NO140012B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DERIVATIVES OF NAFTYRIDINE - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DERIVATIVES OF NAFTYRIDINE Download PDF

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NO140012B
NO140012B NO741744A NO741744A NO140012B NO 140012 B NO140012 B NO 140012B NO 741744 A NO741744 A NO 741744A NO 741744 A NO741744 A NO 741744A NO 140012 B NO140012 B NO 140012B
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naphthyridin
carbon atoms
general formula
chloro
equal
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NO140012C (en
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Claude Cotrel
Cornel Crisan
Claude Jeanmart
Mayer Naoum Messer
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Rhone Poulenc Sa
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Priority claimed from FR7408730A external-priority patent/FR2263752A1/en
Priority claimed from FR7408728A external-priority patent/FR2286642A2/en
Application filed by Rhone Poulenc Sa filed Critical Rhone Poulenc Sa
Publication of NO741744L publication Critical patent/NO741744L/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

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  • Organic Chemistry (AREA)
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  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pain & Pain Management (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pyridine Compounds (AREA)

Description

Foreliggende oppfinnelse angår fremgangsmåter for fremstilling av nye derivater av naftyridin med den generelle formel: The present invention relates to methods for the production of new derivatives of naphthyridine with the general formula:

samt syreaddisjonssalter derav, der Y angir et hydrogenatom, as well as acid addition salts thereof, where Y denotes a hydrogen atom,

et halogenatom, en alkylgruppe inneholdende 1-4 karbonatomer, en alkoksygruppe hvis alkyldel inneholder,1 - 4 karbonatomer eller en cyangruppe, der Z angir et hydrogenatom, et halogenatom, en alkoksygruppe hvis alkyldel inneholder 1-4 karbonatomer eller en nitrogruppe, og der (1) n er lik 0, hvorved R angir en alkylgruppe inneholdende 1-4 karbonatomer, en alkenylgruppe inneholdende 2-4 karbonatomer, en alkynylgruppe inneholdende 2-4 karbonatomer, eller en hydroksyalkylgruppe hvis alkyldel inneholder 1-4 karbonatomer, eller (2) n er lik 1, hvorved R angir en alkylgruppe inneholdende 1-4 karbonatomer, en hydroksyalkylgruppe hvis alkyldel inneholder 1-4 karbonatomer. a halogen atom, an alkyl group containing 1-4 carbon atoms, an alkoxy group whose alkyl part contains,1-4 carbon atoms or a cyano group, where Z denotes a hydrogen atom, a halogen atom, an alkoxy group whose alkyl part contains 1-4 carbon atoms or a nitro group, and where ( 1) n is equal to 0, whereby R denotes an alkyl group containing 1-4 carbon atoms, an alkenyl group containing 2-4 carbon atoms, an alkynyl group containing 2-4 carbon atoms, or a hydroxyalkyl group whose alkyl part contains 1-4 carbon atoms, or (2) n is equal to 1, whereby R denotes an alkyl group containing 1-4 carbon atoms, a hydroxyalkyl group whose alkyl part contains 1-4 carbon atoms.

De nye forbindelser med formelen (i) der n er lik 0 kan ifblge oppfinnelsen fremstilles ved at et klorkarbonylpiperazin med den generelle formel: der R angir et hydrogenatom, en alkylgruppe, en alkenylgruppe, en alkynylgruppe, eller en hydroksyalkylgruppe som ovenfor angitt, omsettes med et derivat av naftyridin med den generelle formel: According to the invention, the new compounds with the formula (i) where n is equal to 0 can be prepared by reacting a chlorocarbonylpiperazine with the general formula: where R denotes a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, or a hydroxyalkyl group as indicated above, with a derivative of naphthyridine with the general formula:

der Y og Z har de ovenfor angitte betydninger. where Y and Z have the meanings given above.

Vanligvis omsetter man en forbindelse med formelen (II) med et alkalimetallsalt, eventuelt fremstilt in situ, av en forbindelse med formelen (III), hvorved man arbeider i et vannfritt organisk opplbsningsmiddel slik som dimetylformamid eller tetrahydrofuran, ved en temperatur under 60°C. Usually, a compound of the formula (II) is reacted with an alkali metal salt, optionally prepared in situ, of a compound of the formula (III), whereby one works in an anhydrous organic solvent such as dimethylformamide or tetrahydrofuran, at a temperature below 60°C.

Reaksjonen kan også gjennomføres ved at et salt av en forbindelse med formelen (II), fortrinnsvis hydrokloriden, omsettes med en forbindelse med formelen (III), hvorved man arbeider i pyridin og eventuelt i nærvær av et tertiært amin slik som trietylamin, hvilket frigjor forbindelsen med formelen (II) fra dettes salt. The reaction can also be carried out by reacting a salt of a compound of the formula (II), preferably the hydrochloride, with a compound of the formula (III), whereby one works in pyridine and possibly in the presence of a tertiary amine such as triethylamine, which releases the compound with the formula (II) from its salt.

Naftyridinderivatet med den generelle formel (III) kan fremstilles ved partiell reduksjon av et imid med den generelle formel: The naphthyridine derivative of the general formula (III) can be prepared by partial reduction of an imide of the general formula:

der Y og Z har de ovenfor angitte betydninger. where Y and Z have the meanings given above.

Reduksjonen gjennomføres vanligvis ved hjelp av et alkalimetall-borhydrid, hvorved man arbeider i organisk opp-løsning eller i vannholdig organisk opplbsning, slik som i en blanding av dioksan og metanol, en blanding av dioksan og vann, en blanding av metanol og vann eller en blanding av etanol og vann. The reduction is usually carried out with the aid of an alkali metal borohydride, whereby one works in organic solution or in an aqueous organic solution, such as in a mixture of dioxane and methanol, a mixture of dioxane and water, a mixture of methanol and water or a mixture of ethanol and water.

Den partielle reduksjon av en forbindelse med formelen (IV) kan kan fore til isomere produkter som kan separeres ved hjelp av fysikalsk-kjemiske metoder slik som frak-sjonert krystallisasjon eller kromatografi. The partial reduction of a compound with the formula (IV) can lead to isomeric products which can be separated using physico-chemical methods such as fractional crystallization or chromatography.

Imidet med den generelle formel (IV) kan fremstilles ved at et 2-aminonaftyridin med den generelle formel: The imide with the general formula (IV) can be prepared by a 2-aminonaphthyridine with the general formula:

der Y har den ovenfor angitte betydning, omsettes med et an-hydrid med den generelle formel: der Z har den ovenfor angitte betydning, hvorved reaksjonen eventuelt forloper via et mellomprodukt med den generelle formel: where Y has the meaning given above, is reacted with an anhydride of the general formula: where Z has the meaning given above, whereby the reaction possibly proceeds via an intermediate with the general formula:

der Y og Z har den ovenfor angitte betydning. where Y and Z have the above meaning.

Reaksjonen mellom 2-aminonaftyridinet med formelen (V) og anhydridet med formelen (VI) utfores vanligvis ved opp-varming i et organisk opplosningsmiddel slik som eddiksyre, dimetylformamid, acetonitril eller fenyleter. The reaction between the 2-aminonaphthyridine of the formula (V) and the anhydride of the formula (VI) is usually carried out by heating in an organic solvent such as acetic acid, dimethylformamide, acetonitrile or phenyl ether.

Ringslutningen av en forbindelse med formelen (VII) til en forbindelse med formelen (IV) kan utfores enten ved opp-varming med acetylklorid i eddiksyre éller eddiksyreanhydrid, eller ved omsetning med et kondensasjonsmiddel slik som N,N'-dicykloheksylkarbodiimid, i dimetylformamid ved en temperatur nær 20°C. The cyclization of a compound of the formula (VII) to a compound of the formula (IV) can be carried out either by heating with acetyl chloride in acetic acid or acetic anhydride, or by reaction with a condensing agent such as N,N'-dicyclohexylcarbodiimide, in dimethylformamide at a temperature close to 20°C.

De nye forbindelser med formelen (I), der n er lik The new compounds of formula (I), where n is equal to

0 eller 1, og R har den ovenfor angitte tilsvarende betydning, kan ifblge oppfinnelsen fremstilles ved at et piperazin med den generelle formel: 0 or 1, and R has the corresponding meaning given above, according to the invention, can be produced by a piperazine with the general formula:

der n er lik 0 eller 1, og R har den ovenfor angitte betydning, omsettes med et blandet karbonat med den generelle formel: where n is equal to 0 or 1, and R has the above meaning, is reacted with a mixed carbonate of the general formula:

der Y og Z har den ovenfor angitte betydning og Ar angir en fenylgruppe som eventuelt er substituert med en alkylgruppe inneholdende 1-4 karbonatomer eller med en nitrogruppe. where Y and Z have the above meaning and Ar denotes a phenyl group which is optionally substituted with an alkyl group containing 1-4 carbon atoms or with a nitro group.

Reaksjonen gjennomføres vanligvis i et vannfritt organisk opplosningsmiddel slik som acetonitril eller dimetylformamid ved en temperatur nær 20°C. The reaction is usually carried out in an anhydrous organic solvent such as acetonitrile or dimethylformamide at a temperature close to 20°C.

Forbindelsen med formelen (VIII) der n er lik 0 og R angir en metylgruppe, samt dettes dihydroklorid, kan fremstilles ved oksydasjon av en tert.butyl-(4-metyl-l-piperazi-nyl)karboksylat ved hjelp av 4-nitroperbenzosyre i vannfri kloroform ved en temperatur som ikke overstiger 40°C. Man er-statter deretter 'tert.butyloksykarbonylgruppen med et hydrogenatom ved at man under tilbakelbp oppvarmer hydrokloridet av l-metyl-4-tert.butyloksykarbonylpiperazin-l-oksyd i eta-nolisk medium i nærvær av vannfri hydrogenklorid. De andre forbindelsene med formelen (VIII) kan fremstilles på analog måte. The compound with the formula (VIII) where n is equal to 0 and R denotes a methyl group, as well as its dihydrochloride, can be prepared by oxidation of a tert-butyl-(4-methyl-1-piperazinyl)carboxylate with the aid of 4-nitroperbenzoic acid in anhydrous chloroform at a temperature not exceeding 40°C. The tert-butyloxycarbonyl group is then replaced with a hydrogen atom by refluxing the hydrochloride of 1-methyl-4-tert-butyloxycarbonylpiperazine-1-oxide in an ethanolic medium in the presence of anhydrous hydrogen chloride. The other compounds with the formula (VIII) can be prepared in an analogous manner.

