JPS647074B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel and pharmaceutically useful compounds of the general formula (In the formula, R represents hydrogen, lower alkyl, di-lower alkylamino lower alkyl. Ar is halogen,
having 1 to 3 substituents selected from lower alkyl, cycloalkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, carboxymethoxy, lower alkoxycarbonylmethoxy, and di-lower alkylamino lower alkoxy in any combination at any position; Indicates phenyl, methoxynaphthyl, and methylindolyl, which may be ) and its acid addition salts.

To explain the above definition in more detail, lower alkyl includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.
Di-lower alkylamino-lower alkyl refers to dimethylaminomethyl, diethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, etc.
Halogens include fluorine, chlorine, bromine, and iodine.
Cycloalkyl refers to cyclopropyl, cyclopentyl, cyclohexyl, etc. Lower alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. Lower alkoxycarbonyl refers to methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl, etc., lower alkoxycarbonylmethoxy means methoxycarbonylmethoxy, ethoxycarbonylmethoxy,
Propoxycarbonylmethoxy, isopropoxycarbonylmethoxy, butoxycarbonylmethoxy, etc., and dilower alkylamino lower alkoxy include dimethylaminoethoxy, diethylaminoethoxy, dimethylaminopropoxy, etc.

The compound of the present invention represented by the general formula () can be produced, for example, by the method shown below.

Method 1 General formula (wherein, R has the same meaning as above) and a compound represented by the general formula Ar-Mg-X () (wherein, Ar has the same meaning as above, and X represents a halogen) A Grignard reagent or an organic lithium compound represented by the general formula Ar-Li () (wherein Ar has the same meaning as above) is mixed with a non-aqueous solvent (ether, tetrahydrofuran, dioxane,
A method in which the product is reacted by a conventional method in a solvent such as benzene, toluene, or a mixed solvent thereof, and then the product is hydrolyzed.

Method 2 General formula (In the formula, Ar has the same meaning as above, and Y represents a halogen.) A compound represented by the general formula (In the formula, R has the same meaning as above.) A base (hydrogen A method of reacting in the presence of sodium chloride, sodium amide, sodium alkoxide, potassium carbonate, etc.) at room temperature to heat, preferably at room temperature to 100°C, for 1 hour to 24 hours.

The raw material compound (), for example, has the general formula (In the formula, Y has the same meaning as above.) and the compound (),
It is prepared by reacting under similar conditions as described in Method 2.

In addition, the raw material compound (), for example, has the general formula (In the formula, Y has the same meaning as above.) A compound represented by the general formula ArH () (In the formula, Ar has the same meaning as above.) A normal Friedel-Crafts reaction conditions, e.g. aluminum chloride,
It is prepared by reacting in a solvent such as carbon disulfide, dichloroethane, or tetrachloroethane in the presence of a catalyst such as ferric chloride or zinc chloride.

The compound of the present invention () is a basic substance, and if necessary, a pharmaceutically acceptable acid addition salt, for example,
Can be converted to hydrochloride, hydrobromide, sulfate, oxalate, fumarate, maleate, mandelate, citrate, tartrate, salicylate.

The compounds represented by the general formula () and their acid addition salts have anti-inflammatory, analgesic, antipyretic, platelet aggregation-inhibiting, and thromboxane _A2 biosynthesis-inhibiting effects, and are anti-inflammatory, analgesic, and antipyretic agents. It is also useful for the prevention and treatment of thrombosis, stroke, myocardial infarction, acute cardiac death, angina, hypertension, asthma, nephritis, etc.

When used as a medicine, the compound of the present invention can be administered orally by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc. in the form of powder, granules, tablets, capsules, injections, etc. Or it can be administered parenterally. The dosage may vary depending on the target disease and symptoms, but 1 kg of human body weight
per day, preferably in the range of 0.01 to 50 mg/day.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Reference Example 1 Suspend 19.1 g of 50% sodium hydride in 250 ml of dimethylformamide, and add 29.6 g of imidazole over 15 minutes while occasionally cooling with ice. After stirring for 1 hour at room temperature, 50 g of 2-chloro-3-cyanopyridine are added. The reaction begins with heat generation50
Cool with water to an extent that does not exceed ℃ and stir for 2 hours. The reaction solution is poured into ice water, and the precipitated semi-solid is extracted with ethyl acetate, washed with water, dried, and concentrated. When the residue was recrystallized from 250 ml of toluene, 2-(imidazole-
1-yl)-3-cyanopyridine has a melting point of 111-113
Obtained 50 g as white crystals at ℃.

