WO2011132048A1 - Composés hétéroaryle en tant qu'inhibiteurs de la pde 10a - Google Patents

Composés hétéroaryle en tant qu'inhibiteurs de la pde 10a Download PDF

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WO2011132048A1
WO2011132048A1 PCT/IB2011/000842 IB2011000842W WO2011132048A1 WO 2011132048 A1 WO2011132048 A1 WO 2011132048A1 IB 2011000842 W IB2011000842 W IB 2011000842W WO 2011132048 A1 WO2011132048 A1 WO 2011132048A1
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phenyl
pyridin
ylmethoxy
quinolin
substituted
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PCT/IB2011/000842
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Laxmikant Atmaram Gharat
Lakshminarayana Narayana
Pravin Sabhajit Yadav
Neelima Khairatkar-Joshi
Malini Bajpai
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Glenmark Pharmaceutical S.A.
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Publication of WO2011132048A1 publication Critical patent/WO2011132048A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to heteroaryl compounds and their use in treating or preventing diseases, conditions and/or disorders by inhibiting phosphodiesterase 10A (PDE 10 A) enzyme.
  • PDE 10 A phosphodiesterase 10A
  • 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 and serve as secondary messengers in several cellular pathways.
  • a principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
  • PDE's encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity.
  • the PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation and sensitivity to inhibitors.
  • PDE's are differentially expressed throughout the body, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDE's isozymes can serve distinct physiological functions.
  • the murine homologue has also been cloned [Soderling, S. et al., Proc. Natl. Acad. Sci. USA vol. 96 p. 7071 -7076, ( 1999)] and N-terminal splice variants of both the rat and human genes have been identified [ otera, J. et al., Biochem. Biophys. Res. Comm. vol. 261 , p. 551 -557, (1999); Fujishige, K. et al., Eur. J. Biochem. vol. 266, p. 1 1 1 8- 1 127, ( 1 999)]. There is a high degree of homology across species.
  • the mouse PDE 10A 1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • the affinity of PDE10 for cAMP is higher than for cGMP.
  • approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE10 is a unique cAMP-inhibited cGMPase [Fujishige et al., J. Biol. Chem. vol. 274, p. 18438-18445, (1999)].
  • the PDE10 family of polypeptides shows a lower degree of sequence homology to previously identified PDE families. These low degrees of sequence homology of PDE10 family of polypeptide make them insensitive to certain inhibitors that are known to be specific for other known PDE families (US 6,350,603, incorporated herein by reference).
  • PDEI OA which is one of the PDE subtypes
  • the expression of its mRNA has been identified in many tissues and organs such as striatum, testis, kidney, thyroid gland, pituitary gland, thalamus, cerebellum, heart, lungs and placenta, cells such as aortic smooth muscle cells and aortic endothelial cells, cells of cancers such as lung small cell carcinoma, breast cancer and large bowel cancer. Accordingly, the possibility that PDEI OA is involved in diseases related to these cells, tissues and organs has been demonstrated [J. Biol. Chem. vol. 274, p. 1 8438 ( 1999); Gene, vol. 234, p. 109 ( 1999) and WO 01 /29199].
  • PDEI OA is selectively expressed in dopamine receptive medium spiny neurons, and considerable data suggests that cAMP and cGMP signalling pathways play significant roles in the regulation of medium spiny neuron excitability. Additional studies with papaverine, a potent inhibitor of PDEI OA, confirm that PDEI OA regulates both cAMP and cGMP in vivo in rats [J. A. Siuciak, et al. Neuropharmacology, vol. 5 1 , p. 386- 396, (2006)].
  • PDE I OA inhibitors are useful for treating and/or preventing various diseases caused by enhanced activity of PDEI OA, possibly with reduced side effects (for example, a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor).
  • a neural disease such as Parkinson's disease, Huntington disease or Alzheimer's disease, dyskinesia, hypogonadism, diabetes, an ischemic heart disease, hypertension, an inflammatory disease, a disease of the digestive system, an allergic disease, osteoporosis, pain or a malignant tumor.
  • WO 2003/000269, WO 2003/0141 15, WO 2003/0141 16, WO 2003/0141 17, WO 2003/051877, WO 2006/034491 and WO 2006/034512 describe PDE10 inhibitors for treatment of neurodegenerative diseases, cancer, diabetes and its related disorders.
  • WO 2006/072828, WO 2008/084299, WO 2003/093499, WO 2005/082883, WO 2005/120514, WO 2006/01 1040, WO 2006/070284, WO 2007/077490, WO 2007/085954, WO 2007/096743, WO 2007/129183, WO 2008/001 182, WO 2008/0041 17, WO 2008/020302, WO 2009/070584, WO 2009/068320, WO 2009/068246 and WO 2009/036766 describe PDE10 inhibitors for treatment of obesity, diabetes, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
  • WO 2009/029214, WO 2009/025839 and WO 2009/025823 describe PDE 10 inhibitors for treatment of obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder and obsessive-compulsive disorder.
  • WO 2009/1431 78, WO 2009/152825, WO 2009/158393, WO 2009/158467, WO 2009/158473, WO 2010/006130, WO 2010/017236, WO 2010/027097 and WO 2010/030027 describe PDE 10 inhibitors for treatment of anxiety, schizophrenia, drug addiction, movement disorder, certain central nervous system disorders, neurodegenerative and psychiatric disorders.
