JPS6038392B2 - Naphthyridine derivatives and their production method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel therapeutically useful naphthyridine derivatives, processes for their production, and pharmaceutical compositions containing them.

The present invention relates to an improvement or modification of the invention disclosed in Hakamaseki No. 49-52378. Special clique 1977
-52378, the applicant has proposed the general formula [wherein one of the symbols =X- represents =N1, and the other three
Each represents a group, where Y is a hydrogen or halogen atom, and the number of carbon atoms is 1.
~4 alkyl group, an alkoxy group having 1 to 4 carbon atoms, or a cyano or nitro group, symbols =A- and =A, one represents a group =CH- or =N-, provided that =A- When representing CH-, =AI- represents the group =CH- or =N-, and when =A- represents =N-, =A, one represents =N-, and the symbol Z is a hydrogen or halogen atom. , represents an alkyl or alkoxy group having 1 to 4 carbon atoms, or a nitro group, and m is 0 or an integer of 1 to 4.
4, and [i} n represents 0 and R is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, and 2 to 4 carbon atoms.
represents an alkenyl group, an alkynyl group having 2 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, or a phenyl group, or where n represents 1 and R represents 1 carbon number.
-4 representing an alkyl or hydroxyalkyl group or a phenyl group] and acid addition salts thereof.

These naphthyridine derivatives have useful pharmacological properties and are particularly active as tranquilizers and stimulants. Furthermore, as a result of experiments and research, the symbol X- at the 8-position after naphthyridine in the above general formula represents =N-, the symbol =X- at the 5-position and the 6-1st position represents =CH-, and the symbol The symbol X in the - position represents (Y represents a halogen atom), the symbols A and A, each represent a group=CH1, Z represents a trifluoromethyl group, m represents 1, and n represents 0 It has now been found that compounds having the general formula in which Ta.

Therefore, the present invention is based on the general formula [YI represents a halogen atom, RI has 1 to 1 carbon atoms]
4 representing an alkyl group] and acid addition salts thereof.

According to the invention, the compound of general formula 0 is a compound of general formula [wherein,
RI is as defined above] with a naphthyridine derivative of the general formula [where Y is as defined above].

Usually, a compound of general formula m is reacted with an alkali metal salt of a compound of general formula N, optionally prepared in situ, and the reaction is carried out in an anhydrous organic solvent such as dimethylformamide or tetrahydrofuran at a temperature below 60°C. It is done.

The reaction can also be carried out using an acid addition salt, preferably a hydrochloride, of a compound of general formula m in pyridine and optionally with a tertiary amine (
This can also be carried out by liberating the compound of general formula m from the above-mentioned salt by reaction in the presence of triethylamine (for example, triethylamine).

The naphthyridine derivative of the general formula W has the general formula [wherein YI
is as defined above] by partial reduction of the imide to convert one of the carbonyl groups into a hydroxymethylene group.

The reduction is generally carried out using an alkali metal borohydride in an organic solution or an aqueous-organic solution such as a dioxane and methanol solution or a mixture of dioxane and water or a mixture of methanol and water or a mixture of ethanol and water. It is done.

Partial reduction of imides of general formula V gives isomeric products which can be separated by physico-chemical methods, such as fractional crystallization or chromatography.

Imides of the general formula V are prepared by reacting 2-aminonaphthyridine of the general formula [wherein YI is as defined above] with a hydrothermal product of the general formula, optionally using intermediates as intermediates of the general formula [formula wherein YI is as defined above.

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

Cyclization of the intermediate product of general formula V to form an imide product of general formula V can be carried out by heating with acetyl chloride in acetic acid or acetic anhydride, or in dimethylformamide at a temperature below 10°C. For example, this can generally be carried out by using a condensing agent such as N,N'-dicyclohexylcarposiimide.

According to another feature of the invention, the compound of the general formula D comprises a piperazine of the general formula [wherein RI is as defined above] a compound of the general formula and Ar represents a phenyl group optionally surrounded by an alkyl group having 1 to 4 carbon atoms or a nitro group].

The reaction is generally carried out in an anhydrous organic solvent such as acetonitrile at a temperature of about 20 DEG C., e.g. Hybrid carbonates of general formula I can do it.

