SI8110467A8 - Process for preparing salts of o-(2,6-dichloroanylino)-phenyl-acetic acid - Google Patents

Description

TECHNICAL PROBLEM

There is a need to find a process in which new o- (2,6-dichloroanilino) -phenyloic acid salts are produced in a technologically advantageous manner and with good yield and purity without having a good anti-inflammatory and analgesic effect without would indicate the disadvantages of the compounds of the prior art.

BACKGROUND OF THE INVENTION

The new salts of o- (2,6-dichloroanilino) -phenylacetic acid, which can be prepared by the process of the invention, are novel compounds and have not been described in the literature so far, neither by themselves nor by the processes for their preparation.

In U.S. Pat. 3 558 690 describes o- (2,6-dichloroanilino) -phenylacetic acid of the formula ^R 1 / CH-COOH (lilac).

^R 2 in which it represents a group of the formula ^χ ι \ Λ

· (Ha) in which X is 2,6-dichloroanilino, X ₂ and X _{2 are} hydrogen and R _{2 is} hydrogen, or its inorganic salts. Sodium or. potassium salt of the age by hydrolysis

1- (2,6-Dichlorophenyl) -2-indolinone, resp. 2- (2,6-dichloroanilino) -phenylacetonitrile with NaOH and KOH (without salt isolation) and neutralized

2- (2,6-dichloroanilino) phenylacetic acid with NaOH or. KOH. Other salts are not listed. The corresponding organic salts are not specifically described. This compound or its salts with bases are used e.g. as non-steroidal anti-inflammatory agents in the treatment of inflammatory processes.

In this case, the corresponding preparations are predominantly oral, further enteral or parenteral, but side effects occur in this mode of administration, especially in the gastrointestinal area, e.g. ulcer formation on the mucous membranes of the digestive tract. The aim of the treatment of various forms of inflammatory diseases, especially the rheumatism of the soft parts, is to avoid as much as possible the side effects predominantly related to systemic treatment. For this purpose, treatment for external use is especially offered if the transport of the substance into the inflammatory area is to be ensured. The success of the treatment

However, percutaneous administration often fails due to the fact that when using the active ingredients of formula (lilac), it only fails to deliver the active ingredient in a therapeutically effective amount through the skin to the diseased tissue.

DESCRIPTION OF THE TECHNICAL PROBLEM SOLUTION WITH EXAMPLES

The invention relates to a process for the preparation of new salts of o- (2,6-dichloroanilino) -phenylacetic acid of the formula

R.

R.

(I) wherein R. represents a group of formula

(Ha) in which 2,6-dichloroanilino-, i ⁿ ^ 3 is hydrogen, R ^ is hydrogen and one of the residues R ^, R ^ as well as R ^ is tris- (hydroxymethyl) -methyl and the remainder is hydrogen, one of the radicals R1, R3, as well as R4 represents hydrogen and the rest ethyl, 2-hydroxyethyl, 2-hydroxypropyl or together 3-oxa-1,5-pentylene or R8 is hydrogen, R4 is methyl and D-pentahydroxyhexyl is derived from D-glucamine, or the residues R ^, R ^ as well as R ^ each represent 2-hydroxyethyl.

The invention further relates to a process for the preparation of new compounds of formula I, in particular such compounds, wherein R1 is a group of formula Ha, in which 2,6-dichloroanilino, X2 and R4 are hydrogen, R8 is hydrogen and one of the radicals R1, R4 as well as R4 represent hydrogen and the rest represent ethyl or represent the radicals R4, R4 and R4 2-hydroxyethyl.

In the foregoing and hereinafter, they are meant by organic residues and compounds labeled “lower, preferably containing up to and including 7, especially up to and including 4 carbon atoms.

In the context of the present text, the general definitions used primarily have the following meanings: hydroxy lower alkyl contains in particular a hydroxy group and is e.g. hydroxymethyl, 2-hydroxy ethyl, 2- or 3-hydroxypropyl or 2-, 3- or 4-hydroxybutyl.

