JPS5883676A - Novel amide ester compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula (R is pyridinecarbonyl) and its pharmaceutically acceptable salt. EXAMPLE:2-Palmitoylaminoethyl isonicotinate. USE:A drug having antiphlogistic and immune-enhancing action. Since it increases fat solubility and promotes absorption from the intestine, a given effect can be obtained by its small amount, has a little side effects such as gastroenteric disorder, etc. and strengthens pharmaceutical action. PROCESS:For example, 2-palmitoylamino ethanol is reacted with a carboxylic acid anhydride or a carboxylic acid halide or a palmitic acid halide is reacted with a carboxylic acid 2-aminoethyl ester, to give an amide ester compound shown by the formula.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel amide ester compound, and more particularly to a novel ester compound of 2-valmitoylaminoethanol and pyridinecarboxylic acid.

2-Valmitoylaminoethanol itself is known to have anti-inflammatory and immune-enhancing effects.

However, when this compound is administered as a drug, the dosage is large (therefore, toxicity and side effects are problematic).

The present inventors added 2-balmitoylaminoethanol to 2-balmitoylaminoethanol.
By binding pyridinecarboxylic acid, fat solubility is increased, and absorption from the i-tube is therefore prevented, so the desired effect can be obtained with a small dose, side effects such as gastrointestinal disorders are small, and the above-mentioned pharmacological effects are An enhanced pharmaceutically useful compound was obtained.

The compound of the present invention is a novel amide ester compound represented by general formula (1).

CH3(CH2)]ACONHCH2CH20R(I)
(wherein, R represents pyridine carbonyl) In the general formula (1), R is particularly picolinic acid, nicotinic acid,
It is a pyridine carbonyl derived from isonicotinic acid.

The compounds of the present invention include pharmaceutically acceptable salts of the compound represented by the general formula (1), such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydrometic acid, phosphoric acid, etc. Inorganic acids, and acetic acid, formic acid, sulfamic acid, pyruvic acid, cinnamic acid, ascorbic acid, sinuic acid, malic acid, maleic acid, malonic acid, gluconic acid, succinic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfone Examples include salts with acids and organic acids such as naphthalenesulfonic acid.

The compound of the present invention can be synthesized by a conventional esterification reaction or amidation reaction, for example, by reacting 2-balmitoylaminoethanol with a carboxylic acid anhydride or a carboxylic acid halide, or by reacting palmitic acid with a carboxylic acid anhydride or a carboxylic acid halide. It can be synthesized by reacting a halide with 2-aminoethyl ester of carboxylic acid, and these reactions can be carried out in the presence of a base as appropriate.

In the reaction, an appropriate base such as sodium carbonate or potassium carbonate is added in an inert solvent such as benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide, chloroform, methylene chloride, dichloroethane, or pyridine. , calcium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, pyridine, triethylamine, etc., by heating appropriately, the desired product can be synthesized.

Isolation and purification of the compound of the present invention can be carried out by conventional methods, and the objectives can be achieved by recrystallization using an appropriate solvent, chromatography, reprecipitation, etc. The obtained compound has melting point, IR, NMR, and UV.

Identification was done through elemental analysis etc.

The compounds of the present invention can be synthesized by other ester synthesis methods, such as direct synthesis from 2-balmitoylaminoethanol and carboxylic acid, transesterification, synthesis using nitrile derivatives corresponding to carboxylic acids, or other conventional methods. Amide synthesis method, for example, amine decomposition method of palmitic acid ester,
It can also be synthesized using an amidation exchange reaction.

The present invention will be specifically explained below using examples.

Example 1 10 g of isonicotinic acid chloride and 18 g of 2-valmitoylaminoethanol were added to 60-g of anhydrous benzene,
After adding pyridine 30-, the mixture was heated under reflux for 6.5 hours. - After standing overnight, the precipitated crystals are collected by filtration, washed with distilled water, and recrystallized from % methanol (Incorporated Foundation) to give platinum needle-like crystals of 2-balmitoylaminoethyl isonicotinate.15.
2 g was obtained.

m, p, 90.0-92.0℃IR(K
B r ) 73280.30?5.2940.29
02°2840, 1?25.1635.1553am-
INMR (AcOH-d4): δ-0,7-1,0(3
H.

m), 1.1 -2.5 (28H, m)
, 3.68 (2H, t, J=5b), 4; 46
(2H, t.

J=5Hz), 8,00 (2H,d, J=7H
z).

8.78 (2H, d, J-7 device 2) Example 2゜Dissolve 5.0 g of 2-aminoethyl nicotinate dihydrochloride in 30-pyridine, and dissolve 7.0 g of palmitic acid chloride.
After adding g, the mixture was stirred at elevated temperature for 3 hours. After cooling, distilled water was added, and the resulting precipitate was collected by filtration and re-crystallized from young percent methanol to obtain 5.9 g of white crystals of 2-balmitoylaminoethyl nicotinate.

m, p, 91.5-93.5℃IR
(KB r) :3310.30?0.2948.2
910.2850°1718, 1635.1582.1
5481-IN MR(A c OHd4) 'δ=
0.7-1.0 (31(.

m), 1.1-2.4 (28H, m>, 3
．． 67 (2H, t, J=5b), 4.45 (2H, t
.

J-511g), 1.63 (I Hld d, J
x-5Hz.

J2-8h), 8.5 (IH, d, J=8-).

8.8 (IH, d, J=5k), 9.18 ('I
H.

Next, the pharmacological effects of the compounds of the present invention will be described.

The compounds used as test drugs are as follows.

PEA i 2-balmitoylaminoethanol P
EANi 2-balmitoylaminoethyl nicotinate PEAL1 2-balmitoylaminoethyl isonicotinate 1, carrageenan edema inhibitory effect The test drug was orally administered to 1 group of 10 male rats, and the test drug was gradually administered to the right hind paw. 0.1-1% carrageenan was injected subcutaneously as an inflammatory substance. Thereafter, the paw volume was measured over time, and the edema rate and suppression rate were calculated. The results are shown in Table 1.

Table 1 Test drug Dose Edema rate (%) Suppression rate (%) Control -” 84.5±5.1- PEA 250mg/Kg S8.6±6.8
30.7PEAN 250I+ 3'7.9±4.
4' 55.12, Paper disk method (inhibitory effect on granulation growth) A paper disk was inserted subcutaneously into the bilateral fossa of 10 male rats per group, and after orally administering the test drug for 6 days, the granulation was removed. It was removed and the effect was determined.

The results are shown in Table 2.

Table 2 vs. II 30.9+3.0 - PEA 200mg/Kg 25.8±2.5 16
．． As is clear from the results of 5 or more pharmacological tests, the compound of the present invention has a higher
It has good edema-suppressing effects and granulation growth-inhibiting effects, and therefore can reduce dosage and alleviate side effects. It is a therapeutically useful anti-inflammatory analgesic, and is also expected to be effective in boosting immunity and treating infectious diseases. Ru.

The compound of the present invention can be combined with a suitable pharmaceutical carrier or diluent to form a medicament, and can be formulated into a periphery for oral or parenteral administration by conventional methods.

For formulation, the compounds of the present invention may be used in the form of pharmaceutically acceptable salts as described above, and the compounds of the present invention may be used alone or in appropriate combinations, and may be used in combination with other pharmaceutically active ingredients. It may also be used as a combination agent.

For oral use, it can be taken as is or in combination with excipients such as lactose and starch, binders such as cellulose and gelatin, disintegrants such as carboxymethyl cellulose, and lubricants such as talc and magnesium stearate. , can be formulated as tablets, capsules, pills, powders, or granules.

Further, it can be combined with vaseline, paraffin, or other ointment bases to form an ointment, and may also be mixed with a suitable base such as cocoa butter to form a layer agent.

For parenteral use, as an injection, aqueous solvent or vegetable oil,
It can be a solution or suspension in a non-aqueous solvent such as propylene glycol. In this case, it may be formulated in the presence of a suitable solubilizing agent such as sodium acetate, sodium citrate, etc.

The desired dosage of the compound of the present invention varies depending on the subject to be administered, the method of administration, the period of administration, etc., but it is generally preferable to orally administer the compound of the present invention to adults at 100 to 3,000 μl per day.Parenteral administration In this case, a dose level that is 3-10 times lower than the above dose is desirable.

Below, medicines containing the compound of the present invention as an active ingredient are shown below.
A formulation example of the i-composition is shown.

Prescription example 1. (Tablet) Compound of the present invention (Lactose)
130 Corn starch ω Magnesium stearate 10 Prescription example 2. (
Capsule) Compound of the present invention 100 lactose
200 prescription examples 3. (Injection) Compound of the present invention 1O Solubilizing agent Appropriate amount 1

Claims (1)

[Claims] (1) A compound represented by the general formula (■) and a pharmaceutically acceptable salt thereof. CH3(CH2)14CON)ICH2CH20R(1
) (wherein R represents pyridine carbonyl) (2,
Claim 1: An anti-inflammatory analgesic agent containing a compound represented by the general formula (R) according to claim 11 or a pharmaceutically acceptable salt thereof as an active ingredient.