CH475199A - Process for the production of new substituted phenylacetic acids - Google Patents

Description

  

  



  Process for the production of new substituted phenylacetic acids
The present invention relates to a process for the preparation of new substituted phenylacetic acids and their salts.



   Substituted phenylacetic acids of the general form flour,
EMI1.1
 in which
Rt is a lower alkyl or alkoxy group, a halogen atom up to atomic number 35 or the trifluoromethyl group,
R2 is hydrogen or a substituent as defined for Rt, R3 is hydrogen, a lower alkyl or alkoxy group or a halogen atom up to atom number 35,
R4 is hydrogen, a lower alkyl or alkoxy group, a halogen atom up to atom number 35 or the trifluoromethyl group,
Rs represent a lower alkyl group and Ro and R7 represent hydrogen, lower alkyl groups or benzyl groups, and their salts with inorganic and organic bases have not yet become known.

   As has now been found, the compounds of general formula I and their salts have valuable pharmacological properties, in particular anti-inflammatory (anti-inflammatory), analgesic and antipyretic activity with a favorable therapeutic index. They can be used orally, rectally or, especially in the form of aqueous solutions of their salts, also parenterally, especially intramuscularly, for the treatment of rheumatic, arthritic and other inflammatory diseases. The anti-inflammatory effectiveness can be demonstrated in animal experiments, for example, on UV erythema in guinea pigs and on bolus alba edema in rats.



   In addition, these substances have the ability to absorb UV rays at 290-300 m, and are therefore used as UV absorbers for cosmetic purposes, eg. B. suitable in sun protection creams because they absorb the harmful, reddening rays, while they let through the desired tan over 315 m, 4.



   In the compounds of general formula I and the corresponding starting materials mentioned below, Rt to R4 are independently of one another as lower alkyl groups, for example methyl or ethyl groups. Some of the symbols mentioned can e.g. B. also n-propyl, isopropyl, n-butyl, sec. Butyl or tert. Mean butyl groups. Lower alkoxy groups or halogen atoms Rt to R4 are, for. B. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or isobutoxy groups or chlorine, fluorine or bromine atoms.



     Rt is e.g. B. the methyl, ithyl, n-propyl, n-butyl or isobutyl group. As lower alkyl groups, Rt and R7 are primarily methyl or ethyl groups, especially in addition to a hydrogen atom as R7, n-propyl, isopropyl, n-butyl, isobutyl, tert. Butyl, n-pentyl or isopentyl groups into consideration.



   To prepare an acid of the general formula I and its salts with inorganic and organic bases, a compound of the general formula II is hydrogenolyzed with elimination of the benzyl radical.
EMI2.1
 in which Rl-R7 have the meaning given under formula I, with catalytically activated hydrogen and, if desired, converts a compound of the general formula I obtained into a salt with an inorganic or organic base.



   The esters of general formula II are obtained, for example, from the nitriles by reaction with solutions of hydrogen chloride and the benzyl alcohol desired as the ester component in ether and subsequent decomposition of the imidoester hydrochloride initially formed by means of water, or also directly by heating the nitriles in benzyl alcohol-containing hydrogen chloride solutions with a suitable water content receive.



   The new substituted phenylacetic acids of the general formula I and their salts with inorganic and organic bases can be administered orally, rectally or parenterally, in particular intramuscularly.



  They can also be used externally, incorporated into ointment or sun oil bases.



   Suitable salts for therapeutic use are those with pharmacologically acceptable inorganic and organic bases; H. with bases which, in the dosages in question, show no physiological intrinsic effect or have a desired effect, e.g. B. in parenteral forms of administration in particular a local anesthetic effect. Suitable salts are e.g. B. sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts with ethylamine, triethylamine, ethanolamine, diethanolamine, diethylaminoethanol, ethylenediamine, benzylamine, procaine, pyrrolidine, piperidine, morpholine, l- Ethylpiperidine or 2-piperidinoethanol.



   The daily internal doses of free acids of the general formula I or of pharmacologically acceptable salts thereof for the treatment of rheumatic, arthritic and other inflammatory diseases range between 10 and 1000 mg for adult patients. Suitable dosage unit forms, such as dragees, tablets, capsules, suppositories or ampoules, preferably contain 5300 mg of a free acid or a pharmacologically acceptable salt thereof.



   Unit dosage forms for oral use contain as active ingredient preferably between 1 / o and 90 / o of an acid of the general formula 1 or a pharmacologically acceptable salt thereof. To produce them, the active ingredients are combined e.g.