Det blandede karbonat med formelen (IX) kan fremstilles ved at et klorformiat med den generelle formel: The mixed carbonate with the formula (IX) can be prepared by a chloroformate with the general formula:

der Ar har den ovenfor angitte betydning,omsettes med en forbindelse med den generelle formel (III). where Ar has the meaning stated above, is reacted with a compound of the general formula (III).

Denne reaksjon gjennomfares vanligvis i et basisk organisk opplosningsmiddel slik som pyridin ved en tempera- This reaction is usually carried out in a basic organic solvent such as pyridine at a temperature

tur mellom 0 og 20°C. trip between 0 and 20°C.

Forbindelsene med den generelle formel (I) der n er lik 1, og R angir en alkylgruppe, eller en hydroksyalkylgruppe som ovenfor angitt, kan ifblge oppfinnelsen fremstilles ved oksydasjon av en forbindelse med den generelle formel (i), der n er lik 0 og R har den ovenfor angitte betydning. The compounds with the general formula (I) where n is equal to 1, and R denotes an alkyl group, or a hydroxyalkyl group as indicated above, can according to the invention be produced by oxidation of a compound with the general formula (i), where n is equal to 0 and R has the above meaning.

Oksydasjonen gjennomføres vanligvis ved hjelp av en organisk persyre slik som 3-klorperbenzosyre eller 4-nitroperbenzosyre, i et organisk opplosningsmiddel slik som kloroform og ved en temperatur nær 20°C. The oxidation is usually carried out using an organic peracid such as 3-chloroperbenzoic acid or 4-nitroperbenzoic acid, in an organic solvent such as chloroform and at a temperature close to 20°C.

De nye forbindelsene med den generelle formel (I) kan eventuelt renses ved tillempning av fysikalske metoder (slik som destillasjon, krystallisasjon, kromatografi) eller kjemiske metoder (slik som dannelse av salter, krystallisasjon av disse og etterfølgende spalting i alkalisk medium; ved disse operasjoner er arten av saltets anion likegyldig, og det eneste vilkår er at saltet er godt definert og lett å kry-stallisere) . The new compounds with the general formula (I) can optionally be purified by the application of physical methods (such as distillation, crystallization, chromatography) or chemical methods (such as the formation of salts, their crystallization and subsequent cleavage in an alkaline medium; in these operations the nature of the salt's anion is indifferent, and the only condition is that the salt is well defined and easy to crystallize).

De nye forbindelsene med den generelle formel (I) The new compounds of the general formula (I)

kan omdannes til addisjonssalter med syrer. can be converted into addition salts with acids.

Addisjonssaltene kan oppnås ved at de nye forbindelsene omsettes med syrer i egnede opplosningsmidler. Som organiske opplosningsmid?.er kan man f. eks. anvende alkoholer, etere, ketoner eller klorerte opplosningsmidler. Det dannede saltet faller ut etter eventuell konsentrasjon av oppløsning-en, og det separeres ved filtrering eller dekantering. The addition salts can be obtained by reacting the new compounds with acids in suitable solvents. As organic solvents, you can e.g. use alcohols, ethers, ketones or chlorinated solvents. The formed salt precipitates after any concentration of the solution, and it is separated by filtration or decantation.

De nye forbindelsene med formelen (i) samt disses syreaddisjonssalter oppviser interessante farmakologiske egenskaper. De har vist seg spesielt virksomme som beroligende midler og som midler moi konvulsjoner. The new compounds of formula (i) as well as their acid addition salts exhibit interesting pharmacological properties. They have proven particularly effective as sedatives and as anticonvulsants.

Ved oral inngivelse til mus har forbindelsene vist seg virksomme i doser på mellom 0,1 og 100 mg/kg, spesielt ved følgende forsbk: Slagsmål fremkalt ved elektriske stbt ifblge en teknikk som tilsvarer den som er beskrevet av Tedeschi et al. When administered orally to mice, the compounds have been shown to be effective in doses of between 0.1 and 100 mg/kg, especially in the following experiments: Fights induced by electric shocks according to a technique corresponding to that described by Tedeschi et al.

(J. Pharmacol. 125, 28 (1959)); (J. Pharmacol. 125, 28 (1959));

Konvulsjoner fremkalt ved hjelp av pentetrazol ifblge en teknikk tilsvarende den som er beskrevet av Everett og Richards ( J. Pharmacol. 81. 402 (1944)); Convulsions induced by pentetrazole according to a technique similar to that described by Everett and Richards (J. Pharmacol. 81. 402 (1944));

Supramaksimalt elektrosjokk ifblge den teknikk som Supramaximal electroshock according to the technique which

er beskrevet av Swinyard et al. (J. Pharmacol. 106, 319 (1952)); is described by Swinyard et al. (J. Pharmacol. 106, 319 (1952));

Lokomotorisk aktivitet ifblge den teknikk som er beskrevet av Courvoisier (Congres des Médecins Aliénistes et Neurologistes, Tours (8. - 13. juni 1959)) og Julou (Bulletin de la Société de Pharmacie de Lille, nr. 2, januar 1967, side 7). Locomotor activity according to the technique described by Courvoisier (Congres des Médecins Aliénistes et Neurologistes, Tours (8 - 13 June 1959)) and Julou (Bulletin de la Société de Pharmacie de Lille, No. 2, January 1967, page 7 ).

De nye forbindelsene med formelen (I) oppviser dess-uten en kun ubetydelig giftighet. Ved oral inngivelse til mus er DL^Q, dvs. den dose som fremkaller dbden hos 50% av for-søksdyrene, vanligvis stbrre enn 300 mg/kg. The new compounds with the formula (I) also exhibit only negligible toxicity. When administered orally to mice, the DL^Q, i.e. the dose that induces death in 50% of the test animals, is usually greater than 300 mg/kg.

Av meget spesiell interesse er de forbindelser med den generelle formel der Y har den ovenfor gitte betydning, Of very particular interest are the compounds with the general formula where Y has the meaning given above,

Z angir et hydrogenatom og R har den ovenfor gitte betydning når n er lik 0, eller R betyr en metylgruppe når n er lik 1;. samt addisjonssalter derav med syrer. Z denotes a hydrogen atom and R has the meaning given above when n is equal to 0, or R means a methyl group when n is equal to 1;. as well as addition salts thereof with acids.

For medisinske formål kan de nye forbindelsene med formelen (i) anvendes enten i form av baser eller i form av farmasøytisk godtagbare addisjonssalter, dvs. salter som er ugiftige i de anvendte doser. For medical purposes, the new compounds of formula (i) can be used either in the form of bases or in the form of pharmaceutically acceptable addition salts, i.e. salts which are non-toxic in the doses used.

Som eksempel på farmasbytisk godtagbare addisjonssalter skal nevnes salter med uorganiske syrer (slik som hydro-klorider, sulfater, nitrater, fosfater) eller salter med organiske syrer (slik som acetater, propibnater, succinater, benzoater, fumarater, maleater, teofyllinacetater, salicylat-er, fenolftalinater, metylen-bis-P-oksinaftoater) eller salter med substitusjonsderivater av disse syrer. Examples of pharmaceutically acceptable addition salts include salts with inorganic acids (such as hydrochlorides, sulphates, nitrates, phosphates) or salts with organic acids (such as acetates, propibnates, succinates, benzoates, fumarates, maleates, theophylline acetates, salicylates , phenolphthalinates, methylene-bis-P-oxynaphthoates) or salts with substituted derivatives of these acids.

Oppfinnelsen skal illustreres nærmere ved folgende, ikke begrensende, eksempler. The invention shall be illustrated in more detail by the following, non-limiting, examples.

Eksempel 1 Example 1

Til en suspensjon av 12,4 g 2-(7-klor-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on i 125 cm^ vannfri dimetylformamid settes på én gang 2,1 g natriumhydrid (50% i mineralolje), idet man utvendig kjoler ved hjelp av et isbad. Når gassutviklingen har opphort, tilsetter man en opplosning av 11,3 g l-klorkarbonyl-4-metylpiperazin i 110 cn<r> vannfri dimetylformamid under fortsatt utvendig kjbling. Etter avslut-tet tilsetning omrorer man reaksjonsblandingen i 14 timer ved 0°C og deretter 6 timer ved 22°C. Reaksjonsblandingen helles på 800 g is. Det utkrystalliserte produkt separeres ved filtrering og vaskes med 240 cnr ■ x vann. Produktet torkes i luft, og herved oppnås 13 g av et urent produkt med et smeltepunkt på 210 o C. Ved omkrystallisering i 900 cnr 3 acetonitril oppnås 8,5 g 2-(7-klor-l,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med et smeltepunkt på 204°C. 2.1 g of sodium hydride (50 % in mineral oil), dressing the outside using an ice bath. When gas evolution has ceased, a solution of 11.3 g of 1-chlorocarbonyl-4-methylpiperazine in 110 cc of anhydrous dimethylformamide is added with continued external stirring. After the addition has been completed, the reaction mixture is stirred for 14 hours at 0°C and then 6 hours at 22°C. The reaction mixture is poured onto 800 g of ice. The crystallized product is separated by filtration and washed with 240 cnr ■ x water. The product is dried in air, and this gives 13 g of an impure product with a melting point of 210 o C. By recrystallization in 900 cnr 3 acetonitrile, 8.5 g of 2-(7-chloro-1,8-naphthyridin-2-yl) is obtained )-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with a melting point of 204°C.

Utgangsforbindelsen 2-(7-klor-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on kan fremstilles ved at det settes 1,72 g kaliumborhydrid til en suspensjon av 17,7 g 2-(7-klor-1,8-naf tyridin-2-yl) f talimid i 87 cm^ dioksan og 26,4 cnr5 av en mettet vandig opplosning av dinatriumfosfat under utvendig kjoling ved hjelp av et isbad. Etter 14 timers omroring lar man temperaturen stige til nær 20°C, hvoretter det omrores ytterligere 2 timer, og det tilsettes deretter 400 cm mettet vannopplbsning av dinatriumfosfat. Den dannede utfelling separeres ved filtrering og vaskes med 225 cm kaldt vann. The starting compound 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one can be prepared by adding 1.72 g of potassium borohydride to a suspension of 17.7 g of 2-(7- chloro-1,8-naphthyridin-2-yl)f thalimide in 87 cm^ dioxane and 26.4 cnr5 of a saturated aqueous solution of disodium phosphate under external cooling by means of an ice bath. After 14 hours of stirring, the temperature is allowed to rise to close to 20°C, after which stirring is continued for a further 2 hours, and 400 cm3 of a saturated aqueous solution of disodium phosphate is then added. The precipitate formed is separated by filtration and washed with 225 cm of cold water.