  • the present invention relates to compounds of formula (1):
  • ring Ar 1 and Ar 2 are independently selected from aryl, heteroaryl and heterocyclyi;
  • R 1 , R 8 and R 9 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalky!oxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R a , -C(0)OR a , - C(0)NR a R b , -CR a R b NR a R c , -NR a R b ,
  • R 2 , R 3 , R 10 and R 1 1 are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)OR a and -NR a R b ; or R 2 and R 3 or R 10 and R n , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
  • R 4 , R 7 and R 12 which may be the same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)OR a , -C(0)NR a R b , -S(0)NR a R b , -S0 2 NR a R b , - S(0)R a and -S0 2 R a ;
  • R 3 and R 6 which may be the same or different, are independently selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R , -C(0)NR a R b , -C(0)OR a , -CR'R'WR', -NR a R b , - NR a CONR b R c , -NR a C(0)OR b , -N(R a )SOR b , -N(R a )S0 2 R b , -NR a C(0)R b , -NR a C(S)R b , - -
  • R 4 and R 5 together with the atoms to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally include one or more heteroatoms selected from O, N, or S;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'n' is an integer ranging from 1 to 3, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive
  • 'q' is an integer ranging from 0 to 4, both inclusive
  • 'r is an integer ranging from 1 to 3, both inclusive.
  • the compounds of formula (I) may involve one or more embodiments. It is to be understood that the embodiments below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
  • ring Ar 3 and Ar 4 are independently selected from aryl, heteroaryl and heterocyclyl;
  • R 1 , R 9 , R 13 and R 14 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyi, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R ⁇ -C(0)OR a , - C(0)NR a R , -CR'R'WR 0 , -NR a R b , -NR a C(0)
  • R 10 and R" which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)OR a and -NR a R b ; or R 10 and R 1 1 , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S; R 12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloa!kyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a ,
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • m ' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive;
  • 'r' is an integer ranging from 1 to 3, both inclusive;
  • 't' is an integer ranging from 0 to 4, both inclusive;
  • 'u' is an integer ranging from 0 to 4, both inclusive.
  • R 9 is halogen (e.g., fluorine) and 'q' is 1.
  • ring Ar 3 is aryl, preferably phenyl.
  • R 13 is halogen (e.g., fluorine), substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl) or OR a ; wherein R a is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl.
  • 't' is 1 or 2.
  • compounds of the formula (II) in which A is -(C O)-(CR l 0 R") r -, wherein both R 10 and R n are hydrogen and 'r' is 1.
  • ring Ar 4 is aryl, preferably phenyl.
  • R 14 is halogen (e.g., fluorine or chlorine), substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl, ethyl or r-butyl), haloalkyl (e.g., trifluoromethyl), cycloalkyl (e.g., cyclopropyl) or OR a ; wherein R a is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl.
  • 'u' is 1 , 2 or 3.
  • B is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
  • R 1 , R 9 and R 13 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyi, arylalkyloxy, heteroaryl, heteroaralkyi, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R a , -C(0)OR a , - C(0)NR a R b , -CR a R b NR a R c , -NR a R b ,
  • R l 0 and R 1 ' which may be the same or different, are independently selected from hydrogen, halogen, hydroxyl, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -C(0)OR a and -NR a R b ; or R 10 and R n , together with the carbon atom to which they are attached may form cyclic ring, which may be monocyclic, bicyclic or tricyclic rings; substituted or unsubstituted; saturated, unsaturated or partially saturated; the cyclic ring may optionally contain one or more heteroatoms selected from O, N or S;
  • R 12 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)OR a , -C(0)NR a R b , - S(0)NR a R , -S0 2 NR a R b , -S(0)R a and -S0 2 R a ;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive;
  • 'r' is an integer ranging from 1 to 3, both inclusive;
  • 't' is an integer ranging from 0 to 4, both inclusive.
  • specifically provided are compounds of the formula (III) in which A is -(CO)-. According to another embodiment, specifically provided are compounds of the formula (III) in which A is -(C 0)-(CH 2 ) , wherein 'r' is 1 , 2 or 3.
  • B is substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl, ethyl, propyl or butyl) or substituted or unsubstituted haloalkyl (preferably trifluoromethyl).
  • D is selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, aryl, heteroaryl and heterocyclyl;
  • R 1 , R 9 and R 14 which may be the same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyi, arylalkyloxy, heteroaryl, heteroaralkyi, heterocyclyl, heterocyclylalkyl, -OR a , -OC(0)R a , -OC(0)NR a R b , -C(0)R a , -C(0)OR a , - C(0)NR a R , -CR a R b NR a R c , -NR a R b , -C(0)OR a
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 4, both inclusive;
  • 'u' is an integer ranging from 0 to 4, both inclusive.
  • R 1 is r unsubstituted heteroaryl, preferably unsubstituted heteroaryl, more prefera and 'm' is 1.
  • R 14 is halogen, preferably fluorine and 'u' is 2.
  • D is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • ring Ar 1 is selected from aryl, heteroaryl and heterocyclyl
  • R 1 and R 8 are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR A , -OC(0)R A , -
  • R 6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)NR a R b , -C(0)OR a , - CR ⁇ 'WR 0 , -NR a R b , -NR a CONR b R c , -NR a C(0)OR b , -N(R a )SOR b , -N(R a )S0 2 R b , - NR a C(0)R b , -NR a C(S)R b , -NR a C(S)NR b
  • R 7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl. alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R a , -C(0)OR a , -C(0)NR a R ⁇ - S(0)NR a R b , -S0 2 NR a R b , -S(0)R a and -S0 2 R a ;
  • R a , R b and R c which may be the same or different, are independently selected from hydrogen, halogen, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl;
  • 'm' is an integer ranging from 0 to 4, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive.
  • R 6 is substituted or unsubstituted aryl, preferably substituted aryl, more preferably substituted phenyl; wherein the substituent is halogen preferably chlorine.
  • R 7 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • ring Ar' is aryl, preferably phenyl.
