CH617696A5 - Process for the preparation of new derivatives of isoindoline - Google Patents

Abstract

New derivatives of isoindoline of general formula (I) in which Y and R have the meaning given in Claim 1, and of their additional salts with acids, are prepared by reaction of an R-substituted chlorocarbonylpiperazine with an isoindoline of general formula (III). These new compounds are particularly useful as tranquilising agents and anticonvulsants. <IMAGE> <IMAGE>

Description

The present invention relates to a process for the preparation of the corresponding compounds in the formula of which three of the J symbols Z represent hydrogen atoms and the fourth represents the radical -CF3, that is to say the new derivatives of the isoindoline of general formula:

(I)

and their addition salts with acids.

4s In the general formula (I),

Y represents a hydrogen or halogen atom or an alkyl radical containing 1 to 4 carbon atoms, alkyloxy of which the alkyl part contains 1 to 4 carbon atoms, cyano or nitro and,

su R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, alkenyl containing 2 to 4 carbon atoms, alkynyl containing 2 to 4 carbon atoms, hydroxyalkyl in which the alkyl part contains 1 to 4 carbon atoms or phenyl.

55 According to the invention, the new products of general formula (I) are obtained by the action of a chlorocarbonyl-1 piperazine of general formula:

Cl -

CO - ^ - R

NOT /

(not)

(II) in which R is defined as above, on an isoindoline derivative of general formula:

3

617,696

(III)

CF,

/AT

\ î / \ p

(IV)

in which Y is defined as above.

Generally, the reduction is carried out by means of an alkaline borohydride, operating in organic solution such as the dioxane-methanol or dioxane-water or methanol-water or ethanol-water mixture.

The partial reduction of the product of general formula (IV) can lead to isomeric products which can be separated by physicochemical methods such as fractional crystallization or chromatography.

The imide of general formula (IV) can be obtained by the action of a 2-amino naphthyridine of general formula:

v \ / N>

(V)

2S ~ V \ / ~

in which Y is defined as above, on an anhydride of general formula:

CF,

(VI)

optionally via a product of general formula:

CF

■ € r

^ V ^ COOH

not a word

H-

(VII)

in which Y is defined as above.

Generally, a product of general formula (II) is reacted with an alkaline salt, optionally prepared in situ, of a product of general formula (III), by operating in an anhydrous organic solvent such as dimethylformamide or tetrahy-drofuran. at a temperature below 60 ° C.

The reaction can also be carried out by reacting a salt of the product of general formula (II), preferably the hydrochloride, with a product of general formula (III) by operating in Pyridine and optionally in the presence of a tertiary amine such as triethylamine which releases the product of general formula (II) from its salt.

The isoindoline derivative of general formula (III) can be obtained by partial reduction of an imide of general formula:

in where Y is defined as above.

Generally, the reaction of 2-amino-naphthyridine of general formula (V) with the anhydride of general formula (VI) is carried out by heating in an organic solvent such as acetic acid, dimethylformamide, acetonitrile or phenyl oxide.

Generally the cyclization of the product of general formula (VII) into the product of general formula (IV) can be carried out either by heating with acetyl chloride in acetic acid or acetic anhydride, or by the action of an agent. of con-2ndensation such as N, N'-dicyclohexylcarbodiimide in dimethylformamide at a temperature below 100 ° C.

The new products of general formula (I) can optionally be purified by physical (such as distillation, crystallization, chromatography) or chemical (such as salt formation, crystallization thereof and decomposition in an alkaline medium; in this operation; the nature of the anion of the salt is indifferent, the only condition being that the salt is well defined and easily crystallizable). The new products according to the invention can be converted into addition salts with acids.

The addition salts can be obtained by the action of the new compounds on acids in suitable solvents. As organic solvents, use is made, for example, of alcohols, ethers, ketones or chlorinated solvents; the salt formed precipitates after optional concentration of its solution and is separated by filtration or decantation.

