[go: up one dir, main page]

WO2012172093A1 - Dérivé de dihydroindolizine à titre de modulateurs des récepteurs métabotropes de glutamate - Google Patents

Dérivé de dihydroindolizine à titre de modulateurs des récepteurs métabotropes de glutamate Download PDF

Info

Publication number
WO2012172093A1
WO2012172093A1 PCT/EP2012/061527 EP2012061527W WO2012172093A1 WO 2012172093 A1 WO2012172093 A1 WO 2012172093A1 EP 2012061527 W EP2012061527 W EP 2012061527W WO 2012172093 A1 WO2012172093 A1 WO 2012172093A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethynyl
dihydroindolizin
dihydropyrrolo
pyrazin
phenylethynyl
Prior art date
Application number
PCT/EP2012/061527
Other languages
English (en)
Inventor
Ronalds Zemribo
Juris Fotins
Ulrich Abel
Holger Kubas
Udo Meyer
Falko Ernst Wolter
Mirko Hechenberger
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 WO2012172093A1 publication Critical patent/WO2012172093A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems

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.
  • 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.
  • class C GPCRs the class to which mGluR5 belongs
  • the orthosteric ligand e.g.
  • glutamate binds to a distinct module at the N-terminus of the receptor, the venus fly trap module (Bockaert, et al., The EMBO Journal, 1999, 18, 1723-1729). Moreover, within the helix bundle of mGluR5 a binding site for allosteric ligands, exemplified by MPEP, exists.
  • 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), multiple system atrophy, olivoponto-cerebellar atrophy, synucleinopathies, alpha-synucleinopathies, Lewy body dementia, neurodegeneration with Brain Iron Accumulation, Parkinson-plus syndrome, Pick's disease, progressive supranuclear palsy (PSP), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17
  • 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.
  • mGluR5 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, medulloblastonna, cancer of skin cells, melanoma, malignant melanoma, epithelial neoplasm, lymphoma
  • 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 and cognitive deficits in schizophrenia as well as cognitive deficits in various forms of dementia and mild cognitive impairment.
  • Silent modulators may be useful for attenuation of disease states emerging from disregulation of a natural ligand for the allosteric site.
  • mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
  • 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, dopaminominnetic-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.
  • An additional object of the invention is the provision of processes for producing the heterocyclic derivatives.
  • R 1 represents aryl, heteroaryl, cycloC 3-7 alkyl or heterocyclyl, wherein the cycloC 3-7 alkyl and heterocyclyl groups may be optionally fused with an aryl or heteroaryl ring;
  • R 2 and R 3 which may be the same or different, each independently represent H, Ci -6 alkyl, F, OH, C-i -6 alkoxy, or R 2 and R 3 together with the carbon atom to which they are attached form a carbonyl group, or R 2 and R 3 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 4 and R 5 which may be the same or different each independently represent H, C-i-6alkyl or F or R 4 and R 5 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from d-6 alkyl, F, oxo, and acyl;
  • X represents CR 6 R 7 or NR 8 ;
  • R 6 and R 7 which may be the same or different, each independently represent H, C-i-6alkyl, F, amino, Ci-6alkylamino or di-(Ci-6alkyl)amino or R 6 and R 7 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i-6 alkyl, F, oxo, and acyl; or R 3 and R 6 , together with the carbon atoms to which they are attached, may form a 4 to 7 membered ring wherein the ring may optionally contain one or two heteroatoms selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 8 represents H, C h alky!, acyl, aryl, heteroaryl, aryl-C-i-6alkyl, heteroaryl-C-i-6alkyl, or di- (C-i-6 alkyl)aminosulfonyl; or R 2 and R 8 together with the atoms to which they are attached, may form a 4 to 7 membered ring wherein the ring may optionally contain one or two additional heteroatoms selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl which is optionally substituted by one or more halogen atoms, F, oxo, and acyl;
  • Y represents a bond, CR 9 R 10 or -CR 9 R 10 -CH 2 -;
  • R 9 and R 10 which may be the same or different, each independently represent H, C-i-6alkyl or F or R 9 and R 10 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 11 represents H, halogen, C h alky!, aryl, heteroaryl, cycloC3-7alkyl or heterocyclyl;
  • a further aspect of the invention relates to a compound of Formula I, wherein R 1 represents aryl or heteroaryl.
  • Such a compound of Formula I wherein X represents CR 6 R 7 and Y represents a bond, CR 9 R 10 , or -CR 9 R 10 -CH 2 -.
  • Such a compound of Formula I wherein R 6 and R 7 each independently represent H or Ci -6 alkyl, and Y represents CR 9 R 10 or -CR 9 R 10 -CH 2 -, wherein R 9 and R 10 each represent H.
  • Such a compound of Formula I wherein X represents NR 8 and Y represents CR 9 R 10 or -CR 9 R 10 -CH 2 -.
  • Such a compound of Formula I wherein R 8 represents H, C h alky!, C-i- 6 alkylcarbonyl, di-(Ci -6 alkyl)aminocarbonyl, arylcarbonyl, heterocyclylcarbonyl, aryl or aryl-C-i -6 alkyl and R 9 and R 10 each represent H.
  • Such a compound of Formula I wherein R 8 represents H, methyl, ethyl, propyl, butyl, teff-butylcarbonyl, dimethylaminocarbonyl, pyrrol id inocarbonyl, phenyl, benzyl, wherein the phenyl moiety may be optionally substituted by one or more substituents selected from F and C h alky! (e.g., methyl) and wherein the methylene moiety may be optionally substituted by C h alky! (e.g., methyl), or phenethyl.
