JPS632433B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel amide ester compound,
Specifically, the present invention relates to a novel ester compound of 2-palmitoylaminoethanol and pyridinecarboxylic acid. 2-palmitoylaminoethanol itself is known to have anti-inflammatory and immune-enhancing effects. However, when this compound is administered as a drug, the dose is large, and therefore toxicity and side effects are problematic. The present inventors have discovered that by binding pyridinecarboxylic acid to 2-palmitoylaminoethanol, the fat solubility is increased and absorption from the intestinal tract is promoted, so that the desired effect can be obtained with a small dose. ,
A pharmaceutically useful compound with fewer side effects such as gastrointestinal disorders and enhanced pharmacological action was obtained. The compound of the present invention is a novel amide ester compound represented by the general formula (). CH ₃ (CH ₂ ) ₁₄ CONHCH ₂ CH ₂ OR () (In the formula, R represents pyridine carbonyl.) In the above general formula (), R is particularly pyridine derived from picolinic acid, nicotinic acid, or isonicotinic acid. It is carbonyl. The compounds of the present invention include pharmaceutically acceptable salts of the compound represented by the general formula (), such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and phosphoric acid. , and acetic acid, formic acid, sulfamic acid, pyruvic acid, cinnamic acid, ascorbic acid, oxalic acid, malic acid, maleic acid, malonic acid, gluconic acid, succinic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, Examples include salts with 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-palmitoylaminoethanol with a carboxylic acid anhydride or a carboxylic acid halide, or by reacting a palmitic acid halide with a carboxylic acid anhydride or a carboxylic acid halide. It can be synthesized by reacting 2-aminoethyl ester of carboxylic acid with 2-aminoethyl ester of carboxylic acid, and these reactions can be carried out in the presence of an appropriate base. In the reaction, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide,
a suitable base in an inert solvent such as chloroform, methylene chloride, dichloroethane, or pyridine;
For example, the desired product can be synthesized by heating appropriately in the presence of sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, sodium acetate, potassium acetate, pyridine, triethylamine, and the like. Isolation and purification of the compound of the present invention can be carried out by conventional methods, including recrystallization using an appropriate solvent,
The purpose can be achieved by chromatography, reprecipitation, etc. The obtained compound has melting point, IR,
Identification was performed using NMR, UV, elemental analysis, etc. The compounds of the present invention can be synthesized using other ester synthesis methods, such as direct synthesis from 2-palmitoylaminoethanol and carboxylic acid, transesterification, synthesis using a nitrile derivative corresponding to carboxylic acid,
Alternatively, it can be synthesized using other conventional amide synthesis methods, such as the amine decomposition method of palmitic acid ester or the 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-palmitoylaminoethanol were added to 60 ml of anhydrous benzene, and after adding 30 ml of pyridine, the mixture was heated under reflux for 6.5 hours. After standing overnight, the precipitated crystals were collected by filtration, washed with distilled water, and recrystallized from 80% methanol to obtain 15.2 g of white needle-like crystals of 2-palmitoylaminoethyl isonicotinate. mp 90.0−92.0℃ IR (KBr): 3280, 3075, 2940, 2902, 2840,
1725, 1635, 1553 cm ^-1 NMR (AcOH-d ₄ ): δ = 0.7-1.0 (3H, m),
1.1−2.5 (28H, m), 3.68 (2H, t, J=5
Hz), 4.46 (2H, t, J=5Hz), 8.00 (2H,
d, J = 7 Hz), 8.78 (2H, d, J = 7 Hz) Example 2 2-aminoethyl nicotinate dihydrochloride 5.0
g was dissolved in 30 ml of pyridine, 7.0 g of palmitic acid chloride was added, and the mixture was stirred at 80° C. for 3 hours.
After cooling, add distilled water and filter the formed precipitate.
% methanol to obtain 5.9 g of white crystals of 2-palmitoylaminoethyl nicotinate. mp 91.5−93.5℃ IR (KBr): 3310, 3070, 2948, 2910, 2850,
1718, 1635, 1582, 1548 cm ^-1 NMR (AcOH-d ₄ ): δ = 0.7-1.0 (3H, m),
1.1−2.4 (28H, m), 3.67 (2H, t, J=5
Hz), 4.45 (2H, t, J=5Hz), 7.63 (1H,
dd, J ₁ = 5Hz, J ₂ = 8Hz), 8.5 (1H, d, J
= 8Hz), 8.8 (1H, d, J = 5Hz), 9.18
(1H, s) Next, the pharmacological effects of the compounds of the present invention will be described.
The compounds used as test drugs are as follows. PEA; 2-palmitoylaminoethanol PEAN; 2-palmitoylaminoethyl nicotinate PEAI; 2-palmitoylaminoethyl isonicotinate 1 Carrageenin edema inhibitory effect The test drug was orally administered to 10 male rats per group,
1% as an inflammatory substance under the skin of the right hind footpad 30 minutes later.
0.1 ml of carrageenan was injected. 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] 2. Effect of suppressing granulation growth using the paper disc method A paper disc was inserted subcutaneously into both axilla regions of 10 male rats per group, and the test drug was orally administered for 6 days, after which the granulation was removed. The effectiveness was determined. The results are shown in Table 2.

[Table] As is clear from the results of the above pharmacological tests, the compound of the present invention has a better edema-inhibiting effect and granulation growth-inhibiting effect compared to 2-palmitoylaminoethanol, and therefore can reduce the dosage and cause side effects. It is a therapeutically useful anti-inflammatory and analgesic agent that can alleviate the symptoms of cancer, and is also expected to have effects such as immune enhancement and infectious disease treatment. 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 dosage form for oral or parenteral administration by a conventional method. 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 pharmaceuticals. It may also be used as a combination agent with active ingredients. For oral dosage forms, it may be used as is or in combination with excipients such as float sugar and starch, binders such as cellulose and gelatin, disintegrants such as carboxymethylcellulose, and lubricants such as talc and magnesium stearate. It can be formulated as a tablet, capsule, pill, powder, or granule. Further, it can be made into an ointment by combining it with vaseline, paraffin, or other ointment base, or it can be made into a suppository by mixing it with a suitable base such as cocoa butter. For parenteral use, an injection can be prepared as a solution or suspension in an aqueous solvent or a non-aqueous solvent such as vegetable oil or 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 preferred dosage of the compound of the present invention is to
Although it varies depending on the administration method, administration time, etc., the compound of the present invention is generally administered at a dose of 100 mg per day for adults.
Preferably, 3000 mg is administered orally. For parenteral administration, dosage levels 3-10 times lower than those indicated above are desirable. Examples of formulations of pharmaceutical compositions containing the compound of the present invention as an active ingredient are shown below. Formulation example 1 (Tablet) Ingredients per tablet (mg) Compound of the present invention 50 Lactose 130 Corn starch 60 Magnesium stearate 10 Formulation example 2 (Capsule) Ingredients per capsule (mg) Compound of the present invention 100 Lactose 200 Prescription Example 3 (Injection) Ingredients per ampoule (mg) Compound of the present invention 10 Solubilizing agent Appropriate amount Distilled water for injection Appropriate amount 1ml

Claims (1)

[Claims] 1. A compound represented by the general formula () and a pharmaceutically acceptable salt thereof. CH ₃ (CH ₂ ) ₁₄ CONHCH ₂ CH ₂ OR () (In the formula, R represents pyridine carbonyl.) 2 General formula () according to claim 1
An anti-inflammatory and analgesic agent containing a compound represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient.