WO2012085166A1 - Metabotropic glutamate receptor modulators - Google Patents

Metabotropic glutamate receptor modulators Download PDF

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Publication number
WO2012085166A1
WO2012085166A1 PCT/EP2011/073711 EP2011073711W WO2012085166A1 WO 2012085166 A1 WO2012085166 A1 WO 2012085166A1 EP 2011073711 W EP2011073711 W EP 2011073711W WO 2012085166 A1 WO2012085166 A1 WO 2012085166A1
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amino
dihydroquinazolin
methyl
disorder
disease
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PCT/EP2011/073711
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French (fr)
Inventor
Ulrich Abel
Bjoern Krueger
Holger Kubas
Udo Meyer
Ronalds Zemribo
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Merz Pharma Gmbh & Co. Kgaa
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Publication of WO2012085166A1 publication Critical patent/WO2012085166A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

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.
  • 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.
  • An additional object of the invention is the provision of processes for producing the heterocyclic derivatives.
  • Y represents CR 6 R 7 , NR 8 , O or S;
  • R 1 represents H, C h alky!, or F;
  • R 2 represents H, Ci -6 alkyl, or F; or
  • R 3 represents H, C h alky!, or F;
  • R 4 represents H, Ci -6 alkyl, or F;
  • R 5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC 3 - 6 alkyl, and heterocyclyl;
  • R 6 represents H, Ci -6 alkyl, or F
  • R 7 represents H, C h alky!, or F; or R 6 and R 7 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-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, and oxo;
  • R 8 represents H, 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, C 3 - 6 cycloalkyl, Ci -6 alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci -6 alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkylcarbonyl, Ci-6alkoxycarbonyl 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
  • a further aspect of the invention relates to a compound of Formula I, wherein X represents CH 2 and Y represents CR 6 R 7 wherein R 6 and R 7 each represent H.
  • a further aspect of the invention relates to a compound of Formula I, wherein R 3 and R 4 each represent H or Ci -6 alkyl or R 3 and R 4 together with the carbon atom to which they are attached form a saturated 3-7 membered ring.
  • 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, cyano, Ci -6 alkoxy, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkylthio, difluoromethyl, and difluromethoxy; pyridyl optionally substituted by one or more substituents selected from halogen, Ci- 6 alkyl, amino, Ci- 6 alkoxy, and cyano; pyrimidyl optionally substituted by d- 6 alkyl; cyclohexyl optionally substituted by Ci- 6 alkyl; or piperidyl optionally substituted by Ci -6 alkyl or Ci -6 alkylcarbonyl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
  • R 1 -R 7 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 1 -R 4 , R 6 , and R 7 each represent H and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IA wherein R 1 -R 4 , R 6 , and R 7 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 7 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 1 , R 2 , R 6 , and R 7 each represent H; R 3 and R 4 each represent H or Ci -6 alkyl (e.g. , methyl or ethyl) or R 3 and R 4 combine to form a 3-7 membered ring (e.g., a cyclopropane ring); and R 5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC 3 - 6 alkyl, and heterocyclyl.
  • R 1 , R 2 , R 6 , and R 7 each represent H; R 3 and R 4 each represent H or C h alky! (e.g. , methyl or ethyl) or R 3 and R 4 combine to form a 3-7 membered ring (e.g., a cyclopropane ring); and R 5 represents phenyl optionally substituted by one or more substituents selected from halogen, cyano, Ci -6 alkoxy, trifluoromethoxy, Ci -6 alkyl, Ci -6 alkylthio, difluoromethyl, and difluromethoxy; pyridyl optionally substituted by one or more substituents selected from halogen, Ci- 6 alkyl, amino, Ci- 6 alkoxy, and cyano; pyrimidyl optionally substituted by C h alky!; cyclohexyl optionally substituted by Ci -6 alkyl; or pipe
  • Such a compound of Formula IB wherein R 1 -R 4 each represent H; R 6 and R 7 each represent Ci -6 alkyl (e.g., methyl); and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • R 1 -R 4 each represent H; R 6 and R 7 each represent C h alky! (e.g., methyl); and R 5 represents phenyl optionally substituted by one or more substituents selected from C h alky! and halogen.
  • Such a compound of Formula IB wherein R 1 and R 2 each represent Ci -6 alkyl (e.g., methyl); R 4 -R 7 each represent H; and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • a further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula I
  • R 1 -R 5 and R 8 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 8 represents C h alky! (e.g., methyl) and R 5 represents a monocyclic moiety selected from aryl and heteroaryl.
  • Such a compound of Formula IC wherein R 8 represents C h alky! (e.g., methyl) and R 5 represents phenyl or pyridyl optionally substituted by one or more substituents selected from Ci -6 alkyl, cyano, Ci -6 alkoxy, and halogen.
  • 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 neuro-protection.
  • 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 ⁇ ' or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R 5 is as defined above for Formula I, wherein
  • 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 ⁇ '
  • 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 IB'
  • the invention also relates to a process for the synthesis or preparation of compounds of Formula IB" and/or IB'"
  • R 1 -R 2 and R 6 -R 7 represent methyl and R 5 is as defined above for Formula I, wherein a substituted cyclohexane-1 ,3-dione of Formula XII
  • 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 IC
  • 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- 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- (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 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 alkylcarbonyl, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)amino, Ci- 6 alkylcarbonylamino, oxo, Ci- 6 alkoxyimino, /V-Ci -6 alkylaminocarbonyl, /V,/V-di-(Ci -6 alkyl)amin
  • 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, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkylthio, Ci-6alkoxyCi-6alkyl, amino, hydroxy, nitro, cyano, formyl, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, d- 6 alkylcarbonyloxy, C-i-ealkylcarbonyloxyd-ealkyl, C-i -6 alkylamino, di-(Ci -6 alkyl)amin
  • 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- 6alkenyl, Ci -6 alkoxy, Ci -6 alkylthio, amino, hydroxy, nitro, cyano, Ci-6
  • 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, nap
  • 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 1 -6 alkyl, C 2-6 alkenyl, Ci -6 alkoxy, amino, hydroxy, nitro, cyano, Ci- 6 alkoxycarbonyl, Ci- 6 alkylcarbonyl, Ci- 6 alkylamino, and di-(Ci- 6 alkyl)amino, Ci-
  • 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.
  • 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.
  • intermediate 3 may be reacted with guanidine hydrochloride to yield 5,6,7,8-tetrahydroquinazolin-2-amine (5, which compound is also commercially available), which is converted to compound ⁇ ' either directly by palladium-catalyzed coupling with halide 6 or via conversion to aryl halide 7 (for example, by Sandmeyer reaction), which is then reacted with the corresponding primary amine 8.
  • 5-substituted cyclohexane-1 ,3-dione 9 is converted to dimethylaminomethylene derivative 10 by means of dimethylformamide dimethyl acetal (DMF-DMA). Condensation with substituted guanidine 4 leads to compound IB'.
  • aryl amine 11 can be formed from intermediate 10 and guanidine hydrochloride. Subsequent palladium-catalyzed coupling with halide 6 provides compound IB'.
  • a third synthetic route towards compounds of Formula IB' starts with intermediate 11 , which is converted to the corresponding aryl halide 12 (for example, via Sandmeyer reaction) and subsequently reacted with primary amine 8 to provide compound IB'.
  • Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (18) and ethyl 3- (methylamino)propanoate (20) are synthesized according to procedures described elsewhere (See Palenki, et al., Bioorqanic & Medicinal Chemistry Letters, 2000. 10(15), 1645-1648 and Dyck, et al. , Journal of Medicinal Chemistry, 2005, 48(12), 4100-41 10). Cyclization of ester 22 to pyridopyrimidone 23 is accomplished by means of a strong base (such as NaH).
  • a strong base such as NaH
  • 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.
  • the pharmaceutical 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".
  • 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
  • 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.
  • 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.
  • Tablets may be coated by methods well known in the art.
  • 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.
  • Compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes 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.
  • 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).
  • 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.
  • 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
  • DAST diethylaminosulfur trifluoride
  • DCM dichloromethane
  • DEE diethyl ether
  • DIPEA diethyl ether
  • DMF ⁇ /,/V-diisopropylethylamine (/V-ethyl-/V-isopropylpropan-2-amine
  • DMF as ⁇ /,/V-dimethylformamide
  • DMF-DMA as ⁇ /,/V-dimethylformamide dimethyl acetal
  • EtOAc as ethyl acetate
  • EtOH as ethanol
  • MeOH as methanol
  • MTBE methyl fe/f-butyl ether (or 2-methoxy-2-methylpropane)
  • reaction mixture is extracted with DCM or EtOAc.
  • the combined organic phases are dried with Na 2 SO 4 and concentrated at reduced pressure.
  • the obtained residue is purified by flash column chromatography or preparative HPLC.
  • [00131 ]/V-arylation can also be accomplished starting from 2-chloro-8-methyl-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one, which is prepared in two steps from either ethyl 8-methyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6- carboxylate or the corresponding decarboxylated analog 8-methyl-2-(methylthio)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one via the 2-hydroxy derivative.
  • reaction can also be run in DMF at 120 °C for 4 h. After cooling to room temperature the crude product is precipitated by adding saturated NaHC0 3 solution. The formed precipitate is filtered off, washed with water (2x20 mL), dried and purified by column chromatography (silica gel, DCM/EtOAc, 5: 1 ) to give the final compound.
  • Ethyl 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5- carboxylate [00134]A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10.00 g, 43.0 mmol), ethyl 3-(methylamino)propanoate (7.00 g, 53.4 mmol) and TEA (8.00 mL, 57.3 mmol) in ACN (120 mL) is refluxed for 16 h, cooled down to room temperature and concentrated in vacuo. The obtained residue is purified by column chromatography (silica gel, DCM/EtOAc, 4: 1 ) to give the title compound (14.55 g, 99%) as a yellow thick oil.
  • This intermediate is reacted with 4-bromo-3-fluorobenzonitrile (240 mg, 1.2 mmol), CS 2 CO 3 (652 mg, 2.0 mmol), Pd(OAc) 2 (16 mg, 0.07 mmol), XanthPhos (58 mg, 0.1 mmol), and THF (2 ml_) under argon atmosphere at 100 °C for 1 h under microwave irradiation, cooled down to room temperature and filtered through a pad of silica gel, which is washed with THF. The filtrate is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, MeOH/DCM, 100:1 ) to provide the title compound (105 mg, 35%) as a white solid.
  • reaction mixture is stirred at room temperature for 4 h and
  • Example 27 2 -((4-Chlorophenyl)amino)-6 8 , -dihydro-5 , H-spiro[cyclopropane-1,7 , -quinazolin]- 5'-one
  • HgCI 2 (3.830 g, 14.10 mmol) is added to a mixture of 6-methoxypyridin-3-amine (1 .364 g, 1 1 .0 mmol), TEA (5.5 mL, 39.6 mmol), and /V',/V"-di-Boc-thiourea (3.630 g, 13.2 mmol) in DCM (45 mL) at 0 °C and vigorous stirring. The reaction mixture is stirred at room temperature for 18 h and filtered through Celite. The filtrate is washed with water. The organic phase is dried over MgS0 4 and concentrated.
  • the obtained residue is purified by column chromatography (silica gel, EtOAc/DCM/hexane, 1 :5:5), washed with cold hexane and dried to obtain /V',/V"-di-Boc-protected 1 -(6-methoxypyridin-3- yl)guanidine (3.520 g, 87%) as a white solid, which is subsequently deprotected using TFA (12 mL) in DCM (30 mL) for 4 h at room temperature giving the corresponding TFA salt (2.512 g, 66%) as a white solid.
  • the instant compounds 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 normal 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: mg
  • the film coating material consists of:
  • a suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows: mg
  • 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 5 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 active principles of the present invention, and pharmaceutical compositions containing them and method of treating therewith, are characterized by unique and advantageous properties.
  • the compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics.
  • PH]MPEP (2-methyl-6-(phenylethynyl)pyridine binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes
  • the supernatant and the buffy coat are centrifuged at 48,000 x g for 20 minutes in the presence of 50 mM 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 mM 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).
  • Incubations 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).
  • scintillation liquid 5 ml Ultima Gold, Perkin Elmer, Germany
  • CHO-K1 cells CHO-K1 cells
  • mGluR5 human metabotropic glutamate receptor mGluR5
  • the standard growth medium used contains the appropriate inducer isopropyl-p-D-thiogalactopyranosid (IPTG) to achieve optimal receptor expression.
  • IPTG inducer isopropyl-p-D-thiogalactopyranosid
  • Ca-Kit is reconstituted in an assay buffer containing 20 mM 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 pm) 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% C0 2 / 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
  • 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).
  • Example 27 one 0.242 n.d.
  • Human mGluR5 values were obtained with CHO-cells stably expressing human mGluR5:
  • IC 50 values below 460 nM were determined in at least independent triplicates. Estimated values (est.) rely on one single point experiment performed in quadruplicate. rpA data were generated with rat primary astrocytes. IC 50 values are geometric mean of at least three experiments, each performed in quadruplicate.
  • 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.

Abstract

The invention relates to heterocyclic derivatives as well as their pharmaceutically acceptable salts. The invention further relates to a process for the preparation of such compounds. The compounds of the invention are mGluR5 modulators and are therefore useful for the control and prevention of acute and/or chronic neurological disorders.

Description

METABOTROPIC GLUTAMATE RECEPTOR MODULATORS
FIELD OF THE INVENTION
[0001 ] 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.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] At present, eight different members of these mGluRs are known. On the basis of structural parameters such as sequence homology, the second messenger system utilized by these receptors and their different affinity to low-molecular weight compounds, these eight receptors may be divided into three groups. 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. [0004] 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.
[0005] 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.
[0006] Therefore, 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 β-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 deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, hyperacusis, L-dopa-induced dyskinesias, L- dopa-induced dyskinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, neuroleptics-induced dyskinesia, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium, diabetes, hyperammonemia and liver failure and sleep disturbances.
[0007] 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, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, and other tumours.
[0008] 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.
[0009] Further indications for 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.
[0010] 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. [001 1 ] Moreover, mGluR modulators may have activity when administered in combination with other substances exhibiting neurological effects via different mechanisms.
[0012] 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).
[0013] Simultaneous administration of 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.
[0014] In the literature, several types of modulators of mGluR5 have already been described.
THE PRESENT INVENTION
[0015] It now has been found that certain 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.
OBJECTS OF THE INVENTION
[0016] It is an object of the present invention to provide novel pharmaceutical compounds which are mGluR5 modulators and pharmaceutical compositions thereof. It is a further object of the invention to provide a novel method of treating, eliminating, alleviating, palliating, modifying, or ameliorating undesirable CNS disorders which involve abnormal glutamate neurotransmission, and/or to provide symptomological effects, by employing a compound of the invention or a pharmaceutical composition containing the same.
[0017] An additional object of the invention is the provision of processes for producing the heterocyclic derivatives.
