Methods of Treating Mammals Suffering From Inflammation and Pain

1. Field of the Invention

The invention relates to methods and pharmaceutical preparations for the alleviation of pain and/or inflammation in mammals, including humans, suffering from pain and/or inflammation.

2. Brief Description of the Prior Art

The prior art literature is replete with disclosures of the synthesis and therapeutic properties of a large number of organic acid compounds useful as analgesics and as anti-inflammatory agents. For example, o-acetylsalicylic (U.S. Pat. Nos. 2,731,492; 2,890,240; 3,235,583) and 2-(3'-chloro-2'-methylanilino) pyridine-3-carboxylic acids (British Pat. No. 1,147,702) are known to have an analgesic effect. [3'-(trifluoromethyl) phenyl] anthranylic (Wilkinson, Finar J. Chem. Soc. 32, 1948), N-(2',3'-xylyl) anthranylic (Belgium Pat. No. 605,302) and 2 (3'-trifluoromethyl) anilino) pyridine-3-carboxylic acids (Netherland Pat. No. 6,414,717) are known to have an anti-inflammatory effect when administered to mammals. However, these anti-inflammatory and analgesic phenyl- and pyridine-3-carboxylic acids are also known to have an ulcerogenic side-effect. In hope of reducing this side-effect, different derivatives of the above-described compounds were synthesized. Thus, aminoalkyl esters of 2-anilino nicotinic acids are described in French Pat. No. 2,187,317; glyceryl esters of 2-anilino-nicotinic acids are disclosed in Swiss Pat. No. 534,130 and South African Pat. No. 6,802,185. Also, different esters of N-phenyl-anthranylic acids were prepared as were aminoalkyl esters (Belgian Pat. Nos. 612,424 and 630,053), ethyl and methyl esters (French Pat. No. M--2948), methyl ester (Japanese Pat. No. 75 11.904) and glyceryl esters (U.S. Pat. No. 3,852,333 and South African Pat. No. 70-07385) in hopes of finding related anti-inflammatory and analgestic compounds free of the ulcerogenic side-effects. So also, various salts of phenyl and pyridine-3-carboxylic acids were synthesized and evaluated. For example, arginine, lysine, choline and aluminum salts are described in Japanese Pat. Nos. 71-29,735; 72-21,597 and 74-125,512; German Pat. Nos. 2,253,134 and 2,442,817; and Argentinian Pat. No. 197,737. However, the search for analgesic and anti-inflammatory compounds free of ulcerogenic activity has not heretofore been completely successful.

We have now found a class of compounds which have analgesic and anti-inflammatory activity without the characteristic ulcerogenic side-effects mentioned above. This side-effect (described in the literature; see Sherrer and Whitehouse, Anti-inflammatory Agents, Chemistry and Pharmacology, 13-1, Academic Press, New York 1974) has an ulcerogenic effect on the gastric epithelium. The esters of phenyl-carboxylic acids of general formula (I) infra., were tested on mammals and the test results showed an increased anti-pharmacological activity (possibly due to an enhanced gastrointestinal absorption) and non-ulcerogenic effects. It is believed that the compounds of general formula (I) are absorbed through gastrointestinal epithelium where they are hydrolyzed by enzymes in the recipient mammal's blood, to corresponding pharmacologically active acids.

The invention comprises a method of alleviating pain and inflammation in mammals, including humans, suffering from pain and inflammation, which comprises; administering to the mammal an effective amount of a compound selected from those of the formula: ##STR1## wherein X represents a moiety of formula: ##STR2## and R and R.sub.1 taken together form the divalent moiety of formula: ##STR3## and R.sub.2 is selected from an acetoxy group and a group of the formula: ##STR4## wherein R.sub.3 is selected from the group consisting of hydrogen and methyl, R.sub.4 is selected from the group consisting of methyl and trifluoromethy; and the pharmaceutically acceptable acid addition salts thereof.

The invention also comprises pharmaceutical compositions for treating pain and inflammation in a mammal, which comprises; an effective amount of the above-described compounds of formula (I) in admixture with a pharmaceutical carrier.

