JPH0339053B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel aromatic acetylenecarboxylic acid amide derivative and a method for producing the same. More specifically, the present invention provides general formulas having antispasmodic action. (In the formula, R ₁ and R ₂ may be the same or different and are each a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group.) This invention relates to amide derivatives and methods for producing the same.

The compound represented by the general formula (1) of the present invention is a novel compound that has not been described in any literature, and has a remarkable smooth muscle relaxing effect in mammals including humans, and can be used to treat various gastrointestinal disorders such as gastric, duodenal ulcers, and gastritis. , enteritis,
It is extremely useful as a drug for treating spasmodic pain in cholecystitis, cholelithiasis, biliary dyskinesia, etc., as well as bronchial asthma and hypertension. The present invention thus provides aromatic acetylenecarboxylic acid amide derivatives useful as pharmaceuticals, and also provides a method for producing the same.

In the present invention, the term "lower acyl group" refers to an acyl group having 2 to 7 carbon atoms, and includes cyclic or branched acyl groups when the group has 4 or more carbon atoms. The term "lower alkyl group" refers to an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and includes cyclic or branched groups when the group has 3 or more carbon atoms. A "halogen atom" is either a chlorine atom, a bromine atom, or an iodo atom.

The smooth muscle relaxing effect of the compound of general formula (1) of the present invention depends on the positions and types of substituents on both rings. For example, R ₃ is preferably a hydrogen atom, and the carboxyl group is preferably substituted at the 2-position. Furthermore, compounds in which R ₁ and R ₂ are alkyl groups are preferred, and compounds in which R 1 and R 2 are methyl groups are particularly preferred. The substitution positions of the alkoxyl group are preferably the 3rd and 4th positions.

Examples of the compound represented by the general formula (1) of the present invention include N-(2-carboxyphenyl)-3-
(3,4-dimethoxyphenyl)propionic acid amide, N-(2-carboxyphenyl)-3-(3,
4-dihydroxyphenyl) propylic acid amide,
Examples include N-(2-carboxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)propionic acid amide, and among these compounds, N-(2-carboxyphenyl)- 3-(3,
4-dimethoxyphenyl)propionic acid amide is preferred.

The compound of the general formula (1) of the present invention has the general formula (R′ ₁ and R′ ₂ in the formula may be the same or different and are each a lower acyl group or a lower alkyl group, R′ ₃ is a lower alkyl group, and X ₁ and X ₂ are the same as each other. or a different halogen atom.) It can be produced by dehydrohalogenating a dihalogen compound represented by (or a different halogen atom) and then hydrolyzing it if necessary.

The dihalogen compound of general formula (2) used as a raw material in this production method is a new compound, and can be produced as follows.

That is, the general formula (R′ ₁ and R′ ₂ in the formula have the same meanings as above.) A halogenating agent such as chlorine, bromine, etc. is added to the nuclear-substituted cinnamic acid represented by the general formula (R′ ₁ and R′ ₂ in the formula have the same meanings as above, and
is a chlorine atom or a bromine atom. ), a reactive functional derivative of this dihalocarboxylic acid derivative and a general formula It can be produced by reacting with an aminobenzoic acid ester derivative represented by the formula ( _R'3 in the formula has the same meaning as above). Also, the general formula (R′ ₁ , R′ ₂ and R′ ₃ in the formula have the same meanings as above.) It can also be produced by directly adding a halogen to the nuclear-substituted cinnamic acid amide benzoate derivative represented by be able to.

Such dihalocarboxylic acid derivatives include erythro and threo forms in their steric structure, and either of them can be used in the production method of the present invention.

Examples of the reactive functional derivatives of the dihalocarboxylic acid derivatives include acid halides, acid anhydrides, mixed acid anhydrides, etc., and these can be easily produced by known methods. For example, acid halides can be produced by reacting with thionyl chloride, thionyl bromide, etc., and mixed acid anhydrides can be produced by reacting with ethyl chlorocarbonate, benzenesulfonic acid chloride, p-toluenesulfonic acid chloride, etc.

The dehydrohalogenation reaction in the production method of the present invention can be carried out by a method known per se. Normally, various strong base substances such as sodium hydroxide, potassium hydroxide, sodium ethylate, etc. are used in such dehydrohalogenation reactions, but in the case of this production method, the final target product has an amide bond. Therefore, the basic substances that can be used are limited. Examples of basic substances that can be used in this production method include 1,5-diazabicyclo[3,
4,0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane (DABCO),
Examples include 1,8-diazabicyclo[5,4,0]-7-undecene (DBU),
DBU is preferred.

To suitably carry out the production method of the present invention, the α,β-dihalo-phenylpropionylaminobenzoic acid ester derivative represented by general formula (2) is dissolved in an appropriate amount of an inert organic solvent, such as dimethyl sulfoxide. , add 2 to 3 equivalents of DBU to this,
Incubate at 50-70°C for 10-30 minutes. After cooling, add water and benzene to the reaction solution, separate the benzene layer,
This is washed with dilute hydrochloric acid, an aqueous sodium bicarbonate solution, and water, and after drying, the solvent is distilled off under reduced pressure, and the residue is recrystallized with an appropriate solvent to obtain the desired product. Alternatively, the compound represented by general formula (2) can be used in an inert solvent,
For example, it is dissolved in benzene, toluene, etc., and 1 to 2 equivalents of CBU is added thereto, stirred and reacted at room temperature for 3 to 24 hours. After the reaction is complete, insoluble matter is filtered off,
The filtrate is washed with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution and water, and after drying, the solvent is distilled off under reduced pressure, and the residue is recrystallized with an appropriate solvent to obtain a Z-form α-halocarboxylic acid amide derivative, This is dissolved in an appropriate amount of an inert solvent such as dimethyl sulfoxide at 50-70°C.
The product is reacted with 1 to 2 equivalents of DBU for 10 to 30 minutes, and treated and purified in the same manner as above to obtain the desired product.

The aromatic acetylenecarboxylic acid amide derivative represented by the general formula (1) of the present invention has a remarkable smooth muscle relaxing effect in mammals including humans, and can be used to treat various gastrointestinal disorders such as gastric, duodenal ulcers, gastritis, and enteritis. It is extremely useful as a drug for treating spasmodic pain such as cholecystitis, cholelithiasis, and biliary dyskinesia, as well as bronchial asthma and hypertension. The smooth muscle relaxing effect of this compound was confirmed by the Maqnus method using isolated gastrointestinal tract, etc.
In isolated guinea pig ileum, it exhibits a dose-dependent effect at a concentration of about 10 ^-5 molar, and at a concentration of 10 ^-4 molar, it exhibits a smooth muscle relaxing effect comparable to that of papaverine.

Hereinafter, the content of the present invention will be explained in more detail with reference to Reference Examples and Examples. Note that all melting points in each reference example and example are uncorrected.

Reference Example 1 A solution of 8.0 g of bromine in dry chloroform was added to a solution of 10.4 g of (E)-3-(3,4-dimethoxyphenyl)propenoic acid dissolved in 500 ml of dry chloroform.
20 ml of the mixture was added dropwise over 30 minutes while stirring under ice cooling, and the reaction was continued for an additional hour after the addition. The reaction solution was concentrated under reduced pressure, and the resulting white crystals were recrystallized from chloroform-hexane to give erythro-2,3-dibrom-3-(3,4-dimethoxyphenyl)propionic acid with a melting point of 144-147°C. 15.2g was obtained.

Elemental analysis value (as C ₁₁ H ₁₂ Br ₂ O ₄ ) C% H% Calculated value 35.90 3.29 Measured value 35.92 3.06 Infrared absorption spectrum (KBr) νCH: 3300cm ^-1 νCO: 1750cm ^-1 Nuclear magnetic resonance spectrum (90MHz, d ₆ −DMSO) δ: 3.70 (6H, s), 5.28 (1H, d), 5.48 (1H,
d), 6.8-7.4 (3H, m), 9.4-10.0 (1H, br) Erythro-2,3-dibrom-3-(3,4-
12.0 g of dimethoxyphenyl)propionic acid was suspended in 20 ml of thionyl chloride, 0.1 ml of N,N-dimethylformamide was added, and the mixture was stirred at 50°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a residual oil. This residual oil was dissolved in 40 ml of dry methylene chloride, and this solution was added dropwise over 30 minutes to a solution of 4.9 g of methyl anthranilate and 3.2 g of pyridine dissolved in 40 ml of dry methylene chloride while stirring under ice cooling. After reacting at room temperature for 16 hours, the reaction solution was
% aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue to crystallize it, and recrystallization from benzene-hexane gave erythro-2-bromo-3 with a melting point of 130-132°C.
-chloro-3-(3,4-dimethoxyphenyl)-
10.5 g of N-(2-methoxycarbonylphenyl)propionamide was obtained.

Elemental analysis value (as C ₁₉ H ₁₉ BrClNO ₅ ) C% H% N% Calculated value 49.96 4.19 3.07 Measured value 49.99 3.97 2.94 Infrared absorption spectrum (KBr) νNH: 3260cm ^-1 νCO: 1710cm ^-1 , 1690cm ^-1 Nuclear magnetism Resonance spectrum (90MHz, CDCl ₃ ) δ: 3.82 (3H, s), 3.85 (3H, s), 3.90 (3H,
s), 4.67 (1H, d), 5.39 (1H, d), 6.7~
7.7 (5H, m), 8.05 (1H, dd), 8.74 (1H,
dd), 11.50 (1H, s) Reference example 2 (E)-3-(3,4-dimethoxyphenyl)-
Dissolve 12.7 g of N-(2-methoxycarbonylphenyl)propenoic acid amide in 200 ml of chloroform,
Add 40 ml of chloroform solution of 6.0 g of bromine to this solution.
was added dropwise over 30 minutes while stirring under ice-cooling, and the reaction was allowed to proceed for an additional hour after the addition. The reaction solution was concentrated under reduced pressure, and hexane was added to the residue for crystallization. After dissolving this crystal in benzene and treating it with activated carbon, hexane was added to recrystallize it, and the melting point was 129.5.
Erythro-2,3-dibromo-3-(3,4-dimethoxyphenyl)-N-(2
11.5 g of -methoxycarbonylphenyl)propionamide was obtained.

Elemental analysis value (as C ₁₉ H ₁₉ Br ₂ NO ₅ ) C% H% N% Calculated value 45.53 3.82 2.79 Measured value 45.70 3.74 2.67 Infrared absorption spectrum (KBr) νNH: 3260cm ^-1 νCO: 1710cm ^-1 , 1690cm ^-1 Nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 3.83 (3H, s), 3.87 (3H, s), 3.90 (3H,
s), 4.85 (1H, d), 5.46 (1H, d), 6.7~
7.8 (5H, m), 8.05 (1H, dd), 8.74 (1H,
dd), 11.53 (1H, s) Example 1 Erythro-2-bromo-3-chloro-3-(3,
4.6 g of 4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide and 1,
Dissolve 3.2 g of 8-diazabicyclo[5,4,0]-7-undecene in 50 ml of dimethyl sulfoxide,
The mixture was stirred and reacted at 60°C for 15 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with benzene. The organic layer was washed successively with a 5% aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and a mixed solvent of ether and hexane (1:1) was added to the residue for crystallization. The crystals were recrystallized from benzene-hexane to obtain 1.48 g of 3-(3,4-dimethoxyphenyl-N-(2-methoxycarbonylphenyl)propionic acid amide) having a melting point of 141-142°C.

Elemental analysis value (as C ₁₉ H ₁₇ NO ₅ ) C% H% N% Calculated value 67.25 5.05 4.13 Measured value 67.37 4.95 3.92 Infrared absorption spectrum (KBr) νNH: 3200cm ^-1 νC≡C: 2200cm ^-1 νCO: 1700cm ^{- 1} , 1650cm ^-1 nuclear magnetic resonance spectrum (90MHz, CDCl ₃ ) δ: 3.84 (6H, s), 3.89 (3H, s), 6.7-7.7
(5H, m), 8.02 (1H, dd), 8.67 (1H, dd),
11.28 (1H, s) Example 2 Erythro-2-bromo-3-chloro-3-(3,
457 mg of 4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide was suspended in 10 ml of benzene, and 320 mg of 1,8-diazabicyclo[5,4,0]-7-undecene was added thereto at room temperature for 16 hours. Stirred for an hour. After removing the insoluble precipitate by filtration, the filtrate was diluted with benzene, washed successively with a 5% aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution, and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from benzene-hexane to give (Z)-2-bromo-3- with a melting point of 147-148°C.
(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propenoic acid amide 307
I got mg.

Elemental analysis value (as C ₁₉ H ₁₈ BrNO ₅ ) C% H% N% Calculated value 54.30 4.32 3.33 Measured value 54.23 4.23 3.09 Infrared absorption spectrum (KBr) νNH: 3200cm ^-1 νCO: 1700cm ^-1 , 1650cm ^-1 Nuclear magnetism Resonance spectrum (90MHz, _CDCl3 ) δ: 3.87 (6H, s), 3.89 (3H, s), 6.8-7.7
(5H, m), 8.05 (1H, dd), 8.30 (1H, s),
8.78 (1H, dd), 11.95 (1H, s) (Z)-2-bromo-3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propenoic acid amide 840 mg and 1, 320 mg of 8-diazabicyclo[5,4,0]-7-undecene was suspended in 10 ml of dimethyl sulfoxide and heated at 60℃ for 15 minutes.
Stir for a minute. After cooling, water was added to the reaction solution, acidified with hydrochloric acid, and extracted with benzene. The organic layer was washed with an aqueous sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the residue to crystallize it, and recrystallization from benzene-hexane yielded 3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl). 340 mg of propynic acid amide was obtained. The physical properties of this product were the same as those of the compound obtained in Example 1.

Example 3 3-(3,4-dimethoxyphenyl)-N-(2
-Methoxycarbonylphenyl) propylic acid amide (2.0 g) was suspended in 60 ml of ethanol, 3 ml of 2N sodium hydroxide was added, and the mixture was stirred at room temperature for 16.5 hours. After concentrating the reaction solution and washing the residue with ether and methylene chloride, a 10% aqueous hydrochloric acid solution was added, followed by extraction with ethyl acetate. After washing the ethyl acetate layer with water, it was dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the remaining crystals were recrystallized from ethyl acetate to give N-(2
1.3 g of -carboxyphenyl)-3-(3,4-dimethoxyphenyl)propionic acid amide was obtained.

Elemental analysis value (as C ₁₈ H ₁₅ NO ₅ ) C% H% N% Calculated value 66.45 4.65 4.31 Measured value 66.37 4.50 4.21 Infrared absorption spectrum (KBr) νC≡C: 2200cm ^-1 νCO: 1660cm ^-1 Nuclear magnetic resonance spectrum (90MHz, _d6 -DMSO) δ: 3.78 (6H, s), 6.9-7.8 (5H, m), 8.01
(1H, dd), 8.39 (1H, dd), 11.52 (1H, s) Example 4 1,8-diazabicyclo[5,4,0]-7-
Erythro-2,3-dibrom-3-(3,
7.5 g of 4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propionamide was suspended and stirred at room temperature for 17.5 hours. After removing insoluble matter by filtration, the filtrate was washed successively with a 5% aqueous hydrochloric acid solution, an aqueous sodium bicarbonate solution, and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the remaining crystals, and the crystals were collected by filtration. The obtained crystals were recrystallized from benzene-hexane to give (Z)-2
-bromo-3-(3,4-dimethoxyphenyl)-
3.4 g of N-(2-methoxycarbonylphenyl)propenoic acid amide was obtained. The physical properties of this product were the same as those of the compound obtained in Example 2. The obtained (Z)-2-bromo-3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl)propenoic acid amide was dissolved in dimethyl sulfoxide in the same manner as in Example 2. 3-(3,4-dimethoxyphenyl)-N-(2-methoxycarbonylphenyl) ) Propynic acid amide was obtained. The physical properties of this product were the same as those of the compound obtained in Example 1.

Example 5 The following compound was able to be produced by performing substantially the same operations as in Examples 4 and 3 using the corresponding raw materials.

N-(2-ethoxycarbonylphenyl)-3-
(4-Hydroxy-3-methoxyphenyl)propionic acid amide Melting point 151-153℃ Infrared absorption spectrum (KBr) νOH: 3080cm ^-1 νC≡C: 2200cm ^-1 νCO: 1680cm ^-1 Nuclear magnetic resonance spectrum (90MHz, d ₆ −DMSO) δ: 1.31 (3H, t), 3.79 (3H, s), 4.31 (2H,
q), 6.75-8.30 (7H, m), 9.77 (1H, s),
10.98 (1H, s) N-(2-carboxyphenyl)-3-(4-hydroxy-3-methoxyphenyl)propionic acid amide Melting point 188-191℃ (decomposition) Infrared absorption spectrum (KBr) νC≡C : 2200cm ^-1 νCO: 1680cm ^-1 , 1630cm ^-1 Nuclear magnetic resonance spectrum (90MHz, _d6 -DMSO) δ: 3.74 (3H, s), 6.6~8.5 (7H, m), 9.2~
9.9 (1H, br.), 11.42 (1H, s)

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ and R ₂ may be the same or different and each is a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group.) derivative. 2 General formula (In the formula, R ₁ and R ₂ may be the same or different and are each a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group.) The aromatic acetylenecarboxylic acid amide derivative described in 1. 3 General formula (In the formula, R ₁ and R ₂ may be the same or different and are each a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group.) The aromatic acetylenecarboxylic acid amide derivative described in 1. 4. The aromatic acetylenecarboxylic acid amide derivative according to claim 3, wherein R ₁ and R ₂ are lower alkyl groups. 5. The aromatic acetylenecarboxylic acid amide derivative according to claim 3, wherein R ₁ and R ₂ are methyl groups, and R ₃ is a hydrogen atom. 6 General formula (R′ ₁ and R′ ₂ in the formula may be the same or different and are each a lower alkyl group or a lower alkyl group, R′ ₃ is a lower alkyl group, and X ₁
and X ₂ are the same or different halogen atoms) is dehydrohalogenated and then optionally hydrolyzed. (In the formula, R ₁ and R ₂ may be the same or different and each is a hydrogen atom or a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group.) Method for producing derivatives.