HRP20192009T1 - Spojevi izoksazol hidroksamske kiseline kao inhibitori lpxc-a - Google Patents

Spojevi izoksazol hidroksamske kiseline kao inhibitori lpxc-a Download PDF

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HRP20192009T1
HRP20192009T1 HRP20192009TT HRP20192009T HRP20192009T1 HR P20192009 T1 HRP20192009 T1 HR P20192009T1 HR P20192009T T HRP20192009T T HR P20192009TT HR P20192009 T HRP20192009 T HR P20192009T HR P20192009 T1 HRP20192009 T1 HR P20192009T1
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methyl
hydroxy
isoxazol
butanamide
methylsulfonyl
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Jiping Fu
Xianming Jin
Subramanian Karur
Guillaume LAPOINTE
Ann Marie Madera
Zachary Kevin Sweeney
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Novartis Ag
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial 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
    • 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
    • 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
    • C07D413/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D413/12—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 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Engineering & Computer Science (AREA)
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  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Claims (15)

1. Spoj formule (I): ili njegova farmaceutski prihvatljiva sol, pri čemu: X je -NH- i R1 je -CH(OH)-Y; ili X je -CH2- i R1 je -CH(OH)-Y ili -SO2R2 gdje je R2 C1-C3 alkil; R3 je H ili halo; Y je odabran iz 5-članog heteroaril prstena koji sadrži 1-3 heteroatoma odabranih između N, O i S kao članova prstena, fenila i C1-3 alkila i svaki Y je opcionalno supstituiran s jednim do tri R4; svaki R4 je neovisno odabran između halo, C1-3 alkila i C3-6 cikloalkila, pri čemu C1-3 alkil i C3-6 cikloalkil su svaki opcionalno supstituirani sa do tri skupine odabrane između halo, CN i –OH; L je -C≡C- ili -CR5=CR5-; R5 je neovisno odabran pri svakom pojavljivanju između H, halo i metila; i Z je odabran između C1-6 alkila, C3-C6 cikloalkila, piridinila i fenila, od kojih je svaki opcionalno supstituiran sa do tri skupine odabrane između halogena, hidroksi, C1-4 alkoksi, C1-4 haloalkoksi, CN i C1-4 alkila koji je opcionalno supstituiran s jednom do tri skupina odabranih između halogena, hidroksi, amino, CN i C1-3 alkoksi; ili, kada je L -CR5=CR5-, Z uzet zajedno s jednom od R5 skupina i bilo koji atomi koji povezuju Z s R5 skupinom mogu tvoriti 3-7-članu cikloalkil ili cikloalkenil skupinu koja je opcionalno supstituirana sa do tri skupine odabrane između halogena, hidroksi, C1-4 alkoksi, C1-4 haloalkoksi, CN i C1-4 alkila koji je opcionalno supstituiran s jednom do tri skupina odabranih između halogena, hidroksi, amino, CN i C1-3 alkoksi.
2. Spoj u skladu s patentnim zahtjevom 1, pri čemu je R1 -SO2R2.
3. Spoj u skladu s patentnim zahtjevom 1 ili 2, pri čemu je X -CH2-.
4. Spoj u skladu s bilo kojim od patentnih zahtjeva 1-3, pri čemu je Z C1-C4 alkil ili C3-C6 cikloalkil i Z je opcionalno supstituiran sa do tri skupine odabrane između halogena, C1-4 alkoksi, C1-4 haloalkoksi, CN i C1-4 alkila opcionalno supstituiranih s jednom do tri skupina odabranih između halogena, hidroksi, amino, CN i C1-3 alkoksi.
5. Spoj u skladu s bilo kojim od prethodnih patentnih zahtjeva, pri čemu je L -C=C- .
6. Spoj u skladu s patentnim zahtjevom 1, pri čemu je spoj formule (II):
7. Spoj u skladu s patentnim zahtjevom 1, pri čemu je spoj odabran iz skupine koja se sastoji od (R)-4-(5-(ciklopropiletinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-(ciklobutiletinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-(3,3-dimetilbut-1-in-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-N-hidroksi-2-metil-2-(metilsulfonil)-4-(5-(prop-1-in-1-il)izoksazol-3-il)butanamida, (R)-4-(5-(but-1-in-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-N-hidroksi-2-metil-4-(5-(3-metilbut-1-in-1-il)izoksazol-3-il)-2-(metilsulfonil)butanamida, (R)-N-hidroksi-2-metil-2-(metilsulfonil)-4-(5-(pent-1-in-1-il)izoksazol-3-il)butanamida, (R)-N-hidroksi-2-metil-4-(5-((1-metilciklopropil)etinil)izoksazol-3-il)-2-(metilsulfonil)butanamida, (R)-4-(5-(5-fluorobut-1-in-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-(5-fluoropent-1-in-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-(5,5-difluoropent-1-in-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-((3,3-difluor)etinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-((3-fluorociklobutil)etinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-N-hidroksi-4-(5-(5-hidroksi-5-metilheks-1-in-1-il)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, (R)-N-hidroksi-4-(5-((3-(metoksimetil)ciklobutil)etinil)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, (R)-N-hidroksi-4-(5-((3-(2-hidroksipropan-2-il)ciklobutil)etinil)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, N-hidroksi-4-(5-((4-(hidroksimetil)fenil)etinil)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, N-hidroksi-4-(5-((4-(2-hidroksietil)fenil)etinil)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, N-hidroksi-4-(5-((4-(2-hidroksi-1-metoksietil)fenil)etinil)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, N-hidroksi-2-metil-2-(metilsulfonil)-4-(5-(feniletinil)izoksazol-3-il)butanamida, N-hidroksi-4-(5-((4-((R)-2-hidroksipropil)fenil)etinil)izoksazol-3-il)-2-metil-2-(metilsulfonil)butanamida, (R)-N-hidroksi-4-(5-((4-((S)-2-hidroksi-1-metoksietil)fenil)etinil)-izoksazol-3-il)-2-metil-2-(metilsulfonil)-butanamida, (R)-4-(5-((4-((S)-1,2-dihidroksietil)fenil)etinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (R)-4-(5-((4-((R)-1,2-dihidroksietil)fenil)etinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamida, (2S,3R)-2-(((5-(ciklopropiletinil)izoksazol-3-il)metil)amino)-N,3-dihidroksi-2-metil-3-(5-metilizoksazol-3-il)propanamid, (2S,3R)-2-(((5-(ciklobutiletinil)izoksazol-3-il)metil)amino)-N,3-dihidroksi-2-metil-3-(5-metilizoksazol-3-il)propanamid, (2S,3R)-N,3-dihidroksi-2-metil-3-(5-metilizoksazol-3-il)-2-(((5-(feniletinil)izoksazol-3-il)metil)amino)propanamid, N,3-dihidroksi-3-(5-(hidroksimetil)izoksazol-3-il)-2-metil-2-(((5-(feniletinil)izoksazol-3-il)metil)amino)propanamid, (2S,3R)-N,3-dihidroksi-2-(((5-(6-metoksiheks-1-in-1-il)izoksazol-3-il)metil)amino)-2-metil-3-(5-metilizoksazol-3-il)propanamid, 2-(((5-(ciklopropiletilin) izoksazol-3-il)metil)amino)-3-(5-ciklopropilizoksazol-3-il)-N,3-dihidroksi-2-metilpropanamid, (R,E)-4-(5-(but-1-en-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid, (R,E)-4-(5-(2-ciklopropilvinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid, (R,E)-4-(5-(but-2-en-2-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid, (R,Z)-4-(5-(but-2-en-2-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid, (R,Z)-4-(5-(2-ciklopropil-1-fluorovinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid, (R,E)-4-(5-(2-ciklopropil-1-fluorovinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid, (R,Z)-4-(5-(2-ciklopropil-2-fluorovinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid i (R)-4-(5-(cikloheks-1-en-1-il)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid ili njegova farmaceutski prihvatljiva sol.
8. Spoj u skladu s patentnim zahtjevom 1, koji je (R)-4-(5-(ciklopropiletinil)izoksazol-3-il)-N-hidroksi-2-metil-2-(metilsulfonil)butanamid ili njegova farmaceutski prihvatljiva sol.
9. Farmaceutski pripravak, koji sadrži: spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 8 i farmaceutski prihvatljiv nosač.
10. Farmaceutska kombinacija, koja sadrži: spoj u skladu s bilo kojim od patentnih zahtjeva 1 do 8, antibakterijski učinkovitu količinu drugog terapeutskog sredstva i farmaceutski prihvatljiv nosač.
11. Farmaceutska kombinacija u skladu s patentnim zahtjevom 10, pri čemu je drugo terapeutsko sredstvo odabrano iz skupine koja se sastoji od ampicilina, piperacilina, penicilina G, tikarcilina, imipenema, meropenema, azitromicina, eritromicina, aztreonama, cefepima, cefotaksima, ceftriaksona, ceftazidima, ciprofloksacina, levofloksacina, klindamicina, doksiciklina, gentamicina, amikacina, tobramicina, tetraciklina, tigeciklina, rifampicina, vankomicina i polimiksina.
12. Spoj u skladu s patentnim zahtjevima 1 do 8 ili njegova farmaceutski prihvatljiva sol, za uporabu kao lijek.
13. Spoj u skladu s patentnim zahtjevima 1 do 8 ili njegova farmaceutski prihvatljiva sol, za uporabu u liječenju gram–negativne bakterijske infekcije.
14. Spoj u skladu s patentnim zahtjevima 1 do 8 ili njegova farmaceutski prihvatljiva sol, za uporabu u liječenju gram–negativne bakterijske infekcije, pri čemu je bakterijska infekcija odabrana iz vrsta Pseudomonadales i Enterobacteriaceae koje su odabrane iz skupine koja se sastoji od vrsta Pseudomonas, Acinetobacter, Stenotrophomonas, Burkholderia, Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Shigella, Providencia, Morganella, Cedecea, Yersina i Edwardsiella i Escherichia coli.
15. Spoj za uporabu u skladu s patentnim zahtjevom 13, pri čemu se spoj formule (I) koristi u kombinaciji s imunomodulatorom.
HRP20192009TT 2014-12-16 2019-11-06 Spojevi izoksazol hidroksamske kiseline kao inhibitori lpxc-a HRP20192009T1 (hr)

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Application Number Priority Date Filing Date Title
US201462092402P 2014-12-16 2014-12-16
PCT/IB2015/059631 WO2016097995A1 (en) 2014-12-16 2015-12-15 Isoxazole hydroxamic acid compounds as lpxc inhibitors
EP15816893.0A EP3233843B1 (en) 2014-12-16 2015-12-15 Isoxazole hydroxamic acid compounds as lpxc inhibitors

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