JPS6160832B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to an imidazole derivative represented by and its acid addition salt. In the formula, R ¹ and R ² are the same or different and each represents hydrogen, lower alkyl (linear or branched alkyl having 1 to 4 carbon atoms), lower alkoxy, halogen (fluorine, chlorine, bromine, iodine), ^R3 represents hydrogen or lower alkyl, and n represents an integer of 1 or 2. The compound of the present invention () has the general formula [In the formula, R ¹ , R ² , R ³ , and n have the same meanings as above,
X represents a leaving group (chlorine, bromine, iodine, hydroxyl group, lower alkylsulfonyloxy, arenesulfonyloxy, di-lower alkylamino, etc.). ]
It is produced by reacting the compound represented by the above with imidazole. More specifically, in the case of the reaction of a compound of the general formula () in which X is a reactive acid residue with imidazole in the process of the invention, an excess of imidazole is advantageously used as a deoxidizing agent or pyridine , organic bases such as picoline or triethylamine, or hydroxides, carbonates, bicarbonates of alkali metals such as potassium or sodium,
Inert solvents (water, lower alcohols, acetone, methyl ethyl ketone, ether, benzene,
Toluene, dioxane, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide,
dimethylacetamide, etc.) at temperatures from room temperature to below reflux of the solvent used. Further, when X is a hydroxyl group, the reaction is carried out by using an excess of imidazole, preferably using p-toluenesulfonic acid as a catalyst, and heating to 100 to 220°C. Further, when X represents di-lower alkylamino, the reaction is carried out by reacting the compound with imidazole under reflux in a suitable solvent (toluene, xylene, mesitylene, etc.). As a modified method, di-lower alkylamino can be converted into a mono- or quaternary salt with an alkylating agent such as methyl iodide or benzyl bromide, and then reacted with imidazole. The target product () thus produced can be purified as a free base or as a pharmacologically acceptable acid (hydrochloric acid, hydrobromic acid, sulfuric acid,
Phosphoric acid, acetic acid, maleic acid, fumaric acid, lactic acid,
It can also be isolated as an acid addition salt by treatment with tartaric acid, citric acid, p-toluenesulfonic acid, etc.). The thus obtained compound of the present invention () and its acid addition salt have a selective biosynthesis inhibitory effect on thromboxane A2, and are also effective against experimental platelet aggregation induced by adenosine diphosphate (ADP) or arachidonic acid (AA). It also has a strong inhibitory effect on Furthermore, certain compounds of the present invention have antihypertensive and central nervous system depressing effects. Therefore, it is useful as a medicine such as an antithrombotic agent, an antihypertensive agent, an antiarteriosclerotic agent, and a psychotropic agent. When the compound of the present invention is used as a medicine, it can be formulated into tablets, capsules, injections, etc. as appropriate. And usually 0.1 ~ once per adult
Administered at a rate of 20mg/Kg. Test Example Platelet aggregation inhibitory effect Using male guinea pigs weighing 400 to 500 g, blood was collected from the abdominal aorta under ether anesthesia to obtain citrated blood. Centrifuge this at 1700 rpm for 3 minutes,
The supernatant was used as platelet-rich plasma (PRP). In the in vitro test, 3 μl of the test solution was added to 0.3 ml of PRP, and 2 minutes later, adenosine diphosphate (ADP) or arachidonic acid (AA) was added.
Platelet aggregation ability was measured at °C. In in vitro tests,
The test solution was orally administered to guinea pigs, blood was collected 1 hour later to obtain PRP, and platelet aggregation ability was measured in the same manner. In addition, platelet aggregation ability was measured using Born's method (GVR
Borm, J. Physiol. 162.67 (1962)). The effect of the test compound was expressed as an inhibition rate (%) relative to the aggregation area of the control group. The results are shown in Tables 1 and 2.

