FI58119B - FRAMEWORK FOR THE FRAMEWORK OF DIBENSYLGLYCOLSYRADERIVAT MED TERAPEUTISK NETWORK - Google Patents

Description

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Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) P 2362708.9 (71) Warner-Lambert Company, 201 Tabor Road, Morris Plains, New Jersey, 07950, USA (72) Wolf-Dieter Vigelius, Denzlingen, Gerhard Satzinger, Denzlingen,

Manfred Herrmann, Gundelfingen, Federal Republic of Germany Förbunds-republiken Tyskland (DE) (7I +) Oy Kolster Ab (5I +) Method for the preparation of therapeutically active dibenzylglycolic acid derivatives - Förfarande för framställning av di-bensylglykols

The invention relates to a process for the preparation of therapeutically active dibenzyl glycolic acid derivatives of the formula N-CH. C-0-a 1 k-N v (l) W \ /

C

<ΓΛ / \

Wherein R 1 and R 2, which may be the same or different, represent a hydrogen or halogen atom or an alkyl or alkoxy group having 1 to 3 carbon atoms, R 1 and R 2, which may be the same or different, may be the same or different, represent an alkyl group having 1 to 3 carbon atoms or R 1 and together with the nitrogen atom attached to them form a piperidyl group which may be substituted by one or more alkyl groups having 1 to 2 58119 carbon atoms, a phenyl group or an A, A pentamethylene group; a morpholino group or a hexamethyleneimino group, R 1 is an alkyl or alkoxyalkyl group having 1 to 5 carbon atoms or a Bent alkyl group and alk is a straight-chain or branched alkylidene group having 2 to 3 carbon atoms, and their quaternary lower alkyl ammonium salts thereof or for the preparation of pharmacologically acceptable acid addition salts with organic acids.

In the general formula (I) above, the halogen towers are a fluorine, chlorine or bromine tower, of which a chlorine tower is preferable.

Substituent R ,. is preferably a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, methoxymethyl or benzyl radical.

Preferred branched or straight chain alkylidene radicals are the ethylene, trimethylene and propylene radicals.

Preferred are compounds of general formula (I) in which R 1 and R 2 are the same or different hydrogen or chlorine atoms or methyl or methoxy radicals, R 1 and R 2 are, together with the nitrogen atom to which they are attached, piperidine or 2,2,6,6- tetramethylpiperidine-morpholine ring, is a methyl, ethyl or benzyl radical and alk is an ethylene radical.

Particularly interesting representatives of the new compounds (I) are acetyldibenzylglycolic acid / 3-piperidinoethyl ester hydrochloride and acetyldibenzylglycolic acid N- (2,2,6,6-tetramethylpiperidino) ethyl ester.

In Bull. Soc. Pharm. Lille, 1, 31- ^ 1/1968 describes dibenzyl-1-glycolic acid derivatives whose hydroxyl group is not esterified and which have an anticonvulsant effect (see Chem. Abs., 69, 106-76). In addition to the anticonvulsant effect, the dibenzyl glycolic acid derivative was also shown to have an antihypertensive effect (see Bull. Soc. Pharm. Lille, 2, 79-85/1968, Chem. Abs., 70,66567 s).

It has now surprisingly been found that the new compounds of general formula (I) are characterized by a very high antihypertensive and secretion-reducing effect. Compared to the antihypertensive effect of many known substances, i.e. for the reduction of blood pressure in animals under normal pressure when administered parenterally, the novel compounds according to the present invention are mainly effective only against hypertension. Blood pressure can be reduced rapidly and for a long time to normal levels without the risk of low blood pressure when administered not only orally but also parenterally. Some of the new compounds (I) also have an interesting secretion-reducing effect, so they are particularly well suited for the treatment of gastric diseases causing hyperacidity.

The invention is characterized in that the compound of formula 351111 9 R.

^> -CH2 ^ COOH

(ll) / ΓΚ. / \

V> - CH2 0H

where R 1 and R 2 are as defined above, is reacted with an acid halide or anhydride of a compound of formula (IIi) hooc-r 5 (H1) wherein R 1 is as defined above, after which the product thus obtained is reacted in its Na salt form with With a halide derivative of the compound of formula (IV), HO-alk-fT (IV) in which R 1, R 2 and alk have the same meaning as above, and that the compound obtained is, if desired, converted into a quaternary lower ammonium salt or an inorganic or with an organic acid to an acid addition salt i.

A compound of general formula (II) in which both R 1 and R 2 represent a hydrogen atom is commonly known as oxatolyl acid (see Beilstein, 10, H 350). A process for the preparation of oxatolyl acid is described in Chem. Berichte, 13, p. 2220 and Helv. Chim. Acta, 28, 7 ^ ~ 7 ^ 6/19 ^ 5 · These methods can also be used in the preparation of phenyl-substituted oxatolyl acid derivatives used in accordance with the present invention. Particularly suitably, oxatolylic acid and its phenyl-substituted derivatives can be prepared by reacting diethyl oxalate with an optionally phenyl-substituted benzylmagnesium halide according to the Grignard method. In this case, solvent- and method-specific variables specific to Grignard synthesis can be used.

