NO853695L - ISOXAZOLCARBOXYLIC ACID DERIVATIVES, PREPARATION AND USE THEREOF. - Google Patents

ISOXAZOLCARBOXYLIC ACID DERIVATIVES, PREPARATION AND USE THEREOF.

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Publication number
NO853695L
NO853695L NO853695A NO853695A NO853695L NO 853695 L NO853695 L NO 853695L NO 853695 A NO853695 A NO 853695A NO 853695 A NO853695 A NO 853695A NO 853695 L NO853695 L NO 853695L
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Norway
Prior art keywords
isoxazole
alkyl
dihydro
indenyl
tetramethyl
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Application number
NO853695A
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Norwegian (no)
Inventor
Fritz-Frieder Frickel
Axel Nuerrenbach
Hans Theobald
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Basf Ag
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Publication of NO853695L publication Critical patent/NO853695L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Dermatology (AREA)
  • Toxicology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Oppfinnelsen vedrører fremstilling av nye isoxazolkarboksylsyrederivater . The invention relates to the production of new isoxazole carboxylic acid derivatives.

Fra europeisk OS 98 591 fremgår at vinyltetrahydronafta-liner substituert med en tiofenring har rodentizide egenskaper. From European OS 98 591 it appears that vinyltetrahydronaphthalenes substituted with a thiophene ring have rodenticidal properties.

Det ble nå funnet at isoxazolkarboksylsyrederivater med formel I It was now found that isoxazole carboxylic acid derivatives of formula I

hvori in which

1 2 1 2

R og R er hydrogenatomer eller metylgrupperR and R are hydrogen atoms or methyl groups

R 3 og R 4hydrogenatomer, C-^^-alkylgrupper eller metoksygrupperR 3 and R 4 hydrogen atoms, C 1-3 alkyl groups or methoxy groups

R^ et hydrogen- eller halogenatom eller en C^_^-alkyl- eller C^_g-alkoksygruppe R^ a hydrogen or halogen atom or a C^_^-alkyl or C^_g-alkyl group

R et hydrogenatom eller en C-^_g-alkyl eller C-^g-cykloalkyl-gruppe R is a hydrogen atom or a C 1-6 alkyl or C 1-6 cycloalkyl group

A en metylen- eller etylenrest, eventuelt substituert med c^_4~alkylgruppe r, og A a methylene or ethylene residue, optionally substituted with a c^_4~alkyl group r, and

R 7 tetrazolyl-eller 2-oksazolinresten eller en nitril- ellerR 7 the tetrazolyl or 2-oxazoline residue or a nitrile or

8 9 10 C2_10-ketalgruppe eller betyr resten-CH(R )-R eller -CO-R , hvori 8 9 10 C2_10 ketal group or means the residue -CH(R )-R or -CO-R , in which

R g er et hydrogenatom eller en C,_^-alkylgruppeR g is a hydrogen atom or a C 1-4 alkyl group

9 8 11 12 13 11 R er samme som R eller en rest -OR eller NR R (med R i betydningen av et hydrogenatom, en C, ,-alkyl-, C2_2ø~alkanoyl- 9 8 11 12 13 11 R is the same as R or a residue -OR or NR R (with R in the sense of a hydrogen atom, a C, , -alkyl-, C2_2ø~alkanoyl-

"12 13. eller eventuelt substituert benzoylgruppe og medR<XA>og R i betydningen hydrogenatomer, C^_^-alkyl-, C2_2g~alkanoyl- eller eventuelt substituerte benzoylgrupper) "12 13. or optionally substituted benzoyl group and with R<XA> and R in the sense of hydrogen atoms, C^_^-alkyl-, C2_2g~alkanoyl- or optionally substituted benzoyl groups)

R<x>^ et hydrogen- eller halogenatom, azido-, imidazol- eller en triazolrest, en C,_4-alkylgruppe eller en rest -OR<14>eller R<x>^ a hydrogen or halogen atom, azido-, imidazole- or a triazole residue, a C,_4-alkyl group or a residue -OR<14>or

1516 14 1516 14

-NR R (med R i betydningen et hydrogenatom, en C1_g-alkyl-, eventuelt med en eller flere hydroksygrupper eller en C1_4~alkoksygruppe substituert C1_<g->alkyl, eventuelt substituerte aryl- eller i aryIdelen substituerte aralkylgrupper, og med R<15>-NR R (with R in the sense of a hydrogen atom, a C1_g-alkyl-, optionally with one or more hydroxy groups or a C1-4~ alkoxy group substituted C1_<g->alkyl, optionally substituted aryl- or in the aryl part substituted aralkyl groups, and with R< 15>

og R i betydningen hydrogenatomer, C1__g-alkyl-f eventuelt med en eller flere hydroksygrupper substituerte C2_g-alkylrester and R in the sense of hydrogen atoms, C1__g-alkyl-f optionally with one or more hydroxy groups substituted C2_g-alkyl radicals

