CH617935A5 - Preparation of new isoindoline derivatives - Google Patents

Abstract

New derivatives of isoindoline of general formula (I) in which Y represents a hydrogen or halogen atom or an alkyl radical containing 1 to 4 carbon atoms, an alkyloxy radical containing 1 to 4 carbon atoms, a cyano radical or a nitro radical and R represents a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, an alkenyl radical containing 2 to 4 carbon atoms, an alkynyl radical containing 2 to 4 carbon atoms, a hydroxyalkyl radical containing 1 to 4 carbon atoms or a phenyl radical, and their addition salts with acids, are prepared by reaction of a piperazine of general formula (II) with a mixed carbonate of general formula (III) with Ar = optionally substituted phenyl. These new compounds are particularly useful as tranquilising and anticonvulsant agents. <IMAGE> <IMAGE> <IMAGE>

Description

617,935

2

CLAIM

Process for the preparation of a new isoindoline derivative of general formula:

0

) Ai J-

n n '

hjsT

n - r on a mixed carbonate of general formula: // -

cf 1

XfsT

- 0 - Ar in which R and Y have the corresponding definitions and Ar represents an optionally substituted phenyl radical, then optionally transforms the product obtained into an addition salt with an acid.

In patent No. 592662, compounds of general formula have been described:

0

in which the symbols represent in particular: A and Ai the grouping 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.

The present invention relates to a process for the preparation of the corresponding compounds in the formula of which three of the symbols Z represent hydrogen atoms and the fourth represents the radical - cf3, that is to say new derivatives of iso-indoline of general formula:

/ * ''

o-co-n n - r

X

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 to 4 carbon atoms, alkynil containing 2 to 4 carbon atoms, hydroxyalkyl in which the alkyl part contains 1 to 4 carbon atoms or phenyl,

as well as its addition salts with acids, characterized in that a piperazine of general formula is reacted:

cf;

11 r ^ Y \ il

(I)

x- V.

o-co-n n - r

X /

20 and their addition salts with acids.

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 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.

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

NOT

HN N - R (II)

35 ^ ^

in which R is defined as above, on a mixed carbonate of general formula:

vv ~

(III)

- CO - 0 - Ar in which Y is defined as above and Ar represents a phenyl radical optionally substituted, for example by an alkyl radical containing 1 to 4 carbon atoms or by a nitro radical.

Generally the reaction is carried out in an organic solvent such as acetonitrile at a temperature in the region of 20 ° C.

The mixed carbonate of general formula (III) can be obtained 55 by the action of a chloroformate of general formula:

Cl — CO — O — Ar (IV)

in which Ar is defined as above, on a product of general formula:

60

0 he

M

M,

(V)

in which Y has the corresponding definition.

3

617,935

The reaction is generally carried out in a basic organic solvent such as pyridine at a temperature between 0 and 20 ° C.

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

(VI)

in which Y is defined as above.

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

Partial reduction of the product of general formula (VI)

can lead to isomeric products which can be separated by physicochemical methods such as fractional crystallization or chromatography.

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

(VII)

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

(VIII)

optionally via a product of general formula:

(IX)

V \

COOH

in which Y is defined as above.

Generally, the reaction of 2-amino naphthyridine of general formula (VII) with the anhydride of general formula (VIII) 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 (IX) into the product of general formula (VI) can be carried out either by heating with acetyl chloride in acetic acid or acetic anhydride, or by the action of a condensing agent 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 health pharmacological 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:

20 - 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 Swinyard technique and 25 coll. ["J. Pharmacol. ", 106, 319 (1952)], and

- locomotor activity according to the Courvoisier technique ["Congress of alienist doctors and neurologists", Tours,

(8/13 June 1959)] and Julou (“Bulletin of the Lille Pharmacy Society”, N ° 2, January 1967, p. 7).

Furthermore, they have only a low toxicity; their lethal dose 50% (dl50) is generally greater than 300 mg / kg p.o. in mice.

Of very particular interest are the products of general formula (I) in which Y represents a halogen atom and R 35 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 iso-indolinone-1.

40 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 doses of use.

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, fuma-rates, maleates, theophylline acetates, salicylates, phenolphthalates, methylene-bis-P-oxynaphthoates) or derivatives of these acids.

The following example illustrates the invention.

