HRP20240414T1 - Supstituirani indazoli, postupak za njihovu pripremu, farmaceutske formulacije koje ih sadrže i njihova upotreba za pripremu lijekova - Google Patents

Supstituirani indazoli, postupak za njihovu pripremu, farmaceutske formulacije koje ih sadrže i njihova upotreba za pripremu lijekova Download PDF

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HRP20240414T1
HRP20240414T1 HRP20240414TT HRP20240414T HRP20240414T1 HR P20240414 T1 HRP20240414 T1 HR P20240414T1 HR P20240414T T HRP20240414T T HR P20240414TT HR P20240414 T HRP20240414 T HR P20240414T HR P20240414 T1 HRP20240414 T1 HR P20240414T1
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pain
alkyl
disorders
hydrogen
methyl
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HRP20240414TT
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Ulrich Bothe
Holger Siebeneicher
Nicole Schmidt
Reinhard Nubbemeyer
Ulf Bömer
Judith GÜNTHER
Holger STEUBER
Martin Lange
Christian Stegmann
Andreas Sutter
Alexandra RAUSCH
Christian Friedrich
Peter Hauff
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Bayer Pharma Aktiengesellschaft
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02Silicon compounds
    • C07F7/08Compounds having one or more C—Si linkages
    • C07F7/18Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804Compounds having Si-O-C linkages

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Epidemiology (AREA)
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  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
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  • Heart & Thoracic Surgery (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Claims (22)

1. Spojevi opće formule (I) [image] u kojoj: R1 je C1-C6-alkil, gdje je C1-C6-alkil radikal monosupstituiran s radikalom R7SO2 ili R7SO ili gdje je radikal C1-C6-alkil polisupstituiran s radikalom R7SO2 ili R7SO i mono- ili polisupstituiran s halogenom, hidroksilom, nesupstituiranim ili mono- ili poli-halogen-supstituiranim C3-C6-cikloalkilom, radikal R6 ili R8O; R2 i R3 uvijek imaju istu definiciju i oba su ili vodik ili C1-C6-alkil; R4 je halogen, cijano, nesupstituiran ili pojedinačno ili višestruko, identično ili različito supstituiran C1-C6-alkil ili nesupstituiran ili pojedinačno ili višestruko, identično ili različito supstituiran C3-C6-cikloalkil, i supstituenti su odabrani iz skupine koja sadrži halogen i hidroksil; R5 je vodik, halogen ili nesupstituiran ili mono- ili poli-halogen-supstituiran C1-C6-alkil; R6 je nesupstituiran ili mono- ili di-metil-supstituiran monociklički, zasićeni heterocikl koji ima 4 do 6 atoma u prstenu, koji sadrži heteroatom ili heteroskupinu iz skupine O, S, SO i SO2; R7 je C1-C6-alkil, gdje je radikal C1-C6-alkil nesupstituiran ili mono- ili polisupstituiran identično ili različito s halogenom, hidroksilom ili C3-C6-cikloalkilom; ili R7 je C3-C6-cikloalkil; R8 je C1-C6-alkil, gdje je radikal C1-C6-alkil nesupstituiran ili mono- ili polisupstituiran identično ili različito sa halogenom; i dijastereomeri, enantiomeri, soli, solvati ili solvati njihovih soli.
2. Spojevi prema zahtjevu 1, naznačeni time što R1 je C1-C6-alkil, gdje je C1-C6-alkil radikal monosupstituiran s R7SO2 ili R7SO ili gdje je radikal C1-C6-alkil polisupstituiran s radikalom R7SO2 ili R7SO i mono- ili polisupstituiran s fluorom, hidroksilom, radikalom R6 ili R8O; R2 i R3 uvijek imaju istu definiciju i oba su ili vodik ili C1-C3-alkil; R4 je halogen, cijano ili C1-C3-alkil, gdje je radikal C1-C3-alkil nesupstituiran ili mono- ili polisupstituiran identično ili različito s halogenom ili hidroksilom; R5 je vodik, fluor, klor ili C1-C3-alkil; R6 je oksetanil ili tetrahidrofuranil; R7 je C1-C4-alkil, gdje je C1-C4-alkil radikal nesupstituiran ili monosupstituiran s hidroksilom ili s ciklopropilom ili supstituiran s tri atoma fluora; R8 je nesupstituiran C1-C4-alkil radikal ili trifluor-supstituiran radikal C1-C4-alkil.
3. Spojevi prema zahtjevu 1 ili 2, naznačeni time što R4 je difluormetil, trifluormetil ili metil.
4. Spojevi prema zahtjevu 1, 2 ili 3, naznačeni time što R5 je vodik ili fluor.
5. Spojevi prema zahtjevu 1, 2, 3 ili 4, naznačeni time što R2 i R3 oba su ili vodik ili metil.
6. Spojevi prema zahtjevu 2, naznačeni time što R1 je C2-C6-alkil, gdje je radikal C2-C6-alkil monosupstituiran s R7SO2; R2 i R3 uvijek imaju istu definiciju i oba su ili vodik ili metil; R4 je nesupstituiran ili mono- ili poli-halogen-supstituiran C1-C3-alkil radikal ili a C1-C3-alkil radikal supstituiran s jednom hidroksilnom skupinom ili radikal C1-C3-alkil supstituiran s jednom hidroksilnom skupinom i tri atoma fluora; R5 je vodik, fluor ili C1-C3-alkil; R7 je C1-C3-alkil.
7. Spojevi prema zahtjevu 6, naznačeni time što R1 je a metil-SO2-supstituiran C2-C4-alkil radikal; R2 i R3 uvijek imaju istu definiciju i oba su vodik ili metil; R4 je metil, etil, trifluor-C1-C3-alkil, difluor-C1-C3-alkil, hidroksimetil, 1-hidroksietil, 2-hidroksipropan-2-il i 2,2,2-trifluor-1-hidroksietil; R5 je vodik, fluor ili metil.
8. Spojevi prema zahtjevu 7, naznačeni time što R1 je 2-(metilsulfonil)etil ili 3-(metilsulfonil)propil; R2 i R3 oba su metil ili vodik; R4 je difluormetil, trifluormetil ili metil; R5 je vodik ili fluor.
9. Spojevi prema zahtjevu 8, naznačeni time što R1 je 3-(metilsulfonil)propil ili 2-(metilsulfonil)etil; R2 i R3 oba su metil; R4 je difluormetil ili trifluormetil; R5 je vodik.
10. Spojevi prema zahtjevu 8, naznačeni time što R1 je 3-(metilsulfonil)propil ili 2-(metilsulfonil)etil; R2 i R3 oba su metil; R4 je metil; R5 je fluor, gdje R5 je u orto položaju prema R4.
11. Spojevi prema zahtjevima 1-10 kako slijedi: 1) N-{6-(2-hidroksipropan-2-il)-2-[3-(metilsulfonil)propil]-2H-indazol-5-il}-6-(trifluormetil)piridin-2-karboksamid 2) N-{6-(2-hidroksipropan-2-il)-2-[2-(metilsulfonil)etil]-2H-indazol-5-il}-6-(trifluormetil)piridin-2-karboksamid 3) 6-(difluormetil)-N-{6-(2-hidroksipropan-2-il)-2-[2-(metilsulfonil)etil]-2H-indazol-5-il}piridin-2-karboksamid.
12. Spoj opće formule (I) kako je definiran u bilo kojem od zahtjeva 1 do 11 naznačen time što je za upotrebu u postupku liječenja i/ili profilakse bolesti.
13. Spoj opće formule (I) kako je definiran u bilo kojem od zahtjeva 1 do 11 naznačen time što je za upotrebu u postupku liječenja i/ili profilakse neoplastičnih poremećaja, dermatoloških poremećaja, ginekoloških poremećaja, kardiovaskularnih poremećaja, plućnih poremećaja, oftalmoloških poremećaja, neuroloških poremećaja, metaboličkih poremećaja, jetrenih poremećaja, upalnih poremećaja, autoimunih poremećaja i boli.
14. Spoj opće formule (I) kako je definiran u bilo kojem od zahtjeva 1 do 11 naznačen time što je za upotrebu u postupku liječenja i/ili profilakse limfoma, makularne degeneracije, psorijaze, eritemskog lupusa, multiple skleroze, KOPB-a, gihta, NASH-a, fibroze jetre, inzulinske rezistencije, metaboličkog sindroma, spondiloartritisa i reumatoidnog artritisa, endometrioze i boli povezane s endometriozom i drugih simptoma povezanih s endometriozom kao što je dismenoreja, dispareunija, disurija i dishezija.
15. Spoj opće formule (I) kako je definiran u bilo kojem od zahtjeva 1 do 11 naznačen time što je za upotrebu u postupku liječenja i/ili profilakse boli uključujući akutnu, kroničnu, upalnu i neuropatsku bol, poželjno hiperalgezije, alodinije, boli od artritisa (kao što je osteoartritis, reumatoidni artritis i spondiloartritis), predmenstrualne boli, boli povezane s endometriozom, postoperativne boli, boli od intersticijskog cistitisa, CRPS (kompleksnog regionalnog bolnog sindroma), trigeminalne neuralgije, boli od prostatitisa, boli uzrokovane ozljedama leđne moždine, boli uzrokovane upalom, boli u donjem dijelu leđa, boli uzrokovane rakom, boli povezane s kemoterapijom, neuropatije uzrokovane liječenjem HIV-a, boli uzrokovane opeklinama i kronične boli.
16. Spoj opće formule (I) kako je definiran u bilo kojem od zahtjeva 1 do 11 naznačen time što je za upotrebu kao lijek.
17. Spoj opće formule (I) za upotrebu prema zahtjevu 16, naznačen time što se lijek koristi za liječenje i/ili profilaksu neoplastičnih poremećaja, dermatoloških poremećaja, ginekoloških poremećaja, kardiovaskularnih poremećaja, plućnih poremećaja, oftalmoloških poremećaja, neuroloških poremećaja, metaboličkih poremećaja, jetrenih poremećaja, upalnih poremećaja, autoimunih poremećaja i boli.
18. Spoj opće formule (I) za upotrebu prema zahtjevima 16 i 17 za liječenje i/ili profilaksu limfoma, makularne degeneracije, psorijaze, eritemskog lupusa, multiple skleroze, KOPB-a, gihta, NASH-a, fibroze jetre, inzulinske rezistencije, metaboličkog sindroma, spondiloartritisa i reumatoidnog artritisa, endometrioze i boli povezane s endometriozom i drugih simptoma povezanih s endometriozom kao što je dismenoreja, dispareunija, disurija i dishezija.
19. Spoj opće formule (I) za upotrebu prema zahtjevima 16 i 17 za liječenje i/ili profilaksu boli uključujući akutnu, kroničnu, upalnu i neuropatsku bol, poželjno hiperalgezije, alodinije, boli od artritisa (kao što je osteoartritis, reumatoidni artritis i spondiloartritis), predmenstrualne boli, boli povezane s endometriozom, postoperativne boli, boli od intersticijskog cistitisa, CRPS (kompleksnog regionalnog bolnog sindroma), trigeminalne neuralgije, boli od prostatitisa, boli uzrokovane ozljedama leđne moždine, boli uzrokovane upalom, boli u donjem dijelu leđa, boli uzrokovane rakom, boli povezane s kemoterapijom, neuropatije uzrokovane liječenjem HIV-a, boli uzrokovane opeklinama i kronične boli.
20. Lijek koji sadrži spoj formule (I) kako je definiran u bilo kojem od zahtjeva 1 do 11 u kombinaciji s inertnom, netoksičnom, farmaceutski prikladnom pomoćnom tvari.
21. Postupak za pripremu spojeva opće formule (III) iz spojeva opće formule (II) [image] u kojima R1 je 2-(metilsulfonil)etil ili 3-(metilsulfonil)propil; R4 je difluormetil, trifluormetil ili metil; R5 je vodik ili fluor; reakcijom (II) s odgovarajućim supstituiranim alkil halogenidima ili alkil 4-metilbenzensulfonatima u prisutnosti kalijevog karbonata.
22. Spojevi opće formule (III): [image] u kojoj R1 je 2-(metilsulfonil)etil ili 3-(metilsulfonil)propil; R4 je difluormetil, trifluormetil ili metil; i R5 je vodik ili fluor, i dijastereomeri, enantiomeri, soli, solvati ili solvati njihovih soli.
HRP20240414TT 2014-11-26 2015-11-25 Supstituirani indazoli, postupak za njihovu pripremu, farmaceutske formulacije koje ih sadrže i njihova upotreba za pripremu lijekova HRP20240414T1 (hr)

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EP14195032 2014-11-26
EP19191936.4A EP3674298B9 (de) 2014-11-26 2015-11-25 Substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate, die diese enthalten, sowie deren verwendung zur herstellung von arzneimitteln

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HRP20200974TT HRP20200974T1 (hr) 2014-11-26 2020-06-19 Supstituirani indazoli, postupak za njihovu pripremu, farmaceutske formulacije koji ih sadrže i njihova upotreba za pripravu lijekova

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