The reaction is generally carried out in a basic organic solvent such as pyridine at a temperature of 0 to 20<0>C. The naphthyridine derivatives of general formula 0 obtained by the above process can be prepared by physical methods such as distillation, crystallization or chromatography or by e.g. formation of the salt, crystallization of the salt and decomposition of the salt in an alkaline medium. It can be purified by chemical methods such as

When carrying out chemical methods, the anionic nature of the salt is not important; the only requirement is that the salt must be clearly and easily recrystallizable.
The naphthyridine derivative of general formula (b) can be converted into an acid addition salt by a method known per se. Acid addition salts are
It can be obtained by reacting a naphthyridine derivative with an acid in a suitable solvent. As organic solvents, mention may be made of alcohols, ethers, ketones or chlorinated hydrocarbons. After concentrating the solution as necessary, the generated salt is
Precipitate and isolate by filtration or filtration. As mentioned above, naphthyridine derivatives of general formula 0 and their acid addition salts have valuable pharmacological properties.
They are particularly active as tranquilizers and locksmiths. They have been shown to be active in animals (Mus musculus), especially when administered neat orally at doses of 0.1 to 100 o'kg/animal body weight in the following tests: Tedeschi et al.0. P
harmacol. 12528 (1959) {ii} Everett and Richards
ship) [J. PM macol. 81, 402 (1 basis 4)
] using pentetrazole according to a method similar to that of [1].

{iii} Swinyard (SMn cooperation d) et al. [J.
Pharmacol. 106.319 (1952)].

Rib CouWoisier [Co
Set Neur for ngesdeS Med≦CinS, AIi≦niS.

logiSteS-Tokawas-(195g hand June 8-1
3rd)] and Julou [Bulleti
n de la SMie de Pharmacie
deLille, M. 2. Motor activity according to the method of [January 1967, p. 7]. Moreover, they exhibit low toxicity, with their 50% lethal dose (LD
5o) is generally 9/k9 of 300 when given orally.
The amount is greater than the animal's weight.

Of particular importance are naphthyridine derivatives in which YI represents a chlorine atom in the general formula 0, especially 2-(7-chloro-1,8-naphthyridin-2-yl)-(4-methylpiverazin-1-yl) Rubonyloxy-5-trifluoromethylisoindolin-1-one and its acid addition salt.

For therapeutic purposes, the naphthyridine derivatives of general formula 1 can be used as such or as non-rhombic acid addition salts, i.e. containing anions which are relatively harmless to animal organisms in therapeutic doses of the salts. (e.g. hydrochloride, sulfate,
Nitrate, phosphate, acetate, propionate, succinate, benzoate, fumarate, maleate, tartrate, theophylline acetate, salicylate, phenolphthalinate and methylene-pi-3-hydroxynaphthoic acid It can also be used in the form of a salt), so that the advantageous physiological properties inherent in the base are not compromised by the side effects attributable to the anion.

The following examples illustrate the preparation of naphthyridine derivatives of formula 0 by the method of the present invention. Example 11-Chlorocarbonyl-4-methylpiverazine hydrochloride (7.
5 cc), methylene chloride (pseudo-occ), triethylamine (10.2 cc; 14.2 cc) and pyridine (66 cc).
cc) in a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-13-hydroxy-5-trifluoromethyl-isoindolin-1-one (4.8 pm) at 20-21°C. added.

After 5 hours, further 1-chlorocarbonyl-4-methylpiverazine hydrochloride (7.6 night) was added.

Continue the rope prayer for 1 hour, then pour the mixture into water (480cc)
was hydrolyzed with. The organic phase was decanted and the aqueous layer was extracted with methylene chloride (300 cc). The organic layers were combined, washed with water (150 cc), and then dried over anhydrous sodium sulfate (15 cc). After filtration and concentration to dryness, the residual light (9.5 pm) was tritylated with water (100 cc). After filtration, the product was washed with water (60 cc) and then recrystallized from dichloroethane (42 cc). The dry precipitate was soaked with water (37 cc) for 1 hour, filtered, washed and dried. As a result, 2-(7-chloro-1,8-naphthyridin-2-yl) with a melting point of 22
-3-(4-methylpiverazin-1-yl)-carbonyloxy-5-trifluoromethyl-isoindoline-
1-on (3.3 hours) was obtained. 2-(7-chloro-1,8-naphthyridin-2-yl)-1-3-hydroxy-5-trifluoromethylisoindolin-1-one and its isomers, 2-(7-chloro.