eller R"*"^ og R sammen med nitrogenatomet de er bundet til,;i betydningen en aryl- eller tetrazolylgruppe, samt eventuelt deres fysiologiske salter er gode legemiddelvirkestoffer. ;Av forbindelsen med formel I er de foretrukne som har E-konfigurasjon, og i hvilke R 1 og R 2 betyr metylgrupper og A en metylen- eller etylenrest substituert med en metylgruppe. Som halogenatomer for R<x>(^ er fluor og klor foretrukne. Substituerte benzoylgrupper har som substituenter fortrinnsvis halogenatomer - spesielt fluor og klor - og/eller metyl-, metoksy- eller nitrogrupper. ;Som arylgrupper er fenylgrupper foretrukne, hvilke kan være substituert med metyl-, metoksy- eller nitrogruppe; som aralkylgruppe er benzylgruppen foretrukket, hvilken i aryldelen kan være substituert med en metyl- eller metoksygruppe eller med halogen. Som heterocykliske rester kommer fortrinnsvis pyrrolidino-, piperidino- eller morfolinresten i betraktning. ;Typiske eksempler på forbindelser fremstilt ifølge oppfinnelsen er de følgende isoxazolforbindelser, som i isoxazolringens 3-stilling også er substituert med de videre nedenfor førte rester. ;5-t2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl") isoxazol ;5-12-(1,1,2,3,3,-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl}isoxazol ;5-C2-(5,5,8,8-Tetrametyl-5,6,7,8-tetrahydronaft-2-yl)-1--propenylj isoxazol ;5-[2-(3,8,8-Trimetyl-5,6,7,8-tetrahydronaft-2-yl)-1-prope-nyl]isoxazol ;5-[ 2-(3-Metoksy-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-propenylJisoxazol ;5-f2-(3,5,5,8,8-Pentametyl-5,6,7,8-tetrahydronaft-2-yl)-1--propenylj isoxazol ;5-(2-(3-Etyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2--yl)-1-propenylJ isoxazol ;5-C2-(3-Propyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-l-propenyl}isoxazol 5-[2-(3-butyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2-yl)-l-propenyljisoxazol ;5-C2-(3-(1-Metylety1)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl) -l-propenyl}isoxazol ;5-12-(3-Butyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)1-propenyl] isoxazol ;5- 12-(3- a-Metyletyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl )-1-propenylJ isoxazol ;5-^2-(3-(2-Metylpropyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl) -l-propenyl3 isoxazol ;5-[2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1--propenyl}isoxazol ;5-[2-(6-Ety1-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl}isoxazol ;5~r 2-(6-Propyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-inde-nyl )-l-propenyl} isoxazol ;5-C 2-(6-Butyl-l,l,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--l-propenyl}isoxazol ;5-{2-(6-(1-Metyletyl)-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)--indenyl)-1-propenyl}isoxazol ;5-t 2-(6-(2-Metylpropyl)-1,1,3,3-tetrametyl-2,3-dihydro--5(1H)-indenyl)-l-propenyllisoxazol ;5-£2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl}isoxazol ;5-f2-(6-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl ) -1-propenyl isoxazol ;5-L2-(6-Propyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H) - indenyl)-1-propenylJ isoxazol ;5-^2-(6-Butyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl) -1-propenyl]isoxazol ;5-t2-(6-(1-Metyletyl)-1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-inden<y>l)-1-pro<p>en<y>lJ isoxazol ;5-T2-(6-(2-Metylpropyl)-1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl)-l-propenyl]isoxazol ;5-[ 2-(3-Fluor-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-propenyl] isoxazol ;5-£2-(3-Fluor-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-etyenyl] isoxazol ;5-[2-(3-Fluor-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-butenyl]isoxazol ;5-[2-(3-Fluor-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl) -2-cyklopropyl-l-etenyl]]isoxazol ;5- 12-(1,1,2,3,3-Pentamety1-2,3-dihydro-5(1H)-indenyl)-1- -etenyl]isoxazol ;5-f2- (1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1--etenyl] isoxazol ;5-[2-(5,5,8,8-Tetrametyl-5,6,7,8-tetrahydronaft-2-yl)-1--etenyl] isoxazol ;5-t2-(3,8,8-Trimetyl-5,6,7,8-tetrahydronaft-2-yl)-1-etenyl]-isoxazol ;5-C 2-(3-Metoksy-5,6,7,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-l-etenyl]isoxazol ;5- 12-(3,5,5,8,8-Pentametyl-5,6,7,8-tetrahydronaft-2-yl)-1--etenyl]isoxazol ;5-[2- (3-Ety1-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2--yl)-1-etenyl)isoxazol ;5-[2-(3-Propyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-etenyl]isoxazol ;5-L2-(3-Butyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-etenyl]isoxazol ;5- C2-(3-(1-Metylpropyl)-5,5,8,8-tetramety1-5,6,7,8-tetra-hydronaf t-2-yl ) -1-etenyl]isoxazol ;5-[2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1--etenyl]isoxazol ;5-C2-(6-Etyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--1-etenyl]isoxazol ;5-[2-(6-Propyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-inde-nyl).-l-etenyl] isoxazol ;5-C2-(6-Butyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--1-etenyl] isoxazol 5-[ 2-(6-(1-Metyletyl)-1,1,3,3-tetrematy1-2,3-dihydro-5(1H)--indenyl)-1-etenyl] isoxazol ;5-[2-(6-(2-Metylpropyl)-1,1,3,3-tetrametyl-2,3-dihydro--5(1H)-indenyl)-1-etenyl]isoxazol ;5-[2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-1--etenyl]isoxazol ;5-C 2-(6-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl)-1-etenyl] isoxazol ;5-[2-(6-Propyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)--indenyl)-1-etenyl]isoxazol ;5-[2-(6-Butyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl ) -1-etenyl] isoxazol ;5-[2-(6-(1-Metyletyl)-1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl)-1-etenyl]isoxazol ;5-[2-(6-(2-Metylpropyl)-1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl-l-etenyl]isoxazol ;5-(2-(1,1,3,3,-Tetrametyl-2,3-dihydro-5(1H)-idenyl)-1--butenyl]isoxazol ;5-[2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-idenyl)-1--butenyl]isoxazol ;5-[2-(5,5,8,8-Tetrametyl-5,6,7,8-tetrahydronaft-2-yl)-1--butenyl]isoxazol ;5-t2-(3,8,8-Trimetyl-5,6,7,8-tetrahydronaft-2-yl)-1-bute-nyl] isoxazol ;5-f2-(3-Metoksy-5,5,8,8-tetrametyl-5,6,7,8-tetrahydro-naf t-2-yl) -l-butenyl] isoxazol ;5-(2-(3,5,5,8,8-Pentametyl-5,6,7,8-tetrahydronaft-2-yl)--1-butenyl]isoxazol ;5-C2-(3-Propyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-butenyl] isoxazol ;5-£2-(3-Butyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-1-butenyl] isoxazol ;5-[2-(3-(1-Metyletyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl)-1-butenylJ isoxazol ;5-C2-(3-(2-Metylpropyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl)-1-butenyl]isoxazol ;5-[2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-1--butenyl]isoxazol ;5-[2-(6-Etyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--1-butenyl]isoxazol ;5-L 2-(6-Propyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-inde-nyl )-1-butenyl]isoxazol ;5-£2-(6-Butyl-l,1,3,3-tetramety1-2,3-dihydro-5(1H)-inde-nyl) -1-butenyl]isoxazol ;5-[2-(6-1-Metyletyl)-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)--indenyl)-1-butenyl]isoxazol ;5-C2-(6-(2-Metylpropyl)-1,1,3,3-tetrametyl-2,3-dihydro--5(1H)-indenyl)-1-butenyl isoxazol ;5-[2-(6-(2-Metylpropyl)-1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl)-l-butenyl]isoxazol ;5-C2-(6-(1-Metyletyl)-1,1,2,3,3-pentametyl-2,3-dihydro- -5(1H)-indenyl)-1-butenyl]isoxazol ;5-[2-(6-Butyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl )-1-butenyl}isoxazol ;5-[2-(6-Propyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H) - indenyl)-1-butenyl]isoxazol ;5-[2-(6-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl) -1-butenyl] isoxazol ;5-£2-(l,l,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-1--propenyl]isoxazol ;5-[2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-2-cyklo-propyl)-1-etenyl]isoxazol ;5-C2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2--(cyklopropyl)-1-etenyl]isoxazol ;5- 12-(5,5,8,8-Tetramety1-5,6,7,8-tetrahydronaft-2-yl)-2--(cyklopropyl)-1-etenyl] isoxazol ;5-[2-(3,8,8-Trimetyl-5,6,7,8-tetrahydronaft-2-yl)-2-(cyklo-propyl) -1-etenyl] isoxazol ;5-[2-(3-Metoksy-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-2-(cyklopropyl)-1-etenyl] isoxazol ;5-[2-(3,5,5,8,8-Pentametyl-5,6,7,8-tetrahydronaft-2-yl)-2--(cyklopropyl)-1-etenyl] isoxazol ;5- [2-(3-Etyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2--yl)-2-(cyklopropyl)-1-etylJisoxazol ;5-[2-(3-Propyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-2-(cyklopropyl)-1-etenyl]isoxazol ;5-[2-(3-Butyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-2-(cyklopropyl)-l-eteny]J isoxazol ;5-[2-(3-(1-Metyletyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl) -2-(cyklopropyl)-l-etenyl]isoxazol ;5-[2-(3-(2-Metylpropyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl) -2-(cyklopropyl)-1-etenylJisoxazol ;5-[2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl)-2--(cyklopropyl)-1-etenyl] isoxazol ;5-L2-(6-Etyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--2-(cyklopropyl)-1-etenyl}isoxazol ;5- 12-(6-Propyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-idenyl)--2-(cyklopropyl)-l-etenyl]isoxazol ;5-[2-(6-Butyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--2-(cyklopropyl)-1-etenylj isoxazol ;5-[2-(6-(1-Metyletyl)-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)--indenyl)-2-(cyklopropyl)-l-etenyl]isoxazol 5-[2-(6-(2-Metylpropyl)-1,1,3,3-tetrametyl-2,3-dihydro--5(1H)-indenyl)-2-(cyklopropyl)-1-etenyl]isoxazol 5-[2-(6-(2-Metylpropyl)-1,1,2,3,3-pentamety1-2,3-dihydro--5(1H)-indenyl)-2-(cyklopropyl)-1-etenyl]isoxazol 5-£ 2-(6-(1-Metyletyl)-1,1,2,3,3-pentamety1-2,3-dihydro--5(1H)-indenyl)-2-(cyklopropyl)-1-etenyl]isoxazol 5-[2-(6-Butyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl )-2-(cyklopropyl)-1-etenyl]isoxazol ;5-f 2-(6-Propyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl )-2-(cyklopropyl)-1-etenyl]isoxazol ;5-[2-(6-Etyl-l,1,2,3,3,3-pentamety1-2,3-dihydro-5(1H)-inde-nyl) -2-(cyklopropyl)-1-etenyl]isoxazol ;5-[2-(1,1,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-2--(cyklopropyl)-1-etenyl]isoxazol ;5-£2-(1,1,3,3-Tetrametyl-2,3-dihydro-5(1H)-indenyl)-3--metyl-buten-l-yl]isoxazol ;5-£2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)-3--metyl-buten-l-yl]isoxazol ;5- [2-(5,5,8,8-Tetrametyl-5,6,7,8-tetrahydronaft-2-yl)-3--metyl-buten-l-yl]isoxazol ;5-t2-(3,8,8-Trimetyl-5,6,7,8-tetrahydronaft-2-yl)-3-metyl--buten-l-ylj isoxazol ;5-£2-(3-Metoksy-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft--2-yl)-3-metyl-buten-l-yl]isoxazol ;5-[2-(3-Fluor-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2--yl)-3-metyl-buten-l-yl]isoxazol ;5-£2-(3,5,5,8,8-Pentametyl-5,6,7,8-tetrahydronaft-2-yl)--3-metyl-buten-l-yl]isoxazol ;5-[2-(3-Etyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2--yl)-3-metyl-buten-l-ylJ isoxazol ;5-£.2- (3-Propyl-5 ,5,8, 8-tetrametyl-5,6,7,8-tetrahydronaf t--2-yl)-3-metyl-buten-l-yl]isoxazol ;5-£2-(3-Butyl-5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2--yl)-3-metyl-buten-l-yl]isoxazol ;5-£2-(3-(1-Metyletyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra-hydronaf t-2-yl) -3-metyl-buten-l-ylJ isoxazol 5-t2-(3-(2-Metylpropyl)-5,5,8,8-tetrametyl-5,6,7,8-tetra- ;hydronaft-2-yl)-3-metyl-buten-l-yl]isoxazol ;5-[2-(1,1,3,3,6-Pentametyl-2,3-dihydro-5(1H)-indenyl-3-metyl-buten-l-yl]isoxazol ;5-C2-(6-Etyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--3-metyl-buten-l-yl] isoxazol ;5-[2-(6-Propyl-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)-inde-nyl )-3-metyl-buten-l-yl]isoxazol ;5-[2-(6-Butyl-l,1,3,3-tetrametyl-2,3-dihydro-5(1H)-indenyl)--3-metyl-buten-l-yl]isoxazol ;5-£2-(6-(1-Metyletyl)-1,1,3,3-tetrametyl-2,3-dihydro-5(1H)--indenyl)-3-metyl-buten-l-yl] isoxazol ;5-[2-(6-(2-Metylpropyl)-1,1,3,3-tetramety1-2,3-dihydro--5(1H)-indenyl)-3-metyl-buten-l-yl]isoxazol ;5-[2-(6-(2-Metylpropyl)-1,1,2,3,3-pentamety1-2,3-dihydro--5(1H)-indenyl)-3-metyl-buten-l-yl]isoxazol ;5-[2-(6-(1-Metyletyl)-1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl)-3-metyl-buten-l-yl] isoxazol ;5-[2-(6-Butyl-l,1,2,3,3-pentamety1-2,3-dihydro-5(1H)-inde-nyl) -3-metyl-buten-l-yl]isoxazol ;5-£2-(6-Propyl-l,1,2,3,3-pentamety1-2,3-dihydro-5(1H) - indenyl)-3-metyl-buten-l-yl]isoxazol ;5-£2-(6-Etyl-l,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-inde-nyl) -3-metyl-buten-l-yl]isoxazol ;5-[2-(l,l,2,3,3,6-Heksametyl-2,3-dihydro-5(1H)-indenyl)-3--metyl-buten-l-yl]isoxazol ;5-£2-(5,5,8,8-Tetrametyl-l-metoksy-4-metyl-5,6,7,8-tetra-hydro-naft-2-y1)-1-etenyl]isoxazol ;Disse forbindelser er i isoxazolringens 3-stilling substituert med de følgende typiske rester: 3-Karboksy-, 3-metoksykarbonyl, 3-etoksykarbonyl-, 3-pro-pyloksykarbonyl-, 3-(1-metyl)etoksykarbonyl-, 3-butoksykarbonyl-, 3-oktyloksykarbonyl-, 3-(2-metoksy)etoksykarbonyl-, 3-(2-hyd-roksy)-etoksykarbonyl -, 3-(2,3-dihydroksy)propoksykarbonyl, 3-benzyloksykarbonyl-, 3-cyano-, 3-formyl-, 3-hydroksymetyl-, 3-metyl-, 3-etyl, 3-propyl-, 3-klorformyl-, 3-fluorformyl-, 3-azidoformyl-, 3-acetyl-, 3-metoksymetylT, 3-etoksymetyl-, 3-propyloksymetyl-, 3-butyloksymetyl-, 3-benzyloksymetyl- ; 3-acetoksymetyl-, 3-propionyloksymetyl-, 3-heksadecanoyloksy-metyl-, 3-aminometyl-, 3-benzoyloksymetyl-, 3-(3,4-dimetoksy)- benzoyloksymetyl-, 3-metylaminometyl-, 3-etylaminometyl-, 3-butylaminometyl-, 3-propylaminometyl-, 3-acetyl-, 3-benzoyl-aminometyl-, 3-(4-metoksy)benzoylaminometyl-, 3-acetylamino-metyl-, 3-propionylaminometyl-, 3-palmitoylaminometyl-, 3-N-imi-dazolyl)-karbonyl-, 3-(N-triazolyl)-karbonyl-. ;Forbindelsene som fremstilles ifølge oppfinnelsen kan fremstilles på forskjellig i og for seg kjente måter. For eksempel kan man omsette en karbonylforbindelse med formel (II) ; hvori A, R<1>, R<2>, R<3>,R<4>, r<5>og R<6>har de ovenfor angitte betyd-ninger med en fosforforbindelse med formel (III) ; 17 18 ;hvori R betyr en C^^-alkylgruppe og R en C1_7-alkylgruppe, en karbo-C1_g-alkoksygruppe, eller en C-L_4-alkoksymetyl-C1_4-alkoksymetylgruppe ifølge den såkalte Wittig-Horner-reaksjonen. Man arbeider hensiktsmessig i et løsningsmiddel i nærvær av de vanlige basiske forbindelser for Wittig-Horner-reaksjoner. ;Omsetningen ifølge Wittig-Horner forløper ved en temperatur opptil 100°C, hensiktsmessig ved 20-50°C. Omsetningen kan utføres ved atmosfærisk trykk eller i lukket apparatur under høyere trykk, eventuelt under oppvarming til det angitte temperaturområdet. ;Man kan utføre denne omsetning i nærvær av et fortynnings-eller løsningsmiddel, f.eks. en av de lavere mettede dialkyl-etere, dialkylglykoletere eller cykliske etere, såsom dietyleter, etyl-tert.-butyleter, 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et aromatisk hydrokarbon, såsom benzen eller et alkyl-benzen, såsom toluen eller xylen, eller et mettet alifatisk hydrokarbon, såsom heksan, heptan eller isooktan, et lavere alifatisk keton, såsom aceton, metyletylketon eller metyliso butylketon, et dialkylformamid, såsom dimetyl eller dietylformamid, eller i blandinger av de nevnte løsningsmidler. Fortrinnsvis anvender man cykliske etere såsom dioksan eller tetrahydrofuran og spesielt dimetylformamid eller blandinger derav, hvor en omsetning generelt forløper ved en temperatur opptil 30°C. ;Omsetningene foretas i nærvær av et deprotoneringsmiddel for fosfatet (III). Egnet er alkalimetallhydrider og alkali-metallamider, spesielt av natrium og kalium, natrium- og kalium-saltene av dimetylsulfoksyd, alkyllitiumforbindelser såsom n-butyllitium eller alkalimetallalkoholater, fortrinnsvis natrium-metanolat og natriumetanolat. ;Isoxazolsyreestrene med formel (I), i hvilke R 7 betyr en karbo-C^_Q-alkoksy-gruppe, overføres hvis dette er ønsket i de frie karboksylsyrer ved esterforsåpning. Omvendt kan den frie syren på kjent måte forestres. ;Hydrolysen forløper på vanlig måte ved generelt opptil 120°C og utføres fortrinnsvis ved romtemperatur. ;Den kan utføres ved atmosfæretrykk eller i lukket apparatur under høyere trykk. ;Hensiktsmessig utføres forsåpningen, henholdsvis forestringen i nærvær av et fortynnings- eller løsningsmiddel, f.eks. en dialkylglykoleter eller cyklisk eter, såsom 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et lavere alifatisk keton, såsom aceton, metyletylketon eller metylisobutylketon, forestringen spesielt i den påtenkte lavere alifatiske alkohol såsom metanol, etanol, propanol eller isopropanol, eventuelt i nærvær av vann, henholdsvis i blandinger av de nevnte løsningsmidler med vann. ;Foretrukne løsningsmidler er vandige blandinger av etanol og metanol, hvorunder omsetningen utføres ved reaksjonsblandingens kokepunkt. ;Forsåpningen foretas fortrinnsvis i nærvær av alkali, såsom alkalimetallhydroksyder, alkalimetallkarbonater og hydrogenkarbonater, spesielt av natrium og kalium, organiske tertiere baser, såsom pyridin eller lavere trialkylaminer, såsom trimetyl- eller trietylamin i nærvær av vann. Derunder kan den anvendte base anvendes i forhold til esteren i støkiometrisk mengde eller i et lite overskudd. Fortrinnsvis anvendes natrium- eller kaliumhydroksyd. ;Forestringen skjer med fordel under innledning av saltsyre-gass i den alkoholiske reaksjonsblanding. Metylesteren kan også fremstilles ved innvirkning av diazometan på den fri syre. ;Karboksylsyrer med den generelle formel (I), i hvilke da;R 7 står for COOH, kan man overføre i reaktive syrederivater med formel (IV) ; ; hvori;A, R1, R2, R3, R4, R5, R6 og n har de ovenfor angitte betyd-ninger og X betyr en vanlig, reaktiv rest av et blandet syre-anhydrid eller et halogen. Disse omsettes hensiktsmessig med et løsningsmiddel og eventuelt i nærvær av et syrebindende ;middel med amider ; ; eller alkoholer HOR<xx>til amider og ;estere. Betegnelsen X i formelen (IV) betyr et halogenatom, spesielt klor eller også brom, eller f.eks. N-hydroksysuccinimid-resten. Disse omsetninger av IV forløper ved en temperatur på opptil 50°C ved atmosfæretrykk eller i lukket apparatur under høyere trykk. ;Man kan utføre disse omsetninger i nærvær av et fortynnings-eller løsningsmiddel, f.eks. en lavere mettet dialkyleter, dialkylglykoletere eller cykliske etere, såsom dietyleter, etyl-tert.-butyleter, 1,2-dimetoksyetan, tetrahydrofuran eller dioksan, et aromatisk hydrokarbon, såsom benzen eller en alkylben-zen, såsom toluen eller xylen, eller et mettet alifatisk hydrokarbon, såsom héksan, heptan eller isooktan, et lavere alifatisk keton, såsom aceton, metyletylketon eller metylisobutylketon, ;et dialkylformamid, såsom dimetyl- eller dietylformamid, eller i blandinger av de nevnte løsningsmidler. Fortrinnsvis anvender man lineære eller cykliske etere såsom dietyleter eller tetra-hydrof uran samt spesielt dimetylformamid, hvorunder omsetningen generelt forløper ved en temperatur opptil 30°C. ;Normalt foretas omsetningen i nærvær av en base som syrebindende middel. Egnede baser er alkalimetallkarbonater, hyd rogenkarbonater, spesielt av natrium og kalium, organiske tertiære baser såsom pyridin eller lavere trialkylaminer, såsom trimetyl- eller trietylamin. Derunder anvendes basen i forhold til anvendt isoxazolsyrehalogenid i støkiometrisk mengde eller i lite overskudd. ;En annen mulighet for fremstilling av forbindelsene går ut fra de tilsvarende syrer med formel IV, hvorunder X i dette tilfellet står for OH, og man foretar omsetningen i nærvær av et aktiverende, vannavspaltende middel for karboksylgruppen i ;et løsningsmiddel med aminer ; ; Som vannavspaltende aktiverende reagenser kan de vanlige reagenser ved peptidsyntesen anvendes, slik som de som f.eks. er beskrevet av Schroder og Lubke i "The Peptides", band I, Academic Press, N.Y., 1965, s. 77 til 128. Det generelle prin-sipp ved omsetningen består i aktiveringen av karbonylgruppen, f.eks. ved behandling av et karbodiimid, såsom N,N'-dicyklo-heksylkarbodiimid, eller ved forbigående dannelser av syre-azidet, et blandet anhydrid (f.eks. med kullsyremonoestere), eller en aktivert ester (f.eks. p-nitrofenylesteren) eller et heterocyklisk amid (f.eks. et imidazolid) av den tilsvarende karboksylsyre (IV). ;Behandlingen av en forbindelse med aktivert karboksylgruppe ;med aminer ; fører da til de ønskede forbindelser. Akti-verings- og sammenknytningsreaksjonene kan utføres i løsnings-midler, fortrinnsvis i N,N-dimetylformamid, tetrahydrofuran, dioksan, metylenklorid, nitrometan, acetonitril, dimetylsulfoksyd, N,N-dimetylacetamid og heksametylfosforsyretriamid. En egnet temperatur for begge trinn, dvs. reaksjonen av syre med koblingsmidlet og reaksjonen av det aktiverte mellomprodukt med aminene ; ligger f.eks. mellom 20 og 100°C. Man kan ;derunder enten gå frem trinnvis, idet man isolerer det aktiverte mellomproduktet før tilsetningen av aminet, og med fordel idet man bringer reaksjonspartnerne i rekkefølge uten isolering av ;mellomtrinn til omsetning. Ved en foretrukket sammenknyttings-metode anvender man N,N-karbonyldiimidazol og arbeider i dimetylformamid, hvorunder reaksjonstemperaturen for begge trinn ligger på 20 til 60°C. ;For fremstilling av de tilstrebede amider, i hvilke R<x>~<*>betyr hydrogen, er den direkte aminolyse av estere (med resten -OR<14>), med primære aminerH2N-R<15>ved romtemperatur uten løs-ningsmiddel, eller eventuelt i nærvær av et organisk løsnings-middel, såsom alkoholer, etere, dialkylformamider eller blandinger av disse løsningsmidler foretrukket. or R"*"^ and R together with the nitrogen atom to which they are bound, in the sense of an aryl or tetrazolyl group, as well as possibly their physiological salts are good