GB2093449A

GB2093449A - Ammonium salt of a substituted carboxylic acid

Info

Publication number: GB2093449A
Application number: GB8204370A
Authority: GB
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1981-02-16
Filing date: 1982-02-15
Publication date: 1982-09-02
Also published as: CS227038B2; WO1982002889A1; ZM882A1; MC1492A1; PL136406B1; AU8049982A; ZW2782A1; MA19380A1; PT74427A; FI820465L; FR2499980A1; GR81389B; FR2499980B1; IT8247797A0; DE3205077A1; MTP906B; PL235083A1; BE892146R; LU83138A1; BG37225A3

Abstract

The compounds have the formula (FORMULA) wherein R<u1>u is a tri-(hydroxy methyl)-methyl group and R<u2>u and R<u3>u are hydrogen or R<u1>u and R<u2>u are each an ethyl, 2-hydroxy ethyl or 2-hydroxypropyl group and R<u2>u is hydrogen or R<u1>u and R<u2>u are together a 3-oxa-1,5-pentylene group and R<u3>u is hydrogen or R<u1>u is 2, 3, 4, 5, 6-penta-hydroxy-n-hexyl group, R<u2>u is methyl and R<u1>u is hydrogen or R<u1>u, R<u2>u and R<u3>u are a 2-hydroxyethyl group. The compounds have an anti inflammatory and analgesic activity.

Description

SPECIFICATION Ammonium Salt of a Substituted Carboxylic Acid, Process for its Manufacture, its Use and Pharmaceutical Preparation Containing Same The invention relates to a novel ammonium salt of a substituted carboxylic acid, especially to N methyl-D-glucammonium-[o-(2,6-di-chloroanilino)]-phenylacetate of the formula I

wherein H--AmO denotes the N-methyl-D-glucammonium cation of N-methyl-D-glucamine (1 methylamino- 1 -deoxy-D-sorbitol) having the formula HN(CH3)-CH2-CH(0H)-CH(0H)-CH(0H)-CH(0H)-CH20H (Ill), to processes for its manufacture, to its use as active ingredients of medicines as well as to pharmaceutical preparations, which contain this salt.

The o-(2,6-dichloroanilino)-phenyl acetic acid, forming the basis of the salt of formula I and the sodium and potassium salt thereof as well as their anti-inflammatory and analgesic activities are known.

The sodium salt is used, for example, as a non-steroidal anti-inflammatory agents for treating inflammatory conditions. The preparations containing these compounds are administered for the most part orally and also enterally or parenterally. However, these preparations are at present, for several reasons, not fully satisfying. Thus, on oral administration side-effects are observed, especially of a gastro-intestinal nature, for example ulceration of the nucosae of the gastro-intestinal tract. Parenteral application is restricted by the poor water-solubility of the sodium salt. This disadvantage is to be observed especially in injectionable solutions for intramuscular administration and makes necessary to inject relatively large volumes which, in many incidences, is followed by interolable local irritations.

These and other known disadvantages of sodium o-(2,6-dichloroanilino)-phenyl acetate are avoided or at least alleviated considerably by the provision of the novel salt of formula I. Thus, the salt according to the invention is considerably better tolerated on oral administration and is also by a factor of about three more soluble in water than the sodium salt. Although the novel salt of formula I exhibits the same favourable pharmacological properties as the known sodium salt, in an activity of at least comparable strength, it is considerably better suited for oral as well as for parenteral administration.

Thus, the novel salt of formula I shows pronounced anti-inflammatory and analgetical activities and, compared with sodium o-(2,6-dichloroanilino)-phenylacetate, better gastro-intestinal tolerability.

The anti-inflammatory activity can be demonstrated, for example, by the marked reduction in the swelling, in rat's paw in the carrageneen edema test on oral administration of 1 to 10 mg/kg, approximately.

Assays using the compound of formula I in the phenyl-p-benzoquinone writhing test (J.

Pharmacol. Therap. 125, 237, 1959) in the dosage range from 2 to 20 mg/kg p.o., approximately indicate a marked analgesic activity.

