KR840001238B1 - The method of preparation of novel subsituted heterocyclic phenoxy amines - Google Patents

Abstract

Novel substd. heterocyclic phenoxy amines of formula (I) are prepd. by reacting 3, 5-dihalophenols of formula (5) with amines of formula (6). m is 0 or 2; n is 0 or 2 (m+n=2); A is alkoxy or alkenyl oxy; X is halogen; R is alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkylalkyl, or cycloalkenylalkyl; and Y is a removable anion.

Description

Process for preparing new substituted heterocycle phenoxyamine

The present invention relates to a process for the preparation of novel substituted heterocycle phenoxyamines of the following general formula (1), which are useful as local anesthetics.

Food

m is 0 or 2

n is 0 or 2 (under m + n = 2 condition)

A is hydrogen, ethoxy, linear or branched propoxy, methoxy such as butoxy, alkoxy, vinyloxy, propenyloxy (allyl), butenyloxy, pentenyloxy, hex having 1-4 carbon atoms in the alkyl group Alkenyloxy having 2-6 carbon atoms in an alkenyl group such as cenyloxy,

X is halogen such as F, Cl, Br,

R is lower alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclobutyl, methylcyclopentyl, having 1-6 carbon atoms such as H, methyl, ethyl, linear or branched propyl, butyl, pentyl or hexyl, Cycloalkyl with 3 or more carbon atoms, such as methylcyclohexyl, ethylcyclohexyl, alkenyl, cyclobu, with 2-6 carbon atoms, such as vinyl, propyl (2) (allyl), butenyl, pentenyl, hexenyl Cycloalkenyl, cycloalkyl or cycloalkenyl lower alkyl having three or more carbon atoms such as tenyl, cyclopentenyl, cyclohexenyl, methylcyclobutenyl, methylcyclopentenyl, methylcyclohexenyl, ethylcyclohexenyl Cycloalkyl, cycloalkenyl and lower alkyl groups are as described above) such as cyclopropylmethyl, cyclopropylethyl, cycle Butyl-methyl, cyclobutyl-ethyl, cyclopentyl-methyl, cyclopentyl-ethyl, methyl cyclopentenyl, cyclopentenyl ethyl, cyclohexylmethyl, cyclohexyl-ethyl, cyclohexenyl-methyl, cyclohexenyl-ethyl.

The present invention also includes pharmaceutically acceptable acid addition salts of the general formula (1), tetravalent ammonium salts thereof, N-oxides thereof and the like.

Compounds of the present invention according to the examples can be represented by the following general formulas (2) and (3), the compound of the general formula (3) is the most preferred one.

Wherein R, A and X are as described above.

Especially preferable are compounds of the following general formula (4).

Food

[A, is H, methoxy, ethoxy and X, is Cl or Br and R is as described above.]

The presence of subsidiary carbon in such compounds may result in the formation of racemates or optically active forms after decomposition.

The products of the present invention exhibit interesting pharmacological properties as particularly anesthetics for the central nervous system.

Thus, the onset includes the use of the compound of formula (1) as a medicament.

The present invention also relates to a pharmaceutical composition comprising, as a main component, at least one compound of formula (1) and a pharmaceutical inert excipient.

The present invention also relates to a process for preparing the compound of formula (1) by condensing a phenol corresponding to formula (5) with a compound of formula (6).

Food,

[A, m, n, X and E are as described above and Y is an anionic moiety that can be removed, such as a halogen atom, in particular chlorine, bromine or iodine.]

These compounds may form salts. They can be resolved into their pharmacologically active optical isomers by reaction with any active acid.

The phenols of general formula (5) are used in the form of pulmonary noles of alkali metals, in particular sodium pulmonate, for example produced by reaction of phenols with alcoholates of phenols.

The reaction between the compound of formula (5) and compound of formula (6) is carried out in an inert organic solvent such as toluene, xylene. It is also carried out at the reflux temperature of the reaction mixture.

The compound is isolated and prepared by purification, such as extraction, formation of acid, recrystallization, chromatography, according to conventional methods.

Salt formation of the compound of formula (1) is preferably carried out by adding hydrochloric acid, hydrobromic acid, inorganic acid such as phosphoric acid, or organic acid such as fumaric acid, citric acid or oxalic acid.

Compounds of formula (1) may also react with alkylsulfates or halides to provide tetravalent ammonium salts, for example.

Compounds of formula (1) can be oxidized in themselves by known methods, for example hydrogen peroxide and manganese dioxide to produce the corresponding N-oxides.

The decomposition of the compound of formula (1) is carried out with any active acid.

Starting material of the general formula (5), wherein X is chlorine, may be prepared by acylation, chlorination, and deacetylation of spent phenol.

The starting material of formula (5), wherein X is bromine, can be prepared by brominating 0-nitrophenol, alkylation of waste phenol, reduction of nitro groups, diazotization and decomposition.

The starting material of formula (6) may be prepared according to the 40th method described in [YAO-HUA-WU and JR CORRIGAN, JORG CHEM (1961) 1531 waste paper].

The present invention will be described in detail based on the following examples.

Example 1

[1-Methyl-4- [2-methoxy-3,5-dichlorophenoxy] hexamethylene imine]

[1-Methyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine]

Dissolve 13 g of sodium in 180 ml ethanol in a 2 l round flask equipped with a sealed stirrer, reflux cooler and thermometer, and in this solution 108 g of 3,5-dichloroguayacol (0.56 mol) and 300 ml Anhydrous roluene was added.

The cooler was replaced with a 40 cm Vigreux column and the entire amount of alcohol was removed by azeotropic middle flow. As the alcohol was removed, the sodium salt of 3,5-dichloroguayacol was determined to be a thick mass. At the end of the midstream stage, the same amount of rolluene as carried over was added and cooled.

The vilux column was replaced again with a reflux condenser and 103 g of 1-methyl-2- (2-chloroethyl) pyrrolidine (0.56 mol + 25% excess) was added. The resulting mixture was slowly refluxed. Heat was generated to quickly fluidize the mixture.

