JPS6233227B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to imidazole derivatives and their salts, their synthesis and intermediates therefor, pharmaceutical compositions containing these compounds and the use of these compounds as medicines. Thromboxane A ₂ (TXA ₂ ), a potent stimulator of platelet aggregation, is produced in platelets from the prostaglandin endoperoxides PGG ₂ and PGH ₂ . Prostacyclin (PGI ₂ ), which has potent anti-aggregation activity, is also known as PGG ₂
and produced from PGH ₂ (in blood vessel walls),
It has been suggested that the balance between TXA ₂ production and PGI ₂ production is a controlling factor in thrombus formation. Therefore, it is desirable for the treatment and prevention of thromboembolic diseases to be able to selectively inhibit TXA ₂ synthetase, thereby improving the production of the anti-aggregating substance PGI ₂ . It is known that imidazole and 1-methylimidazole inhibit to some extent the enzymatic conversion of endoperoxides (PGG ₂ and PGH ₂ ) to thromboxane A ₂ by platelet microsomes [Moncada et al. , Prostaglandins, 13/4 , 611-618,
1977]. Certain 1-n-alkylimidazoles, particularly 1-n-dodecylimidazole and its higher congeners, have been described as capable of lowering serum cholesterol levels [UK Patent No. 1364312]
No.: Biochem. Huamacol. (Biochem.
Pharmacol.), 24 , 1902-1903, 1975]. According to the present invention, TXA ₂
It has now been discovered that synthetic enzymes can be inhibited.
Compounds of formula () and their salts are hereinafter referred to as "active compounds". The compound of formula () is novel and has the formula: [In the formula, A is -CH ₂ - or -CH ₂ -CH=CH-
a group, n is an integer of at least 1, and each R substituent, which may be the same or different when n is greater than 1, represents a lower alkyl group having 1 to 4 carbon atoms; provided that (a) when A is -CH ₂ -, n is at least 2; (b) when A is -CH ₂ CH=CH- and n is at least 2, R can also represent chlorine; and (c) when A is a -CH ₂ CH=CH- group and n is 1, R is not an alkyl group] or this It is an acid addition salt of a 1-aryl-alkylimidazole compound such as. A valuable group of compounds of formula () is those in which the aromatic ring is substituted with at least two lower alkyl groups, in particular one substituent is in the 4-position of the benzene ring and A is methylene (--CH ₂ -)or()
The coordination of the formula is either -CH ₂ -CH=CH- (cis or trans, or a cis/trans mixture - cinnamyl compound). Preferred compounds when A is unsaturated are those in which the aromatic ring has an alkyl or chloro substituent. Compounds of formula () can also be used as their acid addition salts, particularly as their pharmaceutically acceptable acid addition salts. Particularly preferred compounds are: 1-(3,4-dimethylbenzyl)imidazole, 1-(2,4-dichlorocinnamyl)imidazole, i.e. 1-[3-(2,4-dichlorophenyl)propen-2-yl ] imidazole, 1-[3-(2,6-dichlorophenyl)propen-2-yl]imidazole and acid addition salts thereof. Other suitable compounds include: 1-(2,4,6-trimethylbenzyl)imidazole, 1-[3-(4-chlorophenyl)prope-2
-yl]imidazole, 1-[3-(3,4-dimethylphenyl)prop-2-yl]imidazole, and acid addition salts thereof. Compared to imidazole and 1-methylimidazole, compounds of formula () are more potent inhibitors of TXA ₂ synthase. Many of the present compounds (for example, in formula (), R is 3,4-dimethyl and A is -CH ₂ - or -CH ₂ -CH=CH- in the configuration of formula ()) are also Its action is more selective and does not inhibit other anti-aggregation prostaglandin-producing enzymes. Compounds of formula () also do not produce the side effects found in the case of imidazoles when administered in vivo. The compound of formula () can further inhibit platelet aggregation in vivo, and can also dissolve platelet aggregation.
