NO834401L

NO834401L - PYRAZOLO (4.3-B) (1.4) OXASINES, THE PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS A MEDICINE

Info

Publication number: NO834401L
Application number: NO834401A
Authority: NO
Inventors: Romanis Fruchtmann; Harald Horstmann; Mithat Mardin; Wolfgang Opitz; Bernhard Pelster; Siegfried Raddatz
Original assignee: Troponwerke Gmbh & Co Kg
Priority date: 1982-12-14
Filing date: 1983-11-30
Publication date: 1984-06-15
Also published as: EP0111809A1; IL70424A0; FI834549A0; ES8406490A1; DK574483D0; FI834549A; AU2213183A; PT77789B; PT77789A; DK574483A; GR81347B; ES528013A0

Abstract

Pyrazolo[4,3-b][1,4]oksaziner med den generelle formel I i deres isomere former Ia og Ib såvel enkeltvis som også i blanding. hvori R og R^ blant annet kan bety^ hydrogen, metyl og/eller fenyl, 4-klorfenyl, 4-metoksyfenyl,. R 2 kan blant annet bety hydrogen, met;•eller etyl og. . R3 kan blant annet bety hydrogen, metyl, 3,4-diklorbemzyl, 2-fenoksyetyl, B-naftoksyetyl, benzyloksykarbonyl, formyl, acetyl og karboksymetyl og. R 5 kan blant annet bety hydrogen, metyl, propyl og isopropyl.Det omtales også fremgangsmåte til deres fremstilling. og deres anvendelse som legemiddel, spesielt deres anvendelse som lipoksygenasehemmere, legemidler som inneholder disse og deres fremstilling.Pyrazolo [4,3-b] [1,4] oxazines of the general formula I in their isomeric forms Ia and Ib both individually and in admixture. wherein R 1 and R 2 may include hydrogen, methyl and / or phenyl, 4-chlorophenyl, 4-methoxyphenyl, inter alia. R 2 can mean, inter alia, hydrogen, meth; or ethyl and. . R 3 may include hydrogen, methyl, 3,4-dichlorobemzyl, 2-phenoxyethyl, β-naphthoxyethyl, benzyloxycarbonyl, formyl, acetyl and carboxymethyl and. R 5 can mean, inter alia, hydrogen, methyl, propyl and isopropyl. The process for their preparation is also mentioned. and their use as medicaments, in particular their use as lipoxygenase inhibitors, medicaments containing them and their preparation.

Description

Oppfinnelsen vedrører pyrazolo[4,3-b][1,4]-oksaziner, en fremgangsmåte til deres fremstilling, deres'anvendelse som legemiddel, spesielt deres anvendelse til behandling av betennelses og/eller allergiske prosesser og fremstillingen av disse legemidler. The invention relates to pyrazolo[4,3-b][1,4]-oxazines, a process for their preparation, their use as medicine, in particular their use in the treatment of inflammatory and/or allergic processes and the preparation of these medicines.

Ved de hittil vanlige antiflogistika dreier det seg over-veiende om cyklooksygenasehemmere, som hemmer avbygningen av arachidonsyre til betennelsesbefordrende metabolitter. The hitherto common antiphlogistics are predominantly cyclooxygenase inhibitors, which inhibit the breakdown of arachidonic acid into inflammation-promoting metabolites.

Disse antiflogistika har følgende ulemper: Ved hemming av emzymet cyclooxygenase kommer til en vidtrekkende prostaglandinsyntetasehemming, til en stimulering av den alternative lipoxygenasevei og videre til en proinflammator- These antiphlogistics have the following disadvantages: By inhibiting the enzyme cyclooxygenase, there is a far-reaching prostaglandin synthetase inhibition, to a stimulation of the alternative lipoxygenase pathway and further to a proinflammatory

isk resp. astmatisk virkning og gastrotoksisitet (sammenlign K. Brune et al., J. Pharm. Pharmacol. 33.'127-128, 1981). ice or asthmatic effect and gastrotoxicity (compare K. Brune et al., J. Pharm. Pharmacol. 33.'127-128, 1981).

I noen tid har man forsøkt å finne stoffer som griper inn iFor some time, efforts have been made to find substances that intervene

den alternative arachidonsyreavbygning, altså virker som lipoxygenasehemmer. Det er allerede kjent noen få lipoksygenasehemmere som Nordihydroguaretsyre, 3-amino-l-(3-trifluormetylfenyl)-pyrazolin, fenidon og 5,8,11,14-eikosatetrainsyre. Deres virkning er imidlertid meget svak, for det meste er hovedvirkningen en cyklooksygenase-hemmevirkning, og noen, f.eks. 3-amino-l-(trifluormetylfenyl)-pyrazolin viser ved oral administrering toksiske bivirkninger. Det består derfor et behov av oralt virksomme forbindelser, the alternative arachidonic acid breakdown, thus acts as a lipoxygenase inhibitor. A few lipoxygenase inhibitors are already known, such as Nordihydroguaretic acid, 3-amino-1-(3-trifluoromethylphenyl)-pyrazoline, phenidone and 5,8,11,14-eicosatetraenoic acid. However, their effect is very weak, mostly the main effect is a cyclooxygenase inhibitory effect, and some, e.g. 3-amino-1-(trifluoromethylphenyl)-pyrazoline shows toxic side effects when administered orally. There is therefore a need for orally active compounds,

som ikke har slike uønskede bivirkninger.which do not have such unwanted side effects.

Overraskende ér de nye pyrazolo[4,3-b][1,4]oksaziner ifølge oppfinnelsen potente hemstoffer av lipoksygenase. Delvis hemmer de lipoksygensae allerede i slike konsentrasjoner, Surprisingly, the new pyrazolo[4,3-b][1,4]oxazines according to the invention are potent inhibitors of lipoxygenase. They partially inhibit lipoxygensae already in such concentrations,

hvor cyklooksygenasen ennu ikke påvirkes.where the cyclooxygenase is not yet affected.

De nye forbindelser ifølge oppfinnelsen stimulerer ogsåThe new compounds according to the invention also stimulate

syntesen av prostacyklin i arterielle kar in vitro. Forbindelsene ifølge oppfinnelsen stimulerer også på kaninaortastrimler prostacyklinsyntesen. the synthesis of prostacyclin in arterial vessels in vitro. The compounds according to the invention also stimulate prostacyclin synthesis in rabbit aortic strips.

De nye forbindelser ifølge oppfinnelsen har en anti-flogistisk virkning i hjelp av Carrageenan indusert ødemodell, når det administreres systemisk, spesielt oralt og lokalt, spesielt kutant. The new compounds according to the invention have an anti-phlogistic effect by means of the Carrageenan-induced waste model, when administered systemically, especially orally and locally, especially cutaneously.

De nye forbindelser ifølge oppfinnelsen har videre en antimetastatisk virkning. The new compounds according to the invention also have an antimetastatic effect.

De nye forbindelser ifølge oppfinnelsen virker analgetisk,The new compounds according to the invention have an analgesic effect,

og er virksomme i hyperalgesiprøven ifølge Randall-Selitto.and are effective in the hyperalgesia test according to Randall-Selitto.

De nye lipoksygenasehemmende pyrazolo-oksaziner ifølge oppfinnelsen tilsvarende formel (I) er anvendbare såvel enkeltvis tilsvarende formel Ia eller Ib som også som blanding av Ia og Ib som legemiddel ved behandling av betennelses og allergiske prosesser. De kan spesielt finne anvendelse som antif logistika, antirheumatika ,' anti-atherosklerotika, analgetika, antitrombotika, antiarthrotika, antiastmatika, antiallergika, antipsoriatika, antimetastatika og gastroprotektiva. The new lipoxygenase-inhibiting pyrazolo-oxazines according to the invention corresponding to formula (I) can be used both individually corresponding to formula Ia or Ib and also as a mixture of Ia and Ib as a drug in the treatment of inflammatory and allergic processes. They can especially be used as anti-logistics, anti-rheumatics, anti-atherosclerotics, analgesics, anti-thrombotics, anti-arthrotics, anti-asthmatics, anti-allergics, anti-psoriatics, anti-metastatics and gastro-protectants.

De nye pyrazolo[4,3-b][1,4]oksaziner ifølge oppfinnelsen til-svarer den generelle formel I i deres isomere former Ia og Ib : The new pyrazolo[4,3-b][1,4]oxazines according to the invention correspond to the general formula I in their isomeric forms Ia and Ib:

