KR840002140B1 - Process for preparing imidazole derivatives - Google Patents

Abstract

Imidazoles [I; Y = S, sulfinyl or sulfonyl; Z = (un)substituted thienyl, Ph were prepd. from the reaction of II and Z-CHO. Thus, 3,3,6,6-tetramethyl-4,5-thiepanedione was heated with PhCHO and NH4OAc to give 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl 1-H- thiepino[4,5-d imidazole.

Description

Method for preparing imidazole derivative

The present invention relates to novel imidazole derivatives of the general formula (I) which are useful for the treatment of diabetes or prevention of thrombosis and methods for the preparation of physiologically nontoxic acid salts, especially inorganic acid salts thereof.

In the above formula,

X is hydrogen or C _1-4 alkyl;

Y is sulfur, sulfinyl group or sulfonyl group,

의 그룹이고, 여기에서 R¹, R²및 R³는 수소, 메틸, 불소, 하이드록시, 메톡시 또는 메틸티오 이거나, 인접한 탄소원자상에 존재하는 R¹, R²및 R³중의 두개는 함께 메틸렌 디옥시 또는 에틸렌디옥시를 형성하거나, R¹, R²및 R³중의 하나는 모노- 또는 디-(C₁-C₄알킬)-아미노이며, 나머지 둘은 수소이다.Z is thienyl or a general formula optionally substituted by methyl or fluorine

Wherein R ¹ , R ² and R ³ are hydrogen, methyl, fluorine, hydroxy, methoxy or methylthio, or two of R ¹ , R ² and R ³ present on adjacent carbon atoms together are methylene Form dioxy or ethylenedioxy, or one of R ¹ , R ² and R ³ is mono- or di- (C ₁ -C ₄ alkyl) -amino and the other two are hydrogen.

The present invention relates in particular to a method for preparing imidazole derivatives of the general formula (Ia) and physiologically toxic acid addition salts thereof.

In the above formula,

Y is sulfur, sulfinyl group or sulfonyl group;

의 그룹이며, 여기에서 R¹, R²및 R³는 수소, 메틸, 불소, 하이드록시, 메톡시 또는 메틸티오이거나, 인접한 탄소원자상에 존재하는 R¹, R²및 R³중의 두개는 함께 메틸렌디옥시 또는 에털렌디옥시를 형성하거나, R¹, R²및 R³중의 하나는 모노-또는 디-(C₁-C₄알킬)-아미노이며, 나머지 둘은 수소이다.Z is thienyl or a general formula

Wherein R ¹ , R ² and R ³ are hydrogen, methyl, fluorine, hydroxy, methoxy or methylthio, or two of R ¹ , R ² and R ³ present on adjacent carbon atoms together are methylene Form a dioxy or etherylenedioxy, or one of R ¹ , R ² and R ³ is mono- or di- (C ₁ -C ₄ alkyl) -amino and the other two are hydrogen.

The term "(C ₁ -C ₄ ) -alkyl" as used herein refers to a straight chain alkyl group, which includes methyl, ethyl, n-propyl and n-butyl.

Preferred compounds of the formula (Ia) are those in which Y is sulfur and / or z is phenyl, p- (fluoro or methoxy) -phenyl, 3,4,5-trimethoxyphenyl, 3,4-methylenedi Compound that is oxyphenyl or 2-thienyl.

2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4, 5-d] imidazole and 2- (p-fluorophenyl Particularly preferred is (-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole.

The present invention also provides pharmaceutical formulations as well as the compounds of formulas (I) and (Ia) and their physiologically toxic acid addition salts.

Physiologically nontoxic inorganic salts include hydrochloride, hydrobromide, sulfate and phosphate.

The compounds and salts according to the present invention are reacted with diketone of general formula (II) and aldehyde of general formula (III) in the presence of a polar solvent containing ammonium ions to obtain a compound of general formula (I) wherein X is hydrogen. Alternatively, when preparing a compound of formula (I) wherein X is (C ₁ to C ₄ ) alkyl, the compound of formula (I) wherein X is hydrogen is alkylated, and optionally Y is sulfur The compound of formula I) is oxidized to give a compound of formula (I) wherein Y is sulfinyl, which may optionally be prepared by converting the compound of formula (I) to its physiologically toxic salt.

In the above formula,

Y and Z are as defined above. As ammonium ions, ammonium salts, preferably ammonium salts of carboxylic acids such as ammonium acetate are used. Polar solvents include dimethyl sulfoxide and dimethylformamide. The reaction of the diketone of the general formula (II) with the aldehyde of the general formula (III) is carried out while heating to the reflux temperature, preferably at 50 to 120 ° C, in particular at 90 to 100 ° C.

