IL44815A - 3-(piperazin-1-yl) carbonyloxy (naphthyridin-2-yl) isoindolinones pyrrolo (3,4-b) pyrazines and pyrrolo (3,4-b) pyridines processes for the preparation thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

1417935 Naphthyridine derivatives RHONEPOULENC SA 13 May 1974 [15 May 1973 14 March 1974 (2)] 21081/74 Heading C2C Novel compounds I (in which one symbol X is =N-and the others are all -CY=; Y is H, halo, 1-4 C alkyl or alkoxy, CN or NO 2 ; A is =CH- and A 1 is =CH- or =N- or A is =N- and A 1 is =N-; Z is H, halo, 1-4 C alkyl or alkoxy or NO 2 ; m is 0 or 1-4; and (i) n is O or R is H, 1-4 C alkyl, 2-4 C alkenyl or alkynyl, 1-4 C hydroxyalkyl or phenyl or (ii) n is 1 and R is 1-4 C alkyl or hydroxyalkyl or phenyl) and acid addition salts thereof are prepared by (i) reaction of a piperazine II with a naphthyridine III or an alkali metal derivative thereof; (ii) reaction of a piperazine VIII with a mixed carbonate IX (in which Ar is phenyl which may be substituted by 1-4 C alkyl or NO 2 ) or (iii) oxidation of a compound I in which n is 0 to give a compound in which n is 1. Compounds III may be prepared by reaction of a compound V with a compound VI to give a compound VII cyclization of the compound VII to give an imide IV which is then partially reduced. Compounds VIII in which n is 1 may be prepared by oxidation of those in which n is 0. Compounds IX may be prepared by reaction of a chloroformate CICOOAr with a compound III. 2 - Amino - 7 - methoxy - 1,8 - naphthyridine is prepared by reaction of sodium methoxide with 2 - acetamido - 7 - chloro - 1,8 - naphthyridine. Pharmaceutical compositions useful as anticonvulsants and tranquillizers comprise a compound I or a suitable salt thereof in combination with a carrier or diluent. [GB1417935A]

Description

(>*~2-3*τ*Ί*η&κ3) »¾ρικ »3Ϊ: (V l-3*?KnB?D)-3 VWVBl 0»3 RVB (b-4,3) 1VM«D ,0*313» >*Π3»Κ1» ♦* ninpii manyni onsan o»s»Vnn ,o»3»*r»i»B ( r4,3) 3-(Piperazin-1 -yl) carbonyloxy (nap^thyridin-2-yl) isoindolinonss, pyrrolo (3,4-b) pyrazinea and pyrrolo (3t4-b) pyridines', processes for the Vs. preparation thereof and pharmaceutical compositions w containing the same ■ ί r ThlB Invention relates to new therapeutically useful naphthyridine derivatives, to processes for their preparation and pharmaceutical compositions containing them.

The new naphthyridine derivatives of the present invention are those of the general formula: wherein one Ϊ represents a hydrogen or halogen (preferably .chlorine or bromine) atom, an alkyl radioal containing 1 to 4 carbon atoms (preferably methyl), an alkoxy radical containing 1 to 4 carbon atoms (preferably methoxy), or a cyano radical, or two Ϊ represent said alkyl radicals, the other Y being hydrogen the symbols =A-- and represent a group <=CH- or ^- representing a group =CH- or «48- when =A- represents =CH- and ^A^- representing =K- when A represents =N-, the symbol Z represents a hydrogen or halogen atom, an alByl or alkoxy radical containing 1 to 4 carbon atoms, or the nitro radical, m represents zero or one (preferably zero), and (i) n represents zero and R represents a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms (e.g. ethyl, isopropyl, t.-butyl or, more especially, methyl), an alkenyl radical containing carbon atoms (e.g. allyl), an alkynyl radical containing 2 to 4 r carbon atoms (e.g. propargyl), a hydroxyalkyl radical containing 1 to 4 carbon atoms (e.g. 2-hydroxyethyl) 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.

According to a feature of the invention, the compounds of general formula I wherein £ represents zero are prepared · ,iby the process which comprises reacting a chlorocarbonylpiperazine of the general formula: (wherein R represents a hydrogen atom or an alkyl, alkenyl, alkynyl, hydroxyalkyl or phenyl radical) with a naphthyridine derivative of the general formula) wherein Y, A, A^, Z and m are as hereinbefore defined.

Generally, a compound of general .formula II is reacted with an alkali metal salt, optionally prepared i situ, of a compound of general formula III, the reaction being 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 II, preferably the hydrochloride, with a compound of general formula III, working in pyridine and optionally in the presence of a tertiary amine (e.g. triethylamine) which liberates the compound of general formula II from its salt.

The naphthyrldine derivatives of general formula III can be obtained by partial reduction of an imide of the general formula: (wherein Ϊ, A, , Z and m are 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 aqueous-organic solution, such as a mixture of dioxan and methanol or a mixture of dioxan and vrater or a miiture of methanol and water or a mixture of ethanol and water.

The partial reduction of an .-imide of general formula IV can lead to isomeric products which can be separated by physico-chemical methods such as fractional crystallisation or chromatography. ) The imides of general formula IV can be prepared by reacting a 2-aminonaphthyridine of the eneral formula: (wherein Ϊ is as hereinbefore defined) with an anhydride of the general formula: (wherein A, A^ , Z and m are as hereinbefore, defined), optionally forming as an intermediate a product of the general formula: . wherein Y, A, , Z and m are as hereinbefore defined* The reaction of the 2-aminonahthyridine of general formula V with the anhydride of general formula' Yl is generally carried out by heating in an organic solvent, for example acetic acid, dimethyl-formamide, acatonitrile or diphenyl ether.

The cyclisation of the intermediate product of general formula VII to form an almlde product of general formula IV 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 K^'-dicyclohexyl-carbodiimide in dimethylformamide at o a temperature of about 20 C.

According to another feature of the invention, the compounds of general formula I wherein n is zero or 1 and R has the corresponding meanings given above are prepared by the process which comprises reacting a piperazine of the general formula: " - R (0)n VIII (wherein ri is zero or 1 and R is as hereinbefore defined) with a mixed carbonate of the general formula: wherein Y, A, A^ , Z and.m are as hereinbefore defined, and Ar represents a phenyl radical optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or a hitro radical. The reaction is generally carried out in an anhydrous organic solvent, e.g. aceto-nitrile or dimeth lforinamide, at a temperature of about 20°c, e.g. 15° to 25°C.

The piperazine compound of general formula VIΠ wherein n represents 1 and. R represents the methyl radical and its dihydrochloride can be obt ined by oxidation of t.-butyl (4-methylpiperazin-l-yl)carboxylate by means of 4-nitroperbenzoic acid in anhydrous chloroform at a temperature not exceeding 40°C. , followed by replacement of the t.-butoxycarbonyl group by a hydrogen atom by heating l-methyl-4-t.-butoxycarbonyl-piperazine-l-oxide hydrochloride under reflux in an ethanolic medium in the presence of anhydrous hydrochloric acid. The other piperazine compounds of general formula VIII can be obtained in a similar manner.

The mixed carbonates of general formula IX can be prepared, by reacting a chloroformate of the general formula: CI - CO ~ 0 - Ar X (wherein Ar is as hereinbefore defined) with a naphthyridine derivative of general formula III. The reaction i3 generally carried, out in a basic organic solvent, e.g. pyridine, at a temperature between 0° and 20 °C.

According to another feature of the invention, the compounds of general formula I wherein n represents 1 and. R represents an alkyl, hydroxyalkyl or phenyl radical are obtained, by the process which comprises the oxidation of a corresponding compound, of general formula I wherein n represents zero and R is as defined, above.

The oxidation is generally carried out by means of an organic peracid, e.g. 3-chloroper enzoic acid or 4-nitroperbenzoic acid, in an organic solvent, e.g. chloroform, and at a temperature of about 20°C.

The naphthyridine derivatives of general formula I 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 crystallisable.

The naphthyridine derivatives of general formula I 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 d.ecantation.

The naphthyridine derivatives of the invention and their acid addition salts possess valuable pharmacological properties; they are particularly active as tranquillisers and. anti-convulsant 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., 12 r 28 (1959)], (il) convulsion with pentetrazole according to a technique similar to that of Everett and Richards [j.Pharmacol. , 81_, 402 (1944)], (iii) supramaximal electroshook according to the technique of Swinyard et al [j. Pharmacol., 319 (1952)3, and (iv) locomotor activity according to the technique of Courvoisier [Congres dee Medicine, Alienistes Neurologistes -Tours - (8/l3th June 1959)3 and Julou (Bulletin de la Soci^te" de Pharmacie de Lille, No. 2, Jan. 1967» p. 7).

Furthermore, they exhibit only low toxicity; their 5C lethal dose t e case of mice is£generally greater than 300 mg./kg. animal body weight when administered orally. wherein one or alkoxy radical containing 1 to.4 carbon atoms, or a cyano radical, the other Ϊ being hydrogen or both Y represent said alkyl radicals, °¾A- and represent a group =CH- or =ϋ-, representing «CH- or when «*A- represents =CH- and representing =N- when =A- represents =N-, and, n represents zero and R represents an alkyl radical containing 1 to 4 carbon atoms (preferably methyl), an alkenyl radical containing 2 to 4 carbon atoms, an alkynyl radical containing 2 to . carbon atoms or a hydroxyalkyl radical containing 1 to 4 carbon atoms , or n represents 1 and R represents the methyl radical, and their acid addition salts, are of very particular interest. Of outstanding value are the compounds 2-(7-bromo-l ,8-naphthyridin-2-yl)-3-(4-methylpiperazin-1-yl )carbonyloxy-isoindolin-l-one , 2-( 7-cyano-l ,8-naphthyrid.in-2-yl) -3-( -methylpiperasin-l-yl)carbonyloxy-isoindolin-l-one, 2-(7-chloro-1 ,8-naphthyrid.in-2-yl ) -3- [4-( 2-hydroxyethyl)-piperazin-l-yl]carbonyloxy-isoindolin 1-one, 3-(4-allylpiperazin-l-yl)carbonyloxy-2-(7-chloro-1 ,8-naphthyridin-2-yl ) isoindolin-l-one , 2-(7-chloro-l ,8-naphthyrid.in-2-yl)-3-(4-ethylpiperazin-l-yl) carbonyloxy-i3oindolin-l-on , 2-(7-chloro-l ,8-naphthyridin-2-yl ) -3- ( -propargylpiperazin-l-yl)carbonyloxy-isoindolin-l-one , 2-(7-chloro-l ,8-naphthyrid.in-2-yl)-3-(4-t. -butylpiperazin methylpiperazine-1-oxide , 6-( 7-chloro-l ,8-naphthyridin-2 yl )-5-(4-methylpiperazin-l-yl )carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine and, more especially, 2-( 7-chloro-l ,8-naphthy idin-2-yl)-3-( -methylpiperazin-l-yl )carbonyloxy-isoindolin-l-one , and. their acid, addition salts.

For therapeutic purposes, the naphthyridine derivatives of general formula I 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 doses of the salts (such as hydrochlorides, sulphates, nitrates, phosphates, acetates, propionates, succinates benzoates, fumarates, maleates, tartrates, theophyl-linacetates, salicylates, phenolphthalinates and methylene-bis-p-hydroxynaphthoates) so that the beneficial physiological properties inherent in the bases are not vitiated by side-effects ascribable to the anions.

The following Examples illustrate the preparation of naphthyridine derivatives of this invention, EXAMPLE 1 Sodium hydride (50% dispersion in mineral oil) (2,1 g,) is added all at once to a suspension of 2-(7-chloro-1 ,8-naphthyridin-2-yl )-3-hydroxy-isoindolin-l-one (12,4 g, ) in anhydrous dimethylformamide (125 cc,), whilst cooling externally with an ice bath. When the evolution of gas has ceased, a solution of l-chlorocarbonyl-4-methyl-piperazine (11,3 g, ) in anhydrous dimethylformamide (110 cc, is added, the external cooling being maintained, After the end of the addition, the reaction mixture is stirred for 14 hours at 0°C. , and then for 6 hours at 22°C. The reaction mixture is then poured, onto ice (800 g. ) . The product which crystallises is filtered off, washed with water (240 cc, ) and dried, in air to yield, a crude product (13 g, ) which melts at about 210°C, On recrystallisation from aceto-nitrile (900 cc. ) , 2-(7-chloro-l ,8-naphthyridin-2-yl)-3-( -methylpiperazin-l-yl )carbonyloxy-isoindolin-l-one (8.5 g.), melting at 204°C, , is obtained. 2-( 7-Chloro-l ,8-naphthyridin-2-yl )-3-hydroxy-isoindolin-l-one can be prepared by adding potassium borohydride (1.72 g, ) to a suspension of 2-(7-chloro-l ,8-naphthyrid.in-2-yl)phthalimide (17,7 g. ) in dioxan (87 cc.) and. a saturated, aqueous solution of disod um phosphate (26.4 cc.), whilst cooling externally with an ice bath.