The method and compositions of the invention are useful for alleviating inflammation and pain associated with inflammation in mammals, including humans, with minimum potential for ulcerogenic side-effects. More specifically, the method and compositions of the invention are useful for the treatment of inflammation and pain associated with a variety of clinical conditions such as rheumatoid arthritis, osteoarthritis, phlebitis, rheumatoid fever fibrositis, tendinitis, bursitis, inflammation and pain provoked by infectious disease (in conjunction with appropriate treatment of the infection) and like clinical conditions.

Compounds of the formula (I) given above were heretofore known. Representative of such compounds are the phthalidylic esters of O-acetylsalicyclic, N-(2,3-xylyl) anthranilic and N-[(3-trifluoromethyl) phenyl] anthranilic acids and the like. Methods for the preparation of the compounds of formula (I) are also known. One such process comprises the reaction between a previously salified phenyl-carboxylic acid of formula II and a compound of formula (III), infra.

The synthesis' scheme is illustrated in the formulae: ##STR5## wherein X, R, R.sub.1 and R.sub.2 are as previously defined; A can be a hydrogen atom or a base, and B can be hydroxyl or halogen.

The preparation of salified phenyl-carboxylic acids of formula II is likewise well known. More specifically the salification of phenyl-carboxylic acids may be performed with an inorganic or organic base of formula: ##STR6## wherein R.sub.5, R.sub.6 and R.sub.7 independently are selected from hydrogen, aryl, alkyl or aliphatic alcohol radicals, such as: diethylamine, diethanolamine, benzylamine, cyclohexylamine, and the like. Triethylamine is the organic base preferentially used. The molar ratio of the reactants may be in a range of 1.3-2 moles of base for each mole of acid, and the reaction is preferably carried out in polar solvents such as acetone, dimethylacetamide, dimethylformamide and the like at a temperature of 20.degree.-25.degree. C.

After the salification of the acid, the product salt is then reacted with the compound of formula (III) in a ratio of 1-1.5 moles of the compound (III) for each mole of acid of formula (II) to obtain compounds of the general formula (I). For example, using 3-bromophthalide as the compound (III), phthalydil esters are prepared. 3-bromophthalide is a known compound synthesized by bromination of phthalide with N-bromosuccinimide in the presence of a catalyst and anhydrous carbon tetrachloride (Org. Synth. 42, 26, 1962) or by adding gaseous bromide into a previously melted phthalide at a temperature of 140.degree.-155.degree. C. (Org. Synth., Coll. Vol. 3, 737, 1955).

The reaction between 3-bromophthalide and phenyl-carboxylic salts is advantageously carried out in a reaction mixture which comprises a solvent or mixture of them, in which the reactants and the product compound are perfectly soluble. Further, since the presence of water hydrolyzes 3-bromophthalide to phthalaldehydric acid (Org. Synth. Coll. Vol. 3, 737, 1955), the reaction medium is preferably anhydrous.

The separation of the compounds of formula (I) from the producing reaction mixtures depends on the reaction medium and physico-chemical properties of each compound. For example, phthalydil esters of N-(2',3'-xylyl) anthranylic, and N (3'-trifluoromethyl) phenyl) anthranylic methylanilino) acids may be separated by adding water to the reaction medium when it consists of acetone to precipitate the desired product. The precipitate may be filtered, washed and if desired recrystallized to obtain the desired product in relatively pure forms.

The compounds (1) may be used in the present invention in either the free acid form or in the form of an acid addition salt. The acid addition salts may be prepared by reacting the free compound (1) with a stoichiometric proportion of an appropriate acid such as hydrochloric acid. The method is well known to those skilled in the art, and may be carried out in aqueous or non-aqueous media such as ethanol, ether, ethyl acetate and the like.

The pharmaceutically acceptable acid addition salts may be used for the same purposes as the free acid. Illustrative of pharmaceutically acceptable acid addition salts are those formed upon reaction of the compounds (1) with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, succinic acid, benzoic acid, salicyclic acid, pamoic acid, cyclohexanesulfamic acid and the like.

