RU2005717C1 - Process for preparing aralkylamine derivatives or their acid addition salts - Google Patents

Abstract

FIELD: clinical chemistry. SUBSTANCE: process for preparing aralkylamine derivatives of the general formula I

, wherein X is hydrogen, (C₁-C₄) alkoxycarbonyl; R₁ is (lower) alkyl ; R₂ is unsubstituted phenyl or which may be substituted by one substituting group, hydroxyl or (C₁-C₄) alkoxy group, or two (C₁-C₄) alkoxy groups; m is 1,2; n is 2-6; A is six-member or five-member which is unsubstituted, or optionally substituted by oxo group or hydroxyl group, or A is ring of formula II

; B is benzene ring which may have three substitutes selected from a group consisting C₁-C₄ alkoxy group, OCH₂O group or pyrrolidine group, or their acid addition salts is characterized by reacting compound of formula III

, wherein Y is halogen; X is (C₁-C₄) alkoxycarbonyl; A ring is substituted by oxo group; B ring is as defined above or may be substituted by halo group, with compound of formula HN(R₁)CH₂R₂, wherein R₁ end R₂ are as defined above followed by decarboxylation, if any, or if A ring is substituted by oxo group, by reduction of it to hydroxyl with subsequent splitting off, if any, such group, and reacting with pyrrolidine, provided that B ring is substituted by halo group. EFFECT: lower toxicity and higher inhibiting capacity to choline esterase. 3 tbl

Description

 The invention relates to a method for producing new biologically active derivatives of aralkylamines, which may find application in medicine.

 A number of compounds are known that have the ability to increase the functioning of the brain of the elderly, for example, cholinesterase inhibitor physostigmine.

 However, physostigmine has several disadvantages, among which there is a small productivity of action and a high toxicity potential.

 The purpose of the invention is a method for producing new derivatives of aralkylamines of new compounds with greater activity, less toxicity and a longer action.

, где Х - водород или алкоксикарбонил (С₁-С₄);
R₁ - низший алкил;
R₂ - фенил, незамещенный или замещенный одним заместителем - или гидроксигруппой, или (С₁-С₄)алкоксигруппой, или двумя (С₁-С₄)алкоксигруппами;
m = 1, 2;
n = 2-6;
A - шестичленное или пятичленное кольцо без заместителей или включающее следующие заместители: оксо- или гидроксильную группу или А = кольцо

В - бензольное кольцо, которое может включать один-три заместителя из группы (С₁-С₄) алкокси- или группу -ОСН₂О-, или пирролидиногруппу или их кислотно-аддитивных солей, заключающийся в том, что соединение формулы II

, где у - галоид;
кольцо В имеет указанные значения или замещено галоидом;
кольцо А замещено оксогруппой;
Х - алкоксикарбонил (С₁-С₄) с соединением формулы III H

CH₂R₂
R₁ и R₂ - указаны выше;
с последующим в случае необходимости декарбоксилированием, или, если кольцо А замещено оксогруппой ее восстановлением до гидроксигруппы с последующим при необходимости отщеплением этой группы и, если кольцо В замещено галоидом, взаимодействием с пирролидином и целевой продукт выделяют в свободном виде или в виде кислотно-аддитивной соли.The goal is achieved by the proposed method for producing derivatives of aralkylamines of the general formula I

where X is hydrogen or alkoxycarbonyl (C ₁ -C ₄ );
R ₁ is lower alkyl;
R ₂ is phenyl unsubstituted or substituted by one substituent or a hydroxy group, or a (C ₁ -C ₄ ) alkoxy group, or two (C ₁ -C ₄ ) alkoxy groups;
m is 1, 2;
n is 2-6;
A is a six-membered or five-membered ring without substituents or comprising the following substituents: an oxo or hydroxyl group or A = ring

B is a benzene ring, which may include one to three substituents from the group (C ₁ -C ₄ ) alkoxy or the group-OCH ₂ O-, or the pyrrolidino group or their acid addition salts, wherein the compound of formula II

where y is a halogen;
ring B has the indicated meanings or is substituted by a halogen;
ring A is substituted by an oxo group;
X is alkoxycarbonyl (C ₁ -C ₄ ) with a compound of formula III H

CH ₂ R ₂
R ₁ and R ₂ are as defined above;
followed by, if necessary, decarboxylation, or if ring A is replaced by an oxo group and reduced to a hydroxy group, followed by optionally cleavage of this group and, if ring B is substituted by halogen, reacted with pyrrolidine and the target product is isolated in the free form or in the form of an acid addition salt .

In working and reference examples, elution during column chromatography is monitored by thin layer chromatography (TLC), unless otherwise indicated. For TLC control, MerK 60 F ₂₅₄ plates are used as TLC plates, the developing solvent is an eluent for column chromatography, and a UV detector is used to detect spots. To identify fractions enriched in the target compound, the detection method consists of spraying TLC plates with a 48% HBr solution, hydrolysis with heating, spraying with ninhydrin and reheating to detect a color change to red-reddish-purple. For column chromatography, Merk silica gel was used under the name Kiesel gel 60 (70-230 mesh), unless otherwise indicated.

It should also be noted that the terms "atmospheric temperature" and "room temperature" in the both cases are used to designate the temperature range of 5-40 ^{° C,} and the term "atmospheric pressure" is used to denote a pressure of about one atmosphere. Unless otherwise indicated, all percentages (%) are by weight.

.Reference Example 1. 2- (5-Bromopentyl) -5,6-dimethoxy-1-indanone-2-carboxylic acid ethyl ester

.

To a solution of 5,6-dimethoxy-1-indanone-2-carboxylic acid ethyl ester (1 g) in dimethylformamide (10 ml) was added sodium hydride (0.11 g) and the mixture was stirred at room temperature for 30 minutes. Then 1,5-dibromopentane (1.8 g) was added and the mixture was stirred for another 2 hours. Then, by adding water, the reaction was stopped and the product was extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The oily residue was subjected to silica gel column chromatography (dichloromethane-ethyl acetate 20: 1 v / v as an eluent), the fractions enriched by the compound proposed were combined. After distilling off the solvent to give 1.1 g of colorless crystals of melting point 85-87 ° ^C.

Elemental analysis. Calculated for C ₁₈ H ₂₅ BrO ₅ : C 55.22; H 6.10.

 Found: C, 55.31; H 6.05.

 Reference example 2. According to the method of the reference example, the compounds shown in table. 1.

.PRI me R 1. Ethyl 5,6-dimethyl-2 / 5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl / - 1-indanone-2-carboxylic acid

.

 2- (5-Bromopentyl) -5,6-dimethoxy-1-indanone-2-carboxylic acid ethyl ester solution (0.16 g, see Reference Example 1) N-ethyl-N - / (2-methoxyphenyl) methyl / amine (0.13 g) in toluene (5 ml) is boiled for 16 hours, after which the solvent is distilled off. The residue oil obtained is chromatographed on a silica gel column (ethyl acetate-methanol 20: 1 (v / v)) and the fractions enriched in the main compound are combined. After distilling off the solvent under reduced pressure, 0.15 g of a colorless oil is obtained.

 Elemental analysis.

Calculated for C ₂₉ H ₃₉ NO ₆ :
C 70.00; H 7.90; N, 2.81.

 Found: C, 69.85; H 7.91; N, 2.68.