After stirring for 14 hours, the mixture is allowed to return to a temperature of about 20°C, , stirring is carried out for a further 2 hours, and then a saturated aqueous solution of disodium phosphate (400 cc. ) is added. The precipitate which forms is filtered off and washed with cold water (225 cc. ) . After drying in air, 2-(7-chloro-1 ,8-naphthyridin-2-yl ) -3-hydroxy-isoindolin-l-one (17,5 g. ) , melting at 248°C. , is obtained. 2-(7-Chloro-l ,8-naphthyridin-2-yl )phthalimide can be prepared, by heating a mixture of 2-(7-hydroxy-l,8-naphthyridin-2-yl)phthalimide (26.3 g. ) with phosphorus oxychloride (79 cc.) and dimethylformamide (3,5 cc. ) under reflux until the evolution of gas ceases, After cooling, the reaction mixture is poured, into ice-water (650 cc. ) without exceeding 25°C. The product obtained, is filtered off, washed with water (150 cc. ) and dried. to constant weight to give 2-(7-chloro-l ,8-naphthyridin-2-yl)phthalimid.e (24.1 g. ) melting at 268°C. 2-(7-Hydxoxy-l ,8-naphthyridin-2-yl )phthalimid.e can be prepared by heating a mixture of 2-amino-7-hyd.roxy-1 ,0-naphthyridine (25 g. ) with phthalic anhydride (70 g. ) in acetic acid. (1,400 cc. ) under reflux for 3 hours. After cooling, an insoluble material is filtered off. The crystals obtained are filtered off, washed successively with diethyl ether (60 cc, ) , water (90 cc, ) , a saturated solution of sodium bicarbonate (120 cc. ) and finally water (60 cc. ) . The crystals are dried to constant weight and 2-( 7-hydroxy-1 ,8-naphthyridin-2-yl ) hthalimide (17 g.), melting at 370°C. , is thus obtained. 2-Amino-7-hyd.roxy-l,8-naphthyridine can be prepared according to the method described by S, Carboni et al, Gazz. Chim. Ital., 1498 (1965).

EXAMPIE 2 Triethylamine (5*6 cc. ) followed by anhydrous pyridine (25 cc) are added to a suspension of 2-(7-chloro-1 ,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (5· 12 g) and 1-chlorocarbonyl-4-methylpiperazine hydrochloride (5.97 g. ) in methylene chloride (50 cc), whilst keeping the temperature at about 25°C. The reaction mixture is then heated at a temperature of about 50°C. for 1 hour and is then stirred for 18 hours at a temperature of about 20°C. Methylene chloride (■ 50 cc.) and water ( 100 cc.) are then added. The aqueous layer is decanted and then washed three times with methylene chloride (50 cc;). The organic layers are combined and washed with water (50 cc), dried over anhydrous sodium sulphate and then concentrated to dryness under reduced pressure. On recrystallisation of the resulting residue from acetonitrile (100 cc), 2-(7-chloro-1 ,8-mphthyri±Ln-2-yl)-3-(4-methylpiperazine-1-yl) carbonyloxy-isoindolin-1-one (2.5 g. ), melting at 203°C, is obtained.

EXAMPLE ¾r Sodium hydride (50% dispersion in mineral oil) (0.8 g. ) is added to a suspension of 2-(7-m thoxy-l,8-naphthyridin-2-yl)-3-hydroxy-isoind.olin-l-one (4.63 g, ) in anhydrous dimethylformamide (45 cc. ) , whilst keeping the temperature between 18-20°C. The reaction mixture is stirred for a further 4 hours 30 minutes, A solution of l-chlorocarbonyl- -methylpiperazine (2.7 g, ) in anhydrous dimethylformamide (25 cc.) is then added over the course of 15 minutes and. at a temperature of 20°C. The suspension is stirred, for 17 hours at a temperature of about 20 °C, , and then anhydrous hexamethylphosphotriamide (7 cc,) is added. After 15 minutes, the reaction mixture is poured into ice-water ( 500 g. ) . The precipitate is filtered off and. washed with water. (45 cc.), A product (6,1 g, ) is obtained and is recrystallised from diisopropyl ether (1 , 500 cc, ) , 2-(7-Methoxy-l ,8-naphthyridin-2-yl)-3-( -methylpiperazin-l-yl )car onyloxy-isoindolin-l-one (3 g, ) , melting at 191 °C, , is thus obtained, The 2-(7-methoxy-l ,8-naphthyridin-2-yl )-3-hydroxy-isoindolin-l-one can be prepared, in the following way: Preparation of 2-acetylamino-7-chloro-l ,8-naphthyrid.ine , m.p, 251-253°C., according to S. Carboni et al [Gazz.

Chim.Ital., 9J5, 1492 (1965)].

Preparation of 2-amino-7-methoxy-l,8-naphthyridine (1,0 g. ) , m.p. 156°C. , by reacting sodium methoxide (1.8 g. ) with 2-acetylamino-7-chloro-l,8-naphthyridine (2.2 g. ) in anhydrous methanol (40 cc. ) under reflux for 45 minutes.

Preparation of 2-(7-met_hoxy-l,8-naphthyridin-2-yl)-phthalimide (20 g. ) , m.p. 295°C. , by reacting phthalic anhydride (10 g. ) with 2-amino-7-methoxy-l ,8-naphthyridine (12 g. ) in diphenyl ether (240 cc. ) for 10 minutes at 160°C.

Preparation of 2- ( 7-methoxy-l ,8-naphthyrid.in-2-yl )-3-hydroxy-isoindolin-l-one (18.6 g. ) , m.p. 218°C. , by reacting potassium borohydride (3.55 g. ) with 2-(7-methoxy-1 ,8-naphthyridin-2-yl)phthaliinid.e (20 g. ) in dioxan (200 cc. ) and a saturated aqueous solution of disodium phosphate (40 cc. ) for 4 hours at a temperature of about 20 °C. but starting with 2-(7-bromo-l ,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-l-one (8 g. ) in anhydrous dimethyl-formamide (240 cc. ) , sodium hydride (50% dispersion in mineral oil) (1.2 g. ) and l-chlorocarbonyl-4-methyl-piperazine (4.1 g. ) in anhydrous dimethylformamide (40 cc.). After stirring at 26°C. for 18 hours, the reaction mixture is poured into ice-water (1,500 cc.).

The insoluble matter (7.3 g. ) is filtered off and. dissolved in a mixture (73 cc. ) of methylene chloride and ethyl acetate (80-20 by volume). The solution obtained is passed through a column of silica gel (73 g. ). Elution is first carried out with a mixture (5,750 cc.) of methylene chloride and. ethyl acetate (80-20 by volume); the corresponding eluates are discarded, Elution is then carried, out with pure ethyl acetate (1,250 cc.) and. then with a mixture ( 1 , 250 ccr ) of ethyl acetate and methanol ( 50-50 by volume); the corresponding eluates are combined and concentrated to dryness, A residue ( 3 g. ) is obtained which is dissolved, in ethanol (90 ccj, A solution of oxalic acid ( 0. 53 g. ) in ethanol ( 10. 5 cc. ) is added, to the solution obtained. The mixture is stirred, for 1 hour and the precipitate which forms is filtered off and. washed with ethanol ( 6 cc,). A product ( 1.8 g, ) , melting at 260 °C. , is thus obtained and is treated, with a saturated, solution of sodium bicarbonate ( 50 cc. ) and methylene chloride (40 ccj, The organic layer is isolated, by decanting, dried, over anhydrous potassium carbonate and concentrated to dryness. A residue weighing 1 , 2 g, is obtained, and is recrystallised from ethanol. (80 cc.), 2-( 7-Bromo-l ,8-naphthyridin-2-yl J-S-^-methyl- piperazin-l-yDcarbonylcxy-isoindolin-l -one ( 0.9 g. ) , melting at 225-230°C. , is thus obtained. 2- ( 7-Bromo-l ,8-naphthyridin~2-yl ) -3-hydroxy- isoindolin-l-one can be prepared in the following way: Preparation of 2-( 7-bromo-l ,8-naphthyridin-2-yl)- phthalimide (23.6 g. ) , m„p0 265°C„ , by heating a mixture of 2-( 7-hydroxy-l,8-naphthyridin-2~yl)phthalimide ( 20. 5 g. ) and. phosphorus pentabromide (30. 3 g. ) in bromoform ( 205 cc. ) and. dimethylformamide ( 7 cc.) for 1 hour at a temperature of about 100 °c„ Preparation of 2~( 7-bromo-l ,8-naphthyridin-2-yl)- 3-hydroxy-isoindolin-l-one (8.2 g. ) , m.p. 264°C. , from 2-( 7-bromo-l,8-naphthyrid.in-2-yl)phthalimide ( 10.6 g. ) and. potassium borohydride ( 1 , 2 g„ ) in a mixture ( 200 cc. ) of methanol and dioxan (50^-50 by volume) at a temperature of about 20°C.

EXAMPLE Following the procedure of Example but starting with 2-(7-cyano-l ,8~naphthyridin-2-yl)-3-hydroxy-isoind.olin-1-one (4.7 g. ) , sodium hydride (50% dispersion in mineral oil) (1.5 g* ) , l-chlorocarbonyl-4-methylpiperazine (5.04 g. ) , anhydrous tetrahydrofuran (97 cc. ) and anhydrous hexamethylphosphotriamide (25 cc. ) , a crude product (5.7 g„ ) is obtained which is then dissolved, in methylene chloride (100 cc. ) 0 The resulting solution is passed through a column of silica gel (57 g. ) . Elution is carried out successively with methylene chloride (2,400 cc. ) , ethyl acetate (1,400 cc.) and. then a mixture (200 cc. ) of ethyl acetate and methanol (50-50 by volume), collecting 200 cc. fractions. The last eight fractions are combined, and concentrated to dryness. The residue, weighing 3.4 g. , is recrystallised from acetonitrile (250 cc. ) to yield. 2-(7-cyano-l,8-naphthyrid.in-2-yl)-3-( -methylpiperazin-l-yl ) carbonyloxy-isoindolin-l-one (2.6 g. ) melting at 266-2680Co 2-( 7-Cyano-l , 8-naphthyridin-2-*yl ) -3-hydroxy-isoind.olin-1-one can be prepared in the following way: Preparation of 2-(7-cyano-l ,8-naphthyridin-2-yl)phthalimid.e (7.3 g. ) , m.p. 320°C„ , by heating 2-(7-bromo-l ,8-naphthyrid.in-2-yl)phthalimide (17.7 g. ) with cuprous cyanide (9 g. ) in nitrobenzene (177 cc. ) at 160-165°C. for 1 hour. Insoluble matter is removed by carrying out a hot filtration and the filtrate is then cooled. The product which crystallises is filtered off and then recrystallised from dime hylformamlde (70 cc)* Preparation of 2-(7-cyano-1 ,8-naphthyrldin-2- 1)-3-hydroxy-isoindolih-1-one (4*7 g.)» m.p* 260°C., from 2-(7-cyano-1 ,8-naphthyridin-2-yl)phthalimide (5.8 g.) and sodium borohydride (1.04 g) in methanol 290 cc.) at a temperature between 23 and 27°C.

EXAMPLE 6 v 1-Chloroearbonyl-4-methylpiperazine (12 g. ) is added to a suspension of 5-hydroxy-6-(5-methyl-1 ,8- naphthyridine-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3»4-b]-pyrazine (7.2 g. ) in anhydrous pyridine (123 cc). The reaction mixture is then heated at a temperature of about 50°C. for 2 hours. After cooling, the suspension obtained is poured into a mixture of water (750 cc), a saturated aqueous solution of sodium bicarbonate (250 cc) and methylene chloride (250 cc).

