DE2754234A1 - 1- (NAPHTHYLAETHYL) IMIDAZOLE DERIVATIVES AND PROCESS FOR THE PREPARATION - Google Patents

Description

l- (NaphthylEthyl) imidazole derivatives and processes for their

Preparation The present invention relates to certain 1- (naphthylethyl) imidazole derivatives. In particular, the present invention relates to compounds of the following formula: wherein Z is the hydroxymethylene or carbonyl group, as well as pharmaceutically acceptable acid addition salts thereof. The term "pharmaceutically acceptable acid addition salts" refers to salts of the free bases of the formula I which have the desired pharmacological properties and are not undesirable either biologically or in other respects. Such salts can be mixed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic acids, for example acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid; Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, etc., are formed.

Compounds of the formula I in which Z is the hydroxymethylene group have a chiral center.

Thus, these compounds can be in one of their optically active forms or as a racemic mixture. Unless otherwise stated, the compounds described herein are in the racemic form.

The scope of the present invention is by no means intended to apply to the racemic forms, but also includes the individual optical isomers of the compounds according to the invention.

If desired, the compounds of the formula I, in which Z denotes the hydroxymethylene group, in optically active form by the usual an known splitting measures, for example by separation, e.g. by fractional crystallization, of the diastereomeric salts, which for example by reacting the racemic compounds of the formula I in which Z is the hydroxymethylene group means with an optically active acid or by separating the diastereomers Esters which are obtained by reacting a racemic alcohol in which Z is the hydroxymethylene group means to be formed with an optically active acid. Examples such optically active acids are the optically active forms of camphor-10-sulfonic acid, a-Bromocampfer - sulfonic acid, camphor acid, methoxyacetic acid, tartaric acid, malic acid, Diacetyltartaric acid, pyrrolidone-5-carboxylic acid, etc., The separated, pure diastereomers Salts or esters can be known in Way, forming the appropriate optical isomers of the desired compounds are split.

The compounds of the formula I have a broad spectrum with respect to their effect on the central nervous system. You have anticonvulsants in particular (as evidenced by the electroshock maximum convulsive method), appetite suppressant, antidepressant and muscle relaxant properties as well as other effects, such as the inhibition of gastric secretion and an antihypertensive effect.

An object of the present invention is to provide a method for curative or prophylactic treatment of convulsions in humans and animals, by adding a therapeutically effective amount of a compound of formula I or one pharmaceutically acceptable acid addition salts thereof. Another goal the present invention relates to pharmaceutical preparations which for the treatment and / or prevention of convulsion in humans and animals is valuable are and a compound of formula I or a pharmaceutically acceptable acid addition salt thereof mixed with a pharmaceutically acceptable, non-toxic carrier, contain.

For these purposes, in particular compounds of the formula I, wherein Z denotes the carbonyl group, preferably.

The present invention also relates on a method of inhibiting gastric secretion in humans and animals by a therapeutically effective amount of a compound of formula I or a pharmaceutically permissible acid addition salts thereof administered.

The present invention further relates to pharmaceuticals Preparations which are useful for inhibiting gastric secretion in humans and animals, such preparations being a compound of the formula I or a pharmaceutical acceptable acid addition salt thereof mixed with a pharmaceutically acceptable, non-toxic carrier.

When carrying out the above-described methods according to the invention a therapeutically effective amount of a compound of formula I or one pharmaceutical preparation containing such a compound in per se for one of ordinary skill in the art either individually or in conjunction with another compound according to the invention or with other compounds according to the invention or administered to other pharmaceutical agents.

These compounds or preparations can be administered orally or parenterally, i.e. intramuscularly, subcutaneously or intravenously, either in solid form or in liquid Form, e.g. in the form of tablets, solutions, suspensions, etc., as described below Oral administration is preferred.

Administration can be in single unit dosage forms continuous therapy or done ad libitum. The method according to the invention can be used when specific symptom treatment is required is, i.e. therapeutic, or it can be continuous or prophylactic Treatment to be made.

In view of what has just been said, as well as in view of the severity the disease, the age of the individual to be treated, etc., becomes the most effective Dose largely fluctuate, but this was determined by routine tests by the person skilled in the art can be.