  • R 11 represents H, halogen, or cycloC 3 -7alkyl.
  • R 1 represents phenyl optionally substituted by one or more substituents selected from F, C h alky!, cyano, and fluoromethyl; pyridyl optionally substituted by one or more substituents selected from amino and Ci -6 alkylamino; thienyl optionally substituted by one or more chlorine atoms; or dihydroindolizinyl.
  • Such a compound of Formula I wherein represents phenyl substituted by one or more fluorine atoms and one or more C-i -6 alkyl (e.g., methyl) groups.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
  • R 1 represents aryl, heteroaryl, cycloC 3-7 alkyl or heterocyclyl, wherein the cycloC 3-7 alkyl or heterocyclyl group may be optionally fused with an aryl or heteroaryl ring;
  • R 4 and R 5 which may be the same or different each independently represent H, C-i -6 alkyl or F or R 4 and R 5 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i-6 alkyl, F, oxo, and acyl;
  • R 11 represents H, halogen, C-i -6 alkyl, aryl, heteroaryl, cycloC 3- 7alkyl or heterocyclyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • a further aspect of the invention relates to a compound of Formula IA, wherein R 1 represents aryl or heteroaryl;
  • R 4 and R 5 which may be the same or different, each independently represent H, C-i- 6 alkyl or F; or R 4 and R 5 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 6 and R 7 which may be the same or different, each independently represent H, C-i -6 alkyl or F; or R 6 and R 7 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i-6 alkyl, F, oxo, and acyl;
  • R 9 and R 10 which may be the same or different, each independently represent H, C-i- 6 alkyl or F or R 9 and R 10 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from Ci -6 alkyl, F, oxo, and acyl.
  • R 1 represents phenyl optionally substituted by one or more substituents selected from F, C-i -6 alkyl, cyano, and fluoromethyl; pyridyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; thienyl optionally substituted by one or more chlorine atoms; or dihydroindolizinyl.
  • Such a compound of Formula IA wherein represents phenyl substituted by one or more fluorine atoms and one or more C h alky! (e.g., methyl) groups.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
  • R 1 represents aryl, heteroaryl, cycloC 3-7 alkyl or heterocyclyl, wherein the cycloC 3-7 alkyl or heterocyclyl group may be optionally fused with an aryl or heteroaryl ring;
  • R 4 and R 5 which may be the same or different each independently represent H, Ci -6 alkyl or F or R 4 and R 5 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 6 and R 7 which may be the same or different, each independently represent H, C-i-6alkyl, F, amino, Ci-6alkylamino or di-(Ci-6alkyl)amino or R 6 and R 7 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i-6 alkyl, F, oxo, and acyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • R 1 represents phenyl optionally substituted by one or more substituents selected from fluoro and cyano or pyridyl optionally substituted by one or more amino groups,
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IC
  • R 1 represents aryl, heteroaryl, cycloC 3-7 alkyl or heterocyclyl, wherein the cycloC 3-7 alkyl or heterocyclyl group may be optionally fused with an aryl or heteroaryl ring;
  • R 4 and R 5 which may be the same or different each independently represent H, Ci -6 alkyl or F or R 4 and R 5 together with the carbon atom to which they are attached form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from d-6 alkyl, F, oxo, and acyl;
  • R 6 and R 7 which may be the same or different, each independently represent H, C-i-6alkyl, F, amino, Ci-6alkylamino or di-(Ci-6alkyl)amino or R 6 and R 7 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 9 and R 10 which may be the same or different, each independently represent H, C-i -6 alkyl or F or R 9 and R 10 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C h alky!, F, oxo, and acyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IC wherein R 8 and R 9 each independently represent H or C-i -6 alkyl.
  • Such a compound of Formula IC wherein R 1 represents phenyl optionally substituted by one or more fluorine atoms or pyridyl optionally substituted by one or more amino groups.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula ID wherein R 1 , R 4 , R 5 , and R 9 -R 11 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • R 8 represents represents H, C h alky!, C-i- 6 alkylcarbonyl, di-(Ci- 6 alkyl)aminocarbonyl, arylcarbonyl, heterocyclylcarbonyl, aryl or aryl-Ci -6 alkyl.
  • Such a compound of Formula ID wherein R 8 represents H, methyl, ethyl, propyl, butyl, te/t-butylcarbonyl, dimethylaminocarbonyl, pyrrol id inocarbonyl, phenyl, or benzyl, wherein the phenyl moiety may be optionally substituted by one or more substituents selected from F and Ci -6 alkyl (e.g., methyl) and wherein the methylene moiety may be optionally substituted by C h alky! (e.g., methyl), or phenethyl.
  • R 8 represents H, methyl, ethyl, propyl, butyl, te/t-butylcarbonyl, dimethylaminocarbonyl, pyrrol id inocarbonyl, phenyl, or benzyl
  • the phenyl moiety may be optionally substituted by one or more substituents selected from F and Ci -6 al
  • R 1 represents phenyl optionally substituted by one or more substituents selected from F, Ci -6 alkyl, cyano, and fluoromethyl or pyridyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IE
  • R 1 , R 4 , R 5 , and R 9 -R 11 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • R 1 represents phenyl optionally substituted by one or more substituents selected from F, Ci -6 alkyl, cyano, and fluoromethyl or pyridyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IF
  • R 1 , R 4 , R 5 , Y, and R 11 are as defined above for Formula I;
