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WO2011132051A2 - Composés tricycliques en tant qu'inhibiteurs de la phosphodiestérase-10 - Google Patents

Composés tricycliques en tant qu'inhibiteurs de la phosphodiestérase-10 Download PDF

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Publication number
WO2011132051A2
WO2011132051A2 PCT/IB2011/000846 IB2011000846W WO2011132051A2 WO 2011132051 A2 WO2011132051 A2 WO 2011132051A2 IB 2011000846 W IB2011000846 W IB 2011000846W WO 2011132051 A2 WO2011132051 A2 WO 2011132051A2
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Prior art keywords
substituted
unsubstituted
pyrrolidin
pyridin
benzofuro
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WO2011132051A3 (fr
Inventor
Laxmikant Atmaram Gharat
Jitendra Maganbhai Gajera
Neelima Khairatkar-Joshi
Malini Bajpai
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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    • 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
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D405/14—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 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present patent application relates to tricyclic compounds and their use in treating or preventing diseases, conditions and/or disorders by inhibiting Phosphodiesterase- 10 (PDE- 10) enzyme.
  • PDE- 10 Phosphodiesterase- 10
  • 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.
  • Human PDE 10 was identified by identification of cDNA fragments published in the National Center for Biotechnology Information (NCBI) Expressed Sequence Tags (EST) database (Loughney et al., W099/42596). While PDE 10 was found to share homology with known PDE's, no function could be identified for PDE 10. PDE 10 has been identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed mouse PDE 10A as the first member of the PDE 10 family of PDE's [Fujishige et al., J. Biol. Chem. vol. 274, p.18438- 1 8445, ( 1999); Loughney, K. et al., Gene vol.
  • NCBI National Center for Biotechnology Information
  • EST Expressed Sequence Tags
  • 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 [Kotera, J. et al., Biochem. Biophys. Res. Comm. vol. 261 , p. 551-557, (1999); Fujishige, K. et al., Eur. J. Biochem. vol. 266, p. 11 18-1 127, (1999)]. There is a high degree of homology across species.
  • the mouse PDE 10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • the affinity of PDE 10 for cAMP is higher than for cGMP.
  • approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE 10 is a unique cAMP-inhibited cGMPase [Fujishige et al., J. Biol. Chem. vol. 274, p. 18438-18445, (1999)].
  • the PDE 10 family of polypeptides shows a lower degree of sequence homology to previously identified PDE families. These low degrees of sequence homology of PDE 10 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).
  • PDE 10A 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 PDE 1 OA is involved in diseases related to these cells, tissues and organs has been demonstrated [J. Biol. Chem. vol. 274, p. 18438 (1999), Gene, vol. 234, p. 109 (1999) and WO 01/29199].
  • neurodegenerative diseases There are very few effective treatments for neurological disorders characterized by progressive cell loss, known as neurodegenerative diseases, as well as those involving acute cell loss, such as stroke and trauma.
  • neurodegenerative diseases such as those involving acute cell loss, such as stroke and trauma.
  • neurosis which has been linked to altered striatal function relating to changes in expression of the enzyme PDE 10A [J. A. Siuciak, et al. Neuropharmacology, vol. 51 , p. 374-385, (2006)].
  • Striatal dysfunction is implicated in a number of CNS disorders including psychosis, schizophrenia, obsessive-compulsive disorders, Parkinson's disease and Huntington's disease.
  • PDE 10A knock-out mice provide evidence that PDE 10A functions to inhibit striatal output by reducing spiny medium neuron excitability.
  • PDE 10A 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 PDE 10A confirm that PDE 10A regulates both cAMP and cGMP in vivo in rats [J. A. Siuciak, et al. Neuropharmacology, vol. 51 , p. 386-396, (2006)].
  • PDE 1 OA inhibitors are useful for treating and/or preventing various diseases caused by enhanced activity of PDE 1 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 certain PDE 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 certain PDE 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 certain PDE inhibitors for treatment of obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder and obsessive-compulsive disorder.
  • WO 2009/143178, WO 2009/152825, WO 2009/158393, WO 2009/158467, WO 2009/1 58473, WO 2010/006130, WO 2010/017236, WO 2010/027097 and WO 2010/030027 describe certain PDE 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 the formula (I):
  • A, B, D and E may be same or different and are independently selected from carbon and nitrogen;
  • Z is independently selected from carbon and nitrogen, with the proviso that at least one of Z is nitrogen;
  • X is oxygen, sulphur, -S(0) t or -NR a ;
  • Y is oxygen or sulphur
  • L is a bond or independently selected from (C]-C 6 ) alkylene, (C 2 -C 6 ) alkenylene, (C 2 - C 6 ) alkynylene and carbonyl group;
  • R is independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
  • R 1 and R 3 which may be same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstitute
  • R 2 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 5 , -C(0)NR 5 R 6 , -(CH 2 ) k C(0)OR 5 and -S(0) t R 5 ;
  • R 5 and R 6 which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 7 and - C(0)NR 7 R 8 ;
  • R' and R° which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl;
  • R a is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 5 , -C(0)NR 5 R 6 , -C(0)OR 5 , -S(0) t R 5 , -S(0)NR 5 R 6 , and -S0 2 NR 5 R 6 ; at each occurrence, 'e' and 'f , which may be same or different, are independently an integer selected from 0, 1 or 2, with the proviso that e + f is 1 to 3, both inclusive;
  • 'm' is an integer ranging from 0 to 3, both inclusive;
  • 'k' is an integer ranging from 0 to 3, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 2, both inclusive.
