DE3137674C2 - - Google Patents

Description

The invention relates to new imidazole derivatives and pharmaceutical compositions containing these derivatives.

So far, as compounds that have an inhibitory Effect on the biosynthesis of thromboxane A₂ (hereinafter with TXA₂ abbreviated) exercise z. B.

• (i) sodium p-benzyl-4 - ([- oxo-2- (4-chlorobenzyl) -3-phenylpropyl] - phenylphosphonate (N-0164),
• (ii) 2-isopropyl-3-nicotinylindole (L-8027),
• (iii) 9,11-epoxymethanoprostanoic acid and
• (iv) imidazole,

known. In this context is referred to the reference "Annaual Review of Biochemistry 47, 1002-1004 (1978) ".  

In addition, it has recently been found by the applicant that imidazole derivatives with various substituents in the 1-position have a strongly inhibiting effect on the biosynthesis of TXA₂. Reference is made to DE-OS 29 17 456, 29 05 811 and 29 23 815. These known compounds either have an alkyl substituent on the α- C atom to the carboxy group or are not substituted at all at this point. They thus differ structurally from the compounds of the formula (I) claimed according to the invention.

Extensive series of tests have been carried out by the applicant carried out to find new imidazole derivatives which strongly inhibit the biosynthesis of TXA₂. The applicant has found that this achieved with the imidazole derivatives according to the invention can be.

The object of the invention, i. H. the provision new imidazole derivatives with a more inhibitory Effect on the biosynthesis of TXA₂, will by new imidazole derivatives of the general formula I

in which m represents an integer from 5 to 7, R¹ represents a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms, and one of the substituents R² and R³ represents a hydrogen atom and the other represents a halogen atom or a phenyl group, or R² and R³ together - (CH₂) _n -, in which n represents an integer from 4 to 6, or = CH₂, and the non-toxic salts of these derivatives. These new imidazole derivatives according to the invention have a particularly strong inhibitory effect on the biosynthesis of TXA₂ and are therefore suitable in the treatment of diseases which are caused by TXA₂, such as. B. inflammation, cerebral apoplexy, myocardial infarction, acute cardiac death, cardiostenosis and thrombus.

Examples of straight-chain or branched alkyl groups, which have 1 to 4 carbon atoms and by R 1 are methyl, ethyl, propyl and butyl a hydrogen atom or a methyl or ethyl group.

The alkylene group which is represented by - (CH₂) _m - means pentamethylene, hexamethylene and heptamethylene. Hexamethylene is preferred.

According to the invention, the compounds of the formula (I) in which one of the substituents R² and R³ represents a hydrogen atom and the other represents a phenyl group, or R² and R³ together represent - (CH₂) _n - and the other symbols have the meanings defined above, ie compounds of the general formula IA or IB

or

with all or specified symbols above were defined by the reaction of an imidazole metal salt, e.g. B. a silver salt or an alkali metal salt, with a halogen compound accordingly of the general formula IIA or IIB,

where X represents a halogen atom and the other symbols have the meanings given above.

Suitable solvents are in the above order settlement reaction those solvents which the reaction do not affect why in general benzene, Toluene, xylene, N, N-dimethylformamide, acetonitrile or a lower alcohol is used. The reaction can be carried out at a temperature of 0 to 150 ° C,  generally at room temperature at reflux temperature of the solvent used.

Compounds of the general formula (I), wherein one of the substituents R² and R³ is a hydrogen atom represents and the other represents a halogen atom and the other symbols have the meanings given above have, d. H. Compounds of the general formula IC,

with all of the symbols defined above, are the halogenation of an alcohol compound general formula III

all of the symbols have been defined above are received.

The reaction is carried out according to conventional methods Conversion of an alcohol compound to a halogen compound carried out, d. H. with a halogen acid, such as hydrobromic acid or thionyl chloride.

Compounds of the general formula (III) can be obtained from Compounds of the general formula IIC

are produced, in which all symbols the above have given meanings with the above for the preparation of the compounds of the general Formula (IA) or (IB) specified methods.

Compounds of the general formula (I), in which R² and R³ together = CH₂ and the other symbols represent have the meanings given above, d. H. links of the general formula ID

where all symbols have the meanings given above can by dehydrating one Alcohol of the general formula IV

where all symbols have the meanings given above have to be manufactured.

The reactions are affected by usual dehydration Use of an acid catalyst to obtain an olefinic connection carried out, preferably using phosphoric acid under reduced Pressure at a temperature of 150 to 180 ° C.

