NO140062B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE AMINO DERIVATIVES OF PYRAZOLOPYRIDINE KETONES - Google Patents

ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE AMINO DERIVATIVES OF PYRAZOLOPYRIDINE KETONES Download PDF

Info

Publication number
NO140062B
NO140062B NO741752A NO741752A NO140062B NO 140062 B NO140062 B NO 140062B NO 741752 A NO741752 A NO 741752A NO 741752 A NO741752 A NO 741752A NO 140062 B NO140062 B NO 140062B
Authority
NO
Norway
Prior art keywords
pyrazolo
pyridine
benzoyl
hydrogen
alkyl
Prior art date
Application number
NO741752A
Other languages
Norwegian (no)
Other versions
NO741752L (en
NO140062C (en
Inventor
Theodor Denzel
Hans Hoehn
Original Assignee
Squibb & Sons Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc
Publication of NO741752L publication Critical patent/NO741752L/en
Publication of NO140062B publication Critical patent/NO140062B/en
Publication of NO140062C publication Critical patent/NO140062C/en

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Description

I tysk offentliggjørelsesskrift nr. 2.225.433, In German Publication No. 2,225,433,

publisert 7. desember 1972, er det beskrevet amino-derivater av pyrazolo[3,4-b]pyridin-5-ketoner og salter derav, som er nyttige som anti-inflammatoriske midler og som har følgende formel published December 7, 1972, discloses amino derivatives of pyrazolo[3,4-b]pyridine-5-ketones and salts thereof which are useful as anti-inflammatory agents and which have the following formula

hvor where

R^ er hydrogen, lavere alkyl, fenyl eller fenyl-lavere-alkylen, R 1 is hydrogen, lower alkyl, phenyl or phenyl-lower alkylene,

1*2 er hydrogen- eller- lavere alkyl, 1*2 is hydrogen or lower alkyl,

R^ og .R^ er hver hydrogen, lavere alkyl, lavere alkanoyi, halogen-lavere alkanoyi, R7,Rg-fenyl, fenyl-lavere alkylen, di-lavere-alkylamino-lavere-alkylen eller-R^-"og R^ danner sammen<1>R^ and R^ are each hydrogen, lower alkyl, lower alkanoyi, halogeno-lower alkanoyi, R7,Rg-phenyl, phenyl-lower alkylene, di-lower-alkylamino-lower-alkylene or-R^-"and R^ form together<1>

med det nitrogen hvortil de er festet, en av de heterbcykliske grupper Rg,R^Q-aziridinyl, Rg ,R^Q-pyrrolidino, Rg , R10'-piperid'ino, ' R9»R10-pyrazolyl, Rg>R1Q-pyrimidinyl, Rg,R1Q-pyridazinyl :v; : with the nitrogen to which they are attached, one of the heterbicyclic groups Rg,R^Q-aziridinyl, Rg ,R^Q-pyrrolidino, Rg ,R10'-piperid'ino, ' R9»R10-pyrazolyl, Rg>R1Q-pyrimidinyl , R 8 , R 10 -pyridazinyl :v; :

eller Rg,R10-piperazinyl, "<:>" - or Rg,R10-piperazinyl, "<:>" -

R^ er lavere alkyl, cykloalkyl, fenyl eller R^,Rg-fenyl," ,- R^ is lower alkyl, cycloalkyl, phenyl or R^,Rg-phenyl," ,-

Rg er hydrogen-, lavere ^alkyl eller fenyl, - '• ! Rg is hydrogen, lower ^alkyl or phenyl, - '• !

R^ og Rg er hver hydrogen, halogen eller.trifluormetyl, og R 1 and R 8 are each hydrogen, halogen or trifluoromethyl, and

Rg og R^0 er (hver hydrogen, lavere alkyl eller hydroksy-lavéré-ålkyi, Rg and R^0 are (each hydrogen, lower alkyl or hydroxy-lavéré alkyl,

og syreaddis j.onssalter .derav... "■ ■'■ and syreaddis j.onssalter .hence... "■ ■'■

Det er kjent at disse forbindelser har antiinflammatoriske egenskaper og at de er nyttige som antiinflammatoriske midler, f.eks. til å redusere lokale betennelser så som de som er av ødematøs natur eller som stammer fra proliferasjon av bindevev i forskjellige pattedyr-arter så som rotter, hunder og lignende, som vist ved karragen-ødem-prøven på rotter. These compounds are known to have anti-inflammatory properties and to be useful as anti-inflammatory agents, e.g. to reduce local inflammations such as those of an edematous nature or arising from the proliferation of connective tissue in various mammalian species such as rats, dogs and the like, as shown by the carrageenan edema test in rats.

