CS247083B2 - Production method of the new derivatives of bicyclo(3,2,1) octan-3-carboxyl acid - Google Patents

Abstract

La présente invention est relative à des dérivés de l'acide bicyclo (3.2.1.) octane carboxylique de formule générale suivante: dans laquelle R représente un radical alcoyle inférieur droit ou ramifié, Z représente le groupement OX dans lequel X est l'hydrogène ou un métal alcalin, ou Z représente encore le groupe R1

• N< dans lequel R_l et R₂, identiques ou différents sont l'hy-R2
• drogène ou un radical alcoyle inférieur.

Ces composés sont utilisables en thérapeutique notamment en raison de leurs activités anticonvulsivante et antianoxique.

Description

The present invention relates to a process for the preparation of novel bicyclo [3,2,1] octane-3-carboxylic acid derivatives.

These substances can be represented by the general formula I

(0 where where

R 1 and R 2, the same or different, are hydrogen or methyl,

The above compounds may exist in the form of several stereoisomers, all of which isomers and mixtures thereof are included within the scope of the invention.

Compounds which contain a bicyclooctanecarboxylic acid structure are known in the art.

Buchta and Billenstein (Ann. Chem. 1966, 692, 42-52) prepared compounds in which the meanings of Z and R are shown in the following table:

Table

R is a straight or branched chain alkyl radical of 1 to 3 carbon atoms,

Z represents an OX group in which X represents a hydrogen atom or an alkali metal atom, or Z represents a group of the general formula

COOC2H5

COOC2H5 COOH

H

H

OC2H5

OH

OH

OC2H5

OH

Ri / N \

R2

Takefumi 1978, 26, 8, derivatives, and Osam in Chem. Pharm. Bull.

589-2,593 disclose the preparation of which R is hydrogen (v) and Z is C6H5 or -OC6H5.

Nelson, McEven and Lawton in J. Org. Chem. 1969, 34, 5, 1225 to 1229 disclose the preparation of a derivative of the formula

—COQCC

The derivatives described in Buchta et al., Takefumi et al., And Nelson et al. Have not been subjected to any toxicopharmaceutical tests.

Accordingly, the present invention provides a novel process for the preparation of the compounds of formula (I), characterized in that the 8-oxobicyclo (3,2,1) octane-3-methylcarboxylate of formula (II) is converted wherein:

R ‘has the top. this meaning a

B is an alkali metal atom, and the intermediate is then converted by treatment with an alkyl halide of formula

R - X where

R is as hereinbefore defined, at a temperature of -20 to -10 ° C for a compound of formula V (i) by treatment of an acid of formula III with potassium hydroxide and hydrazine in a polar solvent at a temperature of 190 to 200 ° C

COOR

COOH (v) wherein (ni) this acid is converted to the corresponding ester of formula IIIb

(IIIb) where R 'is a straight or branched chain lower alkyl, this ester is reacted with a strong base such as sodium amide, lithium dimethylamide or lithium diisopropylamide prepared in the reaction mixture in a solvent such as tetrahydrofuran at -70 to 80 ° C to form an organometallic intermediate of formula IV

R and R 'are as defined above, and converted by heating to reflux to an acid of formula I wherein Z is OH and compounds of formula I wherein Z is other than OH groups.

Compounds of formula II can be obtained by the method of Nelson et al., J. Org. Chem. 1969, 34, 1225-1129, which describes a process for preparing the corresponding ethyl ester.

The compound of formula III is described in E. Buchta et al., Ann. Chem. 1986, 692, 42, 52, however, this material can be obtained by other means.

