NO743534L - - Google Patents
Info
- Publication number
- NO743534L NO743534L NO743534A NO743534A NO743534L NO 743534 L NO743534 L NO 743534L NO 743534 A NO743534 A NO 743534A NO 743534 A NO743534 A NO 743534A NO 743534 L NO743534 L NO 743534L
- Authority
- NO
- Norway
- Prior art keywords
- carbon atoms
- compounds
- formula
- isoquinoline
- alkyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye, heterocykliske forbindelser med formel The present invention relates to a method for the production of new, heterocyclic compounds with the formula
hvori R betyr lavere alkyl eller cykloalkyl med 3 til 7 karbonatomer, med alkyl med 1 til k karbonatomer substituert cykloalkyl med 3 til 7 karbonatomer, oc-dialkylpropynyl,eller oc-dialkylallyl med 5 til 9 karbonatomer, hydroksyalkyl med 2 til 7 karbonatomer, hvis hydroksygruppe er skilt fra det nitrogenatom, hvortil R er bundet, ved minst 2 karbonatomer, fenetyl, med halogen, alkyl eller alkoksy med 1 til h karbonatomer substituert fenetyl eller adamantylresten, R^ står for hydrogen, halogen, alkyl eller alkoksy med 1 til h karbonatomer, for i 5-?6- eller 7-stillingen bundet trifluormetyl eller for en i h- eller 5-stilling bundet nitro- eller A-NH-gruppe, hvori A betyr formyl eller en alkanoylgruppe med 2 til h karbonatomer og R2betyr hydrogen'eller, når R1betyr alkyl med 1 til h karbonatomer, også alkyl med 1 til h karbonatomer eller, når R^betyr alkoksy med 1 til h karbonatomer, også alkoksy med 1 til k karbonatomer, idet 8-stillingen av isokinolinringen er usubstituert, og en mulig forekommende halogen-substituent i 3- eller ^-stilling ikke står for fluor, og syreaddisjonssalter derav. wherein R means lower alkyl or cycloalkyl of 3 to 7 carbon atoms, with alkyl of 1 to k carbon atoms substituted cycloalkyl of 3 to 7 carbon atoms, oc-dialkylpropynyl, or oc-dialkylallyl of 5 to 9 carbon atoms, hydroxyalkyl of 2 to 7 carbon atoms, if hydroxy group is separated from the nitrogen atom to which R is bound by at least 2 carbon atoms, phenethyl, with halogen, alkyl or alkoxy with 1 to h carbon atoms substituted phenethyl or the adamantyl residue, R^ stands for hydrogen, halogen, alkyl or alkoxy with 1 to h carbon atoms, for trifluoromethyl bonded in the 5-?6- or 7-position or for a nitro or A-NH group bonded in the h- or 5-position, in which A means formyl or an alkanoyl group with 2 to h carbon atoms and R2 means hydrogen or, when R1 means alkyl with 1 to h carbon atoms, also alkyl with 1 to h carbon atoms or, when R^ means alkoxy with 1 to h carbon atoms, also alkoxy with 1 to k carbon atoms, the 8-position of the isoquinoline ring being unsubstituted, and a muli g occurring halogen substituent in the 3- or ^-position does not represent fluorine, and acid addition salts thereof.
Hvis R står for den ovenfor definerte alkyl- eller hydroksyalkyl-rest, er denne foretrukket forgrenet, spesielt i a-stillingen til det nitrogenatom som den er bundet-til. Spesielt foretrukne alkyl-rester er isopropyl, tert.butyl, 3-pentyl og tert.pentyl. If R stands for the alkyl or hydroxyalkyl residue defined above, this is preferably branched, especially in the a-position of the nitrogen atom to which it is attached. Particularly preferred alkyl residues are isopropyl, tert-butyl, 3-pentyl and tert-pentyl.
Hvis R står for den ovenfor definerte alkylcykloalkylgruppe, så betyr dennes alkylsubstituent spesielt metyl. Eksempler på If R stands for the alkylcycloalkyl group defined above, then its alkyl substituent means in particular methyl. Examples of
interessante alkylcykloalkylgrupper er 1-metylcyklopropyl og 1-metylcykloheksyl. interesting alkylcycloalkyl groups are 1-methylcyclopropyl and 1-methylcyclohexyl.
Hvis R står for det ovenfor definerte oc-dialkylpropynyl eller a-dialkylally1, så er de deri inneholdte alkylgrupper foretrukket identiske og betyr spesielt metyl. If R stands for the above-defined α-dialkylpropynyl or α-dialkylally, then the alkyl groups contained therein are preferably identical and mean in particular methyl.
