NO137011B

NO137011B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF DIURETICALLY PYRIDO (3,4-D) PYRIDAZINE DERIVATIVES

Info

Publication number: NO137011B
Application number: NO477572A
Authority: NO
Inventors: Shojiro Yurugi; Shintaro Kikuchi; Yoshikazu Oka; Akio Miyake; Katsumi Ito; Kiyoshi Omura
Original assignee: Takeda Chemical Industries Ltd
Priority date: 1971-12-28
Filing date: 1972-12-27
Publication date: 1977-09-05
Also published as: CA987323A; FR2166101B1; FR2166101A1; CH590278A5; BE793345A; NO137011C; NL7217773A; DE2262912A1

Description

Foreliggende oppfinnelse angår fremstilling av nye The present invention relates to the production of new

diuretisk virksomme pyrido(3,4-d)pyridazinderivater. diuretically active pyrido(3,4-d)pyridazine derivatives.

Det har vært syntetisert mange typer diuretika, og noen av dem har vært anvendt i praksis, og som typiske eksempler kan nevnes klortiazid-derivater, acetazolamid, triamteren, trifrocin og furosemid. Many types of diuretics have been synthesized, and some of them have been used in practice, and typical examples include chlorothiazide derivatives, acetazolamide, triamterene, trifrocin and furosemide.

De kjente diuretika har imidlertid ikke særlig tilfredsstillende virkning på grunn av en eller flere ulemper slik som at de fremmer en utskillelse av kalium såvel som natrium, frembringer bivirkninger (f.eks. øker innholdet av glukose og urinsyre i blodet) ved langtidstilførsel, og viser relativt lav diuretisk aktivitet og temmelig høy toksisitet. However, the known diuretics do not have a particularly satisfactory effect due to one or more disadvantages such as that they promote excretion of potassium as well as sodium, produce side effects (e.g. increases the content of glucose and uric acid in the blood) with long-term administration, and show relatively low diuretic activity and fairly high toxicity.

Ifølge foreliggende oppfinnelse er det tilveiebragt nye pyrido(3,4-d)pyridazinderivater som ikke har de ovenfor omtalte ulemper, og som har den generelle formel: According to the present invention, new pyrido(3,4-d)pyridazine derivatives have been provided which do not have the above-mentioned disadvantages, and which have the general formula:

hvor R-^ er hydrogen eller en lavere alkylgruppe med 1-4 karbonatomer, R_ er en alkylgruppe med 1-4 karbonatomer, en benzyl- eller fenetylgruppe, eller en substituert eller usubstituert fenyl-, naftyl-, furyl- eller pyridyl-gruppe, hvor substituenten er en lavere alkoksygruppe med 1-3 karbonatomer, en lavere alkylgruppe med 1-3 karbonatomer, halogen eller nitro, R, er hydrogen eller en lavere alkoksygruppe med 1-4 where R-^ is hydrogen or a lower alkyl group with 1-4 carbon atoms, R_ is an alkyl group with 1-4 carbon atoms, a benzyl or phenethyl group, or a substituted or unsubstituted phenyl, naphthyl, furyl or pyridyl group, where the substituent is a lower alkoxy group with 1-3 carbon atoms, a lower alkyl group with 1-3 carbon atoms, halogen or nitro, R, is hydrogen or a lower alkoxy group with 1-4

karbonatomer og hvor R4 er en substituert eller en usubstituert morfolino-, piperidino- eller pyrrolidinogruppe hvor substituenten kan være metyl eller etyl, samt farmasøytisk akseptable salter derav. carbon atoms and where R4 is a substituted or an unsubstituted morpholino, piperidino or pyrrolidino group where the substituent can be methyl or ethyl, as well as pharmaceutically acceptable salts thereof.

Alkylgruppen med 1-4 karbonatomer kan eksemplifiseres ved metyl, etyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl eller t-butyl. The alkyl group with 1-4 carbon atoms can be exemplified by methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl.

Den lavere alkoksygruppen med 1-4 karbonatomer kan f.eks. være metoksy, etoksy, n-propoksy, i-propoksy, n-butoksy, i-butoksy eller s-butoksy, t-butoksy. The lower alkoxy group with 1-4 carbon atoms can e.g. be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy or s-butoxy, t-butoxy.

Den lavere alkoksygruppen med 1-3 karbonatomer kan være metoksy, etoksy, n-propoksy eller i-propoksy; alkylgruppen med 1-3 karbonatomer kan være metyl, etyl, n-propyl, i-propyl, mens halogenet kan være klor, brom, fluor eller jod. The lower alkoxy group with 1-3 carbon atoms can be methoxy, ethoxy, n-propoxy or i-propoxy; the alkyl group with 1-3 carbon atoms can be methyl, ethyl, n-propyl, i-propyl, while the halogen can be chlorine, bromine, fluorine or iodine.

Farmasøytisk akseptable salter av forbindelsen med formel I omfatter tilsvarende uorganiske salter slik som salt-syresalt, svovelsyresalt, salpetersyresalt og lignende, såvel som tilsvarende organiske syrer slik som oksalsyresalt, fumar-syresalt, vinsyresalt, maleinsyre og lignende. Pharmaceutically acceptable salts of the compound of formula I include corresponding inorganic salts such as hydrochloric acid salt, sulfuric acid salt, nitric acid salt and the like, as well as corresponding organic acids such as oxalic acid salt, fumaric acid salt, tartaric acid salt, maleic acid and the like.