  • ring Ar 1 is selected from aryl, heteroaryl and heterocyclyl
  • R 6 is selected from hydrogen, halogen, haloalkyl, hydroxyl, cyano, nitro, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, cyanoalkyl, cyanoalkyloxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R A , -C(0)NR A R B , -C(0)OR A , - CR WR 0 , -NR A R B , -NR A CONR B R°, -NR A C(0)OR B , -N(R A )SOR B , -N(R a )S0 2 R B , - NR A C(0)R B , -NR A C(S)R B , -NR A C(S)NR B R C , -SONR A R B , -S0 2 NR A R
  • R 7 is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, -C(0)R , -C(0)OR A , -C(0)NR A R B , - S(0)NR A R B , -S0 2 NR A R , -S(0)R A and -S0 2 R A ;
  • R 9 is independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, haloalkoxy, cyanoalkyl, cyanoalkyloxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, aryloxy, aralkyl, arylalkyloxy, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, -OR A , -OC(0)R A , - OC(0)N R A R B , -C(0)R A , -C(0)OR A , -C(0)NR A R B , -CR'R'WR", -NR A R B , -NR A C(0)NR B R C , - NR A C(0)OR B , -N(R A )S(0)R
  • R 16 and R 1 7 which may be the same or different, are independently selected from hydrogen and substituted or unsubstituted alkyl;
  • 'q' is an integer ranging from 0 to 4, both inclusive.
  • R 6 is substituted or unsubstituted aryl, preferably substituted aryl, more preferably substituted phenyl; wherein the substituent is halogen preferably chlorine.
  • R 7 is substituted or unsubstituted alkyl, preferably unsubstituted alkyl, more preferably methyl or ethyl.
  • ring Ar 1 is aryl, preferably phenyl.
  • R 16 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • R 17 is hydrogen or substituted or unsubstituted alkyl (preferably unsubstituted alkyl, more preferably methyl).
  • the present invention also provides a pharmaceutical composition that includes at least one compound described herein and at least one pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
  • the compounds described in the present patent application may be associated with a pharmaceutically acceptable excipient, such as a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting PDE10A, which is related to a variety of disease states.
  • the present invention further provides a method of inhibiting PDE 10A in a subject in need thereof by administering to the subject one or more compounds described herein in an amount effective to cause inhibition of such receptor.
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • alkyl refers to a hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1 -methylethyl (isopropyl), n-butyl, n-pentyl and 1 , 1 -dimethylethyl (t-butyl). Unless set forth or recited to the contrary, all alkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon chain containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond. Examples of such alkenyl moiety include, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl (allyl), wo-propenyl, ' 2-methyl- l -propenyl, 1 -butenyl and 2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbyl radical having at least one carbon-carbon triple bond, and having 2 to about 12 carbon atoms (with radicals having 2 to about 10 carbon atoms being preferred). Examples of such alkynyl moiety include, but are not limited to, ethynyl, propynyl and butynyl. Unless set forth or recited to the contrary, al l alkynyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxy refers an alkyl group attached via an oxygen linkage to the rest of the molecule. Examples of such alkoxy moiety include, but are not limited to, -OCH 3 and - OC 2 H 5 . Unless set forth or recited to the contrary, all alkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • alkoxyalkyl or “alkyloxyalkyl” refers to an alkoxy or alkyloxy group as defined above directly bonded to an alkyl group as defined above.
  • Example of such alkoxyalkyl moiety includes, but are not limited to, -CH 2 OCH 3 and -CH 2 OC 2 H 5 .
  • all alkoxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkyl refers to at least one halo group (selected from F, CI. Br or I), linked to an alkyl group as defined above.
  • haloalkyl moiety include, but are not l im ited to, trifluoromethyl, difluoromethyl and fluoromethyl groups. Unless set forth or recited to the contrary, all haloalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogen atoms.
  • haloalkoxy include but are not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichlorormethoxy, trichloromethoxy and 1 -bromoethoxy.
  • all haloalkoxy groups described herein may be straight chain or branched, substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by hydroxyl groups.
  • Examples of hydroxyalkyl moiety include, but are not limited to -CH2OH and -C2H 4 OH .
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups or sprirobicyclic groups, e.g., sprio(4,4)non-2-yl, spiro[3,3]heptanyl, spiro[3,4]octanyl and spiro[4,4]heptanyl. Unless set forth or recited to the contrary, all cycloalkyl groups described herein may be substituted or unsubstituted.
  • cycloalkylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms directly attached to an alkyl group.
  • the cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • Examples of cycloalkylalkyl moiety include, but are not limited to cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless set forth or recited to the contrary, all cycloalkylalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. Unless set forth or recited to the contrary, all cycloalkenyl groups described or claimed herein may be substituted or unsubstituted.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic and tricyclic aromatic systems, such as phenyl, naphthyl, tetrahydronapthyl, indanyl and biphenyl. Unless set forth or recited to the contrary, all aryl groups described herein may be substituted or unsubstituted.
  • aryloxy refers to an aryl group as defined above attached via an oxygen linkage to the rest of the molecule.
  • Examples of aryloxy moiety include, but are not limited to phenoxy and naphthoxy. Unless set forth or recited to the contrary, all aryloxy groups described herein may be substituted or unsubstituted.
  • arylalkyl refers to an aryl group as defined above directly bonded to an alkyl group as defined above.
  • Examples of arylalkyl moiety include, but are not limited to - CH 2 C6H 5 and -C2H4C6H5. Unless set forth or recited to the contrary, all arylalkyl groups described herein may be substituted or unsubstituted.
  • arylalkyloxy refers to an arylalkyl group attached via an oxygen linkage to the rest of the molecule.
  • arylalkyloxy moiety include, but are not limited to - OCH2C6H5 and -OC2H4C6H5. Unless set forth or recited to the contrary, all arylalkyloxy groups described herein may be substituted or unsubstituted.