SUMMARY OF THE INVENTION
[0018] What we therefore believe to be comprised by our invention may be summarized inter alia in the following words:
A compound selected from those of Formula I
Figure imgf000007_0001
wherein
X represents CH2 or C=0;
Y represents CR6R7, NR8, O or S; R1 represents H, Chalky!, or F; R2 represents H, Ci-6alkyl, or F; or R1 and R2 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-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(C-i-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo; R3 represents H, Chalky!, or F; R4 represents H, Ci-6alkyl, or F; or R3 and R4 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-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;
R6 represents H, Ci-6alkyl, or F;
R7 represents H, Chalky!, or F; or R6 and R7 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-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, and oxo;
R8 represents H, Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkyl, Ci-6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkylcarbonyl, Ci-6alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di- (Ci-6alkyl)amino, /V,/V-di-(Ci-6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that the compound of formula (I) may not represent:
2-((2,4-Dichlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((2,4-Dimethylphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((2-Methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((2-Methoxyphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3-(Trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3,4-Dimethylphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3,5-Dimethoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Ethylphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Ethylphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Fluorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Fluorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Methoxyphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, 2-(Cyclopentylamino)-77-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-(Cyclopropylamino)-77-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-(m-Tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-(Phenylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-(p-Tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
77-Dimethyl-2-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydroquin
77-Dimethyl-2-((4-phenoxyphenyl)amino)-7,8-dihydroquinazolin-5(6H)-one
77-Dimethyl-2-(m-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
77-Dimethyl-2-(phenylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-((4-phenoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-(p-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
77-Dimethyl-2-(p-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-(phenylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3,5-Dimethylphenyl)amino)- 7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-( r?-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one, or
7-Methyl-2-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydroquinazoli
[0019] A further aspect of the invention relates to a compound of Formula I, wherein X represents CH2 and Y represents CR6R7 wherein R6 and R7 each represent H.
[0020] A further aspect of the invention relates to a compound of Formula I, wherein X represents C=0 and Y represents CR6R7 wherein R6 and R7 each represent H.
[0021 ] A further aspect of the invention relates to a compound of Formula I, wherein R3 and R4 each represent H or Ci-6alkyl or R3 and R4 together with the carbon atom to which they are attached form a saturated 3-7 membered ring.
[0022] A further aspect of the invention relates to a compound of Formula I, wherein X represents C=0 and Y represents CR6R7 wherein R6 and R7 each represent Ci-6alkyl.
[0023] A further aspect of the invention relates to a compound of Formula I, wherein X represents C=0 and Y represents NR8 wherein R8 represents Ci-6alkyl. [0024] A further aspect of the invention relates to a compound of Formula I, wherein R5 represents phenyl optionally substituted by one or more substituents selected from halogen, cyano, Ci-6alkoxy, trifluoromethoxy, Ci-6alkyl, Ci-6alkylthio, difluoromethyl, and difluromethoxy; pyridyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, amino, Ci-6alkoxy, and cyano; pyrimidyl optionally substituted by d- 6alkyl; cyclohexyl optionally substituted by Ci-6alkyl; or piperidyl optionally substituted by Ci-6alkyl or Ci-6alkylcarbonyl.
[0025] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IA
Figure imgf000011_0001
wherein R1-R7 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0026] Such a compound of Formula IA, wherein R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0027] Such a compound of Formula IA, wherein R1-R4, R6, and R7 each represent H and R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0028] Such a compound of Formula IA, wherein R1-R4, R6, and R7 each represent H and R5 represents phenyl optionally substituted by one or more halogen atoms.
[0029] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula IB
Figure imgf000012_0001
wherein R1-R7 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0030] Such a compound of Formula IB, wherein R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl.
[0031 ] Such a compound of Formula IB, wherein R1, R2, R6, and R7 each represent H; R3 and R4 each represent H or Ci-6alkyl (e.g. , methyl or ethyl) or R3 and R4 combine to form a 3-7 membered ring (e.g., a cyclopropane ring); and R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl.
[0032] Such a compound of Formula IB, wherein R1, R2, R6, and R7 each represent H; R3 and R4 each represent H or Chalky! (e.g. , methyl or ethyl) or R3 and R4 combine to form a 3-7 membered ring (e.g., a cyclopropane ring); and R5 represents phenyl optionally substituted by one or more substituents selected from halogen, cyano, Ci-6alkoxy, trifluoromethoxy, Ci-6alkyl, Ci-6alkylthio, difluoromethyl, and difluromethoxy; pyridyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, amino, Ci-6alkoxy, and cyano; pyrimidyl optionally substituted by Chalky!; cyclohexyl optionally substituted by Ci-6alkyl; or piperidyl optionally substituted by d. 6alkyl or Ci-6alkylcarbonyl.
[0033] Such a compound of Formula IB, wherein R1-R4 each represent H; R6 and R7 each represent Ci-6alkyl (e.g., methyl); and R5 represents a monocyclic moiety selected from aryl and heteroaryl. [0034] Such a compound of Formula IB, wherein R1-R4 each represent H; R6 and R7 each represent Chalky! (e.g., methyl); and R5 represents phenyl optionally substituted by one or more substituents selected from Chalky! and halogen.
[0035] Such a compound of Formula IB, wherein R1 and R2 each represent Ci-6alkyl (e.g., methyl); R4-R7 each represent H; and R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0036] A further aspect of the invention relates to a compound of Formula I, which is selected from those of Formula I
Figure imgf000013_0001
wherein R1-R5 and R8 are as defined above for Formula I, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0037] Such a compound of Formula IC, wherein R8 represents Chalky! (e.g., methyl) and R5 represents a monocyclic moiety selected from aryl and heteroaryl.
[0038] Such a compound of Formula IC, wherein R8 represents Chalky! (e.g., methyl) and R5 represents phenyl or pyridyl optionally substituted by one or more substituents selected from Ci-6alkyl, cyano, Ci-6alkoxy, and halogen.
[0039] Specific compounds of Formula I within the present invention include, but are not limited to, the following compounds:
/V-Phenyl-5,6,7,8-tetrahydroquinazolin-2-amine,
/V-(4-Fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,
/V-(3-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,
/V-(4-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,
2-((3-Fluorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one, 2-((3-Chlorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2- ((4-Chlorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
3- ((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitnle,
4- ((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitnle,
2-((3-Methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((3-Fluorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((3-Chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((4-Chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((4-Bromophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-3-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (rac)-4-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (rac)-7-Methyl-2-((4-(trifluoromethoxy)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-3-Fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzonitrile,
(rac)-7-Methyl-2-(pyndin-3-ylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((6-Chloropyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-7-Methyl-2-((6-methylpyridin-3-yl)am
(rac)-2-((6-Aminopyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one,
(rac)-2-((4-Chlorophenyl)amino)-7-ethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3-Fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Chlorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
4-((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinazolin-2-yl)amino)benzonitnle,
2'-((4-Chlorophenyl)amino)-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinazolin]-5'- one,
2-((3-Chlorophenyl)amino)-8,8-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
8,8-Dimethyl-2-( r?-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
8-Methyl-2-(phenylamino)-7,8-dihydropyndo[2,3-d]pynmidin-5(6/-/)-one,
2-((3-Fluorophenyl)amino)-8-methyl-7,8-dihydropyndo[2,3-d]pynmidin-5(6/-/)-one,
2- ((3-Chlorophenyl)amino)-8-methyl-7,8-dihydropyndo[2,3-d]pynmidin-5(6/-/)-one,
3- ((8-Methyl-5-oxo-5,6,7,8-tetrahydropyndo[2,3-d]pynmidin-2- yl)amino)benzonitrile, 8-Methyl-2-(m-tolylamino)-7,8-^
2-((3-Methoxyphenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pynmid
one,
4-((5'-Oxo-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinazolin]-2'- yl)amino)benzonitrile,
2-((3-(Methylthio)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((4-(Difluoromethyl)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-2-((4-(Difluoromethoxy)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-2-((6-Methoxypyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-7-Methyl-2-((4-methylcyclohexyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((1 -lsopropylpiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-2-((1 -Acetylpiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((5-Chloropyridin-2-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-6-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)nicotinonitrile,
(rac)-7-Methyl-2-((5-methylpyridin-2-yl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-Fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzonitrile,
(rac)-7-Methyl-2-((2-methylpyrimidin-5-yl)amino)-7,8-dihydroquinazolin-5(6H)-one^ and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
[0040] Moreover, 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. [0041 ] In a further aspect, 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. Moreover, 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.
[0042] 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. b) 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. c) Positive modulation of mGluR5 may be particularly useful for: Alzheimer's disease, positive and/or negative symptoms of schizophrenia, cognitive impairment, or for cognitive enhancement and/or neuroprotection.
[0043] 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.
[0044] Further, 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. Such 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.
[0045] Moreover, 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.
[0046] Further, the invention relates to 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.
[0047] Moreover, 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.
[0048] In a yet further aspect, 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.
[0049] A further aspect of the invention relates to 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 neuro-protection.
[0050] This invention also relates to 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.
[0051 ] The invention also relates to 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).
[0052] 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.
[0053] Furthermore, 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.
[0054] The invention also relates to a process for the synthesis or preparation of a compound of Formula ΙΑ'
Figure imgf000019_0001
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I, wherein
cyclohexanone of Formula II
Figure imgf000020_0001
is reacted with 1 -ie/f-butoxy-/V,/V,/V', '-tetramethylmethanediamine of Formula III
Figure imgf000020_0002
at elevated temperature to yield a compound of Formula IV
Figure imgf000020_0003
which is reacted with a guanidine of Formula V
NH H
to yield a compound of Formula ΙΑ', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0055] The invention also relates to a process for the synthesis or preparation of a compound of Formula ΙΑ'
Figure imgf000020_0004
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I, wherein a compound of Formula IV
Figure imgf000020_0005
prepared as described above, is treated with guanidine hydrochloride to yield a compound of Formula V
Figure imgf000021_0001
which is reacted with a compound of Formula VI
R5-Hal VI,
under palladium-catalyzed coupling conditions to yield a compound of Formula ΙΑ', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0056] The invention also relates to a process for the synthesis or preparation of a compound of Formula ΙΑ'
Figure imgf000021_0002
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I, wherein a compound of Formula V
Figure imgf000021_0003
prepared as described above, is converted to an aryl halide of Formula VII
Figure imgf000021_0004
which is treated with an amine of Formula VIII
R5-NH2 VIM,
to yield a compound of Formula ΙΑ', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0057] The invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
Figure imgf000021_0005
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R3 and R4 represent methyl and R5 is as defined above for Formula I, wherein a substituted cyclohexane-1 ,3-dione of Formula IX
Figure imgf000022_0001
is treated with dimethylformamide dimethyl acetal to yield a compound of Formula X
Figure imgf000022_0002
which is reacted with a guanidine of Formula V
NH H
to yield a compound of Formula IB', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0058] The invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
Figure imgf000022_0003
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R3 and R4 represent methyl and R5 is as defined above for Formula I, wherein a compound of Formula X
Figure imgf000022_0004
prepared as described above, is treated with guanidine hydrochloride to yield a compound of Formula XI
Figure imgf000023_0001
which is reacted with a compound of Formula VI
R5-Hal VI,
under palladium-catalyzed coupling conditions to yield a compound of Formula IB', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0059] The invention also relates to a process for the synthesis or preparation of a compound of Formula IB'
Figure imgf000023_0002
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R3 and R4 represent methyl and R5 is as defined above for Formula I, wherein a compound of Formula XI
Figure imgf000023_0003
prepared as described above, is converted to an aryl halide of Formula XII
Figure imgf000023_0004
which is treated with an amine of Formula VIII
R5-NH2 VIM,
to yield a compound of Formula IB', which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0060] The invention also relates to a process for the synthesis or preparation of compounds of Formula IB" and/or IB'"
Figure imgf000024_0001
IB" IB'"
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R1-R2 and R6-R7 represent methyl and R5 is as defined above for Formula I, wherein a substituted cyclohexane-1 ,3-dione of Formula XII
Figure imgf000024_0002
is treated with dimethylformamide dimethyl acetal to yield a compound of Formula XIV
Figure imgf000024_0003
which is reacted with a guanidine of Formula V
NH
A R5
H
to yield a mixture of the compounds of Formula IB" and IB'", which are separated (for example, by means of preparative HPLC) to yield a compound of Formula IB" and a compound of Formula IB'" which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0061 ] The invention also relates to a process for the synthesis or preparation of a compound of Formula IC
Figure imgf000024_0004
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I and R8 represents methyl, wherein a compound of Formula XV
Figure imgf000025_0001
is subjected to cyclization conditions (e.g., using a strong base such as sodium hydride or sodium fe/f-butoxide) to yield a compound of Formula XVI
Figure imgf000025_0002
which is subjected to decarboxylation conditions (e.g., treatment with trifluoroacetic acid) to yield a compound of Formula XVI
Figure imgf000025_0003
which is treated with m-chloroperoxybenzoic acid to yield the corresponding sulfonyl intermediate, which is then reacted with an amine of of Formula VIII
R5-NH2 VIM,
to yield a compound of Formula IC, which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0062] The invention also relates to a process for the synthesis or preparation of a compound of Formula IC
Figure imgf000025_0004
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I and R8 represents methyl, wherein a compound of Formula XVI
Figure imgf000026_0001
prepared as described above, is converted to a compound of Formula XVIII
XVIII,
Figure imgf000026_0002
which compound is converted to a compound of Formula XIX (e.g., via treatment with
Figure imgf000026_0003
which is treated with an amine of of Formula VIII
R5-NH2 VIM,
to yield a compound of Formula IC, which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
[0063] The invention also relates to a process for the synthesis or preparation of a compound of Formula IC
or an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R5 is as defined above for Formula I and R8 represents methyl, wherein a compound of Formula XVII
Figure imgf000026_0005
prepared as described above, is converted to a compound of Formula XVIII XVIII,
Figure imgf000027_0001
which compound is converted to a compound of Formula XIX (e.g., via treatment with
Figure imgf000027_0002
which is treated with an amine of of Formula VIII
R5-NH2 VIM,
to yield a compound of Formula IC, which may be converted, if desired, to an optical isomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, or polymorph.
DETAILED DESCRIPTION OF THE INVENTION
[0064] For the purpose of the present invention, in the compounds of Formula I 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. Thus, for example, (Ci-3)alkyl refers to alkyl of one to three carbon atoms (i.e. 1 , 2 or 3 carbon atoms), inclusive, (i.e., methyl, ethyl, propyl, and isopropyl), straight and branched forms thereof, (C-i-6) for instance refers to a radical of one to six carbon atoms (i.e. 1 , 2, 3, 4, 5 or 6 carbon atoms).
[0065] As used herein, the following definitions are applicable unless otherwise described, the term "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 tert -butyl.
[0066] The term "C2-6alkenyl" represents straight or branched chain alkenyl groups. [0067] The term "Ci-6alkoxy" represents straight or branched chain -0-Ci-6alkyl groups. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy, sec-butoxy, fe/f-butoxy.
[0068] The term "acyl" represents Ci-6alkylcarbonyl, trifluoroacetyl, hydroxy- Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, /V-Ci-6alkylaminocarbonyl, Λ/,/V-di- (Ci-6alkyl)aminocarbonyl, Ci-6alkoxy-Ci-6alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, cyclo-C3-i2alkylcarbonyl, aryl-Ci-6alkylcarbonyl, heteroaryl-Ci-6alkylcarbonyl, arylamino- Ci-6alkylcarbonyl, heteroarylamino-Ci-6alkylcarbonyl, heterocyclylcarbonyl and heterocyclyl-Ci-6alkylcarbonyl.