hver gang enkeltvis tilsvarende formel Ia eller Ib som også i blanding av formlene Ia og Ib, her betegnet som I, idet R og R"*" kan være like eller forskjellige og bety hydrogen, ;alkyl med 1 til 18 C-atomer og fenyl eventuelt substituert med inntil 5 like eller forskjellige substituenter fra gruppen alkyl med 1 - 6 C -atomer, ;cykloalkyl med 3 til 6-C-atomer, aralkyl med 7 til 22 C-atomer, aryl med 6 til 14 C-atomer, mono- og ;dialkylamino med 1 til 12 C-atomer, arylamino med;6 til 10 C-atomer, aryloksy med 6 til 10 C-atomer, alkyltio med 1 til 12 C-atomer, aryltio med 6 til 10 C-atomer, aralkoksy med 7 til 22 C-atomer, ;aralkylamino med 7 til 16 C-atomer, karboksy, karbalkoksy med 2 til 13 C-atomer,"karbamoyl, mono-og dialkylkarbamoyl med 1 til 12 C-atomer, alkylsulfonyl med 1 til 12 C-atomer, arylsulfonyl med 6 til 14 C-atomer, halogenalkyl med inntil 12 C-atomer, ;eventuelt en eller flere ganger substituert med F, Cl, Br og/eller J, hydroksyalkyl med 1 til 12 C-atomer, aminoalkyl med 1 til 12 C-atomer, ;alkoksykarbonylaminoalkyl med 3 til 13 C-atomer, halogenalkoksy med inntil 12 C-atomer, eventuelt en eller flere ganger substituert med F, Cl, Br v. og/eller J, halogen som F, Cl, Br og J, amino, acylamino med 2 til 7 C-atomer, karbamoylamino, sulfonylamino, hydroksy, acyloksy med 2 til 7 C-atomer, sulfonamido, nitro, formyl, alkylkarbonyl med 2 til 13 C-atomer, arylkarbonyl med 7 til 15 C-atomer, metylenkarboksy, metylenkarboksyalkyl ;med 3 til 8 C-atomer, etylenkarboksyalkyl med 4 til ;9 C-atomer eller propylenkarboksyalkyl med 5 til 10 ;C-atomer,;R 2 og R 3kan være like eller forskjellige og bety hydrogen, ;alkyl med 1 til 18 C-atomer, idet alkylresten kan være en eller flere ganger avbrutt med oksygen, svovel eller nitrogen videre betyr alkenyl eller alkinyl med 2 til 12 C-atomer, arylalkyl med 7 til 12 C-atomer, idet alkenyl-, alkinyl- og aralkylresten eventuelt kan være avbrutt en eller flere ganger med oksygen, svovel eller nitrogen, betyr videre aryl med 6 til 14 C-atomer, 5- til 6-leddet heteroaryl med inntil ;4 heteroatomer fra rekken N, 0 og S, 5- til 6-leddet heterparylalkyl med inntil 4 heteroatomer fra rekken ;N, 0 og S med 1 til 12 C-atomer i alkylkjeden, alkylkarbonyl med 2 til 13 C-atomer, arylkarbonyl med 7 til 15 C-atomer, eventuelt med inntil 5 like eller forskjellige substituenter fra gruppen alkyl med 1 til 18 C-atomer, cykloalkyl med 3 til 6 C-atomer, aralkyl med 7 til 22 C-atomer, aryl med 6 til 14 C-atomer, mono- og dialkylamino med 1 til 12 C-atomer, arylamino med 6 til 10 C-atomer, aryloksy med 6 til 10 C-atomer, alkyltio med 1 til 12 C-atomer, aryltio med' 6 til 10 C-atomer, aralkoksy med 7 til 22 C-atomer, aralkylamino med 7 til 16 C-atomer, karboksy, karbalkoksy med 2 til 13 C-atomer, karbamoyl, mono-og dialkylkarbamoyl med 1 til 12 C-atomer, alkylsulfonyl med 1 til 12 C-atomer, arylsulfonyl med 6 til 14 C-atomer, halogenalkyl med inntil 12 C-atomer, eventuelt en gang eller flere ganger substituert med F, Cl, Br og/eller J, hydroksyalkyl med 1 til 12 C-atomer, aminoalkyl med 1 til 12 C-atomer, alkoksykarbonylaminoalkyl med 3 til 13 C-atomer, halogenalkoksy med inntil 12 C-atomer, eventuelt en eller flere ganger substituert med F, Cl, Br eller/og J, halogen som F, Cl, Br eller/og J, amino, acylamino med 2 til 7 C-atomer, sulfonamido, nitro, formyl, metylenkarboksy, metylenkarboksyalkyl med 3 til 8 C-atomer, etylenkarboksyalkyl med 4 til 9 C-atomer eller propylenkarboksyalkyl med for 5-til 6-leddet heteroarylkarbonyl med inntil 4 hetero-atomerffra rekken N, 0 og,S og ;betyr hydrogen, en uforgrenet, forgrenet eller cyklisk alkylrest, hver gang med 1 til 6 C-atomer, som eventuelt kan være substituert med hydroksy, karboksy, formyl, acetyl, alkoksy, alkyltio, halogen, nitro, eller kan være substituert med frie aminogrupper, videre betyr en aromatisk eller heteroaromatisk rest med inntil 4 heteroatomer fra rekken N, 0 og S, som eventuelt kan være substituert med alkyl, alkoksy , ;alkyltio eller halogen eller betyr en på samme måte substituert aralkyl- eller heteroaralkylrest. ;Foretrukket er pyrazolo[4,3-b][1,4]okaziner med den generelle formel (I), i deres isomere former tilsvarende formel Ia og Ib, hvori hver gang ;1 2 ;R og R kan være like eller forskjellige og betyr fenyl, ;eventuelt med inntil 5 like eller forskjellige substituenter fra gruppen alkyl med 1 til 6 C-atomer, aralkyl med 7 til 15 C-atomer, fenyl eller naftyl, mono- og dialkylamino med 1 til 8 C-atomer, arylamino med 6 til 10 C-atomer, aryloksy med 6 til 10 C-atomer, alkyltio med 1 til 12 C-atomer, aralkoksy med 7 til 16 C-atomer, aralkylamino med 7 til 16 C-atomer, ;karboksy, karbalkoksy med 2 til 7 C-atomer, karbamyl, mono- og dialkylkarbamoyl med 1 til 6 C-atomer, alkylsulfonyl med 1 til 12 C-atomer, arylsulfonyl med 6 til 14 C-atomer, halogenalkyl med inntil 6 C-atomer, eventuelt en eller flere ganger substituert med F, Cl eller/og Br, hydroksyalkyl med ;1 til 6..'C-a tome r, aminoalkyl med 1 til 6 C-atomer, alkoksykarbonylaminoalkoksy med 3 til 9 C-atomer, halogenalkoksy med inntil 6 C-atomer, eventuelt en eller flere ganger substituert med F, Cl eller/og Br, halogen som F, Cl og Br, amino, acylamino med 2 til 7 C-atomer, karbonylamino, sulfonylamino, ;hydroksy, acyloksy med 2 til 7 C-atomer, sulfonamido, nitro, formyl, alkylkarbonyl med 2 til 7 C-atomer, arylkarbonyl med 7 til 11 C-atomer, metylenkarboksy, metylenkarboksyalkyl med 3 til 8 C-atomer, etylenkarboksyalkyl med 4 til 9 C-atomer og propylenkarboksyalkyl substituert. ;2 3 ;R og R kan være like eller forskjellige og bety hydrogen, ;alkyl med 1 til 12 C-atomer, idet alkylresten kan være avbrutt en eller flere ganger med oksygen, svovel ;eller nitrogen, betyr videre alkenyl eller alkinyl med 2 til 6 C-atomer, aralkyl med 7 til 12 C-atomer, idet alkenyl-, alkinyl- og aralkylresten eventuelt kan være avbrutt en eller flere ganger med oksygen, svovel eller nitrogen, betyr videre fenyl og naftyl, 5- til 6-leddet heteroaryl med inntil tre heteroatomer fra rekken N, 0 og S, 5- til 6-leddet heteroarylalkyl med inntil tre heteroatomer fra rekken N, 0 og S med 1 til 6 C-atomer i alkylkjeden, betyr videre alkylkarbonyl med 2 til 13 C-atomer, arylkarbonyl med 7 til 11. C-atomer, eventuelt kan være substituert med inntil 5 like eller forskjellig substituenter fra gruppen alkyl med 1 til 6 C-atomer, cykloalkyl med 3 til 6 C-atomer, aralkyl med 7 til 11 C-atomer, arylamino med 6 til 10 C-atomer, aryloksy med 6 til 10 C-atomer, alkyltio med 1 til 6 C-atomer, aryltio med 6 til 10 C-atomer, aralkoksy med 7 til 12 C-atomer, aralkylamino med 7 til 12 C-atomer, karboksy, karbalkoksy med 2 til 7 C-atomer, karbamoyl, mono- og dialkylkarbamoyl med 1 til 6 C-atomer, alkylkarbonyl med 1 til 12 C-atomer, alkylsulfonyl med 1 til 12 C-atomer, arylsulfonyl med 6 til 14 C-atomer, halogenalkyl med inntil 6 C-atomer, eventuelt en eller flere ganger substituert med F, ;Cl eller/og Br, hydroksyalkyl med 1 til 6 C-atomer, aminoalkyl med 1 til 6 C-atomer, alkoksykarbonylaminoalkoksy med 3 til 9 C-atomer, halogenalkoksy med inntil 6 C-atomer, eventuelt en eller flere ganger substituert med F, Cl eller/og Br, halogen som F, Cl eller/og Br, amino, acylamino med 2 til 7 C-atomer, karbamoylamino, sulfonylamino, hydroksy, acyloksy med 2 til 7 C-atomer, sulfonamido, nitro, formyl, alkylkarbonyl med 2 til 13 C-atomer, arylkarbonyl med 7 til 15 C-atomer, metylenkarboksy, metylenkarboksyalkyl med 3 til 8 C-atomer, etylenkarboksyalkyl med 4 til 9 C-atomer eller propylenkarboksyalkyl med 5 til 10 C-atomer og 5- til 6-leddet heteroarylkarbonyl med inntil 3 heteroatomer fra rekken N, 0 og S og ;R 5 betyr hydrogen, en .uforgrenet,forgrenet eller;cyklisk alkylrest, hver gang med 1 til 6 C-atomer,;som eventuelt kan være substituert med hydroksy, karboksy, formyl, acetyl, alkoksy, alkyltio, halogen, nitro, substituert eller frie aminogrupper, betyr videre en aromatisk eller heteroaromatisk rest med inntil 4 heteroatomer fra rekken N, 0 og S, som eventuelt kan være substituert med alkyl, alkoksy, alkyltio eller halogen, eller betyr en på samme måte substituert aralkyl- eller heteroaralkylrest. ;Spesielt foretrukket er de nye forbindelser ifølge oppfinnelsen med de generelle formler I a og Ib, hvori ;R og R"*" kan være like eller forskjellige og bety hydrogen, each time individually corresponding to formula Ia or Ib as also in a mixture of formulas Ia and Ib, here denoted as I, as R and R"*" can be the same or different and mean hydrogen, alkyl with 1 to 18 C atoms and phenyl optionally substituted with up to 5 identical or different substituents from the group alkyl with 1 to 6 C atoms, cycloalkyl with 3 to 6 C atoms, aralkyl with 7 to 22 C atoms, aryl with 6 to 14 C atoms, mono - and ;dialkylamino with 1 to 12 C atoms, arylamino with;6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 12 C atoms, arylthio with 6 to 10 C atoms, aralkyloxy with 7 to 22 C atoms, ;aralkylamino with 7 to 16 C atoms, carboxy, carbaloxy with 2 to 13 C atoms,"carbamoyl, mono- and dialkylcarbamoyl with 1 to 12 C atoms, alkylsulfonyl with 1 to 12 C atoms -atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 12 C atoms, optionally substituted one or more times with F, Cl, Br and/or J, hydroxyalkyl with 1 to 12 C atoms, aminoalkyl m ed 1 to 12 C-atoms, ;Alkoxycarbonylaminoalkyl with 3 to 13 C-atoms, Halogen-Alkoxy with up to 12 C-atoms, optionally one or more times substituted with F, Cl, Br v. and/or J, Halogen such as F, Cl , Br and J, amino, acylamino with 2 to 7 C atoms, carbamoylamino, sulfonylamino, hydroxy, acyloxy with 2 to 7 C atoms, sulfonamido, nitro, formyl, alkylcarbonyl with 2 to 13 C atoms, arylcarbonyl with 7 to 15 C atoms, methylenecarboxy, methylenecarboxyalkyl ;with 3 to 8 C atoms, ethylenecarboxyalkyl with 4 to ;9 C atoms or propylenecarboxyalkyl with 5 to 10 ;C atoms,;R 2 and R 3 can be the same or different and mean hydrogen , ;alkyl with 1 to 18 C atoms, since the alkyl residue can be interrupted one or more times with oxygen, sulfur or nitrogen further means alkenyl or alkynyl with 2 to 12 C atoms, arylalkyl with 7 to 12 C atoms, since alkenyl -, the alkynyl and aralkyl residue may optionally be interrupted one or more times with oxygen, sulfur or nitrogen, further means aryl with 6 to 14 C atoms, 5- to 6-membered heteroaryl with up to 4 heteroatoms from the series N, 0 and S, 5- to 6-membered heterparylalkyl with up to 4 heteroatoms from the series ;N, 0 and S with 1 to 12 C atoms in the alkyl chain, alkylcarbonyl with 2 to 13 C atoms, arylcarbonyl with 7 to 15 C atoms, optionally with up to 5 identical or different substituents from the alkyl group with 1 to 18 C atoms, cycloalkyl with 3 to 6 C atoms atoms, aralkyl with 7 to 22 C atoms, aryl with 6 to 14 C atoms, mono- and dialkylamino with 1 to 12 C atoms, arylamino with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 12 carbon atoms, arylthio with 6 to 10 carbon atoms, aralkyl with 7 to 22 carbon atoms, aralkylamino with 7 to 16 carbon atoms, carboxy, caralkyloxy with 2 to 13 carbon atoms, carbamoyl, mono- and dialkylcarbamoyl with 1 to 12 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 12 C atoms, optionally one or more times substituted with F, Cl, Br o g/or J, hydroxyalkyl with 1 to 12 C atoms, aminoalkyl with 1 to 12 C atoms, alkyloxycarbonylaminoalkyl with 3 to 13 C atoms, halogenoalkyl with up to 12 C atoms, optionally substituted one or more times with F, Cl , Br or/and J, halogen such as F, Cl, Br or/and J, amino, acylamino with 2 to 7 C atoms, sulfonamido, nitro, formyl, methylenecarboxy, methylenecarboxyalkyl with 3 to 8 C atoms, ethylenecarboxyalkyl with 4 to 9 C atoms or propylene carboxyalkyl with for 5- to 6-membered heteroarylcarbonyl with up to 4 hetero-atoms from the series N, 0 and,S and ;means hydrogen, an unbranched, branched or cyclic alkyl residue, each time with 1 to 6 C- atoms, which may optionally be substituted with hydroxy, carboxy, formyl, acetyl, alkoxy, alkylthio, halogen, nitro, or may be substituted with free amino groups, further means an aromatic or heteroaromatic residue with up to 4 heteroatoms from the series N, 0 and S , which may optionally be substituted with alkyl, alkoxy, alkylthio or halogen a or means a similarly substituted aralkyl or heteroaralkyl radical. Preferred are pyrazolo[4,3-b][1,4]ocazines of the general formula (I), in their isomeric forms corresponding to formulas Ia and Ib, wherein each time ;1 2 ;R and R can be the same or different and means phenyl, optionally with up to 5 identical or different substituents from the group alkyl with 1 to 6 C atoms, aralkyl with 7 to 15 C atoms, phenyl or naphthyl, mono- and dialkylamino with 1 to 8 C atoms, arylamino with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 12 C atoms, aralkyl with 7 to 16 C atoms, aralkylamino with 7 to 16 C atoms, ;carboxy, caralkyloxy with 2 to 7 C atoms, carbamyl, mono- and dialkylcarbamoyl with 1 to 6 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 6 C atoms, possibly one or more times substituted with F, Cl or/and Br, hydroxyalkyl with ;1 to 6..'C atoms, aminoalkyl with 1 to 6 C atoms, alkyloxycarbonylaminoalkoxy with 3 to 9 C atoms, halogenoalkyl with up to 6 C -atoms, optionally substituted one or more times with F, Cl or/and Br, halogen such as F, Cl and Br, amino, acylamino with 2 to 7 C atoms, carbonylamino, sulfonylamino, hydroxy, acyloxy with 2 to 7 C -atoms, sulfonamido, nitro, formyl, alkylcarbonyl with 2 to 7 C atoms, arylcarbonyl with 7 to 11 C atoms, methylenecarboxy, methylenecarboxyalkyl with 3 to 8 C atoms, ethylene carboxyalkyl with 4 to 9 C atoms and propylene carboxyalkyl substituted. ;2 3 ;R and R can be the same or different and mean hydrogen, ;alkyl with 1 to 12 C atoms, the alkyl residue can be interrupted one or more times by oxygen, sulfur ;or nitrogen, further means alkenyl or alkynyl with 2 to 6 C atoms, aralkyl with 7 to 12 C atoms, as the alkenyl, alkynyl and aralkyl residue may optionally be interrupted one or more times by oxygen, sulfur or nitrogen, further means phenyl and naphthyl, the 5- to 6-membered heteroaryl with up to three heteroatoms from the series N, 0 and S, 5- to 6-membered heteroarylalkyl with up to three heteroatoms from the series N, 0 and S with 1 to 6 C atoms in the alkyl chain, further means alkylcarbonyl with 2 to 13 C- atoms, arylcarbonyl with 7 to 11 C atoms, optionally may be substituted with up to 5 identical or different substituents from the group alkyl with 1 to 6 C atoms, cycloalkyl with 3 to 6 C atoms, aralkyl with 7 to 11 C atoms atoms, arylamino with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 6 C atoms, arylthio with 6 to 10 C atoms, aralkyl with 7 to 12 C atoms, aralkylamino with 7 to 12 C atoms, carboxy, caralkyloxy with 2 to 7 C atoms, carbamoyl, mono- and dialkylcarbamoyl with 1 to 6 C atoms , alkylcarbonyl with 1 to 12 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 6 C atoms, possibly one or more times substituted with F, ;Cl or/and Br, hydroxyalkyl with 1 to 6 C-atoms, aminoalkyl with 1 to 6 C-atoms, alkyloxycarbonylamino-alkyl with 3 to 9 C-atoms, halogeno-alkyloxy with up to 6 C-atoms, optionally substituted one or more times with F, Cl or/and Br, halogen such as F, Cl or/and Br, amino, acylamino with 2 to 7 C atoms, carbamoylamino, sulfonylamino, hydroxy, acyloxy with 2 to 7 C atoms, sulfonamido, nitro, formyl, alkylcarbonyl with 2 to 13 C -atoms, arylcarbonyl with 7 to 15 C atoms, methylenecarboxy, methylenecarboxyalkyl with 3 to 8 C atoms, ethylenecarboxyalkyl with 4 to 9 C atoms or propylenecarboxy alkyl with 5 to 10 C atoms and 5 to 6-membered heteroarylcarbonyl with up to 3 heteroatoms from the series N, 0 and S and ;R 5 means hydrogen, an unbranched, branched or cyclic alkyl residue, each time with 1 to 6 C atoms, which may optionally be substituted with hydroxy, carboxy, formyl, acetyl, alkoxy, alkylthio, halogen, nitro, substituted or free amino groups, further means an aromatic or heteroaromatic residue with up to 4 heteroatoms from the series N, 0 and S , which may optionally be substituted with alkyl, alkoxy, alkylthio or halogen, or means a similarly substituted aralkyl or heteroaralkyl residue. Particularly preferred are the new compounds according to the invention with the general formulas I a and Ib, in which R and R"*" can be the same or different and mean hydrogen,

