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WO2012085167A1 - Modulateurs des récepteurs glutamatergiques métabotropes - Google Patents

Modulateurs des récepteurs glutamatergiques métabotropes Download PDF

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Publication number
WO2012085167A1
WO2012085167A1 PCT/EP2011/073712 EP2011073712W WO2012085167A1 WO 2012085167 A1 WO2012085167 A1 WO 2012085167A1 EP 2011073712 W EP2011073712 W EP 2011073712W WO 2012085167 A1 WO2012085167 A1 WO 2012085167A1
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amino
dihydropyrido
chlorophenyl
pyrimidin
alkyl
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PCT/EP2011/073712
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English (en)
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Ulrich Abel
Bjoern Krueger
Holger Kubas
Udo Meyer
Ronalds Zemribo
Gints Smits
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2012085167A1 publication Critical patent/WO2012085167A1/fr

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    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms

Definitions

  • the present invention relates to heterocyclic derivatives, which may act as novel metabotropic glutamate receptor (mGluR) modulators, methods for their synthesis and the treatment and/or prevention of various diseases and disorders, including neurological disorders, by administration of such derivatives.
  • mGluR metabotropic glutamate receptor
  • Neuronal stimuli are transmitted by the central nervous system (CNS) through the interaction of a neurotransmitter released by a neuron, which neurotransmitter has a specific effect on a neuroreceptor of another neuron.
  • L-glutamic acid is considered to be a major excitatory neurotransmitter in the mammalian CNS, consequently playing a critical role in a large number of physiological processes.
  • Glutamate-dependent stimulus receptors are divided into two main groups. The first group comprises ligand-controlled ion channels whereas the other comprises metabotropic glutamate receptors (mGluR). Metabotropic glutamate receptors are a subfamily of G-protein-coupled receptors (GPCR). There is increasing evidence for a peripheral role of both ionotropic and metabotropic glutamate receptors outside the CNS e.g, in chronic pain states.
  • mGluRI and mGluR5 belong to Group I which are positively coupled to phospholipase C and their activation leads to a mobilization of intracellular calcium ions.
  • mGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to Group III, both of which are negatively coupled to adenylyl cyclase, i.e., their activation causes a reduction in second messenger cAMP and thus a dampening of neuronal activity.
  • the mGluR5 modulators have been shown to modulate the effects of the presynaptically released neurotransmitter glutamate via postsynaptic mechanisms (receptors). Moreover, as these modulators may be both positive and/or negative mGluR5 modulators, such modulators may increase or inhibit the effects mediated through these metabotropic glutamate receptors.
  • Modulators which are negative mGluR5 modulators decrease the effects mediated through metabotropic glutamate receptors. Since a variety of pathophysiological processes and disease states affecting the CNS are thought to be related to abnormal glutamate neurotransmission, and mGluR5 receptors are shown to be expressed in many areas of the CNS and in PNS (peripheral nervous system), modulators of these receptors could be therapeutically beneficial in the treatment of diseases involving CNS and PNS.
  • mGluR5 positive or negative modulators may be administered to provide neuroprotection and/or disease modification in the following acute or chronic pathological conditions or to provide a symptomatological effect on the following conditions: 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, hepatic encephalopathy, Huntington's disease, motor neuron diseases, amyotrophic lateral sclerosis (ALS), olivopontocerebellar atrophy, post-operative cognitive deficit (POCD), systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, Neuronal Ceroid Lipofuscinosis, neurodegenerative cerebellar ataxias, Parkinson's disease, Parkinson's dementia, mild cognitive impairment, cognitive deficits in various forms of mild cognitive impairment, cognitive impairment
  • mGluR5 negative or positive modulators may also be administered to provide inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS.
  • MGIuR5 modulators may be administered to provide therapeutic intervention in neoplasia, hyperplasia, dysplasia, cancer, carcinoma, sarcoma, oral cancer, squamous cell carcinoma (SCC), oral squamous cell carcinoma (SCC), lung cancer, lung adenocarcinoma, breast cancer, prostate cancer, gastric cancer, liver cancer, colon cancer, colorectal carcinoma, rhabdomyosarcoma, brain tumour, tumour of a nerve tissue, glioma, malignant glioma, astroglioma, neuroglioma, neuroblastoma, glioblastoma, medulloblastoma, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lympho
  • mGluR5 positive or negative modulators may also be administered to provide disease modification and/or to provide a symptomatological effect on the following conditions: diabetes, hyperammonemia and liver failure.
  • mGluR5 negative or positive modulators include those indications wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, for example cognitive enhancement, learning impairment and/or neuroprotection.
  • Positive modulators may be particularly useful in the treatment of positive and negative symptoms in schizophrenia and cognitive deficits in various forms of dementia and mild cognitive impairment.
  • mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
  • Simultaneous administration of Group I mGluR modulators and NMDA receptor antagonists has also been shown to provide neuroprotection in animal models (Zieminska et al. Acta Neurobiol. Exp., 2006, 66, 301 -309; Zieminska et al. Neurochemistry International, 2003, 43, 481 -492; and Zieminska et al. Neurochemistry International, 2006, 48, 491 -497).
  • Group I mGluR modulators and compounds such as L-DOPA, dopaminomimetics, and/or neuroleptics may be useful in treating various conditions including drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias.
  • heterocyclic derivatives are potent mGluR5 modulators. Therefore, these substances may be therapeutically beneficial in the treatment of conditions which involve abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
  • These substances may be administered in the form of a pharmaceutical composition, wherein they are present together with one or more pharmaceutically acceptable diluents, carriers, or excipients.
