JPS6317865A - Imidazole derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R1 is H or CH3; group shown by formula II is single bond (in this case R2 is aryl, aralkyl, heteroaryl, etc.; X-A is case where X is O or NH and A is aryl or X is O or S and A is alkyl, aralkyl, alkenyl, etc.) or unsaturated double bond (in this case R2 is H, alkyl, alkenyl, alkynyl, etc.; X is S; A is alkyl, aralkyl, alkenyl, etc.)], its pharmaceutically acceptable ester, amide or salt. EXAMPLE:4-[1-Phenyl-2-(imidazol-1-yl)ethylthio]butyric acid methyl ester. USE:A remedy for circulatory diseases resulting from thromboxane A2. PREPARATION:A compound shown by formula III is reacted with a compound shown by formula IV (R2 and X-A are the above-mentioned groups when group shown by formula II is single bond; W is eliminable group; R3 is H or carboxyl- protecting group) and optionally the protecting group is removed to give a compound shown by formula V among compounds shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel imidazole derivative useful as a therapeutic agent for cardiovascular diseases caused by thromboxane A2, and a method for producing the same.

Tromphochi, a potential stimulator of platelet aggregation, is produced;
It has been suggested that the balance between the production of TXA2 and PG-2 is a regulatory factor in thrombus formation. Therefore,
In the treatment or prevention of thrombosis, it is desirable to selectively suppress TXA2 synthesis and thereby promote the production of PG-2, which has an anti-platelet aggregation effect.

In recent years, imidazole and 1-methylimidazole have been discovered as compounds having such TXA2 biosynthesis inhibitory activity (Needleman et al., Prostaglandins, Vol. 13, p. 61, 1977), but from the perspective of @note etc. , there is no practical base ζ available at the end.

As a result of many years of intensive research into the synthesis of compounds that have TXA2 biosynthesis inhibitory activity, the present inventors have found that a compound having the general formula (1) below has a strong inhibitory activity. From this, we discovered that the uninvented compound (1) is useful as a therapeutic agent for &2 breath caused by TXA2, and completed the invention.

Constitution of the Invention The object compounds of the present invention are imidazole derivatives having the general formula and their pharmacologically acceptable esters, amides or salts.

In the above formula, R1 represents a hydrogen atom or a methyl group, ==
The symbol represented by represents a single bond or an unsaturated dime bond.

= represents a single bond, and R2 is an aryl group.

It represents an aralkyl group, a heteroaryl group, or a heteroaralkyl group, and the above R2 group is further substituted with a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, a trifluoromethyl group, or a halogen atom. You can also do γ.

The X-A group is O or NH-aryl, O or S-alkyl, O or S-aralkyl, O or S-alkenyl, O or S-alkynyl.

selected from the group consisting of 0 or S-cycloalkyl, 0 or S-alkylcycloalkyl, O or S-alkylcycloalkenyl, 0 or S-heteroaryl and 0 or S-heteroaralkyl groups, where the A group is further lower alkyl group, lower alkoxy group, hydroxyl group, cyano group,
It may be substituted with a trifluoromethyl group or a halogen atom.

Further, when == represents an unsaturated double bond, R2 is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylalkyl group, a cycloalkenylalkyl group, an aryl group,
The above R2 represents an aralkyl group, an aralkenyl group, an aralkynyl group, a heteroaryl group or a heteroaralkyl group.
The group may be further substituted with a lower alkyl group, a lower alkoxy group, a hydrophilic group, a cyano group, a nitro group, an amino group, a trifluoromethyl group or a halogen atom. Kill to 7ra, s-fulkenyl,
n, A from the group consisting of s-furkynyl, S-cycloalkyl, s-furkylcycloalkyl, S-alkylcycloalkenyl, S-cycloalkenyl, S-heteroaryl, S-heteroaralkyl and S-aryl;
The above substituents have the same meaning as described above.

In the general formula (1), R1 is preferably a hydrogen atom or a methyl group.

When the symbol represented by =: represents a single bond.

R2 is, for example, an aryl group such as phenyl, α-su7tyl, β-naphthyl, for example benzyl.

7ralkyl group having 1 to 3 carbon atoms in the alkyl moiety such as 7enethyl, α-methylbenzyl, 3-phenylglobil, α-naphthylmethyl, β-naphthylethyl 1 For example, 2-furyl, 3-furyl, 2-chenyl, 3-fenyl, 2-thiazolyl, 4-thiazolyl, 2-pyridyl.

3-pyridyl, 4-pyridyl, 2-pyrazinyl.

5 or 6 heteroaryl groups containing one or more heteroatoms such as 1-methylpyrrol-2-yl, methane or sulfur atoms, e.g. furfuryl, 2-tenyl, 3-tenyl , 1-imidazolylmethyl, 1゜2.4-triazol-1-ylmethyl,
2-pyridylmethyl, 2-pyrimidylmethyl, 2-furylethyl, 2-chenylethyl, 2-pyridylethyl,
Alkyl such as 3-pyridylethyl, 4-pyridylethyl, 2-thiazolylethyl can also be an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; e.g. methoxy,
Ethoxy.

Lower alkoxy groups such as n-propoxy, isopropoxy, n-butoxy, isobutoxy; hydroxyl groups; cyano groups: nitro groups; amino groups, trifluoromethyl groups: substituted with halogen atoms such as fluorine, chlorine, and bromine You can also do it.

