JPS6116380B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel 5-(2,4-difluorophenyl)-2-hydroxybenzoate, a pharmaceutical composition containing the benzoate as an active ingredient, a method for producing the same, and analgesia in mammals. Concerning how to induce. More particularly, the present invention provides lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid and pharmaceutical compositions for oral, rectal, parenteral and topical administration and such compositions. The present invention relates to a method for inducing analgesia in a mammal by administering the same to the mammal. French Patent No. 1522570, US Patent No. 3714226
and South African Patent No. 67/1031 patent phenylbenzoic acids and their pharmaceutically acceptable salts having anti-inflammatory properties. The patent discloses 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid. The patent also discloses salts of phenylbenzoic acid with choline and S-methylmethionine, but 5-(2,4-difluorophenyl)-2-
Salts of hydroxybenzoic acid and amino acids are not disclosed or even suggested. Similarly, French Patent No. 2288729 has 5-(2,
Although a method for producing 4-difluorophenyl)-2-hydroxybenzoic acid has been disclosed and patented, the patent does not disclose or suggest salts of the compound with amino acids. French Patent No. 1295304 discloses acetylsalicylates with lysine, which have the advantage over acetyl salts of being water-soluble, thus allowing parenteral administration of acetylsalicylic acid. However, chlorination does not modify the activity of acetylsalicyl salts. The inventors surprisingly found that 5-(2,4
The lysine and arginine salts of -difluorophenyl)-2-hydroxybenzoic acid are 5-(2,4-
It not only allows the parenteral administration of difluorophenyl)-2-hydroxybenzoic acid, but also gives high blood concentrations with respect to the free acid after oral administration and therefore compared to the bioavailability of the free acid. It was found that lysine and arginine salts demonstrated better bioavailability. Additionally, we have found that the lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid cause less ulceration than the corresponding free acid when administered orally. Ta. Thus, the object of the invention is to solve the following general formula (): (wherein, X is _-CH2- and -C(NH)-NH
An object of the present invention is to provide lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid represented by the following formula. 5-(2,4-difluorophenylphenyl)-
The amino acids lysine and arginine used to chlorinate 2-hydroxybenzoic acid may be in the natural L form or the D form, and may also be in the racemic DL form. The novel salt according to the present invention has the following formula (): 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid is expressed by the following formula (): (wherein X has the same meaning as defined in parentheses) by direct salification with the amino acid represented by the formula. 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid, which is insoluble in water, is added in small portions to a stoichiometric amount of an aqueous solution of an amino acid of formula (2) as a solid. Add as. The salt of formula () thus obtained can be isolated by conventional means, such as lyophilization or solvating with a suitable solvent. Chlorination also removes excess organic solvents, such as benzene,
It can also be carried out in the presence of toluene, acetone, methylene chloride, etc., and the precipitate-forming salt (of formula ()) is then crystallized simply by filtration or from a water/organic solvent. isolated by either. The novel compounds according to the invention have anti-inflammatory and analgesic effects that are superior to the corresponding free acids. The anti-inflammatory activity of this compound was evaluated in rats using a typical carrageenan edema method. product, weight
150-200g Sprague-Dawley
Dawley) was administered subcutaneously to rats. 5-(2,4-
Difluorophenyl)-2-hydroxybenzoic acid was used as a control compound. The test results are listed in Table 1. In the table, representative compound 2 of the present invention
species, 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt and 5-
The activity of (2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-arginine salt is compared to that of the free acid.

【table】

TABLE From the table above, it can be seen that the representative compound of the invention and the control compound show carrageenan-induced edema at approximately the same dosage, but the lysine and arginine salts have a clearly more favorable therapeutic index. The analgesic effect is due to brewer's yeast administered subcutaneously to rat footpads.
Evaluation was performed using the hindlimb pressurization method (Randall-Selitto method) by injecting 0.05 ml of % suspension. Immediately after administration and 30, 60, 120 and 180 minutes later, the pressure on the painful hind paw required to induce a writhing response was measured. Test compounds were administered simultaneously with inflammatory agents. 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-resine salt, which is a representative compound of the present invention, is added to 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid. dose of 3
Administered at a dose of 4.75 mg/Kg, corresponding to mg/Kg. As a control compound, 5-
(2,4-difluorophenyl)-2-hydroxybenzoic acid, acetylsalicylic acid at a dose of 30 mg/Kg and acetylsalicylic acid lysine salt at a dose of 54 mg/Kg corresponding to acetylsalicylic acid 30 mg/Kg were used. Table 2 lists the % change in pressure required to produce a pain response with respect to control animals.