  • R 1 represents H, Ci -6 alkyl, or F;
  • R 2 represents H, C h alky!, or F; or
  • R 3 represents H, C h alky!, or F
  • R 4 represents H, C h alky!, or F
  • R 3 and R 4 together with the carbon atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci -6 alkylamino, di-(C-i -6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC 3-6 alkyl, and heterocyclyl;
  • R 6 represents H, C h alky! which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di-(Ci -6 alkyl)amino, or F;
  • R 7 represents C h alky!, which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di-(C-i -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, or NR 11 R 12 ; or R 6 and R 7 together with the carbon atoms to which they are attached form a 3- 7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkoxy, amino, hydroxy, cyano, acyl, Ci -6 alkylamino, di-(C-i -6 alkyl)amin
  • R 8 represents Ci -6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, aryl, heteroaryl, Ci- 6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di- (C-i -6 alkyl)amino, cycloC 3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, heteroarylcarbonyl, Ci- 6 alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl,
  • alkylaminosulfonyl wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, C-i- 6 alkylamino, and di-(C-i- 6 alkyl)amino, or ⁇ /,/V-di- (Ci- 6 alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di- (C-i -6 alkyl)amino;
  • R 9 represents H, C h alky!, or F;
  • R 10 represents H, Ci -6 alkyl, or F; or R 9 and R 10 together with the carbon atom to which they are attached form a 3-
  • R 11 represents H, C h alky!, or cycloC3-6alkyl
  • R 12 represents H, Ci -6 alkyl, or cycloC 3-6 alkyl; or R 11 and R 12 together with the nitrogen atom to which they are attached form a 3-7 membered ring which may be saturated or unsaturated, wherein the ring may optionally contain one or two heteroatoms selected from sulfur, oxygen, and nitrogen and wherein the ring may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, C h alky!, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci -6 alkylcarbonylamino, and oxo; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that: if R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group, then R 8 may also represent H
  • a further aspect of the invention relates to a compound of Formula I, wherein R 8 represents C h alky!
  • halogen trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, d- 6 alkylamino, and di-(C-i -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, aryl, heteroaryl, d- 6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, d- 6 alkylamino, and di-(C-i- 6 alkyl)amino, cycloC 3 - 6 alkylcarbonyl, arylcarbonyl,
  • Ci -6 alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, C-i -6 alkylamino, and di-(Ci -6 alkyl)amino, aminocarbonyl, N- C-i- 6 alkylaminocarbonyl, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy,
  • alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, d -6 alkoxy, amino, hydroxy, d -6 alkylamino, and di-(d -6 alkyl)amino, or ⁇ /,/V-di- (Ci- 6 alkyl)aminosulfonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy,
  • a further aspect of the invention relates to a compound of Formula I, wherein R 1 and R 2 together with the carbon atom to which they are attached form a carbonyl group, and X represents NR 8 , wherein R 8 represents H.
  • a further aspect of the invention relates to a compound of Formula I, wherein R 1 and R 2 represent H, and X represents NR 8 , wherein R 8 represents Ci -6 alkylcarbonyl, cycloC 3 - 6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci- 6 alkoxycarbonyl, /V-C-i- 6 alkylaminocarbonyl, /V./V-di ⁇ Ci-ealky aminocarbonyl, ⁇ /,/V-di-
  • R 8 represents C-i- 6 alkylcarbonyl, cycloC3-6alkylcarbonyl, arylcarbonyl, Ci-6alkoxycarbonyl, A/-Ci-6alkylaminocarbonyl, N,N- di-(Ci-6alkyl)aminocarbonyl, Ci-6alkylsulfonyl, cycloC3-6alkylsulfonyl, ⁇ /,/V-di- (Ci-6alkyl)aminosulfonyl, or heteroaryl.
  • Such a compound of Formula I wherein represents optionally substituted pyridyl or tetrazolyl.
  • a further aspect of the invention relates to a compound of Formula I, wherein R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, and cyano.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
  • R 3 -R 5 and R 8 -R 10 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IA wherein R 3 , R 4 , R 8 , R 9 , and R 10 each represent H and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IA wherein R 3 , R 4 , R 8 , R 9 , and R 10 each represent H and R 5 represents phenyl optionally substituted by one or more halogen atoms.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
  • R 1 -R 4 , R 9 -R 12 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IB wherein R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • R 3 , R 4 , R 9 , and R 10 each represent H
  • R 11 and R 12 represent C h alky! (e.g., methyl or ethyl) or R 11 and R 12 together with the nitrogen atom to which they are attached combine to form a 3-7 membered saturated ring
  • R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IB wherein R 3 , R 4 , R 9 , and R 10 each represent H, R 11 and R 12 together with the nitrogen atom to which they are attached combine to form piperidino, and R 5 represents phenyl optionally substituted by one or more halogen atoms.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
  • R 1 -R 5 and R 8 -R 10 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IC wherein R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IC wherein R 1 -R 4 , R 9 , and R 10 each represent H; R 5 represents a monocyclic moiety selected from aryl and heteroaryl; and R 8 represents Ci -6 alkylcarbonyl, cycloC 3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, d.
  • R 8 represents Ci- 6 alkylcarbonyl, cycloC 3 - 6 alkylcarbonyl, arylcarbonyl, Ci- 6 alkoxycarbonyl, /V-Ci- 6 alkylaminocarbonyl, N,N- di-(Ci- 6 alkyl)aminocarbonyl, Ci- 6 alkylsulfonyl, cycloC 3 - 6 alkylsulfonyl, ⁇ /,/V-di- (Ci- 6 alkyl)aminosulfonyl, or heteroaryl.