The invention will be illustrated by the following examples:

Example 1

Process for the preparation of 3-methylbicyclo (3,2,1) octane-3-carboxylic acid (derivative No. 1)

4 7 0 8'4

a) Method for the preparation of 8-oxobicyclo [3,2.1] octane-3-methylcarboxylate (Formula II)

To a solution of 53 g (0.386 moles) of freshly distilled N-cyclopentenylpyrrolidine and 118 ml (0.85 moles) of anhydrous triethylamine in 400 ml of anhydrous acetonitrile was added, under a nitrogen atmosphere, 100 g (0.386 moles) of dibromomethylisobutyrate in 250 ml of anhydrous. acetonitrile, maintaining the temperature of the mixture below 35. Deň: 32 ° C. The reaction mixture was then heated for 15 hours at 60 ^Q C was added 28 ml of acetic acid in 150 ml water and the mixture is heated to boiling under reflux. The acetonitrile was removed in vacuo and water (1000 ml) was added. Then mix. extracted several times with methylene chloride. By vacuum distillation, a total of 45 g of the title product was obtained in a yield of 64%.

b) Method for producing bicyclo (3,2,1) octane-3- carboxylic acid (Formula III)

A mixture of 32 g (0.176 mol) of the derivative of formula II obtained in the preceding step, 31 g of potassium hydroxide, 21 ml of 98% hydrazine hydrate and 220 ml of diethylene glycol is gradually heated to 190 to 200 ° C.

The mixture was then heated at 200 ° C for 4 hours. During this heating, methanol and water are removed by distillation. After cooling, the mixture is poured into 1000 ml of water. The resulting aqueous solution was washed with ether and then acidified with concentrated hydrochloric acid. The acid of formula III obtained is extracted with methylene chloride. In this way, 23.4 g of a colorless crystalline solid are obtained in a yield of 87%.

c) The process for the preparation of bicyclo (3,2,1) octane-3-methylcarboxylate g (0.15 mol) of the acid of formula III obtained in the previous step is refluxed for 20 hours with 75 ml of dichloroethane, 22 ml. methanol and 1 ml of concentrated sulfuric acid. After cooling, 300 ml of ether are added, the mixture is washed with water and then with 2 N potassium bicarbonate. Some of the organics are distilled off to give a total of 23 g of bicyclo (3,2,1-ketane-4-methylcarboxylate) in 91% yield. boiling point 64-65 ° C at 13 Pa.

d) A process for the preparation of 3-methylbicyclo (3,2,1) octane-3-methylcarboxylate

In an anhydrous nitrogen atmosphere, 110 ml (0.17 mol) of butyllithium in hexene (1.56 M) was placed in a 3-necked flask, and

120 ml of anhydrous tetrahydrofuran. The solution was cooled to 0 ° C and then added

17.2 g (0.17 mol) anhydrous. dilsopropylamine in solution in 30 ml tetbahydbrfuban. The mixture was stirred at 0 ° C for 15 min and then cooled to -70 to -80 ° C, then 23 g (0.137 mol) of the ester obtained above in solution in 20 ml of tetrahydrofuran was slowly added and the temperature is maintained at -70 for an hour. to -80 ° C. It is added at the same temperature

24.2 g (0.17 mol) of methyl iodide in 25 ml of hexamethylphosphoric triamide. The temperature was then allowed to rise to -20 to -10 ° C and the mixture was allowed to stand at this temperature for 4 hours.

The mixture is then hydrolyzed with water and mixed with benzene. The organic phase is washed several times with a 10% hydrochloric acid solution and then with 2 N potassium hydrogen sulphate. by this distillation. phase, 24 g of 3-methylbicyclo (3.2.1) octane-3-methylcarbxylate are obtained in 92% yield, b.p.

e) Methods for the preparation of the acid ketone The ethyl ester (3,2,1) octane-3-carboxylic acid (0.133 mol) of the ester obtained in the previous step is heated to 160 ° C under reflux for 5 hours with 14.5 g of potassium hydroxide and 1 g of sodium hydroxide. 000 ml glycol.

After cooling, 200 ml of water are added and the mixture is extracted with ether. The aqueous phase was separated and acidified. The acidic phase is extracted with benzene. 14 g of colorless crystals are obtained in a yield of 62%, m.p. 109 DEG-110 DEG C. after overfilling from hexane.

