GB2060638A - Lysine and arginine 5-(2,4-difluorophenyl)-2-hydrobenzoic acid salts, pharmaceutical compositions containing them and their use - Google Patents

Abstract

The invention provides salts of 5-(2,4-difluorophenyl)-salicylic acid of formula <IMAGE> in which X represents -CH2- or -C(NH)-NH-. These salts can be obtained by direct salification at room temperature. They are useful as analgesics and for treating inflammatory conditions, by oral, rectal, topical or parenteral administration. They may be made into pharmaceutical compositions with appropriate pharmaceutical carriers.

Description

SPECIFICATION Lysine and arginine 5-(2,4-difluorophenyl )-2-hydroxybenzoic acid salts, pharmaceutical compositions containing them, and their use The present invention relates to 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid salts, pharmaceutical compositions containing them and their use.

More particularly, the present invention provides, as new compounds, the lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid, and pharmaceutical compositions containing the same useful for oral, rectal, parenteral and topical administration. These new compounds and compositions are useful for inducing analgesia in mammals.

French Patent No. 1 ,522,570, U.S. Patent No. 3,714,226 and South African Patent No. 67/1031 claim phenylbenzoic acids having anti-inflammatory activity and their pharmaceutically acceptable salts. These patents refer to 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid without giving its physicochemical characteristics or any example of preparation. The same patents also refer in general terms to the salts of the phenylbenzoic acids with choline and S-methylmethionine. No salts of 5-(2,4 difluorophenyl)-2-hydroxybenzoic acid with other aminoacids are suggested.

Similarly, French Patent No. 2,288,729 describes and claims a process for the preparation of the 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid, but this patent does not describe or suggest any salt with aminoacids.

French Patent No. 1,295,304 describes the lysine salt of acetylsalicylic acid salt which has the advantage, as compared with acetylsalicylic acid, of being water-soluble, thus allowing parenteral administration of acetylsalicylic acid. However, this salification does not modify the pharmacological activity of acetylsalicylic acid.

We have now surprisingly found that the lysine and arginine salts of 5-(2,4-difluorophenyl)-2hydroxybenzoic acid not only allow parenteral administration of 5-(2,4-difluorophenyl)-2hydroxybenzoic acid but also make possible, after oral administration, higher blood ievels of the parent free acid, thus demonstrating a better bio-availability of the lysine and arginine salts compared with the free acid. The lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid are also less ulcerogenic than the corresponding free acid when administered orally.

The novel lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid of the present invention have the following formula:

in which X represents -CH2- or -C(NH)-NH-.

the lysine and arginine salifying the 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid may be in the natural L form or in the D form as well as in the racemic DL form.

The salts of the present invention are prepared by direct salification of 5-(2,4-difluorophenyl)-2hydroxybenzoic acid:

with the aminoacid of formula:

where X is as hereinbefore defined.

The 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid (II), which is insoluble in water, is added as a solid in small portions to an aqueous solution of the stoichiometric amount of the aminoacid (Ill). The salt of formula I thus obtained can be isolated by the usual techniques, for example by lyophilization or by precipitation with a suitable non-solvent.

The salification can also be carried out in the presence of an excess of an organic solvent such as, for example, benzene, toluene, acetone, or methylene chloride. The salt (I) which forms precipitates and can then be isolated either by simpie filtration or by crystallization from water/organic solvent.

The new salts of the present invention show anti-inflammatory and analgesic activities superior to those of the corresponding free acid.

Their anti-inflammatory activity has been evaluated in the rat by means of the classic carrageenin induced oedema test. The salts were administered subcutaneously to Sprague-Dawley rats weighing 150 to 200 g. each. 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid was used as the reference compound.

The results of this test are summarized in Table 1, where the activity of two representative salts of the present invention, DL-lysine 5-(2,4-difluorophenyl)-2-hydroxybenzoate and D,L-arginone 5-(2,4 difluorophenyl)-2-hydroxybenzoate, is compared with that of the free acid.

TABLE 1

LD 50 ED 50 mg/kg mg/kg Therapeutic Relative Compound rat/orally rat Index activity 5-(2,4-cii f luoropheny 1)- 710.6 9.6 74.02 1 2-hydroxybenzoic acid D L-lysine 5-(2,4- 1059.2 10.8 98.07 1.3 difluorophenyl)-2 hydroxybenzoate DL-arginine5-(2A- 1267.4 11.2 113.16 1.52 difluorophenyl)-2 hydroxy benzoate It appears from this Table that the compounds of the present invention and the reference free acid inhibit the carrageenin-induced oedema at about the same doses but with a Therapeutic Index which is clearly favourable to the lysine and arginine salts.

The analgesic activity has been evaluated in the Randall-Selitto test, based on the implantation in the rat paw of 0.05 ml of a 5% suspension of beer yeast. At the time 0 and after 30, 60, 120 and 180 minutes the pressure to the painful paw necessary to elicit the response (squeak) was measured. The compounds under examination were administered concurrently with the inflammatory agent.

A representative compound of the present invention, DL-lysine 5-(2,4-difluorophenyl)-2hydroxybenzoate, was administered at a dose of 4.75 mg/kg, corresponding to a dose of 3 mg/kg of 5 (2,4-difluorophenyl)-2-hydroxybenzoic acid. As reference compounds, 5-(2,4-difluorophenyl)-2- hydroxybenzoic acid at a dose of 3 mg/kg, acetylsalicylic acid at a dose of 30 mg/kg, and lysine acetylsalicylate at a dose of 54 mg/kg corresponding to 30 mg/kg of acetylsalicylic acid, were used.

Table II shows the percent variation, with respect to the controls, of the pressure exerted on the inflamed paw necessary to elicit the response to the pain.

TABLE II

7 %variataon after minutes Administration Dose Compound route mg/kg 30 60 120 180 5-(2,4-difluorophenyl)- Oral 3 + 14.6 + 41.8 + 64.3 + 52.5 2-hydroxybenzoic acid DL-lysine 5-(2,4- Oral 4.75 + 26.3 + 48.2 + 64.1 + 54.0 difluorophenyl)-2- Intramuscular 4.75 + 51.0 + 66.6 + 62.0 + 53.4 hydroxybenzoate intravenous 4.75 + 52.1 + 73.5 + 73.0 + 56.9 Acetylsalicylic acid Oral 30 + 15.8 + 43.7 + 65.9 + 57.5 Lysineacetylsalicylate Intramuscular 54 + 45.0 + 51.8 + 63.5 + 55.8 N.B. The above data are statistically significant.

It appears from the Table that the compound of the present invention shows a more rapid onset of activity than that of the reference compounds by oral administration. In fact, already at the end of the first half-hour, it shows an almost double activity compared with the corresponding free acid, and with acetylsalicylic acid. It is also more active than lysine acetylsalicylate by parenteral administration.

Furthermore, the salts of the present invention are less ulcerogenic than the corresponding free acid. It is known that many anti-inflammatory drugs produce irritative and ulcerative phenomena on the mucosa of the gastro-intestinal tract. In the rat, these appear as small bleeding areas in the stomach which may be true erosions of uicerative-perforating type. 5-(2,4-difluorophenyi)-2-hydroxybenzoic acid does not induce ulcerative phenomena at a dose of 250 mg/kg, but such phenomena are evident at a dose of 500 mg/kg. On the other hand, the lysine and arginine salts only begin to become ulcerogenic at very high doses. For example, the DL-lysine and DL-arginine salts of 5-(2,4-difluorophenyl)-2hydroxybenzoic acid do not induce any ulcerogenic damage at the dose of 700 mg/kg.

Thus, the compounds of the present invention can be administered by the oral, parenteral or rectal route alone or in the form of pharmaceutical compositions, which may also contain other ingredients useful in inflammatory conditions, such as vitamin C or corticosteroids. The present invention therefore includes within its scope pharmaceutical compositions containing the compounds of formula 1 above as active ingredients in admixture with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention can be in the form of tablets, powders, granules, capsules, suspensions, syrups, suppositories or solutions for injection.

For parenteral administration, liquid unit dosage forms can be prepared. For this purpose, a measured amount of active ingredient is placed in a vial, and the vial and its contents are sterilized and sealed. An accompanying vial of sterile water for injection is provided as a vehicle. Advantageously, the sterile water can have dissolved therein a local anesthetic and buffering agent. Alternatively, a parenteral preparation can be prepared by dissolving the active ingredient in sterile water for injection with or without additional adjuvants, and sterilizing the vials after filling.

Pharmaceutical compositions for oral administration include, in addition to the active substance, one or more organic or mineral carriers which are pharmaceutically acceptable and compatible with the active ingredient, as well as sweetening agents, flavouring agents, preserving agents and the like.

Tablets can be prepared by utilising, as carriers, inert diluents such as calcium carbonate, sodium carbonate, lactose, talc, granulating and disintergrating agents, such as starch and alginic acid, binding agents such as starch, gelatine and gum acacia, and lubricating agents such as magnesium stearate and stearic acid. The tablets may or may not be coated.

Capsules may contain the active substance either alone or in admixture with inert solid diluents such as, for example, calcium carbonate, calcium phosphate and kaolin.