Representative antiinflammatoriske data, basert på karragen-ødem-prøven, for forbindelsene åpenbart i tysk pffentlig-gjørelsesskrift nr. 2.225.433, er vist i tabell I. Representative anti-inflammatory data, based on the carrageenan edema test, for the compounds disclosed in German Patent Publication No. 2,225,433 are shown in Table I.

Som det kan sees fra tabell I fremviser de forbindelser As can be seen from Table I, they exhibit compounds

som har den minste substitusjon i de forskjellige stillinger, de høyeste nivåer med antiinflammatorisk aktivitet. Således er forbindelse 1, hvor er fenyl, og hvor det er de minst mulige substitusjoner ved de andre steder, det vil si hvor R^, R2, R^, R4which have the smallest substitution in the different positions, the highest levels of anti-inflammatory activity. Thus, compound 1, where is phenyl, and where there are the fewest possible substitutions at the other sites, i.e. where R^, R2, R^, R4

og Rg alle er hydrogen, uten sammenligning det mest aktive anti-inf lammatoriske middel, målt ved standard-karragen-ødem-prøveh på rotter, sammen med forbindelse 20 som skiller seg fra forbindelse 1 ved etylsubstitusjon i R^-stillingen. Men hvilken som helst ytterligere substitusjon på de forskjellige steder resulterer generelt i en markert minskning i antiinflammatorisk aktivitet til nivåer hvor forbindelsene ikke er kommersielt konkurransedyktige som antiinflammatoriske midler. and Rg are all hydrogen, by far the most active anti-inflammatory agent as measured by the standard carrageenan edema test in rats, along with compound 20 which differs from compound 1 by ethyl substitution at the R^ position. However, any further substitution at the various sites generally results in a marked decrease in anti-inflammatory activity to levels where the compounds are not commercially competitive as anti-inflammatory agents.

Selv om de minst substituerte forbindelser i serien, Although the least substituted compounds in the series,

det vil si forbindelsene 1 og 20, er av spesiell interesse som anti-inf lammatoriske midler på grunn av deres høye nivå med anti-inf lammatorisk aktivitet, blir deres terapeutiske potensial for-minsket på grunn av deres markerte nivåer med urindrivende aktivitet. Substitusjon i de forskjellige stillinger nedsetter den urindrivende aktivitet til akseptable nivåer (0-2). Men sammen med forminskningen av urindrivende aktivitet er det også en markert minskning i antiinflammatorisk aktivitet, til nivåer hvor that is, compounds 1 and 20 are of particular interest as anti-inflammatory agents due to their high level of anti-inflammatory activity, their therapeutic potential is diminished due to their marked levels of diuretic activity. Substitution in the different positions reduces the diuretic activity to acceptable levels (0-2). But along with the reduction in diuretic activity, there is also a marked reduction in anti-inflammatory activity, to levels where

forbindelsene ikke er kommersielt konkurransedyktige som anti-inf lammatoriske midler. the compounds are not commercially competitive as anti-inflammatories.

Men vi har oppdaget, når man går videre med forbindelse 1 hvor Rr er fenyl og de andre stillinger er usubstituerte, det vil si But we have discovered, when proceeding with compound 1 where Rr is phenyl and the other positions are unsubstituted, that is

og spesielt velger substitueringen i R^-stillingen innenfor en svært begrenset gruppe alkyl- eller cykloalkylsubstituenter med forgrenet kjede og med formelen and in particular chooses the substitution in the R^ position within a very limited group of branched-chain alkyl or cycloalkyl substituents and of the formula

hvor R' og R" uavhengig av hverandre er hydrogen eller metyl, og hvor den stiplede linje betyr en binding som danner en cyklopropyl-ring, eller to hydrogenatomer, resulterer i forbindelser som har et akseptabelt lavt nivå med urindrivende aktivitet og et nivå med antiinflammatorisk aktivitet som er sammenlignbart med eller over-skrider aktivitetsnivåene til den usubstituerte forbindelse 1 eller dens R^etyl-substituerte derivatforbindelse 20. Vi har også, i motsetning til tendensen i tabell I, funnet at denne ønskelige kombinasjon av lav urindrivende aktivitet og høy anti-inf lammatorisk aktivitet blir opprettholdt når R^-fenylringen i formel I ovenfor blir substituert med en halogen-, lavere alkyl-eller lavere alkoksy-gruppe.. wherein R' and R" are independently hydrogen or methyl, and wherein the dashed line means a bond forming a cyclopropyl ring, or two hydrogen atoms, results in compounds having an acceptably low level of diuretic activity and a level of anti-inflammatory activity that is comparable to or exceeds the activity levels of the unsubstituted compound 1 or its R^ethyl-substituted derivative compound 20. We have also, contrary to the trend in Table I, found that this desirable combination of low diuretic activity and high anti- Inflammatory activity is maintained when the R^-phenyl ring in formula I above is substituted with a halogen, lower alkyl or lower alkoxy group.