  • ' is an integer ranging from 1 to 2, 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.
  • A, B, D and E may be same or different and are independently selected from carbon and nitrogen; with the proviso that at least one of A, B, D and E is nitrogen and remaining are independently carbon;
  • X is oxygen, sulphur, -S(0) t or -NR a ;
  • L is a bond or independently selected from (C] -C6) alkylene, (C2-C 6 ) alkenylene, (C 2 - C 6 ) alkynylene and carbonyl group;
  • R is independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
  • R 1 , R 3 and R 4 which may be same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroarylalkyl, substitute
  • R ⁇ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 5 , -C(0)NR 5 R 6 , -(CH 2 ) k C(0)OR 5 and -S(0) t R 5 ;
  • R 5 and R 6 which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 7 and - C(0)NR 7 R 8 ;
  • R and R which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyi, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl;
  • R a is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 5 , -C(0)NR 5 R 6 , -C(0)OR 5 , -S(0),R 5 , -S(0)NR 5 R 6 , and -S0 2 NR 5 R 6 ;
  • 'k' is an integer ranging from 0 to 3, both inclusive;
  • 'n' is an integer ranging from 0 to 3, both inclusive;
  • 'p' is an integer ranging from 0 to 3, both inclusive;
  • 'q' is an integer ranging from 0 to 2, both inclusive.
  • 't' is an integer ranging from 1 to 2, both inclusive.
  • R is -C(0)R 5 j wherein R 5 is heterocyclyl, preferably piperidine.
  • R is -C(0)OR 5 , wherein R 5 is preferably hydrogen or alkyl (for example methyl or ethyl).
  • R is alkyl (for example methyl, ethyl, propyl, «-butyl, n-butyl, /-butyl, ⁇ -propyI, «-pentyl, rc-hexyl, z ' so-pentyl, tteo-pentyl, n-octyl etc.).
  • R 5 is substituted or unsubstituted alkyl preferably methyl or ethyl, wherein substituent is selected from alkoxy, preferably methoxy.
  • R is aryl, preferably phenyl or naphthalene.
  • R is substituted aryl, preferably substituted phenyl, wherein the substituents on phenyl (substituent may be at any carbon) may be one or more and are independently selected from cyano, halogens (for example fluorine, chlorine, bromine or iodo), alkyl (for eg.
  • haloalkyl for example trifluoromethyl
  • alkoxy for example methoxy
  • haloalkoxy for example trifiuoromethoxy
  • alkoxycarbonyl or -COOR ⁇ wherein R x is hydrogen or alkyl (e.g. ethyl).
  • R is substituted aryl, preferably substituted phenyl, wherein the substituents on phenyl (substituent may be at any carbon) may be one or more and are independently selected from aryl (for example phenyl), or substituted or unsubstituted heteroaryl (for example 3,5-dimefhyl-isoxazolyl, 2-methylpyrazolyl, pyridyl, pyrimidine, pyrazine).
  • R is heteroaryl or heterocyclyl, preferably pyridyl, morpholinyl, quinolinequinolinyl, haloquinolinyl or quinoxalinyl.
  • R 2 is substituted or unsubstituted haloalkyl, preferably unsubstituted haloalkyl, more preferably difluoromethyl (-CHF 2 ).
  • R is substituted or unsubstituted cycloalkylalkyl, preferably unsubstituted cycloalkylalkyl, more preferably cyclopropylmefhyl.
  • X is oxygen, sulphur, -S(0) t or -NR a ;
  • L is a bond or selected from (Ci-C 6 ) alkylene, (C 2 -C 6 ) alkenylene, (C 2 -C 6 ) alkynylene and carbonyl group;
  • R is independently selected from hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl,
  • R 2 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 3 , -C(0)NR 5 R 6 , -(CH 2 ) k C(0)OR 5 and -S(0),R 5 ;
  • R 5 and R 6 which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 7 and - C(0)NR 7 R 8 ;
  • R 7 and R 8 which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl; at each occurrence, R a is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl,
  • 'k' is an integer ranging from 0 to 3, both inclusive;
  • 'n' is an integer ranging from 0 to 5, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 2, both inclusive.
  • 't' is an integer ranging from 1 to 2, both inclusive.
  • the compounds of formula (III) 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.
  • L is (Ci-C 6 ) alkylene, preferably methylene, ethylene, propylene pentylene or hexylene.
  • R is unsubstituted aryl, preferably phenyl or naphthalene.
  • R is substituted aryl, preferably substituted phenyl, wherein one or more substituents on the phenyl may be same or different and are independently selected from halogens (e.g., fluorine, chlorine, bromine or iodine), haloalky] (preferably trifluoromethyl), -OR 5 and -COOR 5 .
  • R 5 is hydrogen or alkyl (e.g., methyl, ethyl).
  • R is substituted or unsubstituted heteroaryl, preferably unsubstituted heteroaryl more preferably quinoline or benzoxazole.
  • R is substituted or unsubstituted heterocyclyl, preferably unsubstituted heterocyclyl, more preferably morpholinyl.
  • R is unsubstituted heteroarylalkyl (preferably oxadiazolylmethyl).
  • R is hydrogen, or -C(0)R 5 , wherein R 3 is heterocyclyl preferably morpholinyl.
  • R 2 is -(CH 2 ) k C(0)OR 5 .
  • R 5 is hydrogen or alkyl, preferably ethyl; and 'k' is 1.