  • R 3 represents H, C-i -6 alkyl, F, OH, C-i -6 alkoxy;
  • R 2 and R 8 together with the atoms to which they are attached, form a 4 to 7 membered ring wherein the ring may optionally contain one or two additional heteroatoms selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C h alky! which is optionally substituted by one or more halogen atoms, F, oxo, and acyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • Such a compound of Formula IF wherein R 2 and R 8 together with the atoms to which they are attached form an oxazine ring which is substituted by one or more substituents selected from C h alky! which is optionally substituted by one or more fluorine atoms, C-i- 6 alkoxycarbonyl, di-(Ci- 6 alkyl)aminocarbonyl, and heterocyclylcarbonyl .
  • [001 10]A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IG
  • R 1 represents aryl, heteroaryl, cycloC 3 -7alkyl or heterocyclyl, wherein the cycloC 3 -7alkyl and heterocyclyl groups may be optionally fused with an aryl or heteroaryl ring;
  • X represents CR 6 R 7 or NR 8 ;
  • R 6 and R 7 which may be the same or different, each independently represent H, C-i-6alkyl, F, amino, Ci-6alkylamino or di-(Ci-6alkyl)amino or R 6 and R 7 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i-6 alkyl, F, oxo, and acyl; or R 3 and R 6 , together with the carbon atoms to which they are attached, may form a 4 to 7 membered ring wherein the ring may optionally contain one or two heteroatoms selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C-i -6 alkyl, F, oxo, and acyl;
  • R 8 represents H, C h alky!, acyl, aryl, or heteroaryl
  • Y represents a bond, CR 9 R 10 or -CR 9 R 10 -CH 2 -;
  • R 9 and R 10 which may be the same or different, each independently represent H, C-i-6alkyl or F or R 9 and R 10 , together with the carbon atom to which they are attached, form a 3 to 6 membered ring, wherein the ring may optionally contain a heteroatom selected from O, S and N, and wherein the ring may be optionally substituted with one or more substituents selected from C h alky!, F, oxo, and acyl; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
  • [001 1 1 ]A further aspect of the invention relates to a compound of Formula IG, wherein R 1 represents aryl or heteroaryl.
  • R 1 represents phenyl optionally substituted by one or more substituents selected from F, Ci -6 alkyl, cyano, and fluoromethyl; pyridyl optionally substituted by one or more substituents selected from amino and Ci-6alkylamino; or thienyl.
  • Specific compounds of Formula I within the present invention include, but are not limited to, the following compounds:
  • 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, 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 deficits 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 schizophrenia, cognitive deficit
  • 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.
  • a further aspect of the invention relates to the use of isotopic derivatives of the compounds of Formula I as PET or SPECT ligands.
  • 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, pharmaceuctically 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 at 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 at 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 or atypicals such as clozapine, risperidone or olanzapine).
  • dopaminomimetics such as antiparkinsonian dopaminomimetics, including bromocriptine, cabergolin, ropinirole, pramiperole, pergolide, rotigotine
  • neuroleptics such as classical neuroleptics, including haloperidol, perphenazin
  • 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 ⁇ '
  • R 1 is as defined above for Formula I, wherein the
  • R 1 is as defined above for Formula I, wherein the
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IA"
  • R 1 is as defined above for Formula I, wherein the
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IA'"
  • R 1 is as defined above for Formula I, wherein the
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula lA'"
  • R 1 is as defined above for Formula I, wherein the
  • the invention also relates to a process for the synthesis or preparation of a compound of Formula IA""
  • R 1 is as defined above for Formula I and R 4 represents H or methyl, wherein a compound of Formula VIII
  • 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 C j indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (Ci -3 )alkyl refers to alkyl of one to three carbon atoms (i.e.
  • C-i-6 refers to a radical of one to six carbon atoms (i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms).
  • Ci-6alkyl represents straight or branched chain alkyl groups. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and terf-butyl.
  • C 2 - 6 alkenyl represents straight or branched chain alkenyl groups.
  • Ci -6 alkoxy represents straight or branched chain -O-C-i -6 alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, terf-butoxy.
  • acyl represents Ci -6 alkylcarbonyl, trifluoroacetyl, hydroxy- Ci -6 alkylcarbonyl, Ci -6 alkoxycarbonyl, A/-Ci -6 alkylaminocarbonyl, ⁇ /,/V-di- (Ci- 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 alkyr' represents monocyclic, 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, C-i -6 alkoxy, amino, hydroxy, cyano, C-i -6 alkoxycarbonyl, Ci -6 alkylamino, and di-(Ci -6 alkyl)amino, C-i -6 alkyl- carbonylamino, oxo, Ci -6 alkoxyimino, A/-Ci -6 alkylamin
  • cycloC 3-7 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, C-i -6 alkyl, C 2-6 alkenyl, C-i -6 alkoxy, amino, hydroxy, cyano, C-i -6 alkoxycarbonyl, C-i -6 alkylcarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, oxo, Ci-6alkoxyimino, A/-Ci -6 alkylaminocarbonyl, N,N-di-(Ci -6 alkyl)anrii