alkyl med 1 til 6 C-atomer, eventuelt substituert med inntil 5 fluoratomer og/eller betyr fenyl, eventuelt substituert med inntil 5 substituenter fra gruppen alkyl med 1 til 4 C-atomer pri; alkylgruppe, alkoksy med 1 til 3 C-atomer, aryloksy med 6 C-atomer og med F, Cl, Br, NO,,, NH2, NH-laverealkyl, N(laverealkyl^/ alkyltio med 1 til 6 C-atomer, alkylsulfonyl med 1 til 6 C-atomer, med aminokarbonyl og aminosulfonyl, alkyl with 1 to 6 C atoms, optionally substituted with up to 5 fluorine atoms and/or means phenyl, optionally substituted with up to 5 substituents from the group alkyl with 1 to 4 C atoms pri; alkyl group, alkoxy with 1 to 3 C atoms, aryloxy with 6 C atoms and with F, Cl, Br, NO,,, NH2, NH-lower alkyl, N(lower alkyl^/ alkylthio with 1 to 6 C atoms, alkylsulfonyl with 1 to 6 C atoms, with aminocarbonyl and aminosulfonyl,

2 3 2 3

R og R er like eller forskjellige og betyr alkyl med inntilR and R are the same or different and mean alkyl with up to

6 C-atomer, arylalkyl med 3 til 13 C-atomer, eventuelt 6 C atoms, arylalkyl with 3 to 13 C atoms, optionally

substituert med inntil 5 F, Cl eller Br, aryloksyalkyl med 7 til 16 C-atomer, formyl, alkylkarbonyl med 2 til 13 C-atomer, karboksyalkyl med 2 til 7 C-atomer og arylalkyloksykarbonyl med 8 til 16 C-atomer, og substituted with up to 5 F, Cl or Br, aryloxyalkyl of 7 to 16 C atoms, formyl, alkylcarbonyl of 2 to 13 C atoms, carboxyalkyl of 2 to 7 C atoms and arylalkyloxycarbonyl of 8 to 16 C atoms, and

R^ betyr hydrogen, en uforgrenet eller forgrenet alkylrest med 1 til 6 C-atomer, som eventuelt kan være substituert med alkoksy, eller betyr en aryl- eller heteroarylrest; foretrukket er fenyl- eller pyridyl-rester, som eventuelt er substituert med fluor, R 1 means hydrogen, an unbranched or branched alkyl radical with 1 to 6 carbon atoms, which may optionally be substituted with alkoxy, or means an aryl or heteroaryl radical; preferred are phenyl or pyridyl residues, which are optionally substituted with fluorine,

klor, alkyl eller alkoksy.chlorine, alkyl or alkoxy.

De nye forbindelser ifølge oppfinnelsen med generelle formler Ia og Ib lar seg fremstille ved The new compounds according to the invention with general formulas Ia and Ib can be prepared by

a) 1,4-oksaziner med den generelle formel II, hvoria) 1,4-oxazines of the general formula II, wherein

1 2 1 2

R, R og R har ovennevnte betydning, omsettes med et N,N-dialkylamid med den generelle formel VI R, R and R have the above meaning, are reacted with an N,N-dialkylamide of the general formula VI

(sammenlign. Che.Ber. 92, 837, 1959 og J.Het. Che. 19, 1493, 1982) med den for R 5 ovenfor angitte betydning og fosforoksyklorid i form av en Vilsmeier-Haack-reaksjon og de derved dannede salter med den generelle formel III, omsettes med hydraziner med den generelle formel IV (compare. Che.Ber. 92, 837, 1959 and J.Het. Che. 19, 1493, 1982) with the meaning given for R 5 above and phosphorus oxychloride in the form of a Vilsmeier-Haack reaction and the thereby formed salts with of the general formula III, is reacted with hydrazines of the general formula IV

Omsetningene av saltene med den generelle formel III ;'.med hydrazinene med den generelle formel IV foregår fortrinnsvis i polare oppløsningsmidler, f.eks. i alkanoler, uten kata-lysator eller også i nærvær av organiske baser, som f.eks. trietylamin, ved temperaturer mellom -20 og + 100°C. Restene The reactions of the salts of the general formula III with the hydrazines of the general formula IV preferably take place in polar solvents, e.g. in alkanols, without a catalyst or also in the presence of organic bases, such as e.g. triethylamine, at temperatures between -20 and + 100°C. The leftovers

12 3 5 12 3 5

R, R , R , R og R har ovennevnte betydninger.R, R, R, R and R have the above meanings.

