HRP20200974T1 - Supstituirani indazoli, postupak za njihovu pripremu, farmaceutske formulacije koji ih sadrže i njihova upotreba za pripravu lijekova - Google Patents

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

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HRP20200974T1
HRP20200974T1 HRP20200974TT HRP20200974T HRP20200974T1 HR P20200974 T1 HRP20200974 T1 HR P20200974T1 HR P20200974T T HRP20200974T T HR P20200974TT HR P20200974 T HRP20200974 T HR P20200974T HR P20200974 T1 HRP20200974 T1 HR P20200974T1
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Croatia
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trifluoromethyl
hydroxy
indazol
carboxamide
alkyl
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HRP20200974TT
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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
Peter Hauff
Christian Friedrich
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Bayer Pharma Aktiengesellschaft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic 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
    • C07D405/14—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds 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)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Claims (19)

1. Spojevi opće formule (I) [image] naznačeni time što: R1 je C1-C6-alkil, gdje je skupina C1-C6-alkil nesupstituirana ili mono- ili polisupstituirana istovjetno ili različito s halogenom, hidroksilom, nesupstituiranom ili mono- ili poli-halogen-supstituiranom skupinom C3-C6-cikloalkil, ili R6 ili skupinom R8O, ili skupinom odabranom od: [image] gdje * predstavlja mjesto vezanja skupine za ostatak molekule; R2 i R3 uvijek imaju istu definiciju i oba su ili vodik ili C1-C6-alkil; R4 je halogen, cijano, nesupstituirana ili jednostruko ili višestruko, istovjetno ili različito supstituirana skupina C1-C6-alkil ili nesupstituirana ili jednostruko ili višestruko, istovjetno ili različito supstituirana skupina C3-C6-cikloalkil, a supstituenti su odabrani iz skupine koju čine halogen i hidroksil; R5 je vodik, halogen ili nesupstituirana ili mono- ili poli-halogen-supstituirana skupina C1-C6-alkil; R6 je nesupstituirani ili mono- ili di-metil-supstituirani monociklički zasićeni heterocikal koji ima 4 do 6 atoma u prstenu, koja sadrži heteroatom ili heteroskupinu odabranu iz skupine koju čine O, S, SO i SO2; R8 je C1-C6-alkil, gdje je skupina C1-C6-alkil nesupstituirana ili mono- ili polisupstituirana istovjetno ili različito s halogenom; i dijastereomeri, enantiomeri, soli, solvati ili solvati njihovih soli.
2. Spojevi prema patentnom zahtjevu 1, naznačeni time što R1 je C1-C6-alkil, gdje je skupina C1-C6-alkil nesupstituirana ili mono- ili polisupstituirana istovjetno ili različito s fluorom, hidroksilom ili skupinom 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 skupina C1-C3-alkil nesupstituirana ili mono- ili polisupstituirana istovjetno ili različito s halogenom ili hidroksilom; R5 je vodik, fluor, klor ili C1-C3-alkil; R6 je oksetanil ili tetrahidrofuranil; R8 je nesupstituirana skupina C1-C4-alkil ili skupina C1-C4-alkil supstituirana s tri fluora.
3. Spojevi prema patentnom zahtjevu 1 ili 2, naznačeni time što R4 je difluorometil, trifluorometil ili metil.
4. Spojevi prema patentnom zahtjevu 1, 2 ili 3, naznačeni time što R5 je vodik ili fluor.
5. Spojevi prema patentnom zahtjevu 1, 2, 3 ili 4, naznačeni time što R2 i R3 su oba ili vodik ili metil.
6. Spojevi prema patentnom zahtjevu 2, naznačeni time što R1 je C2-C6-alkil, gdje je skupina C2-C6-alkil nesupstituirana, ili skupina C2-C6-alkil je mono-, di- ili supstituirana s tri fluora ili skupina C2-C6-alkil je monosupstituirana s hidroksilom, R6, ili R8O, ili R1 je oksetanil-supstituirana skupina C1-C3-alkil; R2 i R3 uvijek imaju istu definiciju i oba su ili vodik ili metil; R4 je nesupstituirana ili mono- ili poli-halogen-supstituirana skupina C1-C3-alkil ili skupina C1-C3-alkil supstituirana s jednom hidroksil skupinom ili skupina C1-C3-alkil supstituirana s jednom hidroksil skupinom i tri fluorova atoma; R5 je vodik, fluor ili C1-C3-alkil; R8 je C1-C4-alkil, gdje je skupina C1-C4-alkil nesupstituirana ili mono-, di- ili supstituirana s tri fluora.
