WO2011073119A1 - Mk2 inhibitors - Google Patents

Mk2 inhibitors Download PDF

Info

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
Authority
WO
WIPO (PCT)
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
Application number
PCT/EP2010/069465
Other languages
English (en)
French (fr)
Inventor
Tjeerd Andries Barf
Arthur Oubrie
Carsten Schultz - Fademrecht
Eduard Willem Zwart
Niels Hoogenboom
Sander Martijn De Wilde
Allard Kaptein
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon NV
Original Assignee
Organon NV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to CA2780290A priority Critical patent/CA2780290C/en
Priority to AU2010333024A priority patent/AU2010333024B2/en
Priority to US13/514,865 priority patent/US8772286B2/en
Priority to RU2012129887/04A priority patent/RU2012129887A/ru
Priority to IN4978DEN2012 priority patent/IN2012DN04978A/en
Priority to MX2012006778A priority patent/MX2012006778A/es
Priority to BR112012013199A priority patent/BR112012013199A8/pt
Priority to EP10795655.9A priority patent/EP2513111B1/en
Application filed by Organon NV filed Critical Organon NV
Priority to JP2012542575A priority patent/JP5859454B2/ja
Priority to CN201080056801.XA priority patent/CN102712641B/zh
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

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • 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
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring 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
    • A61K31/495—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
    • 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
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • 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
    • 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
    • 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
    • A61K31/47—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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Neurosurgery (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Transplantation (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Toxicology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Urology & Nephrology (AREA)
PCT/EP2010/069465 2009-12-14 2010-12-13 Mk2 inhibitors Ceased WO2011073119A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR112012013199A BR112012013199A8 (pt) 2009-12-14 2010-12-13 Composto, composição farmacêutica, e , uso de um composto
US13/514,865 US8772286B2 (en) 2009-12-14 2010-12-13 MK2 inhibitors
RU2012129887/04A RU2012129887A (ru) 2009-12-14 2010-12-13 Ингибиторы мк2
IN4978DEN2012 IN2012DN04978A (https=) 2009-12-14 2010-12-13
MX2012006778A MX2012006778A (es) 2009-12-14 2010-12-13 Inhibidores de proteina cinasa 2 activada por proteina cinasa activada por mitogeno.
EP10795655.9A EP2513111B1 (en) 2009-12-14 2010-12-13 Mk2 inhibitors
JP2012542575A JP5859454B2 (ja) 2009-12-14 2010-12-13 Ｍｋ２インヒビター
CA2780290A CA2780290C (en) 2009-12-14 2010-12-13 Mk2 inhibitors
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
US14/297,167 US9102676B2 (en) 2009-12-14 2014-06-05 MK2 inhibitors
US14/795,085 US20160159800A1 (en) 2009-12-14 2015-07-09 Mk2 inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US28609109P 2009-12-14 2009-12-14
EP09179043.6 2009-12-14
EP09179043 2009-12-14
US61/286,091 2009-12-14

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US13/514,865 A-371-Of-International US8772286B2 (en) 2009-12-14 2010-12-13 MK2 inhibitors
US14/297,167 Continuation US9102676B2 (en) 2009-12-14 2014-06-05 MK2 inhibitors

Publications (1)

Publication Number Publication Date
WO2011073119A1 true WO2011073119A1 (en) 2011-06-23

Family

ID=41565893

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2010/069465 Ceased WO2011073119A1 (en) 2009-12-14 2010-12-13 Mk2 inhibitors

Country Status (13)