Fortrinnsvis omsettes saltene med den generelle formel III med hydraziner med den generelle formel IV i etanol ved værelsetemperatur til koketemperatur, spesielt ved 80°C, Preferably, the salts of the general formula III are reacted with hydrazines of the general formula IV in ethanol at room temperature to boiling temperature, especially at 80°C,

for å få de nye forbindelser ifølge oppfinnelsen,in order to obtain the new compounds according to the invention,

elleror

b) oksaziner med den generelle formel II, hvorib) oxazines of the general formula II, wherein

1 2 1 2

R, R og R har ovennevnte betydning, omsettes med karboksyl-syreestere med den generelle formel VII R, R and R have the above meaning, are reacted with carboxylic acid esters of the general formula VII

hvori R 5har ovennevnte betydning (eksklusiv hydrogen) og R betyr en laverealkylrest, fortrinnsvis metyl eller etyl, i dimetylsulfoksyd eller karboksylsyreester selv som opp-løsningsmiddel med natriumhydrid til 2-acyl-l,4-oksazinon VIII (sammenlign Arch. Pharm. 312, 302, 1979). 2-acyl-l,4-oksa-zinonene VIII omsettes videre til tioner IX (med P4S^Q, sammenlign blant annet Tetrahedron 2_5, 517, 1969 eller med Lawesson's Reagens, sammenlign bl.a. Org. Prep. Proe. Int. 12, 203, 1980). Deres kondensasjon med hydraziner IV gir forbindelsene ifølge oppfinnelsen med de generelle formler Ia og Ib. De nye forbindelser ifølge oppfinnelsen med de generelle isomere former ifølge formel Ia og Ib, hvori R 3 betyr alkylkarbonyl og/eller arylalkylkarbonyl med ovennevnte betydning lar seg fremstille, idet man omsetter de nye forbindelser ifølge oppfinnelsen med de generelle formler Ia og Ib, hvori R 2 og/eller R 3betyr hydrogen, acyleringsmidler, f.eks. syrehalogenider eller syreanhydrider med den generelle 4 2 3 formel V, hvori R har samme betydning som R eller R , i nærvær av en hjelpebase, f.eks. pyridin. in which R 5 has the above meaning (excluding hydrogen) and R means a lower alkyl residue, preferably methyl or ethyl, in dimethyl sulfoxide or carboxylic acid ester itself as solvent with sodium hydride to 2-acyl-1,4-oxazinone VIII (compare Arch. Pharm. 312, 302, 1979). The 2-acyl-1,4-oxa-zinones VIII are further converted to ions IX (with P4S^Q, compare among others Tetrahedron 2_5, 517, 1969 or with Lawesson's Reagents, compare among others Org. Prep. Proe. Int. 12, 203, 1980). Their condensation with hydrazines IV gives the compounds according to the invention with the general formulas Ia and Ib. The new compounds according to the invention with the general isomeric forms according to formulas Ia and Ib, in which R 3 means alkylcarbonyl and/or arylalkylcarbonyl with the above-mentioned meaning can be prepared by reacting the new compounds according to the invention with the general formulas Ia and Ib, in which R 2 and/or R 3 means hydrogen, acylating agents, e.g. acid halides or acid anhydrides of the general 4 2 3 formula V, in which R has the same meaning as R or R , in the presence of an auxiliary base, e.g. pyridine.

De for gjennomføring av oppfinnelsen egnede forbindelser med formel I er kjent eller lar seg fremstille etter kjente metoder (sammenlig Shah et al., Indian Journal of Chemistry 1_, 1006, 1969 og 10, 820-, 1972) . The compounds of formula I suitable for carrying out the invention are known or can be prepared by known methods (together Shah et al., Indian Journal of Chemistry 1_, 1006, 1969 and 10, 820-, 1972).

De for gjennomføring av oppfinnelsen egnede hydraziner med den generelle formel IV er kjent eller lar seg fremstille etter kjente metoder. The hydrazines of the general formula IV suitable for carrying out the invention are known or can be prepared by known methods.

Spesielt foretrukne eksempler og de nye forbindelser ifølge oppfinnelsen er (sammenlign tabell 1): 3,7-dimetyl-5-fenylpyrazol[4,3-b][l,4]oksazin Particularly preferred examples and the new compounds according to the invention are (compare Table 1): 3,7-dimethyl-5-phenylpyrazol[4,3-b][1,4]oxazine

3 , 7-dimetyl-5-,-6-dif enylpyrazol [4 , 3-b] [l,4]oksazin 3,7-dimetyl-5,6-di-(4-klorfenyl)pyrazol[4,3-b][1,4]-oksazin 3,7-dimetyl-5,6-di-(4-metoksyfenyl)pyrazol[4,3-b][1,4]oksazin 1- acetyl-3,7-dimetyl-5,6-difenylpyrazol[4,3-b][1,4]-oksazin 7-metyl-3-propyl-5,6-difenylpyrazol[4,3-b][1,4]oksazin 7-metyl-3-isopropyl-5,6-difenylpyrazol[4,3-b][1,4]-oksazin 3-(4-klorfenyl)-7-metyl-5,6-difenylpyrazol[4,3-b][1,4]oksazin 3-(3-pyridyl)-7-metyl-5,6-difenylpyrazol[4,3-b][1,4]-okasazin 7-metylpyrazol[4,3-b][1,4]oksazin 3 , 7-dimethyl-5-,-6-diphenylpyrazole [4 , 3-b] [l,4]oxazine 3,7-dimethyl-5,6-di-(4-chlorophenyl)pyrazole[4,3- b][1,4]oxazine 3,7-dimethyl-5,6-di-(4-methoxyphenyl)pyrazolo[4,3-b][1,4]oxazine 1- acetyl-3,7-dimethyl- 5,6-diphenylpyrazol[4,3-b][1,4]-oxazine 7-methyl-3-propyl-5,6-diphenylpyrazol[4,3-b][1,4]oxazine 7-methyl-3 -isopropyl-5,6-diphenylpyrazole[4,3-b][1,4]-oxazine 3-(4-chlorophenyl)-7-methyl-5,6-diphenylpyrazole[4,3-b][1,4 ]oxazine 3-(3-pyridyl)-7-methyl-5,6-diphenylpyrazolo[4,3-b][1,4]-oxazazine 7-methylpyrazolo[4,3-b][1,4]oxazine

1,7-resp. 2,7-dimetylpyrazol[4,3-b][l,4]oksazin 2- (3,4-diklorbenzyl)-7-metylpyrazol[4,3-b][1,4]oksazin 1- resp. 2-(2-fenoksyetyl)-7-metyl^4,3-b][1,4]oksazin 1- resp. 2-(Ø-naftoksyetyl)-7-metylpyrazol[4,3-b][1,4]-oksazin 5-fenylpyrazol[4,3-b][1,4]oksazin 1,7-resp. 2,7-dimethylpyrazole[4,3-b][1,4]oxazine 2-(3,4-dichlorobenzyl)-7-methylpyrazole[4,3-b][1,4]oxazine 1- resp. 2-(2-phenoxyethyl)-7-methyl^4,3-b][1,4]oxazine 1- resp. 2-(O-naphthoxyethyl)-7-methylpyrazolo[4,3-b][1,4]oxazine 5-phenylpyrazolo[4,3-b][1,4]oxazine

2- metyl-5-fenylpyrazol[4,3-b][l,4]oksazin 2- methyl-5-phenylpyrazol[4,3-b][1,4]oxazine

7-metyl-5-fenylpyrazol[4,3-b][1,4]oksazin7-methyl-5-phenylpyrazolo[4,3-b][1,4]oxazine

1,7- resp. 2,7-dimetyl-5-fenylpyrazol[4,3-b][1,4]oksazin 2-formyl-7-metyl-5-fenylpyrazol[4,3-b][1,4]oksazin 2-acetyl-7-metyl-5-fenylpyrazol[4,3-b][1,4]oksazin 2-benzyloksykarbonyl-7-metyl-5-fenylpyrazol[4,3-b][1,4]oksazin 7-metyl-5,6-difenylpyrazol[4,3-b][1,4]oksazin 1.7- or 2,7-dimethyl-5-phenylpyrazole[4,3-b][1,4]oxazine 2-formyl-7-methyl-5-phenylpyrazole[4,3-b][1,4]oxazine 2-acetyl- 7-methyl-5-phenylpyrazol[4,3-b][1,4]oxazine 2-benzyloxycarbonyl-7-methyl-5-phenylpyrazol[4,3-b][1,4]oxazine 7-methyl-5, 6-Diphenylpyrazol[4,3-b][1,4]oxazine

7-metyl-5,6-di-(4-metoksyfenyl)-pyrazol[4,3-b][l,4]oksazin 1,7- resp. 2,7-dimetyl-5,6-difenylpyrazol[4,3-b][1,4]oksazin 1,7- resp. 2,7-dimetyl-5,6-di-(4-klorfenyl)-pyrazol-[4,3-b]-[l,4]oksazin 7-methyl-5,6-di-(4-methoxyphenyl)-pyrazolo[4,3-b][1,4]oxazine 1,7- resp. 2,7-dimethyl-5,6-diphenylpyrazol[4,3-b][1,4]oxazine 1,7- resp. 2,7-dimethyl-5,6-di-(4-chlorophenyl)-pyrazole-[4,3-b]-[1,4]oxazine

2-aceryl-7-metyl-5,6-difenylpyrazol[4,3-b][1,4]oksazin 2-karboksymetyl-7-metyl-5,6-difenylpyrazol[4,3-b][l,4]oksazin 2-Aceryl-7-methyl-5,6-diphenylpyrazole[4,3-b][1,4]oxazine 2-Carboxymethyl-7-methyl-5,6-diphenylpyrazole[4,3-b][1,4 ]oxazine

Påvisning av de lipoksygenasehemmende egenskaper av de nye forbindelser ifølge oppfinnelsen foregår analogt metoden av Detection of the lipoxygenase-inhibiting properties of the new compounds according to the invention takes place analogously to the method of

Bailey et al., J. Biol. Chem. 255, 5996, 1980 og ifølge Blackwell og Flower, Prostaglandins 16, 417, 1978. Ved Bailey et al., J. Biol. Chem. 255, 5996, 1980 and according to Blackwell and Flower, Prostaglandins 16, 417, 1978. By

denne prøvemetode undersøkes metabolismen av radiaktivt markerte arachidonsyrer på voksne humantrobozyter. Ved denne in-vitro-prøve ekstraheres de radioaktivt markerte metabolitter fra reaksjonsblandingen og adskilles tynnskiktkromatografisk. Autoradiogrammet vurderes med tynnskiktscanner. Ved disse prøvebetingelser adskilles markerte metabolitter fra de ikke omsatte arachidonsyrer og er deretter å vurdere. Fordel-ingen av radioaktiviteten på de under metaboliseringen dannede cyklooksygenaseprodukter tromboxan B ? (TXB2) og 12-hydroksy-5,8,10-heptadekatriensyre (HHT) resp. lipoksy-genaseproduktet 12-hydroksy-5,8,11,14-eikosatetraensyre (HETE) under innvirkning av inhibitorene viser en grad for hemming av enzymene. This test method examines the metabolism of radioactively labeled arachidonic acids on adult human thrombocytes. In this in-vitro test, the radioactively labeled metabolites are extracted from the reaction mixture and separated by thin-layer chromatography. The autoradiogram is evaluated with a thin-slice scanner. Under these test conditions, marked metabolites are separated from the unconverted arachidonic acids and are then assessed. The distribution of the radioactivity on the cyclooxygenase products formed during the metabolism thromboxane B ? (TXB2) and 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) resp. the lipoxygenase product 12-hydroxy-5,8,11,14-eicosatetraenoic acid (HETE) under the influence of the inhibitors shows a degree of inhibition of the enzymes.