The aqueous layer is decanted and washed four times with methylene chloride (100 cc). The organic layers are combined, washed four times with water (100 cc), dried over anhydrous sodium sulphate, filtered and evaporated to dryness under reduced pressure. The residue obtained is dissolved in methylene chloride (50 cc) and the resulting sodium is filtered through silica gel (200 g. ) in a column 3.8 cm. in diameter. Elution is carried out with pure methylene chloride (1,000 cc) and then with a mixture (800 cc.) of methylene chloride and methanol (95-5 by volume). These eluates are discarded. Elution is then carried out with a mixture ( 1,200 cc) of methylene chloride and methanol (95-5 by volume); the corresponding eluate is concentrated to dryness under reduced pressure. After recrystallisatio of the residue from acetonitrile (40 cc.) , 6-(5-methyl-1 ,8-naphthyridin-2-yl ) -5-(4-methyipiperazin-l-yl )-carbonyloxy-7^oxo-6,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine (5.1 g. ), which melts at 184°C. , is obtained. 5-Hyd.roxy-6-( 5-methyl-l ,8-naphthyridin-2-yl ) - 7-oxo-6f7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine , m.p. 260°C, with decomposition, can be prepared by reacting potassium borohydride with 6-(5-methyl-l,8-naphthyridin-2-yl) -5,7-dioxo-6,7-d.ihydr0-5H-pyrrolo[3 ,4-b]pyrazine in a mixture of dioxan and water (97-3 by volume) at a temperature of about 20°C. 6-( 5- ethyl-l ,8-naphthyridin-2-yl)-5,7-d.ioxo-6,7-d.ihydro-5H-pyrrolo[3 ,4-b]pyrazine can be prepared, by adding., dicyclohexylcarbodiimide (258 g. ) to a suspension of 3-(5-methyl-1 ,8-naphthyrid.in-2-yl) carbamoyl-pyrazine-2-carboxylic acid. (77 g, ) in anhydrous dimathylforma ide (2,500 cc.). The reaction mixture is then stirred for 72 hours at a temperature of about 20°C, The dicyclohexylurea which has crystallised is then filtered, off and washed, with dimethylformamide (300 cc, ) and diisopropyl ether (200 cc. ) . Diisopropyl ether (25 litres) is then added to. the filtrate. The product which crystallises is filtered, off and. then washed with diisopropyl ether (2,000 cc. ) to yield, after drying, 6-( 5-methyl-l ,8-naphthyrid.in-2-yl)-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine (60.9 g. ) , which melts with decomposition at 265°C. 3-( 5-Methyl-l ,8-naphthyridin-2-yl )carbamoyl-pyrazine-2-carboxylic acid, m.p. 265°C. with decomposit on, can be prepared by condensing pyrazine-2 ,3-dicarboxylic acid anhydride with 2-amino-5-methyl-l,8-naphthyridine in refluxing acetonitrile. 2-Amino-5-niethyl-l ,8-naphthyridine can be prepared according to the method, described by E, V. Brown, J, Org. Chem. 30, 1607 (1965).

Pyrazine-2 ,3-dicarboxylic acid anhydride can be prepared according to the method, described by S. Gabriel and A. Sonn, Chem. Ber. , 40, 4850 (1907).

EXAMPLE 7 Sodium hydride (50% dispersion in mineral oil) (1.83 g. ) is added all at once to a suspension of 7-hydroxy-6-(7-chloro-l ,8-naphthyridin-2-yl)-5-oxo-pyrrolo[3 ,4-b]pyridine (5.4 g, ) in anhydrous dimethylform- amide (55 cc.). When the evolution of gas has ceased, a solution of l-chlorocarbonyl-4-methylpiperazine (6.2 g. ) in anhydrous dimethylformamide (62 cc. ) is added over the course of 5 minutes. The reaction mixture is stirred for 2 hours at a temperature of about 20°C. and then anhydrous hexamethylphosphotriamide (70 cc. ) is added. After standing for 18 hours, the reaction mixture is poured into ice-water (550 cc.). The precipitate which appears is filtered off, washed, with water (4 cc. ) and. dried; a crude product (2.6 g. ) is thus obtained,' The aqueous filtrate is extracted, three times with methylene chloride (100 cc.). The combined, extracts are washed with water (150 cc. ) , dried, over sodium sulphate and concentrated to a volume of 50 cc. Diisopropyl ether (110 cc.) is then added, and the product which crystallises is filtered off; a crude product (1.1 g. ) is thus obtained.

All the crude product (3,7 g, ) is dissolved, in methylene chloride (90 cc. ) and. the solution obtained, is passed, through a column of silica gel (37 g. ) .

Elution is first carried out with methylene chloride (6 κ 90 cc.) and then with a mixture (3 x 40 cc. ) of methylene chloride and methanol (50-50 by volume). The last three fractions are concentrated, to dryness and a wet product (3,7 g. ) is obtained which is recrystallised. from the dimethyl ether of glycol (600 cc,). 6-(7-Chloro-1 ,8-naphthyridin-2-yl ) -7-(4-methylpiperazin-l-yl)-carbonyloxy-5-oxo-pyrrolo[3 ,4-b]pyridine (1.85 g. ) , melting at 270°C. , is thus obtained. 7-Hydroxy-6-( 7-chloro-l,8-naphthyrid,in-2-yl )-5-oxo-pyrrolo[3 ,4-b]pyridine can be prepared in the following way: Preparation of 2-(7-hydroxy-l ,8-naphthyrid.in-2-yl)-quinolinimide (31.6 g. ) , m.p, 364°C, , from 2-amino-7-hydroxy-l,8-naphthyrid.ine (24,2 g. ) , quinolinic anhydride (45 g. ) in acetic acid (120 cc, ) and acetic anhydride (45 cc.) at 130-135°C. for 1 hour.

Preparation of 2-( 7-chloro-l,8-naphthyridin-2-yl)quino-linimide (11,4 g. ) , m.p, 278°C. , from 2-(7-hydroxy-l ,8-naphthyridin-2-yl)quinolinimid.e (14g. ) in phosphorus oxychloride (80 cc, ) and dimethylformamide (2 cc, ) for 1 hour at 95-97 °C, Preparation of 6-(7-chloro-l ,8-naphthyridin-2-yl )-7-hyd.roxy-5-oxo-pyrrolo[3 ,4-b]pyridine (7.1 g, ) , m.p. 290°C., from 2-(7-chloro-l,8-naphthyridin-2-yl)quinol-inimide (10.4 g. ) and, potassium borohydride (1.36 g. ) in a mixture (410 cc. ) (50-50 by volume) of methanol and dioxan at 10-15°C. for 30 minutes.

EXAMPLE VSr % 1 Following the procedure of Example Sr but starting with a suspension of 6-(7-methy1-1 ,8-naphthyridin-2-yl)-7-hydroxy-5-oxo-pyrrolo[3 ,4-bjpyridine (2.7 g. ) in anhydrous tetrahydrofuran (27 cc, ) , sodium hydride (50% dispersion in mineral oil) (0,885 g. ) and 1-chloro-carbonyl-4-methylpiperazine (3 g, ) dissolved in anhydrous tetrahydrofuran (30 cc, ) , a reaction mixture is obtained, which is poured into ice-water (210 cc.). The mixture is extracted with methylene chloride (3 x 400 cc,). The combined extracts are dried over potassium carbonate and are concentrated to dryness, A residue weighing 4.9 g, is thus obtained and is triturated with diisopropyl ether (60 cc.). The precipitate which appears is filtered, off. The resulting product (3.6 g. ) is dissolved in methylene chloride (72 cc. ) , and. the solution is passed through a column of silica gel (36 g. ) . Elution is carried out successively with methylene chloride (3 x 500 cc. ) , a mixture (3 x 500 cc. ) of methylene chloride and ethyl acetate (50-50 by volume), pure ethyl acetate (3 x 500 cc.) and a mixture (4 x 500 cc, ) of ethyl acetate and methanol (90-10 by volume). The last four eluates are concentrated to dryness and the residue obtained is reccystallised. from acetonitrile (58 cc.), 6-(7-Methyl-1 ,8-naphthyrid.in-2-yl ) -7-( 4-methylpiperazin-l-yl ) -carbonyloxy-5-oxo-pyrrolo[3 ,4-b]pyridine (1.12 g, ) , melting at 226°C. , is thus obtained. : · ϊ·". 6-(7-MGthyl-l ,3-naphthyrid.in-2-yl )-7-hydroxy-5- oxo-pyrrolo[3,4-b]pyridine can be prepared in the following way: Preparation of 3-N-( 7-methyl-l,8-naphthyrid.in-2-yl)carba-5 moyl-pyridine-2-carboxylic acid by heating 2-amino-7- methyl-1 ,8-naphthyrid.ine (10.6 g. ) and quinolinic anhydride (10,9 g. ) in acetonitrile (200 cc. ) under reflux for 15 minutes. A product (16.1 g. ) , which melts at 220°C. , is thus obtained, 0 Preparation of (7-methyl-l ,8-naphthyridin-2-yl)quinolininid,e by treating the aforesaid acid with acetyl chloride (2.8 cc. ) in acetic acid. (40 cc.). The mixture is kept at 85°C. for 30 minutes and is then cooled and filtered.

A product (5.2 g. ) , melting at 270°C. , is collected, 5 Preparation of 6-(7-methyl-l,8-naphthyrid.in-2-yl )-7- hydroxy-5-oxo-pyrrolo[3 , -b]pyridine (2.7 g.), m.p. 260°C, , from 2-( 7-methyl-l ,8-naphthyridin-2-yl )quinolin- imide (3.7 g, ) and sodium borohydride (0,69 g. ) in methanol (38 cc. ) , 0 EXAMPLE k 4-Methylpiperazine (8 g. ) is added all at once to a suspension of 2-(l,8-naphthyridin-2-yl)-3-phenoxy- carbonyloxy-isoindolin-l-one (5.6 g, ) in acetonitrile (100 cc, ) . The solution obtained is stirred for 6 hours 5 at a temperature of about 20°C. The reaction mixture is poured, into a suspension of ice (100 g. ) in methylene chloride (300 cc.). An 8% aqueous solution of sodium bicarbonate (200 cc. ) is added to the suspension obtained.

The organic phase is decanted and the aqueous phase is ext acted, with methylene chloride (400 cc.). The combined organic phases are dried, over anhydrous potassium carbonate (10 g. ) and concentrated to dryness. The oily residue (8 g. ) is taken up in refluxing diisopropyl ether (100 cc,). On cooling the solution, crystals are deposited and, are filtered, off. 3-(4-Methylpiperazin-1-yl )carbonyloxy-2-(1 , 8-naphthyridin-2-yl ) isoindolin-l-one (2.9 g. ), which melts at 183 °C. , is thus obtained. 2-(1 ,8-Naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one can be prepared in the following way: Preparation of 2-amino-l ,8-naphthyridine , m.p. 141 °C. , according to W.W. Paudler and T.J. Kress, J. Org. Chem. , 33, 1384 (1968).

Preparation of 2-(l,8-naphthyrid.in-2-yl)phthalimide (8.6 g. ) , m.p, 250°C,, by reacting 2-amino-l ,8-naphthyrid.ine (9.9 g. ) with phthalic anhydride (10.2 g. ) in dimethylfor-mamide (75 cc.) at 150°C. for 1 hour 30 minutes. -Preparation of 2-(1 ,8-naphthyridin-2-yl ) -3-hydroxy- isoindolin-l-one (6,7 g. ) , m.p, 228°C. , by reacting potassium borohydride (1.27 g. ) with 2-(l,8-naphthyridin-2-yl)-phthalimide (8.6 g, ) in dioxan (78 cc, ) and a saturated, aqueous solution of disodium phosphate (15.6 cc. ) at 20°C. Preparation of 2-(l,8-naphthyrid.in-2-yl)-3-phenoxycarbonyl-oxy-isoindolin-l-one (5.6 g, ) , m,p, 110-112°C,, by reacting phenyl chloroformate (5.6 g. ) with 2-(l,8-naphthyridin-2-yl)-3-hydroxy-isoind.olin-l-one (3,9 g, ) in anhydrous pyridine (70 cc. ) at a temperature of about 20°C, EXAMPLE 10 Ί Following the procedure of ExampleA* but starting with 2-(7-methyi^l ,8-naphthyrid.in-2-yl )-3-phenoxycarbonyl-oxy-isoindolin-l-one (4.9 g. ) and.4-iiiethylpiperazine (6 g. ) in acetonitrile (40 cc. ) and. stirring the reaction mixture for 24 hours at 25°C , a crude product (4,2 g. ) is obtained. This product is triturated, in diethyl ether (42 cc. ) and then recrystallised. from diisopropyl ether (300 cc. ) , 2-(7-Methyl-l ,8-naphthyrid.in-2-yl )-3-(4-methylpiperazin-l-yl)carbonyloxy-isoindolin-l-one (1.1 g. ) , melting at 190°C. , is thus obtained, 2-( 7-Methyl-l ,8-naphthyridin-2- yl )-3-phenoxycar-bonyloxy-isoindolin-l-one can be prepared in the following way: Preparation of 2-amino-7-methyl-l,8-naphthyrid.ine, m.p. 186 -187 °C, , according to E.V. Brown, J. Org. Chem. , 30, 1607 (1965).

