DE2431360A1 - O-Substd thymotic acid cpds - prepd by reacting thymotic acid with opt substd alkyl halide and hydrolysing resulting ester - Google Patents

Abstract

O-Substd. thymotic acid derivs. of formula (I): (where R is an opt. unsatd. 2-4C hydrocarbon gp. or is a gp. of formula -(CH2)n-NR2R3 in which n is 1, 2, 3 or 4 and R2 and R3 are alkyl), e.g. 2-allyloxy-3-isopropyl-6-methylbenzoic acid, salts resulting from neutralisation of the COOH gp. of (I), and acid addition salts and quat. ammonium salts of (I; R = -(CH2)n-NR2R3) are new cpds. (I) are analgesics and antitussives with low toxicity.

Description

o-Thymotinic acid derivatives, processes for their preparation and containing them Medicinal preparations The invention relates to new ether derivatives of o-thymotinic acid, a process for their production and their use in particular in pharmaceuticals for xuman and veterinary medicine.

The new compounds according to the invention have the general formula in which R is a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms or a group of the formula in which n stands for a number from 1 to 4 and R2 and R3 are identical or different lower alkyl radicals. The invention further encompasses the salts of these compounds formed by neutralization of the carboxyl group, their salts with acids when R is a basic nitrogen-containing group, and their quaternary ammonium salts when R is a nitrogen-containing group.

Examples of acid addition salts are the salts with mineral acids (added. hydrochloric acid, sulfuric acid and phosphoric acid) and organic acids (to 3. tartaric acid, Citric acid and oxalic acid).

The invention is also directed to the creation of these derivatives according to an experienced person, which is characterized in that o-2hymotinic acid is added in the presence of sodium hydride with an alkyl halide of the formula RZ, in which R has the meaning given above and Z is a halogen atom a derivative of the formula which releases the acid function by hydrolysis and leads to the desired derivative of the formula (I), which is optionally converted into the salt. The hydrolysis of the compound (II) is advantageously carried out in an alkaline medium.

The derivatives of the general formula (II) are new compounds that fall within the scope of the invention.

The production of the connections according to the invention is carried out by the the following examples are explained.

Example 1 Preparation of 2-allyloxy-3-isopropyl-6-methylbenzoic acid (Derivative 1) a) Preparation of 2-allyloxy-3-isopropyl-6-methylallylbenzoate In a 250 ml three-necked flask with magnetic stirrer, Thermometer, feed funnel and condenser with attached calcium chloride tube, 2.7 g (0.0565 Mol) sodium hydride (50% suspension) and 50 ml of dimethylformamide added, whereupon Dropwise a solution of 5 g of o-thymotinic acid (0.0257 Mol) in 20 ml of dimethylformamide is added. Slight heating occurs (4OOC).

At the same time a pale gray gel is formed. Then there will be Stirred for 20 minutes, after which a solution of 4.5 g of allyl bromide was added dropwise with stirring (0.0578 mol) in 20 ml of dimethylformamide is added. After the addition is complete stirred for 30 minutes at room temperature, whereupon the dimethylformamide under reduced The pressure is evaporated. The residue is taken up in 200 ml of benzene. This solution is poured into 50 ml of IN NaOH and 100 ml of ice water. The aqueous phase is decanted and extracted with benzene. The benzene extracts are washed over with water dried anhydrous sodium sulfate and evaporated under reduced pressure. This gives 6.8 g of the derivative of the formula (II), which without purification for the next stage is used.

b) Production of 2-allyloxy-3-isopropyl-6-methylbenzoic acid in one equipped with a magnetic stirrer and condenser, 3.2 g (0.0117 mol) of des according to section (a) prepared ester, 35 ml ethanol and 3.5 ml KOH (density 1.38) given. The mixture is refluxed with stirring for 64 hours. To After cooling, the ethanol is evaporated off under reduced pressure and the residue taken up in 50 ml of water.

The aqueous phase is washed three times with methylene chloride and then acidified with 2N hydrochloric acid. The oil formed is extracted with ether. the The ether phase is washed with a saturated sodium chloride solution, over anhydrous Dried sodium sulfate and then evaporated under reduced pressure. After recrystallization from hexane, 0.65 g (yield 23.5) of 2-allyloxy-3-isopropyl-6-methylbenzoic acid are obtained obtained in the form of colorless crystals.