Ifølge foreliggende oppfinnelse fremstilles forbin-delsene med formel I ved at man According to the present invention, the compounds of formula I are prepared by

A) omsetter en forbindelse med den generelle formel: A) reacts a compound with the general formula:

hvor hver av R^, R2 og R^ har den ovenfor angitte betydning, og X er halogen eller en tiogruppe, med en substituert eller usubstituert morfolin-, piperidin- eller pyrrolidin-forbindelse, hvor substituenten kan være metyl eller etyl, eller B) oksyderer en forbindelse med den generelle formel: where each of R^, R2 and R^ has the above meaning, and X is halogen or a thio group, with a substituted or unsubstituted morpholine, piperidine or pyrrolidine compound, where the substituent can be methyl or ethyl, or B) oxidizes a compound with the general formula:

hvor hver av gruppene P^, R-^ og R^ har den ovenfor angitte betydning, og R^ er en benzyl-, allyl- eller t-butylgruppe, med kaliumferricyanid, oksygen eller nitrobenzen, where each of the groups P^, R-^ and R^ has the above meaning, and R^ is a benzyl, allyl or t-butyl group, with potassium ferricyanide, oxygen or nitrobenzene,

og, om ønsket, omdanner en således erholdt forbindelse til et farmasøytisk akseptabelt salt derav. and, if desired, converting a compound thus obtained into a pharmaceutically acceptable salt thereof.

Nevnte halogenatomer representert ved X kan være klor, brom, fluor eller jod. Said halogen atoms represented by X can be chlorine, bromine, fluorine or iodine.

Utgangsforbindelsene (II) og (III) kan fremstilles ved kjente fremgangsmåter eller analoge fremgangsmåter til disse. The starting compounds (II) and (III) can be prepared by known methods or methods analogous thereto.

Utgangsforbindelsen med generell formel (II) hvor X er et halogen, kan f.eks. fremstilles ved en fremgangsmåte hvor man omsetter en forbindelse med følgende generelle formler: The starting compound with general formula (II) where X is a halogen, can e.g. is produced by a process where a compound with the following general formulas is reacted:

(IV) eller (V): (IV) or (V):

hvor hver R-^, R2 og R, har samme betydning som angitt ovenfor, where each R 1 , R 2 and R 1 have the same meaning as indicated above,

og Rg er en lavere alkylgruppe med 1-3 karbonatomer, med hydrazin, hvorved man får fremstilt en forbindelse med følgende generelle formel (VI): and Rg is a lower alkyl group with 1-3 carbon atoms, with hydrazine, whereby a compound with the following general formula (VI) is produced:

hvor hver R^, R2 og R^ har samme betydning som angitt ovenfor, hvoretter man omsetter nevnte fremstilte forbindelse (VI) med fosfor oksyhalogenid for derved å få fremstilt en forbindelse med følgende generelle formel (VII): where each R^, R2 and R^ has the same meaning as stated above, after which said prepared compound (VI) is reacted with phosphorus oxyhalide to thereby obtain a compound with the following general formula (VII):

hvor R-^, R2 og R^ har samme betydning som angitt ovenfor, og Y er halogen. where R 1 , R 2 and R 2 have the same meaning as stated above, and Y is halogen.

Utgangsforbindelsen (II) hvor X er en tiogruppe, kan fremstilles ved en fremgangsmåte som omfatter at man omsetter forbindelsen med generell formel VII med en hydrosulfidmetall-forbindelse slik som natriumhydrosulfid, hvorved man får fremstilt en forbindelse med følgende generelle formel (VIII): The starting compound (II) where X is a thio group, can be prepared by a method which comprises reacting the compound of general formula VII with a hydrosulfide metal compound such as sodium hydrosulfide, whereby a compound of the following general formula (VIII) is produced:

hvor hver R-^, R2 og R^ har samme betydning som angitt ovenfor, hvoretter man omsetter denne forbindelse (VIII) med en forbindelse med følgende generelle formel (IX): hvor R er en lavere alkylgruppe med fra 1 til 3 karbonatomer, en aralkylgruppe med fra 7 til 8 karbonatomer så som benzyl eller fenetyl eller en aromatisk gruppe så som fenyl eller tolyl og Z er et halogenatom eller en aromatisk sulfonyloksy-gruppe som p-toluensulfonyloksygruppe, hvorved man får fremstilt en forbindelse med følgende generelle formel (X): hvor R^, R2, R^ og R har samme betydning som angitt ovenfor, og hvor man eventuelt kan omsette den fremstilte forbindelse (X) med et oksydasjonsmiddel slik som hydrogenperoksyd, m-klorper-benzoesyre, pereddiksyre eller lignende, hvorved man får fremstilt en forbindelse vist ved følgende generelle formler (XI) og/eller (XII): where each R-^, R 2 and R^ has the same meaning as indicated above, after which this compound (VIII) is reacted with a compound of the following general formula (IX): where R is a lower alkyl group having from 1 to 3 carbon atoms, a aralkyl group with from 7 to 8 carbon atoms such as benzyl or phenethyl or an aromatic group such as phenyl or tolyl and Z is a halogen atom or an aromatic sulfonyloxy group such as p-toluenesulfonyloxy group, whereby a compound of the following general formula (X) is produced : where R^, R2, R^ and R have the same meaning as stated above, and where the compound (X) produced can optionally be reacted with an oxidizing agent such as hydrogen peroxide, m-chloroper-benzoic acid, peracetic acid or the like, whereby one obtains prepared a compound shown by the following general formulas (XI) and/or (XII):

hvor hver R^, R2, R-j og R har samme betydning som angitt ovenfor . where each R 1 , R 2 , R 1 and R 2 have the same meaning as indicated above.

