Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
  • C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
  • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/40—Unsaturated compounds
  • C07C59/76—Unsaturated compounds containing keto groups
  • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
  • C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof

Definitions

• Ammonium salts of a substituted carboxylic acid process for their preparation, their use and pharmaceutical preparations containing them
• R 1 is tri- (hydroxy) methyl and R 2 and R 3 are hydrogen, or both R 1 and R 2 are each ethyl, 2-hydroxyethyl or 2-hydroxypropyl and R 3 is hydrogen, or R 1 and R 2 together represent 3-oxa-1,5-pentylene and R 3 represents hydrogen, or R 1 represents 2,3,4,5,6-pentahydroxy-n-hexyl, R 2 represents methyl and R 3 represents Are hydrogen, or R 1 , R 2 and R 3 are 2-hydroxyethyl, processes for their preparation, their use as active pharmaceutical ingredients, and pharmaceutical preparations which contain these salts.
• the sodium salt of diclofenac is difficult to process in topically applicable forms of administration.
• the salt of the formula I in which R 1 is the 2,3,4,5,6-pentahydroxy-n-hexyl radical, R 2 is methyl and R 3 is hydrogen, is primarily the salt of diclofenac with 1 -Deoxy1- (methylamino) -D-glucite (N-methyl-D-glucamine or meglumine), further.
• the salt of the formula I in which R 1 and R 2 are ethyl and R 3 are hydrogen, excellent anti-inflammatory and analgesic properties and, compared to the sodium salt of diclofenac, better gastrointestinal tolerance and, in addition, significantly better solubility, for example three times the water solubility on.
• the anti-inflammatory efficacy can be demonstrated, for example, by the significant reduction in swelling in the test model of the Carrageneen paw edema of the rat in the dose range from about 1 to about 10 mg / kg p.o., and the analgesic effect e.g. using the phenyl-p-benzoquinone writhing test (J. Pharmacol. Exptl. Therap., Vol. 125, p. 237 (1959)) in the dose range from about 2 to about 20 mg / kg p.o. to prove.
• the ulcer index test in the following experimental set-up: rats (per dose, 5 males and females, 220-280 g) are given orally 21 and 6 hours before the autopsy, the test preparation is administered orally using a gastric tube. The gastric mucosa is examined for ulcers and evaluated in terms of number and severity in an index system from 0-14; incidence (percentage of infected animals) is also determined. The dose of the test preparation which produces an ulcer index of 3 is determined, if necessary with the aid of interpolation methods, as a measure of the presence of gastrointestinal ulceration.
• the salts of the formula I, and in particular the preferred salt of diclofenac with 1-deoxy-1- (methylamino) -D-glucite, and the corresponding diethylammonium salt, are therefore antioxidants and analgesics, in particular for oral or parenteral use, and also for topical use Application, usable.
• the invention also relates to processes for the preparation of the new salts of the formula I, which are carried out by methods known per se. So you can 2- (2,6-dichloro-anilino) - ⁇ henylacetic acid or a salt other than a salt of the formula I with a base with the amine of the formula R 1 -N (R 2 ) -R 3 (II) or a Convert the acid addition salt from it.
• Salts with bases of diclofenac that can be used as starting materials are e.g. Metal, e.g. Alkali and alkaline earth metal, such as sodium, potassium or calcium salts, preferably those whose base components form a salt which is sparingly soluble in the reaction medium with the acid component of an acid addition salt of the amine of the formula II.
• Metal e.g. Alkali and alkaline earth metal, such as sodium, potassium or calcium salts, preferably those whose base components form a salt which is sparingly soluble in the reaction medium with the acid component of an acid addition salt of the amine of the formula II.
• the reaction is advantageously carried out in the presence of an inert solvent or diluent, for example alcohols, such as lower alkanols, for example methanol or ethanol, ethers, such as di-lower alkyl ethers, for example diethyl ether, cyclic ethers, for example dioxane or tetrahydrofuran, ketones, such as di-lower alkyl ketones, for example acetone , Carboxylic acid esters, such as lower alkanecarboxylic acid, lower alkyl esters, for example ethyl acetate, amides, such as N, N-di-lower alkyl amides of lower alkane carboxylic acids, for example N, N-dimethylformamide, sulfoxides, such as di-lower alkyl sulfoxides, for example dimethyl sulfoxides, or water or mixtures thereof.
• an inert solvent or diluent for example alcohols
• the invention further relates to pharmaceutical preparations containing salts of the formula I and processes for their preparation. These are those for enteral, such as oral or rectal, and / or partial administration, and for topical use, which contain the active ingredient alone or together with a pharmaceutically usable carrier material.
• the new pharmaceutical preparations are, for example, those in unit dosage forms, such as oral preparations, for example dragées, tablets and capsules, rectal preparations, for example suppositories, or parenteral preparations usually in ampoule form.