7. Spojevi prema patentnom zahtjevu 6, naznačeni time što R1 je skupina C2-C5-alkil supstituirana s hidroksilom ili C1-C3-alkoksi ili trifluorometoksi ili 2,2,2-trifluoroetoksi ili trifluorometilom ili je oksetan-3-il-supstituirana skupina C1-C2-alkil; R2 i R3 uvijek imaju istu definiciju i oba su vodik ili metil; R4 je metil, etil, trifluoro-C1-C3-alkil, difluoro-C1-C3-alkil, hidroksimetil, 1-hidroksietil, 2-hidroksipropan-2-il i 2,2,2-trifluoro-1-hidroksietil; R5 je vodik, fluor ili metil.
8. Spojevi prema patentnom zahtjevu 7, naznačeni time što R1 je 4,4,4-trifluorobutil, 3-hidroksi-3-metilbutil, 3-hidroksibutil, 3-metoksipropil, 3-hidroksipropil, 3-hidroksi-2-metilpropil, 3-hidroksi-2,2-dimetilpropil, 3-trifluorometoksipropil, 2-metoksietil ili 2-hidroksietil; R2 i R3 su oba metil ili vodik; R4 je difluorometil, trifluorometil ili metil; R5 je vodik ili fluor.
9. Spojevi prema patentnom zahtjevu 8, naznačeni time što R1 je 3-hidroksi-3-metilbutil, 3-hidroksibutil, 3-hidroksi-2-metilpropil ili 3-hidroksi-2,2-dimetilpropil; R2 i R3 su oba metil; R4 je difluorometil ili trifluorometil; R5 je vodik.
10. Spojevi prema patentnom zahtjevu 8, naznačeni time što R1 je 3-hidroksi-3-metilbutil, 3-hidroksibutil, 3-hidroksi-2-metilpropil ili 3-hidroksi-2,2-dimetilpropil; R2 i R3 su oba metil; R4 je metil; R5 je fluor, gdje je R5 u orto položaju prema R4.
11. Spojevi prema patentnom zahtjevu 1-10 naznačeni time što su kako slijedi: 1) N-[6-(2-Hidroksipropan-2-il)-2-(2-metoksietil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 2) N-[6-(Hidroksimetil)-2-(2-metoksietil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 3) N-[6-(2-Hidroksipropan-2-il)-2-(3-metoksipropil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 4) N-[6-(Hidroksimetil)-2-(3-metoksipropil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 5) N-[2-(2-Hidroksietil)-6-(2-hidroksipropan-2-il)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 6) N-[6-(2-Hidroksipropan-2-il)-2-(3-hidroksipropil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 7) N-[2-(2-Hidroksietil)-6-(hidroksimetil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 8) N-[6-(2-Hidroksipropan-2-il)-2-(oksetan-3-ilmetil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 9) N-[6-(Hidroksimetil)-2-(oksetan-3-ilmetil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 10) N-[2-(3-Hidroksi-3-metilbutil)-6-(2-hidroksipropan-2-il)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 11) 6-(Difluorometil)-N-[2-(3-hidroksi-3-metilbutil)-6-(2-hidroksipropan-2-il)-2H-indazol-5-il]piridin-2-karboksamid 12) 6-(Difluorometil)-N-[6-(2-hidroksipropan-2-il)-2-(3-hidroksipropil)-2H-indazol-5-il]piridin-2-karboksamid 13) N-[6-(2-Hidroksipropan-2-il)-2-(4,4,4-trifluorobutil)-2H-indazol-5-il]-6-(trifluorometil)piridin-2-karboksamid 14) N-{6-(2-Hidroksipropan-2-il)-2-[3-(trifluorometoksi)propil]-2H-indazol-5-il}-6-(trifluorometil)piridin-2-karboksamid 15) N-{6-(2-Hidroksipropan-2-il)-2-[3-(2,2,2-trifluoroetoksi)propil]-2H-indazol-5-il}-6-(trifluorometil)piridin-2-karboksamid 16) 5-Fluoro-N-[2-(3-hidroksi-3-metilbutil)-6-(2-hidroksipropan-2-il)-2H-indazol-5-il]-6-metilpiridin-2-karboksamid 17) N-[2-(3-Hidroksi-3-metilbutil)-6-(2-hidroksipropan-2-il)-2H-indazol-5-il]-6-metilpiridin-2-karboksamid 18) 6-(2-Hidroksipropan-2-il)-N-[6-(2-hidroksipropan-2-il)-2-(4,4,4-trifluorobutil)-2H-indazol-5-il]piridin-2-karboksamid 19) N-{2-[2-(1-Hidroksiciklopropil)etil]-6-(2-hidroksipropan-2-il)-2H-indazol-5-il}-6-(trifluorometil)piridin-2-karboksamid.
12. Spoj opće formule (I) kako je definirano u bilo kojem od zahtjeva 1 do 11 naznačen time što je za liječenje i/ili profilaksu bolesti.
13. Spoj opće formule (I) kako je definirano u bilo kojem od zahtjeva 1 do 11 naznačen time što je za uporabu u postupku 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 bola.
14. Spoj opće formule (I) kako je definirano u bilo kojem od zahtjeva 1 do 11 naznačen time što je za uporabu u postupku za liječenje i/ili profilaksu limfoma, makularne degeneracije, psorijaze, eritemskog lupusa, multiple skleroze, KOPB, gihta, nealkoholnog steatohepatitisa, jetrene fibroze, otpornosti na inzulin, metaboličkog sindroma, spondiloartritisa i reumatoidnog artritisa, endometrioze i bola povezanog s endometriozom i drugih simptoma povezanih s endometriozom kao što su dismenoreja, dispareunija, disurija i dishezija.
15. Spoj opće formule (I) kako je definirano u bilo kojem od zahtjeva 1 do 11 naznačen time što je za uporabu u postupku za liječenje i/ili profilaksu bola uključujući akutni, kronični, upalni i neuropatski bol, po mogućnosti od hiperalgezije, alodinije, bola zbog artritisa (kao što je osteoartritis, reumatoidni artritis i spondiloartritis), predmenstrualni bol, bol povezan s endometriozom, postoperativni bol, bol od intersticijskog cistitisa, CRPS (kompleksni regionalni bolni sindrom), trigeminalne neuralgije, bola zbog prostatitisa, bola uzrokovanog ozljedama leđne moždine, bola izazvanog upalom, bola u donjem dijelu leđa, bola zbog raka, bola povezanog s kemoterapijom, neuropatije uzrokovane liječenjem HIV-a, bola izazvanog opekotinama i kroničnog bola.
16. Lijek naznačen time što sadrži spoj s formulom (I) kako je definirano u bilo kojem od zahtjeva 1 do 11 u kombinaciji s inertnom, netoksičnom, farmaceutski prikladnom pomoćnom tvari.
17. Postupak za pripremanje spojeva opće formule (III) iz spojeva opće formule (II) [image] naznačen time što R1 je 4,4,4-trifluorobutil, 3-hidroksi-3-metilbutil, 3-metoksipropil, 3-hidroksipropil, 3-hidroksi-2-metilpropil, 3-hidroksi-2,2-dimetilpropil, 3-trifluorometoksipropil, 2-metoksietil ili 2-hidroksietil; R4 je difluorometil, trifluorometil ili metil; R5 je vodik ili fluor; putem reakcije (II) s odgovarajućim supstituiranim alkil-halogenidima ili alkil 4-metilbenzensulfonatima u prisutnosti kalijevog karbonata.
18. Spojevi opće formule (III) [image] naznačeni time što R1 je 4,4,4-trifluorobutil, 3-hidroksi-3-metilbutil, 3-metoksipropil, 3-hidroksipropil, 3-hidroksibutil, 3-hidroksi-2-metilpropil, 3-hidroksi-2,2-dimetilpropil, 3-trifluorometoksipropil, 2-metoksietil, 2-hidroksietil, ili 2-(1-hidroksiciklopropil) etil; R4 je difluorometil, trifluorometil ili metil; i R5 je vodik ili fluor; i dijastereomeri, enantiomeri, soli, solvati ili solvati njihovih soli.
19. Spojevi opće formule (III), kako slijedi: metil 5-{[(5-fluoro-6-metilpiridin-2-il)karbonil]amino}-2-(3-hidroksi-3-metilbutil)-2H-indazol-6-karboksilat i metil 2-(3-hidroksi-3-metilbutil)-5-({[6-(trifluorometil)piridin-2-il]karbonil}amino)-2H-indazol-6-karboksilat.
HRP20200974TT 2014-11-26 2020-06-19 Supstituirani indazoli, postupak za njihovu pripremu, farmaceutske formulacije koji ih sadrže i njihova upotreba za pripravu lijekova HRP20200974T1 (hr)

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EP14195032 2014-11-26
PCT/EP2015/077596 WO2016083433A1 (de) 2014-11-26 2015-11-25 Neue substituierte indazole, verfahren zu ihrer herstellung, pharmazeutische präparate, die diese enthalten sowie deren verwendung zur herstellung von arzneimitteln
EP15800828.4A EP3224254B1 (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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