KR800000854B1 - Process for preparing naphthyridine derivative - Google Patents

Abstract

Title compds. (I; Y=H, halogen, C1-4 alkyl, alkoxy, cyano, nitro; R=H, C1-4 alkyl, C2-4 alkenyl, alkinyl, C1-4 hydroxyalkyl or phenyl) were prepd. by reaction of carbonate(II) and piperazine(III; Ar=C1-4 alkyl or phenyl). Thus, 8.5 cc N-methylpiperazine and 1.42 g 2-(7-chloro-1,8-naphthylidine-2-yl)-3-phenoxy-carbonyloxy-5-trifluoro-methyl-isoindoline-1- one which was suspended in acetonitrile were treated at 20-21≰C for 2 hr to give 9.2 g 2-(7-chloro-1,8-naphthylidine-2-yl)-3-(4-methylpiperazine-1-yl)-carbonyloxy-5-trifluoromethyl-isoindoline-1-one.

Description

Preparation of naphthyridine derivatives

The present invention relates to a novel naphthyridine derivative represented by the following general formula (II) which is therapeutically useful and a process for preparing acid addition salts thereof.

Food,

Y represents hydrogen or a halogen atom, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, cyano or a nitro group,

R represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, an alkenyl group of 1-4 carbon atoms, an alkynyl group of 2-4 carbon atoms, a hydroxy alkyl group of 1-4 carbon atoms, or a phenyl group.

The present invention is an improved invention of the applicant's patent application No. 2252/1974. The invention of patent application No. 2522/1974 relates to a naphthyridine derivative represented by the following general formula (I).

Food,

를 표시하며(여기서 Y는 수소 또는 할로겐원자, 탄소원자수 1-4개의 알킬기, 탄소원자수 1-4개의 알콕시기, 시아노 또는 니트로기를 표시함), =A- 및 =A₁-는 =CH- 또는 =N-기를 표시하되, =A₁-는 =A-이 =CH-를 표시할 때 =CH-또는 =N-기를 표시하고, A가 =N-를 표시할 때 =N-기를 표시하며,One of = X- represents = N-, the other three are each

Where Y represents hydrogen or a halogen atom, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, a cyano or a nitro group, and = A- and = A ₁ -represent = CH- Or = N-group, where = A ₁ -indicates = CH- or = N-group when = A- indicates = CH-, and = N-group when A indicates = N- ,

Z represents a hydrogen or halogen atom, an alkyl or alkoxy group having 1-4 carbon atoms, or a nitro group, m represents an integer of 0 or 1-4,

(i) n represents 0,

R represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, an alkenyl group of 2-4 carbon atoms, an alkynyl group of 2-4 carbon atoms, a hydroxy alkyl group of 1-4 carbon atoms, or a phenyl group,

(ii) n represents 1 and r represents alkyl or hydroxy alkyl having 1 to 4 carbon atoms, or phenyl.

These naphthyridine derivatives have useful pharmacological properties and are particularly effective as neurostabilizers and anticonvulsants. In addition, the compound of the general formula (1) shows that = X- in the 8-position of the naphthyridine nucleus represents = N-, and X in the 7-position Group (where Y is as described above), A and A ₁ each represent a = CH- group, Z represents a trifluoromethyl group, m represents 1, n represents 0, When R is as described above, it has been found to have the same useful pharmacological properties as the naphthyridine derivative represented by the previously known alban formula (1).

According to the present invention, the compound of formula (II) may be prepared by reacting riperazine of the following formula (III) with a mixed carbonate of the following formula (IV).

R and Y are as described above,

Ar represents a phenyl group optionally substituted by an alkyl group or a nitro group having 1 to 4 carbon atoms.

The reaction is generally carried out in a dry organic solvent such as acetonitrile at a temperature of about 20 ° C., for example 15-25 ° C.

Mixed carbonates of formula (IV) can be prepared by reacting chloroform acid of formula (V) with a naphthyridine derivative of formula (VI).

Food,

Y and Ar are as described above.

The reaction is generally carried out in a basic organic solvent, for example pyridine, at a temperature in the range of 0-20 ° C.