Foreliggende oppfinnelse er derfor rettet mot fremstilling av forbindelser med formel The present invention is therefore directed towards the production of compounds with formula

hvor R' og R" uavhengig av hverandre er hydrogen eller metyl, where R' and R" independently of each other are hydrogen or methyl,

R"' betyr hydrogen, halogen, C^-C^-alkyl eller C^-C^-alkoksy, og den stiplede linje representerer en binding som danner en cyklo-propylring, eller to hydrogenatomer. R"' means hydrogen, halogen, C₁-C₁-alkyl or C₁-C₁- alkoxy, and the dashed line represents a bond forming a cyclopropyl ring, or two hydrogen atoms.

Som tidligere nevnt innehar forbindelsen med den forut-gående formel III en enestående kombinasjon av høy anti-inf lammatorisk aktivitet og et ubetydelig nivå med urindrivende aktivitet, hvor nevnte enestående kombinasjon blir tilskrevet og karakterisert ved substitusjon i R^-stillingen med cykloalkyl eller alkyl med en forgrenet kjede, idet nevnte substituent har den spesifikke delformel As previously mentioned, the compound of the preceding formula III possesses a unique combination of high anti-inflammatory activity and a negligible level of diuretic activity, said unique combination being attributed and characterized by substitution in the R 1 position with cycloalkyl or alkyl with a branched chain, said substituent having the specific partial formula

og omfatter isopropyl, sek.butyl, 3-pentyl, cyklopropyl, 2-metyl-cyklopropyl og 2,3-dimetylcyklopropyl. and includes isopropyl, sec-butyl, 3-pentyl, cyclopropyl, 2-methylcyclopropyl and 2,3-dimethylcyclopropyl.

Tabell II, som sammenligner den antiinflammatoriske aktivitet til representative forbindelser med formel I, hvor forskjellen bare består i substitueringen i 4-stillingen med cykloalkyl- eller alkylgrupper som til dels faller inn under delformel II, viser ytterligere den enestående aktivitet til forbindelsene med formel III fremstilt i henhold til foreliggende oppfinnelse, samt deres fysiske konstanter, dvs. her smeltepunktene til identifikasjon derav, og som dels har homolog betydning som spesifikt kjent fra ovennevnte tyske offentliggjørelsesskrift nr. 2.225.433. Table II, which compares the anti-inflammatory activity of representative compounds of formula I, where the difference consists only in the substitution in the 4-position with cycloalkyl or alkyl groups that partly fall under partial formula II, further shows the outstanding activity of the compounds of formula III prepared according to the present invention, as well as their physical constants, i.e. here the melting points for identification thereof, and which partly have a homologous meaning as specifically known from the above-mentioned German publication no. 2,225,433.

De nye forbindelser med formel III fremstilles i henhold til foreliggende oppfinnelse ved at et 5-benzoyl-4-alkoksy eller halogen-lH-pyrazolo[3,4-b]pyridin med formelen hvor X er klor, brom eller alkoksy, og R"' er som tidligere angitt, omsettes med et amin med formelen The new compounds of formula III are prepared according to the present invention by a 5-benzoyl-4-alkoxy or halo-1H-pyrazolo[3,4-b]pyridine of the formula where X is chlorine, bromine or alkoxy, and R" ' is, as previously indicated, reacted with an amine with the formula

hvor R<1> og R" er som tidligere angitt. Denne omsetning blir ut-ført ved å behandle reaktantene enten ved romtemperatur eller ved forhøyede temperaturer. I noen tilfeller kan det være fordelaktig å anvende en autoklav. Fremstillingen av utgangsmaterialet med formel IV hvor R"' er hydrogen og X er alkoksy, hvor alkoksy-gruppen er etoksy, er belyst i eksempel 1 (a) - (d). R"'-gruppen kan varieres ved å anvende en etoksy-metylensubstituert benzoyleddiksyre-etylester ved prosessen i eksempel 1 (a). Alkoksy-gruppen (X) kan varieres ved å anvende et annet alkylhalogenid i stedet for etyljodid anvendt i eksempel l(c). Alternativt kan hydroksy-produktet i eksempel l(b) omsettes med et bestemt fosfor-halogenid som ligner fosforoksyklorid for eventuelt å danne et utgangsmateriale med formel IV hvor X er klor eller brom. where R<1> and R" are as previously stated. This reaction is carried out by treating the reactants either at room temperature or at elevated temperatures. In some cases it may be advantageous to use an autoclave. The preparation of the starting material with formula IV where R"' is hydrogen and X is alkyloxy, where the alkyloxy group is ethoxy, is illustrated in example 1 (a) - (d). The R"' group can be varied by using an ethoxy-methylene substituted benzoylacetic acid ethyl ester in the process of Example 1 (a). The alkoxy group (X) can be varied by using another alkyl halide instead of ethyl iodide used in Example 1(c ).Alternatively, the hydroxy product in example 1(b) can be reacted with a specific phosphorus halide similar to phosphorus oxychloride to optionally form a starting material of formula IV where X is chlorine or bromine.