The compounds 1-(3,4-dimethylbenzyl)imidazole, 1-(2,4-dichlorcinnamyl)imidazole and 1-(2,6-dichlorcinnamyl)imidazole, and their salts particularly exhibit such properties. show. Imidazole of formula ( ) and its acid addition salts can be prepared by any method known in the art for the synthesis of compounds of similar structure. Generally, these methods combine the imidazole ring with the rest of the molecule; transform the precursor molecule by removal of a functional group; and form the desired compound from the corresponding pyrazole, imidazoline, or other unsaturated analog. It depends on a lot of things. The most convenient method of synthesis is imidazole (formula) or a salt thereof and formula (): [formula] [formula] where R, n and A are as defined for the formula, and Z is a leaving group. ) with an aryl alkylating agent. This reaction is well established in the literature and the leaving group can be selected from a variety of substituents, in particular halo (preferably chloro or bromo) or p-toluenesulfonyloxy groups, as well as other arylsulfonyloxy, alkanesulfonyl Oxy or arylalkylsulfonyloxy groups can also be used. This reaction is preferably carried out in an alkanol in the presence of an acid acceptor, such as an alkali metal alkoxide such as sodium methoxide or potassium tert-butoxide. The leaving group itself can be formed in situ from the corresponding alkal (Z=OH) by reaction with a hydrohalic acid (e.g. hydrochloric acid) or a Lewis acid (e.g. aluminum chloride) (see JP-A-52-131577). , the resulting reactant of formula is reacted directly with imidazole without prior isolation. Alternatively, an alkanol (Z=OH) or a derivative thereof (e.g.,
105060) or in the presence of a dehydrating agent such as sulfuric acid or sulfate (see Japanese Patent Publication No. 105061/1983). Among the precursor molecules that can be converted to compounds of formula () or their acid addition salts are those of formula () [wherein A, n and R are as defined in the formula, and Q ¹ , Q ² , Q ³ and Q ⁴ are the same or different, at least one of which is a group that can be removed, for example by reduction or oxidation. , the remaining groups being hydrogen or groups that can be removed in the same way or in a different way (e.g. carboxyl groups removed by decarboxylation - see formula ( ))
and y is zero or an integer, but the sum of y and n does not exceed 5] or an addition salt thereof. Q ¹ , Q ² , Q ³ and Q ⁴
For example, thio (-SH), alkylthio (-S
-Alkyl, where alkyl has 1 to 4 carbon atoms
or halo (preferably chloro or bromo). The conditions for this reaction are based on
It is selected according to the properties of Q ¹ , Q ² , Q ³ and Q ⁴ . Desulfurylation can be carried out by oxidative or reductive methods using, for example, nitric acid or Raney nickel; reductive dehalogenation can be carried out using zinc and acetic acid or Raney nickel, or also other known in the art or described in the literature. It can be carried out using the following reagents. Another example of a group is the expression (): [In the formula, A, n and R are as defined for the formula, and at least one of R ¹ , R ² and R ⁴
one is carboxyl or its derivatives (e.g.
esters such as alkyl esters, acid halides such as chlorides, or nitriles), and others hydrogen or carboxyl or derivatives thereof). A compound of formula ( ) can be converted to an imidazole of formula ( ) by any suitable decarboxylation of the compound, which can be as simple as heating, with or without the use of a catalyst such as copper. Imidazole of formula () is also of formula (): [wherein [Formula] is 1-imidazoline, 1-imidazole or 1-pyrazole, A ¹ is a linear or branched saturated or unsaturated acyclic hydrocarbon group that may include a keto group, and R ³ is (where R and n are as defined for the formula) and when A is unsaturated R can also be nitro, provided that at least one of N, A ¹ and R ³ is One can also be made from a compound of 1-imidazole, a saturated acyclic hydrocarbon group and a compound of the formula [formula] with the proviso that it is not a [formula] group as defined for the formula. Namely, imidazoline (): (In the formula, one of ... represents another bond,
