WO2007023242A1 - Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors - Google Patents

Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors Download PDF

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Publication number
WO2007023242A1
WO2007023242A1 PCT/GB2005/003285 GB2005003285W WO2007023242A1 WO 2007023242 A1 WO2007023242 A1 WO 2007023242A1 GB 2005003285 W GB2005003285 W GB 2005003285W WO 2007023242 A1 WO2007023242 A1 WO 2007023242A1
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WIPO (PCT)
Prior art keywords
quinolin
dihydro
dimethyl
ylethynyl
phenylethynyl
Prior art date
Application number
PCT/GB2005/003285
Other languages
English (en)
French (fr)
Inventor
Christopher Graham Raphael Parsons
Aigars Jirgensons
Ieva Jaunzeme
Ivars Kalvinsh
Markus Henrich
Maksims Vanejevs
Tanja Weil
Valerjans Kauss
Wojciech Danysz
Claudia Jatzke
Original Assignee
Merz Pharma Gmbh & Co. Kgaa
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
Application filed by Merz Pharma Gmbh & Co. Kgaa filed Critical Merz Pharma Gmbh & Co. Kgaa
Priority to PCT/GB2005/003285 priority Critical patent/WO2007023242A1/en
Priority to TW095130667A priority patent/TWI329635B/zh
Priority to AU2006283359A priority patent/AU2006283359B2/en
Priority to EP06779201A priority patent/EP1931635A1/en
Priority to ARP060103692A priority patent/AR056044A1/es
Priority to EA200800660A priority patent/EA200800660A1/ru
Priority to JP2008527513A priority patent/JP2009506018A/ja
Priority to MX2008001871A priority patent/MX2008001871A/es
Priority to BRPI0615059-4A priority patent/BRPI0615059A2/pt
Priority to KR1020087004382A priority patent/KR20080031972A/ko
Priority to CNA2006800260106A priority patent/CN101223142A/zh
Priority to CA2610873A priority patent/CA2610873C/en
Priority to PCT/GB2006/003170 priority patent/WO2007023290A1/en
Publication of WO2007023242A1 publication Critical patent/WO2007023242A1/en
Priority to ZA200710668A priority patent/ZA200710668B/xx
Priority to IL189617A priority patent/IL189617A/en
Priority to NO20081428A priority patent/NO20081428L/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/435—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
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • R 1 represents aryl or heteroaryl
  • aryl represents an unsubstituted phenyl ring or a phenyl ring that is substituted with 1 , 2, 3, 4 or 5 substituents, that may be the same of different, which substituents are selected from the group consisting of Ci -6 alkyl, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, Ci -6 alkoxy, which is optionally substituted with one or more fluorine, chlorine or bromine atoms, cycloC 3 -i 2 alkyl, hydroxyl, F, Cl 1 Br, I, CN, nitro, di-Ci -6 alkylamino, N ⁇ cycloC 3- i 2 alkyl-N- Ci-ealkylamino, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, A-
  • composition comprising, together with one or more pharmaceutically acceptable excipients or vehicles, a compound of Formula I
  • R 1 represents aryl or heteroaryl
  • hydrohalic acids such as hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1 ,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
  • the salt form can be converted by treatment with alkali into the free base form.
  • the active ingredients of the invention may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as coated or uncoated tablets or filled capsules, or liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use; in the form of suppositories or capsules for rectal administration or in the form of sterile injectable solutions for parenteral (including intravenous or subcutaneous) use.
  • Nanoparticle formulation 10 g of polybutylcyanoacrylate nanoparticles contain:
  • the medium Prior to addition of agonist or antagonist the medium was aspirated and cells were loaded for 2 h at RT with 150 ⁇ L of loading buffer consisting of Ca- sensitive dye (MD # R8033) reconstituted in sodium chloride (123 rriM), potassium chloride (5.4 mM), magnesium chloride (0.8 nriM), calcium chloride (1.8 mM), D-glucose (15 mM), and HEPES (20 mM), pH 7.3. Subsequently, plates were transferred to FLIPR to detect calcium increase with the addition of DHPG (300 ⁇ iw) or L-quisqualate (100 nM) measured as relative fluorescence units (RFU). If antagonists were tested, these compounds were pre-incubated for 10 min at RT before addition of the respective agonist.
  • Ca- sensitive dye MD # R8033