4 58119

The quaternary ammonium salts of the compounds of general formula (I) can be prepared in a conventional manner by reacting the free base with an alkyl halide. For example, ethanol or nitromethane can be used as a solvent for quaternization.

Salts of the free amines of general formula (I) may be prepared by reacting with equimolar amounts of inorganic or organic acids in a solvent. Thus, for example, an anhydrous acid component, e.g. hydrogen chloride, is flowed or added to a suitable base I. As a suitable solvent, for example, ethyl acetate, ether or methanol can be used.

Pharmacologically acceptable salts include, for example, those formed with the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, benzenesulfonic acid, naphthalene-1,5-disulfonic acid, acetic acid, oxalic acid, salicylic acid, succinic acid, succinic acid, succinic acid

The compounds of general formula (i) of the present invention, their pharmacologically tolerable quaternary lower alkyl ammonium salts and salts of the compounds with inorganic or organic acids may be administered in or outside the gastrointestinal tract in admixture with a liquid or solid pharmaceutical diluent or carrier. As an injection medium, it is recommended to use water containing the usual additives for injection solutions, e.g. stabilizers, solubilizers and buffers. Such additives include, for example, ethanol, complexing agents (e.g., ethylenediaminetetraacetic acid and its non-toxic salts), tartrate and citrate buffers, and high molecular weight polymers (e.g., liquid polyethylene oxide) to control viscosity. Examples of solid carriers are starch, milk sugar, mannitol, methylcellulose, talc, high dispersed silicic acids, high molecular weight fatty acids (e.g. stearic acid), gelatin, agar, potassium phosphate, magnesium stearate, animal and vegetable fats and solid high fats. If desired, oral forms may contain flavoring and / or sweetening agents.

The administration of the compounds of the present invention will depend on the nature and severity of the disease being treated. Oral administration in hypertension is recommended. In this case, the single dose should be about 20-500 mg, and when administered subcutaneously or intravenously, the single dose should be 2-50 mg.

In gastric diseases, the single oral dose is 20-500 mg. In such conditions, parenteral administration is less appropriate.

The following pharmacological studies demonstrate the efficacy of the compounds of the present invention.

Pharmacological tests:

The antihypertensive effect of acetyldibenzylglycolic acid H-piperidinoethyl ester hydrochloride (substance A) was demonstrated in awake rats by the following experiments:

The right kidney was ligated in 42 Vfistar male rats, weighing 100 g, as described by Grollmann (see Proc. Soc. Exp. Biol. Med., 57-102-104, 1944) to generate chronic hypertension. Ten days later, the left kidney was removed.

Measurement of arterial blood pressure was performed in anesthetized rats using the method of Friebel and Vreden (see Arch. Exp. Path. U. Pharmakol., 2J2, 419-422, 1956). Blood pressure was measured from the tails of experimental animals. The pulse curves thus obtained were recorded with microphones and read on oscillographs, the blood pressure being determined with a mercury pressure gauge.

e 58119

Blood pressure was measured twice a week on Mondays and Thursdays, averaged x with standard deviations, and plotted.

If the arterial blood pressure of the animals had reached or exceeded 160 mm Hg in 4-6 weeks after renal removal, these animals were considered to have hypertension. Animals whose blood pressure had not increased correspondingly were excluded from this experiment.

From this time, test compounds and control solution were administered to the stomach by gavage. Administered to: 1. control animals 1 ml of 0.9% sodium chloride solution in the stomach / 10C g body weight; 2. For experimental animals, 100 mg / kg of substance A was sawn in $ 0.9 as sodium chloride solution.

The concentration of substance A was chosen so that all doses could be administered in all cases in 1 ml of physiological sodium chloride solution.

On the days of measuring the blood pressure of the animals, the administration of the test compound or the control solutions took place JO minutes before the pressure of each animal.

Score:

Substance A had a reproducible antihypertensive effect in the stomach up to 75 mg / kg. On average, arterial blood pressure drops by as much as 20-30 mm Hg three days after starting treatment. Within two weeks, the decrease is up to 60 mm Hg, which only starts to increase after two weeks after cessation of administration. When administered by the stomach at an LD50 of 821 mg / kg, this compound achieved a good therapeutic index of 10.75 · Most drug compounds for the treatment of hypertension, e.g. Rauwolfia alkaloids, are administered with urinary agents as the agents alone cannot lower blood pressure due to renal impairment in rats. blood pressure. In comparison, substance A has a particularly good and long-lasting antihypertensive effect.