Etter tbrking i luft oppnår man 17,5 g 2-(7-klor-l,8-naftyridin- 2-yl)-3-hydroksyidoindolin-l-on med et smeltepunkt på 248°C. After drying in air, 17.5 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyidoindolin-1-one with a melting point of 248°C are obtained.

2-(7-klor-l,8-naftyridin-2-yl)ftalimidet kan fremstilles ved at man under tilbakelbp oppvarmer en blanding av 26,3 g 2-(7-hydroksy-l,8-naftyridin-2-yl)ftalimid, 79 cm<3> fos- The 2-(7-chloro-1,8-naphthyridin-2-yl)phthalimide can be prepared by heating under reflux a mixture of 26.3 g of 2-(7-hydroxy-1,8-naphthyridin-2-yl) phthalimide, 79 cm<3> phos-

foroksyklorid og 3,5 cm^ dimetylformamid inntil gassutviklingen opphorer. Etter avkjbling helles reaksjonsblandingen i 650 cm 3 isvann uten at temperaturen får stige over 25 oC. Det oppnådde produkt separeres ved filtrering, vaskes med 150 cnr<5 >vann og torkes til konstant vekt. Man oppnår herved 24,1 g 2-(7-klor-l,8-naftyridin-2-yl)ftalimid med et smeltepunkt på 268°C. phoroxychloride and 3.5 cm^ of dimethylformamide until gas evolution ceases. After cooling, the reaction mixture is poured into 650 cm 3 of ice water without allowing the temperature to rise above 25 oC. The product obtained is separated by filtration, washed with 150 ml of water and dried to constant weight. This gives 24.1 g of 2-(7-chloro-1,8-naphthyridin-2-yl)phthalimide with a melting point of 268°C.

2-(7-hydroksy-l,8-naftyridin-2-yl)ftalimidet kan fremstilles ved at man under tilbakelbp i 3 timer oppvarmer en blanding av 25 g 2-amino-7-hydroksy-l,8-naftyridin og 70 g ftalsyreanhydrid i 1400 cm eddiksyre. Etter avkjbling separeres et uopploselig stoff ved filtrering. De oppnådde kry-stallene filtreres av og vaskes deretter i tur og orden med 60 cnr 3 eter, 90 cnr 3 vann, 120 cm 3 av en mettet natriumbikar-bonatopplosning og 60 cm vann. Man torker deretter til konstant vekt og oppnår 17 g 2-(7-hydroksy-l,8-naftyridin-2-yl)-ftalimid med et smeltepunkt på 370°C. The 2-(7-hydroxy-1,8-naphthyridin-2-yl)phthalimide can be prepared by heating a mixture of 25 g of 2-amino-7-hydroxy-1,8-naphthyridine and 70 g under reflux for 3 hours phthalic anhydride in 1400 cm acetic acid. After cooling, an insoluble substance is separated by filtration. The crystals obtained are filtered off and then washed in turn with 60 cnr 3 of ether, 90 cnr 3 of water, 120 cm 3 of a saturated sodium bicarbonate solution and 60 cm of water. It is then dried to constant weight and 17 g of 2-(7-hydroxy-1,8-naphthyridin-2-yl)-phthalimide with a melting point of 370°C is obtained.

2-amino-7-hydroksy-l,8-naftyridin kan fremstilles ifblge den fremgangsmåte som er beskrevet av S. Carboni et al. i "Gazz. Chim. Ital.", 95, 1498 (1965). 2-amino-7-hydroxy-1,8-naphthyridine can be prepared according to the method described by S. Carboni et al. in "Gazz. Chim. Ital.", 95, 1498 (1965).

Eksempel 2 Example 2

Til en suspensjon av 3,12 g 2-(7-klor-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on og 5,97 g hydroklorid av l-klorkarbonyl-4-metylpiperazin i 50 cm metylenklorid setter man 5,6 cm 3 trietylamin og deretter 25 cnr 3 vannfri pyridin, idet temperaturen holdes nær 25°C. Reaksjonsblandingen oppvarmes deretter til en temperatur nær 50°C i 1 time, hvoretter den omrbres i 18 timer ved en temperatur nær 20°C. Der-3 3 To a suspension of 3.12 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one and 5.97 g of 1-chlorocarbonyl-4-methylpiperazine hydrochloride in 50 cm methylene chloride, 5.6 cm 3 of triethylamine and then 25 cm 3 of anhydrous pyridine are added, the temperature being kept close to 25°C. The reaction mixture is then heated to a temperature close to 50°C for 1 hour, after which it is stirred for 18 hours at a temperature close to 20°C. There-3 3

etter tilsettes 50 cn<r> metylenklorid og 100 cnr vann. Vann-sjiktet dekanteres og vaskes deretter 3 ganger med 50 cnr■5 metylenklorid. De organiske sjiktene forenes og vaskes med 50 cm ■5 vann, torkes over vannfri natriumsulfat og konsentreres til torr tilstand under redusert trykk. Ved omkrystallisering av den således oppnådde rest i 100 cnr ■5 acetonitril oppnår man 2,5 g 2-(7-klor-l,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)-karbonyloksyisoindolin-l-on med et smeltepunkt på 203°C. then add 50 cn<r> methylene chloride and 100 cnr water. The water layer is decanted and then washed 3 times with 50 ml of methylene chloride. The organic layers are combined and washed with 50 cm 5 of water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. By recrystallization of the thus obtained residue in 100 ml of acetonitrile, 2.5 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methyl-1-piperazinyl)-carbonyloxyisoindoline are obtained -l-one with a melting point of 203°C.

Eksempel 3 Example 3

Til en suspensjon av 4,63 g 2-(7-metoksy-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on i 45 cm^ vannfri dimetylformamid settes ved en temperatur mellom 18 og 20°C 0,8 g natriumhydrid (50% i mineralolje). Reaksjonsblandingen omrores i 4 timer og 30 minutter. Man tilsetter deretter i lop-et av 15 minutter og ved en temperatur på 20°C en opplosning av 2,7 g l-klorkarbonyl-4-metylpiperazin i 25 cm^ vannfri dimetylformamid. Man omrorer suspensjonen i 17 timer ved en temperatur nær 20°C, hvoretter man tilsetter 7 cir.^ vannfri heksametylfosfotriamid. Etter 15 minutter heller man reaksjonsblandingen i 500 g isvann. Den dannede utfelling separeres ved"filtrering og vaskes deretter i 45 cnr vann. Man oppnår 6.1 g av et produkt som omkrystalliseres i 1500 cm^ isopropyl-eter. Man oppnår herved 3 g 2-(7-metoksy-l,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med et smeltepunkt på 191°C. To a suspension of 4.63 g of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one in 45 cm^ of anhydrous dimethylformamide is added at a temperature between 18 and 20°C 0 .8 g of sodium hydride (50% in mineral oil). The reaction mixture is stirred for 4 hours and 30 minutes. A solution of 2.7 g of 1-chlorocarbonyl-4-methylpiperazine in 25 cm^ of anhydrous dimethylformamide 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 close to 20°C, after which 7 cc of anhydrous hexamethylphosphotriamide are added. After 15 minutes, the reaction mixture is poured into 500 g of ice water. The precipitate formed is separated by filtration and then washed in 45 ml of water. 6.1 g of a product is obtained which is recrystallized in 1500 cm^ of isopropyl ether. This gives 3 g of 2-(7-methoxy-1,8-naphthyridine- 2-yl)-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with a melting point of 191°C.

Utgangsforbindelsen 2-(7-metoksy-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on kan fremstilles på fblgende måte: The starting compound 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one can be prepared in the following way:

2-acetylamino-7-klor-l,8-naftyridin (smeltepunkt 2-acetylamino-7-chloro-1,8-naphthyridine (m.p

251 - 253°) fremstilles ifb"lge S. Carboni et al. (Gazz. Chim. Ital., 95, 1492 (1965)). 251 - 253°) is prepared according to S. Carboni et al. (Gazz. Chim. Ital., 95, 1492 (1965)).

1,0 g 2-amino-7-metoksy-l,8-naftyridin (smeltepunkt 156°C) fremstilles ved at 1,8 g natriummetylat omsettes med 2.2 g 2-acetylamino-7-klor-l,8-naftyridin i 40 cn<r> vannfri metanol under tilbakelopskoking i 45 minutter. 20 g 2-(7-metoksy-l,8-natyridin-2-yl)ftalimid (smeltepunkt 295°C) fremstilles ved at 10 g ftalsyreanhydrid omsettes med 12 g 2-amino-7-metoksy-l,8-naftyridin i 240 cnr fenyleter i 10 minutter ved l60°C. 1.0 g of 2-amino-7-methoxy-1,8-naphthyridine (melting point 156°C) is prepared by reacting 1.8 g of sodium methylate with 2.2 g of 2-acetylamino-7-chloro-1,8-naphthyridine in 40 cn<r> anhydrous methanol under reflux for 45 minutes. 20 g of 2-(7-methoxy-1,8-nathyridin-2-yl)phthalimide (melting point 295°C) is prepared by reacting 10 g of phthalic anhydride with 12 g of 2-amino-7-methoxy-1,8-naphthyridine in 240 cnr phenyl ether for 10 minutes at 160°C.

18,7 g 2-(7-metoksy-l,8-naftyridin-2-yl)-3-hydrok-syisoindolin-l-on (smeltepunkt 218°C) fremstilles ved at 3,55 g kaliumborhydrid omsettes med 20 g 2-(7-metoksy-l,8-naftyridin-2-yl)ftalimid i 200 cm^ dioksan og 40 cm^ av en mettet vann-opplosning av dinatriumfosfat i 4 timer ved en temperatur nær 20°C. 18.7 g of 2-(7-methoxy-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one (melting point 218°C) is prepared by reacting 3.55 g of potassium borohydride with 20 g of 2 -(7-methoxy-1,8-naphthyridin-2-yl)phthalimide in 200 cc of dioxane and 40 cc of a saturated aqueous solution of disodium phosphate for 4 hours at a temperature near 20°C.