Preparation of 2-(7-methyl-l,8-naphthyridin-2-yl)phthal-imide (5.4 g. ) by reacting 7-methyl-2-amino-l ,8-naphthyridine (3.18 g. ) with phthalic anhydride (2.96 g. ) in diphenyl ether (60 cc. ) for 1 hour at 170 °C.

Preparation of 2-(7-methyl-l,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-l-one (5.8 g. ) , m.p. 208°C. , by reacting potassium borohydride (0,9 g. ) with 2-(7-methyl-1 ,8Hr.aphthyridin-2-yl)phthalimide (6.2 g.) in a mixture (60 cc. ) of methanol and dioxan (50-50 by volume) , Preparation of 2-(7-methyl-l£rhaphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (4.9 g. ) , m.p. 220°C. with decomposition, by reacting phenyl chloroformate (9,2 g. ) with 2-(7-methyl-l ,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-l-one (5.8 g0 ) in anhydrous pyridine (160 cc.) at 5°C„ for 15 minutes and then for 1 1/2 hours at 25°C.

EXAMPLE 13- The procedure of Example H£ is followed but starting with 2-(7-chloro-l ,8-naphthyridin-2-yl )-5-chloro-3-phenoxycarbonyloxy~isoindolin-l-one (1.25 g. ) and 4-methylpiperazine (1„07 g. ) in acetonitrile (33 cc. ) and stirring for 24 hours at a temperature of about 20°C. Prom the reaction mixture, the resulting precipitate is filtered off and washed successively with acetonitrile (6 cc, ) and. diethyl ether (6 cc.).

The product obtained (0,93 g„ ) is dissolved in methylene chloride (35 cc. ) ,and the solution passed through a column of silica gel (10 g, ) . Elution is carried, out with methylene chloride (16 x 20 cc. ) ; the corresponding eluates are discarded, Elution is then carried out with ethyl acetate (5 x 20 ccj; the corresponding eluates are combined and concentrated, under reduced pressure, A crystalline residue (0,9 g, ) is obtained, and. is suspended in ethyl acetate (20 cc). The crystals are filtered off and. dried, to yield 3-(4-methylpiperazin-l-yl)carbonyloxy-5-chloro-2-(7-chloro~l,8-naphthyrid.in-2-yl)isoindolin-l-one (0.75 g. ) melting at 255°C. 2-(7-Chloro-l ,8-naphthyridin-2-yl )-3-phenoxycar-bonyloxy-5-chloro-isoindolin-l-one can be prepared in the following way: Preparation of 4-chlorophthalic anhydride, m.p. 96°C. , according to E.E. Ayling, J. Chem. Soc. , 1929. 253.

Preparation of 2-amino~7-hydroxy-l , 8-naphthyridine , m.p. 300-305°C, , according to S„ Carboni ct al, Ann, Chim.

(Roma), 54, 883 (1964).

Preparation of 2~(7-hydroxy-l ,8-naphthyridin-2-yl)-5-chlorophthalimide (7 g. ) , m.p, 320°C. , by reacting 2-amino-7-hydroxy-l, 8-naphthyridine (9.5 g, ) with 4-chlorophthalic anhydride (21.5 g. ) in acetic acid (450 cc. ) for 1 hour at 116°C.

Preparation of 2-(7-chloro-l , 8-naphthyridin-2-yl) -5-chlorophthalimide (6.4 g. ) , m.p. 280°C. , by reacting phosphorus oxychloride (70 cc. ) with 2-( 7-hydroxy-1 ,8-naphthyridin-2-yl)-5-chlorophthalimide (7 g. ) in the presence of dimethylformamide (0.7 cc.).

By reacting potassium borohydride (0.75 g, ) with 2-(7-chloro-1 , 8-naphthyridin-2~yl ) -5-chlorophthalimide (6.4 g. ) in a mixture (300 cc. ) of dioxan and methanol (50-50 by volume), a mixture (5.2 g. ) of 2-(7-chloro-l,8-naphthyrid.in-2-yl ) -5-chloro-3-hydroxy-isoindolin-l-one and 2-(7-chloro-1,8-naphthyridin-2-yl) -6-chloro-3-hydroxy-isoindolin-l-one is obtained. This mixture is recrystallised firstly from dichloroethane (700 cc. ) and then a second time from the same solvent (315 cc.). A product (1.51 g. ) is thus obtained and. is recrystallised successively from bromoform (38 cc. ) and. then from a mixture (104.5 cc. ) of dichloroethane and ethanol (91-9 by volume ) . 2-( 7-Chloro-1 ,8-naphthyridin-2-yl )-5-chloro-3-hydroxy-isoind.olin-l-one (0,65 g.) is thus obtained.

Preparation of 2-(7-chloro-l,8-naphthyrid.in-2-yl)-5-chloro-3-phenoxycarbonyloxy-isoind.olin-l-one (1.6 g. ) , m.p. 220-230°C. , from 2-( 7-chloro-l ,8-naphthyridin-2-yl)-5-chloro-3-hydroxy-isoindolin-l-one (1 g. ) and phenyl chloroformate (1.36 g. ) in anhydrous pyridine (15 cc.).

I* EXAMPLE A The procedure of Example JLi" is followed but starting with 2-( 5-chloro-l ,8-naphthyrid.in-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (6.7 g. ) , 4-methylpiporazine (15.8 g. ) and dimethylformamide (32 cc. ) and. stirring for 15 minutes at 23°C. The reaction mixture is then diluted by adding diisopropyl ether (320 cc.). The precipitate i3 filtered off, washed, with diisopropyl ether (3 x 30 cc. ) and then dried, A product (3,8 g, ) is obtained, which is recrystallised. from acetonitrile (300 cc.) to yield 2-( 5-chloro-l ,8-naphthyridin-2-yl)-3-(4-methylpipera2in-l-yl)carbonyloxy-isoindolin-l-one (2.9 g. ) melting at 240°C. 2-( 5-Chloro-l ,8-naphthyrid.in-2-yl )-3-phenoxy-carbonyloxy-isoind.olin-1-one can be prepared in the following way: Preparation of 2-amino-5-hydroxy-l ,8-naphthyridine, m.p. 300-305°C. , according to S. Carboni et al, Gazz. Chim.

Ital., 101, 136 (1971).

Preparation of 2-( 5-hydroxy-l ,8-naphthyridin-2-yl )-phthalimide (9.9 g. ) , m.p. 310°C. , by reacting phthaiic anhydride (17.8 g. ) with 2-amino- -hydroxy-l ,8-naphthyridine (9.65 g. ) in acetic acid. (150 cc. ) and acetic anhydride (30 cc.) at 124°C. for 2 hours. · Preparation of 2-(5-chloro-l,8-naphthyridin-2-yl)-phthalimide (6.1 g* ) , m.p. 280°C. , by reacting phosphorus oxychloride (90 cc, ) with 2-( 5-hydroxy-l ,8-naphthyridin-2-yl)phthalimide (9 g, ) in the presence of dimethylformamide (3 cc.) for 1 hour at 107°C.

Preparation of 2-( 5-chloro-l ,8-naphthyrid.in-2-yl)-3-hydroxy-isoindolin-l-one (5.1 g. ) , m.p. 260-262°C., by reacting potassium borohydride (0,88 g, ) with 2-( 5-chloro-l,8-naphthyridin-2-yl)phthaliniide (5.95 g. ) in a mixture (65 cc. ) of methanol and. dioxan (50-50 by volume) at 21°C. for 24 hours.

Preparation of 2-( -chloro-l,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (6.7 g. ) , m.p, 212°C. , by reacting phenyl chloroformate (7,4 g, ) with 2-( 5-chloro-l ,8-naphthyrid.in-2-yl)-3-hydroxy-isoind.olin-1-one (4.9 g, ) in anhydrous pyridine (120 cc, ) between 3° and 6°C, for 18 hours, EXAMPLE Anhydrous piperazine (5,15 g, ) is added to a suspension of 2-(7-chloro-l ,8-naphthyrid.in-2-yl)-3-phenoxycarbonyloxy-isoind.olin-1-one (5.2 g. ) in aceto-nitrile (32 cc.). The reaction mixture is stirred, for 1 hour at a temperature of about 20°C. and. diisopropyl ether (150 cc, ) is then added. The insoluble product is filtered off and. washed, with a mixture (20 cc. ) of acetonitrile and diisopropyl ether (50-50 by volume) ■ind. then with diisopropyl ether (50 cc.). After recrystallisation of the product thus obtained, from a mixture (160 cc.) of acetonitrile and methanol (90-10 by volume), 2-(7-chloro-l,8-naphthyridin-2-yl)-3-(piperazin~l-yl)carbonyloxy-isoindolin-l-one (2.4 g. ) , melting with decomposition at 245°C. , is obtained. 2-( 7-Chloro-l ,8-naphthyrid.in-2-yl )-3-phenoxy-carbonyloxy-isoindolin-l-one can be prepared in the following way: Phenyl chloroformate (126 g, ) is added to a suspension of 2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-l-one (86.5 g.) in pyridine (980 cc, ) , whilst keeping the temperature at about 2 °C. The reaction mixture is then stirred, for 3 hours at a temperature of about 20°C. and is thereafter poured into ice-water (9,000 cc.). The product which crystallises is filtered, off and washed, with water (6 x 500 cc.) and then with acetonitrile (3 x 200 cc. ) . After drying, 2-( 7-chloro-l ,8-naphthyridin-2-yl )-3-phenoxycarbonyloxy-isoindolin-l-one (96.7 g. ) , which melts with decomposition at 235°C., is obtained. 2-( 7-Chloro-l ,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-l-one can be prepared, as described in Example 1.

EXAMPLE -3r6- 13- Following the procedure of Example Ό> but starting with 2-(7-chloro-l ,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (3.45 g. ) and. l-(2-hydroxyethyl)piperazine (5.2 g. ) in acetonitrile (21 cc. ) , 2-( 7-chloro-l ,8-naphthy idin —2-yl )-3-[4-( 2-hydroxyethyl )-piperazin-l-yl]carbonyloxy-isoindolin-l-one (2 g. ) melting at 179-180°C• » is obtained. starting with 2-(7-chloro-l,8-naphthyridin-2-yl) -3-phenoxycarbonyloxy-isoind.olin-l-one (3.45 g. ) and. 1-allylpiperazine (5.05 g, ) in acetonitrile (21 cc, ) , 3-(4-allylpiperazin-l-yl )carbonyloxy-2-( 7-chloro-l ,8-naphthyridin-2-yl)isoind.olin-l-one (1.65 g. ) , melting at 186-187 °C • » is obtained. starting with 2-(7-chloro-l ,8-naphthyrid.in-2-yl )-3-phenoxycarbonyloxy-isoindolin-l-one (2.58 g. ) and 1-ethyl piperazine (3.42 g. ) in acetonitrile (16 cc, ) , 2-(7-chloro-1 ,8-naphthyridin-2-yl )-3-(4-ethylpiperazin-l-yl )-carbonyloxy-isoindolin-l-one (1.4 g, ) , melting at 195°C. , is obtained. starting with 2-(7-chloro-l ,8-napht_hyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (4.32 g. ) and.1-propargylpiperazine (6.2 g, ) in acetonitrile (27 cc. ) , 2-(7-chloro-1 ,8-naphthyridin-2-yl)-3-(4-propargylpip-erazin-l-yl)carbonyloxy-isoind.olin-l-one (2.05 g. ) , melting at 210°C. , is obtained. starting with 2-(7-chloro-l ,8-naphthyridin-2-yl)-3 phenoxycarbonyloxy-isoindolin-l-one (2.47 g. ) and 1-isopropylpiperazine (3.66 g. ) in acetonitrile (15 cc. ) , 2-( 7-chloro-l ,8-naphthyridin-2-yl)-3-(4-isopropyl-piperazin-l-yl)carbonyloxy-isoindolin-l-one (2.25 g. ) , melting at 203-204°C. , is obtained.

