CH535232A - Phenylacetic acid esters - analgesic, antiphlogistic, anti-pyretic - Google Patents

Abstract

(A) Substituted phenylacetic acids and -esters (I): R1 = H, alkyl, alkenyl or alkinyl; R2 = H, alkyl, alkoxy or halogen; R3, R4 and R5 are H or alkyl. (B) Salts of (I) with inorganic and organic bases. Compounds (I) have analgesic-, antiphlogistic- and antipyretic activity with very favourable therapeutic index. They may be used to alleviate or remove pain as well as in the treatment of rheumatic- and other inflammatory processes. 0.20 mol of (p-aminophenyl) acetic acid (Radiszewski, Ber. 2, 209; Bedson, J.Chem. Soc 37, 92) and 0.20 mol of 2.5- dimethoxytetrahydrofuran are refluxed in 40 ml glacial acetic acid for 30 minutes. After cooling the mixture is poured into 160 ml. water, the crystals filtered off, washed with water and dried for 15 hours at 70 deg.C. The brown powder obtained is extracted with benzene. Evaporation of the extract gives the (p-(1-pyrryl) phenyl) acetic acid.

Description

  

  
 



   The present invention relates to a process for the preparation of new, substituted phenylacetic acids and their esters, as well as their salts, with valuable pharmacological properties.



   Substituted phenylacetic acids and their esters according to formula I,
EMI1.1
 in which R2 is hydrogen, a lower alkyl or alkoxy group or a halogen atom and R3, R4 and Rs independently of one another are hydrogen or lower alkyl groups, and salts of the carboxylic acids falling under the formula I with inorganic and organic bases have not yet been described.



   As has now been found, these new substances have valuable pharmacological properties, in particular analgesic, antipyretic and anti-inflammatory effectiveness with a very favorable therapeutic index. These properties characterize them as active ingredients for the relief and elimination of pain of various origins and for the treatment of rheumatic and other inflammatory disease processes. Administration can take place orally, rectally or parenterally.



   In the compounds of the formula I and the associated starting materials mentioned below, R2 as a lower alkyl group is e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl group and, as halogen atom, e.g. Chlorine, bromine or fluorine. Lower alkyl groups R3 and R4 are e.g. Methyl, ethyl, n-propyl or isopropyl groups. A lower alkyl group Rs is e.g. the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl or n-hexyl group.



   To prepare the compounds of the formula I and the salts of the carboxylic acids falling under this formula with inorganic and organic bases, a compound of the formula II is used
EMI1.2
 in which R2, R3 and R4 have the meaning given under formula I, in the presence of a silver salt, silver oxide, copper or platinum as a catalyst with water or a lower alkanol, and if desired converts a carboxylic acid obtained into a salt with an inorganic or organic one Base over. For example, a solution of the diazoketone of the formula II is slowly added to an aqueous solution of silver nitrate and sodium thiosulfate or to a suspension of silver oxide in an aqueous solution of sodium thiosulfate, the temperature of the aqueous solution or

  Suspension amounts to approx. 60-700. According to an advantageous modification of the method, freshly prepared silver oxide is added in portions to a solution of the diazoketone in a lower alkanol at its boiling point until no more nitrogen evolution can be detected.



  Starting materials of the formula II can be prepared in a manner known per se by reacting p (I-pyrryl) benzoyl chloride substituted according to the definition for R2, R3 and R4 with diazomethane. The acid chlorides required are in turn obtained by condensation of p-aminobenzoic acid, which may be substituted according to the definition for R2, with a compound of the formula III
EMI2.1
 in which at most two R in each unit are lower alkyl groups and the remaining hydrogen atoms, X and X independently of one another radicals of the formulas R6-O and R6-CO-O-, in which R6 stands for an optionally halogen-substituted hydrocarbon radical, also chlorine or bromine atoms, or X together with Y also represents the oxo radical = 0, Y and Y independently of one another radicals of the formulas R6-O- or R6-CO-O- or both together represent the epoxy radical -0-, or each together with Z or

  Z each represent an additional bond according to the dotted lines, and Z and Z denote hydrogen atoms, provided they do not have the aforementioned meaning, and n denotes zero or a lower whole number, and subsequent treatment of the optionally substituted p- (1-pyrryl) obtained -benzoic acid with thionyl chloride in the presence of an acid-binding agent, such as Pyridine, or available with oxalyl chloride.



   Salts of carboxylic acids falling under the formula I which can be prepared if desired are e.g. the sodium, potassium, lithium, magnesium, calcium and ammonium salts, as well as salts with ethylamine, triethylamine, 2-amino-ethanol, 2,2'-imino-diethanol, 2-dimethylamino-ethanol, 2-diethylamino-ethanol Ethylenediamine, benzylamine, procaine, pyrrolidine, piperidine, morpholine, 1-ethyl-piperidine or 2-piperidino ethanol or with basic ion exchangers.



   The new compounds of the formula I and the salts of the free acids falling under this formula are, as mentioned above, administered orally, rectally or parenterally. The daily doses range between 50 and 3000 mg for adult patients. Suitable dosage unit forms, such as dragees, tablets, suppositories or ampoules, preferably contain 10-500 mg of a compound of the formula I or a salt of a free acid falling under this formula with a pharmaceutically acceptable inorganic or organic base as active ingredient.



   In unit dose forms for oral use, the content of active ingredient is preferably between 10% and 90%.



  To produce such unit dosage forms, the active ingredient is combined e.g. 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, to tablets or to dragee cores. The latter is coated, for example, with concentrated sugar solutions, which e.g.



  Arab 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.



  for labeling different doses of active ingredients. 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 (Na2S2Os) 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.



   Unit forms for rectal use are e.g. Consider suppositories, which consist of a combination of an active ingredient with a suppository base based on natural or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatin rectal capsules which contain a combination of the active ingredient with polyethylene glycols.



   Ampoule solutions for parenteral, in particular intramuscular or intravenous administration contain e.g. a compound of the formula I in a concentration of preferably 0.5-5% as an aqueous dispersion prepared with the aid of customary solubilizers and / or emulsifiers and optionally stabilizers, or an aqueous solution of a pharmaceutically acceptable, water-soluble salt of one of the formula I falling free acid.



   Other parenteral forms of administration that can be used are, for example, lotions, tinctures and ointments for percutaneous use prepared with the usual auxiliaries.



   The following instructions are intended to explain the production of tablets, coated tablets, etc. in more detail: a) 1000 g of active ingredient, e.g. [p- (1 -Pyrryl) -phenyl] -acetic acid are mixed with 550 g of lactose and 292 g of potato starch, the mixture with an alcoholic solution of 8 g
Gelatin moistened and granulated through a sieve. After drying, 60 g of potato starch, 60 g of talc, 10 g of magnesium stearate and 20 g of highly dispersed silicon dioxide are mixed in and the mixture is compressed to form 10,000 tablets of 200 mg each
Weight and 100 mg active ingredient content, which, if desired, can be provided with partial notches for finer adjustment of the dosage.

 

   b) 200 g of active ingredient, e.g. [p- (1-Pyrryl) -phenyl} -acetic acid are mixed well with 16 g of corn starch and 6 g of highly dispersed silicon dioxide. The mixture is made with a solution of
2 g stearic acid, 6 g ethyl cellulose and 6 g stearin in approx.



   70 ml of isopropyl alcohol moistened and filtered through a sieve III (Ph.



   Helv. V) granulated. The granulate is dried for about 14 hours and then passed through Sieve III-IIIa. It is then mixed with 16 g of corn starch, 16 g of talc and 2 g of magnesium stearate and pressed into 1000 coated tablets. These are coated with a concentrated syrup of 2 g Lacca, 7.5 g gum arabic, 0.15 g color, 2 g highly dispersed silicon dioxide, 25 g talc and 53.35 g sugar and dried. The dragees obtained weigh 360 mg and each contain 200 mg of active ingredient.



   c) 50.0 g of [p- (1-pyrryl) phenyl] acetic acid are dissolved in a mixture of 232 ml of 1N sodium hydroxide solution and 500 ml of boiled, pyrogen-free water and the solution is made up to 2000 ml with the same water. The solution is filtered, filled into 1000 ampoules of 2 ml each and sterilized. A 2 ml ampoule contains 50 mg 2- [p- (1-pyrryl) -phenylj-acetic acid as the active ingredient in the form of the sodium salt.



   d) 50 g of [p- (1-pyrryl) -phenyl] -acetic acid and 1950 g of finely grated suppository base (e.g. cocoa butter) are mixed thoroughly and then melted. 1000 suppositories of 2.0 g are poured from the melt, which is kept homogeneous by stirring. They each contain 50 mg of active ingredient.



   e) 60.0 g of polyoxyethylene sorbitan monostearate, 30.0 g of sorbitan monostearate, 150.0 g of paraffin oil and 120.0 g of stearyl alcohol are melted together, 50.0 g of [p- (1-pyrryl) phenyl] acetic acid (finely powdered) are added and 590 ml of water preheated to 40D are emulsified. The emulsion is stirred until it cools to room temperature and filled into tubes.