medicinal active substances. Of the compounds of formula I, those having the E configuration, and in which R 1 and R 2 mean methyl groups and A is a methylene or ethylene residue substituted with a methyl group, are preferred. As halogen atoms for R<x>(^, fluorine and chlorine are preferred. Substituted benzoyl groups have as substituents preferably halogen atoms - especially fluorine and chlorine - and/or methyl, methoxy or nitro groups. As aryl groups, phenyl groups are preferred, which may be substituted with a methyl, methoxy or nitro group; as an aralkyl group, the benzyl group is preferred, which in the aryl part can be substituted with a methyl or methoxy group or with halogen. As heterocyclic residues, the pyrrolidino, piperidino or morpholine residue is preferably considered. ;Typical examples of compounds produced according to the invention are the following isoxazole compounds, which in the 3-position of the isoxazole ring are also substituted with the residues listed further below. ;5-t2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H )-indenyl)-1-propenyl") isoxazole; 5-12-(1,1,2,3,3,-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl}isoxazole; 5-C2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-1--propenyl isoxazole;5-[2-(3, 8,8-Trimethyl-5,6,7,8-tetrahydronaphth-2-yl)-1-propenyl]isoxazole ;5-[ 2-(3-Methoxy-5,5,8,8-tetramethyl-5 ,6,7,8-tetrahydronaphth--2-yl)-1-propenylisoxazole ;5-f2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl) -1--propenyl isoxazole;5-(2-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2--yl)-1-propenyl isoxazole;5- C2-(3-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1-propenyl}isoxazole 5-[2-(3-butyl-5, 5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-1-propenylisoxazole;5-C2-(3-(1-Methylethyl)-5,5,8,8-tetramethyl- 5,6,7,8-tetra-hydronaphth-2-yl)-1-propenyl}isoxazole;5-12-(3-Butyl-5,5,8,8-tetramethyl-5,6,7,8 -tetrahydronaphth--2-yl)1-propenyl]isoxazole;5-12-(3-a-Methylethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetra-hydronaphth-2 -yl)-1-propenyl isoxazole;5-^2-(3-(2-Methylpropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetra-hydronaphth-2-yl) -1-propenyl3 isoxazole ;5-[2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1--propenyl}isoxazole ;5-[2- (6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl} soxazole ;5~r 2-(6-Propyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl )-1-propenyl} isoxazole ;5-C 2-( 6-Butyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl}isoxazole ;5-{2-(6-(1-Methylethyl)-1 ,1,3,3-tetramethyl-2,3-dihydro-5(1H)--indenyl)-1-propenyl}isoxazole ;5-t 2-(6-(2-Methylpropyl)-1,1,3, 3-tetramethyl-2,3-dihydro--5(1H)-indenyl)-1-propenylisoxazole;5-£2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5 (1H)-indenyl)--1-propenyl}isoxazole;5-f2-(6-Ethyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl) -1-propenyl isoxazole;5-L2-(6-Propyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl1 isoxazole;5-^2 -(6-Butyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl]isoxazole;5-t2-(6-(1- Methylethyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-inden<y>l)-1-pro<p>en<y>lJ isoxazole ;5-T2 -(6-(2-Methylpropyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-1-propenyl]isoxazole;5-[ 2-(3 -Fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1-propenyl]isoxazole;5-£2-(3-Fluoro-5,5,8 ,8-tet ramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1-ethyenyl]isoxazole;5-[2-(3-Fluoro-5,5,8,8-tetramethyl-5,6,7, 8-tetrahydronaphth--2-yl)-1-butenyl]isoxazole ;5-[2-(3-Fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl ) -2-cyclopropyl-1-ethenyl]]isoxazole;5- 12-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1- -ethenyl]isoxazole ;5-f2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1--ethenyl] isoxazole ;5-[2-(5,5,8 ,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-1--ethenyl] isoxazole ;5-t2-(3,8,8-Trimethyl-5,6,7,8-tetrahydronaphth- 2-yl)-1-ethenyl]-isoxazole;5-C 2-(3-Methoxy-5,6,7,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1- ethenyl]isoxazole ;5- 12-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)-1--ethenyl]isoxazole ;5-[2-(3 -Ethy1-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2--yl)-1-ethenyl)isoxazole;5-[2-(3-Propyl-5,5,8 ,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1-ethenyl]isoxazole ;5-L2-(3-Butyl-5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphth--2-yl)-1-ethenyl]isoxazole;5-C2-(3-(1-Methylpropyl)-5,5,8,8-tetramethyl-5,6,7,8-te tra-hydronaphth-2-yl)-1-ethenyl]isoxazole;5-[2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1- -ethenyl]isoxazole ;5-C2-(6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--1-ethenyl]isoxazole ;5-[2- (6-Propyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl).-1-ethenyl] isoxazole; 5-C2-(6-Butyl-1,1 ,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--1-ethenyl] isoxazole 5-[ 2-(6-(1-Methylethyl)-1,1,3,3-tetramethyl -2,3-dihydro-5(1H)--indenyl)-1-ethenyl] isoxazole ;5-[2-(6-(2-Methylpropyl)-1,1,3,3-tetramethyl-2,3- dihydro--5(1H)-indenyl)-1-ethenyl]isoxazole ;5-[2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl) -1--ethenyl]isoxazole;5-C 2-(6-Ethyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-ethenyl] isoxazole ;5-[2-(6-Propyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)--indenyl)-1-ethenyl]isoxazole ;5-[2- (6-Butyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-ethenyl]isoxazole;5-[2-(6-(1- Methylethyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-1-ethenyl]isoxazole ;5-[2-(6-(2-Methylpropyl)- 1,1,2,3,3-pentamethyl- 2,3-dihydro--5(1H)-indenyl-1-ethenyl]isoxazole;5-(2-(1,1,3,3,-Tetramethyl-2,3-dihydro-5(1H)-idenyl) -1--butenyl]isoxazole ;5-[2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-idenyl)-1--butenyl]isoxazole ;5-[ 2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-1--butenyl]isoxazole;5-t2-(3,8,8-Trimethyl-5, 6,7,8-tetrahydronaphth-2-yl)-1-butenyl]isoxazole;5-f2-(3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro- naphth-2-yl)-1-butenyl]isoxazole;5-(2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)--1- butenyl]isoxazole ;5-C2-(3-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1-butenyl]isoxazole ;5-£2- (3-Butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-1-butenyl]isoxazole;5-[2-(3-(1-Methylethyl) -5,5,8,8-tetramethyl-5,6,7,8-tetra-hydronaphth-2-yl)-1-butenyl1 isoxazole;5-C2-(3-(2-Methylpropyl)-5,5 ,8,8-tetramethyl-5,6,7,8-tetra-hydronaphth-2-yl)-1-butenyl]isoxazole ;5-[2-(1,1,3,3,6-Pentamethyl-2 ,3-dihydro-5(1H)-indenyl)-1--butenyl]isoxazole ;5-[2-(6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H) -indenyl)--1-bu thenyl]isoxazole ;5-L 2-(6-Propyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl )-1-butenyl]isoxazole ;5-£2 -(6-Butyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)-1-butenyl]isoxazole;5-[2-(6-1-Methylethyl) -1,1,3,3-tetramethyl-2,3-dihydro-5(1H)--indenyl)-1-butenyl]isoxazole;5-C2-(6-(2-Methylpropyl)-1,1,3 ,3-tetramethyl-2,3-dihydro--5(1H)-indenyl)-1-butenyl isoxazole ;5-[2-(6-(2-Methylpropyl)-1,1,2,3,3-pentamethyl -2,3-dihydro--5(1H)-indenyl)-1-butenyl]isoxazole;5-C2-(6-(1-Methylethyl)-1,1,2,3,3-pentamethyl-2,3 -dihydro- -5(1H)-indenyl)-1-butenyl]isoxazole ;5-[2-(6-Butyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H) -indenyl)-1-butenyl}isoxazole;5-[2-(6-Propyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1- butenyl]isoxazole;5-[2-(6-Ethyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-butenyl]isoxazole;5- £2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl)-1--propenyl]isoxazole;5-[2-(1,1,3 ,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-2-cyclopropyl)-1-ethenyl]isoxazole ;5-C2-(1,1,2,3,3-Pentamethyl-2 ,3-dihyd rho-5(1H)-indenyl)-2-(cyclopropyl)-1-ethenyl]isoxazole;5- 12-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2- yl)-2-(cyclopropyl)-1-ethenyl]isoxazole;5-[2-(3,8,8-Trimethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-(cyclo- propyl) -1-ethenyl] isoxazole ;5-[2-(3-Methoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-2-(cyclopropyl) -1-ethenyl]isoxazole;5-[2-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-(cyclopropyl)-1-ethenyl ] isoxazole ;5- [2-(3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2--yl)-2-(cyclopropyl)-1-ethylIsoxazole ;5 -[2-(3-Propyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-2-(cyclopropyl)-1-ethenyl]isoxazole; 5-[ 2-(3-Butyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-2-(cyclopropyl)-1-ethenyl]isoxazole;5-[2 -(3-(1-Methylethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-(cyclopropyl)-1-ethenyl]isoxazole; 5-[2-(3-(2-Methylpropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-2-(cyclopropyl)-1- ethenylisoxazole;5-[2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-2--(cy chloropropyl)-1-ethenyl] isoxazole ;5-L2-(6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--2-(cyclopropyl)-1 -ethenyl}isoxazole;5- 12-(6-Propyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-idenyl)--2-(cyclopropyl)-1-ethenyl]isoxazole ;5-[2-(6-Butyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--2-(cyclopropyl)-1-ethenyl isoxazole ;5-[ 2-(6-(1-Methylethyl)-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)--indenyl)-2-(cyclopropyl)-1-ethenyl]isoxazole 5-[ 2-(6-(2-Methylpropyl)-1,1,3,3-tetramethyl-2,3-dihydro--5(1H)-indenyl)-2-(cyclopropyl)-1-ethenyl]isoxazole 5-[ 2-(6-(2-Methylpropyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-2-(cyclopropyl)-1-ethenyl]isoxazole 5 -£ 2-(6-(1-Methylethyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-2-(cyclopropyl)-1-ethenyl] isoxazole 5-[2-(6-Butyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-(cyclopropyl)-1-ethenyl]isoxazole ;5-f 2-(6-Propyl-1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-2-(cyclopropyl)-1-ethenyl]isoxazole ;5-[2-(6-Ethyl-1,1,2,3,3,3-pentamethyl-2,3-dihydro-5(1H)-inde- nyl)-2-(cyclopropyl)-1-ethenyl]isoxazole;5-[2-(1,1,2,3,3,6-Hexamethyl-2,3-dihydro-5(1H)-indenyl)-2 --(cyclopropyl)-1-ethenyl]isoxazole ;5-£2-(1,1,3,3-Tetramethyl-2,3-dihydro-5(1H)-indenyl)-3--methyl-butene-1 -yl]isoxazole; 5-[2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-3-methyl-buten-1-yl]isoxazole; 5-[2-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-3--methyl-buten-l-yl]isoxazole;5-t2-(3 ,8,8-Trimethyl-5,6,7,8-tetrahydronaphth-2-yl)-3-methyl--buten-1-yl isoxazole; 8-tetramethyl-5,6,7,8-tetrahydronaphth--2-yl)-3-methyl-buten-1-yl]isoxazole;5-[2-(3-Fluoro-5,5,8,8- tetramethyl-5,6,7,8-tetrahydronaphth-2--yl)-3-methyl-buten-1-yl]isoxazole;5-£2-(3,5,5,8,8-Pentamethyl-5, 6,7,8-tetrahydronaphth-2-yl)-3-methyl-buten-1-yl]isoxazole;5-[2-(3-Ethyl-5,5,8,8-tetramethyl-5,6, 7,8-tetrahydronaphth-2-yl)-3-methyl-buten-1-yl)isoxazole;5-£,2-(3-Propyl-5,5,8,8-tetramethyl-5,6,7, 8-tetrahydronaphth-2-yl)-3-methyl-buten-1-yl]isoxazole;5-£2-(3-Butyl-5,5,8,8-tetramethyl-5,6,7,8 -tetrahydronaphth-2-yl)-3-methyl-bu then-1-yl]isoxazole;5-£2-(3-(1-Methylethyl)-5,5,8,8-tetramethyl-5,6,7,8-tetra-hydronaphth-2-yl) - 3-methyl-buten-1-yl] isoxazole 5-t2-(3-(2-Methylpropyl)-5,5,8,8-tetramethyl-5,6,7,8-tetra-;hydronaphth-2-yl) -3-methyl-buten-1-yl]isoxazole;5-[2-(1,1,3,3,6-Pentamethyl-2,3-dihydro-5(1H)-indenyl-3-methyl-butene- 1-yl]isoxazole;5-C2-(6-Ethyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--3-methyl-buten-1-yl] isoxazole; 5-[2-(6-Propyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)-3-methyl-buten-1-yl]isoxazole; 5-[2-(6-Butyl-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)-indenyl)--3-methyl-buten-1-yl]isoxazole;5-£ 2-(6-(1-Methylethyl)-1,1,3,3-tetramethyl-2,3-dihydro-5(1H)--indenyl)-3-methyl-buten-1-yl]isoxazole;5- [2-(6-(2-Methylpropyl)-1,1,3,3-tetramethyl-2,3-dihydro--5(1H)-indenyl)-3-methyl-buten-1-yl]isoxazole ;5 -[2-(6-(2-Methylpropyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-3-methyl-buten-1-yl] isoxazole;5-[2-(6-(1-Methylethyl)-1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-3-methyl-butene-1 -yl]isoxazole;5-[2-(6-Butyl-1,1,2 ,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-3-methyl-buten-1-yl]isoxazole;5-£2-(6-Propyl-1,1,2 ,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-3-methyl-buten-1-yl]isoxazole;5-£2-(6-Ethyl-1,1,2,3 ,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-3-methyl-buten-1-yl]isoxazole;5-[2-(1,1,2,3,3,6 -Hexamethyl-2,3-dihydro-5(1H)-indenyl)-3--methyl-buten-1-yl]isoxazole;5-£2-(5,5,8,8-Tetramethyl-1-methoxy- 4-methyl-5,6,7,8-tetra-hydro-naphth-2-yl)-1-ethenyl]isoxazole ; These compounds are substituted in the 3-position of the isoxazole ring with the following typical residues: 3-Carboxy-, 3 -methoxycarbonyl, 3-ethoxycarbonyl-, 3-propyloxycarbonyl-, 3-(1-methyl)ethoxycarbonyl-, 3-butoxycarbonyl-, 3-octyloxycarbonyl-, 3-(2-methoxy)ethoxycarbonyl-, 3-(2- hydroxy)-ethoxycarbonyl -, 3-(2,3-dihydroxy)propoxycarbonyl, 3-benzyloxycarbonyl-, 3-cyano-, 3-formyl-, 3-hydroxymethyl-, 3-methyl-, 3-ethyl, 3- propyl-, 3-chloroformyl-, 3-fluoroformyl-, 3-azidoformyl-, 3-acetyl-, 3-methoxymethylT, 3-ethoxymethyl-, 3-propyloxymethyl-, 3-butyloxymethyl-, 3-benzyloxymethyl- ; 3-acetoxymethyl-, 3-propionyloxymethyl-, 3-hexadecanoyloxymethyl-, 3-aminomethyl-, 3-benzoyloxymethyl-, 3-(3,4-dimethoxy)-benzoyloxymethyl-, 3-methylaminomethyl-, 3-ethylaminomethyl-, 3-butylaminomethyl-, 3-propylaminomethyl-, 3-acetyl-, 3-benzoyl-aminomethyl-, 3-(4-methoxy)benzoylaminomethyl-, 3-acetylamino-methyl-, 3-propionylaminomethyl-, 3-palmitoylaminomethyl-, 3 -N-imidazolyl)-carbonyl-, 3-(N-triazolyl)-carbonyl-. The compounds produced according to the invention can be produced in various ways known per se. For example, a carbonyl compound of formula (II) can be reacted; in which A, R<1>, R<2>, R<3>, R<4>, r<5> and R<6> have the meanings indicated above with a phosphorus compound of formula (III); 17 18 ; in which R means a C 1-4 -alkyl group and R a C 1-7 -alkyl group, a carbo-C 1-6 -alkyl group, or a C-L-4-alkoxymethyl-C 1-4-alkyloxymethyl group according to the so-called Wittig-Horner reaction. One conveniently works in a solvent in the presence of the usual basic compounds for Wittig-Horner reactions. The reaction according to Wittig-Horner takes place at a temperature of up to 100°C, suitably at 20-50°C. The reaction can be carried out at atmospheric pressure or in closed apparatus under higher pressure, possibly during heating to the indicated temperature range. This reaction can be carried out in the presence of a diluent or solvent, e.g. one of the lower saturated dialkyl ethers, dialkyl glycol ethers or cyclic ethers, such as diethyl ether, ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene or an alkyl benzene such as toluene or xylene , or a saturated aliphatic hydrocarbon, such as hexane, heptane or isooctane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide, such as dimethyl or diethylformamide, or in mixtures of the aforementioned solvents. Preferably, cyclic ethers such as dioxane or tetrahydrofuran and especially dimethylformamide or mixtures thereof are used, where a reaction generally proceeds at a temperature of up to 30°C. The reactions are carried out in the presence of a deprotonating agent for the phosphate (III). Suitable are alkali metal hydrides and alkali metal amides, especially of sodium and potassium, the sodium and potassium salts of dimethylsulfoxide, alkyllithium compounds such as n-butyllithium or alkali metal alcoholates, preferably sodium methanolate and sodium ethanolate. The isoxazole acid esters of formula (I), in which R 7 means a carbo-C 1 -C 6 -alkyl group, are transferred, if desired, into the free carboxylic acids by ester saponification. Conversely, the free acid can be esterified in a known manner. ;The hydrolysis normally takes place at generally up to 120°C and is preferably carried out at room temperature. ;It can be carried out at atmospheric pressure or in closed apparatus under higher pressure. ;Appropriately, the saponification or esterification is carried out in the presence of a diluent or solvent, e.g. a dialkyl glycol ether or cyclic ether, such as 1,2-dimethoxyethane, tetrahydrofuran or dioxane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, the esterification especially in the contemplated lower aliphatic alcohol such as methanol, ethanol, propanol or isopropanol, optionally in the presence of water, respectively in mixtures of the aforementioned solvents with water. Preferred solvents are aqueous mixtures of ethanol and methanol, during which the reaction is carried out at the boiling point of the reaction mixture. The saponification is preferably carried out in the presence of alkali, such as alkali metal hydroxides, alkali metal carbonates and hydrogen carbonates, especially of sodium and potassium, organic tertiary bases, such as pyridine or lower trialkylamines, such as trimethyl or triethylamine in the presence of water. Below that, the base used can be used in relation to the ester in a stoichiometric amount or in a small excess. Sodium or potassium hydroxide is preferably used. The esterification takes place advantageously with the introduction of hydrochloric acid gas into the alcoholic reaction mixture. The methyl ester can also be prepared by the action of diazomethane on the free acid. Carboxylic acids of the general formula (I), in which R 7 stands for COOH, can be converted into reactive acid derivatives of formula (IV); ; wherein; A, R1, R2, R3, R4, R5, R6 and n have the above meanings and X means a common, reactive residue of a mixed acid anhydride or a halogen. These are suitably reacted with a solvent and possibly in the presence of an acid-binding agent with amides; ; or alcohols HOR<xx>to amides and ;esters. The designation X in formula (IV) means a halogen atom, especially chlorine or also bromine, or e.g. the N-hydroxysuccinimide residue. These reactions of IV take place at a temperature of up to 50°C at atmospheric pressure or in closed apparatus under higher pressure. These reactions can be carried out in the presence of a diluent or solvent, e.g. a lower saturated dialkyl ether, dialkyl glycol ethers or cyclic ethers, such as diethyl ether, ethyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane, an aromatic hydrocarbon such as benzene or an alkylbenzene such as toluene or xylene, or a saturated aliphatic hydrocarbon, such as hexane, heptane or isooctane, a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone, a dialkylformamide, such as dimethyl or diethylformamide, or in mixtures of the aforementioned solvents. Linear or cyclic ethers such as diethyl ether or tetrahydrofuran and especially dimethylformamide are preferably used, during which the reaction generally proceeds at a temperature of up to 30°C. Normally, the reaction is carried out in the presence of a base as an acid-binding agent. Suitable bases are alkali metal carbonates, hydrogen carbonates, especially of sodium and potassium, organic tertiary bases such as pyridine or lower trialkylamines such as trimethyl or triethylamine. In this case, the base is used in relation to the isoxazole acid halide used in a stoichiometric amount or in a small excess. Another possibility for the preparation of the compounds starts from the corresponding acids of formula IV, where X in this case stands for OH, and the reaction is carried out in the presence of an activating, water-splitting agent for the carboxyl group in a solvent with amines; ; As water-splitting activating reagents, the usual reagents for peptide synthesis can be used, such as those which e.g. is described by Schroder and Lubke in "The Peptides", volume I, Academic Press, N.Y., 1965, pp. 77 to 128. The general principle of the reaction consists in the activation of the carbonyl group, e.g. by treatment with a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by transient formation of the acid azide, a mixed anhydride (e.g. with carbonic acid monoesters), or an activated ester (e.g. the p-nitrophenyl ester) or a heterocyclic amide (eg an imidazolide) of the corresponding carboxylic acid (IV). ;The treatment of a compound with an activated carboxyl group ;with amines ; then leads to the desired compounds. The activation and coupling reactions can be carried out in solvents, preferably in N,N-dimethylformamide, tetrahydrofuran, dioxane, methylene chloride, nitromethane, acetonitrile, dimethylsulfoxide, N,N-dimethylacetamide and hexamethylphosphoric acid triamide. A suitable temperature for both steps, i.e. the reaction of the acid with the coupling agent and the reaction of the activated intermediate with the amines; lies e.g. between 20 and 100°C. You can then either proceed step by step, isolating the activated intermediate before the addition of the amine, and advantageously bringing the reaction partners in sequence without isolating the intermediate for conversion. In a preferred linking method, N,N-carbonyldiimidazole is used and work is done in dimethylformamide, during which the reaction temperature for both steps is 20 to 60°C.; For the production of the desired amides, in which R<x>~<*>means hydrogen, is the direct aminolysis of esters (with the residue -OR<14>), with primary amines H2N-R<15> at room temperature without solvent, or optionally in the presence of an organic solvent, such as alcohols, ethers, dialkylformamides or mixtures of these solvents are preferred.

Et karboksylsyrehalogenid med formel (IV), fortrinnsvis syrekloridet, kan ved omsetning med 2-aminoetanol eller 2-amino--2-metylpropanol-l og etterfølgende cyklisering overføres i et oksazolinderivat med formel (I). A carboxylic acid halide of formula (IV), preferably the acid chloride, can be converted into an oxazoline derivative of formula (I) by reaction with 2-aminoethanol or 2-amino-2-methylpropanol-1 and subsequent cyclization.

En karboksylsyre, en karboksylsyreester eller et karboksyl-syreamid med formel (I) kan på i og for seg kjent måte reduseres til alkoholene, henholdsvis aminene med formel (I). Med fordel utføres reduksjonen ved hjelp av et metallhydrid eller alkali-metallhydrid i nærvær av et egnet løsningsmiddel. Som metallhydrider anvendes fortrinnsvis komplekse metallhydrider såsom litiumaluminiumhydrid eller diisobutylaluminiumhydrid. Som løs-ningsmiddel anvendes ved arbeidet med litiumaluminiumhydrid etere, såsom dietyletere, dioksan eller tetrahydrofuran. Ut-fører man imidlertid reduksjonen med diisobutylaluminiumhydrid eller et alkoksynatriumaluminiumhydrid, foretrekkes anvendelsen av hydrokarboner såsom heksan eller toluen. A carboxylic acid, a carboxylic acid ester or a carboxylic acid amide of formula (I) can be reduced to the alcohols or amines of formula (I) in a manner known per se. Advantageously, the reduction is carried out using a metal hydride or alkali metal hydride in the presence of a suitable solvent. Complex metal hydrides such as lithium aluminum hydride or diisobutylaluminum hydride are preferably used as metal hydrides. When working with lithium aluminum hydride, ethers such as diethyl ether, dioxane or tetrahydrofuran are used as solvents. However, if the reduction is carried out with diisobutylaluminum hydride or an alkoxysodium aluminum hydride, the use of hydrocarbons such as hexane or toluene is preferred.

