WO2012164085A1 - Antagonistes de la glycine b - Google Patents

Antagonistes de la glycine b Download PDF

Info

Publication number
WO2012164085A1
WO2012164085A1 PCT/EP2012/060433 EP2012060433W WO2012164085A1 WO 2012164085 A1 WO2012164085 A1 WO 2012164085A1 EP 2012060433 W EP2012060433 W EP 2012060433W WO 2012164085 A1 WO2012164085 A1 WO 2012164085A1
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
chloro
carboxylic acid
oxo
quinoline
Prior art date
Application number
PCT/EP2012/060433
Other languages
English (en)
Inventor
Ulrich Abel
Angela Hansen
Falko Ernst Wolter
Bjoern Krueger
Valerjans Kauss
Jevgenijs Rozhkovs
Valentina SEMENIHINA
Irena Piskunova
Juris PELSS
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
Publication of WO2012164085A1 publication Critical patent/WO2012164085A1/fr

Links

Classifications

    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • 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
    • C07D417/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel 2(1 H)-quinolinone derivatives which may act as glycine B antagonists, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such substances.
  • Glutamate is a major excitatory transmitter in the central nervous system and it has become clear in recent years that it is also very important in the peripheral nervous system (PNS). Glutamate is believed to be involved in many pathological and excitotoxic processes; therefore, there is a great deal of interest in the development of glutamate antagonists for therapeutic uses. Glutamate activates three major types of ionotropic receptors: a-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA), kainate, and N-methyl-D-aspartate (NMDA) as well as several types of metabotropic receptors. Antagonism of NMDA receptors potentially has a wide range of therapeutic applications. Functional inhibition of NMDA receptors may be achieved through actions at different recognition sites, such as the primary transmitter site, the strychnine insensitive glycine site (glycine B), the polyamine site, and the phencyclidine site located inside the cation channel.
  • glycine B strychnine insensitive gly
  • Receptor desensitization may represent a physiological process serving as an endogenous control mechanism to prevent long term neurotoxic activation of glutamate receptors but allow their transient physiological activation.
  • the co-agonist glycine is an endogenous ligand inhibiting such desensitization via activation of the glycine B site. It is noteworthy that ischemia increases not only the concentration of extracellular glutamate but also that of glycine and, although this latter effect is less pronounced, it actually persists for a longer period of time.
  • glycine B antagonists may restore normal synaptic transmission under such conditions by increasing NMDA receptor desensitization to its physiological level. It has been suggested that glycine B antagonists may offer a better therapeutic window than agents acting at other recognition sites of the NMDA receptor complex.
  • glycine B antagonists may be useful for the treatment and/or prevention of pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example neuropathy induced by nociception, inflammation, ischemia, viral infection (herpes zoster virus, HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), complex regional pain syndrome, carpal tunnel syndrome, arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • pain including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including,
  • Blood-brain barrier impermeable glycine B antagonists which are restricted to action in the PNS, may be particularly useful since such antagonists do not exhibit CNS side effects.
  • Glycine B antagonists may also be useful for the treatment and/or prevention of acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug-induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivoponto-cerebellar atrophy, Parkinson's disease, Neuronal
  • R 1 is e. g., hydrogen, alkyl, allyl or propargyl
  • R 2 is e.g, hydroxy, alkoxy, alkylamino, dialylamino etc.
  • R 3 and R 4 are, independently, hydrogen or alkyl
  • R 5 is hydrogen, chlorine or bromine
  • R represents e.g., hydrogen atom, an amino group, a carboxy or C 2- 6 alkoxycarbonyl group
  • R 1 is a group of part formula (i) wherein n is zero or 1 , preferably zero
  • T represents e.g, cyano, carboxy or five- or six-membered heteroaromatic ring
  • R 2 , R 3 , R 4 and R 5 represent e.g, hydrogen, hydrocarbon, heterocyclic group, halogen, cyano, nitro, as selective non-competitive antagonists on NMDA receptors and/or antagonists of AMPA receptors.
  • R 1 , R 2 and R 3 areindependently, hydrogen, halogen, alkyl, nitro, cyano or aminosulfonyl, is disclosed in US Patent No. 5,536,709.
  • R 1 , R 2 and R 3 are as described above, which are useful (by blocking AMPA/kainate receptor) as inhibitors of the pathological phenomena associated with hyperactivation of the excitating amino acid dependant pathways of neurotransmission, from compounds of formula (3) is also disclosed.
  • W represents e.g, -O-, -S(O) r , -CR 3 R 4 -, -NR 5 -, (where R 3 , R 4 and R 5 represent hydrogen or alkyi);
  • R 1 represents e.g, hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl;
  • R 2 represents e.g, hydrogen, alkyi, -OR 6 (where R 6 represents hydrogen, alkyi, alkenyl, alkynyl, aryl, heteroaryl, heteroarylalkyl, cycloalkyl or cycloalkylalkyl), -NR 7 R 8 (where R 7 and R 8 independently represent hydrogen, alkyi, alkenyl, alkynyl, acyl, aryl, etc.); R a represents hydrogen or alkyi;
  • X represents e.g, -
  • A denotes a single bond or methylene
  • V denotes a single bond or methylene
  • T denotes a hydroxyl group, amino group, alkoxycarbonyl, carboxyl
  • R denotes a nitro group or halogen atom
  • R 1 denotes a hydroxyl group or lower alkoxy group
  • n 0, 1 or 2;
  • X 1 represents halogen, nitro, or C-i -6 alkyl
  • X 2 represents hydrogen, halogen, nitro, trifluoromethyl, C h alky! or C-i-6alkoxy;
  • R represents hydrogen or Ci -6 alkyl;
  • R 3 represents hydrogen, C-i -6 alkyl, C 3-6 alkenyl, Ci -6 alkylsulfonyl, aryl, heteroaryl, cyclo- C3-i2alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, aryl -Chalky! or heteroaryl-C-i-6alkyl;
  • R 4 represents hydrogen, C-i -6 alkyl, C 3-6 alkenyl, Ci -6 alkylsulfonyl, aryl, heteroaryl, cyclo- C 3- i 2 alkyl, cyclo-C 3- i2alkyl-Ci -6 alkyl, aryl-Ci -6 alkyl, heteroaryl-Ci -6 alkyl, hydroxy-C-i -6 alkyl, carbamoyl-Ci-6alkyl, Ci-6alkoxy-Ci-6alkyl or C(O)-R 5 ; wherein R 5 represents COOH, Ci -6 alkyl, cyclo-C 3- i 2 alkyl optionally condensed to a benzene ring, cyclo-C 3- i 2 alkyl-Ci -6 alkyl, hydroxy-Ci -6 alkyl, carboxy-Ci -6 alkyl, amino- Ci-6alkyl, aryl, heteroaryl, heteroaryl-he
  • Such a compound of Formula I, wherein n is 1 and R 1 and R 2 together with the carbon atom to which they are attached represent a carbonyl group (C O).
  • R 5 represents aryl, heteroaryl, aryl- C-i-6alkyl, heteroaryl-C-i-6alkyl, arylcarbonyl, arylamino, heteroarylamino, or aryl- Ci-6alkylamino.
  • Such a compound of Formula I wherein the aryl or heteroaryl moiety is optionally substituted by one or more substituents selected from halogen, Ci_6alkoxy, nitro, C-
  • substituents selected from halogen, Ci_6alkoxy, nitro, C-
