ME02394B - Pirazolohinolinski derivati kao inhibitori pde9 - Google Patents

Pirazolohinolinski derivati kao inhibitori pde9

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Publication number
ME02394B
ME02394B MEP-2016-65A MEP201665A ME02394B ME 02394 B ME02394 B ME 02394B ME P201665 A MEP201665 A ME P201665A ME 02394 B ME02394 B ME 02394B
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ME
Montenegro
Prior art keywords
group
pyrazolo
methoxy
dimethylpyridin
compound
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MEP-2016-65A
Other languages
German (de)
English (en)
French (fr)
Inventor
Yoshihiko Norimine
Kunitoshi Takeda
Koji Hagiwara
Yuichi Suzuki
Yuki Ishihara
Nobuaki Sato
Original Assignee
Eisai R&D Man Co Ltd
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Publication of ME02394B publication Critical patent/ME02394B/me

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • 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
    • A61K31/4353Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic 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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

LISTA SEKVENCI
<110> Eisai R&D Management Co., Ltd.
<120> Derivati pirazolohinolina
<130> ECL11-020
<150> US 61/544860
< 151> 2011-10-07
<150> US 61/550623
< 151> 2011-10-24
<150> US 61/558110
< 151> 2011-11-10
<150> US 61/580903
< 151> 2011-12-28
<160> 2
<170> PatentIn verzija 3.1
<210> 1
< 211> 22
< 212> DNA
< 213> Veštačka
<220>
< 223> hPDE9-1
<400> 1
aggatgggat ccggctcctc ca    22
<210> 2
< 211> 21
< 212> DNA
< 213> Veštačka
<220>
< 223> hPDE9A-3
<400> 2
caggcacagt ctccttcact g    21
 

Claims (18)

1.Jedinjenje ili njegova farmakološki prihvatljiva so, naznačeno time, što je predstavljeno sa formulom (1):u kojojR1 je atom vodonika;R2 je aromatska prstenska grupa koja je izabrana iz grupe koja obuhvata fenilnu grupu, piridilnu grupu, i pirimidinilnu grupu, pri čemu dva atoma u aromatskom prstenu, koja su susedna atomu ugljenika koji je spojen na pirazolo[4,3-c]hinolinski prsten, svaki nezavisno poseduju supstituent koji je izabran iz Grupe A1, a ostali atomi na aromatskom prstenu nezavisno ponekad sadrže supstituent koji je izabran iz Grupe B1;R3 je atom vodonika, ili atom fluora;R4 je atom vodonika;R5 je oksepanilna grupa, dioksepanilna grupa, tetrahidropiranilna grupa, ili tetrahidrofuranilna grupa koja ponekad sadrži metoksi grupu;R6 je atom vodonika;Grupa A1 sadrži halogen atom, C1-6 alkilnu grupa koja ponekad sadrži 1 do 3 halogena atom, i C1-6 alkoksi grupu; aGrupa B1 se sastoji od halogenog atoma, cijano grupe, C1-6 alkilne grupe koja ponekad sadrži 1 do 3 halogena atoma, C1-6 alkoksi-C1-6 alkilne grupe, C1-6 alkoksi grupe koja ponekad sadrži 1 do 3 halogena atoma, i tetrahidropiranilne grupe,pod uslovom da kada R2 je 3-piridilna grupa, supstituent na poziciji 4 je halogeni atom, ili C1-6 alkilna grupa koja ponekad sadrži 1 do 3 halogena atoma.
2.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 1, naznačeno time, što R2 je aromatska prstenska grupa koja je izabrana iz grupe koja obuhvata fenilnu grupu, 3-piridilnu grupu, 4-piridilnu grupu, i 5-pirimidinilnu grupu, pri čemu dva atoma u aromatskom prstenu koja su susedna atomu ugljenika, koji je spojen na pirazolo[4,3-c]hinolinski prsten, svaki nezavisno sadrže supstituent koji je izabran iz Grupe A2, a ostali atomi u aromatskom prstenu nezavisno ponekad sadrže supstituent koji je izabran iz Grupe B2; R5 je 4-oksepanilna grupa, 1,4-dioksepan-6-il grupa, 3,4,5,6-tetrahidro-2H-3-piranilna grupa, 3,4,5,6-tetrahidro-2H-4-piranilna grupa, ili 3-tetrahidrofuranilna grupa; Grupa A2 se sastoji od atoma hlora, i metilne grupe koja ponekad sadrži 1 do 2 atoma fluora, etilne grupe, metoksi grupe, i etoksi grupe; a Grupa B2 se sastoji od atoma fluora, atoma hlora, cijano grupe, metilne grupe koja ponekad sadrži 1 do 3 atoma fluora, etilne grupe, metoksimetilne grupe, metoksi grupe koja ponekad sadrži 1 do 3 atoma fluora, etoksi grupe, izopropiloksi grupe, i 3,4,5,6-tetrahidro-2H-4-piranilne grupe.
3.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 2, naznačeno time, što R3 je atom fluora.
4.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 1, naznačeno time, što R3 je atom vodonika; a R5 je tetrahidropiranilna grupa, ili tetrahidrofuranilna grupa koja ponekad sadrži metoksi grupu.
5.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 2, naznačeno time, što R3 je atom vodonika; a R5 je 3,4,5,6-tetrahidro-2H-3-piranilna grupa, 3,4,5,6-tetrahidro-2H-4-piranilna grupa, ili 3-tetrahidrofuranilna grupa.
6.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 1, naznačeno time, što R2 je aromatska prstenska grupa koja je izabrana iz grupe koja obuhvata fenilnu grupu, 3-piridilnu grupu, i 4-piridilnu grupu, pri čemu dva atoma u aromatskom prstenu koja su susedna atomu ugljenika, koji je spojen na pirazolo[4,3-c]hinolinski prsten, svaki nezavisno sadrže supstituent koji je izabran iz Grupe A3, a ostali atomi u aromatskom prstenu nezavisno ponekad sadrže supstituent koji je izabran iz Grupe B3; R3 je atom vodonika; R4 je atom vodonika; R5 je 3,4,5,6-tetrahidro-2H-4-piranilna grupa, ili 3-tetrahidrofuranilna grupa; Grupa A3 se sastoji od metilne grupe, i metoksi grupe; a Grupa B3 se sastoji od metilne grupe, metoksi grupe, i metoksimetilne grupe.
7.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 1, naznačeno time, što je izabrano iz sledeće grupe: 1)7-(6-metoksi-2,4-dimetilpiridin-3-il)-1-(tetrahidro-2H-piran-4-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 2)7-(2-metoksi-4,6-dimetilpiridin-3-il)-1-(tetrahidro-2H-piran-4-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 3)(S)-7-(6-izopropiloksi-2,4-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 4)8-fluoro-7-(2-metoksi-4,6-dimetilpiridin-3-il)-1-(tetrahidro-2H-piran-4-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 5)1-(1,4-dioksepan-6-il)-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 6)1-(1,4-dioksepan-6-il)-7-(2-metoksi-4,6-dimetilpiridin-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 7)(S)-8-fluoro-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 8)7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidro-2H-piran-4-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 9)(-)-7-(2-metoksi-4,6-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 10)(-)-7-(6-metoksi-2,4-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 11)(S)-8-fluoro-7-(2-metoksi-4,6-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 12)(S)-7-(6-etoksi-2,4-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on, 13)(S)-8-fluoro-7-(6-metoksi-2,4-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-((5H)-on, i 14)(S)-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on.
8.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja 7-(6-izopropiloksi-2,4-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on.
9.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja (S)-7-(6-izopropiloksi-2,4-dimetilpiridin-3-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on
10.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja 8-fluoro-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on.
11.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja (S)-8-fluoro-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on:
12.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja 7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on.
13.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja (S)-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1-(tetrahidrofuran-3-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on:
14.Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 7, naznačeno time, što predstavlja 1-(1,4-dioksepan-6-il)-7-(2-metoksi-3,5-dimetilpiridin-4-il)-1H-pirazolo[4,3-c]hinolin-4(5H)-on:
15.Farmaceutska kompozicija, naznačena time, što sadrži jedinjenje ili njegovu farmakološki prihvatljivu so u skladu sa zahtevom 1 kao aktivni sastojak.
16.Farmaceutska kompozicija u skladu sa zahtevom 15, naznačena time, što se upotrebljava kao inhibitor PDE9.
17.Farmaceutska kompozicija u skladu sa zahtevom 15, naznačena time, što se upotrebljava u postupku za povećavanje koncentracije intracerebralnog cGMP.
18. Jedinjenje ili njegova farmakološki prihvatljiva so u skladu sa zahtevom 1, naznačeno time, što se upotrebljava za poboljšanje kognitivnih poremećaja kod Alzheimer-ove bolesti.
MEP-2016-65A 2011-10-07 2012-10-04 Pirazolohinolinski derivati kao inhibitori pde9 ME02394B (me)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US201161544860P 2011-10-07 2011-10-07
US201161550623P 2011-10-24 2011-10-24
US201161558110P 2011-11-10 2011-11-10
US201161580903P 2011-12-28 2011-12-28
EP12837953.4A EP2769980B1 (en) 2011-10-07 2012-10-04 Pyrazoloquinoline derivative as pde9 inhibitors
PCT/JP2012/075748 WO2013051639A1 (ja) 2011-10-07 2012-10-04 ピラゾロキノリン誘導体

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