Country Link
US (3) US8772286B2 (https=)
EP (1) EP2513111B1 (https=)
JP (2) JP5859454B2 (https=)
KR (1) KR20120104241A (https=)
CN (2) CN102712641B (https=)
AU (1) AU2010333024B2 (https=)
BR (1) BR112012013199A8 (https=)
CA (1) CA2780290C (https=)
HK (1) HK1210159A1 (https=)
IN (1) IN2012DN04978A (https=)
MX (1) MX2012006778A (https=)
RU (1) RU2012129887A (https=)
WO (1) WO2011073119A1 (https=)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9969726B2 (en) 2014-06-10 2018-05-15 Sanford-Burnham Medical Research 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
WO2024125451A1 (en) * 2022-12-11 2024-06-20 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Piperindin-ones derivatives, preparation methods and medicinal uses thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2010333024B2 (en) * 2009-12-14 2014-09-18 Merck Sharp & Dohme B.V. MK2 inhibitors
CN102936216B (zh) * 2012-12-05 2015-03-04 南京药石药物研发有限公司 7,9-二氧代-2,6-氮杂-螺[3.5]壬-2-甲酸叔丁酯及其中间体的制备方法
JP2016518316A (ja) * 2013-03-15 2016-06-23 セルジーン アビロミクス リサーチ， インコーポレイテッド Ｍｋ２阻害剤およびそれらの使用
CN108794496B (zh) * 2018-04-28 2020-04-24 北京施安泰医药技术开发有限公司 一类cdk抑制剂、其药物组合物、制备方法及用途
CN114105834B (zh) * 2022-01-26 2023-04-25 寿光诺盟化工有限公司 一种n,n,n,n-四烯丙基氧代双苯磺酰胺的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058762A1 (en) 2002-12-20 2004-07-15 Pharmacia Corporation Mitogen activated protein kinase-activated protein kinase-2 inhibiting compounds
WO2005013986A1 (en) 2003-08-08 2005-02-17 Pharmacia Italia S.P.A. Pyridylpyrrole derivatives active as kinase inhibitors
WO2005014572A1 (en) 2003-08-08 2005-02-17 Pharmacia Italia S.P.A. Pyrimidylpyrrole derivatives active as kinase inhibitors
WO2009010488A1 (en) * 2007-07-16 2009-01-22 Novartis Ag Heterocyclic compounds useful as mk2 inhibitors

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103626742B (zh) * 2005-11-01 2017-04-26 塔格根公司 激酶的联-芳基间-嘧啶抑制剂
AU2010333024B2 (en) * 2009-12-14 2014-09-18 Merck Sharp & Dohme B.V. MK2 inhibitors

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058762A1 (en) 2002-12-20 2004-07-15 Pharmacia Corporation Mitogen activated protein kinase-activated protein kinase-2 inhibiting compounds
WO2005013986A1 (en) 2003-08-08 2005-02-17 Pharmacia Italia S.P.A. Pyridylpyrrole derivatives active as kinase inhibitors
WO2005014572A1 (en) 2003-08-08 2005-02-17 Pharmacia Italia S.P.A. Pyrimidylpyrrole derivatives active as kinase inhibitors
WO2009010488A1 (en) * 2007-07-16 2009-01-22 Novartis Ag Heterocyclic compounds useful as mk2 inhibitors

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"Handbook of Chemistry and Physics", 2004
ANDERSON ET AL., J. MED. CHEM., vol. 50, 2007, pages 2647 - 2654
BIO ET AL., SYNTHESIS, vol. 6, 2008, pages 891 - 896
EICHELBERGER ET AL., TETRAHEDRON, vol. 58, 2002, pages 545 - 559
FUNDING ET AL., J. INVEST. DERMATOL., vol. 129, 2009, pages 891 - 898
GENNARO, A.R. ET AL.: "Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS & WILKINS
GREENE; WUTS: "Protective Groups in Organic Synthesis"
HEGEN ET AL., J. IMMUNOL., vol. 177, 2006, pages 1913 - 1917
HOSOMI ET AL., CHEM. LETTERS, vol. 7, 1984, pages 1117 - 1120
JAGAVELU ET AL., CIRC. RES., vol. 101, 2007, pages 1104 - 1112
JOHANSEN ET AL., J. IMMUNOL., vol. 176, 2006, pages 1431 - 1438
JONES ET AL., OSTEOARTHRITIS & CARTILAGE, vol. 17, 2009, pages 124 - 131
KOTLYAROV ET AL., MOLL. CELL. BIOL., vol. 22, 2002, pages 4825 - 4835
KOTLYAROV ET AL., NAT. CELL BIOL., vol. 1, 1999, pages 94 - 97
LANGLI ET AL., TETRAHEDRON, vol. 52, 1996, pages 5625 - 38
LOMBART ET AL., BIOORG. MED. CHEM. LETTERS, vol. 17, 2007, pages 4333 - 4337
SU ET AL., BIOCHIM. BIOPHYCICA ACTA, vol. 1783, 2008, pages 1623 - 1631
T. HIGUCHI; V. STELLA, PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, vol. 14, 1987
T. HIGUCHI; W. STELLA, PRO-DRUGS AS NOVEL DELIVERY SYSTEMS, vol. 14
THOMAS ET AL., J NEUROCHEM, vol. 105, 2008, pages 2039 - 2052
TIETZ ET AL., AM. J. PHYSIOL. GASTROINTEST. LIVER PHYSIOL., vol. 290, 2006, pages 1298 - 1306
VANOTTI ET AL., J. MED. CHEM., vol. 51, 2008, pages 487 - 501
VASSE ET AL., TETRAHEDRON, vol. 59, 2003, pages 4911 - 4921
WANG ET AL., J. BIOL. CHEM., vol. 277, 2002, pages 43968 - 43972
ZHANG ET AL., BIOORG. MED. CHEM. LETTERS, vol. 19, 2009, pages 1101 - 1104