In general, the effective amount of anticonvulsant to be used will be at about 0.1 to about 300 mg / kg body weight per day, and preferably at about 1 to about 100 mg / kg body weight per day. In other words, wants this said that on average in an adult one was therapeutically effective Amount according to preferred embodiments at about 70 mg to about 7 g per Is administered per day and per patient. A therapeutically effective dose for inhibition the gastric secretion is from about 0.1 to about 300 mg / kg body weight per day and preferably at about 0.25 to about 100 mg / kg of body weight per day. In other words, this means that in an adult im average the therapeutically effective amount according to preferred embodiments is approximately 18 mg to about 7 g per day per patient.

For the manufacture of the pharmaceutical preparations described here you can use solid or liquid pharmaceutical carriers. So leave the preparations in the form of tablets, pills, capsules, powders, sustained-release preparations, Solutions, suspensions, elixirs, etc.

produce. The various oils, including Petroleum oil, animal oils, vegetable oils or synthetic oils, e.g. peanut oil, Soybean oil, mineral oil, sesame oil, etc., in question. Water, saline solutions, aqueous Dextrose and glycols are preferred liquid carriers and are particularly so with regard to injectable solutions. Suitable pharmaceutical carriers include Starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, Lime, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skimmed milk, glycerine, propylene glycol, water, ethanol, etc. Suitable pharmaceutical carriers and their preparation are described by E.W, Martin in "Remington's Pharmaceutical Sciences ". Such preparations contain in any case a therapeutically effective amount of the active ingredient together with a suitable one Amount of carrier in order to make a suitable one in this way Dosage form allow for appropriate administration to the patient.

The compounds according to the invention can be prepared according to those known per se Establish methods. So you can, for example, compounds of the formula I, wherein Z denotes the carbonyl group, prepare in a manner which corresponds to the method according to U.S. Patent 3,717,655 (Godefrol et al.) Is analogous. This method is that a haloethylnaphthyl ketone with imidazole in an inert organic solvent implements. The halomethylnaphthyl ketones used as starting materials are known compounds or can be obtained by halogenating a corresponding methylnaphthyl ketone obtained in a manner known per se, for example using cupribromide will. The preparation of ketones of the formula I by the above method can be found in an inert organic solvent such as dimethylformamide at a temperature between approximately -10 "C and 40" C.

The preparation of compounds of formula I in which Z is the hydroxymethylene group means, can by reducing a corresponding ketone or an acid addition salt thereof under customary conditions, for example by using sodium tetrahydroborate in a protic solvent, e.g. methanol, at a temperature between -20 oC and 20 T.

The compounds of the formula I in which Z is the hydroxymethylene group can also be prepared according to the following reaction scheme: wherein the epoxide of formula III or the halohydride of formula IV is treated with imidazole and / or an alkali metal salt thereof (preferably the sodium salt) in a polar aprotic solvent, e.g. dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, at a temperature between approximately 0 Cc and 100 Cc /. Treatment of the epoxy requires 1 mole of imidazole in the presence of 0.05 to 1 mole of imidazole salt.

Treatment of a halohydrin requires just over 1 mole Imidazole salt, as the halohydrin is first converted to the epoxide in situ.

The compounds of the formula I according to the invention permit isolate as free bases. Because some of these compounds are in the form of bases Represent oils or rubber-like products and / or are not water-soluble it is often more favorable to isolate such compounds as acid addition salts and to be marked. These salts are in a customary manner, for example by reaction the free base with a suitable, inorganic or organic acid, such as e.g. one of the pharmaceutically acceptable acids mentioned above. If so desired can be such salts easily by treating with a base, such as potassium or Convert sodium carbonate or potassium or sodium hydroxide into the free base.

In summary, it should be mentioned that the present invention generally provides a process for the preparation of a compound of the following formula and in the form of a free base, namely in which Z denotes the hydroxymethylene or carbonyl group, or a pharmaceutically acceptable, non-toxic acid addition salt thereof, this process consisting in that (a) a compound of the formula I in which Z denotes the carbonyl group is prepared by reacting a halomethylnaphthyl ketone with imidazole or (b) a compound of the formula I in which Z is the hydroxymethylene group by reducing a compound of the formula I in which Z is the carbonyl group, or (c) a compound of the formula I in which Z is the hydroxymethylene group by reaction of a compound of the following formulas: wherein X represents a halogen atom, produces with imidazole and / or an alkali metal salt thereof and (d) optionally converts a free base into the corresponding acid addition salt or (e) converts an acid addition salt optionally into the corresponding free base.