[Table] The following can be understood from the above table. That is, representative compounds of the present invention have a more rapid onset of activity than the control compound when administered orally. In fact, already in the first half hour the representative compounds of the invention are approximately twice as active with respect to the corresponding free acid as well as acetylsalicylic acid. Representative compounds of the invention are also more active than acetylsalicylic acid lysine salt when administered parenterally. Furthermore, the novel salt compounds of the present invention are less ulcerogenic than the corresponding free acids. It is well known that many anti-inflammatory drugs induce irritation and ulceration phenomena in the gastrointestinal tract. The phenomenon manifests in rats as areas of small bleeding within the stomach, leading to erosion of penetrating ulcers. 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid does not induce ulceration phenomena at a dose of 250 mg/Kg, whereas such phenomena
It is clearly expressed at doses of mg/Kg. On the other hand, lysine and arginine salts begin to ulcerate at very high doses. For example, D,L-lysine and D,L-arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid do not induce any ulcer damage even at a dose of 700 mg/Kg. Thus, the compounds of the invention can be administered alone or in the form of a pharmaceutical preparation by oral, parenteral or rectal administration, and may also be supplemented with other agents useful in inflammatory conditions such as vitamin C or corticosteroids. Can be administered with ingredients. Another object of the present invention is to provide a pharmaceutical composition containing the compound represented by the above formula () as an active ingredient together with a pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention includes tablets, powders, granules,
They may take the form of capsules, suspensions, syrups, suppositories or injectable solutions. For parenteral administration, unit fluid dosage forms can be prepared. In preparing parenteral dosage forms, a weighed amount of active ingredient is transferred to a vial and the vial and its contents are sterilized and sealed. Sterile water for injection in a co-use vial is provided as the vehicle. Sterile water conveniently dissolves local anesthetics and buffers. Separately,
Formulations for parenteral administration are prepared by dissolving the active ingredient in sterile water for injection with or without the further addition of adjuvants and then filling vials followed by sterilization. Pharmaceutical preparations for oral administration, in addition to the active ingredient,
It contains one or more organic or inorganic carriers that are pharmaceutically acceptable and compatible with the active ingredient, as well as sweeteners, flavoring preservatives, and the like. Tablets may contain as carriers granulating and disintegrating agents such as calcium carbonate, sodium carbonate, lactose, talc, starch and alginic acid, starch,
They can be made with binders such as gelatin and gum arabic, and lubricants such as magnesium stearate and stearic acid. Tablets may be coated or uncoated. Capsules may contain the active ingredient alone or in admixture with inert solid diluents such as calcium carbonate, calcium phosphate and kaolin. Granules for reconstitution into liquid oral formulations are made using water-soluble diluents. The active ingredient is mixed with a water-soluble diluent such as sutucarose, glucose, etc., with a binder such as acacia gum gelatin, or gelatin or methylcellulose solution. The mixture is passed through a screen to form granules and the resulting granules are then dried. Optionally, suspending agents such as tragacanth are included in the composition. Similarly, solutions, suspensions, syrups and elixirs can be prepared using the excipients customary for the preparation of such preparations, such as suspending agents such as methylcellulose, tragacanth and sodium alginate, lysine or polyoxyethylene sorbitan. The active ingredient may be contained in admixture with a wetting agent, such as a wetting agent, and a preservative, such as ethyl p-hydroxybenzoate. Solutions are administered in dosage units of one spoonful of the preparation, corresponding to, for example, 5 ml, containing the calculated amount of active ingredient. Liquid preparations can also be administered in dosage units as an aqueous solution obtained by dissolving a dosage unit formulation containing the given active ingredient in water. The compositions of the present invention may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, and coloring agents, to provide an aesthetically pleasing and palatable formulation. Compositions of the invention contain about 100 to about 200 mg of active ingredient per dosage unit. Preferred dosage units contain 250 to 750 mg of active ingredient. In order to induce analgesia or inflammation reduction in mammals, 5-
A daily dose of about 200 to 2000 mg of the lysine and arginine salts of (2,4-difluorophenyl)-2-hydroxybenzoic acid is administered to the mammal. from about 350 to about 500 active ingredients in dosage unit form.
The above-described pharmaceutical composition containing mg is preferably administered orally twice a day to obtain sufficient activity. In the case of severe painful inflammatory conditions, or particularly severe painful inflammatory conditions, a pharmaceutical composition as described above containing from about 250 to about 750 mg of active ingredient in a dosage unit may be used to obtain a sufficient therapeutic effect. to 1
It may be administered intramuscularly two or three times a day. Similar compositions may be administered intravenously or rectally. In the following, embodiments of the invention will be described in a non-limiting manner. Example 1 500 ml of ethanol in which 50 g of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid was dissolved
An aqueous solution of 29.2 g of D,L-lysine is added to the solution under stirring at room temperature (approximately 20 DEG C.), and the reaction mixture is then left under stirring for approximately 3 hours to completely salinate. After cooling at a temperature of about 5°C, the precipitate formed was filtered, washed with a small amount of ethanol and dried under reduced pressure to give 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L- Obtain 75 g of lysine salt in colorless microcrystalline form. Molecular weight = 396.40 Analysis for C ₁₉ H ₂₂ F ₂ N ₂ O ₅ C% H% N% Theoretical value 57.57 22.18 7.07 Actual value 57.55 22.20 7.09 IR spectrum: Characteristic absorption bands at 1600 cm ^-1 and 1390 cm ^-1 By the same method, 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D-lysine salt and L-lysine salt are obtained. Example 2 A solution of 8.71 g of D,L-arginine in water was added to a solution of 12.5 g of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid in a mixture of 100 ml of acetone and 50 ml of water at room temperature ( Add it little by little while stirring at a temperature of about 20°C. The reaction mixture is stirred for 3 hours and optionally replenished with evaporated acetone.
When the salification is complete, the reaction mixture is filtered, washed repeatedly with acetone and dried under reduced pressure. Thus, 5-(2,4-difluorophenyl)-2
-Hydroxybenzoic acid D,L-arginine salt 20g
is obtained as a colorless microcrystalline substance. Molecular weight = 424.42 Analysis for C ₁₉ H ₂₂ F ₂ N ₄ O ₅ C% H% N% Theoretical value 53.77 5.22 13.20 Actual value 53.75 5.23 13.22 In the same manner, 5-(2,4-difluorophenyl)-2- D-arginine salt and L-arginine salt of hydroxybenzoic acid are obtained. Example 3 Tablet: 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt 250g Lactose 197.5g Corn starch 25g Colloidal silicic acid 10g Soluble starch 15g Magnesium stearate 2.5g Active ingredients Mix with some of the excipients and then granulate with an aqueous solution of soluble starch. After drying the granules,
The remaining excipients are added and the mixture is compressed into tablets. Thus, 1000 tablets each containing 250 mg of the active ingredient and weighing 500 mg, or 700 tablets containing 350 mg of the active ingredient and weighing 700 mg are obtained. Similarly, tablets containing D,L-arginine salt are obtained. Example 4 Capsule: 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt 400 mg Solid inert diluent (starch, lactose, kaolin) 500 mg Similarly, 5-(2-hydroxybenzoic acid D,L-lysine salt) 500 mg ,4-difluorophenyl)-
2-Hydroxybenzoic acid D, L. Arginine salt 425
Capsules containing mg. Example 5 Materials for 1000 suppositories: 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid DL-lysine salt 500g Cocoa butter (total amount) 2000g The active ingredient was ground as finely as possible, Homogeneous suspension of the carrier in the melt. 1 tablet weighs 2g
and a suppository containing 500mg of the active ingredient.
Get 1000 tablets. Similarly, suppositories containing D,L-arginine salts are obtained. Example 6 Ampoules: a 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt 250 mg Sodium chloride 15 mg Distilled water (total amount) 2.5 ml b 5-(2,4-difluoro phenyl)-2-hydroxybenzoic acid D,L-lysine salt 350mg Sodium chloride 15mg Distilled water (total amount) 3ml c 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt 395mg Sodium chloride 15mg Distilled water (total amount) 3ml d 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-arginine salt
425 mg Sodium chloride 15 mg Distilled water (total amount) 3 ml Example 7 Capsules: 600 mg of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt, solid inert diluent (starch, lactose) , kaolin) 400mg Similarly, 5-(2,4-difluorophenyl)-
2-hydroxybenzoic acid D,L-arginine salt
Capsules containing 635 mg are obtained. Example 8 Granules are made for reconstitution into a liquid oral dosage form having the following composition: 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt 400 mg Sutucarose 5200mg Citric acid 10mg Disodium citrate 90mg Sodium paraoxybenzoic acid salt 25mg Sweetener (Sacchulin) 15mg Flavoring agent (Orange) 50mg Granules obtained in a conventional manner are each containing active ingredients.
Introduced into a sugarcane containing 400mg. Dissolved in water - the content of the sachet is a suitable dosage unit, which, when administered to adult patients with symptoms of pain (headache, arthralgia) or inflammation, provides a satisfactory analgesic effect and a reduction in inflammation. Provides symptom relief. Very satisfactory results are obtained when such compositions are administered twice a day. In a similar manner, 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt is obtained. Example 9 The procedure described in Example 8 contained granules for reconstitution into a liquid oral formulation containing 425 mg each of D, L-arginine 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid. and 635mg
Prepare a sac containing. Administration of such compositions twice daily to adult patients with pain or inflammatory symptoms provides analgesia and relief of inflammatory symptoms.

Claims (1)

[Claims] 1 General formula () (wherein, X is _-CH2- and -C(NH)-NH
A compound selected from the group consisting of lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid represented by: 2. The compound according to claim 1, which is 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-lysine salt. 3 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid D,L-arginine salt,
A compound according to claim 1. 4 General formula (): (wherein, X is _-CH2- and -C(NH)-NH
5-(2,4-difluorophenyl)-2-hydroxybenzoic acid represented by the following formula (): 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid is prepared in the solid state by the following formula (): (wherein, X has the same meaning as defined in formula ()) A method characterized by adding a stoichiometric amount to an aqueous solution of an amino acid represented by: 5. The method according to claim 4, characterized in that the reaction is carried out in the presence of an excess of organic solvent. 6 The following formula () as the active ingredient: (wherein, X is _-CH2- and -C(NH)-NH
A compound selected from the group consisting of lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid represented by An anti-inflammatory agent contained in the mixture. 7. An anti-inflammatory agent according to claim 6, which in single dose form contains from 150 mg to 2000 mg of active ingredient per dose unit in a mixture with a pharmaceutically acceptable carrier.