Lipoksygenasehemmingen av forbindelsene ifølge oppfinnelsen lar seg måle.på hemmingen av HETE-syntesen. Det viser seg at syntesen av TXB2og HHT forblir upåvirket mens arachidon-syreomsetningen avtar. Som det fremgår av den følgende tabell bevirker forbindelsen ifølge oppfinnelsen en tydelig hemming av småplatelipoksygenasen (HETE-syntesen). The lipoxygenase inhibition of the compounds according to the invention can be measured by the inhibition of HETE synthesis. It appears that the synthesis of TXB2 and HHT remains unaffected while arachidonic acid turnover decreases. As can be seen from the following table, the compound according to the invention causes a clear inhibition of platelet lipoxygenase (HETE synthesis).

Analogt ovennevnte prøve lar det seg påvise de lipoksygenasehemmende egenskaper av de nye forbindelser ifølge oppfinnelsen også på Leukozyter. De polymorfkjernede leukozyter hos mennesker og kaniner metaboliserer arachidonsyrer til 5-hydroksy-5,8,11,14-eikosatetraensyre (5-HETE) og Leukotrien B^Analogous to the above-mentioned test, it is possible to demonstrate the lipoxygenase-inhibiting properties of the new compounds according to the invention also on Leukocytes. The polymorphonuclear leukocytes of humans and rabbits metabolize arachidonic acids to 5-hydroxy-5,8,11,14-eicosatetraenoic acid (5-HETE) and Leukotriene B^

(5S, 12R-dihydroksy-6-cis, 8,10 trans, 14 ciseikosatetra-ensyre). Hemmingen av frigjøringen av 5-HETE og Leukotrien B^fra Leukozyter er et mål for den lipoksygenasehemmende effekt av de nye forbindelsene ifølge oppfinnelsen (sammenlign tabell (5S, 12R-dihydroxy-6-cis, 8,10 trans, 14 ciseicosatetraenoic acid). The inhibition of the release of 5-HETE and Leukotriene B^ from Leukocytes is a measure of the lipoxygenase inhibitory effect of the new compounds according to the invention (compare table

A) . A).

Prøven med humanleukozyter gjennomføres ifølge Borgeat og Samuelsson (J.Biol. Chem. 254, 2643, 1979 og Proe.Nati. Acad. Sei. U.S.A. 16, 2148, 1979), med kaninleukozyter ifølge The test with human leukocytes is carried out according to Borgeat and Samuelsson (J.Biol. Chem. 254, 2643, 1979 and Proe.Nati. Acad. Sei. U.S.A. 16, 2148, 1979), with rabbit leukocytes according to

Walker og Parish (Intern. Archs. Allergy Appl. Immun. 6jj, 83, 1981). Walker and Parish (Intern. Archs. Allergy Appl. Immun. 6jj, 83, 1981).

Påvisningen av den prostacyclin-stimulerende virkning foregikk ved bestemmelse av frigjøring av prostacyklin etter en times inkubasjon av kaninaortastrimler med forbindelsen ifølge oppfinnelsen (analogt ifølge Moncada et al., Lancet 1977, I, 18) og etterfølgende radioimmunologisk bestemmelse av den stabile prostacyklinmetabolitt 6-keto-PGF la (B.M. Peskar et al., FEBS Letters 121, 25, 1980). The demonstration of the prostacyclin-stimulating effect took place by determining the release of prostacyclin after one hour's incubation of rabbit aortic strips with the compound according to the invention (analogously according to Moncada et al., Lancet 1977, I, 18) and subsequent radioimmunological determination of the stable prostacyclin metabolite 6-keto -PGF la (B.M. Peskar et al., FEBS Letters 121, 25, 1980).

Forbindelsene ifølge oppfinnelsen er også virksomme in-vivo. Denne virkning påvises ved måling av hemming av leukozyt-migrasjon etter i og for seg kjente metoder (sammenlign Higgs et al., Biochemical Pharmacology 28, 1959, (1979) og The compounds according to the invention are also effective in vivo. This effect is demonstrated by measuring the inhibition of leukocyte migration according to methods known per se (compare Higgs et al., Biochemical Pharmacology 28, 1959, (1979) and

Eur. J. Pharmacol. 6j>, 81 (1981)). Forbindelsene ifølge oppfinnelsen reduserer også ødemdannelsen i Carrageenan-betennelsesmodellen (sammenlign tabell C) og metastasering av B-16 melanom (ifølge Honn, et.al. Science 212, 1981). Eur. J. Pharmacol. 6j>, 81 (1981)). The compounds of the invention also reduce edema formation in the Carrageenan inflammation model (compare Table C) and metastasis of B-16 melanoma (according to Honn, et.al. Science 212, 1981).

Forbindelsene ifølge oppfinnelsen er også virksomme in vivoThe compounds according to the invention are also active in vivo

i Hyperalgesi-prøver ifølge Randall-Selitto, sammenlign tabell B (Randall, L.O., Selitto, J., Arch. Int. Pharmakodyn, 111, 209-219, 1957). in Hyperalgesia tests according to Randall-Selitto, compare Table B (Randall, L.O., Selitto, J., Arch. Int. Pharmakodyn, 111, 209-219, 1957).

En ytterligere gjenstand for oppfinnelsen er derfor dessuten anvendelse av en eller flere av forbindelsene ifølge den generelle formel I ved bekjempelse av sykdommer, fortrinnsvis betennelsesprosesser, spesielt som Lipoxygenase-hemmere og/eller som analgetika som karvegg- og/eller cytoprotektiva, spesielt som antitrombotikum, antimetastatikum, antiallergikum, anti-astmatikum, Ulcus-Preventivum og/eller anurektikum. A further object of the invention is therefore also the use of one or more of the compounds according to the general formula I in combating diseases, preferably inflammatory processes, especially as Lipoxygenase inhibitors and/or as analgesics as vessel wall and/or cytoprotective agents, especially as antithrombotics, anti-metastatic, anti-allergic, anti-asthmatic, Ulcus-Preventivum and/or anuretic.

De nye virksomme stoffer kan på kjent måte overføres i de vanlige formuleringer som tabletter, kapsler, drageer, piller, granulater, aerosoler, siruper, emulsjoner, suspensjoner og oppløsninger, under anvendelse av inerte, ikke-toksiske farmasøytisk egnede bærestoffer eller oppløsningsmidler. Herved skal den terapeutisk virksomme forbindelse hver gang være tilstede i en konsentrasjon på ca. 0,5 til 90 vekts-% The new active substances can be transferred in a known manner in the usual formulations such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic pharmaceutically suitable carriers or solvents. Hereby, the therapeutically active compound must each time be present in a concentration of approx. 0.5 to 90% by weight

av den samlede blanding, dvs. i mengder som er tilstrekkelig til å oppnå det angitte doseringsspillerom. of the overall mixture, i.e. in quantities sufficient to achieve the indicated dosage margin.

Formuleringene fremstilles eksempelvis ved drøying av de virksomme stoffer med- oppløsningsmidler og/eller bærestoffer, eventuelt under anvendelse av emulgeringsmidler og/eller dispergeringsmidler, idet f.eks. i tilfelle anvendelse av vann som fortynningsmiddel kan eventuelt organiske opp-løsningsmidler anvendes som hjelpeoppløsningsmidler. The formulations are prepared, for example, by mixing the active substances with solvents and/or carriers, possibly using emulsifiers and/or dispersants, as e.g. in the case of using water as a diluent, organic solvents can optionally be used as auxiliary solvents.

Som hjelpestoffer skal det eksempelvis anføres:As excipients, for example, the following must be stated:

Vann, ikke-toksiske organiske oppløsningsmidler, som paraffiner (f.eks. jordoljefraksjoner), planteoljer, (f.eks. jordnøttp/ sesamolje), alkoholer (f.eks. etylalkohol, glycerol), Water, non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils, (e.g. peanut/sesame oil), alcohols (e.g. ethyl alcohol, glycerol),

glykoler (f.eks.propylenglykol, polyetylenglykol), N-alkyl-pyrrolidoner, faste bærestoffer, som f.eks. naturlig stenmel (f.eks. kaoliner, leirjord, talkum, kritt), syntetisk glycols (e.g. propylene glycol, polyethylene glycol), N-alkyl pyrrolidones, solid carriers, such as e.g. natural stone flour (e.g. kaolins, clays, talc, chalk), synthetic

stenmel (f.eks. høydispers kieselsyre, silikater), sukker (f.eks. roer-, melke- og druesukker), emulgeringsmiddel, som ikke-ionogene anioniske emulgatorer (f.eks. polyoksyetylen-fettsyre-ester, polyoksyetylen-fettalkohol-eter, alkyl-sulfonater og arylsulfonater), dispergeringsmidler (f.eks. lignin, sulfitavlut, metylcellulose, stivelse og polyvinyl-pyrrolidon) og glidémidler (fortrinnsvis magriesiumstearat, talkum, stearinsyre og natriumlaurylsulfat). rock flour (e.g. highly dispersed silicic acid, silicates), sugar (e.g. beet, milk and grape sugar), emulsifier, such as non-ionic anionic emulsifiers (e.g. polyoxyethylene fatty acid ester, polyoxyethylene fatty alcohol ether, alkyl sulphonates and aryl sulphonates), dispersants (eg lignin, sulphite liquor, methyl cellulose, starch and polyvinyl pyrrolidone) and glidants (preferably magnesium stearate, talc, stearic acid and sodium lauryl sulphate).

Applikasjonen foregår fortrinnsvis oralt eller parenteralt, fortrinnsvis kutant. I tilfelle oral anvendelse kan tabletten-., selvsagt foruten de nevnte bærestoffer også inneholde tilset- ninger som natriumcitrat, kalsiumkarbonat og dikalsiumfosfat sammen med forskjellige tilslagsstoffer, som stivelse, fortrinnsvis potetstivelse, gelatin og lignende. Videre kan det medanvendes glidemiddel som magnesiumstearat, natriumlaurylsulfat og talkum til tabletteringen. I til- The application preferably takes place orally or parenterally, preferably cutaneously. In the case of oral use, the tablet can, of course, in addition to the aforementioned carriers also contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various aggregates, such as starch, preferably potato starch, gelatin and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In to-

felle vandige suspensjoner og/eller eliksirer som er tenkt for oral anvendelse kan de virksomme stoffer dannes foruten med de ovennevnte hjelpestoffer med forskjellige smaks-forbedrere eller farvede resp. farvegivende stoffer. trap aqueous suspensions and/or elixirs that are intended for oral use, the active substances can be formed besides with the above-mentioned excipients with various flavor enhancers or colored resp. coloring substances.