and A, n and R are as defined for the formula) by heating to 250° C. under pressure in the presence of palladium, nickel or platinum, or with a dehydrating agent such as selenium or copper oxide. Dehydrogenation to the corresponding imidazole can be achieved in the presence of a catalyst. The pyrazole compounds () can optionally be treated by UV irradiation under an inert atmosphere (e.g. argon), e.g. in 1,2-dimethoxyethane, at room temperature or elevated temperature [e.g. Ring Transformations of Heterocycles
Heterocycles), Van der Plas, Academic Press, 1973, p. 261]. An unsaturated imidazole of the formula [wherein A ¹ and/or) R(R ³
Compounds which are unsaturated) can be reduced to the corresponding slightly saturated or fully saturated compounds with noble metal catalysts, such as platinum or palladium, in alkanols (with the exception that the aromatic nucleus is not reduced). When R is amino in the final product, the precursor group can be a nitrogen-containing group that can be reduced to amino, such as nitro. For example, the expression A compound of formula (wherein R and n are as defined for the formula) can have its keto moiety reduced to a --CH ₂ -- group, for example, by Clemmensen reduction. If one or more of the R groups are saturated or unsaturated alkyl groups, these groups can be introduced into the phenyl ring by Friedel-Crafts or similar Lewis acid-catalyzed reactions of this type: where A, R and n are as defined for the formula, x is an integer less than or equal to n, and Z ¹ is a leaving group suitable for use in this type of alkylation. , for example, a halo). Compounds of formula () are also of formula (where A, R and n are as defined for the formula and X ² is a leaving group), preferably in the presence of an acid acceptor. . Compounds of formula () are also of formula (wherein A, R and n are as defined for the formula) [wherein either X ³ and Y ³ is a leaving group such as halo or hydroxy and the other is hydrogen, or X ³ and Y ³ are both halo, or taken together or an acetal derivative thereof (e.g. ^, both X ³ and Y ³ are alkoxy), and X ⁴ and Y ⁴ are as defined for X ³ and Y ³ ; It can also be produced by reacting with a compound (which may be the same as or different from Y ³ ). For example, the expression (where R and n are as defined for the formula, X ^- is an anion, and A ² is a linear or branched saturated or unsaturated acyclic carbonized is a hydrogen group, and A ³ is a saturated or unsaturated acyclic hydrocarbon group that may include hydrogen or a keto group, provided that A ² and A ³ do not contain more than 2 carbon atoms in total. The imine salt of ) can be reduced to the corresponding compound of formula ( ), for example, with zinc and hydrochloric acid. Intermediates used in the reactions can also be made by conventional methods known in the art. That is, the 1-pyrazole and 1-imidazoline intermediates (formula) can be prepared by alkylating the pyrazole and imidazoline in a manner similar to that described above for the preparation of the corresponding imidazoles. Intermediates of formula ( ) can be prepared by known methods, preferably by halogenation of the corresponding alcohol (formula, Z=-OH), and in such compounds A
Alcohols which are unsaturated may be conveniently prepared from paraformaldehyde and a precursor molecule having an unsaturated A group containing two carbon atoms [Br. Chemi. Soshi. Japan (Bull.Chem.Soc.
Japan.), 46/8, 2512-5, 1973]. ()
Substituted imidazole intermediates of formula
Edition, K. Manufactured with reference to Hoffmann, Interscience Publications Inc., New York, 1973. for example,
2-thioimidazole of the formula () is the formula (): (where R ⁵ is alkyl, aryl or arylalkyl) with thiocyanate. Pharmaceutically acceptable addition salts of compounds of formula ( ) may be prepared by any method known in the art. In particular, they may be prepared by treating the parent imidazole with a suitable acid. Examples of addition salts of compounds of formula () include salts derived from the following acids: oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid. , acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid and benzenesulfonic acid. Imidazole of formula ( ) can be used in combination with phosphodiesterase inhibitors, which act on platelet aggregation in different ways and thus further increase its action synergistically. Phosphodiesterase inhibitors suitable for use in enhancing the anti-aggregation effect of the active compounds of the invention include compounds such as the following or their pharmaceutically acceptable salts: (a) Xanthine derivative: Theophylline (3,7-dihydro-1,3-