  • R 2 is cycloalkyl (preferably cyclopentyl), substituted or unsubstituted alkyl (preferably substituted or unsubstituted methyl, wherein substituent(s) are independently heterocyclylalkyl, preferably methylenepyrrolidine) or haloalkyl (preferably difluoromeihyl)
  • X is oxygen, sulphur, -S(0) t or -NR a ;
  • L is a bond or selected from (Ci-C 6 ) alkylene, (C 2 -C 6 ) alkenylene, (C 2 -C 6 ) alkynylene and carbonyl group;
  • Ar 1 and Ar 2 are independently selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl group and substituted or unsubstituted heterocyclyl; at each occurance, R 1 , R 3 and R 4 , which may be same or different, are independently selected from halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl.
  • R 2 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R : ', -C(0)NR 5 R 6 , -(CH 2 ) k C(0)OR 5 and -S(0) t R 5 ;
  • R 5 and R 6 which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 7 and - C(0)NR 7 R 8 ;
  • R and R which may be same or different, are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heteroarylalkyl;
  • R 9 and R 10 are independently selected from, halogen, hydroxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkyl, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, -C(0)R 5 , -C(0)NR 5 R 6 , -(CH 2 )
  • R a is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, -C(0)R 5 , -C(0)NR 5 R 6 and -S(0) t R 5 ;
  • 'k' is an integer ranging from 0 to 3, both inclusive;
  • 'n' is an integer ranging from 0 to 5, both inclusive;
  • 'p' is an integer ranging from 0 to 4, both inclusive;
  • 'q' is an integer ranging from 0 to 2, both inclusive;
  • 't' is an integer ranging from 0 to 2, both inclusive;
  • 'u' and 'v' are an integer ranging from 0 to 4, both inclusive.
  • the compounds of formula (III) 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.
  • R 9 is halogen (e.g., fluorine, chlorine, bromine or iodine) and 'u' is 1.
  • R 10 is alkyl preferably methyl and V is 0 or 1.
  • R is alkyl, preferably methyl or haloalkyl, preferably difluoromethyl.
  • particularly contemplated are compounds of the formula (I), (II), (III) or (IV), which possess IC 5 o of less than 500 nM, preferably, less than 100 nM, more preferably, less than 50 nM with respect to PDE10A activity as measured by method as described in the present patent application.
  • compound of the formula (I), (II), (III) or (IV) of the present invention which selectively inhibits PDE10 activity over other PDE isozymes (i.e., a selective PDE10 inhibitor).
  • the compound selectively inhibits PDE 10 activity over PDE 4.
  • compounds of the present invention which are at least 10-fold or at least 100-fold selective over other PDE's, (e.g., PDE 4).
  • compounds of the formula (I) which possess in vitro metabolic stability, in liver microsomes of human and / or rat (SDrat or Wrat), greater than 20%, more preferably greater than 40 %.
  • 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.
  • a method for preventing, ameliorating or treating a disease, disorder or syndrome modulated by PDE-10 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of one or more compounds of Formula (I), Formula (II), Formula (III) or Formula (IV) or a pharmaceutically acceptable salt, tautomer or stereoisomer, thereof, or a pharmaceutical composition as described herein.
  • the compounds and pharmaceutical compositions of the present invention are useful for inhibiting PDE 10, which is related to a variety of disease states.
  • the present invention further provides a method of inhibiting PDE 10 receptors 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 includes, but are not limited to, ethenyl, 1 -propenyl, 2-propenyl (allyl), « ⁇ -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, all 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, -OCH3 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 H5. Unless set forth or recited to the contrary, 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 limited to, trifluoromethyl, difluoromethyl. 2,2,2-trifluoroethyl 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, trifiuoromethoxy, 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 hydroxy! groups.
  • Examples of hydroxyalkyl moiety include, but are not limited to -CH 2 OH and -C 2 H 4 OH. Unless set forth or recited to the contrary, all hydroxyalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • cyanoalkyl refers to an alkyl group as defined above wherein one to three hydrogen atoms on different carbon atoms is/are replaced by cyano groups.
  • Examples of cyanoalkyl moiety include, but are not limited to -CH 2 CN and -C 2 H 4 CN. Unless set forth or recited to the contrary, all cyanoalkyl groups described herein may be straight chain or branched, substituted or unsubstituted.
  • 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.
  • cycloalkenylalkyl refers to a cyclic ring-containing radical having 3 to about 8 carbon atoms with at least one carbon-carbon double bond, directly attached to an alkyl group.
  • the cycloalkenylalkyl 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. Unless set forth or recited to the contrary, all cycloalkenylalkyl 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 C 6 H 5 and -C 2 H 4 C 6 H 5 . 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. Examples of arylalkyloxy moiety include, but are not limited to - OCH 2 C 6 H 5 and -OC 2 H 4 C 6 H5. 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 alky] 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 heteroarylalkyl groups described herein may be substituted or unsubstituted.
  • a "selective PDE10 inhibitor” can be identified, for example, by comparing the ability of a substance to inhibit PDE10 activity to its ability to inhibit PDE enzymes from the other PDE families. For example, in this invention a substance may be assayed for its ability to inhibit PDE 10 activity, as well as PDE 4, as described in the examples below.
  • selective PDE 10 inhibitor refers to a substance, for example an organic molecule that effectively inhibits an enzyme from the PDE 10 family to a greater extent than any other PDE enzyme, particularly any enzyme from the PDE 4.
  • a selective PDE 10 inhibitor is a substance, for example organic molecule can reduce PDE 10 activity at least 10-fold or at least 100-fold or at least 200-fold compared to other PDE's, (e.g., PDE 4) (as measured by its IC50 values, for instance, as determined by the methods described in the examples below).