The new products according to the invention as well as their addition salts have pharmacological and health-promoting properties. They have been shown to be particularly active as tranquilizers and anticonvulsants.

In animals (mice), they have been shown to be active at doses between 0.1 and 100 mg / kg p.o., in particular in the following tests:

45 - electric battle using a technique similar to that of Tedeschi et al. [J. Pharmacol., 125, 28 (1959)]

- convulsion with pentetrazol according to a technique similar to that of Everett and Richards [J. Pharmacol., 81.402 (1944)]

- supramaximal electroshock according to the technique of Swinyard s ,, et al. [J. Pharmacol., 106,319 (1952)]

and locomotor activity according to the Courvoisier technique [Congress of Alienist Doctors and Neurologists-Tours- (June 8/13, 1959)] and Julou (Bulletin of the Society of Pharmacy of Lille, n ° 2, January 1967, page 7).

55 Furthermore, they have only a low toxicity; their lethal dose 50% (DLS0) is generally greater than 300 mg / kg p.o. in mice.

Of particular interest are the products of general formula (I) in which Y represents a halogen atom and fi „R represents an alkyl radical containing 1 to 4 carbon atoms as well as their addition salts with acids. Among these products, mention may be made in particular of (7-chloro-naphthyridine-1,8 yl-2) -2 (4-methyl-piperazinyl-1) 3-carbonyloxy-5-trifluoromethyl-isoindolinone-1.

, lS For medicinal use, use is made of the new compounds either in the form of bases or in the form of pharmaceutically acceptable addition salts, that is to say nontoxic at the doses of use .

617,696

4

As examples of pharmaceutically acceptable addition salts, there may be mentioned salts of mineral acids (such as hydrochlorides, sulfates, nitrates, phosphates) or organic acids (such as acetates, propionates, succinates, benzoates, fumarates, maleates, theophyllineacetates, salicylates, phenol-phthalinates, methylene bis- ß-oxynaphtoates) or derivatives of. substitution of these acids.

The following examples show how the invention can be put into practice.

Example 1

To a suspension of 4.8 g of (choro-7 naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoromethyl-5 isoindolinone-1 in 480 cm3 of methylene chloride, 10.2 g (14.2 cm3 ) of triethylamine and 66 cm 3 of pyridine, 7.5 g of chlorocarbonyl-1 methyl-4 piperazine hydrochloride are added at 20-21 ° C. After 5 hours, another 7.6 g of chlorocarbonyl-1 methyl hydrochloride are added -4 piperazine. Stirring is continued for 15 hours then hydrolysis with 480 cm3 of water. The organic layer is separated by decantation and the aqueous layer is extracted with 300 cm 3 of methylene chloure. The organic layers are combined, washed with 150 cm3 of water, then dried over 15 g of anhydrous sodium sulfate. After filtration and concentration to dryness, the residue (9.5 g) is triturated with 100 cm3 of water. After filtration, the product is washed with 60 cm3 of water and then recrystallized from 42 cm3 of dichloroethane. The dry precipitate is stirred for 1 hour with 37 cm3 of water, filtered, washed and dried. 3.3 g of (chloro-7 naphthyridin-1,8 yl-2) -2 (methyl-4 piperazinyl-1) -carbonyloxy-3 trifluoromethyl-5 isoindolinone-1, melting at 222 ° C., are thus obtained.

(7-chloro-naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoro-methyl-5 isoindolinone-1 and its isomer (chloro-7 naphthyridine-1,8 yI-2) -2 hydroxy-3 trifIuormethyl- 6 isoindolinone-1 can be prepared as follows:

To a suspension of 83.6 g of trifluoromethyl-5 N- (chloro-. 7 naphthyridine-1,8 yl-2) phthalimide in 420 cm3 of dioxane, 12 g are added, at a temperature of 15-18 ° C potassium borohydride. Stirred further for 2 hours, then cooled externally by an ice bath. The precipitate formed is separated by filtration, then washed with 40 cm3 of a methanol-dioxane mixture (1—1 by volume). The precipitate is separated by filtration, dried and then stirred for 30 minutes with 200 cm 3 of the same mixture, then the precipitate is separated by filtration, heated to reflux with 200 cm 3 of ethanol. After cooling the suspension and filtration, 21.9 g of (chloro-7 naphthyridin-1.8 yl-2) -2 hydroxy-3 trifluoromethyl-5 isoindolinone-1 are obtained, melting at a temperature above 300 ° C.