Granules for reconstitution to form a liquid oral preparation can be prepared by using watersoluble diluents. The active ingredient is mixed with an appropriate water-soluble diluent, for example, sucrose or glucose, and with a binding agent, such as acacia mucilage, or gelatine or methylcellulose solution. The mixture is passed through a sieve to form granules, which are then dried. If necessary, a suspending agent such as gum tragacanth is included in the composition.

Similarly, solutions, suspensions, syrups and elixirs may contain the active ingredient in admixture with any conventional excipient utilized for the preparation of such compositions, e.g. a suspending agent such as methylceilulose, gum tragacanth or sodium alginate, a wetting agent such as lecithin or polyoxyethylene sorbitan, or a preservative such as ethyl parahydroxybenzoate.

The liquid prepartions are administered in dosage units, e.g. a teaspoon of composition, corresponding to 5 ml, containing the calculated amount of active ingredient. The liquid preparations can also be administered in dosage units as a water solution obtained by dissolving in water a dosage unit of composition containing a predetermined amount of active ingredient.

The composition of the present invention may contain one or more conventional adjuvants, such as sweetening agents, flavouring agents, colouring agents, in order to provide an appealing and palatable preparation.

The compositions of the present invention normally contain from 100 to 2000 mg of active ingredient per dose unit. Preferred dosage units contain from 250 to 750 mg of active ingredient.

In order to induce analgesia or relief of inflammation in mammals, the lysine and arginine salts of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid of formula 1 above, are administered to the mammals at a daily dose which is usually from 200 to 2000 mg.

Preferably, a pharmaceutical composition as described above containing from 350 to 500 mg of active ingredient in dosage unit form, is administered orally twice a day to give a satisfactory degree of activity.

In cases of more severe pain or in particularly severe inflammatory conditions, a pharmaceutical composition as described above containing from 250 mg to 750 mg of active ingredient in dosage unit form can be administered intramuscularly twice or three times a day in order to achieve a therapeutically satisfactory result.

Similar compositions can be administered intravenously or rectally.

The following Examples illustrate the invention.

EXAMPLE 1 To a solution of 50 g of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid in 500 ml of ethanol, an aqueous solution of 29.2 g of DL-lysine is added with stirring at room temperature (about 20"C) and the reaction mixture is allowed to stand with stirring for about three hours until salification is complete.

After cooling at about 50C, the precipitate which forms is filtered off, washed with small amounts of ethanol and dried under reduced pressure to obtain 75 g of DL-lysine 5-(2,4-difluorophenyl)-2- hydroxybenzoate in the form of a colourless microcrystalline powder.

Molecular weight = 396.40 Analysis for C1gH22F2N205 C% H% N% calculated 57.57 22.18 7.07 found 57.55 22.20 7.09 IR: characteristic bands at 1 600 and 1 390 cm-' In the same manner, the D-lysine and the L-lysine 5-(2,4-difluorophenyl)-2-hydroxybenzoates are prepared.

EXAMPLE 2 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 an aqueous solution of 8.71 g of DL-arginine is added in small amounts with stirring at room temperature (about 200 C). The reaction mixture is stirred for three hours, replacing, if necessary, the acetone which evaporates. When the salification is over, the reaction mixture is filtered, and the residue is washed repeatedly with acetone and dried under reduced pressure. Thus, 20 g of DL-arginine 5-(2,4-difluorophenyl)-2-hydroxybenzoate are obtained as a colourless microcrystalline powder.

Molecular weight = 424.42 Analysis for C19H22F2N4O5 C% H% N% Calculated 53.77 5.22 13.20 found 53.75 5.23 13.22 In the same manner, the D-arginine and the L-arginine 5-(2,4-difluorophenyl)-2-hydroxybenzoates are obtained.

EXAMPLE 3 Tablets.

DL-lysine 5-(2,4-difiuornphenyl)- 2-hydroxybenzoate 250 g lactose 197.5 g corn starch 25 g colloidal silicic acid 10 g soluble starch 15 g magnesium stearate 2.5 g The active ingredient is mixed with part of the excipient and granulated with a solution of the soluble starch in water. After the granulate has been dried the remaining excipients are added and the mixture is pressed into tablets. Thus 1000 tablets each weighing 500 mg and containing 250 mg of active ingredient or about 700 tablets each weighing 700 mg and containing 350 mg of active ingredient are obtained. Tablets containing the DL-arginine salt may be prepared similarly.