Utgangsforbindelsen med generell formel III kan f.eks. fremstilles ved en fremgangsmåte som omfatter at man fremstiller en forbindelse med generell formel (XIII): The starting compound with general formula III can e.g. is prepared by a method which comprises preparing a compound of general formula (XIII):

hvor hver R2, R^, R 4 og R^ har samme betydning som angitt ovenfor, på samme måte som nevnt i forbindelse med fremgangsmåte (A), hvoretter man hydrogenerer den fremstilte forbindelse med formel XIII i nærvær av en katalysator slik som palladium-karbon. where each R 2 , R 4 , R 4 and R 4 have the same meaning as indicated above, in the same manner as mentioned in connection with method (A), after which the prepared compound of formula XIII is hydrogenated in the presence of a catalyst such as palladium- carbon.

Med hensyn til fremgangsmåte (A) hvor man går ut fra en forbindelse II hvor X er halogen, kan reaksjonen utføres i nærvær eller fravær av et oppløsningsmiddel. Man kan anvende ethvert oppløsningsmiddel som ikke forstyrrer reaksjonen, slik som f.eks. alkoholer som metylalkoholer, etylalkohol, etc, etere slik som tetrahydrofuran, etyleter, etc, hydrokarboner og halogenerte hydrokarboner slik som benzen, kloroform, etc, estere som etylacetat, etc For å fjerne det hydrogenhalogenid som fremstilles under reaksjonen kan man i reaksjonssystemet inkorporere en egnet base (f.eks. pyridin, N,N-dimetylanilin, etc.) som en syreakseptor. With regard to method (A) starting from a compound II where X is halogen, the reaction can be carried out in the presence or absence of a solvent. You can use any solvent that does not interfere with the reaction, such as e.g. alcohols such as methyl alcohols, ethyl alcohol, etc., ethers such as tetrahydrofuran, ethyl ethers, etc., hydrocarbons and halogenated hydrocarbons such as benzene, chloroform, etc., esters such as ethyl acetate, etc. To remove the hydrogen halide produced during the reaction, a suitable base (eg pyridine, N,N-dimethylaniline, etc.) as an acid acceptor.

Mengden av det substituerte eller usubstituerte morfolin, piperidin eller pyrrolidin i forhold til forbindelsen med generell formel (II) er vanligvis ikke mindre enn 2 mol pr. mol av forbindelse (II). Når man anvender et overskudd av det cykliske amin, vil det cykliske amin også tjene som et oppløs-ningsmiddel såvel som en syreakseptor. The amount of the substituted or unsubstituted morpholine, piperidine or pyrrolidine relative to the compound of general formula (II) is usually not less than 2 mol per moles of compound (II). When an excess of the cyclic amine is used, the cyclic amine will also serve as a solvent as well as an acid acceptor.

Reaksjonstemperaturen er vanligvis i området fra -20 til 300°C, fortrinnsvis 15 - 150°C. Reaksjonen vil vanligvis være fullstendig i løpet av et tidsrom på 1-5 timer. The reaction temperature is usually in the range from -20 to 300°C, preferably 15 to 150°C. The reaction will usually be complete within a period of 1-5 hours.

Med hensyn til fremgangsmåte (A) hvor man går ut fra en forbindelse med formel (II), hvor X er en tiogruppe, kan reaksjonsbetingelsene være de samme som i fremgangsmåte (A) når X var halogen. Men det er i dette tilfelle tilrådelig for å få et høyere utbytte at reaksjonen utføres under forhøyet trykk på 1 - 100 atmosfærer ved temperatur på 20 - 300°C, mest foretruk-ket i området 50 - 250°C. With regard to method (A) where one starts from a compound of formula (II), where X is a thio group, the reaction conditions can be the same as in method (A) when X was halogen. But in this case it is advisable to obtain a higher yield that the reaction is carried out under elevated pressure of 1 - 100 atmospheres at a temperature of 20 - 300°C, most preferably in the range 50 - 250°C.

Når man i fremgangsmåte 3 anvender kaliumferricyanid, er det anbefalt at reaksjonsblandingen holdes alkalisk. When potassium ferricyanide is used in method 3, it is recommended that the reaction mixture be kept alkaline.

Man kan anvende ethvert oppløsningsmiddel som ikke forstyrrer reaksjonen, slik som vann, et hydrokarbonoppløs-ningsmiddel som benzen, toluen og xylen; et halogenert hydro-karbon slik som kloroform, karbontetraklorid og diklormetan; et eteroppløsningsmiddel slik som tetrahydrofuran og dietyleter, eller blandinger av disse. Any solvent which does not interfere with the reaction can be used, such as water, a hydrocarbon solvent such as benzene, toluene and xylene; a halogenated hydrocarbon such as chloroform, carbon tetrachloride and dichloromethane; an ether solvent such as tetrahydrofuran and diethyl ether, or mixtures thereof.

Reaksjonen utføres ved temperaturer fra -10 til 150°C, fortrinnsvis fra 20 - 100°C. Reaksjonen vil vanligvis være fullstendig i en reaksjonsperiode på 1 - 10 timer. The reaction is carried out at temperatures from -10 to 150°C, preferably from 20 to 100°C. The reaction will usually be complete in a reaction period of 1 - 10 hours.

Mengden av oksydasjonsmidlet i forhold til utgangsforbindelsen i formel III er vanligvis 1-50 mol, fortrinnsvis 1,2 - 20 mol pr. mol av forbindelsen med formel (III). The amount of the oxidizing agent in relation to the starting compound in formula III is usually 1-50 mol, preferably 1.2-20 mol per moles of the compound of formula (III).

Etter en reaksjon ifølge fremgangsmåte (A) eller (B) kan reaksjonsproduktet normalt innvinnes fra reaksjonsblandingen i form av en fri base på vanlig kjent måte, slik som konsentra-sjon, utkrystallisasjon, kromatografi eller lignende. Reaksjonsproduktet kan også omdannes til et farmasøytisk akseptabelt salt på en i seg selv kjent fremgangsmåte. After a reaction according to method (A) or (B), the reaction product can normally be recovered from the reaction mixture in the form of a free base in a commonly known manner, such as concentration, crystallization, chromatography or the like. The reaction product can also be converted into a pharmaceutically acceptable salt by a method known per se.