  • 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, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, and serine), salts of non-natural amino acids (such as D-
  • 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/ro tamers. 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 PDE 10 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 further provides a method of treating a disease, condition or disorder modulated by a PDE 10, 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 PDE 10 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
  • 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 PDE 10.
  • 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 I disorder, bipolar II 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 compounds described herein can be prepared using techniques known to one skilled in the art, for example through the reaction sequences depicted in Scheme 1 , 2, 3 and 4. Furthermore, in the following scheme, where specific acids, bases, reagents, coupling agents, solvents, etc. are mentioned, it is understood that other suitable acids, bases, reagents, coupling agents etc. may be used and are included within the scope of the present invention. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. The compounds obtained by using the general reaction sequences may be of insufficient purity.
  • the starting materials for the below reaction schemes are commercially avai lable or can be prepared according to methods known to one skilled in the art or by methods disclosed herein.
  • the compounds according to the present invention may be prepared through the reaction scheme as follows, wherein A, B, D, E, R, R 1 , R 2 , R 3 , R 4 , R 9 , R 10 , R a , L, X, Z, Ar 1 , Ar 2 , n, p, q, u and v are defined above.
  • the compound of formula [(11), Scheme- 1 ) can be prepared as depicted in scheme- 1 and scheme-2.
  • a compound of formula ( 1 ) wherein G is halogen can be converted to the compound of formula (2) under catalytic reduction conditions for example utilizing palladium on carbon in presence of hydrogen gas and in suitable solvent (for example liquor ammonia).
  • the compound of formula (2) can be further converted to the compound of formula (3) (where G is halogen) by reacting with suitable halogenating agent for example N- halosuccinimide in suitable solvent.
  • the compound of formula (7) can be obtained by reacting the compound of formula ( 3) with the compound of formula (4) where R b is alkyl preferably methyl (e.g. methyl acrylate), in a suitable reagent and solvent under Heck coupling reaction conditions well known in the art.
  • the compound of formula (7) can also be prepared by using compound of formula (5) in two subsequent reactions that is: formula ( 5) (wherein R4 may be hydrogen) can first be reacted with compound of formula R 4 CH(COOH) 2 , wherein R4 may be hydrogen (e.g..
  • the compound of formula (7) can be treated with compound of formula R 4 CH 2 -N0 2 (wherein R 4 may be hydrogen, e.g. nitromethane) to yield compound of formula (8).
  • the compound of formula (8) can be cyclized (reductive cyclization) to a compound of formula (9). for example by reduction of the compound of formula ( 8) followed by cyclization e.g.. the reduction may be performed using hydrogen and Raney nickel catalyst, suitable solvent for example alcohol, (methanol ) and ammonium hydroxide.
  • the compound of formula ( 9) can be further converted to a compound of formula (II) by reacting with the compound of formula R-L-Lev (wherein Lev is a good leaving group such as bromo, chloro, iodo etc) under suitable dehydrohalogenation conditions well known in the art of organic chemistry.
  • the compound of formula [(5), Scheme- 1 A] can be prepared as depicted in scheme- 1 A.
  • a compound of formula ( 10), wherein Hal is a halogen, preferably fluorine, bromine or iodine and W is a N0 2 , NH 2 , Br, or I, can be reacted with a compound of formula ( 1 1 ) wherin FL) is hydrogen and X is oxygen (e ,g.,isovanillin) to give the compound of formula ( 12).
  • the compound of formula (5) can be obtained by cyclization of compound of formula ( 12) in the presence of a suitable reagent, for example palladium acetate in presence of potassium carbonate or sodium acetate or under acdic condition for example using sulfuric acid, phosphoric acid etc.
  • a suitable reagent for example palladium acetate in presence of potassium carbonate or sodium acetate or under acdic condition for example using sulfuric acid, phosphoric acid etc.
  • the compound of formula (8) can be hydrolyzed to the acid intermediate of formula ( 1 3) under basic condition (e.g., aq. NaOH) in suitable solvent (methanol, ethanol etc).
  • the acid intermediate of formula ( 1 3) can be converted to the diastereomeric mixture of formula ( 1 4) using various basic resolving agents (e.g., (S)-(-) a-methyl benzyl amine).
  • the diastereomeric mixture ( 14) can be resolved into its respective diastereomers ( 14a) and ( 14b) which could be cyclised under reductive conditions (e.g., Zinc/acetic acid, raney nickel/triethyl amine, H 2 /Pd on carbon etc.) to obtain the compound of general formula (9a) and (9b) respectively.
  • reductive conditions e.g., Zinc/acetic acid, raney nickel/triethyl amine, H 2 /Pd on carbon etc.
  • These can be further derivatized to the compound of formula (lla) and (lib), (Scheme-2) by sequential transformation as described in synthetic scheme 1 .
  • the compound of formula ( 1 5) can be condensed with an active methylene compound of formula R H(COOH) 2 wherein R* may be hydrogen or alkyl such as methyl (e.g., malonic acid) in the presence of suitable catalyst (e.g., piperidine) to give the compound of formula ( 16).
  • suitable catalyst e.g., piperidine
  • the esterification of compound of formula ( 16) can be carried out under basic condition (e.g., potassium carbonate) by reacting it with compound of formula R b -Lev (wherein R b may be alkyl such as methyl and Lev may be good leaving group such as bromo. chloro, sulphate etc, e.g.. methyl iodide, dimethyl sulphate) to afford compound of formula ( 1 7).