The naphthyridine derivative of formula (VI) can be prepared by partially reducing the amide of formula (VII) to convert one of the carbonyl groups to a hydroxymethylene group.

Food,

Y is as described above.

Reduction reactions are generally carried out with alkali metal borohydrides in organic or aqueous organic solutions such as a mixture of dioxane and methanol, a mixture of dioxane and water, or a mixture of ethanol and water.

Partial reduction of the imide represented by the general formula can be converted into isomeric products that can be separated by physicochemical methods such as fractional crystallization or chromatography.

The imide of formula (VII) can be prepared by reacting 2-aminonaphthyridine of formula (X) with an anhydride of formula (X) to optionally form the product of formula (X) as an intermediate. have.

Food,

Y is as described above.

The reaction between 2-aminonaphthyridine of general formula and anhydride of general formula is generally carried out by heating in an organic solvent such as acetic acid, dimethylformamide, acetonitrile or diphenyl ether.

The reaction to cyclize the intermediate of formula (X) to form the imide product of formula (III) is generally heated with acetyl chloride in acetic or acetic anhydride or N in dimethylformamide at temperatures below 100 ° C. It may be prepared by the action of a condensing agent such as, N'-dicyclohexylcarbodiimide.

The naphthyridine derivatives of formula (II) obtained according to the method described above are purified by physical methods such as distillation, crystallization or chromatography, or by chemical methods such as salt formation, crystallization of salts and decomposition of salts in alkaline media. can do.

Salt and anionic properties are not important in the practice of the above-mentioned chemical methods, but salts should be well formed and easily crystallized.

Naphthyridine derivatives of the general formula (II) can be converted into acid addition salts by known methods. Acid addition salts are obtained by reacting an acid with a naphthyridine derivative in a suitable solvent. As the organic solvent, alcohols, ethers, ketones or chlorinated hydrocarbons can be used. The salt formed is concentrated by solution and then precipitated and isolated by filtration or race.

As mentioned above, naphthyridine of formula (II) and acid addition salts thereof have important pharmacological action, and are particularly effective as neurostable and anticonvulsants. Compounds of formula (II) in animals (rats) have been demonstrated to be effective at doses in the range of 0.1-100 mg / kg of animal body weight, especially in the following tests.

i) Tedeschic at al [J. pharmacol., 125 28 (1959)].

ii) Everett and Richards [J. pharmacol., 81, 402 (1944)] convulsion test by pentetrazol according to the method similar to the method of.

iii) Swinyard et al [J. pharmacol., 106, 319 (1952)].

s, des Med

cins, Ali

nistes et Neurologistes-Tours-(8/13 th June 1959)] 및 Julou(Bulletin de la Soci

t

de pharmacie de Lille, No 2 Jan 1967. p. 7)의 방법에 따른 운동시험.iv) Courvosier [Congr

s, des Med

cins, Ali

nistes et Neurologistes-Tours- (8/13 th June 1959)] and Julou (Bulletin de la Soci

t

de pharmacie de Lille, No 2 Jan 1967. p. Exercise test according to 7).

In addition, the compound of formula (II) shows low toxicity, that is, 50% lethal dose (LD ₅₀ ) in rats is generally 300 mg / kg body weight when administered orally.

Particularly important as the naphthyridine derivative of formula (II) is a compound in which Y represents a halogen atom (especially a chlorine atom), and R represents an alkyl group having 1-4 carbon atoms and acid addition salts thereof. (7-chloro-1,8-naphthyridin-2-yl) -3- (4-methylpiperazin-1-yl) carbonyloxy-5-trifluoromethyl-isoindolin-1-one and its Acid addition salts.

Naphthyridine derivatives of general formula (II) can be used as such for therapeutic purposes or in the form of non-toxic acid addition salts, i.e. the salts (hydrochlorides, sulfates, nitrates, Phosphate, acetate, propionate, succinate, benzoate, fumarate, maleate, tartarate, theophylline acetate, salicylate, phenolphthalate and methylene-bis-β-hydroxynaphthoate) It is used in the form of salts containing anions that are relatively harmless to animal organisms.

Hereinafter, the present invention will be described in detail with reference to the following examples.