Et amin eller en alkohol med formel (I) kan på i og forAn amine or an alcohol of formula (I) can on i and for

seg kjent måte med et alkanoylhalogenid eller -anhydrid, et aralkylhalogenid eller -anhydrid eller et aroyl eller hetero-aroylhalogenid eller anhydrid hensiktsmessig i et inert fortynnings- eller løsningsmiddel, f.eks. et lavere alifatisk keton, såsom aceton, metyletylketon eller metylisobutylketon, known manner with an alkanoyl halide or anhydride, an aralkyl halide or anhydride or an aroyl or hetero-aroyl halide or anhydride suitably in an inert diluent or solvent, e.g. a lower aliphatic ketone, such as acetone, methyl ethyl ketone or methyl isobutyl ketone,

et dialkylformamid såsom dimetylformamid eller dietylformamid, eller med overskudd acyleringsmiddel som fortynnings- eller løsningsmiddel, overføres i de tilstrebede amider av estere med formel (I). Hensiktsmessig utføres omsetningen i nærvær av en base som syrebindende middel i et temperaturområde som ligger mellom -20°C og reaksjonsblandingens kokepunkt. Egnede baser er alkalimetallkarbonater, hydrogenkarbonater, hydroksyder a dialkylformamide such as dimethylformamide or diethylformamide, or with excess acylating agent as diluent or solvent, is transferred into the desired amides of esters of formula (I). The reaction is conveniently carried out in the presence of a base as an acid-binding agent in a temperature range between -20°C and the boiling point of the reaction mixture. Suitable bases are alkali metal carbonates, hydrogen carbonates, hydroxides

eller alkoholater, spesielt av natrium og kalium, basiske oksyder, såsom aluminiumoksyd eller kalsiumoksyd, organiske tertiære baser, såsom pyridin, eller lavere trialkylaminer, såsom trimetyl eller trietylamin. Derunder kan basene anvendes i katalytisk mengde eller i støkiometrisk mengde, henholdsvis i lite overskudd i forhold til det anvendte alkyleringsmiddel. or alcoholates, especially of sodium and potassium, basic oxides, such as alumina or calcium oxide, organic tertiary bases, such as pyridine, or lower trialkylamines, such as trimethyl or triethylamine. Below that, the bases can be used in a catalytic amount or in a stoichiometric amount, respectively in a small excess in relation to the alkylating agent used.

En alkohol med formel (I) kan omsettes med alkylhalogenider R<xx->J, R<lx->Br eller Rlx-Cl i nærvær av alkalimetallhydrider, fortrinnsvis natriumhydrid eller i nærvær av alkyllitiumforbindelser, fortrinnsvis n-butyllitium i et organisk løsnings-middel såsom tetrahydrofuran, dioksan, 1,2-dimetoksyetan, metyl-tert.-butyleter eller ved anvendelse av natriumhydrid eller i dimetylformamid i et temperaturområde mellom -10°C og 4 0°C til en eter med formel (I). An alcohol of formula (I) can be reacted with alkyl halides R<xx->J, R<lx->Br or Rlx-Cl in the presence of alkali metal hydrides, preferably sodium hydride or in the presence of alkyllithium compounds, preferably n-butyllithium in an organic solution agent such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methyl tert-butyl ether or by using sodium hydride or in dimethylformamide in a temperature range between -10°C and 40°C to an ether of formula (I).

En alkohol med formel (I) kan med egnede oksydasjonsmidler, fortrinnsvis mangan(IV)-oksyd, eventuelt på et uorganisk bære-materiale såsom kiselgel eller aluminiuoksyd oksyderes til et aldehyd med formel (I). Med fordel arbeider man i et inert organisk løsningsmiddel, f.eks. et hydrokarbon såsom heksan eller i en eter, såsom f.eks. tetrahydrofuran eller i blandinger av de nevnte løsnings- og fortynningsmidler i temperaturområdet mellom -10°C og 30°C. Den nødvendige reaksjonstid er i det vesentlige avhengig av oksydasjonsaktiviteten til det anvendte mangan(IV)-oksyd. An alcohol of formula (I) can be oxidized to an aldehyde of formula (I) with suitable oxidizing agents, preferably manganese (IV) oxide, optionally on an inorganic support material such as silica gel or aluminum oxide. It is advantageous to work in an inert organic solvent, e.g. a hydrocarbon such as hexane or in an ether such as e.g. tetrahydrofuran or in mixtures of the aforementioned solvents and diluents in the temperature range between -10°C and 30°C. The required reaction time is essentially dependent on the oxidation activity of the manganese(IV) oxide used.