[0069] The term "cycloC3-i2alkyl" 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-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, C-i-6alkylamino, and di-(C-i-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, C-i-6alkoxyimino, /V-Ci-6alkylaminocarbonyl, Λ/,/V-di- (C-i-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy.
[0070] The term "cycloC3-6alkyl" 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-6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, cyano, Ci-6alkoxycarbonyl, Ci-6alkylcarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkylcarbonylamino, oxo, Ci-6alkoxyimino, /V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy.
[0071 ] The term "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, Ci-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkylthio, Ci-6alkoxyCi-6alkyl, amino, hydroxy, nitro, cyano, formyl, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, d- 6alkylcarbonyloxy, C-i-ealkylcarbonyloxyd-ealkyl, C-i-6alkylamino, di-(Ci-6alkyl)amino, cycloC3-i2alkylamino, Ci-6alkylcarbonylamino, phenylcarbonylamino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci-6alkyl)aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, cycloCs-^alkyl, pyridyl, and Ci-6alkylenedioxy.
[0072] The term "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-6alkyl, hydroxyCi-6alkyl, C2-6alkenyl, Ci-6alkoxy, Ci-6alkylthio, amino, hydroxy, nitro, cyano, Ci-6alkylcarbonyl, Ci-6alkoxycarbonyl, Ci-6alkoxycarbonyloxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino, cycloCs-^alkylamino, Ci-6alkylcarbonylamino, aminocarbonyl, /V-Ci-6alkylaminocarbonyl, /V,/V-di-(Ci- 6alkyl)aminocarbonyl, pyrrolidinyl, piperidinyl, morpholinyl, cycloC3-i2alkyl, d. 6alkylenedioxy, aryl, and pyridyl. Representative 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, quinolizinyl, phthalazinyl, and pteridinyl.
[0073] The term "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, C1 -6alkyl, C2-6alkenyl, Ci-6alkoxy, amino, hydroxy, nitro, cyano, Ci-6alkoxycarbonyl, Ci-6alkylcarbonyl, Ci-6alkylamino, and di-(Ci-6alkyl)amino, Ci-6alkyl- carbonylamino, oxo, C-i-6alkoxyimino, /V-Ci-6alkylaminocarbonyl, Λ/,/V-di- (Ci-6alkyl)aminocarbonyl, arylCi-6alkoxycarbonyl, and Ci-6alkylenedioxy; examples of such heterocyclyl groups include piperidinyl, morpholinyl, thiomorpholinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, or piperazinyl, wherein the heterocyclic ring or ring system is linked to the group to which it is attached optionally via nitrogen or a carbon atom.
[0074] The term "halogen" represents fluorine, chlorine, bromine and iodine.
[0075] 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).
[0076] 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.
[0077] 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). [0078] The term "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.
[0079] In addition, using methods known to those skilled in the art, 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.
[0080] The term "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).
[0081 ] The phrase "pharmaceutically acceptable", as used in connection with 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). The term "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.
[0082] 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.
[0083] It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric, or stereoisomeric form, or mixture thereof, of a compound of the invention, which possesses the useful properties described herein.
The following Schemes 1 -4 describe the preparation of compounds of Formula I of the present invention. All of the starting materials may be prepared by procedures described in these schemes, by procedures well known to one of ordinary skill in organic chemistry, or may be obtained commercially. All of the final compounds of the present invention may be prepared by procedures described in these charts or by procedures analogous thereto, which would be well known to one of ordinary skill in organic chemistry. All of the variables used in Schemes 1 -4 are as defined below or as in the claims. Compounds containing one or more chiral centers may be prepared as racemates or mixtures of various stereoisomers and then separated. However, they also may be prepared by a special enantioselective synthesis. For several of the chiral compounds, the enantiomers differ in pharmacological activity. cheme 1 - S nthesis of com ounds of Formula ΙΑ'.
Figure imgf000033_0001
x = Cl, Br
[0084] Reaction of cyclohexanone 1 with 1 -ie f-butoxy-/V,/V,/V',/V'- tetramethylmethanediamine (2) at elevated temperature leads to dimethylaminomethylene derivative 3, which is subsequently treated with substituted guanidine 4 to provide compound ΙΑ'. Alternatively, intermediate 3 may be reacted with guanidine hydrochloride to yield 5,6,7,8-tetrahydroquinazolin-2-amine (5, which compound is also commercially available), which is converted to compound ΙΑ' either directly by palladium-catalyzed coupling with halide 6 or via conversion to aryl halide 7 (for example, by Sandmeyer reaction), which is then reacted with the corresponding primary amine 8.
Scheme 2 - Synthesis of compounds of Formula IB'.
Figure imgf000034_0001
X = CI, Br
[0085] 5-substituted cyclohexane-1 ,3-dione 9 is converted to dimethylaminomethylene derivative 10 by means of dimethylformamide dimethyl acetal (DMF-DMA). Condensation with substituted guanidine 4 leads to compound IB'. Alternatively, aryl amine 11 can be formed from intermediate 10 and guanidine hydrochloride. Subsequent palladium-catalyzed coupling with halide 6 provides compound IB'. A third synthetic route towards compounds of Formula IB' starts with intermediate 11 , which is converted to the corresponding aryl halide 12 (for example, via Sandmeyer reaction) and subsequently reacted with primary amine 8 to provide compound IB'.
Scheme 3 - S nthesis of compounds of Formulas IB" and IB'".
Figure imgf000034_0002
[0086] 6,6- and 8,8-dimethylated derivatives IB" and IB'" are accessible analogously to the synthesis route described in Scheme 2 starting with 4-substituted cyclohexane-1 ,3- dione 13. In the final step both possible regioisomers are formed, which may then be separated (for example, by means of preparative HPLC).
Scheme 4 - Synthesis of compounds of Formula IC
Figure imgf000035_0001
[0087] Ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (18) and ethyl 3- (methylamino)propanoate (20) are synthesized according to procedures described elsewhere (See Palenki, et al., Bioorqanic & Medicinal Chemistry Letters, 2000. 10(15), 1645-1648 and Dyck, et al. , Journal of Medicinal Chemistry, 2005, 48(12), 4100-41 10). Cyclization of ester 22 to pyridopyrimidone 23 is accomplished by means of a strong base (such as NaH). After decarboxylation with TFA the resulting 8-methyl- 2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one (24) is converted to the compound IC by coupling with a corresponding amine 8 after treatment with m- chloroperoxybenzoic acid. Alternatively, intermediate 23 is transformed to the corresponding chloride 26 via hydroxyl derivative 25. The obtained aryl chloride 26 may then be reacted with amine 8 to provide compound IC
[0088] It will be appreciated that in the above transformations it may be necessary or desirable to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions.
[0089] Pure 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. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases.
[0090] 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.
[0091 ] 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 12C are substituted by 14C, where one or more fluor atoms are substituted by 18F 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.
ADDITION SALTS
[0092] For therapeutic use, salts of the compounds of Formula I are those wherein the counterion is pharmaceutically acceptable. However, 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. Conversely, the salt form may be converted by treatment with alkali into the free base form.
PHARMACEUTICAL COMPOSITIONS
[0093] The active ingredients of the compounds of the invention, together with one or more excipients such as adjuvants, carriers, or diluents, 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.
[0094] The pharmaceutical 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.
[0095] The term "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, 20th Edition, describes suitable pharmaceutical carriers in "Remington: The Science and Practice of Pharmacy".
METHOD OF TREATING
[0096] Due to their high degree of activity and their low toxicity, together presenting a most favorable therapeutic index, 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.
[0097] The term "treat" is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Within the meaning of the present invention, 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.
[0098] The term "combination" is used herein to define a single pharmaceutical composition (formulation) 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.
[0099] Within the meaning of the present invention, 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. For the sequential administration to be considered "conjoint", however, 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. For example, 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. [00100]The term "therapeutically 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.
[00101 ]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, 20th 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.
[00102]For oral administration in the form of a tablet or capsule, 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 acacia, tragacanth or alginates), buffer salts, carboxymethylcellulose, polyethyleneglycol, waxes, and the like. For oral administration in liquid form, 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.
[00103]Tablets may be coated by methods well known in the art. 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.
[00104]Compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines, as is well known.
[00105]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. Furthermore, 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.
[00106]For administration by inhalation, 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. In the case of a pressurized aerosol, 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.
[00107]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. The 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. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[00108]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).
[00109]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. [001 10]As disclosed herein, 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.
[001 1 1 ]Toxicity and therapeutic efficacy of the compositions of the invention may be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (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.
[001 12]From the Examples described herein below, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
[001 13]The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions.
[001 14]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.
[001 15]These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
[001 16]These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement.
[001 17]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.
[001 18]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. [001 19] Representative pharmaceutical 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.
EXPERIMENTAL PART
[00120]The compounds and their preparation of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention.
[00121 ]Hereinafter, "ACN" is defined as acetonitrile, "Boc" as fe/f-butyloxycarbonyl, "DAST" as diethylaminosulfur trifluoride, "DCM" as dichloromethane, "DEE" as diethyl ether, "DIPEA" as Λ/,/V-diisopropylethylamine (/V-ethyl-/V-isopropylpropan-2-amine), "DMF" as Λ/,/V-dimethylformamide, "DMF-DMA" as Λ/,/V-dimethylformamide dimethyl acetal, "EtOAc" as ethyl acetate, "EtOH" as ethanol, "MeOH" as methanol, "MTBE" as methyl fe/f-butyl ether (or 2-methoxy-2-methylpropane), "PdCI2(dppf)*DCM" as 1 , 1 '- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex, "Pd2dba3" as tris(dibenzylideneacetone)dipalladium(0), "TEA" as triethylamine, "XanthPhos" as (9,9-dimethyl-9/-/-xanthene-4,5-diyl)bis(diphenylphosphine), and "THF" as tetrahydrofuran.
General Procedure 1 - Preparation of substituted guanidines
[00122] To a stirred solution of an appropriate amine in EtOH at 20 °C an aqueous HNO3 solution (67%, d=1 .4), and subsequently cyanamide are added. The resulting solution is stirred at reflux for 4-8 h. Then the mixture is cooled to 15 °C and DEE is added to induce crystallization of the product. The formed suspension is stirred at 20 °C for 15 min or overnight. The precipitate is filtered off, washed with a mixture of DEE and EtOH (3: 1 ), and air-dried to provide the title compound. General Procedure 2 - Ring closure reaction towards 2-amino-7,8- dihydroquinazolone derivatives
[00123]A mixture of optionally substituted 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione (1 .0 mmol), a corresponding guanidine (1-1.4 eq.) and TEA (0.3 mL) in EtOH (6 mL) is refluxed for 3-24 h. The reaction progress is monitored by TLC or HPLC. The resulting mixture is cooled down to room temperature and diluted with water. The formed precipitate is filtered off, washed with water and recrystallized from MeOH or another appropriate solvent to provide the final compound.
[00124] In cases in which the product does not precipitate after dilution with water, the reaction mixture is extracted with DCM or EtOAc. The combined organic phases are dried with Na2SO4 and concentrated at reduced pressure. The obtained residue is purified by flash column chromatography or preparative HPLC.
Preparation 1
2-((Dimethylamino)methylene)cyclohexane-1,3-dione
[00125] A mixture of cyclohexane-1 ,3-dione (22.40 g, 200 mmol), DMF-DMA (47.7 g, 400 mmol) and ACN (200 mL) is stirred at room temperature overnight and concentrated in vacuo. The mixture is triturated with DEE, filtered, washed with DEE and dried in vacuo to provide the title compound (13.90 g, 59%) as a brown solid.
Preparation 2
2-((Dimethylamino)methylene)-5-methylcyclohexane-1,3-dione
[00126]A mixture of 5-methylcyclohexane-1 ,3-dione (18.50 g, 146.0 mmol), DMF-DMA (34.90 g, 293.0 mmol) and EtOAc (150 mL) is stirred at room temperature overnight and concentrated in vacuo. The mixture is triturated with DEE, filtered, washed with DEE, and dried in vacuo to provide the title compound (21.90 g, 84%) as a light yellow solid.
Preparation 3 2-((Dimethylamino)methylene)-5,5-dimethylcyclohexane-1 ,3-dione
[00127]The title compound is prepared according to the procedure described in Preparation 2 from 5,5-dimethylcyclohexane-1 ,3-dione (4.91 g, 35.0 mmol), DMF-DMA (8.34 g, 70.0 mmol) and ACN (35 mL) resulting in 4.72 g (69%) of the final product as an orange solid.
Preparation 4
2-((Dimethylamino)methylene)-4,4-dimethylcyclohexane-1 ,3-dione
[00128]The title compound is prepared according to the procedure described in Preparation 2 from 4,4-dimethylcyclohexane-1 ,3-dione (4.91 g, 35.0 mmol), DMF-DMA (8.34 g, 70.0 mmol) and ACN (35 mL) resulting in 2.71 g (39%) of the final product as a yellow solid.
General procedure 3 - /V-Arylation reaction towards 2-amino-7,8- dihydropyrido[2,3-d]pyrimidone derivatives
General Procedure 3a - Starting from 8-methyl-2-(methylthio)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00129] To a stirred solution of 8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3- d]pyrimidin-5(6/-/)-one in toluene (5-10 mL) m-chloroperoxybenzoic acid is added at a temperature below 30 °C and the resulting mixture is stirred at the same temperature for 0.5 h. An appropriate amine and Λ/,/V-diisopropylethylamine are added at a temperature below 30 °C, and the mixture is stirred at room temperature for 2 h. Then toluene (5 mL) and isopropanol (8 mL) are added, and the mixture is washed with 1 N aqueous NaOH solution (4 mL) and 15% aqueous NaCI solution (4 mL). The organic layer is dried over Na2S04 and concentrated in vacuo. The obtained residue is purified by column chromatography (silica gel, hexane/EtOAc, 2: 1 ) to give the final compound. [00130]Alternatively, the oxidized intermediate 8-methyl-2-(methylsulfonyl)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one may also be separated before it is reacted with the corresponding amine.
General Procedure 3b - Starting from 2-chloro-8-methyl-7,8-dihydropyrido[2,3- d]pyrimidin-5(6H)-one
[00131 ]/V-arylation can also be accomplished starting from 2-chloro-8-methyl-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one, which is prepared in two steps from either ethyl 8-methyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-6- carboxylate or the corresponding decarboxylated analog 8-methyl-2-(methylthio)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one via the 2-hydroxy derivative.
[00132]To a suspension of 2-chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6/-/)- one and an appropriate amine (1 eq.) in 1 -butanol aqueous 1 N HCI solution is added. The resulting solution is heated at 90 °C for 1 h. The mixture is allowed to cool to room temperature, concentrated to dryness and partitioned between EtOAc (20 mL) and saturated aqueous NaHC03 solution (20 mL). The layers are separated, and the organic layer is washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue is purified by flash column chromatography (silica, gradient 30% to 60% EtOAc/heptane) to provide the final compound.
[00133]The reaction can also be run in DMF at 120 °C for 4 h. After cooling to room temperature the crude product is precipitated by adding saturated NaHC03 solution. The formed precipitate is filtered off, washed with water (2x20 mL), dried and purified by column chromatography (silica gel, DCM/EtOAc, 5: 1 ) to give the final compound.