Also, if == is an unsaturated double bond, sR2 is a hydrogen atom;
For example, methyl, ethyl, n-propyl, inglovir,
n-butyl, isobutyl, 5ea-butyl&tert
- 1 to 6 carbon atoms such as butyl, n-pentyl, impentyl, neopentyl, n-hexyl, isohexyl
straight-chain or branched alkyl groups; for example, alkenyl groups having 2 to 4 carbon atoms such as vinyl, allyl, impropenyl, 2-butenyl; for example, ethynyl, 2-
Alkynyl groups having 2 to 4 carbon atoms such as propynyl, 2-butynyl; e.g. cyclopropyl, cyclobutyl,
cyclopentyl.

A cycloalkyl group having 3 to 6 carbon atoms such as cyclohexyl; for example, 2-cyclohexenyl.

3-cyclohexenyl, 2-cyclopentenyl.

Cycloalkenyl i such as 3-cyclopentenyl; cycloalkenylalkyl groups such as 2-cyclohexenylmethyl, 2-cyclopentenylmethyl, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, 3- A cycloalkylalkyl group having 3 to 6 ring carbon atoms and an alkyl moiety having 1 to 3 carbon atoms, such as cyclopentylglobil, cyclohexylmefkh2-cyclohexylethyl, and 3-cyclohexylpropyl; for example, phenyl,
Ori-ru groups such as α-naphthyl, β-naphthyl: For example, benzyl, phenethyl, α-methylbenzyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylethyl where the number of carbon atoms in the alkyl moiety is 1 to 3 aralkyl groups; for example, an aralkenyl group such as cinnamyl;
For example 2- frills.

3-furyl, 2-chenyl, 3-chenyl, 2-thiazolyl, 4-thiazolyl, 2-pyridyl.

3-pyridyl, 4-pyridyl, 2-pyrazinyl.

one or more such as 1-methylpyrrol-2-yl
5- or 6-membered heteroaryl group containing L or more heteroatoms consisting of oxygen, nitrogen or sulfur atoms; e.g. furfuryl, 2-tenyl, 3-tenyl, 1-imidazolylmethyl, 12.4-triazole -1-ylmethyl,
2-Pyridylmethyl h 2-pyrimidylmethyl, 2-furylethyl, 2-chenylethyl, 2-bilysylethyl, 3-pyridylethyl, 4-pyridylethyl, 2-thiazolylethyl, etc. where the number of carbon atoms in the alkyl moiety is 1 to 2
5- or 6-membered rings as described above, and the R2 group furthermore represents a lower alkyl group such as methyl, ethyl, n-propyl, impropyl, n-butyl, isobutyl; for example methoxy, ethoxy, Lower alkoxy groups such as n-propoxy, impropoxy, n-butoxy, isobutoxy: hydroxy group; cyano group;
Nitro group; amino group.

Trifluoromethyl group; for example, may be substituted with a halogen atom such as fluorine, chlorine, or bromine.

When == represents a single bond, the X-A group is O or NH-
Aryl, O or S-alkyl, 0 or S-aralkyl% 0 or S-alkenyl, O or S-alkynyl, 0 or S-cycloalkyl, 0 or S-alkylcycloalkyl% O or S-alkylcycloalkenyl, o or S-heteroaryl and O or +2
n selected from the group consisting of 8-heteroaralkyl;

In addition, if =: is an unsaturated double bond, S-alkyl
-aralkyl, S-alkenyl, S-alkynyl, S-
cycloalkyl, s-fur*lycycloalkyl, S-
Alkylcycloalkenyl, S-cycloalkenyl, S
-heteroaryl, S-heteroaralkyl, and S-aryl group, where the A group preferably has the same meaning as an alkyl, alkenyl, alkynyl, or cycloalkyl group defined by R2. , an alkylcycloalkyl group (!In the case of the cycloalkylalkyl group added with R2, the alkyl group and the cycloalkyl group have the opposite bonding mode (X-Am, for example, a kenyl group can also be knitted) The bonding mode of the cycloalkenyl group and the alkyl group of the cycloalkenyl alkyl group defined by R2 is reversed (X-A loaryl, heteroaralkyl, allyl group is the heteroaryl defined by R2,
Same meaning as heteroaralkyl and aryl group. The A group can further be a lower alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl; in turn methoxy, ethoxy, n-propoxy,
Lower alkoxy groups such as impropoxy, n-butoxy, and imbutoxy; hydroxyl groups, diano groups; nitro groups, amino groups, trifluoromethyl groups; for example, may be substituted with halogen atoms such as fluorine, chlorine, and bromine.

In addition, in the compound Iζ of the present invention having the general formula (1), when &------ is a single bond, optical isomers based on the asymmetric carbon atom exist, and these isomers is shown in a single formula, the scope of the description of the present invention is not limited thereby and is intended to include stereoisomers and racemic mixtures thereof. Also, =
When is an impossible double bond, geometric isomers of E and Z exist, and these isomers are shown in a single formula.
However, the scope of the present invention is not limited by this, and includes monomers, dimeres, and x,zQ compounds.

In addition, the object compound (1) of the present invention undergoes metabolic activation in the main body and has favorable pharmacokinetic properties, such as lower esters such as methyl, ethyl, n-propyl, isoglobil, n-butyl, and inbutyl. Alkyl group 1
For example, acetoxymethyl, propionyloxymethyl,
Lower alkanoyloxyalkyl groups such as pivaloyloxymethyl 1 e.g. 1-ethoxycarbonyloxyethyl, 1-21proboxycarbonyloxyethyl &1
- IA such as impropoxycarbonyloxyethyl
&Am koxycarbonyloxyalkyl group, tumeridyl its structure.