  • heterocyclic ring or “heterocyclyl” unless otherwise specified refers to substituted or unsubstituted non-aromatic 3 to 15 membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur.
  • the heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.
  • heterocyclic ring or heterocyclyl may optionally contain one or more olefinic bond(s).
  • heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, dioxaphospholanyl, decahydroisoquinolyl, indanyl, indolinyl, isoindolinyl, isochromanyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl,
  • heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclyl groups described herein may be substituted or unsubstituted.
  • heterocyclylalkyl refers to a heterocyclic ring radical directly bonded to an alkyl group.
  • the heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heterocyclylalkyl groups described herein may be substituted or unsubstituted.
  • heteroaryl refers to substituted or unsubstituted 5 to 14 membered aromatic heterocyclic ring radical with one or more heteroatom(s) independently selected from N, O or S.
  • the heteroaryl may be a mono-, bi- or tricyclic ring system.
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl ring radicals include, but are not limited to oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pteridinyl, purinyl, quinoxalinyl, quinolyl, isoquinolyl, thiadiazolyl, indoli
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless set forth or recited to the contrary, all heteroarylalkyi groups described herein may be substituted or unsubstituted.
  • treating or “treatment” of a state, disorder or condition includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (b) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; or (c) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • subject includes mammals (especially humans). Other mammals include domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
  • a “therapeutically effective amount” means the amount of a compound that, when administered to a subject for treating a state, disorder or condition, is sufficient to effect such treatment.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the subject to be treated.
  • salts forming part of this patent application include salts derived from inorganic bases (such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn), salts of organic bases (such as N,N'-diacetylethylenediamine, glucamine, triethylamine, choline, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, and thiamine), salts of chiral bases (such as alkylphenylamine, glycinol, and phenyl glycinol), salts of natural amino acids (such as glycine, alanine, valine, leucine, isoleucine, norleucine.
  • inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, and Mn
  • organic bases such as N,N'-diacetylethylenediamine, glucamine, triethylamine, cho
  • tyrosine cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine
  • salts of non-natural amino acids such as D-isomers or substituted amino acids
  • salts of guanidine salts of substituted guanidine (wherein the substituents are selected from nitro, amino, alkyl, alkenyl or alkynyl), ammonium salts, substituted ammonium salts and aluminum salts.
  • salts include acid addition salts (where appropriate) such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.
  • acid addition salts such as sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates (such as trifluoroacetate), tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates and ketoglutarates.
  • Compounds described herein can comprise one or more asymmetric carbon atoms and thus can occur as racemic mixtures, enantiomers and diastereomers. These compounds can also exist as conformers/rotamers. All such isomeric forms of these compounds are expressly included in the present patent application. Although the specific compounds exemplified in this application may be depicted in a particular stereochemical configuration, compounds having either the opposite stereochemistry at any given chiral centre are envisioned as a part thereof. In addition, compounds of Formula I can exist in different geometrical isomeric forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. The various isomeric forms of the compounds of the present invention may be separated from one another by methods known in the art or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
  • the pharmaceutical composition of the present patent application comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof.
  • the compounds described herein may be associated with one or more pharmaceutically acceptable excipients, carriers, diluents or mixture thereof in the form of capsule, sachet, paper or other container.
  • suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmetic pressure, buffers, sweetening agents, flavoring agents, colorants or any combination of the foregoing.
  • the pharmaceutical composition of the patent application may be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing methods known in the art.
  • compositions of the present patent application may be prepared by conventional techniques, e.g., as described in Remington: The Science and Practice of Pharmacy, 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound is mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a vehicle, excipient or medium for the active compound.
  • the active compound is adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the route of administration may be any route which effectively transports the active compound of the patent application to the appropriate or desired site of action.
  • Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment).
  • the oral route is preferred.
  • Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch and/or potato starch. A syrup or elixir is used in cases where a sweetened vehicle is employed.
  • Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Suitable doses of the compounds for use in treating the diseases and disorders described herein can be determined by those skilled in the relevant art.
  • Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects.
  • the daily dosage of the PDEI OA inhibitors can range from about 0.1 to about 30.0 mg/Kg.
  • Mode of administration, dosage forms, suitable pharmaceutical excipients, diluents or carriers can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present patent application.
  • the present patent application provides a method of treating a disease, condition or disorder modulated by a PDEI OA, in a subject by administering to the subject in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition described herein.
  • the present patent application further provides a method of treating diseases, disorders or conditions, modulated by a PDE10A in mammals including human, of neuropsychiatric, neurodegenerative, neurological, neuroendocrinological nature such as, but not limiting to, schizophrenia, psychoses, schizoaffective disorders, positive symptoms of schizophrenia including delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, paranoia, paranormal behaviors, negative symptoms of schizophrenia like deficits of normal emotional responses or of other thought processes including flat or blunted affect and emotion, poverty of speech (alogia), inability to experience pleasure (anhedonia), lack of desire to form relationships (asociality), and lack of motivation (avolition) leading to poor quality of life, functional disabilities typically regarded as manifestations of psychosis and other comorbidities like cognitive, executive, attention, learning, memory, spatial memory and social cognitive functions, Tic disorders like Tourette's syndrome, autism, autism spectrum disorders, attention deficit hyperactivity disorders (ADHD), pediatric
  • This patent application also provides a method of 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 effective in treating said disorder or condition.
  • the phrase "deficiency in attention and/or cognition” as used in the phrase “disorder comprising as a symptom a 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 occur in age-related cognitive decline.
  • disorders that comprise as a symptom a deficiency in attention and/or cognition that can be treated according to the present patent application 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, Multiple sclerosis, Amyotrophic lateral sclerosis, Down's syndrome 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, Multiple sclerosis, Amyotrophic lateral sclerosis, Down's syndrome or AIDS-related dementia
  • delirium amnes
  • This patent application also provides a method of 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 effective in treating said disorder or episode.