  • 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, C-i- 6 alkyl, hydroxyC-i- 6 alkyl, C 2 - 6 alkenyl, C-i- 6 alkylthio, Ci- 6 alkoxyCi- 6 alkyl, amino, hydroxy, nitro, cyano, formyl, C-i- 6 alkylcarbonyl, C-i- 6 alkoxycarbonyl, C-i -6 alkylcarbonyloxy, Ci -6 alkylcarbonyloxyCi -6 alkyl, Ci -6 alkylamino, di-(C
  • 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, C-i -6 alkyl, hydroxyC-i -6 alkyl, C 2-6 alkenyl, C-i -6 alkoxy, C-i -6 alkylthio, amino, hydroxy, nitro
  • 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-i -6 alkyl, C 2- 6alkenyl, C-i -6 alkoxy, amino, hydroxy, nitro, cyano, C-i -6 alkoxycarbonyl, C-i -6 alkylcarbonyl, Ci -6 alkylamino, and di-(Ci -6 alkyl
  • halogen represents fluorine, chlorine, bromine and iodine.
  • [00162]Memantine is a systemically-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, 74:135-146; 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.
  • 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 is not critical, provided that it is non-toxic and does not substantially interfere with the desired pharmacological activity.
  • IC are prepared by Sonogashira coupling of 2-iodo-6,7-dihydroindolizin-8(5H)-one (5a), 2-iodo-7-methyl-6,7-dihydroindolizin-8(5H)-one (6a), 2-iodo-7,7-dimethyl-6,7- dihydroindolizin-8(5H)-one (7a), 6-iodo-2,3-dihydro-1 H-pyrrolizin-1 -one (5b), 6-iodo-2- methyl-2,3-dihydro-1 H-pyrrolizin-1 -one (6b), 6-iodo-2,2-dimethyl-2,3-dihydro-1 H- pyrrolizin-1 -one (7b), 2-iodo-7,8-dihydro-5H-pyrrolo[1 ,2-a]azepin-9(6H)-one (5c), 2- iodo-8-methyl-7,8-dihydro-5/-
  • 2,3-dihydro-1 H-pyrrolizin-1 -one (2b) is synthesized from 3- aminopropanoic acid via 4-(1 H-pyrrol-1 -yl)propanoic acid (1 b) and 7,8-dihydro-5H- pyrrolo[1 ,2-a]azepin-9(6H)-one (2c) is similarily synthesized via 5-(1 H-pyrrol-1 - yl)pentanoic acid .
  • the methylation can be performed after the iodination step, thus converting 2-lodo-6,7-dihydroindolizin- 8(5H)-one (5a), 6-iodo-2,3-dihydro-1 H-pyrrolizin-1 -one (5b) or 2-iodo-7,8-dihydro-5H- pyrrolo[1 ,2-a]azepin-9(6H)-one (5c), to their methylated analogues 6a, 6b, 6c and further to 7a , 7b and 7c.
  • Scheme 2 Synthesis of 6-substituted dihydroindolizin-8(5H)-ones
  • 2-lodo-6-methyl-6,7-dihydroindolizin-8(5H)-one (14a) and 2-iodo-6,6-dimethyl-6,7-dihydroindolizin-8(5/-/)-one (14b) are prepared by iodination of 6-methyl-6,7-dihydroindolizin-8(5H)-one (13a) or 6,6-dimethyl-6,7- dihydroindolizin-8(5H)-one (13b) accordingly.
  • Compounds 13a and 13b are synthesized from 4-amino-3-methylbutanoic acid (11a) or 4-amino-3,3-dimethylbutanoic acid (11 b) via 3-methyl-4-(1 H-pyrrol-1 -yl)butanoic acid (12a) and 3,3-dimethyl-4-(1 H-pyrrol-1 - yl)butanoic acid (12b) in close analogy to the method described in the literature (J. Org. Chem., 2009, 74 (8), 3160-63) for 6,7-dihydroindolizin-8(5H)-one (2, Scheme 1 ).
  • ketone 5a is brominated in 3-position by means of /V-bromosuccinimide in DMF to give dihalogenated intermediate 28 followed by a Sonogashira coupling reaction with an appropriate acetylene 29 to furnish compounds of general structure 30.
  • the bromo substituent may be substituted by alkyl or aryl groups using boronic acids (31 ) in a Suzuki coupling reaction to provide compounds of general formula 32.
  • Ketone 5a may be transformed into oxime 33 in the presence of sodium acetate and hydroxylamine hydrochloride. Oxime 33 is then converted into the corresponding tosylate 34 using a standard protocol.
  • a-Amino group is introduced in Neber rearrangement reaction in the presence of potassium f-butoxide, which gives (in rather low yield) a mixture of aminoketone 35 and its dimethyl acetal, which is hydrolyzed during work up into aminoketone 35.
  • Acylation of aminoketone 35 with chloroacetyl chloride gives the corresponding amide 36.
  • the carbonyl group is reduced with DIBALH to give alcohol 37, which cyclizes in the presence of sodium hydride to provide the morpholinone derivative 38. Reduction of this lactam with LAH provides the key intermediate morpholine 39.
  • Morpholine 39 may be /V-alkylated under standard reaction conditions with an appropriate alkyl halide and then coupled with an arylacetylene to provide compound 40.
  • morpholine 39 may be acylated with acyl chlorides, chloroformates and carbomoyl chlorides to give the corresponding /V-acyl derivatives, which may be coupled with an arylacetylene to provide the compound 40.
  • 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. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Pure 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 fluorine 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, and the parenteral route, respectively.
  • 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 dopaminominnetic, 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 dopaminominnetic, 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 (such as
  • 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, 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 may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • Formulations 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 nanopartide formulations, thus to produce medicaments for oral, injectable, or dermal use, also in accord with the foregoing.
  • DCM dichloromethane
  • BuLi as n-butyllithium
  • DBU as 1 ,8-diazabicyclo[5.4.0]undec-7-ene
  • DIPEA as ⁇ /,/V-diisopropylethylamine
  • DMAP 4-dimethylaminopyridine
  • DMF ⁇ /,/V-dimethylformamide
  • EtOAc as ethyl acetate
  • LDA lithium diisopropylamide
  • MeOH as methanol
  • Pd(dppf)CI 2 as 1 ,1 '-bis(diphenylphosphino)ferrocenepalladium(ll)dichloride
  • TAF as tetrabutylammonium fluoride
  • TAA triethylamine
  • THF tetrahydrofuran
  • the precipitate is recrystallized from ethyl acetate to give 4800 mg of 2-iodide (5) and 1700 mg of 2,3-diiodide.