Forbindelsen med formel (I) kan ha enhetlig cis- eller trans-struktur eller være blandinger av de to E/Z-isomere. The compound of formula (I) can have a uniform cis or trans structure or be mixtures of the two E/Z isomers.

En isomerblanding kan dessuten ikke utelukkes ved de foran-nevnte omsetninger. Den i slike tilfeller, f.eks. resulterende blanding av forbindelsen med formel (I) kan bestemmes kvantita-13 Furthermore, an isomer mixture cannot be ruled out in the aforementioned reactions. In such cases, e.g. resulting mixture of the compound of formula (I) can be determined quantitatively-13

tivt ved HPLC-analyse eller ved en CNMR-spektral analyse, og den ønskede isomere eventuelt isoleres ved fraksjonert krystal-liser ing eller kromatografi med f.eks. kiselgelsøyler eller preparativ HPL-kromatografi i ren isomerform. tively by HPLC analysis or by a CNMR spectral analysis, and the desired isomer is possibly isolated by fractional crystallization or chromatography with e.g. silica gel columns or preparative HPL chromatography in pure isomeric form.

Noen av forbindelsene fremstilt ifølge foreliggende oppfinnelse har et surt hydrogenatom og kan derfor på vanlig måte overføres i et fysiologisk fordragelig, godt vannløselig salt. Egnede salter er f.eks. ammonium, alkalimetall, spesielt av natrium, kalium og litium, jordalkalimetallsalter, spesielt av kalsium eller magnesium samt salter med egnede organiske baser, såsom med lavere alkylaminer, f.eks. metylamin eller etylamin, med substituerte lavere alkylaminer, spesielt hydroksysubsti-tuert alkylaminer såsom dietanolamin, trietanolamin eller tris--(hydroksymetyl)-aminometan, piperidin eller morfolin. Some of the compounds produced according to the present invention have an acidic hydrogen atom and can therefore be transferred in the usual way in a physiologically tolerable, well water-soluble salt. Suitable salts are e.g. ammonium, alkali metal, especially of sodium, potassium and lithium, alkaline earth metal salts, especially of calcium or magnesium as well as salts with suitable organic bases, such as with lower alkylamines, e.g. methylamine or ethylamine, with substituted lower alkylamines, especially hydroxy-substituted alkylamines such as diethanolamine, triethanolamine or tris-(hydroxymethyl)aminomethane, piperidine or morpholine.

Aminer med formel (I) fremstilt ifølge oppfinnelsen lar seg på i og for seg kjent måte overføre i deres syreaddisjons-salter med fysiologisk fordragelige syrer. Som vanlig fysiologisk fordragelige organiske eller uorganiske syrer kommer f.eks. saltsyre, hydrogenbromid, fosforsyre éller svovelsyre i betraktning, og som organiske syrer, f.eks. oksalsyrer, maleinsyrer, fumarsyrer, melkesyre, vinsyre, eplesyre, sitronsyre, salicyl-syre, adipinsyre eller benzosyre, og kan finnes i Fortschritten der Arzneimittelforschung Band 10, side 224-225, Birkhauser Verlag, Basel og Stuttgart, 1966. Amines of formula (I) prepared according to the invention can be transferred in a manner known per se into their acid addition salts with physiologically tolerable acids. As usual physiologically tolerable organic or inorganic acids come e.g. hydrochloric acid, hydrogen bromide, phosphoric acid or sulfuric acid in consideration, and as organic acids, e.g. oxalic, maleic, fumaric, lactic, tartaric, malic, citric, salicylic, adipic or benzoic acids, and can be found in Fortschritten der Arzneimittelforschung Band 10, pages 224-225, Birkhauser Verlag, Basel and Stuttgart, 1966.

Forbindelsen fremstilt ifølge oppfinnelsen og deres fysiologiske fordragelige salter kan på grunn av deres farmakologiske egenskaper anvendes ved topisk og systemisk terapi og også pro-fylakse av prekanzeroser og karzinomer i huden, slimhinner og indre organer samt ved topiske og systemisk terapi av akne, psoriasis og andre dermatologiske sykdommer som henger sammen med patologisk forandret horndannelse samt for behandling av revmatiske sykdommer, spesielt av slike av betennelses- eller degenerativ type, som angriper ledd, muskler, sener og andre deler av bevegelsesapparatet. Et foretrukket indikasjonsområde er ved siden av terapi av dermatologiske sykdommer den profylak-tiske og terapeutiske behandling av prekanzeroser og tumorer. The compounds produced according to the invention and their physiologically tolerable salts can, due to their pharmacological properties, be used in topical and systemic therapy and also in the prophylaxis of precanceroses and carcinomas of the skin, mucous membranes and internal organs as well as in topical and systemic therapy of acne, psoriasis and other dermatological diseases associated with pathologically altered horn formation as well as for the treatment of rheumatic diseases, especially those of an inflammatory or degenerative type, which attack joints, muscles, tendons and other parts of the musculoskeletal system. A preferred area of indication is, in addition to the therapy of dermatological diseases, the prophylactic and therapeutic treatment of precancers and tumors.

De farmakologiske virkninger kan f.eks. vises i de etter-følgende forsøksmodeller: Forbindelsene fremstilt ifølge foreliggende oppfinnelse opphever på marsvin treakealvev keratini-seringen som følger in vitro av vitamin-A-mangel. Denne kera-tinisering hører til karcinogenesens tidlige fase, som i en lignende teknikk in vivo etter igangsetning ved kjemiske forbindelser inhiberes med energirik stråling eller etter viral celletransformasjon med forbindelsen med formel (I). Denne metodikk er beskrevet i Cancer Res. 36, 964-972 (1976) eller Nature 250, 64-66 (1974) og Nature 253, 47-50 (1975). The pharmacological effects can e.g. is shown in the following experimental models: The compounds produced according to the present invention abolish in guinea pigs the keratinisation of the triac alve tissue which follows in vitro from vitamin A deficiency. This keratinization belongs to the early phase of carcinogenesis, which in a similar technique in vivo after initiation by chemical compounds is inhibited with high-energy radiation or after viral cell transformation with the compound of formula (I). This methodology is described in Cancer Res. 36, 964-972 (1976) or Nature 250, 64-66 (1974) and Nature 253, 47-50 (1975).

Dertil inhiberes formeringshastigheten til bestemte ond-artet forandrede celler av forbindelsen fremstilt ifølge oppfinnelsen. Denne metodikk er å lese i J. Nati. Cancer Inst. In addition, the rate of reproduction of certain malignantly changed cells is inhibited by the compound produced according to the invention. This methodology can be read in J. Nati. Cancer Inst.

60, 1035-1041 (1978),Experimental Cell Research 117, 15-22 60, 1035-1041 (1978), Experimental Cell Research 117, 15-22

(1978) og Proe. Nati.Acad. Sei. USA 77, 2936-2940. (1978) and Proe. Nati.Acad. Pollock. USA 77, 2936-2940.

Den antiartritiske virkningen til forbindelsen fremstilt ifølge oppfinnelsen kan på vanlig måte bestemmes i dyreeksperi-menter i Adjuvans-Arthritis-modellen. Den dermatologiske aktivitet, f.eks. for behandling av akne, kan blant annet påvises med den komedolytiske aktivitet og evnen til å redusere antall cyster i modellen Rhino-mus. The antiarthritic effect of the compound produced according to the invention can be determined in the usual way in animal experiments in the Adjuvant Arthritis model. The dermatological activity, e.g. for the treatment of acne, can be demonstrated, among other things, with the comedolytic activity and the ability to reduce the number of cysts in the Rhino mouse model.

Denne metode er beskrevet av L.H. Kligman et al i The Journal of Investigative Dermatology 73, 354-358 (1979) og av J.A. Mezick et al. i "Models of Dermatology" (Ed. Maibach, Lowe), Vol. 2, s. 59-63, Karger, Basel 1985). This method is described by L.H. Kligman et al in The Journal of Investigative Dermatology 73, 354-358 (1979) and by J.A. Mezick et al. in "Models of Dermatology" (Ed. Maibach, Lowe), Vol. 2, pp. 59-63, Karger, Basel 1985).

Forsøkssubstansen ble påført hele ryggpartiet til Rhino-mus i en egnet bærer (100 ill) en gang daglig i fem på hverandre følgende dager pr. uker. Omtrent 72 timer etter den siste behandling ble rygghuden fjernet og plassert 18 timer ved 4-6°C The test substance was applied to the entire back of Rhino mice in a suitable carrier (100 μl) once a day for five consecutive days per weeks. Approximately 72 hours after the last treatment, the dorsal skin was removed and placed for 18 hours at 4-6°C

i 0,5% eddiksyre. Deretter ble en ca. 2 x 5 cm 2 stor flate skåret ut, epidermis skrellet av, lagt på et objektglass (med den dermale side oppad)og spylt vannfri ved hjelp av alkohol/- xelen inntil epidermis syntes gjennomsiktig. Prøven ble fiksert ved overdekning med Permount og vurdert mikroskopisk. Diamete-ren av 10 utriculi ble målt i 5 fritt valgte felt og derav behandlet man ved sammenligning med den ubehandlede kontrollgruppe den gjennomsnittlige reduksjon av utriculustverrsnittet. Den følgende tabell viser de oppnådde resultater. in 0.5% acetic acid. Subsequently, an approx. A 2 x 5 cm 2 large area was cut out, the epidermis peeled off, placed on a slide (with the dermal side up) and rinsed without water using alcohol/xel until the epidermis appeared transparent. The sample was fixed by coverslipping with Permount and assessed microscopically. The diameter of 10 utricles was measured in 5 freely chosen fields and from this the average reduction of the utricle cross-section was treated by comparison with the untreated control group. The following table shows the results obtained.

Følgelig inneholder et terapeutisk middel for topisk og systemisk anvendelse en forbindelse med formel (I) samt vanlige bærestoffer eller fortynningsmidler. Fremstillingen av det terapeutiske midlet eller preparat skjer med de . vanlige flytende eller faste bærestoffer eller fortynningsmidler og de på vanlig måte anvendte farmasøytisk tekniske hjelpestoffer avhengig av denønskede applikasjonsmåte og med en dosering som er egnet for anvendelsen på vanlig måte, f.eks. ved blanding av virkestoffet med de vanlige faste eller flytende bære- og hjelpestoffer i slike preparater. Accordingly, a therapeutic agent for topical and systemic use contains a compound of formula (I) as well as common carriers or diluents. The production of the therapeutic agent or preparation takes place with the . usual liquid or solid carriers or diluents and the commonly used pharmaceutical technical aids depending on the desired method of application and with a dosage that is suitable for the use in the usual way, e.g. by mixing the active substance with the usual solid or liquid carriers and auxiliary substances in such preparations.

Midlene kan tilsvarende gis oralt, parenteralt eller topisk. Slike preparater er f.eks. tabletter, filmtabletter, drageer, kapsler, piller, pulvere, løsninger eller suspensjoner, infu-sjons- eller injeksjonsløsninger samt pastaer, salter, geler, kremer, lotioner, puddere, løsninger eller emulsjoner og sprays. The agents can correspondingly be given orally, parenterally or topically. Such preparations are e.g. tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions, infusion or injection solutions as well as pastes, salts, gels, creams, lotions, powders, solutions or emulsions and sprays.

De terapeutiske midler kan inneholde forbindelsen som skal anvendes ved lokal anvendelse i 0,001 til 1%-ig konsentrasjon, fortrinnsvis i 0,001 til 0,l%ig konsentrasjon, og ved systemisk anvendelse fortrinnsvis i en enkelt dose på 0,1 til 50 mg, og kan gis daglig i en eller flere doser avhengig av sykdommens art og styrke. The therapeutic agents may contain the compound to be used for local application in 0.001 to 1% concentration, preferably in 0.001 to 0.1% concentration, and for systemic application preferably in a single dose of 0.1 to 50 mg, and can be given daily in one or more doses depending on the nature and strength of the disease.

