JPS622586B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel imidazole derivatives and pharmaceuticals containing the same. More specifically, in order to specifically inhibit the biosynthesis _of thromboxane A ₂ (hereinafter referred to as TXA ₂ ),
General formula useful as a therapeutic agent for various diseases caused by TXA ₂ , such as inflammation, stroke, myocardial infarction, acute heart disease, angina, thrombosis, etc. [In the formula, m represents an integer from 4 to 9, R ¹ represents a hydrogen atom or a straight chain or branched alkyl group having 1 to 12 carbon atoms, and R ² and R ³ represent one hydrogen atom and the other represents a halogen or phenyl group,
Or R ² and R ³ together - (CH ₂ ) _o - or =
CH ₂ is represented, and n represents an integer of 4 to 6. ] and its pharmaceutically acceptable non-toxic salts. R ¹ in the general formula () represents carbon number 1-
12 straight-chain or branched-chain alkyl groups include methyl,
Examples include ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and isomers thereof, and preferred R ¹ is a hydrogen atom or a methyl or ethyl group. Examples of the alkylene group represented by the -(CH ₂ ) _n - group include tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, and nonamethylene, and preferred -(CH ₂ ) m ^- groups include pentamethylene, hexamethylene, or Heptamethylene is particularly preferred, and hexamethylene is particularly preferred. Preferred pharmaceutically acceptable acid addition salts are inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate. , citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and isethionate. Conventionally, compounds that inhibit TXA ₂ biosynthesis include (i) sodium p-benzyl-4-[1-oxo-2-(4-chlorobenzine)-3-phenylpropyl] phenylphosphonate (N −0164), (ii)
2-isopropyl-3-nicotinylindole (L-8027), (iii) 9,11-epoxymethanoprostanoic acid, (iv) imidazole, etc.
Review of Biochemistry (Annual
Review of Biochemistry), Volume 47, pages 1002-1004 (1978). 〕It has been known. Furthermore, it has recently been discovered that imidazole derivatives having various substituents at the 1-position of imidazole strongly inhibit the biosynthesis of TXA ₂ (Japanese Patent Application Laid-open No. 109973/1989, 54-
109974, 54-112862, 54-112863, 54-
144369, 54-163573, 55-313, 55-28927
Please refer to the specifications of et al. ) The present inventors have conducted research to find a new imidazole derivative that strongly inhibits the biosynthesis of TXA ₂ , and as a result, they have discovered that the compound of the present invention achieves that objective, and have completed the present invention. According to the present invention, one of R ² and R ³ represents a hydrogen atom and the other represents a phenyl group, or R ² and R ³ together represent -(CH ₂ ) _o -, and the other symbols are as above. Compounds of general formula () expressing the same meaning, i.e. or [In the formula, all symbols have the same meanings as above. ] is a metal salt of imidazole, such as a silver salt or an alkali salt such as sodium or

[Formula] [In the formula, X represents a halogen atom, and the other symbols have the same meanings as above. ] It is obtained by reacting a halogen compound shown in the following. Any solvent may be used as long as it does not participate in the reaction, but benzene, toluene,
Xylene, N,N-dimethylformamide, acetonitrile, lower alkanol, etc. are used.
The reaction is carried out at a temperature of 0°C to 150°C, usually from room temperature to the reflux temperature of the solvent. A compound of general formula () in which one of R ² and R ³ represents a hydrogen atom and the other represents a halogen atom, and the other symbols have the same meanings as above, i.e. [In the formula, all symbols have the same meanings as above. ] The compound has the general formula [In the formula, all symbols have the same meanings as above. ] It can be obtained by halogenating the alcohol compound shown. This reaction is carried out using a reaction commonly used to convert an alcohol compound into a halogen compound, such as reaction with a halogen acid such as hydrobromic acid or thionyl chloride. The compound of the general formula () can be obtained by the method described above to obtain the compound of the general formula (A) or (B). [In the formula, all symbols have the same meanings as above. ] Obtained from the compound shown. Compounds of the general formula () where R ² and R ³ together represent =CH ₂ and other symbols have the same meanings as above, i.e. [In the formula, all symbols have the same meanings as above. ] The compound has the general formula [In the formula, all symbols have the same meanings as above. ] It can be obtained by dehydrating the alcohol compound shown. This reaction is based on the usual reaction of obtaining an olefin compound by acid-catalyzed dehydration of an alcohol compound.