Preparation 5
Ethyl 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5- carboxylate [00134]A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10.00 g, 43.0 mmol), ethyl 3-(methylamino)propanoate (7.00 g, 53.4 mmol) and TEA (8.00 mL, 57.3 mmol) in ACN (120 mL) is refluxed for 16 h, cooled down to room temperature and concentrated in vacuo. The obtained residue is purified by column chromatography (silica gel, DCM/EtOAc, 4: 1 ) to give the title compound (14.55 g, 99%) as a yellow thick oil.
Preparation 6
Ethyl 8-methyl-2-(methylthio)-5-oxo-5,6,7,8 etrahydropyrido[2,3-d]pyrimidine carboxylate
[00135]NaH (60% in oil, 2.31 g, 57.8 mmol) is dissolved in fe/f-butanol (30 mL). Then a solution of ethyl 4-((3-ethoxy-3-oxopropyl)(methyl)amino)-2-(methylthio)pyrimidine-5- carboxylate (12.55 g, 38.3 mmol) in toluene (200 mL) is added at room temperature. The reaction mixture is refluxed for 0.5 h, cooled down to room temperature and neutralized with 5% aqueous HCI solution. The organic layer is separated, and the aqueous layer is extracted with DCM (2x200 mL). The combined organic phases are dried over Na2S04 and concentrated in vacuo. The residue is purified by column chromatography (silica gel, DCM/EtOAc, 5: 1 ) to give the title compound (10.70 g, 99%) as a yellow solid.
Preparation 7
8-Methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00136]A mixture of ethyl 8-methyl-2-(methylthio)-5-oxo-5,6,7,8-tetrahydropyrido[2,3- d]pyrimidine-6-carboxylate (10.50 g, 37.3 mmol) and 1 N aqueous NaOH solution (75 mL, 75 mmol) in EtOH (40 mL) is refluxed for 4 h, cooled down to room temperature, diluted with water (200 mL), and neutralized with 1 N aqueous HCI solution. Then the mixture is extracted with DCM (2x400 mL), and the combined extracts are dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica gel, DCM/EtOAc, 5: 1 ) to give the title compound (3.50 g, 45%) as a yellowish solid. Preparation 8
2-Hydroxy-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00137]To a suspension of ethyl 8-methyl-2-(methylthio)-5-oxo-5, 6,7,8- tetrahydropyrido[2,3-d]pyrimidine-6-carboxylate (6.82 g, 21 .33 mmol) in EtOH (100 mL) aqueous 1 N NaOH solution (107 mL) is added, and the mixture is stirred at 90 °C for 16 h. The reaction mixture is concentrated to dryness, and the solid residue is stirred in DCM/MeOH 9: 1 (500 mL) for 3 h. The suspension is filtered, and the filtrate is concentrated in vacuo to give crude 3.56 g of the title compound as a yellow solid, which is used in the next step without further purification.
[00138]8-methyl-2-(methylthio)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one may also serve as starting material to provide the title compound.
Preparation 9
2-Chloro-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00139]A suspension of 2-hydroxy-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6/-/)- one (3.56 g, 13.51 mmol) in phosphoryl trichloride (50 mL) is heated at 80 °C for 64 h. The reaction mixture is allowed to cool to room temperature, concentrated and successively stripped with toluene (2x250 mL), DEE (2x250 mL) and DCM (2x250 mL). The residue is partitioned between EtOAc (500 mL) and saturated aqueous NaHCO3 solution (500 mL). The layers are separated, and the organic layer is washed with brine (500 mL), dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (silica, gradient 20% to 60% EtOAc/heptane) to give 786 mg (29% for 2 steps) of the title compound as a yellow solid.
Example 1
yV-phenyl-5,6,7,8-tetrahydroquinazolin-2-amine
[00140] A suspension of Cs2CO3 (133 mg, 0.41 mmol), PdCI2(dppf)*DCM (20 mg, 0.03 mmol), 2-bromo-5,6,7,8-tetrahydroquinazoline (58 mg, 0.27 mol), and aniline (35 mg, 0.38 mmol) in toluene (1 mL) is heated at 100 °C for 6 h under argon atmosphere, then cooled to room temperature and evaporated. The residue is partitioned between water and EtOAc. The organic layer is dried over Na2S04, filtered and evaporated. The residue is purified by flash column chromatography on silica gel (EtOAc/hexane) to provide the title compound (22 mg, 36%).
1H NMR (CDCIs), δΗ, 1 .78-1.92 (m, 4H), 2.63 (t, 2H), 2.75 (t, 2H), 6.95-7.02 (m, 2H), 7.31 (t, 2H), 7.62 (d, 2H), 8.1 1 (s, 1 H).
LC/MS (M+H)+ = 226
Example 2
yV-(4-Fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine
[00141 ]A suspension of Cs2C03 (138 mg, 0.42 mmol), PdCI2(dppf)*DCM (23 mg, 0.028 mmol), 2-bromo-5,6,7,8-tetrahydroquinazoline (60 mg, 0.28 mol) and 4-fluoroaniline (50 mg, 0.39 mmol) in toluene (1 mL) is heated at 100 °C for 16 h under argon atmosphere, then cooled to room temperature and evaporated. The residue is partitioned between water and EtOAc. The organic layer is dried over Na2S04, filtered and evaporated. The residue is purified by flash column chromatography on silica gel (EtOAc/hexane) to provide the title compound (10 mg, 15%).
1H NMR (CDCI3), δΗ, 1 .78-1.92 (m, 4H), 2.62 (t, 2H), 2.74 (t, 2H), 6.96-7.06 (m, 3H), 7.51 -7.60 (m, 2H), 8.09 (s, 1 H).
LC/MS (M+H)+ = 244
Example 3
yV-(3-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine
[00142]1 -ie/f-Butoxy-/V,/V,/V\/V'-tetramethylmethanediamine (522 mg, 3.00 mmol) is added dropwise to cyclohexanone (306 mg, 3.00 mmol) under argon atmosphere at room temperature. The reaction mixture is stirred at room temperature for 24 h and then at 1 10 °C for 1 h. The resulting mixture is concentrated under reduced pressure to give crude 2-((dimethylamino)methylene)cyclohexanone (280 mg) as a brown oil, which is used in the next reaction step without additional purification.
[00143]A mixture of crude 2-((dimethylamino)methylene)cyclohexanone (270 mg, approx. 1 .74 mmol), 1 -(3-chlorophenyl)guanidine nitrate (404 mg, 1 .74 mmol), and TEA (0.6 ml_) in EtOH (6 ml_) is refluxed for 6 h, cooled down to room temperature and diluted with water. The formed precipitate is collected by filtration, washed with water and crystallized from MeOH to provide the title compound (100 mg, 13% for two steps) as a beige solid.
1H NMR (De-DMSO), δΗ, 1 .63-1 .83 (m, 4H), 2.53-2.63 (m, 2H), 2.63-2.73 (m, 2H), 6.88 (d, 1 H), 7.22 (dd, 1 H), 7.63 (d, 1 H), 7.95 (s, 1 H), 8.19 (s, 1 H), 9.51 (br s, 1 H).
LC/MS (M+H)+ = 260, 262.
Example 4
yV-(4-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine
[00144]A suspension of Cs2C03 (138 mg, 0.42 mmol), PdCI2(dppf)*DCM (23 mg, 0.028 mmol), 2-bromo-5,6,7,8-tetrahydroquinazoline (60 mg, 0.28 mol) and 4-chloroaniline (50 mg, 0.39 mmol) in toluene (1 ml_) is heated at 100 °C for 16 h under argon atmosphere, then cooled to room temperature and evaporated. The residue is partitioned between water and EtOAc. The organic layer is dried over Na2S04, filtered and evaporated. The residue is purified by flash column chromatography on silica gel (EtOAc/hexane) to provide the title compound (26 mg, 35%).
1H NMR (CDCI3), δΗ, 1.81 -1 .92 (m, 4H), 2.63 (t, 2H), 2.75 (t, 2H), 7.10 (br. s, 1 H), 7.23- 7.27 (m, 2H), 7.57 (d, 2H), 8.1 1 (s, 1 H).
LC/MS (M+H)+ = 260, 262 Example 5
2-((3-Fluorophenyl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00145]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(3-fluorophenyl)guanidine to provide the title compound (132 mg, 51 %) as a beige solid.
1H NMR (CDCI3), δΗ, 2.01 -2.1 1 (m, 2H), 2.56 (t, 2H), 2.92 (t, 2H), 6.83 (t, 1 H), 7.33 (dd, 1 H), 7.54 (d, 2H), 7.80 (d, 1 H), 8.82 (s, 1 H), 10.38 (br s, 1 H).
LC/MS (M+H)+ = 258
Example 6
2-((3-Chlorophenyl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00146]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(3-chlorophenyl)guanidine to provide the title compound (185 mg, 68%) as a yellowish solid.
1H NMR (De-DMSO), δΗ, 2.01 -2.1 1 (m, 2H), 2.56 (t, 2H), 2.91 (t, 2H), 7.06 (d, 1 H), 7.32 (t, 1 H), 7.72 (d, 1 H), 7.96 (s, 1 H), 8.82 (s, 1 H), 10.33 (br s, 1 H).
LC/MS (M+H)+ = 274, 276
Example 7
2- ((4-Chlorophenyl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00147]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(4-chlorophenyl)guanidine to provide the title compound (199 mg, 73%) as a beige solid.
1H NMR (De-DMSO), δΗ, 1 .99-2.09 (m, 2H), 2.54 (t, 2H), 2.88 (t, 2H), 7.35 (d, 2H), 7.81 (d, 2H), 8.79 (s, 1 H), 10.33 (br s, 1 H).
LC/MS (M+H)+ = 274, 276
Example 8
3- ((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile [00148]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(3-cyanophenyl)guanidine to provide the title compound (147 mg, 56%) as a beige solid.
1H NMR (De-DMSO), δΗ, 2.01 -2.1 1 (m, 2H), 2.57 (t, 2H), 2.93 (t, 2H), 7.45 (d, 1 H), 7.52 (t, 1 H), 8.05 (d, 1 H), 8.26 (s, 1 H), 8.84 (s, 1 H), 10.47 (br s, 1 H).
LC/MS (M+H)+ = 265
Example 9
4-((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile
[00149]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(4-cyanophenyl)guanidine to provide the title compound (167 mg, 63%) as a beige solid.
1H NMR (De-DMSO), δΗ, 2.03-2.13 (m, 2H), 2.58 (t, 2H), 2.94 (t, 2H), 7.75 (d, 2H), 8.01 (d, 2H), 8.86 (s, 1 H), 10.64 (br s, 1 H).
LC/MS (M+H)+ = 265
Example 10
2-((3-Methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00150]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(3-methoxyphenyl)guanidine to provide the title compound (31 mg, 12%) as a white solid.
1H NMR (De-DMSO), δΗ, 2.01 -2.1 1 (m, 2H), 2.55 (t, 2H), 2.89 (t, 2H), 3.22 (s, 3H), 6.62 (d, 1 H), 7.20 (t, 1 H), 7.34 (d, 1 H), 7.52 (s, 1 H), 8.79 (s, 1 H), 10.15 (br s, 1 H).
LC/MS (M+H)+ = 270
Example 11
(rac)-2-((3-Fluorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one [00151 ]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(3-fluorophenyl)guanidine to provide the title compound (206 mg, 71 %) as a white solid.
1H NMR (CDCI3), δΗ, 1 .18 (d, 3H), 2.25-2.45 (m, 2H), 2.60-2.76 (m, 2H), 2.96-3.06 (m, 1 H), 6.79 (dd, 1 H), 7.18-7.34 (m, 2H), 7.49 (br s, 1 H), 7.75 (d, 1 H), 8.96 (s, 1 H).
LC/MS (M+H)+ = 272
Example 12
(rac)-2-((3-Chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00152]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(3-chlorophenyl)guanidine to provide the title compound (191 mg, 61 %) as a light yellow solid.
1H NMR (CDCI3), δΗ, 1 .17 (d, 3H), 2.25-2.45 (m, 2H), 2.60-2.77 (m, 2H), 2.96-3.06 (m, 1 H), 7.07 (d, 1 H), 7.25 (dd, 1 H), 7.45 (d, 1 H), 7.53 (br s, 1 H), 7.86 (s, 1 H), 8.95 (s, 1 H). LC/MS (M+H)+ = 288, 290
Example 13
(rac)-2-((4-Chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00153]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(4-chlorophenyl)guanidine to provide the title compound (199 mg, 73%) as a grey solid.
1H NMR (CDCI3), δΗ, 1 .16 (d, 3H), 2.25-2.45 (m, 2H), 2.60-2.77 (m, 2H), 2.93-3.04 (m, 1 H), 7.31 (d, 2H), 7.52 (br s, 1 H), 7.61 (d, 2H), 8.93 (s, 1 H).
LC/MS (M+H)+ = 288, 290
Example 14
(rac)-2-((4-Bromophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one [00154]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(4-bromophenyl)guanidine to provide the title compound (175 mg, 48%) as a light grey solid.
1H NMR (De-DMSO), δΗ, 1 .08 (d, 3H), 2.24-2.42 (m, 2H), 2.53-2.61 (m, 1 H), 2.65-2.77 (m, 1 H), 2.85-2.95 (m, 1 H), 7.49 (d, 2H), 7.78 (d, 2H), 8.79 (s, 1 H), 10.34 (br s, 1 H). LC/MS (M+H)+ = 332, 334
Example 15
(rac)-3-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile
[00155]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(3-cyanophenyl)guanidine to provide the title compound (135 mg, 45%) as a white solid.
1H NMR (De-DMSO), δΗ, 1 .09 (d, 3H), 2.25-2.45 (m, 2H), 2.54-2.62 (m, 1 H), 2.69-2.79 (m, 1 H), 2.90-3.00 (m, 1 H), 7.46 (d, 1 H), 7.53 (dd, 1 H), 8.06 (d, 1 H), 8.28 (s, 1 H), 8.84 (s, 1 H), 10.52 (s, 1 H).
LC/MS (M+H)+ = 279
Example 16
(rac)-4-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile
[00156]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(4-cyanophenyl)guanidine to provide the title compound (257 mg, 85%) as a light yellow solid.
1H NMR (CDCIs), δΗ, 2.26-2.46 (m, 2H), 2.63-2.80 (m, 2H), 2.97-3.00 (m, 1 H), 7.59 (br s, 1 H), 7.63 (d, 2H), 7.83 (d, 2H), 8.99 (s, 1 H).
LC/MS (M+H)+ = 279
Example 17
(rac)-7-Methyl-2-((4-(trifluoromethoxy)phenyl)amino)-7,8-dihydroquinazolin-5(6H)- one [00157]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(4-(trifluoromethoxy)phenyl)guanidine to provide the title compound (54 mg, 14%) as a white solid.
1H NMR (De-DMSO), δΗ, 1 .07 (d, 3H), 2.24-2.42 (m, 2H), 2.53-2.61 (m, 1 H), 2.63-2.75 (m, 1 H), 2.85-2.95 (m, 1 H), 7.30 (d, 2H), 7.88 (d, 2H), 8.79 (s, 1 H), 10.36 (br s, 1 H). LC/MS (M+H)+ = 338
Example 18
(rac)-3-Fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzonitrile
[00158]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with guanidine hydrochloride to give the intermediate 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one. This intermediate is reacted with 4-bromo-3-fluorobenzonitrile (240 mg, 1.2 mmol), CS2CO3 (652 mg, 2.0 mmol), Pd(OAc)2 (16 mg, 0.07 mmol), XanthPhos (58 mg, 0.1 mmol), and THF (2 ml_) under argon atmosphere at 100 °C for 1 h under microwave irradiation, cooled down to room temperature and filtered through a pad of silica gel, which is washed with THF. The filtrate is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, MeOH/DCM, 100:1 ) to provide the title compound (105 mg, 35%) as a white solid.