Dimethyl- 1H -purine-2,6-dione and its salts; 3-isobutyl-1-methyl-xanthine; Caffeine (3,7-dihydro-1,3,7
-trimethyl- 1H -purine-2,6-dione) and its salt; and aminophylline [adduct of theophylline and 1,2-ethanediamine (2:1)]. (b) Isoquinoline derivatives, such as: papaverine [1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline] and salts thereof; and 6,7-diethoxy-1-(4,5- diethoxybenzyl) isoquinoline or its salts, such as its hydrochloride. (c) Derivatives of pyrimide (5,4-d-pyrimidine), such as: dipyridamole [2,2',2-(4,8-
Dipiperidino-pyrimide [5,4-d]pyrimidine-2,6-diyldinitrilo)-tetraethanol] and its salts; 2,2',2-[[4-(1-piperidinyl)pyrimide [5,4-d] Pyrimidine-2,
6-diyl]dinitrilo]tetrakisethanol and its salt; and 2,4,6-tri-4-morpholinylpyrimide[5,4-d]pyrimidine and its salt. (d) a derivative of thieno[3,2-d]pyrimidine,
For example: N-[4-(4-morpholinyl)thieno[3,2-d]pyrimidin-2-yl]-1,
2-ethanediamine. (e) Pyrazolo[3′,4′:2,3]pyrido[4,5
-b] [1,5] Benzodiazepine -6- (3
Derivatives of H )-one, for example: 3-ethyl-7,12-dihydro-7,12-dimethyl-pyrazolo[4',5':5,6]pyrido[4,3-b]-1,5- Benzodiazepines
6( 3H )-one; 10-chloro-3-ethyl-7,12-dimethyl-7,12-dihydropyrazolo[4',3':5,
6] Pyrido[4,3-b][1,5]benzodiazepine-6-( 3H )-one. (f) 1 H - or 2 H -pyrazolo [3,4-b]
Derivatives of pyridine, for example: 4-(butylamino)-1-ethyl-1 H -
Pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester; 4-(butylamino)-1 H -pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester; 4-chloro-1- Ethyl-3-methyl-1 H
-pyrazolo[3,4-b]pyridine-5-acetonitrile; 1-ethyl-4-(isopropylidenehydrazino)-3-methyl-1 H -pyrazolo[3,4
-b] Pyridine-5-carboxylic acid ethyl ester or a salt thereof such as its hydrochloride hemihydrate;
and 2-methyl-6-phenyl-4-(1-piperidinyl) -2H -pyrazolo[3,4-b]pyridine or a salt thereof, such as its hydrochloride. (g) 5H -Flow[3,4-e]pyrazolo-
[3,4-b] pyridin-5-one derivative,
For example: 4-(butylamino)-1-ethyl-1,7
-dihydro-7-hydroxy- 5H -flow-
[3,4-e]pyrazolo[3,4-b]pyridin-5-one. and (h) derivatives of derivatives of 1(2 H )-naphthalenone, such as: 2-[(dimethylamino)methyl]-3,4
-dihydro-7-methoxy-1( 2H )-naphthalenone or a salt thereof, such as its 1:1 hydrochloride. The active compounds of the invention are particularly useful for the treatment and/or prevention of thromboembolic disease in mammals, including humans. "thromboembolic disease"
The term "embolic disorders" should be understood to include diseases whose etiology involves platelet aggregation. The active compounds are useful both in cases where it is desired to inhibit platelet aggregation and/or to reduce platelet adhesion, and are therefore useful in the treatment or prevention of thrombosis formation in mammals, including humans. . For example, this compound can be used to treat myocardial infarcts, cerebro-vascular thrombosis, and ischaemic peripheral vascular disease.
vascular disease); for the treatment and prevention of post-surgical thrombosis; and for promoting patency of vascular grafts associated with surgery. The active compounds of the invention can also be combined with blood, blood products, blood substitutes and other artificial extracorporeal circulations and the original body, separated and stored or prepared for transplantation, and combined with a new body. It is useful as an additive to fluids used for dispersing isolated body parts, such as extremities and organs. This compound can also be used to develop new methods and techniques for organ and limb transplantation in laboratory animals such as cats, dogs, rabbits, monkeys and rats for these purposes. The active compounds of the invention also exhibit some vasodilatory effect on blood vessels and therefore have use as antihypertensive agents in the treatment of hypertension in mammals, including humans. The amount of active compound required for therapeutic or prophylactic effect will vary depending on the route of administration and the condition being treated. Generally, suitable dosages of active compound for mammals, including humans, are between 0.1 and 300 mg/kg body weight;
In particular it will be in the range 0.5 to 10 mg/kg body weight, for example 2 mg/kg. Suitable single oral doses for adults are in the range of 50 to 600 mg, e.g.