Hvis R står for en med de ovenfor definerte rester substituert fenetylgruppe, så er denne fenetylrest spesielt mono-'eller d.isubstituert. Hvis den er substituert med halogen, står halogenet for fluor, klor eller brom, foretrukket for fluor eller klor. Mulig forekommende alkyl- eller alkoksysubstituenter av fenetyl-resten inneholder foretrukket 1 eller 2, spesielt 1 karbonatom. If R stands for a phenethyl group substituted with the residues defined above, then this phenethyl residue is particularly mono- or di-substituted. If substituted with halogen, the halogen is fluorine, chlorine or bromine, preferably fluorine or chlorine. Possible alkyl or alkoxy substituents of the phenethyl residue preferably contain 1 or 2, especially 1 carbon atom.
Hvis R.| står for halogen, så betyr dette fluor, klor eller brom, foretrukket fluor eller klor. If R.| stands for halogen, then this means fluorine, chlorine or bromine, preferably fluorine or chlorine.
Hvis R^og/eller R2står for alkyl eller alkoksy med 1 til 'karbonatomer, inneholder disse rester spesielt 1 ■ eller 2, foretrukket 1 karbonatom. If R 1 and/or R 2 stand for alkyl or alkoxy with 1 to 1 carbon atoms, these residues especially contain 1 or 2, preferably 1 carbon atom.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at enten The peculiarity of the method according to the invention is that either
a) forbindelser med formela) compounds with formula
hvori R^og R2har den ovennevnte betydning og X betyr en anionisk wherein R 1 and R 2 have the above meaning and X means an anionic
avgangsgruppe, omsettes med forbindelser med formelleaving group, is reacted with compounds of formula
hvori R har den ovennevnte betydning, eller wherein R has the above meaning, or
b) forbindelser med formelb) compounds with formula
hvori R, R1og R~har den ovennevnte "betydning, og wherein R, R1 and R~ have the above meaning, and
betyr means
en hydrolytisk avspaltbar rest, hydrolyseresa hydrolytically cleavable residue, is hydrolyzed
og de erholdte forbindelser med formel I utvinnes i form av basene eller som syreaddisjonssalter. and the obtained compounds of formula I are recovered in the form of the bases or as acid addition salts.
Fra de fri baser lar seg på kjent måte syreaddisjonssalter frem-stille og omvendt. Acid addition salts can be prepared from the free bases in a known manner and vice versa.
Fremgangsmåten i henhold til oppfinnelsen kan g'jennomfores analogt med kjente metoder. The method according to the invention can be carried out analogously to known methods.
X står for eksempel for klor eller brom eller for lavere alkyltio som metyltio. X stands, for example, for chlorine or bromine or for lower alkylthio such as methylthio.
Omsetningen i henhold til fremgangsmåten a) skjer f.eks. ved henstand av en losning av en forbindelse med formel II og en forbindelse med formel III i et under reaksjonsbetingelsene inert organisk losningsmiddel, f.eks. en lavere alkanol som etanol, og i nærvær av et basisk kondensasjonsmiddel, f.eks. et alkalimetall-alkoholat som kalium-tert.butylat. Reaksjonstemperaturen kan variere mellom omtrent 0 og 80°G, men man arbeider hensiktsmessig ved romtemperatur. For påskyndelse av omsetningen kan det foretas omroring. Reaksjonsvarigheten avhenger selvfølgelig også av reaksj onstemperaturen. The turnover according to procedure a) takes place e.g. in the case of a solution of a compound of formula II and a compound of formula III in an organic solvent inert under the reaction conditions, e.g. a lower alkanol such as ethanol, and in the presence of a basic condensing agent, e.g. an alkali metal alcoholate such as potassium tert-butylate. The reaction temperature can vary between approximately 0 and 80°G, but it is appropriate to work at room temperature. Agitation can be done to speed up turnover. Of course, the reaction duration also depends on the reaction temperature.
Oksazolidiner er lett hydrolyserbare (se Chemical Reviews 23.315-317 (1953). I forbindelsene med formel IV kan Z og Z<1>derfor stå for restene av e't vilkårlig alifatisk eller aromatisk aldehyd Oxazolidines are easily hydrolyzable (see Chemical Reviews 23,315-317 (1953). In the compounds of formula IV, Z and Z<1> can therefore stand for the residues of any aliphatic or aromatic aldehyde
eller keton or ketone
f.eks. propionaldehyd, benzaldehyd, aceton, e.g. propionaldehyde, benzaldehyde, acetone,
etc. Hydrolysen av forbindelsene med formel IV gjennomfores hensikt-messig under sure betingelser. etc. The hydrolysis of the compounds of formula IV is conveniently carried out under acidic conditions.
Som egnede syrer anvendes spesielt fortynnede syrer, f.eks. mellom 0,5 til 3N, foretrukket mineralsyre, f.eks. 1N saltsyre eller 1N svovelsyre. Particularly diluted acids are used as suitable acids, e.g. between 0.5 to 3N, preferably mineral acid, e.g. 1N hydrochloric acid or 1N sulfuric acid.
Reaksjonstemperaturen velges hensiktsmessig mellom 0 og omtrent 80°C. The reaction temperature is suitably chosen between 0 and approximately 80°C.