Example 2 Preparation of 2- (ß-Dimethylaminoethoy) -3-isopropyl-6-methyl-benzoic acid (Derivative WrO2) a) Production of 2- (ß-dimethylaminoethoxy) -3-isopro-1-6-methyl-ß-dimethylaminoethyl benzoate In a 500 ml three-necked flask fitted with a magnetic stirrer, thermometer, dropping funnel and condenser with attached calcium chloride tube, 10.8 g (0.224 Mol) of sodium hydride (50% suspension) and 100 ml of dimethylformamide were added. then a solution of 20 g (0.102 mol) of tbymotinic acid in 60 ml of dimethylformamide were added. The grayish suspension obtained is heated to i200C heated, whereupon 67.1 ml (0.235 mol) of a solution of 3n-2-chloro-1-dimethylaminoethane in toluene can be added. The temperature is held at 130 ° C. for 4 hours, whereupon the dimethylformamide is evaporated under reduced pressure. The residue will dissolved in 200 ml of ether and the resulting solution in 140 ml of 1N NaOH and 250 ml of ice water is poured. The aqueous phase is decanted and extracted with ether. the Ether extracts are washed with water and dried over anhydrous sodium sulfate and evaporated under reduced pressure. This gives 33.1 g of a brown oil obtained, which is used without purification in the following step.

The dioxalate of this derivative has after recrystallization from ethanol a melting temperature of 160-161 ° C.

b) Preparation of 2- (ß-dimethylaminoethoxy) -3-isopropyl-6-methylbenzoic acid. 17 g (0.05 mol) of the ester obtained in section (a) and 170 ml of ethanol are added to a 500 ml flask equipped with a manual stirrer and condenser and 17 ml of KOH (density 1.38) are added. The mixture is heated under a reflux condenser with stirring for 60 hours, the ethanol is evaporated off under reduced pressure and the residue is dissolved in 100 ml of water. The aqueous phase is washed three times with ether, neutralized with 6N hydrochloric acid and then extracted with methylene chloride. This gives 15.4 g of an oil which is immediately converted into the hydrochloride. In this way, after recrystallization from a mixture of ethanol and ethyl acetate, 7.3 g of 2- (β-dimethylaminoethoxy) -3-isopropy1-6-methylbenzoic acid are obtained. In the manner described above, further derivatives of the formula (1) are prepared in the The following table gives the key figures for some of these derivatives as an example. Derivative R melting release solvent Nr5 temp00C booty for crystal % lization 3 -CH2-CH2-CH3 86-87 53 heptane 4 -CH2-CH2-CH2-CH3 94-95 48 @ 1H ~~~ 50-5- ~ 2'- He ptan 5 .6. -CX2-CHs ... . 7-118 54 Xexan CH3 7 -CS2-CH2-No 2 5XCl 188wo90 60 Xthyl acetate- O2H5 ethanol OH 8 OH2-OH2-OH2-N \ HOl 152-154 14 Ethyl acetate CH3 Xthanol The results of the toxicological and pharmacological studies show the low toxicity and the antitussive and analgesic properties of the derivatives according to the invention.

Accordingly, the invention also encompasses pharmaceutical preparations in particular cough suppressant and analgesic effect, which is a derivative as an active ingredient of the formula (I) or a pharmaceutically acceptable salt of this derivative.

I) Toxicological investigation This investigation provided the evidence the low toxicity and the good tolerance of the derivatives according to the invention. For example, the LD50 / 24 hours determined on the mouse is for intravenous VeraD sequencing (per kg body weight) 240 mg for derivative number 1, 860 mg for derivative number 2, 160 mg for derivative # 3, 185 mg for derivative # 4, 170 meg for derivative # 5, 215 mg for the derivative # 6, 560 mg for the derivative # 7 and 490 m for the Derivative # 8.

II) Pharmacological investigations 1) Cough suppressant effect These Effect was determined by the -Salle-Brunaud method (Arch. Int. Pharmacodyn, 1-2 (1960) 120-12).

The guinea pig used as an experimental animal, which in a Hermetically sealed space is enclosed before and after the treatment with the medicament according to the invention of the action of a cough triggering Subjected by means (aerosol, one third of which consists of ammonia). The Susten Movements be using a Marey capsule before treatment and at different times registered after treatment. This way the percentage fluctuations the number of coughing movements for each group of test animals and the percentage effect intended as a cough suppressant, this effect averages 80% after 30 minutes, 72 after 60 minutes and 56% after 90 minutes.

2) Analgesic effect The tests were carried out according to 2 methods: A) Acetic acid method according to Koster, Anderson and de Beer (Fed. Proced. 18, 1959, 412, 1,626 Intraperitoneal injection of a dilute acetic acid solution causes Mice under the influence of the pain repeated characteristic stretching movements emerged. The administration of the medicament according to the invention in the animals of treated group at a dose of 100 mg / kg orally 30 minutes before the intraperitoneal Injection of acetic acid shows that compared to the comparison group, the number of Stretching movements in the following 50 minutes is much less.