It can be a pharmacologically acceptable ester or amide such as a group.

In addition, the target compound of the present invention <1) is described in a neutral form, but depending on the requirements, it may be added as a hydrochloride, hydrobromide, nitrate,
Mineral salts such as phosphate, sulfonates such as methanesulfonate, benzenesulfone ram, p-toluenesulfonate.

Acetate, trifluoroacetate, aspartate, glutamate, oxalate, tartrate.

It can be formed into pharmacologically acceptable acid addition salts such as organic salts such as citrate, maleate, fumarate, lactate, salicylate, malonate, succinate, etc. Also, depending on the requirements, inorganic metal salts such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, alkaline or ammonium salts, cyclohexylammonium salts, diisopropylammonium salts.

It can be in the form of pharmacologically acceptable base addition salts such as ammonium salts such as triethylammonium salts, basic amino acid salts such as lysine salts, and arginine salts. Furthermore, esters and amides that undergo metabolic activation in vivo and have favorable pharmacokinetic properties can also be converted into the above-mentioned acid addition salt form.

The compound represented by the general formula (1) of the present invention can be produced by the method shown below.

(■) (Aotl;) (Ia) (IV) (B story) X-A-co
oa5 (lb) In the above formula, h R1+ R2* haoken a
children, alkanesulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, trihalogenomethanesulfonyloxy groups such as fluoromemensulfonyloxy, or arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy represents a group, and R3 represents a water atom or (=a group representing a carboxy group described later).

Method A is a method for producing an imidazole brocade compound having the general formula (la,) which is the object compound of the invention.
This is achieved by reacting a chemical compound having a monomer formula (II) with a salt of a compound having a button.

In carrying out method A of the present invention, one reaction is carried out in a suitable pot in an inert υ agent, rL6゜' as a bath agent with antiphase, and sometimes there is no limitation unless 'IA' is given to the unreacted. , 9th grade contains halogenated hydrocarbons such as chloroform, dichloromethane, and dichloroethane, acetone, ketones such as methyl ethyl ketone, ethers, tetrahydrofuran, dioxane ethers, aromatic hydrocarbons such as benzene and toluene, and acetonitrile. Nitriles such as ethyl formate, esters such as ethyl acetate, alcohols such as methanol, ethanol M, N,
In the case of amide stones such as N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitromethane, or mixtures of these organic bath agents, di1Hii! *Mineral acids such as Shiosan, Tadahikado, organic acids such as triflu, single-mouth acetic acid, acetic acid, p-toluenesulfonic acid, Lewis acids such as boron trifluoride etherate, azodicarboxylic acid diester MK is carried out by reacting with a compound having the formula (1) in the presence of a binding agent such as routriphenylphosunein.

When W in compound (n) is a leaving group other than a hydroxyl group, triethylamine as an acid binder, any alkali metal bicarbonate or carbonate, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, etc. gamma performed in the presence of things,
Preferably, the compound having the general formula (1) is first converted into an alkali metal salt or an organic base salt by a conventional method in the presence of a solvent, and then the reaction is carried out.

The reaction temperature is not particularly limited, but it is usually carried out at about -10°C to 100°C. The reaction time varies mainly depending on the reaction temperature, the type of raw material compound, etc., but it is from several tens of minutes to 100 minutes.
It's time.

After completion of the reaction, the target compound (Ia) of the five reactions is collected from the reaction mixture according to a conventional method. For example, an organic solvent that is immiscible with water is added to the reaction mixture, the organic bath agent is separated, washed with water, and then the bath agent is distilled off. The obtained target compound can be further purified, if necessary, by a conventional method such as recrystallization, reprecipitation or chromatography.

Method B is a method for producing an imidazole derivative having the general formula (Ib, l'E), which is the object compound of the present invention, by reacting a compound having the general formula (1) with a compound having the general formula (1). be.

In carrying out method B, one reaction is an inert detergent such as a titanium halide compound, aluminum chloride, boron trifluoride etherate, or stannic chloride, and particularly preferred is a titanium halide such as titanium tetrachloride. Compounds and aluminum chloride thicken. Furthermore, in the case of a titanium halide 8-product such as titanium tetrachloride, it is desirable to carry out the reaction in the presence of a tertiary amine such as triethylamine or diisopropylethylamine. The reaction is carried out in an inert a solvent, but there are no particular limitations on the solvent used as long as it does not interfere with the reaction.

Halogenated hydrocarbons such as chloroform, dichloromethane, cycloemene, and ethers.

Unaethers such as tetrahydrofuran and dioxane,
Aromatic hydrocarbons such as benzene and toluene, and nitriles such as acetonitrile.

Hydrocarbons such as hexane and cyclohexane.

Examples include carbon disulfide, nitromethane, and a mixed solvent of these organic solvents.

There is no particular limitation on the reaction temperature, but it is usually 0°C to 200°C.
It is held at around ℃. The reaction time varies depending on the main lζ reaction temperature, the type of raw material compound, etc., and ranges from several tens of minutes to one hour.
It is 00 hours.

