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WO2014071044A1 - Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a) - Google Patents

Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a) Download PDF

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Publication number
WO2014071044A1
WO2014071044A1 PCT/US2013/067821 US2013067821W WO2014071044A1 WO 2014071044 A1 WO2014071044 A1 WO 2014071044A1 US 2013067821 W US2013067821 W US 2013067821W WO 2014071044 A1 WO2014071044 A1 WO 2014071044A1
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Prior art keywords
methyl
dimethoxyisoquinolin
disorder
quinolin
dimethoxy
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PCT/US2013/067821
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English (en)
Inventor
Bertrand Leblond
Eric Beausoleil
Anne-Sophie Casagrande
Laurent J.R. DESIRE
Matthew P. Pando
John E. Donello
Rong Yang
Thierry Taverne
Cedric Chauvignac
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ExonHit Therapeutics SA
Allergan Inc
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ExonHit Therapeutics SA
Allergan Inc
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Publication of WO2014071044A1 publication Critical patent/WO2014071044A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • Phosphodiesterases are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates.
  • the cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively.
  • cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal
  • cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP.
  • a principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
  • the PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors.
  • PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both.
  • PDE10 is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed human PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. , 274, 18438- 18445, 1999; Loughney, K. et al., Gene, 234, 109-1 17, 1999). The murine homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA, 96, 7071 -7076, 1999) and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J.
  • the mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • PDE10A also is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed only in testis and brain
  • PDE10 protein (Menniti, F.S., Stick, CA Seeger, T.F., and Ryan, A.M., Immunohistochemical localization of PDE10 in the rat brain, William Harvey Research Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001 ).
  • PDE10A was shown to be highly expressed in retinal neurons including photoreceptors.
  • the levels of PDE10A transcript and protein display daily rhythms which could be seen in preparations of the whole retina (Wolloscheck T. et al, Brain Res. , 201 1 ,1376, 42-50. Epub 2010 Dec 29).
  • the tissue distribution of PDE10A indicates that PDE10A inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDE10 enzyme, especially neurons that comprise the basal ganglia, and the PDE10A inhibitors of the present invention would therefore be useful in treating a variety of associated neuropsychiatric conditions involving the basal ganglia such as neurological and psychiatric disorders, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like, and may have the benefit of not possessing unwanted side effects, which are associated with the current therapies on the market.
  • US 2003/0032579 discloses a method for treating certain neurologic and psychiatric disorders with the PDE10A inhibitor papaverine.
  • the method relates to psychotic disorders such as schizophrenia, delusional disorders and drug-induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including
  • Parkinson's disease and Huntington's disease Other indications which may be treated using a PDE10A inhibitor are described in WO 20055120514.
  • PDE inhibitors A variety of therapeutic uses for PDE inhibitors has been reported including obtrusive lung disease, allergies, hypertension, angina, congestive heart failure, depression and erectile dysfunction (WO 2001041807, incorporated herein by reference). Furthermore, publications (WO 2005120514, WO 2005012485, Cantin et al., Bioorg. & Med. Chem. Lett, 17, 2869-2873, 2007) suggest that PDE1 OA inhibitors may be useful for treatment of obesity and non-insulin dependent diabetes.
  • WO2012/1 12946 discloses substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A).
  • WO 201 1 1 10545, WO 201 1051342 disclose respectively imidazo[1 ,2-a]pyrazine derivatives, imidazo[1 ,2- b]pyridazine derivatives PDE10A inhibitors useful for the treatment or prevention of neurological, psychiatric and metabolic disorders in which the PDE10 enzyme is involved.
  • WO 2012007006, WO 2012000519, WO 201 1072695, WO 201 1072697, WO 201 1072694, WO 201 1072696, WO 2010145668 disclose respectively triazolo- and pyrazoloquinazoline derivatives, aryl- and heteroarylamide derivatives, phenylimidazole derivatives comprising an ethynylene linker, heteroaromatic aryl triazole derivatives, heteroaromatic phenylimidazole derivatives, 2-arylimidazole derivatives, novel phenylimidazole derivatives as PDE10A inhibitors reported to be useful for the treatment of psychiatric and neurodegenerative disorders including schizophrenia as well as bipolar disorders, anxiety, stress disorders and Alzheimer's, Parkinson's and Huntington's disease, dementia and attention deficit/hyperactivity disorder.
  • WO 201 1 150156 discloses heteroaryl compounds as PDE10A inhibitors useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and metabolic disorders, including, but not limited to, e.g., neurological disorders, psychosis, schizophrenia, obesity, and diabetes.
  • PDE10A inhibitors useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.
  • WO 201 1053559 or WO 201 1022213 or WO 2010138430 and WO 2010138585 or WO 2010138430 disclose respectively aryl or amino or alkoxy tetrahydro-pyridopyrimidine derivatives or pyrimidinones as PDE10A inhibitors useful for the treatment of neurological and psychiatric disorders including schizophrenia, delusional disorders, drug induced psychosis, anxiety, movement, mood and neurodegenerative disorders.
  • WO 2010138577 discloses radiolabeled pyrimidinone compounds which are useful as radiotracers for quantitative imaging of PDE10A in mammals.
  • Pharmaceuticals SA disclose respectively aryl substituted olefinic compounds, tricyclic compounds, and heteroaryl compounds as PDE10A inhibitors reported to be useful for the treatment of schizophrenia.
  • WO 201 1 163355 & WO 2010090737 disclose respectively fused heterocyclic compounds and pyridazinone compounds as PDE1 OA inhibitors useful for the treatment of schizophrenia.
  • phenoxymethyl heterocyclic compounds as PDE10A inhibitors useful for the treatment of schizophrenia, bipolar disorder, Huntington's disease, obesity and metabolic syndrome, among other disorders.
  • WO 20101 17926 discloses substituted triazolopyridines and analogs thereof as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, psychosis, Alzheimer's disease, bipolar disorder, depression, obesity, diabetes and metabolic syndrome.
  • WO 201 1051324 and WO 2010097367 disclose radiolabeled fluorinated azole PDE10A ligands reported to be useful in positron emission tomography imaging and quantification of PDE10A enzymes.
  • PDE10A inhibitors reported to be useful for the treatment of schizophrenia, cognitive disorders, anxiety, substance abuse and dependence, Parkinson's disease, mood disorders, neurodegenerative disorders, stroke, diabetes and cancer, among other disorders.
  • WO 201 1 143366, WO 201 1 143365, WO 201 1 143495, WO 2010077992, and WO 2010057126 disclose respectively
  • heteroaryloxycarbocyclyl compounds nitrogen heterocyclic compounds, heteroaryloxyheterocyclyl compounds, aminopyridine and carboxypyridine compounds, and pyridine and pyrimidine derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder, obesity, non-insulin dependent diabetes.
  • Therapies GmbH - Wyeth disclose respectively substituted imidazo[1 ,5- a]quinoxalines and triazine derivatives as inhibitors of phosphodiesterases, particularly PDE10A and PDE2A, described as useful for the treatment of pain, cognitive disorders, diabetes, obesity, extrapyramidal disorders, epilepsy and psychiatric disorders such as depression, anxiety, schizophrenia and attention deficit/hyperactivity disorders.
  • JP 201 1201873, WO 201 1 105628, and WO 2010027097 disclose respectively trisubstituted pyrimidine compounds, pyrazolopyrimidine compounds, and tri-substituted pyrimidine compounds and their use as PDE10A inhibitors reported to be useful for the treatment of schizophrenia, anxiety, drug addiction, cognitive and mood disorders.