Preferably it is carried out at a temperature of ~180°C. The compound of the general formula () can be obtained by the method described above to obtain the compound of the general formula () or (B). [In the formula, all symbols have the same meanings as above. ] Obtained from the compound shown. General ^formulas (A), (B), (
The compound of C), (D), () or () is R ¹
General formula (A), (B), (C), (D), () or () in which represents a straight or branched chain alkyl group having 1 to 12 carbon atoms, and other symbols have the same meanings as above. It can also be obtained by hydrolyzing the compound under alkaline conditions. Hydrolysis is carried out using water-miscible solvents, such as ethers such as tetrahydrofuran or methanol,
It is carried out in an aqueous solution of an alkali metal hydroxide or carbonate, such as sodium or potassium, in the presence or absence of a lower alkanol such as ethanol. Compounds of general formula () in which R ¹ represents a straight or branched alkyl group having 1 to 12 carbon atoms and other symbols have the same meanings as above, R ¹ represents a hydrogen atom and the other symbols have the same meanings as above. It can also be obtained by esterifying a compound of general formula () having the same meaning as , by a known method of converting a carboxylic acid into an ester, such as a method using a diazoalkane. The compound of general formula () can be purified by conventional purification methods such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel, thin layer chromatography, column chromatography, or recrystallization method. It is refined in Pharmaceutically acceptable acid addition salts have the general formula ()
It can be obtained by a known method of adding a desired inorganic or organic acid to the compound represented by. Metal salts of imidazole include alkali metal hydrides such as sodium hydride, alkali metal alcoholates such as sodium methoxide, alkali metal carbonates such as sodium carbonate or potassium carbonate, sodium hydroxide or potassium hydroxide. It is obtained by reacting an alkali metal hydroxide or silver oxide with imidazole in an inert solvent. These metal salts may be used in isolation, or a solution thereof may be used to carry out the desired reaction. The halogen compound represented by the general formula () is known per se or can be obtained by using a known method. For example, general formula (A),
The compound (B) or (D) has the general formula [In the formula, one of R ⁴ and R ⁵ represents a hydrogen atom,
the other represents a phenyl group or a hydroxymethyl group, or R ⁴ and R ⁵ taken together -(CH ₂ ) _o
-, and R ¹ and n have the same meanings as above. ] The compound represented by the formula is converted into a lithium compound using a lithiation agent such as lithium _{diisopropylamide} , and then _the general formula represent ] It is obtained by reacting a halogen compound shown in the following. This reaction can be carried out using inert organic solvents such as tetrahydrofuran, diethyl ether, hexane,
It is carried out in hexamethylphosphamide (HMPA) or a mixed solvent of two or more thereof at a low temperature from room temperature to -78°C. The compound of general formula (C) can be obtained by the reaction steps shown in the following scheme. In the formula, R ⁶ represents a straight or branched alkyl group having 1 to 4 carbon atoms, and the other symbols have the same meanings as above. To explain the diagram, a compound of general formula (X) is a compound of general formula () and a compound of general formula CH ₃ COOR ⁶
(R ⁶ represents the same meaning as above) by the method described above to obtain the compound of general formula (A), (B) or (D). The compound of general formula () can be obtained by a known method of converting a carboxylic acid ester into a formyl group using a compound of general formula (X), for example, a method using diisobutylaluminum halide. The obtained aldehyde ( ) is converted into cyanohydrin ( ) by a known method, hydrolyzed, and optionally esterified to obtain a compound of general formula (C). Acid addition salts of imidazole derivatives represented by the general formula () can be prepared by adding the compound represented by the general formula () to a compound represented by the general formula () in a suitable solvent, and adding a suitable acid such as hydrochloric acid. Inorganic acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, or acetic acid, lactic acid, tartaric acid, benzoic acid, citric acid, methanesulfonic acid, ethanesulfonic acid,