  • Such a compound of Formula IC wherein R 1 -R 4 , R 9 , and R 10 each represent H; R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, C h alky!, and cyano; and R 8 represents Ci- 6 alkylcarbonyl, cycloC 3-6 alkylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, Ci -6 alkoxycarbonyl, N-C ⁇ ⁇ . 6 alkylaminocarbonyl, /V,/V-di-(Ci- 6 alkyl)aminocarbonyl, ⁇ /,/V-di-
  • R 8 represents Ci -6 alkylcarbonyl, cycloC 3-6 alkylcarbonyl, arylcarbonyl, Ci -6 alkoxycarbonyl, /V-Ci -6 alkylaminocarbonyl, N,N- di-(Ci -6 alkyl)aminocarbonyl, Ci -6 alkylsulfonyl, cycloC 3-6 alkylsulfonyl, ⁇ /,/V-di- (Ci -6 alkyl)aminosulfonyl, or heteroaryl.
  • Such a compound of Formula IC wherein R 1 -R 4 , R 9 , and R 10 each represent H; R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, and cyano; and R 8 represents optionally substituted pyridyl, tetrazolyl, pyrimidyl, furyl, thiazolyl, or imidazolyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula ID
  • R 1 -R 5 and R 9 and R 10 are as defined above for Formula I and
  • R 13 represents Ci -6 alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, cycloC 3-6 alkyl, heterocyclyl, aryl, heteroaryl, Ci- 6 alkoxy which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, d- 6 alkylamino, and di-(C-i- 6 alkyl)amino, aminocarbonyl, /V-C-i- 6 alkylamino, wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci- 6 alkoxy, amino, hydroxy, C-
  • Such a compound of Formula ID wherein R 13 represents Ci -6 alkyl, cycloC 3- 6 alkyl, heterocyclyl, aryl, Ci- 6 alkoxy, /V-C-i- 6 alkylamino, /V,/V-di-(Ci- 6 alkyl)amino, N-C- ⁇ . 6 alkyl-/V-cycloC 3-6 alkylamino, or / -Ci-ealkyl-Z -cycloCs-ealkyl-d-ealkylamino.
  • Such a compound of Formula ID wherein R 1 -R 4 , R 9 , and R 10 each represent H and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula ID wherein R 3 , R 4 , R 8 , R 9 , and R 10 each represent H and R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, Ci -6 alkyl, and cyano.
  • 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 the treatment and/or prevention of a condition or disease associated with abnormal glutamate neurotransmission, including a condition or disease which is affected or facilitated by modulation of the mGluR5 receptor, including for the conditions or diseases selected from those described earlier in the description.
  • 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 the treatment and/or prevention of a CNS disorder.
  • 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 the treatment and/or prevention of abnormal glutamate neurotransmission.
  • the invention additionally relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for modulation of the mGluR5 receptor.
  • the invention furthermore relates to such a compound for treatment, prevention and or modulation of a condition or disease selected from those described earlier in the description.
  • the invention still further relates to such a compound for treatment, prevention and or modulation of a a physiological parameter, such as cognitive disorder, whether or not a specific identifiable condition exists.
  • a further aspect of 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 the treatment and/or prevention of a condition associated with abnormal glutamate neurotransmission or in which modulation of mGluR5 receptors results in therapeutic benefit.
  • the conditions which may be treated have already been described above.
  • Such conditions and indications include: a) For mGluR5 modulators: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic- induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, Huntington's chorea, epilepsy, Alzheimer's disease, positive and negative symptoms of schizophrenia, cognitive impairment, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), migraine, irritable bowel syndrome (IBS), or for cognitive enhancement and/or neuroprotection.
  • Negative modulation of mGluR5 may be particularly useful for: chronic pain, neuropathic pain, diabetic neuropathic pain (DNP), cancer pain, pain related to rheumathic arthritis, inflammatory pain, L-dopa-induced dyskinesias, dopaminomimetic-induced dyskinesias, L-dopa-induced dyskinesias in Parkinson's disease therapy, dopaminomimetic-induced dyskinesias in Parkinson's disease therapy, tardive dyskinesias, Parkinson's disease, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), generalized anxiety disorder, substance-induced anxiety disorder, eating disorders, obesity, binge eating disorders, migraine, irritable bowel syndrome (IBS), functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Huntington's chorea and/or epilepsy.
  • Positive modulation of mGluR5 may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of
  • a further aspect of 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 the treatment of binge eating disorders.
  • the invention relates to the use of a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for the preparation of a medicament for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission.
  • a use includes the use of such a compound for the preparation of a medicament for the prevention and/or treatment of a condition or disease in an animal including a human being which condition or disease is affected or facilitated by modulation of the mGluR5 receptor.
  • the invention relates to a method for treating or preventing a condition associated or disease associated with abnormal glutamate neurotransmission, including a condition or disease which is affected or facilitated by modulation of the mGluR5 receptor, including for the conditions or diseases selected from those described earlier in the description.
  • 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, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, together with one or more pharmaceutically acceptable excipients.
  • the mGluR modulators as described above are expected to have a high activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
  • the invention thus relates to a compound of Formula I as defined above or an optical isomer, pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof for Neuroprotection and/or for cognitive enhancement in combination with at least one NMDA receptor antagonist such as Memantine.
  • a further aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least two different active ingredients, selected from least one compound of Formula I as defined above, and, additionally, at least one NMDA-antagonist, together with one or more pharmaceutically acceptable excipients.
  • These compositions may be used for the treatment of CNS-related diseases, cognitive enhancement and for neuro-protection.