This invention relates also to pharmaceutical dosage unit forms for systemic administration (oral, topical and parenteral administration) which are useful in treating inflammation and pain in mammals, including humans. The term "dosage unit form" as used in this specification and in the claims refers to physically discrete units suitable as unitary dosage for mammalian subjects, each unit containing a predetermined quantity of the essential active ingredient, i.e.; a compound (1) or a pharmaceutically acceptable acid addition salt thereof, calculated to produce the desired effect in combination with the required pharmaceutical means which adapt said ingredient for systemic administration. Examples of dosage unit forms in accordance with this invention are tablets, capsules, orally administered liquid preparations in liquid vehicles, sterile preparations in liquid vehicles, sterile preparations in liquid vehicles for intramuscular and intravenous administration, suppositories, and sterile dry preparations for the extemporaneous preparation of sterile injectable preparations in a liquid vehicle. Solid diluents or carriers for the solid oral pharmaceutical dosage unit forms are selected from the group consisting of lipids, carbohydrates, proteins and mineral solids, for example, starch, sucrose, kaolin, dicalcium phosphate, gelatin, acacia, corn syrup, corn starch, talc and the like. Capsules, both hard and soft, are formulated with conventional diluents and excipients, for example, edible oils, talc, calcium carbonate, calcium stearate, magnesium stearate and the like. Liquid pharmaceutical preparations for oral administration may be prepared in water or aqueous solutions which advantageously contain suspending agents, such as for example, sodium carboxymethylcellulose, methylcellulose, acacia, polyvinyl pyrrolidone, polyvinyl alcohol and the like. In the instance of injectable forms, they must be sterile and must be fluid to the extent that easy syringeability exists. Such preparations must be stable under the conditions of manufacture and storage, and ordinarily contain in addition to the basic solvent or suspending liquid, preservatives in the nature of bactericidal and fungicidal agents, for example, parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and the like. In many cases it is preferable to include isotonic agents, for example, sugars or sodium chloride. Carriers and vehicles include vegetable oils, water, ethanol, and polyols, for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like. Any solid preparations for subsequent extemporaneous preparation of sterile injectable preparations are sterilized, preferably by exposure to a sterilizing gas, such as for example, ethylene oxide. The aforesaid carriers, vehicles, diluents, excipients, preservatives, isotonic agents and the like constitute the pharmaceutical means which adapt the preparations for systemic administration.

The pharmaceutical dosage unit forms are prepared in accordance with the preceding general description to provide an effective amount of the essential active ingredient (a compound of formula (I)) per dosage unit form in admixture with the means for adaptation to systemic administration. In general, the unit dose form will contain 3 to 70 percent by weight of the essential active ingredient.

It will be appreciated that the exact dosage of a compound of the formula (I) constituting an effective amount for treatment of a mammal according to the method of the invention will vary greatly depending on the specific nature of the clinical condition being tested, severity of the condition, species of mammal; age, weight and condition of the mammal, mode of administration of the dosage form and the specific compound of formula (I) being administered. The exact dose required for a given situation may be determined by administration of a trial dose and observation of the clinical response. In general, an effective amount to be administered will be within a range of from about 0.1 mg per kg. to about 50 mg. per kg. of body weight of the recipient, daily. Preferably 0.5 mg./kg. to about 25 mg./kg. daily is provided. In most instances, a single administration will effect the desired response and bring about the result desired. In cases such as the treatment of epidermal conditions however, it may be desirable to repeat the administrations several times.

The following examples and preparations describe the manner and process of making and using the invention and set forth the best mode contemplated by the inventor of carrying out the invention but are not to be construed as limiting.

o-Acetylsalicylic acid (18 g) and triethylamine (21 ml) were stirred at a temperature of 20.degree.-25.degree. C. for 30 minutes in 500 ml of acetone. When dissolution was completed, 3-bromophthalide (32 g) was added and the mixture refluxed 2 hours. The reaction mixture was then cooled to 20.degree.-25.degree. C. and poured into distilled water (500 ml). The resulting mixture was extracted with 200 ml of dichloromethane twice, discarding the acetone layer. After the organic solution was washed with 200 ml portions of distilled water twice, 5 g of anhydrous sodium sulfate were added and the mixture filtered. After filtration the organic filtrate was evaporated, the residue was taken up with previously warmed methanol. Decolorizing carbon (1 g) and filtering aid (1 g) were added. The methanolic solution was filtered, and the filtrate was cooled, first to room temperature, and subsequently in an ice/water bath. The solid precipitate was collected by filtration, and dried under vacuum at 40.degree. C. to obtain a yield (83.9%; 26.2 g) of crude phthalidyl o-acetylsalicylate (m.p. 85.degree. C.-88.degree. C.).

