CS196323B2 - Method of producing novel derivatives of isoindoline - Google Patents

Abstract

1498348 Naphthyridine derivatives RHONEPOULENC SA 17 Sept 1976 [22 Sept 1975] 38671/76 Addition to 1417935 Heading C2C Novel compounds II in which Y is H, halogen, C 1-4 alkyl, C 1-4 alkoxy, CN or NO 2 and R is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 hydroxyalkyl or phenyl, and acid addition salts thereof, are prepared by (a) reacting a compound IV with a 1-R-2-chlorocarbonyl-piperazine, or (b) reacting a mixed carbonate of a compound IV with a 1-R-piperazine. Compounds IV are prepared by partial reduction of corresponding imides which are themselves prepared by reacting a trifluoromethyl-substituted anhydride with a 2-amino- 7-Y-naphthyridine. 4 - Trifluoromethyl - phthalic anhydride is prepared by converting 2-amino-4-trifluoromethylbenzoic acid to the methyl ester, diazotizing the ester and reacting the diazo compound with KCN to form methyl 2-cyano-4-trifluoromethylbenzoate, hydrolysing this to form 4-trifluoromethyl-phthalic acid and cyclizing this to form the desired anhydride. Pharmaceutical compositions useful as tranquillizers and anticonvulsants comprise a compound II or a non-toxic acid addition salt thereof, together with a pharmaceutical carrier. The compositions may be in a form suitable for oral, parenteral, rectal or topical administration.

Description

Proprietor of the patent RHONE-POULEC S.A, PARIS (France) (54) Production method of new isoindoline derivatives

Belgian Patent No. 815,019 discloses compounds of the general formula

where they mean

A and A 1 are CH, n O,

X at position 5 and 6 at CH, at position 7 at CY and at position 8 nitrogen,

Z independently of one another hydrogen or halogen, alkoxy radicals of 1-4 carbon atoms or nitro; and

R is hydrogen, alkyl or hydroxyalkyl of 1-4 carbon atoms, alkenyl or alkynyl of 2-4 carbon atoms or phenyl.

The present invention relates to a process for the preparation of novel isoindoline derivatives of the formula wherein all three Z are hydrogen and the fourth is -CF1, the novel isoindoline derivatives of formula I,

where it means

Y is a halogen atom and

R is C1-C4 alkyl, as well as acid addition salts of these compounds.

According to the invention, the novel isoindoline derivatives of the formula I can be prepared by treatment with 1-chlorocarbonylpiperazine of the formula II,

196223 ci-co-

(fi) where

R is as defined above, to an isoindoline derivative of formula III,

where

Y is as defined above.

Typically, a compound of formula II is reacted with an alkali salt of a derivative of formula III, optionally prepared directly in the reaction mixture, in an anhydrous organic solvent such as dimethylformamide or tetrahydrofuran at a temperature below 60 ° C.

The reaction may also be carried out by reacting a salt of a compound of formula II, preferably a hydrochloride, with a compound of formula III in pyridine, optionally in the presence of a tertiary amine such as triethylamine, which liberates the compound of formula II from its salt. '

The isoindoline derivative of formula III can be obtained by partial reduction of an imide of formula IV,

where

Y is as defined above.

The reduction is usually carried out with an alkali metal borohydride in an organic solvent or a mixture of an organic solvent and water, for example in a mixture of dioxane and methanol, dioxane and water, methanol and water, or ethanol and water.

Partial reduction of the compound of formula (IV) can result in the formation of isomeric products which can then be separated by physicochemical methods, for example, by fractional crystallization or chromatography.

The imide of formula IV can be obtained by treatment with 2-aminonaphthyridine of formula V,

Ί v —UmX. (IN) where Y has the upper hand said importance,

to the anhydride of formula VI,

optionally via an intermediate of formula (VII),

where

Y is as defined above.

The reaction of the 2-aminonaphthyridine of formula V with the anhydride of formula VI is usually carried out by heating in an organic solvent such as acetic acid, dlmethylformamide, acetonitrile or phenyloxide.

The cyclization of a compound of formula VII to a compound of formula IV is usually carried out by heating with acetyl chloride in acetic acid or acetic anhydride or by treatment with a condensing agent such as N, N‘-dicyclohexylcarbodilmide in dimethylformamide at a temperature below 100 ° C.

The novel compounds of formula (I) may optionally be purified by physical means such as distillation, crystallization, chromatography, or chemical methods, for example salt formation, by crystallization of the salt followed by decomposition in an alkaline medium; in the course of this process, the nature of the salt anion is indifferent, it is only necessary for the salt to crystallize easily and be stable.

The novel compounds of the present invention can be converted into acid addition salts.

Acid addition salts can be obtained by treating the acids with new compounds in a suitable solvent. Suitable organic solvents are alcohols, ethers, ketones or chlorinated solvents, and the salt formed precipitates upon possible concentration of the solution and is separated by filtration or by alloying.