  • the invention thus additionally provides a composition comprising at least two different active ingredients, selected from least one compound of Formula I as defined above, and, additionally, at least one NMDA-antagonist for the treatment of any of the conditions indicated herein, including CNS-related diseases, cognitive enhancement and for neuroprotection.
  • This invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a compound of Formula I as described above and an NMDA receptor antagonist, including compositions wherein the NMDA receptor antagonist is e.g. Memantine and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
  • the NMDA receptor antagonist is e.g. Memantine and pharmaceutically acceptable salts, polymorphs, hydrates and solvates thereof.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least two different active ingredients, selected from at least one compound of Formula I as defined above, and, additionally, at least one active ingredient selected from L-DOPA, other dopaminomimetics (such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine), and neuroleptics (such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide).
  • dopaminomimetics such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine
  • neuroleptics such as classical neuroleptics, including haloperidol, perphenazin, chlorpromazine, metoclopramide.
  • the invention also relates to a method of providing neuroprotection in a living animal, including a human, comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a composition as described above.
  • the invention relates to the use of a composition as described above for the manufacture of a medicament to provide neuroprotection in an animal, including a human.
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula ⁇ '
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IC
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IC
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula ID'
  • R 5 represents aryl or heteroaryl and R 13 is as defined above for Formula ID, wherein a com ound of Formula XIV
  • 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.
  • (d ⁇ alkyl refers to alkyl of one to three carbon atoms (i.e.
  • Ci -6 alkyl represents straight or branched chain alkyl groups. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert -butyl.
  • C 2 - 6 alkenyl represents straight or branched chain alkenyl groups.
  • Ci -6 alkoxy represents straight or branched chain -0-Ci -6 alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, fe/f-butoxy.
  • acyl represents Ci -6 alkylcarbonyl, trifluoroacetyl, hydroxy- Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl, /V-Ci -6 alkylaminocarbonyl, ⁇ /,/V-di- (C-i- 6 alkyl)aminocarbonyl, Ci- 6 alkoxy-Ci- 6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C 3- i 2 alkylcarbonyl, aryl-Ci -6 alkylcarbonyl, heteroaryl-Ci -6 alkylcarbonyl, arylamino- Ci -6 alkylcarbonyl, heteroarylamino-Ci -6 alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci- 6 alkylcarbonyl.
  • cycloC 3- i 2 alkyl represents monocyclic or bicyclic, or tricyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1 ]heptyl and adamantanyl, which 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, trifluoromethoxy, Ci -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, cyano, Ci -6 alkoxycarbonyl, C-i -6 alkylamino, and di-(C-i -6 alkyl)amino, Ci -6 alkyl- carbonylamino, oxo, C-i -6 alkoxyimino, /V-Ci -6 alkylamin
  • cycloC 3-6 alkyl represents monocyclic alkyl groups, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, which 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, trifluoromethoxy, Ci -6 alkyl, C 2- 6 alkenyl, Ci -6 alkoxy, amino, hydroxy, cyano, Ci -6 alkoxycarbonyl, Ci -6 alkylamino, and di- (C-i -6 alkyl)amino, Ci -6 alkylcarbonylamino, oxo, C-i -6 alkoxyimino, /V-d. 6 alkylaminocarbonyl, /V,/V-di-(Ci -6 alkyl)aminocarbonyl, aryl
  • aryl represents phenyl or naphthyl, wherein the phenyl or naphthyl group is 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, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, d.
  • heteroaryl represents an aromatic 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, or a bicyclic group comprising a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6 membered ring containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, wherein the heteroaryl group 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, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, Ci -6 alkyl, hydroxyCi -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, nitro, cyano, Ci -6 alkylcarbonyl, Ci
  • heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazolyl, triazolyl, thiadiazolyl, thiazolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, purinyl, benzofuryl, benzothienyl, indolyl, indolizinyl, isoindolyl, indolinyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, isoquinolinyl, quinolizin
  • 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, C h alky!, C2- 6 alkenyl, amino, hydroxy, nitro, cyano, Ci- 6 alkoxycarbonyl, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, oxo, Ci- 6
  • halogen represents fluorine, chlorine, bromine and iodine.
  • the compounds of the present invention are usually named according to the lUPAC or CAS nomenclature system. Abbreviations which are well known to one of ordinary skill in the art may be used (e.g. "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “min” for minute or minutes, “h” for hour or hours, and “rt” for room temperature).
  • Memantine also known as 1 -amino-3,5-dimethyladamantane, is disclosed, U.S. Patent Nos. 4, 122, 193; 4,273,774; and 5,061 ,703, the subject matter of which patents is hereby incorporated by reference.
  • Memantine is a system ically-active noncompetitive NMDA receptor antagonists having moderate affinity for the receptor. It exhibits strong voltage dependent characteristics and fast blocking/unblocking kinetics (see e.g. Gortelmeyer et al., Arzneim-Forsch/Drug Res., 1992, 42:904-913; Winblad et al., Int. J. Geriat. Psychiatry, 1999, 14: 135-146; Rogawski, Amino Acids, 2000, 19: 133-49; Danysz et al., Curr. Pharm. Des., 2002, 8:835-43; Jirgensons et. al. Eur. J. Med. Chem., 2000, 35: 555- 565).
  • analog or “derivative” is used herein in the conventional pharmaceutical sense, to refer to a molecule that structurally resembles a reference molecule, 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.
  • 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, greater ability to penetrate blood-brain barriers, 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 may 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, amino, and thio 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.
  • Compounds 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 is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • ⁇ -Alanine ester 1 is acylated with methylmalonylchloride (2).