  • Such a compound of Formula I, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and imidazopyridazinyl.
  • the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyr
  • Such a compound of Formula I wherein R 5 represents adamantyl, adamantyl- methyl, cyclohexyl substituted by aryl, cyclopentyl subsituted by aryl, cyclobutyl optionally substituted by aryl, cyclopropyl optionally substituted by aryl or heteroaryl, piperidinyl substituted by aryl, isochromanyl, or tetrahydroisoquinolinyl.
  • Such a compound of Formula I, wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, C h alky!, cyclo- C 3- i 2 alkyl, C-i -6 alkoxy, hydroxy-C-i -6 alkyl, C-i ⁇ alkoxy-
  • Such a compound of Formula I wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent triazolyl optionally substituted by C h alky!, aryl, heteroaryl, cyclo-C 3- i 2 alkyl, aryl-Ci -6 alkyl, or heteroaryl-Ci -6 alkyl, pyrrolyl optionally substituted by C-i-6alkylcarbonyl, aryl -C h alky!, or heteroaryl-C-i-6alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
  • Such a compound of Formula I, wherein R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring selected from oxazole, thiazole, imidazole, pyrazole, 1 ,2,4-oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and benzothizaolyl, which may be optionally subsituted by aryl-C-i-6alkyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA:
  • Such a compound of Formula IA wherein R 5 represents COOH, Chalky!, hydroxy-C-i-6alkyl, carboxy-C-i-6alkyl, amino-Ci-6alkyl, aryl, heteroaryl, aryl-C-i-6alkyl, heteroaryl-C-i-6alkyl, arylcarbonyl, cyclo-Cs- ⁇ alkyl, cyclo-C3-i2alkyl-Ci-6alkyl, or heterocyclyl.
  • Such a compound of Formula IA wherein R 5 represents aryl, heteroaryl, aryl- C-
  • Such a compound of Formula IA, wherein the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl, pyrazinyl, pyrrolyl, tetrazolyl, imidazopyridinyl, and imidazopyridazinyl.
  • the heteroaryl moiety is selected from thiophenyl, benzofuranyl, benzothiophenyl, pyridinyl, quinolinyl, pyrimidinyl, thiazolyl, benzothiazolyl, triazolyl, oxazolyl, pyrazolyl, pyridazinyl, benzooxadiazolyl,
  • Such a compound of Formula IA wherein R 5 represents cyclo-Cs- ⁇ alkyl optionally substituted by aryl or heteroaryl, cyclo-C3-i2alkyl-Ci- 6 alkyl, or heterocyclyl optionally substituted by aryl.
  • Such a compound of Formula IA wherein R 5 represents adamantyl, adamantyl- methyl, cyclohexyl substitued by aryl, cyclopentyl subsituted by aryl, cyclobutyl optionally substituted by aryl, cyclopropyl optionally substituted by aryl or heteroaryl, piperidinyl substituted by aryl, isochromanyl, or tetrahydroisoquinolinyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of formula IB:
  • Such a compound of Formula IB wherein R 4 represents Ci -6 alkyl, C 3-6 alkenyl, aryl, heteroaryl, cyclo-C3-i2alkyl, cyclo-C3-i2alkyl-Ci- 6 alkyl, aryl -C h alky!, heteroaryl- C-i- 6 alkyl, hydroxy-Ci ⁇ alkyl, carbamoyl-Ci- 6 alkyl or Ci- 6 alkoxy-Ci- 6 alkyl.
  • R 4 represents benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, or pyridinyl- methyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
  • Such a compound of Formula IC wherein X 1 represents halogen and X 2 represents hydrogen or halogen.
  • Such a compound of Formula IC wherein R 1 represents hydrogen or C h alky! (e.g., methyl).
  • Such a compound of Formula IC wherein R 4 represents hydrogen, C h alky!, C 3-6 alkenyl, aryl, heteroaryl, cyclo-C 3- i 2 alkyl, cyclo-Cs- ⁇ alkyl-C-i ⁇ alkyl, aryl-Ci -6 alkyl, heteroaryl-Ci -6 alkyl, hydroxy-Ci -6 alkyl, carbamoyl-Ci -6 alkyl or C-i ⁇ alkoxy-C-i ⁇ alkyl.
  • Such a compound of Formula IC wherein R 4 represents methyl, benzyl, wherein the phenyl moiety may be optionally substituted by one or more halogen atoms, pyridinyl-methyl, pyridinyl optionally substituted by one or more substituents selected from nitro, Ci-6alkylcarbonylamino, and CONH 2 , benzoxazole, or benzothiazole.
  • Such a compound of Formula IC wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent a 5-, 6- or 7-membered ring which may be saturated or unsaturated, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen and/or be condensed to aromatic or heteroaromatic ring selected from benzene, furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, pyridine, pyrimidine, pyrazine, pyridazine, and wherein the ring may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, oxo, acylamino, C-i -6 alkyl, cyclo-C 3- i 2 alkyl, C-i -6 alkoxy, hydroxy-C-i -6 alkyl, Ci -6 alkoxy-C
  • Such a compound of Formula IC wherein R 3 and R 4 together with the nitrogen atom to which they are attached represent triazolyl optionally substituted by C h alky!, aryl, heteroaryl, cyclo-C 3- i 2 alkyl, aryl-C-i -6 alkyl, or heteroaryl-Ci -6 alkyl, pyrrolyl optionally substituted by C-i- 6 alkylcarbonyl, aryl -C h alky!, or heteroaryl-C-i- 6 alkyl, pyrazolyl optionally substituted by aryl, piperidino, pyrrolidino, or isoindolyl optionally substituted by one or more oxo groups.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula I
  • R 2 and R 3 together with the carbon and nitrogen atoms to which they are attached represent a 5-membered heteroaromatic ring which may be optionally fused to a benzene ring, wherein, in addition to the nitrogen atom, the ring may contain additional heteroatoms selected from sulfur, oxygen and nitrogen; wherein the heteroaromatic ring may be optionally substituted by aryl-C-i-6alkyl, and wherein X 1 and X 2 are as defined above for Formula I.
  • Such a compound of Formula ID wherein X 1 represents halogen and X 2 represents hydrogen or halogen.
  • heteroaromatic ring selected from oxazole, thiazole, imidazole, pyrazole, 1 ,2,4- oxadiazole, 1 ,3,4-oxadiazole, 1 ,3,4-thiadiazole, 1 ,2,3-triazole, 1 ,2,4-triazole, tetrazole and benzothizaolyl, which may be optionally subsituted by aryl-C-i-6alkyl.
  • heteroaromatic ring selected from 1 ,2,4-oxadiazole, which may be optionally substituted by subsituted by aryl-Ci -6 alkyl, 1 ,3,4-oxadiazole, which may be optionally substituted by subsituted by aryl-Ci_6alkyl, and benzothiazolyl.
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for use in therapy.
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for the treatment or prevention of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including for the conditions selected from those described earlier in the description.
  • Such conditions include pain, including acute pain, chronic pain, allodynia, hyperalgesia, visceral pain, phantom pain, post-operative pain, neuropathic pain, peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (IBD), irritative bowel syndrome (IBS), arthritis including rheumatoid arthritis, osteoarthritis (degenerative joint disease), multiple sclerosis (MS) and gout (metabolic arthritis).
  • peripheral neuropathy including, for example peripheral neuropathy induced by nociception, inflammation, ischemia, viral infection (HZV), traumatic and other mechanical nerve injury, cancer, chemotherapy induced pain, diabetes mellitus, HIV infection, fibromyalgia, trigeminus neuralgia, inflammatory bowel diseases (