The following description is provided to those skilled in the art To make invention more understandable.

The following examples are in no way intended to be of a restrictive nature be, but only the invention closer explain.

Example 1 An ice-cooled sludge of 35 g of imidazole in 25 ml of dimethylformamide was mixed with 24.9 g of bromomethyl-2-naphthyl ketone offset. Then the mixture was stirred for 2 hours at room temperature and then allowed to cool to room temperature and finally stand overnight calmly. The solution was poured into water and the resulting sticky> solid material filtered off, washed with water and dissolved in benzene. Then was the resulting benzene solution dried azeotropically, whereby l- (2-naphthoylmethyl) imidazole was obtained, which by adding ethereal hydrogen chloride to complete Precipitation was converted into the corresponding hydrochloride. The salt was through Bred addition of ethyl acetate to crystallize and the resulting solid Recrystallized material from a mixture of methanol and acetone, whereby one colorless needles of 1- (2-naphthoylmethyl) imidazole hydrochloride, melting point 226 to 228.5 Cc (dec.).

Example 2 To 9.4 g of the above-mentioned l- (2-naphthoylmethyl) - imidazole hydrochloride an excess of sodium tetrahydroborate was added to 200 ml of methanol at 0 to 5% stirred in.

After stirring at 0 ° C. for 30 minutes, the reaction mixture dried to dryness evaporated. The resulting residue was treated with 200 ml of water and that The product which crystallized out was filtered off, washed with water and extracted from ethyl acetate recrystallized, l- [2-hydroxy-2- (2-naphthyl) ethyl-imidazole in the form of not quite white leafy structures with a melting point of 156 to 160.5 Cc (weak Dec.) Received.

Example 3 10.1 g of methyl 1-naphthyl ketone in 50 ml of a mixture of chloroform and ethyl acetate (in a mixing ratio of 1: 1) was with 26.5 g copper (II) bromide treated.

The resulting reaction mixture was stirred vigorously for so long heated to boiling under reflux until the evolution of hydrogen bromide ceased Has. After the reaction had ended, the solvent was removed and the reaction mixture was removed mixed with ether. Then the copper (I) bromide was removed by filtration. Evaporation of the filtrate under reduced pressure gave crude bromomethyll-naphthyl ketone.

The bromomethyl-1-naphthyl ketone thus obtained was on this treated according to the manner described in Example 1, wherein l- (l-naphthoylmethyl) imidazole was obtained, which after recrystallizing twice from benzene, colorless flakes of melting point 113.5 to 117 Cc.

Example 4 To 7.0 g of the above l- (l-naphthoylmethyl) imidine 50 ml Methanol azole / an excess of sodium tetrahydroborate was stirred in at 0 to 5 "C. After stirring for 30 minutes, the solvent was removed under residue with water treated. The product was filtered off, washed with water and extracted from ethyl acetate recrystallized, giving 5.60 g of snow-white microcrystals, consisting of l- [2-Hydroxy-2- (l-naphthyl) ethyl] imidazole, melting point 112.5 to 115 Cc (below weak decomposition).

Example 5 Ethereal hydrogen chloride was added dropwise to 100 ml of a solution of 1.0 g of 1-t2-naphthoylmethyl) imidazole / anhydrous benzene so added long until the precipitation was complete. Then the product was filtered, washed with ether, air dried and made from a mixture of methanol and acetone recrystallized, 1- (2-naphthoylmethyl) imidazole hydrochloride, Melting point 226 to 228.5 "C (dec.).

All compounds of the formula I, which are obtained as free bases, into the corresponding acid addition salts by treating them with a suitable acid, e.g. hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, Pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, Fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, Ethanesulfonic acid, p-toluenesulfonic acid, etc. treated.

Example 6 1.0 g of 1- (2-naphthoylmethyl) imidazole hydrochloride was added suspended in 50 ml of ether and the suspension so long with an excess dilute aqueous potassium carbonate solution stirred until the salt completely dissolved was. The organic layer was then separated, washed twice with water, dried over magnesium sulfate and evaporated to give 1- (2-naphthoylmethyl) imidazole received.

In a similar way, all of the acid addition salts could be used Convert compounds of the formula I into the corresponding free bases.

Example 7 Maximum Electric Shock Convulsions in Mice This test was in the usual way and essentially according to the information given in Swinyard et al., J.

Pharm. Exp. Ther., Vol. 106, pp. 319-330 (1952).