The invention is based on the surprising finding that the compounds of formula (I) are characterized by excellent percutaneous penetration and resorption properties.

In addition, the compounds of formula I to be used in the invention exhibit pronounced anti-inflammatory and analgesic properties. Anti-inflammatory efficacy can be demonstrated e.g. with a distinct reduction in swelling of the rat paw in a model of Kaolich paw edema induced by Helv. Physiol. Acta 25 ^, 156 (1967), in which a gel containing about 0.5 to 5% of the active substance is massaged into the clipped skin on the back of experimental animals. (Lit .: Arznemittel-Forschung 27 (I), 1326, 1977). In addition, anti-inflammatory efficacy can be inferred from the external use of the active substance, e.g. in the form of a gel containing about 0.5 to 5% of the active substance by inhibiting abscess formation triggered by subcutaneous injection of carragenin in the rat. (Lit .: Arzneim. Forsch. 27 (Ό, 1326 ^ 1977).

The compounds of formula I are therefore well-suited as percutaneously useful anti-inflammators and also as analgesics.

The invention relates in particular to the preparation processes described in the examples.

The compounds of formula I may also be obtained in the form of their hydrates or may include other solvents used for crystallization.

A preferred variant of the process is e.g. characterized in that the organic carboxylic acid of formula ^R 1 / CH-COOH (lilac) or a base salt thereof, other than a salt of formula I, is treated with at least an equimolar amount of an amine of formula

wherein R 2, R 4, R 4, and R 4 have the meanings given above, or with its acid addition salt, at room temperature to boiling point.

The molar ratio of the acids of the formula lil and the amines of the formula Illb depends on the choice of the desired salts or the. of the number of substituted amino groups in the corresponding compound of formula Illb.

As the acid addition salts of amines of the formula Illb we use, e.g. suitable hydrohalides such as hydrochlorides.

The reaction of the compounds of the formula lyl with the compounds of the formula Illb is conveniently carried out in an inert solvent or. diluent, if necessary by cooling or heating, preferably at room temperature, in a closed container and / or under an inert gas atmosphere, e.g. nitrogen.

Suitable solvents and diluents are suitable e.g. water, alcohols, such as lower alkanols, e.g. methanol or ethanol, ethers, such as dichloalkyl ethers, e.g. diethyl ether, such as cyclic ethers, e.g. dioxane or tetrahydrofuran, ketones, such as dinylalkyl ketones, e.g. acetone, carboxylic acid esters, such as lower alkanecarboxylic acid esters, e.g. acetic acid ethyl ester, amides such as N, N-dialkylalkylamides, e.g. Ν, Ν-dimethylformamide, sulfoxides, such as dinylalkyl sulf · oxides, e.g. dimethyl sulfoxides, or mixtures thereof.

The starting materials of the lilac and Hib formulas are known.

The invention also relates to those embodiments of the process in which starting materials are prepared in situ, or in which the starting material is obtained under the reaction conditions of a derivative and / or used in the form of a mixture of isomers or pure isomers.

The starting materials of the formula lyl can be formed under the reaction conditions e.g. from suitable esters, such as lower alkyl esters, by hydrolysis in the presence of a base such as an amine, e.g. diethylamine. An amine of the formula Hib can be used e.g. in the form of an acid addition salt, such as a hydrohalide, e.g. of hydrochloride, and released in the presence of a base such as an amine.

In the process of the present invention, such starting materials which give rise to particularly valuable compounds are preferably used.

Pharmaceutical preparations for exterior use contain pharmaceutically useful compounds of formula I together with pharmaceutically useful adjuvants or excipients. The daily dosage of the active substance depends on the age and individual condition as well as the mode of administration.

Pharmaceutical preparations for external use are primarily concerned with creams and gels, further pastes, foams, tinctures and solutions containing about 0.5 to about 5% of the active ingredient.

Creams or lotions are oil-in-water emulsions containing more than 5θ% water. Fatty alcohols, for example, are used as an oil base. lauryl, cetyl or aryl alcohol, fatty acids such as palmitic or stearic acid, liquid to solid waxes, e.g. isopropyl myristate, lanolin or beeswax, and / or hydrocarbons, e.g. petrolatum or paraffin oil. Surfactants having predominantly hydrophilic properties, such as suitable non-ionic emulsifiers, e.g. fatty acid esters of polyalcohols or their adducts with ethylene oxide, such as polyglycerol fatty acid esters or fatty acid esters of polyoxyethylene sorbitans (Tveens), further polyoxyethylene fatty alcohol alcohols or esters of polyoxyethylene fatty acid alkaline fatty acids, sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate commonly used in the presence of fatty alcohols, e.g. cetyl alcohol or stearyl alcohol. Additions to the aqueous phase are, among other things, agents that prevent the drying of creams, e.g. polyalcohols such as glycerol, sorbitol, propylene glycol and / or polyethylene glycols, further preservatives, fragrances, etc.

Ointments or lotions are water-in-oil emulsions containing up to 70% and preferably from about 20% to about

50% water or water phase. As a fat phase, hydrocarbons, e.g. petroleum jelly, paraffin oil and / or solid paraffins containing, preferably, hydroxyl compounds, such as fatty alcohols or esters thereof, for the purpose of binding water to suitable water. cetyl alcohol or lanolin alcohols or. lanolin. Emulsifiers are suitable lipophilic substances such as sorbitan fatty acid esters (Spans), e.g. sorbitan oleate and / or sorbitan isostearate. Additives to the aqueous phase are, among other things, humectants such as polyalcohols, e.g. glycerol, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances, etc.

Microemulsions are isotropic systems based on the following four components: water, emulsifier, surfactant, e.g. Eumulgin, lipid, as a non-polar oil, e.g. paraffin oil, and alcohol with a lipophilic group, e.g. 2-octyldodecanol. Optionally, other additives can be added to the microemulsions.

Grease oils are free of water and contain hydrocarbons in particular, e.g. paraffin, petroleum jelly and / or liquid paraffins, further naturally or partially synthetic fat, e.g. coconut fatty acid triglyceride, or preferably hydrogenated oils, e.g. hydrogenated arachis or castor oil, further fatty acid and glycerol partial esters, e.g. glycerol mono- and distearate, as well as e.g. fatty alcohols mentioned in connection with ointments enhancing water absorption capacity, emulsifiers and / or additives

For gels, a distinction is made between aqueous and anhydrous gels and gels with little water consisting of swollen gel-forming materials. First of all, we use transparent hydrogels based on inorganic or organic macromolecules. High molecular weight inorganic constituents with gel formation properties are predominantly water-containing silicates such as aluminum silicates, e.g. bentonite, magnesium aluminum silicates, e.g. Veegum, or colloidal quartz, e.g. Aerosil. As high molecular weight organic substances we use e.g. natural, synthetic or synthetic macromolecules. Natural and semi-synthetic polymers are derived e.g. from polysaccharides with a wide variety of carbohydrate units such as cellulose, starches, tragacanth, arabic gum, agar-agar, gelatin, alginic acid and its salts, e.g. sodium alginate, and their derivatives, such as lower alkyl celluloses, e.g. methyl or ethyl celluloses, carboxy or hydroxyl alkyl celluloses, e.g. carboxy methyl or hydroxyethyl cellulose. The units of the aintatic h macromolecules that form the gels are e.g. suitably substituted unsaturated aliphatic such as vinyl alcohol, vinyl pyrrolidine, acrylic or methacrylic acid. Examples of such polymers include polyvinyl alcohol derivatives, such as Polyviol, polyvinyl pyrrolidines, such as Collidon, polyacrylates, and the like. polymethacrylates such as Rohagit S or Eudispert. Gels can be added to conventional additives, such as preservatives or fragrances.

Pastes are creams and ointments with ingredients that absorb secretions, such as with metal oxides, e.g. titanium oxide or zinc oxide, further talc and / or aluminum silicates, which are intended to bind the moisture or secretions present.