Example 2

Process for preparing sodium 3'-methylbicyclo [3.2.1] octane-3-carboxylate (derivative No. 2)

16.8 g (0.01 mol) of the acid prepared in Example 1 are mixed with a solution of sodium methylate prepared from 2.3 g of sodium in methanol. The mixture was heated at 50 ° C for 15 minutes and then the methanol was evaporated in vacuo. The colorless crystals of sodium 3-methylbenzyl (3.2.1) rectane-3-carboxylate were washed with ether and dried. The total yield is 95 percent of the theoretical, mp 270 ° C.

Example 3

Process for the preparation of 3-ethylbicyclo (3,2,1) octane-3-carboxylic acid (derivative No. 3)

In the manner described in Example 1, 3-ethylbicyclo (3.2.1) octane-3-methylcarboxylate, b.p. 91-92 [deg.] C at 590 Pa, was successively prepared from the appropriate reactants, followed by 3-ethylbicyclo (3.2, 3.2). 1) octane-3-carboxylic acid, m.p. 81-82 ° C.

Example 4

Process for the preparation of 3-isopropylbicyclo (3,2,1) octane-3-carboxylic acid (derivative No. 4)

In the manner described in Example 1, 3-isopropylbicyclo (3,2,1) octane-3-methylcarboxylate, b.p. 2.1) octane-3-carboxylic acid, m.p. 72-74 ° C.

Example 5

Process for the preparation of 3-methylbicyclo (3,2,1-octane-3-carboxamide (derivative No. 5)

8.7 g (0.0517 mol) of the acid prepared according to Example 1 in solution in 50 ml of dichloroethane and 10 ml of thionyl chloride are refluxed for 5 hours. The mixture is evaporated to dryness and the acid chloride distilled under vacuum, boiling point 45-48 ° C at 40 Pa. Dichloromethane saturated with ammonia was then added.

The mixture was evaporated to dryness, the amide was washed with water. In this way, 48 g of colorless crystals with a melting point of 110 DEG-111 DEG C. are obtained after recrystallization from isopropyl ether in a yield of 56%.

Example 6

Process for the preparation of 3-ethylbicyclo (3,2,1) octane-3-carboxamide (derivative No. 6)

The procedure described in Example 5 gave derivative No. 3 and 3-ethylbicyclo (3,2,1) octane-3-carboxamide of melting point 101 ° C.

Example 7

Process for the preparation of 3-isopropylbicyclo (3,2,1) octane-3-carboxamide (derivative No. 7)

Following the procedure described in Example 5, 3-isopropylbicyclo (3,2,1) octane-3-carboxamide of melting point 142 ° C was obtained from derivative No. 4.

Example 8

Process for the preparation of N-methyl-4-methyl-cyclo (3,2,1) octane-3-carboxamide (derivative No. 8) g (0.037 mol) of 3-methylbicyclo (3.2.1) octanecarboxylic acid chloride (see method of Example 5) The mixture is treated with a solution of 70 ml of dichloroethane, 46.6 g of methylamine and

5.2 ml of trlethylamine at 0 ° C - The mixture was allowed to stand for 4 hours. After evaporation of the solvent, 50 ml of water are added and the amide is extracted with ether and then purified on a silica gel column. 5.1 g of colorless crystals of melting point 91 DEG C. are obtained in this way.

The results of the toxicological and pharmacological tests described below show the interesting properties of the derivatives produced by the process according to the invention, in particular their low toxicity and very good tolerability, as well as good anticonvulsant and antianoxic properties.

Thus, the compounds obtained by the process of the present invention can be formulated for their anticonvulsant and antianoxic properties into medicaments which can be used against the aforementioned disease states.

All toxicopharmacological assays were performed on male Charles River (CD1) mice.

Toxicological tests:

The compounds produced by the process of the invention are well tolerated and their toxicity is low.