For the demonstration of the superior gastro-intestinal tolerability, the ulcus-index method can be applied, for example, in the following way: The preparation to be tested is administered, by means of stomach tube, to groups of 10 rats (5 males, 5 females, 220-280 g of body weight, Tierfarm Sisseln) 21 and 6 hours before autopsy. In.the autopsies, the gastric nucosae are examined for gastric ulcerations. Number and severeness of the ulcera are estimated and characterised in an index system ranging from 0 to 14. Also the incidence (fraction of animals with gastric ulcers) is evaluated and taken into consideration. The dose level which produces an ulcus-index of 3 is determined as a measure of gastric ulcerogenity, when necessary, by interpolation.

The compound of formula I is according to these findings, most suitable as anti-inflammatory and analgetical agent, especially for oral or parenteral administration.

The invention relates likewise to processes for the manufacture of the novel compound of formula I, which is prepared by methods known per se.

For example, a preferred process variant is characterised in that o-(2,6-dichloroanilino)-phenyl acetic acid of the formula

or a salt thereof with a base different from the salt of formula I is reacted with N-methyl-D-glucamine of the formula HN(CH3)-CH2-CH(0H)-CH(0H)-CH(0H)-CH(0H)-CH20H (III) or with an acid addition salt thereof. Preferably, at least an equimolecuiar amount of N-methyl-Dglucamine or of an acid addition salt thereof is applied.

Salts of compounds of the formula 11 that can be used according to the process are especially salts with bases that can be removed from the reaction mixture, for example that are more volatile or weaker than the amine of the formula Ill or form with the compound of the formula ll more readilysoluble salts than this, for example ammonium salts with ammonia; and also salts with bases that on reaction with a suitable salt of the amine of the formula Ill form sparingly soluble salts, such as calcium salts.

Saits of amines of the formula Ill that can be used according to the process are, for example, salts of the same with acids that can be removed from the reaction mixture, for example corresponding ammonium salts of volatile acids or of acids that are more weakly acidic than the corresponding salts of the formula I, such as salts of amines of the formula Ill with volatile inorganic acids, for example hydrohalides, or salts with volatile carboxylic acids or mono- or di-thiocarboxylic acids, for example salts with lower alkanoic acids, carbonic acid or dithiocarbonic acid or semi-esters or semi-amides thereof, inter alia corresponding acetates, carbonates and bicarbonates, carbamates or dithiocarbamates or lower alkoxyformates, and also ammonium hydroxides of the formula H-Amd'OHs The reaction is carried out in customary manner, advantageously in a solvent or diluent, if necessary with the removal, such as the distillative or azeotropically distillative removal, of volatile reactants, such as water, ammonia, carbon dioxide, carbon disuiphide or a resulting hydrohalic acid or lower alkanoic acid, or with the precipitation of sparingly soluble salts, for example calcium sulphate, and/or while heating.

In a preferred form of the process, for example the acid of the formula II is reacted in an organic solvent, such as a lower alkyl-lower alkanoate, e.g. ethyl acetate, directly with the amine of the formula 111.

In a further preferred process variant, the acid of the formula II is reacted with the carbonate, bicarbonate or carbamate of the amine of the formula Ill with the removal of the resulting carbon dioxide and, where applicable, ammonia.

In a further preferred process variant, the ammonium salt of the acid of the formula II derived from ammonia is reacted with the amine, advantageously with the distillative removal of the resulting ammonia or bonding thereof to an acidic ion exchanger.

In a further preferred process variant, the starting material used is sodium o-(2,6-dichloroanilino)phenyl acetate and this is reacted, in a solvent in which the resulting sodium chloride is more sparingly soluble than the resulting salt of the formula I, with a salt of the amine other than a salt of the formula I, for example a hydrochloride.

The invention also relates to those embodiments of the process in which a compound obtainable as an intermediate at any process stage is used as the starting material and the missing process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the form of a derivative thereof.

Thus, the acid of formula II can be formed in situ by hydrolysis of one of its esters, for example, of a lower alkyl ester thereof, in the presence of a base, such as ammonia or volatile amine, for example, diethyl amine. N-methyl-D-glucamine may likewise be used in an acid addition salt form, such as in the form of a hydrohalide, and set free with the acid of a base, such as ammonia or volatile amine.

The invention also relates to pharmaceutical preparations containing the salt of formula I.

With respect to this, the invention relates namely to the pharmaceutical preparations and to the processes for their manufacture described in the examples herein.