   The following examples explain the preparation of the new compounds of the formula I in more detail. The temperatures are given in degrees Celsius.



   example 1
7.4 g of p- (1-pyrryl) -benzoic acid are refluxed with 3.3 ml of thionyl chloride and 4.8 g of pyridine in 100 ml of methylene chloride for 3 hours in a nitrogen atmosphere. The reaction mixture is then evaporated in vacuo and 100 ml of tetrahydrofuran are added to the residue, some of which remains undissolved. The resulting suspension of crude acid chloride is added dropwise to a mixture of 200 ml of 0.6N ethereal diazomethane solution and 50 ml of dioxane, while cooling with ice, and the whole is then stirred for 18 hours at room temperature. The result is a solution that is freed from a slight cloudiness by filtration through Hyflo (diatomaceous earth) and evaporated at 30 ° under reduced pressure.



   The remaining, crude 4- (1-pyrryl) -2-diazoacetophenon is abs in 180 ml. Dissolved methanol, the solution heated to boiling under reflux and added in portions with silver oxide (made from 2 g of silver nitrate and washed with methanol) until no more gas evolution can be detected, which takes about 4 hours. The silver precipitate is filtered off and the filtrate is evaporated in vacuo. The partially crystalline crude [p- (1-pyrryl) -phenyl] -acetic acid methyl ester remains.



   The p- (1-pyrryl) -benzoic acid used as starting material is obtained as follows: a) The p- (1-pyrryl) -benzoic acid ethyl ester is prepared from 2,5 dimethoxytetrahydrofuran and 4-amino-benzoic acid ethyl ester, melting point 75- 760 (from methanol), b.p. 140-145o1 0.01 torr.



   b) A solution of 32 g of p- (1-pyrryl) -benzoic acid ethyl ester and 12 g of sodium hydroxide in 600 ml of ethanol is heated to boiling under reflux for 2 hours, a crystalline precipitate gradually forming. The reaction mixture is then concentrated to approx. 200 ml under reduced pressure and the precipitated sodium salt is dissolved by adding 200 ml of water. While stirring, this solution is slowly brought to pH 5 with glacial acetic acid, the desired p- (1-pyrryl) -benzoic acid precipitating as a fine, thick paste. The precipitate is filtered off with suction, washed in portions with 100 ml of water and dried at 70 for 7 hours in a vacuum drying cabinet. The p- (1-pyrryl) benzoic acid obtained in this way melts at 265-270 ° with decomposition.

 

   Example 2
5.7 g of [p- (1-pyrryl) phenyl] acetic acid are suspended in 40 ml of isopropanol. A homogeneous solution is obtained by adding 8 ml of triethylamine. This is mixed with 20 ml of ether and filtered. After adding so much petroleum ether (bp 40-600) that the resulting cloudiness still dissolves, the salt gradually crystallizes on cooling. After drying at 200 torr for 12 hours, the triethylammonium salt of [p- (1-pyrryl) -phenylj-acetic acid melts at 67-73.

 

Claims (1)

PATENT CLAIM Process for the preparation of substituted phenylacetic acids and their esters according to the formula I. EMI3.1 in which R2 is hydrogen, a lower alkyl or alkoxy group or a halogen atom and R3, R4 and Rs are independently hydrogen or lower alkyl groups, and salts of the carboxylic acids falling under the formula I with inorganic and organic bases, characterized in that one Compound of formula II EMI4.1 in which R2, R3 and R4 have the meaning given above, reacts in the presence of a silver salt, of silver oxide, copper or platinum as a catalyst with water or a lower alkanol, and, if desired, converts a carboxylic acid obtained into a salt with an inorganic or organic base.