IE43551B1

IE43551B1 - Naphthyridine derivatives

Info

Publication number: IE43551B1
Application number: IE2064/76A
Authority: IE
Original assignee: Rhone Poulenc Sa
Priority date: 1975-09-22
Filing date: 1976-09-17
Publication date: 1981-03-25
Also published as: AU502308B2; CH617935A5; AT349024B; NO145098B; ES451741A2; DK142365B; JPS60100579A; ZA765589B; FI762699A; JPS5239700A; CH617696A5; NL7610201A; FI59595B; HU176005B; IE43551L; BE846409R; CS196323B2; FR2324305B2; AU1789376A; FI59595C

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

‘ THIS INVENTION relates to new therapeutically useful naphthyridine derivatives, to processes for their preparation and pharmaceutical compositions containing them. It is’ an improvement in or 'modification of the invention described and claimed in the specification of our Patent Specification No. 39263.

In the Specification of our Patent Specification No. 39263 we have described and claimed naphthyridine derivatives of the general formula: wherein one of the symbols =X- represents =N- and the other three each represent a group =G- in which Y Y represents a hydrogen or halogen atom, an alkyl radical containing 1 to 4 carbon atoms, an alkoxy radical containing 1 to 4 carbon atoms, or a cyano or nitro radical, the symbols =A- and =Αη- represent a group =CH- or =N-, =Aj- representing a group =CH- or =N- when =A- represents =CH- and =A^- representing =N- when A represents =N-, the symbol 2 represents a hydrogen or - 2 halogen atom, an alkyl or alkoxy radical containing 1 to 4 carbon atoms, or the nitro radical, m represents zero or an integer from 1 to 4, and (i) n represents zero and R represents a hydrogen atom, 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, or (ii) n represents 1 and R represents an alkyl or hydroxyalkyl radical containing 1 to 4 carbon atoms, or a phenyl radical, and acid addition salts thereof.

Those naphthyridine derivatives possess useful pharmacological properties, and are particularly active as tranquillisers and anti-convulsant agents.

It has now been found as a result of further research and experimentation that compounds of the general formula indicated above wherein the symbol =X- in the 8position of the naphthyridine nucleus represents =N- and the symbols «X- in the 5- and 6-positions represent =CHand the symbol X in the 7-position represents a group = A and A^ each represent a group =CH-, Z represents a trifluoromethyl radical, m represents 1, n represents zero and R is as hereinbefore defined, also possess the same useful pharmacological properties possessed by the hitherto known, class of naphthyridine derivatives of general formula I.

The present invention is therefore concerned with new naphthyridine derivatives of the general formula: wherein Y represents a hydrogen or halogen atom, an alkyl ’ radical containing 1 to 4 carbon atoms, an alkoxy radical containing 1 to 4 carbon atoms, or a cyano or nitro radical, and R represents a hydrogen atom, 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 acid addition salts thereof.

According to a feature of the invention, the compounds of general formula IX are prepared by the process which comprises reacting a chlorocarbonylpiperaaine of the general formula: Cl-CO-N III - li oa; (wherein R is derivative of as hereinbefore defined) with a naphthyridine the general formula: wherein Y is as hereinbefore defined.

Generally, a compound of general formula III is reacted with an alkali metal salt, optionally prepared in situ, of a compound of general formula IV, and the reaction is carried out in an anhydrous organic solvent, e.g. dimethylformamide or tetrahydrofuran, at a temperature below 60°C.

The reaction can also be carried out by reacting an acid addition salt of a compound of general formula III, preferably the hydrochloride, working in pyridine and optionally in the presence of a tertiary amine (e.g. triethylamine) which liberates the compound of general formula XII from its salt.

The naphthyridine derivatives of general formula IV can be obtained by the partial reduction of an imide of the general formula: (wherein Y is as hereinbefore defined) to convert one of the carbonyl groups to a hydroxymethylene group.

The reduction is generally carried out by means of an alkali metal borohydride in organic or aqueousorganic solution, such as a mixture of dioxan and methanol or a mixture of dioxan and water or a mixture of methanol and water or a mixture of ethanol and water.

The partial reduction of an imide of general formula V can lead to isomeric products which can be separated by physico-chemical methods such as fractional crystallisation or chromatography.

The imides of general formula V can be prepared by reacting a 2-aminonaphthyridine of the general formula: (wherein Y is as hereinbefore defined) with an anhydride of the general formula: optionally forming as an intermediate a product of the general formula: VIII wherein Y is as hereinbefore defined.