  • the resulting diester 3 is cyclized to lactam 4, which is subsequently decarboxylated to piperidine-2,4-dione (5).
  • Treatment of intermediate 5 with dimethylformamide dimethyl acetal (DMF-DMA) at elevated temperature results in the formation of dimethylaminomethylene derivative 6, which is reacted with an appropriate guanidine 7 to provide a compound of Formula ⁇ '.
  • DMF-DMA dimethylformamide dimethyl acetal
  • the Boc group is cleaved with trifluoroacetic acid (TFA) to provide an amine 16, which is acylated using acyl chlorides, chloroformates, sulfonyl or carbamoyl chlorides, or alkylated with alkyl halides to provide compounds of Formula IC
  • Amine 16 may also be reacted with isocyanates or isothiocyanates to give ureas or thioureas, or it can be arylated to give the corresponding /V-aryl derivatives.
  • deprotected piperidone 17 may be directly reacted with an appropriate acylating or alkylating reagent to obtain ketone 18, which is subsequently converted to dimethylaminomethylene derivative 19 by means of DMF-DMA.
  • the final compound IC is formed analogously to the above described method using substituted guanidine 7 in the presence of triethylamine or another suitable base.
  • R 5' aryl or eteroaryl
  • BOC-protected intermediate 14 is reacted with methyl carbarn imidothioate (20) under acidic conditions at elevated temperature to form intermediate 21 , which is deprotected and converted to the corresponding acylated compound 23.
  • intermediate 21 is deprotected and converted to the corresponding acylated compound 23.
  • oxidizing reagent like mCPBA the mesylate group is substituted by an arylamine 25 to provide compounds of formula ID'.
  • stereoisomeric forms (including optical isomers) of the compounds and the intermediates of this invention may be obtained by the application of art-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 (optically active isomers) may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • stereoisomeric forms may also be derived from the corresponding pure stereoisomeric form of appropriate starting materials, provided that the reaction occur stereoselectively.
  • Stereoisomeric forms of Formula I are included within the scope of this invention.
  • Compounds of Formula I which are marked by radioactive atoms may be obtained using art-known procedures. Typical compounds include those where one or more hydrogens are substituted by tritium, where one or more 12 C are substituted by 14 C, where one or more fluor atoms are substituted by 18 F or other isotopes. These may be used for the treatment of diseases (e.g. cancer) but also for diagnostic purposes.
  • the radioactive atoms exchanged in the molecule are often isotopes of carbon, hydrogen, halogen, sulphur or phosphorus.
  • Compounds of the Formula I which are marked by radioactive atoms are included within the scope of this invention.
  • 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 may 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 the like acids.
  • the salt form may be converted by treatment with alkali into the free base form.
  • the active ingredients of the compounds of the invention may be placed into the form of pharmaceutical compositions, unit dosages or dosage forms.
  • the pharmaceutical compositions may be employed as solid dosage forms, such as powders, granules, pellets, coated or uncoated tablets or filled capsules, or liquid dosage forms, such as solutions, suspensions, emulsions, or capsules filled with the same, or semi solid dosage forms, such as gels, creams and ointments.
  • the active ingredient(s) dissolution and release profiles of the pharmaceutical dosage forms may be varied from seconds to months.
  • compositions are designed for the use in animals and humans and may be applied via all application routes.
  • Preferred application routes will be the oral route, the dermal route, the pulmonary route, the nasal route, the rectal route, the parenteral route.
  • 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 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.
  • carrier applied to pharmaceutical compositions of the invention refers to a diluent, excipient, or vehicle with which an active compound is administered.
  • Such pharmaceutical carriers may be sterile 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”. METHOD OF TREATING
  • 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, preferably concurrently, simultaneously, or together with one or more pharmaceutically-acceptable excipients, carriers, or diluents, especially and preferably 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.
  • compositions comprising a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic), in a formulation known in the art, or two separate pharmaceutical compositions (formulations), one comprising a compound of the present invention as formulated above and one comprising a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in a formulation known in the art, to be administered conjointly.
  • a second active ingredient e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic
  • the term “conjoint administration” is used to refer to administration of a compound of the present invention and a second active ingredient (e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic) in one composition, or simultaneously in different compositions, or sequentially.
  • a second active ingredient e.g., an NMDA receptor antagonist, L-DOPA, a dopaminomimetic, or a neuroleptic
  • the sequential administration to be considered “conjoint”
  • the compound of the present invention and the NMDA receptor antagonist must be administered separated by a time interval that still permits the resultant beneficial effect in a mammal.
  • the compound of the present invention and the NMDA receptor antagonist must be administered on the same day (e.g., each - once or twice daily), including within an hour of each other, and including simultaneously.
  • 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.
  • 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 active agents 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 pharmaceutical compositions 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 active drug component of Formula I may be combined with 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., magnesium stearate, talc, or silica, steric acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate, and the like); disintegrants (e.g., potato starch or sodium starch glycolate); and/or wetting agents (e.g., sodium lauryl sulphate), coloring and flavoring agents, gelatin, sweeteners, natural and synthetic gums (
  • binding agents e.g., pregelatinized maize starch
  • the drug components may be combined with nontoxic, pharmaceutically acceptable inert carriers (e.g., ethanol, glycerol, water), 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), and the like.
  • Stabilizing agents such as antioxidants (BHA, BHT, propyl gallate, sodium ascorbate, citric acid) may also be added to stabilize the dosage forms.
  • compositions of the invention containing as active compound a compound of Formula I 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.
  • Liposome delivery systems such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
  • 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.
  • Active drugs 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.
  • active drug 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.