  • This patent application also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal a therapeutically effective amount of a compound of formula I in inhibiting PDE1 OA.
  • mood disorders and mood episodes that can be treated according to the present patent application 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 ] disorder, bipolar 11 disorder and cyclothymic disorder.
  • This patent application further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
  • 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 be treated according to the present patent application 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.
  • 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 or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
  • this patent application provides a pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders or drug addiction, comprising a therapeutically effective amount of a compound of the present invention in treating said disorder or condition.
  • this patent application provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis, anxiety disorders, movement disorders, mood disorders, and neurodegenerative disorders, which method comprises administering a therapeutically effective amount of a compound of the present invention in treating said disorder.
  • this patent application provides a method of treating the disorders above, where the disorders are 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; posttraumatic 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 disease or condition selected from obesity or related diseases, conditions; diabetes (including Type I and Type II diabetes); diabetic complications; glucose
  • the compound of formula (l a) is converted into compound of formula (2) by reacting with a substituted alkyl halide at a temperature range of 0-100°C using a suitable solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedures known in the art of organic synthesis.
  • a suitable solvent for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g.,
  • a compound of formula (2) can also be prepared by the reaction of a compound of formula (l a) with a substituted hydroxy compound under Mitsunobu conditions.
  • Compound of formula (2) can also be prepared by the reaction of a compound of formula ( l b) with an appropriately substituted hydroxy compound in the presence of a base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like using a suitable solvent (for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.).
  • a base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for
  • Compound of formula (2) is converted into compound of formula (3) under reductive conditions utilizing iron or tin metal in a mineral acid like hydrochloric acid or catalytic reduction condition utilizing palladium or platinum on carbon in presence of hydrogen gas and the like.
  • Compound of formula (3) can be converted to a compound of formula (4) by reacting with a substituted halide compound at a temperature (0-100°C) using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like following procedures known in the art of organic synthesis.
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, di
  • compound of formula (4) can be prepared by reacting the compound of formula (3) with an aldehyde under reductive amination conditions utilizing sodium borohydride, sodium triacetoxyborohydride and the like in an appropriate solvent (for e.g., dichloromethane, dichloroethane etc.) at a temperature range of 0-50°C.
  • an appropriate solvent for e.g., dichloromethane, dichloroethane etc.
  • Compound of formula (4) can also be prepared by reacting compound of formula (3) with an acid chloride or substituted carbamate derivative in the presence of a base (for e.g.
  • Compound of formula (4) can be converted to a compound of formula (IA) by reacting with a carboxylic acid derivative under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino) phosphoniumhexafluorophosphate (BOP reagent) etc.) in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a coupling agent for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino) phosphoniumhexafluorophosphate (BOP reagent) etc.
  • BOP reagent benzotriazol-l -yloxytris(
  • compound of formula (1A) can also be prepared by reacting a compound of formula (4) with an acid chloride, substituted isothiocyanate derivative or substituted carbamate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.).
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.
  • Compound of formula (3) can be converted to a compound of formula (5) by reacting with carboxylic acid compounds under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, BOP reagent etc.) in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a coupling agent for e.g., carbodiimide, BOP reagent etc.
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.
  • compound of formula (5) can also be prepared by reacting a compound of formula (3) with an acid chloride, substituted isothiocyanate derivative or substituted carbamate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.
  • Compound of formula (5) can be converted to a compound of formula (IA) by reacting with a substituted alkyl halide or acyl halide at 0-100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.) and the like.
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.)
  • Compound of formula (IA) can also be prepared by reacting compound of formula (5) with an acid chloride or substituted carbamate derivative in a presence of a suitable base (for e.g. triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformam ide, dimethyl sulfoxide etc.).
  • a suitable base for e.g. triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane, tetrahydrofuran, dimethylformam ide, dimethyl sulfoxide etc.
  • X is O or S
  • Y is -(CR 10 R 1 1 ) r - or -NR 12 -
  • Compound of formula ( l a) is converted into compound of formula (6) by reacting with a substituted 2-chloromethylquinoline at a temperature range of 0- 100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.) in the presence of suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydroxide (for e.g., sodium hydroxide etc.).
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • suitable base such as alkali metal carbonate (for e.g., potassium carbonate etc.), alkali metal hydride (for e.g., sodium hydride etc.) or alkali metal hydro
  • compound of formula (6) can also be prepared by reacting compound of formula ( l a) with a substituted hydroxy 1 compound of quinoline derivative under Mitsunobu conditions.
  • Compound of formula (6) is converted to a compound of formula (7) under reductive conditions utilizing iron or tin metal in a mineral acid like hydrochloric acid or catalytic reduction condition utilizing palladium or platinum on carbon in presence of hydrogen gas and the like.
  • Compound of formula (7) can be converted to a compound of formula (8) by reacting with an substituted alkyl halide at 0-100°C using an appropriate solvent (for e.g.
  • alkali metal carbonate for e.g. potassium carbonate etc.
  • alkali metal hydride for e.g., sodium hydride etc.
  • alkali metal hydroxide for e.g., sodium hydroxide etc.
  • formula (8) could also be prepared by reacting a compound of formula (7) with an aldehyde compound under reductive amination conditions utilizing sodium borohydride, sodium triacetoxyborohydride and the like in an appropriate solvent (for e.g., dichloromethane, dichloroethane etc.) at a temperature range of 0-50°C.
  • an appropriate solvent for e.g., dichloromethane, dichloroethane etc.
  • Compound of formula (8) can be converted to a compound of formula (IIA) by reacting with a carboxylic acid derivative under standard amidation conditions utilizing a coupling agent (for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) etc.) in the presence of suitable base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane, tetrahydrofuran, dimethylformamide etc.).