The inhibitory effect on the secretion of ethyl dihentyl glycolic acid (1- (2,2,6,6-tetramethyl lipiperidino) ethyl ester (substance B) was demonstrated by the following experiments:

In rat experiments, using the Shay method, dose-dependent inhibition of gastric secretion ($ 17) was achieved at 15 mg / kg in the stomach and inhibition of secretion was almost complete ($ 96) at 250 mg / kg. The change in pH (pH 1.5 to pH 7) occurred almost parallel in the said dosing range.

When Pavlov was used in dogs, a dose of 50 mg / kg in the stomach prevented spontaneous excretion of at least 30-50 hours from baseline and at the same time increased t> h by up to 100 />. No side effects were observed.

In mouse toxicity studies, only a small side effect of 1600 mg B / kg in the stomach was observed in experimental animals. Thus, the toxicity is very low.

τ 58119

The following examples illustrate the present invention.

Example 1

Asetyylidibentsyyliglykolihappo p-piperidinoetyyliesterihydvokloridi

Dissolve 120.5 g (0.47 moles) of dibenzyl glycolic acid and 50.5 g (0.5 moles) of triethylamine in two liters of crystallized benzene, was added dropwise over 1 hour with stirring and boiling 39.7 g (0.5 moles, i.e.

36.1 ml) of acetyl chloride in 100 ml of crystallized benzene and the reaction mixture was boiled for 16 hours. After cooling, the precipitated triethylamine hydrochloride is removed by filtration, the filtrate is evaporated and the syrupy residue is crystallized by vigorous stirring in 600 ml of a 1: 5 mixture of diethyl ether and benzene. The product is isolated by suction filtration, washed with 250 ml of petroleum ether and dried. 99 g ($ 70.6% of theory) of acetyldi-benzylglycolic acid are obtained, m.p. 102-103 ° C.

The acetyldibenzylglycolic acid thus obtained is dissolved in 200 ml of ethanol, which is added to a solution of 7.6 g (0.33 mol) of sodium in 200 ml of ethanol and, with stirring at boiling temperature, stirred dropwise from 50 .mu.l of a benzene solution containing 97.4 g ( 0.33 mol) of Ν-β-chloroethylpiperidine and the reaction mixture is boiled for four hours. After cooling, the precipitated sodium chloride is removed by filtration, the filtrate is evaporated, the residue is dissolved in 500 ml of ether, filtered and stirred in 250 ml of ethyl acetate saturated with hydrogen chloride to precipitate the salt completely. The hydrochloride is isolated by suction filtration and crystallized from five liters of ethyl acetate. 100 g ($ 68 of theory) of acetyldibenzylglycolic acid-β-piperidinoethyl ester hydrochloride, m.p. 174 ° C.

The dibenzyl glycolic acid used as a starting material can be prepared as follows:

According to Grignard, react 75 g (3.2 moles) of magnesium and 390 g (3 moles) of benzyl chloride in 600 ml of dry ether and allow to boil for 30 minutes. Upon external cooling with ice water, a solution of 146 g (1 mol) of diethyl oxalate in half a liter of dry ether is added dropwise with stirring and the reaction mixture is heated under reflux for 16 hours. When cooling from the outside on ice, carefully add one liter of 4N hydrochloric acid. The separated aqueous phase is extracted with one liter of ether and the combined ether phases are shaken several times with all one liter of saturated potassium bicarbonate solution, dried and evaporated. The residue is boiled for two hours in 2.5 liters of 10 liters of methanolic potassium hydroxide solution and evaporated. The residue was dissolved in three liters of water, extracted twice with 500 ml portions of ether and made strongly acidic with concentrated hydrochloric acid. The dibenzyl glycolic acid formed is isolated by suction filtration, washed with 300 ml of benzene and the residue is boiled in 2.5 liters of benzene using a water separator until no more water distills off. Upon cooling, the crystallized product is isolated by suction filtration and dried. 120.5 g (47% of theory) of dibenzyl glycolic acid are obtained, m.p. 156 ° C.

The starting Ν-β-chloroethylpiperidine is prepared as follows:

Dissolve 92.1 g (0.5 mol) of Ν-β-clobritylpiperidine hydrochloride in 100 ml of water, basify with 10N sodium hydroxide solution and extract three times with a total of 500 ml of ether. The ether phases are dried, evaporated in vacuo at 25 [deg.] C. and the residue is fractionated »59 g (80% of theory) of .beta.-β-chloroethylpiperidine are obtained, b.p. 70 ° C / 12 mm Hg. The distillate must be immediately diluted with the same amount of benzene and stored at -15 ° C.