EXAMPLE 2£ lc( Followingtb¾ procedure of Example J? but starting with 2-(7-chloro-l,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (9,9 g, ) and 1-phenylpiperazine (18.6 g. ) in acetonitrile (75 cc. ) , 2-( 7-chloro-l,8-naphthyridin-2-yl)-3-(4-phenylpiperazin-1-yl ) carbonyloxy-isoindolin-l-one (1.8 g. ) , melting at 217 °C. , is obtained.

EXAMPLE 2Q Following the procedure of Example J.-5* but starting with 2-(7-chloro-l,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-l-one (5.1 g. ) and. 1-t.-butylpiperazine (5 g. ) in acetonitrile (31 cc. ) , 2-(7-chloro-1 ,8-naphthyridin-2-yl)-3-(4-t. -butylpiperazin-1-yl)carbonyloxy-isoindolin-l-one (3.3 g, ) , melting at 240°C. , is obtained. l-t.-Butylpiperazine can be prepared in the following way: A solution (447 cc. ) of sodium ethoxide in ethanol of concentration 1.34 moles per litre, followed by a solution (1,305 cc, ) of ammonia in ethanol of concentration 4.6 moles per litre, are add.ed. to a suspension of N,N-bis(2-chloroethyl)butylamine hydrochloride (140.7 g. ) in ethanol (750 cc.). The reaction mixture is then heated at a temperature of about 60°C. for 1 hour, whilst keeping the ammonia refluxing by means of a condenser containing solid carbon dioxide. The ammonia is then albwed to dissipate, and the reaction mixture is cooled to a temperature of about 20°C. under a stream of nitrogen. A solution (894 cc. ) of sodium ethoxide in ethanol of concentration 1.34 moles per litre is then added. The sodium chloride which precipitates is filtered off and, then washed with ethanol (150 cc.). The filtrate is concentrated to dryness under reduced, pressure and the residue obtained is taken up in diethyl ether (300 cc.). The insoluble product is filtered, off and. washed with diethyl ether (60 cc. ) . The filtrate is concentrated, to dryness and then distilled under reduced, pressure. l-t.-Butylpiperazine (8.8 g. ) , which boils at 85-86°C. under a pressure of 28 mm.Hg, is thus obtained, ,N-bis( 2-Chloroethyl )butylamine hydrochloride can be prepared, according to the method described by A, Katritsky, J. Chem. Soc. B, 556 (1966).

EXAMPLE £8-21 A 3.16N solution (6,7 cc. ) of sodium methoxide in methanol is added, to a suspension of 1-methylpiperazine-1-oxide dihydrochloride (2,0 g, ) in anhydrous methanol (10 cc,). After stirring for 10 minutes at 25°C. , the suspension is treated with decolourising charcoal (0.1 g. ) and then filtered. The methanolic filtrate is evaporated under reduced pressure (20 mm.Hg) at 40°C, maximum. The oily residue (2,0 g, ) is dissolved, in anhydrous aceto-nitrile (50 cc, ) and. 2-(7-chloro-l ,8-naphthyridin-2-yl)-3- phenoxycarbonyloxy-isoindolin-l-one (2,15 g. ) is added. The reaction mixture is heated for 4 hours at 50°C, and. then stirred, for 48 hours at a temperature of about 25°C. , filtered and. concentrated, under reduced, pressure. The residue (3,8 g, ) is dissolved, in methylene chloride ( 0 cc. ) . The solution is passed, through a column of Merck silica (0,02-0.05) (60 g, ) . Elution is carried out successively with: methylene chloride (50 cc. ) ethyl acetate (50 cc. ) , a mixture (50 cc. ) of ethyl acetate and. methanol (80-20 by volume), a mixture (50 cc.) of ethyl acetate and. methanol (50-50 by volume), and finally with the same mixture of solvents (100 cc.). This last fraction is evaporated, under reduced pressure. The residue obtained. (0,9 g, , m.p, about 200°C, ) is dissolved, in acetonitrile (10 cc, ) and distilled, water (1 cc, ) , near the boiling point. After cooling to 2°C, , the crystals which have appeared are filtered, off, washed with ice-cold acetonitrile (0,5 cc, ) and dried, under reduced pressure (20 mm.Hg). 4-^[2-(7-chloro-l,8-niaphthyridin-2-yl)-3-oxo-isoindolin-l-yl methyl-piperazine-l-oxide dihydrate (0,62 g, ) , melting at about 200°C, (decomposition), is obtained, 1-Methylpiperazine-l-oxid.e dihydrochloride can be prepared, in the following way: Preparation of t,-butyl (4-methylpiperazin-l-yl)carboxylate (as an oil; 15.0 g, ) by reacting t,-butyl azidoformate (12.9 g. ) with 1-methylpiperazine (9.5 g. ) in water (30 cc. ) and. tetrahydrofuran (15 cc. ) , and. gradually adding 5N sodium hydroxide solution (19 cc, ) at a temperature of about 20°C.

Preparation of l-methyl-4-t.-butoxycarbonyl-piperazine-l-oxide hydrochloride (8.7 g. ) , m.p. 233°C. , by reacting 4-nitroperbenzoic acid (34.0 g. ) with t. -butyl (4-methyl-piperazin-l-yl)-carboxylate (24.2 g, ) in anhydrous chloroform (240 cc. ) , at a temperature not exceeding 40°C.

Preparation of 1-methylpiperazine-l-oxide dihydrochloride (5,5 g,), m.p. 205°C. , by reacting anhydrous gaseous hydrogen chloride (2.35 g.) with l-methyl-4-t.-butoxy-carbonyl-piperazine-1-oxide hydrochloride (8.1 g.) in anhydrous ethanol (60 cc. ) , under reflux for 30 minutes.

EXAMPLE ^a . 1-M thylpiperazine (5.75 cc. ) is added to a suspension of 6-(7-chloro-l ,8~naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-6 ,7-dihydro-5H-pyrrolo[3 , -b]-pyrazine (5 g. ) in acetonitrile (31 cc,). The reaction mixture is stirred, for 1 hour at a temperature of about 20°C, and diisopropyl ether (50 cc, ) is then added.. The suspension obtained is then poured, into diisopropyl ether (300 cc, ) and. the insoluble product is filtered off and. washed, with diisopropyl ether (40 cc. ) . After drying, a product (3.6 g. ) , which melts at about 185°C. , is obtained, and is dissolved, in methylene chloride (150 cc.). The resulting solution is filtered, over silica gel (95 g, ) in a column 3.2 cm in diameter. Elution is carried, out successively with methylene chloride (1,000 cc, ) , a mixture ( 500 cc. ) of methylene chloride and ethyl acetate (72-25 by volume), a mixture (300 cc. ) of methylene chloride and ethyl acetate (50-50 by volume) and pure ethyl acetate (1,500 cc.). These eluates are discarded. Elution is then carried out with a mixture (1,750 cc. ) of ethyl acetate and methanol (90-10 by volume) ; the corresponding eluate is concentrated to dryness under reduced pressure. On recrystallising the residue from acetonitrile (38 cc,), 6-(7-chloro-l,8-naphthyridin-2-yl)-5-(4-methyl-piperazin-l-yl )carbonyloxy-7-oxo-6 ,7-dihyd.ro-5H-pyrrolo-[3 ,4-b]pyrazine (1.3 g. ) , melting at 245°C. , is obtained, 6-(7-Chloro-l ,8-naphthyridin-2-yl )-7-oxo-5-phenoxycarbonyloxy-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine can be prepared by adding phenyl chloroformate (9.4 g. ) to a suspension of 6-(7-chloro-l,8-naphthyridin-2~yl)-5-hydroxy-7-oxo-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine (6.3 g. ) in anhydrous pyridine (63 cc. ) , with stirring and. whilst keeping the temperature at about 5°C. When the addition is complete, the reaction mixture is gradually heated to 60°C. and this temperature is maintained, for 1 hour. The reaction mixture is cooled and is then poured into distilled water (350 cc. ) whilst keeping the temperature at about 10°C. The insoluble product is filtered off, and washed successively with water (120 cc. ) , acetonitrile (40 cc. ) and diisopropyl ether (40 cc.). After drying, 6-(7-chloro-l,8-naphthyridin-2-yl ) -7-oxo-5-phenoxycarbonyloxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (7.2 g. ) , melting at 270°C. , is obtained. 6-(7-Chloro~l , 8-naphthyridin-2-yl ) -5-hydroxy-7-oxo-6 ,7-dihydxo-5H-pyrrolo[3 ,4-b]pyrazine can be prepared, by adding potassium borohydride (0.97 g. ) to a suspension of 6-(7-chloro-l ,8-naphthyrid.in-2-yl )-5j7-dioxo-6,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine (7.45 g. ) in a mixture (288 cc. ) of dioxan and. methanol (50-50 by volume), with stirring and whilst keeping the temperature at about 3°C, After stirring for 2 hours at a temperature of about 3°C., the insoluble product is filtered, off and. washed successively with a mixture (24 cc. ) of dioxan and methanol (50-50 by volume), water (24 cc. ) , a mixture (24 cc. ) of dioxan and. methanol (50-50 by volume) and diisopropyl ether (12 cc.). After drying, 6-(7-chloro-l,8-naphthy-ridin-2-yl )-5-hydroxy-7-oxo-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]-pyrazine (5.3 g, ), melting with decomposition at 270°C. , is obtained. 6-(7-Chloro-l ,8-naphthyridin-2-yl )-5, 7-d.ioxo-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine can be prepared by adding 6-(7-hydroxy-l ,8-naphthyridin-2-yl )-5,7-dioxo-6 ,7-dihyd.ro-5H-pyrrolo[3 ,4-b]pyrazine (32 g. ) gradually, and. at a temperature of about 1 °C, , to a solution of dimethylformamide (3.8 cc, ) in phosphorus oxychloride (128 cc.). When the addition is complete, the reaction mixture is heated under reflux for half an hour and. is then cooled, and, poured in small portions into crushed, ice (1.3 kg,). The insoluble product is filtered off and. then washed with water until the wash liquors are at pH 5, After drying, 6-(7-chloro-l ,8-naphthyridin-2-yl )-5,7-dioxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine (21,3 g. ) , melting with decomposition at about 340°C. , is obtained. 6-( 7-Hydroxy-l , 8-naphthyridin-2-yl )- , 7-dioxo-6,7-d.ihyd,ro-5H-pyrrolo[3,4-b]pyrazine can be prepared by heating under reflux a suspension of 2-amino-7-hydroxy-! ,8-naphthyridine (22.4 g. ) and. pyrazine-2 ,3-dicarboxylic acid anhydride (23 g. ) in acetic acid. (280 cc.). After refluxing for 1 hour,the reaction mixture is cooled, to a temperature of about 30°Cf and acetic anhydride (280 cc, ) is added. The reaction mixture is again heated, under reflux for 10 minutes and. is then cooled to a temperature of about 20°C. The insoluble product is filtered, off and then washed with acetic acid (40 cc. ) and diisopropyl ether (200 cc.). After drying, 6-( 7-hydroxy-l ,8-naphthyridin-2-yl )-5, 7-dioxo-6,7-d.ihyd.ro-5H-pyrrolo[3 ,4-b]-pyrazine (32.1 g, ) , melting at 373°C., is obtained. 2-Amino-7-hydroxy-l ,8-naphthyridine can be prepared, according to the method, described, by S, Carboni et al, Gazz. Chim. Ital. , 9J5, 1498 (1965).

EXAMPLE -2 2 1-Methylpiperazine (8.15 g.) is added to a suspension of 6-(7-methoxy-l,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]-pyrazine (5 g. ) in dimethylformamid.e (50 cc.). The reaction mixture is stirred, for 7 minutes at a temperature of about 17 °C. and, diisopropyl ether (250 cc. ) is then added. The insoluble product is filtered, off, washed, with diisopropyl ether (30 cc, ) and. dried. The product obtained, is dissolved in methylene chloride (130 cc. ) , and the solution chromatographed. on silica gel (90 g, ) in a column 2,4 cm, in diameter, Elution is carried out successively with a mixture (130 cc. ) of methylene chloride and ethyl acetate (75-25 by volume), a mixture (130 cc, ) of methylene chloride and. ethyl acetate ( 50-50 by volume ) , a mixture ( 130 cc. ) of methylene chloride and. ethyl acetate (25-75 by volume), pure ethyl acetate ( 780 cc. ) , a mixture ( 390 cc. ) of ethyl acetate and. methanol ( 98-2 by volume), a mixture ( 390 cc. ) of ethyl acetate and methanol ( 96-4 by volume) and. a mixture ( 650 cc. ) of ethyl acetate and. methanol ( 90-10 by volume). These eluates are discarded..