   B. with solid, powdery carriers such as lactose, sucrose, sorbitol, mannitol; Starches, such as potato starch, corn starch or amylopectin, also laminaria powder or citrus pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights, to tablets or to dragee-ilerns. The latter is coated, for example, with concentrated sugar solutions, which z. B. can contain arabic gum, talc and / or titanium dioxide, or with a paint dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, e.g. B. to identify different drug doses.

   Push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer, such as glycerine, are suitable as further oral unit forms. The former contain the active ingredient preferably as granules mixed with lubricants such as talc or magnesium stearate, and optionally stabilizers such as sodium metabisulphite (Na2S203) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, it also being possible for stabilizers to be added.



   As unit dosage forms for rectal use, for. B. suppositories into consideration, which are composed of a combination of an acid of the general formula I or a suitable salt thereof with a suppository base based on natural or synthetic triglycerides, e.g. B. cocoa butter, of polyethylene glycols of suitable molecular weight or of suitable higher fatty alcohols, as well as gelatin rectal capsules, which contain a combination of an active ingredient or a suitable salt thereof with polyethylene glycols of suitable molecular weight.



   Ampoules for parenteral, especially intramuscular administration preferably contain a water-soluble salt, e.g. the sodium salt, a substituted phenylacetic acid of the general formula I, in a concentration of preferably 0.550 / o, optionally together with suitable stabilizers and buffer substances in aqueous solution.



   The following example explains the implementation of the method according to the invention in more detail, but is not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius.



   example
1.3 g of [o- (N-methyl-a, a, a-trifluoro-m-toluidino) -phenyl] -acetic acid benzyl ester (oil) are dissolved in 50 ml of abs.



  Dissolved methanol and, after adding 0.2 g of 100% Pd-carbon, hydrogenated at low pressure and room temperature. The hydrogenation has ended after 3 hours. The catalyst is filtered off and the filtrate is concentrated to dryness under 11 torr at 400. The residue is dissolved in 40 ml of ether. The ether solution is mixed with 10 ml of 2-n. Sodium carbonate solution extracted. The sodium carbonate solution is separated off and acidified by adding 2-n. Hydrochloric acid. The excreted oil is extracted with ether. The ether solution is washed with a little water, dried over sodium sulfate and concentrated under 11 torr at 400. The residue is crystallized from petroleum ether.

   The [o- (N-methyl-a, a, a-trifluoro-m-toluidino) -phenyl] -acetic acid melts at 92 to 94.



   The [o- (N-methyl u, a, a-tnfluoro-m-taluidino) -phenyl] -acetic acid benzyl ester used as starting material is prepared as follows:
In a solution of 3 g of [o- (N-methyl-a, a, a-trifluoro- m-toluidino) phenyl] acetonitrile in 2 ml of benzyl alcohol abs. and 50 ml ether abs. hydrochloric acid gas is passed in at 0 "-5" C for 3 hours. The experiment is then left to stand at room temperature overnight. The solution is then evaporated to dryness under 11 torr at 40.degree. The residue, a yellow oil, is distributed between 140 ml of water and 150 ml of ether and the whole is heated under reflux on the steam bath for 6 hours.

   It is then cooled, the ether phase is separated off and the aqueous solution is extracted again with 200 ml of ether. The combined ether solutions are dried over sodium sulfate and evaporated under a water jet vacuum at 400 ° C. The residue is treated with a little ether and the crystals which have precipitated out (1.4 g discarded) are filtered off with suction.



  The mother liquor is evaporated to dryness under 11 torr at 400.degree. The residue, 1.3 g of yellow oil, is chromatographed on 30 g of neutral aluminum oxide (action level I) with the eluent ether.



  The pure [o- (N-methyl-a, a, a-trifluoro-m-toluidino) -phenyl] -acetic acid benzyl ester is obtained in fractions 4 to 18 as a yellow oil, which under high vacuum at 145 C / 0.005 Torr is distilled.

 

Claims (1)

PATENT CLAIM Process for the preparation of new substituted phenylacetic acids of the general formula I, EMI3.1 in which R1 is a lower alkyl or alkoxy group, a halogen atom up to atomic number 35 or the trifluoromethyl group, Rs is hydrogen or a substituent as defined for Rt, Rs hydrogen, a lower alkyl or alkoxy group or a halogen atom up to atom number 35, R4 is hydrogen, a lower alkyl or alkoxy group, a halogen atom up to atom number 35 or the trifluoromethyl group, Rs is a lower alkyl group and Ro and R7 denote hydrogen, lower alkyl groups or benzyl groups, and their salts with inorganic and organic bases, characterized in that a benzyl ester of the general formula II, in which RtR, have the meaning given under formula I, catalytically hydrogenolyzed with cleavage of the benzyl radical and, if desired, a compound of the general formula I obtained is converted into a salt with an inorganic or organic base.