Groups of 10 male mice each from the Hilltop ICR strain each weighing 20 to 30 g were intraperitoneally with a solution or Suspension of the compound to be tested in saline solution 15 minutes before treatment treated with a maximal transcorneal electric shock (50 milliamps, 0.2 seconds). The mice were observed to detect the onset of spasm of the tonic extensors, of tonic flexors, clonic convulsions, and death. An active ingredient was able to induce spasms of the tonic extensors, which were immediate after the electric shock occurred, suppress the ED50 values (and the 95 above Trust values) were the following; ED50 mS / kg compound (95 S Confidence limit 1- (2-naphthoylmethyl) imidazole 23 (20-25) 1- [2-hydroxy-2- (2-naphthyl ) ethyl] imidazole 74 (55-110) 1- (l-naphthoylmethyl) imidazole approx. 60 1- [2-hydroxy-2- (l-naphthyl) ethyl] imidazole 37 (32-53) Example 8 groups of 3 male mice each from the ICR strain each weighing 18 to 24 g were each with a single dose of the invention Compounds treated intraperitoneally. The following dosages were used : 1, 3, 10, 30, 100, 300 and 1,000 mg / kg, respectively. After. five days was the Mortality determined. The LD50 values were as follows: Compound LD50 (mg / kg) 1- (2-Naphthoylmethyl) imidazole 100-300 1- [2-Hydroxy-2- (2-naphthyl) ethyl] imidazole 300-1,000 1- [2-hydroxy-3- (1-naphthyl) ethyl] imidazole 300-1,000 1- (1-naphthoylmethyl) imidazole 100-300 Example 9 The following is a pharmaceutical preparation for oral administration, which can be obtained with the compounds according to the invention can produce explained.

The compound according to the invention was l- (2-naphthoylmethyl) imidazole or another active ingredient is used.

Weight of active ingredient 200 magnesium stearate 3 starch 30 lactose 116 Polyvinylpolypyrrolidone 3 The above ingredients were combined and taken under Granulated use of methanol as a solvent.

This mass was then dried and formed into tablets, each containing 200 mg of active ingredient on a suitable tableting machine deformed.

Claims (8)

Claims (£ 1 - compounds of the following formula: where Z is the hydroxymethylene or carbonyl group, and the pharmaceutically acceptable acid addition salts thereof. 2. - A compound according to claim 1, wherein Z is the carbonyl radical. 3. - The compound according to claim 2, which consists of 1- (2-naphthoylrnethyl) imidazole or a pharmaceutically acceptable acid addition salt thereof. 4. A compound according to claim 1, wherein Z is the hydroxymethylene group means. 5. - A compound according to claim 4, which consists of 1-E2-hydroxy-2- (1-naphthyl) ethyl) imidazole or a pharmaceutically acceptable acid addition salt thereof. 6. - Pharmaceutical preparation for the prevention and treatment of convulsions in humans and animals, characterized in that it contains a therapeutically effective amount of a compound of the following formula: wherein Z is the hydroxymethylene or carbonyl group, or a pharmaceutically acceptable acid addition salt thereof mixed with a pharmaceutically acceptable, non-toxic carrier. 7. - Pharmaceutical plant for the inhibition of gastric secretion in humans and animals, characterized in that it contains a therapeutically effective amount of a compound of the following formula: wherein Z is the hydroxymethylene or carbonyl group, or a pharmaceutically acceptable acid addition salt thereof mixed with a pharmaceutically acceptable, non-toxic carrier. 8. - Process for the preparation of a compound which, in the form of the free base, corresponds to the following formula: wherein Z denotes the hydroxymethylene or carbonyl group, or a pharmaceutically acceptable acid addition salt thereof, characterized in that (a) a compound of the formula I, in which Z denotes the carbonyl group, is prepared by reacting a halomethylnaphthyl ketone with imidazole or (b) a compound of Formula I, in which Z is the hydroxymethylene group, is prepared by reducing a compound of the formula I in which Z is the carbonyl group, or (c) a compound of the formula I in which Z is the hydroxymethylene group, by reaction of a compound of the following formulas: wherein X represents a halogen atom, is prepared with imidazole and / or an alkali metal salt thereof and (d) a free base obtained in this way is optionally converted into the corresponding acid addition salt or (e) an acid addition salt obtained in this way is optionally converted into the corresponding base is convicted.