CS226200B2 - Method of preparing 4-amino-5-alkylsulphonylortho-anisamide derivatives - Google Patents

Description

(54) A method for producing 4-amino-5-alkylsulfonyl orthoanisamide derivatives,

The present invention provides a process for the preparation of novel 4-amino-5-alkylsulfonyl orthoanisemide derivatives of formula (I)

(I) where

R1 is methyl, ethyl, R1 is methyl, ethyl, propyl or alkyl and propyl or isopropyl, as well as their N-oxides, their quaternary ammonium salts, pharmacologically acceptable acid salts, and their dextrorotatory and levorotatory isomers, and The process according to claim 1, characterized in that the acid of the general formula II

COOH

OCH ₃ ^ 2θ2 ^

NH, (II) wherein

R 1 is as defined above, or to any of its reactive derivatives, such as an acid halide, alkyl ester, reactive ester, e.g., methoxymethyl ester or cyanomethyl, ester, aromatic ester, N-hydroxyimidestar, symmetrical anhydride or mixed anhydride from a formic halide ester, azide, hydrazide, azolid, acidic isothiocyanate, trichloroacetophenone or triphenylphosphine derivative, is treated with a dihaloalkylamine of formula IV

H ₂ N - CH 3 - ((IV)

Hal Hal where

Hal is chlorine or bromine, whereupon the compound of formula (V) is obtained

where

Rg, as defined above, is reacted with an amine of formula VI

H ₂ NR, (VI) wherein

R1 has the above-mentioned meaning

Amidification can be carried out directly in the reaction mixture or after isolation of the intermediate from the reaction mixture.

Equally well, the free acid and the free amine can be reacted in the presence of a condensing agent such as silicon tetrachloride, trichlorophenylsilane, phosphoric anhydride, carbodiimide or alkoxyacetylene.

The amidification may be carried out in a solvent or in the absence of a solvent.

A solvent which is inert to the reaction may be used, for example, alcohols, polyols, ketones, benzene, toluene, dioxane, chloroform or diethylene glycol dimethyl ether. The solvent may also be an excess of the amine used as starting material. The reaction mixture is preferably heated during the reaction, for example to the boiling point of the solvent used.

The compounds of the invention may optionally be reacted with pharmaceutically acceptable acids, inorganic or organic,

for example with hydrochloric, hydrobromic, sulfuric, phosphoric, oxalic, acetic, tartaric, citric or methanesulfonic acid to form acid addition salts.

If desired, the resulting product can be reacted with helides or alkyl sulfates to form quaternary ammonium salts.

The resulting product can also be oxidized in a known manner, for example with hydrogen peroxide and manganese dioxide, to give the corresponding N-oxides.

The invention will be illustrated by the following examples.

Example 1

N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide

Mixed ethylbicarbonate anhydride and 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid

77.7 g of 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid and 500 ml of anhydrous dioxane are placed in a flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, followed by 30.3 g of triethylamine.

The mixture was cooled to 20 ° C and then 32.5 g of ethyl chloroformate was added dropwise while maintaining the temperature of the reaction mixture at 20 ° C.

The mixture was stirred, filtered and the filtrate evaporated in vacuo. The residue is dissolved in 500 ml of carbon tetrachloride and crystallization is initiated by the addition of several crystals.

The crystals formed upon cooling of the mixture were collected by filtration, washed and dried.

74 g (74.5%) of the title anhydride, m.p. 77 ° C.

N- (2,5-dichloropentyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide

4.33 g of 2,5-dichloropentylamine hydrochloride, 65 ml of dimethylformamide and 2.27 g of triethylamine are placed in a flask equipped with a stirrer, a thermometer and a reflux condenser, and then 7.47 g of mixed ethylhydrogen carbonate anhydride and 2-methoxy-4- are added. amino-5-ethylsulfonylbenzoic acid.

The mixture was stirred at room temperature for one hour, then 100 ml of water and 10 ml of hydrochloric acid were added.

The suspension obtained is evaporated to dryness in vacuo and the residue is dissolved in 100 ml of water.

The crystals formed were collected by filtration, washed with water and dried at 50 ° C.

6.5 g of N- (2,5-dichloropentyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide, m.p. 109 [deg.], Are obtained in 73% yield.

N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide

5.95 g of N- (2,5-dichloropentyl) -2-methoxy-4-amino-5-ethylsulfonylbenzemide and 22 ml of a 56% aqueous solution of ethylamine are placed in a flask equipped with a stirrer.