Forbindelsene med formel III danner lett salter, og The compounds of formula III readily form salts, and

deres fremstilling omfattes også av denne oppfinnelse. Saltene innbefatter syreaddisjonssalter, spesielt de som er ikke-toksiske og fysiologisk akseptable. Basene med formel III danner salter ved omsetning med en rekke uorganiske og organiske syrer og tilveiebringer syreaddisjonssalter, innbefattet f.eks. hydrohalogenidene (spesielt hydrokloridet), sulfat, nitrat, fosfat, oksalat, tartrat, maleat, citrat, acetat, askorbat, succinat, benzensulfonat, toluen-sulfonat, cykloheksansulfonat, cykloheksansulfamat etc. Syreaddis jonssaltene tilveiebringer ofte et bekvemt middel til å isolere produktet, f.eks. ved å danne og utfelle saltet i et bestemt opp-løsningsmiddel hvori saltet er uoppløselig, og så efter separering av saltet, å nøytralisere med en base så som bariumhydroksyd eller natriumhydroksyd, for å erholde den frie base med formel III. their manufacture is also covered by this invention. The salts include acid addition salts, especially those which are non-toxic and physiologically acceptable. The bases of formula III form salts by reaction with a number of inorganic and organic acids and provide acid addition salts, including e.g. the hydrohalides (especially the hydrochloride), sulfate, nitrate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, benzenesulfonate, toluenesulfonate, cyclohexanesulfonate, cyclohexanesulfamate, etc. The acid addition salts often provide a convenient means of isolating the product, f .ex. by forming and precipitating the salt in a particular solvent in which the salt is insoluble, and then after separating the salt, to neutralize with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of formula III.

Det kan så bli dannet andre salter fra den frie base ved omsetning med en ekvivalent med syre. Other salts can then be formed from the free base by reaction with an equivalent of acid.

Forbindelsene fremstilt i henhold til denne oppfinnelse har antiinflammatoriske egenskaper og er nyttige som anti-inf lammatoriske midler, f.eks. til å redusere lokale betennelser så som slike av ødematøs natur eller som stammer fra proliferasjon av bindevev i forskjellige pattedyr-arter så som rotter, hunder og lignende, når de blir gitt oralt med doser på omkring 5 til 50 mg/kg/dag, fortrinnsvis 5 til 25 mg/kg/dag, med bare en enkel eller ved 2 til 4 oppdelte doser, som vist ved karragen-ødem-prøven på rotter. The compounds prepared according to this invention have anti-inflammatory properties and are useful as anti-inflammatory agents, e.g. to reduce local inflammations such as those of an edematous nature or arising from the proliferation of connective tissue in various mammalian species such as rats, dogs and the like, when administered orally at doses of about 5 to 50 mg/kg/day, preferably 5 to 25 mg/kg/day, with only a single or in 2 to 4 divided doses, as shown by the carrageenan edema test in rats.

De følgende eksempler skal belyse oppfinnelsen. The following examples shall illustrate the invention.

Alle temperaturangivelser er angitt som °C. All temperature indications are given as °C.

Eksempel 1 Example 1

5- benzoyl- 4- sek. butylamino- lH- pyrazolo[ 3, 4- b1pyridin 5- benzoyl- 4- sec. butylamino-1H-pyrazolo[3,4-b1pyridine

a) [[[ 1-( 2- furyl) metylpyrazolyl] amino] metylen] benzoyleddiksyre-etylester a) [[[ 1-(2- furyl) methylpyrazolyl] amino] methylene] benzoylacetic acid ethyl ester