For tilfelle parenteral anvendelse kan det anvendes opp-løsninger av de virksomme stoffer under anvendelse av egnede flytende bærematerialer. For parenteral use, solutions of the active substances can be used using suitable liquid carrier materials.

Vanligvis har det vist seg fordelaktig ved intravenøs applikasjon å administrere mengder på ca. 0,01 til 10 mg/kg, fortrinnsvis ca. 0,05 til 5 mg/kg legemsvekt pr. dag for å oppnå virksomme resultater, og ved oral applikasjon utgjør doseringen ca. 0,05 til 100 mg/kg, fortrinnsvis 0,1 til 10 mg/kg legemsvekt pr. dag. Generally, it has been found advantageous by intravenous application to administer amounts of approx. 0.01 to 10 mg/kg, preferably approx. 0.05 to 5 mg/kg body weight per day to achieve effective results, and with oral application the dosage is approx. 0.05 to 100 mg/kg, preferably 0.1 to 10 mg/kg body weight per day.

Allikevel kan det eventuelt være nødvendig å avvike fra de nevnte mengder, nemlig i avhengighet av legemsvekt, resp. Even so, it may be necessary to deviate from the mentioned quantities, namely depending on body weight, resp.

typen av applikasjonsmåte men også på grunn av typen og deres individuelle forhold overfor medikamenter resp. arten av dets formulering og tidspunktet resp. intervallet hvortil administrering foregår. Således kan det i noen tilfelle være tilstrekkelig å komme ut med mindre enn ovennevnte minste mengde, mens i andre tilfelle nevnte øvre grense må overskrides. I tilfelle applikasjon av større mengder kan det være å an-befale å fordele disse i flere enkeltinngivinger over dagen. De ovennevnte anførsler gjelder for applikasjon såvel i human-også som i veterinærmedisinen på samme måte. the type of application method but also because of the type and their individual relationship to drugs or the nature of its formulation and the time resp. the interval to which administration takes place. Thus, in some cases it may be sufficient to come out with less than the above-mentioned minimum amount, while in other cases the mentioned upper limit must be exceeded. In the case of application of larger amounts, it may be advisable to distribute these in several individual applications throughout the day. The above-mentioned statements apply to application in both human and veterinary medicine in the same way.

Oppfinnelsen skal forklares nærmere ved hjelp av eksempler. The invention shall be explained in more detail by means of examples.

Eksempel 1 Example 1

7-metylpyrazolo[4,3-b][1,4]oksazin 7-Methylpyrazolo[4,3-b][1,4]oxazine

Ved 0°C tildryppen man i en oppløsning av 12,2 ml (0,133 mol) fosforoksyklorid i 32,5 ml abs. 1,2-dikloretan 12,4 ml (0,16 mol) dimetylformamid. Man lot omrøre 10 minutter ved denne temperatur. Dertil dryppet man under omrøring 15,0 g (0,13 mol) N-metylmorfolin-3 i 32,5 ml absolutt 1,2-dikloretan, således at 5°C ikke ble overskredet. Den dannede kraftige rødfarvede oppløsning omrørte man ennu i 30 minutter ved 0°C, tre timer ved værelsetemperatur og en time ved 4 5°C. Deretter avdestillerte man oppløsningsmidlet ved maksimalt 40°C badtemperatur i vakuum (Rotavapor). Residuumet opptok man i 170 ml etanol og dryppet under omrøring til den til 0°C avkjølte, klare, røde oppløsning 50 ml (1,03 mol) hydrazinhydrat. Ved tildrypning falt det med en gang ut en klumpet,rød utfelling (hydrazon). Man omrørte ennu en time ved 5°C og to timer ved værelsetemperatur, idet utfellingen etterhvert oppløste seg og det oppsto en klar, mørkerød farvet oppløsning. Man avdampet alkoholen i vakuum (Rotavapor) og renset residuumet søylekromatografisk (kiselgel 60, Merck; elueringsmiddel:diklormetan/metanol = 9/1). At 0°C, a solution of 12.2 ml (0.133 mol) phosphorus oxychloride in 32.5 ml abs. 1,2-dichloroethane 12.4 ml (0.16 mol) dimethylformamide. It was allowed to stir for 10 minutes at this temperature. In addition, 15.0 g (0.13 mol) of N-methylmorpholine-3 in 32.5 ml of absolute 1,2-dichloroethane were added dropwise while stirring, so that 5°C was not exceeded. The strongly red colored solution formed was stirred for a further 30 minutes at 0°C, three hours at room temperature and one hour at 45°C. The solvent was then distilled off at a maximum 40°C bath temperature in vacuum (Rotavapor). The residue was taken up in 170 ml of ethanol and 50 ml (1.03 mol) of hydrazine hydrate was added dropwise with stirring to the clear, red solution cooled to 0°C. On dripping, a lumpy, red precipitate (hydrazone) immediately fell out. The mixture was stirred for another hour at 5°C and two hours at room temperature, as the precipitate gradually dissolved and a clear, dark red colored solution was formed. The alcohol was evaporated in vacuo (Rotavapor) and the residue was purified by column chromatography (silica gel 60, Merck; eluent: dichloromethane/methanol = 9/1).

Røde krystaller, smp.: 115,5 - 117°CRed crystals, mp: 115.5 - 117°C

Utbytte: 3,8 g (21% av det teoretiske)Yield: 3.8 g (21% of the theoretical)

C beregnet 51,75 % funnet 51,75%C calculated 51.75% found 51.75%

H beregnet 6,52%, funnet 6,50%.H calculated 6.52%, found 6.50%.

N beregnet 30,20%, funnet 30,25%.N calculated 30.20%, found 30.25%.

Eksempel 2 Example 2

2-metyl-5-fenylpyrazolo[4,3-b][1,4]oksazin 2-methyl-5-phenylpyrazolo[4,3-b][1,4]oxazine

Til en oppløsning av 9 ml (0,128 mol) dimetylformamid dryppet man under avkjøling (5 til 10°C) 11 ml (0,113 mol) 2-fenyl-morfolon-5 i 25 ml abs. 1,2-dikloretan. Man lot det ennu etteromrøre i en time og oppvarmet deretter to timer ved 70°C. Etter oppløsningens avkjøling utrystet man den med 30 ml av en vandig natriumacetatoppløsning (12 g). Den organiske fase ble avskilt og vasket med vandig 0,5 molar natriumhydrogenkarbonatoppløsning inntil det ikke mere opp-tråtte gassutvikling. Etter tørkning med natriumsulfat avdamper man i vakuum oppløsningsmidler (Rotavapor) og opptok det orangerøde, flytende residuum i 20 ml etanol. Hertil dryppet man langsomt ved værelsetemperatur 6,0 g (0,128 mol) hydrazinhydrat i 5 ml etanol og oppvarmet deretter ennu i en time under tilbakeløp. Man avdestillerte alkoholen i vakuum (Rotavapor) og renset residuumet søylekromatografisk (Kieselgel 60, Merck; elueringsmiddel:diklormetan/metanol = 10/1). Omkrystallisering foregikk fra diklormetan/diisopropyleter. To a solution of 9 ml (0.128 mol) of dimethylformamide, while cooling (5 to 10°C), 11 ml (0.113 mol) of 2-phenyl-morpholone-5 in 25 ml of abs. 1,2-dichloroethane. It was allowed to stir again for one hour and then heated for two hours at 70°C. After the solution had cooled, it was shaken with 30 ml of an aqueous sodium acetate solution (12 g). The organic phase was separated and washed with aqueous 0.5 molar sodium bicarbonate solution until no more gas evolution occurred. After drying with sodium sulfate, solvents are evaporated in a vacuum (Rotavapor) and the orange-red, liquid residue is taken up in 20 ml of ethanol. In addition, 6.0 g (0.128 mol) of hydrazine hydrate was added slowly at room temperature in 5 ml of ethanol and then heated for another hour under reflux. The alcohol was distilled off in vacuum (Rotavapor) and the residue was purified by column chromatography (Kieselgel 60, Merck; eluent: dichloromethane/methanol = 10/1). Recrystallization took place from dichloromethane/diisopropyl ether.

Farveløse krystaller, smeltepunkt: 14.6°CColorless crystals, melting point: 14.6°C

Utbytte: 1,9 g (17% av det teoretiske)Yield: 1.9 g (17% of the theoretical)

C beregnet 66,96%, funnet 67,05%C calculated 66.96%, found 67.05%

H beregnet 6,08%, funnet 5,94%H calculated 6.08%, found 5.94%

Eksempel 3 Example 3

cis-7-metyl-5,6-difenylpyrazolo[4,3-b][l,4]oksazin cis-7-methyl-5,6-diphenylpyrazolo[4,3-b][1,4]oxazine

Man drypper til 15 ml dimetylformamid (som reaksjonsdeltager og oppløsningsmiddel) langsomt under omrøring 3,5 g = 2,2 ml (0,023 mol) fosforoksyklorid. Derved oppvarmet oppløsningen seg omtrent håridvarm. I denne oppløsning satte man etterhvert 3,0 g (0,0112 mol) cis-2,3-difenyl-4-metylmorfolon-5. I løpet av to timer lot man det avkjøle under omrøring til værelsetemperatur• ■ Man omrørte tre ganger med 20 ml dietyleter og dekanterte hver gang eteren av. Residuumet krystal-liserte. Man opptok det i 50 ml etanol og tildryppet under omrøring og avkjøling 5,6.g (0,0112 mol) hydrazinhydrat i 50 ml etanol. Deretter oppvarmet man 6 timer til kokning. Ved avkjøling falt det ut gule krystaller; krystalliseringen ble fullstendiggjort ved ytterligere avkjøling i kjøleskap og omkrystallisering foregikk fra etanol. 3.5 g = 2.2 ml (0.023 mol) phosphorus oxychloride is slowly added dropwise to 15 ml of dimethylformamide (as reaction participant and solvent) while stirring. Thereby, the solution heated up to approximately hair temperature. 3.0 g (0.0112 mol) of cis-2,3-diphenyl-4-methylmorpholone-5 was eventually added to this solution. In the course of two hours, it was allowed to cool while stirring to room temperature• ■ It was stirred three times with 20 ml of diethyl ether and each time the ether was decanted off. The residue crystallized. It was taken up in 50 ml of ethanol and, while stirring and cooling, 5.6 g (0.0112 mol) of hydrazine hydrate in 50 ml of ethanol were added dropwise. It was then heated to boiling for 6 hours. On cooling, yellow crystals precipitated; the crystallization was completed by further cooling in a refrigerator and recrystallization took place from ethanol.