It can be obtained by reacting stoichiometric amounts of organic acids such as benzenesulfonic acid, toluenesulfonic acid, and isethionic acid. Neutral salts can be prepared by mixing the acid represented by the general formula () in which R ¹ represents a hydrogen atom with a suitable base such as an alkali metal or alkaline earth in a suitable solvent. It is obtained by reacting stoichiometric amounts of similar metal hydroxides or carbonates or organic amines. Preferably, the acid addition salt or neutral salt is a non-toxic salt. Here, non-toxic salts are relatively harmless to animal tissues, and when used in therapeutically necessary amounts, the effective pharmacological properties of the compound represented by the general formula () may be due to side effects caused by its anions or cations. refers to salts of anions or cations which are not impaired by Preferably the salt is water soluble. Suitable acid addition salts include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, or acetates, lactates, tartrates, ammonium Examples include organic acid salts such as fragrant, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, and isethionate. Suitable neutral salts include, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, ammonium salts and pharmaceutically acceptable (non-toxic) amine salts. Suitable amines that form such salts with carboxylic acids are well known and include, for example, amines that could theoretically be obtained by replacing one or more hydrogen atoms of ammonia with other groups. The groups may be the same or different when one or more hydrogen atoms are substituted, but for example have 1 to 6 carbon atoms.
alkyl groups, and hydroxyalkyl groups having 1 to 3 carbon atoms. Suitable non-toxic amine salts include tetraalkylammonium salts such as tetramethylammonium, and methylamine salts, dimethylamine salts, cyclopentylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts, diethanolamine salts, Examples include organic amine salts such as lysine salts and alginate salts. Imidazole derivatives represented by the general formula () and their non-toxic salts have the activity of inhibiting TXA ₂ biosynthesis, so it is desirable to control TXA ₂ biosynthesis in mammals including humans. It is useful for controlling when For example, in a laboratory experiment, the activity of thromboxane synthetase in rabbit platelets was investigated.
The concentration required for 50% inhibition is 2.5 × 10 ^-8 molar concentration of 1-(7-carboxy-7-chloroheptyl) imidazole hydrochloride;・
Hydrochloride has a molar concentration of 3.8 × 10 ^-8 , and 1-(7-carboxy-7,7-pentanoheptyl) imidazole hydrochloride has a molar concentration of 4.6 × 10 ^-8 , and 1-
The concentration of (7-carboxy-7-octenyl)imidazole hydrochloride was 1.6×10 ⁻⁸ molar. Controlling the biosynthesis of TXA ₂ is effective in preventing and treating inflammation, stroke, myocardial infarction, acute heart disease, angina pectoris, thrombosis, etc. in mammals including humans, especially humans. For these purposes, they are usually administered systemically, for example orally or rectally, or parenterally. Dosage depends on age, symptoms,
Although it varies depending on the therapeutic effect, administration method, processing time, etc., it is usually orally administered in the range of 10 mg to 1 g, and especially when urgent treatment is required, 0.01
Administered intravenously in the range of ~10 mg or 1
Continuous intravenous infusion in the range of ~100 μg/hour. As for the toxicity of the compound of the present invention, it was confirmed that the LD ₅₀ value was 5000 mg/Kg or more by oral administration to rats, and it is considered that the compound can be used as a drug. Solid formulations for oral administration include tablets, pills, powders and granules. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as calcium carbonate, potato starch, alginic acid or lactose. The formulations may contain additives other than diluents, for example lubricants such as magnesium stearate, in a conventional manner. Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs, including commonly used inert diluents such as water or liquid paraffin. including.