After the completion of the reaction, the target compound of one reaction is subjected to reaction 1 according to the conventional method.
It is collected from kelp. For example, add an organic bath agent that is immiscible with water to the reaction mixture i, and add the organic bath agent j to 1iJ1! ,
After washing with water, the solvent is distilled off to obtain n. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography.

When (1) has a carboxyl protecting group at R3, it is generally removed by methods known in the art. Preferably, linear alkyl esters such as methyl esters, ethyl esters, etc. are removed by alkaline hydrolysis.

The tert-butyl ester is removed with trifluoroacetic acid. The protecting group for carboxylic acid is benzyl.

The solvent used in rL1 below is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol can be used.

Agents are preferred. The reaction temperature is usually 0'C~! It is around 1 reaction time (= raw material compound and ≠ - ka = stand-up time - 4 depending on the type of starting agent).

Usually it is 5 minutes to 12 hours.

When the reaction is completed, the target compound of the reaction is removed from the carboxyl group by a conventional method from the reaction mixture. For example, it can be obtained by removing insoluble matter precipitated from the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent.

The target compound thus obtained can be purified, if necessary, by conventional methods such as recrystallization, two-minute weir chromatography, column chromatography, etc.

In addition, compounds containing carboxylic acids (5ζ) can be converted into pharmacologically acceptable esters or amides that undergo metabolic activation in vivo using techniques known in the art and that also have favorable pharmacokinetic properties. Ru.

The imidazole-containing conductor of the present invention represented by the general formula <1) can be converted into a pharmacologically acceptable salt of 6σ according to a conventional method, if necessary.

Specific compounds having the general formula (1) that can be obtained by the present invention include, for example, the compounds listed below and their pharmacologically acceptable esters, amides, and salts, but are limited to stiff compounds. It is not something that will be done.

Effects of the Invention The imidazole conductor represented by the general formula (1) of the present invention is a chemical compound described in the literature, and is a compound that is used in the production of platelet microorganisms in salivary mammary glands, including humans. It inhibits thromboxane synthetase in the seam and exhibits a strong and specific TXA2 biosynthesis inhibitory effect. That is, the compound of the present invention, for example, the compound of Example 12, inhibits TXA2 biosynthesis by 50% at 10-8 mol 1 degree, or is extremely weak in inhibiting cyclooxygenase and prostacyclin synthetase. In addition, in an in vivo experimental system, oral administration of the compounds of the present invention has been found to be effective in preventing embolism mortality in rabbits and mice caused by direct injection of arachidonic acid.

Therefore, the imidazole derivative of the present invention is useful as a therapeutic agent for diseases caused by 'rxA2, such as inflammation, hypertension, thrombosis, cerebral hemorrhage, asthma, etc., and particularly for the treatment of thromboembolism in mammals including humans. and/or useful for prophylaxis. For example, one compound of the invention is useful for the treatment and prevention of myocardial infarction, cerebrovascular thrombosis, and ischemic peripheral vascular disease; for the treatment and prevention of post-surgical thrombosis; and for promoting the patency of transplanted blood vessels after surgery. It is.

The dosage of the compound of the present invention necessary for the therapeutic or preventive effects of the above diseases varies depending on the dosage form, age, type of symptoms to be treated, etc., but oral administration for adults is usually administered three times a day. It is divided into 50 to 1800m+9.

Although the compounds of the invention can be administered neat, it is usually preferable to present them as a pharmaceutical formulation. The formulation may include oral dosage forms such as tablets, capsules, powders, and syrups, and parenteral dosage forms such as suppositories, subcutaneous or intravenous injections.

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

Example 1 Methyl 4-mercaptobutyrate (974Q) was dried N,N-
The mixture was bath-dissolved in dimethylformamide (7.8 m/m), and 55% sodium hydride (316i + 9.45 m mineral oil) was added under water cooling, followed by stirring at room temperature for 30 minutes. To this solution was added a bath solution of 1-(2-chloro-2-phenylethyl)imidazole (1,5&) in dry ON, N-dimethylformamide (9rr, t), and
Heated at -60°C for 8 hours. After the reaction, one reaction solution was poured into brine, washed with ether, washed with water, and dried over anhydrous magnesium sulfate to remove the entanglement agent. The residue was subjected to column chromatography using silica gel (developing agent, ethyl acetate:hexane).
4:1), the target compound (1,399
)was gotten.

Neat -+.

Infrared absorption spectrum ShimaXCm41730,
1600, 1510 nuclear magnetic resonance spectrum <c
Dct5) δppm: 1.48~! ,04 (2H,
m), 2.18-2.55 (4H.

m), 3.63 (3H, s), 3.87-4.48 (3
H.

m), 6.75 (IH,s), 6.9
8 (I H,s).

7.18-7.40 (6: l, s) Example 2 Methyl 4-[1-phenyl-2-(imidazol-1-ylnoethylthio]butyrate (1,35!') was dissolved in methanol (18 ml) in a bath. and IN-sodium hydroxide (1
8g] was added thereto, and the mixture was stirred at room temperature for 3 hours. Distill the solvent,
IN sodium hydroxide (9-) was added to the residue, extracted with chloroform, and the aqueous layer was acidified (pH 2~2) using 6N hydrochloric acid.
3).