  • the compound of formula ( 1 7) can be directly obtained by reacting the compound of formula ( 1 5) with compound of formula R 4 CH(COOR b )2, wherein R may be alkyl (e.g. alky 1 malonate) under suitable Knoevenagel condensation reaction conditions for example in presence of catalytic amount of piperidine.
  • the compound of formula ( 17) can be reacted with compound of formula R 4 CH 2 -N0 2 (wherein R 4 is hydrogen) in the presence of a base preferably 1 , 1 ,3,3- tetramethyl guanidine to yield compound of formula (18) (where R 4 is hydrogen).
  • the compound of formula ( 1 8) can be converted to compound of formula ( 19) under reductive condition followed by cyclization in the presence of suitable reagent (e.g., raney nickel/triethyl amine. Zinc/acetic acid, H 2 /Pd on carbon etc.) by procedures known in the art of organic synthesis.
  • suitable reagent e.g., raney nickel/triethyl amine. Zinc/acetic acid, H 2 /Pd on carbon etc.
  • Compound of formula (III) can be prepared by the reaction of compound of formula ( 19) with halo compound of formula R-L-Lev (wherein, Lev may be good leaving group such as bromo.
  • Halogenated compound of formula (21 ) (wherein Hal is iodo, chloro or bromo) can be prepared by the reaction of compound of formula ( 19) with cyclic halo compound of formula (20) (wherein Lev is good leaving group such as bromo, chloro, iodo etc) in the presence of suitable base (e.g., sodium hydride) in suitable solvent (e.g., dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.).
  • suitable base e.g., sodium hydride
  • suitable solvent e.g., dimethylformamide, dimethylsulphoxide, tetrahydrofuran etc.
  • the halogenated compound of formula (21 ) can be subjected to palladium (0) catalyzed C-C coupling (e.g., Suzuki coupling) reactions with appropriate boronic acid of formula (22) to give compound of formula (IV).
  • a compound of formula ( 19) may be directly converted to a compound of formula (IV) by reacting with compound of formula (23) (wherein Lev is good leaving group such as bromo, chloro, iodo etc.) in the presence of suitable reagent (e.g., sodium hydride) by following procedures known in the art of organic synthesis.
  • suitable reagent e.g., sodium hydride
  • a compound of formula (24) can be prepared by the dealkylation of the compound of formula (21 ), (wheirin R 2 is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl preferably cyclopentyl) using suitable reagents and conditions such as acidic conditions using acid like HBr (48%) in acetic acid.
  • the halogenated compound of formula (21 ) can be further subjected to palladium (0) catalyzed C-C coupling (e.g., Suzuki coupling) reactions with appropriate boronic acid of formula (22) to give compound of formula (IV).
  • palladium (0) catalyzed C-C coupling e.g., Suzuki coupling
  • Compound of formula ( 15) may be prepared through the reaction scheme as follows.
  • the compound of formula (26) can be prepared by the reaction of compound of formula (25) under basic conditions using base such as ;?-butyl lithium in the presence of suitable reagents (e.g., iri methyl borate).
  • the compound of formula (26) can be alkylated using an alkylating agent such as alkyl halide (e.g., methyl iodide, cyclopentyl bromide) under basic conditions (e.g., potassium salts in dimethylformamide or dimethyl sulphoxide, NaH in dimethylformamide or dimethyl sulphoxide) to yield the alkylated product of formula (27).
  • alkylating agent such as alkyl halide (e.g., methyl iodide, cyclopentyl bromide)
  • basic conditions e.g., potassium salts in dimethylformamide or dimethyl sulphoxide, NaH in dimethylformamide or dimethyl sulphoxide
  • Compound of formula (27) can be reacted with formylating reagent (e.g., ⁇ , ⁇ -dichloro methyl methyl ether) or acylating reagent (R COCl wherein R 4 may be hydrogen or alkyl such as methyl such as Acetyl chloride) in the presence of Lewis acid catalyst (e.g., A1C1 3 , SnCl 4 , T1CI4, FeCb, ZnCli etc) to afford carbonyl compound of formula (28).
  • Lewis acid catalyst e.g., A1C1 3 , SnCl 4 , T1CI4, FeCb, ZnCli etc
  • the compound of formula (28) can be optionally substituted using suitable substitution reagents by following procedures known in the art of organic synthesis to obtain optionally substiututed compound of formula ( 1 5), (Scheme-3A).
  • the compound of formula (30) can be prepared by the de-alkylation of compound of formula 29 (wheirin R 2 is cycloalkyl preferably cyclopentyl) under acidic conditions using acid such as HBr (48%) in acetic acid.
  • the compound of formula (30) can be alkylated using an alkylating agent such as halomefhane (e.g., chloro difluoro methane) under basic conditions (e.g., potassium salts in dimethylformamide or dimethyl sulphoxide, NaH in dimethylformamide or dimethyl sulphoxide) to yield the alkylated product of formula (29).
  • a compound of formula (29) can be optionally substituted using suitable substitution reagents by following procedures known in the art of organic synthesis to obtain optionally substituted compound of formula ( 1 5).
  • the compound of formula (33) can be cyclised using metal compound or metal catalysed coupling condition (e.g., palladium acetate in dimethylformamide or glacial acetic acid, nickel catalyst in pyridine or dimethylformamide, tetrakistriphenylphosphinepalladium in dimethylformamide and the like), to yield the tricyclic compound of formula ( 1 5).