Instead of the diketone of formula (II), the corresponding α-ketol can be used as starting material. In this case, the reaction must be carried out in the presence of an oxidizing agent such as copper (II) acetate or lead (IV) acetate.

The alkylation reaction reacts the N-unsubstituted compound of formula (I) with an alkali metal hydride (e.g. sodium hydride) in anhydrous solvents such as dimethylformamide, and the resulting compound is an alkyl halide (e.g. methyl iodide). Id).

The reaction for the corresponding sulfoxide conversion of a compound of formula (I) wherein Y is sulfur is carried out in a solvent such as aqueous methanol, conveniently using an oxidizing agent such as sodium periodate at low temperatures, preferably at about 0-5 ° C. Can be done.

The compounds according to the invention and their physiologically toxic acid addition salts can be used as medicaments. They inhibit platelet aggregation and show hypoglycemic activity. Therefore, these compounds can be used to prevent thrombosis or to treat diabetes.

Compounds of formula (I) according to the invention are pharmaceutical, for example, pharmaceutical, organic or inorganic inert carriers suitable for enteral or parenteral administration with these compounds or salts thereof (e.g. water, gelatin, gum arabic, lactose) Ozone, starch, magnesium stearate, talc, vegetable oil, polyalkylene glycol or waseline). Pharmaceutical formulations may take the form of solids such as tablets, suppositories, capsules or liquid forms such as liquids, suspensions or emulsions. Pharmaceutical formulations may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, hydrating agents, emulsifiers, osmotic salts or buffers. They may also contain other therapeutically valuable substances. The compound according to the invention is preferably administered orally. For adults, the daily parenteral dose is 0.5-30 mg / kg body weight and the parenteral dose is 0.05-10 mg / kg body weight.

The aggregation-inhibitory activity of the compounds of the present invention is described by BORN; Nature 194, 927 (1962) and Michael and Berne MICHAL and BORN; Nature 231,220 (1971). The maximum coagulation rate is taken as the test variable and the effective concentration (EC ₅₀ ) is determined from the dose-activity curve.

The venous blood of the human body, to which the citrate salt is added, is concentrated to obtain platelet rich plasma. Test using a suspension of the test substance in 0.9% sodium chloride. 0.18 ml of citric acid-plasma is treated with 10 µl of a suspension of the test compound and incubated at 37 ° C. for 10 minutes, and then 10 µl of the collagen-fiber source is added to start aggregation. The results are shown in Table 1:

TABLE 1 Collagen-induced platelet aggregation

Hypoglycemic activity is demonstrated by the following method:

After 24 hours of starving, 12 of them were given arabic rubber (control), and 6 of them were orally administered 0.3 mmol / kg of test substance (test group), and after 100 minutes, 5% / kg body weight. A suspension of 1.6 g of glucose in 10 ml of gum arabic is orally administered. Rats are sacrificed 20 minutes after glucose administration. Plasma is obtained from blood added with heparin. The glucose concentration in plasma is measured according to the hexokinase method. Mean glucose concentrations are shown in Table II, expressed as a percentage of the control.

TABLE 2 Plasma Glucose Concentration

The following examples illustrate the invention:

Example 1

16 g of 3,3,6,6-tetramethyl-4,5-thipandione and 8 g of benzylaldehyde are dissolved in 200 ml of dimethyl sulfoxide, 60 g of anhydrous ammonium acetate is added with stirring, and the mixture is heated at 90 ° C. .

After cooling, the reaction mixture is poured into ice-water with stirring and the solution is alkalized with concentrated sodium hydroxide and extracted with ether. The organic phase is washed with ice-water and concentrated to dryness. Cover the residue with petroleum ether and rub it with a glass rod. The precipitate is filtered off and recrystallized from toluene. 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole having a melting point of 225 to 227 ° C. is obtained. do. When preparing hydrochloride, 500 mg of base is dissolved in 50 ml of ether and etheric hydrochloric acid is added dropwise with stirring until the product no longer separates. The precipitate is filtered off and washed with ether and ethanol. After filtration and drying, 600 mg of salt having a melting point of 300 ° C. is obtained.

Example 2

In the same manner as in Example 1, the following compounds were prepared.