Eksempel 4 Example 4

Man arbeider på samme måte som i eksempel 3, men You work in the same way as in example 3, but

går ut fra 8 g 2-(7-brom-l,8-naftyridin-2-yl)-3-hydroksyisoin-dolin-l-on i 240 cm - z. vannfri dimetylformamid, 1,2 g natriumhydrid (50% i mineralolje) og 4,1 g l-klorkarbonyl-4-metyl- starting from 8 g of 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one at 240 cm - z. anhydrous dimethylformamide, 1.2 g of sodium hydride (50% in mineral oil) and 4.1 g of 1-chlorocarbonyl-4-methyl-

piperazin i 40 cnr ■ 7. vannfri dimetylformamid, og reaksjonen gjennomfbres ved 26°C i 18 timer. Man oppnår herved en reaksjonsblanding som helles i 1500 cm isvann. Det ulbselige stoff (7,3 g) separeres ved filtrering og opplbses deretter i 73 cm av en blanding av metylenklorid og etylacetat i et volumforhold på 80:20. Den oppnådde opplosning fores gjennom en kolonne med 73 g silikagel. Man eluerer forst med 5750 cm^ av en blanding av metylenklorid og etylacetat i et volumforhold 80:20. Det herved oppnådde eluat kasseres. Deretter eluerer man ved 1250 cm' ren etylacetat og deretter med 1250 cm av en blanding av like volumdeler etylacetat og metanol. De herved oppnådde eluater forenes og konsentreres til torr tilstand. Man oppnår en rest som veier 3 g, og denne opplbses i 90 cm ■ z. etanol. Til den oppnådde opplbsningen settes en opplosning av 0,53 g oksalsyre i 10,5 cnr ■ z. etanol. Herved oppnås det 1,8 g av et produkt som smelter ved 260°C. piperazine in 40 cnr ■ 7. anhydrous dimethylformamide, and the reaction is carried out at 26°C for 18 hours. This results in a reaction mixture which is poured into 1500 cm of ice water. The insoluble substance (7.3 g) is separated by filtration and then dissolved in 73 cm of a mixture of methylene chloride and ethyl acetate in a volume ratio of 80:20. The obtained solution is passed through a column with 73 g of silica gel. First elute with 5750 cm 2 of a mixture of methylene chloride and ethyl acetate in a volume ratio of 80:20. The resulting eluate is discarded. You then elute with 1250 cm' of pure ethyl acetate and then with 1250 cm of a mixture of equal parts by volume of ethyl acetate and methanol. The eluates thus obtained are combined and concentrated to dryness. A residue weighing 3 g is obtained, and this is dissolved in 90 cm ■ z. ethanol. A solution of 0.53 g of oxalic acid in 10.5 cnr ■ z is added to the solution obtained. ethanol. This gives 1.8 g of a product which melts at 260°C.

-z. -z.

Dette produktet behandles med 50 cm av en mettet natriumbi-karbonatopplbsning og 40 cn<r> metylenklorid. Det organiske sjiktet separeres ved dekantering, torkes over vannfri kaliumkarbonat og konsentreres til torr tilstand. Man oppnår en rest som veier 1,2 g og som omkrystalliseres i 80 cnr - z. etanol. Herved oppnår man 0,9 g 2-(7-brom-1,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med et smeltepunkt på 225 - 230°C. This product is treated with 50 cc of a saturated sodium bicarbonate solution and 40 cc of methylene chloride. The organic layer is separated by decantation, dried over anhydrous potassium carbonate and concentrated to dryness. A residue weighing 1.2 g is obtained which is recrystallized in 80 cnr - z. ethanol. This gives 0.9 g of 2-(7-bromo-1,8-naphthyridin-2-yl)-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with a melting point of 225 - 230°C .

Utgangsforbindelsen 2-(7-brom-1,8-naftyridin-2-yl)-3-hydroisoindolin-l-on kan fremstilles på fblgende måte: 23,6 g 2-(7-brom-l,8-naftyridin-2-yl)ftalimid med smeltepunkt 265°C fremstilles ved at man i 1 time og ved en temperatur nær 100°C oppvarmer en blanding av 20,5 g 2-(7-hydroksy-l,8-naftyridin-2-yl)-ftalimid og 30,3 g fosforpenta-3 3 The starting compound 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroisoindolin-1-one can be prepared in the following way: 23.6 g of 2-(7-bromo-1,8-naphthyridin-2 -yl)phthalimide with a melting point of 265°C is prepared by heating a mixture of 20.5 g of 2-(7-hydroxy-1,8-naphthyridin-2-yl)- phthalimide and 30.3 g of phosphorus penta-3 3

bromid i 205 cnr bromoform og 7 cm dimetylformamid. bromide in 205 cnr bromoform and 7 cm dimethylformamide.

8,2 g 2-(7-brom-l,8-naftyridin-2-yl)-3-hydroksyiso-indolin-l-on med smeltepunkt 264°C fremstilles ved at 10,6 g 2-(7-brom-l,8-naftyridin-2-yl)-ftalimid omsettes med 1,2 g kaliumborhydrid i 200 cm •5 av en blanding av like volumdeler metanol og dioksan ved en temperatur nær 20°C. 8.2 g of 2-(7-bromo-1,8-naphthyridin-2-yl)-3-hydroxyiso-indolin-1-one with a melting point of 264°C is prepared by combining 10.6 g of 2-(7-bromo- 1,8-naphthyridin-2-yl)-phthalimide is reacted with 1.2 g of potassium borohydride in 200 cm •5 of a mixture of equal parts by volume of methanol and dioxane at a temperature close to 20°C.

Eksempel 5 Example 5

Ved å arbeide på samme måte som i eksempel 3, men ved å gå ut fra 4,7 g 2-(7-cyan-l,8-naftyridin-2-yl)-3-hydroksyiso-indolin-l-on, 1,5- g natriumhydrid (50% i mineralolje), 5,04 g 1- klorkarbonyl-4-metylpiperazin, 97 cm^ vannfri tetrahydrofuran og 25 cnr vannfri heksametylfosfotriamid oppnår man 5,7 g av et urent produkt, som opplbses i 100 cnr5 metylenklorid. Den oppnådde opplosning fores gjennom en kolonne på 57 g silikagel. Man eluerer i tur og orden med 2400 cn<r> metylenklorid, 1400 cnr 3 etylacetat og 200 cnr 3 av en blanding av like volumdeler etylacetat og metanol, og man samler opp eluatet i fraksjoner på 200 cnr■ x. De 8 siste fraksjonene forenes og konsentreres til tbrr tilstand. Man oppnår en rest som veier 3,4 g og denne omkrystalliseres fra 250 cnr<5> acetonitril. Herved oppnår man 2,6 g 2-(7-cyan-l,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med et smeltepunkt på 266 - 268°C. By working in the same way as in example 3, but starting from 4.7 g of 2-(7-cyan-1,8-naphthyridin-2-yl)-3-hydroxyiso-indolin-1-one, 1 .5 g of sodium hydride (50% in mineral oil), 5.04 g of 1-chlorocarbonyl-4-methylpiperazine, 97 cm^ of anhydrous tetrahydrofuran and 25 cnr of anhydrous hexamethylphosphotriamide, one obtains 5.7 g of an impure product, which is dissolved in 100 cnr5 methylene chloride. The obtained solution is passed through a column of 57 g of silica gel. One elutes in turn with 2400 cn<r> methylene chloride, 1400 cnr 3 ethyl acetate and 200 cnr 3 of a mixture of equal parts by volume ethyl acetate and methanol, and the eluate is collected in fractions of 200 cnr■ x. The last 8 fractions are combined and concentrated to tbrr state. A residue weighing 3.4 g is obtained and this is recrystallized from 250 cnr<5> acetonitrile. This gives 2.6 g of 2-(7-cyano-1,8-naphthyridin-2-yl)-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with a melting point of 266 - 268°C .

Utgangsforbindelsen 2-(7-cyan-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on kan fremstilles på fblgende måte: 7,3 g 2-(7-cyan-l,8-naftyridin-2-yl)ftalimid med smeltepunkt 320°C fremstilles ved at man i 1 time oppvarmer en blanding av 17,7 g 2-(7-brom-l,8-naftyridin-2-yl)ftalimid og 9 g kobber(I)cyanid i 177 cm^ nitrobenzen til 160 - 165°C. Et ulbselig stoff separeres ved filtrering i varm tilstand, hvoretter filtratet avkjbles. Det herved utkrystalliserte produkt separeres ved filtrering og omkrystalliseres i 70 cn<r >dimetylformamid. The starting compound 2-(7-cyan-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one can be prepared in the following way: 7.3 g of 2-(7-cyan-1,8-naphthyridin-2 -yl)phthalimide with a melting point of 320°C is prepared by heating a mixture of 17.7 g of 2-(7-bromo-1,8-naphthyridin-2-yl)phthalimide and 9 g of copper (I) cyanide for 1 hour in 177 cm^ nitrobenzene to 160 - 165°C. An insoluble substance is separated by filtration in a hot state, after which the filtrate is cooled. The thus crystallized product is separated by filtration and recrystallized in 70 cn<r>dimethylformamide.

4,7 g 2-(7-cyan-l,8-naftyridin-2-yl)-3-hydroksyiso-indolin-l-on med smeltepunkt 260°C fremstilles ved at 5,8 g 2- (7-cyan-l,8-naftyridin-2-yl)ftalimid omsettes med 1,04 g natriumborhydrid i 290 cm metanol ved en temperatur mellom 23 og 27°C. 4.7 g of 2-(7-cyan-1,8-naphthyridin-2-yl)-3-hydroxyiso-indolin-1-one with a melting point of 260°C is prepared by adding 5.8 g of 2-(7-cyan- 1,8-Naphthyridin-2-yl)phthalimide is reacted with 1.04 g of sodium borohydride in 290 cm of methanol at a temperature between 23 and 27°C.