Reaksjonsvarigheten er avhengig av reaksjonsbetingelsene. The reaction duration depends on the reaction conditions.
De. således erholdte forbindelser med formel I kan isoleres fra reaksjonsblandingen og renses etter kjente metoder. The. thus obtained compounds of formula I can be isolated from the reaction mixture and purified according to known methods.
1-klor- eller 1-brom-forbindelsene med formel II er kjente (Heiv. Chim. Acta £2 1755-1762 (1969)) eller kan fremstilles analogt med kjente metoder. The 1-chloro or 1-bromo compounds of formula II are known (Heiv. Chim. Acta £2 1755-1762 (1969)) or can be prepared analogously by known methods.
De 1 -(lavere)alkyltio-forbindelser med formel II kan fremstilles ved omsetning mellom tilsvarende 1-klor-forbindelser og tiourin-.stoff, f.eks. ved romtemperatur i metanol, og alkylering av de således erholdte 1-merkapto-forbindelser. The 1-(lower)alkylthio compounds of formula II can be prepared by reaction between corresponding 1-chloro compounds and thiourea, e.g. at room temperature in methanol, and alkylation of the 1-mercapto compounds thus obtained.
Forbindelsene med formel III kan fremstilles ved at 1,2-dihydroksy-3-klorpropan eller glycidol omsettes med aminer med formel The compounds of formula III can be prepared by reacting 1,2-dihydroxy-3-chloropropane or glycidol with amines of formula
hvori R har den ovennevnte betydning. wherein R has the above meaning.
Forbindelser med formel IV erholdes ved omsetning av forbindelser med formel II med forbindelser med formel hvori R, Z og Z1 har den ovennevnte "betydning. Omsetningen gjennom-føres i et .under reaks j ons be ting els ene inert organisk løsnings-middel. Man arbeider hensiktsmessig i nærvær av en base. Reaksjonstemperaturen kan variere mellom romtemperatur og svakt forhoyet temperatur. Reaksjonen varer noen timer.. Compounds of formula IV are obtained by reaction of compounds of formula II with compounds of formula in which R, Z and Z1 have the above meaning. The reaction is carried out in an inert organic solvent under reaction conditions. works appropriately in the presence of a base. The reaction temperature can vary between room temperature and slightly elevated temperature. The reaction lasts a few hours..
Forbindelsene med formel -VI erholdes f.eks. ved omsetning av forbindelser med formel I;II med de tilsvarende aldehyder eller ketoner.'The compounds of formula -VI are obtained, e.g. by reacting compounds of formula I; II with the corresponding aldehydes or ketones.'
I den utstrekning fremstillingen av utgangsproduktene ikke er beskrevet, er disse kjente eller kan fremstilles etter i og for seg kjente metoder henhv." analogt med de her beskrevne eller analogt med i og for seg kjente fremgangsmåter. To the extent that the production of the starting products is not described, these are known or can be produced according to per se known methods, respectively analogous to those described here or analogous to per se known methods.
Forbindelsene med formel 1 utmerker seg i den farmakologiske utproving ved interessante virkninger og kan folgelig anvendes som medisin. The compounds of formula 1 stand out in the pharmacological testing with interesting effects and can therefore be used as medicine.
Således viser forbindelsene på spontantslående, isolert marsvin-forkammer en hemming av den positivinotrope adrenalinvirkning, idet denne antagonistiske virkning opptrer ved en badkonsentrasjon på 0,005 til 2,5 mg/l. Ved infusjonsforsok i narkotisert katt forer de ved doser på 0,02 til 0,6 mg/kg til en hemming av den ved isoproterenol betingede tachycardie og blodtrykkssenkning. Thus, the compounds show an inhibition of the positivinotropic adrenaline action on spontaneously beating, isolated guinea pig atria, this antagonistic action occurring at a bath concentration of 0.005 to 2.5 mg/l. In infusion trials in anesthetized cats, doses of 0.02 to 0.6 mg/kg lead to inhibition of isoproterenol-induced tachycardia and lowering of blood pressure.
De nye substanser fremviser folgelig en blokkerende virkning påThe new substances therefore exhibit a blocking effect on
de adrenergiske B-reseptorer. De kan folgelig blant annet anvendes for profylakse og terapi av koronarsykdommer, spesielt for the adrenergic B receptors. They can therefore, among other things, be used for the prophylaxis and therapy of coronary diseases, especially for
behandling av Angina-pectoris, for behandling av det hyperkinetiske hjertesyndrom og de fra en muskulær-hypertrofisk subvalvulær aortastenose resulterende tilstander. treatment of Angina pectoris, for the treatment of the hyperkinetic heart syndrome and those resulting from a muscular-hypertrophic subvalvular aortic stenosis.
På grunn av deres antiarrytmiske virkning er forbindelsene også egnet for behandling av hjerterytme-forstyrrelser. Due to their antiarrhythmic action, the compounds are also suitable for the treatment of heart rhythm disorders.