  • a coupling agent for e.g., carbodiimide, benzotriazol-l -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent) etc.
  • suitable base for e.g., triethylamine, diisoprop
  • formula (IIA) can also be prepared by reacting a compound of formula (8) with an acid chloride, substituted carbamate derivative or substituted isothiocyanate derivative in the presence of a base (for e.g., triethylamine, diisopropylethylamine etc.) in an appropriate solvent (for e.g., dichloromethane. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide etc.).
  • a base for e.g., triethylamine, diisopropylethylamine etc.
  • an appropriate solvent for e.g., dichloromethane. tetrahydrofuran, dimethylformamide, dimethyl sulfoxide etc.
  • a compound of formula ( 10) is converted to a compound of formula (1 1) by reacting with a substituted 2- chloromethylquinoline at a temperature range of 0-100°C using an appropriate solvent (for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.) in the presence of a suitable base such as alkali metal carbonate (for e.g., potassium carbonate), alkali metal hydride (for e.g., sodium hydride) or alkali metal hydroxide (for e.g., sodium hydroxide) and the like by following procedure known in the art of organic synthesis.
  • an appropriate solvent for e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran etc.
  • a suitable base such as alkali metal carbonate (for e.g., potassium carbonate), alkali metal hydride (for e.g., sodium
  • Compound of formula (1 1 ) is converted to a compound of formula (7) under deprotection conditions utilizing a deprotecting reagent (for e.g., Cone. HCI, saturated ethyl acetate in HCI gas, methanol saturated with HCI gas, p-toluenesulphonic acid etc.) and the like by following procedure known in the art of organic synthesis.
  • a deprotecting reagent for e.g., Cone. HCI, saturated ethyl acetate in HCI gas, methanol saturated with HCI gas, p-toluenesulphonic acid etc.
  • compound of formula (12) is converted to a compound of formula (13), by reacting it with an appropriate substituted or unsubstituted acyl halide at elevated temperature (60°C to 120°C) in a suitable solvent (for e.g., acetonitrile, dimethylformamide, ethanol, dimethoxyethane, dioxane, dimethylsulphoxide etc.) by following procedures known in the art.
  • a suitable solvent for e.g., acetonitrile, dimethylformamide, ethanol, dimethoxyethane, dioxane, dimethylsulphoxide etc.
  • Compound of formula (13) is converted to a compound of formula (14) where Hal is halogen, by reacting it with halogenating agents such as N-bromosuccinimide or N-iodosuccinimide at -20°C to 100°C, in a suitable solvent such as diethylether, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide or the like by following procedure known in the art.
  • halogenating agents such as N-bromosuccinimide or N-iodosuccinimide at -20°C to 100°C
  • Compound of formula (14) is converted to a compound of formula (15) by reacting with 4-hydroxyphenylboronic acid in presence of palladium metal or palladium complex such as dichlorobis(triphenylphosphine)palladium(ll), tetrakis(triphenylphosphine) palladium(O), dichlorobis(diphenylphosphinopropane)palladium, tris(dibenzylideneacetone) dipalladium or the like as a catalyst, in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, dimethylsulphoxide or water or a mixture of them in the temperature range of 25°C to 100°C.
  • palladium metal or palladium complex such as dichlorobis(triphenylphosphine)palladium(ll), tetrakis(triphenylphosphine) palladium(O), dichlorobis(diphenylphosphinopropan
  • Compound of formula (15) is converted to a compound of formula (16) by reacting with an a-haloester derivative in presence of a base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, dimethylformamide or dimethylsulphoxide in the temperature range of 25°C to 100°C.
  • a base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, methanol, ethanol, tetrahydrofuran or the like in presence of water in the temperature range of 25°C to 100°C.
  • Compound of formula (17) is converted to a compound of formula ( 18) (where Ar is aryl, heteroaryl or heterocyclyl ring), by reacting it with a phenol containing an electron withdrawing group especially a nitro group, by activating the acid, as acidchloride by reacting it with thionyl chloride or oxalyl chloride, using EDCI .HCI or t BOP reagent, in the presence of a base such as triethylamine, diisopropylethylamine or the like in a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran or the like in the temperature range of 25°C to 100°C.
  • a base such as triethylamine, diisopropylethylamine or the like
  • a solvent such as dichloromethane, dimethylformamide, tetrahydrofuran or the like in the temperature range of 25°C to 100°C.
  • Compound of formula (18) is converted to a compound of formula (IB) by reacting with a compound of formula (19) in the presence of a base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a solvent such as tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • a base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride
  • a solvent such as tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • compound of formula (17) can also be converted to a compound of formula (IB) by activating it as an acidchloride and reacting it with the compound of formula (19) in the presence of a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a appropriate solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride
  • a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • Compound of formula ( 17) can also be converted to a compound of formula (IB) by activating it in the presence of a substituted carbodiimide or BOP reagent and reacting it with a compound of formula (19) in the presence of a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride in a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • a suitable base such as triethylamine, diisopropeylethylamine or an alkalimetal hydride
  • a suitable solvent such as dichloromethane, tetrahydrofuran, dimethylformamide or the like in the temperature range of 25°C to 100°C.
  • compound of formula (19a) can optionally be converted to a compound of formula (19) (where R is alkyl), by reacting with an alkyl halide in the presence of a base such as triethylamine, diisopropylethylamine or an alkali metal hydride in a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc., at 0°C to 100°C.
  • a base such as triethylamine, diisopropylethylamine or an alkali metal hydride
  • a solvent such as tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.
  • Compound of formula (19) and (19a) are converted to compound of formula (20) (where Hal is halogen), by reacting with a substituted a-halo acylhalide derivatives in the presence of a suitable base such as triethylamine, diisopropylethylamine or alkalimetal hydride in an appropriate solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc., at 0°C to 100°C.