Compounds of the general formula IV can be obtained from  Compounds of the general formula IID prepared will:

where all symbols are those given above Have meanings with the help of the above for the Preparation of the compounds of general formula IA or IB method described.

Compounds of the general formula IA, IB, IC, ID, III or IV, wherein R¹ represents hydrogen atom and the other symbols have the meanings given above can also by hydrolyzing compounds of the general formula IA, IB, IC, ID, III or IV, wherein R¹ is a straight chain or branched alkyl group with 1 to 4 carbon atoms represents, and the other symbols the above Have meanings under alkaline conditions be preserved.

The hydrolysis is carried out in aqueous solution of a hydroxide or carbonate of an alkali metal salt such as sodium or potassium, in the presence or absence of a water miscible Solvent, e.g. B. an ether such as tetrahydrofuran, or a lower alcohol such as methanol or ethanol.

Compounds of general formula I, wherein R¹ is a straight-chain or branched alkyl group with 1 to 4  Represents carbon atoms and the other symbols can have the meanings given above also by esterification of compounds of the general Formula I wherein R1 represents a hydrogen atom and the other symbols have the meanings given above have, according to known methods of esterification a carboxylic acid be, e.g. B. the method using a Diazole alkane.

The compounds of general formula I are after conventional methods cleaned, e.g. B. by distillation at normal pressure or under reduced pressure, or by HPLC, thin layer chromatography, column chromatography on silica gel or recrystallization.

Imidazole salts can be made by reaction an imidazole with an alkali metal hydride, such as sodium hydride, an alkali metal alcoholate such as sodium methoxide, an alkali metal carbonate such as sodium or potassium Carbonate, an alkali metal hydroxide such as sodium or Potassium hydroxide, or a silver oxide in an inert Solvent. These metal salts can be isolated Compounds or used as a saline solution.

The halogen compounds of the general formula II are known as such or are made by known methods produced. For example, connections of the general formula IIA, IIB or IID by Reaction of compounds of the general formula V:  

wherein one of the substituents R⁴ and R⁵ represents a hydrogen atom, the other represents a phenyl group or a hydroxymethyl group, or R⁴ and R⁵ together - (CH₂) _n - mean, R¹ and n have the meanings given above, using a lithium compound, such as . As butyllithium or lithium diisopropylamide, to obtain a lithium compound and reaction of the compound obtained with halogen compounds of the general formula VI

X- (CH₂) _m -X (VI)

wherein X and m have the meanings given above, prepared.

The reaction is carried out in an inert organic solvent, e.g. B. in tetrahydrofuran, diethyl ether, Hexane or Hexamethylphosphamid, or in a mixture of two or more of these solvents, with lower ones Temperatures from -78 ° C to room temperature.

The compounds of the general formula IIC can are produced by a series of reactions that are given schematically below.  

Scheme

wherein R⁶ is a straight-chain or branched alkyl group with 1 to 4 carbon atoms and the others Symbols have the meanings given above.

With reference to the scheme, connections of the general formula VIII from compounds of general Formula VII and compounds of general Formula: CH₃COOR⁶, wherein R⁶ is the above Has meaning, according to a method described above for the preparation of the compounds of the general Formula IIA, IIB or IID manufactured. Compounds of the general formula IX are made from Compounds of the general formula VIII per se known methods for converting an ester Carboxylic acid in a formyl group, e.g. B. using of diisopropyl aluminum hydride.  

Aldehyde compounds of the general formula IX which can be obtained in this way in compounds the general formula X by means of known Process, and compounds of the general formula X can be hydrolyzed and - if this is desired - while maintaining the connections of the general formula IIC are esterified.

Acid addition salts of imidazole derivatives of the general Formula I can from the compounds of general Formula I according to methods known per se are produced, e.g. B. by implementing stoichiometric Amounts of a compound of general formula I. with a suitable acid, e.g. B. an inorganic Acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, Sulfuric acid, phosphoric acid or nitric acid, or an organic acid, such as acetic acid, lactic acid, Tartaric acid, benzoic acid, citric acid, methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or isethionic acid, in a suitable Solvent.

Neutral salts can be made from the general acids Formula I, wherein R¹ represents a hydrogen atom, are produced by methods known per se, e.g. B. by implementing stoichiometric amounts Acid of the general formula I and a suitable one Base, e.g. B. an alkali or alkaline earth metal hydroxide or carbonate, or an organic amine, in one suitable solvent. The acid addition salts are preferably used and the neutral salts non-toxic salts represents.  