The mixture was stirred until the solids were completely dissolved, then the solution was heated to 40-45 ° C until the reaction was complete.

The solvent was evaporated and the residue was mixed with 100 ml of water and 5 ml of sodium hydroxide solution.

The solution is extracted twice with methylene chloride, the organic phase is dried over magnesium sulphate, filtered and the solvent is evaporated off under vacuum.

The residue is dissolved in 10 ml of acetone at the boiling point of the crystals formed after cooling, separated by filtration and dried at 50 ° C.

3 g of N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide are obtained in a yield of 54%, m.p.

Example 2

N- (1-methyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsalphonylbenzamide g N- (2,5-dichloropentyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide and 50 ml of methylamine is placed in a container which is hermetically sealed and allowed to stand at room temperature for several days.

The excess methylamine was evaporated and the residue was mixed with 300 ml of water. The mixture was then acidified to pH 1 by addition of 1.18 hydrochloric acid, and the solution was filtered.

40% sodium hydroxide is added to the filtrate until pH 10, the precipitate formed is filtered off, washed with water, dried at 40 ° C, recrystallized from 110 ml of ethanol and dried at 60 ° C.

Yield 18.6 g of N- (1-methyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5'-ethylsulphonylbenzamide, m.p. 157 ° C.

Example 3

N- (1-allyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide

A 250 ml flask equipped with a stirrer, a thermometer and a condenser was charged with 7.9 g of N- (2,5-dichloropentyl-2-methoxy-4-amino-5-ethylsulfonylbenzamide and 7.7 g of allylamine). at room temperature and then poured into 150 ml of water.

10 ml of 40% sodium hydroxide are added and the suspension obtained is extracted four times with 70 ml of methylene chloride.

The organic solution is washed three times with 50 ml of water, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo.

The residue is treated three times with 10 ml of ether and the crystals formed are filtered off, dried and recrystallized from ethanol.

2.8 g of N- (1-allyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide are obtained in a yield of 37%, m.p.

Examples 4 to 6

The following compounds were prepared according to the above examples using the appropriate starting materials:

N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-propylsulfonylbenzamide, m.p. 106 ° C.

N- (1-methyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide, m.p. 190 ° C.

N- (1-ethyl-2-pyrrolidinylmethyl) -2-methoxy-4-emino-5-methylsulfonylbenzamide, m.p. 151 ° C.

The compounds of the present invention may be formulated as capsules, tablets, pills, granules or injectable solutions. The preparation of these dosage forms is known per se. Longer additives which are inert to the compounds of the invention, such as, for example, laviline, alkali metal lauryl sulfate, sucrose, and other carriers commonly used for this purpose may be used.

The compounds of the invention may be administered at doses of 50 to 750 mg per day or in divided doses. The preferred dose is 150 to 200 mg per day.

The following examples describe pharmaceutical preparations which contain as active ingredient any of the compounds produced by the process according to the invention.

Example 7

Tablets

The tablet can be made from the following mixture:

Component Mg N- (1-ethyl-2-pyrrolidilmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide 100 ALIGN! dry starch 20 May lactose 100 ALIGN! methylcellulose 1,500 cps 1.5 levilit 9.5 magnesium stearate 4

Example 8

Tablets

The tablet can be made from the following mixture:

Component Mg N- (1-Methyl-2-pyrrolidylmethyl) -2- -methoxy-4-amino-5-ethylsulfonyl- benzamide 50 lactose '50 dried starch 10 methylcellulose 1,500 cps (3% water) 0,687 levilit 6,803 magnesium stearate 2.51 Example 9 Solution for injection Solution for injection It is possible to prepare of the following components:

Component Mg N- (1-allyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulphonylbenzamide 100 ALIGN! 1 N hydrochloric acid 0.26 ml sodium chloride 8

The mixture is made up to a volume of 2 ml with water for injection.

In the preparation of tablets, the active ingredient selected is mixed with starch and lactose and the resulting mixture is granulated with the addition of methylcellulose. Levillite, magnesium stearate and talc are added to the granulate prior to compression.

The methylcellulose may be replaced by any other granulating agent such as methylcellulose, polyvinylpyrrolidone or starch paste.

Magnesium stearate can be replaced by stearic acid. In the preparation of injectable solutions, the active substance can be dissolved in hydrochloric, levulic, gluconic or glucoheptanoic acid.

A solution prepared from the same conditions is converted to an isotonic solution by addition of an alkali metal chloride such as sodium chloride and then a preservative is added.

The preservative may also be omitted. The ampoules are filled under nitrogen and sterilized at 100 ° C for 30 minutes.

The acute toxicity of the compounds of the invention was studied in mice. LD ^ q for male mice is shown in the following table:

^LD 50 P ^R0 ®ySí male mg / kg

Merge- nina Intravenously. Intraperitoneally Podkožně Orally 1 56 to 60 175 to 180 224 to 250 1,024 to 1,054 2 56 to 57 210 to 217 280 1,320 to 1,330 3 · 106 to 107 216 to 217 312 to 330 2,232 to 2,375 4 39.8 188 254 to 263 1 564 to 1 621 5 44.8 122 to 128 137 to 49 1,109 to 1,160 6 62 to 64 304 to 322 380 to 396 1 166 to 1 260 7 43 to 46.8 160 to 165 140 to 144 570 to 629 8 46.5 to 50 234 to 238 208 to 225 625 to 660 9 54 200 to 216 202.5 996 to 1,050

1: N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide

2: N- (1-Methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide

3: N- (1-Allyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide

4: dextrorotatory N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide tartrate

5: Left-handed N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide tartrate

6: dextrorotatory N- (1-methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide

7: N- (1-Ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-propylsulfonylbenzamide

8: N- (1-ethyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulphonylbenzamide

9: N- (1-Methyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide.

The cataleptic effect was monitored as follows.

Benzamides were administered subcutaneously to male rats. The criterion for the cataleptic state was the immobility of the animal for 30 seconds, the animal having its hind paws stretched out and placed on wooden blocks 4 cm high, i.e. in an unusual and uncomfortable position.

The cataleptic effect is measured at its maximum, i.e. 5 to 7 hours after administration of the active ingredient.

At a subcutaneous dose of 200 mg / kg, the benzamides 1 to 4 and 6 to 8 had absolutely no cataleptic activity, Compound No. 5 induces a ketaleptic state in only 30% of the test animals after 7 hours.

Further pharmacodynamic experiments have been carried out with the compounds according to the invention, in particular with regard to their anti-vomiting effect compared to epomorphine.

The experiment was performed on dogs according to Chen and Anson.

The compounds of the invention are administered subcutaneously 30 minutes before epomorphine, which is also administered subcutaneously at a dose of 100 µg / kg.

The results are shown in the following table.

EDjq for antiapomorphine effect in dogs at subcutaneous dose, expressed in µg / kg

Compound 1 2 3 4 5 6 7 8 9 ^ 50 0.29 0.8 0.65 12 0.28 8 1.6 2.7 7

The results of this assay demonstrate antagonism to apomorphine, which is 5 to 20 times greater than that of known compounds, suggesting that the compounds of the invention have a strong central nervous system effect. Furthermore, experiments on antlaerotonin effect were carried out, not on gastric ulcers in rats and bronchial spasms in guinea pigs.

The antlaerotonin effect on gastric ulcers in rats was studied under the following conditions.

mg / kg serotonin was administered subcutaneously to female rats in two portions over a 16 hour period. The study drug was administered subcutaneously at the same time as serotonin, also in two portions at increasing doses. A group of 30 animals was used for each dose, as a control group 60 animals were used.

The animals were sacrificed 22 hours after the first injection of serotonin and after withdrawal the stomachs were examined. The degree of protection for each dose was determined as a percentage, after which the ED ₅₀ , i.e. the dose protecting 50% of the test animals from gastric ulceration, was determined.

The results are shown in the following table:

ED <? Q for antieerotonin effect on gastric ulceration in rats, expressed in mg / kg by subcutaneous administration of the active substance

Compound

ED

0.4 0.63 0.46

0.34 to 0.44 3.2 3 1.14

The antiserotonin effect on bronchial spasm was studied in guinea pigs under the following conditions.

The bronchial spasm was recorded according to the method of Konzett and Rossler, in which the urine trachea is connected to a pump that provides artificial respiration and delivers a constant volume of air that is slightly higher than the animal's resorption capacity in physiological rhythm. The excess air, which varies according to the bronchial diameter, is discharged to a separate pressure gauge, which measures the air volume at each inhalation.

The guinea pigs are pre-anesthetized with ethyl carbamate, then serotonin is administered to an intravenous guinea pig at a dose of 50 µg / kg, causing a bronchial spasm.

The test substance is administered intravenously and serotonin is administered after 1 minute. Percentage of bronchial spasm inhibition is measured for each dose of effective dose, and ED ₅₀ for antiserotonin effect in the bronchial spasm in guinea pig is determined.

The results are shown in the following table:

ED ₁₀ for antiserotonin effect in guinea pig bronchospasm, expressed in µg / kg by intravenous administration

Compound 1 4 ^ED 50 74 106

The antiserotonin properties clearly distinguish the compounds of the invention from the sulpyride, for which the antiserotonin effect in gastric ulcers in HO rats is mg / kg

The low toxicity of the compound of the invention and the absence of any undesirable side effects, such as catalexia, which routinely accompanies the administration of this type of compounds have made it possible to use the compounds in clinical trials. These tests have confirmed the potent psychotropic properties of the compounds of the invention, particularly with regard to the combination of antiapomorphine and antiserotonin activity, which is surprising to the degree found. These include the following types of effect:

- the effect on the elimination of various states associated with immobility, for example in the case of autism

- treatment of sudden delirium attacks,

- antimigraine action.

In addition, the compounds of the invention can be used in the elimination of drug habits.

Because of their psychostimulatory effects, the compounds of the invention reduce the risk of relapse upon withdrawal of the habit-forming substance. The compounds of the invention do not themselves induce addiction.

They also have no sedative effect and are therefore not intended or recommended for the treatment of acute psychotic conditions and excitations.

«1

Clinical trials were carried out on several hundred patients at daily doses of 50 to 750 mg and confirmed the therapeutic properties of the compounds of the invention, and the doses were well tolerated.

For example, a dose of 200 mg per day for compound 1 was taken orally or intramuscularly in 30 patients, alcoholics or heroin addicts. In 28 cases a very rapid effect occurred and patients required additional doses of the compounds of the invention. The effect of the compounds of the invention is different from opiates and pain relievers. The patients were not dependent on the compounds according to the invention on their sudden withdrawal. No side effects of a neurologic nature were observed.

patients with sudden delirium attacks were treated with a daily dose of 350 mg of Compound 2 by oral or intramuscular administration. In 38 cases a very good antipsychotic effect was observed in sudden delirium attacks. There was also an antidepressant effect with very good tolerability in all cases.

patients with catatonic hebephrenia were treated with Compound No. 1 at a dose of 100 to 300 mg per day by oral or intramuscular administration, in 13 cases removal of immobility was observed, sometimes with improvement of mental state and possibility of contact with the patient.

Compound 1 was administered at a dose of 300 mg daily to a patient with frequent migraines. These migraines prevented 3-4 days a month from doing any work. The frequency of migraine had been decreasing for the first month, and migraine had disappeared completely since the second month, with only 100 mg per day.

Compound 1 was administered at a daily dose of 300 mg, given in three single doses to twin brothers who suffered from vomiting-associated migraine every month. In one of the twins the migraine disappeared immediately. For the second one, the pain had completely disappeared since the second month, and there were several more vomiting attacks.

Compound 2 was administered continuously at a dose of 2 tablets daily, i.e. at a daily dose of 200 mg to a woman who had had migraine attacks for 4 years. These seizures could not be treated with ergotamine and caffeine or any preventive means. After administration of the compound of the invention, only 1 to 2 seizures per month occurred instead of the original 10 to 15, and the intensity of these seizures decreased and could be completely eliminated with 2 tablets of ergotamine and caffeine.

Compound 2 was administered at a dose of 300 mg daily to a woman with near-constant occipital headache and migraine on the right with hypersensitivity to light and nausea. Since the third week, migraine has completely disappeared.

Claims (1)

object of the invention A process for the preparation of 4-amino-5-alkylsulfonyl orthoanisamides of the formula I CONH — CH3— < | ² N 1 / ^OCH 3 I (I) n ₂ 1 1 kde R 1 represents methyl, ethyl, propyl or allyl and R ₂ represents methyl, ethyl, propyl or Isopropyl and their N-oxides, quaternary ammonium salts, salts with an acid, the pharmacologically acceptable, and their dextrorotatory and levorotatory isomers, characterized by treating the acid of formula II COOH R ₂ O ₂ S (II) where R ₂ has the above meaning, or one of its reactive derivatives, halo alkyl amine of the formula IV H ₂ N-CH ₂ Γ3 Hal Hal (IV) where Hal and na represents a chlorine atom, or a bromine compound thus obtained, of the general formula R ₂ o ₂ s wherein Rg and Hal are as defined above with an amine of formula VI (V) HgH-R, (VI) wherein R &lt; ₁ & gt _; is as defined above, and the resulting compound of formula (I) is optionally converted into a pharmacologically acceptable N-oxide or salts thereof or its dextrorotatory and levotatory isomers.