Administer 150 mg three times a day. While it is possible for the active compounds of the invention to be administered as the neat chemical, it is preferable to use them as pharmaceutical compositions. For both veterinary and human medical use, the compositions of the invention contain an active compound as defined above together with one or more acceptable carriers for formulation and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to its recipient. The unit dosage form of the composition is 60 mg of active compound.
It may contain from 1.5g to 1.5g. Compositions of the invention include those suitable for oral, rectal, vaginal or parenteral (including subcutaneous, intramuscular and intravenous) administration. Suitable compositions include tablets, capsules and injectable suspensions or solutions. The compositions may be conveniently manufactured and presented in unit dosage form by any of the methods well known in the pharmaceutical arts. All methods involve the active compound (in the form of a base or pharmaceutically acceptable acid addition salt);
The method includes the step of bringing into association with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by homogeneously and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation. It will be clear from the foregoing that the present invention provides the following features: (a) Novel 1-arylalkyl imidazoles of formula () and acid addition salts thereof. (b) A method for producing imidazole of formula () and its acid addition salt. (c) A pharmaceutical composition comprising an imidazole of formula () or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. (d) A method for producing a pharmaceutical composition containing imidazole of formula () or a pharmaceutically acceptable acid addition salt thereof. (e) A method for the treatment or prevention of thromboembolic disease in a mammal or mammalian tissue, including a human or human tissue, comprising administering an active compound. (f) A 1-arylalkyl imidazole of formula () or a salt thereof as an active agent for the treatment of thromboembolic diseases in mammals or mammalian tissues, including humans or human compositions. The following examples are intended to illustrate the invention and should not be considered as limiting the invention. All temperatures are given in degrees Celsius. Example 1 Production of 1-(3,4-dimethylbenzyl)imidazole 1-chloromethyl-3,4-dimethylbenzene (34.76 g, 0.225 mol) was mixed with dry methanol (100 g, 0.225 mol).
ml) of imidazole (13.6 g, 0.2 mol) and sodium bicarbonate (16.8 g, 0.2 mol). Following the addition, the reaction mixture is stirred and heated to reflux for 3 hours. After cooling, the reaction mixture is filtered and the liquid is evaporated under reduced pressure to give a yellow oil. The residue was extracted with chloroform (3 x 100 ml) and the combined extracts were washed with saturated saline (100 ml). The chloroform solution is dried over magnesium sulfate and then concentrated under reduced pressure. The resulting oil is purified using a silica gel column and ethyl acetate/methanol (9:1) as eluent. The product fractions are collected, concentrated, and the resulting oil is distilled to produce 1-(3,4
-dimethylbenzyl)imidazole is obtained. boiling point
128-130°/0.3mmHg. Example 2 Salt of 1-(3,4-dimethylbenzyl)imidazole A Hydrogen fumaric acid salt A solution of fumaric acid (0.29 g, 0.0025 mol) in hot ethanol (10 ml) is dissolved in hot ethanol (10 ml).
to a stirred solution of 1-(3,4-dimethylbenzyl)imidazole (0.46 g, 0.0025 mol) in the solution. After boiling for 0.25 hours, the solution is evaporated to give a white solid. This solid was recrystallized from ethyl acetate to give 1-(3,4-dimethylbenzyl)
Imidazole hydrogen fumarate hexahydrate is obtained as a white solid. Melting point 138-140°. B Hydrogensuccinate 1-(3,4-dimethylbenzyl)imidazole (0.46 g, 0.0025 in hot ethanol (10 ml)
Add hot ethanol (20 mol) to a stirred hot solution of
Add a hot solution of succinic acid (0.295 g, 0.0025 mol) in ml). After boiling for 0.25 h, the solution is evaporated under reduced pressure to obtain a white solid. This solid is recrystallized from ethyl acetate/petroleum ether (boiling point 40-60) to obtain 1-(3,4-dimethylbenzyl)imidazole hydrogen succinate as white crystals. Melting point 134-135°. C Hydrogen oxalate Oxalic acid (0.225 ml) in dry ethanol (10 ml)
g, 0.0025 mol) of 1-(3,4-dimethylbenzyl)imidazole (0.46 g, 0.0025 mol)
mol) in hot ethanol (20 ml).