Under the designation "non-toxic salts" as they used in this description is understood Salts, their anions or cations are proportional are harmless to the animal organism if they are used in therapeutic doses, so that the beneficial pharmacological properties of the compounds of general formula I not be adversely affected by side effects that these are anions or cations. Preferably the salts are water soluble.

Suitable acid addition salts of imidazole derivatives are e.g. B. inorganic acid salts, such as. B. hydrochloride, Hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or organic salts, such as acetate, lactate, tartrate, Benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, Toluenesulfonate or isethionate.

Suitable neutral salts include the alkali salts, e.g. B. the sodium or potassium salts, the alkaline earth metal salts, e.g. B. the calcium or magnesium salts, and the ammonium salts, as well as pharmaceutically acceptable (i.e. non-toxic) Amine salts. Amines used to form such salts Carboxylic acids are generally known and suitable include e.g. B. amines, which are theoretically derived by replacing one or more hydrogen atoms of the Ammoniaks by groups that are the same or different are when more than one hydrogen atom is exchanged will, and z. B. selected from alkyl groups with 1 to 6 carbon atoms and hydroxyalkyl groups with 2 or 3 carbon atoms.  

Suitable non-toxic amine salts are e.g. B. Tetraalkyl ammonium salts such as tetramethylammonium salts and others organic amine salts, such as methylamine salts, dimethylamine salts, Cyclopentylamine salts, benzylamine salts, phenethylamine salts, Piperidine salts, monoethanolamine salts, Diethanolamine salts, lysine salts and argin salts.

The imidazole derivatives of the general formula I and their non-toxic salts have an inhibitory Effect on the biosynthesis of TXA₂ and are therefore suitable for controlling the biosynthesis of TXA₂ in mammals, including humans if this it is asked for.

For example, in standard laboratory tests
1-7-carboxy-7-chloroheptyl) imidazole hydrochloride,
1- (7-carboxy-7-phenylheptyl) imidazole hydrochloride,
1- (7-carboxy-7,7-pentanoheptyl) imidazole hydrochloride,
1- (7-carboxy-7-octenyl) imidazole hydrochloride
a 50% inhibition of thromboxane synthetase from platelet microsomes in rabbits at a molar concentration of 2.5 × 10 ^-8 , 3.8 × 10 ^-8 , 4.6 × 10 ^-8 and 1.6 × 10 ^-8 .

Controlling the biosynthesis of TXA₂ is important in preventing and treating inflammation, cerebral apoplexy, myocardial infarction, acute cardiac death, cordiostenosis and thrombus in mammals, including humans, especially in People. For this purpose, the connections according to systematically administered the invention in general,  e.g. B. orally, rectally or parenterally.

The doses depend on the age, the symptoms, the desired therapeutic effect, the ver doses, duration of treatment and the like. In general, about 10 mg to 1 g administered orally and 0.01 mg to 10 mg for intravenous Injections used. 1 µg to 100 µg per hour are suitable for continuous intravenous infusions, especially if emergency or intensive care is required.

It could be confirmed that the LD₅₀ value was above 5000 mg / kg when administered orally to rats. With it the compounds according to the invention via a low toxicity and are therefore particularly suitable for use as pharmaceuticals.

Solid compositions for oral administration include pressed tablets, pills, dispersible powders and granules. In such solid compositions one or more active connections with at least one an inert extender, such as calcium carbonate, potato starch, Alginic acid or lactose, mixed. These Compositions can also, like this in practice In addition to the inert extenders, additional ones are common Contain substances, e.g. B. lubricants, such as Magnesium stearate. Liquid compositions for oral Administration include pharmaceutically acceptable emulsions, Solutions, suspensions, syrups and elixirs, which contain inert thinners, as they are known by the expert  commonly used, such as B. water or liquid Paraffin.

In addition to the inert diluents, such compositions also contain auxiliaries, such as. B. wetting agents and suspending agents, sweeteners, Flavors, perfuming agents and preservatives Agents.

The compositions according to the invention for oral administration also include capsules of absorbable materials which are one or more active substances with or without the addition of thinners, Contain extenders or exipients.

Solid compositions for intrarectal administration comprise suppositories which are known per se Be formulated and one or more active Connections included.