I ovennevnte forbindelser med generell formel I såvel som deres farmasøytisk akseptable salter har en effektiv diuretisk virkning. En spesielt foretrukken forbindelse med formel I er 1,4-dimorfolino-7-fenylpyrido(3,4-d)pyridazin. Mer detaljert har forbindelser med formel I følgende egenskaper: In the above compounds of general formula I as well as their pharmaceutically acceptable salts have an effective diuretic action. A particularly preferred compound of formula I is 1,4-dimorpholino-7-phenylpyrido(3,4-d)pyridazine. In more detail, compounds of formula I have the following properties:

(1) En effektiv og sterk diuretisk virkning'. (1) An effective and strong diuretic action'.

(2) Ekstremt lav toksisitet, (2) Extremely low toxicity,

(3) de induserer gjennom urinen en utskillelse av en stor mengde natriumioner, men induserer en relativt liten utskillelse av kaliumioner som er et viktig element i menneskekroppen. Utskillelsesforholdet i urinen for Na<+>/K<+> er således meget høyt for forbindelser (I). (4) Forbindelser med formel I gir et markert ytterligere diuretisk utslag i dyr som allerede underkastes maksimal diurese ved hjelp av kjente diuretika. Dette tyder på at mekanismen for den diuretiske virkning for de fremstilte forbindelser er forskjel-lig fra dem man finner i kjente diuretika. En kombinasjon mellom forbindelser med formel I og andre kjente diuretika kan således bety en sterk øket diuretisk effekt. (3) they induce through the urine an excretion of a large amount of sodium ions, but induce a relatively small excretion of potassium ions which is an important element in the human body. The excretion ratio in the urine for Na<+>/K<+> is thus very high for compounds (I). (4) Compounds of formula I give a marked additional diuretic effect in animals which are already subjected to maximal diuresis by means of known diuretics. This suggests that the mechanism for the diuretic effect of the compounds produced is different from those found in known diuretics. A combination between compounds of formula I and other known diuretics can thus mean a strongly increased diuretic effect.

Forbindelser fremstilt ifølge foreliggende oppfinnelse kan således brukes som diuretika og kan tilføres for dette formål som sådanne eller i form av et farmasøytisk akseptabelt preparat i blanding med et egnet og vanlig fortynningsmiddel eller bæremiddel. Compounds produced according to the present invention can thus be used as diuretics and can be supplied for this purpose as such or in the form of a pharmaceutically acceptable preparation in admixture with a suitable and usual diluent or carrier.

Det farmasøytiske preparat kan være i form av tablet-ter, granulater, pulver, kapsler, injeksjonsoppløsninger og kan tilføres oralt eller parenteralt. The pharmaceutical preparation can be in the form of tablets, granules, powders, capsules, injection solutions and can be administered orally or parenterally.

Vanlige daglige doser av forbindelser med formel I ligger i området 10 - 200 mg for en voksen pasient ved oral til-førsel, eller i området 5 - 100 mg ved parenteral tilførsel. Usual daily doses of compounds of formula I are in the range of 10 - 200 mg for an adult patient by oral administration, or in the range of 5 - 100 mg by parenteral administration.

I de etterfølgende eksempler har "vektdeler" det samme forhold til "volumdeler" som gram har til milliliter. In the following examples, "parts by weight" have the same relationship to "parts by volume" as grams have to milliliters.

(1) Fremstilling av 1,4-diklor-7-(p-metoksyfenyl)-5-metyl-pyrido( 3, 4- d) pyridaziner (1) Preparation of 1,4-dichloro-7-(p-methoxyphenyl)-5-methyl-pyrido(3,4-d)pyridazines

lo vektdeler 3,4-dietoksykarbonyl-6-(p-metoksyfenyl)-2-metylpyridin ble tilsatt 4° volumdeler hydrazinhydrat, og den resulterende blanding kokt under tilbakelop i 3 timer. De utfelte krystaller ble oppsamlet ved filtrering, vasker med etanol og suspendert i loo volumdeler vann. Blandingen ble surgjort ved å tilsette eddiksyre, hvorved man oppnådde 1,2,3,4-tetrahydro-7-(p-metoksyfenyl)-5-metyl-l,4-dioksopyrido(3,4-d)-pyridazin som fargelose finkrystaller. En blanding ble fremstilt fra 3,0 vektdeler av disse fine krystaller, 45 volumdeler fosfor oksy-klorid og 4>5 volumdeler N,N-dimetylanilin. Blandingen ble oppvarmet til en temperatur fra 90 til loo°C i tre timer. Reaksjonsblandingen ble så hensatt ved romtemperatur over natten. De utfelte krystaller ble oppsamlet ved filtrering, vasket med eter og omkrystallisert fra kloroform hvorved man oppnådde den foronskede forbindelse som smeltet ved 214 til 219°C (dekomponering) som blekt gule nåler. (2) Fremstilling av l,4-dimetylmercapto-7-fenyl-pyrido-(3,4-d) pyridazin. 10 parts by weight of 3,4-diethoxycarbonyl-6-(p-methoxyphenyl)-2-methylpyridine was added to 4 parts by volume of hydrazine hydrate, and the resulting mixture refluxed for 3 hours. The precipitated crystals were collected by filtration, washed with ethanol and suspended in 10 parts by volume of water. The mixture was acidified by adding acetic acid, whereby 1,2,3,4-tetrahydro-7-(p-methoxyphenyl)-5-methyl-1,4-dioxopyrido(3,4-d)-pyridazine was obtained as colorless fine crystals . A mixture was prepared from 3.0 parts by weight of these fine crystals, 45 parts by volume of phosphorus oxychloride and 4>5 parts by volume of N,N-dimethylaniline. The mixture was heated to a temperature of 90 to 100°C for three hours. The reaction mixture was then allowed to stand at room temperature overnight. The precipitated crystals were collected by filtration, washed with ether and recrystallized from chloroform to give the phoronized compound melting at 214 to 219°C (decomposition) as pale yellow needles. (2) Preparation of 1,4-dimethylmercapto-7-phenyl-pyrido-(3,4-d)pyridazine.