I'he reaction of the 2-aminonaphthyridine of general formula VI with the anhydride of general formula VII is generally carried out by heating in an organic solvent, for example acetic acid, dimethylformamide, acetonitrile or diphenyl ether.

The cyclisation of the intermediate product of general formula VIII to form an imide product of general formula V can generally be effected either by heating with acetyl chloride in acetic acid or acetic anhydride, or by the action of a condensation agent such as Ν,Ν'-dicyclohexylcarbodiimide in dimethylformamide at a temperature below 100°C.

According to another feature of the invention, - 7 the compounds of general formula II are prepared by the process which comprises reacting a piperazine of the general formula: IX (wherein R is as hereinbefore defined) with a mixed carbonate of the general formula: wherein Y is as hereinbefore defined, and Ar represents a phenyl radical optionally substituted by an alkyl radical containing 1 to 4 carbon atoms· or a nitro radical. The reaction is generally carried out in an anhydrous organic solvent, e.g. acetonitrile, at a temperature of about 20°C., e.g. 15° to 25°C.

The mixed carbonates of general formula X can be prepared by reacting a chloroformate of the general formulas Cl - CO - 0 - Ar XI (wherein Ar is as hereinbefore defined) with a naphthyridine derivative of general formula IV. The reaction is generally carried out in a basic organic solvent, e.g. pyridine, at a - 8 temperature between 0° and 20°C.

The naphthyridine derivatives of general formula II obtained by the aforementioned processes can be purified by physical methods such as distillation, ' crystallisation or chromatography, or by chemical methods such as the formation of salts, crystallisation of the salts and decomposition of them in an alkaline medium, in carrying out the said chemical methods the nature of the anion of the salt is immaterial, the only requirement being that the salt must be well-defined and readily recrystallisable.

The naphthyridine derivatives of general formula XI may be converted by methods known per se into acid addition salts. The acid addition salts may be obtained by the action of acids on the naphthyridine derivatives in appropriate solvents. As organic solvents there may be used alcohols, ethers, ketones or chlorinated hydrocarbons. The salt which is formed is precipitated, if necessary after concentration of the solution, and is isolated by filtration or decantation.

As mentioned hereinbefore the naphthyridine derivatives of general formula IX and their acid addition salts possess valuable pharmacological properties; they are particularly active as tranquillisers and anti25 eonvulsant agents. In animals (mice) they have proved active as such at doses of between 0.1 and 100 mg./kg. animal body weight when administered orally, in particular in the following tests: (i) electric battle test according to a technique similar to that of Tedeschi et al [j. Pharmacol., 125, (1959)], (ii) convulsion with pentetrazole according to a technique similar to that of Everett and Richards [j. Pharmacol., 81, 402 (1944)], (iii) supramaximal electroshock according to the technique of Swinyard et al [j. Pharmacol., IOS, 319 (1952)], and (iv) locomotor activity according to the technique of Courvoisier [Congres des Medecins, Alienistes et ! Neurologistes - Tours - (8/13th June 1959)] and Julou (Bulletin de la Societe de' Pharmacie de Lille, No. 2, Jan. 1967, p. 7).

Furthermore, they exhibit only low toxicity? their 50% lethal dose (bDgQ) in the case of mice is generally greater than 300 mg./kg. animal body weight • when administered orally.

Of outstanding importance are those naphthyridine ' derivatives of general formula II in which Y represents a halogen atom (preferably a chlorine atom) and R represents an alkyl radical containing 1 to 4 carbon atoms, and their - 10 4 3 1 acid addition salts, more particularly 2-(7-chloro-l,8naphthyridin-2-yl)-3-(4-methylpiperazin-l-yl)carbonyloxy5-trifluoromethyl-isoindolin-l-one and its acid addition salts· For therapeutic purposes, the naphthyridine derivatives of general formula II may be employed as such or in the form of non-toxic acid addition salts, i.e. salts containing anions which are relatively innocuous to the animal organism in therapeutic dcses of the salts (such as hydrochlorides, sulphates, nitrates, phosphates, acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, theophyllinacetates, salicylates, phenolphthalinates and methylene-bis-βhydroxynaphthoates) so that the beneficial physiological properties inherent in the bases are not vitiated by side-effects ascribable to the anions.

The. fallowing Examples illustrate the preparation of naphthyridine derivatives of general formula II by processes of the present invention.

EXAMPLE 1 l-Chlorocarbonyl-4-methylpiperazine hydrochloride (7.5 g.) is added to a suspension of 2-(7-chloro-l,8naphthyridin-2-yl)-3-hydroxy-5-trifluoromethyl~isoindolin1-one (4.8 g.) in methylene chloride (480 cc.), triethylamine (10.2 g.; 14.2 cc.) and pyridine (66 cc.) at 20-21°C. £3551 After 5 hours, further l-chlorocarbonyl-4-methylpipera2ine hydrochloride (7.6 g.) is added. Stirring is continued for 15 hours and the mixture is then hydrolyzed with water (480 cc.). The organic phase is decanted off and the agueous layer is extracted with methylene chloride (300 cc.) The organic layers are combined, washed with water (150 cc.) and then dried over anhydrous sodium sulphate (15 g.).

After filtering and concentrating to dryness, the residue (9.5 g.) is triturated with water (100 cc.). After filtration, the product is washed with water (60 cc.) and then recrystallised from dichloroethane (42 cc.). The dry precipitate is stirred for 1 hour with water (37 cc.), filtered off, washed and dried. This gives 2-(7-chloro1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-l-yl)5 carbonyloxy-5-trifluoromethyl-isoindolin-l-one (3.3 g.) melting at 222°C. 2-(7-Chloro-l,8-naphthyridin-2-yl)-3-hydroxy-5trifluoromethyl-isoindolin-l-one and its isomer, 2-(7chloro-1,8-'naphthyridin-2-yl)-3-hydroxy-6-trifluoromethylt isoindolin-l-one, can be prepared as follows: Potassium borohydride (12 g.) is added, at a temperature of 15-18°C., to a suspension of 5-trifluoromethyl-N-(7-chloro-l,8-naphthyridin-2-yl)-phthalimide (83.6 g.) in methanol.(420 cc.) and dioxan (420 cc.) at a temperature of 15-18°C. ’ The mixture is stirred for a - 12 further 2 hours and is then cooled externally with an ice bath. The precipitate formed is filtered off and then washed with a methanol-dioxan mixture (1-1 by volume: cc.). The precipitate is again filtered off, dried, then stirred for 30 minutes with the same mixture (200 cc.), and then filtered off and heated under reflux with echanol (200 cc.). After cooling the suspension, and filtering, 2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-S-trifluoromethyl-isoindolin-l-one (21.9 g.), melting at a temperature above 300°C., is obtained.

The solution obtained after filtering the reaction mixture and the liquors from the washes with the methanoldioxan mixture are combined. Water (2,500 cc.) is added The precipitate which forms is filtered off, washed with water (600 cc.) and then recrystallised twice from a methanol-dioxan mixture (5-5 by volume). This gives 2(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-6-trifluoromethyl-isoindolin-l-one (15.3 g.) melting at 265°C.

-Trifluoromethyl-N-(7-chloro-l,8-naphthyridin2-yl)-phthalimide can be prepared in the following manner: 4-Trifluoromethyl-phthalic anhydride (73.5 g.) and N-hydroxysuccinimide (50.2 g.) in dimethylformamide (1,500 cc.) are heated for 18 hours at 75-78°C. 2-Amino7-chloro-l,3-naphthyridine (61.4 g.) and N,S'-dicyclohexylcarbodiimide (l40 g.) are then added and the mixture is - 13 4355 1 heated for a further 3 hours at the same temperature.

After cooling, the precipitate formed is filtered off and washed with dimethylformamide (100 cc.) and then with diisopropyi ether (200 cc.). Water (1,500 cc.) is added to the reaction mixture. The precipitate which forms is filtered off and washed with methylene chloride (1,500 cc.). The two combined precipitates are taken up in methylene chloride (8 litres). An insoluble material is filtered off and the filtrate is then concentrated to dryness. This 2.0 gives 5-trifluoromethy1-N-(7-chloro-l,8-naphthyridin-2yl)-phthalimide (83.6 g.) melting at 265°C. 4-Trifluoromethyl-phthalic anhydride can be prepared in the following manner: 4-Trifluoromethyl-phthalic acid (106.6 g.) and .5' acetic anhydride (215 cc.) are heated under reflux for 30 minutes. After concentrating under reduced pressure (30 mm.Hg) the residue is stirred with cyclohexane (420 cc.). After filtering and drying, 4-trifIuoromethyl-phthaJic anhydride (73.5 g.), melting at 54°C., is obtained. ) 4-Trifluoromethyl-phthalic acid can be prepared • in the following manner: Methyl 2-cyano-4-trifluoromethyl-benzoate (102.3 g.), sodium hydroxide pellets (108 g.), water (900 cc.) and methanol (1,900 cc.) are heated under reflux for 12 hours.