• Oral preparations contain, for example, from about 10 to about 80, preferably from about 20 to about 50 percent by weight, non-aqueous injection solutions, for example from about 0.5 to about 10, preferably from about 0.5 to about 5 percent by volume, and aqueous injection solutions, for example from about 0.3, preferably from about 0.5 percent by volume, until the active ingredient is saturated.
• the oral pharmaceutical preparations can be used in a manner known per se, e.g. by means of conventional mixing, granulating and
• Suitable carriers are in particular fillers such as sugar, e.g. Lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, e.g. Tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch paste e.g. using corn, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants, such as the starches mentioned above, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or salts thereof such as sodium alginate. Aids are primarily flow regulators and lubricants, e.g. Silicic acid, talc, stearic acid, or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol.
• sugar e.g. Lactose, sucrose
• suppositories into consideration consist of a combination of the active ingredient with a suppository base.
• Suitable base materials are e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols, and mixtures thereof.
• gelatin rectal capsules can also be used, which contain a combination of the active ingredient with a base material; as basic materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbon in question.
• aqueous solutions are suitable, furthermore suspensions of the active ingredient, such as corresponding oily injection suspensions, suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous Injection suspensions, which can contain viscosity-increasing substances, for example sodium carboxymethyl cellulose, sorbitol and / or dextran and, if appropriate, also stabilizers.
• the topical pharmaceutical preparations that can be used are primarily creams, ointments, pastes, foams, tinctures and solutions which contain from about 0.5% to about 10%, such as from about 0.5 to about 5%, of the active ingredient.
• Creams are oil-in-water emulsions that contain more than 50% water.
• the main oils used are fatty alcohols, e.g. Lauryl, cetyl or stearyl alcohol, fatty acids e.g. Palmitic or stearic acid, liquid to solid waxes, e.g. Isopropyl myristate, wool wax or beeswax, and / or hydrocarbons, e.g. Vaseline (petrolatum) or paraffin oil.
• Suitable emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, e.g.
• Fatty acid esters of polyalcohols or ethylene oxide adducts thereof such as polyglycerol fatty acid esters, or polyoxyethylene sorbitan fatty acid esters (Tweens) or polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, e.g. Sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are commonly used in the presence of fatty alcohols, e.g. Cetyl alcohol or stearyl alcohol.
• Additions to the water phase include Agents that prevent the cream from drying out, e.g. Polyalcohols, such as glycerin, sorbitol, propylene glycol and / or polyethylene glycols, also preservatives, fragrances, etc.
• Ointments are water-in-oil emulsions that contain up to 70%, but preferably from about 20% to about 50%, water or aqueous phases.
• the fatty phase primarily includes hydrocarbons, for example petroleum jelly, paraffin oil and / or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohols, or wool wax in order to improve their water binding capacity.
• Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (spans), for example sorbitan oleate and / or sorbitan isostearate.
• Additives to the water phase include humectants, such as polyalcohols, e.g. glycerin, propylene glycol, sorbitol and / or polyethylene glycol, as well as preservatives, fragrances etc.
• Fatty ointments are anhydrous and contain hydrocarbons, e.g. Paraffin, petroleum jelly and / or liquid paraffins, also natural or partially synthetic fats, e.g. Coconut fatty acid triglyceride, or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate, as well as e.g. the fatty alcohols, emulsifiers and / or additives mentioned in connection with the ointments, which increase the water absorption capacity.
• hydrocarbons e.g. Paraffin, petroleum jelly and / or liquid paraffins
• natural or partially synthetic fats e.g.
• coconut fatty acid triglyceride or preferably hardened oils, e.g. hydrogenated peanut or castor oil, also fatty acid partial esters of glycerin, e.g. Glycerol mono- and distearate
• Pastes are creams and ointments with secretion absorbing powder components such as metal oxides, e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
• metal oxides e.g. Titanium oxide or zinc oxide, also talc and / or aluminum silicates, which have the task of binding moisture or secretions.
• Foams are administered from pressurized containers and are liquid oil-in-water emulsions in aerosol form, with halogenated hydrocarbons such as chlorofluoro-lower alkanes e.g. Dichlorodifluoromethane and dichlorotetrafluoroethane can be used as blowing agents.
• the oil phase used includes Hydrocarbons, e.g. Paraffin oil, fatty alcohol, e.g. Cetyl alcohol, fatty acid esters, e.g. Isopropyl myristate, and / or other waxes.
• the emulsifiers used include Mixtures of those with predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those with predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). In addition, there are the usual additives such as preservatives, etc.
• Tinctures and solutions usually have an aqueous-ethanol base, which, among other things, contains polyalcohols, eg glycerol, glycols, and / or polyethylene glycol, as humectants to reduce the Evaporation and refatting substances, such as fatty acid esters with low polyethylene glycols, ie lipophilic substances soluble in the aqueous mixture as a replacement for the fatty substances extracted from the skin with the ethanol, and, if necessary, other auxiliaries and additives can be added.