The mixture was extracted with chloroform and adjusted to pH 6.0 using 7N water and aqueous ammonia. Extracted with chloroform, dried over anhydrous magnesium sulfate, distilled off the solvent, crystallized with inpropyl ether, and collected the resulting crystals to obtain the target compound (1,02&) or Qp124-12.
8℃ Infrared absorption spectrum νKBr +1 ・Cs
.

maX 3450, 1710, 1515, 1
500 nuclear magnetic resonance spectrum (DMSO-d4) δpp
rQ: 1.46-1.90 (2H, rn),
2.00-2.62 (4H.

m), 4.00-4.60 (3H, m), 6.78 (I
H.

s ), 7.07 (I H, s )
, 7.33 (S H,s ).

7.48 (IH,a) Example 3 Methyl 3-merca-7-toprobionate (872R9)
was dissolved in dry kN,N-dimethylformamide (7.8ml), and 55% sodium hydride (316xy
, 45% mineral oil] and then stirred at room temperature for 30 minutes. To this solution was added a solution of t-<2-chloro-2-phenylethyl)imidazole (1,5 L) dissolved in dry N,N-dimethylformamide (9-), and 50
Heated at -60'C for 5 hours. After hair removal, treatment and purification in the same manner as in Example 1 yielded the oily target compound (1, 15,
9) was obtained.

Infrared absorption spectrum νNeat +1.

maX “・1730, 1600, 1580, 1
500 Nuclear Magnetic Resonance Spectrum (CDCts) δppm
:2.26~279 (4H, m), 3.66
(3H, s).

3,! 13 ~ 4.50 (3H, m)
, 6.76 (I H,s).

6.98 (1'H, s), 7.30 (6H,
s) Practical Example 4 3-Methyl [1-722-2-(imidazol-1-ylnoethylthio]propionate (1,IJI) is dissolved in methanol (15m) and 1N-hydroxylated) IJium (Is m/)' and stirred at room temperature for 2 hours.

After the reaction, the reaction mixture was treated in the same manner as in Example 2 to obtain the target compound (ssa+*g).

Cop IIQ-H7°C Infrared absorption spectrum νKBr −+ ・Eax
“・3420, 1,690, 1525.14
95 nuclear magnetic resonance spectrum k (DMSO-d6) δpp
m: 2.22 to 2-70 (-4H, m), 4
．． 23~5.20 (3[(.

m), 6.80 (IH,s), 7.0
6 (I H,s).

7.31 (5H, s), γ, 4
9 (I H,s) Example 5 Methyl 4-acetylthiocrotonate (1,0, li'
) in dried N,N-dimethylformamide (10*)+1
Dissolve and add a methanol bath solution of 1M sodium methoxide (5,8g) and a solution of 1-(2-chloro-2-phenylethyl)imidazole (1,01) in N,N-dimethylformamide almost simultaneously under water cooling. The mixture was stirred at room temperature for 1.5 hours, and further heated at about 68° C. for 4 hours. After the reaction, the mixture was treated and purified as in Example 1 and by colleagues to obtain the target compound (IT3η) in the form of an oil.

1730, 1670, 1655, 1605, 1
505 Example 6 4-[1-phenyl-2-(imidazol-1-yl)
Methyl ethylthiofcrotonate (17° true 9) was dissolved in methanol (1,1-), and 1N-sodium hydroxide (
1.1m) was added thereto, and the mixture was stirred at room temperature for 4 hours. reaction'fL
Methanol was distilled off under reduced pressure, and the remaining bath g was poured into a Rover column (Merck, Ricroprep RP-8, size B).
) and from the part eluted with 10% methanol water,
The target compound (hygroscopicity, 89 m+9) was obtained as a colorless powder.

Nuclear magnetic resonance spectrum (D20) σppm: 136~
3.78 (2H, m), 4.60-5.25
(3H.

m), 6.20 to 6.60 (I
H, m), 7.30 ~ 8.08 (
9H) Example T Ethyl 2-mercaptothiazole-4-carboxylate (4
98Q) 'jr Dry Dry N-N-Dimethylformamide P! Lt) and added 55 polyhydric sodium purple (1) 6 m + 9.45% Miuraru Ilf under ice-cooling,
The mixture was stirred at room temperature for 30 minutes. A bath solution in which 1-(2-10 rho 2-phenylethylquimidazole (5001,9) was dissolved in dry N,N-dimethylformamide (3-) was added to this solution and heated at 60-10°C for 4 hours. After the reaction, the reaction mixture was treated and purified in accordance with Example 1 and colleagues to obtain the target compound (4651) 9) in the form of an oil.

Infrared absorption spectrum　νゝJeat　-+　.

Cm.

ax 1720, 1600, 1505 nuclear magnetic resonance spectrum (CDCJ!5) δppm: 1.43
(3H, t, J = 7.0 Hz
), 4.05-5.28 (5H, m),
6.96 (2H, s), 7.05
~7,'50 (6H, m), 8.10
(I H,s) Example 8 2-[1-phenyl-2-(imidazol-1-yl) bolic acid
Ethyl thiocthiazole-4-carboxylate (44
61)g) was dissolved in methanol (5-), IN-sodium hydroxide (5-) was added, and the mixture was stirred at room temperature for 3 hours.

The solvent was distilled off, and 1N sodium hydroxide (3m) was added to the residue.
Then, the aqueous layer was made acidic (pH 2 to 3) using 6N hydrochloric acid. Then, the pH was adjusted to 6.5 using basic ammonia water. Extracted with chloroform and anhydrous
After drying with magnesium tate and distilling off the bath agent, the desired crystalline compound (72Q) was obtained.

mp　　　2(N　-204°C Infrared absorption spectrum νKBr +l.