Example:

To a suspension of 14.2 g of (7-chloro-naphthyridine-1,8 yl-55 2) -2 trifluoromethyl-5 phenoxycarbonyloxy-3 iso-indolinone-1 in 280 cm3 of acetonitrile, is added, at a similar temperature at 20 ° C, 8.5 cm3 of N-methylpiperazine. Stir 2 h at 20-21 ° C. Dilute with 1000 cm3 of water and extract the suspension with 1100 cm3 of ethyl ether. It is dried over 100 g of anhydrous potassium carbonate 60, then the solvent is filtered and distilled under reduced pressure (20 mm of mercury) at a temperature in the region of 30 ° C; the residue is recrystallized from 70 cm3 of boiling acetonitrile. 9.2 g of (chloro-7 naphthyridine-1,8 yl-2) -2 (methyl-4 pipera-zinyl) carbonyloxy-3 trifluoromethyl-5 iso-indolinone-1 are thus obtained, melting at 65 219-221 ° C. .

(7-chloro-naphthyridine-1,8 yl-2) -2 phenoxycarbonyloxy-3 trifluoromethyl-5 iso-indolinone-1 can be prepared as follows:

617935

To a suspension of 11.2 g of (7-chloro-naphthyridine-1,8 yl-2) -2 3-hydroxy-trifluoromethyl-5 iso-indolinone-1, in 100 cm 3 of pyridine, is added, in the space of 24 min, 14.1 g of phenyl chloroformate maintaining the temperature in the region of 18 ° C. The mixture is stirred for another 30 min, then poured onto 720 cm 3 of ice water. The precipitate is drained and washed on the filter with 250 cm3 of water. 15 g of (chloro-7 naphthyridine-1,8 yl-2) -2 phenoxycarbonyloxy-3-trifluoromethyl-5 iso-indolinone-1 are thus obtained, melting at 214-216 = C.

(7-chloro-naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoromethyl-5 iso-indolinone-1 and its isomer (chloro-7 naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoromethyl- 6 iso-indolinone-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 methanol and 420 cm3 of dioxane, is added, at a temperature of 15-18 ° C, 12 g of potassium borohydride. Stirred further for 2 h, 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, then stirred for 30 min 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 (7-chloro-naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoromethyl-5 iso-indolinone-1 are obtained, melting at a temperature above 300 ° C. .

The solution obtained after filtration of the reaction mixture 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, then recrystallized 2 times from a methanol / dioxane mixture (5/5 by volume). 15.3 g of (chloro-7 naphthyridine-1,8 yl-2) -2 hydroxy-3 trifluoromethyl-6 iso-indolinone-1 are thus obtained, melting at 265 ° C.

Trifluoromethyl-5 N- (chloro-7 naphthyridine-1,8 yl-2) phthalimide can be prepared in the following manner:

73.5 g of 4-trifluoromethyl phthalic anhydride, 50.2 g of N-hydroxysuccinimide in 1500 cm3 of dimethylformamide are heated for 18 h at 75-78 ° C. 61.4 g of 2-chloro-chloro are then added -7 naphthyridine-1.8 and 140 g of N, N'-dicyclohexylcarbo-diimide, then the mixture is further heated for 3 h at the same temperature. After cooling, the precipitate formed is separated by filtration, washed with 100 cm3 of dimethylformamide, then with 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 l of methylene chloride. An insoluble material is separated by filtration, then the filtrate is concentrated to dryness. 83.6 g of trifluoromethyl-5 N- (chloro-7 naphthyridine-1,8 yl-2) phthalimide, melting at 265 ° C., are thus obtained.

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 min at reflux. After concentration under reduced pressure (30 mm of mercury), the residue is stirred with 420 cm3 of cyclohexane. After filtration and drying, 73.5 g of trifluoromethyl-4 phthalic anhydride, melting at 54 ° C., are obtained.

4-Trifluoromethyl phthalic acid can be prepared as follows:

102.3 g of 2-cyano-4-trifluoromethyl-benzoate, 108 g of sodium hydroxide tablet, 900 cm3 of water and 1900 cm3 of methanol are heated at reflux for 12 h. 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 1 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 prepared as follows:

144.6 g of 2-amino-4-methyl trifluoromethyl benzoate 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 h 30 min at 0-1 ° C. The reaction mixture is filtered, then added in 1 h 20, drop by drop, to a solution maintained at 4-5 ° C of 226 g of copper sulphate, 261 g of potassium cyanide in 1320 cm3 of water [prepared solution according to Gabriel, "Ber.", 52.1089 (1919)]. During the addition of the diazo compound, the pH is maintained at 6-7 by addition of a 10% sodium carbonate solution. Stirring is continued, allowing the temperature to rise to 20 ° C. It is then extracted with 3 l 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, 1.511 of methanol and 506 cm 3 of boron trifluorare etherate are heated at reflux for 99 h. The solution obtained is added to 350 g of sodium carbonate in 2.8 kg of ice water. The mixture is stirred for 15 min, then extracted with 31 ml 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 2-amino-4-methyl trifluoromethyl benzoate, melting at 64 ° C., are obtained.

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

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R