1H NMR (De-DMSO), δΗ, 1 .07 (d, 3H), 2.24-2.44 (m, 2H), 2.53-2.61 (m, 1 H), 2.65-2.75 (m, 1 H), 2.85-2.95 (m, 1 H), 7.67 (d, 1 H), 7.85 (d, 1 H), 8.13 (dd, 1 H), 8.80 (s, 1 H), 10.16 (br s, 1 H).
LC/MS (M+H)+ = 297 Example 19
(rac)-7-Methyl-2-(pyridin-3-ylamino)-7,8-dihydroquinazolin-5(6H)-one
[00159]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(pyridin-3-yl)guanidine to provide the title compound (156 mg, 57%) as a white solid. 1H NMR (CDCI3), δΗ, 1 .17 (d, 3H), 2.27-2.45 (m, 2H), 2.62-2.76 (m, 2H), 2.96-3.06 (m, 1 H), 7.31 (br, 1 H), 7.60 (br, 1 H), 8.23 (d, 1 H), 8.37 (br, 1 H), 8.83 (br, 1 H), 8.96 (s, 1 H). LC/MS (M+H)+ = 255
Example 20
(rac)-2-((6-Chloropyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00160]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(6-chloropyridin-3-yl)guanidine to provide the title compound (153 mg, 49%) as a light beige solid.
1H NMR (De-DMSO), δΗ, 1 .07 (d, 3H), 2.25-2.42 (m, 2H), 2.53-2.61 (m, 1 H), 2.65-2.77 (m, 1 H), 2.86-2.96 (m, 1 H), 7.44 (d, 1 H), 8.26 (d, 1 H), 8.77 (s, 1 H), 8.80 (s, 1 H), 10.48 (br s, 1 H).
LC/MS (M+H)+ = 289, 291 Example 21
(rac)-7-Methyl-2-((6-methylpyridin-3-yl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00161 ]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(6-methylpyridin-3-yl)guanidine to provide the title compound (107 mg, 36%) as a beige solid.
1H NMR (De-DMSO), δΗ, 1 .07 (d, 3H), 2.24-2.42 (m, 2H), 2.42 (s, 3H), 2.53-2.61 (m, 1 H), 2.63-2.75 (m, 1 H), 2.85-2.95 (m, 1 H), 7.19 (d, 1 H), 8.06 (d, 1 H), 8.67 (s, 1 H), 8.77 (s, 1 H), 10.23 (br s, 1 H).
LC/MS (M+H)+ = 269
Example 22
(rac)-2-((6-Aminopyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00162]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with guanidine hydrochloride to give the intermediate 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one. A mixture of this intermediate (266 mg, 1 .5 mmol), di-Boc-protected 5-bromopyridin-2 -amine (700 mg, 1.9 mmol), Cs2C03 (978 mg, 3.0 mmol), Pd(OAc)2 (24 mg, 0.1 mmol), and XanthPhos (87 mg, 0.15 mmol) in THF (5 ml_) is stirred under argon atmosphere at 90 °C for 2 h under microwave irradiation, cooled down to room temperature and filtered. The filtrate is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, NH4OH/EtOH/DCM, 1 :3: 100) giving di-Boc-protected 2-((6- aminopyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (190 mg, 37%) as an oil, which is dissolved in DCM (4 ml_) and treated with TFA (1 ml_) at room
temperature. The reaction mixture is stirred at room temperature for 4 h and
concentrated at reduced pressure. The obtained residue is purified by preparative HPLC (C18, acetonitrile/water+TFA) and washed with hexane to provide the title compound (47 mg, 44%) as a white ditrifluoroacetate salt.
1H NMR (De-DMSO), δΗ, 1 .07 (d, 3H), 2.24-2.42 (m, 2H), 2.53-2.61 (m, 1 H), 2.63-2.75 (m, 1 H), 2.85-2.95 (m, 1 H), 3.39 (br, 2H+H20), 6.95 (d, 1 H), 7.62 (br, 2H), 8.06 (d, 1 H), 8.44 (s, 1 H), 8.78 (s, 1 H), 10.29 (s, 1 H).
LC/MS (M+H)+ = 270
Example 23
(rac)-2-((4-Chlorophenyl)amino)-7-ethyl-7,8-dihydroquinazolin-5(6H)-one
[00163]To a suspension of 5-ethylcyclohexane-1 ,3-dione (0.40g, 2.85 mmol) in abs. benzene (5 ml_) DMF-DMA (0.51 g, 4.28 mmol) is added, and the mixture is heated at reflux for 4 h and evaporated to give 2-((dimethylamino)methylene)-5-ethylcyclohexane- 1 ,3-dione. This intermediate is dissolved in abs. EtOH (5 ml_) and 1 -(4- chlorophenyl)guanidine (0.48 g, 2.85 mmol) is added. The mixture is heated at reflux for 8 h. After cooling the reaction mixture is evaporated to dryness, and the residue is purified by flash column chromatography to provide the title compound (0.1 1 g, 13%) as a grey solid.
1H NMR (CDCI3), δΗ, 1 .00 (t, 3H), 1 .53 (q, 2H), 2.01 -2.40 (m, 2H), 2.59-2.79 (m, 2H), 3.03 (dd, 1 H), 7.32 (d, 2H), 7.53 (s, 1 H), 7.62 (d, 2H), 8.94 (s, 1 H).
LC/MS (M+H)+ = 302 Example 24
2-((3-Fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6H)-one
[00164]According to General Procedure 2, 2-((dimethylamino)methylene)-5,5- dimethylcyclohexane-1 ,3-dione is reacted with 1 -(3-fluorophenyl)guanidine to provide the title compound (57 mg, 20%) as a white solid.
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.48 (s, 2H), 2.85 (s, 2H), 6.84 (dd, 1 H), 7.34 (dd, 1 H), 7.56 (d, 1 H), 7.82 (d, 1 H), 8.83 (s, 1 H), 10.40 (br s, 1 H).
LC/MS (M+H)+ = 286
Example 25
2-((4-Chlorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6H)-one
[00165]According to General Procedure 2, 2-((dimethylamino)methylene)-5,5- dimethylcyclohexane-1 ,3-dione is reacted with 1 -(4-chlorophenyl)guanidine to provide the title compound (1 12 mg, 37%) as a grey solid.
1H NMR (De-DMSO), δΗ, 1 .04 (s, 6H), 2.47 (s, 2H), 2.83 (s, 2H), 7.36 (d, 2H), 7.83 (d, 2H), 8.80 (s, 1 H), 10.32 (br s, 1 H).
LC/MS (M+H)+ = 302, 304
Example 26
4-((7,7-Dimethyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile
[00166]According to General Procedure 2, 2-((dimethylamino)methylene)-5,5- dimethylcyclohexane-1 ,3-dione is reacted with 1 -(4-cyanophenyl)guanidine to provide the title compound (123 mg, 42%) as a yellowish solid.
1H NMR (De-DMSO), δΗ, 1 .05 (s, 6H), 2.50 (s, 2H), 2.88 (s, 2H), 7.77 (d, 2H), 8.03 (d, 2H), 8.87 (s, 1 H), 10.69 (br s, 1 H).
LC/MS (M+H)+ = 293
Example 27 2,-((4-Chlorophenyl)amino)-6 8,-dihydro-5,H-spiro[cyclopropane-1,7,-quinazolin]- 5'-one
[00167](1 -Ethoxycyclopropoxy)trimethylsilane (7.58 g, 43.5 mmol), 1 - (triphenylphosphoranylidene)propan-2-one (18 g, 56.5 mmol) and p-toluenesulfonic acid (0.75 g, 4.35 mmol) are dissolved in 1 ,2-dichlorobenzene (50 ml_), and the mixture is heated to 100 °C for 4 h, then cooled to room temperature and directly purified by flash column chromatography on silica gel (eluent first petroleum ether, then DCM) to provide the intermediate 1 -cyclopropylidenepropan-2-one (2.67 g, 64%).
[00168]NaH (0.7 g, 80% suspension in toluene) is washed twice with benzene and suspended in THF (35 ml_). Dimethylmalonate (1 .74 g, 13.2 mmol) is added, followed by slow addition of 1 -cyclopropylidenepropan-2-one (1 .15 g, 12.0 mmol). The mixture is heated at reflux for 4 h. Then a solution of KOH (1 .54 g, 27.5 mmol) in water (10 ml_) is added, and the mixture is refluxed for 1 h. The mixture is cooled and treated with aqueous HCI to adjust the pH to 1 , then extracted with EtOAc. The organic layer is dried over anhydrous Na2S04, evaporated, and the residue is purified by flash column chromatography on silica gel to provide spiro[2.5]octane-5,7-dione (1 .3 g, 54%) as an oil.
[00169]Spiro[2.5]octane-5,7-dione (390 mg, 2.82 mmol) is dissolved in EtOAc (20 ml_), and DMF-DMA (503 mg, 4.22 mmol) is added. The mixture is refluxed for 12 h, then evaporated to dryness to give an intermediate enamine. 180 mg (0.93 mmol) of this intermediate together with 1 -(4-chlorophenyl)guanidine (157 mg, 0.93 mmol) and TEA (470 mg, 4.66 mg) are dissolved in abs. EtOH (94 ml_). The mixture is heated at reflux for 72 h, then cooled. The formed precipitate is filtered, washed with DEE and dried to provide the title compound (70 mg, 25%).
1H NMR (CDCI3), δΗ, 0.52 (s, 4H), 2.49 (s, 2H), 2.81 (s, 2H), 7.31 (d, 2H), 7.61 (d, 2H), 7.64 (s, 1 H), 8.99 (s, 1 H).
LC/MS (M+H)+ = 300
Example 28 2-((3-Chlorophenyl)amino)-8,8-dimethyl-7,8-dihydroquinazolin-5(6H)-one
[00170]According to General Procedure 2, 2-((dimethylamino)methylene)-4,4- dimethylcyclohexane-1 ,3-dione is reacted with 1 -(3-chlorophenyl)guanidine. The two formed regioisomers are separated by column chromatography to provide the title compound (240 mg, 20%) as a white solid.
1H NMR (De-DMSO), δΗ, 1 .38 (s, 6H), 1 .99 (t, 2H), 2.61 (t, 2H), 7.08 (d, 1 H), 7.36 (t, 1 H), 7.70 (d, 1 H), 8.1 1 (s, 1 H), 8.83 (s, 1 H), 10.37 (br s, 1 H).
LC/MS (M+H)+ = 302, 304
Example 29
8,8-Dimethyl-2-(An-tolylamino)-7,8-dihydroquinazolin-5(6H)-one
[00171 ]According to General Procedure 2, 2-((dimethylamino)methylene)-4,4- dimethylcyclohexane-1 ,3-dione is reacted with 1 -( r?-tolyl)guanidine. The two formed regioisomers are separated by column chromatography to provide the title compound (218 mg, 19%) as a yellowish solid.
1H NMR (De-DMSO), δΗ, 1 .36 (s, 6H), 1 .98 (t, 2H), 2.31 (s, 3H), 2.59 (t, 2H), 7.21 (t, 1 H), 6.87 (d, 1 H), 7.60 (d, 1 H), 7.68 (s, 1 H), 7.79 (s, 1 H), 10.07 (br s, 1 H).
LC/MS (M+H)+ = 282
Example 30
8-Methyl-2-(phenylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00172]According to General Procedure 3a, 8-methyl-2-(methylthio)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one (209 mg, 1 .00 mmol) is reacted with m- chloroperoxybenzoic acid (297 mg, 1 .72 mmol), Λ/,/V-diisopropylethylamine (0.523 mL, 3.00 mmol) and aniline (0.103 g, 1 .1 1 mmol) to provide the title compound (72 mg, 28%) as a white solid.
1H NMR (CDCIs), δΗ, 2.68 (t, 2H), 3.22 (s, 3H), 3.58 (t, 2H), 7.08 (t, 1 H), 7.34 (t, 2H), 7.48 (br s, 1 H), 7.63 (d, 2H), 8.65 (s, 1 H).
LC/MS (M+H)+ = 255 Example 31
2-((3-Fluorophenyl)amino)-8-methyl-7,8-dihy
[00173]According to General Procedure 3a, 8-methyl-2-(methylthio)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one (418 mg, 2.0 mmol) is reacted with m- chloroperoxybenzoic acid (594 mg, 3.4 mmol), /V,/V-diisopropylethylamine (1 .046 ml_, 6.0 mmol) and 3-fluoroaniline (246 mg, 2.2 mmol) to provide the title compound (25 mg, 5%) as a white solid.
1H NMR (CDCIs), δΗ, 2.69 (t, 2H), 3.23 (s, 3H), 3.60 (t, 2H), 6.76 (dd, 1 H), 7.15 (d, 1 H), 7.25 (dd, 1 H), 7.48 (br s, 1 H), 7.73 (d, 1 H), 8.64 (s, 1 H).
LC/MS (M+H)+ = 273
Example 32
2- ((3-Chlorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00174]According to General Procedure 3a, 8-methyl-2-(methylthio)-7,8- dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one (418 mg, 2.0 mmol) is reacted with m- chloroperoxybenzoic acid (594 mg, 3.4 mmol), /V,/V-diisopropylethylamine (1 .046 ml_, 6.0 mmol) and 3-chloroaniline (282 mg, 2.2 mmol) to provide the title compound (57 mg, 10%) as a white solid.
1H NMR (CDCI3), δΗ, 2.69 (t, 2H), 3.23 (s, 3H), 3.60 (t, 2H), 7.04 (d, 1 H), 7.23 (dd, 1 H), 7.32 (d, 1 H), 7.48 (br s, 1 H), 7.95 (s, 1 H), 8.64 (s, 1 H).
LC/MS (M+H)+ = 289, 291
Example 33
3- ((8-Methyl-5-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2- yl)amino)benzonitrile
[00175]According to General Procedure 3b, 2-chloro-8-methyl-7,8-dihydropyrido[2,3- d]pyrimidin-5(6/-/)-one (140 mg, 0.7 mmol) is reacted with 3-aminobenzonitrile (87 mg, 0.8 mmol) to provide the title compound (1 10 mg, 55%) as a yellowish solid. 1H NMR (CDCI3), δΗ, 2.71 (t, 2H), 3.25 (s, 3H), 3.62 (t, 2H), 7.33 (d, 1 H), 7.41 (dd, 1 H), 7.60 (br s, 1 H), 7.62 (d, 1 H), 8.28 (s, 1 H), 8.64 (s, 1 H).
LC/MS (M+H)+ = 280
Example 34
8-Methyl-2-(m-tolylamino)-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)-one
[00176]According to General Procedure 3b, 2-chloro-8-methyl-7,8-dihydropyrido[2,3- d]pyrimidin-5(6/-/)-one (100 mg, 0.51 mmol) is reacted with m-toluidine (54 μΙ_, 0.51 mmol) to provide the title compound (79 mg, 58%) as a light yellow solid.
