NO156608B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE AMIDES OF 4-AMINO ACID ACID. - Google Patents

Abstract

1. Claims for the Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE Amides of 4-aminobutyric acid corresponding to general formula : see diagramm : EP0046707,P19,F3 in which : R designates a linear or branched alkyl group having from 1 to 7 carbon atoms or a cycloalkyl group ; m represents an integer of from 0 to 3 ; n represents an integer of from 0 to 2, on condition that m + n is equal to or greater than 1 ; X represents hydrogen, a lower alkyl group (1 to 4 carbons), a phenylalkyl group in which the phenyl group is possibility substituted, R1 and R2 considered separately designate hydrogen, a linear or branched alkyl group having from 1 to 18 carbon atoms, an aralkyl group, a cycloalkyl group or a possibly substituted phenyl group, or R1 and R2 considered together with the nitrogen atom to which they are attached represent a heterocycle with 5 or 6 groupings possibly comprising a second heteroatom such as pyrrolidine, morpholine, piperazine or pyridine and its partially or totally hydrogenated derivatives. 1. Claims for the Contracting State : AT Process for preparing amides of 4-aminobutyric acid corresponding to general formula (I) : see diagramm : EP0046707,P20,F3 in which : R designates a linear or branched alkyl group having from 1 to 7 carbon atoms or a cycloalkyl group ; m represents an integer of from 0 to 3 ; n represents an integer from 0 to 2, condition that m + n is equal to or greater than 1 ; X represents hydrogen, a lower alkyl group (1 to 4 carbons), a phenylalkyl group in which the phenyl group is possibly substituted, R1 and R2 considered separately designate hydrogen, a linear or branched alkyl group having from 1 to 18 carbon atoms, an aralkyl group, a cycloalkyl group or a possibly substituted phenyl group, or R1 and R2 considered together with the nitrogen atom to which they are attached represent a theterocycle with 5 or 6 groupings possibly comprising a second heteroatom such as pyrrolidine, morpholine, piperazine or pyridine and its partially or totally hydrogenated derivatives, characterized in that the starting product is constituted by an aminoacid of formula : see diagramm : EP0046707,P20,F4 in which m, n and X are such as defined above and R' is a hydrogen atom or a lower alkyl group (1 to 4 carbon atoms), said product is reacted on an acid chloride of formula R-COCI so as to convert the amine of the starting product into an amide radical and the product obtained is subjected to an amidification with a product of formula see diagramm : EP0046707,P21,F1

Description

The invention relates to a method for the production of therapeutically active amides of 4-aminobutyric acid, these derivatives particularly having a pharmacological effect on the central nervous system.

The derivatives produced according to the invention are products corresponding to the general formula:

where:

R is a straight-chain or branched alkyl group with 1-7 carbon atoms, or a cycloalkyl group; m is an integer that is 0-3; n is an integer that is 0-2, where m+n is equal to or greater than 1; X is hydrogen, an alkyl group with 1-4 carbon atoms, a phenyl-alkyl group where the phenyl group is optionally substituted with two methoxy groups; and R 2 are each hydrogen, a straight-chain or branched alkyl group of 1-18 carbon atoms, a benzyl group, a group or R^ and R 2 form, together with the nitrogen atom to which they are attached, a morpholine, pyrrolidine, pyridine group or a group These compounds show interesting activities on the central nervous system and can especially be used as sedatives, sedatives, hypnotics or anxiolytics. The method according to the invention is characterized in that a compound of the formula where m, n and X have the above-mentioned meaning, and R' is H or lower alkyl, is reacted with an acid chloride of the formula R-COC1 to convert the amine into an amide, as the reaction is carried out in a suitable solvent and in the presence of an acid acceptor, and the product obtained is subjected to amidification using an amine of formula

The reaction scheme for the method according to the invention is thus as follows:

From the amino acids or esters 1_ known compounds, the acids or amide esters 2 are obtained by the action of acid chloride R-COC1 in a suitable solvent, for example water, ether or a lower aliphatic alcohol and in the presence of a mineral or organic hydrogen acid acceptor, and especially sodium carbonate or triethylamine.

The acids or esters amide 2 are isolated in the reaction mixture and are most often used as they are without purification for the following step.

The amidification reaction of product 2 can be carried out according to different methods.

When R<1> is lower alkyl, the reaction can be carried out in solution in a lower aliphatic alcohol or by using an excess

of amine

as a solvent. One usually works

at a temperature between 0 and 50 C and for a period of from 1 hour to several days.