Gulaktige krystaller,smeltepunkt 270°C under spaltning Utbytte: 2,5 g (76% av det teoretiske) Yellowish crystals, melting point 270°C during cleavage Yield: 2.5 g (76% of theoretical)

C beregnet 74,20%, funnet 74,38%C calculated 74.20%, found 74.38%

H beregnet 5,88%, funnet 6,03%.H calculated 5.88%, found 6.03%.

Eksempel 4Example 4

3,7-dimetyl-5,6-difenylpyrazolo[4,3-b][l,4]oksazin 3,7-dimethyl-5,6-diphenylpyrazolo[4,3-b][1,4]oxazine

54 g (0,2 mol) 4-metyl-2,3-difenylmorfolon-5- og 98,7 g (0,64 mol) fosforoksyklorid i 250 ml etylenklorld oppvarmes til kokning. Derved farver oppløsningen seg brun til mørke-brun. Til den kokende oppløsning drypper man i løpet av 2,5 timer 56,2 g (0,64 mol) nydestillert dimetylacetamid. Deretter avdamper man oppløsningsmidlet i vakuum og opp- 54 g (0.2 mol) of 4-methyl-2,3-diphenylmorpholone-5- and 98.7 g (0.64 mol) of phosphorus oxychloride in 250 ml of ethylene chloride are heated to boiling. As a result, the solution turns brown to dark brown. 56.2 g (0.64 mol) of freshly distilled dimethylacetamide are added dropwise to the boiling solution over the course of 2.5 hours. The solvent is then evaporated in a vacuum and

tar residuumet under isavkjøling i 500 ml etanol. Man blander med 300 ml hydrazinhydrat (6,2 mol) og oppvarmer 18 timer til kokning. Etter oppløsningsmidlets avdampning i vakuum opptar man residuumet i 1 liter vann og ekstraherer fire ganger med 250 ml diklormetan. Man tørker med natriumsulfat, inndamper i vakuum til tørrhet og opptar det brunaktige residuum under svak oppvarming i 250 ml eddiksyreetylester. Ved -18°C utkrystalliserer det ønskede produkt. takes the residue under ice-cooling in 500 ml of ethanol. It is mixed with 300 ml of hydrazine hydrate (6.2 mol) and heated to boiling for 18 hours. After the solvent has evaporated in vacuo, the residue is taken up in 1 liter of water and extracted four times with 250 ml of dichloromethane. It is dried with sodium sulphate, evaporated in vacuo to dryness and the brownish residue taken up under gentle heating in 250 ml ethyl acetate. At -18°C the desired product crystallizes out.

Man frasuger, vasker med diisopropyleter og petroleterSuction is applied, washing with diisopropyl ether and petroleum ether

(40-60) og tørker..(40-60) and dries..

Farveløse krystaller, smeltepunkt: 237-239°C (under spaltning). Colorless crystals, melting point: 237-239°C (under decomposition).

Utbytte: 25,9 g (42,4% av det teoretiske)Yield: 25.9 g (42.4% of the theoretical)

Fra moderluten lar det seg i tillegg dessutten utvinne 5,6 g (9,1% av det teoretiske). In addition, 5.6 g (9.1% of the theoretical) can be extracted from the mother liquor.

Deretter samlet utbytte: 31,5 g(53,5% av det teoretiske). Then total yield: 31.5 g (53.5% of the theoretical).

Eksempel 5Example 5

7-metyl-3-propyl-5,6-difenylpyrazolo[4,3-b][1,4]oksazin 7-methyl-3-propyl-5,6-diphenylpyrazolo[4,3-b][1,4]oxazine

8 g (0,03 mol) 4-metyl-2,3-difenylmorfolon-5 og 13,8 g = 8,4 ml (0,09 mol) fosforoksyklorid oppvarmes i 100 ml etylen klorid til 50°C og blandes.ved denne temperatur med 10,4 g (0,09 mol) N,N-dimetylsmørsyreamid i 100 ml etylenklorid under omrøring. For å akselerere den for langsomme omsetning (DC-kontroll), oppvarmes ennu 4 timer til kokning. Etter oppløsningsmidlets avdampning i vakuum tar man det tørre residuum i 100 ml etanol og blander så langsomt med 51,6 g = 50 ml (1,03 mol) hydrazinhydrat, således at 5°C ikke overskrides. Deretter oppvarmer man ennu 6 timer til kokning. Man avdamper oppløsningsmidlet i vakuum og opptar residuumet i 150 ml vann og ekstraherer fire ganger med ca. 70 ml eddiksyreetylester. Etter tørkning med natriumsulfat inndampes i vakuum til et lite volum og søylekromatograferes (kiselgel 60, elueringsmiddel: diklormetan: metanol = 20:1 til 10:1). 8 g (0.03 mol) 4-methyl-2,3-diphenylmorpholone-5 and 13.8 g = 8.4 ml (0.09 mol) phosphorus oxychloride are heated in 100 ml ethylene chloride to 50°C and mixed at this temperature with 10.4 g (0.09 mol) of N,N-dimethylbutyric acid amide in 100 ml of ethylene chloride with stirring. To accelerate it for slow turnover (DC control), heat another 4 hours to boiling. After evaporation of the solvent in a vacuum, the dry residue is taken in 100 ml of ethanol and then slowly mixed with 51.6 g = 50 ml (1.03 mol) of hydrazine hydrate, so that 5°C is not exceeded. It is then heated for another 6 hours until boiling. The solvent is evaporated in vacuo and the residue taken up in 150 ml of water and extracted four times with approx. 70 ml acetic acid ethyl ester. After drying with sodium sulfate, it is evaporated in vacuo to a small volume and column chromatographed (silica gel 60, eluent: dichloromethane: methanol = 20:1 to 10:1).

Farveløse krystaller, smeltepunkt 164°C.Colorless crystals, melting point 164°C.

Utbytte: 4,0 g (40% av det teoretiske).Yield: 4.0 g (40% of the theoretical).

Eksempel 6 Example 6

1-acetyl-3,7-dimetyl-5,6-difenylpyrazolo[4,3-b][1,4]-oksazin 1-acetyl-3,7-dimethyl-5,6-diphenylpyrazolo[4,3-b][1,4]-oxazine

2.2 g (0,0072 mol) 3,7-dimetyl-5,6-difenylpyrazolo-[4,3-b][1,4]-oksazin suspenderes i 50 ml dietyleter, blandes med 2,4 ml = 2.3 g (0,029 mol) pyridin og avkjøles til 0°C. Ved 0 til 5°C dryppes til denne suspensjon under omrøring en oppløsning av 1 "ml = 1,1 g (0,014 mol) acetylklorid i 10 ml dietyleter. 2.2 g (0.0072 mol) of 3,7-dimethyl-5,6-diphenylpyrazolo-[4,3-b][1,4]-oxazine is suspended in 50 ml of diethyl ether, mixed with 2.4 ml = 2.3 g ( 0.029 mol) of pyridine and cooled to 0°C. At 0 to 5°C, a solution of 1 ml = 1.1 g (0.014 mol) of acetyl chloride in 10 ml of diethyl ether is added dropwise to this suspension with stirring.

Man lar det ennu omrøre 1 time og oppvarmer til værelsetemperatur. DC-kontroll viser fullstendig omsetning. Det rystes på It is left to stir for a further 1 hour and heated to room temperature. DC control shows complete turnover. It is shaken

is og ekstraheres tre ganger med hver gang ca. 50 ml diklormetan. Etter tørkning med natriumsulfat og inndampning til lite volum renses søylekromatografisk (Kieselgel 60, elueringsmiddel: Diklormetan/metanol = 10/1). ice and extracted three times with each time approx. 50 ml dichloromethane. After drying with sodium sulfate and evaporation to a small volume, the mixture is purified by column chromatography (Kieselgel 60, eluent: dichloromethane/methanol = 10/1).

Farveløse krystaller, smeltepunkt: 160,2°C.Colorless crystals, melting point: 160.2°C.

Utbytte: 1,6 g(64,0% av det teoretiske).Yield: 1.6 g (64.0% of the theoretical).

Analogt disse eksempler ble det fremstilt følgende forbindelser ifølge oppfinnelsen: Analogous to these examples, the following compounds according to the invention were prepared:

Analogt-;eksempel j42'blendet"oppnådd ølgende.^fgrbindelser framtfbel 1 - £ fgu. heJ. lo " i ssx; -:^s Analogous-;example j42'blended"achieved ølgende.^fgrconnections framtfbel 1 - £ fgu. heJ. lo " in ssx; -:^p