  • the filtrate is extracted with EtOAc, dried over anhydrous sodium sulfate, and the solvent is evaporated in vacuo.
  • the residue is purified by flash column chromatography, using hexanes/ethyl acetate mixture as an eluent, providing 1220 mg of 2-iodide (5a) and 1460 mg of 3-iodide.
  • the combined yield of title compound 5a is 6020 mg (60%).
  • the 2,3-diodide by-product can be converted to 2-iodide (5a) by its treatment at low temperature with BuLi or isopropylmagnesium bromide and quenching the reaction mixture with water.
  • the LDA solution is cooled to -78 °C and added via cannula to a stirred solution of 6,7-dihydroindolizin-8(5H)-one (2a) (1400 mg, 10.36 mmol, 1 eq.) in 12 mL of THF under argon.
  • the mixture is stirred for 1 h at -78 °C, then methyl iodide (1617 mg, 1 1 .39 mmol, 1 .1 eq.) is added dropwise, and the mixture is stirred for 3 h at -78 °C and then allowed to warm to room temperature.
  • a saturated solution of ammonium chloride is added, and the mixture is extracted with DCM.
  • the LDA solution is cooled to -78 °C and added via cannula to a stirred solution of 7-methyl-6,7-dihydroindolizin-8(5/-/)-one (3a) in 4 mL of THF under argon.
  • the mixture is stirred for 1 h at -78 °C.
  • Methyl iodide (470 mg, 3.32 mmol, 1 .1 eq.) is added dropwise, and the mixture is stirred for 3 h at -78 °C and then allowed to warm to room temperature.
  • a saturated solution of ammonium chloride is added, and the mixture is extracted with DCM.
  • the organic phase is dried over anhydrous Na 2 SO 4 , and the solvent is evaporated. Purification of the residue by flash column chromatography provides 428 mg (87%) of the title compound as yellow crystals.
  • the title compounds are prepared by iodination of 6-methyl-6,7-dihydroindolizin- 8(5H)-one (13a), 6,6-dimethyl-6,7-dihydroindolizin-8(5H)-one (13b), 7-methyl-6,7- dihydroindolizin-8(5H)-one (3a), or 7,7-dimethyl-6,7-dihydroindolizin-8(5H)-one (4a) correspondingly, using identical procedures to that described for 2-iodo-6,7- dihydroindolizin-8(5H)-one (5a, Preparation 1 ).
  • the obtained residue is purified by column chromatography (silica gel, hexane/ethyl acetate) followed by preparative TLC (silica gel, hexane/EtOAc, 4:1 ) to give 8,8-dimethyl-7,8-dihydro-5H-pyrrolo[1 ,2-a]azepin-9(6/-/)-one (1 10 mg, 24%) as a brown oil.
  • 6-((4-Fluorophenyl)ethynyl)-2,3-dihydro-1 H-pyrrolizin-1-one [00291 ]According to General Procedure 1 , 6-iodo-2,3-dihydro-1 /-/-pyrrolizin-1 -one is reacted with 1 -ethynyl-4-fluorobenzene to provide the title compound as a colorless solid.
  • the obtained residue is purified by column chromatography (silica gel, DCM/EtOH) and preparative TLC (silica gel, hexane/EtOAc, 1 : 1 ) to provide the title compound (51 mg, 26%) as a beige solid.
  • the obtained residue is purified by column chromatography (silica gel, DCM/MeOH, 15:1 ) to furnish 8-iodo-2,3,4,5-tetrahydro-1 H-pyrrolo[1 ,2-a][1 ,4]diazepin-1 -one (980 mg, 65%) as beige crystalline solid.
  • the reaction mixture is stirred at room temperature for 18 h, concentrated at reduced pressure, diluted with DCM (20 mL), washed with an aqueous citric acid solution (10%), dried over MgSO 4 , and concentrated at reduced pressure.
  • the obtained residue is purified by column chromatography (silica gel, DCM/MeOH, 30:1 ) and by preparative HPLC (C18, acetonitrile/water) to provide the title compound (84 mg, 47%) as a white powder.
  • reaction mixture is cooled to room temperature, poured into saturated aqueous NH 4 CI solution (25 mL) and extracted with EtOAc (2x20 mL). The combined organic layers are dried over Na 2 SO and concentrated in vacuo. Purification by column chromatography (silica, 50% EtOAc/heptane, isocratic), followed by recrystallization from / ' -PrOH ( ⁇ 4 mL) and air-drying provides the title compound (123 mg, 64%) as a beige powder.
  • the title compound can be prepared from the corresponding anisole derivative (synthesized from 2-iodo-6,7-dihydroindolizin-8(5H)-one and 4- methoxyphenylacetylene following General Procedure 1 , yield: 84%) by means of a demethylation reaction using BBr 3 (yield: 21 %).
  • Example 80 52 mg, 0.21 mmol is dissolved in dry THF (1 .5 mL). To the formed solution sodium hydride (60% in oil, 14 mg, 0.35 mmol) is added, and the resulting mixture is stirred at room temperature for 15 min. Then methyl iodide (28 ⁇ , 0.44 mmol) is added. The reaction mixture is stirred at 30 °C for 2 h, concentrated at reduced pressure, diluted with water (5 mL), and extracted with DCM (10 mL). The organic phase is separated, dried over MgSO 4 , and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, hexane, then
  • the obtained residue is purified by column chromatography (silica gel, hexane, DCM/MeOH, 10:1 ), washed with diethyl ether (3 mL) and air-dried to furnish 8-iodo-2-methyl-2,3,4,5-tetrahydro-1 H-pyrrolo[1 ,2- a][1 ,4]diazepin-1 -one (458 mg, 86%) as off-white crystals.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention concerne des dérivés hétérocycliques de formule I - les substituants R1 à R5 dans la formule I étant tels que définis dans les revendications, ainsi que leurs sels de qualité pharmaceutique. Cette invention concerne en outre un procédé de préparation desdits composés. Les composés selon l'invention sont des modulateurs de mGluR5 et sont par conséquent utiles pour la prise en charge et la prévention des troubles neurologiques aigus et/ou chroniques.
PCT/EP2012/061527 2011-06-17 2012-06-15 Dérivé de dihydroindolizine à titre de modulateurs des récepteurs métabotropes de glutamate WO2012172093A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201161520939P 2011-06-17 2011-06-17
EP11170288.2 2011-06-17
EP11170288 2011-06-17
US61/520,939 2011-06-17