The foams are given e.g. from pressure vessels and are liquid, water-in-water emulsions in the form of an aerosol, using halogenated hydrocarbons such as chlorofluoro-lower alkanes as propellants, e.g. dichlorodifluoromethane and dichlorotetrafluoroethane. We use hydrocarbons as the oil phase, e.g. paraffin oil, fatty alcohols, e.g. cetyl alcohol, fatty acid esters, e.g. isopropyl myristate, and / or other waxes. Emulsifiers are used, inter alia, for mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tveens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans).

These include the usual additives, such as preservatives, etc.

Tinctures and solutions generally have an ethanol base, to which water and poly alcohols are added, as appropriate, e.g. glycerol, glycols and / or polyethylene glycol as moisture retaining agents to reduce evaporation and re-fatty substances as fatty acid esters with lower polyethylene glycols, i.e. water-soluble lipophilic substances as a substitute for fat-stripped ethanol and, if necessary, other excipients and additives.

The preparation of pharmaceutical preparations for external use is carried out in a manner known per se, e.g. by dissolving or suspending the active substance in the substrate or, if necessary, in a portion of the substrate. When administered as a solution, it is generally dissolved in one of the two phases before emulsifying; in the form of a suspension, after emulsification, it is mixed with a portion of the substrate and then added to the remainder of the preparation.

The following examples illustrate the invention described above, but should not in any way limit its scope.

Temperatures are given in degrees Celsius.

EXAMPLE 1

To a solution of 2 g of 2- (2,6-dichloroanilino) -phenyl-acetic acid in 40 ml of ether was added 2 ml of diethylamine. The solution was heated to reflux for 10 minutes, cooled and evaporated under reduced pressure, crystallizing diethylammonium-2- (2,6-dichloroanilino) -phenyl acetate. The colorless crystals were filtered off (mp 110 ° -115 °, decomposition) and dried under high vacuum at room temperature.

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EXAMPLE 2

A solution of 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 250 ml of acetic acid ethyl ester was added dropwise at room temperature with vigorous stirring for 10 minutes.

4.55 g of tris- (hydroxymethyl) -methylamine dissolved in

ΊΟ ml of water. The salt is immediately eliminated. The mixture was then stirred at room temperature for half an hour and the solvent was removed on Rotavap. The white crystalline residue was dissolved at about 5θ ° of acetone / water (1: 1). Evaporate the hot solution on Rotavap until the first crystals are eliminated. It is then allowed to crystallize at 0 °. The separated white flake crystals are sucked off and dried under high vacuum. The tris- (hydroxymethyl) -methyl-ammonium-2- (2 _and 6-dichloroanilino) -phenyl acetate thus obtained has a m.p. 202 to 204 °.

EXAMPLE 5

To a solution of 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 230 ml of acetic acid ethyl ester was added dropwise at room temperature and, under vigorous stirring, 5.52 g of triethanolamine dissolved in 30 ml of acetic acid ethyl ester. The salt is eliminated immediately. The mixture was then stirred at room temperature for about half an hour and the solvent removed on Rotavap. The white crystalline residue was dissolved in a little hot ethanol and crystallized at 0 °. The white crystals are aspirated and dried under high vacuum. Triethanolammonium 2- (2,6-dichloroanilino) -phenyl acetate was melted at 137 to 138 °.

IR IKER 4

To a solution of 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 23θ ml of acetic acid ethyl ester was added dropwise at room temperature and with vigorous stirring for 10 min 3.89 g of diethanolamine suspended in 30 ml of acetic acid ethyl ester. The resulting salt is immediately eliminated. The mixture was then stirred at room temperature for half an hour and the solvent was removed on Rotavap. The yellowish crystalline residue was dissolved in a little boiling ethanol. The solution was allowed to stand at 0 °, crystallizing diethanolammonium-2- (2,6-dichloroanilino) -phenylacetate having a melting point of 13 ° to 132 °.

EXAMPLE 5

To a solution of 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 23θ ml of acetic acid ethyl ester was added dropwise at room temperature and stirred vigorously for 10 min.

3.22 g of morpholine in JO ml of acetic acid ethyl ester. About 10 minutes after the addition of morpholine, salt is eliminated. It is then stirred for another hour at room temperature and the solvent is removed on Rotavap. Something dissolves the white crystalline residue in boiling ethanol. At 0 ° it crystallizes out morpholinium-2- (2,6-dichloroanilino) -phenyl acetate, which melts at 162 to 165 °.

PR IMER 6

To a solution of 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 230 ml of acetic acid ethyl ester was added dropwise at room temperature and stirred vigorously for 5 min.

4.93 ε of diisopropanolamine in 30 ml of acetic acid ethyl ester.

After a short time, salt is eliminated. Stir for another 1 hour and. remove the solvent at Rotavap and dissolve the white crystalline residue in a little boiling ethanol. The solution was allowed to stand at 0 °, crystallizing diisopropanolammonium-2- (2,6-dichloroanilino) -phenylacetate from the ground. 165 to 170 °.

EXAMPLE 7

A suspension of 6.64 g of N-methyl-D-glucamine in 100 ml of ethanol was stirred together with 10 g of 2- (2,6-dichloroanilino) -phenylacetic acid in 230 ml of acetic acid ethyl ester at room temperature overnight under nitrogen. After 2 hours white, fine crystals are eliminated. Then remove the solvent on Rotavap and white, dissolve the sticky residue in a little hot water. Then allow the clear solution to cool slowly to 0 ° and allow it to stand at 0 ° overnight. The oiled, semi-crystalline mass which is filtered off through a Celite and cloth filter over 2 days is eliminated. The residue was dried for 1 week at 60 ° / 133 mbar and then dusted. N-methyl-Dglucammonium-2- (2,6-dichloroanilino) -phenyl acetate was melted at 127-130 °.

In vitro release of anti-inflammatory acid salts from the cream base in the case of diclofenac salts

In vitro absorption of active ingredients from the cream base is considered as a test model for the determination of percutaneous penetration and resorption properties. A substrate consisting of 10 to 44% propylene glycol, 10% macromolecular polyethylene glycol, 12% dense liquid paraffin oil, 22% white petroleum jelly, 7% microcrystalline wax, 0 to 34% glycerin, 0.2% parabens was chosen as the comparative test substance. and 5% of the active substance.

The method

To release the diclofenac salt (2- (2,6-dichloroanilino) phenylacetic acid), the cream was eluted with the respective salt in a phosphate buffer cell at pH 6. The cell is a Plexiglas diffusion cell in which the cream is exposed on a surface of 37 cm. ² and 0.4 mm thick laminarner in the acceptor medium (phosphate buffer with pH 6). For separation, a porous polycarbonate film is used which has no effect on the release rate or the amount released. Acceptor phase dosing maximizes synchronous conditions.

Results

Comparison of the release rate of 2- (2,6-dichloroanilino) -phenylacetic acid sodium salt with the following comparators diethylammonium 2- (2,6-dichloroanilino) -phenylacetate, triethanolammonium 2- (2,6-dichloroanilino) -phenylacetate, diethylammonium 2- (2 , 6-dichloroanilino) -phenylacetate and morpholinium 2- (2,6-dichloroanilino) -phenylacetate showed that the release of di-oz. triethanolammonium salts higher by a factor of 1.3, diethylammonium salts by a factor of 1.4 and morofolinium salts by a factor of 1.5 than the release of sodium salts. Thus, diclofenac salts with organic amines from the cream base release significantly faster than the corresponding sodium salt .

STATEMENT OF THE BEST, APPLICANT KNOWLEDGE WAY

FOR ECONOMIC EXPLOITATION OF THE INVENTION

To a solution of 2 g of 2- (2,6-dichloroanilino) -phenyl-acetic acid in 40 ml of ether was added 2 ml of diethylamine. The solution was heated to reflux for 10 minutes, cooled and evaporated under reduced pressure, crystallizing diethylammonium-2- (2,6-dichloroanilino) -phenyl acetate. The colorless crystals were filtered off (m.p. 11 ° -115 °, decomposition) and dried under high vacuum at room temperature.

