WO2011073119A1 - Mk2 inhibitors - Google Patents

Mk2 inhibitors Download PDF

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Publication number
WO2011073119A1
WO2011073119A1 PCT/EP2010/069465 EP2010069465W WO2011073119A1 WO 2011073119 A1 WO2011073119 A1 WO 2011073119A1 EP 2010069465 W EP2010069465 W EP 2010069465W WO 2011073119 A1 WO2011073119 A1 WO 2011073119A1
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Prior art keywords
pyrrolo
piperidine
alkyl
cycloalkyl
diseases
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2010/069465
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English (en)
French (fr)
Inventor
Tjeerd Andries Barf
Arthur Oubrie
Carsten Schultz - Fademrecht
Eduard Willem Zwart
Niels Hoogenboom
Sander Martijn De Wilde
Allard Kaptein
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Organon NV
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Organon NV
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Publication date
Priority to JP2012542575A priority Critical patent/JP5859454B2/ja
Priority to RU2012129887/04A priority patent/RU2012129887A/ru
Priority to CN201080056801.XA priority patent/CN102712641B/zh
Priority to IN4978DEN2012 priority patent/IN2012DN04978A/en
Priority to BR112012013199A priority patent/BR112012013199A8/pt
Priority to CA2780290A priority patent/CA2780290C/en
Priority to AU2010333024A priority patent/AU2010333024B2/en
Priority to US13/514,865 priority patent/US8772286B2/en
Application filed by Organon NV filed Critical Organon NV
Priority to EP10795655.9A priority patent/EP2513111B1/en
Priority to MX2012006778A priority patent/MX2012006778A/es
Publication of WO2011073119A1 publication Critical patent/WO2011073119A1/en
Anticipated expiration legal-status Critical
Priority to US14/297,167 priority patent/US9102676B2/en
Priority to US14/795,085 priority patent/US20160159800A1/en
Ceased legal-status Critical Current

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic 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
    • C07D471/12—Heterocyclic 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 three hetero rings
    • C07D471/20—Spiro-condensed systems
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    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • 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
    • A61K31/444—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
    • A—HUMAN NECESSITIES
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    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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

Definitions

  • the present invention relates to pyrrolo[3,2-c]pyridin]-4'( H)-one derivatives, to pharmaceutical compositions comprising the same and to the use of said compounds for the manufacture of medicaments for the treatment of immunological disorders and oncology.
  • R2 has to be introduced after the Hantzsch or Paal-Knorr condensation reaction with an art-known Suzuki, Stille (when Y is a bond) or Buchwald (when Y is -C(O)NH-) coupling utilizing Pd-catalyzed chemistry and a chlorine as the leaving group as in (IV).
  • the resulting enol ether derivative (Via) can be brominated to a- bromoketone derivative (Ila) as described by Vanotti et al [J. Med. Chem. (2008), 51, 487-501].
  • Intermediates of the type (II) can be readily used in the Hantzsch or Paal- Knorr condensation reaction.
  • the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
  • the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray.
  • Neurodegenerative diseases that can be treated or prevented include, among others, Alzheimer's disease, Parkinson's disease, cerebral ischaemia, and traumatic neurodegenerative disease.
  • the used method was a 25-minute run, that consists of continuous flow of 0.3 % TFA-solution in water combined with a 10 - 80% or 10 - 100% gradient of acetonitrile with water as the counter eluent.
  • Step 6 tert-butyl 2'-f2-fbenzofuran-2-yl)pyrimidin-4-yl)-5'-f4-methoxybenzyl)-4'- oxo-l' ⁇ ' ⁇ ' ⁇ '-tetrahydrospiroipiperidine ⁇ '-pyrrolo ⁇ -clpyridinel-l- carboxylate ( A6)
  • Example 1 6 2'-f2-f4-acetylphenyl)pyrimidin-4-yl)-5'.,6'-dihydrospiro[piperidine-
  • Example 1 8 N-f5-f4-f4'-oxo-l',4',5',6'-tetrahydrospiro[piperidine-4,7'- pyrrolo [3,2-cl pyridinel -2 '-yl)pyrimidin-2-yl)pyridin-2-yl)acetamide
  • Example 1 1 (76.9 mg, 0.193 mmol) was suspended in acetonitrile (6 mL). Formaldehyde (37 %, 0.101 mL, 1.348 mmol), sodium cyanoborohydride (36.3 mg, 0.578 mmol) and some drops of acetic acid were added to the suspension and the mixture was stirred 15 h at room temperature. The reaction mixture was brought onto a SCX-column and was rinsed with MeOH. The product was washed off the column using 0.7M NH 3 in MeOH. After concentration of the product under vacuum the residue was purified by semi-preparative HPLC (Method A) and isolated as TFA-salt.
  • Example 2 2 '-( 2-( benzofuran-2-yl)pyrimidin-4-yl)- l-ethyl-5 ',6 '- dihydrospiro [piperidine-4,7'-pyrrolo [3,2-cl pyridinl -4'(1 'H)-one
  • Step 4 2-tert-butyl 10-methyl 8-(4-methoxybenzyl)-9,ll-dioxo-2,8- diazaspiro [5.51 undecane-2, 10-dicarboxylate ( C4)
  • Step 5 tert-butyl 8-f4-methoxybenzyl)-9,ll-dioxo-2,8-diazaspiro[5.51undecane-2- carboxylate (C5)
  • Step 3 4-tert-butyl 2-methyl 2-fhydroxymethyl)morpholine-2,4-dicarboxylate ⁇ E31
  • Example 13 1 N- ⁇ - ⁇ '-oxo-l' ⁇ ' ⁇ ' ⁇ '-tetrahydrospiroipiperidine-S '- pyrrolo[3.,2-clpyridinel-2'-yl)pyrimidin-2-yl)-4-ftrifluoromethyl)benzamide
  • Serial dilution log 10 from 2 mM to 63.2 nM of test compounds are made in 100% DMSO.
  • the dilutions in DMSO are then diluted 50-fold in KR-buffer of which 5 ⁇ is used in the assay, leading to a final compound concentration range in the assay from 10 ⁇ ⁇ 0.316 nM.
  • 5 ⁇ of test compound in K buffer (final DMSO concentration in the assay is 0.5%) is mixed with 5 ⁇ /well of 0.1 U/mL MK2 enzyme (active enzyme (peptide 46- end (Millipore), final concentration in the assay is 25 mU/rnL).
  • FP signal is read. Fluorescence at 535 nm is measured using parallel and perpendicular filters to determine differences in rotation due to binding of the phosphorylated substrate peptide to the beads. Values are calculated as percentage of the difference in readout ( ⁇ ) of the controls with and without ATP. EC50 values are determined by curve fitting of the experimental results using Activity Base. Examples 1 14, 1 18, 1 19, 1 20, 1 26, 1 33, 1 34, 2_2, 2_3, 3_2, 7_1, 9_3, 10 1, 13 1, 13 2 have a pEC50 value of 6.5 - 7.5.
  • Examples 1_2, 4_3, 6_1, 8_2, 8_3, 11_1, 12 1, 12_2 have a pEC50 value of > 8.5
  • Example 15
  • the calibration line is built with different concentrations of the test compound (standards), prepared from the same 10 mM DMSO stock solution.
  • a volume (7 uL) from the same DMSO stock solution was diluted with DMSO (273 uL) leading to a solution with concentration of 0.25 mM.
  • three different injection volumes (0.2, 1, 1.8 uL) were injected on UPLC.
  • the respective peak areas are plotted against amount of compound to build up the calibration line.
  • the calibration line is used to determine the amount of dissolved compound in each sample, selecting the injection that gave peak areas closest to the peak area range of the calibration standards. This result was then converted to the solubility in mg/L.

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PCT/EP2010/069465 2009-12-14 2010-12-13 Mk2 inhibitors Ceased WO2011073119A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
AU2010333024A AU2010333024B2 (en) 2009-12-14 2010-12-13 MK2 inhibitors
CN201080056801.XA CN102712641B (zh) 2009-12-14 2010-12-13 Mk2抑制剂
IN4978DEN2012 IN2012DN04978A (cg-RX-API-DMAC7.html) 2009-12-14 2010-12-13
BR112012013199A BR112012013199A8 (pt) 2009-12-14 2010-12-13 Composto, composição farmacêutica, e , uso de um composto
CA2780290A CA2780290C (en) 2009-12-14 2010-12-13 Mk2 inhibitors
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US12637436B2 (en) 2014-06-10 2026-05-26 Sanford Burnham Prebys Medical Discovery Institute Metabotropic glutamate receptor negative allosteric modulators (NAMs) and uses thereof
WO2020011731A1 (en) * 2018-07-12 2020-01-16 UCB Biopharma SRL Spirocyclic indane analogues as il-17 modulators
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