Eksempel 6 Example 6

Til en suspensjon av 5,6 g 2-(1,8-naftyridin-2-yl)-3- fenoksy-karbonyloksyisoindolin-l-on i 100 cm - z. acetonitril settes på én gang 8 g 4-metylpiperazin. Man omrbrer den oppnådde opplosning i 6 timer ved en temperatur nær 20°C. Man heller deretter"reaksjonsblandingen i en suspensjon av 100 g is i 300 cm - z. metylenklorid. Til den oppnådde suspensjon settes 200 cnr - z av en 8%-ig vannopplbsning av natriumbikarbonat. Man dekanterer den organiske fase og ekstraherer vannfasen med 400 cm^ metylenklorid. De forenede organiske faser torkes over 10 g vannfritt kaliumkarbonat og konsentreres til torr tilstand. Den oljeaktige rest på 8 g oppnås i 100 cm^ iso-propyleter under tilbakelopskoking. Ved avkjbling faller krystaller ut, og disse separeres ved filtrering. Man oppnår herved 2,9 g 3-(4-metyl-l-piperazinyl)-karboksyloksy-2-(1,8-naftyridin-2-yl)isoindolin-l-on med et smeltepunkt på 183°C. To a suspension of 5.6 g of 2-(1,8-naphthyridin-2-yl)-3-phenoxy-carbonyloxyisoindolin-1-one in 100 cm - z. of acetonitrile, 8 g of 4-methylpiperazine are added at once. The obtained solution is stirred for 6 hours at a temperature close to 20°C. The reaction mixture is then poured into a suspension of 100 g of ice in 300 cm - z of methylene chloride. To the obtained suspension is added 200 cnr - z of an 8% water solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with 400 cm ^ methylene chloride. The combined organic phases are dried over 10 g of anhydrous potassium carbonate and concentrated to dryness. The oily residue of 8 g is obtained in 100 cm^ of isopropyl ether under reflux. Upon cooling, crystals precipitate out, and these are separated by filtration. This is obtained thereby 2.9 g of 3-(4-methyl-1-piperazinyl)-carboxyl-2-(1,8-naphthyridin-2-yl)isoindolin-1-one with a melting point of 183°C.

Utgangsforbindelsen 2-(1,8-naftyridin-2-yl)-3-fen-oksykarbonyloksyisoindolin-l-on kan fremstilles på fblgende måte: 2-amino-l,8-naftyridin med smeltepunkt 141°C fremstilles ifblge W.W. Paudler og T.J. Kress (J. Org. Chem., 33, 1384 (1968)). The starting compound 2-(1,8-naphthyridin-2-yl)-3-phen-oxycarbonyloxyisoindolin-1-one can be prepared in the following way: 2-amino-1,8-naphthyridine with melting point 141°C is prepared according to W.W. Paudler and T.J. Kress (J. Org. Chem., 33, 1384 (1968)).

8.6 g 2-(1,8-naftyridin-2-yl)ftalimid med smeltepunkt 250°C fremstilles ved at 9,9 g 2-amino-l,8-naftyridin omsettes med 10,2 g ftalsyreanhydrid i 75 cnr dimetylformamid ved 150°C i 1 time og 30 minutter. 8.6 g of 2-(1,8-naphthyridin-2-yl)phthalimide with a melting point of 250°C is prepared by reacting 9.9 g of 2-amino-1,8-naphthyridine with 10.2 g of phthalic anhydride in 75 cnr of dimethylformamide at 150 °C for 1 hour and 30 minutes.

6.7 g 2-(l,8-naftyridin-2-yl)-3-hydroksyisoindolin-1- on med smeltepunkt 228°C fremstilles ved at 1,27 g kaliumborhydrid omsettes med 8,6 g 2-(1,8-naftyridin-2-yl)ftalimid i 78 cm dioksan og 15,6 cm av en mettet vannopplbsning av dinatriumfosfat ved 20°C. 6.7 g of 2-(1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one with a melting point of 228°C is prepared by reacting 1.27 g of potassium borohydride with 8.6 g of 2-(1,8-naphthyridine -2-yl)phthalimide in 78 cm of dioxane and 15.6 cm of a saturated aqueous solution of disodium phosphate at 20°C.

5,6 g 2-(1,8-naftyridin-2-yl)-3-fenoksykarbonyloksy-isoindolin-l-on med smeltepunkt 110 - 112°C fremstilles ved at 5,6 g fenylklorformiat omsettes med 3,9 g 2-(l,8-naftyridin-2- yl)-3-hydroksyisoindolin-l-on i 70 cnr ■ 7. vannfri pyridin ved en temperatur nær 20°C. 5.6 g of 2-(1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one with a melting point of 110 - 112°C is prepared by reacting 5.6 g of phenylchloroformate with 3.9 g of 2- (1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one in 70 cnr ■ 7. anhydrous pyridine at a temperature close to 20°C.

Eksempel 7 Example 7

Man arbeider på samme måte som i eksempel 6, men går ut fra 4,9 g 2-(7-metyl-l,8-naftyridin-2-yl)-3-fenoksykarbo-nyloksyisoindolin-l-on og 6 g 4-metylpiperazin i 40 cm acetonitril. Reaksjonen gjennomføres ved 25°C i 24 timer, hvorved man oppnår 4,2 g av et urent produkt. Dette produkt rives i 42 cnr 3 eter og omkrystalliseres derettter i 300 cm 3 isopropyl-eter. Man oppnår herved 1,1 g 2-(7-metyl-l,8-naftyridin-2-yl)-3- (4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med et smeltepunkt på 190°C. One works in the same way as in example 6, but starts from 4.9 g of 2-(7-methyl-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one and 6 g of 4- methylpiperazine in 40 cm acetonitrile. The reaction is carried out at 25°C for 24 hours, whereby 4.2 g of an impure product is obtained. This product is triturated in 42 cm 3 ether and then recrystallized in 300 cm 3 isopropyl ether. This gives 1.1 g of 2-(7-methyl-1,8-naphthyridin-2-yl)-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with a melting point of 190°C.

Utgangsforbindelsen 2-(7-metyl-l,8-naftyridin-2-yl)-3-fenoksykarbonyloksyisoindolin-l-on kan fremstilles på folgende måte: 2-amino-7-metyl-l,8-naftyridin med smeltepunkt 186 - 187°C fremstilles ifolge E.V. Brovm (J. Org. Chem. 30, 1607 The starting compound 2-(7-methyl-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one can be prepared as follows: 2-amino-7-methyl-1,8-naphthyridine with melting point 186 - 187 °C is produced according to E.V. Brovm (J. Org. Chem. 30, 1607

(1965)). (1965)).

5,4 g 2-(7-metyl-l,8-naftyridin-2-yl)ftalimid fremstilles ved at 3,18 g 7-metyl-2-mino-l,8-naftyridin omsettes med 2,96 g ftalsyreanhydrid i 60 cnr<5> fenyleter i 1 time ved 170°C. 5.4 g of 2-(7-methyl-1,8-naphthyridin-2-yl)phthalimide is prepared by reacting 3.18 g of 7-methyl-2-mino-1,8-naphthyridine with 2.96 g of phthalic anhydride in 60 cnr<5> phenyl ether for 1 hour at 170°C.

5,8. g 2-(7-metyl-l,8-naftyridin-2-yl)-3-hydroksyiso-indolin-l-on med smeltepunkt 208°C fremstilles ved at 0,9 g kaliumbrohydrid omsettes med 6,2 g 2-(7-metyl-l,8-naftyridin-2-yl) f talimid i 60 cnr5 av en blanding av like volumdeler metanol og dioksan. 5.8. g of 2-(7-methyl-1,8-naphthyridin-2-yl)-3-hydroxyiso-indolin-1-one with a melting point of 208°C is prepared by reacting 0.9 g of potassium brohydride with 6.2 g of 2-( 7-methyl-1,8-naphthyridin-2-yl)phthalimide in 60 cnr5 of a mixture of equal parts by volume of methanol and dioxane.

^,9 g 2-(7-metyl-l,8-naftyridin-2-yl)-3-fenoksykar-bonyloksyisoindolin-l-on med smeltepunkt 220°C under spalting fremstilles ved at 9,2 g fenylklorformiat omsettes med 5,8 g 2- (7-metyl-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on i 160 cnr 3 vannfri pyridin ved 5 oC i lbpet av 15 minutter og deretter ved 25°C i 1 time og 30 minutter. ^.9 g of 2-(7-methyl-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one with a melting point of 220°C during cleavage is prepared by reacting 9.2 g of phenylchloroformate with 5, 8 g of 2-(7-methyl-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one in 160 cnr 3 of anhydrous pyridine at 5 oC for 15 minutes and then at 25°C for 1 hour and 30 minutes.

Eksempel 8 Example 8

Man arbeider på samme måte som i eksempel 6, men går ut fra 1,25 g 2-(7-klor-l,8-naftyridin-2-yl)-5-klor-3-fenoksy-karbonyloksyisoindolin-l-on og 1,07 g 4-metylpiperazin i 33 cnr acetonitril. Reaksjonen gjennomføres ved en temperatur nær 20°C i 24 timer, hvorved man oppnår en reaksjonsblanding, hvorfra en felling separeres ved filtrering. Denne felling vaskes i tur og orden med 6 cnr 3 acetonitril og 6 cm 3 eter. Herved oppnår man 0,93 g av et produkt som opploses i 35 cn<r >metylenklorid. Den' oppnådde opplosning ledes gjennom en kolonne med 10 g silikagel. Man eluerer 16 ganger med 20 cn<r >metylenklorid hver gang. De herved oppnådde eluater kasseres. Man eluerer deretter 5 ganger med 20 cm^ etylacetat. De herved oppnådde eluater forenes og konsentreres under redusert trykk. Man oppnår en krystallisert rest med en vekt på 0,9 g. Denne rest suspenderes i 20 cn<r> etylacetat. De dannede krystaller separeres ved filtrering og torkes. Man oppnår herved 0,75 g 3- (4-met.yl-l-piperazinyl)karbonyloksy-5-klor-2-(7-klor-l, 8-naftyridin-2-yl)-isoindolin-l-on med et smeltepunkt på 255°C. One works in the same way as in example 6, but starts from 1.25 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phenoxy-carbonyloxyisoindolin-1-one and 1.07 g of 4-methylpiperazine in 33 cnr of acetonitrile. The reaction is carried out at a temperature close to 20°C for 24 hours, whereby a reaction mixture is obtained, from which a precipitate is separated by filtration. This precipitate is washed in turn with 6 cnr 3 of acetonitrile and 6 cm 3 of ether. This gives 0.93 g of a product which is dissolved in 35 cn<r>methylene chloride. The obtained solution is passed through a column with 10 g of silica gel. Elute 16 times with 20 cn<r>methylene chloride each time. The resulting eluates are discarded. The mixture is then eluted 5 times with 20 cc of ethyl acetate. The eluates thus obtained are combined and concentrated under reduced pressure. A crystallized residue with a weight of 0.9 g is obtained. This residue is suspended in 20 ml of ethyl acetate. The crystals formed are separated by filtration and dried. This gives 0.75 g of 3-(4-methyl-1-piperazinyl)carbonyloxy-5-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-isoindolin-1-one with a melting point of 255°C.