  • Such conditions also include acute insults, including cerebral ischemia, cerebral infarct, brain oedema, anoxia, inner ear insult, inner ear insult in tinnitus, head or brain or spinal cord trauma, head or brain or spinal cord injuries, trauma, sound- or drug- induced inner ear insult, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, acute pain, hypoxia, perinatal hypoxia, and ischaemia; chronic insults, such as neurodegenerative disorders, including Morbus Huntington, Alzheimer's disease Creutzfeld-Jakob ' s syndrome/disease, bovine spongiform encephalopathy (BSE) prion related infections, diseases involving mitochondrial dysfunction, diseases involving ⁇ -amyloid and/or tauopathy, Down's syndrome, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, Parkinson's disease, Neuronal Ceroid Lipofuscinosis, AIDS dementia complex,
  • the invention relates to a compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof for use in the treatment or prevention of NMDA excitotoxicity or malfunctioning glutamatergic neurotransmission.
  • the invention relates to the use of a compound of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically- acceptable acid or base addition salt, hydrate, or solvate thereof for the manufacture of a medicament for the prevention and/or treatment of a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission.
  • a use includes the use of such a compound for the manufacture of a medicament for the prevention and/or treatment of a condition in an animal including a human being which condition is associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description.
  • the invention relates to a method for treating or preventing a condition associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission, including conditions selected from those described earlier in the description, such method comprising administering to a living animal, including a human, a therapeutically effective amount of a compound selected from those of Formula I as defined above or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof.
  • a further aspect of the invention relates to such a method wherein the compound is administered in the form of a pharmaceutical composition thereof comprising at least one compound of Formula I in combination with one or more pharmaceutically- acceptable diluents, excipients, or carriers.
  • the compounds of the invention are suitable for administration in monotherapy or for combination therapy with other pharmaceutically active compounds.
  • suitable other pharmaceutically active compounds include immunomodulators and agents active against central nervous system disorders such as other NMDA agonists or antagonists including glycine B antagonists.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient at least one compound of Formula I as defined above, or an optical isomer, polymorph, analog, derivative, prodrug, pharmaceutically-acceptable acid or base addition salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable excipients or vehicles.
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix Cj_j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • C h alky! refers to alkyl of one to three carbon atoms, inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof.
  • Ci-6alkyl represents straight or branched chain alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms
  • examples of such alkyl groups include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, iso-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, iso-pentyl, 2-methylbutyl, tert-amyl, neopentyl, n- hexyl, 2-hexyl, 3-hexyl, 1 -methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 2-e
  • C3-6alkenyl represents straight or branched chain alkenyl groups having 3, 4, 5 or 6 carbon atoms.
  • cycloCs- ⁇ alkyl represents monocyclic or bicyclic, or tricyclic alkyl groups having 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, wherein the "cycloC3-i 2 alkyl"-ring is optionally substituted by one or more (e.g., 1 , 2, 3, or 4) substituents selected from halogen, hydroxy, oxo, aryl, and heteroaryl.
  • Ci- 6 alkoxy represents straight or branched chain -O-Ci_ 6 alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, terf-butoxy.
  • Ci- 6 alkylamino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with a C h alky! group as defined above.
  • alkylamino groups include methylamino, ethylamino, propylamino, isopropylamino, te/?-butylamino.
  • di-(Ci-6alkyl)amino refers to an amino moiety in which the nitrogen atom of the amino group is substituted with two C h alky! groups, which may be the same or different, as defined above.
  • di-Ci- 6 alkylamino groups include dimethylamino, diethylamino and N-methyl-N-isopropylamino.
  • aryl represents phenyl or naphthyl, or phenyl substituted by one or more (e.g., 1 , 2, 3, 4, or 5) substituents selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH 2 , trifluoromethyl, C h alky!, phenyl, heteroaryl, heterocyclyl, hydroxy-Ci -6 alkyl, carboxy-Ci -6 alkyl, carbamoyl-Ci -6 alkyl, heteroaryl-Ci -6 alkyl, amino- Ci -6 alkyl, Ci -6 alkylcarbonyl, Ci -6 alkylaminocarbonyl, heteroarylaminocarbonyl, di-(Ci- 6 alkyl)aminocarbonyl, hydroxy-Ci- 6 alkylaminocarbonyl; C-i ⁇ alkoxy, hydroxy- C-i-6alkoxy, trifluoromethoxy, phenoxy
  • heteroaryl represents an aromatic 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group containing a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or with a 5-6 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl is optionally substituted by one or more substituents (e.g., 1, 2, 3, 4, or 5) selected from halogen, amino, hydroxy, nitro, cyano, COOH, CONH 2 , trifluoromethyl, Ci -6 alkyl, phenyl, imidazolyl, pyrazolyl, hydroxy-Ci -6 alkyl, carboxy-Ci -6 alkyl, carbamoyl- C-i-6alkyl, heteroaryl-C-i-6alkyl, amino-Ci-6alkyl, hetero
  • acyl represents C-i-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, carboxy-Ci-6alkylcarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C 3- i 2 alkylcarbonyl, aryl-Ci -6 alkylcarbonyl, heteroaryl- Ci_6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
  • heterocyclyl represents a saturated or unsaturated non-aromatic 3 to 12 membered ring comprising one to four heteroatoms selected from oxygen, sulfur and nitrogen, and a saturated or unsaturated non-aromatic bicyclic ring system having 3 to 12 members comprising one to six heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heterocyclic ring or ring system may be optionally substituted by one or more (e.g., 1, 2, 3, 4, or 5) substituents, which may be the same or different, selected independently from halogen, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Chalky!, C2-6alkenyl, C-i ⁇ alkoxy, amino, hydroxy, nitro, cyano, Ci -6 alkoxycarbonyl, Ci -6 alkylcarbonyl, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, Ci -6 alkyl-
  • halogen represents fluorine, chlorine, bromine and iodine.
  • analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule (such as 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid), but has been modified in a targeted and controlled manner to replace one or more specific substituents of the reference molecule with an alternate substituent, thereby generating a molecule which is structurally similar to the reference molecule.
  • reference molecule such as 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid
  • Synthesis and screening of analogs ⁇ e.g., using structural and/or biochemical analysis), to identify slightly modified versions of a known compound which may have improved or biased traits (such as higher potency and/or selectivity at a specific targeted receptor type, fewer side effects, etc.) is a drug design approach that is well known in pharmaceutical chemistry.