Recrystallization from methanol gave a yield of 77.4% (24.18 g) of phthalidyl o-acetylsalicylate (m.p. 87.degree.-89.degree. C.).

Into 400 ml of acetone, 48.2 g of N (2',3'-dimethylphenyl) anthranylic acid was suspended. To this suspension, triethylamine (56 ml) was added, and after stirring for 30 minutes, 3-bromophthalide (63.9 g) was poured into the mixture. A white precipitate formed. The reaction mixture was refluxed for 2 hours, then mixed with distilled water and then cooled to ambient temperature while stirring. The resulting mixture was extracted with 200 ml portions of ethyl acetate 4 times and the acetone-water layer separated and discarded. To the remaining organic phase, 40 g of anhydrous sodium sulfate was added. Sodium sulfate was separated by filtration and the filtrate was concentrated to 1/8 of its initial volume, working under vaccum at a temperature of 40.degree.-50.degree. C. The concentrated organic solution was cooled to 0.degree.-5.degree. C. and allowed to stand until a compound crystallized. The compound was filtered by suction, and dried under vacuum for 16 hours. Yield: 83.9% (62.3 g) of phthalydil N-(2', 3'-xylyl) anthranylate (m.p. 163.degree.-164.degree. C.).

The procedure of Preparation III was repeated using N (3'-trifluoromethylphenyl) anthranylic acid (56.2 g) in place of the N (2', 3'-dimethylphenyl) anthranylic acid. A yield of 77.7% (63.93 g) of phthalydil ester of N (3'-trifluoromethylphenyl)-anthranylic acid (m.p. 130.degree.-131.degree. C.) was obtained.

Three thousand tablets for oral use, each containing 500 mg of essential active ingredient (e.g. an amount of phthalidyl-o-acetylsalicylate (Preparation 1, supra.) equivalent in anti-inflammatory and analgesic activity to 500 mg of o-acetylsalicylic acid), were prepared from the following ingredients:

The essential active ingredient was ground through a 0.25 mm sieve opening screen. The powdered active ingredient, with 50% of the total amount of magnesium stearate to be used, colloidal silicic acid and Avicel.RTM. pH 102 were passed through a 40 mesh sieve, mixed for 20 minutes and then slugged. The slugs were broken down by forcing through a screen No. 11, and mixed with the remaining magnesium stearate and compressed into tablets.

One tablet given orally 1 or 2 times a day is useful in the relief of nociceptive effect and inflammation in adult humans provoked by infective disease, or other etiological causes.

Three thousand capsules for oral use, each containing 250 mg of phthalydil-o-acetylsalicylate as the essential active ingredient, were prepared from the following ingredients:

In accordance with the active ingredient potency, the amount of lactose was adjusted to achieve a weight of 900 mg for each capsule. The ingredients were passed through a 40 mesh sieve and mixed for 30 minutes. Hard gelatin capsules No. 0 were filled using Zanazi, model RV-59 equipment. The capsules were preserved in airtight, light-resistant containers.

This combination of active materials is effective in reducing inflammation and pain in humans. The dose is one to three capsules administered orally, depending on the severity of the condition.

An ointment containing 3% of essential active ingredient (e.g. an amount of phthalidyl N-(2',3'-xylyl) anthranilate equivalent to 3% of N-(2'-3'-xylyl (anthranylic acid) was prepared from the following ingredients:

Cetyl alcohol, stearyl alcohol, Span.RTM. 80, isopropyl miristate and liquid petrolatum were melted into a heating mixer, and 50% of the total amount of methylparaben and isopropylparaben were added. The mixture was maintained at 60.degree.-70.degree. C. Purified water was poured into another heating mixer, and heated to 80.degree. C. The remaining methylparaben and propylparaben were added and dissolved. Polysorbate 60 and sorbitol solution were poured into the heated water and the temperature was maintained at 60.degree.-70.degree. C. Then, the aqueous solution was mixed with the first preparation, forming an oil in water emulsion. When the temperature diminished to 40.degree.-45.degree. C., the powdered essential active ingredient was added, maintaining the stirring until the mixture reached room temperature.