Utgangsforbindelsen 2-(7-klor-l,8-naftyridin-2-yl)-5- klor-3-fénoksykarbonyloksyisoindolin-l-on kan fremstilles på folgende måte: 4-klorftalsyreanhydrid med smeltepunkt 96°C fremstilles ifblge E.E. Ayling (J. Chem. Soc. 1929, 253). 2-amino-7-hydroksy-l,8-naftyridin med smeltepunkt 300 - 305°C fremstilles ifblge S. Carboni et al.(Ann. Chim. (Roma) 54, 883 (1964)). 7 g 2-(7-hydroksy-l,8-naftyridin-2-yl)-5-klorftal-imid med smeltepunkt 320°C fremstilles ved at 9,5 g 2-amino-7-hydroksy-l,8-naftyridin omsettes med 21,5 g 4-klorftalsyreanhydrid i 450 cnr 3 eddiksyre i 1 time ved 116 oC. The starting compound 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phenoxycarbonyloxyisoindolin-1-one can be prepared in the following way: 4-chlorophthalic anhydride with a melting point of 96°C is prepared according to E.E. Ayling (J. Chem. Soc. 1929, 253). 2-amino-7-hydroxy-1,8-naphthyridine with melting point 300 - 305°C is prepared according to S. Carboni et al. (Ann. Chim. (Rome) 54, 883 (1964)). 7 g of 2-(7-hydroxy-1,8-naphthyridin-2-yl)-5-chlorophthalimide with a melting point of 320°C is prepared by adding 9.5 g of 2-amino-7-hydroxy-1,8-naphthyridine react with 21.5 g of 4-chlorophthalic anhydride in 450 cnr 3 acetic acid for 1 hour at 116 oC.

6,4 g 2-(7-klor-l,8-naftyridin-2-yl)-5-klorftalimid med smeltepunkt 280 o C fremstilles ved at 70 cnr 3 fosforoksy-klorid omsettes med 7 g 2-(7-hydroksy-l,8-naftyridin-2-yl)-5-klorftalimid i nærvær av 0,7 cnr 3 dimetylformamid. 6.4 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chlorophthalimide with a melting point of 280 o C is prepared by reacting 70 cnr 3 phosphorus oxychloride with 7 g of 2-(7-hydroxy 1,8-naphthyridin-2-yl)-5-chlorophthalimide in the presence of 0.7 cnr 3 dimethylformamide.

Ved omsetning av 0,75 g kaliumborhydrid med 6,4 g 2- (7-klor-l,8-naftyridin-2-yl)-5-klorftalimid i 300 cm<5> av en blanding av like volumdeler dioksan og metanol oppnår man By reacting 0.75 g of potassium borohydride with 6.4 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chlorophthalimide in 300 cm<5> of a mixture of equal volumes of dioxane and methanol obtains Mon

5,2 g av en blanding av 2-(7-klor-l,8-naftyridin-2-yl)-5-klor-3- hydroksyisoindolin-l-on og 2-(7-klor-l,8-naftyridin-2-yl)-6- klor-3-hydroksyisoindolin-l-on. Man omkrystalliserer denne blanding en fbrste gang i 700 cm 3 dikloretan og deretter en andre gang i 315 cnr 3 av samme opplosningsmiddel. Man oppnår herved 1,51 g av et produkt som man omkrystalliserer fSrst i 38 cm^ bromoform og deretter i 104,5 cnr<5> av en blanding av dikloretan og etanol i et volumforhold på 91:9. Man oppnår herved 0,65 g 2-(7-klor-l,8-naftyridin-2-yl)-5-klor-3-hydrok-syisoindolin-l-on. 5.2 g of a mixture of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxyisoindolin-1-one and 2-(7-chloro-1,8-naphthyridine) -2-yl)-6-chloro-3-hydroxyisoindolin-1-one. This mixture is recrystallized a first time in 700 cm 3 of dichloroethane and then a second time in 315 cnr 3 of the same solvent. This gives 1.51 g of a product which is recrystallized first in 38 cm^ of bromoform and then in 104.5 cnr<5> of a mixture of dichloroethane and ethanol in a volume ratio of 91:9. 0.65 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxyisoindolin-1-one is thereby obtained.

1,6 g 2-(7-klor-l,8-naftyridin-2-yl)-5-klor-3-fen-.oksykarbonyloksyisoindolin-l-on med smeltepunkt 220 - 230°C fremstilles ved at 1 g 2-(7-klor-l,8-naftyridin-2-yl)-5-klor-3-hydroksyisoindolin-l-on omsettes med 1,36 g fenylklorformiat 1.6 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-phen-.oxycarbonyloxyisoindolin-1-one with melting point 220 - 230°C is prepared by 1 g of 2- (7-chloro-1,8-naphthyridin-2-yl)-5-chloro-3-hydroxyisoindolin-1-one is reacted with 1.36 g of phenylchloroformate

3 3

i 15 cn<r> vannfri pyridin. in 15 cn<r> anhydrous pyridine.

Eksempel 9 Example 9

En suspensjon av 3,45 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fenoksykarbonyloksyisoindolin-l-on og 5,20 g l-(2-hydroksyetyl)piperazin i 21 cm^ acetonitril omrbres i 5 timer ved en temperatur-nær 20°C. Suspensjonen filtreres og det faste produkt vaskes med 2x2 cnr - z. acetonitril, hvoretter det torkes. Man oppnår herved 1,7 g av et produkt som smelter A suspension of 3.45 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one and 5.20 g of 1-(2-hydroxyethyl)piperazine in 21 cc of acetonitrile stirred for 5 hours at a temperature close to 20°C. The suspension is filtered and the solid product is washed with 2x2 cnr - z. acetonitrile, after which it is dried. This gives 1.7 g of a product which melts

o 3 and 3

ved 175 C. Man setter 250 cn<r> destillert vann til moder- at 175 C. One adds 250 cn<r> of distilled water to the mother-

luten. Etter én natts ro separeres de dannede krystaller ved filtrering, hvoretter de vaskes med 3 x 20 cnr5 destillert vann og torkes. Man oppnår herved 1,25 g av et produkt som smelter ved 160°C. De oppnådde faste produkter forenes og omkrystalliseres i 20 cn<r> acetonitril. Man oppnår herved 2 g 2- (7-klor-l,8-naftyridin-2-yl)-3-^5-(2-hydroksyetyl)-l-piperazinyl7-karbonyloksyisoindolin-l-on med smeltepunkt 179 - 180°C. the lye. After one night's rest, the formed crystals are separated by filtration, after which they are washed with 3 x 20 cnr5 of distilled water and dried. This gives 1.25 g of a product which melts at 160°C. The solid products obtained are combined and recrystallized in 20 ml of acetonitrile. 2 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-[5-(2-hydroxyethyl)-1-piperazinyl-7-carbonyloxyisoindolin-1-one with a melting point of 179 - 180°C are thereby obtained .

Utgangsforbindelsen 2-(7-klor-l,8-naftyridin-2-yl)-3- fenoksykarbonyloksyisoindolin-l-on kan fremstilles på fol- The starting compound 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one can be prepared on fol-

gende måte: way:

Til en suspensjon av 86,5 g 2-(7-klor-l,8-naftyridin-2-yl)-3-hydroksyisoindolin-l-on i 980 cnr5 pyridin setter man 126 g fenylklorformiat mens temperaturen holdes nær 25°C. To a suspension of 86.5 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-1-one in 980 cnr5 of pyridine is added 126 g of phenylchloroformate while the temperature is kept close to 25°C.

Man omrbrer deretter reaksjonsblandingen i 3 timer ved en temperatur nær 20°C, hvoretter man heller reaksjonsblandingen i 9000 cnr isvann. Det herved utkrystalliserte produkt sepa- The reaction mixture is then stirred for 3 hours at a temperature close to 20°C, after which the reaction mixture is poured into 9000 ml of ice water. The thus crystallized product sepa-

reres ved filtrering, vaskes med 6 x 500 cm vann og deretter med 3 x 200 cnr •z acetonitril. Etter tbrking oppnår man 96,7 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fenoksykarbonyloksyisoindolin-1-on som smelter ved 235°C under spalting. purified by filtration, washed with 6 x 500 cm of water and then with 3 x 200 cnr •z of acetonitrile. After drying, 96.7 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one is obtained which melts at 235°C during cleavage.

2-(7-klor-l,8-naftyridin-2-yl)-3-hydroksyisoindolin- 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxyisoindolin-

1-on kan fremstilles på samme måte som beskrevet i eksempel 1. Eksempel 10. 1-one can be prepared in the same way as described in example 1. Example 10.

Ved å arbeide på samme måte som i eksempel 9, men By working in the same way as in example 9, but

ved å gå ut fra 3,45 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fen-oksykarbonyloksyisoindolin-l-on og 5,05 g 1-allylpiperazin i 21 cnr<5> acetonitril oppnår man 1,65 g 3-(4-allyl-l-piperazinyl)-karbonyloksyl-2-(7-klor-l,8-naftyridin-2-yl)isoindolin-l-on med et smeltepunkt på 186 - 187°C. starting from 3.45 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phen-oxycarbonyloxyisoindolin-1-one and 5.05 g of 1-allylpiperazine in 21 cnr<5> acetonitrile yields 1.65 g of 3-(4-allyl-1-piperazinyl)-carbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)isoindolin-1-one with a melting point of 186 - 187 °C.

Eksempel 11 Example 11

Ved å arbeide på samme måte som i eksempel 9, men By working in the same way as in example 9, but

ved å gå ut fra 2,58 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fen-oksykarbonyloksyisoindolin-l-on og 3,42 g 1-etylpiperazin i 16 cnr5 acetonitril oppnår man 1,4 g 2-(7-klor-l,8-naftyridin- by starting from 2.58 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phen-oxycarbonyloxyisoindolin-1-one and 3.42 g of 1-ethylpiperazine in 16 cnr5 of acetonitrile, one obtains 1.4 g of 2-(7-chloro-1,8-naphthyridine-

2-yl)-3-(4-etyl-I-piperazinyl)-karbonyloksyisoindolin-l-on med et smeltepunkt på 195°C. 2-yl)-3-(4-ethyl-1-piperazinyl)-carbonyloxyisoindolin-1-one with a melting point of 195°C.