Elution is then carried, out with a mixture ( 1 ,300 cc. ) of ethyl acetate and, methanol ( 90-10 by volume). The corresponding eluate is concentrated, to dryness under reduced pressure. After recrystallising the residue from acetonitrile ( 62 cc. ) , 6- ( 7-methoxy-l , 8-naphthyridin-2-yl ) -5- ( 4-methylpiperazin-l-yl ) carbonyloxy-7-oxo-6 , 7-dihyd.ro- 5H-pyrrolo[ 3 ,4-b]pyrazine ( 1. 8 g. ) , melting at 237 °C , is obtained. 6- ( 7-Methoxy-l , 8-naphthyridin-2-yl ) -7-oxo-5-phenoxycarbonyloxy-r6 , 7-dihydro-5H-pyrrolo[ 3 ,4-b]pyrazine , m.p. 2 5 °C. , can be prepared by reacting phenyl chloro-formate with 5-hydroxy-6- ( 7-methoxy-l , 8-naphthyridin-2-yl ) -7-oxo-6 , 7-d,ihydro-5H-pyrrolo[3 ,4~b]pyrazine in anhydrous pyridine at a temperature of about 20°C. 5-Hydroxy-6- ( 7-methoxy-l , 8-naphthyridin-2-yl ) -7-oxo-6 , 7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine, m.p. 255°C. , can be prepared by reacting potassium borohydride with 6- ( 7-methoxy-1 , 8-naphthyridin-2-y 1 ) -5 , 7-dioxo-6 , 7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine in a mixture of dioxan and water ( 98-2 by volume) at a temperature of about 20°C. 6- ( 7-Methoxy-l , 8-naphthyridin- 2-yl ) -5, 7-dioxo-6 , 7-dihydro-5H-pyrrolo[ 3 ,4-b]pyrazine, m.p. 296°C. ,can be prepared by reacting pyrazine-2,3-dicarboxylic acid anhydride with 2-amino-7-me hoxy-l ,8-naphthyridine in acetic acid, in the presence of acetic anhydride at the reflux temperature.

EXAMPLE ¾- 23· Following the procedure of Example ^ but starting with 6-(5,7-dimethyl-l,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]-pyrazine (2.8 g. ) and. 1-methylpiperazine (7 cc. ) in dimethylformamide (7 cc. ) , 6-(5,7-d.imethyl-l,8-naphthyridin-2-yl )-5-(4-methylpiperazin-l-yl )carbonyloxy-7-oxo-6,7-d,ihydro-5H-pyrrolo[3 ,4-b]pyrazine (0.7 g. ) , melting at 255°C. , is obtained. 6-( 5,7-Dimethyl-l ,8-naphthyrid.in-2-yl)-7-oxo-5-phenOxycarbonyloxy-6 ,7-dihydro-5H-pyrrolo[3 f -b]-pyrazine, m.p* 220°C. , can be prepared by reacting phenyl chloroformate with 6-( 5,7-dimethyl-1 ,8-naphthyridin-2-yl )-5-hydroxy-7-oxo-6 ,7-dihyd.ro-5H-pyrrolo[3 ,4-bjpyrazine in anhydrous pyridine at a temperature of about 2°C. 6-( 5, -Dimethyl-l ,8-naphthyrid.in-2-yl)-5-hydroxy-7-oxo-6 ,7-dihyd.ro-5H-pyrrolo[3 ,4-b]pyrazine , m.p. 265°C, with decomposition, can be prepared by reacting potassium borohydride with 6-( 5,7-dimethyl-1,8-naphthyridin-2-yl)-5,7-dioxo-6,7-dihyd,ro-5H-pyrrolo-[3,4-b]pyrazine in a mixture of dioxan and water (99-1 by volume) at a temperature of about 20°C. 6-( 5,7-Dimethyl-l ,8-naphthyridin-2-yl)-5,7-dioxo-6 ,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine can. be prepared, by heating under reflux a suspension of 3-(5,7- dimethy1-1 ,8-naphthyridin-2-yl )carbamoyl-pyrazine-2-carboxylic acid (12 g. ) in thionyl chloride (120 cc. ) .

When the evolution of gas has ceased, the reaction mixture is cooled to a temperature of about 5°C. and diisopropyl ether (200 cc. ) i3 then added. The insoluble product is filtered, off and washed, with diisopropyl ether (60 cc. ) . After drying, 6-(5,7-d.imethyl-l,8-naphthyridin-2-yl)-5,7-dioxo-6,7-d.ihydro-5H-pyrrolo[3 ,4-b]pyrazine (11.5 g. ) , melting at about 250°C. with decomposition, is obtained. 3-( 5,7-Dimethyl-1 ,8-naphthyrid.in-2-yl)carbamoyl-pyrazine-2-carboxylic acid, m.p. 255°C. with decomposition, can be prepared, by reacting pyrazine-2 ,3-dicarboxylic acid, anhydride with 2-amino-5,7-dimethyl-l,8-naphthyrid.ine in anhydrous dimethylformamide at a temperature of about 100°C. 2-i;-mino-5,7-d.imethyl-l,8-naphthyrid.ine, which melts at 225-226°C. , can be prepared, according to the method, of J, Bernstein et al, J, Amer, Chem. Soc. , 69, 1151 (1947).

EXAMPLE -2? A solution of 3-chloroperbenzoic acid. (1.77 g. ) in chloroform (60 cc.) is added to a solution of 6-(7-chloro-1 ,8-naphthyridin-2-yl )-5-(4-methylpiperazin-l-yl )-carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3 ,4-b]pyrazine (2.7 g, ) in chloroform (45 cc. ). The reaction mixture is stirred for 1 hour at a temperature of about 20°C, and. a saturated, aqueous solution of sodium bicarbonate (40 cc. ) and. methylene chloride (50 cc. ) are then added. The aqueous layer is decanted, and then washed, twice with methylene chloride (50 cc ) , The organic layers are combined, washod twice v/ith water (30 cc, ), dried ove anhydrous sodium, sulphate and chen ' concentrated to dryness under reduced pressure. The residue is dissolved in methylene chloride (50 ce.) and -the resulting solution is filtered through silica gel. (25 g. ) in a column 1.8 cm. in diameter. Elutio is carried ou successively wit a rd-xtur,e (620. cc. ) o methylene*,chloride,,and. methanol; (94-6': by volume) and a mixture (190 cc. ) of methylene chloride ' and. methanol (90-10 by volume) . These eluates are discarded, Elution is then carried out successively with a mixture (140 cc.) of methylene chloride and methanol (90-10 by volume), a mixture (330 cc. ) of methylene chloride and methanol (85-15 by volume) and a mixture (330 cc.) of methylene chloride and methanol (80-20 by volume) ; the corresponding eluates are combined and concentrated to dryness under reduced pressure. After recrystallising the residue; thus obtained from methanol. (20 cc, ) , :·. 4- 5-[6-(7-chloro-l ,S-naphthyridin-2-yl)-7~oxo~6 ,7-dihydro~5H-pyrrolo [3 ,4-b]pyrazinyl]oxycarbonyi} -1-methylpiperazine-l-oxide (0.6 g. ) , .melting with. , decomposition at 245°C. , is obtained.

EXAMPLE 2& .

Triethylamine (3-4 cc. eouivalent to 2.44 g.), - . V~C. followed by pyridine (15 cc.) are added, to a suspension o 2-(7-chloro-l ,8-naphthyridin-2-yl)-5-fluoro-3-hydroxy-l-isoindolinone (2 g. ) and 4-cJaiorocarbonyl-l~methyl-!pipera- .. zine hydrochloride (3.6 g. ) in methylene chloride (30 cc. ) . The suspension obtained is heated to the reflux temperature (55°C) for 1 hour and further 4-chlorocarbonyl-l-methyl-piperazine (3-6 g.) and: triethylamine (3-4 cc.) are then added The mixture is further heated to the reflux temperature for 5 minutes, " After cooling, methylene chloride (30 cc. ) and water (60 cc. ) are added. . After phase separation, the . aauecus layer is extracted with methylene chloride (60 cc). The organic extracts are dried over anhydrous sodium sul-. -phate. After filtration and concentration, the residue is triturated in water (30 cc). The precipitate is: filtered, off and dried in air. The crude product is recrystallised from acetonitriie (64 cc. ) . The product is filtered off and then washed with isopropyl ether- (60 cc . ). This gives 2-(7-chloro-l,8-naphthyridin-2-.yl)-5-fluoro-3-(4-methyl-piperazinyl)-carboriyloxv-l->isoindolinone (0.8 g ) melting at 247-248°C. • ·' .2-(7-ch¼oro l>,8-nap^ · ··. hydroxy-l-isoindolinpne can be prepared in the following . manner: 2^iacetoxymethylr-4-fluor.o-N-(7-chloro--l ,8-naphthyri-din-2-yl)~benz mide ' (6 g. ) are added to a solution of : sulphuric acid (d = 1.83) (12 cc. ) i water (48 cc. ) . ¼The ' . . .' .. " ■ mixture iz heated to the reflux, temperature for 15 minutes;. After cooling, the precipitate is filtered off , •washed with . water (60 cc.) and then dried. to constan weight. This gives 2-(7-chloro-l ,8-naphthyridin-2-yl)-5-fluoro-3-hydroxy- 1-isoindolinone (2 g.) melting at 245-250°C. 2-Diacetoxymethyl-4-fluoro-N-(7-chloro-l,8--naphthyridin-2-yl)-benzamide can be prepared in the , following manner: Sulphuric acid, (d = 1.83) (l6.4 cc. ) is added to a suspension of 4-fluoro-2-irethyl-N-C7-chloro-l ,8-naphthyridin- 2-yl)-benzamide (10.3 g. ) in acetic anhydride (120 cc. ) cooled externally by means of an ice bath, the temperature being maintained below 10°C. Afte cooling to 2°C by means of a mixture of ethanol and solid carbon dioxide , . chromic anhydride (8.9 g.) is added whilst maintaining the temperature at 2°C. The reaction mixture is stirred for. a further 1.hour 30 minutes at 2°C and is then poured into iced water (700 g. ) . . The precipitate formed is filtered off and. then, washed with iced: water' (450 cc). After drying, 2— · diacetoxymethyl-4-fluoro-N-(7-chloro-l ,8-naphthyridin.-2-yl)-benzainide (6. g.. ) meltin at about 182-185°C is obtained;. .4-Fluoro-2-methyl- -(7-chloro-l ,8-naphthyridin-2-yl)-benzamide can. be prepared in. the^ following, manner: a.. solution of 2-amirto-7-chloro-l,8-naphthyridine (7.5 g.) i acetonitrile (72 cc.) and pyridine (18 cc.) is added over the course of 2 minutes,, at a temperature of 24-36°C, to 4-fluoro-2-methyl-benzoyl chloride (7.2 g. ). . The precipitate formed"' durin the reaction is. filtered, off ,; . washed with. acetonitrile (15 cc.) and then, recrystallised from aceto- nitrile (280 cc). . ^ The mother liquors from, the reaction are concen—· ' trated. After dissolving in methylene chloride (500 cc.) and washing with an 8% strength sodium bicarbonate solution (100 cc. ), a second crop is obtained, which is recrystallised from, acetonitrile (80 cc). This gives 4-fluoro-2-methyl- N-(7-chloro-l , 8-naphthyridin-2~yl)-benzamide (a total of - 9.5 g. ) melting at 145-150°CV 4-Fluoro-2-methyl-benzcyl chloride is obtained by reaction of thipnyl chloride at the reflux temperature wit —fluorp-2-methyl-benzoic acid, which can in turn be prepared according to BUU-ΗΟΪ and XUONG, J. Chem. Soc. p. 386 (1953) . · . . . . ' · » ■ ·■ · EXAMPLE -3-9 ~7 On following the procedure of Example -26-, but starting from 2-(7-chloro-l, 8-haphthyridin-2-yl) -3-hydroxy- ' 5-nitro-l-isoindolinone (5 g. ) and 4-chlorocarbonyi-l- me hyl-piperazine hydrochloride (12.2 g. ) in methylene · chloride (460 cc ) in the presence, of triethylamine. ( 9.5 cc ) and pyridine (46 cc), a crude product (5 - 1 g.) is . obtained, which is chromatographed on a column containing '.silica (0.2 - 0.05' mm). (100 g:. ) . The column is eluted wit chloroform, fractions of 100 cc being collected.