Example 1

2- (7-chloro-1,8-naphthyridin-2-yl) -3-phenoxy-carbonyloxy- in which N-methylpiperazine (8.5 cc) is suspended in acetonitrile (280 cc) at about 20 ° C. 5-trifluoro-methyl-isoindolin-1-one (14.2 g) was added. After stirring at 20-21 ° C. for 2 hours, the reaction mixture was diluted with water (1,000 cc), extracted with diethyl ether, dried over anhydrous potassium carbonate (100 g), filtered and filtered under reduced pressure (20 mmHg) at a temperature of about 30 ° C. The solvent was distilled off.

2- (7-chloro-1,8-naphthyridin-2-yl) -3- (4-methylpiperazin-1-yl) recrystallized from boiling acetonitrile (70 cc) and dissolved at 219-221 ° C. Carbonyloxy-5-trifluoromethyl-isoindolin-1one (9.2 g) was obtained.

2- (7-Chloro-1,8-naphthyridin-2-yl) -3-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one can be prepared as follows. Phenyl chloroformate (14.1 g) was suspended in pyridine (100 cc) for 24 minutes while maintaining the temperature at about 18 ° C. 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy- To 5-trifluoromethyl-isoindolidin-1-one (11.2 g) was added. After stirring for 30 minutes, the reaction mixture was poured into ice-water (720 cc). The precipitate was filtered off and washed with water (250 cc). 2- (7-Chloro-1,8-naphthyridin-2-yl) -3-phenoxy carbonyloxy-5-trifluoromethyl-isoindolin-1-one (15 g) dissolved at 214-216 ° C Got.

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

5-trifluoromethyl-N- (7-chloro-1,8-naphthyridin-2-yl) -phthalimide (83, suspended in methanol (420 cc) and dioxane (420 cc) at 15-18 ° C. 6 g) suspension was added with calidium borohydride (12 g) at 15-18 ° C., the mixture was further stirred for 2 hours, and then cooled externally with an ice bath to form a precipitate formed by filtration and separation of the methanol-dioxane mixture (1- 1). 1 volume; washed with 40 cc), and then the precipitate was filtered and dried again, stirred for 30 minutes with the same mixture (200 cc), filtered and heated under reflux with ethanol (200 cc), cooled and filtered. 7-Chloro-1,8-naphthyridin-2-yl) -3-hydroxy-5-trifluoromethyl-isoindolin-1-one (21 g) is obtained.

Melting Point: 300 ℃ or higher

The reaction mixture was filtered and the liquid obtained by washing with a methanol-dioxane mixture was combined, and a precipitate formed by adding water (2,500 cc) was filtered off, washed with water (600 cc), and then washed from methanol-dioxane mixture 5: 5. Recrystallization twice gives 2- (7-chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-isoindolin-1-one (15.3 g).

Melting Point: 265 ℃

5-trifluoromethy-N- (7-chloro-1,8-naphthyridin-2-yl) phthalimide can be prepared by the following method.

4-trifluoromethyl-phthalic anhydride (73.5 g) and N-hydroxy succinimide (50.2 g) in dimethylformamide (1,500 cc) were heated at 75-78 ° C. for 18 hours and 2- Amino-7-chloro-1,8-naphthyridine (61.4 g) and N, N'-dicyclohexyl-carbodiimide (140 g) were added, followed by further heating at the same temperature for 3 hours, and the precipitate formed was filtered off and dimethyl. Washed with formamide (100 cc) followed by diisopropyl ether (200 cc), and the precipitate formed by adding water (1,500 cc) to the reaction mixture was filtered and washed with methylene chloride (1,500 cc) to form two precipitates combined. Dissolve in methylene chloride (8 L), filter the insoluble material, and concentrate the filtrate to dryness. 5-Trifluoromethyl-N- (7-chloro-1,8-naphthyridin-2-yl) -phthalimide (83.6 g) is obtained.

Melting Point: 265 ℃

4-trifluoromethyl-phthalic anhydride can be prepared by the following method.