When R' is H, this acid can for example be converted into a lower ester, in which case the reaction is carried out as described above, for example by converting this acid into a mixed anhydride. Such a conversion is carried out by allowing the acid to react with ethyl chloroformate in the presence of an alkaline material, for example triethylamine. One works in a suitable solvent, for example tetrahydrofuran, at a temperature of from 0 to 40°C and without the need to isolate this mixed anhydride. •

The following examples, which are not meant to be limiting, make it easier to understand the idea of the invention.

Example 1

10-butyl-4,9-dioxo-5,10-diazatetradeca (CM 40039)

(I) R = CH 3 -(CH 2 ) 2 -; m = n = 1; X = H; R x =R 2 = -(CH 2 ) 3 CH 3 .

a) To a solution of 10.3 g of 4-aminobutyric acid in 110 ml

of an aqueous solution of 2N sodium carbonate cooled on ice

11.7 g of butyryl chloride are added dropwise while stirring.

After the addition is complete, the agitation continues i

4 hours.

The aqueous solution is washed with methylene chloride, acid

then make the water phase and saturate with sodium chloride. It is extracted with methylene chloride, dried over sodium sulphate and evaporated to dryness under vacuum. The solid evaporation residue is stirred three times with 300 ml of pentane and dried under vacuum. The yield is 9.1 g, which is used as is for the following operation.

b) The acid obtained above (9.1 g) is dissolved in

200 ml dry tetrahydrofuran. 6.06 g of triethylamine is added

and 6.51 g of ethyl chloroformate by maintaining the temperature below or at 5°C. Stirring is carried out for 1 hour and then 7.74 g of dibutylamine are added dropwise. This is allowed to stand overnight with stirring at ambient temperature.

The insoluble material is filtered and the solvent is evaporated to dryness. The evaporation residue is taken up in ether and the solution is washed with a dilute hydrochloric acid solution, after which a dilute sodium carbonate solution is added and finally an aqueous solution saturated with sodium chloride. The ether solution is dried over sodium sulphate, the solvent is evaporated to dryness and the evaporation residue is distilled under vacuum. 6.2 g of a pale yellow liquid is obtained. Boiling point at 0.01 mm: 170°C.

Example 2

One works as indicated in example 1, but varies the amine that was used in section b).

The products (I) are thus obtained: R = CH3(CH2)2, m = n =

1, X = H, which appears from table I below.

Example 3

You work as indicated in example 1, but vary on

on the one hand the acid chloride used in the first step and possibly, on the other hand, the amine used in the second step.

The products (I) described in are thus obtained

table II below.

Example 4

5- butyl- 12- ethyl- 13- methyl- 6, ll- dioxo- 5, 10- diaza-pentadecane

(CM 40195)

a) To 9.18 g of the benzyl ester hydrochloride of 4-aminobutyric acid dissolved in 100 ml of tetrahydrofuran, add 8.08 g

triethylamine. Cool using an ice bath and then add, dropwise, 6.5 g of the acid chloride of 2-ethyl-3-methyl-pentanoic acid. This is allowed to stand overnight with stirring at ambient temperature and then the reaction mixture is filtered and the solvent is evaporated to dryness.

The evaporation residue is taken up in ethyl acetate, washed with water and then with a dilute sodium carbonate solution, again with water and then with a dilute hydrochloric acid solution and finally with a saturated sodium chloride solution. The solution is dried over sodium sulfate and the solvent is evaporated to dryness under vacuum.

11 g of the benzyl ester of 7-ethyl-8-methyl- are thus obtained. 6-oxo-5-aza-1-decanoic acid. This ester (11 g) is dissolved

in 150 ml of ethanol (96%) and hydrogenate at atmospheric pressure in the presence of 1 g of palladium over carbon with 10% palladium. After the reaction is complete, the catalyst is filtered and evaporated to dryness under vacuum. To the evaporation residue which has been taken up in 100 ml of anhydrous ether, 6 g of dicyclohexylamine are added and this is allowed to stand overnight at 0°C. The formed salt is dewatered and washed with ether, weight: 7.8 g.

The salt thus obtained is dissolved in 100 ml of water. The solution is cooled in ice and acidified with concentrated hydrochloric acid to pH = 1.5. The solution is saturated with sodium chloride and extracted with ethyl acetate. The organic solution is washed three times with a saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness.

3.9 g of 7-ethyl-8-methyl-6-oxo-5-aza-1-decanoic acid is thus obtained.

b) According to the technique described in the example

1 b), dibutylamine is allowed to react with this acid. On the same

way one obtains CM 40195 in the form of an oil; kp./0.01 mm : 200°C.

Example 5

4, 12- dioxo- 5, 13- diaza-heptadecane (CM 40387)

a) To an ice-cooled solution of 5.2 g of 7-aminoheptanoic acids

in 80 ml of 4N sodium carbonate is added slowly while stirring

4.8 g of butyryl chloride. Agitation is continued for 4 hours and then acidified to pH = 2 with hydrochloric acid. Extract with ethyl acetate, dry the solution over sodium sulphate and evaporate the solvent to dryness under vacuum.