  • 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.
  • the therapeutics according to the present invention containing as active compound a compound of Formula I 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, dichlorotetra-fluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g. , dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, 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 may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Formations comprising 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 may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • compositions may take such forms as excipients, suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • 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).
  • rectal administration e.g., as suppositories or retention enemas (e.g., containing conventional suppository bases such as cocoa butter or other glycerides).
  • compositions containing a compound of Formula I 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.
  • Compositions of the 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 may 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.
  • compositions of the invention may 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 instant compounds of Formula I represent a novel class of mGluR5 modulators. In view of their potency, they will be useful therapeutics in a wide range of disorders, in particular CNS disorders, which involve excessive glutamate induced excitation.
  • Neuroprotection as well as cognitive enhancement may also be achieved by administration of the instant compounds in combination with a NMDA receptor antagonist like Memantine.
  • 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 manufacture of a medicament for 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 Group I mGluR modulator 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.
  • ACN is defined as acetonitrile
  • Boc as fe/f-butyloxycarbonyl
  • DCM dichloromethane
  • DEE diethyl ether
  • DMAP as 4- dimethylaminopyridine
  • DIPEA N,N- diisopropylethylamine
  • DF-DMA N,N- dimethylformamide
  • EDC EDC
  • EDC EDC
  • EDC as 1 -ethyl-3-(3-dimethylaminopropyl) carbodiimide (/V 1 -((ethylimino)methylene)-/V 3 ,/V 3 - dimethylpropane-1 ,3-diamine
  • O-Dimethylhydroxylamine hydrochloride (0.13 g, 1 .28 mmol) is added to a solution of 2-((3-chlorophenyl)amino)-5,6,7,8-tetrahydroquinazoline-6-carboxylic acid 0.30 g, 0.98 mmol), HOBt hydrate (0.20 g, 1 .28 mmol), EDC (0.25 g, 1 .28 mmol) and DIPEA (0.56 mL ,3.26 mmol) in dry DMF (3 mL), and the resulting mixture is stirred at room temperature for 24 h.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :5) and washed with DEE/hexane mixture (1 : 1 ) to give an impure mixture of fe/f-butyl 2-((3-chlorophenyl)amino)-5-methyl-7,8-dihydropyrido[4,3- d]pyrimidine-6(5/-/)-carboxylate and fe/f-butyl 2-((3-chlorophenyl)amino)-7-methyl-7,8- dihydropyrido[4,3-d]pyrimidine-6(5/-/)-carboxylate (in total 369 mg).
  • the formed solid is collected by filtration, washed with acetone/DEE (1 :1 ) and air-dried to obtain a mixture of ⁇ /-(3- chlorophenyl)-5-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine and ⁇ /-(3- chlorophenyl)-7-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (496 mg, 97%) as a white solid.
  • Example 75 the title compound (78 mg, 13%) is separated as a white solid.
  • compositions according to the present invention may be processed into tablets, coated tablets, capsules, drip solutions, suppositories, injection and infusion preparations, and the like and may be therapeutically applied by the oral, rectal, parenteral, and additional routes.
  • Representative pharmaceutical compositions according to the present invention follow:
  • Tablets suitable for oral administration which contain the active ingredient may be prepared by conventional tabletting techniques.
  • any usual suppository base may be employed for incorporation thereinto by usual procedure of the active ingredient, such as a polyethyleneglycol which is a solid at room temperature but which melts at or about body temperature.
  • a suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg
  • Another suitable formulation for a tablet containing 100 mg is as follows:
  • the film coating material consists of:
  • Capsule Formulation A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows:
  • a suitable formulation for an injectable solution is as follows:
  • a suitable formulation for 1 liter of a an oral solution containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows: mg
  • Another suitable formulation for 1 liter of a liquid mixture containing 20 milligrams of active ingredient in one milliliter of the mixture is as follows:
  • Active Ingredient 10 Oleic acid Ethanol Purified Water Tetrafluoroethane
  • Polybutylcyanoacrylate nanoparticles are prepared by emulsion polymerization in a water/0.1 N HCI/ethanol mixture as polymerizsation medium. The nanoparticles in the suspension are finally lyophilized under vacuum.
  • 1.0 g of the suspension contains the following:
  • Hypromellose is dispersed in water homogeneously with a high speed mixer/blender. After about one hour of hydration time of the hypromellose, the active ingredient is blended homogeneously into the hypromellose solution. The viscosity of the suspension may be adjusted by the amount of hypromellose, resulting in a very stable suspension with a very slow tendency of particle sedimentation and particle agglomeration.
  • the active ingredient is dissolved in DMSO by stirring and heating (solution 1 ).
  • the mannitol is dissolved in WFI (solution 2).
  • solution 1 After cooling down to room temperature solution 1 is mixed with solution 2 by continuous stirring.
  • the solution is sterilized by filtration of by autoclaving.
  • the supernatant and the buffy coat are centrifuged at 48,000 x g for 20 minutes in the presence of 50 m M Tris-HCI, pH 8.0.
  • the pellet is then re-suspended and centrifuged two to three more times at 48,000 x g for 20 minutes in the presence of 50 mM Tris-HCI, pH 8.0. All centrifugation steps are carried out at 4 °C. After resuspension in 5 volumes of 50 m M Tris-HCI, pH 8.0, the membrane suspension is frozen rapidly at -80 °C.
  • the membrane suspensions are thawed and washed four times by resuspension in 50 mM Tris-HCI, pH 8.0, and centrifugation at 48,000 x g for 20 minutes and finally re-suspended in 50 mM Tris-HCI, pH 7.4.