2- (3,4-methylenedioxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole , Melting point: 179 to 180 ° C

2- (3,4-methylenedioxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole Hydrochloride, Melting Point: 270 ° C (Decomposition)

Example 3

4 g of 3,3,6,6-tetramethyl-4,5-thiphandione, 2.72 g of anisealdehyde and 15 g of anhydrous ammonium acetate are dissolved in 50 ml of dimethyl sulfoxide. The reaction is carried out at 95 ° C. for 4 hours with stirring.

The reaction mixture is poured into ice-water and the mixture is alkalized with ammonia and then extracted with ether. The combined extracts are washed with water, dried and the solvent is removed. The residue is dissolved in ether and treated until it starts to cloud with petroleum ether. After the product has crystallized, the crystals are filtered off and washed with ether. Recrystallization from n-heptane 2- (p-methoxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetra-methyl-1-H having a melting point of 175 to 176 ° C. -Thiepino [4,5-d] imidazole is obtained. Melting Point of Hydrochloride: 250 ° C (Decomposition)

Example 4

In the same manner as in Example 3, the following compounds were prepared:

2- (m-methoxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, Melting point: 185-187 degreeC, hydrochloride melting point: 280 degreeC (decomposition)

2- (0-methoxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, Melting point: 140-141 degreeC, hydrochloride melting point: 245 degreeC (decomposition)

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (p-tolyl) -1-H-thiepino [4,5-d] imidazole, Melting point: 211 to 213 ° C, hydrochloride melting point: 270-275 ° C

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (m-tolyl) -1-H-thiepino [4,5-d] imidazole, Melting point: 237 to 240 ° C, hydrochloride melting point: 260 ° C (decomposition)

2- (p-methylthiophenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, Melting point: 165-167 degreeC, hydrochloride melting point: 270-280 degreeC (decomposition)

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (0-tolyl) -1-H-thiepino [4,5-d] imidazole, Melting point: 110 to 115 ° C, hydrochloride melting point: 275 ° C (decomposition)

p- (4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazol-2-yl) -phenol, melting point: 255 ° C, hydrochloride melting point: 300 ° C (decomposition)

m- (4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1H-thiepino [4,5-d] imidazol-2-yl) -phenol Melting point: 118 to 120 ℃, Melting Point of Hydrochloride: 300 ℃ (Decomposition)

0- (4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazol-2-yl) -phenol, melting point: 204-206 degreeC, hydrochloride melting point: 250 degreeC (decomposition)

2- (4,6-dimethylphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, melting point : 142 to 144 ° C, melting point of hydrochloride: 310 ° C (decomposition)

2- (3,4-dimethylphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, melting point : 218-220 degreeC, hydrochloride melting point: 275 degreeC (decomposition)

2- (3,4-dimethoxyphenyl) -4,5,7,8-tetrahydr-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole , Melting point: 138 to 140 ° C, hydrochloride melting point: 140 ° C (decomposition)

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (2,4,5-trimethoxyphenyl) -1-H-thiepino [4,5-d] Imidazole, melting point: 141 to 143 ° C, hydrochloride melting point: 218 to 220 ° C

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (2,4,6-trimethoxyphenyl) -1-H-thiepino [4,5-d] Imidazole, melting point: 141 to 142 ° C, hydrochloride melting point: 235 to 240 ° C (decomposition)

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (3,4,5-trimethoxyphenyl) -1-H-thiepino [4,5-d] Imidazole, melting point: 188 to 190 ° C, hydrochloride melting point: 290 ° C (decomposition)

2- (3,4-ethylenedioxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole , Melting point: 178 to 180 ° C, hydrochloride melting point: 195 ° C (decomposition)

2- [p- (diethylamino) -phenyl] -4,5,7,8-tetra-hydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] Imidazole, melting point: 190 to 192 ° C, hydrochloride melting point: 250 ° C (decomposition)

4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-2- (2-thienyl) -1-H-thiepino [4,5-d] imidazole, Melting point: 213 To 215 ° C, hydrochloride melting point: 250 ° C (decomposition)

2- (m-fluorophenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, Melting point: 199 to 200 ° C, hydrochloride point: 290 ° C (decomposition)

2- (0-fluorophenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, Melting point: 98-99 degreeC, hydrochloride melting point: 300 degreeC (decomposition)

2- (p-fluorophenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole, Melting point: Melting | fusing point of hydrochloride: 195-198 degreeC: 300 degreeC (decomposition).

Example 5

4 g of 3,3,6,6-tetramethyl-4,5-thiepanedione and 3.6 g of 3,4-methylenedioxy-5-methoxybenzaldehyde were dissolved in 50 ml of dimethylformamide, followed by 15.5 g of anhydrous ammonium acetate. Add. The reaction is carried out with stirring at 95 ° C. for 5 hours.