Example 2

Acetyldibenzylglycolic acid P- (2,2,6β-tetramethylpiperidino) ethyl ester

Dissolve 3 * 1 g (0.134 mol) of sodium in 150 ml of ethanol. To this solution is added 40 g (0.134 moles) of acetyldibenzylglycolic acid in 150 ml of ethanol and the reaction mixture is heated to boiling. 27.5 g (0.134 mol) of 1- (i-chloroethyl) -2,2,6,6-tetramethylpiperidine in 27.5 g of benzene are then added dropwise and the reaction mixture is refluxed for 16 hours. After cooling, the precipitated sodium chloride is removed by filtration and the filtrate is evaporated. The residue is dissolved in a liter of ether, filtered, evaporated and the oily residue is crystallized from 100 ml of benzene, isolated by filtration and recrystallized from 100 ml of benzene. 34 g (54 * 5 of theory) of acetyldibenzylglycolic acid p- (2,2,6,6-tetramethylpiperidino) ethyl ester are obtained, mp 82.1 ° C.

The starting 1- (β-chloroethyl) -2,2,6,6-tetramethylpiperidine is prepared as follows:

Dissolve 56 g (0.4 mol) of 2,2,6,6-tetramethylpiperidine, 20 g (0.46 mol) of ethylene oxide and 1 ml of concentrated hydrochloric acid in 100 ml of methanol under ice-cooling and then heat in a glass autoclave for four hours at 100 ° C: in. After cooling, the reaction mixture is evaporated. 60 g of 1- (H-hydroxyethyl) -2,2,6,6-tetramethylpiperidine are obtained, m.p. 96-97 ° C.

The product thus obtained is dissolved in 150 ml of benzene and, under ice-cooling, a mixture of 75 ml of thionyl chloride and 150 ml of benzene is added dropwise. The reaction mixture is then allowed to boil for three hours and, after cooling, the hydrochloride is isolated by suction filtration. 60 g of 1- (β-chloroethyl) -9,511,9,2,9,9-tetraraethylpiperidine hydrochloride are obtained, m.p. 210-212 ° C, which is converted into the free base in the usual way with aqueous sodium hydroxide solution, b.p. 111 ° C (cf. R. B. Moffett and B. D. Aspergren, J. A. C.S., 82, 1612, 1960).

In a similar manner, the following compounds are obtained by reacting the sodium salt of acetyldibenzylglycolic acid with p-diroethylaminoethyl chloride to give acetyldibenzylglycolic acid 6-dimethylaminoethyl ester, which, after reacting with oxalic acid, is isolated. 144-145 ° C; β-diethylaminoethyl chloride, acetyldibenzylglycolic acid-3-diethylaminoethyl ester is obtained, which after reaction with oxalic acid is isolated as oxalate, m.p. 136 ° C; b-dimethylaminopropyl chloride, acetyldibenzylglycolic acid p-dimethylaminopropyl ester is obtained, which after reaction with oxalic acid is isolated as oxalate, m.p. 154-155 ° C; γ-dimethylaminopropyl chloride, acetyldibenzylglycolic acid γ-dimethylaminopropyl ester is obtained, which after reaction with oxalic acid is isolated as oxalate, 125-127 ° C; 6-pyrrolidinoethyl chloride, acetyldibenzylglycolic acid β-pyrrolidinoethyl ester is obtained, which after reaction with oxalic acid is isolated as oxalate, m.p. 180 to 180.5 ° C; β-morpholinoethyl chloride, acetyldibenzylglycolic acid p-morpholinoethyl ester is obtained, which after reaction with oxalic acid is isolated as oxalate, m.p. 112.5 to 113 ° C; 1-piperidino-2-chloropropane, acetyldibenzylglycolic acid β-piperidinopropyl ester is obtained which, after reaction with naphthalene-1,5-disulfonic acid, is isolated as heminaphthalene-1,5-disulfonate, m.p. 190 # 8 ° C; 2-piperidino-1-chloropropane, acetyldibenzylglycolic acid (3-piperidinopropyl ester is obtained) which, after reaction with naphthalene-1,5-disulfonic acid, is isolated as heminaphthalene-1,5-disulfonate, mp 189.2 ° C; acetyldibenzylglycolic acid-γ-piperidinopropyl ester, which after reaction with oxalic acid is isolated as oxalate, mp 156 DEG C. b- (2-methylpiperidino) -ethyl chloride, obtained as acetyldibenzylglycolic acid 117 ° C, 10,581.19 3- (3-methylpiperidino) ethyl chloride, acetyldibenzylglycolic acid 3- (3-methylpiperidino) ethyl ester is obtained, which is isolated as an oxalate by reaction with oxalic acid, mp 104-105 ° C 3- ( 4-methylpiperidino) ethyl chloride, acetyldibenzylglycolic acid 3- (4-methylpiperidino) ethyl ester is obtained, which is isolated as oxalate after reaction with oxalic acid, mp 158 ° C.

The starting 3- (4-methylpiperidino) ethyl chloride was prepared as follows:

56.3 g (0.7 mol, 47 ml) of ethylene chlorohydrin are added dropwise with stirring to 138.9 g (1.4 mol) of 4-methylpiperidine. After boiling for three hours and cooling, the reaction mixture is stirred several times with a total of 1.5 liters of ether, the precipitated 4-methylpiperidine hydrochloride is isolated by filtration, the residue is evaporated and the residue thus obtained is fractionated in a vacuum. 91 * 78 (8.63 mol) of 4-methylpiperidinoethanol are obtained. This is dissolved in 580 nl of anhydrous bercene with stirring and stirred in a solution of 151 * 2 g (1.26 moles) of thionyl chloride in 100 ml of anhydrous benzene, the temperature being maintained at 25-30 ° C. After boiling for 38 minutes with the hydrochloride, m.p. 142-144 ° C, isolated by suction filtration and washed with ether. Yield 123 g (98.5 and theoretical).

Dissolve 40 g (0.2 mol) of β-4-methylpiperidinoethyl chloride hydrochloride in 100 ml of water, basify with aqueous sodium hydroxide solution and extract several times with a total of one liter of ether. The ether phases are dried and the residue obtained is distilled. 26.7 g ($ 83 of theory) of 3-4-methylpiperidinoethyl chloride, b.p. 75-76 ° / 12 mm Hgj 3- (2,6-dimethylpiperidino) ethyl chloride, ethyldibenzylglycolic acid 3- (2,6-dimethylpiperidino) ethyl ester is obtained, which is isolated as oxalate by reaction with oxalic acid, m.p. Ll6-115 ° C.

Example 3

Acetyl dibenzyl glycolic acid 3- (4-phenylpiperidino) ethyl ester oxalate

13 * 5 8 (0.067 mol) of p- (4-phenylpiperidino) -ethyl chloride in 20 ml of ethanol are added dropwise to a solution of 20 g (0.067 mol) of the sodium salt of acetylbenzylglycolic acid in 140 ml of ethanol. The reaction solution is allowed to boil for 16 hours, filtered and the filtrate is evaporated. The residue is dissolved in 200 ml of ether, the oxalate is precipitated by adding a dry, saturated ethereal solution of oxalic acid and the oxalate is crystallized twice from 500 ml portions of ethanol. 22.6 g (60% of theory) of acetyldibenzylglycolic acid 8- (4-phenylpiperidino) ethyl ester oxalate are obtained, m.p. 146 ° C.

11 58119 The starting p- (4-phenylpiperidiphtho) ethyl chloride is prepared as follows:

After heating for five hours at about 120 ° C, 75 S (0.46 mol) of p-4-phenylpiperidine and 38 g (0.46 mol) of 2-chloroethanol are heated. After cooling, the reaction mixture is dissolved in 500 ml of water, basified with potassium carbonate, extracted with one liter of ether, dried, evaporated and the residue is distilled under high vacuum. 55 g (61% of theory) of p- (4-phenyl-piperidino) -ethanol, b.p. 155 ° C / 0.2 mm Hg, which is dissolved in 500 ml of chloroform. The corresponding hydrochloride is then precipitated by the addition of dry hydrogen chloride. 50 ml of thionyl chloride are added, the reaction mixture is heated under reflux for five hours and cooled. The precipitate is isolated by filtration, dissolved in 30 ml of water and basified with 10N aqueous sodium hydroxide solution. The precipitated base is extracted with 500 ml of ether, dried and evaporated. 45 g (75 ° of theory) of p- (4-phenylpiperidino) ethyl chloride are obtained.

Example 4

Acetyl dibenzyl glycolic acid p- (4,4-pentamethylene piperidino) ethyl ester oxalate

Dissolve 2.02 g (0.088 mol) of sodium in 50 ml of absolute ethanol and 26.3 g (0.088 mol) of acetyldihenzylglycolic acid in 50 ml of absolute ethanol and combine and add dropwise with stirring to a boiling solution of 10 g of benzene (10 g). 0.088 moles) of p- (4,4-pentamethylenipiperidino) ethyl chloride. After boiling for four hours, the reaction mixture is cooled, the precipitated sodium chloride is filtered off, the filtrate is evaporated, the residue is dissolved in 500 ml of dry ether, filtered and stirred with a dry ethereal oxalic acid solution until precipitation of the salt is complete. The oxalate is isolated by filtration and crystallized twice from 600 ml portions of a 1: 5 mixture of ethanol and ethyl sebacate. 20 g (40% of theory) of acetyldibenzylglycolic acid p- (4,4-pentamethylene-piperidino) -ethyl ester oxalate are obtained, m.p. 163 »3 ° C.

The starting H- (4-4-pentamethylenepiperidino) ethyl chloride is prepared as follows:

Boil for about eight hours 5 ° g (0 * 25 mol) of cyclohexanediacetic acid aminoethanol and a spatula-tipped piperidine acetate 500 ml s of xylene with a water separator connected until 9 ml of water have separated. After evaporation of the solvent, the residue is fractionated under high vacuum. 45 g ($ 70 of theory) of p, p-pentamethylene-N- (p-hydroxyethyl) -glutarimide, b.p. 162-165 ° C / 0.05 mm Hg.

To a solution of 52 g (0.23 moles) of p, p-pentamethylene-N- (p-hydroxyethyl) glutarimide in 500 ml of anhydrous benzene is added dropwise, with stirring under nitrogen, a solution of 240 ml (0.8 ) moles) of sodium dihydro-bis- (2-methoxyethoxy) aluminate from a solution of 70 in 150 ml of absolute benzene. The internal temperature of the reaction mixture must not exceed 30 ° C. After boiling for 24 days under a nitrogen blanket, the reaction mixture is cooled to ice temperature, stirred very carefully with about 200 ml of water, the aluminum hydroxide is removed by filtration, the filtrate is dried and evaporated and the residue is fractionated in vacuo. 29.7 g (65% of theory) of p- (4,4-pentamethylene-piperidino) -ethanol are obtained, b.p. 156-L60 ° C.

Dissolve 29.5 g (0.15 mol) of β- (4,4-pentamethylenepiperidino) ethanol in 100 ml of chloroform saturated with hydrogen chloride, add 90 ml of thionyl chloride and boil the reaction mixture for three hours. After about two-thirds of the reaction mixture has been evaporated, 200 ml of carbon tetrachloride are added. The mixture is then stirred for 30 minutes and about two-thirds of the solvent is removed by distillation. This step is repeated, the solvent is removed by filtration and the residue is stirred for one hour in 200 ml of ether. The crude hydrochloride (23 g, m.p. 262.5 ° C) is suspended in 100 ml of water, made strongly basic with 0.1 N aqueous sodium hydroxide solution and the mixture is extracted several times with a total of 500 ml of ether. After drying and evaporation of the combined ether extracts, 19 g (19/6 of theory) of β- (4-4-pentamethylenepiperidino) ethyl chloride are obtained. The base can be stored by diluting it with the same amount of benzene and storing it at -15 ° C.

Example -5

After standing for 20 hours, 9 to 5 g (0.02 mol) of acetyldibenzylglycolic acid N-piperidinoethyl ester (see e.g. 1), 20 g (0.2 mol) of methyl bromide and a spatula-tipped potassium broride in 50 ml of nitroacetane are allowed to stand. After evaporation in vacuo, the residue is recrystallized from 25 ml of a 1: 9 mixture of ethanol and ethyl acetate. 7-4 g ($ 74 of theory) of acetyldibenzylglycolic acid P-piperidinoethyl ether methyl bromide are obtained, m.p. 206-207 ° C.

Example 6

Acetyldibenzylglycolic acid p-hexamethyleneiminoethyl ester hydrochloride

In the same manner as in Example 1, acetyldibenzylglycolic acid is reacted with Ν-β-chloroethylhexamethyleneimine to give acetyldibenzylglycolic acid β-hexamethyleneiminoethyl ester hydrochloride, m.p. 155-154 ° C.

Example 7

Acetyldibenzylglycolic acid-β-hexamethyleneiminoethyl ester methyl bromide 13,581 19

In a manner similar to Example 5, the free base described in Example 6 is reacted with methyl bromide in nitromethane in acetyldibenzylglycolic acid-8-hexamethyleneiminoethyl ester ethyl bromide, sn. 198.5 ° C.

Example 8

Propionyl dibenzyl glycolic acid (i-dimethylaminoethyl ester oxalate

Dissolve 1.5 g (0.065 mol) of sodium in 50 ml of absolute ethanol mixed with 20.4 g (0.065 mol) of propionyldibenzylglycolic acid in 50 ml of absolute ethanol and add 7.03 g (0.065 mol) of p-dimethylaminoethyl chloride as benzene oxide. After boiling for about eight hours, the reaction mixture is cooled, the precipitated sodium chloride is removed by filtration and the filtrate is evaporated. The residue is dissolved in ether and, after treatment with charcoal, a saturated, dry ethereal solution of oxalic acid is stirred until precipitation is complete. The oxalate is isolated by filtration and crystallized twice from 250 ml portions of isopropanol. 8.8 g (28.5% of theory) of propionyl dibenzyl glycolic acid p-dimethylaminoethyl ester oxalate are obtained, m.p. 157-138 ° C.

The starting propionyldibenzylglycolic acid is prepared as follows:

51.2 g (0.2 moles) of dibenzyl glycolic acid and 52 g (0.4 moles) of propionic anhydride are boiled for four hours. After the excess propionic anhydride and the propionic acid formed have been removed by distillation with a water bath in vacuo, the residue is dissolved in 50 ml of alcohol and poured with stirring into 800 ml of dilute ammonia solution (lsl). After standing for about two hours, the mixture is filtered and the residue is acidified under cooling with hydrochloric acid. The precipitated oily acid is extracted with a total of about 500 ml of silage. ether and the ether is evaporated. The remaining oily product (24 e, 38.5 f of theoretical) is used without purification in a further reaction. However, oily propionyldibenzylglycolic acid can be crystallized by treating several Compare with hexate, m.p. about 80 ° C.