For den ovennevnte anvendelse varierer den dose som anvendes selvfolgelig alt etter den anvendte forbindelse, tilforselsmåten og den onskede behandling. Vanlig oppnås dog tilfredsstillende resultater med doser på omtrent 0,01 mg til 1,5 mg/kg kroppsvekt, og denne dose kan om nodvendig tilfores i 2 til *f deldoser eller også som retardform. For storre pattedyr ligger dagsdosen ved omtrent 2 til 100 mg. For orale tilførsler inneholder deldosene omtrent 0,5 til 50. mg av de nye forbindelser ved siden av faste eller flytende bærersubstanser eller -fortynningsmidler. For the above-mentioned application, the dose used naturally varies according to the compound used, the method of administration and the desired treatment. Usually, however, satisfactory results are achieved with doses of approximately 0.01 mg to 1.5 mg/kg body weight, and this dose can, if necessary, be administered in 2 to *f partial doses or also as a slow-release form. For larger mammals, the daily dose is approximately 2 to 100 mg. For oral administration, the partial doses contain about 0.5 to 50 mg of the new compounds in addition to solid or liquid carriers or diluents.
Forbindelsene fremviser videre interessante stoffskiftevirkninger. • Således bevirker de i isolerte fettceller av det epididymale fett-vev i rotter (metoden etter M. Rodbell J.biol. chem. 239 (196*0 37-5-380) ved en konsentrasjon på ca. 0,1 til 10 mg/l en betydelig hemming av den ved isoproterenol stimulerbare glycerol-frigivelse - og hemmer i rotter den ved isoprenalin stimulerte lipolyse (glycerolutskilling) og glycogenolyse (plasmaglucosestigning) ved doser på fra 0,1 til ca. 1 mg/kg (ID^-verdier). The compounds also exhibit interesting metabolic effects. • Thus they cause in isolated fat cells of the epididymal fat tissue in rats (the method according to M. Rodbell J.biol. chem. 239 (196*0 37-5-380) at a concentration of approx. 0.1 to 10 mg /l a significant inhibition of isoproterenol-stimulated glycerol release - and in rats inhibits isoprenaline-stimulated lipolysis (glycerol separation) and glycogenolysis (plasma glucose rise) at doses of from 0.1 to about 1 mg/kg (ID^ values ).
På grunn av deres metaboliske virkning kan disse forbindelser anvendes ved tilstander som forer til en ved psykisk stress uonsket mobilisasjon av fettsyrer. Due to their metabolic effect, these compounds can be used in conditions which lead to an unwanted mobilization of fatty acids due to psychological stress.
For den ovennevnte anvendelse varierer den dose som anvendes selvfolgelig alt etter den anvendte forbindelse, tilforselsmåten og den onskede behandling. Vanlig oppnås dog tilfredsstillende resultater med doser på omtrent 0,02 til 5 mg/kg kroppsvekt. For storre pattedyr ligger dagsdosen i området fra omtrent 1 til 100 mg av den anvendte forbindelse. Dosen kan tilfores i 2 til h deldoser eller også som retardform. For oral tilforsel inneholder deldosene omtrent 0,25 til 50 mg av de nye forbindelser ved siden For the above-mentioned application, the dose used naturally varies according to the compound used, the method of administration and the desired treatment. Usually, however, satisfactory results are obtained with doses of approximately 0.02 to 5 mg/kg body weight. For larger mammals, the daily dose is in the range from about 1 to 100 mg of the compound used. The dose can be given in 2 to 1 hour partial doses or also as a slow-release form. For oral administration, the partial doses contain approximately 0.25 to 50 mg of the new compounds at the side
av de vanlige hjelpestoffer.of the usual excipients.
For den siste anvendelse egner seg særlig forbindelser med formel I hvori R står for en i oc-stilling til det nitrogenatom hvortil For the latter application, compounds of formula I in which R stands for an i oc position to the nitrogen atom to which
R er bundet, forgrenet rest. Særlig interessante er forbindelsene' med formel I hvori R er bundet til nitrogenet med et tertiært karbonatom. R is bound, branched residue. Of particular interest are the compounds of formula I in which R is bound to the nitrogen with a tertiary carbon atom.
Som medisin kan forbindelsene med formel I henhv. deres fysiologisk tålbare syreaddisjonssalter tilfores alene eller i egnet preparat-form med farmakologisk indifferente hjelpestoffer. As medicine, the compounds of formula I or their physiologically tolerable acid addition salts are administered alone or in suitable preparation form with pharmacologically indifferent excipients.
I de etterfølgende eksempler, som skal illustrere oppfinnelsen nærmere, er alle temperaturangivelser i °C og er ukorrigert. In the following examples, which shall illustrate the invention in more detail, all temperature indications are in °C and are uncorrected.
