JPS61271273A - Isoindolinone derivative - Google Patents

Abstract

NEW MATERIAL:The isoindoline derivative of formula I (R<1> is H or lower alkyl; R<2> is H, lower alkyl or acyl). EXAMPLE:N-4-(isoindolyl-2-one)-salicylic acid. USE:A medicinal drug having especially high anti-inflammatory and antithrombotic activities as well as analgesic action and antipyretic action. PREPARATION:The compound of formula I can be produced economically in high yield, by (1) reacting the compound of formula II (R<3> is alcohol residue) with the compound of formula III in an alcohol solvent (e.g. methanol, ethanol, propanol, etc.) at room temperature or under heating to obtain the compound of formula IV, (2) cooling the reaction mixture solution on an ice bath without separating the produced compound from the solution and adding 1-3mol of sodium borohydride or potassium borohydride as a reducing agent based on 1mol of the compound of formula IV, and (3) carrying out the reaction of the components at room temperature for 0.5-10hr after the addition of the reducing agent.

Description

Detailed Description of the Invention (a) Industrial Application Field The present invention relates to a novel isoindolinone derivative, particularly an isoindolinone derivative that has anti-inflammatory and antithrombotic effects and is useful as a pharmaceutical. It is related to.

(b) Conventional technology Conventionally, isoindolinone derivatives include 2-(4-(
1-oxo-2-isoindolinyl)phenyl]propionic acid derivatives (Japanese Patent Publication No. 11827/1982, Japanese Patent Publication No. 29492/1982, 50156/1985, etc.) or isoindolinyl phenylcarbonylpropionic acid derivatives ( JP-A-53-12852, etc.) are known.

However, there is no description of salicylic acid derivatives having isoindolinone as the core, nor is there any suggestion thereof.

(c) Problems to be Solved by the Invention The object of the present invention is to synthesize salicylic acid derivatives having isoindolinone as a core.

Another object of the present invention is to develop isoindolinone derivatives having excellent pharmacological effects such as anti-inflammatory, antithrombotic, analgesic, and antipyretic effects.

The present invention relates to a novel isoindolinone derivative represented by the following general formula (1) (wherein R is a hydrogen atom or a lower alkyl group, and R2 is a hydrogen atom, a lower alkyl group, or an acyl group). It is something.

In the general formula (1), R is a hydrogen atom or methyl,
Ethyl, n-propyl, isopropyl.

A lower alkyl group such as n-butyl or isobutyl, and R2 is a hydrogen atom or methyl, ethyl, or n-propyl.

Lower alkyl groups such as isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, isohexyl, or acetyl, benzoyl, substituted benzoyl (e.g., halogen atom).

Lower alkyl group, lower alkoxy group, nitro group.

It means an acyl group such as a benzoyl group substituted with 1 to 3 trifluoromethyl groups or a nicotinoyl group.

Furthermore, the substitution positions of the partial ○OR and -OR in general formula (I) are not particularly limited and may be substituted arbitrarily.

Next, the method for producing the isoindolinone derivative of the present invention will be described (II) (III) (wherein, R1 is a hydrogen atom or a lower alkyl group, and R2 and R have the same meanings as above). To explain, 0-phthalaldehyde acid or ester represented by the general formula (n) and the general formula (
III) aromatic amine derivative and an organic solvent (e.g.
benzene, toluene, xylene.

The benzylidene derivative represented by the general formula (IV) is obtained by reacting in dioxane, chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, propatool, etc.) at room temperature or under heating.

Next, the isolated benzylidene derivative of general formula (IV) is suspended in alcohol and cooled on ice. A reducing agent, sodium borohydride or potassium borohydride, is added thereto in mols 1 to 3 times the amount of general formula (■). After the addition is completed, the temperature is returned to room temperature and the reaction is allowed to proceed for about 0.5 to 10 hours, whereby the target compound represented by general formula (I) can be obtained in good yield.

Alternatively, 0-phthalaldehyde acid or ester of general formula (II) and aromatic amine derivative of general formula (I) are reacted in an alcohol solvent (e.g., methanol, ethanol, propatool, etc.) at room temperature or under heating. Then, the general formula (I
A benzylidene derivative represented by V) is immediately produced. Next, without isolating and purifying the benzylidene derivative, while cooling the reaction mixture solution on a water bath, 1 to 3 times the mole of sodium borohydride or potassium borohydride as a reducing agent is added. After the addition is complete, the temperature is returned to room temperature and the reaction is allowed to proceed for about 0.5 to 10 hours, thereby making it possible to obtain the target compound represented by general formula (1) in an economical manner and in good yield.

In addition, these manufacturing methods are only examples, and it can also be manufactured by other known methods.

Incidentally, among the compounds of the present invention, some of the compounds having 〇〇H groups or -011 groups can be converted into inorganic salts or organic salts as required. In other words, these include pharmacologically acceptable salts, such as metal salts such as sodium and potassium, alkaline earth metal salts such as calcium, and salts with inorganic bases such as aluminum salts. , or ammonium salts, trimethylamine, triethylamine, arginine.

Examples include organic bases such as lysine.

Furthermore, the compound of the present invention can be formulated with various pharmaceutical inert carriers to form various pharmaceutical formulations such as tablets, capsules, ointments, creams, gels, lotions, herbal medicines, sprays, syrups, and injections. Can be done.

(e) Effect The isoindoline derivative of the present invention has been shown to have anti-inflammatory and antithrombotic effects in animal experiments using rats and mice, and has also been shown to have analgesic and antipyretic effects.

(F) EXAMPLES The present invention will be explained in more detail with reference to Examples below, but of course the present invention is not limited only to these Examples.

Example 1 1.5 g of 0-phthalaldehydic acid and 1.5 g of 4-aminosalicylic acid were added to 30+ sl of methanol and stirred at room temperature for about 30 minutes to precipitate crystals.

While cooling and stirring this reaction solution on a water bath, 0.5 g of sodium borohydride, which is a reducing agent, is gradually added. After the addition, the temperature was returned to room temperature and the mixture was stirred for about 3 hours. The precipitated crystals were collected by filtration, dried, and recrystallized from dimethylformamide to give N-4-(
2.4 g of isoindoly-2-one)-salicylic acid was obtained.

Structural formula % formula % () Infrared absorption spectrum vc=o 1680 cm mass spectrum M7C3 Example 2 1.5 g of 0-phthalaldehydic acid and 1.5 g of 4-aminosalicylic acid were added to 30 ml of ethanol and stirred at room temperature for about 30 minutes. This produces a white crystalline benzylidene compound. Next, the obtained benzylidene compound 2.7
g is suspended in 30 ml of ethanol, and 0.6 g of potassium borohydride is gradually added while stirring and cooling in a water bath. After the addition, the mixture was returned to room temperature and stirred for about 5 hours. The precipitated crystals were collected by filtration, dried, and recrystallized from dimethylformamide to obtain 264 g of the compound shown in Example 1 as colorless prism crystals.

Melting point 278-280℃ (decomposition) Infrared absorption spectrum Ric=o 1680cm mass spectrum
M7C3 Examples 3-6 The compounds shown in the following table were synthesized by the methods of Examples 1-2.

(G) Effects of the Invention The present invention provides novel isoindolinone derivatives that have not been described in any literature.

In addition, the compounds of the present invention have significant anti-inflammatory, antithrombotic, and
It has pharmacological effects such as analgesic and antipyretic effects, and is industrially useful as a pharmaceutical.

Claims (1)

[Claims] 1. General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ Isoindolinone derivatives represented.