  • analogs and derivatives of the compounds of the invention can be created which have improved therapeutic efficacy, i.e., higher potency and/or selectivity at a specific targeted receptor type, either greater or lower ability to penetrate mammalian blood-brain barriers ⁇ e.g., either higher or lower blood-brain barrier permeation rate), fewer side effects, etc.
  • prodrug is used herein in the conventional pharmaceutical sense, to refer to a molecule which undergoes a transformation in vivo (e.g., an enzymatic or chemical transformation) to release an active parent drug.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared by chemically modifying a functional group present in the compound of Formula I such that the chemically modified compound may undergo a transformation in vivo (e.g., enzymatic hydrolysis) to provide the compound of Formula I.
  • Examples of functional groups present in the compounds of Formula I which may be modified to produce prodrugs include carboxy, hydroxy and amino groups.
  • Prodrugs of the compounds of Formula I of the present invention may be prepared according to conventional techniques which have been described in the art (see, for example, Stella V., et al., Prodrugs: Challenges and Rewards, AAPS Press/Springer, New York, 2007).
  • compositions of the invention refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a mammal ⁇ e.g., human).
  • pharmaceutically acceptable may also mean approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.
  • compositions of the present invention may be in the form of pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” refers to those salts which possess the biological effectiveness and properties of the parent compound and which are not biologically or otherwise undesirable. The nature of the salt or isomer is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • a subset of the compounds of Formula I may be prepared by "click" reaction of azides 14 with an appropriate acetylene derivative 15 in the presence of catalytic amount of copper salt as shown in Scheme 2.
  • Azide 14 may be prepared from corresponding bromide 13 which, in turn, is obtained by hydrolysis of ester 8.
  • Another subset of the compounds of Formula I may be prepared by reaction of bromides 8 via an in-situ formation of azides and subsequent reaction of the intermediates formed with an appropriate acetylene derivative 15 in the presence of a ruthenium catalyst as shown in Scheme 2 to yield derivatives 31.
  • HCI in dioxane may be used as an appropriate medium for the hydroylsis of the ester and the methoxy group present in derivatives 31 to yield compounds of Formula I.
  • Another subset of the compounds of Formula I may be prepared by alkylation of amine 16 with bromide 8 and cleavage of intermediate ester 17 by such a common reagents as HBr in acetic acid or HCI in dioxane, as shown in Scheme 3.
  • compounds of Formula I may be prepared by direct alkylation of amine 16 with bromide 13.
  • Scheme 3 Synthesis of compounds of Formula I by alkylation of amines with bromides 8 and 13
  • Compounds of Formula I may be prepared by condensation of carboxylic acid 20 with amine 16 in the presence of condensing agents commonly used for amide bond formation, as shown in Scheme 4.
  • Carboxylic acid 20 may be synthesized by reaction of bromide 8 with di-tert-butyl malonate, providing triester 18 which is selectively cleaved by trifluoroacetic acid to give monoester 19 which, in turn, is thermally decarboxylated.
  • a subset of the compounds of Formula I may be prepared by carbamoylation of bromide 8 by molybdenum carbonyl amine complex in diglyme [Ren W., Yamane M. J. Org. Chem. 2010, 75, 3017-3020.], as shown in Scheme 5.
  • the procedure may be performed by stepwise preparation of molybdenum pentacarbonyl amine (22) complex or via generation of complex 22 in situ and bromide 8 and tributylamine may be added to the same bulb.
  • Scheme 5 Synthesis of compounds of Formula I by carbamoylation of bromide 8 by molybdenum carbonyl amine complex
  • Compounds of Formula I may be prepared via functionalization of the amino group of aminoethylquinoline 25 which may be condensed with appropriate carboxylic acid, or may be alkylated, arylated or acylated by haloderivative 26, as shown in Scheme 6.
  • Amine 25 may be prepared by cleavage of N-tert-butoxycarbonyl group of quinoline 24, which, in turn, is synthesized from carboxylic acid 20 under treatment with diphenyl phosphoranylazide.
  • Compounds of Formula I may be prepared by hydrolysis of the ester group and the methoxy group of quinoline-3-carboxylic acid derivatives 28 and 30, as shown in Scheme 7.
  • HBr in acetic acid or HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • the quinoline-3-carboxylic acid derivatives 30 may, in turn, be synthesized by reaction of ester 28 with derivative 29, wherein R 4 may be alkyl, heteroaryl or acyl and X represents a halogen atom, in the presence of an appropriate base.
  • Inorganic base e.g., potassium carbonate
  • organic base e.g., triethylamine
  • quinoline-3-carboxylic acid derivatives 30 is via an amide bond formation reaction which involves reaction of amino-derivative 28 with carboxylic acid 29 (Scheme 7) in the presence of a condensing agent (e.g., EDCI with or without HOBT) in an appropriate solvent (e.g., DCM).
  • a condensing agent e.g., EDCI with or without HOBT
  • an appropriate solvent e.g., DCM
  • Quinolines 30 may also be prepared by condensation of carbaldehydes 12 with amines 16 followed by reduction of intermediate imine bond with e. g., sodium borohydride.
  • Quinoline derivatives 28 may, in turn, be prepared from amine 10 by the procedures analogous to the synthesis of quinoline derivatives 30.
  • amine 10 may be alkylated, heteroarylated or acylated with corresponding halogenide 26 in the presence of an appropriate inorqanic base (e.g., potassium carbonate) or organic base (e.g., triethylamine).
  • an appropriate inorqanic base e.g., potassium carbonate
  • organic base e.g., triethylamine
  • quinoline-3-carboxylic acid derivatives 28 may be synthesized by an amide bond formation reaction which involves reaction of amine 10 with carboxylic acid 26 in the presence of condensing agent (e.g., EDCI with or without HOBT) and base (e.g., DMAP and Et.3N) in an appropriate solvent (e.g., DCM).
  • condensing agent e.g., EDCI with or without HOBT
  • base e.g., DMAP and Et.3N
  • an appropriate solvent e.g., DCM
  • Necessary amines 10 may be prepared by reduction of azides 9, for example, by triphenylphosphazene reaction with water (Scheme 1 ).
  • Azides 9 may, in turn, be prepared by reaction of bromides 8 with sodium azide in an appropriate solvent (e.g., DMF).
  • Bromides 8 are synthesized by bromination of 8-methyl-quinolines 7 with NBS in the presence of dibenzoyi peroxide or AIBN. Bromination of 8-methyl-quinolines 7 with an excess of NBS in the presence of dibenzoyi peroxide or AIBN may be used to obtain dibromides 11.
  • Dibromides 11 may, in turn, be transformed to carbaldehydes 12 in hydrolytic conditions (e.g., calcium carbonate in a mixture of water and dioxane).