Preparations according to the invention for parenteral Administration include sterile aqueous or non- aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or suspending Media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic Esters, such as ethyl oleate. These funds can also Auxiliaries, such as preserving, wetting, emulsifying or contain dispersing agents. You can also be sterilized, e.g. B. by means of filtration a filter that retains the bacteria  Incorporation of sterilizing agents into the By means of radiation. You can also in In the form of sterile, solid agents, those in sterile water or another sterile injectable medium dissolved immediately before use will.

The following reference examples and examples are intended explain the invention in more detail without limiting it. Mean in the reference examples and in the examples the abbreviations TLC, IR, NMR, MS each "thin layer chromatography", "Infrared absorption spectrum", "nuclear magnetic resonance spectrum" and "mass spectrum". If solvent ratios in the chromatographic Separation specified, so refer the relationships to the volume. The solvents in Brackets for thin layer chromatography mean the one used Development solvents. If not different the infrared spectra are given by means of the liquid film method and the nuclear magnetic resonance spectra added in deuterochloroform (CDCl₃) solution.

Reference Example 1 7-Bromoheptanoic acid t-butyl ester

To 6.94 mL diisopropylamine in 100 mL anhydrous Tetrahydrofuran was added dropwise to 34 mL of a 1.45 M Solution of n-butyllithium in hexane at -70 ° C and  the mixture was stirred for 15 minutes.

To this solution was added dropwise a solution of 6.63 ml of t-butyl acetate in 30 ml of anhydrous tetrahydrofuran and the mixture was stirred for 30 minutes, and then 8 ml of 1,5-dibromopentane in 10 ml of anhydrous tetrahydrofuran was added and this mixture was stirred for 5 minutes . Then 17 ml of hexamethylphosphamide were added, the mixture was stirred at -78 ° C for 1 hour and at -40 to -30 ° C for 30 minutes. An aqueous ammonium chloride solution was added to the reaction mixture. The aqueous layer was separated from the organic layer. The aqueous layer was extracted with diethyl ether. The extract was added to the organic layer and washed with water, a saturated aqueous sodium chloride solution and dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1: 1) as the eluent. 8.5 g of the compound mentioned in the heading were obtained, which had the following physical characteristics:
TLC (benzene): Rf = 0.64.

Reference Example 2 7-bromoheptanaldehyde

To 8.5 g of 7-bromoheptanoic acid t-butyl ester (prepared as described in Reference Example 1) in 80 ml of methylene chloride, 18.2 ml of a 25% strength diisobutylaluminum hydride solution in toluene were added dropwise at -78 ° C. over the course of 1 hour. The solution was stirred at the same temperature, then 5 mL of methanol was added at a temperature of 0 to 10 ° C and then 10 mL of water. The mixture was stirred at 30 to 40 ° C for 1 hour. The precipitated crystals were filtered out and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of methylene chloride and cyclohexane (1: 1) as the eluent. 5.28 g of the title compound were obtained, which had the following physical characteristics:
TLC (benzene): Rf = 0.44.

Reference example 3 1-bromo-7-hydroxyoctannitrile

To 253 mg of sodium cyanide in 8.6 ml of water, 983 mg of the aldehyde, the preparation of which is described in Reference Example 2, and 10 mg of ice and 1.47 ml of a saturated aqueous sodium bisulfate solution were slowly added dropwise with vigorous stirring. After the mixture was stirred vigorously for 1.5 hours, it was extracted with diethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and concentrated under reduced pressure. 560 mg of the title compound were obtained, which had the following physical characteristics:
TLC (benzene: ethyl acetate = 2: 1): Rf = 0.56.

Reference example 4 8-Bromo-2-hydroxyoctanoic acid methyl ester

1 mL of a 47% aqueous solution of hydrobromic acid solution was added to 560 mg of the nitrile, the preparation of which was described in Reference Example 3. The mixture was stirred at 70 to 80 ° C for 1 hour and then extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. 2 ml of diethyl ether were added to the residue obtained, and a solution of diazomethane in diethyl ether was added until there were no more insoluble materials. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and benzene (1:10) as the eluent. 188 mg of the title compound were obtained, which had the following physical characteristics:
TLC (benzene: ethyl acetate = 4: 1): Rf = 0.44;
IR: µ = 3500, 2950, 2870, 1740 cm ^-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 8-Bromo-2,2-pentanooctanoic acid ethyl ester

To 25 mL of a 0.282 molar solution of lithium diisopropylamide 1 g was added dropwise in tetrahydrofuran Ethyl cyclohexane carboxylate in 5 mL tetrahydrofuran added at -70 ° C, the mixture was at stirred at the same temperature for 50 minutes. To this A mixture of 1.86 g of 1,6-dibromohexane in 4 ml of tetrahydrofuran was added added at -70 ° C and the mixture for 5 minutes long stirred.

2.68 mL of hexamethylphosphamide were added to the mixture at the same temperature within 30 minutes and stirred at -30 ° C for 1 hour. The extract was washed with water, a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using methylene chloride and cyclohexane (1: 1) as the eluent. 1.12 g of the title compound were obtained, which had the following physical characteristics:
TLC (benzene): Rf = 0.74;
IR: µ = 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

To 147 g of sodium hydride (63% content), which was suspended in 5 ml of N, N-dimethylformamide, 263 mg of imidazole were added and the mixture was stirred at a temperature of 110 to 120 ° C. for 10 minutes. To this mixture, 1.11 g of the bromide prepared in Reference Example 5 in 3 mL of N, N-dimethylformamide was added, and the mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure. To the residue was added diethyl ether containing a small amount of water, and the solution was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a mixture of chloroform and methanol (9: 1) as the eluent. 967 mg of the title compound were obtained, which had the following physical characteristics:
TLC (chloroform: methanol = 9: 1): Rf = 0.30;
IR: µ = 3400, 2950, 2860, 1725, 1510, 1460, 1450, 1370, 1230, 1200, 1135, 1020, 900 cm ^-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).

Example 2 1- (7-methoxycarbonyl-7-hydroxyheptyl) imidazole

The compound having the following physical characteristic was obtained by using 1-bromo-7-hydroxyoctanoic acid methyl ester instead of the bromide used in Example 1. The preparation procedure was carried out in the same manner as described in Example 1.
TLC (chloroform-methanol = 9: 1): Rf = 0.57.

Example 3

The following compounds were obtained by instead of of cyclohexane carboxylic acid ethyl ester as he was used in Reference Example 5, respectively 1-hydroxypropionic acid ethyl ester or phenylacetic acid ethyl ester used and the same procedure as described in Reference Example 5 and Example 1 was applied.

• (a) 1- (7-ethoxycarbonyl-7-phenylheptyl) imidazole
  TLC (chloroform: methanol = 10: 1): Rf = 0.36.
• (b) 1- (7-ethoxycarbonyl-7-hydroxymethylheptyl) imidazole
  TLC (chloroform: methanol = 9: 1): Rf = 0.59.

Example 4 1- (7-carboxy-7,7-phentanoheptyl) imidazole hydrochloride

A mixture of 810 mg of that described in Example 1 and prepared ester, 4.2 mL ethanol and 6.1 mL of a 2N sodium hydroxide solution was 16 hours long stirred at a temperature of 80 to 85 ° C; then the reaction mixture was reduced Pressure concentrated and the residue twice with chloroform washed; then the solution was through concentrated azeotropic distillation with t-butanol. The residue was dissolved in a 3N hydrochloric acid solution Adjusted pH 3, concentrated under reduced pressure and further by azeotropic distillation with t-butanol concentrated.

A mixture of ethanol and diethyl ether (95: 5) was added to the residue and the crystals obtained were washed with diethyl ether. 140 mg of the title compound were obtained, which had the following physical properties:
Melting point: 158 to 160 ° C;
TLC (ethyl acetate: water: acetic acid = 3: 1: 1): Rf = 0.67;
IR μ = 3400, 3100, 3045, 2945, 2855, 1710, 1580, 1540, 1470, 1450, 1410, 1385, 1295, 1215, 1180, 1170, 1135, 1085 cm ^-1 ;
NMR: δ = 8.90-8.50 (1H, m), 7.95-7.10 (2H, m), 4.26 (2H, t).

Example 5 1- (7-carboxy-7-phenylheptyl) imidazole hydrochloride

A mixture of 119 mg of the ester described and prepared in Example 3 (a), 1 ml of ethanol and 0.38 ml of a 2N sodium hydroxide solution were treated under reflux for 4 hours and 5 ml of water were added. The mixture was then concentrated under reduced pressure. Water was added to the residue and the solution extracted with diethyl ether. The aqueous layer was acidified to pH 1 with a dilute hydrochloric acid solution and concentrated under reduced pressure, and further concentrated by azeotropic distillation with t-butanol. The residue was diluted with absolute ethanol and the insoluble constituents were removed therefrom; the solution was then concentrated under reduced pressure. Repeating the same procedure, 56 mg of the title compound was obtained, which had the following physical characteristics:
IR: µ = 3600-2300, 1709, 1572, 1448, 1186, 1083, 721, 696 cm ^-1 ;
NMR (D₂O 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), 81 (100).

