DE3613223A1 - IMIDAZOLIUMARYLALKANOIDS, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

DESCRIPTION

The invention relates to aryl alkanoids of imidazole of the general formula (I)

Ar-CH-COO ^ NH

Ll

The starting acids used to produce the imidazolium salts are well known. Examples are 2- (4-isobutylphenyl) propionic acid (ibuprofen), (p-isobutylphenyl) acetic acid (Ibufenac), 2- (3-Benzoylphenyl) propionic acid (Ketoprofen), 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3-indolylacetic acid (Indomethacin) and other well known anti-inflammatory agents (sulindac, etc.).

All of these acids have an anti-inflammatory, anti-pyretic effect and analgesic activity, which, as is generally the case with all NSAID compounds, of one gastric toxicity (B. Scott, Brit. Med. J. 1, 489, 1979). This gastrotoxic activity can lead to cause gastric ulcers and severely affect the therapeutic applicability and their clinical Limit usage.

The salts of the general formula (I) surprisingly show compared to the acids from which they are derived or compared to other known salts in equivalent doses a considerably stronger inflammatory

inhibitory, analgesic and antipyretic effect without accompanying ulcerogenic or gastrotoxic symptoms. You can therefore stay in the clinic for long periods of time can be used more safely and effectively. It was also found that the compounds (I) the number and reduce the severity of ulcers caused in animals by agents such as reserpine and corticosteroids will.

The invention also relates to processes for the preparation of the compounds (I) by forming the salts of imidazole with the corresponding acid in almost stoichiometric proportions in the presence of solvents or solvent mixtures. From these the salt can be obtained either by spontaneous crystallization or by gradual removal from the solution by adding a solvent in which the salt is not soluble, or by evaporating the with the solvent used in the reaction.

The invention also includes medicaments which contain one or more compounds (I) as active ingredients. Such Medicines can be used in human and / or veterinary medicine as oral, parenteral, rectal or topical preparations, particularly in the case of pathological conditions of the inflammation type, pain type or fever type.

Toxicological and pharmacological properties

The tests given below use the ibuprofen imidazolium salt, the naproxen imidazolium salt and the ketoprofen imidazolium salt for convenience as "Salt A", "Salt B" and "Salt C" are referred to.

Acute toxicity tests showed an LD ^ value for both male and female rats of 1205 mg / kg for A, of

780 mg / kg for B and 915 mg / kg for C.

Chronic toxicity tests performed in the rat by oral Administration of the salts carried out over 15 weeks with doses of 50 and 100 mg / kg showed normal Growth and normal haematological and blood chemistry values. It should be noted that in these experimental animals the gastric and intestinal mucosa did not show any ulcers or hemorrhagic phenomena, which are common the administration of ibuprofen, naproxen and ketoprofen accompany.

It should be noted in particular that in the rat, after ligation of the pilorus according to Schay or after injection of Reserpine, administration of ibuprofen, naproxen and ketoprofen the number and severity of gastric produced Ulcers increased 2 to 5 times. In contrast, the administration of equimolar amounts of the Salts A, B and C indicate the number and severity of lesions induced by these manipulations.

When the carrageenin-induced edema test was carried out in the rat as a measure of anti-inflammatory activity, des Hot plate tests in the mouse as a measure of analgesic activity and the yeast-induced fever test the rat was found to compare the equimolar amounts of the three above acids with their respective Salts A, B and C was extremely beneficial for the salts. This shows that the latter has a significantly greater anti-inflammatory effect have analgesic and antipyretic activity.

The invention is illustrated in the examples.

Example 1 Salt A.

1 mole of ibuprofen was dissolved in 1000 ml of anhydrous acetone. 1.05 mol of imidazole were dissolved in this solution in 500 ml of anhydrous acetone. After thorough stirring, the solvent became dry under reduced pressure Pressure evaporated. A somewhat hygroscopic oily mass was obtained which had the following chemical-physical properties and analytical values:

Elemental analysis;

CHN

Calculated % 66.19 7, 64 9 , 65 Found % 66.25 7 79 9 , 48. IR spectrum: according to the structure NMR spectrum: confirms the structure

Example 2 Imidazolium 2- (6-methoxy-2-naphthy1) propionate

1 mole of 2- (6-methoxy-2-naphthyl) propionic acid was dissolved in 1000 ml of anhydrous ethanol. To this solution, 1.05 mol of imidazole dissolved in 500 ml of anhydrous acetone was added. After thorough stirring, and about 20 minutes of heating at 50 ⁰ C the solution was cooled and slowly treated with petroleum ether until a slight turbidity. The mixture was then allowed to crystallize in the cold overnight. The salt was in the form of crystals

obtained, which were collected, washed on a filter paper and dried: melting point between 143 and 146 ⁰ C (uncorrected).