  • PDE10A inhibitors described as useful for the treatment of neurological and psychiatric disorders such as schizophrenia and post-traumatic stress disorder as well as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, pain, sleep disorders, bipolar disorder and multiple sclerosis.
  • US 2010016303 & WO 2009152825 disclose novel phenylimidazole derivatives as PDE10A enzyme inhibitors to be useful in the treatment of psychiatric and neurological disorders such as schizophrenia, cognition deficits, Parkinson's disease, Alzheimer's disease, Huntington's disease and substance abuse, among others.
  • WO 2010006130 discloses vicinal substituted cyclopropyl compounds as PDE10A inhibitors.
  • WO 2009070583 discloses pyrido(3,2-e)pyrazines as inhibitors of PDE10A that are considered to have potential in the treatment of psychosis, mood diseases, anxiety, neurodegenerative disorders, obesity, diabetes, metabolic diseases, pain.
  • WO 2009068320 & WO 2009070584 disclose aryl and heteroaryl fused imidazo(1 ,5-a)pyrazines as inhibitors of PDE1 OA that are active compounds for treating central nervous system diseases of mammals, including humans.
  • WO 2009152825 & WO 2009036766 disclose respectively novel phenylimidazole derivatives and cyanoisoquinoline derivatives as PDE10A inhibitors.
  • WO 2009143178, WO 2008064342 & US 2008300240 disclose quinoline derivatives as PDE10A inhibitors active in psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders.
  • WO 2009025839 & WO 2009025823 disclose cinnoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder and obsessive-compulsive disorder.
  • WO 2009029214 (Amgen Inc. - Memory Pharmaceuticals Corp.) discloses isoquinolone derivatives as PDE10A inhibitors that are considered to have potential in the treatment of schizophrenia, bipolar disorder, obsessive- compulsive disorder, obesity and diabetes.
  • WO 2008032171 discloses dibenzofuran as inhibitors of PDE4 and PDE1 OA with potential utility in the treatment of asthma, chronic obstructive pulmonary disease, allergic rhinitis, atopic dermatitis, multiple sclerosis, Huntington disease, Alzheimer's disease, Parkinson's disease, schizophrenia and depression, among other disorders.
  • WO 2008020302 discloses heteroaromatic quinoline-based compounds as selective PDE10A inhibitors.
  • WO 2008006372 discloses 6,7-dialkoxyquinazoline and 6,7-dialkoxyisoquinoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment of psychiatric and neurological disorders such as schizophrenia, cognition deficits, Parkinson's disease, Alzheimer's disease, dementia, epilepsy, multiple sclerosis and Huntington's diseases.
  • WO 20080041 17 & WO 2006072828 disclose respectively selective azole compounds and heteroaromatic quinoline compounds as PDE10A inhibitors that are considered to have potential in the treatment of psychotic, anxiety, movement, mood and neurodegenerative disorders and obesity.
  • WO 2007137819 & WO 2007137820 disclose respectively 4-amino-pyrido(3,2-e)pyrazines and pyrido(3,2-e)pyrazines as PDE10A inhibitors. More particularly, the inventions relate to the treatment of neurologic and psychiatric disorders, for example psychosis and disorders comprising cognitive deficits as symptoms.
  • WO 2007103554, WO 2007098214 & WO 2007098169 disclose cinnoline derivatives as PDE10A inhibitors that are considered to have potential in the treatment psychiatric disorders such as schizophrenia, bipolar disorders and obsessive-compulsive disorder.
  • WO 2007096743 & WO 2007085954 disclose respectively substituted quinazolines and aminophthalazine compounds as PDE10A inhibitors that are considered to have potential in the treatment of psychotic disorders, anxiety disorders, movement disorders such as Parkinson and Huntington diseases, mood disorders, obesity and drug addiction.
  • WO 2006089815 & WO 2006075012 disclose novel pyrrolodihydroisoquinolines as PDE10A inhibitors with potential utility in the treatment of neurological and psychiatric disorders, in diabetes therapy and in the regulation of fertility.
  • WO 2006071988 & WO 2006028957 disclose respectively thienopyrimidine derivatives and 4-substituted-4,6- dialkoxy-cinnoline derivatives as PDE1 OA inhibitors that are considered to have potential in the treatment of psychosis, including schizophrenia, bipolar disorder and obsessive-compulsive disorder, Alzheimer's disease and movement disorders such as Parkinson's disease.
  • Other conditions include epilepsy, multiple sclerosis, Huntington's disease, disorders relating to the basal ganglia, diabetes and obesity.
  • WO 2006070284 & WO 200601 1040 disclose respectively pyrrolidyl derivatives of heteroaromatic compounds, and quinazolin-4-yl-piperidine and cinnolin-4-yl derivatives as PDE10A inhibitors that are considered to have potential in the treatment of CNS disorders, including schizophrenia, delusional disorders, drug-induced psychosis, anxiety, mood and movement disorders, neurodegenerative disorders and drug addiction.
  • WO 2005082883 discloses tetrahydroisoquinolinyl derivatives of quinazoline and isoquinoline as PDE10A inhibitors that are claimed for use in the treatment of psychotic disorders, anxiety and movement disorders including Parkinson's disease and Huntington's disease, among other conditions.
  • WO 2006034512 & WO 2006034491 disclose PDE1 OA inhibitors described as useful for the treatment of diabetes and related disorders. Pyrrolodihydroisoquinolines and variants thereof are disclosed as inhibitors of PDE10A in WO 2005003129 and WO 2005002579 (Nycomed GmbH).
  • WO 2004005291 & WO 2004005290 (Bayer Healthcare AG) disclose hetero-cyclically substituted imidazotriazines as PDE10A inhibitors described as useful for the treatment of neurodegenerative conditions, particularly
  • Parkinson's disease and schizophrenia and cancer.
  • WO 2004002484 discloses quinoline derivatives as PDE10A inhibitors with potential in the treatment of Parkinson's disease, dyskinesia, anxiety, stress, mood and cognitive disorders, drug abuse, schizophrenia, cerebrovascular disorders, erectile dysfunction, diabetes, ischemic cardiopathies, renal disorders, peripheral vascular disease, hypertension, urinary incontinence, autoimmune diseases, respiratory disorders, allergies, pain, osteoporosis, cancer.
  • WO 20030141 16 (Bayer Healthcare AG) discloses pyrrolo[2.1 - a]isoquinoline derivatives as PDE10A inhibitors with potential in the treatment of cancer.
  • WO 2003000693 (Bayer Healthcare AG) discloses imidazotriazines for use as PDE1 OA inhibitors considered to have potential in the treatment of Parkinson's disease. All the above-mentioned publications are incorporated herein by reference.
  • the compounds of the invention offer alternatives to current marketed treatments for neurodegenerative and/or psychiatric disorders, which are not efficacious in all patients.
  • the present invention provides compounds that are PDE10A enzyme inhibitors, in particular selective PDE10A enzyme inhibitors.
  • the present invention further provides compounds which have such activity.
  • the invention also provides an effective treatment, in particular long-term treatment, of a human patient, without causing the side effects typically associated with current therapies for neurological and psychiatric disorders. Further aspects of the invention will become apparent upon reading the present specification.
  • the present invention relates to compounds of Formula (I):
  • R 1 is selected from the group of H, optionally substituted (CrC 6 )alkyl, optionally substituted (C3-C6)cycloalkyl and optionally substituted aryl;
  • R 2 is H
  • R 3 and R independently represent a (CrC 3 )alkyl group;
  • R 5 is H;
  • R6 and R 7 are independently H;
  • R' is H or (CrC 6 )alkyl
  • Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl.