Eksempel 1 : 1-(2=hydroksy=3-isoprop_ylaminoDrop_ok Example 1: 1-(2=hydroxy=3-isoprop_ylaminoDrop_ok
isokinolin. (fremgangsmåte b)isoquinoline. (method b)
1 g 1 -(3-isopropyl-2-fenyl-5-oksazolidinylmetoksy)-7-metoksy-isokinolin oppvarmes til 80°C i 10 minutter i 10 ml 1N saltsyre. Reaksjonsblandingen ekstraheres med eter. Den eteriske fase kastes og den vandige fase gjores alkalisk med pottaske, ekstraheres med eter, eterf asen torres- over magnesiumsulfat og inndampes, hvorved det dannes et krystallisat som i metanol tilsettes maleinsyre. Ved tilsetning av eter faller 1 -(2-hydroksy-3-isopropylaminopropoksy)-7-metoksy-isokinolin ut som hydrogenmaleinat. Smeltepunkt 1M+-11+6°C. 1 g of 1 -(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxy-isoquinoline is heated to 80°C for 10 minutes in 10 ml of 1N hydrochloric acid. The reaction mixture is extracted with ether. The ethereal phase is discarded and the aqueous phase is made alkaline with pot ash, extracted with ether, the ethereal phase is dried over magnesium sulphate and evaporated, thereby forming a crystallisate to which maleic acid is added in methanol. On addition of ether, 1-(2-hydroxy-3-isopropylaminopropoxy)-7-methoxy-isoquinoline precipitates as hydrogen maleate. Melting point 1M+-11+6°C.
Det som utgangsmaterial anvendte 1 -(3-isopropyl-2-fenyl-5-oksa-zolidinyl-metoksy)-7-metoksyisokinolin kan fremstilles på folgende måte: ,0,3 g kalium loses i 15 ml absolutt tert.butanol og tilsettes 1,5 g 1- klor-7-metoksy-isokinolin og 1,7 g 5-hydroksymetyl-3-isopropyl-2- fenyl-oksazolidin. Etter at losningen var oppvarmet i 1 time ved 50°C ble den inndampet til torrhet. Produktet behandles med vann, ekstraheres med eter, eterfasen torres og eteren avdestilleres. 1 -(3-isopropyl-2-fenyl-5-oksazolidinylmetoksy)-7-metoksy-isokinolin erholdes som en olje. The 1-(3-isopropyl-2-phenyl-5-oxa-zolidinyl-methoxy)-7-methoxyisoquinoline used as starting material can be prepared in the following way: dissolve 0.3 g of potassium in 15 ml of absolute tert.butanol and add 1 .5 g of 1-chloro-7-methoxy-isoquinoline and 1.7 g of 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine. After the solution was heated for 1 hour at 50°C, it was evaporated to dryness. The product is treated with water, extracted with ether, the ether phase is dried and the ether is distilled off. 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-7-methoxyisoquinoline is obtained as an oil.
Det for omsetningen anvendte 5-hydroksymetyl-3-isopropyl-2-fenyl-oksazolidin, kokepunkt q q3<=><1>33 til131+°C, erholdes ved koking av 1,2-dihydroksy-3-isopropylaminopropan med et overskudd av benzaldehyd i benzen under vannutskiller. 1 ,2-dihydroksy-3-isopropylamino-propan, kokepunkt q ^ = 96 til 98°C, erholdes ved oppvarming av 1,2-dihydroksy-3-klor-propan i et 1 5-dobbelt overskudd av isopropylamin i bomberor ved 100°C. The 5-hydroxymethyl-3-isopropyl-2-phenyl-oxazolidine used for the reaction, boiling point q q3<=><1>33 to 131+°C, is obtained by boiling 1,2-dihydroxy-3-isopropylaminopropane with an excess of benzaldehyde in benzene under water separator. 1,2-dihydroxy-3-isopropylamino-propane, boiling point q ^ = 96 to 98°C, is obtained by heating 1,2-dihydroxy-3-chloro-propane in a 1.5-fold excess of isopropylamine in a bomb retort at 100 °C.
Eksempel 2; lzi2-hydroksy=3-isopropylaminop_ropok Example 2; 12-hydroxy=3-isopropylaminopropoc
(fremgangsmåte b)(method b)
2,0 g 1 -(3-isopropyl-2-fenyl-5-oksazolidinylmetoksy)-isokinolin oppvarmes i 1 time ved 50°C med 20 ml 1N saltsyre. Reaksjons-- blandingen ekstraheres med metylenklorid. Metylenkloridfasen kastes og den vandige fase tilsettes pottaske til alkalisk reaksjon og ekstraheres deretter tre ganger med metylenklorid. Disse tre 2.0 g of 1-(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-isoquinoline is heated for 1 hour at 50°C with 20 ml of 1N hydrochloric acid. The reaction mixture is extracted with methylene chloride. The methylene chloride phase is discarded and pot ash is added to the aqueous phase for an alkaline reaction and then extracted three times with methylene chloride. These three
ekstrakter torres over magnesiumsulfat og inndampes. Resten omsettes i tetrahydrofuran med maleinsyre til 1 -(2-hydroksy-3-isopropylamino-propoksy)-isokinolin-hydrogenmaleinat med smeltepunkt 166 til 167°C. extracts are dried over magnesium sulfate and evaporated. The residue is converted in tetrahydrofuran with maleic acid to 1-(2-hydroxy-3-isopropylamino-propoxy)-isoquinoline hydrogen maleate with a melting point of 166 to 167°C.