The pharmaceutical preparations according to the invention, which contain compounds of the formula I are those which are intended for enteral, such as oral or rectal, and parenteral administration and for topical application to warm-blooded animals and which contain the pharmacological active ingredient on its own or together with a pharmaceutically usable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the age and the individual condition and also on the mode of administration. In the normal case, an approximate daily dose of about 75-250 mg, in the case of oral administration, and of about 20-100 mg in the case of parenteral administration, advantageously divided into severai equal partial doses, is to be estimated for a warmblooded animal weighing about 75 kg.

The novel pharmaceutical preparations are, above all, pharmaceutical preparations intended for enteral and parenteral administration, for example, those in the form of dosage units, such as sugarcoated tablets, tablets, capsules or suppositories and especially parenteral preparations in the form of ampoules. Oral preparations contain, for example, approximately 10 to 80, especially approximately 20 to 50, percent-by-weight, non-aqueous solutions for injection, for example, approximately 0.5 to 10, especially approximately 0.5 to 5, percent-by-volume, or aqueous solutions for injection, for example, from about 0.3, especially from about 0.5 percent-by-volume up to a concentration approximately saturation, and preparations for topical administration from about 0.5 to 10, e.g. 0.5 to 5, percent-byweight of the active ingredient.The preparations are manufactured in a manner known per se, for example by conventional mixing, granulating, sugar-coating, dissolving or lyophilising methods. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, granulating a resulting mixture if desired and processing the mixture or granules, if desired or if necessary after adding suitable adjuncts, to tablets or sugar-coated tablet cores.

Suitable carriers are, in particular fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes, using, for example, maize, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such as the above starches, and also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Adjuncts are in particular glidants and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethyleneglycol.Sugar-coated tablet cores are provided with suitable coatings which can be resistant to gastric juices, using, inter alia, concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, laquers dissolved in suitable organic solvents or solvent mixtures, or, for the preparation of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments can be added to the tablets or the coatings of sugar-coated tablets, for example for identification or to indicate different doses of active ingredient.

Further pharmacetucal preparations for oral administration are hard gelatine capsules made of gelatin and also soft, sealed capsules made of gelatin and plasticiser, such as glycerol or sorbitol. The dryfilled capsules can contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.

Pharmaceutical preparations for rectal administration are, for example, suppositories, which consist of a combination of an active ingredient with a suppository base. Examples of suitable suppository bases are natural or synthetic triglycerides, paraffin hydrocarbons polyethylene glycols or high alkanols or mixtures thereof. Gelatin rectal capsules, which contain a combination of the active ingredient with a base, can also be used; base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Preparations suitable for parenteral administration are, in particular, aqueous solutions of the active ingredient as well as suspensions of the active ingredient, such as corresponding oily injection suspensions, for which suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, may be used, or aqueous injection suspensions which contain substances increasing the viscosity, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilisers.

Pharmaceutical preparations for topical application are, in particular, creams, ointments, pastes, foams, tinctures and solutions.

Creams are oil-in-water emulsions which contain more than 50% of water. Substances used as the fatty phase are, in particular fatty alcohols, for example lauryl alcohol, cetyl alcohol or stearyl alcohol, fatty acids, for example palmitic acid or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example petroleum jelly (petrolatum) or paraffin oil.Suitable emulsifiers are surface-active substances with primarily hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), and also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl-sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are customarily used in the presence of fatty alcohols; for example cetyl alcohol or stearyl alcohol.Additives to the aqueous phase are, inter alia, agents which reduce the drying-out of the creams, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes and the like.

Ointments are water-in-oil emulsions which contain up to 70%, but preferably from about 20% to about 50%, of water or aqueous phases. The oleaginous phase comprises, in particular, hydrocarbons, for example, petroleum jelly,paraffin oil and/or hard paraffins, which preferably contain hydroxy compounds suitable for improving the water-binding capacity, such as fatty alcohols or esters thereof, for example, cetyl alcohol or wool wax alcohols, or wool wax. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, inter alia, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes and the like.

Fatty ointments are anhydrous and contain, as the base, in particular hydrocarbons, for example paraffin, petroleum jelly and/or liquid paraffins, and also natural or partially synthetic fat, for example coconut fatty acid triglyceride, or preferably hydrogenated oils, for example hydrogenated pea-nut oil or castor oil, and also fatty acid partial fatty acid esters of glycerol, for example glycerol mono- and distearate, and for example, the fatty alcohols, emulsifiers and/or additives for increasing in absorption of water, which have been mentioned in connection with the ointments.