After boiling for 0.25 hours, the solution is evaporated to give a white solid. This solid is recrystallized from ethanol/petroleum ether (boiling point 40-60°) to yield 1-(3,4-dimethylbenzyl)imidazole hydrogen oxalate as a white solid. Melting point 92-93°. Example 3 Production of 1-[3-(2,4-dichlorophenyl)prop-2-yl]imidazole 1-chloro-3-(2,4-dichlorophenyl)prop-2-ene (11.1 g, 0.05 mol) was added to butane. Add dropwise to a stirred solution of imidazole (3.4 g, 0.05 mol) and potassium tert-butoxide (5.6 g, 0.05 mol) in -1-ol (100 ml). Following the addition, stir the reaction mixture;
Heat to reflux for 3.5 hours. After cooling, the reaction mixture is filtered and the liquid is concentrated under reduced pressure. Then add hydrochloric acid (150ml,
2M) and dilute the aqueous mixture with ether (1 x 60
ml). The acidic solution is then made basic with sodium hydroxide solution (10M) and the resulting oil is extracted with chloroform. The chloroform extracts are collected and dried over sodium sulfate. Evaporation of the chloroform under reduced pressure gives a pale yellow oil. This oil is purified using silica gel, eluting with ethyl acetate/methanol (9:1).
The product fractions are collected and concentrated, and the resulting oil is distilled to yield 1-[3-(2,4-dichlorophenyl)prop-2-yl]imidazole. boiling point 144
-148°/0.007mmHg. Example 4 Production of 1-[3-(2,6-dichlorophenyl)propen-2-yl]imidazole 1-chloro-3-(2,6-dichlorophenyl)propen-2-ene (11.1 g, 0.05 mol) was added to butane. Add dropwise to a stirred solution of imidazole (3.4 g, 0.05 mol) and potassium tert-butoxide (5.6 g, 0.05 mol) in -1-ol (100 ml). Following the addition, the reaction mixture is stirred and heated to reflux for 3.5 hours. After cooling, the reaction mixture is filtered and the liquid is concentrated under reduced pressure. The residue is then treated with hydrochloric acid (150
ml, 2M) and the aqueous mixture was diluted with ether (1x
Wash with 60ml). The acidic solution is then made basic with sodium hydroxide solution (10M) and the resulting oil is extracted with chloroform. Collect the chloroform extract,
Dry over magnesium sulfate. Evaporation of the chloroform under reduced pressure gives a pale yellow oil. The product was purified using silica gel column with ethyl acetate/
Purify by elution with methanol (9:1). The product fractions are collected and concentrated, and the resulting oil is distilled to yield 1-[3-(2,6-dichlorophenyl)propen-2-yl]imidazole. Boiling point 156-158°/0.02mmHg. Example 5 Biochemical Results Equine platelets are prepared from complete equine blood by differential centrifugation. Approximately 10 ⁶ platelets are homogenized in 1 ml of 100 mM Tris buffer PH 7.4. Various concentrations of active compound are added and the reaction set is incubated for 5 minutes at ambient temperature. arachidonic acid labeled in each test tube.
Arachidonic acid containing 10 ⁶ disintegrations per minute (DPM)
Add 20 nM and incubate the tubes for 3 minutes at 37°C in a rocking water bath. After incubation, the radioactive product is extracted from the acidified aqueous phase with ethyl acetate, then concentrated and then applied onto silica gel using fluoroform/methanol/acetic acid/water (90:8:1: 0.8) by thin layer chromatography. The amount of thromboxane produced is measured by scraping off a band with radioactivity corresponding to thromboxane _B2 ,
Assess radioactivity with a liquid scintillation counter. The concentration of active compound that reduces the enzyme activity by 50% (ED ₅₀ ) is determined. The results are shown in Table A. The selectivity of the active compound is determined in a manner similar to that described above, measuring the amounts of PGE, PGF and PGD produced. The greater the selectivity, the more anti-aggregating prostaglandin is produced. The ED ₅₀ and selectivity results are shown in Table A.