Eksempel 12 Example 12

Ved å arbeide på samme måte som i eksempel 9, men By working in the same way as in example 9, but

ved å gå ut fra 4,32 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fen-oksykarbonyloksyisoindolin-l-on og 6,2 g 1-propargylpiperazin i 27 cnr5 acetonitril oppnår man 2,05 g 2-(7-klor-l, 8-naf tyri-din- 2-yl)-3-(4-propargyl-l-piperazinyl)karbonyloksyisoindolin-1- on med et smeltepunkt på 210°C. by starting from 4.32 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phen-oxycarbonyloxyisoindolin-1-one and 6.2 g of 1-propargylpiperazine in 27 cnr5 acetonitrile one obtains 2.05 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-propargyl-1-piperazinyl)carbonyloxyisoindolin-1-one with a melting point of 210°C.

Eksempel 13 Example 13

Ved å arbeide på samme måte som i eksempel 9, men ved å gå ut fra 2,47 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fen-oksykarbonyloksyisoindolin-l-on og 3,66 g 1-isopropylpipera-zin og 15 cn<r> acetonitril oppnår man 2,25 g 2-(7-klor-l,8-naftyridin- 2-yl)-3-(4-isopropyl-l-piperazinyl)karbonyloksyiso-indolin-l-on med et smeltepunkt på 203 - 204°C. By working in the same way as in example 9, but starting from 2.47 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phen-oxycarbonyloxyisoindolin-1-one and 3 .66 g of 1-isopropylpiperazine and 15 ml of acetonitrile yield 2.25 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-isopropyl-1-piperazinyl) carbonyloxyiso-indolin-l-one with a melting point of 203 - 204°C.

Eksempel 14 Example 14

Ved å arbeide på samme måte som i eksempel 9, men ved å gå ut fra 5,1 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fenok-sykarbonyloksyisoindolin-l-on og 5 g 1-tert.butylpiperazin i 31 cnr5 acetonitril oppnår man 3,3 g 2-(7-klor-l,8-naftyridin-2- yl)-3-(4-tert.butyl-l-piperazinyl)karbonyloksyisoindolin-l-on med et smeltepunkt på 240°C. By working in the same way as in example 9, but starting from 5.1 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxyisoindolin-1-one and 5 g 1-tert.butylpiperazine in 31 cnr5 acetonitrile yields 3.3 g 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-tert.butyl-1-piperazinyl)carbonyloxyisoindolin-1 -on with a melting point of 240°C.

1-tert.butylpiperazin kan fremstilles på fblgende måte: Til en suspensjon av 140,7 g N,N-bis(2-kloretyl)-butylamin-hydroklorid i 750 cnr 3 etanol setter man 447 cnr 3 av en etanolopplbsning av natriumetylat inneholdende 1,34 mol/ltr. og deretter 1305 cm 3 av en etanolopplbsning av ammoniakk inneholdende 4,6 mol/ltr. Reaksjonsblandingen oppvarmes deretter til en temperatur nær 60°C i 1 time, hvorved ammoniakken får lbpe tilbake ved hjelp av en kjoler inneholdende fast karbon-dioksyd. Ammoniakken tillates deretter å dampe av, og man avkjbler reaksjonsblandingen til en temperatur nær 20°C under en strbm av nitrogengass. Man tilsetter deretter 894 cm av en etanolopplbsning av natriumetylat, inneholdende 1,34 mol/ltr. Det utfelte natriumklorid separeres ved filtrering og vaskes med 150 cnr 3 etanol. Filtratet konsentreres til torr tilstand 1-tert.butylpiperazine can be prepared in the following way: To a suspension of 140.7 g of N,N-bis(2-chloroethyl)-butylamine hydrochloride in 750 cnr 3 of ethanol, 447 cnr 3 of an ethanol solution of sodium ethylate containing 1 .34 mol/l. and then 1305 cm 3 of an ethanol solution of ammonia containing 4.6 mol/litre. The reaction mixture is then heated to a temperature close to 60°C for 1 hour, whereby the ammonia is recovered by means of a colander containing solid carbon dioxide. The ammonia is then allowed to evaporate, and the reaction mixture is cooled to a temperature close to 20°C under a stream of nitrogen gas. 894 cm of an ethanol solution of sodium ethylate, containing 1.34 mol/litre, is then added. The precipitated sodium chloride is separated by filtration and washed with 150 cnr 3 of ethanol. The filtrate is concentrated to dryness

under redusert trykk, og den oppnådde rest opptas i 300 cm^ eter. Det ulbselige produkt separeres ved filtrering og vaskes med 60 cn<r> eter. Filtratet konsentreres til torr tilstand og destilleres deretter under redusert trykk. Man oppnår herved 8,8 g 1-tert.butylpiperazin med et kokepunkt på under reduced pressure, and the residue obtained is taken up in 300 cm^ of ether. The insoluble product is separated by filtration and washed with 60 cn<r> of ether. The filtrate is concentrated to dryness and then distilled under reduced pressure. 8.8 g of 1-tert.butylpiperazine with a boiling point of

85 - 86°C under et trykk på 28 mm Hg. 85 - 86°C under a pressure of 28 mm Hg.

Hydrokloridet av N,N-bis(2-kloretyl)butylamin kan fremstilles ifblge den fremgangsmåte som er beskrevet av A. Katritsky (J. Chem. Soc. B, 556 (1966)). The hydrochloride of N,N-bis(2-chloroethyl)butylamine can be prepared according to the method described by A. Katritsky (J. Chem. Soc. B, 556 (1966)).

Eksempel 15 Example 15

Til en suspensjon av 2,0 g dihydroklorid av 1-metylpiperazin-l-oksyd i 10 cnr 3 vannfri metanol setter man 6,7 cnr3 av en 3,l6N metanolopplbsning av natriummetylat. Etter 10 minutters omrbring ved 25°C setter man 0,1 g avfargingskull til suspensjonen, hvoretter kullet fjernes ved filtrering. Det metanoliske filtrat dampes inn under redusert trykk (20 mm Hg) ved hbyst 40°C. Den oljeaktige resten på 2,0 g opploses i 50 cnr vannfri acetonitril, hvoretter man tilsetter 2,15 g 2-(7-klor-l,8-naftyridin-2-yl)-3-fenoksykarbonyloksy-isoindolin-l-on. Reaksjonsblandingen oppvarmes i 4 timer til 50°C, omrbres deretter i 48 timer ved en temperatur nær 25°C, filtreres og konsentreres under redusert trykk. Resten på 3,8 g opplbses i 50 cm metylenklorid. Oppløsningen ledes gjennom en kolonne med 60 g silikagel "Merck" (0,02 - 0,05). To a suspension of 2.0 g of dihydrochloride of 1-methylpiperazine-1-oxide in 10 cnr 3 of anhydrous methanol is added 6.7 cnr 3 of a 3.16N methanol solution of sodium methylate. After stirring for 10 minutes at 25°C, 0.1 g of decolorizing charcoal is added to the suspension, after which the charcoal is removed by filtration. The methanolic filtrate is evaporated under reduced pressure (20 mm Hg) at a maximum of 40°C. The oily residue of 2.0 g is dissolved in 50 cnr of anhydrous acetonitrile, after which 2.15 g of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one are added. The reaction mixture is heated for 4 hours to 50°C, then stirred for 48 hours at a temperature close to 25°C, filtered and concentrated under reduced pressure. The residue of 3.8 g is dissolved in 50 cm methylene chloride. The solution is passed through a column with 60 g of silica gel "Merck" (0.02 - 0.05).

3 3 Man eluerer med i tur og orden 50 cn<r> metylenklorid, 50 cm etylacetat, 50 cm ■5 av en blanding av etylacetat og metanol i volumforholdet 80:20, 50 cnr •5 av en blanding av like volumdeler etylacetat og metanol, og til slutt 100 cnr ■5 av samme opp-lbsningsmiddelblanding. Denne siste eluatfraksjon dampes inn under redusert trykk. Den oppnådde resten (0,9 g; smeltepunkt nær 200°C) opplbses i 10 ctdP acetonitril og 1 cm^ destillert vann ved en temperatur nær koketemperaturen. Etter 3 3 Elute with, in turn, 50 cn<r> of methylene chloride, 50 cm of ethyl acetate, 50 cm ■5 of a mixture of ethyl acetate and methanol in the volume ratio 80:20, 50 cnr •5 of a mixture of equal parts by volume of ethyl acetate and methanol , and finally 100 cnr ■5 of the same solvent mixture. This last eluate fraction is evaporated under reduced pressure. The residue obtained (0.9 g; melting point near 200°C) is dissolved in 10 ctdP of acetonitrile and 1 cm 3 of distilled water at a temperature close to the boiling temperature. After

avkjbling til 2°C separeres de dannede krystaller av ved filtrering, vaskes med 0,5 cn<r> iskald acetonitril og torkes under redusert trykk (20 mm Hg). Man oppnår herved 0,62 g 4-/^2-(7-klor-1,8-naftyridin-2-yl)-3-okso-l-isoindolinyl7oksykarbonyl)-1-metylpiperazin-l-oksyd-dihydrat, som smelter ved en temperatur nær 200°C und spalting. cooling to 2°C, the formed crystals are separated by filtration, washed with 0.5 cn<r> of ice-cold acetonitrile and dried under reduced pressure (20 mm Hg). This gives 0.62 g of 4-(2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl7oxycarbonyl)-1-methylpiperazine-1-oxide dihydrate, which melts at a temperature close to 200°C und cleavage.

Dihydrokloridet av 1-metylpiperazin-l-oksyd kan frem- The dihydrochloride of 1-methylpiperazine-1-oxide can produce

stilles på folgende måte: set as follows:

15,0 g oljeaktig tert.butyl-(4-metyi:-lrpiperazinyI)-karboksylat fremstilles ved at 12,9 g tert.butylazidoformiat omsettes med 9,5 g 1-metylpiperazin i 30 cnr5 vann og 15 cm^ tetrahydrofuran, hvorved man progressivt tilsetter 19 cnr5 5N natriumhydroksydopplosning ved en temperatur nær 20°C. 15.0 g of oily tert-butyl-(4-methyl:-1-piperazinyl)-carboxylate is prepared by reacting 12.9 g of tert-butyl azidoformate with 9.5 g of 1-methylpiperazine in 30 cm3 of water and 15 cm3 of tetrahydrofuran, whereby progressively add 19 cnr5 5N sodium hydroxide solution at a temperature close to 20°C.

