WO2011084486A1 - 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof - Google Patents

1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof Download PDF

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Publication number
WO2011084486A1
WO2011084486A1 PCT/US2010/060514 US2010060514W WO2011084486A1 WO 2011084486 A1 WO2011084486 A1 WO 2011084486A1 US 2010060514 W US2010060514 W US 2010060514W WO 2011084486 A1 WO2011084486 A1 WO 2011084486A1
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alkyl
group
compound
heteroarylr
heterocyclylr
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English (en)
French (fr)
Inventor
John Hood
Sunil Kumar Kc
David Mark Wallace
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Epitherix LLC
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Epitherix LLC
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Priority to JP2012546046A priority Critical patent/JP5822844B2/ja
Priority to EP10842538.0A priority patent/EP2515655B1/en
Priority to BR112012018413A priority patent/BR112012018413A2/pt
Priority to ES10842538.0T priority patent/ES2550820T3/es
Priority to CA2785037A priority patent/CA2785037C/en
Priority to EP17187452.2A priority patent/EP3305073B1/en
Priority to CN201080061866.3A priority patent/CN102821607B/zh
Publication of WO2011084486A1 publication Critical patent/WO2011084486A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/415—1,2-Diazoles
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 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
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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Definitions

  • a longstanding idea in cancer biology is that cancers arise and grow due to the formation of cancer stem cells, which may constitute only a minority of the cells within a tumor but are nevertheless critical for its propagation.
  • Stem cells are appealing as the cell of origin for cancer because of their pre-existing capacity for self- renewal and for unlimited replication.
  • stem cells are relatively long-lived in comparison to other cells within tissues, providing a greater opportunity to accumulate the multiple additional mutations that may be required to increase the rate of cell proliferation and produce clinically significant cancers.
  • Wnt signaling pathway which has been implicated in stem cell self-renewal in normal tissues, upon continuous activation has also been associated with the initiation and growth of many types of cancer. This pathway thus provides a potential link between the normal self-renewal of stem cells and the aberrantly regulated proliferation of cancer stem cells.
  • the compounds provided herein may encompass various stereochemical forms.
  • the compounds also encompasses diastereomers as well as optical isomers, e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • optical isomers e.g. mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds.
  • each bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond.
  • n 0.
  • each R 9 is independently selected from the group consisting of H, Ci_9 alkyl, -CF 3 , -(Ci_9 alkyl) n carbocyclyl, -(Ci_9 alkyl) n heterocyclyl, -(Ci_9 alkyl) n aryl and -(Ci_9 alkyl) n heteroaryl.
  • NaHS0 4 sodium bisulfate
  • N-(5-bromopyridin-2-yl)propionamide (XXXV): White solid (89% yield); ESIMS found C 8 H 9 BrN 2 0 mlz 231 (M+H).
  • Steps 1-2 A solution of 5-bromo-l-(tetrahydro-pyran-2-yl)-lH-pyrazolo[3,4- £]pyridin-3-yl]-carbaldehyde (XI) (0.218 g, 0.70 mmol), bis (pinacolato)diboron (0.213 g, 0.84 mmol), and KOAc (0.206 g, 2.1 mmol) in DMF (10 ml) was purged with argon. PdCl 2 (dppf) 2 . DCM was added to the solution and purged again with argon. The solution was heated at 90°C for 2 h under argon and cooled to the room temperature.
  • XI 5-bromo-l-(tetrahydro-pyran-2-yl)-lH-pyrazolo[3,4- £]pyridin-3-yl]-carbaldehyde
  • XI 5-bromo-l-(tetra
  • Another type of multiparticulate system which is also capable of achieving rapid drug dissolution is that of powders, granules, or pellets from water- soluble excipients which are coated with the drug, so that the drug is located at the outer surface of the individual particles.
  • the water-soluble low molecular weight excipient is useful for preparing the cores of such coated particles, which can be subsequently coated with a coating composition comprising the drug and, preferably, one or more additional excipients, such as a binder, a pore former, a saccharide, a sugar alcohol, a film-forming polymer, a plasticizer, or other excipients used in pharmaceutical coating compositions.
  • Skin cancers and skin disorders including, for example, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, and psoriasis.

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  • Diabetes (AREA)
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  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Pain & Pain Management (AREA)
PCT/US2010/060514 2009-12-21 2010-12-15 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof Ceased WO2011084486A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2012546046A JP5822844B2 (ja) 2009-12-21 2010-12-15 １Ｈ−ピラゾロ［３，４−ｂ］ピリジンおよびその治療的使用
EP10842538.0A EP2515655B1 (en) 2009-12-21 2010-12-15 1h-pyrazolo[3,4-beta]pyridines and therapeutic uses thereof
BR112012018413A BR112012018413A2 (pt) 2009-12-21 2010-12-15 1h-pirazol[3,4-b]piridinas e usos terapêuticos dos mesmos.
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