  • the present invention relates to compounds of Formula (IA):
  • R 1 is selected from the group of H, (CrC 6 )alkyl, (C 3 -C 6 )cycloalkyl and aryl;
  • R 2 is H
  • R 3 and R independently represent a (CrC 3 )alkyl group
  • R 5 is H
  • R6 and R 7 are independently H;
  • R' is H or (Ci-C 6 )alkyl
  • Ar is selected from the group consisting of: an optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl, wherein two optional substituents at adjacent positions of each of said optionally substituted fused nine- to ten-membered heteroaryl, optionally substituted benzo-fused aryl, optionally substituted benzo-fused heteroaryl, optionally substituted benzo-fused hetorocyclyl, and optionally substituted benzo-fused cycloalkyl can be taken together with the atoms to which they are attached to form an aryl; and pharmaceutically acceptable salts, tautomer forms, solvates and esters thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound of Formula (I) or Formula (IA) as set forth above, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present invention provides a method for inhibiting PDE10A in a mammal, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of Formula (I) or (IA) as set forth above or a pharmaceutically acceptable salt thereof.
  • the present invention provides a method for treating a disease in a mammal modulated by PDE10A, comprising administering to said mammal in need thereof, a therapeutically effective amount of at least one compound of Formula (I) or (IA) as set forth above or a pharmaceutically acceptable salt thereof.
  • alkyl alone or in combination with other groups, denotes linear or branched saturated
  • alkyl groups having from 1 to 6 carbon atoms inclusive are methyl, ethyl, propyl (e.g., n-propyl, iso-propyl), butyl (e.g., ferf-butyl, sec-butyl, n-butyl), pentyl (e.g., neo-pentyl), hexyl (e.g., n-hexyl), 2- methylbutyl, 2-methylpentyl and the other isomeric forms thereof.
  • "Alkyl” may be unsubstituted or optionally substituted by one or more "ring system substituents" as defined herein below.
  • halogen denotes a chlorine, bromine, iodine or fluorine atom.
  • acetylaminoalkyl denotes a CH 3 CONH-alkyl group.
  • alkoxy denotes an alkyl-O- group, with alkyl as defined above.
  • alkoxy groups are methoxy, ethoxy, n-propyloxy, isopropyloxy and sec-butyloxy.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1 -decalinyl, norbornyl, adamantyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), - N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Example of such moiety is pyrrolidone, having the structure :
  • aryl refers to monocyclic or polycyclic (e.g. having 2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example, phenyl, naphthyl, antracenyl, phenanthrenyl and the like.
  • an aryl group has from 5 to 20 carbons, in particular from 6 to 14 carbon atoms.
  • Most preferred aryl groups are mono- or bi-cyclic and comprises from 6 to 14 carbon atoms, such as phenyl, a-naphthyl, ⁇ -naphthyl, antracenyl.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • aryloxy denotes an aryl-O- group, with aryl as defined above.
  • heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen, phosphorus or sulfur, alone or in combination.
  • Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl,
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl,
  • alkoxycarbonyl aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio,
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • optionally substituted means optional substitution (i.e., unsubstituted or substituted) with the specified groups, radicals or moieties.
  • R 3 and R 4 are both methyl.
  • the optionally substituted (Ci- C 6 )alkyl of Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, and isobutyl; the optionally substituted aryl is optionally substituted phenyl; and the optionally substituted (C 3 -C 6 )cycloalkyl is selected from the group consisting of cyclopropyl and cyclohexyl.
  • Ri is selected from the group consisting of ethyl, n-propyl, n-butyl, isobutyl, phenyl, cyclopropyl, and cyclohexyl.
  • R' is selected from the group consisting of H and methyl.
  • Ar is a fused nine to ten- membered heteroaryl and is an optionally substituted pyrazolo-pyridyl (e.g., that is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the pyridyl ring.
  • Ar is an optionally substituted benzo-fused aryl and is napthyl, wherein said naphthyl is
  • Ar is an optionally substituted benzo-fused heteroaryl, which is attached to the carbon bearing the R 6 and R 7 groups either through a carbon atom of the benzene ring or through a carbon atom of the heteroaryl ring, and wherein two optional substituents at adjacent positions of said benzofused heteroaryl can be taken together with the atoms to which they are attached to form an aryl.
  • Ar is an optionally substituted said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl,
  • Ar is an optionally substituted said benzo-fused heteroaryl is selected from the group consisting of quinolinyl, benzofuranyl, benzopyrrolyl, benzothiophenyl, benzimidazolyl,
  • Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl.
  • Ar is a benzo-fused hetorocyclyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused heterocyclyl, wherein said benzo-fused heterocyclyl is selected from the group consisting of indolinyl, chrom including alkylchromanyl and dialkyl chromanyl (e.g., tionally substituted dihydro-2H-
  • benzo[6][1 ,4]oxazinyl e.g., each of which is unsubstituted or substituted at a nitrogen or carbon atom with at least one -(Ci-C6)alkyl.
  • Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl.
  • Ar is a benzo-fused cycloalkyl, which is attached to the carbon bearing the R 6 and R 7 groups through a carbon atom of the benzene ring of said benzo-fused cycloalkyl, wherein said benzo-fused cycloalkyl is fluorenyl.
  • the compounds according to the present invention may be prepared by various methods known to those skilled in the art. General and specific methods for the preparation of compounds of formula (I) and (IA) are described herein below.
  • SSA 48072, SSA 48066, SSA 40084 and SSA 48100 were prepared in three synthetic steps from veratrole: a Friedel and Craft acylation of veratrole in anhydrous CH2CI2 with the desired commercially available acid chloride in presence of aluminium trichloride followed by an amination of the obtained ketone with aminoacetaldehyde diethyl acetal, preferentially at reflux in toluene (150°C for 4 h), using a Dean Stark apparatus and finally the reduction of the obtained iminoacetal using sodium borohydride in ethanol at reflux (100°C) (Reaction scheme 1 ).
  • Reaction Scheme 1 Synthetic routes used for the preparation of intermediary compounds TTA 24128B, SSA 39098, SSA 39102, SSA 48060, SSA 48072, SSA 48066, SSA 40084, SSA 48100, TTA 46082B, LPO 22102, ECO 33100, ECO 33118, ECO 33124, ECO 33138, TTA 24150B, TTA 24156B and ANP 31060A.
  • TTA 46082B was prepared in three synthetic steps from 1 -(3,4- dimethoxyphenyl)-2-hydroxyethanone (CAS#37803-48-8): a methylation of 1 - (3,4-dimethoxyphenyl)-2-hydroxyethanone in anhydrous CH 2 CI 2 in presence of silver (I) oxide and iodomethane at RT for 48 h gave 2-methoxy-1 -(3,4- dimethoxyphenyl)ethanone ECO 59016.
  • the intermediates LPO 22102, ECO 33100, ECO 33118, ECO 33124, ECO 33138, TTA 24150B and TTA 24156B were prepared in two synthetic steps by amination of the corresponding commercially available aldehydes with aminoacetaldehyde diethyl acetal, preferentially under reflux in toluene at 1 10°C for 4 hours using a Dean Stark apparatus, followed by a subsequent reduction of the obtained iminoacetals using sodium borohydride in refluxing ethanol (78°C) (reaction scheme 1 ).