In this way, the mean analgesia is determined to be 71%.

b) Method of mechanical stimulation according to Haffner (German Wiss. 55 (1959) 731-733) In this method, a pressure-exerting clamp is attached to the base of the tail attached to a mouse. The number of bites with which the animal tries to to free yourself from the clamp. Reducing the number of bites before and after the oral administration of the medicament according to the invention in a dose of 100 mg / kg enables the percentage mean analgesia to be determined in Dependence on the time is achieved.

Before After Treatment Treatment 30 min. 1 2 3 hrs. Hrs. Hrs.

Mean number of bites in 1 minute 13 2.6 3.7 4.7 5.5 percentages Post-treatment analgesia 80 72 64 58 The results of these examinations suggest the antitussive and analgesic effects of the derivatives according to the invention recognize that can be used to advantage in human and veterinary medicine0 The pharmaceutical preparations according to the invention are useful for oral use Administration formulated in the form of tablets, dragees, capsules, syrup and drops. They can also be used for rectal use in the form of suppositories and also in Formulated in the form of injection solutions.

Each dosage unit expediently contains Sb up to 500 mg, and the daily doses, that can be administered are 50 to 5000 mg.

The following are the compositions of some pharmaceutical preparations as examples called according to the invention.

1) Tablets derivative # 4 0.150 g dicalcium phosphate 0.010 g starch 0.005 g lactose 0.005 g magnesium stearate 0.002 g 2) Dragees core: Derivative # 5 0.100 g glycerin 0.001 g lactose 0.001 g corn starch 0.010 g magnesium stearate 0.005 g talc 0.002 g cover: gum arabic 0.005 g gum varnish 0.001 g castor oil 0.002 g talc 0.002 g tartrazine aluminum lacquer trace sugar 0.010 g white wax 0.002 g carnauba wax 0.001 g 3) capsules derivative No. 2 0.100 g talc 0.002 g magnesium stearate 0.002 g 4) Oral drops derivative no.6 3.000 g Flavored excipient ad 30 ml 5) syrup derivative no.1 3000 g flavored excipient ad 100 ml 6) suppositories Derivative No. 8 0.100 g semi-synthetic triglycerides ad 1 suppository 7) Injection solution Derivative no.3 0.075 g isotonic saline solution ad 2 ml The medicines according to the invention are used in therapy because of their analgesic and antitussive properties Properties applied. Since they have no hemorrhagic effect and neither do they get used to Still causing addiction, they are used as such as pure analgesics for treatment of rheumatic and traumatic diseases, dental diseases, neurological and visceral diseases used. In addition, they are all Ursoruns when coughing acting quickly and leading to its elimination or alleviation in rhinopharyngitis, Bronchitis, whooping cough, smoker's cough, spasmodic cough, and general lung diseases.

Claims (12)

Claims 1) o-Thymotinic acid derivatives of the general formula in which R is a linear or branched, saturated or unsaturated hydrocarbon group having 2 to 4 carbon atoms or a group of the formula in which n is a number from 1 to 4 and R2 and R3 are identical or different lower alkyl radicals, and the salts of these compounds formed by neutralization of the carboxyl group, their addition salts with acids when R is a basic nitrogen-containing group, and their quaternary ammonium salts when R is a nitrogen-containing group. 2) 2-Allyloxy-3-isopropyl-6-methylbenzoic acid and its salts. 3) 2- (p-Dimethylaminoethoxy) -3-isopropyl-6-methylbenzoic acid and its Salts. 4) 2-propoxy-3-isopropyl-6-methylbenzoic acid and its salts. 5) 2-n-Butoxy-3-isopropyl-6-methylbenzoic acid and its salts. 6) 2-Isopropoxy-3-isopropyl-6-methylbenzoic acid and its salts. 7) 2-Isobutoxy-3-isopropyl-6-methylbenzoic acid and its salts. 8) 2- (ß-Diethylaminoethoxy) -3-isopropyl-6-methylbenzoic acid and its Salts. 9) 2- (ß-Dimethylaminopropoxy) -5-isopropyl-6-methylbenzoic acid and their salts. 10) Medicinal preparations with in particular cough suppressants and analnetic effect, characterized by a content of a compound according to Claims 1 to 9 as an active ingredient in connection with pharmaceutically acceptable carriers. 11) Process for the preparation of o-thymotinic acid derivatives according to claim 1 to 9, characterized in that o-thymotinic acid is reacted in the presence of sodium hydride with an alkyl halide of the formula RZ, in which R has the meaning given above and Z is a halogen atom, and the resulting derivative of the formula subject to hydrolysis, thereby releasing the acid function and optionally converting this derivative into the salt. 12) Process according to claim 11, characterized in that the hydrolysis of the derivative (II) is carried out in an alkaline I-leaiumO 13) o-thymotinic acid derivatives of the general formula in which R has the meaning given in claim 1.