En kaliumhydrosulfidmetanolisk opplosning ble fremstilt ved å omsette 7 vektdeler kaliumhydroksyd, 15o volumdeler metanol og hydrogen-sulfidgass ved hjelp av kjente fremgangsmåter. 4>2 vektdeler 1,4-diklor-7-fenyl-pyrido(3,4-d)pyridazin ble tilsatt opplbsningen, og den resulterende blanding ble rort ved romtemperatur i tre timer. Metanolen ble fordampet under redusert trykk, og residumet ble tilsatt 5o volumdeler vann. Den fremstilte opplosning ble surgjort ved å tilsette eddiksyre, hvorved man fikk utfelt gule krystaller. Krystallene ble oppsamlet - ved filtrering, vasket med vann og torket, hvorved man fikk l,4-dimercapto-7-fenyl-pyrido(3,4-d)pyridazin smeltepunkt 212 til 215°C (dekomponering). A potassium hydrosulphide methanolic solution was prepared by reacting 7 parts by weight of potassium hydroxide, 150 parts by volume of methanol and hydrogen sulphide gas using known methods. 4>2 parts by weight of 1,4-dichloro-7-phenyl-pyrido(3,4-d)pyridazine was added to the solution, and the resulting mixture was stirred at room temperature for three hours. The methanol was evaporated under reduced pressure, and 50 parts by volume of water were added to the residue. The prepared solution was acidified by adding acetic acid, whereby yellow crystals were precipitated. The crystals were collected - by filtration, washed with water and dried to give 1,4-dimercapto-7-phenyl-pyrido(3,4-d)pyridazine melting point 212 to 215°C (decomposition).

3,0 vektdeler av denne fremstilte forbindelse ble tilsatt 22o volumdeler en lofo vandig natriumhydroksydopplosning fullt av en tilsetning av 3>7 vektdeler metyliodid. Blandingen ble roret i tre timer ved romtemperatur, og man fikk utfelt krystallet. Disse ble omkrystallisert fra etanol hvorved man fikk l,4-dimetyl-mercapto-7-fenylpyrido(3,4-d) pyridazin som fargelose nåler, smeltepunkt 155°c-(3) Fremstilling av 1,4-dimorfolino-5-benzyl-5,6-dihydro-7-fenylpyrido-(3,4-d) pyridazin. 3.0 parts by weight of this prepared compound was added to 220 parts by volume of a lofo aqueous sodium hydroxide solution complete with an addition of 3>7 parts by weight of methyl iodide. The mixture was stirred for three hours at room temperature, and the crystal was precipitated. These were recrystallized from ethanol whereby 1,4-dimethyl-mercapto-7-phenylpyrido(3,4-d)pyridazine was obtained as colorless needles, melting point 155°c-(3) Preparation of 1,4-dimorpholino-5-benzyl -5,6-dihydro-7-phenylpyrido-(3,4-d)pyridazine.

7,6 vektdeler etyl 2-amino-2-benzylacrylat og 8,1 vektdeler, etyl 2-benzoylacetat ble opplost i lo volumdeler.metanol. Blandingen ble roret ved romtemperatur i fire dogn. Metanolen ble så fjernet ved fordampning under redusert trykk. Residumet ble tilsatt 5° volumdeler hydrazinhydrat og lo volumdeler vann, og den resulterende blanding ble 7.6 parts by weight of ethyl 2-amino-2-benzyl acrylate and 8.1 parts by weight of ethyl 2-benzoyl acetate were dissolved in 1 part by volume of methanol. The mixture was stirred at room temperature for four days. The methanol was then removed by evaporation under reduced pressure. To the residue was added 5° parts by volume of hydrazine hydrate and 1 part by volume of water, and the resulting mixture became

kokt under tilbakelop i 7>5 timer. Etter avkjoling ble de utfelte krystaller oppsamlet ved filtrering og vasket med metanol, hvorved man fikk 9,0 vektdeler l,4-dihydroksy-5-bénzyl-7-fenyl-pyrido(3,4-d) pyridazin hydraziniumsalt. boiled under reflux for 7>5 hours. After cooling, the precipitated crystals were collected by filtration and washed with methanol, whereby 9.0 parts by weight of 1,4-dihydroxy-5-benzyl-7-phenyl-pyrido(3,4-d)pyridazine hydrazinium salt were obtained.

9,0 vektdeler av dette produkt ble suspendert i 2,5% saltsyre og blandingen rort ved romtermpatrur i fem timer. De utfelte krystaller ble oppsamlet ved filtrering og vasket med metanol, hvorved man fikk 7,3 vektdeler l,4-dihydroks<y->5-benzyl-7_<f>enylpyrido-(3,4-d)pyridazin. 9.0 parts by weight of this product were suspended in 2.5% hydrochloric acid and the mixture stirred at room temperature for five hours. The precipitated crystals were collected by filtration and washed with methanol, whereby 7.3 parts by weight of 1,4-dihydroxy<y->5-benzyl-7-<f>enylpyrido-(3,4-d)pyridazine were obtained.