Eksempel 3: lzi2-hydroksy=3-isop_rop_^laminopro Example 3: 1 z 2 -hydroxy=3-isop_rop_^laminopro
isokinolin (fremgangsmåte b)isoquinoline (method b)
3 j0 g 1 -(3-isopropyl-2-fenyl-5-oksazolidinylmetoksy)-6-metoksy-isokinolin tilsettes 25 ml 1N saltsyre og omrores i 2 timer ved romtemperatur. Opparbeidelsen skjer analogt med eksempel 1. Det erholdes 1 -(2-hydroksy-3-isopropylaminopropoksy)-6-metoksy-isokinolin som smelter ved 95 til 97°C. 3 j0 g of 1 -(3-isopropyl-2-phenyl-5-oxazolidinylmethoxy)-6-methoxy-isoquinoline is added to 25 ml of 1N hydrochloric acid and stirred for 2 hours at room temperature. The preparation takes place analogously to example 1. 1-(2-hydroxy-3-isopropylaminopropoxy)-6-methoxy-isoquinoline is obtained which melts at 95 to 97°C.
Eksempel 38 : 1_ = (2=hyd.roksy=3 (2-metyl=3-b^tZ^Z2-yl-amino) - Example 38: 1_ = (2=hydroxy=3 (2-methyl=3-b^tZ^Z2-yl-amino) -
grogoksy)isokinolin (fremgangsmåte a)grogoxy)isoquinoline (method a)
0,86 g kalium loses i *f0 ml tert.butylalkohol og tilsettes 3 ?8 g 1 -(2-metyl-3-butynylamino)-2,3-dihydroksypropanol og deretter 0.86 g of potassium is dissolved in *f0 ml of tert.butyl alcohol and 3 ?8 g of 1 -(2-methyl-3-butynylamino)-2,3-dihydroxypropanol is added and then
3,6 g 1-klorisokinolin. Etter en dags omroring oppvarmes i ytterligere 1 dag ved 50°C. Reaksjonslosningen inndampes'under vakuum. Resten opptas i 1N saltsyre og eter, den vandige fase nøytraliseres med 2N sodalbsning og ekstraheres med metylenklorid. Etter torring over magnesiumsulfat og inndamping erholdes en olje som med fumarsyre i metylenklorid og eter gir bis-fumaratet av den i overskriften nevnte forbindelse med smeltepunkt 176 - 177°C. 3.6 g of 1-chloroisoquinoline. After stirring for one day, heat for a further 1 day at 50°C. The reaction solution is evaporated under vacuum. The residue is taken up in 1N hydrochloric acid and ether, the aqueous phase is neutralized with 2N sodium hydroxide solution and extracted with methylene chloride. After drying over magnesium sulfate and evaporation, an oil is obtained which, with fumaric acid in methylene chloride and ether, gives the bis-fumarate of the compound mentioned in the title with a melting point of 176 - 177°C.
Den anvendte 1 -(2-metyl-3-butynylamino)-2,3-dihydroksypropanol erholdes, ved omsetning av glycidol med ekvimolære mengder 2-amino-2-metyl-3-butyn i etanol. The 1-(2-methyl-3-butynylamino)-2,3-dihydroxypropanol used is obtained by reacting glycidol with equimolar amounts of 2-amino-2-methyl-3-butyne in ethanol.
Analogt med eksempel 38 erholdes de i eksemplene 1 til 2*f. såvel som 26 til 37 beskrevne forbindelser med formel I ved omsetning, av den tilsvarende forbindelse med.formel II med den tilsvarende forbindelse med formel III under anvendelse av fremgangsmåten a. Analogous to example 38, they are obtained in examples 1 to 2*f. as well as 26 to 37 described compounds of formula I by reaction, of the corresponding compound of formula II with the corresponding compound of formula III using method a.
