DK142365B - Analogous process for preparing naphthyridine derivatives or acid addition salts thereof. - Google Patents

Description

(^ RE ^) (11) PUBLICATION MANUAL 142365 DENMARK (51) Int. Cl.3 C 07 D 471/04 § (21) Application No. ^ -2. ^) 0 / ^ 6 (22) Filed on 21 Sep. 1 ^ 76 (24) Race day 21. September 1976 (44) The application presented and,.

the petition published on 2U. OCT>, 1 9 80

DIRECTORATE OF

PATENT AND TRADE MARKET (30) Pnontet requested from it

Sep 22 1975, 7528951, FR

(71) RHONE-POULENC S.A., 22 Avenue Montaigne, Paris 8, FR.

(72) Inventor: Claude Cotrel, 17 A, Avenue du Docteur Arnold Netter, 75012 Paris, FR: Cornel “Crisan, 10 bis rue Mozart, Bceaux (Hauts-de-Seine), fr:

Claude Jeanmart, T5, Rue des Lievres, Brunov (Essonne), FR: Mayer Naoum Messer, “17, Allee des Marguerites, Bievres (Essonne), FR.

(74) Plenipotentiary in the proceedings:

The engineering company Budde, Schou & Co. (54) Analogous process for the preparation of naphthyridine derivatives or acid addition salts thereof.

The invention relates to an analogous process for the preparation of novel naphthyridine derivatives or acid addition salts thereof.

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

A X rrX /% X

I 1 (ZA in Aa / Λ7 / / - \

O-CO-N N-R

Wherein A and A1 represent the group CH, n means zero, and X represents at positions 5 and 6 the group CH, at position 7 the group CY and at position 8 represents a nitrogen atom.

The present invention relates to an analogous process for preparing novel compounds of a similar formula in which three of the symbols Z denote hydrogen atoms and the fourth symbol Z denotes the group -CF 3, i.e. novel naphthyridine derivatives of the general formula (I) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

The process according to the invention is characterized in that a 1-chlorocarbonylpiperazine of the formula / -

Cl - CO - N N - CH, (II) \ _ / 3 is reacted with a naphthyridine derivative of the general formula O. .

du) ^ ii L Jl -γ (III) CF3-L li /

OH

in which Y has the meaning given above, and optionally converting the formed compound into an acid addition salt thereof.

Usually, a compound of formula (II) is reacted with an alkali metal salt, optionally prepared in situ, by a compound of formula (III), working in an anhydrous organic solvent, e.g. dimethylformamide or tetrahydrofuran, at a temperature below 60 ° C.

The reaction can also be carried out in that a salt of the compound of formula (II), preferably a hydrochloride, is reacted with a compound of formula (III), working in pyridine and optionally in the presence of a tertiary amine. , eg. triethylamine which releases the compound of formula (II) from its salt.

The isoindoline derivative of formula (III) can be prepared by partial reduction of an imide of general formula 0, ..

X (iv) r ii / —C / X J · —γ CF3 U li /

ISLAND

in which Y has the meaning given above.

This reduction is usually accomplished by an alkali metal borohydride, working in an organic or aqueous organic solution, such as a mixture of dioxane and methanol, a mixture of dioxane and water, a mixture of methanol and water, or a mixture of ethanol. and water.

The partial reduction of the compound of formula (IV) may lead to isomeric products which can be separated using physicochemical methods, e.g. fractional crystallization or chromatography.

The imides of formula (IV) may be prepared by a 2-amino-naphthyridine of the general formula (V)

Η N-L i 'J-Y

in which Y has the meaning given above, is reacted with an anhydride of formula I in X0 (VI) CF3 ~ Vx \ / o, the reaction optionally proceeding via an intermediate of general formula 4

11 I

_L λ_Y (VII)

CF _L I

J X ^^ COOH

in which Y has the meaning given above.

The reaction between the 2-aminonaphthyridine of formula (V) and the anhydride of formula (VI) is generally carried out by heating in an organic solvent, e.g. acetic acid, dimethylformamide, acetonitrile or phenyl ether.

The cyclization of the compound of formula (VII) to the compound of formula (IV) may occur either by heating with acetyl chloride in acetic acid or acetic anhydride, or by the action of a condensing agent, e.g. N, N'-dicyclohexylcarbodiimide, in dimethylformamide at a temperature below 100 ° C.