• polyalcohols eg glycerol, glycols, and / or polyethylene glycol
• humectants to reduce the Evaporation and refatting substances
• fatty acid esters with low polyethylene glycols such as fatty acid esters with low polyethylene glycols, ie lipophilic substances soluble in the aqueous mixture as a replacement for the fatty substances extracted from the skin with the ethanol, and, if necessary, other aux
• the topical pharmaceutical preparations are produced in a manner known per se, e.g. by dissolving or suspending the active ingredient in the base or in a part thereof, if necessary.
• the active ingredient is processed as a solution, it is usually dissolved by the emulsification in one of the two phases; when processed as a suspension, it is mixed with part of the base after emulsification and then added to the rest of the formulation.
• Example 1 A suspension of 6.64 g of 1-deoxy-1- (methylamino) -D-glucite in 100 ml of ethanol together with 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate at room temperature under nitrogen for 16 Hours stirred. After 2 hours, white, fine crystals fall out. The solvent is then removed under reduced pressure and the white, sticky residue is dissolved in a little hot water. Then the clear solution is slowly left at 0 °. cool and stand at this temperature for 16 hours. An oily, semi-crystalline mass precipitates, which is filtered off over a diatomaceous earth and material filter for 2 days.
• the filter residue is dried for one week at 60 ° / 100 mm Hg and then pulverized.
• the salt of 2- (2,6-dichloro-anilino) phenylacetic acid with 1-deoxy-1- (methylamino) -D-glucite melts at 127-130 °.
• Example 2 10.0 g of 2- (2,6-dichloro-anilino) phenylacetic acid are dissolved in 230 ml of ethyl acetate with stirring. Then 6.64 g of 1-deoxy-1- (methylamino) -D-glucite are added and stirring is continued for 16 hours.
• the precipitate is filtered off, washed with a little ethyl acetate and dried at 60 ° under reduced pressure.
• the crude product is treated with 600 ml of hot isopropanol and the insoluble matter is filtered off.
• the mixture is concentrated to about 500 ml at the boiling point, the mixture is brought to crystallization, the mixture being allowed to stir after 3 hours at room temperature with ice cooling. It is filtered off again, washed with cold isopropanol and dried at 60 ° under reduced pressure to constant weight.
• the salt of 2- (2,6-dichloro-anilino) -phenylacetic acid is thus obtained, with 1-doxy-1- (methylamino) -D-glucite, mp. 142.5145 °.
• Example 3 2 ml of diethylamine are added to a solution of 2 g of 2- (2,6-dichloro-anilino) phenylacetic acid in 40 ml of diethyl ether. The solution is heated under reflux for 10 minutes, cooled and concentrated under reduced pressure, during which the diethylammonium 2- (2,6-dichloro-anilino) phenyl acetate crystallizes out. The colorless crystals are filtered off and dried in a high vacuum at room temperature, mp. 110 ° -115 ° (with decomp.).
• Example 4 To a solution of 10 g of 2- (2,6-dichloro-anilino) phenylacetic acid in 230 ml of ethyl acetate, 4.53 g of tri- (hydroxymethyl) methylamine is dissolved at room temperature and with vigorous stirring within 10 minutes in 10 ml of water, added dropwise. A salt precipitates immediately; the mixture is then stirred for a further half an hour at room temperature and the solvent is removed under reduced pressure. The white, crystalline residue is dissolved in 1000 ml of a 1: 1 mixture of acetone and water at about 50 °. The warm solution is concentrated under reduced pressure until the first crystals precipitate; then allowed to crystallize at 0 °.
• the precipitated white, flaky crystals are filtered off and dried under high vacuum.
• the tri (hydroxymethyl) methylammonium 2- (2,6-dichloro-anilino) phenyl acetate thus obtained melts at 202 ° -204 °.
• Example 5 To a solution of 10 g of 2- (2,6-dichloro-anilino) -phenylacetic acid in 230 ml of ethyl acetate, 5.52 g of tri- (2-hydroxyethyl) amine, dissolved in, at room temperature and with vigorous stirring within 10 minutes 30 ml of ethyl acetate, added dropwise; a salt precipitates immediately. The mixture is then stirred at room temperature for about half an hour and the solvent is removed under reduced pressure. The white, crystalline residue is dissolved in a little hot ethanol and crystallized at 0 °. The white crystals are filtered off and dried under high vacuum. The tri- (2-hydroxyethyl) ammonium 2- (2,6-dichloro-anilino) phenylacetate melts at 137 ° -138 °.