163 g 1-(2-furyl)metyl-5-aminopyrazol (1 mol) og 248 g etoksymetylenbenzoyleddiksyre-etylester (1 mol) blir oppvarmet ved 130°C inntil det ikke avdestilleres mer alkohol (tilnærmet 1 time). Det oljeaktige residuum krystalliserer og gir ved av-kjøling og omkrystallisering fra heksan 310 g med, [[ [1-(2-furyl)-metyl-5-pyrazolyl]amino]metylen]benzoyleddiksyreetylester (85%), sm.p.: 75-77°C. 163 g of 1-(2-furyl)methyl-5-aminopyrazole (1 mol) and 248 g of ethoxymethylenebenzoylacetic acid ethyl ester (1 mol) are heated at 130° C. until no more alcohol is distilled off (approximately 1 hour). The oily residue crystallizes and, on cooling and recrystallization from hexane, gives 310 g of, [[ [1-(2-furyl)-methyl-5-pyrazolyl]amino]methylene]benzoylacetic acid ethyl ester (85%), m.p.: 75-77°C.

b) 5- benzoy1- 4- hydroksy1- 1-( 2- furyl) metyl- lH- pyrazolo[ 3, 4- b]-pyridin b) 5-benzoyl-4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]-pyridine

36,5 g [[[1-(2-furyl)metyl-5-pyrazolyl]amino]metylen]-benzoyleddiksyreetylester blir oppløst i 50 ml difenylester og tilbakeløpsbehandlet ved 260° i 30 minutter. Destillering av oppløsningsmidlet gir en mørk olje som krystalliserer ved tilsetning av metanol. Omkrystallisering fra butylalkohol gir 20 g 5-benzoyl-4-hydroksy-l-(2-furyl)metyl-lH-pyrazolo[3,4-b]pyridin (61%), sm.p. 102°C. 36.5 g of [[[1-(2-furyl)methyl-5-pyrazolyl]amino]methylene]-benzoylacetic acid ethyl ester are dissolved in 50 ml of diphenyl ester and refluxed at 260° for 30 minutes. Distillation of the solvent gives a dark oil which crystallizes on addition of methanol. Recrystallization from butyl alcohol gives 20 g of 5-benzoyl-4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine (61%), m.p. 102°C.

c) 5- benzoyl- 4- etoksy- l-( 2- furyl) metyl- lH- pyrazolo[ 3, 4- b] pyridin c) 5-benzoyl-4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine

3,3 g 5-benzoyl-4-hydroksy-l-(2-furyl)metyl-lH-pyrazolo-[3,4-b]pyridin (0,01 mol) blir oppløst i 20 ml dimetylformamid. 3.3 g of 5-benzoyl-4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo-[3,4-b]pyridine (0.01 mol) are dissolved in 20 ml of dimethylformamide.

2,8 g kaliumkarbonat og 3,1 g etyljodid blir tilsatt og 2.8 g of potassium carbonate and 3.1 g of ethyl iodide are added and

blandingen blir varmet i 12 timer ved 60°C. Overskytende kaliumkarbonat blir frafiltrert og det blir tilsatt vann. 5-benzoyl-4- etoksy-l-(2-furyl)metyl-lH-pyrazolo[3,4-b]pyridin utfelles og blir omkrystallisert fra heksan, utbytte 3 g (86%), sm.p. 70°. the mixture is heated for 12 hours at 60°C. Excess potassium carbonate is filtered off and water is added. 5-benzoyl-4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine precipitates and is recrystallized from hexane, yield 3 g (86%), m.p. 70°.

d) 5- benzoyl- 4- etoksy- lH- pyrazolo[ 3, 4- b] pyridin d) 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine

1,7 g 5-benzoyl-4-etoksy-l-(2-furyl)metyl-lH-pyrazolo-l3,4-b]pyridin (0,005 mol) blir oppløst i 5 ml dietylenglykol-. dimetyleter, det blir tilsatt 1,1 g selendioksyd og blandingen blir oppvarmet under røring ved 160°. Etter tilsetning av en dråpe vann blir temperaturen opprettholdt i 1 time. Blandingen blir varmfiltrert og ved avkjøling felles det ut 5-benzoyl-4-etoksy-lH-pyrazolo[3,4-b]pyridin. Omkrystallisering fra butanol gir 1 g som utbytte (77%), sm.p. 195-197°C. 1.7 g of 5-benzoyl-4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo-13,4-b]pyridine (0.005 mol) is dissolved in 5 ml of diethylene glycol. dimethyl ether, 1.1 g of selenium dioxide is added and the mixture is heated with stirring at 160°. After adding a drop of water, the temperature is maintained for 1 hour. The mixture is filtered hot and, on cooling, 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine precipitates out. Recrystallization from butanol gives 1 g as yield (77%), m.p. 195-197°C.

e) 5- benzoyl- 4- sek. butylamino- lH- pyrazolo[ 3, 4- b] pyridin e) 5- benzoyl- 4- sec. butylamino-1H-pyrazolo[3,4-b]pyridine

2,6 g 5-benzoyl-4-etoksy-lH-pyrazolo[3,4-b]pyridin 2.6 g of 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine

(0,01 mol) og 10 ml sek.butylamin blir tilbakeløpsbehandlet i (0.01 mol) and 10 ml of sec.butylamine are refluxed in

10 timer. Etter denne tid blir det overskytende amin fjernet i vakuum, og residuet av 5-benzoyl-4-sek.butylamino-lH-pyrazolo-[3,4-b]pyridin blir omkrystallisert. Sm.p. 174-175°, 10 hours. After this time, the excess amine is removed in vacuo, and the residue of 5-benzoyl-4-sec-butylamino-1H-pyrazolo-[3,4-b]pyridine is recrystallized. Sm.p. 174-175°,

utbytte 87%. yield 87%.