C71) °ax 3400, 1710, 1610, 1
495 nuclear magnetic resonance spectrum (DMSO-d6) a
ppm: 4.70 (2H, d, J=7.0Hz), 5
．． 16(1)i.

t, J -7,0Hz), 6.85
(I El, s), Otsu 12
(IH,s), 7.25 ~
7.66 (6[(,m).

&27 (I H,s), 8.31 (I H,
s) Example 9 Methyl 4-hydroxybenzoate (1,8g) in 7il-dry N,N-dimethylformamide (13m) ltJM
Then, 55% sodium hydride (506Q) was added under water cooling.

After adding 45 ml of mineral oil, the mixture was stirred at room temperature for 40 minutes. In this fit, 1-(2-chloro-2-phenylethyl), imidazole (2JiM'il-dried N, N-
A solution of dimethylformamide (13rnt) was added and heated at 40-50°C for 5 hours r=+.

After the reaction, 1 Reaction I was poured into salt water, washed with ether extraction water, dried with anhydrous magnesium hydroxide, and the bath agent was distilled off.The residue was subjected to column chromatography using silica gel (developing agent,
Purification with ethyl acetate:methanol (30:1) yields oily 4-[1-phenyl-2-(imidazole-1).
-yl)ethoxy]methyl benzoate (367 doors!?)
was gotten.

Nuclear magnetic resonance spectrum C, CDC15) δppm: 3
．． 83 (3H, s), 4.35 (2H, d
, J = 6.0 Hz, 5.
36 (I H, t, J =
6.0 Hz).

6.92 (I H,a), 7.01 (I H
, a ), 7.32 (5H, s ), 7.44
(1[(,s), 6.80.

7.87 (4H, A2B2, J = 9.0H
z) Example 10 4-[1-phenyl-2-(imidazol-1-yl)
Dissolve nine of ethoxy]methyl benzoates (3281) in methanol (4,1d) and perform IN-hydroxylation) lrum (
4.1 m ) was added, stirred at room temperature for 2.5 hours, and then incubated overnight. The solvent was distilled off, 1N sodium hydroxide (2-) was added to the residue, extracted with chloroform, and the aqueous layer was diluted with 6N
Acidification (pH 2-3) using hydrochloric acid, P removal of the formed crystals, and washing with a small amount of cold water yielded the target product (l18m9).
was obtained o mp147-151°C3450,
1690, 1605, 1585, 1570.

1540, 1510 ゛ Nuclear magnetic resonance spectrum (DMSO-44) δppm
:4.76 (2H, d, J = 6.0 Hz
), 6.02 (IH.

t, J -6,0Hz), 1.43 (5H
, a ) , 7.67 (I H, 8) , 7.00
．． 7.84 (4H, A2B2.

J = 9.0 Hz), 7.86
(I H,s), 9.26 (1H,
s) Example 1) Methyl acid 4-hydroxybenzoate (2!1) Dissolved in 4-)lifluoroacetic acid (30mi) and cooled with water to dissolve 1-[2-hydroxy-2-(2-methoxyphenyl ethyl) ] Imidazole (2,9) was added once for about 20 minutes, stirred at the same temperature for 1.5 hours, and then at room temperature. The solvent was distilled off, ethyl acetate was added to the residue, and hydrogen carbonate was added. It was washed with rum water and saline, and dried over anhydrous sulfuric acid.

The solvent was distilled off, and the residue was subjected to column chromatography using silica gel (developing agent, ethyl acetate:methanol-30
:1), the desired oily compound (6038g
)was gotten.

Infrared absorption spectrum Jea'-1.

α　　　　.

ax 1710, 1605, 1590, 1
510, 1490 nuclear magnetic resonance spectrum (CDCl
5) δppm: 3.84 (3H, e), from 5 (3H, a), 4.33 (2H, d, J
-6,0Hz), 5. al (IH.

t, J=6.0 Hz), 6.86-7.5
6 (7H0m).

6.71, 7.90 (4H, A2B2, j −
9,0Hz) Example 12 (4-[1-(7-medoxyphenyl)-2-(imidazol-1-yl)ethoxy]methyl benzoate (579m
? ) was dissolved in methanol (6.6m), 1N-sodium hydroxide (6.6m) was added, and the mixture was heated at room temperature for 7 hours.
Additionally, the device was installed at night. The bath agent was distilled off, 1N sodium hydroxide (3.3m/)-i was added to the residue, extracted with chloroform, the aqueous layer was acidified (p)12-3) using 6N hydrochloric acid, and concentrated aqueous ammonia was added. was used to adjust the pH to 6.8. The mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crystals were reprecipitated with ethanol-isopropyl ether to obtain the target compound (21) 19). mp 173-178°C infrared absorption spectrum νKBr −+.

Cπ　　　.

5LX 3420, 1690, 1610, 15
90, 1515 nuclear magnetic resonance spectrum (Dl(S
o-ci6) a ppm: 3.93 (3H, s
), 4.48 (2H, d, J
= 6.0 Hz), 5.15 (
IH, br), 5.85 (
IH.

z, J-6,0Hz), 6.7
7-7,92 (1) H, m) Example 13 Ethyl 4-aminobenzoate (4,8 g) was dried with N.