4.2 g of an oil which crystallizes is obtained. One re-crystallises in hexane; m.p.: 68°C.

b) To the solution of 2.3 g of the obtained acid, described above, in 30 ml of dry tetrahydrofuran, 1.1 g is added

triethylamine and then 1.2 g of ethyl chloroformate. This is allowed to stir for 2 hours and then slowly 0.85 g of butylamine in 5 ml of tetrahydrofuran is added to the solution. Stirring is continued for 15 hours at ambient temperature and water is then added and extracted with ethyl acetate. The organic solution is washed with a solution of sodium carbonate, dried over sodium sulfate and the solvent is evaporated to dryness. The evaporation residue is recrystallized in acetonitrile; m.p. 132°C:

Example 6

By working as indicated in example 5 and starting from different amino acids 1. and by varying the reactants R-COC1 and

the products (I) described in the table are obtained

III below.

Example 7

2, 7- dioxo-l, 6- diaza- decane (CM 40401)

(I) R = CH (CH 2 ) 2 -; m = n = 1; X = H; Rx = R2 = H.

a) To a solution of 17 g of 6-oxo-5-aza-l-nonanoic acid (obtained according to Example 1 a) above) in 500 ml absolute

ethanol, add 10 ml of concentrated sulfuric acid and stir for 4 hours at ambient temperature. The solvent is evaporated at 30°C under vacuum and the residue taken up in ice water. Neutralize by adding sodium bicarbonate and then extract with methylene chloride. It is dried over sodium

sulfate and evaporate to dryness.

16 g of the desired ethyl ester are obtained.

b) The 16 g of ethyl ester obtained above are introduced into 300 ml of a solution of 16% ammonia in methanol. Mon

stir for 5 hours at ambient temperature. The solvent is evaporated to dryness and the evaporation residue is taken up in ether. The solid is dewatered and washed with acetonitrile.

Colorless crystals (10 g) are obtained; m.p. 135°C (acetonitrile).

Example 8

6 - (3, 4- dimethoxy- benzyl)- 4, 9- dioxo- 5, 10- diaza- tetradecane

By replacing, in the first reaction, the 4-chlorobenzoyl chloride with an equivalent amount of butyryl chloride.

In the same way, the desired compound is obtained in the form of a colorless solid; m.p.: 152°C.

The products obtained were subjected to various tests concerning their pharmacological activity and in particular their impact on the central nervous system.

A) - Pharmacological activity

1) - Sedative and hypnotic effect

a) Actographic study

The measurement of actography is carried out on mice for 45 min. after

administration of the product. You work with groups on

12 animals, and each of them is isolated for 10 min. before the measurement. Counting of points is carried out by cutting off two beams of light that are perpendicular.

In Table IV below, the results obtained are collected which relate to different products manufactured according to the invention, administered in a dose of 500 mg/kg per orally. The results are expressed as percentage variation of the points obtained in relation to the non-treated control animals.

It can be seen that the products fall into two groups: - products that induce hypomotility, such as 40217, 40039, 40271, 40272, 40319; in the case where the treated animals show a loss of turning reflex, which gives an expression of the correct anesthetic effect of the product, PRR has been noted;

- such products that induce hypermotility, such as 40142, 40398, 40397, 40404, 40253, 40355, 40209; in order to clarify the results obtained, the study for two products has been repeated in an effective dose according to the same procedure.

The results obtained are collected in table V below.

b) Potentiation of pentobarbital anesthesia

The products to be studied were administered by us

to mice at a dose of 500 mg/kg, 1 hour before the pentobarbital was injected intraperitoneally in an amount of 20 mg/kg.

The percentage of animals that have lost the turning reflex is determined. The results are expressed as a percentage or, in some cases, in effective dose 50 (DE 50 ) or as the dose that induces anesthesia in 50% of the treated animals.

The results are set out in Table VI below.

c) Electroencephalographic study

To better understand the hypnotic activity of compounds

which are produced according to the invention, an electroencephalographic study was carried out on one of them, i.e. CM 40039.

Compound 40039 has been studied at a dose of 350 mg/kg p.o. in three rats. After a habituation period of 10 days (light period from eight o'clock to midnight and dark period from midnight to eight o'clock), the animals were recorded for 5 days with the solvent (gum arabic, 10%), and then recorded for 4 days where they received the product at nine o'clock every morning. After this chronic administration, the animals were recorded for 5 following days (control period).