7,3 vektdeler av produktet ble tilsatt en blanding av 7° volumdeler fosforoksyklorid og 14 volumdeler dimetylanilin. Den resulterende blaning ble holt på et nivå av llo°C i en time, hvoretter man fordampet overskuddet av fosforoksyklorid under redusert trykk. Residumet ble tilsatt isvann, og de utfelte krystaller oppsamlet ved filtrering og deretter omkrystallisert fra kloroform-eter, hvorved man oppnådde 8,0 vektdeler 1,4-diklor-5-benzyl-7-fenylpyrido(3>4_d)-pyridazin. 7.3 parts by weight of the product were added to a mixture of 7 parts by volume of phosphorus oxychloride and 14 parts by volume of dimethylaniline. The resulting mixture was held at a level of 110°C for one hour, after which the excess phosphorus oxychloride was evaporated under reduced pressure. The residue was added to ice water, and the precipitated crystals were collected by filtration and then recrystallized from chloroform-ether, whereby 8.0 parts by weight of 1,4-dichloro-5-benzyl-7-phenylpyrido(3>4_d)-pyridazine were obtained.

8,0 vektdeler av produktet ble opplost i 60 volumdeler morfolin. Blandingen ble holdt på 15o°C i to timer, hvoretter overskuddsmehgden av morfolin ble fjernet ved fordampning under redusert trykk. 8.0 parts by weight of the product were dissolved in 60 parts by volume of morpholine. The mixture was kept at 15o°C for two hours, after which the excess amount of morpholine was removed by evaporation under reduced pressure.

Residumet ble tilsatt etanol, og blandingen hensatt ved romtemperatur. De utfelte krystaller ble oppsamlet og vasket med etanol, hvorved man fikk 8,0 vektdeler l,4-dimorfolino-5-benzyl-7-fenyl-pyrido(3,4-d) pyridazin, smeltepunkt 165 til l68°C. Ethanol was added to the residue, and the mixture was left at room temperature. The precipitated crystals were collected and washed with ethanol, whereby 8.0 parts by weight of 1,4-dimorpholino-5-benzyl-7-phenyl-pyrido(3,4-d)pyridazine were obtained, melting point 165 to 168°C.

3,0 vektdeler av produktet ble opplost i 3° volumdeler eddiksyre, hvoretter man tilsatte palladium-karbon. Den katalytiske hydrogenering ble utfort ved atmosfærisk trykk. Etter 21 timers hydrogenering ble katalysatoren fjernet ved filtrering, og filtratet ble konsentrert slik at man fikk utfelt gule krystaller. Krystallene ble vasket med eter, hvorved man fikk 1 vektdel 1,4-dimorfolino-5-benzyl-5,6-dihydro-7-fenylpyrido(3,4-d)-pyridazin, smeltepunkt 168 til 17o°C. 3.0 parts by weight of the product were dissolved in 3 parts by volume of acetic acid, after which palladium carbon was added. The catalytic hydrogenation was carried out at atmospheric pressure. After 21 hours of hydrogenation, the catalyst was removed by filtration, and the filtrate was concentrated so that yellow crystals were precipitated. The crystals were washed with ether, whereby 1 part by weight of 1,4-dimorpholino-5-benzyl-5,6-dihydro-7-phenylpyrido(3,4-d)-pyridazine was obtained, melting point 168 to 17o°C.

EKSEMPEL_1 EXAMPLE_1

0,5 vektdeler 1,4-diklor-7-metyl-8-metoksy-pyrido(3,4-d)pyridazin 0.5 parts by weight 1,4-dichloro-7-methyl-8-methoxy-pyrido(3,4-d)pyridazine

og 3»6 vektdeler morfolin ble oppvarmet til 80 C i 1,5 timer og deretter ble overskuddet av morfolin avdestillert. Residumet ble tilsatt vann, hvoretter man fikk et oljeaktig bunnfall. Denne oljen ble behandlet med en liten mengde metanol, hvorved man fikk krystaller av 7-metyl-8-metoksy-l,4-dimorfolino-pyrido(3,4-d)pyridazin. Om-kryst allisasjon fra en blanding av metanol og vann (1:3) gir krystaller som smelter ved 145 - 146°C. Utbytte: 0,5 vektdeler. and 3.6 parts by weight of morpholine were heated to 80 C for 1.5 hours and then the excess of morpholine was distilled off. The residue was added to water, after which an oily precipitate was obtained. This oil was treated with a small amount of methanol, whereby crystals of 7-methyl-8-methoxy-1,4-dimorpholino-pyrido(3,4-d)pyridazine were obtained. Recrystallisation from a mixture of methanol and water (1:3) gives crystals which melt at 145 - 146°C. Yield: 0.5 parts by weight.

Elementæranalyse for ciyH24°3N5 Elemental analysis for ciyH24°3N5

Beregnet: C,59.11; H, 6.7I; N, 2o.28 Funnet: C,59.1o; H, 6.8l; N, 2o,o9 Calculated: C,59.11; H, 6.7 I; N, 2o.28 Found: C,59.1o; H, 6.8l; N, 2o,o9

I IN

På liknende måte som beskrevet her ble folgende forbindelser frem- In a similar way as described here, the following compounds were produced

stilt. silenced.

EKSEMPEL_2_ EXAMPLE_2_

2,0 vektdeler l,4-diklor-7-fenylpyrido-(3,4-d)pyridazin ble tilsatt 2o volumdeler 2-metyl-morfolin, og den resulterende blanding ble holdt på I30 til 14o°C i 4 timer. Overskuddet av 2-metylmorfolin ble fjernet ved fordampning under edusert trykk. Vann ble tilsatt residumet, hvorved man oppnådde råkrystaller som ble omkrystallisert fra n-heksan slik at man fikk l,4-bis(2'-metylmorfolin)-7-fenylpyrido (3,4-d)pyridazin som gule prismer med smeltepunkt fra 75 til 8l°C. 2.0 parts by weight of 1,4-dichloro-7-phenylpyrido-(3,4-d)pyridazine was added to 20 parts by volume of 2-methyl-morpholine, and the resulting mixture was kept at 130 to 140°C for 4 hours. The excess of 2-methylmorpholine was removed by evaporation under reduced pressure. Water was added to the residue, whereby crude crystals were obtained which were recrystallized from n-hexane so that 1,4-bis(2'-methylmorpholine)-7-phenylpyrido (3,4-d)pyridazine was obtained as yellow prisms with a melting point of 75 to 81°C.