Claims

1. Compounds of the general formula I in their isomeric forms Ia and Ib, both individually and in mixture

while R and R" <*> " can be the same or different and mean hydrogen, alkyl with 1 to 18 C atoms and phenyl, optionally substituted with up to 5 identical or different substituents from the group alkyl with 1 to 6 C atoms, cycloalkyl with 3 to 6 C atoms, aralkyl with 7 to 22 C atoms, aryl with 6 to 14 C atoms, mono- and dialkylamino with 1 to 12 C atoms, arylamino with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 12 C atoms, arylthio# with 6 to 10 C atoms/ aralkyl with 7 to 22 C atoms, aralkylamino with 7 to 16 C atoms, carboxy, carbaloxy with 2 to 13 C atoms, carbamoyl, mono- and dialkylcarbamoyl with 1 to 12 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 12 C atoms, possibly one or more times substituted with F, Cl, Br or/and J , hydroxyalkyl with 1 to 12 C atoms, aminoalkyl with 1 to 12 C atoms, alkoxycarbonylaminoalkyl with 3 to 13 C atoms, halogenoalkyl with up to 12 C atoms, optionally one or more times substi tuated with F, Cl, Br or/and J, halogen such as F, Cl, Br and J, amino, acylamino with 2 to 7 C atoms, carbamoylamino, sulfonylamino, hydroxy, acyloxy with 2 to 7 C atoms, sulfonamido, nitro, formyl, alkylcarbonyl of 2 to 13 C atoms, arylcarbonyl of 7 to 15 C atoms, methylenecarboxy, methylenecarboxyalkyl of 3 to 8 C atoms, ethylene carboxyalkyl of 4 to 9 C atoms or propylene carboxyalkyl of 5 to 10 C atoms , R 2 and R 3 can be the same or different and mean hydrogen, alkyl with 1 to 18 C atoms, wherein the alkyl residue may be interrupted one or more times by oxygen, sulfur or nitrogen, alkenyl or alkynyl with 2 to 12 C atoms, aralkyl with 7 to 12 C atoms, wherein alkenyl, alkynyl - and the aralkyl radicals may optionally be interrupted one or more times by oxygen, sulfur or nitrogen, further means aryl with 6 to 14 C atoms, 5- to 6-membered heteroaryl with up to 4 heteroatoms from the series N, 0 and S, 5- to 6-membered heteroarylalkyl with up to 4 heteroatoms from the series N, 0 and S with 1 to 12 C atoms in the alkyl chain, alkylcarbonyl with 2 to 13 C atoms, arylcarbonyl with 7 to 11 C atoms, optionally with up to 5 equal or various substituents from the group alkyl with 1 to 18 C atoms, cycloalkyl with 3 to 6 C atoms, aralkyl with 7 to 22 C atoms, aryl with 6 to 14 C atoms, mono- and dialkylamino with 1 to 12 C- atoms, arylamino with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 12 C atoms, arylthio with 6 to 10 C atoms, aral coxy with 7 to 22 C atoms, aralkylamino with 7 to 16 C atoms, carboxy, carbaloxy with 2 to 13 C atoms, carbamoyl, mono- and dialkylcarbamoyl. with 1 to 12 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 12 C atoms, possibly one or more times substituted with F, Cl, Br or/and J , hydroxyalkyl with 1 to 12 C-atoms, aminoalkyl with 1 to 12 C-atoms, alkyloxycarbonylamino- alkoxy with 3 to 13 C-atoms, halogenoalkyl with up to 12 C-atoms, optionally substituted one or more times with F, Cl, Br or/ and J, halogen such as F, Cl, Br or/and J, amino, acylamino with 2 to 7 C atoms, sulfonamido, nitro, formyl, alkylcarbonyl with 2 to 13 C atoms, arylcarbonyl with 7 to 15 C atoms, methylenecarboxy, methylenecarboxyalkyl with 3 to 8 C atoms, ethylenecarboxyalkyl with 4 to 9 C atoms or propylenecarboxyalkyl with for 5- to 6-membered heteroarylcarbonyl with up to 4 heteroatoms from the series N, 0 and S and R <5> means hydrogen, an unbranched, branched or cyclic alkyl radical, each time with 3 to 6 C atoms, which is optionally substituted with hydroxy, carboxy, formyl, acetyl, alkoxy, alkylthio, halogen, nitro, or may be substituted free amino groups, further means an aromatic or heteroaromatic radical with up to 4 heteroatoms from the series N, 0 and S, which may optionally be substituted with alkyl, alkoxy, alkylthio or halogen and further means a similarly substituted aralkyl or heteroaralkyl residue.;2. Compound of general formula Ia and Ib according to claim 1, wherein R and R" <*> " can be the same or different and mean hydrogen, alkyl with 1 to 6 C atoms and phenyl, optionally substituted with up to 5 identical or different substituents from the group alkyl with 1 to 6 C atoms, aralkyl with 7 to 15 C atoms, phenyl or naphthyl, mono- and dialkylamino with 1 to 8 C atoms, arylamino with 6 to 10 C atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 12 C atoms, aralkyl with 7 to 16 C atoms, aralkylamino with !7 to 16 C atoms atoms, carboxy, carbaloxy with 2 to 7 C atoms, carbamoyl, mono- and dialkylcarbamoyl with 1 to 6 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 6 C -atoms, optionally substituted with F, Cl or/and Br, hydroxyalkyl with 1 to 6 C atoms, aminoalkyl with 1 to 6 C atoms, amino alkoxycarbonylamino alkoxy with 3 to 9 C atoms, halogen oxy with up to 6 C atoms, optionally substituted with F, Cl and/or Br, halogen such as F, Cl and Br, amino, acylamino with 2 to 7 C atoms, carbonylamino, sulfonylamino, hydroxy, acyloxy with 2 to 7 C atoms, sulfonamido, nitro, formyl, alkylcarbonyl of 2 to 7 C atoms, arylcarbonyl of 7 to 11 C atoms, methylenecarboxy, methylenecarboxyalkyl of 3 to 8 C atoms, ethylene carboxyalkyl of 4 to 9 C atoms and propylenecarboxyalkyl,

2 3 R and R can be the same or different and mean hydrogen, alkyl with 1 to 12 C atoms, wherein the alkyl residue may be interrupted one or more times by oxygen, sulfur or nitrogen, alkenyl or alkynyl with 2 to 6 C atoms, aralkyl with 7 to 12 C atoms, wherein alkenyl, alkynyl - and the aralkyl residue can likewise be interrupted one or more times with oxygen, sulfur or nitrogen, further means phenyl and naphthyl, 5- to 6-membered heteroaryl with up to 3 heteroatoms from the series N, 0 and S, 5- to 6-membered heteroarylalkyl with up to three heteroatoms from the series N, 0 and S with 1 to 6 C atoms in the alkyl chain, alkylcarbonyl with 2 to 13 C atoms, arylcarbonyl with 7 to 11 C atoms, optionally substituted with up to 5 identical or different substituents from the group alkyl with 1 to 6 C atoms, cycloalkyl with 3 to 6 C atoms, aralkyl with 7 to 11 C atoms, phenyl and naphthyl, mono- and dialkylamino with 1 to 8 C atoms, arylamino with 6 to 10 C atoms atoms, aryloxy with 6 to 10 C atoms, alkylthio with 1 to 6 C atoms, arylthio with 6 to 10 C atoms, aralkyl with 7 to 12 C atoms, aralkylamino with 7 to 12 C atoms, carboxy, carbaloxy with 2 to 7 C atoms, carbamoyl, mono- and dialkylcarbamoyl with 1 to 6 C atoms, alkylcarbonyl with 1 to 12 C atoms, alkylsulfonyl with 1 to 12 C atoms, arylsulfonyl with 6 to 14 C atoms, haloalkyl with up to 6 C atoms, optionally substituted one or more times with F, Cl or/and Br, hydroxyalkyl with 1 to 6 C-atoms, aminoalkyl with 1 to 6 C-atoms, alkyloxycarbonylaminoalkoxy with 3 to 9 C-atoms, halogeno-alkyl with up to 6 C-atoms, optionally substituted one or more times with F, Cl or/and Br, halogen such as F, Cl or/and Br, amino, acylamino with 2 to 7 C atoms, carbamoylamino, sulfonylamino, hydroxy, acyloxy with 2 to 7 C atoms, sulfonamido, nitro, formyl, alkylcarbonyl with 2 to 13 C atoms, arylcarbonyl of 7 to 15 C atoms, methylenecarboxy, methylenecarboxyalkyl of 3 to 8 C atoms, ethylene carboxyalkyl of 4 to 9 C atoms or p propylene carboxyalkyl with 5 to 10 C atoms and 5- to 6-membered heteroarylcarbonyl with up to three heteroatoms from the series N, 0 and S, and R 5 means hydrogen, or an unbranched, branched or cyclic alkyl residue, each time with 3 to 6 C atoms, which may optionally be substituted with hydroxy, carboxy, formyl, acetyl, alkoxy, alkylthio? halogen, nitro, substituted or free amino groups, or means an aromatic or heteroaromatic residue with up to 4 heteroatoms from the series N, 0 and S, which may optionally be substituted with alkyl, alkoxy, alkylthio or halogen, or means a similarly substituted aralkyl - or heteroaralkyl residue.

3. Compounds with the general formulas Ia and Ib according to claim 1 or 2, wherein R and R^" can be the same or different and mean hydrogen, alkyl, with 1 to 6 C atoms, optionally substituted with up to 5 fluorine atoms and/or phenyl, optionally substituted with up to 5 substituents from the group alkyl with 1 to 4 C atoms per alkyl group, alkyloxy with 1 to 3 C atoms, aryloxy with 6 C atoms and with F, Cl, Br, N02 , NH2' NH-lower alkY l' N(lower alkyl)2 , alkylthio with 1 to 6 C atoms, alkylsulfonyl with 1 to 6 C atoms, with aminocarbonyl and aminosulfonyl,

2 3 R and R are the same or different and mean hydrogen, alkyl with up to 6 C atoms, arylalkyl with 3 to 13 C atoms, optionally substituted with up to 5 F, Cl or Br, aryloxyalkyl with 7 to 16 C atoms, formyl, alkylcarbonyl with 2 to 13 C atoms, carboxyalkyl with 2 to 7 C atoms and arylalkyloxycarbonyl with 8 to 16 C atoms and R 5 means hydrogen, an unbranched or branched alkyl residue with 1 to 6 C atoms, which may optionally be substituted by alkoxy, or an aryl or heteroaryl residue; phenyl or pyridyl residues are preferred, which may optionally be substituted by fluorine, chlorine, alkyl or alkoxy.

4. Compounds of the general formula I in their isomeric forms Ia and Ib

in which R and R^" mean hydrogen, methyl and/or phenyl, 4-chlorophenyl, 4-Methoxyphenyl R 2 means hydrogen, methyl or ethyl and

3 R means hydrogen, methyl, 3,4-dichlorobenzyl, 2-phenoxyethyl, 3-naphthoxyethyl, benzyloxycarbonyl, formyl, acetyl and carboxymethyl and R 5 means hydrogen, methyl, propyl and isopropyl.

5. Compounds of the general formula Ia and Ib according to one or more of claims 1 to 4 for use in the treatment of diseases.

6. Process for the preparation of compounds of the general formula Ia and Ib according to claims 1 to 4, characterized in that compounds of the general formula II

in which 12 R, R and R have the meaning stated in claim 1 is reacted with N,N-dialkylamide of the general formula VI

with the meaning specified in claim 1 and phosphorus oxychloride, and the salts thus formed are reacted at temperatures between -20°C and + 100°C with hydrazines of the general formula

in which R 3 means hydrogen, alkyl with 1 to 18 C atoms, aralkyl with 7 to 12 C atoms, heteroalkyl, in that the alkyl, aralkyl and heteroaralkyl residues can be interrupted by oxygen, sulfur and nitrogen one or more times, aryl with 6 to 10 C atoms and heteroaryl, in that the aryl and heteroaryl residues can be substituted with up to 5 identical or different substituents from the group alkoxy, alkyl, aralkyl, cycloalkyl, aryl, alkylamino, dialkylamino, arylamino, aryloxy, arylthio, i-alkylthio, carboxy, caralkyloxy, cyano, carbamoyl, sulfonyl, alkylsulfonyl, halogeno, halogen, amino or substituted amino, sulfonamido, methylenecarboxy, methylenecarboxyalkyl or propylenecarboxyalkyl, or the oxazines of formula II, are acylated with carboxylic acid esters VII

with the meaning stated in claim I, the acyl products formed with formula VIII according to claim 1 is sulphurised, and the formed ions with formula IX are reacted with hydrazines with the general formula IV

at temperatures between -20°C and + 100°C.

7. Use of compounds with the general formula I according to claims 1 to 4 in combating diseases, preferably inflammatory processes, especially as lipoxygenase inhibitors and/or as analgesics as vessel wall and/or cytoprotective agents, especially as antithrombotic, antimetastatic, antiallergic, antiasthmatic, ulcer -preventive and/or anuretic.

8. Medicinal product containing at least one compound with the general formula according to claim 1 to 4.

9. Medicine according to claim 8, characterized in that it contains one or more active substances in an amount of 0.5 to 90 percent by weight of the overall formulation.

10. Process for the production of medicinal products, characterized in that compounds of the general formula Ia and Ib according to claims 1 to 3, possibly using common excipients and carriers, are transferred in a suitable application form.