Pastes are creams and ointments containing secretion-absorbing powder consituents, such as metal oxides, for example titanium oxide or zinc oxide, and talc and/or aluminium silicates, the purpose of which is to bind the moisture or secretion present.

Foams are administered from pressurised dispensers and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichiorodifluoromethane and dichlorotetrafluoroethane, being used as propellants. Substances used as the oleaginous phase are, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropyl myristate, and/or other waxes. The emulsifiers used are, inter alia, mixtures of those which have primarily hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens) and those which have primarily lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, the conventional additives, such as preservatives and the like, are used.

Tinctures and solutions in most cases have an aqueous-ethanolic base, to which the following substances are added, inter alia: polyalcohols, for exarhple glycerol, glycols and/or polyethylene glycol, as humectants for reducing evaporation, and fat-restoring substances, such as fatty acid esters with lower polyethylene glycols i.e. lipophilic substances which are soluble in the aqueous mixture, as a replacement for fatty substances which are removed from the skin with the ethanol, and, if necessary, other adjuncts and additives.

The pharmaceutical preparations for topical use are prepared in a manner known per se, for example by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary.

When processing the active ingredient in the form of a solution, it is usually dissolved in one of the two phases before emulsifying, and when processing the active ingredient in the form of a suspension, it is mixed with a part of the base after emulsifying and then added to the remainder of the formulation.

The invention relates further to the use of the compound of formula 1, above all, for the treatment of inflammations, especially of chronical inflammations of rheumatoid origin, predominantly of chronic arthritis.

The following examples illustrate the invention without in any way restricting the scope thereof.

Temperatures are given in degrees Centigrade, pressures in mbars.

Example 1 A suspension of 6.64 g of N-methyl-D-glucamin in 100 ml of ethanol together with 10 g of 2 (2,6-dichloroanilino)-phenyl-acetic acid in 230 ml of ethyl acetate are stirred at room temperature overnight under nitrogen. Fine, white crystals precipitate after 2 hours. The solvent is then removed by rotary evaporation and the white tacky residue is dissolved in a small amount of hot water. The clear solution is slowly cooled to 0 and left to stand overnight at 00. The oily, semi-crystalline precipitate obtained is collected over 2 days on a celite and cloth filter. The filter cake is dried for a week at 600/100 mm Hg and then pulverised. The so obtained N-methyl-D-glucammonium-2-(2,6dichloroanilino)-phenyl-acetate melts at 1270--1300.

Example 2 10.0 g of o-(2,6-dichloroanilino)-phenyl acetic acid are dissolved, with stirring, in 230 ml of ethylacetate. 6.64 g of N-methyl-D-glucamin are added, and stirring is continued 1 6 hours. The precipitate formed is filtered off, washed with a small amount of ethyl acetate and dried at 600 under reduced pressure. The raw-material is triturated with 600 ml of hot isopropanol, cleared from a small fraction of unsoluble material by filtration. The clear solution is concentrated to approximately 500 ml and allowed to cool slowly. After 3 hours, the resulting suspension is stirred with ice-cooling, until crystallisation is complete.The crystals are filtered off, washed with ice-cold isopropanol and dried at 600 under reduced pressure. N-Methyl-D-glucammonium-[o-(2,6dichlornanilino)Jphenyl acetate of m.p. 142.5-145 is obtained.

Example 3 Tablets containing 75 mg of active ingredient, i.e. N-methyl-D-glucammonium-[o-(2,6dichloroanilino)]-phenyl acetate, can be prepared as follows: Constituents (for 10'000 tablets) Active ingredient 750 g Lactose grinded 350 g Col(oidal silicium dioxide 30 g Polyvinylpyrrolidone 50 g Microcrystalline cellulose 400 g Maize starch 690 g Demineralised water q.s.

Preparation All the solid ingredients are first forced through a sieve of 0.6 mm mesh width. The active ingredient and the lactose are then mixed, grinded and granulated with the aid of an aqueous solution of the polyvinylpyrrolidone. The resulting granulate is dried, grinded and thoroughly mixed with the remaining ingredients for 10 minutes. The resulting granulate is then compressed to tablets (9 mm diameter, 230 mg weight).

Example 4 Capsules having a content of 25 mg of N-methyl-D-glucammonium-[o-(2,6-dichloroanilino)j- phenyl acetate (active ingredient) are manufactured, for example, as follows: Ingredients (for 10'000 capsules) Active ingredient 250 g Lactose 450 g Magnesium stearate 50 g The ingredients are mixed in a suitable mixer, forced through a No. 40 sieve and mixed again.