  • metal compound or metal catalysed coupling condition e.g., palladium acetate in dimethylformamide or glacial acetic acid, nickel catalyst in pyridine or dimethylformamide, tetrakistriphenylphosphinepalladium in dimethylformamide and the like
  • the compound of formula (34, Scheme-3D), wherein Hal is a halogen, preferably fluorine, bromine or iodine and W is a halogen, preferably bromine or iodine, can be reacted with compound of formula (35) under basic condition (e.g., potassium salts in dimethylformamide or dimethyl sulphoxide, NaH in dimethylformamide or dimethyl sulphoxide and the like) to obtain compound of formula (36).
  • the compound of formula (36) can be cyclised using metal compound or metal catalysed coupling condition (e.g..
  • the compound of formula ( 18) can be hydrolyzed to the acid intermediate of formula (37) under basic condition (e.g., aq. NaOH) in suitable solvent (methanol, ethanol etc).
  • the acid intermediate of formula (37) can be converted to the diastereomeric mixture of formula (38) using various basic resolving agents (e.g., (S)-(-) a-methyl benzyl amine).
  • the diastereomeric mixture (38) can be resolved into its respective diastereomers (38a) and (38b) which could be cyclised under reductive conditions (e.g..
  • R. R 2 or substitituent e.g R 1 , R 3 , R R 9 or R 10 if present in the formula (I), (II), (III) or (IV) may be transformed into another at a chemically compatible stage of the synthetic sequence, in the presence of suitable reagent by following procedures known in the art of organic synthesis to obtain the final compound of formula formula (I), (II), (III) or (IV).
  • Step 1 4-Methyl phenyl boronic acid.
  • Step-3 - 5-[4-(Bromomethyl)phenyl]pyrimidine
  • Step- 1 3-Fluoro-4-methyl-phenyl-boronic acid
  • Step-3 2-(4-Bromomethyl-3-fluoro-phenyl)-pyrimidine
  • the title compound was prepared by following the similar procedure as described in step-3 of lnermedaite-1 by using 2-(3-fluoro-4-methyl-phenyl)-pyrimidine (0.500 g, 2.659 mmol), N- bromosuccinimide (0.378 g, 2.127 mmol) and AIBN (catalytic amount) carbon tetrachloride (15 mL) to get desired product (0.520 g). !
  • Step- 1 2-(3-Fluoro-4-methyl-phenyl)-pyrazine
  • step-2 of intermediate- 1 The title compound was prepared by following the similar procedure as described in step-2 of intermediate- 1 by using 3-fluoro-4-methyl-phenyl-boronic acid (1.000 g, 8.730 mmol), 2- chloro pyrazine (1.45 g, 9.60 mmol), isopropyl alcohol (1 mL), tetrakis triphenyl phosphine Pd(0) (0.015 g) and sodium carbonate (1.85 g in water) to get desired product (0.950 g).
  • Step- 2 2-(4-Bromomethyl-3-fluoiO-phenyl)-pyrazine
  • the title compound was prepared by following the similar procedure as described in step-3 of lntertmediate-1 by using 2-(3-fluoro-4-methyl-phenyl)-pyrazine (0.200 g, 1.06 mmol), N- bromosuccinimide (0.151 g, 0.851 mmol), AIBN (catalytic amount), carbon tetra chloride (10 mL) to get desired product 0.300 g of desired product.
  • the title compound was prepared by following the similar procedure as described in step -2 of Intermediate- 1 by using 4-methyl phenyl boronic acid (0.300 g, 1.88 mmol), 2-bromo pyrimidine (0.592 g, 2.26 mmol). tetrakis triphenyl phosphine Pd(0) (0.030 g) and isopropyl alcohol (10 mL) to obtain desire product (45 %).
  • the title compound was prepared by following the similar procedure as described in step - 3 of Intertmediate-l by using 2-(4-methylphenyl)pyrimidine (0.270 g, 1.58 mmol), /V-bromo succinimide (0.226 g, 1.27 mmol), catalytic amount of benzoyl peroxide to obtain 0.075 g of desired product.
  • Step- 1 3-Oxo-3-/?-tolyl-piOpionic acid methyl ester
  • the title compound was prepared by following the similar procedure as described in step-3 of lntertmediate- 1 by using 2- -tolyl-pyrazine (0.500 g, 2.94 mmol), N-bromosuccinimide (0.41 8 g, 2.35 mmol), catalytic amount of benzoyl peroxide to obtain of desired product (yield 50 %).
  • Step- 1 - 1 -(4-Bromo-phenyl)-ethanol
  • Step-2 - 1 -Bromo-4-( 1 -bromo-ethyl)-benzene
  • the title compound was prepared by following the similar procedure as described in step-3 of Intertmediate- 1 by using 5-methyl qunaxoline (0.350 g, 2.430 mmol), N-bromosuccinimide (0.389 g, 2.18 mmol), catalytic amount AIBN to obtained desired product (45 %).
  • Step- 1 - 5-Fluoro-8-methyl-quinoline Solution of 2-amino-4-fluoro toluene (2.0 g, 6.0 mmol) and 3-nitro benzene sulphonate (3.6 g, 1 6.0 mmol ) in glycerol/ sulphuric acid was refluxed for 5 h. Allowed the reaction mass to 0°C then added mixture of ethyl acetate and water and basified with sodium hydroxide. Organic layer was washed with brine and dried over anhydrous sodium sulphate and concentrated to obtain desired product. (41 %). ⁇ NMR (DMSO-d 6 ): ⁇ 2.88 (s, 3H), 7.08- 7. 14 (m, 1 H), 7.44-7.50 (m, 2H), 8.41 -8.43 (m, 1 H), 8.98-8.99 (m, l H).