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9969726B2 (en) 2014-06-10 2018-05-15 Sanford-Burnham Medical Research Institute Metabotropic glutamate receptor negative allosteric modulators (NAMS) and uses thereof
EP3154954A4 (en) * 2014-06-10 2018-06-13 Sanford-Burnham Medical Research Institute Metabotropic glutamate receptor negative allosteric modulators (nams) and uses thereof
US10597367B2 (en) 2014-06-10 2020-03-24 Sanford Burnham Prebys Medical Discovery Institute Metabotropic glutamate receptor negative allosteric modulators (NAMs) and uses thereof
US11447453B2 (en) 2014-06-10 2022-09-20 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
CN112334192A (zh) * 2018-07-12 2021-02-05 Ucb生物制药有限责任公司 作为il-17调节剂的螺环茚满类似物
US11458124B2 (en) 2018-07-12 2022-10-04 UCBBiopharma Srl Spirocyclic indane analogues as IL-17 modulators
WO2024125451A1 (en) * 2022-12-11 2024-06-20 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Piperindin-ones derivatives, preparation methods and medicinal uses thereof

Also Published As

Publication number Publication date
JP2016128412A (ja) 2016-07-14
MX2012006778A (es) 2012-07-23
EP2513111A1 (en) 2012-10-24
RU2012129887A (ru) 2014-01-27
CA2780290A1 (en) 2011-06-23
JP2013513585A (ja) 2013-04-22
CN102712641A (zh) 2012-10-03
US20140288109A1 (en) 2014-09-25
JP5859454B2 (ja) 2016-02-10
US20120245175A1 (en) 2012-09-27
KR20120104241A (ko) 2012-09-20
BR112012013199A2 (pt) 2016-03-01
US9102676B2 (en) 2015-08-11
CN102712641B (zh) 2015-12-09
EP2513111B1 (en) 2013-10-02
HK1210159A1 (en) 2016-04-15
IN2012DN04978A (https=) 2015-09-25
BR112012013199A8 (pt) 2018-01-02
AU2010333024B2 (en) 2014-09-18
CA2780290C (en) 2018-01-02
AU2010333024A1 (en) 2012-06-14
US8772286B2 (en) 2014-07-08
US20160159800A1 (en) 2016-06-09
CN104710423A (zh) 2015-06-17

Similar Documents

Publication Publication Date Title
US9102676B2 (en) MK2 inhibitors
AU2019203186B2 (en) P2X7 modulators
CA2976741C (en) 1-cyano-pyrrolidine compounds as usp30 inhibitors
JP6742452B2 (ja) Ｈｂｖ感染の処置および予防のための新規のテトラヒドロピリドピリミジン
AU2003267098B2 (en) Dihydroxypyridopyrazine-1,6-dione compounds useful as HIV integrase inhibitors
WO2015089143A1 (en) Imidazopyridazine compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
AU2018361229B2 (en) IRAK4 inhibitors and uses thereof
AU2022451580B2 (en) Parp7 inhibitor and use thereof
KR102603203B1 (ko) 히스타민 h4-수용체 저해제로서 피리도피리미딘류
US7435735B2 (en) Hydroxy pyridopyrrolopyrazine dione compounds useful as HIV integrase inhibitors
JP2023545065A (ja) オートタキシン抑制剤化合物
JP2023505159A (ja) 自己免疫疾患の処置のためのヒドロピリド［１，２－ａ］ピラジン化合物
AU2014277711B2 (en) MK2 inhibitors
CN115403581A (zh) 作为irak4抑制剂的新型杂环化合物
NZ711699B2 (en) P2x7 modulators

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 201080056801.X

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10795655

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2780290

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2010333024

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 4978/DELNP/2012

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 13514865

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2012542575

Country of ref document: JP

ENP Entry into the national phase

Ref document number: 20127015233

Country of ref document: KR

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: MX/A/2012/006778

Country of ref document: MX

Ref document number: 2010795655

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010333024

Country of ref document: AU

Date of ref document: 20101213

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2012129887

Country of ref document: RU

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112012013199

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112012013199

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20120531