【table】

[Table] In the above table, compounds A, B, C and D mean the following compounds. A: 1-(1,2-dihydronaphthalen-3-ylmethyl)imidazole hydrochloride B: 1-(7-methoxy-1,2-dihydronaphthalen-3-ylmethyl)imidazole hydrochloride C: 1-(6 ,7-dimethyl-1,2-dihydronaphthalen-3-ylmethyl)imidazole hydrochloride monohydrate D: 1-(2-indenylmethyl)imidazole hydrochloride The present invention will be described in detail with reference to Examples below. However, the present invention is not limited thereto. Example 1 8.9 g of 3-chloromethyl-1,2-dihydronaphthalene, 6.8 g of imidazole and potassium carbonate
6.9 g are suspended in 200 ml of acetone and the mixture is stirred and refluxed for 4-5 hours. After cooling, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. After thorough washing with water, dry with Glauber's salt and evaporate the solvent. When the residual oil is subjected to silica gel column chromatography using chloroform as a developing solvent, 1-(1,2-dihydronaphthalen-3-ylmethyl)imidazole is obtained. This was converted into a hydrochloride salt using a conventional method, and when recrystallized from a mixed solvent of acetone and methanol, the melting point was 195.
A hydrochloride salt of ~198°C is obtained. Example 2 2-chloromethyl-5-fluoroindene 9.1
g, imidazole 6.8 g and potassium carbonate 6.9 g
into 200ml of acetone, and add this mixture to 4-5
Stir and reflux for an hour. After cooling, the solvent was distilled off under reduced pressure.
The residue was extracted with ethyl acetate. After washing with water and drying with Glauber's salt, the solvent is distilled off, and the resulting residual oil is subjected to silica gel column chromatography using chloroform as a developing solvent to obtain 1-(5-fluoro-2-indenylmethyl)imidazole as an oil. . This is converted into a hydrochloride salt by a conventional method and recrystallized from acetone to obtain a hydrochloride 1/2 hydrate with a melting point of 95-98°C. Example 3 6.4 g of 6-chloro-3-chloromethyl-1,2-dihydronaphthalene and 5.1 g of imidazole are dissolved in 50 ml of dimethylformamide and left overnight at room temperature. Pour into ice water, make alkaline with potassium carbonate, and extract several times with chloroform. After washing with water and drying with Glauber's salt, the solvent is distilled off, 30% isopropanol hydrochloric acid is added to the resulting residual oil, and the solvent is distilled off. Add acetone to this and cool it on ice to precipitate crystals. When this is recrystallized from a mixed solvent of methanol and acetone, 1-
(6-chloro-1,2-dihydronaphthalene-3
-ylmethyl)imidazole hydrochloride is obtained. Example 4 7-methoxy-3-dimethylaminomethyl-
Stir 6.5 g of 1,2-dihydronaphthalene and 5.1 g of imidazole with 200 ml of xylene and reflux 4.
Do time. After cooling, the solvent was distilled off under reduced pressure and extracted with ethyl acetate. After washing with water and drying with Glauber's salt, the solvent is distilled off, and the residue is subjected to silica gel column chromatography using chloroform as a developing solvent to obtain 1-(7-methoxy-1,2-dihydronaphthalen-3-ylmethyl)imidazole. When this is converted into a hydrochloride salt by a conventional method and recrystallized from acetone, the melting point is
A hydrochloride salt of 176-178°C is obtained. The following compounds can be produced in the same manner as in the above examples. ◎1-(6,7-dimethyl-1,2-dihydronaphthalen-3-ylmethyl)imidazole hydrochloride monohydrate, melting point 188-190℃ ◎1-(8-chloro-1,2-dihydronaphthalene) -3-ylmethyl)imidazole hydrochloride,
Melting point 236-238℃ ◎1-(2-indenylmethyl)imidazole・
Hydrochloride, melting point 178-180℃ ◎1-(5-chloro-2-indenylmethyl)imidazole hydrochloride, melting point 186-189℃ ◎1-(6-chloro-2-indenylmethyl)imidazole hydrochloride , melting point 184-187℃ ◎1-(6-methoxy-2-indenylmethyl)
Imidazole hydrochloride, melting point 152-155℃ ◎1-(6-methylthio-1,2-dihydronaphthalen-3-ylmethyl)imidazole hydrochloride, melting point 147-149℃ ◎1-(5-methyl-2-inde 1-(6-methoxy-1,2-dihydronaphthalen-3-ylmethyl)imidazole hydrochloride, melting point 162-163℃

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ and R ² are the same or different and represent hydrogen, lower alkyl, lower alkoxy, halogen, or lower alkylthio, R ³ represents hydrogen or lower alkyl, and n represents an integer of 1 or 2. ) Imidazole derivatives and acid addition salts represented by: