JPH0427975B2 - - Google Patents

Description

[Detailed description of the invention] The present invention [However, R is hydrogen, an acyl group derived from 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid; 2-(p-isobutylphenyl)-propionic acid; Representation; R ₁
represents a hydrogen atom or a methyl group] and a pharmaceutically acceptable salt as a pharmacologically active ingredient.

N-acetyl-p-aminophenol is known to be useful in medical treatments based on its analgesic activity. However, this compound has certain toxicity upon administration in large doses, especially toxic effects on the liver.

It has been found that certain compounds obtained by the combination of p-aminophenol and various amino acids, especially those compounds in which the symbol R represents a hydrogen atom, have useful analgesic effects in therapeutic doses. . These compounds relieve a variety of pains. The most active representative compounds of these new products have properties superior to the reference product (i.e. N-acetyl-p-aminophenol). It is also less toxic, with a large difference between therapeutic doses and doses that cause undesirable side effects; in addition, its representative compounds are highly water-soluble and have a galenic form. ) can be used for injection. This was not achieved with N-acetyl-p-aminophenol.

Additionally, certain organic acids, such as acetylsalicylic acid, 5-(2,4-difluorophenyl)-acetylsalicylic acid, 1-(p-chlorobenzoyl)-
It is well known that 5-methoxyindoleacetic acids, certain arylpropionic acids and certain anilinophenylcarboxylic acids or acetic acids are used in human medicine as non-steroidal anti-inflammatory and analgesic agents. It was hot.

However, the use of acids of this type has generally been associated with various types of gastrointestinal disorders, especially bleeding and ulcers.

It now surprisingly appears that in compounds of formula, the symbol R is an organic acid; 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid, and 2-(p-isobutylphenyl) - the compound, when representing an acyl group derived from propionic acid, is an active (biological) compound and, compared to the original acid, is less harmful, less ulcerogenic and moreover significantly It has been found to have therapeutic properties.

Accordingly, the present invention relates to compounds of formula and salts thereof formed from pharmaceutically acceptable inorganic or organic acids.

The compound in which the symbol R represents a hydrogen atom can be prepared first from the p-haloacylaminophenol of the formula.

(X represents a halogen atom)
13, 160), and the other raw material, diethylamine, is available as a commercial product.

The inventor used these compounds in chemically pure form according to the tests described below.

In one embodiment, a compound of formula dissolved in an anhydrous solvent is slowly added (at a suitable temperature) to a solution of diethylamine (a secondary amine), and the salt is then filtered; The base was precipitated by evaporating the solvent and adding a solvent such as ethyl acetate or diisopropyl ether.

using a secondary amine as an acid acceptor;
It is thus advantageous to use it in an excess of 100-130%. Tertiary amines such as triethylamine or pyridine may be used as acid acceptors, provided that the salt of the secondary amine is soluble in the solvent used.

A highly preferred embodiment is to carry out the reaction in dry dimethylformamide or anhydrous methyl ethyl ketone.

The preferred temperature for carrying out the reaction is 20-100°C.
is within the range of Reaction times can vary between 2 hours and 5 days.

In one embodiment of product compound isolation, the salt is filtered, the solvent and excess amine are evaporated under vacuum,
The base is precipitated by addition of a suitable solvent such as ethyl acetate or diisopropyl ether.

In another method of isolating this compound, the residue after evaporation in a solvent such as isopropanol, ethyl acetate or acetone is treated with an acid dissolved in alcohol or a gaseous acid to precipitate the desired salt. let

The phenolic compound thus obtained is then converted into the corresponding ester according to the procedure of the invention by reaction with the halide of the organic acid described above. In particular, the chloride of the acid is well known and easy to use.

In one embodiment, the formula (R=H) phenol and the corresponding acid chloride in the presence of a tertiary base in a suitable solvent at a suitable temperature, the reaction mixture is washed with water until neutral, dried and the organic phase is evaporated. and finally reconsolidate the crude product.

In the present invention, the reactants are used in equimolar amounts or, for certain acid chlorides, in 10-15% excess. Preference is given to using tertiary bases such as triethylamine or pyridine as acid acceptors.

A particularly advantageous embodiment consists in reacting suitable amounts of starting compounds in an organic solvent such as methylene chloride, chloroform or dry toluene, with a suitable temperature range for carrying out the reaction ranging from 10 to
The temperature is 110℃. Reaction times can vary from 2 to 24 hours.

The new compounds of formula form salts with acidic substances. The salts are obtained by treating the residue after evaporation in a solvent such as isopropanol, acetone or ether with an acid dissolved in alcohol or with a gaseous acid to precipitate the required salt.

One highly recommended embodiment for obtaining the salt is:
Using an acid chloride and a salt of dialkylaminoacetamidophenol of formula in approximately equimolar amounts, the third
It consists of reacting in the presence of a class base. In this way, the required salt is directly produced and purified by reconsolidation.

As already mentioned, compounds of the formula and R in the formula
and compounds in which R ₁ is hydrogen, i.e. p-N,N-
Diethylglycylamidophenol has an analgesic effect and both analgesic and anti-inflammatory effects.

In the present invention, the compound having a significant analgesic effect is p-N,N-diethylglycylamidophenol and its hydrochloride. In other words, in the mouse acetylcholine test, approximately 100 to approximately 300
The use of doses of mg/Kg showed a high degree of analgesic effect (oral administration; ED ₅₀ approximately 140 mg/Kg).

An example of a compound that has both analgesic and anti-inflammatory effects is 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetate of 4-N,N-diethylaminoacetamidophenyl. and its hydrochloride. The effectiveness of the latter as an analgesic could be demonstrated in the mouse phenylbenzoquinone test using doses of about 0.5 to about 8 mg/Kg (ED ₅₀ approximately 2.3 mg/Kg).

The hydrochloride salt was also shown to exert a high degree of anti-inflammatory activity in inhibiting carrageenan-induced foot sole edema in rats (ED ₅₀ approximately 16.7
mg/Kg). This compound also exhibited anti-arthritic and antipyretic effects.

In the present invention, compounds of the formula or p-N,N
- by using a combination of diethylglycylamidophenol and excipients, carriers or customary inert diluents. , it is possible to advantageously exert the desired therapeutic effect.

The following examples are illustrative of the present invention and are not intended to limit the scope of the present invention.

Example 1 For a solution of 77.5 g (1.06 mol) of diethylamine in anhydrous dimethylformamide (180 ml), 49.3
g (0.265 mol) of N-α-chloroacetyl-p
-A solution of aminophenol in anhydrous dimethylformamide (80ml) was added dropwise. The rate of addition was such that the temperature of the mixture did not exceed 30°C; the mixture was then heated to a temperature of 45°C while stirring.
After heating at ˜50° C. for 2 hours and cooling, the resulting diethylamine hydrochloride was filtered and the solvent was evaporated in vacuo. 450 ml of ethyl acetate was added to the residue (65.7 g) to precipitate a second fraction of diethylamine hydrochloride which was filtered and the mother liquor was acidified with hydrochloric acid dissolved in isopropanol. 50.4 g of p-N,N-diethylglycylamidophenol (melting point 204-206 DEG C.) was thus obtained. Evaporation of the acidic mother liquor recovered 17.4 g of product, which was reconsolidated in 150 ml of absolute ethanol to give 8.6 g of the hydrochloride salt (mp 204-206 DEG C.).
The yield from both fractions was 86%.

Example 2 Following the method described in Example 1, the following compounds were obtained: p-N,N-diethyl-α-alanylamidephenol-HCl, melting point 196-197°C; Example 3 Dry chloroform (500 ml) and triethylamine (21 ml). ;0.15 mole) 56.4g
(0.15 mol) of 1-(4-chlorobenzoyl)-5
38.8 g (0.15 mol) of 4-N,N-N diethylaminoacetamidophenol-HCl was added in portions to the solution of -methoxy-2-methyl-3-indolyl acetyl chloride. The mixture was stirred at ambient temperature for 6 hours, washed with a small amount of water, the chloroform solution was dried over Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. Reconsolidation of the residue in isopropanol yields 4-N,N-diethylaminoacetamidophenyl 1-(4-chlorobenzoyl)-5
-Methoxy-2-methyl-3-indolyl acetate hydrochloride [melting point 179-180°C (decomposition); yield 70%]
was gotten.

Example 4 For a solution of 89.9 g (0.4 mol) of 2-(p-isobutylphenyl)-propionyl chloride in dry methylene chloride (300 ml), 103.2 g of 4-N,
N-diethylamine acetamidophenol-HCl
(0.4 mol) was added followed by 56 ml (0.4 mol) of triethylamine. This mixture was heated under reflux for 2
Heat for an hour, then cool, wash with water, and anhydrous Na ₂ SO ₄
Dry on top and then evaporate under vacuum. The solid residue was reconsolidated in isopropanol. 4-N,N-diethylaminoacetamidophenyl 2-(p-isobutylphenyl)-propionate was thus obtained as the hydrochloride (melting point 153-155°C; yield 80%).

By the above method, 4-N,N-diisopropylaminoacetamidophenyl hydrochloride 2-(p-isobutylphenyl)-propionate [melting point 140~
143°C (decomposition)] was obtained.

Claims (1)

[Claims] 1. The following formula [However, R is hydrogen or 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3
- represents an acyl group derived from an organic acid selected from indolyl acetic acid, 2-(p-isobutylphenyl)-propionic acid; R ₁ represents a hydrogen atom or a methyl group], and its pharmaceutical An analgesic or anti-inflammatory drug, characterized in that it contains a salt acceptable to as a pharmacologically active ingredient.