The following compounds are obtained in a similar manner s proplonyldibenthylglycolic acid p-diethylaminoethyl ester ester, m.p. 125.5-12 ° C, p-opionyldibenzylglycolic acid β-pyrrolidino-ethyl ester oxalate, m.p.

181-182 ° C, propionyl dibenzyl glycolic acid p-piperidinoethyl ester oxalate, m.p. 1 * 3.5-164.5 ° C, 111 58119 propionylbenzyl glycolic acid p-morpholinoethyl ester oxalate, ερ.

134-155 ° C, propionyldibenzylglycolic acid N-dimethylaminopropyl ester oxalate, m.p. 1 / 18-14q ° C.

Example 9

Isob ”tyryldibenzylglycolic acid P-piperidinoethyl ester hydrochloride

Dissolve JO g (0.095 moles) of isobutyryl dibenzyl glycolic acid in 15 ml of ethanol and add to a solution of 2.3 g (0.1 moles) of sodium in 150 ml of ethanol. 1 g (0.095 mol) of p-chloroethylpiperidine in 13 g of benzene are then added and the reaction mixture is boiled for eight hours. After cooling, the precipitated sodium chloride is removed by filtration, the filtrate is evaporated and the residue is dissolved in 200 ml of ethyl acetate mixed with hydrogen chloride-saturated ethyl acetate until precipitation of the salt is complete and then the hydrochloride is isolated by filtration and crystallized three times from 250 ml of acetone and mixture. 11.6 g ($ 24 of theory) of isobutyryl dibenzylglycolic acid i-piperidinoethyl ester hydrochloride, m.p. 139-140 ° C.

The isobutyryl dibenzyl glycolic acid used as starting material is obtained as follows:

Dissolve 25.6 g (0.1 mol) of dibenzyl glycolic acid in 8 g (C, 1 mol) of pyxidine and 200 ml of anhydrous benzene and add dropwise 10 g (0.1 mol) of isobutyric acid chloride in 30 ml of anhydrous benzene. After boiling the reaction mixture for ten hours, the precipitated pyridine hydrochloride is removed by filtration, the filtrate is evaporated and the crude residue is worked up. 30 g ($ 80 of theory) of isobutyryl dibenzyl glycolic acid are obtained, m.p. 75 ° C.

Similarly, reacting dibenzyl glycolic acid with a) pivaloyl chloride, b) 8-piperidinoethyl chloride gives pivaloyl dibenzyl glycolic acid p-piperidinoethyl ester hydrochloride, m.p. 158-159 ° C; a) methoxyacetyl chloride, b) cations with P-piperidinoethyl chloride give cetyldibenzylglycolic acid P-piperidinoethyl ester hydrochloride, m.p.

95-96 ° C a) with phenylacetyl chloride, b) with p-piperidinoethyl chloride to give phenylacetyldibenzyl glycolic acid (p-piperidinoethyl) ester hydrochloride, m.p. 129-150 ° C.

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Acetyl-ο, ο'-dichlorodibenzylglycolic acid (β-piperidinoethyl) ester hydrochloride di 15 5 81 1 9

To a solution of 25 g (0.07 mol) of acetyl-o, o'-dichlorodibenzyl "glycolic acid in ml of ethanol is added a solution of 1.7 g (0.7 mol) of sodium in 100 ml of ethanol. The reaction mixture is heated to boiling point and stirred. slowly to a solution of 10.5 g of h-piperidinoethyl chloride in 10.5 S of benzene The mixture is boiled for 16 hours, evaporated and the residue is dissolved in 500 ml of ether.When adding ethyl acetate saturated with hydrogen chloride, the precipitated salt is isolated by filtration and recrystallized twice 1.5 11.5 g (32%) of acetyl-o, o'-dichlorodibenzylglycolic acid (h-piperidinoethyl) ester hydrochloride, mp 180.9 ° C, are obtained.

The acetyl-o, o * -dichlorodibenzylglycolic acid used as starting material can be prepared as follows:

146 g (1 mole) of oxalic acid diethyl ester dissolved in 1.2 liters of dry ether in a solution of 73 g (3 moles) of magnesium and 480 g (3 moles) of o-chlorobenzyl chloride are slowly added dropwise In 600 ml of dry ether and the reaction mixture is boiled for 16 hours. Under ice-cooling, the mixture is decomposed with 1 liter of 10% hydrochloric acid and the ether phase is isolated, washed with one liter of 10% methanolic potassium hydroxide solution and the residue is boiled for two hours in 2.5 liters of 10% methanolic potassium hydroxide solution. The residue obtained after evaporation is dissolved in three liters of water, extracted twice with 500 ml portions of ether, made strongly acidified with concentrated hydrochloric acid, the acid isolated by filtration and crystallized from two liters of toluene. 130 g ($ 40 of theory) of o, o'-dichlorodibenzyl glycolic acid are obtained, m.p. 165-166 ° C.