Eksempel 2 Example 2

5- p- klorbenzoyl- 4- sek. butylamino- lH- pyrazolo[ 3, 4- b] pyridin 5- p- chlorobenzoyl- 4- sec. butylamino-1H-pyrazolo[3,4-b]pyridine

Ved å erstatte etoksymetylen-benzoyleddiksyre-etylesteren anvendt i eksempel la med en ekvimolar mengde med etoksymetylen-p-klorbenzoyl-eddiksyreetylester og ellers følge fremgangsmåten i eksempel 1 helt ut del (d), blir det fremstilt 5-p-klorbenzoyl-4-etoksy-lH-pyrazolo[3,4-b]pyridin. By replacing the ethoxymethylene-benzoylacetic acid ethyl ester used in example 1a with an equimolar amount of ethoxymethylene-p-chlorobenzoyl-acetic acid ethyl ester and otherwise following the procedure in example 1 all the way to part (d), 5-p-chlorobenzoyl-4-ethoxy -1H-pyrazolo[3,4-b]pyridine.

Ved å innsette produktet ovenfor i stedet for 5-benzoyl-4-etoksy-lH-pyrazolo[3,4-b]pyridinet anvendt ved fremgangsmåten i eksempel l(e), blir det i tittelen angitte produkt erholdt, By inserting the above product in place of the 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine used in the method in example 1(e), the title product is obtained,

sm.p. 216-218°, utbytte 88%. sm.p. 216-218°, yield 88%.

Eksempel 3 Example 3

5- p- toluyl- 4- sek. butylamino- lH- pyrazolo[ 3, 4- b] pyridin 5- p- toluyl- 4- sec. butylamino-1H-pyrazolo[3,4-b]pyridine

Ved å innsette etoksymetylen-p-toluyl-eddiksyre-etylester i eksempel 1 (a), og følge fremgangsmåten i eksempel 1, blir det ovenfor i tittelen angitte produkt erholdt, sm.p. 203-204°, utbytte 91%. By inserting ethoxymethylene-p-toluyl-acetic acid ethyl ester in example 1 (a), and following the procedure in example 1, the product stated above in the title is obtained, m.p. 203-204°, yield 91%.

Eksempel 4 Example 4

5- p- metoksybenzoyl- 4- sek. butylamino- lH- pyrazolo[ 3, 4- b] pyridin 5- p- methoxybenzoyl- 4- sec. butylamino-1H-pyrazolo[3,4-b]pyridine

Ved å innsette etoksymetylen-p-metoksybenzoyleddiksyre-etylester i eksempel 1 (a), og følge fremgangsmåten i eksempel 1, blir det ovenfor i tittelen angitte produkt erholdt, sm.p. 196-19 7°, utbytte 90%. By inserting ethoxymethylene-p-methoxybenzoylacetic acid ethyl ester in example 1 (a), and following the procedure in example 1, the product stated above in the title is obtained, m.p. 196-19 7°, yield 90%.

Eksempel 5 Example 5

5- benzoyl- 4- cyklopropylamino- lH- pyrazolo[ 3, 4- b] pyridin 5- benzoyl- 4- cyclopropylamino- 1H- pyrazolo[ 3, 4-b] pyridine

2,6 g 5-benzoyl-4-etoksy-lH-pyrazolo[3,4-b]pyridin 2.6 g of 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine

blir oppløst i 50 ml n-butyl-alkohol, det blir tilsatt 10 ml cyklopropylamin og blandingen blir oppvarmet i 10 timer i en autoklav ved 160°. Efter denne tid blir overskytende oppløsnings-middel fjernet i vakuum og residuet blir krystallisert og gir 5-benzoyl-4-cyklopropylamino-lH-pyrazolo[3,4-b]pyridin, is dissolved in 50 ml of n-butyl alcohol, 10 ml of cyclopropylamine is added and the mixture is heated for 10 hours in an autoclave at 160°. After this time, excess solvent is removed in vacuo and the residue is crystallized to give 5-benzoyl-4-cyclopropylamino-1H-pyrazolo[3,4-b]pyridine,

sm.p. 256-258°, utbytte 84%. sm.p. 256-258°, yield 84%.