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1430773A CH581113A5 (en) | 1973-10-08 | 1973-10-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO743534L true NO743534L (en) | 1975-05-05 |
Family
ID=4399720
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO743534A NO743534L (en) | 1973-10-08 | 1974-09-30 |
Country Status (21)
| Country | Link |
|---|---|
| JP (1) | JPS5082078A (en) |
| AT (1) | ATA802974A (en) |
| AU (2) | AU498889B2 (en) |
| BE (1) | BE820789A (en) |
| CA (1) | CA1021772A (en) |
| CH (1) | CH581113A5 (en) |
| DD (1) | DD114605A5 (en) |
| DE (1) | DE2447756A1 (en) |
| DK (1) | DK135766B (en) |
| ES (1) | ES430759A1 (en) |
| FI (1) | FI286374A7 (en) |
| FR (1) | FR2247242B1 (en) |
| GB (1) | GB1474775A (en) |
| HU (1) | HU169126B (en) |
| IL (1) | IL45797A (en) |
| NL (1) | NL7413105A (en) |
| NO (1) | NO743534L (en) |
| PH (1) | PH11611A (en) |
| SE (1) | SE7412310L (en) |
| SU (1) | SU567403A3 (en) |
| ZA (1) | ZA746409B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK116976A (en) * | 1975-03-26 | 1976-09-27 | Sandoz Ag | PROCEDURE FOR THE PREPARATION OF ISOQUINOLINE DERIVATIVES |
| US4129565A (en) * | 1975-07-11 | 1978-12-12 | Nisshin Flour Milling Co., Ltd. | Isocarbostyril derivatives |
| DK166478A (en) * | 1977-05-02 | 1978-11-03 | Merck & Co Inc | PROCEDURE FOR THE PREPARATION OF NAPHTHYRIDINES |
| EP0711804A3 (en) | 1994-11-14 | 1999-09-22 | Ciba SC Holding AG | Latent light stabilizers |
| US6426415B1 (en) | 1997-09-03 | 2002-07-30 | Guilford Pharmaceuticals Inc. | Alkoxy-substituted compounds, methods and compositions for inhibiting parp activity |
| US6291425B1 (en) | 1999-09-01 | 2001-09-18 | Guilford Pharmaceuticals Inc. | Compounds, methods and pharmaceutical compositions for treating cellular damage, such as neural or cardiovascular tissue damage |
| US6197785B1 (en) | 1997-09-03 | 2001-03-06 | Guilford Pharmaceuticals Inc. | Alkoxy-substituted compounds, methods, and compositions for inhibiting PARP activity |
| US6346536B1 (en) | 1997-09-03 | 2002-02-12 | Guilford Pharmaceuticals Inc. | Poly(ADP-ribose) polymerase inhibitors and method for treating neural or cardiovascular tissue damage using the same |
| US6635642B1 (en) | 1997-09-03 | 2003-10-21 | Guilford Pharmaceuticals Inc. | PARP inhibitors, pharmaceutical compositions comprising same, and methods of using same |
| US6514983B1 (en) | 1997-09-03 | 2003-02-04 | Guilford Pharmaceuticals Inc. | Compounds, methods and pharmaceutical compositions for treating neural or cardiovascular tissue damage |
| US6395749B1 (en) | 1998-05-15 | 2002-05-28 | Guilford Pharmaceuticals Inc. | Carboxamide compounds, methods, and compositions for inhibiting PARP activity |
| US6387902B1 (en) | 1998-12-31 | 2002-05-14 | Guilford Pharmaceuticals, Inc. | Phenazine compounds, methods and pharmaceutical compositions for inhibiting PARP |
| WO2001090077A1 (en) | 2000-05-19 | 2001-11-29 | Guilford Pharmaceuticals, Inc. | Sulfonamide and carbamide derivatives of 6(5h)phenanthridinones and their uses |
| AU2001275085A1 (en) | 2000-06-01 | 2001-12-11 | Guilford Pharmaceuticals Inc. | Methods, compounds and compositions for treating gout |
| WO2025016273A1 (en) * | 2023-07-14 | 2025-01-23 | 拜西欧斯（北京）生物技术有限公司 | Isoquinoline derivative and pharmaceutical composition comprising same, and uses of isoquinoline derivative and pharmaceutical composition |
-
1973
- 1973-10-08 CH CH1430773A patent/CH581113A5/xx not_active IP Right Cessation
-
1974
- 1974-09-30 NO NO743534A patent/NO743534L/no unknown
- 1974-09-30 SE SE7412310A patent/SE7412310L/xx unknown
- 1974-09-30 DK DK514874AA patent/DK135766B/en unknown
- 1974-10-01 FI FI2863/74A patent/FI286374A7/fi unknown
- 1974-10-03 GB GB4290974A patent/GB1474775A/en not_active Expired
- 1974-10-04 NL NL7413105A patent/NL7413105A/en not_active Application Discontinuation
- 1974-10-04 DD DD181520A patent/DD114605A5/xx unknown