Publications (1)

Publication Number Publication Date
WO2012172093A1 true WO2012172093A1 (fr) 2012-12-20

Family

ID=44281128

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2012/061527 WO2012172093A1 (fr) 2011-06-17 2012-06-15 Dérivé de dihydroindolizine à titre de modulateurs des récepteurs métabotropes de glutamate

Country Status (1)

Country Link
WO (1) WO2012172093A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016092410A1 (fr) 2014-12-09 2016-06-16 Kaunas University Of Technology Nouveaux composés photochromiques et composés intermédiaires pour la production de ceux-ci
JP2017523201A (ja) * 2014-08-01 2017-08-17 ヤンセン ファーマシューティカ エヌ．ベー． ６，７−ジヒドロピラゾロ［１，５−ａ］ピラジン−４（５Ｈ）−オン化合物およびＭＧＬＵＲ２受容体の負のアロステリック調節因子としてのそれらの使用
CN109761977A (zh) * 2019-03-05 2019-05-17 江西省药品检验检测研究院 一种黄精生物碱c及其制备方法与应用
WO2019145214A1 (fr) * 2018-01-26 2019-08-01 Recordati Industria Chimica E Farmaceutica S.P.A Dérivés de pipérazine condensés à base de triazole, d'imidazole et de pyrrole et leur utilisation en tant que modulateurs des récepteur de mglu5
US10512646B2 (en) 2014-08-01 2019-12-24 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
WO2020244637A1 (fr) * 2019-06-06 2020-12-10 Hutchison Medipharma Limited Composés tricycliques et leur utilisation

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122193A (en) 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US4273774A (en) 1978-12-27 1981-06-16 Merz & Co. Central nervous system compositions and method
US5061703A (en) 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
WO2002046166A1 (fr) * 2000-12-04 2002-06-13 F. Hoffmann-La Roche Ag Derives phenylethenyle ou phenylethinyle servant d'antagonistes de recepteur de glutamate
WO2005113541A1 (fr) 2004-05-14 2005-12-01 Vertex Pharmaceuticals, Incorporated Composes pyrroles utilises en tant qu'inhibiteurs de proteines kinases erk, leur synthese, et intermediaires correspondants
WO2007023242A1 (fr) * 2005-08-24 2007-03-01 Merz Pharma Gmbh & Co. Kgaa Tétrahydroquinolinones et leur usage en tant que modulateurs des récepteurs de glutamate métabotropiques
US20080039456A1 (en) 2005-01-06 2008-02-14 Gelder Joel M V Rigidified Compounds for Modulating Heparanase Activity
WO2009090055A1 (fr) 2008-01-17 2009-07-23 Grünenthal GmbH Dérivés de sulfonamides substitués
EP2085398A1 (fr) * 2008-02-01 2009-08-05 Merz Pharma GmbH & Co. KGaA Pyrazolopyrimidines, leur procédé de préparation et leur utilisation en tant que médicament
WO2010031816A1 (fr) * 2008-09-19 2010-03-25 Nerviano Medical Sciences S.R.L. Dérivés de 3,4-dihydro-2h-pyrrolo[1,2-a]pyrazine-1-one
WO2011015343A1 (fr) * 2009-08-05 2011-02-10 Merz Pharma Gmbh & Co. Kgaa Modulateurs des récepteurs métabotropiques du glutamate

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122193A (en) 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US4273774A (en) 1978-12-27 1981-06-16 Merz & Co. Central nervous system compositions and method
US5061703A (en) 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
WO2002046166A1 (fr) * 2000-12-04 2002-06-13 F. Hoffmann-La Roche Ag Derives phenylethenyle ou phenylethinyle servant d'antagonistes de recepteur de glutamate
WO2005113541A1 (fr) 2004-05-14 2005-12-01 Vertex Pharmaceuticals, Incorporated Composes pyrroles utilises en tant qu'inhibiteurs de proteines kinases erk, leur synthese, et intermediaires correspondants
US20080039456A1 (en) 2005-01-06 2008-02-14 Gelder Joel M V Rigidified Compounds for Modulating Heparanase Activity
WO2007023242A1 (fr) * 2005-08-24 2007-03-01 Merz Pharma Gmbh & Co. Kgaa Tétrahydroquinolinones et leur usage en tant que modulateurs des récepteurs de glutamate métabotropiques
WO2009090055A1 (fr) 2008-01-17 2009-07-23 Grünenthal GmbH Dérivés de sulfonamides substitués
EP2085398A1 (fr) * 2008-02-01 2009-08-05 Merz Pharma GmbH & Co. KGaA Pyrazolopyrimidines, leur procédé de préparation et leur utilisation en tant que médicament
WO2010031816A1 (fr) * 2008-09-19 2010-03-25 Nerviano Medical Sciences S.R.L. Dérivés de 3,4-dihydro-2h-pyrrolo[1,2-a]pyrazine-1-one
WO2011015343A1 (fr) * 2009-08-05 2011-02-10 Merz Pharma Gmbh & Co. Kgaa Modulateurs des récepteurs métabotropiques du glutamate

Non-Patent Citations (23)

* 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"
AUST. J. CHEM., vol. 41, 1988, pages 1583
BOCKAERT ET AL., THE EMBO JOURNAL, vol. 18, 1999, pages 1723 - 1729
BOOHER; SENSENBRENNER, NEUROBIOLOGY, vol. 2, no. 3, 1972, pages 97 - 105
CHENG; PRUSSOFF, BIOCHEM. PHARMACOL., vol. 22, 1973, pages 3099 - 3108
DANYSZ ET AL., CURR. PHARM. DES., vol. 8, 2002, pages 835 - 43
FOSTER; WONG, BR. J. PHARMACOL., vol. 91, 1987, pages 403 - 409
G6RTELMEYER ET AL., ARZNEIM-FORSCH/DRUG RES., vol. 42, 1992, pages 904 - 913
J. ORG. CHEM., vol. 74, no. 8, 2009, pages 3160 - 63
JIRGENSONS, EUR. J. MED. CHEM., vol. 35, 2000, pages 555 - 565
LOWRY ET AL., J. BIOL. CHEM., vol. 193, 1951, pages 256 - 275
MILLER ET AL., BRAIN RES., vol. 618, no. 1, 1993, pages 175 - 8
PARSONS ET AL., J. PHARMACOL. EXP. THER., vol. 283, no. 3, 1997, pages 1264 - 1275
RODRIGUEZ ET AL., MOLECULAR PHARMACOLOGY, vol. 68, 2005, pages 1793 - 1802
ROGAWSKI, AMINO ACIDS, vol. 19, 2000, pages 133 - 49
SEIFERT ET AL., NAUNYN SCHMIEDEBERGS ARCH PHARMACOL., vol. 366, 2002, pages 381 - 416
STELLA V. ET AL.: "Prodrugs: Challenges and Rewards", 2007, AAPS PRESS/SPRINGER
VANEJEVS ET AL., J. MED. CHEM., vol. 51, 2008, pages 634 - 647
WINBLAD ET AL., INT. J. GERIAT. PSYCHIATRY, vol. 14, 1999, pages 135 - 146
ZIEMINSKA ET AL., ACTA NEUROBIOL. EXP., vol. 66, 2006, pages 301 - 309
ZIEMINSKA ET AL., NEUROCHEMISTRY INTERNATIONAL, vol. 43, 2003, pages 481 - 492
ZIEMINSKA ET AL., NEUROCHEMISTRY INTERNATIONAL, vol. 48, 2006, pages 491 - 497