Eksempel 6 Example 6

5- benzoyl- 4- isopropylamino- lH- pyrazolo[ 3, 4- b] pyridin- monohydrat 5- benzoyl- 4- isopropylamino- 1H- pyrazolo[ 3, 4-b] pyridine monohydrate

Ved å sette inn isopropylamin i stedet for cyklopropylamin i eksempel 5, blir den ovenfor i tittelen angitte forbindelse fremstilt, sm.p. 191-193°, utbytte 84%. By substituting isopropylamine for cyclopropylamine in Example 5, the above title compound is prepared, m.p. 191-193°, yield 84%.

Eksempel 7 Example 7

5- benzoyl- 4- cyklopropylamino- lH- pyrazolo[ 3, 4- b] pyridin- hydroklorid 5- benzoyl- 4- cyclopropylamino- 1H- pyrazolo[ 3, 4-b] pyridine- hydrochloride

( 1:1) (1:1)

0,1 mol 5-benzoyl-4-cyklopropylamino-lH-pyrazolo[3,4-b]-pyridin blir suspendert i 100 ml HCl-mettet metanol. Blandingen blir tilbakeløpsbehandlet i 1 time, oppløsningsmidlet blir fjernet i vakuum og residuet blir oppløst i en liten mengde med metanol. Ved tilsetning av eter utfelles 5-benzoyl-4-cyklopropylamino-lH-pyrazolo[3,4-b]pyridin-hydroklorid, sm.p. 250-252°. 0.1 mol of 5-benzoyl-4-cyclopropylamino-1H-pyrazolo[3,4-b]-pyridine is suspended in 100 ml of HCl-saturated methanol. The mixture is refluxed for 1 hour, the solvent is removed in vacuo and the residue is dissolved in a small amount of methanol. On addition of ether, 5-benzoyl-4-cyclopropylamino-1H-pyrazolo[3,4-b]pyridine hydrochloride is precipitated, m.p. 250-252°.

Claims (1)

Analogifremgangsmåte fo;r jfremstiilling av terapeutiskAnalogy method for producing therapeutic aktive .forbindelser med formelenactive .compounds with the formula hvor R<1> og R" uavhengig av hverandre er hydrogen eller roehyl, R"' er hydrogen, halogen, C^-C^-alkyl eller C^-C^-alkoksy,, og den stiplede linje representerer en binding som danner en -cyklo-propylring, eller to hydrogenatomer,where R<1> and R" independently of each other are hydrogen or alkyl, R"' is hydrogen, halogen, C₁-C₂ alkyl or C₁-C₂-alkyl, and the dashed line represents a bond that forms a -cyclopropyl ring, or two hydrogen atoms, og deres syreaddisjonssalter,and their acid addition salts, karakterisert ved at en forbindelse med formelencharacterized in that a compound with the formula hvor X er klor, brom eller alkoksy, omsettes med et amin 'med fornelenwhere X is chlorine, bromine or alkoxy, is reacted with an amine 'with the forenyl hvor R" -og R" er som angitt ovenfor,,where R" - and R" are as indicated above,, og, om ønsket, fremstilles syreaddis jonssaltene på kjent, taåte.and, if desired, the acid addition ion salts are prepared in a known manner.
NO741752A 1973-05-17 1974-05-14 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE AMINO DERIVATIVES OF PYRAZOLOPYRIDINE KETONES NO140062C (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US36112073A 1973-05-17 1973-05-17

Publications (3)

Publication Number Publication Date
NO741752L NO741752L (en) 1974-11-19
NO140062B true NO140062B (en) 1979-03-19
NO140062C NO140062C (en) 1979-07-04

Family

ID=23420728

Family Applications (1)

Application Number Title Priority Date Filing Date
NO741752A NO140062C (en) 1973-05-17 1974-05-14 ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE AMINO DERIVATIVES OF PYRAZOLOPYRIDINE KETONES

Country Status (19)