Each 0.05 g of the mixture is introduced into a gelatin capsule of suitable capacity.

Example 5 Solutions for injection containing 2% by weight of N-methyl-D-glucammonium-[o-(2,6 dichloroanilino)]-phenylacetate as the active ingredient, can be manufactured, for example, according to one of the following preparations: Preparation 1 Composition Active ingredient 20 mg Mannitol (pyrogen-free) 6 mg Water for injection ad 1 ml Preparation The required amounts of active ingredient and the mannitol are dissolved, with stirring under nitrogen, in approximately 90% of the amount of water prescribed. After dissolving is complete, the solution is made up with water for injection purposes to the final weight.

The injection solution is sterilised by filtration through a membrane filter (O.22 ym pore size), and is filed under nitrogen into sterilised glass ampoules. The ampoules are closed under nitrogen, and (the closed ampoules) are then treated at 1 200C for 20 minutes in an autoclave.

Preparation 2 Composition Active ingredient 20 mg Benzyl alcohol 40 mg 1,2-Propylen glycol 200 mg Water for injection ad 1 ml Preparation The necessary amounts of mannitol, benzyl alcohol and 1,2-propylene glycol are dissolved, with stirring under nitrogen, in approximately 70% of the prescribed amount of water for injection purposes.

The required amount of active ingredient is added to the solution, and stirring is continued until the active ingredient is completely dissolved. The solution is then made up with water for injection purposes to the final weight.

The injection solution is steriiised by filtration through a membrane filter (40.22 Mm pore size), and is filled under nitrogen into sterlised glass ampoules. The ampoules are closed under nitrogen, and are subsequently treated at 1 2O0C for 20 minutes in an autoclave.

Example 6 A cream, containing 5% N-methyl-D-glucammonium-[o-(2,6-dichloroanilino)]-phenylacetate as the active ingredient, can be manufactured as follows: Composition % (by weight) Active ingredient 5 Fatty-acid with potassium stearate (self-emulgating glycerol monostearate) 17 Decyloleate 5 Propylene glycol 20 Water, de-mineralised ad 100 Preparation The active ingredient is dissolved in the propylene glycol and most of the water required. The selfemulgating glycerol monostearate and the decyloleate are fused and blended. Then, the water-phase is added to the fat-phase and emulgated thoroughly. When required, a fragrance (approximately 0.1% by weight) may be added.

Claims

1. N-Methyl-D-glucammonium-[o-(2,6-dichloroanilino)j-phenyl acetate.

2. A pharmaceutical preparation containing N-methyl-D-glucammonium-[o-(2,6dichloroalinilino)]-phenyl acetate in admixture to conventional pharmaceutical carriers and/or adjuncts.

3. A pharmaceutical preparation according to claim 2 for oral administration, containing approximately 10 to 80 percent-by-weight of the active ingredient.

4. A pharmaceutical preparation according to claim 2 for parenteral administration, containing from about 0.5 percent-by-weight up to approximate saturation of the active ingredient.

5. A pharmaceutical preparation according to claim 2 for topical administration, containing approximately 0.5 to 10 percent-by-weight of the active ingredient.

6. A pharmaceutical preparation according to any one of Examples 3 to 6.

7. Process for the manufacture of N-methyl-D-glucammonium-[o-(2,6-dichloroanilino)]-phenyl acetate, characterised in that o-(2,6-di-chloroanilino)-phenyl acetic acid or a salt thereof different from the salt of formula I is reacted with N-methyl-D-glucamine or an acid addition salt thereof.

8. Process according to claim 7, characterised in that at least an equimolecular amount of N methyl-D-glucamine or of an acid addition salt thereof, respectively, is applied.

9. A process for the manufacture of N-methyl-D-glucammonium-[o-(2,6-dichloroanilino)]-phenyl acetate substantially as hereinbefore described with reference to Example 1 or Example 2.

10. Method of treatment of inflammatory diseases, characterised in that a pharmaceutical preparation according to any one of claims 2 to 6 is administered to a warm-blooded organism in need of such treatment.

11. Use of N-methyl-D-glucammonium-[o-(2,6-dichloroanilino)]-phenyl acetate as antiinflammatory and/or analgetical agent or for the manufacture of anti-inflammatories and/or analgesics.