4-trifluoromethyl-phthalic acid (106.6 g) and acetic anhydride (215 cc) were heated under reflux for 30 minutes, concentrated under reduced pressure (30 mmHg), and the residue was stirred with cyclohexane (420 cc), filtered and dried. Trifluoromethyl-phthalic anhydride (73.5 g) is obtained.

Melting Point: 54 ℃

4-trifluoromethyl-phthalic acid can be prepared by the following method.

Methyl 2-cyano-4-trifluoromethyl-benzoate (102.3 g), sodium hydroxide pellets (108 g), water (900 cc) and methanol (1,900 cc) were heated under reflux for 12 hours and the solution was heated on reflux. (0.6 g) was decolorized and filtered, hydrochloric acid (dd = 1.19, 100 cc) was added, the mixture was extracted with diethyl ether (2.25 L), the organic layer was dried over anhydrous magnesium sulfate (40 g), and the filtrate was concentrated after filtration. 4-trifluoromethyl-phthalic acid (99.1 g) is obtained.

Melting Point: 178 ℃

Methyl 2-cyano-4-trifluoromethyl-benzoate can be prepared by the following method.

Methyl 2-amino-4-trifluoromethyl-benzoate (144.6 g) is suspended in a mixture of ice (1.3 kg), water (730 cc) and hydrochloric acid (d = 1.19, 171.5 cc) and immediately in this suspension After adding a solution of sodium nitrite (49.9 g) dissolved in water (172 cc), the reaction mixture was stirred at 0-1 ° C. for 2 hours 30 minutes, filtered, dissolved in water (1.320 cc), and maintained at 4-5 ° C. To a solution of copper sulfate (226 g) and potassium cyanide (261 g) [solution prepared according to Gabriel, Ber 52, 1089 (1919)] is added over 1 hour 20 minutes. When the diazo compound is added, the pH is maintained at 6-7 by adding a 10% (W / V) sodium carbonate solution. The reaction mixture was then stirred while rising to a temperature of 20 ° C., the mixture was extracted with diethyl ether (3 L), the ether layer was washed with water (150 cc), dried over anhydrous magnesium sulfate (30 g), filtered and concentrated to methyl 2 Cyano-4-trifluoromethyl-benzoate (94.9 g) is obtained.

Melting Point: 52 ℃

Methyl 2-amino-4-trofluoromethyl-benzoate can be prepared by the following method.

2-Amino-4-trifluoromethyl-benzoic acid (141.2 g) Methanol (1,51 L) and Born trifluoride etherate (506 cc) were heated under reflux for 99 hours and the resulting solution was ice-water (2.8 kg). ) Was added to sodium carbonate (350 g), the mixture was stirred for 15 minutes, extracted with diethyl ether (3 L), the ether layer was washed with water (250 cc), dried over anhydrous magnesium sulfate (30 g), concentrated after filtration and methyl 2 -Amino-4-trifluoromethyl-benzoate (137 g) is obtained.

Melting Point: 64 ℃

2-Amino-4-trifluoromethyl-benzoic acid is described in Hauptschein et al., J. Amer. Chem. Soc 76,1051 (1954).

Example 2

2- (7-chloro, 1,8-naphthyridin-2-yl) -3-phenoxycarbonyloxy-6-trifluoromethyl-isoindolin-1 as starting material according to the method of example 1 2- (7-chloro-1,8-naphthyridin-2-yl) -3- (4-methylpiperazin-1-yl) -carbonyloxy at a melting point of 219 ° C. using on and N-methylpiperazine -6-trifluoro-isoindolin-1-one is obtained.

2- (7-Chloro-1,8-naphthyridin-2-yl) -3-hydroxy-6-trifluoromethyl-isoindolin-1-one can be prepared as described in Example 1 have.

Claims (1)

A method for preparing a naphthyridine derivative of formula (II) and an acid addition salt thereof, wherein the piperazine of formula (III) is reacted with a mixed carbonate of formula (IV):

Wherein Y represents hydrogen or a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a cyano or a nitro group, and R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or 2 carbon atoms -4 alkenyl groups, 2-4 alkynyl groups, 1-4 hydroxy alkyl groups or phenyl groups, and Ar represents a phenyl group optionally substituted with 1-4 alkyl or nitro groups.