The novel compounds of general formula (I) may optionally be purified using physical methods such as distillation, crystallization or chromatography, or using chemical methods, e.g. salt formation, crystallization of the salt and decomposition in alkaline medium. In this treatment, the nature of the anion of the salt does not matter and the only condition is that the salt is well defined and easy to crystallize.

The novel compounds of formula (I) can be converted into addition salts with acids.

The addition salts can be prepared by reacting the novel compounds (I) with acids in suitable solvents. As organic solvents, e.g. use alcohols, ethers, ketones or chlorinated solvents. The salt formed precipitates after any concentration of the solution and is separated by filtration or decantation.

The novel compounds of formula (I) and their acid addition salts exhibit interesting pharmacological properties. In particular, they have been found to act as tranquilizers and as anticonvulsants.

The compounds have been found to be effective in oral administration to mice at doses of between 0.1 and 100 mg / kg, especially in the following experiments:

Battles induced by electric shocks according to a technique similar to that described by Tedeschi et al., U2365 J. Pharmacol., 125, 28 (1959).

Cramps induced with pentetrazole according to a technique similar to that described by Everett and Richards, J. Pharmacol., 81, 402 (1944).

Supramaximum electroshock according to the technique described by Swinyard et al., J. Pharmacol., 106, 319 (1952).

Locomotor activity according to the technique described by Courvoisier (Congrés des Médecins Aliémistes et Neurologistes, Tours, June 8-13, 1959), and Julou (Bulletin de la Société de Pharmacie de Lille, January 2, 1967, page 7).

Furthermore, the novel compounds of formula (I) exhibit only a negligible toxicity. When administered orally to mice, the lethal dose (50%) (DL [-q) is usually greater than 300 mg / kg.

Of particular interest is the compound 2- (7-chloro-1,8-naphthyridin-2-yl) -3- (4-methyl-1-piperazinyl) -carbonyloxy-5-trifluoromethylisoindolin-1-one.

From Danish Patent Application No. 2633/74 (disclosure no. 136,819), compounds which are structurally closely related to the compounds of formula (I) are known and that in the said application it is stated that the compounds disclosed therein include: is effective against cramps.

However, the compounds of formula (I) are surprisingly advantageous over the known compounds, cf. the following table, where the compound of the following example is compared with the compound of example 1 in Ans. no.

2633/74. The efficacy of the test compounds against pentetrazole induced seizures was determined at different times (the test method is given above). The following results were obtained: DA50 mg / kg p.o. DA5q mg / kg p.o.

Test ConnectionIse_ after 45 min. after 24 hours

The compound of the following example is 0.6 4.5

The compound of Example 1 in Ans. No. 2633/74 0.1 60

Thus, the compound prepared according to the present method has a much longer lasting effect than the known comparative compound, which is a great advantage of pharmacological use.

6 142365

For medical applications, the compounds of formula (II) may be used either in the form of bases or in the form of pharmaceutically acceptable addition salts, i.e., which are non-toxic in the doses used.

Examples of pharmaceutically acceptable addition salts include salts with inorganic acids, e.g. hydrochlorides, sulfates, nitrates and phosphates, salts with organic acids, e.g. acetates, propionates, succinates, benzoates, fumarates, maleinates, theophylline acetates, salicylates, phenolphthaleinates and methylene-bis-oxy-naphthoates, and salts with substitution derivatives of these acids.

The process of the invention is illustrated in more detail in the following example.

Example

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

2- (7-Chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-trifluoromethyl-isoindolin-1-one and its isomeric 2- (7-chloro-1,8-naphthyridin-2-yl) ) - 3-hydroxy-6-trifluoromethylisoindolin-1-one can be prepared as follows:

To a suspension of 83.6 g of 5-trifluoromethyl-N- (7-chloro-1,8-3-naphthyridin-2-yl) -phthalimide in 420 cm 2 of methanol and 420 cm 2 of dioxane is added 12 g of potassium borohydride at a temperature. at 15-18 ° C. The mixture is stirred for 2 hours, then cooled in an ice bath. The resulting 3 precipitate is separated by filtration and washed with 40 cm of a mixture of equal volumes of methanol and dioxane. The precipitate is separated by filtration and dried, then stirred for 30 minutes with 3 200 cm of the same mixture. The resulting precipitate is separated from 3 by filtration and heated in 200 cm of ethanol under reflux. After cooling the suspension and filtering, 21.9 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-trifluoromethyl-isoindolin-1-one is obtained, m.p. above 300 ° C.