  • the title compound was prepared by following the similar procedure as described in step-3 of Intertmediate- 1 by using 6-methyl quinoline (0.500 g, 3.49 mmol), /V-bromosuccinimide (0.373 g, 2. 16 mmol), AIBN (catalytic amount), carbon tetra chloride ( 10 mL) to get desired product( 60 %).
  • Step- 1 4-Bromo-2,6-difluoro-benzaldehyde
  • Step-3 5-Bromo-2-bromomethyl- l ,3-difluoro-benzene
  • the title compound was prepared by following the similar procedure as described in step-3 of Intertmediate- 1 by using 6-bromo-2-fluoro toluene ( 1 .200 g, 5.08 mmol ). N- bromosuccinimide (0.724 g, 4.06 mmol), AIBN (catalytic amount), carbon tetra chloride (25 mL) to get desired product 0.800 g of desired product ⁇ NMR (300 MHz, DMSO-i3 ⁇ 4: ⁇ 4.46 (s. 2H), 7.25-7.28 (m, 3H).
  • Step 1 Dibenzo[ ,c/]furan-4-ol (lntm- 1 7a)
  • Step 3 4-(Methoxy)dibenzo[6, o furan-l-carbaldehyde (Intm-17c)
  • Step 6 ( ⁇ )-Methyl 3-[4-(methoxy)dibenzo[6,i/]furan-l -yl]-4-nitrobutanoate (Intm-17f) To a solution of methyl 3-[4-(methoxy)dibenzo[6,if
  • Step 7 ( ⁇ )-4-[4-(Methoxy)dibenzo ⁇ b,d] furan-l-yl] pyrrolidin-2-one (Intermediate-! 7)
  • Triethyl amine (50.0 mmol) and raney nickel (catalytic amount) were added to a mixture of methyl 3-[4-(methoxy)dibenzo[>,t]furan-l-yl]-4-nitrobutanoate, obtained in Step 6 (100 mmol) in methanol at room temperature.
  • the reaction mixture was subjected for hydrogenation in Parr apparatus under 55-60 psi pressure for 2-3 hours.
  • Step 1 ( ⁇ )-3-(4-Methoxydibenzo[6,i/]furan-l-yl)-4-nitrobutanoic acid (lntm-17g)
  • Step 2 ( ⁇ )-3-(4-Methoxydibenzo[i,i/]furan-l-yl)- ⁇ -(l-phenylethyl)-4-nitrobutanamide
  • Step 3a (-)-4-[4-(Methoxy) dibenzo [b, d] furan-l-yl] pyrrolidin-2-one (Intermediate- 17 A) To a stirred solution of 3-(4-methoxydibenzo[0,c/]furan-l -yl)-A'-( l-phenylethyl)-4- nitrobutanamide, obtained in Step 2, diastereomer 1 (0.200g, 0.462 mmol) in acetic acid at 90°C was added zinc powder (0.150 g, 2.31 mmol) and the mixture was refluxed for 3 hours. The reaction mixture was filtered through celite bed and bed was washed 2-3 times with ethyl acetate.
  • Step 3b (+)-4-[4-(Methoxy) dibenzo [b, d] furan-l-yl] pyrrolidin-2-one (Intermediate- 17B)
  • Step 1 4-(Cyclopentyloxy) dibenzo [b. d] furan (Intm-18a)
  • Step 3 3-[4-(Cyclopentyloxy)dibenzo[6,i/]furan-l-yl]acrylic acid (Intm-18c)
  • To a mixture of 4-(cyclopenty)oxy)dibenzo[Z?, ⁇ ]furan- l -carbaldehyde, obtained in Step 2 (0. 100 g, 0.356 mmol) in toluene was added malonic acid (0.055 g, 0.528 mmol) fol lowed by catalytic amount of piperidine at room temperature and refluxed (to remove water azeotropically using Dean and Stark apparatus) for 8- 1 0 hours.
  • the mixture was cooled to ambient temperature and extracted with 10% sodium hydroxide solution.
  • Step 4 Methyl-3-[4-(cyclopentyloxy)dibenzo[fr,c/]furan- l -yl]acrylate (Intm- 1 8d)
  • Step 5 ( ⁇ )-Methyl-3-[4-(cyclopentyloxy)dibenzo[ 7,i/]furan- l -yl]-4-nitrobutanoate(Intm- l 8e)
  • a solution of methyl-3-[4-(cyclopentyloxy)dibenzo[ ⁇ ,cf]furan- l -yl]acrylate, obtained in Step 4 (0.500 g, 1 .48 mmol) in nitro methane (5 mL) was added catalytic amount of 1 , 1 ,3,3- tetramethyl guanidine and mixture was refluxed for 7-8 hours.
  • Step 6 ( ⁇ )-4-[4-(Cyclopentyloxy)dibenzo[6,i/]furan- l -yl]pyrrolidin-2-one (Intermediate- 1 8) To a solution of ( ⁇ )-methyl 3-[4-(cyclopentyloxy) dibenzo [b, d] furan- 1 -yl]-4- nitrobutanoate, obtained in Step 5 ( 10 mmol) in methanol was added triethyl amine ( l mL) and catalytic amount of raney nickel catalyst. The resulting suspension was hydrogenated at 55-60 psi pressure for 2-3 hours in a Parr hydrogenator.