In addition to inert diluents, the formulations may also contain auxiliary agents, such as wetting agents, suspending agents, sweetening agents, flavoring agents, perfuming agents or preservatives. Preparations for oral administration according to the invention also include capsules of absorbable materials such as gelatin with or without one or more active substances and diluents or excipients. Solid preparations for rectal administration include suppositories containing one or more active substances and formulated in a manner known per se. Products for parenteral administration according to the invention include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Non-aqueous solvents or suspending agents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such formulations may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. They can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants, or by irradiation. Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use. Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. In addition, "TLC" in reference examples and examples,
The symbols “IR,” “NMR,” and “MS” stand for “thin layer chromatography,” “infrared absorption spectrum,” respectively.
"Nuclear Magnetic Resonance Spectrum" and "Mass Spectrometry" and the proportion of solvent described in the section of separation by chromatography indicates the volume ratio,
The solvent inside the “TLC” box indicates the developing solvent.
"IR" is measured by a liquid film method unless otherwise specified, and "NMR" is measured using a deuterated chloroform (CDC ₃ ) solution unless otherwise specified. Reference Example 1 t-Butyl 7-bromoheptanoate 34 ml of n-butyllithium (1.45 M/hexane solution) was added dropwise to 6.94 ml of diisopropylamine dissolved in 100 ml of anhydrous tetrahydrofuran at -70°C and stirred for 15 minutes. To this, 6.63 ml of t-butyl acetate dissolved in 30 ml of anhydrous tetrahydrofuran was added dropwise, and after stirring for 30 minutes, 8 ml of 1,5-dibromopetane dissolved in 10 ml of anhydrous tetrahydrofuran was added dropwise.
, stir for 5 minutes, add 17 ml of hexamethylphosphamide and incubate at -78°C for 1 hour, at -40°C to -30°C.
Stir for 30 min at °C. An aqueous ammonium chloride solution is added to the reaction mixture, and the organic layer and aqueous layer are separated. The aqueous layer was extracted with ethyl ether, and the organic layers were combined, washed with an aqueous ammonium chloride solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride-cyclohexane (1:1) as an eluent to obtain 8.5 g of the title compound having the following physical properties. TLC (benzene): R=0.64. Reference Example 2 7-Bromoheptyraldehyde To 8.5 g of t-butyl 7-bromoheptanoate (produced in Reference Example 1) dissolved in 80 ml of methylene chloride, 18.2 ml of a 25% toluene solution of diisobutylaluminum hydrand was added at -78°C. It drips over time. Stir at the same temperature for 10 minutes, add 5 ml of methanol at 0°C to 10°C, then add 10 ml of water and mix at 30°C to
Stir at 40℃ for 1 hour. Separate the precipitated crystals, and concentrate the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography using methylene chloride-cyclohexane (1:1) as an eluent to obtain 5.28 g of the title compound having the following physical properties. TLC (benzene): R=0.44. Reference Example 3 8-Bromo-2-hydroxyoctanenitrile Add 983 mg of aldehyde (produced in Reference Example 2) and 10 g of ice to 253 mg of sodium cyanide dissolved in 8.6 ml of water, and add 1.47 ml of saturated sodium hydrogen sulfate while stirring vigorously. Dripping with structure. After stirring vigorously for 1 hour and 30 minutes, extraction was performed with diethyl ether, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 560 mg of the title compound having the following physical properties. TLC (benzene: ethyl acetate = 2:1): R