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/GB2005/003285 2005-08-24 2005-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors WO2007023242A1 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
PCT/GB2005/003285 WO2007023242A1 (en) 2005-08-24 2005-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
TW095130667A TWI329635B (en) 2005-08-24 2006-08-21 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
MX2008001871A MX2008001871A (es) 2005-08-24 2006-08-24 Tetrahidroquinolinonas y su uso como moduladores de receptores de glutamato metabotropicos.
KR1020087004382A KR20080031972A (ko) 2005-08-24 2006-08-24 테트라히드로퀴놀리논 및 향대사성 글루타메이트 수용체의조절제로서의 이들의 용도
ARP060103692A AR056044A1 (es) 2005-08-24 2006-08-24 Tetrahidroquinolinonas y su uso como moduladores de receptores de glutamato metabotropicos
EA200800660A EA200800660A1 (ru) 2005-08-24 2006-08-24 Тетрагидрохинолиноны и их применение в качестве модуляторов метаботропных глутаматных рецепторов
JP2008527513A JP2009506018A (ja) 2005-08-24 2006-08-24 テトラヒドロキノリノン類及び代謝型グルタミン酸受容体のモジュレータとしてのその使用
AU2006283359A AU2006283359B2 (en) 2005-08-24 2006-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
BRPI0615059-4A BRPI0615059A2 (pt) 2005-08-24 2006-08-24 tetrahidroquinolinonas e seu uso como moduladores de receptores metabotrópicos de glutamato
EP06779201A EP1931635A1 (en) 2005-08-24 2006-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
CNA2006800260106A CN101223142A (zh) 2005-08-24 2006-08-24 四氢喹诺酮以及其作为向代谢性谷氨酸受体调节剂的应用
CA2610873A CA2610873C (en) 2005-08-24 2006-08-24 Tetrahydroquinolines and their use as modulators of metabotropic glutamate receptors
PCT/GB2006/003170 WO2007023290A1 (en) 2005-08-24 2006-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
ZA200710668A ZA200710668B (en) 2005-08-24 2007-12-06 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
IL189617A IL189617A (en) 2005-08-24 2008-02-19 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
NO20081428A NO20081428L (no) 2005-08-24 2008-03-18 Tetrahydrokinolinoner og anvendelse derav som modulatorer av metabotrope glutamatreseptorer

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/GB2005/003285 WO2007023242A1 (en) 2005-08-24 2005-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors

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WO2007023242A1 true WO2007023242A1 (en) 2007-03-01

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PCT/GB2006/003170 WO2007023290A1 (en) 2005-08-24 2006-08-24 Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors

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EP (1) EP1931635A1 (pt)
JP (1) JP2009506018A (pt)
KR (1) KR20080031972A (pt)
CN (1) CN101223142A (pt)
AR (1) AR056044A1 (pt)
AU (1) AU2006283359B2 (pt)
BR (1) BRPI0615059A2 (pt)
CA (1) CA2610873C (pt)
EA (1) EA200800660A1 (pt)
IL (1) IL189617A (pt)
MX (1) MX2008001871A (pt)
NO (1) NO20081428L (pt)
TW (1) TWI329635B (pt)
WO (2) WO2007023242A1 (pt)
ZA (1) ZA200710668B (pt)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010084050A2 (en) 2009-01-13 2010-07-29 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
WO2011073339A1 (en) 2009-12-18 2011-06-23 Janssen Pharmaceutica Nv Bicyclic thiazoles as allosteric modulators of mglur5 receptors
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WO2012139876A1 (en) 2011-04-14 2012-10-18 Merz Pharma Gmbh & Co. Kgaa Enteric formulations of metabotropic glutamate receptor modulators
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EA019980B1 (ru) * 2009-12-18 2014-07-30 Янссен Фармацевтика Нв БИЦИКЛИЧЕСКИЕ ТИАЗОЛЫ В КАЧЕСТВЕ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ РЕЦЕПТОРОВ mGluR5
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US9174953B2 (en) 2009-12-18 2015-11-03 Janssen Pharmaceutica Nv Bicyclic thiazoles as allosteric modulators of mGluR5 receptors
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EA020010B1 (ru) * 2009-12-18 2014-07-30 Янссен Фармацевтика Нв БИЦИКЛИЧЕСКИЕ ТИАЗОЛЫ В КАЧЕСТВЕ АЛЛОСТЕРИЧЕСКИХ МОДУЛЯТОРОВ mGluR5 РЕЦЕПТОРОВ
AU2010332819B2 (en) * 2009-12-18 2014-02-27 Janssen Pharmaceutica Nv Bicyclic thiazoles as allosteric modulators of mGluR5 receptors
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WO2011092293A2 (en) 2010-02-01 2011-08-04 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2011095450A1 (en) 2010-02-02 2011-08-11 Novartis Ag Cyclohexyl amide derivatives as crf receptor antagonists
WO2012139876A1 (en) 2011-04-14 2012-10-18 Merz Pharma Gmbh & Co. Kgaa Enteric formulations of metabotropic glutamate receptor modulators
WO2012172093A1 (en) * 2011-06-17 2012-12-20 Merz Pharma Gmbh & Co. Kgaa Dihydroindolizine derivate as metabotropic glutamate receptor modulators
WO2013050527A1 (en) 2011-10-05 2013-04-11 H. Lundbeck A/S Quinazoline derivatives as pde10a enzyme inhibitors
EP2650284A1 (en) * 2012-04-10 2013-10-16 Merz Pharma GmbH & Co. KGaA Heterocyclic derivatives as metabotropic glutamate receptor modulators
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