The DL 50 value determined by oral administration in mice by the Finney method (Probit analysis from University Press Cambridge, 1971) is 3000 mg / kg for derivative No. 5 and greater than 1000 mg / kg for all other compounds produced by the method of the invention .

In addition, experiments carried out on acute toxicity, chronic, subchronic and delayed toxicity and on teratogenic properties did not show any anomalies.

The efficacy of these substances, in particular the sedative effect, was also determined during these experiments. For this purpose, a rotating cylinder experiment was used as described in Boissier, J. R., Therapie 1958, 13, 1074.

This test is based on monitoring the ability of animals to coordinate movements. Animals are placed on a cylinder of diameter 4.8 cm, the roll is rotating at a speed of 4 rpm ^first Usually a wooden cylinder is used. The experiment is performed on mice with an average weight of 22 g. The test substances are administered orally to different groups of 10 mice each. Mice are placed on the roller 15 minutes after administration of the test substance. The percentage of mice that lose parallel reflexes is monitored, that is, they are not held on the roller for at least 2 minutes.

The neurotoxic dose is then calculated as described above by Finney

DNT 50, which expresses the results obtained using a particular test substance. The values obtained for the individual compounds produced by the process of the invention are given below.

compound no.

DNTso

600 mg / kg

365 mg / kg

400 mg / kg

230 mg / kg

500 mg / kg

Pharmacological tests

I. Antispasmodic effect

1. Pentetrazole shock

This experiment was performed on groups of 10 mice that were housed in separate cages according to the method of Cheymol, J. Acta Pharmacol, 1950, 2, 1-55.

The test substance was administered orally, 15 minutes before the intraperitoneal injection of a 125 mg / kg solution of pentetrazole. In each group, a certain percentage of mice that were protected against tonic seizures could be detected. The effective dose of DE 50 was calculated by the Finney method and expressed in mg / kg body weight. The following values were obtained for the individual compounds produced by the process of the invention:

compound no.

120

115

By comparison, the DE 50 for sodium valproate, which is a very potent anticonvulsant drug, is 200 mg / kg.

2. Supramaximal electric shock

This experiment was performed according to the method of Swinyard et al., Am. J. Pharmacol, Ther., 1952, 168-175. The active compounds were administered orally to groups of 10 mice 30 minutes prior to supramaximal electric shock. An alternating current of 50 Hz, 60 V, duration of 0.4 seconds was used, and intraauricular electrodes were used simultaneously. The percentage of animals that did not exhibit tonic hyperextension on electrical stimulation was recorded, expressed as DE 50 in mg / kg.

compound no.

3. Bicucline-induced crisis

The procedure was carried out as described by Pérez de la Mora and Tapia, Biochem. Pharmacol., 1973, 19, 303-310. Test substances were administered orally to groups of 10 mice 30 minutes prior to the injection of 0.65 mg / kg of bicuculin intravenously. The appearance of tonic seizures was recorded 30 minutes after the injection of biculculin. In this way, the following DE 50 values in mg / kg were found for the individual substances produced by the process according to the invention.

compound no.

145

4. Crisis caused by β-mercapto-propionic acid

Acid / Smercaptopropionic is an inhibitor of glucamate decarboxylase (GAD), an enzyme that catalyzes the conversion of glucamate to γ-aminobutyric acid (GABA). The action of this acid is also manifested by a reduction in the ratio of GABA and the development of generalized tonic-clonic seizures 3 to 4 minutes after administration. ((-Mercap1: opropionic acid) was administered to mice intraperitoneally at a dose of 60 mg / kg. The test substances were administered orally 15 minutes prior to the administration of .epsilon.-mercaptopropionic acid. mg / kg.

compound no.

290

530

660

7120

870

II. Antianoxic efficiency ...

This activity was monitored for anoxin in a confined space.

Mice of 20 per group were placed in a glass container and the 200 ml container was hermetically sealed. All treatments were performed intraperitoneally just prior to sealing into a container. The animals were considered dead in respiratory arrest.