In this table, 0 represents no selectivity, + represents low selectivity, ++ represents moderate selectivity, +++ represents high selectivity, and ++++ represents significantly high selectivity. [Table] Example 6 Tablet formulation 1 - (3,4-dimethylbenzyl)imidazole (as salt) 150mg Starch 25mg Polyvinylpyrrolidone 2mg Magnesium stearate 3mg The imidazole salt is ground to a fine powder, blended with starch, then the mixture Granulate with an aqueous solution of polyvinylpyrrolidone. The granules are passed through a 1000μ sieve, dried, sieved again and then the magnesium stearate is added. The mixture is then compressed into tablets. In the same manner, tablets of 1-[3-(2,4-dichlorophenyl)pyropen-2-yl]imidazole and 1-[3-(2,6-dichlorophenyl)propen-2-yl]imidazole are made. Example 7 Tablet formulation Imidazole tablets (150
mg) is prepared in the same way from the following ingredients: imidazole compound (as salt) 150 mg lactose 100 mg starch 30 mg polyvinylpyrrolidone 2 mg magnesium stearate 3 mg In this formulation, lactose is combined with starch. Example 8 Tablet Formulation Imidazole tablets (100 mg) of Example 6 are prepared in the same manner from the following ingredients: Imidazole compound (as salt) 100 mg Sodium starch glycolate 10 mg Polyvinylpyrrolidone 2 mg Magnesium stearate 3 mg Example 9 Tablet Formulation of Example 6 Imidazole tablets (150 mg) are prepared from the following ingredients in the same manner except that the starch, pre-gelled starch and imidazole compound are all blended together before granulation: Imidazole compound (as salt) 150 mg Starch 25 mg , pre-gelled starch 5 mg Magnesium stearate 3 mg Example 10 Injection formulation () imidazole compound 15.0 g Lactic acid, pharmacopoeia appropriate amount to bring the pH to 3.0 Water for injection, pharmacopoeia Amount to bring the total volume to 100.0 ml Active compound Suspend in 3/4 of the amount of water available. Add enough lactic acid to dissolve the compound and reduce the PH to 3.0. Dilute to a certain volume with water for injection. The solution is sterilized by passing it through a 0.22 μm pore size filter membrane. Using sterile precautions, dispense the solution into sterile ampoules at 1 ml/ampule. Each 1 ml ampoule provides 150 mg of the imidazole compound: 1-(3,4-dimethylbenzyl)imidazole hydrogen fumarate. Example 11 Injection formulation () imidazole compound 15.0g Citric acid, pharmacopoeia Adequate amount of chlorcresol to bring the pH to 3.0 0.1g Water for injection Amount to bring the total volume to 100.0ml Add the compound to 1/2 of the final volume of water for injection. suspend Add enough citric acid as a 10% injection solution to dissolve the compound and reduce the PH to 3.0. Dilute to a certain volume with water for injection. Sterilize by passing the solution through a filter membrane with a 0.22 μm pore size. Using sterile precautions, dispense the solution into sterile vials at 25 ml/vial. Cap with a sterile rubber stopper and seal with an aluminum cap. Each 1ml solution contains the compound: 1-(3,4-dimethylbenzyl)imidazole hydrogen fumarate 150
Supply mg. Example 12 Injection preparation 1-[3-(2,
Injectable formulations of 4-dichlorophenyl)propen-2-yl]imidazole and 1-[3-(2,6-dichlorophenyl)propen-2-yl]imidazole salts are prepared. Example 13 The following compounds were prepared by the method described in Example 1 above: (a) 1-(2,4,6-trimethylbenzyl)imidazole (b) 1-[3-(4-chlorophenyl)prope-
2-yl]imidazole (c) 1-[3-(3,4-dimethylphenyl)prop-2-yl]imidazole

Claims (1)

[Claims] 1 Formula: [In the formula, A is -CH ₂ - or -CH ₂ -CH=CH-