This ointment is useful in the treatment of humans for local pain or inflammation and may be topically applied three times a day on the affected area.

One thousand suppositories each weighing 3 g and containing 500 mg of essential active ingredient, were prepared from the following ingredients:

The powdered essential active ingredient is added to the previously melted natural hydrogenated glycerides. The mixture is stirred and maintained at 45.degree.-50.degree. C. for 30 minutes. The suspension is poured into molds and allowed to cool and solidify.

These suppositories are useful in the treatment of pain and inflammation in mammals, when administered at a dose of 1 suppository administered rectally twice a day.

Following the procedure of the preceding Examples 1 to 4, inclusive, dosage forms of the invention are prepared by using an equivalent amount of different compounds of the formula (I) such as for example, phthalidyl N-(2'3'-xylyl) anthranylate, phthalidyl N-(3'-trifluorotolyl) anthranylate and the like.

In the following examples, the compounds of the formula (I) were subjected to comparative pharmacological tests to determine their therapeutic effects.

The method of Winter, Risley and Nuss (Winter, C. A., Risley, E. A. and Nuss G. W., Proc. Soc. Exp. Biol. Med. 111, 544, 1962) was used. Fifteen to twenty male rats of Spargue Dawley strain weighing 150-200 g, were employed for each compound tested. 0.1 ml of 1% carrageenin saline suspension was injected into the subplantar region of the right hind-paw. The test compounds were orally administered 30 minutes prior to the injection of carrageenin and the foot volume was determined 1,3 and 5 hours after the injection of carrageenin. The percent swelling in the foot was obtained by comparing the volume before and after the injection of carrageenin, and the rate of inhibition in the treated animals was calculated. The results are shown in the following table:

The compounds were tested using a tail pressure test and the Randall Selitto's test (Randall, L. O., Selitto, J. J., Arch. Int. Pharmacodyn. 111, 409, 1957).

Tail pressure test: Ten male mice of Rockland strain weighing 20-25 g were used for each compound tested. The response threshold on applying pressure to the tail was determined with an analgesy meter at 15 and 60 minutes after oral administration of the test compound. The pressure at which a struggle was elicited was read.

Randall-Selitto's method: Ten male mice of Rockland strain weighing 25 g were used for each compound tested. 0.1 ml of 1% carrageenin saline suspension was injected into the subplantar region of the right foot. The test compounds were orally administered 30 minutes before the injection. At hourly intervals for 3 hours after the carrageenin injection, the pain threshold for the inflammed feet was measured, determining the amount of pressure with an analgesy meter.

The results of these tests were observed as relative potency, as follows:

Ten male rats of Sprague Dawley strain, weighing 200-300 g were used for each compound tested. According to the method of Shay et al. (Shay, H., Komapov, S. A., Feb. S. S., Meranir, D., Gruenstein, M. Siplet, H. Gastroenterology 5, 43, 1945), under anesthesia, the pylorus was ligated and 4 hours later test compounds were orally administered. The animal was sacrificed 1 hour after compound administration. The stomach was removed and examined for macroscopic damage. The ulceration of the gastric epithelium was evaluated by the following evaluation: 0=no hemorrhage sites; 1=some isolated hemmorrhagic sites; 2=redness of the gastric epithelium; 3=1 to 5 small ulcers with a diameter smaller than 3 mm; 4=many small ulcers; 5=ulcers--greater than 3 mm; 6=perforated ulcer. The results of this test were as follows:

These results indicate, not only that the compounds of formula (I) are less ulcerogenic than their parent acid, but that they have an anti-inflammatory and analgesic activity greater than the parent acid. In accordance with this data, acetylsalicylic derivatives formula (I) are more analgesic than other derivatives described herein. Also, phthalidyl esters of, N-(2',3'-xylyl) anthranylic acid and N-(3'-trifluorotolyl) anthranylic acid act as anti-inflammatory agents more tha as antinociceptive agents.