The solution obtained after filtration of the reaction mixture is combined with the wash solutions from the washings with the mixture of 3 methanol and dioxane. Add 2500 cm of water. The resulting 3 precipitate is separated by filtration, washed with 600 cm of water and recrystallized twice from a mixture of equal volumes of methanol and dioxane. There is thus obtained 15.3 g of 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethylisoindolin-1-one with m.p. 265 ° C.

The compound 5-trifluoromethyl-N- (7-chloro-1,8-naphthyridin-2-yl) -phthalimide can be prepared as follows: 73.5 g of 4-trifluoromethyl-3-phthalic anhydride, 50.2 g of N-hydroxysuccinimide and 1500 cm of dimethylformamide is heated for 18 hours at 75-78 ° C. Then 61.4 g of 2-amino-7-chloro-1,8-naphthyridine and 140 g of Ν, Ν'-dicyclohexylcarbodiimide are added and then heated for an additional 3 hours at the same temperature.

After cooling, the precipitate formed is separated by filtration and washed with 100 cm of dimethylformamide and then with 200 cm of isopropyl ether.

3

Add 1500 cm of water to the reaction mixture. The resulting 3 precipitate is separated by filtration and washed with 1500 cm of methylene chloride. Both precipitates are combined and taken up in 8 liters of methylene chloride. An insoluble substance is separated by filtration and the filtrate is concentrated to dryness. There is thus obtained 83.6 g of 5-trifluoromethyl-N- (7-chloro-1,8-naphthyridin-2-yl) -phthalimide, m.p. 265 ° C.

4-trifluoromethylphthalic anhydride can be prepared in the following 3 ways: 106.6 g of 4-trifluoromethylphthalic acid and 215 cm of acetic anhydride are refluxed for 30 minutes. After concentration under 3 reduced pressure (30 mm Hg), the residue is stirred with 420 cm cyclohexane. After filtration and drying, 73.5 g of 4-trifluoromethylphthalic anhydride are obtained with m.p. 54 ° C.

4-Trifluoromethylphthalic acid can be prepared as follows: 102.3 g of methyl 2-cyano-4-trifluoromethyl benzoate, 108 g of sodium hydroxide 3 (lozenges), 900 cm 2 of water and 1900 cm 2 of methanol are heated to reflux for 12 hours. The solution is then decolorized with 0.6 g bone coal. After filtration, 100 cm of hydrochloric acid (d = 1.19) is added.

Extract 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-trifluoromethylphthalic acid are obtained with m.p. 178 ° C.

Methyl 2-cyano-4-trifluoromethylbenzoate can be prepared as follows: 144.6 g of methyl 2-amino-4-trifluoromethylbenzoate are suspended in a mixture of 1.3 kg of ice, 730 cm of water and 171.5 hydrochloric acid (d = 1.19). To this solution is added at once a 3 solution of 49.9 g of sodium nitrite in 172 cm of water. Stir for 2 hours and 30 minutes at 0.1 ° C. The reaction mixture is filtered and added dropwise over a 1 hour and 20 minutes to a solution (maintained at 4-5 ° C) of 226 g of copper sulfate and 261 g of potassium cyanide in 1320 cm of water. This solution is prepared according to

Gabriel, Reports, _52, 1089 (1919). During the addition of the diazo compound, the pH of 6-7 is maintained by the addition of a 10% sodium carbonate solution. Stirring is continued and the temperature is raised to 20 ° C. It is then extracted with 3 liters of ether. The ether layer 3 is washed with 150 cm of water and then dried over 30 g of anhydrous magnesium sulfate. After filtration and concentration, 94.9 g of methyl 2-cyano-4-trifluoromethyl benzoate are obtained, m.p. 52 ° C.

Methyl 2-amino-4-trifluoromethylbenzoate can be prepared as follows: 141.2 g of 2-amino-4-trifluoromethylbenzoic acid, 1.51 liter of 3 methanol and 506 cm of boron trifluoride etherate are heated to reflux for 99 hours. The resulting solution is added to a solution of 350 g of sodium carbonate in 2.8 kg of ice water. Stir for 15 minutes, then extract with 3 liters of ethyl ether. The ether layer is washed with 250 cm of water and then dried over 30 g of anhydrous magnesium sulfate. After filtration and concentration, 137 g of methyl 2-amino-4-trifluoromethylbenzoate are obtained, m.p. 64 ° C.

2-Amino-4-trifluoromethylbenzoic acid can be prepared according to the method described by Hauptschein et al., J. Amer. Chem.

Soc., 76, 1051 (1954).