbon atoms.

Examples of alkyl groups were methyl, ethyl, propyl, isopropyl, butyl, and examples of cycloalkyl are cyclopentyl, cyclohexyl, cycloheptyl. Heterocyclic ring formed by R ¹ and R ² together with the nitrogen atom to which they are attached include 3 to 6 hexagonal rings such as pyrrolidine, piperidine, azetidine, aziridine, and morpholine. Examples of alkenyl-alkyl are allyl and 2-butenyl, examples of alkyl-cycloalkyl are 4-methyl-cyclohexyl, examples of cycloalkyl-alkyl are cyclohexylmethyl and cyclopentylmethyl, cycloal An example of kenyl-alkyl is cyclohexenylmethyl. Examples of endoalkylene-cycloalkyl are bornyl, norbornyl. Physiologically nontoxic salts of the compounds of formula (I) include alkali metal salts and alkaline earth metal salts (eg sodium salts, potassium salts).

Preferred among the compounds of formula (I) are those in which R ¹ and R ² are each methyl or R ¹ and R ² form a heterocycle with the nitrogen to which they are attached, and R ³ is cyclohexyl, cyclopentyl or cyclopentylmethyl .

The sulfonylurea derivatives according to the present invention are prepared as follows. That is, the sulfonyl isocyanate of the following formula (V) or is prepared by reacting a sulfonyl carbamic acid derivative of the following formula (VI) with an amine of the following formula (VII).

Z is halogen or alkoxy, aryloxy, alkylthio, arylthio, amino, -NHR ³ , arylamino, diarylamino, 1-imidazolyl, 3,5-dimethyl-1-pyrazolyl or triclo And R ¹ , R ² and R ³ are as described above, or two sites of R ² may form a heterocycle with their attached nitrogen.

The reaction is carried out in the presence or absence of a solvent. As the solvent, an inert solvent such as ketone (eg acetone), ether (eg dioxane, tetrahydrofuran) or dimethylformamide can be used.

The temperature at which the reaction occurs is not constant and depends on the reactivity between the reactants between 0 ° C. and the boiling point of the solvent or reaction mixture used. Inorganic bases (eg potassium carbonate or sodium hydroxide) or organic bases (eg sodium alcohol sodium hydride, diethylamine, pyridine) are preferably added to the reaction mixture.

Sulfonyl isocyanates of formula (V) used as starting materials in the present invention are prepared by reacting the corresponding sulfonamides of formula (II) with phosgene.

R ¹ and R ² in the above formula are as described above.

The sulfonylcarbamic acid derivatives of formula (VI) may be selected from the group consisting of sulfonamides of formula (II), Potassium cyanide, alkyl or aryl isocyanate or N, N-2 substituted carbamoyl chloride (Z = amino, substituted amino); Carbonyldiimidazole or carbonyldi (3,5-dimethyl-1-pyrazole) (Z = 1-imidazolyl or 3,5-dimethyl-1-pyrazolyl) or trichloro acetic acid methyl ester (Z = trichloro Romethyl) and the like to prepare.

The compound of formula (I) has a potent hypoglycemic action. The hypoglycemic action of this compound in warm blooded animals is observed by the following method. Three groups of female dogs reared on standard feed are tested for each compound and dose. The animals are first starved for 16 hours, and then the test compound is orally administered in gelatin capsules. Blood was collected before administration, blood was collected at 2, 4, and 5 hours after administration, heparinized, and glucose in plasma was measured using glucose-oxidase method [Analy. Biochem. 3, 131 (1962)] using a Technicon autoanalyser. As a standard, a 4% right albamine solution having a known glucose level is used. The result obtained is evaluated statistically and the blood glucose level as a percentage of the original value is calculated. The results for the three compounds of formula (I) are shown in Table I.

TABLE I

The nontoxicity of the compound of formula (I) is very good. In a 24-hour experiment in mice, LD ₅₀ is greater than 5 g / kg (oral administration).

The dosage of the compound of formula (I) for diabetes is about 10 to 100 mg per day, depending on the patient's requirements and the type of compound being administered.

The sulfonylurea derivative of the present invention can be used as a medicament by mixing it with a pharmaceutically toxic carrier. The carrier may be enteric, transdermal or parenteral inert organic or inorganic inert substance such as water, gelatin, gum arabic, lactose, starch, magnesium, stearate, talc, vegetable oil, polyalkylene glycols, washer Lynn. Pharmaceutical preparations may be prepared in solid form (eg tablets, dragees, suppositories, capsules) or in liquid form (eg liquids, suspensions, emulsions). If necessary, sterilization and / or preservatives, stabilizers, wetting agents, emulsifiers, salts and buffers for controlling osmotic pressure, etc. may be added to the preparations, and other therapeutic agents may also be contained.

The following examples illustrate the invention.

Example 1

To 43 ml of dioxane [[3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazin-7-yl) sulfonyl] 8.0 g of carbamic acid ethyl ester and 2.4 ml of cyclopentylamine The melted mixture was heated under reflux for 2 hours and evaporated in vacuo. The residue was chromatographed on silica gel (400 g) with a solvent with methanol: chloroform = 5: 95 (volume) of 1-cyclopentyl-3-[(3-dimethylcarbamoyl-2,3 having a melting point of 179 to 180 ° C. , 4,5-tetrahydro-1H-3-benzazin-7-yl) sulfonyl] urea is obtained.

Starting materials are prepared as follows.

Stirring a mixture of 7.5 g of 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzasepin-7-sulfonamide, 13.9 g of potassium carbonate, 9.6 ml of chloroformic acid ethyl ester and 150 ml of acetone Heat to reflux for 16 hours, cool to 25 ° C and pour into a mixture of 50 ml of water and 1000 ml of chloroform.

6N sulfuric acid is added with stirring to adjust the pH of the aqueous layer to 2.0, the chloroform layer is separated, dehydrated over sodium sulfate and evaporated in vacuo. Crystallization of the residue with ether gave [[3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazin-7-yl) sulfonyl] carbamic acid having a melting point of 140 to 141 ° C. Ethyl ester is obtained.

Example 2

In a similar manner as in Example 1, [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazin-7-yl) sulfonyl] carbamic acid ethyl ester was cyclopentylmethyl. 1-cyclopentylmethyl-3-[(3-dimethylcarbamoly-2,3,4,5-tetrahydro-1H-3-benzazin-7-yl) having a melting point of 165 to 166 ° C by reaction with an amine. Sulfonyl] urea.

Example 3

In a similar manner as in Example 1, [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazin-7-yl) sulfonyl] carbamic acid ethyl ester was cycloheptylamine And 1-cycloheptyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzapinze-yl) sulfonyl] urea.

Example 4

In a similar manner to Example 1, [(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzoazin-7-yl) sulfonyl] carbamic acid ethyl ester was converted to trans-4. Reacted with methylcyclohexylamine to give 1-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazin-7-yl) sulfonyl] -3- (trans- 4-methylcyclohenyl) urea is prepared.

The following example illustrates a typical pharmaceutical formulation containing one of the sulfonylurea derivatives.

Example A

25.0 mg of 1-cyclohexyl-3-[(2,3,4,5-tetrahydro-3- (1-pyrrolidinylcarbonyl)

-1H-3-benzazin-7-yl) sulfonyl] urea

Lactose 122.0mg

Corn Starch 95.0mg

Talc 7.2mg

Magnesium Stearate 0.8mg

250.0 mg total

Carefully mix the active ingredients with lactose and some of the corn starch and granulate with starch and dry. Dry granules are mixed with the remaining corn starch, talc and magnesium stearate to be compressed.

Claims (1)

A sulfonyl urea derivative of formula (I) and a salt thereof are prepared by reacting a sulfonyl isocyanate of formula (V) or a sulfonylcarbamic acid derivative of formula (VI) with an amine of formula (VIII) How to.

In the above structural formula R ¹ is hydrogen or alkyl of 1 to 6 carbon atoms or cycloalkyl group of 3 to 8 carbon atoms R ² is alkyl having 1 to 6 carbon atoms or cycloalkyl group having 3 to 8 carbon atoms; R ¹ and R ² together with the nitrogen atom to which they are attached form a heterocycle, R ³ is (2 or 3)-(cyclopentene or alkyl which may be substituted by alkyl of 1 to 8 carbon atoms, alkenyl-alkyl of 3 to 8 carbon atoms or cycloalkyl group of 5 to 8 carbon atoms, alkyl of 1 to 4 carbon atoms Cyclohensen) -1-yl group, Alkyl of 1 to 4 carbon atoms-cycloalkyl of 5 to 8 carbon atoms, Endoalkylene-cycloalkyl having 7 to 10 carbon atoms, Cycloalkyl having 3 to 8 carbon atoms-alkyl having 1 to 4 carbon atoms or cycloalkenyl having 1 to 4 carbon atoms-alkyl group having 1 to 4 carbon atoms

In the above structural formula Z is halogen or alkoxy, aryloxy, alkylthio, arylthio, amino, -NHR ³ , arylamino, diarylamino 1-imidazolyl, 3,5-dimethyl-1-pyrazolyl or trichloro methyl group, R ¹ , R ² and R ³ may be the same as described above, or two sites of R ² may form a heterocycle together with the nitrogen atom to which they are attached.