KR100247561B1 - Novel pyridinylmethylamine derivatives, preparation methods thereof, and pharmaceutical compositions containing the same - Google Patents

Abstract

The present invention relates to a novel pyridinylmethylamine derivative, and more particularly, a novel pyri represented by the following structural formula (I) useful as a prophylactic and therapeutic agent for diseases caused by platelet-activating factor (PAF) It relates to a diylmethylamine derivative.

Wherein Py is 3-pyridine or 4-pyridine and R represents -A-Ar.

Here, A represents a C ₁ -C ₂ alkylene group including a C ₁ -C ₂ alkylene group or a carbonyl group, Ar is a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₄ alkyl group, C _1- Or a phenyl group having 1 to 3 functional groups selected from C ₄ alkoxy groups and phenyl groups.

Description

Novel pyridinylmethylamine derivatives, preparation methods thereof, and pharmaceutical compositions containing the same

The present invention relates to a novel pyridinylmethylamine derivative, and more particularly, a novel pyri represented by the following structural formula (I) useful as a prophylactic and therapeutic agent for diseases caused by platelet-activating factor (PAF) It relates to a diylmethylamine derivative.

Where

Py is 3-pyridine or 4-pyridine,

R represents -A-Ar.

Here, A represents a C ₁ -C ₂ alkylene group including a C ₁ -C ₂ alkylene group or a carbonyl group, Ar is a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ -C ₄ alkyl group, C _1- Or a phenyl group having 1 to 3 functional groups selected from C ₄ alkoxy groups and phenyl groups.

In a previous study of platelet activators, Benveniste et al. Found in 1972 a platelet-activating factor (PAF) that strongly induced platelet aggregation in basophil cells in rabbits. It was named.

And, in 1980, Hanahan et al., Such platelet activator is a kind of phosphoglyceride in the form of alkyl ether having an acetyl group in the C-2 position is 1-0- hexadecyl or octadecyl-2-acetyl-sn- It confirmed that it was glyceryl-3-phosphocholine.

In addition, there are many studies on the physiological effects of PAF.Together, PAF is important for various physiological reactions such as platelet aggregation, lowering blood pressure, allergic reactions, smooth muscle contraction, inflammation, analgesic, edema, changes in respiratory and circulatory system. It is an argument.

Therefore, compounds having PAF-antagonism may be usefully used in various diseases caused by PAF, such as inflammatory diseases, allergic diseases, shock, circulatory diseases, myocardial infarction, asthma, pulmonary edema and respiratory diseases. In other words, compounds having medicinal effects such as water solubility, drug persistence, efficacy as injections, PAF-antagonism and certain biometabolism inhibitors, are potent PAF-antagonist compounds, which are useful for the prevention and treatment of diseases caused by PAF. Can be.

It is an object of the present invention to provide a novel pyridinylmethylamine derivative represented by the above formula (I), which is useful as an agent for preventing and treating a disease caused by PAF.

Hereinafter, the present invention will be described in detail.

The present invention relates to a novel pyridinylmethylamine derivative represented by the following structural formula (I).

Wherein Py and R are as defined above.

In addition, the representative compounds of the formula (I) according to the present invention are as follows.

N- (2-dimethylaminoethyl) -N- (4-pyridinylmethyl) -3,5-di-t-butyl-4-hydroxybenzamide maleate (Compound No. 1)

N- (2-dimethylaminoethyl) -N- (4-pyridinylmethyl) -3,4,5-trimethoxybenzamideHCl (Compound No. 2)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -3,5-di-t-butyl-4-hydroxybenzamide maleate (Compound No. 3)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -4-isopropylbenzamideHCl (Compound No. 4)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -4-n-butylbenzamideHCl (Compound No. 5)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -4-butoxybenzamide maleate (Compound No. 6)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -4-phenylbenzamide maleate (Compound No. 7)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -4-methoxyphenylacetamide maleate (Compound No. 8)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) aminoacet-2,4-difluorophenone maleate (Compound No. 9)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -3,5-di-t-butyl-hydroxybenzylamine maleate (Compound No. 10)

N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -2- (4-methoxyphenyl) ethylamine maleate (Compound No. 11)

A schematic synthesis process of the compound of formula (I) of the present invention is based on the following reaction formula A, wherein the compound of formula (I) may be synthesized from the compound of formula (II) and the compounds of formula (III), Compounds of formula (III) may be prepared using pyridinecarboxaldehyde of formula (V) as a starting material.

Scheme A

In the above scheme, Py and R are as defined above, X is a halogen atom, 4-methylbenzenesulfonyloxy group, methanesulfonyloxy group, 4-nitrobenzenesulfonyl oxy group, 4-bromobenzenesulfonyloxy group or A trifluoromethanesulfonyloxy group is shown.

That is, the amine of formula (IV) and the aldehyde of formula (V) are dehydrated at a temperature of 100 to 150 ° C. using a catalyst such as sulfuric acid or p-toluenesulphonic acid in an organic solvent such as benzene or toluene. After obtaining the compound of formula (VI), the compound of formula (VI) is dissolved in an organic solvent such as methanol or ethanol, and reduced to a reducing agent such as NaBH ₄ , LiAlH _{4 at} 0-30 ° C. Get

The compound of formula (II) is then used in the organic solvent such as methylene chloride, pyridine, diethyl ether, dimethyl sulfoxide or dimethylformamide, using a base such as sodium hydroxide, potassium carbonate or triethylamine, The compound is reacted with a compound to obtain a compound of formula (I), which is the target compound of the present invention.

The novel pyridinylmethylamine derivative of the present invention according to the preparation method as described above can be usefully used as a pharmaceutical composition because it has a PAF-antagonism, and is particularly contained as an active ingredient in the prevention and treatment of diseases caused by PAF. Can be effectively used.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the Examples.

[Production example]

4 g of 3-pyridinecarboxaldehyde (V), 4.32 ml of N, N-dimethylethylenediamine (IV) and 200 mg of p-toluenesulphonic acid were added to 100 ml of toluene, boiled and distilled under reduced pressure to remove the organic solvent. 6.61 g (yield 100%) of ethyl-N- (3-pyridinylmethyl) imine (VI) were obtained.

NMR (300MHz, CDCl ₃ ): δ 8.86 (d, 1H, J = 1.8Hz), 8.64 (dd, 1H, J = 4.8Hz, J = 1.5Hz), 8.35 (s, 1H), 8.13-8.09 (m , 1H), 7.35-7.31 (m, 1H), 3.81-3.76 (m, 2H), 2.68 (t, 2H, J = 6.9 Hz), 2.34 (s, 6H)

Dissolve 6.60 g of N-(-2-dimethylaminoethyl) -N- (3-pyridinylmethyl) imine (VI) in 100 ml of methanol, add 2.82 g of NaBH ₄ at 0 ° C, and raise the temperature to 25 ° C. After 3 days distilled under reduced pressure to remove methanol, 40 ml of 1N HCl was added and the pH was adjusted to 9 with 1N NaOH. Extraction was performed four times with 250 ml of methylene glolide, followed by distillation under reduced pressure to obtain 6.16 g (yield 92%) of N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) amine (II). .

NMR (300 MHz, CDCl ₃ ): δ 8.56 (d, 1H, J = 1.8 Hz), 8.50-8.48 (m, 1H), 7.70-7.67 (m, 1H), 7.32-7.22 (m, 1H), 3.82 ( s, 2H), 2.68 (t, 2H, J = 6.3 Hz), 2.42 (t, 2H, J = 6.3 Hz), 2.2 (s, 6H)

Example 1

Synthesis of N- (2-dimethylaminoethyl) -N- (4-pyridinylmethyl) -3,5-di-t-butyl-4-hydroxybenzamide maleate (Compound No. 1)

100 mg of N- (2-dimethylaminoethyl) -N- (4-pyridinylmethyl) amine and 90 μl of triethylamine were dissolved in 50 ml of methylene chloride, and 165 mg of 3,5-di-t-butyl-4-hydroxybenzoyl chloride was added. Add and stir for 30 minutes.

Aqueous NaHCO ₃ solution was added, extraction was performed with methylene chloride, and then the solvent was distilled off under reduced pressure to obtain a residue. The residue was separated by a column filled with silica gel (developing solvent was 5% methanol / chloroform), and then dissolved in acetone, malonic acid was added, followed by filtration to obtain 130 mg (54%) of the title compound as a solid.

Melting Point: 177∼178.4 ℃

EXAMPLES 2-8

Compounds Nos. 2 to 8 were prepared in the same manner as in Preparation Example 1.

Example 9

Synthesis of N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) aminoaceto-2,4-difluorophenonemaleate (Compound No. 9)

100 mg of N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) amine, 117 mg of 2-chloro-2 ', 4'-difluoroacetophenone and 77 mg of K ₂ CO _{3 in} 10 ml of dimethylformamide It is dissolved, reacted at 25 ° C. for 2 hours, and then distilled under reduced pressure to remove the solvent. The residue was separated by a silica gel packed column (developing solvent was 5% MeOH / CHCl ₃ ), and then dissolved in acetone, malonic acid was added, followed by filtration to obtain 65 mg (37%) of the title compound as a solid.

Example 10

Synthesis of N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -3,5-di-t-butyl-4-hydroxybenzylamine maleate (Compound No. 10)

376 mg of N- (2-dimethylaminoethyl) -N- (3-pyridinylmethyl) -3,5-t-butyl-4-hydroxybenzamide (Compound No. 3) prepared above was dissolved in ether, followed by LiAlH. ₄ 28 mg is added and reacted at 60 ° C. for 15 hours, followed by distillation under reduced pressure to remove ether.

The residue was separated by a silica gel-filled column (developing solvent 5% MeOH / CHCl ₃ ) and then dissolved in acetone, malonic acid was added, followed by filtration to obtain 29 mg (8%) of the title compound as a solid.

Nuclear magnetic resonance analysis (NMR) and melting points of the compounds represented by Formula (I) prepared in the above Examples are shown in Table 1 below, and each compound number represents a compound number in the above detailed description.

[Test Example]

(Efficacy search experiment)

Blood samples were collected from New Zealand White rabbits weighing 3 to 3.5 kg, mixed with 3.8% sodium citrate solution in a ratio of 1: 9, and centrifuged at 100 rpm for 10 minutes. Platelet Rich Plasma (PRP) is taken and the blood layer is further centrifuged at 300 rpm for 10 minutes to take up PPP (Platelet Poor Plasma).

PRP was used to measure the platelet number using a Coulter counter and diluted with PPP to adjust the platelet number to 3 × 10 5 / μl.

The pyridinylmethylamine derivatives obtained by the present invention were treated with Chloro-log aggregometer to fix the optical transmittance of PPP to 100% and the optical transmittance of PRP to 0%, and then treated 270 μl of PRP and 30 μl of derivative solution at 37 ° C. for 2 minutes. The platelet aggregation effect was observed by adding 30 μl of platelet activating factor (PAF) at 5 × 10 ⁻⁹ M and 5 × 10 ⁻⁸ M concentrations. At this time, the excipient (0.4% dimethyl sulfoxide solution) instead of the derivative solution was used as a control group, the cohesive force of the control group was set to 100%, the inhibition rate was calculated for each concentration of the drug, and then substituted into the logarithmic linear regression. Was obtained. From this straight line, the IC ₅₀ value of 50% inhibition rate of each derivative was obtained and shown in Table 2 below.

As can be seen in Table 2, it can be seen that the novel pyridinylmethylamine derivative compound according to the present invention has a platelet aggregation inhibitory effect.

Claims (3)

New pyridinylmethylamine derivative represented by the following structural formula (I) Wherein Py is 3-pyridine or 4-pyridine and R represents -A-Ar. Here, A represents a C ₁ to C ₂ alkylene group including a C ₁ to C ₂ alkylene group or a carbonyl group, Ar is a hydrogen atom, a halogen atom, a hydroxyl group, a C ₁ to C ₄ alkyl group, C ₁ to C 1 to 3 has a functional group selected from an alkoxy group and phenyl group in the ₄ or having no phenyl group. The method according to claim 1, wherein A is -CH _2- , -CH ₂ CH _2- , , or Ar is 1 to 3 selected from hydrogen atom, halogen atom, hydroxyl group, methyl group, ethyl group, isopropyl group, n-butyl group, t-butyl group, methoxy group, ethoxy group, n-butoxy group and phenyl group Novel pyridinylmethylamine derivative, characterized in that it is a phenyl group with or without functional groups. A process for preparing the compound of the following formula (I) from the compound of the following formulas (II) and (III). Wherein Py and R are as defined in claim 1, X is a halogen atom, 4-methylbenzenesulfonyloxy group, methylsulfonyloxy group, 4-nitrobenzenesulfonyloxy group, methylsulfonyloxy group, A 4-bromobenzenesulfonyloxy group or a trifluoromethanesulfonyloxy group is shown.