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10512646B2 (en) 2014-08-01 2019-12-24 Janssen Pharmaceutica Nv Substituted 6,7-dihydropyrazolo[1,5-a]pyrazines as negative allosteric modulators of mGluR2 receptors
JP2017523201A (ja) * 2014-08-01 2017-08-17 ヤンセン ファーマシューティカ エヌ．ベー． ６，７−ジヒドロピラゾロ［１，５−ａ］ピラジン−４（５Ｈ）−オン化合物およびＭＧＬＵＲ２受容体の負のアロステリック調節因子としてのそれらの使用
US10023585B2 (en) 2014-12-09 2018-07-17 Kaunas University Of Technology Photochromic compounds and intermediate compounds for production thereof
WO2016092410A1 (fr) 2014-12-09 2016-06-16 Kaunas University Of Technology Nouveaux composés photochromiques et composés intermédiaires pour la production de ceux-ci
IL276223B2 (en) * 2018-01-26 2024-03-01 Recordati Ind Chimica E Farmaceutica S P A TRIAZOLE, IMIDAZOLE AND PYRROLE CONDENSED PIPERAZINE DERIVATIVES AND THEIR USE AS MODULATORS OF mGlu5 RECEPTORS
JP7447020B2 (ja) 2018-01-26 2024-03-11 レコルダーティ インドゥストリア キミカ エ ファルマチェウチカ ソシエタ・ペル・アチオニ トリアゾール、イミダゾールおよびピロール縮合ピペラジン誘導体、およびｍＧｌｕ５受容体のモジュレータとしてのそれらの使用
KR20200120915A (ko) * 2018-01-26 2020-10-22 레코다티인더스트리아치미카이파마슈티카에스.피.에이. mGlu5 수용체의 조절제로서 트리아졸, 이미다졸 및 피롤 축합된 피페라진 유도체 및 이의 용도
CN112041319A (zh) * 2018-01-26 2020-12-04 利康化学与制药工业有限公司 三唑、咪唑和吡咯稠合的哌嗪衍生物及其作为mGlu5受体的调节剂的应用
WO2019145214A1 (fr) * 2018-01-26 2019-08-01 Recordati Industria Chimica E Farmaceutica S.P.A Dérivés de pipérazine condensés à base de triazole, d'imidazole et de pyrrole et leur utilisation en tant que modulateurs des récepteur de mglu5
JP2021512942A (ja) * 2018-01-26 2021-05-20 レコルダーティ インドゥストリア キミカ エ ファルマチェウチカ ソシエタ・ペル・アチオニ トリアゾール、イミダゾールおよびピロール縮合ピペラジン誘導体、およびｍＧｌｕ５受容体のモジュレータとしてのそれらの使用
KR102756573B1 (ko) 2018-01-26 2025-01-20 레코다티인더스트리아치미카이파마슈티카에스.피.에이. mGlu5 수용체의 조절제로서 트리아졸, 이미다졸 및 피롤 축합된 피페라진 유도체 및 이의 용도
US11591337B2 (en) 2018-01-26 2023-02-28 Recordati Industria Chimica E Farmaceutica S.P.A. Substituted [1,2,4]triazolo[4,3-a]pyrazines as modulators of mGlu5 receptors
AU2019212093B2 (en) * 2018-01-26 2024-05-30 Recordati Industria Chimica E Farmaceutica S.P.A Triazole, imidazole and pyrrole condensed piperazine derivatives and their use as modulators of mGlu5 receptors
IL276223B1 (en) * 2018-01-26 2023-11-01 Recordati Ind Chimica E Farmaceutica S P A TRIAZOLE, IMIDAZOLE AND PYRROLE CONDENSED PIPERAZINE DERIVATIVES AND THEIR USE AS MODULATORS OF mGlu5 RECEPTORS
CN112041319B (zh) * 2018-01-26 2024-05-14 利康化学与制药工业有限公司 三唑、咪唑和吡咯稠合的哌嗪衍生物及其作为mGlu5受体的调节剂的应用
CN109761977A (zh) * 2019-03-05 2019-05-17 江西省药品检验检测研究院 一种黄精生物碱c及其制备方法与应用
WO2020244637A1 (fr) * 2019-06-06 2020-12-10 Hutchison Medipharma Limited Composés tricycliques et leur utilisation
CN113966336B (zh) * 2019-06-06 2023-11-07 和记黄埔医药（上海）有限公司 三环类化合物及其用途
EP3980424A4 (fr) * 2019-06-06 2023-03-29 Hutchison Medipharma Limited Composés tricycliques et leur utilisation
CN113966336A (zh) * 2019-06-06 2022-01-21 和记黄埔医药（上海）有限公司 三环类化合物及其用途

Similar Documents

Publication Publication Date Title
EP2462142A1 (fr) Modulateurs des récepteurs métabotropiques du glutamate
EP2054421B1 (fr) Pyrazolopyrimidines, procédé permettant de les préparer et de les utiliser en tant que médicaments
EP2247590A1 (fr) Pyrazolopyrimidines, leur méthode de préparation et leur utilisation comme médicaments
WO2009095253A1 (fr) 6-halo-pyrazolo[1,5-a]pyridines, leur méthode de préparation et leur utilisation comme modulateurs des récepteurs métabotropiques du glutamate (mglur)
WO2010063487A1 (fr) Pyrazolopyrimidines, procédé pour leur préparation et leur utilisation comme médicament
AU2006283359A1 (en) Tetrahydroquinolinones and their use as modulators of metabotropic glutamate receptors
WO2012172093A1 (fr) Dérivé de dihydroindolizine à titre de modulateurs des récepteurs métabotropes de glutamate
WO2012085167A1 (fr) Modulateurs des récepteurs glutamatergiques métabotropes
WO2012019056A1 (fr) Composés d'amino-iso-indole, d'amino-aza-iso-indole, d'amino-dihydro-isoquinoléine et d'amino-benzoxazine en tant que modulateurs de la bêta-sécrétase et leurs méthodes d'utilisation
Hussenether et al. Clozapine derived 2, 3-dihydro-1H-1, 4-and 1, 5-benzodiazepines with D4 receptor selectivity: synthesis and biological testing
JP2005501092A (ja) 治療上有用な四環リガンド
WO2012052451A1 (fr) Modulateurs des récepteurs métabotropes au glutamate
WO2012085166A1 (fr) Modulateurs des récepteurs glutamatergiques métabotropes
CA2810659A1 (fr) Compose quinoxaline
EP2560973A1 (fr) Modulateurs des récepteurs 5-ht et leurs méthodes d'utilisation
EP2650284A1 (fr) Dérivés hétérocycliques comme modulateurs de récepteurs du glutamate métabotropique
AU2013301577B2 (en) Piperazino[1,2-a]indol-1-ones and [1,4]diazepino[1,2-a]indol-1-one
TW201305110A (zh) 促代謝性麩胺酸受體調節劑

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: 12730866

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: 12730866

Country of ref document: EP

Kind code of ref document: A1