=0.56. Reference Example 4 To 560 mg of methyl 8-bromo-2-hydroxyoctanoate nitrile (produced in Reference Example 3) was added 1 ml of hydrobromic acid (47%), stirred at 70°C to 80°C for 1 hour, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Add 2 ml of diethyl ether to the residue and add a solution of diazomethane in diethyl ether until no insoluble residue remains. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography using ethyl acetate-benzene (1:10) as an eluent to obtain 188 mg of the title compound having the following physical properties. TLC (benzene: ethyl acetate = 4:1): R = 0.44. IR: ν=3500, 2950, 2870, 1740cm ^-1 . NMR:
δ=4.4−4.0 (1H, m), 3.7 (3H,
s), 3.3 (2H, t), 3.0 (1H), d),
2.3~1.0 (10H, m). MS (%): m/e=254 (M ⁺ ), 252
(M ⁺ ), 195 (86), 193 (86), 95
(100), 90 (20), 69 (28), 56 (21), 54
(47). Reference example 5 Ethyl 8-bromo-2,2-pentanooctanoate 5 ml of tetrahydrofuran solution of 0.282M lithium diisopropylamide in tetrahydrofuran
Ethyl cyclohexanecarboxylate dissolved in ml
Add 1g dropwise at -70℃ and stir at the same temperature for 50 minutes. Add 1.86 g of 1,6-dibromohexane dissolved in 4 ml of tetrahydrofuran and stir at the same temperature for 5 minutes, then add 2.68 ml of hexamethylphosphamide and stir at the same temperature for 30 minutes and at -30℃ for 1 hour. After that, saturated ammonium chloride aqueous solution was added, extracted with diethyl ether, and the organic layer was diluted with water and
Wash with saturated aqueous ammonium chloride solution and saturated brine, dry over magnesium sulfate, and concentrate under reduced pressure.
The residue was purified by silica gel column chromatography using methylene chloride-cyclohexane (1:1) as an eluent to obtain 1.12 g of the title compound having the following physical properties. TLC (benzene): R = 0.74 IR: ν = 2935, 2850, 1730, 1460, 1450,
1370, 1210, 1195, 1135, 1025 ^{cm -1} . NMR: δ = 4.03 (2H, q), 3.28 (2H,
t), 2.8-0.75 (23H, m). MS (%): m/e = 320 (11), 318 (M ⁺ , 11),
247(14), 245(17), 171(13), 169
(12), 165 (11), 157 (13), 156
(100), 155 (13), 109 (17), 97 (23),
95 (20), 83 (40), 81 (28), 69 (25),
67 (17), 57 (11), 55 (33) 43 (12),
41 (28). Example 1 1-(7-Ethoxycarbonyl-7,7-pentanoheptyl)imidazole 263 mg of imidazole was added to 147 mg of sodium hydride (content 63%) suspended in 5 ml of N,N-dimethylformamide at 110°C to 120°C. 1.11 g of bromide (produced in Reference Example 5) dissolved in 3 ml of N,N-dimethylformamide was added, stirred for 1 hour at the same temperature, and then concentrated under reduced pressure.
Diethyl ether containing a small amount of water was added to the residue, washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using chloroform-methanol (9:1) as an eluent to obtain 967 mg of the title compound having the following physical properties. TLC (chloroform:methanol=9:1)R
=0.30. IR=ν=3400, 2950, 2860, 1725, 1510,
1460, 1450, 1370, 1230, 1200, 1135,
1020,900cm ^-1 . NMR: δ=7.13 (1H, m) 7.0−6.6 (2H, m),
4.05 (2H, q) 3.83 (2H, t), MS (%): m/e = 307 (16), 306 (M ⁺ , 37),
305 (59), 260 (11), 250 (13), 233
(24), 232 (81), 152 (29), 151
(100), 138 (17), 137 (21), 124
(11), 123 (23), 110 (16), 109 (23),
96 (29), 95 (33), 83 (11), 82 (46),
81 (33), 69 (56), 68 (16), 67 (20),
55 (27), 54 (30), 53 (14), 41 (29). Reference Example 6 1-(7-Methoxycarbonyl-7-hydroxyheptyl)imidazole Example 1 and methyl 8-bromo-2-hydroxyoctanoate (produced in Reference Example 4) were used in place of the bromide used in Example 1. Similarly, the title compound having the following physical properties was obtained. TLC (chloroform:methanol=9:1):