8,7 g hydroklorid av l-metyl-4-tert.butyloksykarbo-nylpiperazin-l-oksyd med smeltepunkt 233°C fremstilles ved at 34,0 g 4-nitroperbenzosyre omsettes med 24,2 g tert.butyl-(4-metyl-l-piperazinyl)-karboksylat i 240 cm^ vannfri kloroform ved en temperatur som.ikke overstiger 40°C. 8.7 g of hydrochloride of 1-methyl-4-tert.butyloxycarbonylpiperazine-1-oxide with a melting point of 233°C is prepared by reacting 34.0 g of 4-nitroperbenzoic acid with 24.2 g of tert.butyl-(4-methyl -1-piperazinyl)carboxylate in 240 cc of anhydrous chloroform at a temperature not exceeding 40°C.

5,5 g dihydroklorid av 1-metylpiperazin-l-oksyd med smeltepunkt 205°C fremstilles ved at 2,35 g vannfri, gass-formig hydrogenklorid omsettes med 8,1 g hydroklorid av 1-metyl-4-tert .butyloksykarbonylpiperazin-l-oksyd i 60 cm-5 vannfri etanol under tilbakelbpskoking i 30 minutter. 5.5 g of dihydrochloride of 1-methylpiperazine-1-oxide with a melting point of 205°C is prepared by reacting 2.35 g of anhydrous, gaseous hydrogen chloride with 8.1 g of hydrochloride of 1-methyl-4-tert.butyloxycarbonylpiperazine-1 -oxide in 60 cm-5 anhydrous ethanol under reflux for 30 minutes.

Eksempel 16 - 19 Examples 16 - 19

Ved å arbeide på samme måte som i eksempel 2 og By working in the same way as in example 2 and

gå ut fra egnede utgangsstoffer, fremstilles også folgende forbindelser. starting from suitable starting materials, the following compounds are also produced.

Eksempel 16: 2-(7-klor-l,8-naftyridin-2-yl)-5-fluor-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med smeltepunkt 247 - 248°C. Example 16: 2-(7-chloro-1,8-naphthyridin-2-yl)-5-fluoro-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with melting point 247 - 248°C.

Eksempel 17: 2-(7-klor-l,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)karbonyloksy-5-nitroisoindolin-l-on med smeltepunkt 250°C. Example 17: 2-(7-chloro-1,8-naphthyridin-2-yl)-3-(4-methyl-1-piperazinyl)carbonyloxy-5-nitroisoindolin-1-one with melting point 250°C.

Eksempel 18: 2-(7-klor-l,8-naftyridin-2-yl)-5-met oksy-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med smeltepunkt 206°C. Example 18: 2-(7-chloro-1,8-naphthyridin-2-yl)-5-methoxy-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with melting point 206°C.

Eksempel 19: 2-(7-fluor-1,8-naftyridin-2-yl)-3-(4-metyl-l-piperazinyl)karbonyloksyisoindolin-l-on med smeltepunkt 198 - 200°C. Example 19: 2-(7-fluoro-1,8-naphthyridin-2-yl)-3-(4-methyl-1-piperazinyl)carbonyloxyisoindolin-1-one with melting point 198 - 200°C.

Eksempel 20 Example 20

Ved å arbeide på samme måte som i eksempel 9 og gå ut fra egnede utgangsstoffer fremstilles også 3-/^-(3-buten-l-yl)-l-piperazinyl7karbonyloksy-2-(7-klor-l,8-naftyridin-2-yl)-isoindolin-l-on med smeltepunkt 142°C. By working in the same way as in example 9 and starting from suitable starting materials, 3-(3-buten-1-yl)-1-piperazinyl-7carbonyloxy-2-(7-chloro-1,8-naphthyridine- 2-yl)-isoindolin-1-one with melting point 142°C.

Nær beslektede forbindelser med de samme terapeutiske egenskaper er kjent fra de norske utlegningsskrifter nr. Closely related compounds with the same therapeutic properties are known from Norwegian explanatory documents no.

132.932, 133.142, 136.840 og 136.843 samt fra det svenske utlegnings skrift fir. 384.026. 132,932, 133,142, 136,840 and 136,843 as well as from the Swedish interpretation letter four. 384,026.

De nye forbindelser med formelen (i) oppviser imid-lertid bedre terapeutiske egenskaper enn disse kjente forbindelser, noe som fremgår av de nedenfor folgende sammenlignings-forsbk. Ved de anvendte forsbksmetoder dreier det seg om de som er angitt tidligere. The new compounds with the formula (i), however, exhibit better therapeutic properties than these known compounds, which is evident from the comparative examples below. The experimental methods used are those indicated earlier.

De anvendte sammenligningsforbindelser er som fol-ger: Forbindelsen i henhold til eksempel 6 i 132.932; forbindelsen ifblge eksempel 1 i 133.142; forbindelsen ifblge eksempel 2 i 136.840; forbindelsen ifblge eksempel 1 i 136.843 samt forbindelsen ifblge eksempel 1 i svensk utlegningsskrift 384.026. The comparison compounds used are as follows: The compound according to example 6 in 132,932; the compound according to example 1 in 133,142; the compound according to example 2 in 136,840; the connection according to example 1 in 136,843 and the connection according to example 1 in Swedish interpretation document 384,026.

De oppnådde resultater er sammenfattet i folgende tabell. The results obtained are summarized in the following table.

Claims (1)

Analogifremgangsmåter for fremstilling av nye terapeutisk aktive derivater av naftyridin med den generelle formel:Analogous methods for the preparation of new therapeutically active derivatives of naphthyridine with the general formula: samt syreaddisjonssalter derav, der Y betegner et hydrogenatom, et halogenatom, en alkylgruppe inneholdende 1-4 karbonatomer, en alkoksygruppe hvis alkyldel inneholder 1-4 karbonatomer eller en cyangruppe, der Z betegner et hydrogenatom, et halogenatom, en alkoksygruppe hvis alkyldel inneholder 1-4 karbonatomer eller en nitrogruppe, og der ,(l) n er lik 0, hvorved R angir en alkylgruppe inneholdende 1-4 karbonatomer, en alkenylgruppe inneholdende 2-4 karbonatomer, en alkynylgruppe inneholdende 2-4 karbonatomer, eller en hydroksyalkylgruppe hvis alkyldel inneholder 1-4 karbonatomer, eller (2) n er lik 1, hvorved R angir en alkylgruppe inneholdende 1-4 karbonatomer, en hydroksyalkylgruppe hvis alkyldel inneholder 1-4 karbonatomer,as well as acid addition salts thereof, where Y denotes a hydrogen atom, a halogen atom, an alkyl group containing 1-4 carbon atoms, an alkoxy group whose alkyl part contains 1-4 carbon atoms or a cyano group, where Z denotes a hydrogen atom, a halogen atom, an alkoxy group whose alkyl part contains 1- 4 carbon atoms or a nitro group, and where ,(l) n is equal to 0, whereby R denotes an alkyl group containing 1-4 carbon atoms, an alkenyl group containing 2-4 carbon atoms, an alkynyl group containing 2-4 carbon atoms, or a hydroxyalkyl group whose alkyl part contains 1-4 carbon atoms, or (2) n is equal to 1, whereby R denotes an alkyl group containing 1-4 carbon atoms, a hydroxyalkyl group whose alkyl part contains 1-4 carbon atoms, karakterisert ved at (a) når n er lik 0 og R har den ovenfor angitte tilsvarende betydning, et klorkarbonylpiperazin med den generelle formelcharacterized in that (a) when n is equal to 0 and R has the corresponding meaning indicated above, a chlorocarbonylpiperazine of the general formula der R har den ovenfor angitte betydning, omsettes med et derivat av naftyridin med den generelle formel:where R has the meaning given above, is reacted with a derivative of naphthyridine with the general formula: der Y og Z har den ovenfor angitte betydning; eller at (b) når n er lik 0 eller 1, og R har den ovenfor angitte tilsvarende betydning, et piperazin med den generelle ,formel:where Y and Z have the above meaning; or that (b) when n is equal to 0 or 1, and R has the corresponding meaning given above, a piperazine of the general formula: der n og R har den ovenfor angitte betydning, omsettes med et blandet karbonat med den generelle formel:where n and R have the meaning given above, is reacted with a mixed carbonate of the general formula: der Y og Z har den ovenfor angitte betydning og Ar betyr en fenylgruppe, hvilken eventuelt er substituert; eller at (c) når n er lik 1 og R har den ovenfor angitte tilsvarende betydning, en forbindelse med den generelle formel (i) der n er lik 0, og R har den ovenfor angitte betydning, oksyderes; hvoretter det oppnådde produkt eventuelt omdannes til et addi-sjonssalt med en syre.where Y and Z have the meaning indicated above and Ar means a phenyl group, which is optionally substituted; or that (c) when n is equal to 1 and R has the corresponding meaning indicated above, a compound of the general formula (i) where n is equal to 0, and R has the meaning indicated above, is oxidized; after which the product obtained is optionally converted into an addition salt with an acid.
NO741744A 1973-05-15 1974-05-14 ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTICALLY ACTIVE DERIVATIVES OF NAFTYRIDINE NO140012C (en)

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FR7408730A FR2263752A1 (en) 1974-03-14 1974-03-14 1,8-Naphthyridine derivs - tranquillizers and anti-convulsants
FR7408728A FR2286642A2 (en) 1974-03-14 1974-03-14 2-(Naphthyridin-2-yl)-isoindolin-1-one derivs - contg. 3-(piperazin-1-yl-carbonyloxy) gp., used as tranquillisers and antidepressants

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FR2322600A1 (en) * 1975-09-04 1977-04-01 Rhone Poulenc Ind Pyrrolidinone deriirrivs as tranquillizers - 1-Heterocyclyl-5(1-piperazinyl-carbonyloxy)-2(5H)-pyrrolidinone derivs prepd. from 5-aryloxycarbonyloxy cpds. and piperazine (OE060576)
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