  • Esters 7 may be prepared by esterification of carboxylic acids 6 (e.g., in a mixture of thionyl chloride and methanol), which, in turn, may be obtained by reaction of 2-chloroquinolines 5 with a sodium methoxide solution in methanol.
  • Sodium methoxide solution in methanol may be prepared e. g., by reaction of sodium metal or sodium hydride with methanol.
  • Necessary esters of 2-chloro-8-methyl-quinoline-3-carboxylic acids 5 are synthesized by well known procedures from the corresponding anthranilic acids 1 , aminophenylmethyl alcohols 2, and/or aminobenzaldehydes 3 (Scheme 1 ).
  • aminobenzaldehydes 3 may be condensed with dimethyl malonate in the presence of piperidine to give the methyl ester of 2-oxo-1 ,2-dihydroquinoline-3-carboxylic acid 4 which, in turn, may be transformed to 2-chloro-8-methyl-quinoline-3-carboxylic acid 5 by reaction with phosphorous oxychloride in DMF.
  • Ketone 38 may be synthesized by reaction of amino carboxylic acid 32 with an appropriate reduction agent providing alcohol 33 which is subsequently oxidized to aldehyde 34, which in turn is iodinated to yield intermediate 35.
  • Intermediate 35 may be reacted with dimethyl malonate and POCI3 to yield compound 36 which may be converted to 37 by reaction with sodium hydride and methanol and subsequent treatment with thionylchloride in the presence of methanol.
  • ketone 38 starting from iodide 37.
  • HCI in dioxane may be used as an appropriate medium for the hydroylsis of the ester and the methoxy group present in derivatives 39 to yield compounds of Formula I.
  • Another subset of compounds of Formula I may be prepared by hydrolysis of the ester group and the methoxy group of urea derivatives 40, as schown in scheme 9.
  • HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • Urea derivatives 40 may be prepared from amines 10 by reaction with an appropriate isocyanide, which could be prepared in-situ by reaction of a carboxylic acid with diphenyl phosphorazidate (DPPA), in the presence of a base.
  • An alternative synthesis of urea derivatives 40 may be a reaction of amines 10 with an appropriate amine either in the presence of p-nitrophenylchloroformate or in the presence of phosgene.
  • Scheme 9 Synthesis of compounds of Formula I
  • Compounds of Formula ID' and ID" may be prepared by hydrolysis of the ester group and the methoxy group of heterocyclic derivatives 44 and 45, as schown in scheme 10.
  • Either trimethylsilyl iodide which can be prepared in situ using sodium iodide and trimethylsilyl chloride or HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • the heterocyclic derivatives 44 and 45 respectively, may be prepared from the carboxylic acid 43 by reaction with an appropriate hydrazide or N- hydroxyimidamide in the presence of a condensing agent (e.g. TBTU, CDI) and subsequent treatment with a dehydrating agent (e.g. POCI3).
  • Carboxylic acid 43 may be prepared starting from bromide 41 which may be reacted with allyl tributyltin in presence of a palladium catalyst to yield intermediate 42 which in turn may be reacted with sodium periodate.
  • Another subset of compounds of Formula ID'" may be prepared by hydrolysis of the ester group and the methoxy group of heterocyclic derivatives 46, as shown in scheme 11.
  • HCI in dioxane may be used as an appropriate medium for such hydrolysis.
  • Heterocyclic intermediates 46 may be prepared via Stille coupling of an appropriate tributyl stannane with bromides 41 in presence of a palladium catalyst.
  • R 2 /R 3 combine to form 5-membered heteroaromatic ring [001 1 1 ] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.
  • the reaction products may be isolated and purified by standard laboratory techniques, such as extraction, chromatography and crystallization. Products isolated as a free base may be further converted into a hydrochloride or any other pharmaceutically acceptable salt according to known procedures. Products isolated as a free carboxylic acid may be converted into sodium salt or any other pharmaceutically acceptable salt according to known procedures.
  • Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable, may also find use, for example, in the preparation and purification of pharmaceutically acceptable compounds. All salts whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable salts as mentioned above are meant to comprise the therapeutically active non-toxic salt forms, which the compounds of Formula I are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, e.g.
  • 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 like acids.
  • the salt may be converted to the free base by treatment with alkali.
  • Compounds of Formula I can form pharmaceutically acceptable salts with various basic compounds. Suitable base salts include, but are not limited to, ammonium, potassium, sodium, and choline salts.
  • compositions and unit dosages thereof 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, liquids, such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, or thin films/flash doses, 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.
  • parenteral including intravenous or subcutaneous
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional or new ingredients in conventional or special proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient of the compounds of the present invention commensurate with the intended daily dosage range to be employed.
  • Tablets containing one (1 ) to one hundred (100) milligrams of active ingredient or, more broadly, zero point five (0.5) to five hundred (500) milligrams per tablet, are accordingly suitable representative unit dosage forms.
  • excipient applied to pharmaceutical compositions of the invention refers to an adjuvant, carrier, diluent, or vehicle with which a compound of the present invention is administered.
  • Such pharmaceutical excipients may be sterile or non-sterile excipients commonly used for the formulation and production of solid, semi solid, liquid and sterile pharmaceutical compositions.
  • These excipients may also be liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • A.R. Gennaro, 20 th Edition describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".
  • the excipients may also be combinations of solids and liquids.
  • the active principles of the invention may be administered to a subject, e.g., a living animal (including a human) body, in need thereof, for the treatment, alleviation, or amelioration, palliation, or elimination of an indication or condition which is susceptible thereto, or representatively of an indication or condition set forth elsewhere in this application, including concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, including in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parental (including intravenous and subcutaneous) or in some cases even topical route, in an effective amount.
  • Suitable dosage ranges are 1 -1000 milligrams daily, optionally 10-500 milligrams daily, and optionally 50-500 milligrams daily, depending as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and the preference and experience of the physician or veterinarian in charge.
  • treat is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) and/or reduce the risk of developing or worsening a disease.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a living animal body in need thereof.