Example 6

The following compounds were made, where that prepared in Example 2 and Example 3 (b) Ester instead of the ester used in Example 4 was used. It was made following the same procedure worked as in Example 4, except that the cleaning procedure has not been carried out.

• (a) 1- (7-Carboxy-7-hydroxyheptyl) imidazole hydrochloride
  TLC (ethyl acetate: water: acetic acid = 3: 1: 1 Rf = 0.25;
  IR: m = 3350, 2950, 2870, 1750, 1590, 1560 cm ^-1 ;
  NMR (D₂O 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
  TLC (ethyl acetate: water: acetic acid = 3: 1: 1): Rf = 0.5;
  IR = µ = 3400, 3150, 2500, 1720 cm ^-1 ;
  NMR (D₂O 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 7 1- (7-carboxy-7-chloroheptyl) imidazole hydrochloride

To 140 mg of 1- (7-carboxy-7-hydroxyheptyl) imidazole hydrochloride, which had been prepared as described in Example 6 (a), 0.193 ml of thionyl chloride were added dropwise at a temperature of 0 to 3 ° C. and that Mixture stirred overnight at room temperature; then this was concentrated under reduced pressure. Ice was added to the residue obtained, and the mixture was stirred for 5 minutes and then concentrated under reduced pressure. A small amount of water was added to the residue and the insolubles removed therefrom; the resulting solution was then concentrated under reduced pressure. 149 mg of the title compound were obtained, which had the following physical characteristics:
IR: µ = 3700-2400, 1740, 1580, 1550, 1460, 1190 cm ^-1 ;
NMR (DMSO-D₆ solution): δ = 9.3 (1H, s), 7.95 - 7.6 (2H, d), 4.7 - 4.0 (3H, m).

Example 8 1- (7-carboxy-7-octenyl) imidazole hydrochloride

To 180 mg of 1- (7-carboxy-7-hydroxymethylhetpyl) imidazole hydrochloride, which had been prepared as described in Example 6 (b), two or three drops of phosphoric acid were added and the mixture was reduced under reduced pressure at 160 ° C implemented. The reaction mixture was purified by cellulose column chromatography using a mixture of n-butanol, water and acetic acid (8: 10: 1). The obtained fraction was adjusted to pH 8 with a 1N sodium hydroxide solution to remove the contaminated phosphoric acid. The crystals obtained were removed. The same purification procedure by column chromatography over cellulose was repeated to obtain 78 mg of the title compound, which had the following physical characteristics:
TLC (ethyl acetate: water: acetic acid = 3: 1: 1): Rf = 0.46;
NMR (D₂O 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 9

10 g of 1- (7-carboxy-7-octenyl) imidazole hydrochloride, 10 mg cellulose calcium gluconate (disintegrator), 2 mg Magnesium stearate (lubricant) was mixed and processed into tablets in a conventional manner by each containing 100 mg of the active ingredient.

Claims (8)

1. Imidazole derivatives of the general formula I wherein m represents an integer of 5 to 7, R¹ represents a hydrogen atom or a straight or branched alkyl group having 1 to 4 carbon atoms, and one of the substituents R² and R³ represents a hydrogen atom while the other represents a halogen atom or a phenyl group, or R² and R³ together - (CH₂) _n -, where n represents an integer from 4 to 6, or = CH₂, and pharmaceutically acceptable, non-toxic salts thereof. 2. Compounds according to claim 1, characterized in that R¹ is a hydrogen atom, represents a methyl group or an ethyl group. 3. Compounds according to claim 1, characterized in that m is 6. 4. Connection according to claim 1, characterized in that these 1- (7-carboxy-7- chloroheptyl) imidazole or its hydrochloride represents. 5. A compound according to claim 1, characterized in that this 1- (7-carboxy-7-phenylheptyl) imidazole or its hydrochloride represents.   6. Connection according to claim 1, characterized in that these 1- (7-carboxy-7,7- pentanoheptyl) imidazole or its hydrochloride represents. 7. A compound according to claim 1, characterized in that that these 1- (7-carboxy-7- octenyl) imidazole or its hydrochloride. 8. Pharmaceutical means characterized in that this is an active ingredient at least one general connection Formula I according to claim 1, with those in claim 1 defined symbols, or a pharmaceutical acceptable, non-toxic salt thereof with a pharmaceutical carrier or appropriate coating include.