1H NMR (CDCI3), δΗ, 2.37 (s, 3H), 2.70 (t, 2H), 3.24 (s, 3H), 2.60 (t, 2H), 6.91 (d, 1 H),
7.22-7.26 (m, 1 H), 7.40 (br s, 1 H), 7.46-7.48 (m, 2H), 8.64 (s, 1 H).
LC/MS (M+H)+ = 269
Example 35
2-((3-Methoxyphenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pyrimidin-5(6H)- one
[00177]According to General Procedure 3b, 2-chloro-8-methyl-7,8-dihydropyrido[2,3- d]pyrimidin-5(6/-/)-one (100 mg, 0.51 mmol) is reacted with 3-methoxyaniline (57 μΙ_,
0.51 mmol) to provide the title compound (77 mg, 54%) as a light yellow solid.
1H NMR (CDCI3), δΗ, 2.70 (t, 2H), 3.26 (s, 3H), 2.61 (t, 2H), 3.83 (s, 3H), 6.63-6.66 (m,
1 H), 7.07-7.09 (m, 1 H), 7.22-7.26 (m, 1 H), 7.41 (br s, 1 H), 7.47-7.48 (m, 2H), 8.65 (s,
1 H).
LC/MS (M+H)+ = 285 Example 36
4-((5'-Oxo-6',8'-dihydro-5'H-spiro[cyclopropane-1,7'-quinazolin]-2'- yl)amino)benzonitrile
[00178]Spiro[2.5]octane-5,7-dione (390 mg, 2.82 mmol) is dissolved in EtOAc (20 mL), and DMF-DMA (503 mg, 4.22 mmol) is added. The mixture is refluxed for 12 h, then evaporated to dryness to give an intermediate enamine. 165 mg (1 .1 mmol) of this intermediate together with 1 -(4-cyanophenyl)guanidine (175 mg, 1 .1 mmol) are dissolved in abs. EtOH (8.5 ml_). The mixture is heated at reflux for 30 h, then cooled. The formed precipitate is filtered, washed with DEE and dried to provide the title compound (72 mg, 26%).
1H NMR (CDCIs), δΗ, 0.55 (s, 4H), 2.52 (s, 2H), 2.86 (s, 2H), 7.63 (d, 2H), 7.85 (d, 2H), 7.93 (s, 1 H), 9.04 (s, 1 H).
LC/MS (M+H)+ = 291
Example 37
2-((3-(Methylthio)phenyl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00179]According to General Procedure 2, 2-((dimethylamino)methylene)cyclohexane- 1 ,3-dione is reacted with 1 -(4-(methylthio)phenyl)guanidine to provide the title
compound (260 mg, 76%) as a light yellow solid.
1H NMR (CDCI3), δΗ, 2.1 1 -2.20 (m, 2H), 2.51 (s, 3H), 2.60-2.67 (m, 2H), 2.92-2.98 (m, 2H), 7.02 (d, 1 H), 7.26 (dd, 1 H), 7.37 (d, 1 H), 7.44 (br s, 1 H), 7.73 (s, 1 H), 8.98 (s, 1 H). LC/MS (M+H)+ = 286
Example 38
(rac)-2-((4-(Difluoromethyl)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)- one
[00180]A mixture of 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (531 mg, 3.00 mmol) - which is prepared according to General Procedure 2 from 2- ((dimethylamino)methylene)-5-methylcyclohexane-1 ,3-dione (18.10 g, 0.10 mol) and guanidine hydrochloride (12.35 g, 0.13 mol) in the presence of TEA (50.50 g, 0.50 mol) and EtOH (200 ml_) -, (4-bromophenyl)methanol (617 mg, 3.00 mmol), Pd2dba3 (137 mg, 0.15 mmol), XanthPhos (1 16 mg, 0.20 mmol), Cs2CO3 (1.950 g, 6.00 mmol), and dioxane (10 ml_) is stirred at reflux for 20 h under argon atmosphere, cooled down to room temperature, diluted with DCM, and filtered. The filtrate is concentrated at reduced pressure, and the obtained crude intermediate 2-((4-(hydroxymethyl)phenyl)amino)-7- methyl-7,8-dihydroquinazolin-5(6/-/)-one is diluted with DCM (30 mL). To the obtained solution pyridinium chlorochromate (800 mg, 3.69 mmol) is added, and the resulting mixture is stirred at room temperature for 1 h and filtered. The filtrate is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane, 1 :3) to give 4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzaldehyde (197 mg, 23% for 2 steps) as a beige solid.
[00181 ]To a solution of 4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzaldehyde (190 mg, 0.68 mmol) in DCM (10 mL) DAST (0.13 mL, 1 .01 mmol) is added, and the resulting mixture is stirred at room temperature for 24 h. Then the second portion of DAST (0.13 mL, 1 .01 mmol) is added, and the mixture is stirred at room temperature for 4 days, diluted with DCM (50 mL), and washed with saturated aqueous NaHC03 solution. The organic phase is dried over Na2S04 and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, acetone/DCM, 1 :30) and crystallized from DEE to provide the title compound (43 mg, 21 %) as an orange solid.
1H NMR (CDCIs), δΗ, 1 .09 (d, 3H), 2.30-2.43 (m, 2H), 2.53-2.60 (m, 1 H), 2.68-2.77 (m, 1 H), 2.90-2.97 (m, 1 H), 6.92 (t, 1 H), 7.50 (d, 1 H), 7.92 (d, 1 H), 8.81 (s, 1 H), 10.40 (br s, 1 H).
LC/MS (M+H)+ = 304 Example 39
(rac)-2-((4-(Difluoromethoxy)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)- one
[00182]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(4-(difluoromethoxy)phenyl)guanidine to provide the title compound (210 mg, 66%) as a white solid.
1H NMR (CDCI3), δΗ, 1 .09 (d, 3H), 2.24-2.40 (m, 2H), 2.52-2.60 (m, 1 H), 2.62-2.71 (m, 1 H), 2.86-2.93 (m, 1 H), 7.09 (t, 1 H), 7.13 (d, 1 H), 7.80 (d, 1 H), 8.79 (s, 1 H), 10.21 (br s, 1 H).
LC/MS (M+H)+ = 320 Example 40
(rac)-2-((6-Methoxypyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00183]HgCI2 (3.830 g, 14.10 mmol) is added to a mixture of 6-methoxypyridin-3-amine (1 .364 g, 1 1 .0 mmol), TEA (5.5 mL, 39.6 mmol), and /V',/V"-di-Boc-thiourea (3.630 g, 13.2 mmol) in DCM (45 mL) at 0 °C and vigorous stirring. The reaction mixture is stirred at room temperature for 18 h and filtered through Celite. The filtrate is washed with water. The organic phase is dried over MgS04 and concentrated. The obtained residue is purified by column chromatography (silica gel, EtOAc/DCM/hexane, 1 :5:5), washed with cold hexane and dried to obtain /V',/V"-di-Boc-protected 1 -(6-methoxypyridin-3- yl)guanidine (3.520 g, 87%) as a white solid, which is subsequently deprotected using TFA (12 mL) in DCM (30 mL) for 4 h at room temperature giving the corresponding TFA salt (2.512 g, 66%) as a white solid.
[00184]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(6-methoxypyridin-3-yl)guanidine (TFA salt) to provide the title compound (109 mg, 35%) as a light grey solid.
1H NMR (CDCIs), δΗ, 1 .18 (d, 3H), 2.23-2.44 (m, 2H), 2.58-2.76 (m, 2H), 2.91 -3.00 (m, 1 H), 3.95 (s, 3H), 6.78 (d, 1 H), 7.30 (br s, 1 H), 7.93 (d, 1 H), 8.39 (s, 1 H), 8.92 (s, 1 H). LC/MS (M+H)+ = 285
Example 41
(rac)-7-Methyl-2-((4-methylcyclohexyl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00185]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with frans-1 -(4-methylcyclohexyl)guanidine hydrochloride to provide the title compound (80 mg, 29%) as a white solid.
1H NMR (CDCI3), δΗ, 0.88 (d, 3H), 0.95-1 .10 (m, 2H), 1 .03 (d, 3H), 1 .21 -1 .38 (m, 3H),
1.63-1.74 (m, 2H), 1 .81 -1 .92 (m, 2H), 2.18-2.29 (m, 2H), 2.40-2.60 (m, 2H), 2.68-2.80
(m, 1 H), 3.72-3.87 (m, 1 H), 7.82 (br s, 1 H), 8.55-8.67 (two br s, 1 H).
LC/MS (M+H)+ = 274 Example 42
(rac)-2-((1 -lsopropylpiperidin-4-yl)amino)-7-^
one
[00186]A mixture of 1 -isopropylpiperidin-4-amine (1.420 g, 10.00 mmol), 1 /-/-pyrazole-1 - carboximidamide hydrochloride (1 .480 g, 10.00 mmol), and DIPEA (1 .65 mL, 10 mmol) in DMF (5.5 mL) is stirred at 60 °C for 15 h, cooled down to room temperature, diluted with DEE and stirred at room temperature to complete crystallization. The obtained solid is collected by filtration, washed with DEE (3x20 mL) and air dried to give 1 -(1 - isopropylpiperidin-4-yl)guanidine hydrochloride (1 .910 g, 86%) as a white solid.
[00187]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(1 -isopropylpiperidin-4-yl)guanidine hydrochloride to provide the title compound (94 mg, 14%) as a yellow solid.
1H NMR (CDCIs), δΗ, 1 .04 (d, 6H), 1 .13 (d, 3H), 1 .50-1 .60 (m, 2H), 2.03-2.10 (m, 2H),
2.21 -2.39 (m, 4H), 2.49-2.59 (m, 1 H), 2.61 -2.68 (m, 1 H), 2.70-2.79 (m, 1 H), 2.80-2.90
(m, 3H), 3.92-4.02 (m, 1 H), 5.50 (br s, 1 H), 8.83 (br s, 1 H).
LC/MS (M+H)+ = 303
Example 43
(rac)-2-((1 -Acetyl piperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00188]A mixture of 1 -(4-aminopiperidin-1 -yl)ethanone (1 .42 g, 10.00 mmol), 1 H- pyrazole-1 -carboximidamide hydrochloride (1 .48 g, 10.00 mmol), and DIPEA (1 .65 mL, 10 mmol) in DMF (5.5 mL) is stirred at 60 °C for 15 h, cooled down to room
temperature, diluted with DEE and stirred at room temperature for 10 min. Then the ether solution is decanted and discarded. The obtained slurry is triturated with
DEE/acetonitrile mixture (3:2). The formed solid is collected by filtration, washed with DEE (3x20 mL) and air-dried to give 1 -(1 -acetylpiperidin-4-yl)guanidine hydrochloride (1 .71 g, 77%) as light beige solid. [00189]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(1 -acetylpiperidin-4-yl)guanidine hydrochloride to provide the title compound (65 mg, 21 %) as a white solid.
1H NMR (CDCI3), δΗ, 1 .03 (d, 3H), 1 .30-1 .52 (m, 2H), 1 .76-1 .94 (m, 2H), 2.00 (s, 3H), 2.20-2.30 (m, 2H), 2.44-2.66 (m, 2H), 2.68-2.85 (m, 2H), 3.10-3.20 (m, 1 H), 3.74-3.83 (m, 1 H), 4.03-4.12 (m, 1 H), 4.22-4.29 (m, 1 H), 8.01 (br s, 1 H), 8.62 (two br s, 1 H).
LC/MS (M+H)+ = 303
Example 44
(rac)-2-((5-Chloropyridin-2-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one
[00190]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione (18.10 g, 0.10 mol) is reacted with guanidine
hydrochloride (12.35 g, 130 mmol) in EtOH (200 mL) for 10 h at refluxing. Then the reaction mixture is cooled down to room temperature. The formed solid is collected by filtration, washed with MTBE (2x150 mL) and dried at 60 °C to give the intermediate product 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (10.98 g, 62%) as white solid.
[00191 ]A mixture of 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (490 mg, 2.77 mmol), 5-chloro-2-iodopyridine (862 mg, 3.60 mmol), Cs2CO3 (1.81 g, 5.54 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), and XanthPhos (162 mg, 0.28 mmol) in anhydrous dioxane (8 mL) is stirred at 90 °C for 6 h under argon atmosphere, cooled down to room temperature and filtered. The solid residue is washed with hot MeOH (3x5 mL), and the combined filtrate is concentrated at reduced pressure. The obtained residue is washed with hexane and purified by column chromatography (silica gel, DCM/acetone, 25: 1 ) to provide the title compound (77 mg, 10%) as a pink crystalline solid.
1H NMR (De-DMSO), δΗ, 1 .10 (d, 3H), 2.30-2.45 (m, 2H), 2.60 (d, 1 H), 2.70-2.81 (m, 1 H), 2.92-3.01 (m, 1 H), 7.90 (dd, 1 H), 8.33 (s, 1 H), 8.35 (d, 1 H), 8.85 (s, 1 H), 10.35 (s, 1 H). LC/MS (M+H)+ = 289, 291
Example 45
(rac)-6-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)nicotinonitrile
[00192]2-Amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one is prepared according to the procedure described in Example 44.
[00193]A mixture of 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (170 mg, 1.00 mmol), 6-bromonicotinonitrile (360 mg, 2.00 mmol), CS2CO3 (970 mg, 3.00 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), and XanthPhos (1 10 mg, 0.20 mmol) in dioxane (10 ml_) is stirred under argon atmosphere at 80 °C for 2 h under microwave irradiation in a closed vessel, cooled down to room temperature and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (23 mg, 9%) as a white solid.
1H NMR (CDCI3), δΗ, 1 .21 (d, 3H), 2.31 -2.49 (m, 2H), 2.69-2.82 (m, 2H), 3.06-3.16 (m, 1 H), 7.95 (d, 1 H), 8.65-8.72 (m, 2H), 8.89 (s, 1 H), 9.10 (s, 1 H).
LC/MS (M+H)+ = 280
Example 46
(rac)-7-Methyl-2-((5-methylpyridin-2-yl)amino)-7,8-dihydroquinazolin-5(6H)-one
[00194]2-Amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one is prepared according to the procedure described in Example 44.
[00195]A mixture of 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (340 mg, 2.00 mmol), 2-bromo-5-methylpyridine (680 mg, 4.00 mmol), Cs2C03 (1 .95 g, 6.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), and XanthPhos (220 mg, 0.40 mmol) in dioxane (25 ml_) is stirred under argon atmosphere at 80 °C for 2 h under microwave irradiation in a closed vessel, cooled down to room temperature and concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (76 mg, 14%) as a yellow solid. 1H NMR (CDCI3), δΗ, 1 .19 (d, 3H), 2.27-2.44 (m, 2H), 2.32 (s, 3H), 2.63-2.77 (m, 2H), 3.00-3.1 1 (m, 1 H), 7.53 (m, 1 H), 8.20 (s, 1 H), 8.35 (d, 1 H), 8.47 (s, 1 H), 9.02 (s, 1 H). LC/MS (M+H)+ = 269
Example 47
(rac)-2-Fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzonitrile
[00196]2-Amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one is prepared according to the procedure described in Example 44.