  • the compounds of the present invention may be administered orally, topically, parenterally, or mucosally (e.g. , buccally, by inhalation, or rectally) in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers. It is usually desirable to use the oral route.
  • the compounds of the present invention may be administered orally in the form of a capsule, a tablet, or the like (see Remington: The Science and Practice of Pharmacy, 20 th Edition).
  • the orally administered medicaments may be administered in the form of a time-controlled release vehicle, including diffusion-controlled systems, osmotic devices, dissolution-controlled matrices, and erodible/degradable matrices.
  • the glycine B antagonist active component may be combined with a non-toxic, pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate); lubricants (e.g.
  • binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g., lactose, sucrose, glucose, mannitol, sorbitol and other reducing and non-reducing sugars, microcrystalline cellulose, calcium sulfate, or calcium hydrogen phosphate
  • lubricants e.g.
  • the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g., sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g. , potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (such as acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like.
  • the glycine B antagonist active components may be combined with non-toxic, pharmaceutically acceptable inert carriers (e.g.
  • suspending agents e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats
  • emulsifying agents e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils
  • preservatives ⁇ e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • the tablets may be coated by methods well known in the art.
  • the compounds of the present invention may be also introduced in beads, microspheres or microcapsules, e.g., fabricated from polyglycolic acid/lactic acid (PGLA).
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups, emulsions or suspensions, or they may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Preparations for oral administration may be suitably formulated to give controlled or postponed release of the active compound.
  • the compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • the compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the instant compounds may also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxy-propyl methacrylamide-phenol, polyhydroxy-ethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • the instant compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polyhydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
  • the compounds of the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • the formulations comprising the compounds of the present invention may be delivered parenterally, i.e., by intravenous (i.v.), intracerebroventricular (i.c.v.), subcutaneous (s.c), intraperitoneal (i.p.), intramuscular (i.m.), subdermal (s.d.), or intradermal (i.d.) administration, by direct injection, via, for example, bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions can take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient of the compounds of the present invention can be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds of the present invention may also be formulated for rectal administration, e.g., as suppositories or retention enemas ⁇ e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • compositions comprising glycine B antagonists of the present invention may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient and/or may contain different dosage levels to facilitate dosage titration.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the glycine B antagonists of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the dose of the components in the compositions of the present invention is determined to ensure that the dose administered continuously or intermittently will not exceed an amount determined after consideration of the results in test animals and the individual conditions of a patient.
  • a specific dose naturally varies depending on the dosage procedure, the conditions of a patient or a subject animal such as age, body weight, sex, sensitivity, feed, dosage period, drugs used in combination, seriousness of the disease.
  • the appropriate dose and dosage times under certain conditions can be determined by the test based on the above-described indices but may be refined and ultimately decided according to the judgment of the practitioner and each patient's circumstances (age, general condition, severity of symptoms, sex, etc.) according to standard clinical techniques.
  • Toxicity and therapeutic efficacy of the compositions of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index and it may be expressed as the ratio LD50/ED50.
  • Compositions that exhibit large therapeutic indices are preferred.
  • the method-of-treating a living animal body with a compound of the invention, for the inhibition of progression or alleviation of the selected ailment therein, is as previously stated by any normally-accepted pharmaceutical route, employing the selected dosage which is effective in the alleviation of the particular ailment desired to be alleviated.
  • Use of the compounds of the present invention in the treatment of a living animal for inhibition of progression or alleviation of selected ailments or conditions, particularly ailments or conditions susceptible to treatment with a glycine B is carried out in the usual manner comprising the step of admixing an effective amount of a compound of the invention with a pharmaceutically-acceptable diluent, excipient, or carrier, and the method-of-treating, pharmaceutical compositions, and use of a compound of the present invention in the manufacture of a medicament.
  • compositions prepared by admixing the active ingredient with a suitable pharmaceutically-acceptable excipient, diluent, or carrier include tablets, capsules, solutions for injection, liquid oral formulations, aerosol formulations, TDS formulations, and nanoparticle formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
  • DMF is defined as ⁇ , ⁇ -dimethylformamide
  • HCI hydrochloric acid
  • DMSO dimethyl sulfoxide
  • NH OH ammonium hydroxide solution
  • TAI tetrabutylammonium iodide
  • TAA trifluoroacetic acid
  • TAA triethylamine
  • MeCN acetonitrile
  • AcOH as acetic acid
  • TLC thin layer chromatography
  • HBT as 1 -hydroxybenzotriazole
  • EDC as 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • EtOH as ethanol and "MeOH” as ethanol
  • the title compound is prepared by the following reaction sequence: a) in analogy to the procedure described in Example 5(a), condensation of methyl 8- aminomethyl-6-chloro-2-methoxy-quinoline-3-carboxylate (10a) with (2-trifluoromethoxy- phenyl)-acetic acid gives 6-chloro-2-methoxy-8- ⁇ [2-(2-trifluoromethoxy-phenyl)- acetylamino]-methyl ⁇ -quinoline-3-carboxylic acid methyl ester in 45% yield.
  • the product consists of a mixture - 6-chloro-2-methoxy-8-(1 -oxo-1 ,3- dihydro-isoindol-2-ylmethyl)-quinoline-3-carboxylic acid and its methyl ester (10 :90). Solvent is removed under reduced pressure and the residue is used in the next step without additional purification.

Abstract

L'invention concerne des dérivés de la 2(1H)-quinolinone représentés par la formule (I), ainsi que les sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne de plus un procédé de préparation de tels composés. Les composés de l'invention constituent des antagonistes de la glycine B, et sont par conséquent utiles pour réguler et prévenir divers troubles, y compris des troubles neurologiques.
PCT/EP2012/060433 2011-06-03 2012-06-01 Antagonistes de la glycine b WO2012164085A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161520043P 2011-06-03 2011-06-03
US61/520,043 2011-06-03
EP11168693 2011-06-03
EP11168693.7 2011-06-03

Publications (1)

Publication Number Publication Date
WO2012164085A1 true WO2012164085A1 (fr) 2012-12-06

Family

ID=44544203

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/060433 WO2012164085A1 (fr) 2011-06-03 2012-06-01 Antagonistes de la glycine b

Country Status (1)

Country Link
WO (1) WO2012164085A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4284768A (en) 1980-07-02 1981-08-18 American Home Products Corporation 1,2-Dihydro-4-amino-2-oxo-3-quinoline-carboxylic acid derivatives
US4670462A (en) 1986-03-11 1987-06-02 American Home Products Corporation Substituted 1,3,4,9-tetrahydropyrano(3,4-B)indole-1-acetic acids
WO1993010783A2 (fr) 1991-11-29 1993-06-10 Merck Sharp & Dohme Limited Derives de quinolone et leur utilisation comme antagonistes des recepteurs de ampa et nmda
US5536709A (en) 1993-08-31 1996-07-16 Adir Et Compagnie 2(1H)-quinolone compounds
US6509352B1 (en) 1999-01-08 2003-01-21 Japan Tobacco Inc. 2-oxoquinoline compounds and medicinal uses thereof
US6562839B1 (en) 1999-02-26 2003-05-13 Kyorin Pharmaceutical Co., Ltd. 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both
WO2007043677A1 (fr) 2005-10-14 2007-04-19 Sumitomo Chemical Company, Limited Dérivé d'hydrazide et son utilisation en tant que pesticide
WO2010037533A1 (fr) * 2008-09-30 2010-04-08 Merz Pharma Gmbh & Co Kgaa Antagonistes de la glycine b