The novel compounds of the invention and their addition salts have interesting pharmacological properties. These 'substances are particularly effective' as antispasmodic and tranquilizers. · ‘

In mice, they are effective at doses of 0.1 to 100 mg / kg. when administered orally, in particular in the following tests: - electric shock, as described by Tedeschi et al. [J. Pharmacol., 125, 28 (1959)], - pentetrazole seizures induced by the method of Everett and Richards [J. Pharmacol., 81, 402 (194-4)], the supramaxial electroshock induced by the method of Swinyard et al. (J. Pharmacol., '106, 319 (1952)], the physical activity monitored by the Courvoisier method [ Congrés des Médecins Alienistes · 'et -' Neurologists - Tours - (8/13 June 1959)] and Julou (Bulletin de la Société de Pharmacie de Lilie, No 2, January 1967, p. 7).

Furthermore, the compounds obtained by the process of the invention have low toxicity. Their DL 50 - is usually greater than 300 mg / kg when administered orally in mice.

Particularly valuable is the compound 2- (7-chloro-1,8-naphthyridin-2-yl) - (4-methyl-1-piperazinyl) -3-carbonyloxy-5-trifluoromethyl-1-isoindolinone. .

For medical use, the novel compounds are used either in free form or in the form of their non-toxic salts, or at least non-toxic salts, in the dosages employed.

Examples of non-toxic addition salts include inorganic acid salts, such as hydrochlorides, sulphates, nitrates or phosphates, or organic acid salts, for example, acetates, propionates, succinates, benzoates, fumarates, maleates, thiophylinations. tats, salicylates, phenolphthaleinates, methylene-3-bis-oxynaphthoates, or salts with substitution derivatives of these acids.

The invention will be illustrated by the following examples.

Example 1

To a suspension of 4.8 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -NH-hydroxy-4-trifluoromethyl-1-isoindolinone - in 480 ml - methylene chloride, 10.2 g (14.2 ml) 7.5 g of 1-chlorocarbonyl-4-methylpiperazine hydrochloride are added at 20 DEG to 21 DEG C. After 5 hours, 7.6 g of 1-chlorocarbonyl-4-methylpiperazine hydrochloride are added. The organic layer is decanted and the aqueous layer is extracted with 300 ml of methylene chloride, the organic layers are decanted, washed with 150 ml of water, and then the water is dried over 15 g of anhydrous water. After filtration and evaporation to dryness, 9.5 g of the residue are mixed with 100 ml of water, the solution is filtered and the product is washed with 60 ml of water and recrystallized in 42 ml of dichloroethane and the precipitate is stirred for 1 hour. with 37 ml of water, filtered, washed and dried to give 3.3 g of 2- (7-chloro-1,8-naphthyridine-2-). yl) - (4-methyl-1-piperazinyl) -3-carbonyloxy-5-trifluoromethyl-1H-isoindolinone, m.p. 222 ° C.

2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-difluoromethyl-1-isoindolinone and its isomer 2- (7-chloro-1,8-naphthyridin-2) -yl) -3-hydroxy-6-trifluoromethyl-1-isoindolmonium can be obtained as follows:

To a suspension of 83.6 g of 5-trifluoromethyl-N- (7-chloro-1,8-naphthyridin-2-yl) phthalimide in 420 ml of methanol and 420 ml of dioxane was added at rt. 12 g of potassium borohydride. The reaction mixture was stirred for a further 2 hours and then cooled in an ice bath. The precipitate formed is collected by filtration, washed with 40 ml of a 1: 1 mixture of methanol and dioxane, and the precipitate is collected by filtration, dried and then stirred for 30 minutes with 200 ml of the same mixture. The precipitate is collected by filtration and heated to reflux in 200 ml of ethanol. After cooling the suspension and filtration, 21.9 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-difluoromethyl-1-isoindolinone is obtained in this way. 'melting point higher than 300' st. - Celsius. .

The solution obtained after filtration of the reaction medium - and the 'aliquots' of the mixture of 'methanol' and dioxane used - for 'screening', is combined. - Add 2500 ml of water. The precipitate formed is collected by filtration, washed with '600 ml' of water and recrystallized twice from a 5: 5 by volume mixture of methanol and dioxane. - In this way 15.3 g are obtained. 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-1-isoindolinone, m.p. 265 ° C.

5-Trifluoro-1-N- (7-chloro-1,8-naphthyridin-2-yl) -thalimide can be obtained by the following method:

73.5 g of 4-triflllórmethylftalové anhydride acid - 50.2 g of N-hydroxysuccinimide in 1500 ml of dimethylformamide - - is - heated ^2-18 .. · hours at 75-78 ° C. Then add

61.4 g of 2-amino-4- (4- (4-chloro-1,1'-ethoxy) -8,8- (4-chloro) pyridine and 140 g of N, N'-dicyclohexylcarbodiimide are added and the mixture is stirred. After cooling for 3 hours at the same temperature, the precipitate formed is collected by filtration, washed with 100 ml of dimethylformamide and then with 200 ml of isopropyl oxide.

1500 ml of water are then added to the reaction mixture. The resulting precipitate was collected by filtration and washed with 1500 ml of methylene chloride. The two precipitates were combined and 8 liters of methylene chloride were added. The insoluble material was collected by filtration and the filtrate was evaporated to dryness to give 83.6 g of 5-trifluoromethyl-N- (7-chloro-1,8-naphthyridin-2-yl) phthalimide, m.p. 265 ° C.