  • the intermediary compound ANP 31060A was prepared in two steps by amination of (3,4-dimethoxyphenyl)methanamine with 1 ,1 -dimethoxypropan-2-one, preferentially in refluxing toluene (1 10°C for 4 h) and using a Dean Stark apparatus, followed by a subsequent reduction of the obtained (£)-1 -(3,4-dimethoxyphenyl)-A/-(1 ,1 -dimethoxypropan-2- ylidene)methanamine using sodium borohydride in refluxing ethanol (78°C) (reaction scheme 1 ).
  • the aldehydes LPO 43162A and ANP 49046 were prepared following the procedure described by Sing, Mrityunjay et al. , Tetrahedron letters, 48(34), 5987-90, 2007 and the aldehyde LPO 43136A from the procedure described by Kalluraya, Balakhrishna et al. , Indian Journal of Chemistry, 42B(1 ), 21 1 -214, 2003.
  • the 7-methoxy- and 7-methyl-quinoline-3-carbaldehydes were prepared following the procedure described by Tom, Norma J. et al., Synthesis, (9), 1351 -1355, 2001 .
  • the masked aldehyde 3-(1 ,3-dioxolan-2-yl)-7-methylquinoline SSA 48104 was prepared in two steps from 2-chloro-7-methylquinoline-3- carbaldehyde by treatment with ethane-1 ,2-diol in presence of p- toluenesulfonic acid (PTSA) in toluene followed by a reduction of the chlorine atom of the obtained 2-chloro-3-(1 ,3-dioxolan-2-yl)-7-methylquinoline SSA 48098 by hydrogenation catalyzed by Pd/C 10% in presence of K 2 C0 3 as base and MeOH as solvent.
  • PTSA p- toluenesulfonic acid
  • the masked aldehyde 3-(1 ,3-dioxolan-2-yl)-quinolin-6-ol LPO 55016 was obtained via a similar method as for SSA 48104 from 2-chloro-6- hydroxyquinoline-3-carbaldehyde LPO 50188A.
  • LPO 50188A itself was prepared by treatment of 2-chloro-6-methoxyquinoline-3-carbaldehyde by boron tribromide (BBr 3 ) in dichloromethane.
  • quinolin-6-ol LPO 55016 was O-alkylated by treatment with ethyl 2-bromoacetate and cesium carbonate as a base in acetone for 2 hours at 85°C to yield ethyl 2-((3-(1 ,3-dioxolan-2- yl)quinolin-6-yl)oxy)acetate LPO 55070A (reaction scheme 2).
  • Reaction Scheme 2 Preparation of non-commercially available aldehydes The masked aldehyde 3-(1 ,3-dioxolan-2-yl)-8-(trifluoromethyl)quinolin-5- ol LPO 50180C was prepared by radical trifluoromethylation of dioxolane TTA 46034 using a methodology developed by Langlois B. et al., Tetrahedron Lett., (32), 51 , 7525-7528, 1991 and modified by Baran P. et al., PNAS, 108, 35, 1441 1 -14415, 201 1 (reaction scheme 2).
  • the masked aldehyde 3-(dimethoxymethyl)-5-(trifluoromethyl)quinolin-6- ol ECO 55152 was prepared by radical trifluoromethylation via photoredox catalysis of dimethylacetal ECO 55108C using a methodology developed by MacMillan D. et ai, Nature, 480, 224-228, 201 1 (reaction scheme 2).
  • the 4-chloro-1 -ethyl-1 H-pyrazolo[3,4-6]pyridine-5-carbaldehyde SAO 33058 was obtained in two steps from ethyl 4-chloro-1 -ethyl-1 /-/-pyrazolo[3, 4- 0]pyridine-5-carboxylate (described by Hamblin, J. Nicole et al., Bioorg. Med. Chem. Lett., 18(14), 4237-41 , 2008).
  • Reduction of 4-chloro-1 -ethyl-1 /-/-pyrazolo[3,4-0]pyridine-5-carboxylate by LiBH 4 in THF provided the alcohol SAO 33034 that was oxidized in aldehyde SAO 33058 using Dess-Martin periodinane reagent in dichloromethane for 1 hour at 4°C then overnight at RT (reaction scheme 2).
  • the products obtained by following the reaction scheme 1 may be further modified, for example, by manipulation of substituents.
  • the compounds 42 and 75 were prepared respectively from the compounds 41 and ANP 49102A by reduction of the ester function using sodium borohydride in a mixture of ferf-butanol/MeOH at 140°C for 2 hours in an ace pressure tube (reaction Scheme 3).
  • the compounds 55, 56 and 76 were prepared from the free base of compound 49.
  • the compound 55 can be hydrogenated in presence of hydrogen and 10% Pd/C as catalyst in methanol at room temperature to yield compound LPO 43180.
  • the compound LPO 43180 was acetylated for 2 hours at 4°C in tetrahydrofuran with acetic anhydride, in presence of triethylamine as base, to give the free base of compound 56 that was subsequently transformed in its dihydrochloride salt by treatment with a 1 .75 N HCI solution in methanol at room temperature (reaction scheme 4).
  • the treatment of compound 49 with phosphorus oxychloride for 2 hours at 100°C gave the aryl chloro derivative LPO 50012.
  • the compound LPO 50016 was prepared by a Buchwald-Hartwig reaction of the compound LPO 50012 preferentially at 100°C for 8 hours in toluene with ethylenediamine, in presence of palladium(ll) acetate as catalyst, 2-(di-ferf-butylphosphino)biphenyl (JohnPhos) as ligand, and potassium ferf-butoxide as base.
  • Reaction Scheme 5 Preparation of compounds 77, 113 and 129.
  • the compounds 77 and 113 were preferentially respectively prepared from the aryl chloro derivative LPO 50012 and LPO50042C by a Buchwald- Hartwig reaction, at 170°C for 5 hours (77) or 100°C for 6 hours (113) in toluene with a 2 N solution of diethylamine in tetrahydrofuran, in presence of palladium(ll) acetate as catalyst, JohnPhos as ligand, and potassium tert- butoxide as base.
  • the obtained free bases were transformed into their corresponding dihydrochloride salt 77 and 113 by treatment with a 1 .76 N hydrochloride solution in methanol for 15 minutes at 4°C (reaction scheme 5).
  • the compound 129 was preferentially obtained from LPO 50012 by a Buchwald-Hartwig reaction at 145°C for 25 min in toluene with a 2 N solution of diethylamine in tetrahydrofuran, in presence of palladium(ll) acetate as catalyst, 2-(di-ferf-butylphosphinobiphenyl) as ligand, and potassium ferf-butoxide as base.
  • the A/-oxide derivative 35 was prepared from the free base of compound 10 by oxidation using preferentially mefa-chloroperbenzoic acid in dichloromethane for 24 hours (reaction scheme 6).
  • R ethyl: 83
  • R ethyl: RBO 51116 80%
  • R ethyl: RBO 51118B 80%
  • R n-propyl: 45
  • R n-propyl: LPO 55036C 72%
  • R n-propyl: LPO 55056D 65%
  • R MeOCH,: 163
  • R MeOCH,: 167 20%
  • Reaction Scheme 7 Preparation of compounds 84, 85, 119, 152, 156, 157, 159 and 167.
  • the sulfamide derivatives 159, 156, 84, 85 and 1 19 were prepared respectively from phenols 7, 131 , 83, 45 and 163 in three steps (reaction scheme 7).
  • the phenols 7, 131 , 83, 45 and 163 were treated in DMF with N- phenyl-bis(trifluoromethanesulfonimide) in presence of triethylamine at RT or 40°C to give, respectively, the triflates ANP 57032A, ANP 53184A, RBO 51 116, LPO 55036C and ECO 59060.