Vanlig anvendte farmasøytiske tekniske hjelpestoffer er f.eks. for lokal anvendelse alkoholer, såsom isopropanol, oksetylert ricinusolje, oksetylert hydrogenert ricinusolje, poly-akrylsyre, glycerolmonostearat, paraffinolje, vaseliner, ull-fett, polyetylenglykol 400, polyetylenglykol 400-stearat samt etoksylert fettalkohol, for systemiske anvendelser melkesukker, propylenglykol og etanol, stivelse, talkum, polyvinylpyrrolidon. Preparatene kan eventuelt tilsettes et antioksydasjonsmiddel, f.eks. tokoferol samt butylert hydroksyanisol eller butylert hydroksytoluen eller smaksforbedrende tilsetninger, stabilise-ringsmidler, emulgeringsmidler, glidemidler osv. Forutsetningen er at alle stoffer som anvendes ved fremstillingen av det farma-søytiske preparatet er toksikologisk ubetenkelige og fordragelige sammen med de anvendte virkestoffer. Commonly used pharmaceutical technical aids are e.g. for local use alcohols, such as isopropanol, oxytylated castor oil, oxytylated hydrogenated castor oil, polyacrylic acid, glycerol monostearate, paraffin oil, petroleum jelly, wool grease, polyethylene glycol 400, polyethylene glycol 400 stearate and ethoxylated fatty alcohol, for systemic applications milk sugar, propylene glycol and ethanol, starch , talc, polyvinylpyrrolidone. The preparations can optionally have an antioxidant added, e.g. tocopherol as well as butylated hydroxyanisole or butylated hydroxytoluene or taste-improving additives, stabilizers, emulsifiers, lubricants, etc. The prerequisite is that all substances used in the manufacture of the pharmaceutical preparation are toxicologically safe and tolerable together with the active substances used.

De følgende eksempler illustrerer oppfinnelsen.The following examples illustrate the invention.

Eksempel 1 Example 1

(E)-5-f2-(1,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]isoxazol-3-karboksylsyreetylester (E)-5-f2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]isoxazole-3-carboxylic acid ethyl ester

Til en suspensjon av 300 ml tetrahydrofuran og 9 g 80%-ig natriumhydrid, som forut med petroleter var befridd for 20%-ig paraf f inandel, ble i løpet av 30 min. dryppet en r, Løsning" av--87 , 4g dietyl(3-karboetoksyisoxazol-5)metylenfosfonat i 200 ml tetra-hydrof uran ved ca. 40°C. Deretter rørte man videre i ytterlige-re 15 minutter og dryppet i løpet av 10 minutter til en løsning av 50,6 g 5-acetyl-l,1,2,3,3-pentametylindan i 200 ml tetra-hydrof uran. Etter to timer ble satsen helt i 2 1 isvann og ekstrahert tre ganger med dietyleter. Ekstraktene ble vasket nøytrale med vann, tørket over natriumsulfat og befridd for flyktige bestanddeler på rotasjonsfordamper. Det dannede faste stoff ble gnidd med 100 ml metanol. Etter tørking i en nitrogenatmosfære fikk man tilbake 31,8 g (E)—5— f2—(1,1,2,3,3--pentametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl] -isoxazol-3--karboksylsyreetylester med smp. 90-91°C. To a suspension of 300 ml of tetrahydrofuran and 9 g of 80% sodium hydride, which had previously been freed of 20% paraffin with petroleum ether, was added in the course of 30 min. 4g of diethyl(3-carboethoxyisoxazole-5)methylenephosphonate in 200 ml of tetrahydrofuran at approx. 40°C was added dropwise. The mixture was then stirred for a further 15 minutes and added dropwise during 10 minutes to a solution of 50.6 g of 5-acetyl-1,1,2,3,3-pentamethylindane in 200 ml of tetrahydrofuran.After two hours, the batch was poured into 2 L of ice water and extracted three times with diethyl ether. The extracts were washed neutral with water, dried over sodium sulfate and freed from volatile components on a rotary evaporator. The solid formed was triturated with 100 ml of methanol. After drying in a nitrogen atmosphere, 31.8 g of (E)—5— f2—( 1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl]-isoxazole-3-carboxylic acid ethyl ester with mp 90-91°C.

<X>H-NMR-Spektre viser at det dreier seg om den rene trans-konfigurasjonsisomere tittelforbindelse. <X>H-NMR spectra show that it is the pure trans-configurational isomeric title compound.

Eksempel 2 Example 2

(E)-5- 11-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl] isoxazol-3-karboksylsyre (E)-5- 11-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]isoxazole-3-carboxylic acid

6 g (E)-5-(2-(l,1,2,3,3-Pentametyl-2,3-dihydro-5(lH)-inde-nyl)-1^-propenyl] isoxazol-3-karboksylsyreetylester fikk stå med 1,2 g kaliumhydroksyd i en blanding av 400 ml etanol og 20 ml vann 6 timer ved romtemperatur. Etter at hele reaksjonsmassen var overført i 1.liter vann surgjorde man med 2 N saltsyre, fil-trerte den erholdte fylling fra og gnidde med 100 ml metanol. Etter ny filtrering av krystallisatet og tørking i nitrogenstrøm fikk man tilbake 3,8 g (E)-5-f2-(1,1,2,3,3-pentametyl-2,3-dihyd-ro-5(1H)-indenyl)-1-propenyl] isoxazol-3-karboksylsyre, med smp. 1.68-169°C. XH-NMR-Spektret viser at det dreier seg om den rene isomere tittelforbindelse med transkonfigurasjon, hvilket også er revers-fase HPLC-analyse (RP-C18; 150 bar; etanol/20% vann) bekrefter. Eksempel 3 (E)-5-f2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]isoxazol-3-karboksylsyreamid 4,5 g (E)-5-n-(l,l,2,3,3-Pentametyl-2,3-dihydro-5(lH)--indenyl)-1-propenyl]isoxazol-3-karboksylsyreetylester ble rørt med 150 ml konsentrert ammoniakløsning i 200 ml etanol i 10 timer. Etter overføring av hele reaksjonsmassen i 500 ml vann ble den erholdtefylling filtrert fra og vasket med litt iskald metanol. Etter tørking fikk man tilbake 3,6 g (E)-5-[2-(1,1,2 , - 3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl]isoxazol--3-karboksylsyreamid, smp. 196-197°C. Eksempel 4 (E)-5-f2-(1,1,2,3,3-Pentametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]-N-(2,3-dihydroksypropyl)-isoxazol-3-karboksylsyre-amid. 6 g (E)-5-(2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)-1^-propenyl]isoxazole-3-carboxylic acid ethyl ester was allowed to stand with 1.2 g of potassium hydroxide in a mixture of 400 ml of ethanol and 20 ml of water for 6 hours at room temperature. After the entire reaction mass had been transferred into 1 liter of water, it was acidified with 2 N hydrochloric acid, the resulting mixture was filtered from and rubbed with 100 ml of methanol. After re-filtration of the crystallisate and drying in a stream of nitrogen, 3.8 g of (E)-5-f2-(1,1,2,3,3-pentamethyl-2,3-dihydro -5(1H)-indenyl)-1-propenyl]isoxazole-3-carboxylic acid, mp 1.68-169° C. The XH-NMR spectrum shows that it is the pure isomeric title compound with trans configuration, which is also reverse -phase HPLC analysis (RP-C18; 150 bar; ethanol/20% water) confirms Example 3 (E)-5-f2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]isoxazole-3-carboxylic acid amide 4.5 g ( E)-5-n-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)--indenyl)-1-propenyl]isoxazole-3-carboxylic acid ethyl ester was stirred with 150 ml of concentrated ammonia solution in 200 ml of ethanol for 10 hours. After transferring the entire reaction mass into 500 ml of water, the resulting filling was filtered off and washed with a little ice-cold methanol. After drying, 3.6 g of (E)-5-[2-(1,1,2,-3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl] were recovered isoxazole-3-carboxylic acid amide, m.p. 196-197°C. Example 4 (E)-5-f2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl]-N-(2,3-dihydroxypropyl) -isoxazole-3-carboxylic acid amide.

3,7 g (E)-5-r2-(l,1,2,3,3-Pentametyl-2,3-dihydro-5(lH)--indenyl)-1-propenyl]isoxazol-3-karboksylsyreetylester fikk stå med 25 ml l-amino-2,3-propandiol i 70 ml etanol i 10 timer. Etter overføring av hele reaksjonsmassen til 500 ml vann surgjorde man med 2 N saltsyre. Den erholdte fylling filtreres fra og vaskes med litt metanol. Etter tørking i nitrogenstrøm får man tilbake 2,1 g (E)-5-C2-(1,1,2,3,3-pentamety1-2,3-dihydro--5(1H)-indenyl)-1-propenyl] -N-(2,3-dihydroksypropyl)-isoxazol--3-karboksylsyreamid smp. 150-151°C. 3.7 g of (E)-5-r2-(1,1,2,3,3-Pentamethyl-2,3-dihydro-5(1H)--indenyl)-1-propenyl]isoxazole-3-carboxylic acid ethyl ester was obtained stand with 25 ml of l-amino-2,3-propanediol in 70 ml of ethanol for 10 hours. After transferring the entire reaction mass to 500 ml of water, it was acidified with 2 N hydrochloric acid. The resulting filling is filtered off and washed with a little methanol. After drying in a stream of nitrogen, 2.1 g of (E)-5-C2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl are recovered ] -N-(2,3-dihydroxypropyl)-isoxazole--3-carboxylic acid amide m.p. 150-151°C.

Eksempel 4aExample 4a

Analogt med eksempel 4 får man ut fra (E)-5-[ 2-(1,1,2,3,3--pentametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl]isoxazol-3--karboksylsyreetylester og etanolamin og det ønskede produkt (E)-5-f2-(1,1,2,3,3,-pentametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl]-N-(2-hydroksyetyl)-isoxazol-3-karboksylsyreamid, Analogous to example 4, (E)-5-[2-(1,1,2,3,3--pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl]isoxazole is obtained -3-carboxylic acid ethyl ester and ethanolamine and the desired product (E)-5-f2-(1,1,2,3,3,-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl ]-N-(2-hydroxyethyl)-isoxazole-3-carboxylic acid amide,

smp. 143-144°C. m.p. 143-144°C.

Forbindelsene som er angitt i den etterfølgende tabell ble fremstilt som beskrevet i eksempel 1. The compounds listed in the following table were prepared as described in Example 1.

Eksempel 18 Example 18

Analogt med den arbeidsmetoden som er beskrevet i eksempel 1 fremstilte man ut fra 5-acetyl-l,1,2,3,3-pentametylindan og dietyl(3-metylisoxazol-5-)metylenfosfonat (E)-3-metyl-5-[2--(1,1,2,3,3-pentamety1-2,3-dihydro-5(1H)-indenyl)-l-propenyl3-isoxazol, smp. 120 - 121°C. Analogous to the working method described in example 1, starting from 5-acetyl-1,1,2,3,3-pentamethylindane and diethyl(3-methylisoxazole-5-)methylenephosphonate (E)-3-methyl-5- [2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl-3-isoxazole, m.p. 120 - 121°C.

På samme måte ble de etterfølgende substanser syntetisert. In the same way, the subsequent substances were synthesized.

Eksempel 2 2 Example 2 2

Analogt med den arbeidsmåte som er beskrevet i eksempel 1 fremstilte man ut fra 6-acetyl-l,1,4,4-tetrametyltetralin og dietyl(3-metoksymetylisoxazolyl-5)metylenfosfonat (E)-3-Metoksymetyl-5-[2-(5,5,8,8-tetrametyl-5,6,7,8-tetrahydronaft-2-yl)-1-propenylJisoxazol, med smp. 72-73°C. Analogously to the working method described in example 1, 6-acetyl-1,1,4,4-tetramethyltetralin and diethyl(3-methoxymethylisoxazolyl-5)methylenephosphonate (E)-3-Methoxymethyl-5-[2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-1-propenylisoxazole, m.p. 72-73°C.