4-Trifluoromethylphthalic anhydride can be obtained as follows:

106.6 g of 4-trifluoromethylphthalic acid and 215 ml of acetic anhydride are heated under reflux for 30 minutes. The mixture is then evaporated to dryness under reduced pressure (4 kPa) and the residue is stirred with 420 ml of cyclohexane. After filtration and drying, 73.5 g of 4-trifluoromethylphthalic anhydride are obtained, m.p.

The 4-trifluoromethylphthalic acid is prepared as follows:

102.3 g of 2-cyano-4-trifluoromethyl methyl benzoate, 108 g of tableted sodium hydroxide, 900 ml of water and 1990 ml of methanol are heated under reflux for 12 hours. The resulting solution was decolorized with 0.6 g of activated carbon. After filtration, 100 ml of 1.19 hydrochloric acid are added. The mixture was extracted with 2.25 L of ethyl ether, the organic layer was separated and the water was freed from 40 g of anhydrous magnesium sulfate. After evaporation of the filtrate to dryness, it is obtained in this way

99.1 g of 4-trifluoromethylphthalic acid, m.p. 178 ° C.

2-Cyano-4-trifluoromethylmethylbenzoate can be obtained as follows.

144.6 g of 2-amino-4-trifluoromethylmethylbenzoate are suspended in a mixture of 1.3 kg of ice, 730 ml of water, and 171.5 ml of 1.19 hydrochloric acid. A solution of 49.9 g of sodium nitrite in 172 ml of water was added all at once. The mixture was stirred at 0 to 1 ° C for 2.5 hours. The reaction mixture was filtered, and a solution of 226 g of copper sulfate and 261 g of potassium cyanide in 1320 ml of water was added dropwise over 1 hour 20 minutes, maintaining the solution at 4-5 ° C. Celsius. It is a solution prepared according to Gabriel, Ber., 52, 1089 (1919). During the addition of the diazo compound, the pH is maintained at 6 to 7 by the addition of a 10% sodium carbonate solution. Then the reaction mixture was further stirred while allowing the temperature to rise to 20 ° C. The mixture was extracted with 3 L of ether, the ether layer was washed with 150 ml of water, and then 30 g of anhydrous magnesium sulfate was freed from water. After filtration and evaporation to dryness, this is obtained

94.9 g of 2-cyano-4-trifluoromethylbenzoate, m.p. 52 ° C.

2-Amino-4-trifluoromethylmethyl benzoate can be obtained as follows:

141.2 g of 2-amino-4-trifluoromethylbenzoic acid, 1.51 liters of methanol and 506 ml of boron trifluoride etherate are heated to reflux for 99 hours. The resulting solution was added to a solution of 350 g of sodium carbonate in 2.8 kg of ice and ice. The mixture was stirred for 15 minutes and then extracted with 3 L of ethyl ether. The ether layer was separated, washed with 250 ml of water, and then 30 g of anhydrous magnesium sulfate was freed from water. After filtration and evaporation to dryness, 137 g of 2-amino-4-trifluoromethyl methyl benzoate, m.p. 64 DEG C., are obtained. Celsius.

2-Amino-4-trifluoromethylbenzoic acid can be prepared according to Hauptschein et al., J. Amer. Chem. Soc., 76, 1051 (1954).

Example!

The procedure is as in Example 1, but starting with 4.8 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-1-isoindolinone, 15.1 g of 1-chlorocarbonyl-4-methylplperazine hydrochloride, 14.2 ml (10.2 g) of triethylamine and 66 ml of pyridine in 250 ml of methylene chloride, to give 7.8 g of crude product which is mixed with 50 ml of water. The resulting solid was collected by filtration and washed with 30 mL of water. Recrystallization from 240 ml of isopropanol yielded 4.7 g of 2- (7-chloro-1,8-naphthyridin-2-yl) - (4-methyl-1-piperazinyl) -3-carbonyloxy-6-trifluoromethyl -1-isoindolinone, m.p. 219 ° C.

2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-1-isoindolinone was obtained by the method of Example 1.

Claims (3)

A process for the preparation of the novel Isolndoline derivatives of the general formula I, (H where Y atoin halogen and R1 alkyl having 1 to 4 carbon atoms, as well as 1 acid addition salts of these compounds, characterized by treatment with 1-chlorocarbonylpiperazine of formula (II): R is as defined above, to an isoindoline derivative of the general Formula III wherein Y is as defined above, whereupon the product thus obtained is converted into its acid addition salt. 2. A process according to claim 1 wherein the chlorocarbonylpiperazine of formula II is reacted with an alkali salt of the compound of formula III, optionally prepared directly in the reaction mixture, in an organic solvent, and optionally converting the product to its acid addition salt. 3. The process of claim 1, wherein the chlorocarbonylpiperazine salt of formula II is reacted with a compound of formula III in pyridine, optionally in the presence of a tertiary organic base, and optionally converted to its acid addition salt.