R=0.57. Example 2 1-(7-Ethoxycarbonyl-7-phenylheptyl)imidazole The following physical properties were obtained in the same manner as in Reference Example 5 and Example 1 using ethyl phenyl acetate instead of ethyl cyclohexanecarboxylate used in Reference Example 5. The title compound was obtained. TLC (chloroform:methanol=10:1):
R-0.36. Reference Example 7 1-(7-Ethoxycarbonyl-7-hydroxymethylheptyl)imidazole Same as Reference Example 5 and Example 1, using ethyl 3-hydroxypropionate instead of ethyl cyclohexanecarboxylate used in Reference Example 5. The title compound was obtained with the following physical properties. TLC (chloroform:methanol=9:1):
R=0.59. Example 3 A mixture of 810 mg of 1-(7-carboxy-7,7-pentanoheptyl) imidazole hydrochloride ester (produced in Example 1), 4.2 ml of ethanol, and 6.1 ml of 2N sodium hydroxide was heated at 80°C to 85°C. Stir at °C for 16 hours, concentrate under reduced pressure,
The residue was washed twice with chloroform and azeotroped with t-butanol. The residue was adjusted to pH 3 with 3N hydrochloric acid, concentrated under reduced pressure, and azeotroped with t-butanol. Ethanol-diethyl ether (95:5) was added to the residue, and the resulting crystals were collected and washed with diethyl ether to obtain 140 mg of the title compound having the following physical properties. Melting point: 158℃~160℃ TLC (ethyl acetate:water:acetic acid=3:1:1):
R = 0.67 IR: ν = 3400, 3100, 3045, 2945, 2855,
1710, 1580, 1540, 1470, 1450, 1410,
1385, 1295, 1215, 1180, 1170, 1135,
1085cm ^-1 . NMR: δ=8.90−8.50 (1H, m), 7.95−7.10
(2H, m), 4.26 (2H, t). Example 4 A mixture of 119 mg of 1-(7-carboxy-7-phenylheptyl)imidazole hydrochloride ester (produced in Example 2), 1 ml of ethanol, and 0.38 ml of 2N sodium hydroxide was refluxed for 4 hours, then 5 ml of water was added and the pressure was reduced. Concentrate, add water to the residue, and extract with ether. Water layer with dilute hydrochloric acid
After adjusting the pH to 1 and concentrating under reduced pressure, t-butanol was added and azeotroped. Absolute ethanol was added to the residue to remove insoluble matter, and the mixture was concentrated under reduced pressure. The same operation was repeated to obtain 56 mg of the title compound having the following physical properties. IR: ν=3600−2300, 1709, 1572, 1448,
1186, 1083, 721, 696 cm ^-1 . NMR (heavy aqueous solution): δ=8.72 (1H, m), 7.54
(1H, m), 7.48 (1H, m), 7.37 (5H,
s), 4.21 (2H, t). MS (%): m/e = 242 (57), 151 (49), 138
(41), 137 (58), 96 (57), 95 (95), 91
(48), 82(100). Reference Example 8 Reference Example 6 instead of the ester used in Example 3
Alternatively, the following compound was obtained in the same manner as in Example 3 using the ester produced in Reference Example 7. However, no refining operation was performed. (a) 1-(7-carboxy-7-hydroxyheptyl) imidazole hydrochloride TLC (ethyl acetate:water:acetic acid=3:1:1):
R=0.25. IR: ν=3350, 2950, 2870, 1750, 1590, 1560
cm ^-1 . NMR (heavy aqueous solution): δ=8.8−8.6 (1H, m),
7.6-7.3 (2H, m), 4.4-4.05 (3H,
m), 2.3−1.0 (10H, m). (b) 1-(7-carboxy-7-hydroxymethylheptyl)imidazole hydrochloride TLO (ethyl acetate:water:acetic acid=3:1:1):
R=0.5. IR: ν=3400, 3150, 2500, 1720 ^{cm -1} . NMR (heavy aqueous solution): δ=8.9−8.7 (1H, m),
7.7−7.45 (2H, m), 4.3 (2H, t),
2.8−2.5 (1H, m), 2.2−1.1 (10H,
m). Example 5 1-(7-carboxy-7-chloroheptyl)
Imidazole hydrochloride 0.193 ml of thionyl chloride was added to 140 mg of 1-(7-carboxy-7-hydroxyheptyl) imidazole hydrochloride (produced in Reference Example 8(a)) at 0°C to 30°C.