Reference Example 2 75 g of 6-chloronicotinic acid chloride and 98 g of chlorobenzene were dissolved in 135 ml of dichloroethane, 117 g of anhydrous aluminum chloride was added, and the mixture was refluxed for 1 hour.
Stir for an hour. Pour the reaction solution into ice water, separate the organic layer, wash with water, dry, and concentrate. When the resulting oil is distilled under reduced pressure, 2-chloro-5-(4-chlorobenzoyl)pyridine has a boiling point of 180-190℃/0.2mm.
Obtained 80 g of Hg as a pale yellow oil. This product crystallizes when left to stand, and when recrystallized from toluene, it becomes white crystals with a melting point of 131-133°C.

Example 1 A Grignard reagent is prepared from 4 g of magnesium and 25.9 g of bromobenzene in anhydrous ether according to a conventional method. Meanwhile, 20 g of 2-(1-imidazolyl)-3-cyanopyridine was dissolved in 400 ml of benzene.
Add the aforementioned Grignard reagent to this at 30°C to 35°C. After adding the entire amount, stir at room temperature for 35 minutes. The reaction solution is treated with an aqueous ammonium chloride solution under ice cooling. The benzene layer is separated, dried and concentrated. The resulting oil is purified by column chromatography. The resulting oil is hydrolyzed by stirring with hydrochloric acid at 40° C. for 10 minutes. After the reaction, the mixture is made alkaline with 4N aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer is washed with water, dried, and concentrated to give a pale yellow oil. When this is crystallized from a toluene-hexane mixed solvent and recrystallized from toluene, 2-(1-imidazolyl)-3-benzoylpyridine is obtained as white crystals with a melting point of 99-100°C at 16.7°C.
g can be obtained.

Example 2 A Grignard reagent is prepared from 1.96 g of magnesium and 15.3 g of 4-bromochlorobenzene in anhydrous ether according to a conventional method. On the other hand, 2-(2-methyl-
10 g of 1-imidazolyl)-3-cyanopyridine is dissolved in 150 ml of benzene, and the aforementioned Grignard reagent is added thereto at 30°C to 35°C. After adding the entire amount, stir at room temperature for 1 hour. The reaction solution was treated with an aqueous ammonium chloride solution under ice cooling. The benzene layer is separated, dried and concentrated. The residue is purified by crumb chromatography. The resulting oil is hydrolyzed by stirring with dilute hydrochloric acid at 40° C. for 10 minutes. After the reaction, cool on ice, make alkaline with 4N aqueous sodium hydroxide solution, and extract with chloroform. The chloroform layer is washed with water, dried, and concentrated, and the resulting oil is dissolved in acetone, and a 20% hydrochloric acid-isopropanol solution is added. The precipitated crystals are collected and recrystallized from a dioxane-isopropanol mixed solvent, resulting in 2-(2
8.2 g of -methyl-1-imidazolyl)-3-(4-chlorobenzoyl)pyridine hydrochloride are obtained as white crystals with a melting point of 192-193°C.

Example 3 2.7 g of 50% sodium hydride is suspended in 50 ml of dimethylformamide, and 4.1 g of imidazole is added over 10 minutes while stirring under ice cooling. After stirring for 1 hour at room temperature, 12.5 g of 2-chloro-5-(4-chlorobenzoyl)pyridine are added. 25℃
When heated to a temperature, a reaction starts with exothermic heat, and the mixture is cooled with water to a temperature not exceeding 55°C and stirred for 1 hour. Pour the reaction solution into ice water and collect the precipitated crystals. Toluene-
After washing well with hexane mixed solvent, 60ml of ethanol.
When recrystallized from 2-(1-imidazolyl)-5
-(4-chlorobenzoyl)pyridine has a melting point of 155~
9 g is obtained as white crystals at 157°C.

Example 4 50 ml of toluene and 30 ml of dimethylformamide
Suspend 2.7 g of sodium hydride and add 5 g of 2-methylimidazole while stirring under ice cooling. After stirring for 1 hour at room temperature, 2-chloro-5-
Add 12.5 g of (4-chlorobenzoyl)pyridine. When heated to 25°C, heat is gradually generated and the reaction begins. After stirring at room temperature for 1 hour, the reaction solution was poured into ice water and the precipitated crystals were collected. After washing thoroughly with a toluene-hexane mixed solvent and recrystallizing from ethanol, 2-(2-methyl-1-imidazolyl)-
5-(4-chlorobenzoyl)pyridine has a melting point of 119
Obtained 8.5 g as white crystals at ~121°C.