Stir dropwise 110 g (0.3 mol) of the ο, ο'-dichloro-dibenzylglycolic acid thus obtained and 33 g (0.33 mol) of triethylaraine in 2 liters of dry boiling benzene with 24 ml (0.33 mol) of acetyl chloride , boil for 16 hours, cool, remove the triethylamine hydrochloride by filtration, evaporate the filtrate, stir the residue in 500 ml of a mixture of ether and petrol, filter and dry. 90 g (81.7% of theory) of acetyl-o, o'-dichlorodibenzyl glycolic acid are obtained, m.p. 165 ° C.

In a similar manner, acetyl-o, o'-dichlorodibenzylglycolic acid β- (2,2,6,6-tetramethylpiperidino) ethyl ester hydrochloride, m.p. 181.7 ° C, by reacting acetyl-o, o'-dichlorodibenzylglycolic acid with 8- (2,2,6,6-tetramethylpiperidino) ethyl chloride.

In a similar manner, acetyl-o, o'-dichlorodibenzylglycolic acid 8-hexamethylene-aminoethyl ethyl hydrochloride, m.p. 135.8 ° C, by reacting li-o, o'-dichlorodibenzylglycolic acid with p-hexaroethyleneiminoethyl chloride.

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In a similar manner the following compound is obtained: acetyldi- (o-xylyl) -glycolic acid -piperidinoethyl ester hydrochloride, m.p.

18M ° C.

Claims (1)

17 5 81 1 9 Claim: A process for the preparation of therapeutically active dibenzyl glycolic acid derivatives of the formula R 10 ° 3 W "\ t / ... \, T, 5 r 2 ^ \ = yo wherein R 1 and R 2, which may be the same or different, denote a hydrogen or halogen atom or an alkyl or α-oxy group having 1 to 3 carbon atoms, R 1 and R 2, which may be the same or different, denote an alkyl group having 1 to 3 carbon atoms, or R 1 and R 2 together with the nitrogen atom to which they are attached form a piperidyl group which may be substituted by one or more alkyl groups having 1 to 1 carbon atoms, a phenyl group or an N-pentamethylene group; an alkyl or α 1 coke alkyl group or a benzyl group and alk is a straight-chain or branched alkylidene group having 2 to 3 carbon atoms, and their quaternary lower alkyl ammonium salts and their for the preparation of pharmacologically acceptable acid addition salts with inorganic or organic acids, characterized in that the compound of formula R1 yz \ - r f-ch2, cooh ^ c (M) {/ \ -CH ^ OH> XT is 58119 wherein R 1 and R 2 are as defined above, are reacted with an acid halide or anhydride of a compound of formula (III) hooc-r 5 (III) wherein R 1 is as defined above, after which the product thus obtained is reacted in its Na salt form with the compound of formula (IV). ), R 3 HO-alk-fT (IV) in which R 1, R 2 and alk have the same meaning as above, and that the compound obtained is, if desired, converted into the quaternary previous ammonium salt with a suitable quaternizing agent, or with an inorganic or organic acid to an acid addition salt. 19 5 81 1 9 For the production of dibenzylglycol derivatives with a therapeutic network, the form of V "A_ cn2 CO-alk-N / R3 \ = - \ X c Rk (I) // \ - CH ^ N \) - C -Ri. / 2 11 5 color R ^ och R £, vilka Kari vara lika eller oi i ka, betecknar en väte- eller halogen-Atom ellom en alkyl- eller alkoxygroup med 1 - 3 kolatomer, R ^ och R ^, vilka can the residue be substituted with an alkyl group of 1 to 3 chapters or R 1 and R 2 is a substituent of the same quaternary group as the Sr group of the piperidyl group, which can be substituted with an alkyl group of 1 to 3 phenyl or Α, Α-pentamethylene, pyrrolidinyl, morpholino or hexamethylenimino, R 1 is 1 to 5 cholesterol alkyl or alkoxyalkyl or benzyl and alkyl chelate 2 to 3 cholate eller förgrenad kedja, velvet deras kvaternära lägre-a1 ky 1ammoniumsa1ter och deras pharmacologiskt godtagbara syraadditionssalte r is an organic or organic syrup having the same color as the formulation - CH COOH W \ / c (II) s. · .. / \ '„V- CH, OH vW color R1 and R ^ have an angular characteristic, with a mixture of hydrocarbons or anhydrides to form H00C-R5 (Hl)