  • Reaction Scheme 8 Preparation of compounds 86-89 and 93.
  • the compounds 86-89 and 93 were prepared from aniline RBO 51118B as described in reaction scheme 8.
  • Reaction Scheme 9 Preparation of compounds 90-92 and 94.
  • the amide 91 was prepared by basic hydrolysis of the nitrile 90 that was prepared from inflate RBO 51116 as described in reaction scheme 9.
  • the compounds 92 and 94 were also prepared from triflate RBO 511 16 as described in reaction scheme 9.
  • Reaction Scheme 10 Preparation of compounds 96 to 101 .
  • the compounds 96 to 101 were prepared as described in reaction scheme 10.
  • LPO 55056D 158 160 i) Acetoxyacetylchloride, pyridine, dry THF, 0°C to RT, 1 h, 95%. ii) 2 M LiOH in THF, 70°C, THF, 2 h, 73%.
  • Reaction Scheme 11 Preparation of compounds 158 and 160.
  • the compounds 158 and 160 were prepared as described in reaction scheme 1 1 .
  • Reaction Scheme 12 Preparation of compounds 106, 107, 114, 115, 142, 145, 146, 149, 151 , 153 and 154.
  • the compounds 111 , 112 and 170 were prepared as described in reaction Scheme 13.
  • the compounds 147 and 148 were prepared as described in reaction scheme 14.
  • Reaction Scheme 15 Preparation of compounds 41 , 42, 46, 108, 116, 118, 120, 122, 128, 130, 135, 139,148, 164, 165 and 166.
  • the compounds 41 , 42, 46, 108, 116, 118, 120, 122, 128, 130, 135, 139,148, 164, 165 and 166 were prepared as described in reaction scheme 15.
  • Reaction Scheme 16 Preparation of compounds 125 and 126.
  • the compounds 165 and 166 were prepared as described in reaction scheme 16.
  • Reaction Scheme 17 Preparation of compounds 45, 134, 136 and 140.
  • Reaction Scheme 18 Preparation of compounds 138, 141 and 144.
  • the compounds 138, 141 and 144 were prepared as described in reaction schem
  • Reaction Scheme 19 Preparation of compound 171 .
  • the compound 171 was prepared as described in reaction scheme 19.
  • Another object of the present invention is the intermediate compounds used for the preparation of compounds of formula (I) or (IA).
  • the present invention relates to the intermediate compounds herein below mentioned in the examples.
  • the compounds according to the invention can be in the form of salts, particularly acid or base salts, preferably compatible with pharmaceutical use (i.e. pharmaceutically acceptable salts of the compounds of the invention). It will be appreciated by those skilled in the art that non-pharmaceutically acceptable salts of compounds of formula (I) or (IA) are also part of the present invention, since such non-pharmaceutically acceptable salts can be useful as intermediates in the preparation of pharmaceutically acceptable salts.
  • Salts of compounds of the invention include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium, and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include
  • hydrochloric hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p- toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates,
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium,
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
  • the pharmaceutically acceptable salts can in particular be prepared by reacting the compound of formula (I) or (IA) with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, fonic acid, acetic acid, citric acid, maleic acid, salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane, etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p- toluenesulphonic acid, methanesulfonic acid, fonic acid, acetic
  • Compounds of Formula (I) or (IA) may have optical centers and therefore may occur in different enantiomeric and diastereomeric
  • the present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of Formula (I) or (IA), as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
  • the compounds according to the present invention may be prepared by various methods known to those skilled in the art. General and specific methods for the preparation of compounds of formula (I) or (IA) are described herein below.
  • the compounds of the invention can be administered alone, but are generally administered with a pharmaceutical carrier, with respect to standard pharmaceutical practice (such as described in Remington's Pharmaceutical Sciences, Mack Publishing), in either single or multiple doses.
  • a pharmaceutical carrier with respect to standard pharmaceutical practice (such as described in Remington's Pharmaceutical Sciences, Mack Publishing), in either single or multiple doses.
  • the invention thus also includes a pharmaceutical composition comprising, in a
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed thereby can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can optionally contain additional ingredients such as flavorings, binders, excipients and the like.
  • the compound of the invention may be formulated for oral, ocular, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous), transdermal (e.g. patch) or rectal administration, or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions of the invention can be formulated either as solid or liquid compositions.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g.
  • pregelatinized maize starch polyvinylpyrrolidone or hydroxypropyl
  • methylcellulose methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycolate
  • wetting agents e.g. sodium lauryl sulphate
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g.
  • sorbitol syrup methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g. methyl or propyl p-hydroxybenzoates or sorbic acid
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating 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.
  • a product solution When a product solution is required, it can be made by dissolving the isolated inclusion complex in water (or other aqueous medium) in an amount sufficient to generate a solution of the required strength for oral or parenteral administration to patients.
  • the compounds may be formulated for fast dispersing dosage forms, which are designed to release the active ingredient in the oral cavity. These have often been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the dosages and dosage regimen in which the compounds of formula (I) are administered will vary according to the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired.
  • the compounds according to the invention can be used enterally or parenterally. Orally, the compounds according to the invention are suitably administered in the amount from about 0.1 mg per day to 1 ,000 mg per day. For parenteral, sublingual, intranasal, or intrathecal administration, the compounds according to the invention are suitably used in the amount from about 0.5 to about 100 mg/day; for depo administration and implants from about 0.5 mg/day to about 50 mg/day; for topical administration from about 0.5 mg/day to about 200 mg/day; for rectal administration from about 0.5 mg to about 500 mg. In a preferred aspect, the therapeutically effective amounts for oral administration is from about 1 mg/day to about 100 mg/day; and for parenteral administration from about 5 to about 50 mg daily. In a more preferred aspect, the therapeutically effective amounts for oral administration are from about 5 mg/day to about 50 mg/day.
  • the compounds of the present invention can also be administered intraocularly (e.g., intravitreally (e.g., through injection) subconjunctival ⁇ , or injection into subtenon space).
  • intraocularly e.g., intravitreally (e.g., through injection) subconjunctival ⁇ , or injection into subtenon space.
  • the weight of the device i.e., drug plus carrier/vehicle/excipinent
  • the drug load is normally 10-50%.
  • the drug dose range for intravitreal administration is normally about 100-500 ⁇ g.
  • the drug load can be stretched to 2-65%, i.e., a drug dose range of 20-650 ⁇ g can be used.
  • the device weight may be 1 .5 mg, and for this a drug dose range of 20-975 ⁇ g can be used.
  • Another way of intravitreal delivery is by injecting drug suspension formulation. For this, the dose range is 10-600 ug.
  • An intraocular implant comprising a therapeutically effective amount of a compound of Formula (I) or (IA) (the therapeutic component; the active pharmaceutical ingredient (API)), and a drug release sustaining polymer component associated with the therapeutic compound can also be
  • an "intraocular implant” refers to a device or element that is structured, sized, or otherwise configured to be place in an eye. Intraocular implants are generally biocompatible with physiological conditions of an eye and do not cause adverse side effects.
  • Intraocular implants may be place in an eye without disrupting vision of the eye.
  • the implant may be solid, semisolid, or viscoelastic.
  • the drug release sustaining component is associated with the therapeutic component to sustain release of an amount of the therapeutic component into an eye in which the implant is placed.
  • the therapeutic component may be released from the implant by diffusion, erosion, dissolution or osmosis.
  • the drug release sustaining component may comprise one or more biodegradable polymers or one or more non-biodegradable polymers.
  • biodegradable polymers of the present implants may include poly-lactide-co-glycolide (PLGA and PLA), polyesters, poly (ortho ester), poly(phosphazine), polyphosphate ester), polycaprolactone, natural polymers such as gelatin or collagen, or polymeric blends.
  • the amount of the therapeutic component is released into the eye for a period of time greater than about one week after the implant is placed in the eye and is effective in reducing or treating an ocular condition.
  • the intraocular implant comprises a therapeutic component and a biodegradable polymer matrix.
  • the therapeutic component is associated with a biodegradable polymer matrix that degrades at a rate effective to sustain release of an amount of the therapeutic component from the implant effective to treat an ocular condition.
  • the intraocular implant is biodegradable or bioerodible and provides a sustained release of the therapeutic component in an eye for extended periods of time, such as for more than one week, for example for about one month or more and up to 5 about six months or more.
  • the implant may be configured to provide release of the therapeutic component in substantially one direction, or the implant may provide release of the therapeutic component from all surfaces of the implant.
  • the biodegradable polymer matrix of the foregoing implant may be a mixture of biodegradable polymers or the matrix may comprise a single type of biodegradable polymer.
  • the matrix may comprise a polymer selected from the group consisting of polylactides, poly(lactide-co-glycolides), polycaprolactones, and combinations thereof.
  • the intraocular implant comprises the therapeutic component and a polymeric outer layer covering the therapeutic component.
  • the polymeric outer layer includes one or more orifices or openings or holes that are effective to allow a liquid to pass into the implant, and to allow the therapeutic component to pass out of the implant.
  • the therapeutic component is provided in a core or interior portion of the implant, and the polymeric outer layer covers or coats the core.
  • the polymeric outer layer may include one or more non-biodegradable portions.
  • the implant can provide an extended release of the therapeutic component for more than about two months, and for more than about one year, and even for more than about five or about ten years.
  • One example of such a polymeric outer layer covering is disclosed in U.S. Pat. No. 6,331 ,313.
  • the present implant provides a sustained or controlled delivery of the therapeutic component at a maintained level despite the rapid elimination of the therapeutic component from the eye.
  • the present implant is capable of delivering therapeutically effective amounts of the therapeutic component for a period of at least about 30 days to about a year despite the short intraocular half-lives that may be associated with the therapeutic component.
  • Plasma levels of the therapeutic component obtained after implantation may be extremely low, thereby reducing issues or risks of systemic toxicity.
  • the controlled delivery of the therapeutic component from the present implants would permit the therapeutic component to be administered into an eye with reduced toxicity or deterioration of the blood-aqueous and blood-retinal barriers, which may be associated with intraocular injection of liquid formulations containing the therapeutic component.
  • a method of making the present implant involves combining or mixing the therapeutic component with a biodegradable polymer or polymers. The mixture may then be extruded or compressed to form a single composition. The single composition may then be processed to form individual implants suitable for placement in an eye of a patient.
  • Another method of making the present implant involves providing a polymeric coating around a core portion containing the therapeutic component, wherein the polymeric coating has one or more holes.
  • the implant may be placed in an ocular region to treat a variety of ocular conditions, such as treating, preventing, or reducing at least one symptom associated with nonexudative age related macular degeneration (ARMD), exudative age related macular degeneration, choroidal neovascularization, acute macular
  • ARMD nonexudative age related macular degeneration
  • exudative age related macular degeneration choroidal neovascularization
  • the daily dose may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
  • the present invention also relates to a compound of formula (I) or (IA), or a composition comprising a compound of formula (I) or (IA), for use as a medicament.
  • the compounds according to the invention have been found to have pharmacologically important properties which can be used therapeutically.
  • the compounds of the invention can be used alone, in combination with each other or in combination with other active compounds.
  • the compounds of the invention are inhibitors selective for PDE10A.
  • the invention thus also relates to a compound of formula (I) or (IA) or a
  • the present invention also pertains to a pharmaceutical composition for use in the potential treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention relates to a pharmaceutical composition for potentially treating psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula (I) effective in treating said disorder or condition.
  • psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis
  • anxiety disorders such as panic and obsessive-compulsive disorder
  • movement disorders including Parkinson's disease and Huntington's disease
  • the invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease.
  • certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis
  • anxiety disorders such as panic and obsessive-compulsive disorder
  • movement disorders including Parkinson's disease and Huntington's disease.
  • Examples of psychotic disorders that can potentially be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance- induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
  • Examples of movement disorders that can potentially be treated according to the present invention include but are not limited to Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor.
  • Other disorders that can potentially be treated according to the present invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.
  • the invention in another embodiment, relates to a method for potentially treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides a method for potentially treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of an anxiety disorder or condition in a mammal.
  • anxiety disorders that can potentially be treated according to the present invention include, but are not limited to, panic disorder;
  • agoraphobia a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
  • the invention further provides a method of potentially treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating drug addiction.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • the invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also relates to a compound of formula (I) or (IA), for use in the treatment of a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • a "drug addiction”, as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
  • the invention further provides a method of potentially treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder.
  • the invention also provides a method of potentially treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides a method of potentially treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention also relates to a compound of formula (I) or (IA), for use in the potential treatment of a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human.
  • deficiency in attention and/or cognition refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population.
  • Deficiency in attention and/or cognition also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as it occurs in age-related cognitive decline.
  • disorders that comprise as a symptom a deficiency in attention and/or cognition are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention- deficit/hyperactivity disorder; and age-related cognitive decline.
  • dementia for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia
  • delirium amnestic disorder
  • post-traumatic stress disorder mental retardation
  • a learning disorder for example reading disorder, mathematics disorder, or a disorder of written expression
  • attention- deficit/hyperactivity disorder and age-related cognitive decline
  • the invention also provides a method of potentially treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or episode.
  • the invention also provides a method of potentially treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also relates to a compound of formula (I) or (IA), for use in the treatment of a mood disorder or mood episode in a mammal, including a human
  • mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar II disorder, and cyclothymic disorder.
  • the invention further provides a method of potentially treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention further provides a method of potentially treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides to a compound of formula (I) or (IA), for use in the treatment of a neurodegenerative disorder or condition in a mammal, including a human.
  • a “neurodegenerative disorder or condition” refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • neurotrophic agent refers to a substance or agent that has some or all of these properties.
  • neurodegenerative disorders and conditions that can potentially be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma;
  • neurodegeneration associated with stroke neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
  • the neurodegenerative disorder is Parkinson's disease or Alzheimer's disease.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
  • the neurodegenerative disorder or condition is Huntington's disease.
  • the invention also provides a pharmaceutical composition for potentially treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, comprising an amount of a compound of formula (I) or (IA) effective in treating said disorder or condition.
  • the invention also provides a method of potentially treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders, which method comprises administering an amount of a compound of formula (I) or (IA) effective in treating said disorder.
  • the invention also provides to a compound of formula (I) or (IA), for use in the potential treatment of a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders.
  • a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders.
  • the invention also provides a method of potentially treating disorders selected from the group consisting of: dementia, Alzheimer's disease, multi- infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age- related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive
  • Huntington's disease Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure;
  • neurodegeneration associated with neurotoxin poisoning multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type;
  • schizophreniform disorder schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, which method comprises administering an amount of a compound of Formula (I) or (IA) effective in treating said disorders.
  • the invention thus also provides a compound of formula (I) or (IA), for use in the treatment of the diseases mentioned in the previous sentence.
  • the invention also provides a method for the potential treatment of psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention also provides a method for the potential treatment of diseases of the retina, which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • diseases of the retina the applicants mean any condition of the retina which impairs the normal functioning of the retina, its surrounding tissues, or the eye. These include macular degeneration, myopic retinal degeneration, diabetic
  • retinopathy choroidal neovascularization
  • macular edema also referred to as cystoid macular edema and macular swelling
  • epiretinal membrane macular pucker
  • macular hole retinitis (such as retinitis pigmentosa)
  • macular dystrophies such as Stargardt's juvenile macular degeneration, Best's vitelliform dystrophy, cone dystrophies, and pattern dystrophy of the retinal pigmented epithelium
  • retinal detachment retinal trauma, retinal tumors and retinal diseases associated with them, congenital hypertrophy of the retinal pigmented epithelium, acute posterior multifocal placoid pigment epitheliopathy, acute retinal pigment epithelitis, and uveitis (including crizis, pars planitis, choroiditis, retinitis, and chorioretinitis).
  • the invention relates to a compound of formula (I) or a composition comprising a compound of formula (I) or (IA), for use in a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders, schizophrenia, positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors, hemat
  • ARMD retinitis pigmentosa
  • choroidal ARMD dry ARMD
  • retinitis pigmentosa retinitis pigmentosa
  • neovascularization vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors.
  • the invention further relates to a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders,
  • schizophrenia positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors,
  • ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular Degeneration (ARMD), dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors, which method comprises administering an amount of a compound of formula (I) or (IA) effective in inhibiting PDE10A.
  • the invention further relates to a method for the potential treatment of type I or type II diabetes, impaired glucose tolerance, impaired fasting glucose, metabolic syndrome, metabolism related disorders including excess of body weight or excess of body fat in obese patients, psychotic disorders,
  • schizophrenia positive, negative and/or cognitive symptoms associated with schizophrenia, delusional disorder, substance-induced psychotic disorder, anxiety disorders, panic disorder, obsessive/compulsive disorders, acute stress disorder, generalized anxiety disorder, drug addictions, movement disorders, Parkinson's disease, restless leg syndrome, cognition deficiency disorders, Alzheimer's disease, multi-infarct dementia, mood disorders, depression, bipolar disorders, neuropsychiatric conditions, psychosis, attention- deficit/hyperactivity disorder, attention disorders, diabetes and related disorders, type 2 diabetes mellitus, neurodegenerative disorders, Huntington's disease, multiple sclerosis, stroke, spinal cord injury, solid tumors,
  • ophthalmic diseases such as macular degeneration/retinal degeneration, including wet Age Related Macular Degeneration, dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascularization, vascular diseases/exudative diseases, retinopathy, including diabetic retinopathy, uveitis/retinitis/choroiditis, Stargard's disease, macular edema, retinal detachment, trauma, systemic disorders with associated retinal dystrophies, cone dystrophies, dystrophy of the retinal pigmented epithelium, myopic retinal degeneration, acute retinal pigment epithelitis, retinal tumors, retinal disease associated with tumors, which method comprises administering an amount of a compound of Formula (I) or (IA) effective in treating said disorders.
  • macular degeneration/retinal degeneration including wet Age Related Macular Degeneration, dry ARMD, geographic atrophy, retinitis pigmentosa, choroidal neovascular
  • treating refers to reversing, alleviating, or inhibiting the progress of the disorder to which such term applies, or one or more symptoms of the disorder.
  • the term also encompasses, depending on the condition of the patient, preventing the disorder, including preventing onset of the disorder or of any symptoms associated therewith, as well as reducing the severity of the disorder or any of its symptoms prior to onset.
  • Treating refers also to preventing a recurrence of a disorder.
  • Example 1 preparation of compounds according to the invention
  • the compounds were analyzed by reverse phase high performance liquid chromatography (HPLC) using a Waters Autopurification System equipped with a Waters 2525 Pump, a Waters 2696 photodiode array detector.
  • HPLC reverse phase high performance liquid chromatography
  • the Method A (10 min) was performed with an XTerraTM column (5 ⁇ , C18, 4.5 x 50 mm, Model # 186000482) or an XBridgeTM column (5 ⁇ , C18, 4.5 50 mm, Model # 1860031 13).
  • Solvent A was H 2 0 with 0.05% TFA and solvent B was CH 3 CN with 0.05% TFA.
  • the 10 min gradient run was realized using 1 .0 ml.
  • the reaction mixture was stirred at 0°C for 1 h (see conditions in table 1 a) and was poured into a 3 N HCI solution (typically 15 mL) and CH2CI2 (typically 180 mL) was added. After extraction, the combined separated organic layers were washed with brine (typically 50 mL), dried over MgS0 4 , filtered and evaporated to give after further drying the desired acylated compound. When necessary, the acylated compound was purified by column chromatography (S1O2, see conditions in table 1 a).
  • the aromatic aldehyde or ketone and aminoacetaldehyde diethyl acetal were placed in a 500 mL round-bottom flask and toluene was added (see conditions in table 1 b). The mixture was heated under reflux in a Dean-Stark apparatus (around 4 h, see conditions in table 1 b) until complete separation of water was achieved. Toluene was then evaporated to give after drying the desired iminoacetal in almost quantitative yield.
  • the iminoacetal ANP 31058A was prepared from 3,4-dimethoxybenzylamine (23.2 mmol) and pyruvic aldehyde dimethyl acetal (35.5 mmol) using the same general procedure (see conditions in table 1 b).
  • the desired iminoacetal was dissolved in EtOH and NaBH 4 was added portion wise over a 0.5 h period and the reaction mixture was refluxed for 1 h (see conditions in table 2).
  • the reaction mixture was concentrated under reduced pressure and the obtained residue was poured into water (typically 250 mL).
  • This mixture was extracted using CH2CI2 (typically 3x100 mL) and the combined organic layers were washed with H 2 0 (typically 2x150 mL), brine (typically 50 mL), dried over Mg 2 S0 4 and evaporated to give the desired aminoacetal.
  • Procedures F for preparation of compounds 108, 1 18, 122, 145, 146, 150 and 160 a) Preparation of compounds 108, 118, 122, 145, 146 and 160 (saponification of esters using of KOH, NaOH or LiOH)
  • the derivative LPO 55070A (120 mg, 0.28 mmol) was dissolved in a 37% aqueous HCI solution (1 mL) and AcOH (1 mL). The reaction mixture was stirred at 1 10°C for 4 h. After cooling, the solvents were evaporated and the residue was poured in n-BuOH (60 mL) and a 1 M K 2 C0 3 solution (30 mL) was added. The separated organic layer was washed with brine (20 mL), dried over MgS0 4 , filtered and evaporated. The crude product was purified by column chromatography (Si0 2 , see exact conditions in table 7) to give after evaporation and further drying to the vacuum pump the acid 150.
  • the 2-hydroxyquinoline derivative (free base of 49 or SSA 48042) was stirred in phosphoryl trichloride in an ace pressure tube (Aldrich) at 100-1 10°C for 2 h (see conditions in table 5). After cooling, the mixture was pourred in ice (10 g) and a 1 M aqueous K 2 C0 3 solution (5 mL) and EtOAc (150 mL) were added. The separated organic layer was washed with brine (20 mL), dried over MgS0 4 , filtered and evaporated.