-1,8 naphthyridin-2-yl) -13-hydro. X-6-trifluoromethyl-isoindolin-1-one could be produced as follows. Potassium borohydride (12 cc) and 5-trifluoromethyl-N-(7-chloro-1,8-naphthyridin-2-yl)phthalimide (836 cc) in methanol (420 cc) and dioxane (420 cc) at a temperature of 15-18 1 was added to the suspension at a temperature of 15 to 1.

The mixture was allowed to stand for an additional 2 hours and then cooled externally using an ice rack. The generated precipitate was separated by furnace, and then methanol-
Washed with a dioxane flow (1:1 by volume; 40 cc). The precipitate was filtered again, dried and then soaked in the same working liquid (20
0 cc) for 30 minutes, then furnaced and heated under reflux with ethanol (200 cc).
When the suspension is cooled and filtered, the 2-(7-chloro-1,8-naphthyridine-
2-yl)-3-hydroxy-5-trifluoromethyl-isoindolin-1-one (21.9 pm) was obtained. The solution bound after filtering the reaction mixture and the liquid from the methanol-dioxane wash were combined and water (2500 cc) was added.

The resulting precipitate was filtered out, washed with water (600 cc), and then recrystallized twice from m/- dioxane solution (5:5 by volume). As a result, 2- with a melting point of 265 qo
(7-chloro-1.8-naphthyridine-2-yl)-3
-Hydroxy-6-trifluoromethyl-isoindolin-1-one (15.3 evenings) was obtained. 5-trifluoromethyl-N-(7-chloro-1,8-naphthyridin-2-yl)-phthalimide could be produced as follows.

4-trifluoromethylphthalic anhydride (73.5 min) and N-hydroxysuccinimide (50.2 min) in dimethylformamide (1500 cc) 75-78
qo for 1 hour. Then 2-amino-7-chloro-1,8-naphthyridine- (61.4 m) and N
, N′-Jishik. Hesykylcarbodiimide (140 yen)
was added and the mixture was heated at the same temperature for a further 3 hours. After cooling, the precipitate formed was chopped and washed with dimethylformamide (100 cc) and then diisopropyl ether (200 cc). This reaction mixture was added with water (15
00cc) was added. The resulting precipitate was filtered out and washed with methylene chloride (1500 cc). These two precipitates were combined and dissolved in methylene chloride (8 liters). Insoluble material was removed from the oven, and the oven liquor was then concentrated to dryness.
As a result, 5-trifluoromethyl-
N-(7-chloro-1,8-naphthyridin-2-yl)
-phthalimide (836 units) was obtained. 4-trifluoromethylphthalic anhydride could be produced as follows. 4-Trifluoromethylphthalic acid (10
6.6) and acetic anhydride (215 cc) under reflux.
Heated for 0 minutes.

After concentrating under reduced pressure (30 atmospheres of Hg), the isosasa was mixed with cyclohexane (420 cc). After drying in an oven, 4-trifluoromethylphthalic anhydride (73.5 min) having a melting point of 54°C was obtained. 4-Trifluoromethylphthalic acid could be produced as follows.

Methyl 2-cyano-4-trifluoromethyl-benzoate (102.3 evenings), sodium hydroxide beret (1
08 evening), water (900cc) and methanol (190cc)
0 cc) was heated under reflux for 1 hour.

This solution was decolorized with animal bone charcoal (0.6 mm). After filtration, hydrochloric acid (d=1.19:100 cc) was added, and the mixture was extracted with diethyl ether (2.25 cc). The organic layer was dehydrated with anhydrous magnesium sulfate (40 min). Filtration and concentration of the filtrate yielded 4-trifluoromethylphthalic acid (99.1 min.) with a melting point of 178°C. Methyl 2-cyano 4-trifluoromethyl-penzoate could be produced as follows.