• Example 6 To a solution of 10 g of 2- (2,6-dichloro-anilino) phenylacetic acid in 230 ml of ethyl acetate, 3.89 g of di- (2-hydroxyethyl) amine are suspended in at room temperature and with vigorous stirring within 10 minutes 30 ml of ethyl acetate, added dropwise; the salt formed thereby precipitates out immediately. The mixture is subsequently stirred at room temperature for half an hour and the solvent is removed under reduced pressure. The yellowish, crystalline residue is dissolved in a little boiling ethanol.
• Example 7 3.22 g of morpholine in 30 ml of ethyl acetate are added dropwise to a solution of 10 g of 2- (2,6-dichloroanilino) phenylacetic acid in 230 ml of ethyl acetate at room temperature and with vigorous stirring within 10 minutes. A salt precipitates out about 10 minutes after the addition of the morpholine. Then 1 hour at room temperature stirred and the solvent removed under reduced pressure. The white, crystalline residue is then dissolved in boiling ethanol. At 0 ° the morpholinium-2- (2,6-dichloro-anilino) phenylacetate crystallizes, which melts at 162-165 °.
• the white crystalline precipitate is dissolved in a small amount of hot ethanol and the solution is left to stand at 0 °, the di- (2-hydroxypropyl) ammonium 2- (2,6-dichloroanilino) phenyl acetate crystallizing out, 165- 170 °.
• Example 9 tablets containing 75 mg of the salt of 2- (2,6-dichloro-anilino) phenylacetic acid with 1-deoxy-1- (methylamino) -D-glucite can be prepared as follows:
• Composition for 10,000 tablets: Salt of 2- (2,6-dichloro-anilino) -phenylacetic acid with
• Colloidal silicon dioxide (Aerosil ® 200) 30.0 g
• Microcrystalline cellulose (Avicel ® PH 102) 400.0 g
• Example 10 Capsules containing 25 mg of the salt of 2- (2,6-dichloroanilino) phenylacetic acid and 1-deoxy-1- (methylamino) glucite can be prepared, for example, as follows:
• Composition for 10,000 capsules:
• the ingredients are mixed in a suitable mixer, passed through a sieve (No. 40), mixed again, and 75 mg each of the mixture are filled into gelatin capsules of suitable capacity.
• Example 11 Injection solutions containing 2% by weight of the salt of 2- (2,6-dichloro-anilino) phenylacetic acid and 1-deoxy-1- (methylamino) glucite can be prepared, for example, by one of the following two methods:
• the mannitol and the active ingredient are dissolved in about 90% of the prescribed amount of water while stirring and gassing with nitrogen. After complete dissolution, the solution is made up to the final volume with water.
• the injection solution is sterile filtered through a membrane filter (pore size: ⁇ 0.22 ⁇ m) and filled into sterilized glass ampoules under nitrogen gas and these are sealed under nitrogen gas. The sealed ampoules are heated in an autoclave at 120 ° for 20 minutes.
• the mannitol, the benzyl alcohol and the 1,2-propylene glycol are dissolved in about 70% of the prescribed amount of water with stirring and gassing with nitrogen.
• the active ingredient is added to the solution and the mixture is stirred until completely dissolved and then diluted to the final volume with water.
• the injection solution is sterile filtered through a membrane filter (pore size: ⁇ 0.22 ⁇ m) and filled into sterilized glass ampoules under nitrogen gas, and these are sealed under nitrogen gas. The sealed ampoules are heated in an autoclave at 120 ° for 20 minutes.
• Example 12 A cream containing 5% diethylammonium 2- (2,6-dichloroanilino) phenylacetate can be prepared as follows:
• the active ingredient is dissolved in propylene glycol and water.
• the self-emulsifying glycerol monostearate is melted together with the oleic acid decyl ester. Then the water phase turns into fat phase given and emulsified; if desired, fragrances (0.1%) are added.
• Example 13 An ointment containing 5% diethylammonium 2- (2,6-dichloro-anilino) phenylacetate can be prepared as follows:
• the active ingredient is dissolved in propylene glycol and water.
• the fat components petroleum jelly, wax and sorbitan fatty acid ester are melted together.
• the active ingredient solution is then emulsified into the fat phase and, if desired, fragrances (0.1%) are added.
• Example 14 A transparent hydrogel containing 5% diethylammonium 2- (2,6-dichloro-anilino) phenylacetate can be prepared as follows:
• the acrylic acid polymer and water are dispersed and neutralized with the tri- (2-hydroxyethyl) amine.
• the active ingredient is dissolved in a mixture of isopropanol and propylene glycol.
• the active ingredient solution is then mixed with the gel, it being possible, if desired, to add a fragrance (0.1%).
• Example 15 A cream containing 5% of the salt of 2- (2,6-dichloro-anilino) -phenylacetic acid with 1-deoxy-1- (methyl-anino) -D-glucite can be prepared as follows:
• the cream is produced by the method described in Example 12.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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