  • the obtained ferf-butyl carbamate was then deprotected by stirring with a solution of TFA (1 mL) in CH 2 CI 2 (10 mL) for 1 h at RT. After concentration to dryness, the residue was taken back in EtOAc (150 mL) and a 1 M K 2 CO 3 solution (50 mL) was added. The separated organic layer was washed with H 2 0 (3x20 mL), brine (3x20 mL), dried over Na 2 S0 4 , filtered and evaporated to provide a residue. This residue was purified by flash chromatography (Si0 2 , see exact conditions in table 7) to give, after evaporation after further drying under vacuum, the aminoquinoline 92, 96 or 97.
  • 2-(1 ,3-Dioxolan-2-yl)quinolin-8-ol TTA 46034 500 mg, 2.30 mmol
  • ierf-butyl hydroperoxide 70% solution in water, 1 .5 mL, 16.1 1 mmol
  • sodium trifluoromethanesulfinate (1 .8 g, 1 1 .51 mmol) were dissolved in CH 3 CN (5 mL) and H 2 0 (2.5 mL) in a round bottom flask.
  • Phthalamide derivative LPO 50192C (58 mg, 0.103 mmol) was dissolved in EtOH (1 mL) and hydrazine hydrate (100 ⁇ , 2.06 mmol) was added. The reaction mixture was stirred under N 2 atmosphere at 80°C for 2 h. Phthalhydrazine was filtered off, the filtrate was evaporated, H 2 0 (10 mL) was added and the resulting solution was extracted with CH 2 CI 2 (3x30 mL).
  • the assay utilizes the IMAP technology, which is based on the high affinity binding of phosphate by immobilized metal coordination complexes on nanoparticles.
  • the binding reagent complexes with phosphate groups on nucleotide monophosphate generated from cyclic nucleotides (cAMP/cGMP) through phosphodiesterases.
  • cAMP/cGMP cyclic nucleotides
  • fluorescence polarization detection binding causes a change in the rate of the molecular motion of the phosphate bearing molecule, and results in an increase in the fluorescence polarization value observed for the fluorescent label attached to the substrate.
  • the PDE assay is based on the homogenous time-resolved fluorescence resonance energy transfer (TR-FRET) technology (LANCE ® from Perkin Elmer).
  • TR-FRET fluorescence resonance energy transfer
  • This competition based assay is formatted using a cAMP specific antibody labeled with the dye, Alexa Fluor ® 647, biotin-cAMP and streptavidin labeled with Europium (Eu- SA).
  • Eu- SA Europium
  • PDE activity resulting in the degradation of the cyclic nucleotide, the complex is not formed and a decrease in signal is observed.
  • the phosphodiesterase assay was developed using the LANCE ® cAMP kit
  • the assay buffer contained HBSS with 5 mM HEPES, 0.1 % BSA, and 1 .5 mM MgCI 2 , pH 7.4.
  • PDE1 OA BPS Bioscience was used at 200 pg/well (with a specific activity of 3200 pmole/min ⁇ g with assay conditions: 10 mM Tris-HCI, pH 7.4, 10 mM MgCI 2 , 1 mM MnCI 2 , 200 ⁇ cAMP, 2.5 kU 5' nucleotidase, 37°C, 20 min) and PDE4D3 (BPS Bioscience) was used at 100 pg/well (with a specific activity of 32713 pmole/min ⁇ g with assay conditions: 10 mM Tris-HCI, pH 7.4, 10 mM MgCI 2 , 1 mM MnCI 2 , 200 ⁇ cAMP, 2.5 kU 5' nucleotidase, 37°C, 20 min).
  • Biotin-cAMP tracer supplied in 10 mmol/L Tris-HCI buffered (pH 8.0) salt solution with 1 mmol/L ethylenediaminetetraacetic acid (EDTA), 0.1 % bovine serum albumin (BSA), and 0.05% sodium azide, is used at a dilution of 1 /375.
  • the assay detection mixture contained the LANCE Eu-W8044 labeled streptavidin 1/2250 (supplied in 50 mmol/L Tris-HCI buffered (pH 7.8) salt solution with 0.9% sodium chloride (NaCI), 0.1 % BSA, and 0.05% sodium azide) and the Alexa Fluor ® 647-anti cAMP antibody 1/200 (supplied in 50 mmol/L Tris-HCI buffered (pH 7.8) salt solution with 0.9% NaCI, 0.1 % BSA, and 0.05% sodium azide). Chemical compounds were dissolved in DMSO (final concentration 2% (v/v)).
  • the compounds of the present invention have PDE10A inhibitory activities generally less than 10,000 nM ( ⁇ 10,000 nM). In one embodiment, they have activities less than 1000 nM ( ⁇ 1000 nM); in another embodiment less than 500 nM ( ⁇ 500 nM); in another embodiment less than 100 nM ( ⁇ 100 nM); in another embodiment less than 50 nM ( ⁇ 50 nM); and in another embodiment less than 20 nM ( ⁇ 20 nM)
  • the compounds have also been tested for their activities on PDEs1 -9 and PDE1 1 .
  • the most active PDE10A inhibitors ( ⁇ 20 nM) are all selective (at least 120 to 10000-fold) vs PDEs1 -3, PDEs5-9 and PDE1 1 .

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Abstract

Cette invention concerne des composés de formule (I) ou un sel pharmaceutiquement acceptable de ceux-ci - R', R1 à R7 et Ar étant tels que définis dans la description. Ces composés sont utiles à titre d'inhibiteurs de phosphodiestérase 10 (PDE10A) qui sont utiles pour traiter les maladies du système nerveux central telles que la psychose et également pour traiter, par exemple, l'obésité, le diabète de type II, le syndrome métabolique, l'intolérance au glucose, la douleur et les maladies opthalmiques.
PCT/US2013/067821 2012-11-01 2013-10-31 Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a) Ceased WO2014071044A1 (fr)

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WO2015008008A3 (fr) * 2013-07-19 2015-04-09 Universite Pierre Et Marie Curie (Paris 6) Utilisation de composes pour restaurer la reponse a la lumiere des cellules de la retine
WO2016021706A1 (fr) * 2014-08-08 2016-02-11 カズマパートナーズ株式会社 Composé hétérocyclique condensé
WO2018193387A1 (fr) 2017-04-19 2018-10-25 Pi Industries Ltd. Composés hétérocycliques ayant des propriétés microbiocides
WO2019048989A1 (fr) 2017-09-08 2019-03-14 Pi Industries Ltd. Nouveaux composés hétérocycliques fongicides
WO2019048988A1 (fr) 2017-09-08 2019-03-14 Pi Industries Ltd. Nouveaux composés hétérocycliques fongicides
WO2019125185A1 (fr) * 2017-12-20 2019-06-27 Otago Innovation Limited Composés de quinoléine sulfonamide et leur utilisation en tant qu'agents antibactériens
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WO2021094905A1 (fr) 2019-11-11 2021-05-20 Pi Industries Ltd. Dérivés 1-(4-(4-(5-phényl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipéridine-1-yl)-éthane-1-one et composés associés servant de fongicides pour la protection des récoltes
WO2021094903A1 (fr) 2019-11-11 2021-05-20 Pi Industries Ltd. Dérivés 1-(4-(4-(5-phényl-4,5-dihydroisoxazol-3-yl)thiazol-2-yl)pipéridin-1-yl)-éthan-1-one et composés apparentés utiles en tant que fongicides pour la protection des cultures
WO2021094904A2 (fr) 2019-11-11 2021-05-20 Pi Industries Ltd. Nouvelles sulfilimines ou sulfoximines contenant des composés hétérocycliques fongicides
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