Elementæranalyse for ^23^<2>7^<2>^5 Elementary analysis for ^23^<2>7^<2>^5

Beregnet: 0,68.12; H, 6.7I; N, 17.27 Calculated: 0.68.12; H, 6.7 I; N, 17.27

Funnet: 0,68.27; H, 6.95; N, 16.98 Found: 0.68.27; H, 6.95; N, 16.98

Hvis man i ovennevnte fremgangsmåte anvender samme mengde 2,6-dimetylmorfolin istedetfor 2-metylmorfolin, så oppnår man 1,4-bis(2',6'-dimetylmorfolino)77-fenylpyrido-(3,4-d)pyridazin med et smeltepunkt på 248 til 25o°C som gule fine nåler. If in the above-mentioned method the same amount of 2,6-dimethylmorpholine is used instead of 2-methylmorpholine, then 1,4-bis(2',6'-dimethylmorpholino)77-phenylpyrido-(3,4-d)pyridazine is obtained with a melting point at 248 to 25o°C as yellow fine needles.

Elementæranalyse for CQt-H 0oNj- Elemental analysis for CQt-H 0oNj-

° 31 5 ° 31 5

Beregnet: C, 69.25; H, 7.21; N, l6.l6 Calculated: C, 69.25; H, 7.21; N, l6.l6

Funnet: C, 69.25; H, 7.17; N, 16.19 Found: C, 69.25; H, 7.17; Thu, 16.19

EKSEMPEL_3 EXAMPLE_3

1,0 vektdeler 1,4-dikloro~7-(p-metoksyfenyl)-5-metylpyrido(3,4-d) pyridazin ble tilsatt lo volumdeler morfolin, og den resulterende blanding holdt på 13o°C i tre timer. Overskuddsmengden av morfolin ble fjernet ved fordampning under redusert trykk, hvoretter vann ble tilsatt residumet. Råkrystallene ble oppsamlet ved filtrering og omkrystallisert fra etanol, hvorved man fikk 7-(p-metoksyfenyl)-5-metyl-l,4-dimorfolinopyrido(3,4-d)-pyridazin som grå prismer, smeltepunkt på 2o6 til 2o9°C. 1.0 parts by weight of 1,4-dichloro-7-(p-methoxyphenyl)-5-methylpyrido(3,4-d)pyridazine was added to 10 parts by volume of morpholine, and the resulting mixture was kept at 13o°C for three hours. The excess amount of morpholine was removed by evaporation under reduced pressure, after which water was added to the residue. The crude crystals were collected by filtration and recrystallized from ethanol to give 7-(p-methoxyphenyl)-5-methyl-1,4-dimorpholinopyrido(3,4-d)-pyridazine as gray prisms, mp 2o6 to 2o9°C .

ELEMENTÆRANALYSE FOR CooHor70oNt- ELEMENTARY ANALYSIS FOR CooHor70oNt-

23 27 3 5 23 27 3 5

Beregnet: 0,65.54; H, 6.46; N, 16.42 Calculated: 0.65.54; H, 6.46; N, 16.42

Funnet: 0,65-42; H, 6.26; N, 16.55 Found: 0.65-42; H, 6.26; N, 16.55

De etterfolgende forbindelser med folgende generelle formel: ble fremstilt på liknende måte som beskrevet ovenfor. The following compounds with the following general formula: were prepared in a similar manner as described above.

EKSEMPEL_4 EXAMPLE_4

1 vektdel l,4-dimetylmercapto-7-fenyl-pyrido(3,4-d)pyridazin og lo volumdeler morfolin ble plassert i et ror av glass og glassroret ble lukket. Reaksjonssystemet ble oppvarmet til l8o°C i 8 timer. Overskuddet av morfolin ble fjernet ved fordampning under redusert trykk, hvoretter vann ble tilsatt residumet. De utfelte råkrystaller ble oppsamlet til filtrering. Krystallene ble absorbert på en kolonne pakket med silisiumdioksyd-gel, hvoretter det hele ble elevert med en blanding av aceton og benzen. (1:4). Elevatet ble konsentrert under redusert trykk og omkrystallisert fra metanol hvorved man fikk 1,4-dimorfolino-7-fenyl-pyrido(3,4-d)pyridazin som blekt gule nåler 1 part by weight of 1,4-dimethylmercapto-7-phenyl-pyrido(3,4-d)pyridazine and 10 parts by volume of morpholine were placed in a glass tube and the glass tube was closed. The reaction system was heated to 180°C for 8 hours. The excess morpholine was removed by evaporation under reduced pressure, after which water was added to the residue. The precipitated crude crystals were collected for filtration. The crystals were absorbed on a column packed with silica gel, after which the whole was eluted with a mixture of acetone and benzene. (1:4). The eluate was concentrated under reduced pressure and recrystallized from methanol to give 1,4-dimorpholino-7-phenyl-pyrido(3,4-d)pyridazine as pale yellow needles