The solution obtained after filtration of the reaction medium and the washes with the methanol-dioxane mixture are combined. 2500 cm3 of water are added. The precipitate which forms is separated by filtration, washed with 600 cm3 of water and then recrystallized twice from a methanol-dioxane mixture (5-5 by volume). 15.3 g of (chloro-7 naphtridine-1.8 yl-2) -2 hydroxy-3 trifluoromethyl-6 isoindolinone-1 are thus obtained, melting at 265 ° C.

Trifluoromethyl-5 N- (7-chloro-naphthyridine-1,8 yl-2) phthalimide can be prepared as follows:

73.5 g of 4-trifluoromethyl phthalic anhydride, 50.2 g of N-hydroxysuccinimide in 1500 cm 3 of dimethylformamide are heated for 18 hours at 75-78 ° C. 61.4 g (of 2-chloro amino) is then added -7 naphthyridine-1.8 and 140 g of N, N'-dicyclo-hexylcarbodiimide, then the mixture is further heated for 3 hours at the same temperature After cooling, the precipitate formed is separated by filtration, washed with 100 cm3 of dimethylformamide and then per 200 cm3 of isopropyl ether.

1500 cm3 of water are added to the reaction medium. The precipitate which forms is separated by filtration, washed with 1500 cm 3 of methylene chloride. The two precipitates combined are taken up in 8 liters of methylene chloride. An insoluble material is separated by filtration, then the filtrate is concentrated to dryness. 83.6 g of trifluoromethyl-5 N- (7-chloro-naphthyridine-1,8 yl-2) phthalimide, melting at 265 ° C., are thus obtained.

5 Trifluoromethyl-4 phthalic anhydride can be prepared as follows:

106.6 g of 4-trifluoromethyl phthalic acid and 215 cm 3 of acetic anhydride are heated for 30 minutes at reflux. After concentration under deduced pressure (30 mm of mercury), the residue is stirred with 420 cm 3 of cyclohexane. After filtration and drying, 73.5 g of trifluoromethyl-4 phatalic anhydride, melting at 54 ° C., are obtained.

4-Trifluoromethyl phthalic acid can be prepared as follows:

1 ^ 102.3 g of 2-cyano-4-trifluoromethyl benzoate, 108 g of sodium hydroxide pellets, 900 cm3 of water and 1900 cm3 of methanol are heated at reflux for 12 hours. The solution is discolored with 0.6 g of animal black. After filtration, 100 cm 3 of hydrochloric acid (d = 1.19) are added. Extraction is carried out with 2.25 liters of ethyl ether. The organic layer is dried over 40 g of anhydrous magnesium sulfate. After filtration and concentration of the filtrate, 99.1 g of 4-trifluoromethyl phthalic acid, melting at 178 ° C., is obtained.

Methyl 2-cyano-4-trifluoromethyl benzoate can be

0 prepared as follows:

144.6 g of 2-amino-4-methyl trifluoromethyl benzoate

1 are suspended in a mixture of 1.3 kg of ice, 730 cm3 of water and 171.5 cm3 of hydrochloric acid (d = 1.19). To the solution obtained, a solution of 49.9 g of sodium nitrite in 172 cm 3 of water is added all at once. The mixture is stirred for 2 hours 30 minutes at 0-1 ° C. The reaction mixture is filtered and then added over 1 hour 20 minutes, dropwise, to a solution maintained at 4-5 ° C of 226 g of copper sulphate, 261 g of potassium cyanide in 1320 cm3 of water [solution prepared according to GABRIEL, Ber., 52.1089 (1919)]. During the addition of the diazo compound, the pH is maintained at 6-7 by adding a 10% sodium carbonate solution. Stirring is continued, allowing the temperature to rise to 20 ° C. It is then extracted with 3 liters of ether. The ethereal layer is washed with 150 cm3 of water, then dried over 30 g of anhydrous magnesium sulfate. After filtration and concentration, 94.9 g of methyl cyano-2 trifluoromethyl-4 benzoate, melting at 52 ° C., are obtained.