  • a suitable base such as triethylamine, diisopropylethylamine or alkalimetal hydride
  • an appropriate solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylsulphoxide etc.
  • Compound of formula (20) is further reacted with compound of formula- (15) in presence of a suitable base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride in a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran or dimethylsulphoxide at 25°C to 100°C to obtain a compound of the general formula (IB).
  • a suitable base such as alkali metal carbonate, alkali metal hydroxide or alkali metal hydride
  • a solvent such as acetonitrile, dimethylformamide, tetrahydrofuran or dimethylsulphoxide
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, in suitable solvents of a suitable polarity as the mobile phase.
  • the following abbreviations are used in the text: DMSO-efc: hexadeuterodimethyl sulfoxide; CDCI 3 - deuterated chloroform; J: coupling constant in units of Hz; RT or rt: room temperature (22- 26°C).
  • aq. aqueous; equiv. or eq.: equivalents.
  • Step 1 Preparation of 6-fluoro-quinoline-2-carbaldehyde To a freshly prepared solution of Se0 2 (0.690 g, 6.21 mmol) in 10% water in dioxane (20 mL) at 40-45°C was added 2-methyl-6-fluoro quinoline (0.500 g, 3.1 0 mmol) and the reaction mixture was stirred at 40-45°C for 3-4 hours. The reaction mass was fi ltered through celite bed, filtrate was di luted with water and extracted with dichloromethane.
  • Step 4 Preparation of tert-butyl ⁇ 4-[(6-fluoroquinolin-2-yl)methoxyl]phenyl ⁇ carbamate
  • a suspension of ter/-butyl (4-hydroxyphenyl)carbamate (0.282 g, 1 .35 mmol) and potassium carbonate (0.3 10 g, 2.24 mmol) in tetrahydrofuran at 80-90°C was added 2- chloromethyl-6-fluoro-quinoline, obtained in Step 3 (0.220 g, 1 .12 mmol) and the reaction mixture was stirred at 90- 100°C for 2-3 hours.
  • the reaction mixture was cooled to room temperature and was added aq 10% NaOH solution; a product precipitated.
  • Step 5 Preparation of 4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl amine
  • Step 6 Preparation of [4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl]-pyridin-3-ylmethylamine
  • 4-(6-fluoro-quinolin-2-ylmethoxy)-phenyl amine, obtained in Step 5 0.1 50 g. 0.559 mmol
  • ethylene dichloride 5 mL
  • 3-pyridine carbaldehyde 0.071 g, 0.663 mmol
  • Step 2 Preparation of (4-methyl-thiazol-5-ylmethyl)-[4-(quinolin-2-ylmethoxy)-phenyl]- amine
  • Step 4 Preparation of 2-pyridin-4-yl-4-(quinolin-2-ylmethoxy)-phenyl amine
  • Step 1 Preparation of 2-(4-chlorophenyl)imidazo[2, 1 -b][ 1 ,3]benzothiazole
  • 2-aminobenzothiazole 2.000 g, 13.33 mmol
  • 4-chlorophenacyl bromide 3.4 g, 14.66 mmol
  • Step 2 Preparation of 2-(4-chlorophenyl)-3-iodoimidazo[2, l -6][l ,3]benzothiazole
  • Step 3 Preparation of 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l-Z>][l ,3] thiazole
  • Step 1 Preparation of ethyl ⁇ 4-[2-(4-Chlorophenyl)imidazo[2,l-»][l,3]benzothiazol-3-yl] phenoxy ⁇ acetate
  • 2-(4-chlorophenyl)-3-(4-hydroxyphenyl)benzo[i ]imidazo[2, l - >][ l ,3] thiazole (0.150 g, 0.398 mmol) in dry DMF (3.0 mL) was added ethylbromoacetate (0.080 g, 0.479 mmol) followed by K 2 C0 3 (0.166 g, 1.200 mmol) and the reaction mixture was stirred at room temperature for 12 hours.
  • Step 2 Preparation of ⁇ 4-[2-(4-chlorophenyl)imidazo[2, l -&][l ,3]benzothiazole-3-yl] phenoxy ⁇ acetic acid
  • Step 1 Preparation of ⁇ 4-[2-(4-chlorophenyl)imidazo[2, l - >][ l ,3]benzothiazol-3-yl]phenoxy ⁇ acetyl chloride
  • Step 2 Preparation of 4-nitrophenyl ⁇ 4-[2-(4-chlorophenylimidazo[2, l -6][l ,3]benzothiazoI- 3-yl]phenoxyl ⁇ acetate
  • Step 1 Preparation of 2-(4-chlorophenyl)imidazo[l,2- ]pyrimidine
  • Step 2 Preparation of 3-bromo-2-(4-chIorophenyl)imidazo[ l ,2-a]pyrimidine
  • Examples 2-45 mentioned in Table 5 below were prepared using appropriate starting material and phenylacetic acid derivatives, by following the procedure as described for the preparation of Example 1 .
  • Examples 57-59 mentioned in Table 6 below were prepared using Intermediate 26 and appropriate amine derivatives, by following the procedure as described for the preparation of Example 56.
  • Table 6 Structure, starting material and characterization data for Examples 57-59
  • Examples 61 -68 mentioned in Table 7 below were prepared using appropriate starting material, by following the procedure as described for the preparation of Example 60.
  • Examples 70-72 mentioned in Table 8 below were prepared using appropriate starting material, by following the procedure as described for the preparation of Example 69.
  • Table 8 Structure, starting material and characterization data for Examples 70-72
  • the illustrative examples of the present invention are screened for PDE 10A activity according to a modified procedure described in Sette, C, lona, S. and Conti, M., J. Biol. Chem. 269 ( 12), pp. 9245-9252, 1994.
  • PDE10 enzyme hydrolyses cAMP / cGMP to metabolically inactive 5'-AMP / 5 '- GMP. Inhibition of PDE10 enzyme activity can be quantitated by using a two step radiometric assay. In this assay, PDE10 enzyme converts 3 H-cAMP/ 3 H-cGMP to 3 H-AMP/ 3 H-GMP which is then converted to 3 H-adenosine / 3 H-guanosine using snake venom nucleotidase. The radioactivity released in the supernatant is quantitated as an indicator of PDE 10 enzyme activity.
  • Test compounds or reference compounds such as dipyridamole, IBMX (Calbiochem) and papaverine (Sigma) were dissolved in dimethylsulfoxide (DMSO) to prepare 1 .0 mM stock solution and diluted suitably to get the desired concentration. Final concentration of DMSO in the reaction was 3 % (v/v).
  • Substrate mixture was prepared by mixing H-cAMP (GE Healthcare) and 1 .0 mM cold cAMP (Sigma) in order to get 0.5 ⁇ and 1 .0 ⁇ final concentrations of each respectively in the assay buffer.
  • 1 .0 mg/mL of snake venom nucleotidase (Sigma) was prepared in D/w.
  • PDE10A assay was carried out in 200 ⁇ _. reaction volume by addition of assay buffer containing 10 mM Tris-HCl (pH 7.4), 0.2 mM MgCl 2 , . test compound at required concentration and diluted enzyme. Reaction mixture was incubated at 30 °C for 30 min. The reaction was stopped by heating the plate in boiling water bath for 5 min and then cooling on an ice bath for 1 5 min. This was followed by addition of 50 ⁇ , of Crotalus atrox snake venom 5'-nucleotidase and incubation at 30 °C for 30 min. Thereafter, 400 ⁇ of Dowex was added and incubated on an ice bath for 1 5 min.
  • Reaction mixture was centrifuged and supernatant was used for quantifying radioactivity in the samples. Reaction was measured as counts per minute (cpm) using Packard Biosciences plate reader. An enzyme control without test compounds was run to quantitate maximum PDEI OA reaction. Inhibition of enzyme activity was calculated as a percent of control reaction. IC50 values were calculated from dose response curve by nonlinear regression analysis using GraphPad Prism software.

Abstract

La présente invention a pour objet des composés hétéroaryle en tant qu'inhibiteurs de la phosphodiestérase 10A (PDE 10A). En particulier, la présente invention concerne des composés qui sont utiles pour le traitement ou la prévention de maladies, d'états pathologiques et/ou de troubles par l'inhibition de l'enzyme phosphodiestérase 10A. La présente invention concerne aussi des procédés de préparation des composés décrits dans l'invention et représentés par la forrmule (I), des intermédiaires utilisés dans leur synthèse, et des compositions pharmaceutiques correspondantes.
PCT/IB2011/000842 2010-04-19 2011-04-15 Composés hétéroaryle en tant qu'inhibiteurs de la pde 10a WO2011132048A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
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WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
WO2014002106A1 (fr) * 2012-06-25 2014-01-03 Cadila Healthcare Limited Nouveaux composés pour le traitement de la dyslipidémie et de maladies associées
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
JP2016539968A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾチアゾール誘導体
CN109053623A (zh) * 2018-08-27 2018-12-21 济南悟通生物科技有限公司 一种4-甲基-5-噻唑甲醛的新型制备方法
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11555031B2 (en) 2017-03-20 2023-01-17 The Broad Institute, Inc. Compounds and methods for regulating insulin secretion
US11578066B1 (en) 2019-12-20 2023-02-14 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof

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WO2009070584A1 (fr) * 2007-11-30 2009-06-04 Wyeth Imidazo[1,5-a]pyrazines fusionnées avec aryle et hétéroaryle en tant qu'inhibiteurs de phosphodiestérase 10

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WO2007086584A1 (fr) * 2006-01-30 2007-08-02 Meiji Seika Kaisha, Ltd. NOUVEL INHIBITEUR DE FabK ET DE FabI/K
WO2009070584A1 (fr) * 2007-11-30 2009-06-04 Wyeth Imidazo[1,5-a]pyrazines fusionnées avec aryle et hétéroaryle en tant qu'inhibiteurs de phosphodiestérase 10

Cited By (16)

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Publication number Priority date Publication date Assignee Title
US8772316B2 (en) 2011-02-18 2014-07-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)
US9670181B2 (en) 2011-02-18 2017-06-06 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
WO2014002106A1 (fr) * 2012-06-25 2014-01-03 Cadila Healthcare Limited Nouveaux composés pour le traitement de la dyslipidémie et de maladies associées
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9902710B2 (en) 2013-12-05 2018-02-27 Exonhit Therapeutics, Sa Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
JP2016539968A (ja) * 2013-12-09 2016-12-22 ユーシービー バイオファルマ エスピーアールエル Ｔｎｆ活性のモジュレーターとしてのイミダゾチアゾール誘導体
US10273247B2 (en) 2013-12-09 2019-04-30 Ucb Biopharma Sprl Imidazothiazole derivatives as modulators of TNF activity
US11555031B2 (en) 2017-03-20 2023-01-17 The Broad Institute, Inc. Compounds and methods for regulating insulin secretion
CN109053623A (zh) * 2018-08-27 2018-12-21 济南悟通生物科技有限公司 一种4-甲基-5-噻唑甲醛的新型制备方法
US11578066B1 (en) 2019-12-20 2023-02-14 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof
US11926622B2 (en) 2019-12-20 2024-03-12 Tenaya Therapeutics, Inc. Fluoroalkyl-oxadiazoles and uses thereof
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds

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