Since the containers selected were very small, the motor activity of the animals was also very low, which in principle does not allow a positive result in the form of a soothing effect.

Individual survival observations were performed on groups of animals.

2400

5210

6210

7260

8310

247033

Survival time was prolonged by 0-15% when Compound No. 2 was administered and by 25% when Compound No. 5 was administered.

Toxicological and pharmacological tests make it possible to conclude that the therapeutic index of the compounds. produced by the process of the invention is very favorable because it is toxic and neurotoxic. the dose is very far from the dose of DE 50.

In addition, the compounds produced by the process according to the invention have very interesting anticonvulsant and antianoxic properties, so that they can be widely used for therapeutic purposes.

Dosage forms containing these substances can be administered orally in the form of tablets, dragees, capsules, drops, granules or syrups. They can also be administered rectally in the form of suppositories and parenterally in the form of solutions suitable for injection.

A single dose preferably contains 0.050 to 0.500 g of active ingredient, the daily dose being in the range of 0.050 to 3.00 g of active ingredient, depending on the age of the patient and the severity of the disease.

In the following, the compositions of some of the active ingredient formulations produced by the process of the present invention will be exemplified.

Tablets Derivative No. 2: 0.200 g excipient: calcium silicate, polyvinylpyrrolidone, magnesium stearate, talc, corn starch, titanium dioxide, cellulose acetyl phthalate.

2. Film-coated tablets - dragee derivative No 5: 0,100 g excipient:

starch (Levilit), gelatin, magnesium stearate, rubber lacquer, talc, acacia, sucrose, titanium dioxide.

3. Gelatin capsules derivative No 6: 0.150 g excipient:

talc, magnesium stearate.

4. Syrup derivative No 5: 1,00 g

flavorings up to 100 ml

5. Solution for Injection Derivative No. 7: 0.150 g Isolar solvent to a volume of 5 ml.

6. Lace derivative No. 8: 0.100 g

Semi-synthetic glycerides in an amount usually used to make suppositories.

Due to their neuropsychotropic activity, which is particularly effective against convulsions and anti-anxiety while maintaining alertness, the compounds according to the invention can be used in adults and children for the treatment of acute or chronic conditions such as cyclothymia, manic depression, mania attacks , depressive states, melancholy and various other psychotic and behavioral disorders, as well as all forms of epilepsy and brain aging-related disorders.

Claims (1)

A process for the preparation of novel bicyclo (3,2,1) octane-3-carboxylic acid derivatives of the general formula I BEFORE. MET cqor '(') (III b ⁾ wherein, R 'represents a straight or branched chain lower alkyl, this ester is reacted with a strong base such as sodium amide, lithium dimethylamide or lithium diisopropylamide prepared in the reaction mixture in a solvent , for example tetrahydrofuran, to form an organometallic intermediate of formula IV wherein R is a straight or branched chain alkyl radical of 1 to 3 carbon atoms, Z represents an OX group in which X represents a hydrogen atom or an alkali metal atom, or Z represents a group of the general formula Rl / N \ R2 where R 1 and R 2, the same or different, represent a hydrogen atom or methyl, characterized in that the 8-Oxobicyclo (3,2,1) -octane-3-methylcarboxylate of formula II is converted COOCH ₃ (II) treatment of the acid of formula III (1 V) with potassium hydroxide and hydrazine in a polar solvent at a temperature of 190 to 200 ° C where R ‘is as defined above and B is an alkali metal atom, and the intermediate is then converted by treatment with an alkyl halide of formula R - X where R is as defined above, at a temperature of -20 to -10 ° C to the compound of formula V COOR (V) where R and R 'are as defined above, and converted to an acid of formula I wherein Z is OH and optionally converted to another compound of formula I wherein Z is defined by refluxing , different from OH. this acid is converted to the corresponding ester of formula IHb