Methyl-2-trifluoromethyl-4-benzoate can be prepared as follows:

141.2 g of 2-amino-4-trifluoromethyl benzoic acid, 1.51 liters of methanol and 506 cm 3 of boron trifluoride etherate are heated at reflux for 99 hours. The solution obtained is added to 350 g of sodium carbonate in 2.8 kg of water, ice-cold. The mixture is stirred for 15 minutes, then extracted with 3 liters of ethyl ether. The ethereal layer is washed with 250 cm3 of water, then dried over 30 g of anhydrous magnesium sulfate. After filtration and concentration, 137 g of amino-2 trifluoro-methyl-4-methyl benzoate, melting at 64 ° C., are obtained.

"2-amino-4-trifluoromethyl-4-benzoic acid can be prepared according to HAUPTSCHEIN et al., J. Amer. Chem. Soc., 76, 1051 (1954).

,, n Example 2

By operating as in Example 1, but starting with 4.8 g of (chloro-7naphthyridin-1.8 yl-2) -2 hydroxy-3 trifluoromethyl-6 isoindolinone-1.15.1 g of chlorocarbonyl hydrochloride -1 methyl-4 piperazine, 14.2 cm3 (10.2 g) of triethylamine and 66 „5 cm3 of pyridine in 250 cm3 of methylene chloride, 7.8 g of crude product are obtained which is triturated with 50 cm3 of water. The solid obtained is separated by filtration and washed with 30 cm3 of water. After recrystallization from 240 cm3 of isopropanol, we

obtains 4.7 g of (chloro-7 naphthyridine-1,8 yl-2) -2 (methyl-4 piperazinyl-1) carbonyloxy-3 trifluoromethyl-6 isoindoiinone-1 melting at 219 ° C.

5,617,696

(7-chloro-naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoromethyl-6 isoindoiinone-1 can be prepared as described in Example 1.

Claims (3)

617,696 CLAIMS In the patent 592,662 have been described compounds of 1. Process for the preparation of a new derivative of the isoindo- general formula: general formula line: 0 - R 0) n in which: Y represents a hydrogen or halogen atom or an alkyl radical containing 1 to 4 carbon atoms, alkyloxy of which the alkyl part contains 1 to 4 carbon atoms, cyano or nitro, and the symbol R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, alkenyl containing 2 with 4 carbon atoms, alkynyl containing 2 to 4 carbon atoms, hydroxyalkyl of which the alkyl part contains 1 to 4 carbon or phenyl atoms, as well as its addition salts with acids, characterized in that a chlorocarbonyl-1 piperazine of general formula is reacted: Cl - CO - N y * V X. NOT R on an isoindoline derivative of general formula: CF. in which R and Y have the corresponding definitions, then optionally transforms the product obtained into an addition salt with an acid. 2. Method according to claim 1, characterized in that a chlorocarbonylpiperazine defined as in the claim is reacted with an alkaline salt, optionally prepared in situ, of a naphthyridine derivative defined as in the claim by operating in a organic solvent, then optionally transforms the product obtained into an addition salt with an acid. 3. Method according to claim 1, characterized in that one reacts a salt of a chlorocarbonylpiperazine defined as in the claim on a naphthyridine derivative defined as in the claim by operating in pyridine and optionally in the presence of a tertiary organic base, then optionally transforms the product obtained into an addition salt with an acid in which the symbols represent in particular: A and A! the group CH n the number zero X (in positions 5 and 6) the group CH X (in position 7) the group CY X (in position 8) a nitrogen atom.