The mixture was added dropwise at ℃, stirred overnight at room temperature, and concentrated under reduced pressure.
Ice was added to the residue, stirred for 5 minutes, and then concentrated under reduced pressure. A small amount of water was added to remove insoluble matter, and the residue was concentrated under reduced pressure to obtain 149 mg of the title compound having the following physical properties. IR: ν=3700−2400, 1740, 1580, 1550,
1460, 1190. NMR (DMSO-D ₆ solution): δ = 9.3 (1H, s),
7.95-7.6 (2H, d), 4.7-4.0 (3H,
m). Example 6 1-(7-carboxy-7-octenyl)imidazole hydrochloride 1-(7-carboxy-7-hydroxymethylheptyl)imidazole hydrochloride (Reference Example 8
Add 2 to 3 drops of phosphoric acid to 180 mg (produced in step (b)) and react at 160°C under reduced pressure for 5 hours. The reaction mixture was mixed with n-butanol-water-acetic acid (8:10:
Purify by cellulose column chromatography using 1), then adjust the pH to 8 with 1N sodium hydroxide to remove phosphoric acid, remove the formed crystals, and perform the same purification using a cellulose column. 78mg of the title compound with physical properties of
I got it. TLC ethyl acetate:water:acetic acid=3:1:1):R
=0.46. NMR (heavy aqueous solution): δ=8.83−8.65 (1H, m),
7.62−7.38 (2H, m) 6.23−6.09 (1H,
m), 5.75-5.6 (1H, m), 5.27 (2H,
t), 2.46-2.1 (2H, m), 2.1-1.02
(8H, m). Example 7 10 g of 1-(7-carboxy-7-octenyl) imidazole hydrochloride, 10 mg of cellulose calcium gluconate (disintegrant), and 2 mg of magnesium stearate (lubricant) were mixed in a conventional manner and tableted.
Tablets containing 100 mg of active ingredient in the tablet were obtained.

Claims (1)

[Claims] 1. General formula [In the formula, m represents an integer of 4 to 9, R ¹ represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms, one of R ² and R ³ represents a hydrogen atom, The other one represents a halogen atom or a phenyl group, or ^R2 and ^R3 together represent -( _CH2 ) _o- or = _CH2 , and n represents an integer of 4 to 6. ]
An imidazole derivative or a pharmaceutically acceptable non-toxic salt thereof. 2. The compound according to claim 1, which is 1-(7-carboxy-7-chloroheptyl)imidazole hydrochloride. 3. The compound according to claim 1, which is 1-(7-carboxy-7-phenylheptyl)imidazole hydrochloride. 4. The compound according to claim 1, which is 1-(7-carboxy-7,7-pentanoheptyl)imidazole hydrochloride. 5. The compound according to claim 1, which is 1-(7-carboxy-7-octenyl)imidazole hydrochloride. 6 General formula [In the formula, m represents an integer of 4 to 9, R ¹ represents a hydrogen atom or a straight or branched alkyl group having 1 to 12 carbon atoms, one of R ² and R ³ represents a hydrogen atom, The other one represents a halogen atom or a phenyl group, or ^R2 and ^R3 together represent -( _CH2 ) _o- or = _CH2 , and n represents an integer of 4 to 6. ]
A thromboxane A ₂ biosynthesis inhibitor containing one or more of the imidazole derivatives or pharmaceutically acceptable non-toxic salts thereof as an active ingredient.