Claims (4)

PATENT APPLICATIONS A process for the preparation of a salt of o- (6-dichloroanilino) -phenylacetic acid of the formula wherein R ₁ represents a group of formula ^X 1 / ¾) -¾ (s) · - · - 'in which 2,6-dichloroanilino, Xg and Xg is hydrogen, Rg is hydrogen and one of the residues Rg, R ^ as well. Rg stands for tris- (hydroxymethyl) -methyl and the remainder is hydrogen, one of the residues Rg, R4 as well as Rg represents hydrogen and the rest ethyl, 2-hydroxyethyl, 2-hydroxypropyl or together 3-oxa-1,5-pentylene or Rg is hydrogen, R ^ is methyl and Rg is D-pentahydroxyhexyl derived from D-glucamine, or the residues Rg, R ^ as well as Rg are each 2-hydroxyethyl, characterized in that o- (2,6-dichloroanilino) -phenylacetic acid by formula - ζο ι \ .CH-COOH (lilac) is reacted with at least an equimolar amount of an amine of formula * 3 A 'γ'(nn>), where R ₂ , Rg, R ^ and Rg have the meanings given above, in the presence of solvents, such as diethyl ether or ethyl acetate, at room temperature to the boiling point of the solvent. A process according to claim 1, characterized in that preparing the starting material in situ or starting material is obtained under the reaction conditions of the derivative and / or used in the form of an isomer mixture or pure isomer and / or salt. 3. Salts of o- (6-dichloroanilino) -phenyl-acetic acid of the formula wherein it represents a group of the formula ^X 1 / * 2 S ~ \ Z * 3 · »· · * ^z in which X _{1 is} 2,6-dichloroanilino, and X ^ is hydrogen, R ^ is hydrogen and one of the radicals R ^, R ^ as well as R ^ is tris- (hydroxyethyl) - and ethyl and hydrogen remain, one of the radicals R1, R4 as well as R4 represents hydrogen and the rest ethyl, 2-hydroxyethyl, 2-hydroxypropyl or together 3-oxa-1,5-pentylene or R4 is hydrogen, R1 is methyl and R4 is D-pentahydroxyhexyl derived from D-glucamine, or R4, R4 as well as R3 are each 2-hydroxyethyl, Pharmaceutical preparations comprising a compound of formula I according to claim 3. For CIBA-GEIGY AG: 175O4-I-88-KA -η SUMMARY A process for the preparation of an o- (6-dichloroanilino) phenylacetic acid salt of the formula S (?) ' ³ I ⁴ where R represents a group of formula (I). 1 \ '• -X \ / 3 · * · (Ha) in which X _{1 is} 2,6-dichloroanilino, X ₂ and X _{2 are} hydrogen, R ₂ is hydrogen and one of the residues R 1, R ₂ , and also of R ^ represents tris- (hydroxymethyl) -methyl and the remainder is hydrogen, one of the residues R ^, R ^ as well as R ^ represents hydrogen and the rest ethyl, 2-hydroxyethyl, 2-hydroxypropyl or a total of 3-oxa-1,5 -pentylene or R ^ is hydrogen, R ^ is methyl and R ^ is D-pentahydroxyhexyl derived from D-glucamine, or are the residues R ^ as well as R ^ each is 2-hydroxyethyl, wherein o- (2,6-dichloroanilino) -phenylacetic acid of the formula - 25 ¹ ^ CH-COOH (lilac), or a base salt thereof, which is different from the salt of formula I, is reacted with at least an equimolar amount of an amine of formula wherein R 2, R 4, R 4 and R 4 have the meanings given above; or an acid addition salt thereof, and if necessary by the process the compound of formula I obtained is converted to another compound of formula I and / or the mixture of isomers obtained is separated into components. ' Formula I salts can be used as percutaneously useful anti-inflammatory drugs and analgesics.