EKSEMPEL_5_ EXAMPLE_5_

0,47 vektdeler 1,4-dimorfolino-5-benzy1-5,6-dihydro~7-fenylpyrido (3,4-d)pyridazin ble opplost i 2o volumdeler benzen under oppvarmning, hvoretter 3 vektdeler kaliumferricyanid opplost i 2o volumdeler vann ble tilsatt opplosningen. 1,5 vektdeler kaliumhydroksyd opplost i 3,5 volumdeler ble tilsatt blandingen under roring, og roringen ble fortsatt i ytterligere 1,5 timer. Benzenlaget ble utskilt og vasket med lo volumdeler av en lo% vandig natriumhydroksyd-opplosning og 2 ganger med 5° volumdeler vann. Benzenlaget ble torket over vannfritt natriumsulfat og konsentrert ved fordampning av benzenen under redusert trykk. Residumet ble omkrystallisert fra eter, hvorved man fikk 0,25 vektdeler l,4-dimorfolino-7-fenylpyrido(3,4-d)pyridazin, smeltepunkt 175 til 176°C. 0.47 parts by weight of 1,4-dimorpholino-5-benzy1-5,6-dihydro~7-phenylpyrido (3,4-d)pyridazine were dissolved in 20 parts by volume of benzene under heating, after which 3 parts by weight of potassium ferricyanide dissolved in 20 parts by volume of water were added to the solution. 1.5 parts by weight of potassium hydroxide dissolved in 3.5 parts by volume was added to the mixture with stirring, and stirring was continued for another 1.5 hours. The benzene layer was separated and washed with 10 parts by volume of a 10% aqueous sodium hydroxide solution and twice with 5 parts by volume of water. The benzene layer was dried over anhydrous sodium sulfate and concentrated by evaporating the benzene under reduced pressure. The residue was recrystallized from ether, whereby 0.25 parts by weight of 1,4-dimorpholino-7-phenylpyrido(3,4-d)pyridazine were obtained, melting point 175 to 176°C.

Elementæranalyse for C^ K N^02.l/2H20 Elemental analysis for C^ K N^O2.l/2H20

Beregnet: C, 65.26; H, 6.2S-; N, 18.12 Calculated: C, 65.26; H, 6.2S-; N, 18.12

Funnet: C, 65.26; H, 6 28; N, l8.l8 Found: C, 65.26; H, 6 28; N, l8.l8

EKSEMPEL_6_ EXAMPLE_6_

1 vektdel l,4-dimorfolino-7-fenylpyrido-(3,4-d)pyridazin ble opplost i 5° volumdeler etanol under oppvarmning. lo volumdeler av en lofo etanolisk hydrogenklorid-opplosning ble tilsatt opplosningen, og den resulterende blanding ble avkjolt for derved å få utfelt 1,4-dimor-folino-7-fenylpyrido(3,4-d)pyridazin hydroklorid. Produktet (1 vektdel) ble oppsamlet ved filtrering og omkrystallisert fra 5o volumdeler etanol, hvorved man fikk hoyrent 1,4-dimorfolino-7-fenylpyrido(3,4-d)-pyridazin hydroklorid smeltepunkt på 176 til l8l°C som orange nåler. 1 part by weight of 1,4-dimorpholino-7-phenylpyrido-(3,4-d)pyridazine was dissolved in 5° parts by volume of ethanol while heating. 10 parts by volume of a lofo ethanolic hydrogen chloride solution was added to the solution, and the resulting mixture was cooled to thereby precipitate 1,4-dimorpho-folino-7-phenylpyrido(3,4-d)pyridazine hydrochloride. The product (1 part by weight) was collected by filtration and recrystallized from 50 parts by volume of ethanol, whereby highly pure 1,4-dimorpholino-7-phenylpyrido(3,4-d)-pyridazine hydrochloride melting point of 176 to 181°C was obtained as orange needles.

Elementæranalyse for C21H24°2N5C"'" Elemental analysis for C21H24°2N5C"'"

Beregnet: C 60,93, H 5,84, N 16,92 Calculated: C 60.93, H 5.84, N 16.92

Funnet: C 60,74, H 5,70, N 16,72 Found: C 60.74, H 5.70, N 16.72

Eksempel 7 Example 7

På lignende måte som beskrevet i eksempel 1 fremstilte man følgende pyrido(3,4-d)pyridazinderivater med neden-stående generelle formel: In a similar manner to that described in example 1, the following pyrido(3,4-d)pyridazine derivatives with the following general formula were prepared:

Claims

!• Analogous method for the production of diuretically active pyrido(3,4-d)pyridazine derivatives with the general formula:

where R-^ is hydrogen or a lower alkyl group with 1-4 carbon atoms, R 2 is an alkyl group with 1-4 carbon atoms, a benzyl or phenethyl group, or a substituted or unsubstituted phenyl, naphthyl, furyl or pyridyl group, where the substituent is a lower alkoxy group with 1-3 carbon atoms, a lower alkyl group with 1-3 carbon atoms, halogen or nitro, R^ is hydrogen or a lower alkoxy group with 1-4 carbon atoms and where R^ is a substituted or an unsubstituted morpholino- , piperidino or pyrrolidin group where the substituent can be methyl or ethyl, as well as pharmaceutically acceptable salts thereof, characterized by A) reacting a compound with the general formula:

where each of R-^, R 2 and R^ has the meaning given above, and X is halogen or or a thio group, with a substituted or unsubstituted morpholine, piperidine or pyrrolidine compound, where the substituent may be methyl or ethyl, or B) oxidizes a compound with the general formula:

where each of the groups R 2 , R 3 and R 4 has the above meaning, and R 5 is a benzyl, allyl or t-butyl group, with potassium ferricyanide, oxygen or nitrobenzene, and, if desired, a compound thus obtained is converted into a pharmaceutically acceptable salt thereof.

2. Analogy method according to claim 1, characterized in that starting materials are used where R^ is hydrogen, R2 is phenyl, R^ is hydrogen and R^ is morpholine.