Methyl 2-amino-4-trifluoromethyl-benzoate (144.6 evening) was added to ice (1.3k9) and water (730
cc) and hydrochloric acid (d=1.19:171.5cc).

A solution of sodium nitrite (49.9 g) in water (172 cc) was added all at once to the above suspension. The reaction mixture was heated at 0-1° C. for 2.5 hours, filtered, and then Mix this with water (
A solution of steel sulfate (226 mm) and potassium cyanide (261 mm) in 1320 cc) kept at 4-5 °C (solution prepared according to Gabriel, Be
r. , 52, 1 female 9 (1919)] over a period of 1 hour and 20 minutes.

During the addition of the diazo compound, 10% of sodium carbonate (W
/V) solution was added to keep the pH at 6-7. The rope was continued, and the temperature was increased during that time. The mixture was then extracted with diethyl ether (3 kg). The ether layer is mixed with water (150
cc) and then dehydrated with anhydrous magnesium sulfate (30°C). Filtration and concentration gave methyl 2-cyano-4-trifluoromethyl-benzoate (94.9°C), melting point 520. Amino-4-trifluoromethyl-benzoate could be produced as follows.

2-Amino-4-trifluoromethyl-benzoic acid (14
1.2 pm), methanol (1.51 pm) and trifluoride sheranesate (506 cc) were heated under reflux for 9 hours.

The resulting solution was added to sodium carbonate (350 ml) in ice water (2.8×9). - The mixture was pressed for 15 minutes and then extracted with diethyl ether (3 portions). The ether layer was washed with water (250 cc) and then dehydrated over anhydrous magnesium sulfate (30 cc). After heating and concentrating, methyl 2-amino-4-trifluoromethyl-benzoate (137 ml) was obtained with a melting point of 64 ml. 2-Amino-4-trifluoromethyl-benzoic acid is described by Uptscheinetal [J. A.
C. S. , 70 1051 (1954)].

Example 2 The procedure of Example 1 was followed but methylene chloride (250c
c) 2-(7-chloro-1,8-naphthyridine-2)
-yl)-3-hydroxy-6-trifluoromethyl-isoindolin-1-one (4.8 evening), 1-chlorocarbonyl-4-methylpiverazine hydrochloride (15.1 evening)
, triethylamine (10.2 min): 14.2 cc) and pyridine (66 cc), the crude product (7
．． 8 ml) was obtained, and this was tritylated with water (50 cc).

The resulting solid was filtered out and washed with water (30 cc). Aesop. Recrystallization from Panol (240 cc) yields 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiverazin-1-yl)-carbonyloxy-6-trifluoromethane with a melting point of 219°C. Thiruisoindolin-1-one (4.7 hours) was obtained. 2-(7-chloro-1,8-naphthyridin-2-yl)-8
-Hydroxy-6-trifluoromethylisoindolin-1-one can be prepared as described in Example 1.

Example 3 2-(7-chloro-1,8-naphthyridin-2-yl)
N-Methylpiverazine (85 cc) was added to a suspension of 1-3-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one (14.2 mL) in acetonitrile (280 cc) at a temperature of about 2 psi. Added.

After heating at 20-2100 for 2 hours, the reaction mixture was diluted with water (10
00 cc) and then the suspension was extracted with diethyl ether (1100 cc).

After drying over anhydrous potassium carbonate (100 g), it was filtered and the solvent was distilled off under reduced pressure (20 g) at about 30 p.m. The remaining bamboo was recrystallized with boiling acetonitrile (70cc), and m
．． p. 219-pine 2-(7-chloro-1,8-naphthyridin-2-yl)-131(4-methylpiverazin-1-yl)-carbonyloxy-5-trifluoromethyl-isoindolin-1-one (9. 2 evenings). 2
1-(7-chloro-1,8-naphthyridin-2-yl)-13-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one was obtained as follows: 2-(7-chloro-1,8-naphthyridin-2-yl) -yl)-3-hydroxy-5-trifluoromethyl-isoindolin-1-one (11.2) of pyridine (10
To the suspension in 0 cc) phenyl chloroformate (14.1 cc) was added over 24 min.