a group, n is an integer of at least 1, and each R substituent may be the same or different when n is greater than 1 and represents a lower alkyl group having 1 to 4 carbon atoms, with the proviso that (a) if A is a _-CH2- group, n is at least 2; (b) if A is a _-CH2CH =CH- group, n is at least 2; R can also represent chlorine; and (c) if A is a _-CH2CH =CH- group and n is 1, R is not an alkyl group. Alkylimidazole compounds and acid addition salts of such 1-arylalkyl imidazoles. 2 R and n together form a benzene ring 3,
Claim 1 representing a 4-dimethyl substituent
The 1-arylalkyl imidazole compound described in 1. 3 1-(3,4-dimethylbenzyl)imidazole, 1-(2,4-dichlorcinnamyl)imidazole, 1-(2,6-dichlorcinnamyl)
1-Arylalkylimidazole compound according to claim 1, selected from imidazole and acid addition salts thereof. 4. The 1-arylalkyl imidazole compound according to claim 1, which is 1-(3,4-dimethylbenzyl)imidazole or an acid addition salt thereof. 5. The 1-arylalkyl imidazole compound according to claim 1, which is 1-(3,4-dimethylbenzyl)imidazole. 6 Formula: [In the formula, A is -CH ₂ - or -CH ₂ -CH=CH-
a group, n is an integer of at least 1, and each R substituent may be the same or different when n is greater than 1 and represents a lower alkyl group having 1 to 4 carbon atoms, with the proviso that (a) if A is a _-CH2- group, n is at least 2; (b) if A is a _-CH2CH =CH- group, n is at least 2; R can also represent chlorine; and (c) if A is a _-CH2CH =CH- group and n is 1, R is not an alkyl group. A method for producing alkylimidazole compounds and acid addition salts thereof, comprising: (a) imidazole or a salt thereof with the formula (b) where A, n and R are as defined above and Z is a leaving group; or (b): (In the formula, A, n and R are as defined for the formula, Q ¹ , Q ² , Q ³ and Q ⁴ are the same or different, at least one of them is a group that can be removed by reduction or oxidation, and other are groups or hydrogen with the same or different removable functionality, and Y is 0 or an integer, with the proviso that the sum of y and n does not exceed 5. ; or also formula (c): (where A, n and R are as defined for formula (), and R ¹ , R ² and R ⁴
one of which is carboxyl or a derivative thereof and the other is hydrogen, carboxyl or a derivative thereof); or alternatively (d) of formula: [In the formula, [Formula] is 1-imidazoline, 1-imidazole or 1-pyrazole, and A ¹ is a straight-chain or branched saturated or unsaturated acyclic hydrocarbon group which may include a keto group. and
and R ³ is [formula] (where R and n are as defined for the formula, but if A is unsaturated, R can also be nitro)
, wherein at least one of A ¹ and R ³ is 1-imidazole, a saturated acyclic hydrocarbon group, and a group other than the [Formula] group as defined above]; Or (e) Formula (X): A compound of the formula: RZ ¹ where A, R and n are as defined for the formula and x is an integer less than or equal to n. an alkyl group, and Z ¹ is a leaving group)
or alternatively (f) with a compound of formula (XI): (g) where A, R and n are as defined for the formula and X ² is a leaving group; or (g) formula (XII): (wherein A, R and n are as defined for the formula), a compound of the formula (): (where either X ³ and Y ³ is a leaving group and the other is hydrogen, or X ³ and Y ³ are both halo, or together form a keto group) or form its acetal derivative, and X ⁴
and Y ⁴ are as defined for X ³ and Y ³ and are the same or different from X ³ and Y ³ ); or alternatively (h) of formula (a): [In the formula, R and n are the same as in the ^formula ,
is an anion, A ² is a straight chain or branched saturated or unsaturated acyclic hydrocarbon group that may include a chemical bond or a keto group, and A ³ is a hydrogen or a saturated acyclic hydrocarbon group that may include a keto group. or an unsaturated acyclic hydrocarbon group, provided that A ² and A ³ together do not contain more than 2 carbon atoms.