The solution is decolourized with animal charcoal (0.6 g.). - 14 After filtering, hydrochloric acid (d = 1.19; 100 cc.) is added. The mixture is extracted with diethyl ether (2.25 litres). The organic layer is dried over anhydrous magnesium sulphate (40 g.). After filtering, and concentrating the filtrate, 4-trifluoromethyl-phthalic acid (99.1 g.), melting at 178°C., is obtained.

Methyl 2-cyano-4-trifluoromethyl-benzoate can be prepared in the following manner: 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.). A solution of sodium nitrite (49.9 g.) in water (172 cc.) is added all at once to the solution obtained. The reaction mixture is stirred for 2 hours 30 minutes at 0-l°C. and filtered, and is then added dropwise, over a period of 1 hour 20 minutes, to a solution, kept at 4-5°C., of copper sulphate (226 g.) and potassium cyanide (261 g.) in water (1,320 cc.) [a solution prepared according to Gabriel, Ber., 52, 1089 (1919)). During the addition of the diazo compound, the pH is kept at 6-7 by adding a 10% (w/v) sodium carbonate solution. Stirring is continued whilst allowing the temperature to rise to 20°C. The mixture is then extracted with diethyl ether (3 litres). The ether layer is washed with water (150 cc.) and then dried over anhydrous magnesium sulphate (30 g.). After filtering and - 15 43551 concentrating, methyl 2-cyano-4-trifluoromethyl-benzoate (94.9 g.), melting at 52°C., is obtained..

Methyl 2-amino-4-tri£luoromethyl-benzoate can be prepared in the following manner: 2-Amino-4-trifluoromethyl-benzoic acid (141.2 g.), methanol (1.51 litres) and boron trifluoride etherate (506 cc.) are heated under reflux for 99 hours. The solution obtained is added to sodium carbonate (350 g.) in ice-water (2.8 kg.). The mixture is stirred for 15 minutes .0 and then extracted with diethyl eth er (3 litres). The ether layer is washed with water (250 cc.) and then dried over anhydrous magnesium sulphate (30 g.). After filtering and concentrating, methyl 2-amino-4-trifluoromethyl-benzoate (137 g.), melting at 64°C., is obtained. j 2-Amino-4-trifluoromethyl-benzoic acid can be prepared in accordance with Hauptschein et al., J. Amer. Chem. Soc., 76, 1051 (1954).

EXAMPLE 2 Following the procedure of Example 1 but starting with 2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-6-tri£luoromethyl-isoindolin-l-one (4.8 g.), l-chlorocarbonyl-4methylpiperazine hydrochloride (15.1 g.), triethylamine (10.2 g.; 14.2 cc.) and pyridine (66 cc.) in methylene chloride (250 cc.), a crude product (7.8 g.) is obtained, iyhich is triturated with water (50 cc.)e* The solid - 16 obtained is filtered off and washed with water (30 cc.). After recrystallization from isopropanol (240 cc.), 2-(7chloro-1,8-naphthyridin-2-yl)-3-(4-methylpiperazin-l-yl)carbonyloxy-6-trifluoromethyl-isoindoIin-l-one (4.7 g.), melting at 219°C., is obtained. 2-(7-Chloro-l,8-naphthyridin-2-yl)-3-hydroxy-Strifluoromethyl-isoindolin-l-one can be prepared as described in Example 1.

The present invention includes within its scope pharmaceutical compositions comprising, as active ingredient, at least one of the naphthyridine derivatives of general formula XI, or a non-toxic acid addition salt thereof, in association with a pharmaceutical carrier or coating. The invention includes especially such preparations made up for oral,. parenteral or rectal administration or local application, e.g. as ointments.

Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions the active compound is admixed with at least one inert diluent such as sucrose, lactose or starch.

The compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate. Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and - 17 elixirs containing inert diluents commonly used in the art, such as water and liquid paraffin. Besides inert diluents such compositions may also comprise adjuvants, such as wetting, emulsifying and suspending agents, and sweetening, flavouring and aromatizing agents. The compositions according to the invention, for oral administration, also include capsules of absorbable material such as gelatin containing the active substance with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, .5 and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as preserving wetting, emulsifying and dispersing agents.. They may be sterilised by, for example, filtration through a. bacteriarefcaining filter, by incorporation in the compositions of sterilising agents, by irradiation, or by heating.