Results:

The animals were registered alive at the 24th hour. The statistical study covers a period of 24 hours. A global analysis is made of the three rats by cumulating the 15 control days, the 12 days of treatment and the 15 days of control. In each hour group of 24 hours, the waking time (EV), sleep time (SL), the paradoxical sleep (SP), the 'total sleep (ST), as well as the ratio (in percent) paradoxical sleep/total sleep (SP/ST) are assessed

(Table VII below).

In each period of the study, the recordings did not reveal morphological modifications of the encephalographic diagram.

The compound induces a decrease in arousal significance (-8.1%) that corresponds to a significant increase in light sleep (+6.6%).

This effect persists in the control phase.

2) - Anticonvulsant effect

The anticonvulsant effect was determined in relation to convulsive crises induced by electroshock or by means of bicuculline.

The electroshock (12.5 V for 0.5 sec.) is applied to the mouse

60 min. after administration of the compound orally.

The bicuculline is administered to the mouse intravenously in a

amount of 1 mg/kg, 60 min. after the connection to be studied has been given per us. The protective effect achieved in relation to tonic crises is noted.

By working with different groups of animals with different doses of the compound to be studied, one can determine the effective median dose (DE 50).'

The results are collected in table VIII below and show

the pure anticonvulsant properties of the studied products.

B) - Biochemical study

a) Effect on the GABA level (4-aminobutyric acid)

Compound 40039 was administered 30 min. before the mouse

was killed. The GABA level was assessed on the whole brain (group of 6 animals) (see Table IX below).

Compound 40039 induces a rapid increase in GABA-

degree in the total brain of the mouse.

b) Effect on the central dopaminergy

The effect of the compounds on the central dopaminergy

activity was studied by means of the accumulation of homovanillic acid over a period of 24 hours after administration of the compounds to mice.

The amount of homovanillic acid (HVA) is assessed in the whole brain, as the animals receive an injection of probenecid (200 mg/kg i.p.)

1 hour 30 min. before they are killed (group of 10 animals).

The two compounds induce effects close to the HVA value,

in that they particularly cause an increase in concentration 4 hours after they are administered, and a strong lowering 24 hours after they are administered (see Table X below).

c) Acute toxicity

The compounds to be studied are administered ad

oral route with doses of 500 and 1000 mg/kg to groups of mice. The mice are observed for 24 hours and their mortality recorded.

The results, expressed in percentage mortality, appear in Table XI below.

The results indicate that in a single dose of 500 mg/kg, all have

the studied compounds showed no sign of acute toxicity. At 1000 mg/kg, a very elevated dose, some compounds show a "toxicity of 100%, but in most at-

In other cases, the acute toxicity remains weak or zero.

The experiments thus carried out show that the compounds produced according to the invention present a combination of pharmacological properties which are interesting,

and they have low toxicity. Consequently, they can be used in human therapy, especially for the treatment of neurological and psychological affections.

The compounds produced according to the invention can be used in particular for the treatment of mental or behavioral disorders: nervousness, irritability as well as for the treatment of anxiety states and insomnia.

These compounds can be administered orally or injected. The pharmaceutical preparations can be in solid or liquid form and, for example, take the form of tablets, capsules, granules, suppositories or injectable preparations.

The dosage can vary within wide limits, especially depending on the type and severity of the disorder to be treated, and that according to the method of administration. Most often in adults, orally, the dose will be between 0.100 and 1 g per day, possibly divided into several times.

In the following, a number of examples of pharmaceutical preparations will be given.

Capsules

Pills

Claims (3)

1. Analogous method for the production of therapeutically active 4-amino-butyric acid amides with the following formula: where: R means a straight-chain or branched alkyl group with 1-7 carbon atoms or a cycloalkyl group; - m represents an integer that is 0-3; n represents an integer that is 0-2, with it condition that m+n is equal to or greater than 1; X represents hydrogen, an alkyl group of 1-4 carbons atoms, a phenylalkyl group where the phenyl group is optionally substituted with two methoxy groups; R 1 and R 2 each stand for hydrogen, a straight chain or branched alkyl group with 1-18 carbon atoms, a benzyl group, a group or R1 and R2 represent, together with the nitrogen atom to which they are attached, a morpholine, pyrrolidine, pyridine group or a group characterized by a compound of formula: X Hz N-(CHz)»-CH-(CH2)n-COOR' where m, n and X have the meaning given above, and R' is H or lower alkyl, is reacted with an acid chloride of the formula R-COC1 to convert the amine into an amide, the reaction being carried out in a suitable solvent and in the presence of an acid acceptor, and that the product obtained is subjected to amidification using an amine of the formula 2. Method as stated in claim 1 for the preparation of a compound of formula characterized by using 4-aminobutyric acid as starting material. 3. Process as stated in claim 1 for the preparation of a compound of formula characterized by using 4-aminobutyric acid as starting material.