(CH₂)

Раcтвор этилового эфира 2-(5-бромпентил)-5,6-диметокcи-1-инданон-2-карбоновой киcлоты (0,7 г, cм. ccылочный пример 1) и N-этил-N-/(2-метокcифенил)метил/амина (0,56 г) в толуоле (15 мл) кипятят 12 ч, поcле чего раcтворитель отгоняют при пониженном давлении. Полученное маcло раcтворяют в этаноле (10 мл) и поcле добавления раcтвора гидрокcида калия (0,63 г) в воде (2 мл) cмеcь кипятят 6 ч. Затем раcтворитель отгоняют при пониженном давлении, оcтаток разбавляют водой (50 мл), экcтрагируют дихлорметаном, экcтракт промывают водой и cушат над безводным сульфатом натрия. Растворитель отгоняют при пониженном давлении, остаток хроматографируют на колонке (в качестве элюента - смесь этилацетата с метанолом 20: 1 (об. /об. )). Обогащенные целевым соединением фракции объединяют и растворитель отгоняют. К остатку добавляют 0,56 мл 3 н. этанольного раствора хлористого водорода и после отгонки растворителя получают 0,58 г гигроскопичного аморфного порошка.PRI me R 2. 5,6-Dimethoxy-2- / 5- / 22-ethyl-N - / (2-methoxyphenyl) methyl / -amino / pentyl / -1-indan n, hydrochloride

(CH ₂ )

2- (5-Bromopentyl) -5,6-dimethoxy-1-indanone-2-carboxylic acid ethyl ester solution (0.7 g, see reference example 1) and N-ethyl-N - / (2-methoxyphenyl) methyl / amine (0.56 g) in toluene (15 ml) was boiled for 12 hours, after which the solvent was distilled off under reduced pressure. The resulting oil was dissolved in ethanol (10 ml) and, after adding a solution of potassium hydroxide (0.63 g) in water (2 ml), the mixture was boiled for 6 hours. Then, the solvent was distilled off under reduced pressure, the residue was diluted with water (50 ml), extracted with dichloromethane, the extract is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, the residue is chromatographed on a column (as an eluent, a mixture of ethyl acetate with methanol 20: 1 (v / v)). The fractions enriched in the target compound are combined and the solvent is distilled off. To the residue add 0.56 ml of 3 N. ethanolic solution of hydrogen chloride and after distillation of the solvent, 0.58 g of hygroscopic amorphous powder are obtained.

 Elemental analysis.

Calculated for C ₂₆ H ₃₅ NO ₄ ˙ HCl:
C 67.59; H 7.85; N, 3.03.

 Found: C, 67.31; H 7.66; N, 2.81.

 PRI me R 3. Given in the table. 2 compounds are synthesized essentially as shown in example 2.

(CH₂)

.PRI me R 4. 1,2-Dihydro-5,6-dimethoxy-2- / 5-N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl / -1-hydroxyindene

(CH ₂ )

.

 To a solution of 5,6-dimethoxy-2- (5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl / -1-indano hydrochloride (0.75 g) in methanol (10 ml) sodium borohydride (0.3 g) was gradually added and the mixture was stirred for 6 hours at room temperature. Then, excess sodium borohydride is decomposed by adding water, the solvent is distilled off under reduced pressure, the product is extracted with dichloromethane and washed with water. The dichloromethane layer was dried over anhydrous sodium sulfate, and after distilling off the solvent, 0.63 g of a colorless oil was obtained.

 Elemental analysis.

Calculated for C ₂₆ H ₃₇ NO ₄ :
C 73.04; H 8.72; N, 3.28.

 Found: C, 72.91; H 8.56; N, 3.20.

(CH₂)

.PRI me R 5. 5,6-Dimethoxy-2- / 5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl / indene hydrochloride

(CH ₂ )

.

To a solution of 1,2-dihydro-5,6-dimethoxy-2 / 5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl / -1-hydroxyindene (0.4 g) in a toluene mixture ethanol (10 mL / 2 mL) was added concentrated sulfuric acid (1 drop) and the mixture was stirred for 30 min at 100 ^C. Then, the solvent was distilled off, the residue was diluted with 5% aqueous sodium hydroxide (10 ml) and extracted with dichloromethane. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. 3N was added to the residue. ethanol solution of hydrogen chloride (0.3 ml) and after distillation of the solvent, 0.39 g of a hygroscopic amorphous powder is obtained.

Elemental analysis
Calculated for C ₂₆ H ₃₅ NO ₃ ˙ HCl:
C 70.03; H 8.14; N, 3.14.

 Found: C, 69.94; H 8.01; N, 3.04.

.PRI me R 6. 5,6-Dimethoxy-2- (5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl / - 2-phenyl-1-indenone hydrochloride

.

 Obtained as a colorless amorphous powder according to the method of example 1.

Elemental analysis
Calculated for C ₃₂ H ₂₉ NO ₄ ˙HCl:
C 71.42; H 7.49; N, 2.60.

 Found: C, 71.33; H 7.41; N, 2.46.

(CH₂)

.PRI me R 7. Fumarate 2- / 4- / N-ethyl-N- (phenylmethyl) amino / butyl-5-pyrrolidino-1-indanone

(CH ₂ )

.

A solution of 2- (4-bromobutyl) -5-fluoro-1-indanone-2-carboxylic acid ethyl ester (1.5 g, compound 5 of Reference Example 2) and N-ethyl-N- (phenylmethyl) amine (1.14 g) in toluene (15 ml) is boiled for 16 hours, after which the solvent is distilled off under reduced pressure. The oily residue was subjected to column chromatography on the fractions enriched in ethyl 2- / 4- (N-ethyl-N- (phenylmethyl) amino / butyl / -5-fluoro-1-indanone-2-carboxylic acid, combined and after distillation of the solvent, 1 05 g of colorless oil. The oily product (1 g) was heated in a sealed tube with pyrrolidine (3 ml) for 4 hours at 100 ° ^C. After distillation under reduced pressure, to the residue was added pyrrolidine ethanol (10 ml), water (2 ml) and potassium hydroxide (1 g) and the mixture is boiled for 2 hours. Then, the solvent is distilled off under reduced pressure, the product is extracted with dichloromethane, the extract is washed with water, dried over anhydrous sodium sulfate, followed by distillation of the solvent. The oily residue is subjected to column chromatography (ethyl acetate), the fractions enriched in the target compound are combined, and after distillation under reduced pressure of the solvent, 0.7 g of a colorless oil is obtained, which, together with fumaric acid (0.21 g), are dissolved in methanol to obtain a uniform solution. After distilling off the solvent under reduced pressure, 0.9 g of a colorless amorphous powder is obtained.

Elemental analysis for C ₂₆ H ₃₄ N ₂ O xx C ₄ H ₄ O ₄ .

 Calculated: C 71.12; H 7.56; N, 5.53.

 Found: C, 70.03; H 7.41; N, 5.551.

(CH₂)

.PRI me R 8. Fumarate 2- / 4- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / butyl-5-pyrrolidino-1-indanone

(CH ₂ )

.

 The compound was prepared as described in Example 7 as a colorless amorphous powder.

Elemental analysis for C ₂₇ H ₃₆ N ₂ O ₂ x xC ₄ H ₄ O ₄
Calculated: C 69.38; H 7.51; N, 5.22.

 Found: C, 69.24; H 7.45; N, 5.01.

 PRI me R 9. By the method described in examples 1, 2 or 7, received the following compounds.

(CH₂)

. который представляет собой бесцветное масло.1.2-dihydro-5,6-dimethoxy-2- (5- / N-ethyl-N / (2-methoxyphenyl / methyl / amino / pentyl - 1-hydroxyindene

(CH ₂ )

. which is a colorless oil.

Elemental analysis for C ₂₆ H ₃₇ NO ₄ .

 Calculated: C 73.04; H 8.72; N, 3.28.

 Found: C, 72.91; H 8.56; N, 3.20.

, который представляет собой гигроскопичный аморфный порошок.2. 5,6-Dimethoxy-2- / 5- / N-ethyl-N - / (2-methoxyphenyl / methyl / -amino / pentyl / indene hydrochloride

which is a hygroscopic amorphous powder.

Elemental analysis for C ₂₆ H ₃₅ NO ₃ ˙HCl.

 Calculated: C 70.02; H 8.14; N, 3.14.

 Found: C, 69.94; H 8.01; N, 30.34.

 Preparative example 1.

 1. 5,6-Dimethoxy-2- / 5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl-1-indanone hydrochloride (synthesis of the compound, see Example 2) 1 g 2. Lactose 197 g 3. Corn starch 50 g 4. Magnesium stearate 2 g

 Components (1), (2) and 20 g of corn starch are mixed and granulated with a paste made from 15 g of corn starch and 25 ml of water.

 15 g of corn starch, component (4) are added to the obtained granules, and the mixture is molded using a tablet compression molding machine into tablets (2000 pieces) with a diameter of 3 mm each containing 0.5 mg of component (1).

 Preparative example 2.

1. 5,6-Dimethoxy-2- (5- / N-ethyl-N - / (2-methoxyphenyl) methyl / amino / pentyl-1-indanone hydrochloride (synthesis of the compound, see Example 2) 2 g 2. Lactose 196 g 3. Corn starch 50 g 4. Magnesium stearate 2 g
Components (1), (2) and 20 g of corn starch are mixed and granulated with a paste made from 15 g of corn starch and 25 ml of water. 15 g of corn starch and component (4) are added to the obtained granules, and 2,000 tablets with a diameter of 5 mm, each containing 1 mg of component (1), are molded from the mixture using a tablet pressing molding machine.

 Test Example 1

The anticholinesterase activity of the proposed compound is detected using (acetyl- (3H)) - acetylcholine. A homogenate of fraction S ₁ of the cerebral cortex of male Wistar rats is used as a source of cholinesterase, (acetyl-) ³ H)) - acetylcholine is used as a substrate, and the proposed compound is the test substance. For 30 minutes and after termination of the reaction, the system is shaken with a tocol scintillator to transfer ( ³ H) -acetic acid into the toluene layer. To determine the anticholinesterase activity of the test compound, the radioactivity of the toluene layer is measured using a liquid scintillation counter.

The anticholinesterase activity of the test compound is expressed as a 50% inhibitory concentration (IC ₅₀ ). As a control, the anticholinesterase activity of physostigmine is also determined in a similar way. The results are shown in table. 3.

 From the above results it is obvious that the proposed compounds have high anticholinesterase activity, while they can be classified as low toxic. (56) Weigand Hilgetag. Modern experimental methods in organic chemistry. M.: Chemistry, 1968, p. 413.

Claims (1)

The method of obtaining derivatives of aralkylamines of General formula I

where X is H or alkoxycarbonyl (C ₁ - C ₄ );
R ₁ is lower alkyl;
R _{2 is} phenyl unsubstituted or substituted by one substituent — a hydroxy group or a (C ₁ - C ₄ ) alkoxy group or two (C ₁ - C ₄ ) alkoxy groups;
m is 1, 2;
n is 2-6;
A is a six-membered or five-membered ring without a substituent or comprising the following substituents: an oxo or hydroxyl group or an A ring

B-benzene ring, which may include one to three substituents from the group (C ₁ - C ₄ ) -alkoxy or the group OCH ₂ O - or pyrrolidino group,
or their acid addition salts, wherein the compound of formula II

(CH ₂ ) _n Y
where is the y-halogen,
ring B has the indicated meanings or is substituted by a halogen; ring A is substituted by an oxo group; X-alkoxycarbonyl (C ₁ - C ₄ ), m = 1 or 2, n = 2 - 6, with a compound of formula III
Hn

CH ₂ R ₂
the values of R ₁ and R ₂ are indicated above, followed by decarboxylation, if necessary, or, if ring A is substituted by an oxo group, reduction to a hydroxy group, followed by optionally cleavage of this group, and if ring B is replaced by a halogen interacting with pyrrolidine, and the target product is isolated in free form or in the form of an acid addition salt.

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