Country Link
JP (1) JPS5714674B2 (en)
AR (1) AR201145A1 (en)
AT (1) AT336015B (en)
BE (1) BE815200A (en)
CA (1) CA997351A (en)
CH (1) CH594666A5 (en)
DD (1) DD111379A5 (en)
DE (1) DE2423060A1 (en)
ES (1) ES426359A1 (en)
FI (1) FI55660C (en)
FR (1) FR2229415A1 (en)
HU (1) HU168565B (en)
IL (1) IL44744A (en)
NL (1) NL7406559A (en)
NO (1) NO140062C (en)
PL (1) PL91641B1 (en)
SE (1) SE395150B (en)
SU (1) SU501675A3 (en)
YU (1) YU136874A (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5030665B1 (en) * 1971-04-19 1975-10-02
JPS5539378B1 (en) * 1971-11-22 1980-10-11
JPS5199554U (en) * 1975-02-07 1976-08-10
JPS53130740A (en) * 1977-04-20 1978-11-15 Matsushita Electronics Corp Electrostatic coating apparatus for fluorecent substance
CH623489A5 (en) * 1977-12-08 1981-06-15 Gema Ag
JPS5719051A (en) * 1980-07-07 1982-02-01 Nippon Wagner Supureetec Kk Static painting apparatus
US4811898A (en) * 1987-09-21 1989-03-14 Nordson Corporation Electrostatic powder spray gun with adjustable deflector and electrostatic shield

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA999298A (en) * 1971-05-25 1976-11-02 E.R. Squibb And Sons Amino derivatives of pyrazolopyridine ketones

Also Published As

Publication number Publication date
CH594666A5 (en) 1978-01-13
FI55660C (en) 1979-09-10
IL44744A0 (en) 1974-07-31
AR201145A1 (en) 1975-02-14
ATA413774A (en) 1976-08-15
JPS5018495A (en) 1975-02-26
NL7406559A (en) 1974-11-19
SE395150B (en) 1977-08-01
IL44744A (en) 1978-06-15
CA997351A (en) 1976-09-21
AU6861574A (en) 1975-11-06
FI150274A (en) 1974-11-18
FI55660B (en) 1979-05-31
DE2423060A1 (en) 1974-12-05
JPS5714674B2 (en) 1982-03-25
DD111379A5 (en) 1975-02-12
ES426359A1 (en) 1976-07-01
HU168565B (en) 1976-05-28
BE815200A (en) 1974-11-18
SU501675A3 (en) 1976-01-30
NO741752L (en) 1974-11-19
FR2229415A1 (en) 1974-12-13
PL91641B1 (en) 1977-03-31
NO140062C (en) 1979-07-04
AT336015B (en) 1977-04-12
FR2229415B1 (en) 1977-07-08
YU136874A (en) 1982-06-18

Similar Documents

Publication Publication Date Title
KR880002232B1 (en) Preparation process for quinoline derivatives and their salts
US3700673A (en) 3-4-dihydrobenzo(b) (1,7)naphthyridin-1(2h)-ones
NO169437B (en) 3-AMINO-KINO LINER.
SU727142A3 (en) Method of preparing substituted 1-sulfonidebenzimidazoles
US4020072A (en) 5-Aminomethyl-1H-pyrazolo[3,4-b]pyridines
HU217080B (en) New process for producing imidazo[4,5-c]quinoline-4-amine derivatives
NO134212B (en)
NO140062B (en) ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE AMINO DERIVATIVES OF PYRAZOLOPYRIDINE KETONES
JPS587626B2 (en) Naphthyridine and quinoline
JPH0311067A (en) Excitatory amino acid antagonist
AU674542B2 (en) Process for obtaining benzoxazines useful for the synthesis of ofloxacin, levofloxacin and derivatives thereof
JPS6346077B2 (en)
BG108090A (en) Process for the preparation of mesylates of piperazine derivatives
CS198297B2 (en) Method of producing derivatives of urea
SU416946A3 (en) METHOD OF OBTAINING 1-BENZOTIENO- [2,3-yg] -PYRIMIDINES
US3681360A (en) Antiviral substituted acridanones
HU179391B (en) Process for producing thiasolo-square bracket-2,3-b-square bracket closed-quinasoline derivatives
PT88432B (en) PROCESS FOR THE PREPARATION OF USEFUL 4-OXO-3-KINOLINOCARBOXYL ACID ACIDS AS ANTI-BACTERIAL AGENTS
NO168358B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE BENZOFURO (3,2-C) -KINOLINE COMPOUNDS
SU1579459A3 (en) Method of obtaining derivatives of 1-methylaminoquinolinecarboxylic acid or their salts connecting pharmaceutically acceptable acids
IL28645A (en) Tropine derivatives
US4292323A (en) Phenyl-1,2,3,4-tetrahydrocarbazoles and use thereof
US3313817A (en) 4-alkyl (and alkenyl)-1-oxo-1, 4-dihydro-4, 7-phenanthroline-2-carboxylic acid derivatives
US2681911A (en) 1, 2, 3, 4-tetrahydroisoquinolinalkanol esters of aromatically substituted aliphaticacids and their derivatives
EP0073849A1 (en) Novel phenyl-1,2,3,4-tetrahydrocarbazoles, their preparation and pharmaceutical compositions containing them