  • the amount of protein in the final membrane preparation (500-700 pg/ml) is determined according to the method of Lowry (Lowry O. H. et al. 1951 . J. Biol. Chem. 193, 256-275).
  • [00251 ]lncubations are started by adding [ 3 H]-MPEP (50.2 Ci/mmol, 5 nM, Tocris, GB) to vials with 125-250 g protein (total volume 0.25 ml) and various concentrations of the agents.
  • assays are performed with [ 3 H]-MMPEP (2-(3- methoxyphenylethynyl)-6-methylpyridine hydrochloride) as radioligand.
  • the incubations are continued at room temperature for 60 minutes (equilibrium is achieved under the conditions used).
  • Non-specific binding is defined by the addition of unlabeled MPEP (10 ⁇ ). Incubations are terminated using a Millipore filter system.
  • the samples are rinsed twice with 4 ml of ice-cold assay buffer over glass fibre filters (Schleicher & Schuell, Germany) under a constant vacuum. Following separation and rinse, the filters are placed into scintillation liquid (5 ml Ultima Gold, Perkin Elmer, Germany) and radioactivity retained on the filters is determined with a conventional liquid scintillation counter (Canberra Packard, Germany). Characterization
  • the Kd of [ 3 H]-MPEP of 13.6 nM is determined by Scatchard analysis and used according to the Cheng Prussoff relationship to calculate the affinity of displacers as Kd values (IC 50 of cold MPEP equates to a Kj of 8.2 nM).
  • B max is 0.56 pm / mg protein.
  • Ca-Kit is reconstituted in an assay buffer containing 20 rriM HEPES pH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS).
  • HBBS Hank's balanced salt solution
  • Agonistic compounds to the receptor elicit increases in cytosolic calcium which can be measured as increases in fluorescence signals by use of a fluorescence imaging plate reader (Molecular Devices).
  • a fluorescence imaging plate reader Molecular Devices.
  • To analyze their potency to modulate the Ca-response test compounds dissolved in a final DMSO concentration of 0.5%, are added on-line 5 minutes before the agonist to the receptor (L-quisqualic acid at a concentration giving ⁇ 80% of the maximal signal).
  • astrocyte cultures are prepared from cortices of newborn rats as described by Booher and Sensenbrenner (1972, Neurobiology 2(3):97-105). Briefly, Sprague-Dawley rat pups (2 - 4 d old) are decapitated and neocortices are dissected, disintegrated with a nylon filter (pore size 80 m) and carefully triturated.
  • the cell suspension is plated on poly-D-lysine pre-coated flasks (Costar, Netherlands) and cultivated in Dulbecco's Modified Eagle's Medium (DMEM, Invitrogen, Germany) supplemented with 10% foetal calf serum (FCS, Sigma, Germany), 4 rri M glutamine and 50 pg/ml gentamycin (both Biochrom, Germany) at 37 °C in a humidified atmosphere of 5% CO2 95% air for 7 days with exchanging the medium at day 2 and 6.
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS foetal calf serum
  • FCS foetal calf serum
  • 4 rri M glutamine 4 rri M glutamine
  • 50 pg/ml gentamycin both Biochrom, Germany
  • astrocytes are rinsed with PBS ++ (phosphate buffered saline, Biochrom, Germany) and fed with astrocyte-defined medium (ADM) consisting of DMEM containing 1x G5- supplement (Invitrogen, Germany), 0.5 pg/ml heparan sulfate, and 1 .5 pg/ml fibronectin (both Sigma, Germany) (Miller et al., (1993) Brain Res. 618(1 ): 175-8). 3 days later the medium is exchanged and the cells incubated for another 2-3 days, so that at the time of experiments astrocytes are 14-15 DIV.
  • ADM astrocyte-defined medium
  • the increase of cytosolic calcium after stimulation with the mGluR5 agonist L- quisqualate is measured using a fluorometric imaging plate reader (FLIPR) and the Ca- Kit (both Molecular Devices).
  • FLIPR fluorometric imaging plate reader
  • the medium Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 ⁇ of loading buffer consisting of Ca-sensitive dye reconstituted in sodium chloride (123 rri M), potassium chloride (5.4 rriM), magnesium chloride (0.8 rri M), calcium chloride (1.8 rri M), D-glucose (15 rri M), and HEPES (20 m M), pH 7.3.
  • concentration-response curves for quisqualate are performed in the presence and absence of 10 ⁇ modulator to determine the extent of potentiation / agonist potency increase. Thereafter, concentration-response curves for the positive modulator are performed in the presence of a fixed concentration of quisqualate showing the biggest window for potentiation (normally 10-30 nM).
  • MaxMin maximum minus minimum
  • EC50 and IC50 are calculated according the logistic equation using GraFit 5.0 (Erithacus Software, GB) or Prism 4.0 (GraphPad Software, USA).
  • the compounds of the present invention have a potency (IC 50 ) within a range of about 0.5 nM to about 100 ⁇ .

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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne des dérivés hétérocycliques ainsi que leurs sels de qualité pharmaceutique. La présente invention concerne en outre un procédé de synthèse de tels composés. Les composés selon l'invention sont de modulateurs de mGluR5 et peuvent donc être employés dans la régulation et la prévention des troubles neurologiques aigus et/ou chroniques.