Elemental analysis:

CHN

Calculated % 68 , 44 6th , 08 0 , 39 Found % 68 , 38 6th , 22 9 , 37.

IR spectrum: according to the structure, NMR spectrum; confirms the structure

Example 3 Imidazolium 2- (3-benzoylphenyl) propionate

Using the same molar ratios as in Example 1 of 2- (3-benzoylphenyl) propionic acid and imidazole the salt was obtained as a semi-solid, hygroscopic mass with the following characteristics:

Elemental analysis:

CHN

Calculated % 70.79 5, 63 8th , 69 Found % 70.84 5, 67 8th , 71 IR spectrum: according to the structure NMR spectrum: confirms the structure

Example 4

Tablets that contain imidazolium 2- (6-methoxy-2-naphthyl) propionate as the active ingredient

1000 tablets were produced, each containing 330 mg of active ingredient, 83.5 g of corn starch and 75 g of microgranular cellulose and contained 330 g of active ingredient as a micronized powder. The above substances were mixed thoroughly, and the mixture was then placed in a blender transferred and mixed with 100 g of a 10% gelatin solution in demineralized water. Then the mixture became granulated. The granules were then dried, sieved and 1.5 g of magnesium stearate were added. After further Mixing were made using 0.5 g tablets made either flat or rounded punches. The tablets were made with the following ingredients: 330 mg active ingredient, 75 mg microgranular cellulose, 83.5 mg corn starch, 10 mg gelatin, 1.5 mg magnesium stearate. The rounded tablets can optionally be film-coated.

Example 5

Suppositories that contain imidazolium 2- (3-benzoylpheny1) propionate as the active ingredient

1000 suppositories were prepared as follows: 1870 g of glyceride esters of saturated fatty acids were melted at 70 ⁰ C, then heated to 4O ⁰ C cooled and then added with 130 g of active ingredient. After mixing and filtering through a stainless steel sieve, the preparation was dosed into appropriate containers.

After cooling at 5 ° C, suppositories were made with the following Composition obtained: 130 mg active ingredient, 1870 mg glyceride ester of saturated fatty acids.

Claims (8)

5474 WK / eg Imidazolium arylalkanoids, process for their preparation and medicinal products containing this compound PATENT CLAIMS 1. Imidazolium arylalkanoids of the general formula (I) π © Ar-CH-COO ^ NH η ( I ) I M Π R ^ N ^ wherein Ar is substituted for phenyl, naphthyl, indene or indole with straight-chain or branched alkyl groups, alkoxides, halogens, aryl carbonyls, cycloalkylenes, chlorobenzoyl, Benzylmethylsulfonylene and R represents a hydrogen atom, represents a methyl or an ethyl group. 2. Imidazolium 2- (4-isobutylphenyl) propionate. 3. Imidazolium 2- (6-methoxy-2-naphthyl) propionate. 4. Imidazolium 2- (3-benzoylphenyl) propionate. 5. Process for the preparation of imidazolium arylalkanoids according to claim 1, characterized net that the salt of the acid with the imidazole in
Presence of a solvent or a mixture of
Manufactures solvents from which the salt can be obtained either by spontaneous crystallization or by evaporation or by adding a nonsolvent. 6. The method according to claim 2, characterized in that the reaction with almost stoichiometric Acid and imidazole ratios. 7. Medicines with anti-inflammatory, analgesic and antipyretic activity, characterized in that they have one or more active ingredients Compounds according to claims 1 to 4 contain. 8. Medicament according to claim 7, characterized in that it is in solid, semi-solid or
liquid form for oral, parenteral, or rectal
topical administration in human and / or veterinary medicine.