CS209283B1 - 2-Phenyl-3-aminopropanoic acid derivatives and process for their preparation - Google Patents

Abstract

The invention relates to derivatives of 2-phenyl-3-aminopropanoic acid and their preparation, which consists in the addition of derivatives of phenylacetic acid to the double bond of derivatives of benzylideneamine, respectively. furfurylideneamine. The substances were evaluated in terms of acute toxicity and anti-inflammatory efficacy in comparative tests with Brufen. All substances showed very low toxicity and several substances demonstrated significant anti-inflammatory efficacy

Description

(54) 2-Phenyl-3-aminopropanoic acid derivatives and process for their preparation

The present invention relates to 2-phenyl-3-aminopropanoic acid derivatives and their preparation, which consists in adding phenylacetic acid derivatives to the double bond of benzylidenamine derivatives, respectively. furfurylidenamine. The compounds were evaluated for acute toxicity and anti-inflammatory efficacy in comparative tests with Brufen. All substances showed very low toxicity and several substances showed significant anti-inflammatory activity.

The invention relates to 2-phenyl-3-aminopropanoic acid derivatives of the general formula I

ArCHNHR ¹ rvi

JL · / ArCHCOOR ² R ³ in which R ¹ represents alkyl of 1-4 carbon atoms, phenyl optionally substituted at any position by chlorine, methyl, isopropyl, ethoxycarbonyl or 3,4-methylenedioxy, R ² is hydrogen or ethyl, R ³ is hydrogen, chlorine, alkyl of 1 to 4 carbon atoms or nitro, Ar is 2-furyl or phenyl optionally substituted at any position by a chlorine or fluorine, isopropyl or

3,4-methylenedioxy.

The invention also relates to a process for the preparation of these derivatives having interesting pharmacodynamic properties, in particular anti-inflammatory, analgesic and antipyretic effects. A typical substance according to the invention is ethyl 2- (4-chlorophenyl) -3- (3,4-methylenedioxyphenyl) -3-N-phenylaminopropanoic acid, which has been shown to be ibuprofen, i.e.

2- (p-isobutylphenyl) -propionic acid, at a dose of 100 mg / kg, significant efficacy in the kaolin and adjuvant models of experimental inflammation. Toxicity of all evaluated substances is very low, expressed as LD ₅₀ higher than 1 g / kg.

According to the invention, the novel 2-phenyl-3-aminopropanoic acid derivatives of the formula I are prepared by reacting them with an unsaturated compound of the formula II

ArCH = NR ¹ (II), in which R ¹ and Ar denote the same as in formula I, adds a phenylacetic acid derivative of the general formula III

wherein R ² and R ^{3 are the} same as in Formula I, wherein when using a compound of formula III wherein R ² is ethyl and R ³ has the same meaning as in Formula I, the addition is performed in dimethyl sulfoxide in the presence of an alkali metal alcoholate at room temperature and using a compound of formula III wherein R ² is hydrogen and R ³ has the same meaning as in formula I, the addition is carried out at 100 ° C.

In the first alternative, the reaction is completed in 1 hour; the reaction mixture was neutralized with acetic acid and the solvent was distilled off to give the crude product, which was purified by crystallization.

In a second alternative, the reaction is carried out for 2 hours without the use of a solvent, the crystalline product is filtered off and purified by repeated washing with a boiling solvent.

Further details of the process according to the invention can be seen from the examples.

Example 1

To a solution of 4.5 g of 3,4-methylenedioxybenzylidenaniline and 4.9 g of ethyl 4-chlorophenylacetate in 20 ml of anhydrous dimethyl sulfoxide was added 2 ml of a 0.5 M solution of sodium ethylate in ethanol and the mixture was kept at room temperature for 1 h. After this time, the reaction mixture was neutralized with acetic acid, dimethylsulfoxide was distilled off to dryness under reduced pressure, and the residue was recrystallized from isopropyl alcohol. 3.5 g of 2- (4-chlorophenyl) -3- (3,4-methylenedioxyphenyl) -3-N-phenylaminopropanoic acid ethyl ester are obtained, m.p. M.p. 142-144 ° C.

The following ethyl esters were prepared in the same manner:

2-Phenyl-3- (4-isopropylphenyl) -3-N- (4-methylphenyl) aminopropanoic acid, mp.1.145-147 ° C, 2-phenyl-3- (3,4-methylenedioxyphenyl) -3-N- (4-methylphenyl) aminopropanoic acid, mp 85-95 ° C,

2-phenyl-3- (4-chlorophenyl) -3-N- (4-methylphenyl) -2-phenyl-3- (4-isopropylphenyl) -3-N-phenylaminopropanoic acid, m.p. 148-153 ° C,

2-phenyl-3- (4-isopropylphenyl) -3-N- (4-methylphenyl) aminopropanoic acid, 1.1. 139-142 ° C, 2-phenyl-3- (3,4-methylenedioxyphenyl) -3-N-phenylaminopropanoic acid, m.p. 103-106 ° C, 2-phenyl-3- (3,4-methylenedioxyphenyl) -3-N- (4-chlorophenyl) aminopropanoic acid, mp 143-146 ° C,

2-phenyl-3- (4-chlorophenyl) -3-N- (3,4-methylenedioxyphenyl) aminopropanoic acid, 1.1. 1 ΙΟΙ 12 ° C

2,3-diphenyl-3-N- (3,4-methylenedioxyphenyl) aminopropanoic acid, 1.1. 160-163 ° C, 2-phenyl-3- (4-isopropylphenyl) -3-N- (3,4-methylenedioxyphenyl) aminopropanoic acid, m.p. 134-135 ° C,

2-phenyl-3- (4-fluorophenyl) -3-N-phenylaminopropanoic acid, m.p. 113 - 115 ° C,

2,3-diphenyl-3-N- (4-ethoxycarbonylphenyl) aminopropanoic acid, 1.1. 173-175 ° C,

2,3-diphenyl-3-N- (4-chlorophenyl) aminopropanoic acid, 1.1. 146-147 ° C,

2,3-diphenyl-3-N- (3-chlorophenyl) aminopropanoic acid, 1.1. 123-124 ° C, 2-phenyl-3- (4-chlorophenyl) -3-N- (4-chlorophenyl) aminopropanoic acid, m.p. 118-120 ° C, 2-phenyl-3- (4-chlorophenyl) -3-N-phenylaminopropanoic acid, m.p. 149-151 ° C, 2-phenyl-3- (4-isopropylphenyl) -3-N- (4-chlorophenyl) aminopropanoic acid, m.p. 128-129 ° C, 2-phenyl-3- (4-chlorophenyl) -3-N- (4-ethoxycarbonylphenyl) aminopropanoic acid, mp 133-135 ° C, 2-phenyl-3- (2-chlorophenyl) -3 -N-phenylaminopropanoic acid, 1.1. 121-122 ° C, 2-phenyl-3- (4-isopropylphenyl) -3-N- (4-ethoxycarbonylphenyl) aminopropanoic acid, mp 169171 ° C,

2-phenyl-3- (3,4-methylenedioxyphenyl) -3-N- (4-ethoxycarbonylphenyl) aminopropanoic acid, m.p. 171-180 ° C,

2- (4-ethoxycarbonylphenyl) -3-phenyl-3-N-phenylaminopropanoic acid, m.p. 152-153 ° C; 2- (4-isopropylphenyl) -3- (3,4-methylenedioxyphenyl) -3-N-phenylaminopropanoic acid, m.p. 141-143 ° C

2- (4-isobutylphenyl) -3-phenyl-3-N-phenylaminopropanoic acid, 1.1. 155 DEG -156 DEG C. and 2-phenyl-3- (2-furyl) -3-N-phenylaminopropanoic acid, m.p. 77-79 [deg.] C.

Example 2

A mixture of 3.2 g of 4-isopropylbenzylidene-N-methylamine and 3.4 g of 4-chlorophenylacetic acid was heated to 100 ° C under nitrogen for 2 hours. After cooling, the precipitated crystalline solid is filtered off with suction, stirred with 25 ml of isopropyl alcohol and the suspension is heated to boiling under stirring for 10 minutes. This process

Claims (2)

SUBJECT 1. Derivatives of 2-phenyl-3-aminopropanoic acid of general formula I ArCHNHR ¹ (Ό, in which R ¹ denotes alkyl with 1 to 4 carbon atoms, phenyl, optionally substituted in any position by a chlorine atom, methyl, isopropyl, ethoxycarbonyl or 3,4-methylenedioxy group, R ² denotes a hydrogen atom or an ethyl group, R ³ denotes a hydrogen atom, a chlorine atom, alkyl with 1 to 4 carbon atoms or a nitro group, Ar denotes 2-furyl or phenyl, optionally substituted in any position by a chlorine or fluorine atom, isopropyl or 3,4-methylenedioxy group. 2. The process for producing 2-phenyl-3-aminopropanoic acid derivatives of the general formula I according to point is repeated until the melting point of the undissolved part remains constant. 2.45 g of 2-(4-chlorophenyl)-3-(4-isopropylphenyl)-3-N-methylaminopropanoic acid are obtained, 1.1. 227 to 230 °C. The following acids were prepared by the same method: 2-phenyl-3-(3,4-piethylenedioxyphenyl)-3-N-methylaminoprepane, 1.1. 229—235 °C, 2-(4-ethylphenyl)-3-phenyl-3-N-methylaminopropane, 1.1.158—160 °C, 2-phenyl-3-(3,4-methylenedioxyphenyl)-3-N-isopropylaminopropane, 1.1. 220-221 °C, 2.3-diphenyl-3-N-n-butylaminopropane, 1.1. 225-230 °C, 2-phenyl-3-(4-isopropylphenyl)-3-N-isopropylaminopropane, 1.1. 202—203 °C, 2-phenyl-3-(3,4-methylenedioxyphenyl)-3-N-n-butylaminopropane, 1.1. 216—219 °C, 2-phenyl-3-(4-chlorophenyl)-3-N-n-butylaminopropane, 1.1. 214—215 °C and 2,3-di(4-chlorophenyl)-3-N-methylaminopropanoic acid, mp 203-204 °C. INVENT 1, characterized in that the unsaturated compound of general formula II ArCH = NR ¹ ( ⁿ )> in which R ¹ and Ar are the same as in formula I, is added to a phenylacetic acid derivative of general formula III in which R ² and R ³ are the same as in formula I, whereby when using a compound of general formula III, where R ² is an ethyl group and R ³ has the same meaning as in formula I, the addition is carried out in a dimethyl sulfoxide environment in the presence of an alkali metal alcoholate at room temperature and when using a compound of general formula III, where R ² is a hydrogen atom and R ³ has the same meaning as in formula I, the addition is carried out at a temperature of 100 °C. CORRECTION of the description of the invention to the copyright certificate No. 209 28> Int. Cl? A 61 K >1/195 C 07 O 1<ji/04 ( C 07 C 101/12, 101/16,101/18) In the description of the invention to the author's certificate No. 209 28>, there were several printing errors in the samples in the introductory part of the description of the invention and in the subject. Place: ArCUNHR ¹ ₉ - ÁrCHCOOí? Correctly: ArCHNHR ¹ , - SHCOOET ϋίΐΑΰ FOR INVENTIONS AND DISCOVERIES