- 1974-10-07 BE BE149290A patent/BE820789A/en unknown
- 1974-10-07 PH PH16382A patent/PH11611A/en unknown
- 1974-10-07 CA CA210,857A patent/CA1021772A/en not_active Expired
- 1974-10-07 IL IL45797A patent/IL45797A/en unknown
- 1974-10-07 JP JP49114815A patent/JPS5082078A/ja active Pending
- 1974-10-07 DE DE19742447756 patent/DE2447756A1/en not_active Withdrawn
- 1974-10-07 ES ES430759A patent/ES430759A1/en not_active Expired
- 1974-10-07 AT AT802974A patent/ATA802974A/en not_active Application Discontinuation
- 1974-10-08 AU AU74090/74A patent/AU498889B2/en not_active Expired
- 1974-10-08 FR FR7433761A patent/FR2247242B1/fr not_active Expired
- 1974-10-08 SU SU7402066522A patent/SU567403A3/en active
- 1974-10-08 ZA ZA00746409A patent/ZA746409B/en unknown
- 1974-10-08 HU HUSA2697A patent/HU169126B/hu unknown
- 1974-10-09 AU AU74130/74A patent/AU7413074A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK135766B (en) | 1977-06-20 |
| JPS5082078A (en) | 1975-07-03 |
| CA1021772A (en) | 1977-11-29 |
| PH11611A (en) | 1978-04-12 |
| CH581113A5 (en) | 1976-10-29 |
| ZA746409B (en) | 1976-05-26 |
| SU567403A3 (en) | 1977-07-30 |
| FR2247242B1 (en) | 1978-07-21 |
| DK135766C (en) | 1977-11-21 |
| AU7413074A (en) | 1976-04-15 |
| DE2447756A1 (en) | 1975-04-10 |
| ATA802974A (en) | 1979-07-15 |
| DD114605A5 (en) | 1975-08-12 |
| SE7412310L (en) | 1975-04-09 |
| IL45797A (en) | 1978-04-30 |
| AU7408974A (en) | 1976-04-15 |
| HU169126B (en) | 1976-09-28 |
| AU498889B2 (en) | 1979-03-29 |
| GB1474775A (en) | 1977-05-25 |
| IL45797A0 (en) | 1974-12-31 |
| ES430759A1 (en) | 1977-04-16 |
| NL7413105A (en) | 1975-04-10 |
| BE820789A (en) | 1975-04-07 |
| AU7409074A (en) | 1976-04-15 |
| DK514874A (en) | 1975-06-09 |
| FI286374A7 (en) | 1975-04-09 |
| FR2247242A1 (en) | 1975-05-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO743534L (en) | ||
| EP0077754B1 (en) | Novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivatives | |
| NO167947B (en) | TAPE OR PLATE RECORDING STORAGE DEVICE | |
| PL94252B1 (en) | 1-Oxo-2,2-disubstituted-5-indanyloxy(or thio)alkanoic acids[US3984465A] | |
| US4073909A (en) | Isoquinoline compounds | |
| US3998835A (en) | 1-Substituted amino-3-thieno-[3,2-c]pyridinyloxy-2-propanols | |
| US4067873A (en) | Certain 1-amino-3-(1-isoquinolinyl)oxy-2-propanol derivatives | |
| NZ195702A (en) | 7-(3-(isopropyl or t-butyl)amino-2-hydroxypropoxy)-indolin-2,3-diones | |
| DK159425B (en) | 5-ACYL-3-CYANO-2- (1H) -PYRIDINONES OR ACID ADDITION SALTS THEREOF | |
| GB2056435A (en) | Novel Tetrahydropyridine and Piperidine Substituted Benzofuranes and Related Compounds | |
| NO127149B (en) | ||
| US4032648A (en) | Method and compositions containing thiochroman compounds for treating cardiac rhythm disorders | |
| US3929833A (en) | Organic compounds | |
| NO790948L (en) | PROCEDURE FOR PREPARING DILIGNOL DERIVATIVES | |
| NO121896B (en) | ||
| US4071630A (en) | 1-Substituted-amino-3-(4-furo[3,2-c]pyridinyloxy)-2-propanols | |
| EP0026505B1 (en) | 7,8-substituted-1-phenyl-2,3,4,5-tetrahydro-1-h-3-benzazepines | |
| EP0145361A2 (en) | Acetylene derivatives for the treatment of hypertension and angina | |
| KR870000034B1 (en) | [1-Oxo-2-aryl or thienyl-2-substituted-5-indanyloxy] alkanoic acid production method | |
| US4374261A (en) | 1-Ethyl-1,4-dihydro-6-(2-naphthyl)-4-oxo-nicotinic acid and esters thereof | |
| US4314063A (en) | 1-Ethyl-1,4,5,6-tetrahydro-6-(2-naphthyl)-4-oxo-nicotinic acid and lower alkyl esters thereof | |
| DK156652B (en) | METHOD OF ANALOGUE FOR THE PREPARATION OF PYRIDINYLOXYPROPANOLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE ACID ADDITION SALTS. | |
| EP0026289B1 (en) | Antihypertensive polyhalohydroxyisopropyl phenylalkanoic and phenylalkenoic acids, amides and esters, pharmaceutical compositions therefrom and intermediates thereto | |
| KR850001550B1 (en) | Process for preparation of indole derivatives | |
| NO127923B (en) |