ME01882B - 1 '-supstituisani-karba-nukleozidni prolekovi za antivirusni tretman - Google Patents

1 '-supstituisani-karba-nukleozidni prolekovi za antivirusni tretman

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Publication number
ME01882B
ME01882B MEP-2014-58A MEP5814A ME01882B ME 01882 B ME01882 B ME 01882B ME P5814 A MEP5814 A ME P5814A ME 01882 B ME01882 B ME 01882B
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alkyl
aryl
heterocyclyl
independently
alkynyl
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MEP-2014-58A
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Aesop Cho
Choung U Kim
Adrian S Ray
Lijun Zhang
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Gilead Sciences Inc
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • 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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/10—Oxygen atoms
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
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  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Saccharide Compounds (AREA)

Claims (23)

1.Jedinjenje Formule I: ili njegova farmaceutski prihvatljiva so ili estar; u kojoj: R1 je H, (C1-C8)alkil, (C2-C8)alkenil, ili (C2-C8)alkinil; R2 je OH ili -0C(0)R3; svaki R3 je nezavisno H, OR4, NH(R4), N(R4)2, SR4, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8) karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, aril, heterociklil ili heteroaril; svaki Ra R4 ili R6 je nezavisno (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8) karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C6-C2o)heterociklil ili heteroaril; jedan od W1 ili W2 je i drugi od W1 ili W2 je OR4 ili svaki Rc, Rd ili R5 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C6-C2o)heterociklil ili heteroaril; svaki R8 je halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, NO, N02, CHO, CN, -CH(=NR11), -CH=NNHR11, -CH=N(OR11), -CH(OR11)2, -C(=0)NR11R12, -C(=S)NR11R12, -C(=0)0R11, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C1-C8)karbociklilalkil, (C6-C2o)aril, (C6-C2o)heterociklil, heteroaril, -C(=0)(C1-C8)alkil, -S(0)n(C1-C8)alkil, aril(C1-C8)alkil, OR11 ili SR11; svaki n je nezavisno 0, 1, ili 2; svaki R9 ili R10 je nezavisno H, halogen, NR11R12, N(Rn)OR11, NR11NR11R12, N3, NO, N02, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(OR11)2, -C(=0)NR11R12, -C(=S)NR11R12, -C(=0)0R11, R11, OR11 ili SR11; svaki R11 or R12 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C2-C2o)heterociklil, heteroaril, -C(=0)(C1-C8)alkil, -S(0)n(C1-C8)alkil ili R11 i R12 zajedno sa azotom za koji su oba vezana obrazuju 3 do 7-člani heterociklični prsten gde ma koji ugljenikov atom u pomenutom heterocikličnom prstenu može opciono biti zamenjen sa -O-, -S(0)n- ili -NRa-; i gde je svaki (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C6-C2o) heterociklil, heteroaril u Rc, Rd, R1, R1, R3, R4, R5, R6. R8, R11 ili R12 nezavisno, opciono supstituisan sa jednim ili više halo, hidroksi, CN, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, 0C(0)N(Ra)2, 0C(0)NH(Ra), 0C(0)NH2, C(0)0Ra, 0C(0)0Ra, C(0)Ra, 0C(0)Ra, S(0)nRa. S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, ORa ili Ra. ili njegova farmaceutski prihvatljiva so ili estar, gde je svaki H.
2. Jedinjenje prema zahtevu 1, predstavljeno Formulom II
3.    Jedinjenje prema zahtevu 1 ili 2, u kom je R1 (C1-C8)alkil.
4.    Jedinjenje prema ma kom od zahteva 1 -3, u kom je R2 OH.
5.    Jedinjenje prema ma kom od zahteva 1-4, predstavljeno Formulom III: ili njegova farmaceutski prihvatljiva so ili estar; u kom: R3 je (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8) karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, aril, heterociklil ili heteroaril; svaki Ra ili R6 je nezavisno (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8) karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkik (C6-C2o)aril, (C2-C2o)heterociklil ili heteroaril; jedan od W1 ili W2 je i drugi od W' ili or W2 je OR4 ili svaki Rc ili Rd je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8) karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C6-C2o)heterociklil ili heteroaril; svaki R4 je (C6-C2o)aril ili heteroaril; svaki R8 je halogen, NR11R12, N(R11)OR11, NR11NR11Ri2, N3, -S(0)n(C1-C8)alkil, OR11 ili SR11; svaki n je nezavisno 0, 1, ili 2; svaki R9 je nezavisno H, halogen, NR11R12, N(R11)OR11, NR11NR11R12, N3, OR11 ili SR11; svaki R11 ili R12 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8) karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C2-C2o)heterociklil, heteroaril, -C(=0)(C1-C8)alkil, -S(O)n(C1-C8)alkil ili R11 i R12 zajedno sa azotom za koji su oba vezana obrazuju 3 do 7-člani heterociklični prsten u kome ma koji ugljenikov atom u pomenutom heterocikličnom prstenu može opciono biti zamenjen sa -O-, -S(0)n- ili -NRa-; i gde je svaki (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C2-C2o)heterociklil, heteroaril u Rc, Rd. R3. R4, R6, R8, R11 ili R12 je, nezavisno, opciono supstituisan sa jednim ili više halo, hidroksi, CN, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(OjN(Ra)2, OC(OjNH(Ra), OC(OjNH2, C(OjORa, OC(O)ORa, C(0)Ra, OC(O)Ra, S(0)nRa. S(0)2N(Ra)2, S(O)2NH(Ra), S(0)2NH2, ORa ili Ra.
6. Jedinjenje prema ma kom od zahteva 1 -5, predstavljeno Formulom IV: ili njegova farmaceutski prihvatljiva so ili estar; gde: R3 je (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil ili (C4-C8) karbociklilalkil; svaki Ra je nezavisno (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C2-C2o)heterociklil ili heteroaril; svaki Rc ili Rd je nezavisno H ili metil; R4 je (C6-C20)aril; R6 je (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil ili (C4-C8)karbociklilalkil; svaki R8 je halogen, NR11R12, N(R11)OR11, NRnNR11R12, N3, -S(O)n(C1-C8)alkil, OR11 ili SR11; svaki n je nezavisno 0, 1, ili 2; svaki R9 je nezavisno H, halogen, NRnR12, N(Rn)ORn, NR11NR11R12, N3, OR11 ili SR"; svaki R11 ili R12 je nezavisno H, (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8) karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C2-C2o)heterociklil, heteroaril, -C(=O)(C1-C8)alkil, -S(0)n(C1-C8)alkil ili R11 i R12 zajedno sa azotom za koji su oba vezana obrazuju 3 do 7-člani heterociklični prsten gde ma koji ugljenikov atom iz navedenog heterocikličnog prstena može opciono biti zamenjen sa -O-, -S(0)n- ili -NRa-; i gde je svaki (C1-C8)alkil, (C2-C8)alkenil, (C2-C8)alkinil, (C3-C8)karbociklil, (C4-C8)karbociklilalkil, aril(C1-C8)alkil, heterociklil(C1-C8)alkil, (C6-C2o)aril, (C2-C20) heterociklil, heteroaril u R3, R4. R6, R8, R11 ili R12 je, nezavisno, opciono supstituisan sa jednim ili više halo, hidroksi, CN, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, 0C(0)N(Ra)2, 0C(0)NH(Ra), 0C(0)NH2, C(0)0Ra, 0C(0)0Ra, C(0)Ra, 0C(0)Ra, S(0)nRa. S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, ORa ili Ra.
7.    Jedinjenje prema ma    kom od     zahteva    1 -6, u kom je hiralnost na fosforu     R.
8.    Jedinjenje prema ma    kom od     zahteva    1-6, u kom je hiralnost na fosforu     S.
9.    Jedinjenje prema ma    kom od     zahteva    1-8, u kom je R3 (C1-C8)alkil.
10.    Jedinjenje prema ma kom od zahteva 1-9, u kom je jedan od Rc ili Rd H i drugi od Rc ili Rd je (C1-C8)alkil.
11.    Jedinjenje prema ma kom od zahteva 1-10, u kom je R6 (C1-C8)alkil.
12.    Jedinjenje prema ma kom od zahteva 1-11, u kom je R8 NR11 R12 ili OR11.
13.    Jedinjenje prema ma    kom od    zahteva    1-12, u kom je R4 H ili NR11 R12.
14.    Jedinjenje prema ma    kom od    zahteva    1-13, u kom je svaki R11 i R12 H.
15.    Jedinjenje prema ma    kom od     zahteva    1-14, u kom je R8 NH2 a R9 je H.
16.    Jedinjenje prema ma    kom od     zahteva    1-15, u kom je R4 (C6-C2o)aril.
17.    Jedinjenje prema zahtevu 1, koje je: ili njegova farmaceutski prihvatljiva so ili estar.
18.    Farmaceutska smeša koja sadrži terapeutski efektivnu količinu jedinjenja ili njegove farmaceutski prihvatljive soli ili estra, prema ma kom od zahteva 1-17 i farmaceutski prihvatljiv nosač.
19.    Farmaceutska smeša prema zahtevu 18, koja dalje sadrži najmanje jedan dodatni terapeutski agens, odabran iz grupe koja se sastoji od: interferona, ribavirina ili njihovih analoga, inhibitora HCV NS3 proteaze, NS5a inhibitora, inhibitora alfa-glukozidaze 1, hepatoprotektanata, antagonista mevalonat dekarboksilaze, antagonista sistema renin-angiotenzin, drugih anti-fibrotskih sredstava, nukleozidnih ili nukleotidnih inhibitora HCV NS5B polimeraze, ne-nukleozidnih inhibitora HCV NS5B polimeraze, HCV NS5A inhibitora, TLR-7 agonista, ciklofdinskih inhibitora, HCV IRES inhibitora, farmakokinetskih inhejsera i drugih lekova za lečenje HCV-a.
20.    Jedinjenje, prema ma kom od zahteva 1 do 17, za upotrebu u inhibisanju HCV polimeraze, koje podrazumeva primenjivanje sisaru kome je to neophodno terapeutski efektivne količine jedinjenja ili njegove farmaceutski prihvatljive soli ili estra, prema ma kom od zahteva 1-17.
21.    Jedinjenje, prema ma kom od zahteva 1 do 17, ili farmaceutska smeša prema zahtevu 18 ili zahtevu 19, za upotrebu u lečenju virusne infekcije prouzrokovane hepatitis C virusom, gde tretman podrazumeva primenjivanje sisaru kome je to neophodno terapeutski efektivne količine jedinjenja ili njegove farmaceutski prihvatljive soli ili estra, prema ma kom od zahteva 1 do 17, ili farmaceutske smeše prema zahtevu 18 ili zahtevu 19.
22.    Jedinjenje ili smeša za korišćenje u lečenju virusne infekcije prouzrokovane hepatitis C virusom, prema zahtevu 21, koja dalje uključuje primenjivanje najmanje jednog dodatnog terapeutskog sredstva, odabranog iz grupe koja se sastoji od: interferona, ribavirina ili njihovih analoga, inhibitora HCV NS3 proteaze, NS5a inhibitora, inhibitora alfa-glukozidaze 1, hepatoprotektanata, antagonista mevalonat dekarboksilaze, antagonista sistema renin-angiotenzin. drugih anti-fibrotskih sredstava, nukleozidnih ili nukleotidnih inhibitora HCV NS5B polimeraze, ne-nukleozidnih inhibitora HCV NS5B polimeraze, HCV NS5A inhibitora, TLR-7 agonista, ciklofilinskih inhibitora, HCV IRES inhibitora, farmakokinetskih inhejsera i drugih lekova za lečenje HCV-a.
23.    Jedinjenje prema ma kom od zahteva 1 do 17, ili farmaceutska smeša prema zahtevu 18 ili zahtevu 19, za upotrebu u terapiji.
MEP-2014-58A 2010-05-28 2011-05-26 1 '-supstituisani-karba-nukleozidni prolekovi za antivirusni tretman ME01882B (me)

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US13/117,060 US8415308B2 (en) 2010-05-28 2011-05-26 1′-substituted-carba-nucleoside prodrugs for antiviral treatment
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