[00197]A mixture of 2-amino-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one (340 mg, 2.00 mmol), 4-bromo-2-fluorobenzonitrile (800 mg, 4.00 mmol), Cs2C03 (1.95 g, 6.00 mmol), Pd(OAc)2 (44 mg, 0.20 mmol), and XanthPhos (220 mg, 0.40 mmol) in dioxane (25 mL) is stirred under argon atmosphere at 80 °C for 2 h under microwave irradiation in a closed vessel, cooled down to room temperature and concentrated at reduced pressure The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (35 mg, 12%) as a white solid.
1H NMR (CDCI3), δΗ, 1 .20 (d, 3H), 2.29-2.48 (m, 2H), 2.66-2.81 (m, 2H), 3.03-3.12 (m, 1 H), 7.32 (d, 1 H), 7.55 (dd, 1 H), 7.66 (s, 1 H), 8.06 (d, 1 H), 9.01 (s, 1 H).
LC/MS (M+H)+ = 297
Example 48
(rac)-7-Methyl-2-((2-methylpyrimidin-5-y
[00198]According to General Procedure 2, 2-((dimethylamino)methylene)-5- methylcyclohexane-1 ,3-dione is reacted with 1 -(2-methylpyrimidin-5-yl)guanidine to provide the title compound (62 mg, 10%) as a white solid.
1H NMR (CDCI3), δΗ, 1 .18 (d, 3H), 2.29-2.42 (m, 2H), 2.62-2.74 (m, 2H), 2.73 (s, 3H), 2.96-3.05 (m, 1 H), 7.34 (s, 1 H), 8.97 (s, 1 H), 9.01 (s, 2H). LC/MS (M+H)+ = 270
Table 1
Figure imgf000072_0001
I
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
EXAMPLES OF REPRESENTATIVE PHARMACEUTICAL COMPOSITIONS
[00199] In combination with commonly used solvents, excipients, auxiliary agents and carriers, the instant compounds 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:
(a) Tablets suitable for oral administration which contain the active ingredient, may be prepared by conventional tabletting techniques.
(b) For suppositories, 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 normal room temperature but which melts at or about body temperature.
(c) For parenteral (including intravenous and subcutaneous) sterile solutions, the active ingredient together with conventional ingredients in usual amounts are employed, such as for example sodium chloride and double-distilled water q.s., according to conventional procedure, such as filtration, aseptic filling into ampoules or IV-drip bottles, and autoclaving for sterility. [00200] Other suitable pharmaceutical compositions will be immediately apparent to one skilled in the art.
FORMULATION EXAMPLES
[00201 ]The following examples are again given by way of illustration only and are not to be construed as limiting.
EXAMPLE 1
Tablet Formulation
A suitable formulation for a tablet containing 10 milligrams of active ingredient is as follows: mg
Active Ingredient 10
Lactose 61
Microcrystalline Cellulose 25
Talcum 2
Magnesium stearate 1
Colloidal silicon dioxide 1
EXAMPLE 2
Tablet Formulation
Another suitable formulation for a tablet containing 100 mg is as follows: mg
Active Ingredient 100
Polyvinylpyrrolidone, crosslinked 10
Potato starch 20
Polyvinylpyrrolidone 19
Magnesium stearate 1
Microcrystalline Cellulose 50 Film coated and colored. The film coating material consists of:
Hypromellose 10
Microcryst. Cellulose 5
Talcum 5
Polyethylene glycol 2
Color pigments 5
EXAMPLE 3
Capsule Formulation
A suitable formulation for a capsule containing 50 milligrams of active ingredient is as follows: mg
Active Ingredient 50
Corn starch 26
Dibasic calcium phosphate 50
Talcum 2
Colloidal silicon dioxide 2
filled in a gelatin capsule.
EXAMPLE 4
Solution for injection
A suitable formulation for an injectable solution is as follows:
Active Ingredient mg 10
Sodium chloride mg q.s.
Water for Injection ml_ add 1 .0
EXAMPLE 5
Liquid oral formulation
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
Active Ingredient
Saccharose 250
Glucose 300
Sorbitol 150
Orange flavor 10
Colorant
Purified water
EXAMPLE 6
Liquid oral formulation
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:
G
Active Ingredient 20.00
Tragacanth 7.00
Glycerol 50.00
Saccharose 400.00
Methylparaben 0.50
Propylparaben 0.05 Black currant-flavor 10.00 Soluble Red color 0.02 Purified water add 1000 ml_
EXAMPLE 7
Liquid oral formulation
Another suitable formulation for 1 liter of a liquid mixture containing 2 milligrams of active ingredient in one milliliter of the mixture is as follows:
G
Active Ingredient 2 Saccharose 400
Bitter orange peel tincture 20 Sweet orange peel tincture 15 Purified water add 1000 mL
EXAMPLE 8
Aerosol formulation
180 g aerosol solution contain:
G
Active Ingredient 10 Oleic acid 5 Ethanol Purified Water Tetrafluoroethane
15 ml of the solution are filled into aluminum aerosol cans, capped with a dosing valve, purged with 3.0 bar.
EXAMPLE 9
TDS formulation
100 g solution contain
G
Active Ingredient 10.0
Ethanol 57.5
Propyleneglycol 7.5
Dimethylsulfoxide 5.0
Hydroxyethylcellulose 0.4
Purified water 19.6
1.8 ml of the solution are placed on a fleece covered by an adhesive backing foil. The system is closed by a protective liner which will be removed before use. EXAMPLE 10
Nanoparticle formulation
10 g of polybutylcyanoacrylate nanoparticles contain:
G
Active Ingredient 1 .00
Poloxamer 0.10
Butylcyanoacrylate 8.75
Mannitol 0.10
Sodium chloride 0.05
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.
EXAMPLE 11
Suspension formulation
1.0 g of the suspension contains the following:
9
Active Ingredient 0.10
Hypromellose 0.01
Purified water Ad 1 .0 g
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.
EXAMPLE 12
Solution for Injection
1.0 ml of solution contain:
9
Active Ingredient 0.05
Mannitol q.s.
DMSO 0.10
Water for injection Ad 1 .0 ml
The active ingredient is dissolved in DMSO by stirring and heating (solution 1 ). The mannitol is dissolved in WFI (solution 2). 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.
PHARMACOLOGY
[00202]The active principles of the present invention, and pharmaceutical compositions containing them and method of treating therewith, are characterized by unique and advantageous properties. The compounds and pharmaceutical compositions thereof exhibit, in standard accepted reliable test procedures, the following valuable properties and characteristics.
METHODS
BINDING ASSAYS FOR THE CHARACTERIZATION OF mGluR5 ANTAGONIST PROPERTIES
PH]MPEP (2-methyl-6-(phenylethynyl)pyridine) binding to transmembrane allosteric modulatory sites of mGluR5 receptors in cortical membranes
Preparation of rat cortical membranes:
[00203]Male Sprague-Dawley rats (200-250 g) are decapitated and their brains are removed rapidly. The cortex is dissected and homogenized in 20 volumes of ice-cold 0.32 M sucrose using a glass-Teflon homogenizer. The homogenate is centrifuged at 1000 x g for 10 minutes. The pellet is discarded and the supernatant centrifuged at 20,000 x g for 20 minutes. The resulting pellet is re-suspended in 20 volumes of distilled water and centrifuged for 20 minutes at 8000 x g. Then the supernatant and the buffy coat are centrifuged at 48,000 x g for 20 minutes in the presence of 50 mM 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 mM Tris-HCI, pH 8.0, the membrane suspension is frozen rapidly at -80°C.
[00204]On the day of assay 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).
[Ή]ΜΡΕΡ Assay
[00205] Incubations are started by adding [3H]-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. Alternatively, assays are performed with [3H]-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 μΜ). 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
[00206]Specific binding is extremely high i.e. normally > 85% and essentially independent of buffer (Tris or HEPES both 50 mM) and pH (6.8-8.9). There is a clear saturable protein dependence and the chosen protein concentration used for subsequent assays (500-700 pg/ml) is within the linear portion of this dependence. Cold MPEP displaces hot ligand with an IC50 of 1 1 .2 ± 0.64 nM. The Kd of [3H]-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 (IC50 of cold MPEP equates to a Kj of 8.2 nM). Bmax is 0.56 pm / mg protein.
FUNCTIONAL ASSAY OF mGluR5 RECEPTORS
Cytosolic Calcium studies with stably transfected cells
[00207]Chinese hamster ovary cells (CHO-K1 cells), stably transfected for inducible expression of a human metabotropic glutamate receptor mGluR5, are seeded into black clear bottom 96 well plates at a density of 35.000 cells per well. The standard growth medium used (Dulbecco's modified Eagle Medium, DMEM plus L-proline) contains the appropriate inducer isopropyl-p-D-thiogalactopyranosid (IPTG) to achieve optimal receptor expression. One day after seeding the growth medium is exchanged for reconstituted Ca-Kit (Molecular Devices, USA) and incubated for one hour. Ca-Kit is reconstituted in an assay buffer containing 20 mM HEPES pH 7.4, glutamic-pyruvate transaminase, pyridoxal phosphate and sodium pyruvate in Hank's balanced salt solution (HBBS). 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). 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 culture
[00208]Primary 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 pm) 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% C02 / 95% air for 7 days with exchanging the medium at day 2 and 6.
[00209]After 7 days in vitro (DIV), cells are shaken overnight at 250 rpm to remove oligodendrocytes and microglia. The next day, astrocytes are rinsed twice with CMF- PBS (calcium- and magnesium-free phosphate buffered saline, Biochrom, Germany), trypsinized and subplated on poly-D-lysine pre-coated 96-well plates (Greiner, Germany) at a density of 40,000 cells/well. 24 h after establishing the secondary culture the 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. Immunocytochemistry
[00210]lmmunostaining is performed to confirm the presence of astrocytic markers such as the glial fibrillary acidic protein (GFAP) as well as to monitor the expression of mGluR5 receptors.
Cytosolic Calcium studies with astrocytes
[0021 1 ]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). Prior to addition of agonist or antagonist the medium is aspirated and cells are loaded for 2 h at RT with 150 μΙ 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. Subsequently, plates are transferred to FLIPR to detect calcium increase with the addition of L-quisqualate (100 ηινι) measured as relative fluorescence units (RFU). If antagonists are tested, these compounds are pre-incubated for 10 minutes at RT before addition of the respective agonist.
[00212]For positive modulators, concentration-response curves for quisqualate are performed in the presence and absence of 10 μΜ 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).
Data analysis
[00213]The fluorescence signal increase after addition of agonist reflects the increase of cytosolic calcium. Inconsistencies in the amount of cells per well are normalised by using the spatial uniformity correction of the FLIPR operating software Screenworks. The mean of replicated temporal data (n=3-5) is calculated and used for graphical representation. For the evaluation of the pharmacology, the calcium changes in response to different concentrations of agonist or antagonist are determined using a maximum minus minimum (MaxMin) calculation. [00214]AII responses (RFU-values) are determined as percentage of control (= maximum response). 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 (IC50) within a range of about 0.5 nM to about 100 μΜ.
[00215]Results for representative compounds of the invention are shown in Table A1 .
Table A1
Human Rat (rpA) mGluR5 IC50 mGluR5 IC50
Compound Chemical Name [μΜ] [μΜ]
A/-phenyl-5,6,7,8-tetrahydroquinazolin-2-
Example 1 amine 3.08 n.d.
A/-(4-Fluorophenyl)-5,6,7,8-
Example 2 tetrahydroquinazolin-2-amine 3.46 n.d.
A/-(3-Chlorophenyl)-5,6,7,8-
Example 3 tetrahydroquinazolin-2-amine 0.452 n.d.
A/-(4-Chlorophenyl)-5,6,7,8-
Example 4 tetrahydroquinazolin-2-amine 4.71 n.d.
2-((3-Fluorophenyl)amino)-7,8-
Example 5 dihydroquinazolin-5(6/-/)-one 2.23 n.d.
2-((3-Chlorophenyl)amino)-7,8-
Example 6 dihydroquinazolin-5(6/-/)-one 0.120 n.d.
2-((4-Chlorophenyl)amino)-7,8-
Example 7 dihydroquinazolin-5(6/-/)-one 0.722 n.d.
3-((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-
Example 8 yl)amino)benzonitrile 0.272 n.d.
4-((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-
Example 9 yl)amino)benzonitrile 1.93 n.d. 2-((3-Methoxyphenyl)amino)-7,8-
Example 10 dihydroquinazolin-5(6/-/)-one 5.8 (est.) n.d.
(rac)-2-((3-Fluorophenyl)amino)-7-methyl- 7,8-dihydroquinazolin-5(6/-/)-one
Example 11 2.44 n.d.
(rac)-2-((3-Chlorophenyl)amino)-7-methyl- 7,8-dihydroquinazolin-5(6/-/)-one
Example 12 6.16 n.d.
(rac)-2-((4-Chlorophenyl)amino)-7-methyl- 7,8-dihydroquinazolin-5(6/-/)-one
Example 13 0.0343 n.d.
(rac)-2-((4-Bromophenyl)amino)-7-methyl- 7,8-dihydroquinazolin-5(6/-/)-one
Example 14 0.0661 n.d.
(rac)-3-((7-Methyl-5-oxo-5,6,7,8- tetrahydroquinazolin-2-yl)amino)benzonitrile
Example 15 3.16 n.d.
(rac)-4-((7-Methyl-5-oxo-5,6,7,8- tetrahydroquinazolin-2-yl)amino)benzonitrile
Example 16 0.0831 0.0318
(rac)-7-Methyl-2-((4-
(trifluoromethoxy)phenyl)amino)-7,8-
Example 17 dihydroquinazolin-5(6H)-one 2.81 n.d.
(rac)-3-Fluoro-4-((7-methyl-5-oxo-5,6,7,8- tetrahydroquinazolin-2-yl)amino)benzonitrile
Example 18 2.74 n.d.
(rac)-7-Methyl-2-(pyridin-3-ylamino)-7,8- dihydroquinazolin-5(6/-/)-one
Example 19 2.04 n.d.
(rac)-2-((6-Chloropyridin-3-yl)amino)-7- methyl-7,8-dihydroquinazolin-5(6/-/)-one
Example 20 0.0432 0.0392
(rac)-7-Methyl-2-((6-methylpyridin-3- yl)amino)-7,8-dihydroquinazolin-5(6/-/)-one
Example 21 0.11 1 0.0831
(rac)-2-((6-Aminopyridin-3-yl)amino)-7- methyl-7,8-dihydroquinazolin-5(6/-/)-one
Example 22 4.40 n.d.
(rac)-2-((4-Chlorophenyl)amino)-7-ethyl-
Example 23 7,8-dihydroquinazolin-5(6/-/)-one 1.21 n.d. 2-((3-Fluorophenyl)amino)-7,7-dimethyl-7,8-
Example 24 dihydroquinazolin-5(6/-/)-one 8.1 (est.) n.d.
2-((4-Chlorophenyl)amino)-7,7-dimethyl-
Example 25 7,8-dihydroquinazolin-5(6/-/)-one 0.245 n.d.
4-((7,7-Dimethyl-5-oxo-5,6,7,8-
Example 26 tetrahydroquinazolin-2-yl)amino)benzonitrile 0.463 n.d.
2'-((4-Chlorophenyl)amino)-6',8'-dihydro-
5'/-/-spiro[cyclopropane-1 ,7'-quinazolin]-5'-
Example 27 one 0.242 n.d.
2-((3-Chlorophenyl)amino)-8,8-dimethyl-
Example 28 7,8-dihydroquinazolin-5(6/-/)-one 1.68 n.d.