They may also be manufactured in the form of sterile Solid compositions, which can be dissolved in sterile water or some other sterile injectable medium-immediately before use.

Compositions for rectal administration are 3 3 31 suppositories which contain, in addition to the active substance, excipients such as cacao butter or a suitable wax base.

The percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. The dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment.

In human therapy the compositions when administered orally to an adult should generally give doses between 10 mg. and 500 mg. of active substance per day. In general the physician will decide the posology considered appropriate, taking into account the age and weight and other factors intrinsic to the patient being treated.

The following Example illustrates pharmaceutical compositions according to the Invention.

EXAMPLE 3 Tablets containing 25 mg. of active product and having the following composition are prepared in accordance with the usual technique: 2-(7-chloro-l,8-naphthyridin-2-yl)-3-(4-methylpiperazin-l-yl )carbonyloxy-5-trifluoromethylisoindolin- l-one 0.025 g. starch 0.090 g. - 19 4 Λ « « 8 a ti o ·*· precipitated silica 0.030 g magnesium stearate 0.005 g

Claims

1. WE. CLAIM:

1. Naphthyridine derivatives of the general formula: 5 wherein Y represents a hydrogen or halogen atom, an alkyl radical containing 1 to 4 carbon atoms, an alkoxy radical containing 1 to 4 carbon atoms, or a cyano ox nitro radical, and R represents a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, an alkenyl radical 10 containing 2 to 4 carbon atoms, an alkynyl radical containing 2 to 4 carbon atoms, a hydroxyaikyl radical containing 1 to 4 carbon atoms or a phenyl radical, and acid addition salts thereof.

2. Naphthyridine derivatives according to claim !5 i wherein Y represents a halogen atom and R represents an alkyl radical containing 1 to 4 carbon atoms, and acid addition salts thereof.

3. Naphthyridine derivatives according to claim 2 wherein Y represents a chlorine atom, and acid addition 2o salts thereof.

4. 2-(7-Chloro-l,8-naphthyridin-2-yl)-3-(421 ,ϊ 3 3 S methylpiperazin-l-yl)carbonyloxy-5-trifluoromethylisoindolin-l-one and its acid addition salts.

5. 2-(7-Chloro-l,8-naphthyridin-2-yl)-3(A-methylpiperazin-l^-yllcarbonyloxy-S-trifluoromethyl5 isoindolin-l-one and its acid addition salts.

6. Process for the preparation of a naphthyridine'· derivative as claimed in claim l^which- comprises reacting a·, chlorocarbonylpiperazine of the general formula: C1-C0-N tf-R III 10 (wherein R is as defined in claim 1) with a naphthyridine wherein Y is as defined in claim 1, or an alkali metal derivative thereof. 15

7. Process according to claim 6 in which an alkali metal derivative of the naphthyridine derivative is employed and the reaction is carried out in an anhydrous organic solvent at a temperature below 60°C.

8. A modification of the process 20 according to claim 6 in which an acid addition salt of the chlorocarbonylpiperazine is - 22 :U0l) i employed and the reaction is carried out in pyridine and optionally in the presence of a tertiary amine.

9. Process for the preparation of a naphthyridine derivative as claimed in claim 1 which comprises reacting a piperazine of the general formula: HN N-R IX (wherein R is as defined in claim 1) with a mixed carbonate of the general formula: » wherein Y is as defined in claim 1, and Ar represents a phenyl radical optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or a nitro radical.

10. Process according to any one of claims 6 to 9 followed by the step of converting by methods known per se a naphthyridine base thus obtained into an acid addition 3alt.

11. Process for the preparation of naphthyridine derivatives of the general formula specified in claim 1 substantially as described in Example 1 or 2.

12. Naphthyridine derivatives of the general 23 ΓΊ Ο formula specified in claim 1 and acid addition salts thereof when prepared hy the process claimed in any one of claims 6 to 11.

13. Pharmaceutical compositions which comprise, 5 as active ingredient, at least one naphthyridine derivative as claimed in any one of claims 1 to 5, or a non-toxic acid addition salt thereof, in association with a pharmaceutical carrier or coating.

14. Pharmaceutical compositions according to 10 claim 13 substantially as hereinbefore described with especial reference to Example 3.