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4284768A (en) 1980-07-02 1981-08-18 American Home Products Corporation 1,2-Dihydro-4-amino-2-oxo-3-quinoline-carboxylic acid derivatives
US4670462A (en) 1986-03-11 1987-06-02 American Home Products Corporation Substituted 1,3,4,9-tetrahydropyrano(3,4-B)indole-1-acetic acids
WO1993010783A2 (fr) 1991-11-29 1993-06-10 Merck Sharp & Dohme Limited Derives de quinolone et leur utilisation comme antagonistes des recepteurs de ampa et nmda
US5536709A (en) 1993-08-31 1996-07-16 Adir Et Compagnie 2(1H)-quinolone compounds
US6509352B1 (en) 1999-01-08 2003-01-21 Japan Tobacco Inc. 2-oxoquinoline compounds and medicinal uses thereof
US6562839B1 (en) 1999-02-26 2003-05-13 Kyorin Pharmaceutical Co., Ltd. 6-substituted heteroquinolinecarboxylic acid derivatives and addition salts thereof and processes for the preparation of both
WO2007043677A1 (fr) 2005-10-14 2007-04-19 Sumitomo Chemical Company, Limited Dérivé d'hydrazide et son utilisation en tant que pesticide
WO2010037533A1 (fr) * 2008-09-30 2010-04-08 Merz Pharma Gmbh & Co Kgaa Antagonistes de la glycine b

Non-Patent Citations (21)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy"
A.R. GENNARO: "Remington: The Science and Practice of Pharmacy"
BARON ET AL., EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 323, no. 2-3, 1997, pages 181 - 192
BARON ET AL., J PHARMACOL EXP THER, vol. 279, no. 1, 1996, pages 62 - 68
CHEM. COMMUN., vol. 47, 2011, pages 10608
CHENG; PRUSOFF, BIOCHEMICAL PHARMACOLOGY, vol. 22, 1973, pages 3099 - 108
DICHTER, BRAIN RES, vol. 149, 1987, pages 279
FOSTER; WONG, BR J PHARMACOL, vol. 91, 1987, pages 403 - 409
HARTREE, ANALYTICAL BIOCHEMISTRY, vol. 48, 1972, pages 422 - 427
HOFFNER; WANNER, NEUROSCIENCE LETTERS, vol. 226, no. 2, 1997, pages 79 - 82
J. AM. CHEM. SOC., vol. 132, no. 33, 2010, pages 11629
J. HETEROCYCL. CHEM., vol. 9, 1972, pages 21
J. MED. CHEM., vol. 34, no. 1, 1991, pages 217 - 222
J. MED. CHEM., vol. 39, 1996, pages 197
LI ET AL., PAIN, vol. 109, 2004, pages 443 - 452
LOWRY ET AL., J. BIOLOGICAL CHEMISTRY, vol. 193, 1951, pages 256 - 275
PARSONS ET AL., J PHARMACOL EXP THER, vol. 283, no. 3, 1997, pages 1264 - 1275
PARSONS ET AL., NEUROPHARMACOLOGY, vol. 37, no. 6, 1998, pages 719 - 727
REN W.; YAMANE M., J. ORG. CHEM., vol. 75, 2010, pages 3017 - 3020
ROWLEY M ET AL: "3-ACYL-4-HYDROXYQUINOLIN-2(1H)-ONES. SYSTEMICALLY ACTIVE ANTICONVULSANTS ACTING BY ANTAGONISM AT THE GLYCINE SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 36, no. 22, 29 October 1993 (1993-10-29), pages 3386 - 3396, XP000563863, ISSN: 0022-2623, DOI: 10.1021/JM00074A020 *
STELLA V. ET AL.: "Prodrugs: Challenges and Rewards", 2007, AAPS PRESS/SPRINGER

Similar Documents

Publication Publication Date Title
JP6321045B2 (ja) キナーゼ阻害剤としての複素環式アミド
JP6734860B2 (ja) 置換ピラゾロ［１，５−ａ］ピリミジンおよび医療疾患の治療におけるその使用
US20050171101A1 (en) Phenanthridinones as parp inhibitors
US20120178742A1 (en) Metabotropic glutamate receptor modulators
US20040082607A1 (en) Fused heterocyclic compounds
CA2982588A1 (fr) Inhibiteur de bromodomaine
US8735384B2 (en) Amino heteroaryl compounds as beta-secretase modulators and methods of use
CA2969296A1 (fr) Derives de 2,4-dioxo-quinazoline-6-sulfonamide en tant qu'inhibiteurs de la parg
EP1931657B1 (fr) Nouveaux ligands de kinases a base de quinoline a affinite elevee
CA3166358A1 (fr) Antagonistes de sting a petites molecules
GB2563642A (en) Small molecule modulators of human STING
JP2007507546A (ja) キナーゼ阻害剤としての１，６−二置換アザベンゾイミダゾールの調製
WO2012085167A1 (fr) Modulateurs des récepteurs glutamatergiques métabotropes
EP2438070A1 (fr) Antagonistes de la glycine b
CA3073794A1 (fr) Derives de [1,2,4]thiadiazine fusionnes agissant en tant qu'inhibiteurs de kat de la famille des myst
WO2013030358A1 (fr) Antagonistes de glycine b
WO2012164085A1 (fr) Antagonistes de la glycine b
TW202321232A (zh) 小分子sting拮抗劑
AU2002230126A1 (en) Fused heterocyclic compounds

Legal Events

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

Ref document number: 12725737

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12725737

Country of ref document: EP

Kind code of ref document: A1