8,8-Dimethyl-2-(m-tolylamino)-7,8-
Example 29 dihydroquinazolin-5(6/-/)-one 1.23 n.d.
8-Methyl-2-(phenylamino)-7,8-
Example 30 dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one 2.42 n.d.
2-((3-Fluorophenyl)amino)-8-methyl-7,8-
Example 31 dihydropyrido[2,3-d]pyrimidin-5(6H)-one 0.392 n.d.
2-((3-Chlorophenyl)amino)-8-methyl-7,8-
Example 32 dihydropyrido[2,3-d]pyrimidin-5(6/- )-one 0.0358 0.0435
3-((8-Methyl-5-oxo-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-2-
Example 33 yl)amino)benzonitrile 0.0665 0.0644
8-Methyl-2-(m-tolylamino)-7,8-
Example 34 dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one 0.0704 0.101
2-((3-Methoxyphenyl)amino)-8-methyl-7,8-
Example 35 dihydropyrido[2,3-d]pyrimidin-5(6/-/)-one 1.90 n.d.
4-((5'-Oxo-6',8'-dihydro-5'H- spiro[cyclopropane-1 ,7'-quinazolin]-2'-
Example 36 yl)amino)benzonitrile 0.354 n.d.
2-((3-(Methylthio)phenyl)amino)-7,8-
Example 37 dihydroquinazolin-5(6H)-one 4.29 n.d.
Figure imgf000091_0001
Human mGluR5 values were obtained with CHO-cells stably expressing human mGluR5:
IC50 values below 460 nM were determined in at least independent triplicates. Estimated values (est.) rely on one single point experiment performed in quadruplicate. rpA data were generated with rat primary astrocytes. IC50 values are geometric mean of at least three experiments, each performed in quadruplicate.
[00216]ln conclusion, from the foregoing, it is apparent that the present invention provides novel and valuable applications and uses of the compounds of the present invention, which compounds comprise the active principle according to the present invention, as well as novel pharmaceutical compositions thereof and methods of preparation thereof and of treating therewith.
[00217]The high order of activity of the active agent of the present invention and compositions thereof, as evidenced by the tests reported, is indicative of utility based on its valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies which are responsible for and authorized to pass judgment on such questions.
[00218]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.
[00219]These compounds accordingly find application in the treatment of the disorders of a living animal body, especially a human, as listed earlier in the description.
[00220]These compounds also find application in the treatment of indications in a living animal body, especially a human, wherein a particular condition does not necessarily exist but wherein a particular physiological parameter may be improved through administration of the instant compounds, including cognitive enhancement.
[00221 ] 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.
[00222]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.
[00223] Representative pharmaceutical 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.
* * * * *
[00224]The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description.
[00225]AII patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference.

Claims

1. A compound selected from those of Formula I
Figure imgf000094_0001
wherein
X represents CH2 or C=0; Y represents CR6R7, NR8, 0 or S; R1 represents H, Chalky!, or F; R2 represents H, Ci-6alkyl, or F; or R1 and R2 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-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, d- 6alkylcarbonylamino, and oxo;
R3 represents H, Chalky!, or F;
R4 represents H, Ci-6alkyl, or F; or R3 and R4 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-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, Ci-6alkylamino, di-(Ci-6alkyl)amino, d- 6alkylcarbonylamino, and oxo;
R5 represents a monocyclic moiety selected from aryl, heteroaryl, cycloC3-6alkyl, and heterocyclyl;
R6 represents H, Ci-6alkyl, or F;
R7 represents H, Ci-6alkyl, or F; or R6 and R7 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-6alkyl, Ci-6alkoxy, amino, hydroxy, cyano, acyl, C-i-6alkylamino, di-(C-i-6alkyl)amino, d- 6alkylcarbonylamino, and oxo;
R8 represents H, Ci-6alkyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(C-i-6alkyl)amino, C3-6cycloalkyl, d- 6alkylcarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, C3-6cycloalkylcarbonyl, d- 6alkoxycarbonyl which may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(Ci-6alkyl)amino, aminocarbonyl, /V-C-i- 6alkylaminocarbonyl wherein the alkyl moiety may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, C-i-6alkylamino, and di-(C-i-6alkyl)amino, /V,/V-di-(C-|. 6alkyl)aminocarbonyl, wherein the alkyl moieties may be optionally substituted by one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, Ci-6alkoxy, amino, hydroxy, Ci-6alkylamino, and di-(Ci-6alkyl)amino; and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof; it being understood that the compound of formula (I) may not represent:
2-((2,4-Dichlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((2,4-Dimethylphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((2-Methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((2-Methoxyphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3-(Trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3,4-Dimethylphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3,5-Dimethoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Ethylphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Ethylphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Fluorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Fluorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Methoxyphenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Methoxyphenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-(Cyclopentylamino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-(Cyclopropylamino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-( r?-Tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-(Phenylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-(p-Tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
7,7-Dimethyl-2-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
7,7-Dimethyl-2-((4-phenoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
7,7-Dimethyl-2-( r?-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
7,7-Dimethyl-2-(phenylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-((4-phenoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one, 7-Methyl-2-(p-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
77-Dimethyl-2-(p-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-(phenylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3,5-Dimethylphenyl)amino)- 7,8-dihydroquinazolin-5(6/-/)-one,
7-Methyl-2-( r?-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one, or
7-Methyl-2-((3-(trifluoromethyl)phenyl)amino)-7,8-dihydroquinazoli
2. The compound as claimed in Claim 1 , wherein X represents CH2 and Y represents CR6R7 wherein R6 and R7 each represent H.
3. The compound as claimed in Claim 1 , wherein X represents C=0 and Y represents CR6R7 wherein R6 and R7 each represent H.
4. The compound as claimed in Claim 3, wherein R3 and R4 each represent H or d- 6alkyl or R3 and R4 together with the carbon atom to which they are attached form a saturated 3-7 membered ring.
5. The compound as claimed in Claim 1 , wherein X represents C=0 and Y represents CR6R7 wherein R6 and R7 each represent Ci-6alkyl.
6. The compound as claimed in Claim 1 , wherein X represents C=0 and Y represents NR8 wherein R8 represents Chalky!.
7. The compound as claimed in any of Claims 1 to 6, wherein R5 represents phenyl optionally substituted by one or more substituents selected from halogen, cyano, Ci-6alkoxy, trifluoromethoxy, Ci-6alkyl, Ci-6alkylthio, difluoromethyl, and difluromethoxy; pyridyl optionally substituted by one or more substituents selected from halogen, Ci-6alkyl, amino, Ci-6alkoxy, and cyano; pyrimidinyl optionally substituted by Ci-6alkyl; cyclohexyl optionally substituted by Ci-6alkyl; or piperidinyl optionally substituted by Ci-6alkyl or Ci-6alkylcarbonyl.
8. The compound as claimed in Claim 1 , which is selected from: /V-Phenyl-5,6,7,8-tetrahydroquinazolin-2-amine,
/V-(4-Fluorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,
/V-(3-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,
/V-(4-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-2-amine,
2-((3-Fluorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3-Chlorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
2- ((4-Chlorophenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
3- ((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitnle,
4- ((5-Oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitnle,
2-((3-Methoxyphenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((3-Fluorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((3-Chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((4-Chlorophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((4-Bromophenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-3-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (rac)-4-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)benzonitrile, (rac)-7-Methyl-2-((4-(trifluoromethoxy)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-3-Fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzonitrile,
(rac)-7-Methyl-2-(pyndin-3-ylamino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((6-Chloropyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-7-Methyl-2-((6-methylpyridin-3-yl)am
(rac)-2-((6-Aminopyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6H)-one,
(rac)-2-((4-Chlorophenyl)amino)-7-ethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((3-Fluorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
2-((4-Chlorophenyl)amino)-7,7-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
4-((77-Dimethyl-5-oxo-5,67,8-tetrahydroquinazolin-2-yl)amino)benzonitnle,
2'-((4-Chlorophenyl)amino)-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinazolin]-5'- one,
2-((3-Chlorophenyl)amino)-8,8-dimethyl-7,8-dihydroquinazolin-5(6/-/)-one,
8,8-Dimethyl-2-( r?-tolylamino)-7,8-dihydroquinazolin-5(6/-/)-one, 8-Methyl-2-(phenylamino)-7,8-dihydropyrido[2,3-d]pyr^
2-((3-Fluorophenyl)amino)-8-methyl-7,8-dihydropyrido[2,3-d]pynmidin-5(6H^
2- ((3-Chlorophenyl)amino)-8-methyl-7,8-dihydropyr^
3- ((8-Methyl-5-oxo-5,6,7,8-tetrahydropyndo[2,3-d]pynmidin-2- yl)amino)benzonitrile,
8-Methyl-2-(m-tolylamino)-7,8-dihydropyrido[2,3-d]pynmidin-5(6/-/)-one,
2-((3-Methoxyphenyl)amino)-8-methyl-7,8-dihydropyr^
one,
4- ((5'-Oxo-6',8'-dihydro-5'/-/-spiro[cyclopropane-1 ,7'-quinazolin]-2'- yl)amino)benzonitrile,
2-((3-(Methylthio)phenyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((4-(Difluoromethyl)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-2-((4-(Difluoromethoxy)phenyl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-2-((6-Methoxypyridin-3-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-7-Methyl-2-((4-methylcyclohexyl)amino)-7,8-dihydroquinazolin-5(6/-/)-one, (rac)-2-((1 -lsopropylpiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)- one,
(rac)-2-((1 -Acetylpiperidin-4-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-((5-Chloropyridin-2-yl)amino)-7-methyl-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-6-((7-Methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2-yl)amino)nicotinonitrile,
(rac)-7-Methyl-2-((5-methylpyridin-2-yl)amino)-7,8-dihydroquinazolin-5(6/-/)-one,
(rac)-2-Fluoro-4-((7-methyl-5-oxo-5,6,7,8-tetrahydroquinazolin-2- yl)amino)benzonitrile,
(rac)-7-Methyl-2-((2-methylpyrimidin-5-yl)amino)-7,8-dihydroquinazolin-5(6H)-one, and optical isomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
9. A pharmaceutical composition comprising a compound as claimed in any preceding claim, together with one or more pharmaceutically acceptable excipients.
10. A compound as claimed in any of Claims 1 to 8 for use in the treatment and/or prevention of abnormal glutamate neurotransmission.
1 1 . A compound as claimed in any of Claims 1 to 8, for use in the prevention and/or treatment of a condition or disease selected from Alzheimer's disease, Creutzfeld- Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-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 deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; 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, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumours, diabetes, hyperammonemia and liver failure and sleep disturbances.
Use of a compound as claimed in any of Claims 1 to 8 for the manufacture of a medicament for treating or preventing a condition or disease selected from Alzheimer's disease, Creutzfeld-Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-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 deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa-induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias, dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux-related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive- compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; 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, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumours, diabetes, hyperammonemia and liver failure and sleep disturbances.
A method for treating or preventing a condition or disease associated with abnormal glutamate neurotransmission, or a method for modulating mGluR5 receptors to achieve therapeutic benefit, such method comprising the step of administering to a living animal, including a human, a therapeutically effective amount of a compound of as claimed in any of Claims 1 to 8.
The method as claimed in Claim 13, wherein the condition associated with abnormal glutamate transmission, or wherein modulation of mGluR5 receptors results in therapeutic benefit is selected from: Alzheimer's disease, Creutzfeld- Jakob's syndrome/disease, bovine spongiform encephalopathy (BSE), prion related infections, diseases involving mitochondrial dysfunction, diseases involving β-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 deficits in various forms of dementia, dementia pugilistica, vascular and frontal lobe dementia, cognitive impairment, learning impairment, eye injuries, eye diseases, eye disorders, glaucoma, retinopathy, macular degeneration, head or brain or spinal cord injuries, head or brain or spinal cord trauma, trauma, hypoglycaemia, hypoxia, perinatal hypoxia, ischaemia, ischaemia resulting from cardiac arrest or stroke or bypass operations or transplants, convulsions, epileptic convulsions, epilepsy, temporal lobe epilepsy, myoclonic epilepsy, inner ear insult, inner ear insult in tinnitus, tinnitus, sound- or drug-induced inner ear insult, sound- or drug-induced tinnitus, L-dopa- induced dykinesias, L-dopa-induced dykinesias in Parkinson's disease therapy, dyskinesias, dyskinesia in Huntington's disease, drug induced dyskinesias, neuroleptic-induced dyskinesias, haloperidol-induced dyskinesias,
dopaminomimetic-induced dyskinesias, chorea, Huntington's chorea, athetosis, dystonia, stereotypy, ballism, tardive dyskinesias, tic disorder, torticollis
spasmodicus, blepharospasm, focal and generalized dystonia, nystagmus, hereditary cerebellar ataxias, corticobasal degeneration, tremor, essential tremor, abuse, addiction, nicotine addiction, nicotine abuse, alcohol addiction, alcohol abuse, opiate addiction, opiate abuse, cocaine addiction, cocaine abuse, amphetamine addiction, amphetamine abuse, anxiety disorders, panic disorders, anxiety and panic disorders, social anxiety disorder (SAD), attention deficit hyperactivity disorder (ADHD), attention deficit syndrome (ADS), restless leg syndrome (RLS), hyperactivity in children, autism, dementia, dementia in
Alzheimer's disease, dementia in Korsakoff syndrome, Korsakoff syndrome, vascular dementia, dementia related to HIV infections, HIV-1 encephalopathy, AIDS encephalopathy, AIDS dementia complex, AIDS-related dementia, major depressive disorder, major depression, depression, depression resulting from Borna virus infection, major depression resulting from Borna virus infection, bipolar manic-depressive disorder, drug tolerance, drug tolerance to opioids, movement disorders, fragile-X syndrome, irritable bowel syndrome (IBS), migraine, multiple sclerosis (MS), muscle spasms, pain, chronic pain, acute pain, inflammatory pain, neuropathic pain, diabetic neuropathic pain (DNP), pain related to rheumatic arthritis, allodynia, hyperalgesia, nociceptive pain, cancer pain, posttraumatic stress disorder (PTSD), schizophrenia, positive or cognitive or negative symptoms of schizophrenia, spasticity, Tourette's syndrome, urinary incontinence, vomiting, pruritic conditions, pruritis, sleep disorders, micturition disorders, neuromuscular disorder in the lower urinary tract, gastroesophageal reflux disease (GERD), gastrointestinal dysfunction, lower esophageal sphincter (LES) disease, functional gastrointestinal disorders, dyspepsia, regurgitation, respiratory tract infection, bulimia nervosa, chronic laryngitis, asthma, reflux- related asthma, lung disease, eating disorders, obesity, obesity-related disorders, obesity abuse, food addiction, binge eating disorders, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social phobia, phobic disorders, substance-induced anxiety disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, substance-induced psychotic disorder, or delirium; inhibition of tumour cell growth, migration, invasion, adhesion and toxicity in the peripheral tissues, peripheral nervous system and CNS; 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, lymphoma, myeloma, Hodgkin's disease, Burkitt's lymphoma, leukemia, thymoma, tumours, diabetes, hyperammonemia and liver failure and sleep disturbances.
A pharmaceutical composition comprising a combination of at least one compound as claimed in any of Claims 1 to 8 and at least one NMDA receptor antagonist, together with one or more pharmaceutically acceptable excipients.
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