Dissolved in N-dimethylformamide (20nLI!),
A solution of 1-(2-chloro-2-phenylethyl)imidazole (2y) in dry 73N, N-dimethylformamide was added, and 1) Q was heated at -120°C for 15.5 hours. .

After the reaction, the reaction solution was poured into brine, extracted with ether, washed with water,
It was dried over anhydrous magnesium sulfate and the solvent was distilled off. The washed product was purified by column chromatography using silica gel (developing agent: ethyl acetate-methanol, =IQ:1) to obtain the target compound (22919) as an oil.

Infrared absorption spectrum νNeat -+.

Cl1)゜aX 3350. 3250, 169G, 1605
．． 1530, 1510v;, magnetic resonance spectrum (CDCl3) δppm? 1.31 (3H, z
, J = 7.0 Hz), 4.06-4.
90 (6H, m), 6.80 (I H, s)
, 7.05 (IH,s) , 7.31 (5
H, s), 6.54, 7.84 (4H, A2
B2, J = 9. OHz) Example 14 4-(j-722-2-(imidazol-1-yl)
Ethyl ethylamino]benzoate (213my) was dissolved in methanol (2,5d), added with 1N-sodium hydroxide (2,5d), and heated at room temperature for 2 hours and at 50°C for 4 hours. The common agents were distilled off, IN sodium hydroxide (1,3g) was added to the residue, and the aqueous layer was extracted with chloroform.
It is made acidic (pH 2) using N-hydrochloric acid, and the formed crystals are
5, washed with a small amount of cold water, dried, and precipitated with ethanol-isopropyl ether to obtain the target compound (12S,
1 my) was obtained. m9141-146°C infrared absorption spectrum
(I5, 1530, 1510.

Nuclear-gas resonance vector (DMSu-d6) δppm:
4.32-5.33 (3H, tu),
6.65 (2H, d.

J = 9.0 Hz), 7.18~
7.80 (8H, m).

7.93 (I H,s), 9.30
(I H,s) Example 15 4-Aminobenzo 4rm ethyl (4,2,9) was dried with N.

Dissolved in N-dimethylformamide (17m) and heated to g.
c'1-(2-Chloro-2-phenylethylraimidazole (2 g) was dissolved in dry mN, N-dimethylbormamide, a tc solution was added, and the mixture was heated at IQQ-1)Q°C for 8 hours. After the reaction, the treatment and lamination are carried out in the same manner as in Example 13, resulting in an oily target compound 'v! J (217M+9) was obtained.

Infrared absorption spectrum νNeat -+.

Cl.

ax 3350, 3250, 1695, 1
6G5, 1530.

151Q, 1490 Nuclear magnetic resonance spectrum (CD0t5) δppm: 1.
30 (3H, t, J=7.0Hz), 3.90 (3H.

s), 4.07-5.22 (6H, m
), 6.70-7.50 (7H, m)
, 6.50, 7.1)2 (J H
, A2B2.

J-9,0Hz Example 16 J-(1-(7-medoxyphenyl)-2-(imidazol-1-ylnoethylamino)ethyl benzoate (1)
619) Dissolved in methanol (1,3mj), IN-
Add sodium hydroxide (1.3 m) and leave at room temperature for 4 hours.
Heated at 40°C for 4.5 hours.

After the reaction, the product was treated and purified in the same manner as in Example 14 to obtain the target compound (82Q).

mp 145-150°C Infrared absorption spectrum νKBr −+゛Cm
.

ax 3400, 327G, 1690,
1605, 1530, 1495 nuclear magnetic resonance spectrum (DMSO-d6) δppm: 3.89
(3H, s), 4.30-5.35 (3H, m
).

6.59 (2H, d, J = 9.0 Hz)
, 6.80-123 (8H, m), 9.22
(I H,S) Example 1) 2-(imidazol-1-yl)acetophenone (so
n 19 ) was dissolved in dry tetrahydrofuran (33-), titanium tetrachloride (883 μt) was added under water cooling, the temperature was returned to room temperature, and methyl 4-mercaptobenzoate (as2m
9) and triethylamine (2°3-) in dry tetrahydrofuran (llrnt) for 55 minutes. After cooling, the mixture was heated at about 40°C for 6 hours and at 60°C for 7 hours. The reaction solution was poured into cold aqueous sodium carbonate and extracted with ether, and the ether was washed with brine and dried over anhydrous magnesium sulfate. The bath agent was distilled off and the residue was subjected to column chromatography using silica gel (developing agent,
Purification with ethyl acetate-methanol-30:1) gave the target compound as an oil <60zq).

Infrared absorption spectrum νNea zCI+1-+:
ax 1720. 1690. 1595. 1580. 1
560. 1510 nuclear magnetic resonance spectrum (CDC1S
) Lj pI)m: 3.93 (3H, s),
6.130 (I H,s), 7.02.8.
13 (12H, m ) Example 18 4-[1-phenyl-2-(imidazol-1-yl]
Methyl ethynylthio]benzoate (1) (5N) was dissolved in methanol (1,4mj), IN-sodium hydroxide (1,4-0) was added, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction solution was The medium was mixed with 1N hydrochloric acid (1.4 m), and the solvent was distilled off under reduced pressure.The residue was dissolved in methanol, the insoluble portion was separated from P, and the mother liquor was poured into a Rover column (Merck & Co., lJ Kloblew RP-8, size B), and from the part eluted with 50% methanol water, a powdered target compound (12R
9) was obtained.

Nuclear magnetic resonance spectrum (27tliaaz, cDr
:ts) δpp+n :660-7.98 (13, H
0m) Example 19 Methyl fragrant 2-(imidazol-1-yl)-7-methylacetophenone (2g) e1 bed Tetrahydrofuran (122m
), and under water cooling, titanium tetrachloride (2,2i) was dissolved in W
At the same temperature, methyl 4-mercaptobenzoate (1,7,
9) +7 Ethylamine (56-) dissolved in dry tetrahydrofuran (41ml) was added dropwise over 1.5 hours. 1 hour at the same temperature, 4.5 hours at room temperature,
Heated at 40-50°C for 8 hours. After treatment and purification in the same manner as in Example 17, an oily target compound (141xg) was obtained.

Nuclear magnetic resonance spectrum <cDcts) δppm: 2.
50 (3H, a), 3.91 (3H, a)
, 6.67 (IH,s), 6.90-8.06 (I
IH,z) Example 20 Methyl acid 4-[1-(7-methylphenyl)-2-(imidazol-1-yl)ethynylthio]benzoate (139
xy)e Dissolved in methanol (1,6m), added IN-sodium hydroxide (1,6tILt), and stirred overnight at room temperature. After the reaction, the product was treated and purified in the same manner as in Example 18 to obtain the target compound (41 pieces, 9). mp16
0-165°C KBr-+.

Infrared absorption spectrum νmaxcTn.

Claims (3)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R_1 represents a hydrogen atom or a methyl group, and the symbol represented by ■ represents a single bond or an unsaturated double bond. ■ When represents a single bond, R_2 represents an aryl group, an aralkyl group, a heteroaryl group, or a heteroaralkyl group, and the above R_2 group further represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, a tri- Optionally substituted with a fluoromethyl group or a halogen atom, the X-A group is O or NH-aryl, O or S-alkyl, O or S-aralkyl, O or S
-alkenyl, O or S-alkynyl, O or S-
cycloalkyl, O or S-alkylcycloalkyl, O or S-alkylcycloalkenyl, O or S
-heteroaryl and O- or S-heteroaralkyl groups, and the A group may be further substituted with a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a trifluoromethyl group or a halogen atom. In addition, when ■ represents an unsaturated double bond, R_2 is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylalkyl group, a cycloalkenylalkyl group,
It represents an aryl group, an aralkyl group, an aralkenyl group, an aralkynyl group, a heteroaryl group, or a heteroaralkyl group, and the above R_2 group further represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, a trifluoromethyl group. or may be substituted with a halogen atom, and the X-A group is S-alkyl, S-aralkyl, S-
alkenyl, S-alkynyl, S-cycloalkyl, S
-Alkylcycloalkyl, S-alkylcycloalkenyl, S-cycloalkenyl, S-heteroaryl, S
-heteroaralkyl and S-aryl groups, and the substituents on A have the same meanings as described above. ) and their pharmacologically acceptable esters, amides or salts. (2) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 represents a hydrogen atom or a methyl group, and R_
2 represents an aryl group, an aralkyl group, a heteroaryl group, or a heteroaralkyl group, and the above R_2 is further substituted with a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, a trifluoromethyl group, or a halogen atom. W represents a leaving group. ), the compound represented by the general formula HX-A-COOR_3 (wherein the X-A group is O or NH-aryl, O or S-alkyl, O or S-aralkyl, O or S-
alkenyl, O or S-alkynyl, O or S-cycloalkyl, O or S-alkylcycloalkyl,
O or S-alkylcycloalkenyl, O or S-
selected from the group consisting of heteroaryl and O- or S-heteroaralkyl groups, where the A group is further a lower alkyl group,
May be substituted with a lower alkoxy group, hydroxyl group, cyano group, trifluoromethyl group or halogen atom, R_3
represents a protecting group for a hydrogen atom or a carboxy group. ) or a salt thereof is reacted, and then, if desired, the obtained compound is treated with a carboxyl group protecting group R_
Imidazole derivatives represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, X and A have the same meanings as described above.) and a method for producing a pharmacologically acceptable ester, amide or salt thereof. (3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 represents a hydrogen atom or a methyl group, and R_
2 is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a cycloalkylalkyl group, a cycloalkenylalkyl group, an aryl group, an aralkyl group, an aralkenyl group, an aralkynyl group, a heteroaryl group, or a heteroaralkyl group The above R_2 group may be further substituted with a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a nitro group, an amino group, a trifluoromethyl group, or a halogen atom. ), the compound represented by the general formula HX-A-COOR_3 (wherein, the X-A group is S-alkyl, S-aralkyl, S-aralkyl,
-alkenyl, S-alkynyl, S-cycloalkyl,
S-alkylcycloalkyl, S-alkylcycloalkenyl, S-cycloalkenyl, S-heteroaryl,
selected from the group consisting of S-heteroaralkyl and S-aryl groups, the A group may be further substituted with a lower alkyl group, a lower alkoxy group, a hydroxyl group, a cyano group, a trifluoromethyl group, or a halogen atom, and R_3 is hydrogen Indicates a protecting group for an atom or a carboxy group. ) is reacted, and then, if desired, the resulting compound is subjected to a reaction for removing the protecting group R_3 of the carboxyl group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula , R_1, R_2, X and A have the same meanings as defined above.) and a method for producing an imidazole derivative and a pharmacologically acceptable ester, amide or salt thereof.