Example 5 50 ml of hexamethylphosphoric triamide
% Sodium hydride is suspended, and 3 g of imidazole is added while stirring under ice cooling. 1 at room temperature
After stirring for an hour, 3-(6-chloronicotinoyl)
-Add 6 g of 2-methylindole. 17 at 70℃
After stirring for an hour, the reaction solution is poured into ice water and the precipitated crystals are collected. This is dissolved in dilute hydrochloric acid and extracted with ethyl acetate. Cool the dilute hydrochloric acid layer on ice and make alkaline with 4N aqueous sodium hydroxide solution. The precipitated crystals were dried and then recrystallized from a mixed solvent of ethanol and toluene to obtain 5.3 g of 3-[6-(1-imidazolyl)nicotinoyl]-2-methylindole as pale yellow crystals with a melting point of 229-231°C. It will be done.

The following compounds are obtained in the same manner as in Examples 1 to 5 above.

(6) 2-(1-imidazolyl)-3-(4-chlorobenzoyl)pyridine, melting point 118-120°C (7) 2-(2-diethylaminomethyl-1-imidazolyl)-3-(4-chlorobenzoyl) Pyridine, pale yellow oil, nuclear magnetic resonance spectrum (CDCl ₃ ) δ: 0.76 (6H, t), 2.34 (4H, q),
3.79 (2H, s), 6.7−8.8 (9H) (8) 2-(2-methyl-1-imidazolyl)-3-
Melting point of benzoylpyridine, hydrochloride 193-194℃ (9) 2-(2-methyl-1-imidazolyl)-3-
(4-methoxybenzoyl)pyridine, melting point 148
~149℃ (10) 2-(2-methyl-1-imidazolyl)-3-
(2-methoxybenzoyl)pyridine, pale yellow oil, nuclear magnetic resonance spectrum ( _CDCl3 ) δ:
3.58 (3H, s), 2.26 (3H, s), 6.6-8.7 (9H) (11) 2-(2-methyl-1-imidazolyl)-3-
(3-Trifluoromethylbenzoyl)pyridine, melting point 99-101°C (12) 2-(1-imidazolyl)-5-benzoylpyridine, melting point 142-143°C (13) 2-(1-imidazolyl)-5-( 4-fluorobenzoyl)pyridine, melting point 130-132°C (14) 2-(1-imidazolyl)-5-(4-methylbenzoyl)pyridine, melting point 141-143°C (15) 2-(1-imidazolyl)-5 -(4-methoxybenzoyl)pyridine, melting point 154-157°C (16) 2-(1-imidazolyl)-5-(4-cyclohexylbenzoyl)pyridine, melting point 144-157°C
146℃ (17) 2-(1-imidazolyl)-5-(4-methoxycarbonylbenzoyl)pyridine, melting point
153-155℃ (18) 2-(1-imidazolyl)-5-(3,4-
dimethylbenzoyl)pyridine, melting point 135-137
°C (19) 2-(1-imidazolyl)-5-(3,4-
dimethoxybenzoyl)pyridine, melting point 167~
168℃ (20) 2-(1-imidazolyl)-5-(5-chloro-2-methoxybenzoyl)pyridine, melting point
161～162℃ (21) 2-(1-imidazolyl)-5-(2,5-
dimethoxybenzoyl)pyridine, melting point 128~
129℃ (22) 2-(1-imidazolyl)-5-(2-hydroxy-5-methylbenzoyl)pyridine, melting point 164-166℃ (23) 2-(1-imidazolyl)-5-(2-methoxy- 5-Methylbenzoyl)pyridine, melting point
140～142℃ (24) 2-(1-imidazolyl)-5-(2,4-
dimethoxybenzoyl)pyridine, melting point 137~
138.5℃ (25) 2-(1-imidazolyl)-5-(2-dimethylaminoethoxy-5-methylbenzoyl)
Pyridine, fumarate salt, melting point 165-167℃ (26) 2-(1-imidazolyl)-5-(2-carboxymethoxy-5-methylbenzoyl)pyridine, melting point 201-202℃ (decomposition) (27) 2- (1-imidazolyl)-5-(2,4,
6-trimethylbenzoyl)pyridine, melting point
143～145℃ (28) 2-(1-imidazolyl)-5-[2-(6-
methoxy)naphthoyl]pyridine, melting point 162~
164℃ (29) 2-(1-imidazolyl)-5-(2-ethoxycarbonylmethoxy-5-methylbenzoyl)pyridine, nuclear magnetic resonance spectrum ( _CDCl3 ) δ: 1.27 (3H, t), 2.39 (3H, s),
4.11 (2H, q), 4.52 (2H, s), 6, 6-8.8
(9H).

Claims (1)

[Claims] 1. General formula (In the formula, R represents hydrogen, lower alkyl, di-lower alkylamino lower alkyl. Ar is halogen,
having 1 to 3 substituents selected from lower alkyl, cycloalkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, carboxymethoxy, lower alkoxycarbonylmethoxy, and di-lower alkylamino lower alkoxy in any combination at any position; Indicates phenyl, methoxynaphthyl, and methylindolyl, which may be ) Pyridine derivatives or acid addition salts thereof.