After cooling, the reaction mixture is poured into ice-water with stirring. The mixture is alkalized with ammonia and washed with ether. The organic phase is washed with water, dried and concentrated. The crystalline residue is triturated with ether and petroleum ether and suction filtered. After recrystallization from n-heptane, 2- (5-methoxy-3,4-methylenedioxyphenyl) -4,5,7,8, -tetrahydro-4,4,8,8-tetramethyl- 1H-thiepino [4,5-d] imidazole is obtained. Melting | fusing point: 175-178 degreeC, melting | fusing point of hydrochloride: 300 degreeC (decomposition).

Example 6

1.5 g of 3,3,6,6-tetramethyl-4,5-thiphandione 1,1-dioxide, 7 g of benzaldehyde and 5 g of anhydrous ammonium acetate are dissolved in 16 ml of dimethyl sulfoxide. The reaction mixture is heated to 95 ° C. with stirring, and then left to stand for another 4 hours under the same conditions. The mixture is poured into ice-water with stirring at room temperature, alkalinized with concentrated sodium hydroxide and extracted with ethyl acetate. The organic phase is washed with ice-water, dried and the solvent is distilled off. The residue is treated with ether to crystallize the product. To recrystallize, the material is dissolved in ethyl acetate, filtered and treated with n-hexane. 2-Phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4,5-d] imidazole 6,6-dioxide is obtained.

Melting point: 260-263 degreeC, Melting point of hydrochloride: 300 degreeC.

Example 7

The reaction was carried out in a similar manner to Example 6, where 2- (m-methoxyphenyl) -4,5,7,8-tetrahydro-4,4,8,8-tetramethyl- having a melting point of 217 to 219 ° C. 1-H-thiepino [4,5-d] imidazole 6,6-dioxide is obtained.

Example 8

4.04 g of 5-hydroxy-2,3,6,7-tetrahydro-3,3,6,6-tetramethyl-4 (5H) -thiefinone are dissolved in 100 ml of methanol with stirring at 50 ° C. 5 g of copper (II) acetate hydrate are added followed by 2.12 g of benzaldehyde. Next, 60 ml of concentrated aqueous ammonia solution was added dropwise. The mixture is boiled under reflux for 4 hours and then filtered before dishing. The filter cake is washed with hot methanol and suction dried.

The copper salt precipitate is suspended in aqueous ethanol, acidified with 2N hydrochloric acid and passed through hydrogen sulfide under stirring at 80 ° C. After 3 hours, the copper sulfide is filtered off. The filtrate is concentrated and the suspension is alkalined with concentrated ammonia and extracted with ether. The organic phase is dried and concentrated, and the residue is recrystallized from n-heptane to give 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H-thiepino [4 , 5-d] -imidazole is obtained.

Melting point: 223 to 224 캜.

Example 9

The reaction was carried out in a similar manner to Example 8, and recrystallized from ethanol / n-hexane to be 2-phenyl-4,5,7,8-tetrahydro-4,4,8,8-tetramethyl-1-H- Thiefino [4,5-d] -imidazole 6-oxide is obtained.

Melting point: 273 to 275 ° C, hydrochloride Melting point: 300 ° C

Example 10

In a similar manner as in Example 8, 2- (m-methoxy-phenyl) -4,5,7,8-tetrahydr-4,4,8,8-tetramethyl-1-H-thiepino [4, 5-d] imidazole 6-oxide is obtained. Melting Point: 205-207 ° C

Example 11

Tablets containing the following compositions are prepared by conventional methods:

Example 12

Hard gelatin capsules of the following compositions are prepared by conventional methods:

Example 13

Injectable solutions of the following compositions are prepared by conventional methods:

Claims (1)

The diketone of the formula (II) and the aldehyde of the formula (III) are reacted in the presence of a polar solvent containing ammonium ions. Method for preparing acid addition salts.

Z-CH = O (III) In the above formula, Y is sulfur, sulfinyl group or sulfonyl group; Z is thienyl or a general formula

Wherein R ¹ , R ² and R ³ are hydrogen, methyl, fluorine, hydroxy, methoxy or methylthio, or ^{two of} R ¹ , R ² and R ³ together with adjacent carbon atom phases together Form methylenedioxy or ethylene dioxy, or one of R ¹ , R ² and R ³ is mono- or di- (C _1-4 -alkyl) -amino and the other two are hydrogen.