As soon as the reaction was completed the mixture was reheated under reflux and reflux heating was maintained for 8 hours. The reaction mixture was cooled and then dissolved in 400 ml of water and 80 ml of concentrated hydrochloric acid. The roluene was decanted and washed twice with acidic water.

The aqueous solution was combined and filtered through black to make alkaline by adding 20% ammonia until the color of phenolphthalein changed. The separated oil was decanted and extracted with ether. The ethereal solution was dried over calcium carbonate.

The ether was distilled off and run in vacuo until yield was obtained to yield 182 g of product (theoretical value: 170 g).

T.L.C. According to the analysis [silica MERCK 5554, eluent = benzene, ethanol, ammonia (84: 15: 1)], the obtained product is substantially the same in the following two isomers, namely 1-methyl-4- [2-methoxy- It was a mixture of 3,5-dichlorophenoxy] hexaethylene imine and 1-methyl-2- [2-methoxy-3,5-diclophenoxyethyl] pyrrolidine.

The mixture was dissolved in 400 ml of methyl ethyl ketone and 20.5 g of anhydrous hydrochloric acid (0.56 mol) in 40 ml of methyl ethyl ketone was added as a solution. Once crystals formed, they were left overnight. The hydrochloride was drained, washed with methyl ethyl ketone and dried at 40 ° C. 97 g of product was obtained and the melting point was 155-7 ° C.

T.L.C. According to the analysis, most of this hydrochloride consists of hexamethylene imine derivatives.

The mother liquor was further treated to prepare a pyrrolidine derivative.

Hydrochloride was recrystallized twice in 185 ml and 150 ml acetonitrile, respectively. 69.5 g of 1-methyl-4- [2-methoxy-3,5-dichlorophenoxy] hexaethylene imine hydrochloride with a melting point of 161-162.5 ° C. were collected.

The mother liquor of hydrochloride was dissolved in a small amount of water and methylethylketone was distilled off. The remaining solution was diluted with 325 ml of water and filtered black to make alkaline by adding 20% ammonia until the phenolphthalein color changed. The separated oil was decanted and extracted with etet. The ethereal solution was dried over potassium carbonate and the ether was triturated and then run under vacuum until constant weight. Weight: 82g

82 g of base (0.27 mole) and 31.5 g of fumaric acid (0.27 mole) were dissolved in 230 ml of isopropanol upon heat and cooled, and the precipitate formed by filtration was filtered to obtain 109.5 g of fumarate.

As a result of recrystallization from 275 ml of methanol, 78 g of 1-methyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine fumarate was obtained, which was viscously 179-180 占 폚. T.L.C. The analysis showed that the presence of small amounts of hexamethyleneimino derivatives was not detected by the NMR spectrum.

Example 2

[Priority 1-methyl-2- [2-methoxy-3,5-dichloro-phenoxyethyl] pyrrolidine]

The racemic product of fumarate was made alkaline with aqueous ammonia, converted to base form and extracted with ether. 161 g of base (0.53 mole) was dissolved in 320 mL of methanol, and 199 g of L (+) dibenzoyl tartaric acid (0.53 mole) solution in 400 mL methanol was added to determine dibenzoyl tartarate immediately. After overnight standing, the product was drained, washed with 300 ml of methanol, dried at 40 ° C., and 161 g of a product having a melting point of 160 ° C. was obtained. [α] ²⁰ _D = -37 ° (5% Dimethylformamide solution)

157 g of dibenzoyl tartrate was dissolved in 200 ml of dimethylformamide and then 65 ml of water was added (80% dimethylformamide).

After cooling, the determined salt was drained and washed with 200 ml of 80% dimethylformamide. After washing with water, it was dried at 40 ° C. to collect 136 g of product having a melting point of 140-1 ° C.

[α] ²⁰ _D = -36.5 ° (5% dimethylformamide solution)

136 g of dibenzoyl tartrate, 600 ml of water, 45 ml of 20% ammonia and 300 ml of ether were injected into a 3 l round flask equipped with a stirrer. The precipitated base was immediately dissolved in ether and drained, the aqueous solution was extracted with ether, and the obtained ethereal solution was dried over potassium carbonate, and then ether was run in vacuo until it reached a weight of 61.5 g.

[α] ²⁰ _D = 47.5 ° (5% Dimethylformamide solution)

61.5 g base (0.202 mole) was heated until dissolution occurred in the presence of 170 mL water and 23.5 g fumaric acid (0.202 mole). The resulting boiling solution was filtered black. By cooling it, the fumateate was slowly determined, drained and washed with water and then dried at 40 ° C. 74 g of fumarate having a melting point of 157-157.5 ° C was obtained.

[α] ²⁰ _D = + 19.5 ° (5% dimethylformamide solution)

Example 3

[Left-handed 1-methyl-2- [2-methoxy-3,5-dichloro-phenoxyethyl] pyrrolidine]

In preparing the preferred 1-methyl-2- [2-methoxy-3,5-dichloro-phenoxyethyl] pyrrolidine dibenzoyl stannate, the alcoholic solution containing about 88 g of the base obtained was concentrated. The residue was dissolved in 400 ml of water, 60 ml of 20% ammonia and ether with vigorous stirring.

The precipitated base was dissolved in ether, drained with ethereal solution and the aqueous phase was extracted three times with ether.

The ethereal phases were combined and dried over K ₂ CO ₃ . The ether was distilled off and run in vacuo until yield was obtained to give 69.5 g of base.

67 g of base (0.22 mole) was dissolved in 140 mL of methanol and 165 mL of methane was added 83 g of D (-) dibenzoyl tartaric acid (0.22 mole) solution. Dibenzoyl-tartrate was immediately determined, drained, washed with methanol and dried at 40 ° C. to yield 126 g of product having a melting point of 133-4 ° C. [α] ²⁰ _D = + 37.2 ° (5% Dimethylformamide solution)

124 g of dibenzoyl tartrate was dissolved in water and excess ammonia. The separated base was immediately extracted with ether.

The ethereal solution was drained and the aqueous phase was extracted with ether, then the ethereal phases were combined and dried over potassium carbonate. The ether was distilled off and under vacuum until a content of 50 g was obtained. [α] ²⁰ _D = -44.8 °

54 g of base (0.178 mole), 145 mL of water and 21 g of fumaric acid (0.178 water) were injected into a 500 mL round flask equipped with a reflux condenser and then heated until the mixture dissolved. The resulting boiling solution was filtered through black, cooled to determine the fumarate and drained, washed with wool and dried at 40 ° C.

68 g of product having a melting point of 157-8 ° C. was obtained. [α] ²⁰ _D = -17.8 ° (5% Dimethylformamide solution)

Example 4

[1-allyl-4- [3-methoxy 3,5-dichlorophenoxy] hexamethylene imine]

[1-allyl-2- [2-methoxy 3,5-dichlorooxyethyl] pyrrolidine]

1- 3,5-dichloroguayacol was purified using 246 g of 3,5-dichloroguayacol (1.275 mol) and 221 g of 1-allyl-2- [2-chloroethyl] pyrrolidine (1,275 mol). Substantially equal amounts of two isomers obtained by reaction with methyl-2- [2-chloroethyl] pyrrolidine, namely 1-allyl-4- [2-methoxy 3,5-dichlorophenoxy] hexamethylene imine and 1 411 g of a mixture of allyl-2- [2-methoxy 3,5-dichlorophenoxyethyl] pyrrolidine was obtained.

397 g of a base (1.20 mole) mixture was dissolved in 1.250 mL of acetonitrile and 230 g of tartaric anhydride (1.20 mole) was added. The suspension was heated until all dissolved and the solution was cooled overnight, then the precipitate was drained and washed with 1,200 mL of acetonitrile, dried in air and dried in a drying oven at 40 ° C. 538 g of stannate mixture of both products were obtained. The mixture was recrystallized three times and passed through a black phase in 95 ° alcohol. 227 g of product were obtained whose NMR spectra matched the hexamethylene imine structure. Melting point 90-5 ° C. The acetonitrile and alcohol recrystallization liquid were streamed and run in vacuo. The residue was dissolved in water and filtered black. The salts were precipitated by adding 20% ammonia until the color of the waste nophthalane was changed. The separated oil was decanted and extracted with ether. Extract with ether. The ethereal solution was dried over potassium carbonate and ether was distilled off under vacuum until a yield was obtained. 184 g of base (0.56 mole) was produced, which was dissolved hot in 550 ml of isopropanol and 65 g of fumaric acid (0.56 mole). After cooling, the fumarate was determined, drained, washed with isopropanol, dried in air and dried at a temperature of 40 ° C. to give 141 g of product having a melting point of 135-6 ° C.

140 g of fumarate was recrystallized from 275 mL and 145 mL of isopropanol and finally 190 mL of water, resulting in 90 g of 1-allyl-2- [2-methoxy 3.5-dichlorophenoxyethyl having a melting point of 137-8 ° C. ] Pyrrolidine fumarate was obtained.

Example 5

[1-ethyl-2- [3,5-dichlorophenoxyethyl] pyrrolidine]

19 g of sodium was dissolved in 245 ml of anhydrous alcohol in a 2 L round flask equipped with a sealed stirrer, reflux condenser and thermometer. The ethylate solution was cooled and 133 g of dichlorophenol (0.815 mole) and 430 mL of anhydrous toluene were added. The reflux cooler was replaced with a non-lux column and the alcohol was removed by azeotropic distillation. Precipitating the sodium salt of dichlorophenol produced a thick stirrable medium.

After cooling, the vilux column was replaced with a reflux condenser and 139 g of 1-ethyl-2- [β-chloroethyl] pyrrolidine (0.815 mol + 5%) was added to heat the mixture at reflux for 8 hours. 1-ethyl-2- [β-chloroethyl] pyrrolidine is prepared from its hydrochloride salt immediately before use.

At the end of the reaction, the reaction mixture was dissolved with 1.8 L of water and 85 mL of concentrated hydrochloric acid, decanted over toluene and washed with 100 mL of water and 10 mL of concentrated hydrochloric acid.

The aqueous phases were combined and filtered to black to make alkaline by addition of 20% ammonia until the phenolphthalein changed, the separated oil was extracted with ether, the ethereal solution was dried over potassium carbonate, and the ether was distilled off under vacuum. I was.

Middle oil: 180-2 ℃ 5mmHg pressure, weight: 175g

175 g of base (0.61 mole) was dissolved in 335 ml of methylethylketone and a solution of 22.5 g of anhydrous hydrochloric acid (0.61 mole) of 260 ml of methyl ethyl ketone increment was added until methyl red changed. The hydrochloride was slowly crystallized and drained, washed with 130 ml of methyl ethyl ketone and dried in a drying oven to give 151.6 g of hydrochloride.

Chromatographic analysis of the foreign material (silica MERCK 5554-eluent: benzene-ethanol-ammonia 84: 15: 1) was performed using 1-ethyl-2- [3,5-dichlorophenoxyethyl] pyrrolidine and 1-ethyl-4 Hydrochloride mixture salts of-[3,5-dichlorophenoxy] hexamethylene imine were shown and the mixture contained a high pyrrolidine component.

150 g of hydrochloride mixture was recrystallized from 150 ml and 22 ml of acetonitrile and 46 g of material having a melting point of 138-140 ° C. was collected. After recrystallization from 95 mL and 50 mL of isopropanol, 27 g of product having a melting point of 152-3 ° C. was obtained, and the chromatographic analysis had only a single spot.

Example 6

[1-Methyl-2- [2-methoxy-3,5-dibromophenoxyethyl] pyrrolidine-3,5-dibromo guayacol]

a) Diazolation: 725 ml of concentrated sulfuric acid was injected into a 3 l round flask equipped with a stirrer, thermometer and dropping funnel and 177 g of 3.5-dibromo-0-anisidine (0.63 mol) was added slowly. The solution obtained by raising the temperature to 40 ° C. was cooled and 52.5 g sodium nitrite (0.63 mol + 20% excess) solution in 80 mL water was added dropwise at a temperature of 0-5 ° C.

Upon completion of the diazotization reaction, the mixture was further stirred at 0-5 ° C. for 2 hours and the solution was poured onto 1,200 g of ice to obtain a suspension.

b) Decomposition: 120 g of sulfuric acid lamp was dissolved in 1,400 ml of water vapor in a round flask equipped with Vigrex, and the diazo compound was added dropwise after boiling. The phenol formed by decomposition was steam distilled, and when the injection process was completed, the distillation process was continued. 1 L of water was distilled off and the water was drained to extract the aqueous solution with ether.

The organic phase was dissolved with dilute sodium hydroxide and filtered to acidify the aqueous phase with hydrochloric acid. When the phenol precipitated, the ethereal solution was dried over Na ₂ SO ₄ until extraction with ether yielded. The residue was determined by dissolving with a double volume of petroleum ether, dissolving phenol and then cooling. Drained, washed with petroleum ether and dried in air. Weight: 54 g, Melting point 59-60 ° C. The product obtained after recrystallization from petroleum ether was 43 g of 3,5-dibromo guayacol having a melting point of 63-4 ° C.

[1-Methyl-2- [2-methoxy-3,5-dibromophenoxyethyl] pyrrolidine]

15 g of sodium was dissolved in 215 ml anhydrous ethanol in a 2 l round flask equipped with a stirrer, reflux cooler and thermometer and 187 g of dibromo-guayacol (0.66 mol) in 365 ml of anhydrous toluene was added. . The whole amount of allool was removed by azeotropic distillation, and 190 ml of toluene was added to the obtained concentrated suspension. Cool and add 102.5 g of 1-methyl-2- [β-chloroethyl] pyrrolidine (0.66 mol + 5% excess) and heat under reflux for 8 hours.

The reaction mixture was dissolved with 500 mL of water and 66 mL of hydrochloric acid (d = 1.18), followed by toluene layer and washing with 200 mL of 1/20 dilute hydrochloric acid. The aqueous solutions were combined and filtered black to make alkaline with 20% ammonia.

The decanted oil was extracted with ether. The ethereal solution was dried over K ₂ CO ₃ and the ether was distilled to yield 165 g of base until it was weighed, which, according to CCM analysis, gave the following isomer: 1-methyl-4- [2-methoxy-3, 5-dibromophenoxy] hexamethylene imine and 1-methyl-2- [2-methoxy-3,5-dibromophenoxyethyl] pyrrolidine.

164 g of base (0.448 mole) was dissolved in ethanol and 52 g of fumaric acid (0.448 mole) solution in 685 ml anhydrous alcohol was added. The fumarate is determined by cooling, drained, washed with alcohol and dried. This material is called T.L.C. Analysis indicated that it was an adduct to the pyrrolidine derivatives. Fumarate was presupposed by recrystallization from 320 ml of methanol and recrystallization from 100 ml and 80 ml of dimethylform amide, respectively. 33 g of 1-methyl-2- [2-methoxy-3,5-dibromophenoxyethyl] pyrrolidine fumarate having a melting point of 192 ° C was obtained.

Example 7

[1-ethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine]

292 g of 1-ethyl-2- [β-chloroethyl] pyrrolidine (1.72 mol + 5% excess), optionally prepared from 333 g of guayacol (1.72 mol) and its hydrochloride, using the operating method of the following example The reaction with) results in 414 g of product which, after distillation, distills under 1 mmHg pressure at 173-180 ° C. This material was dissolved in 800 mL methyl ethyl ketone and 47.5 g anhydrous hydrochloric acid solution in 400 mL methyl ethyl ketone was added. The determined hydrochloride was cooled and drained, washed with methyl ethyl ketone and dried in a drying oven at 40 ° C. 306.5 g of hydrochloride having a melting point of 126-8 ° C. was recrystallized from 613 ml of acetone, and 252 g of 1-ethyl-2- [2-methoxy-dichloro-phenoxyethyl] pyrroli having a melting point of 129-130 ° C. Dean hydrochloride was collected.

Example 8

[Priority 1-ethyl-2- [2-methoxy-3,5-dichlorophenoxy ethyl] pyrrolidine]

175 g of 1-ethyl-2- [2-methoxy-3,5-dichloro-phenoxyethyl] pyrrolidine (0.55 mol) was dissolved in 260 ml of 95 ° ethanol. A solution of 82.5 g preferential tartaric acid (0.55 mole) in 260 mL of 95 ° ethanol was added. The tartarate was determined by cooling and maturation. It was drained, washed with 100 ml of 95 ° ethanol and dried at a temperature of 40 ° C., which gave 104 g of preferred stannate. [α] ²⁰ _D = + 21.5 ° (5% aqueous solution)

103.5 g of tartarate was recrystallized from 207 ml of 95 ° ethanol to give 82 g of the product. [α] ²⁰ _D = + 24.3 ° (5% aqueous solution)

81 g of tartarate was dissolved in 425 ml of lukewarm water, 20% ammonia was added to precipitate the base, and the decanted oil was extracted with ether. The ethereal phase was dried and evaporated to give 47.5 g of base. [α] ²⁰ _D = + 55.8 ° (5% Dimethylformamide solution)

46 g of base (0.145 mole) was dissolved in 140 ml of ethyl acetate and 5.5 g of anhydrous hydrochloric acid (0.145 mole) solution in 55 ml ethyl acetate was added. The determined hydrochloride was drained, washed with ethyl acetate and dried in a drying oven at 40 ° C., whereby 47.5 g of a product having a melting point of 121-2 ° C. was obtained. [α] ²⁰ _D = + 18.9 ° (5% aqueous solution)

Example 9

[Left-handed 1-ethyl-2- [2-methoxy-3,5-dichlorophenoxy ethyl] pyrrolidine]

Preferred stannate of 1-ethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine is precipitated on the one hand and recrystallized on the other hand to yield 850 ml of the alcoholic solution. Dissolved with water and concentrated to 840 mL volume.

31 g of potassium chloride (0.375 mol + 10% excess) solution in 140 mL water was added and the precipitated sodium stannate was drained and washed with water.

The solution was made alkaline with 20% ammonia and the separated oil was extracted with ether to dry the ethereal solution over potassium carbonate. The ether was distilled off and terminated in vacuo until a yield was obtained. The resulting 107 g of product was a mixture of about 20% preferred base and 80% left linear base. This product was dissolved in 160 mL of absolute ethanol and 53 g of lefty tartaric acid dissolved hot in 160 mL of ethanol was added. After filtering and cooling the solution, the determined tartarate was drained, washed with 95 ° ethanol and dried in a drying oven at 40 ° C. to obtain 107.5 g. [α] ²⁰ _D = -21.6 ° (5% aqueous solution)

Tartrate was recrystallized from 215 ml of 95 ° ethanol. 95 g of material were collected and found to have a melting point of about 80-85 ° C. It was recrystallized to have a melting point of 102-3 ° C. and contained 1 mole of water. [α] ²⁰ _D = -24.7 ° (5% aqueous solution)

94 g of tartarate was dissolved in lukewarm water.

20% ammonia was added and the precipitated base was extracted with ether to give 52.5 g of base.

[α] ²⁰ _D = -57.5 ° (5% dimethylformamide solution)

51 g of base (0.16 mole) was dissolved in 150 ml of ethyl acetate and 5.9 g of anhydrous hydrochloric acid solution in 65 ml ethyl acetate was added. Hydrochloride was determined, drained, washed with ethyl acetate and dried in a drying oven at 40 ° C. 41.5 g of product having a melting point of 117-119 ° C. were obtained. [α] ²⁰ _D = -20.4 ° (5% aqueous solution)

Example 10

[1-ethyl-2- [2-ethoxy-3,5-dichlorophenoxy ethyl] pyrrolidine]

[2-Ethoxy 3,5-dichlorophenol]

A round flask equipped with a reflux condenser was charged with 152 g of 2-ethoxy phenol (1.15 mol), 136 g of acetic anhydride and 10 drops of concentrated sulfuric acid. The reaction was highly exothermic and the temperature rose to 80 ° C. At the end of the reaction the mixture was heated in a water bath for 15 minutes. Sodium acetate was added to neutralize the sulfuric acid.

345 mL of acetic acid was added in portions while maintaining the temperature at 20-25 ° C. and 271 g of 1,3-dichloro 5,5-dimethyl hydantoin (1.15 mol + 20% excess) was added. The suspension was heated to 50-55 ° C. for 97 hours and the entire amount of hydantoin dissolved rapidly.

The solution was dissolved in 4 L of water, decanted off the chlorinated derivative in solution and immediately deacetylated by heating under reflux in the presence of a dilute caustic soda solution until all dissolved. The solution was diluted with water and concentrated hydrochloric acid was added to precipitate phenol. This was followed by extraction of the aqueous phase with ether, drying of the ether phase over sodium sulfate, and removal of the ether followed by distillation of 2-ethoxy, 3-5-dichlorophenol under vacuum. 166 g of product, which was distilled under a pressure of 15 mmHg at a temperature of 130-4 ° C., were collected and a product having a melting point of 45 ° C. was determined.

[1-ethyl-2- [2-ethoxy-3,5-dichlorophenoxyethyl] pyrrolidine]

Sodium ethylate solution was prepared from 9.2 g sodium and 120 mL anhydrous ethanol and then 83 g 2-ethoxy 3,5-dichlorophenol (0.4 mol) was added. The alcohol was distilled off and 240 mL of anhydrous xylene was added. After the remaining alcohol was removed by azeotropic distillation and cooled, 71 g of 1-ethyl-2- [β-chloroethyl) pyrrolidine (0.4 mol + 10% excess) was added and the reaction product was left overnight.

The mixture was heated and refluxed for 4 hours under reflux and then dissolved with 600 mL of water and 30 mL of concentrated hydrochloric acid. The aqueous phase was decanted and filtered to black, then 60 mL of concentrated ammonia was added to precipitate the base and drain. The aqueous solution was extracted with methylene chloride and the organic phase was dried over potassium carbonate. After removal of the solvent, the residue product was distilled under vacuum to yield 101 g of base having a melting point of 198-200 ° C. at 8 mm Hg.

The base was dissolved in 300 ml anhydrous ethanol and 58.5 g of tartaric anhydride solution was added in 200 ml ethanol. The resulting tartarate was drained, washed with alcohol and dried in air. Melting Point: 95-100 ℃

Recrystallized from 130 ml of ethanol by passing through a black phase, 124 g of 1-ethyl-2- [2-ethoxy-3,5-dichlorophenoxyethyl] pyrrolidine stannate having a melting point of 95-100 ° C was obtained. Melting Point: 95-100 ℃

Example 11

[1-cyclohexyl 4- [2-methoxy 3,5-dichlorophenoxy] hexaethylene imine]

[1-cyclohexyl 2- [2-methoxy 3,5-dichlorophenoxy-ethyl] pyrrolidine]

Using the method of Example 1, 116 g of 3,5-dichloroguayacol (0.6 mole) and 148 g of 1-cyclohexyl 2- [2-chloroethyl) pyrrolidine (0.6 mole + 11%) were reacted As a result, 233 g of product (theoretical value: 222 g) were obtained. According to TLC analysis, the following two isomers were referred to as 1-cyclohexyl 4- [2-methoxy 3,5-dichlorophenoxy] hexamethylene imine and 1-cyclohexyl 2 -[2-methoxy 3,5-dichlorophenoxyethyl] pyrrolidine.

233 g of base was dissolved in 450 cc of water and 53 cc of concentrated hydrochloric acid, the solution was cooled to crystallize, and the mixture was left overnight to give 63 g of hydrochloride. Hydrochloride actually only contained hexaethylene imino derivatives.

The hydrochloride was recrystallized under filtration on black to give 150 g of 1-cyclohexyl 4- [2-methoxy 3,5-dichlorophenoxy] hexamethyleneimine hydrochloride having a melting point of 174-176 ° C.

The aqueous solution was filtered black and made alkaline by addition of 20% ammonia. The decanted oil was extracted with ether and the resulting Eder solution was dried over potassium carbonate and the ether was distilled off and terminated under vacuum until a yield was obtained. Weight: 92g

86 g of base (0.23 mole) was dissolved in 260 ml of acetonitrile and 53 g of phosphoric acid (2 x 0.23 mole), and the phosphate formed precipitated in the form of an oil which was determined after overnight standing. The phosphate was drained and washed with acetonitrile and dried in vacuo over sulfuric acid in air, but half of the product obtained was determined. It was drained, washed with ethanol and dried at a temperature of 40 ° C., and 55 g of 1-cyclohexyl 2- [2-methoxy 3,5-dichlorophenoxyethyl] pyrrolidine bis-phosphate having a melting point of 138-138.5 ° C. was obtained. lost.

Example 12

[1-cyclopropylmethyl-4- [2-methoxy-3,5-dichlorophenoxy] hexamethylene imine]

[1-cyclopropylmethyl-2- [2-methoxy-3,5-dichlorophenoxy methyl] pyrrolidine]

a) 1-cyclopropylmethyl 2- [2-chloroethyl] pyrrolidine, hydrochloride

1) 1-cyclopropylmethyl 2-carethoxymethyl 5-pyrrolidine

78 g of chloroprolylmethylamine (1.1 mole) and 220 g of 3-hexenedioic acid diethyl ester were injected into a 1 L autoclave. The mixture was heated to 165 ° C. and kept at room temperature for 8 hours. After cooling, the product was distilled under vacuum, the alcohol was first removed and then 155 g of compound was distilled at 157-160 ° C., 3 mm Hg.

2) 1-cyclopropylmethyl 2- [2-hydroxyethyl] pyrrolidine

52.5 g of lithium aluminum hydride (2 × 0.69 moles) and 390 mL of anhydrous tetrahydrofuran were injected into a 3 L round flask equipped with a stirrer, reflux cooler and dropping funnel. 155 g of 1-cyclopropylmethyl 2-carethoxymethyl 5-pyrrolidone solution was added dropwise to the suspension for 2 hours and refluxed for 3 and a half hours. After cooling, excess lithium aluminum hydride was removed with 75 mL of water slowly added and externally cooled.

The suspension was treated with 1,050 mL of 6N hydrochloric acid and then with a salt of salt and 580 mL of water. After adding 470 mL of 30% soda alkaline solution, the organic phase was decanted and dried over potassium carbonate. Tetrahydrofuran was evaporated and 1-cyclopropyl methyl 2- (2-hydroxyethyl) pyrrolidine was distilled under vacuum. 102g of a compound (yield: 87.5%) distilled at 125-127 degreeC and 10 mmHg was obtained.

3) 1-cyclopropylmethyl 2- (2-chloroethyl) pyrrolidine, 172 g of 1-cyclopropylmethyl 2- [2-hydroxyethyl] pyrrolidine (1.02 mole) and 510 ml of chloroform Injected into a 3 l round flask equipped with a stirrer, reflux cooler, thermometer and dropping funnel. The solution was cooled to 10 ° C. and maintained at a temperature of 10-15 ° C. during the dropping of 151.5 g of thionylchloride (1.02 mol + 25%). The mixture was heated at reflux for 7 hours and distilled under vacuum until a constant weight was obtained to give 254 g of liquid hydrochloride. The solution was dissolved in water, treated with soda and extracted with ether to give 175 g of amine (yield = 92%).

b) 1-cyclopropylmethyl 4- [2-methoxy-3,5-dichlorophenoxy] hexaethylene imine

1-cyclopropylmethyl 2- [2-methoxy 3,5-dichlorophenoxyethyl) pyrrolidine

174 g of 3,5-dichloroguayacol (0.90 mol) and 186 g of 1-cyclopropylmethyl-2- [2-chloroethyl] -pyrrolidine (0.90 mol) using the method of Example 1 as described above + 10%) to give 329 g of product (theoretical value: 310 g). According to the formula the following two isomers are 1-cyclopropylmethyl-4- [2-methoxy-3,5-dichlorophenoxy] hexaethylene imine and 1-cyclomethyl-2- [2-methoxy-3,5 -Dichlorophenoxyethyl] pyrrolidine.

173 g of tartaric acid (0.9 mole) dissolved in 500 ml of ethanol and 328.5 g of base was added to the resulting solution, and the tartarate was determined slowly. Drained, washed with 300 ml of ethanol and dried at 40 ° C., 389 g of tartaric acid having a melting point of 60-65 ° C. were obtained. The analysis showed a mixture with higher amounts of hexamethylene imino derivatives than pyrrolidino derivatives.

This tartarate was filtered over black and recrystallized from 780 ml of acetonitrile, 510 ml and 645 ml of methyl ethyl ketone in sequence. T.L.C. The analysis produced 189 g of 1-cyclopropylmethyl-4- [2-methoxy-3,5-dichlorophenoxy] hexamethylene imine having a melting point of 71-73 ° C. without one or more points. The alcoholic solution from which tartarate was determined was concentrated to 280 volumes. Diluted with 1 L of water and made alkaline by adding 20% ammonia. The decanted oil was extracted with methylene chloride. The organic phase was dried over potassium carbonate, midstream of methylene chloride and terminated in vacuo until yield. Weight: 76g

69 g of base (0.2 mol) was dissolved in 275 ml of absolute ethanol and 23 g of fumaric acid (0.2 mol) was added to heat the mixture until dissolved. It was cooled, the determined fumarate was drained, washed with 60 ml of ethanol and dried over dry Aubon to give 65 g of product.

This product is mainly a mixture containing pyrrolidino derivatives, filtered through black and recrystallized from 130 ml of 95 ° ethanol. The obtained product was 45 g of 1-cychloropropylmethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine fumarate having a melting point of 162-163 ° C. No hexamethylene imino derivatives were found in the analysis.

Example 13

[1- (1-cyclohexenylmethyl) 2- [2- (2-methoxy-3,5-dichlorophenoxy) ethyl] pyrrolidine]

[1- (1-cyclohexenylmethyl) 4- [2-methoxy-3,5-dichlorophenoxy] azepine]

1) 2- [1- (1-cyclohexenylmethyl) 2-pyrrolidinyl] ethanol

Inject 16.4 g of 2- (2-pyrrolidinyl) ethanol (0.143 mol) and 84.3 ml of 1.78 N alcoholic potassium hydroxide (0.150 mol) into a 500 ml round flask equipped with a stirrer, thermometer, cooler and dropping funnel 28 g of 1-bromomethyl cyclohexene (90% purity) was added dropwise.

The temperature was raised to 20 ° -55 ° C. and a precipitate formed. After 1 hour of reaction, the salts were filtered off and the filtrate was evaporated to dryness.

The residue oil was treated with 150 mL of water and hydrochloric acid until pH = 1. Both extracts were treated simultaneously with 100 ml of ethyl ether, the aqueous phase was made alkaline with soda and then extracted three times with 100 ml of ether.

The extract was dried over magnesium sulfate, filtered and evaporated to dryness. The residue oil was sorted under vacuum to give 20.7 g of a compound (boiling point 100-107 ° C., n ²⁰ _D = 1.506 at 2 mmHg).

2) 2- [1- (1-cyclohexenylmethyl) 2-pyrrolidinyl] gloethanol

17.8 g of 2- [1- (1-cyclohexenylmethyl) 2-pyrrolidinyl] ethanol (0.085 mol) and 50 ml of chloroform were charged into a 250 ml round flask equipped with a stirrer, thermometer, cooler and dropping funnel. After injection into 15.3 ml of thionyl chloride was added dropwise. After cooling, the temperature was maintained at about 20-25 ° C., the mixture was heated under refueling for 3 hours, the solution was evaporated to dryness and the residue was treated with 20 ml of toluene. After evaporation to dryness in vacuo, the residue was suspended in 100 ml of ethyl acetate. The crystals were filtered and dried in a 50 ° C. oven to yield 19.4 g of compound. (Melting point = 122 ° C)

3) 1- (1-cyclohexenylmethyl) 2- [2- (2-methoxy 3,5-dichlorophenoxy) ethyl] pyrrolidine

1- (1-cyclohexenylmethyl) 4- [2-methoxy 3,5-dichlorophenoxy) azepine

60 ml of ethanol were injected into a 250 ml volumetric flask equipped with a stirrer, thermometer, cooler and dropping funnel, followed by the slow addition of 1.4 g of sodium.

After all dissolution, 11.6 g of 3,5-dichloro guayacol was added and the solvent was evaporated in vacuo. The solid residue was dissolved in 60 ml of DMF and the solution was heated to about 100 ° C. and then 8 g of 2- [1- (1-cyclohexenylmethyl) 2-pyrrolidinyl)]-chloroethane ( 0.030 mol) solution was added dropwise. Heated for 2 hours and the solvent was evaporated to dryness in vacuo. The residue was treated with 300 mL of water and the mixture was alkaline with ammonia. The suspension was extracted three times with 100 mL of ether and the organic phase was washed with 100 mL of water. The ethereal solution was dried over magnesium sulfate and the solvent was evaporated to dryness in vacuo to give 12 g of product.

NMR spectra corresponded to those of the mixture containing about 30% pyrrolidine derivatives and 30% 2 azepine isomers. The mixture was dissolved in 40 ml of methyl ethyl ketone and acidified to pH = 1 with a concentrated hydrochloric acid solution in isopropanol. It was determined to mature and the mixture was left overnight.

The crystals were filtered off, washed with isopropanol and dried in a drying oven at 60 ° C. to yield 7.3 g of product, melting at about 172 ° C. NMR spectra corresponded to the mixture containing 80-85% of azepine derivatives. The filtrate was evaporated to dryness and the residue was treated with 65 ml of isopropanol to filter insoluble crystals, washed with isopropanol, and then dried in a drying oven at 50 ° C., where 1 g of product melting at about 160 ° C. was obtained. Corresponds to that of 1- (1-cyclohexenylmethyl) 2- [2- (2-methoxy 3,5-dichlorophenoxy) ethyl] pyrrolidine.

The products according to the invention are used in the form of injectable solutions, ie suppositories or detergent preparations known per se.

The compounds of the present invention can be used for topical injection in the form of ampoules at a dosage of 10 mg / 5 ml. The compounds of the present invention may also be topically applied in the form of habitual compositions.

The following relates to pharmaceutical preparations prepared by conventional methods from the compounds of the invention.

Example A: Injectable Solution (2ml)

1-ethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl) pyrrolidine hydrochloride

10mg

Potassium Chloride 44mg

Appropriate amount of water for injection

Example B: suppository (1000 ml)

1.60 g of 1-methyl-2- [2-methoxy-3,5-dichlorophenoxyethyl) pyrrolidine stannate

1.30 g of methyl parahydroxy benzoate

0.20 g of propyl parahydroxy benzoate

Appropriate amount of water for injection

Example C: Cleaner (100ml)

1-ethyl-2- [2-methoxy 3,5-dichlorophenoxy ethyl) pyrrolidine hydrochloride

0.334 g

52 ° Ethyl Alcohol 52g

Appropriate amount of water for injection

The compounds of the present invention possess interesting pharmacological properties as particularly local anesthetics for the central nervous system.

Toxicity of the compounds of the present invention was determined parenterally (intravenously, intraperitoneally and subcutaneously) and orally in mice. The lethal dose (DL 50) is shown in Table 1. In Table 1 and the following table, the compounds of the present invention are numbered as follows.

TABLE 1

Local anesthesia properties of the compounds of the invention are illustrated by the different tests described below.

Microsurface anesthesia was measured by the Regnier method described in “These Doc Med Paris 1929”. This method is said to investigate the suppression of eyelid reflexes on the cornea of rabbits.

A group of 10 rabbits were taken and two drops of aqueous solution of the product to be irradiated were visually measured and then the degree of corneal anesthesia was compared with the degree of corneal anesthesia obtained by aqueous solution of cocaine hydrochloride at different concentration levels. This test was performed in a cross-test format. The average number of times per hour on the cornea shows no anesthesia and indicates anesthesia intensity. Thus, the% anesthesia according to the concentration can be calculated and the CE 50 can be measured graphically.

CE 50 was used to indicate the concentration of a solution that did not show a sensitive response in 50% of the animals when injected at a given dose.

The activities defined next are listed in Table 2 below.

TABLE 2

Anesthesia conduction effect was performed by the following method.

Micro anesthesia was injected deeply into the upper limb of the rat along the sciatic nerve passage at a rate of 1 ml, resulting in anesthesia of the characteristic distal nerve, which was measured by pinching the middle toe of the foot of the rat's hind limb.

Compounds of the present invention or reference anesthetics (xyllocaine) were injected into a group of 10 large mice at a 1 ml dose for a given concentration.

Thirty minutes, one hour, two hours, and three hours after administration, the three middle toes of the hind limbs were pinched to record the rat's positive response for each.

% Of anesthesia was obtained by adding up the positive responses of the 10 rats. CE 50 was measured graphically by streptococci.

Activity is listed in Table 3.

TABLE 3

Anesthesia Infiltration Rate by Bulbring and Wajda [J. Pharmacol Exp. Ther. (1945) 85 78-84, investigated in guinea pigs according to the method described.

This method is based on the disappearance of skin reflexes caused by guinea pigs as a functional stimulus.

We investigated a group of 10 male rat guinea pigs, and carefully moved the hair from the back of the guinea pigs to the outer surface of 16 cm ² a day ago. Ink was used to define four sites of ABCD: A before left, B after right; C is the left rear region, D is the right rear region.

At the center of each site, the skin reflex situation subject to a single stimulus caused by the pin was examined. 0.2 ml of anesthetic solution in an isotonic solvent for injection of sodium chloride was injected. After 5 minutes, the center of papules in the obtained skin were regularly stimulated at a ratio of stimulation once every 3 seconds until reflections appeared, or the number of times in general anesthesia was 6 times. The cuff of anesthesia lasted every 5 minutes for 30 minutes.

The control is procaine.

A group of 10 guinea pigs was taken for a given concentration of compound and procaine according to the present invention, five were tested in the A portion of several C portions with the compounds of the invention, and the rest in the B and D portions with procaine. It was. The next day, the injection site was switched to perform a crossover test.

Two different bacteria were taken, and the same test was repeated at the other two concentration levels for the compound of the present invention and procaine, and the average of the stimulatory effects obtained in 10 guinea pigs was calculated for each concentration level.

CE 50 was determined by graph average of anesthesia with concentration.

Activity is listed in Table 4 below.

TABLE 4

The results of testing the anesthetic activity of the compounds of the invention were on average 2-4 times greater than the activity of the control anesthetics (xylocaine, procaine and cocaine).

Concerns raised by experiments performed in laboratory animals have been very widely justified in humans with clinical trials of the compounds of the present invention. For example,

)하의 영양실조로 정맥 염후증으로 고통받는 68세 환자.-Various left and right inner and

A 68-year-old patient suffering from venous syndrome due to malnutrition under).

It is currently half-mixed, but suffered from chronic lower limb ulcer disorder, which is the cause of intense ulceration that recurs at night due to Taesun. This was gradually alleviated by the extreme application of a 0.3% 1-ethyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine detergent to relieve itching, and after each application, couch lesions Gradual line disappeared by gradually extending to the disappearance of.

-A 38-year-old patient who underwent bone bonding to the left tibia following a ski accident: Orthopedic healing performed excellent recovery. However, the patient was greatly confused by the substance-free, ie, severe pruritus, in the semi-marriage position.

Pruritus disappeared completely within a week from the first day of application of a 0.3% 1-methyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine detergent that significantly alleviated pruritus.

A 67-year-old patient who suffered for months from severe anal pruritus causes suicidal tendencies due to anorexia and insomnia.

All rectal and dermatological treatments were ineffective.

Pruritus disappeared completely after 3 days of continuous administration by dipping 0.3% 1-methyl-2- [2-phenoxy-3,5-dichlorophenoxy-ethyl] pyrrolidine detergent. This improvement led to a significant appetite recovery to the extent that the patient gained weight to a range unknown to date.

17-year-old patient suffering from stage 4 Hodgkin's disease, one of the predominant signs of intense pruritus on the surfaces of both forearms. In combination with chemotherapy treatment was brushed in 1-methyl-2- [2-methoxy-3,5-dichlorophenoxyethyl] pyrrolidine solution.

Inadequately alleviated but satisfied and the patient was able to sleep again.

For a 47-year-old patient, the epidermal metallic foreign body was easily extracted by infiltrating 2 drops of 1-ethyl-2- [3,5-dichlorophenoxyethyl] pyrrolidine solution.

Claims (1)

Of the newly substituted heterocyclphenoxyamine of the following general formula (1) consisting of reacting 3,5-dihalophenol of the following general formula (5) with an amine of the following general formula (6) in the form of an alkali phenolate: Manufacturing method

Wherein m is 0 or 2 n is 0 or 2 (under m + n = 2) A is alkoxy, alkenyloxy, X is halogen, R is alkyl, cycloalkyl, alkenyl, cycloalkenyl, cycloalkylalkyl , Cycloalkenylalkyl, Y is an anionic moiety that can be removed.