After stirring for an additional 30 minutes, the reaction mixture was poured into ice water (720 cc). The generated sediment is separated into a furnace and poured with water (2
50cc). In this way m. p. 214
2-(7-chloro-1,8-naphthyridin-2-yl)-13-phenoxycarbonyloxy-5-trifluoromethyl-isoindolin-1-one (15
evening) was obtained. The present invention includes within its scope pharmaceutical compositions comprising as active ingredient at least one naphthyridine derivative of general formula I or a non-toxic acid addition salt thereof together with a pharmaceutical carrier or coating. The present invention encompasses formulations specifically formulated for oral, parenteral or rectal administration or for topical application (eg, ointment). Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions, the active compound is mixed with at least one inert diluent, such as sucrose, lactose or starch. The compositions may also contain additional substances other than inert diluents, such as lubricants (eg magnesium stearate), in accordance with the usual sequence. Liquid compositions for oral administration are prepared using inert diluents (
These include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing, for example, water and liquid paraffin. Besides inert diluents, such compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming substances. Compositions of the invention for oral administration also include capsules of absorbable material (eg, gelatin) containing the active substance with or without the addition of diluents or excipients. Compositions of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.

Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. These compositions also
It may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. They can be sterilized, for example, by filtration through a seven-door strainer for bacterial capture, by incorporating a disinfectant into the composition, by irradiation, or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or injectable medium immediately before use. Compositions for rectal administration are suppositories, which contain, in addition to the active substance, excipients such as, for example, cocoa butter or a suitable wax base.

The proportions of active ingredients in the compositions of the invention may vary, but it is necessary to construct the proportions such that a suitable dosage will be obtained. The dosage depends on the desired therapeutic effect, route of administration and duration of treatment. For human therapy, compositions for oral administration to adults should generally provide a dosage of 10 to 500 mg of active substance per day. Generally, the physician will determine the dosage that is considered appropriate, taking into account the age, body mass, and other factors inherent in the patient to be treated. The following examples illustrate the pharmaceutical compositions of the invention. Example 4 Tablets containing 25 o of active substance and having the following composition were prepared according to conventional techniques.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, Y^1 represents a halogen atom, and R^1
represents an alkyl group having 1 to 4 carbon atoms] and acid addition salts thereof. 2. The naphthyridine derivative and acid addition salt thereof according to claim 1, wherein Y^1 represents a chlorine atom. 3 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-5-trifluoromethyl-isoindolin-1-one and its acid addition The compound according to claim 1, which is a salt. 4 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl)carbonyloxy-6-trifluoromethyl-isoindolin-1-one and its acid addition The compound according to claim 1, which is a salt. 5 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is as defined in formula I below] Chlorocarbonylpiperazine is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Formula There are general formulas, chemical formulas, tables, etc., characterized by reacting with a naphthyridine derivative or its alkali metal derivative, where Y^1 is as defined in formula I below] ^1 represents a halogen atom,
and R^1 represents an alkyl group having 1 to 4 carbon atoms] and an acid addition salt thereof. 6. Process according to claim 5, in which an alkali metal derivative of a naphthyridine derivative is used and the reaction is carried out in an anhydrous organic solvent at a temperature below 60°C. 7. A process according to claim 5, in which an acid addition salt of chlorocarbonylpiperazine is used and the reaction is carried out in pyridine, optionally in the presence of a tertiary amine. 8. Any one of claims 5 to 7, comprising a step of converting the naphthyridine base obtained by the method described in claims 5 to 7 into an acid addition salt by a method known per se. Method described. 9 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is as defined in formula I below] Piperazine is expressed by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, Y^1 is as defined in formula I below, and Ar represents a phenyl group optionally substituted with an alkyl group having 1 to 4 carbon atoms or a nitro group]
There are general formula I▲ mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Y^1 represents a halogen atom, and R^1
represents an alkyl group having 1 to 4 carbon atoms] and an acid addition salt thereof. 10. The method according to claim 9, comprising the step of converting the naphthyridine base obtained by the method according to claim 9 into an acid addition salt by a method known per se.