EXAMPLE 4 Capsules are filled with D-Lysine 5-(2,4-difluorophenyl)-2- hydroxybenzoate 400 mg solid inert diluent (starch, lactose, kaolin) 500 mg Capsules each containing 425 mg of DL-arginine 5-(2,4-difluorophenyl)-2-hydroxybenzoate may be prepared similarly.

EXAMPLE 5 Composition for 1000 suppositories: DL-lysine 5-(2,4-difluorophenyl)-2- hydroxybenzoate 5009 cocoa butter to 2000 g The active substance, as finely ground as possible, is homogeneously suspended in the melted cocoa butter. 1000 suppositories each weighing 2 g and containing 500 mg of active ingredient are obtained. Suppositories containing DL-arginine may be prepared similarly.

EXAMPLE 6 Ampoules: a) DL-lysine 5-(2,4-difluorophenyl) 2-hydroxybenzoate 250 mg sodium chloride 15 mg double distilled water to 2.5 ml b) DL-lysine 5-(2,4-difluorophenyi)- 2-hydroxybenzoate 350 mg sodium chloride 15 mg double distilled water to 3 ml c) DL-lysine 5-(2,4-difluorophenyI)- 2-hydroxybenzoate 395 mg sodium chloride 15 mg double distilled water to 3 ml d) DL-arginine 5-(2,4-difluorophenyl) 2-hydroxybenzoate 425 mg sodium chloride 15 mg double distilled water to 3 ml EXAMPLE 7 Capsules: DL-lysine 5-(2,4-difluorophenyl) 2-hydroxybenzoate 600 mg solid inert diluent (starch, lactose, kaolin) 400 mg Capsules containing 635 mg of DL-arginine 5-(2,4-difluorophenyl)-2-hydroxybenzoate each may be prepared similarly.

EXAMPLE 8 Granules for reconstitution into a liquid oral preparation having the following composition are prepared DL-lysine 5-(2,4-difluorophenyl) 2-hydroxybenzoate 400 mg sucrose 5200 mg citric acid 10 mg trisodium citrate 90 mg sodium parahydroxybenzoate .25 mg sweetener (saccharin) 15 mg flavouring (orange) 50 mg The granules, prepared in the usual manner, are introduced into sachets each containing 400 mg of active ingredient. The content of one sachet, dissolved in water, is a suitable dosage unit form which, when administered to an adult human subject suffering from pain (e.g. headache, or articular pain) or from an inflammatory condition, induces satisfactory analgesia and relief of the inflammatory condition.

One administration twice daily of such a composition gives very good results.

A pharmaceutical composition containing 600 mug of DL-lysine 5-(2,4-difluorophenyl)-2hydroxybenzoate per dosage unit may be obtained in a similar manner.

EXAMPLE 9 By operating as described in Example 8, sachets containing granules for reconstitution into a liquid oral preparation and including 425 mg or 635 mg per dosage unti of DL-arginine 5-(2,4 difluorophenyl)-2-hydroxybenzoate are prepared.

One administration of such compositions twice a day to adult human subjects suffering from pain or from an inflammatory condition induces analgesia and relief of the inflammatory condition.

Claims (12)

1. A lysine or arginine salt of 5-(2,4-difluorophenyl)-2-hydroxybenzoic acid of formula:

in which X is -CH2- or -C(NH)-NH-.

2. DL-lysine 5-(2,4-difluorophenyl )-2-hydroxybenzoate.

3. DL-arginine 5-(2,4-difluorophenyl)-2-hydroxybenzoate.

4. A process for preparing a compound according to Claim 1, which comprises adding 5-(2,4difluorophenyl)-2-hydroxybenzoic acid of formula

in the solid state, to an aqueous solution of an aminoacid of formula:

in which X is -CH2- or -C(NH)-NH-, in stoichiometric amount.

5. A process according to Claim 4, in which the reaction is carried out in the presence of an excess of an organic solvent.

6. A process according to Claim 4, substantially as described in Example 1 or 2.

7. A compound as claimed in Claim 1 when prepared by the process claimed in Claim 4, 5, or 6.

8. A pharmaceutical composition including, as active ingredient, a compound as claimed in any one of Claims 1 to 3 or 7 in admixture with a pharmaceutical carrier.

9. A composition as claimed in Claim 8 in dosage unit form containing from 1 50 to 2000 mg of active ingredient per dosage unit in admixture with a pharmaceutical carrier.

10. A composition as claimed in Claim 9 in the form of a tablet, capsule, or sachet for oral administration.

11. A composition as claimed in Claim 8 substantially as described in any one of Examples 3 to 9.

12. A compound as claimed in any one of Claims 1 to 3 or 7 for use in therapy as an analgesic or anti-inflammatory agent.