Fractions 1 to 7 (700 cc.) are discarded and fractions 8 to 26 (1 , 900 cc. ) after concentration yield a product (1.8 g. ) which is recrystallised from a mixture of ethanol and. acetonitrile (l/ by volume). This, gives 2- . · collected.

After concentrating the. various fractions, the product obtained is recrystallised from a mixture of etha ol and acetonitrile (50-50 by volume) (27 cc.)- This gives 2-(7-chloro-l ,8-naphthyridin-2-yl)-5-∑nethoxy-3-(4-methyl-piperazinyl)-earbonyloxy-l-isoindblinone (l g. ) melting at 2o6°c.. '■: '·■:,■■. .' A 2-(7-Chloro-l ,8-naphthyridin-2-yl)-3-hydroxy-5-methoxy-l-isoindolinone can be prepared in the following ' .■■ manner; · ·· ..' A suspension of 4-methoxy-2rmethyl-N-(7-chlbro-i,8-naphthyridin-2-yl)-benzamide (3.3 g.), N-bromosuccin-iinide (4.45 g. ).and azo-bis-isobutyronitrile (0.1 g.) in carbon tetrachloride (350 cc.) is heated to the reflux temperature for 20 hours. . After cooling, the precipitate is filtered off. The filtrate is concentrated to dryness. The. residue from the concentration is taken up in jnethylene chloride (24 cc. ) . The methylene chlorid solution is filtered. The precipitate which has been isolated. s suspended in an.8% strength sodium bicarbonate solution (10 cc.) It is. stirred for 30 minutes. The precipitate is filtered off and then washed with water (6 cc). This gives 2-(7-chlor.o-l,8-naphthyridin -2-yl)-.3-hydrbxy^5-ineth0xy-l-iso~- ' indolinone (0.4 g. ) melting at 215-220°C. 4-Methoxy-2-methyl~N-(7-chloro-l,8-.naphthyridin-2- :: yl.)-benzamide can be prepared in the following manner: . 4-Methoxyr2-methyl-benzoyl chloride. (33 g.) in pyridine. (33.0 -cc. ) are added:, at a temperature of about 20°C, 4481 to 2-amino-7-chloro-l,8-naphthyridine (32 g. ) .. · The reac— tion mixture is stirred for a further 3 hours and is then poured into water (2,700 cc. ) . /'· The precipitate formed is filtered off and washed with water (300 cc.) and: then with ethanol (200 cc). After recrystallisation from ethanol (l ,000 cc..) , 4-methoxy-2-methyl-N-(7-chloro-l ,8-naphthyridin-2-yl)-benzaiiiide (25.5 gV) melting at 190°C are obtained. ' 4-Methoxy-2-methyl-benzoyl chloride (boiling; point/ 0.3 mm Hg = 88°C) can be prepared by reaction of thionyl chloride at the reflux .temperature with 4-methoxy-2-methyl-benzoic acid. .· · ■ 4—Methoxy-2-methyl-benzoic acid can be prepared according to D. PELTIER, Bull. Soc. Chim. Bretagne,. 31, (1956) [Chem. Abstr. 52, 9017 (1958)].

- - EXAMPLE ll On following the procedure of Example .28- but starting from 2-( -chloro-l,8-naphthyridin-"2-yl)~3-hydroxy-6-nitro~ , 1-isoindolinone (7.12 g. ) and 4-chlarocarbonyl-l-methyl-piperazine hydrochloride (15.9 g. ) in methylene chloride . (250 cc), pyridine (100 cc) and triethylamine (12.4 cc. ) , a crude produc (3.6 g. ) is obtained., whic is recrystallised from acetonitrile (25. cc). This gives 2-(7-chloro-l ,8-; naphthyridin--2-yl.)-3-(4-inethylr-piperazinyl,)-carbbnyl.oxy-6-.-7 nitro-l-isoindolinone (l.l g.), melting at 244°G. . 2-(7-Chloro-l ,8-naphthyridin-2-yl)-3-hydroxy-6-nitro-1-isoindolinone can. be prepared i the following manner r 2-(7-Chloro-l ,8-naphthyridin-2-yl)-3-hydroxy-l-isoindolinone (62.4 g. ) is dissolved in sulphuric acid (d =. ethyl acetate (9/1 by volume), and fractions of 50 cc being collected. Fractions 1 to 21 (1,050 cc. ) yield -isoindoli- none starting material (0.9 g.) and. fractions 22 to 25 (200 cc.) yield a product (0.3 g.) which is recrystallised from acetonitrile (6 cc). This- gives.4-chloro-2-(7-chloro-l,8- naphthyridin-2-yl)-3-(4-methyl-piperazinyl)-carbonyloxy-l- isoindolinone (0.2 g.), melting at 191-193°C ... 4-Chloro-2-(7-chloro-l ,8-naphthyridin-2-yl)-3- hydroxy-l-isolndolinone can be. prepared in the following manner:-; ·■ . ' '.''.' Potassium borohydride (3 g. ) is added to 4-chloro- N-(7-chloro~l ,8-naphthyridin-2-yl)-phthalimide (25. g. ) in ' dioxane (500 cc.) and methanol (500 cc). The mixture is stirred for hours at a temperature of about 20QC and water (500 cc. ) is then added. The precipitate is filtered off and washed with water (100 cc.) and the with a mixture (200 cc.) of equal parts of methanol and dioxane. This gives, a crude product (20 g. ) which is chromatographed o silica (O.05 - 0.2 mm) (6 kg.) as indicated below, the eluate being collected in fractions of 5,000 cc. Elution. is carried out first with methylene chloride (10 ,000 cc . ) and then with a mixture of methylene chloride and ethyl acetate (5/ by volume) (40,000 cc ). This eluat , a ter concentration, yields- 4-chloro-2-(7-chloro-l ,8-naphthy idin-2^yl)- . 3-hydroxy-l-isoindolinone (6 g.) melting at 270°C. Thereafter elution is carried out with the same mixture of methylene chloride and ethyl acetate (10,000 cc). This eluate, after concentration, 'gives a mixture (1.6 g. ) of the- isomers 4-chloro-2-(7-chloro-l.,8-naphthyridin-2-yl)-3- . hydroxy-l-isoindolin ne and 7-chloro-2-(7-chloro-l ,8- H.. naphthyridin-2-yl)-3-rhydroxy-l-isoindolinone. Finally, eluticn is carried out again with the same mixture of methylene chloride and ethyl, acetate (20,000 cc.). This, eluate , after concentration, yields 7-chloro-2-(7-chloro-l ,8-naphthyridin-2-yl)-3-hydroxy-l-isoindolinone ' (3.1 g. ) melting at. a temperature above 280°C. 4-Chloro-N-;(7-chloro-l ,8-naphthyridin-2-yl)-phthalimide can be obtained in the following manner: * 3-Chlorophthalic anhydride (15 g. ) and N-hydroxy-succinimide (11.8 g. ) in dimethylformamide (375 cc.) are heated for 18 hours at 75-800C, 2-amino-7-chloro-l,8-: naphthyridine (14.7 g. ) and N^'-dicyclohexylcarbodiimide (34 g.) are then added and the mixture is heated for a further 3 hours at 75-80°C. After cooling, the precipitate is filtered off and washed with dimethylformamide (45 cc.) and ethanol (45 cc). The precipitate obtained is. exhaustively extracted with boiling ethanol (750 cc,).

The product insoluble in ethanol is filtered off, thus givin 4-chloro-N-( -chloro-l,8-naphthyridih-2-yl)--phthalimide; ....·.' (25.2 g. )- melting at a temperature above 280°C. 3-Chlorophthalic anhydride can be- prepared accordin to NEUMAN.et al. , J. Amer. Chem. Soc. , 76, 5004 (1950).

' EXAMPLE'.,3β3\ On . followin the procedure o . Example.2& but, starting: from 7-chloro-2-(7-chloro-l ,8-naphthyridin-2-yl)-3-hydrcxy-1-isoindolinone (3 g. ) , 4-chlorocarbonyl-l-methyl-piper.a2i e. .

After cooling, the reaction mixture is poured onto ice (450 g.). The precipitate, which forms is filtered off and washed with water (75 cc), then with an. B strength, bicarbonate solution (60 cc.) and then again with water (7 cc. ). This gives 6-brom -2-(7-chloro-l,8--naphthyridin--2-.yl)-3~; hydroxy-l-isoindolinorie (6.7 g.) melting above 260°C, with - decomposition. 6-Amino-2-(7-chloro-l ,8-naphthyridin-2-yl)-3- hydroxy-l-isoindolinone can be prepared in the following manner: 2-(7-C loro-l,8-naphthyridin-2-yl)-3-hydroxy-6-^ nitro-l-isoindolinone (14.2 g. ) in methanol (400 cc.) are hydrogenated under a pressure of 10 bars in the presence of · Raney nickel (1.5 g.). The reaction mixture is filtered. The catalyst is dissolved in hydrochloric acid (d ..= 1.19) · (20 cc). The residual, cake . is dissolved in dimethylform- amide (600 cc.) at about 80°C-. The solution is decolorised by means of animal charcoal (2 g. ) and then filtered hot.

Water (1 litre) is added to the filtrate. The precipitate formed is filtered of and then washed with water (50 cc.).. are added successively to a suspension of 6-chloro-2-(7- chloro-1 ,8--naphthyridin-2-.yl)-3-hydroxy-l-is0indolinone (7 g.) and l-chlorocarbonyl-4-methyl-piperazine hydrochloride (20 g.). The. reaction mixture is heated for 4 hours to the reflux. temperature. After cooling, methylene chloride (50 cc.) and water (100 cc.) are added. The organic phase is isolated by decantation. and then washed, by decantation, successively with a normal aqueous sodium hydroxide solution (100 cc. ) and then with water (100 cc.).. . The solution obtained is dried over. magnesium sulphate. nd then concentrated to dryness under reduced pressure. The residue obtained is treated with ethyl acetate (50 cc.) and the insoluble product is filtered off. Recrystallisation of the latter from dimethylformamide gives 6-chloro-2-(7- . chloro-1 ,8-naphthyridin-2~yl)-3-( -methyl-l-piperazinyl)-carbonyloxy-l-isoindolinone (6.1 g.) melting at 256°C,. with decomposition. 6-Chloro-2-(7-chloro-l,8-naphthyridin-2-yl)-3-hydroxy-1-isoindolinqne can be prepared in the following manner: A solution of silver nitrate (12.1 g.) in wate (50 cc.) is added to a solution, of 7-chloro-2-(5-chloro-2-dichloromethyl-benzoylamino)--l,8-naphthyridine (9-5 g.) in dimethylformamide (300 cc.) heated to a temperature of about 110°C. The reaction mixture is further heated to a temperature of about 110°C for 20 minutes and the suspension obtained, is filtered hot- The filtrate obtained is poured into water (500 cc.) and the product which precipitates is filtered off. Recrystallisatio from dimethylformamide gives 6-chioro-2-(7-chloro-l ,8-naphthyrid'in-2-yl)-3-hydroxy-1-isoindolinone (5 g. ) melting at 306°C. 7-Chloro-2-( -chlor0~2-dichloromethyl~benzoylamino) followed, "by a mixture of methylene- chloride and methanol. - (99 : 1 by volume) (1,250 cc). These eluates are combined and evaporated to dryness under reduced pressure. .

Recrystallisation of the residue thus obtained, from, aceto-nitrile (50 cc.) gives 2-(7-chloro-ltS-naphthyTidin--2-yl)-« 3-[¾-(2-methyl-prop-2-en-l-yl)-l-piperazinylj-carbonyloxy-1-isoindolinone (1.9 g. ) melting at 180°C. l-(2-Methyl-prop-2-en-l-yl)-piperazine can be pre— pared in the following manner: Concentrated hydrochloric acid (d =.1.19) (230 cc. ) : is added to a solution of anhydrous pipera2ins (233 g.) in absolute ethanol (600 cc.) whilst maintaining the temperature at about 30°C. The reaction mixture is heated to the reflux temperature and methallyl chloride (124.5 g.) is then added to the solution obtained. The reaction mixture is then heated to the reflux temperature for 8 hours. After cooling, the insoluble product is filtered off and washed with ethanol (3 times 200 cc.-). The filtrate thus obtained: is concentrated to dryness under reduced pressure. The residue is taken up in distilled water (200 cc. ) and. sodium hydroxide, solution (d = 1.33) (200 cc.) and the solution obtained is- extracted by decanting with chloroform (3 times 300 cc. ) .

The aqueous layer is then saturated with .potassium carbonate and again extracted by decanting with chloroform (twice 200 cc.)". The chloroform phases are combined, dried over magnesium sulphate and then concentrated to dryness under, reduced pressure. Fractional distillation under reduced pressure of the residue thus obtained gives l-(.2-methyl-prop.-2 en-l-r-yl)-piperazine (39·5 g.) (boiling point/0.3 mm Hg = 45°C).

. ' · . EXAMPLE > 3g" . \'·- · Following the procedure of Example ·¾£ but starting from 2-(7-chloro-l ,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-1-isoindolinone (4.32 g.) and l-(but-2-en-l-yl)-piperazine (7 g.) in acetonitrile (25 cc), 3-[4-(but-2-cn-l^yl)-1-piperazinyl]-carbonyloxy-2-(7-chloro-l ,8-naphthyridin-2-yl) 1-isoindolinone (1.95 g. ) melting at 190°C is obtained. l-(But-2-en-l-yl)-piperazine can be prepared as described in Example 36 but starting from anhydrous piperazine (258.4 g.), absolute ethanol (700 cc), concentrated hydrochloric acid (d = 1.19) (250 cc.) and crotyl bromide (202 g.). This gives l-(but-2-en-l-yl)-piperazine (110 g. ) (boiling point/5.5 mm Hg = 75-76°C).

' E AMPLE 3β¾<» Following the procedure of Example but starting from: 2-(7-chl.oro-l ,8-naphthyTidin-2-yl)-3-phenoxycarbonyloxy-l-isoindolinone (4. 2 g. ) and 1-(but-3-en-l-yl)-piperazine . (7 g.) in acetonitrile (2 cc), 3-[4-(but-3-en-l-yl)-l-piperazinyl]-carbonyloxy-2-(7-chloro-l ,8-naphthyridin-2-yl)-1-isoindolinone (1.4 g.) melting at l42°C is obtained. l-(But-3-en-l-yl)-piperazine can be prepared: as in Example 36 but starting from anhydrous piperazine (12.7 g. ) , absolute ethanol (70 cc), concentrated hydrochloric acid (d = 1.19) (12.8 cc) and 4-broiDO-but-l-ene (10 g.). 1-(But-3-en-l-yl)-piperazine (8.5 g. ) is obtained, and can be utilised in the- crude form.

EXAMPLE _#.T7 · 4-Chlorocarbonyl-l-methyl-piperazine hydrochloride (9.8 g.) followed "by pyridine (4l cc.) are added to a suspension of 2-(7-fluoro-l,8-naphthyridin-2-yl)-3-hydroxy-l-isoindolinone (4.89 g.) in triethylamine (9. cc.) and methylene chloride (100 cc.) at a temperature of between 21 and 24°C. The mixture is heated to. the reflux temperature (43°C) for 2 hours and is then liydrolysed with iced, water (300 g.). The organic layer is decanted and the aqueous layer is extracted with methylene, chloride (600 cc). The combined organic layers are washed with water (100 cc.) and then dried over anhydrous potassium carbonate (6 g.).

After filtration and concentration, the residue is chromato-graphed on silica (120 g.) (0.05 - 0.2 mm). Elution is carried out using the following solvents: chloroform ...... 100 cc. ethyl acetate ...... 300 cc. ethyl acetate/methanol (90:10 by volume) ...... 400 cc. 100 cc. fractions of eluate being collected.

After evaporation of the last fractions (5 to- 8), a product ( g.) is. obtained which is recrystallised from benzene (22 cc.). This gives 2-(7-fluoro-l ,8-naphthyΓidin-2-yl)-3~(4-ffle.thyl--piperaz.inyl)--carbonyloxy-·l--iso ndolinone (1.75 g.) melting at 198-200°C. .2-( -Fluoro-l ,8-naphthyridin-2-yl)-3-hydroxy-l-v is.oindolinone can be prepared in the following manner: Sodium borohydride (1.58 g.) is added to a suspension of N-(7-flucro-l,8-naphthyridin-2-yl)-phthali ide (11, 4σ, ) in a ture of dioxane and methanol (50-50 by volume) at a temperai-ture of 3- °C. After 10 minutes' reaction, the reaction mixture is poured into iced water. (500 g. )., The precipitate is filtered off, washed with water (120 cc), dried and then recrystallised from toluene .(280 cc. ). This gives- 2-(7-fluoro-1 ,8-naphthyridin-2-yl)-3-hydroxy-l-isoindolinone (4.6 g.) melting at 258°C.

N-(7-Fluoro-l,8-naphthyridin-2-yl)-phthalimide ca be prepared in the following manner: N-(7-Chloro-l,8-naphthyridin-2-yl)-phthalimide (15.45 g.) and silver fluoride (6.35 g.) in nitrobenzene (150 cc.) are heated to the reflux, temperature for 6 hours. After cooling, the reaction mixture is diluted by adding isopropyl ether (550 cc). The precipitate is filtered off and washed with isopropyl ether (200 cc.) and then with water (200 cc.). After drying, the dried precipitate is taken up in chloroform (2,500 cc. ) and the chloroform solution is decolorised with animal, charcoal (2 g.). Afte filtration and, concentration, N-(7-fiuoro~l,S-naphthyridin-2-yl)-phthalimide (11.4 g. ) melting: at 245°C. s obtained.

The present invention includes within its scope pharrnaceuticaJL compositions cornprising, as active ingredient, at least one of the naphthyridine derivatives- of general fonrrula I, 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 pharmaceuti-cally-acceptable emulsions, solutions, suspensions, syrups and 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, 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 bacteria-retaining 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 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, consititute 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 Examples illustrate pharmaceutical compositions according to the invention.

EXAMPLE J8 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-meth l-piperazin-l-yl)carbonyloxy-isoindolin-l~one 0.025 g. starch 0.090 g. precipitated, silica 0.030 g. magnesium stearate 0.005 g.

EXAMPLE ^9 Tablets containing 25 mg. of active product and. having the following composition are prepared, in accordance with the usual technique: 6-(7-chloro-l ,8-naphthyrid.in-2-yl )-7-C4-methylpiperazin-l-yl ) carbonyloxy- 5-oxo-pyrrolo[3 ,4-b]pyrazine 0.025 g. starch 0.090 g. precipitated, silica 0.030 g, magnesium stearate 0.005 g.

Claims (9)

1. We claim. 1, t wherein one Y represents a hydrogen or halogen atom, an alkyl radical containing 1 to 4 carbon atoms, an lkoxy radical containing 1 to 4 carbon atoms, or a cyano radical or two Y represent said alkyl radicals, the other Y being hydrogen^ the symbols =A- and represent a group «=CH- or «=N-, =A^- representing a group =CH- or.«= - when =A-represents <=CH- and representing =iN- when A represents =H-, the symbol Z represents a hydrogen or halogen atom, an alkoxy radical containing 1 to 4 carbon atoms, or the nitro radical, m represents zero or one, 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.

2. Naphthyridine compounds according to claim 1 wherein n represents zero and R represents the methyl group.; 3* Naphthyridine compounds according to claim 1 or 2 wherein m represents zero. 4. Naphthyridine compounds according to any one of the preceding claims wherein Y represents a hydrogen, chlorine or bromine atom, or a methyl, methoxy or cyano radical. 5. ; ' -T". Naphthyridine compounds according to claim 1, 3, 4 or 6 wherein R represents an ethyl, isopropyl, t.-butyl, allyl, propargyl , 2-hydroxyethyl or phenyl radical. 6. t>- ja 2-(7-Chloro-l,8-naphthyridin-2~yl)-3-( -methylpiperazin-l-yl )carbonyloxy-isoindolin-l-one and acid, addition salts thereof. 7. 7 ^ 2-(7-Bromo-l,8-naphthyridin-2-yl)-3-(4-methylpiperazin-l-yl )carbonyloxy-isoindolin-l-one and acid addition salt3 thereof. 8. j? . Γ. 2-(7-Cyano-l,8-naphthyridin-2-yl)-3- ( -methylpiperazin-l-yl ) carbonyloxy-isoindolin-l-one and acid addition salts thereof. 9, < jWT, 2-(7-Chloro-l,8-naphthyridin-2-yl)-3- [4-( 2-hydroxyethyl )-piperazin-l-yl jcarbonyloxy-isoindolin-1-one and acid addition salts thereof. 10. \o 3-(4-Allylpiperazin-l-yl)carbonyloxy-2-(7-chloro-l,8-naphthyridin-2-yl)isoindolin-l-one and. acid addition salts thereof. I . ,1 . 2-(7-Chloro-l,8-naphthyridin-2-yl)-3-( -ethylpiperazin-l-yl ) carbonyloxy-isoindolin-l-one. and. acid addition salts thereof. 112. i 2-(7-Chloro-l,8-naphthyridin-2-yl)-3-(4-propargylpiperazin-l-yl )carbonyloxy-isoindolin-l-one and. acid, addition salts thereof. 1

3. 2-(7-Chloro-l,8-naphthyridin-2~yl)-3- (4-t.-butylpiperazin-1-yl) carbonyloxy-isoindolinl ,V-1-one and acid ... addition salts thereof. , 1

4. 4-[2-(7^hloro-1,8-naphthyridin-2-yl)-3-oxo-isoindolin-1--yl] oxycarbouylj-l-methylpiperazine-1-oxide and acid addition salts thereof. 1

5. 6-(7-Chloro-1 ,8-naphthyridine-2-yl)-5-(4-methylpiperazin-1-yl) carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3»4-b3pyrazine and acid addition salts thereof. 1

6. The naphthyridine derivatives conforming to the general formula specified in claim 1 obtained as products in foregoing Examples 6, 7, 8, 13» 18, 19, 23, 24 and 25, and acid addition salts thereof. 1

7. The naphthyridine derivatives conforming to the general formula specified in claim 1 obtained as products in foregoing Examples 3, 9» 10, 11, and 12, and acid addition salts thereof. 1

8. ' Process for the preparation of naphthyridine derivatives as claimed in claim 1 wherein n, represents zero which comprises reacting a chlorocarbonylplperazine of the general formula. CI - CO - ~ - R V wherein R represents a hydrogen atom, an alkyl radical -containing 1 to 4 carbon atoms, an alkenyl or alkynyl radical containing 2 to 4 carbon atoms a hydroxyalkyl radical containing 1 to 4 carbon atoms or a phenyl radical with a naphthyridine derivative of the general formula! ΟΗ wherein Υ, A, A , Ζ and m are as defined in claim 1 or ·· ;.an alkali metal derivative thereof. 1

9. Procese for the preparation of naphthyridine derivatives as claimed in claim 1 wherein n Represents zero or 1 which comprises reacting a piperazine of the general formula: (wherein n is zero or 1 and R is as defined in claim 1 accordi ng to the definition of Q) with a mixed carbonate of the general formula: wherein Y, A, A Z and m are 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. 20. Process 'for the preparation of naphthyridine derivatives as claimed in claim 1 wherein n represents 1 and R represents an alkyl or hydroxyalkyl group containing 1 to 4 carbon atoms or a phenyl radical which comprises the oxidation of a corresponding naphthyridine derivative of the general formula specified in claim 1 wherein n represents zero and R is as defined above. 18 19 20 21. 24, Process according to claim 2±-j ¾3-or followed, by the step of converting by methods known per se a naphthyridine base thus obtained into an acid addition salt, 22. Process for the preparation of naphthyridine derivatives of the general formula specified, in claim 1 substantially as described in Example l«ea?-3¾ 23. 36, Process for the preparation of naphthyridine derivatives of the general formula specified, in claim 1 6 7 substantially as described in any one of Examples 8-j- 8 13 25 ie-and to-a¾ 24. -3?. Process for the preparation of naphthyridine derivatives of the general formula specified in claim 1 5 substantially as described in any one of Examples 2 , -4- to -3-and~U to 4 ^ 25. as. Naphthyridine derivatives of the general formula specified in claim 1 and acid addition salts thereof when prepared by the process claimed in any one 18 24 of claims -2±- to -22-, 26. a*9. Pharmaceutical compositions v/hich comprise, as active ingredient, at least one naphthyridine derivative 17 as claimed in any one of claims 1 to -2Θ·, or a non-toxic acid addition salt thereof, in association with a pharmaceutical carrier or coating. 27. Pharmaceutical compositions according to 26 claim -S9- substantially as hereinbefore described with 38 39 especial reference to Example 38-or -39-,