Eksempel 23 Example 23

(E)-3-Hydroksymetyl-5-f2-(5,5,8,8-tetrametyl-5,6,7,8-tetra-hydro-naft-2-yl)-1-propenyl)isoxazol (E)-3-Hydroxymethyl-5-f2-(5,5,8,8-tetramethyl-5,6,7,8-tetra-hydro-naphth-2-yl)-1-propenyl)isoxazole

Til en omrørt suspensjon av 1 g litiumaluminumhydrid iTo a stirred suspension of 1 g lithium aluminum hydride i

150 ml dietyleter drypper man en løsning av 5 g (E)-5-[2--(5,5,8,8-tetrametyl-5,6,7,8-tetrahydro-naft-2-yl)-1-propenyl] isoxazol-3-karboksylsyreetylester i 50 ml dietyleter. Etter 3 timer blander man dråpevis med 200 ml av en 10%-ig vandig vinsyreløsning og ekstraherer flere ganger med dietyleter. A solution of 5 g of (E)-5-[2--(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphth-2-yl)-1- propenyl] isoxazole-3-carboxylic acid ethyl ester in 50 ml of diethyl ether. After 3 hours, it is mixed dropwise with 200 ml of a 10% aqueous tartaric acid solution and extracted several times with diethyl ether.

De forenede organiske faser vaskes nøytrale og tørkes med vann-fritt natriumsulfat. Den krystallinske rest som er tilbake etter inndamping omkrystalliseres fra 25 ml metanol. Men får således 2,3 g av tittelforbindelsen, smp. 138-139°C. The combined organic phases are washed neutral and dried with anhydrous sodium sulfate. The crystalline residue that remains after evaporation is recrystallized from 25 ml of methanol. But thus get 2.3 g of the title compound, m.p. 138-139°C.

Eksempel 24Example 24

Analogt med den arbeidsmetode som er beskrevet i eksempel 2 3 fremstilte man ut fra (E)-5-[2-(1,1,2,3,3-pentametyl-2,3-di-hydro-5(1H)-indenyl)-1-propenyl]isoxazol-3-karboksylsyreetylester (E)-3-Hydroksymetyl-5-[2-(1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl)-1-propenyl]isoxazol. Analogous to the working method described in example 2 3 was prepared from (E)-5-[2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)- indenyl)-1-propenyl]isoxazole-3-carboxylic acid ethyl ester (E)-3-Hydroxymethyl-5-[2-(1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)- indenyl)-1-propenyl]isoxazole.

Eksempel 25 Example 25

(E)-3-Acetoksymetyl-5-f 2-(1,1,2,3,3-pentametyl-2,3-dihydro--5(1H)-indenyl)-1-propenyl]isoxazol (E)-3-Acetoxymethyl-5-f 2-(1,1,2,3,3-pentamethyl-2,3-dihydro--5(1H)-indenyl)-1-propenyl]isoxazole

En løsning av 4,9 g (E)-3-hydroksymetyl-5-t2-(1,1,2,3,3--pentametyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl] isoxazol i 25 ml dietyleter og 10 ml pyridin ble dråpevis blandet med 4,7 ml acetylklorid ved 0°C til 5°C. Deretter rørte man videre 3 timer ved romtemperatur, man helte så på vann og ekstraherte med dietyleter. Den organiske fasen ble behandlet med 1 N saltsyre, vasket nøytral med vann og tørket over natriumsulfat. Det faste stoff som var tilbake etter inndampning av løsningen, ble omkrystallisert fra 20 ml etanol. Derved fikk man 5,2 g av tittelforbindelsen, smp. 91 - 92°C. A solution of 4.9 g of (E)-3-hydroxymethyl-5-t2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl ] isoxazole in 25 ml of diethyl ether and 10 ml of pyridine was mixed dropwise with 4.7 ml of acetyl chloride at 0°C to 5°C. The mixture was then stirred for a further 3 hours at room temperature, then poured into water and extracted with diethyl ether. The organic phase was treated with 1 N hydrochloric acid, washed neutral with water and dried over sodium sulfate. The solid that remained after evaporation of the solution was recrystallized from 20 ml of ethanol. This gave 5.2 g of the title compound, m.p. 91 - 92°C.

Eksempel 26Example 26

(E)-3- N-(3-Hydroksy-4-karboksyfenylamino)tiooksometylkar-bamoyl -5- 2-(1,1,2,3,3-pentametyl-2,3-dihydro-5(1H)-indenyl)--1-propenyl isoxazol (E)-3- N -(3-Hydroxy-4-carboxyphenylamino)thioxomethylcarbamoyl -5- 2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl )--1-propenyl isoxazole

I en løsning av 5 g (E)-5- 2-(1,1,2,3,3-pentametyl-2,3-di-hydro-5(1H)-indenyl)-1-propenyl isoxazol-3-karboksylsyre, 30 ml tetrahydrofuran og 1,4 ml pyridin dryppet man 1,2 ml tionyl-klorid. Etter 45 minutter ved romtemperatur tilsatte man denne blandingen 1,6 g kaliumrodanid i 15 ml aceton og etter ytter-ligere 45 minutter 2,8 g 4-amino-2-hydroksybenzosyre i 30 ml tetrahydrofuran. In a solution of 5 g of (E)-5-2-(1,1,2,3,3-pentamethyl-2,3-dihydro-5(1H)-indenyl)-1-propenyl isoxazol-3- carboxylic acid, 30 ml of tetrahydrofuran and 1.4 ml of pyridine, 1.2 ml of thionyl chloride was added dropwise. After 45 minutes at room temperature, 1.6 g of potassium rhodanide in 15 ml of acetone were added to this mixture and after a further 45 minutes 2.8 g of 4-amino-2-hydroxybenzoic acid in 30 ml of tetrahydrofuran.

Etter 8 timer ble hele reaksjonsmassen helt i en løsning av 400 ml metanol og 400 ml vann. Det erholdte faste stoff filtrerer man fra og vasker det på filteret i rekkefølge med metanol og n-heptan. Etter tørking i nitrogenstrøm blir 4,3 g av tittelforbindelsen tilbake, smp. 221-222°C. After 8 hours, the entire reaction mass was poured into a solution of 400 ml of methanol and 400 ml of water. The solid obtained is filtered off and washed on the filter in sequence with methanol and n-heptane. After drying in a stream of nitrogen, 4.3 g of the title compound remain, m.p. 221-222°C.

Claims (2)

1. Fremgangsmåte ved fremstilling av isoxazolkarboksylsyrederivater med formel I 1. Procedure for the preparation of isoxazole carboxylic acid derivatives of formula I hvori R 1 og R <2> betyr hydrogenatomer eller metylgrupper 3 4 R og R hydrogenatomer, C-, ,-alkylgrupper eller metoksygrupper, R 5et hydrogen- eller halogenatom eller en C^ _^ -alkyl eller C-, _6~alkoksygruppe R et hydrogenatom eller en C-L _6 -alkyl eller C3 _6 -cykloalkyl-gruppe A en metylen- eller etylenrest, eventuelt substituert med c^ _4~ alkylgruppe, ogin which R 1 and R <2> mean hydrogen atoms or methyl groups 3 4 R and R hydrogen atoms, C-, ,-alkyl groups or methoxy groups, R 5 a hydrogen or halogen atom or a C^ _^ -alkyl or C-, _6~ alkoxy group R is a hydrogen atom or a C-L-6 alkyl or C3-6 cycloalkyl group A a methylene or ethylene residue, optionally substituted with a c^ _4~ alkyl group, and 7 8 9 IQ R oksazolinresten eller resten -CH(R )-R eller -CO-R hvori R g betyr et hydrogenatom eller en C,_^ -alkylgruppe q o X —j , 2 to i R det samme som R eller en rest -Or <H> eller NR R (med R i betydning et hydrogenatom, en C-, _4-alkyl-, C„_9n -alkanoyl-12 13 . eller eventuelt substituert benzoylgruppe og med R og R i betydningen hydrogenatomer,C^ _^ -alkyl-, C2 _2 g~ alkanoyl- eller eventuelt substituerte benzoylgrupper) R <x> (^ et hydrogen- eller halogenatom, azido-, imidazol- eller 14 triazolresten, en C^_^-alkylgruppe eller en rest -OR eller -NR<15>R<16> (medR<14> i betydning et hydrogenatom, en C1 _g-alkyl-, eventuelt med en eller flere hydroksygrupper eller en c^ _4~ alkoksygruppe substituert C,_o -alkyl-, eventuelt substituert15 aryl- eller i aryIdelen substituert aralkylgruppe, og med R og R 1 fi i betydning hydrogenatomer, C1 _g-alkyl-, eventuelt med en eller flere hydroksygrupper substituerte C9 _fi -alkylrester eller R <15> og R 16 betyr sammen med nitrogenatomet de er bundet til en heterocyklisk rest samt eventuelt deres fysiologisk fordragelige salter, karakterisert ved at man omsetter en karbonylforbindelse med formel (II) 7 8 9 IQ R the oxazoline residue or the residue -CH(R )-R or -CO-R in which R g means a hydrogen atom or a C 1-4 -alkyl group q o X —j , 2 two in R the same as R or a residue -Or <H> or NR R (with R meaning a hydrogen atom, a C-, _4-alkyl-, C„_9n -alkanoyl-12 13 . or optionally substituted benzoyl group and with R and R in the sense of hydrogen atoms, C^ _^ -alkyl-, C2 _2 g~ alkanoyl- or optionally substituted benzoyl groups) R <x> (^ a hydrogen or halogen atom, the azido, imidazole or 14 triazole residue, a C^_^-alkyl group or a residue -OR or -NR<15>R<16> (with R<14> in the sense of a hydrogen atom, a C1_g-alkyl-, optionally with one or more hydroxy groups or a c^_4~ alkoxy group substituted C,_o -alkyl-, optionally substituted 15 aryl - or in the aryl part substituted aralkyl group, and with R and R 1 fi in the sense of hydrogen atoms, C1 _g-alkyl-, optionally with one or more hydroxy groups substituted C9 _fi -alkyl residues or R <15> and R 16 together with the nitrogen atom they are bound to to a heterocyclic residue as well as optionally their physiologically tolerable salts, characterized by reacting a carbonyl compound of formula (II) hvori A, R <1> , R <2> , R <3> ,R<4> ,R<5> og R <6> har de foran angitte betydnin-ger, med en fosforforbindelse med formel (III) in which A, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> have the previously stated meanings, with a phosphorus compound of formula (III) 17 18 hvori R betyr en C^^ -alkylgruppe og R står for en alkylgruppe, en karbo- <C>1 _g-alkoksygruppe, eller en C-L _4 -alkoksy-metyl-C1 _4 -alkoksymetylgruppe ifølge den såkalte Wittig-Horner-reaksjon, og de således erholdte forbindelser om ønsket deretter overfø res i andre forbindelser med formel I.17 18 in which R means a C 1 -alkyl group and R stands for an alkyl group, a carbo- <C> 1 _g - alkoxy group, or a C-L 4 - alkoxy-methyl-C 1 _ 4 - alkoxymethyl group according to the so-called Wittig-Horner reaction, and the thus obtained compounds, if desired, are then transferred into other compounds of formula I. 2. Fremgangsmåte ifølge krav 1, ved fremstilling av (E)-5-^2- -(3-fluor-5,5,8,8-tetramety1-5,6,7,8-tetrahydronaft-2-yl)-1-propenyljisoxazol-3-karboksylsyre, karakterisert ved at man anvender tilsvarende substituerte utgangsmaterialer.2. Process according to claim 1, in the preparation of (E)-5-^2- -(3-fluoro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)-1-propenylisoxazole-3-carboxylic acid, characterized by using correspondingly substituted starting materials.
NO853695A 1984-09-22 1985-09-20 ISOXAZOLCARBOXYLIC ACID DERIVATIVES, PREPARATION AND USE THEREOF. NO853695L (en)

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