PCT/EP2011/073712 2010-12-22 2011-12-21 Modulateurs des récepteurs glutamatergiques métabotropes WO2012085167A1 (fr)

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WO2014051653A1 (fr) * 2012-09-27 2014-04-03 Portola Pharmaceuticals, Inc. Inhibiteurs de kinase à base de dihydropyridone bicyclique
WO2014110000A1 (fr) * 2013-01-11 2014-07-17 Eli Lilly And Company Dérivés de pyrimidine fusionnés à un pyrido ou pyrrolo à titre d'inhibiteurs d'autotaxines pour traiter la douleur
WO2014117919A1 (fr) * 2013-02-04 2014-08-07 Merck Patent Gmbh Modulateurs allostériques positifs de mglur3
WO2014168824A1 (fr) * 2013-04-12 2014-10-16 Eli Lilly And Company Composés dihydropyrido-pyrimidine servant d'inhibiteurs de l'autotaxine
CN104262265A (zh) * 2014-07-21 2015-01-07 湖南华腾制药有限公司 一种四氢喹唑啉衍生物的制备方法
CN105263479A (zh) * 2013-06-12 2016-01-20 诺华股份有限公司 调整释放制剂
US9296747B1 (en) * 2014-10-10 2016-03-29 Allergan, Inc. Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2
CN105829315A (zh) * 2013-12-19 2016-08-03 阿尔麦克探索有限公司 可用作Wee-1激酶抑制剂的嘧啶并嘧啶酮类
CN108368107A (zh) * 2015-08-28 2018-08-03 艾伯维公司 作为s1p调节剂的稠合杂环化合物
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

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US9533986B2 (en) 2012-09-27 2017-01-03 Portola Pharmaceuticals, Inc. Bicyclic dihydropyridone kinase inhibitors
WO2014051653A1 (fr) * 2012-09-27 2014-04-03 Portola Pharmaceuticals, Inc. Inhibiteurs de kinase à base de dihydropyridone bicyclique
EA025106B1 (ru) * 2013-01-11 2016-11-30 Эли Лилли Энд Компани Бициклические пиримидиновые соединения
US8969555B2 (en) 2013-01-11 2015-03-03 Eli Lilly And Company Bicyclic pyrimidine compounds
CN104903327A (zh) * 2013-01-11 2015-09-09 伊莱利利公司 用于治疗疼痛的作为autotaxin抑制剂的吡啶并-或吡咯并-稠合嘧啶衍生物
TWI499591B (zh) * 2013-01-11 2015-09-11 Lilly Co Eli 雙環嘧啶化合物
WO2014110000A1 (fr) * 2013-01-11 2014-07-17 Eli Lilly And Company Dérivés de pyrimidine fusionnés à un pyrido ou pyrrolo à titre d'inhibiteurs d'autotaxines pour traiter la douleur
CN104903327B (zh) * 2013-01-11 2016-09-07 伊莱利利公司 用于治疗疼痛的作为autotaxin抑制剂的吡啶并-或吡咯并-稠合嘧啶衍生物
JP2016505010A (ja) * 2013-01-11 2016-02-18 イーライ リリー アンド カンパニー 二環式ピリミジン化合物
AU2014205642B2 (en) * 2013-01-11 2016-02-25 Eli Lilly And Company Pyrido- or pyrrolo-fused pyrimidine derivatives as autotaxin inhibitors for treating pain
US10059671B2 (en) 2013-02-04 2018-08-28 Prexton Therapeutics Sa Positive allosteric modulators of mGluR3
WO2014117919A1 (fr) * 2013-02-04 2014-08-07 Merck Patent Gmbh Modulateurs allostériques positifs de mglur3
CN104955807A (zh) * 2013-02-04 2015-09-30 默克专利股份公司 mGluR3的正变构调节剂
JP2016506938A (ja) * 2013-02-04 2016-03-07 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ ｍＧｌｕＲ３の正のアロステリックモジュレーター
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US9550774B2 (en) 2013-04-12 2017-01-24 Eli Lilly And Company Dihydropyrido pyrimidine compounds as autotaxin inhibitors
AU2014251250B2 (en) * 2013-04-12 2016-03-17 Eli Lilly And Company Dihydropyrido pyrimidine compounds as autotaxin inhibitors
WO2014168824A1 (fr) * 2013-04-12 2014-10-16 Eli Lilly And Company Composés dihydropyrido-pyrimidine servant d'inhibiteurs de l'autotaxine
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US9850247B2 (en) 2013-12-19 2017-12-26 Almac House Pyrimidopyrimidinones useful as Wee-1 kinase inhibitors
JP2017500335A (ja) * 2013-12-19 2017-01-05 アルマック・ディスカバリー・リミテッドＡｌｍａｃ Ｄｉｓｃｏｖｅｒｙ Ｌｉｍｉｔｅｄ Ｗｅｅ−１キナーゼ阻害剤として有用なピリミドピリミジノン
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CN105829315B (zh) * 2013-12-19 2019-03-08 阿尔麦克探索有限公司 可用作Wee-1激酶抑制剂的嘧啶并嘧啶酮类
CN104262265A (zh) * 2014-07-21 2015-01-07 湖南华腾制药有限公司 一种四氢喹唑啉衍生物的制备方法
US9296747B1 (en) * 2014-10-10 2016-03-29 Allergan, Inc. Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2
US10351532B2 (en) 2014-12-29 2019-07-16 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US10961200B2 (en) 2014-12-29 2021-03-30 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
US11247971B2 (en) 2014-12-29 2022-02-15 The Trustees Of The University Of Pennsylvania Small molecule inhibitors of lactate dehydrogenase and methods of use thereof
CN108368107A (zh) * 2015-08-28 2018-08-03 艾伯维公司 作为s1p调节剂的稠合杂环化合物
US10556907B2 (en) * 2015-08-28 2020-02-11 AbbVie Deutschland GmbH & Co. KG Fused heterocyclic compounds as S1P modulators
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