  • N-bromo succinimide (90 mmol) and benzoyl peroxide (5 mmol) were added to a solution of 2-fluoi -4-iodo- l -methylbenzene ( 100 mmol) in carbon tetrachloride and the mixture was refluxed for 48 hours. The reaction mixture was concentrated under reduced pressure and resultant residue was extracted with ethyl acetate.
  • Step 1 3-Fluoro-4-methyl phenyl boronic acid
  • step 2 To a solution of 5-(3-fluoro-4-methylphenyl) pyrimidine, obtained in step 2 (0.300 g, 1 .59 mmol) in carbon tetrachloride was added N-bromo succinimide (0.227 g, 1 .27 mmol), catalytic amount of azobisisobutyronitrile (AIBN) and resultant mixture was refluxed for 24 hours. The excess amount of solvent was distilled and resultant residue was diluted with water and dichloromethane.
  • N-bromo succinimide 0.227 g, 1 .27 mmol
  • AIBN azobisisobutyronitrile
  • Step 1 ( ⁇ )-4- ⁇ [4-(4-Methoxydibenzo[b,d]furan- 1 -yl)-2-oxopyrrolidin- 1 - yl]methyl ⁇ benzonitrile (Intm-23a)
  • Step 1 5-(4-Methylphenyl)isoxazole.
  • Step- 1 ( ⁇ )-Ethyl-[4-(4-methoxydibenzo[6,J]furan- 1 -yl)-2-oxopyrrolidin- 1 -yljacetate
  • Step 2 ( ⁇ )-[4-(4-Methoxydibenzo[0,i]furan-l-yl)-2-oxopyrrolidin-l-yl]acetic acid
  • aqueous solution of OH (0.137 g, 2.44 mmol)
  • Step 1 4-Hydroxydibenzo[6,c]furan-l-carbaldehyde (Intm-27a)
  • Step 2 4-(Difluoromethoxy)dibenzo[?,iJ r
  • Step 4 Methyl (2£ -3-[4-(difluoromethoxy)dibenzo[6,i]furan-l-yl]acrylate (lntm-27d)
  • (2/)-3-[4-(difluoromethoxy)dibenzo[ ,i ]furan-l-yl]acrylic acid 13 g, 42.72 mmol
  • potassium carbonate 12.28 g, 88.98 mmol
  • methyl iodide 7.57 g, 53.32 mmol
  • Step 6 ( ⁇ )-3-[4-(Difluoromethoxy)dibenzo[0,i/]furan-l-yl]-4-nitrobutanoic acid (Intm-27f) To the solution of ( ⁇ )-3-[4-(difluoromethoxy)dibenzo[6, ⁇
  • Step 7 2-( " 4-(Dir1uoromethoxy)dibenzo[ ⁇ ,( ⁇ furan-l-yl]-A / -(]-phenylethyl)-4-nitrobutanamide
  • benzene 100 mL
  • thionyl chloride 10 mL
  • Step 8 (+)-4-[4-(Difluoromethoxy)dibenzo[6,if)furan-l-yl]pyrrolidin-2-one
  • Step 1 2-[4-(Cyclopentyloxy)dibenzo[ ⁇ ,t/]furan-l-yl]-V-(l-phenylethyr)-4-nitrobutanamide
  • the title compound was prepared according to the procedure as described in step 7 of Intermediate-27 by using ( ⁇ )-3-[4-(cyclopentyloxy)dibenzo[i>,c/]furan-l-yl]-4-nitrobutanoic acid (15.5 g, 40.46 mmol), thionyl chloride (10 mL), (S) (-) a-methyl benzyl amine (12.23 g, 101.150 mmol) and triethyl amine ( 4 mL) to get 3.8 g of the desired product.
  • Step 2 (+)-4-(4-Cyclopentyloxydibenzo[6,cf)furan- 1 -yl)pyrrolidin-2-one (lntm-28b)
  • Step 3 (+)-4-(4-Cyclopentyloxydibenzo[ ⁇ furan-l -y))-l -(4-iodobenzyl)pyrro]idin-2-one
  • Step 4 4-(4-Hydroxydibenzo[6,c/]furan-l-yl)-l-(4-iodobenzyl) pyrrolidin-2-one (Intm-28d)
  • the title compound was prepared according to the procedure as described in step 1 of intermediate-27 by using (+)-4-(4-cyclopentyloxydibenzo[6,(i]furan-l-yl)-l-(4-iodobenzyl) pyrrolidin-2-one (1.0 g, 1.81 mmol), acetic acid (10 mL), (48%) HBr (5 mL) to get 0.500 g of the desired product.
  • Step 5 (+)-4-[4-(Difluoromethoxy)dibenzo[6,i]furan-l-yl]-l -(4-iodo benzyl)pyrrolidin-2- one (Intermediate-28)
  • Step 2 Ethyl 4-(bromomethyl)benzoate (Intermediate-3 1 )
  • Step -1 - ( 2iT)-3-[6-(DifluoiOmethoxy)[ l ]benzofuiO[3,2-c]pyridin-9-yl]acrylic acid ( l a)
  • 6-(difluoromethoxy) [ 1 ] benzofuro [3,2-c] pyridine-9-carbaldehyde (0. 100 g, 0.378 mmol) and catalytic amount of piperidine in toluene, was added malonic acid (0.059 g, 0.567 mmol) at room temperature.
  • the reaction mixture was refluxed for 8 hours to remove water by using Dean and stark apparatus.
  • Step-3 ( ⁇ )-Ethyl 3-[6-(difluoromethoxy)[l ]benzofuro 3,2-c]pyridin-9-yl]-4-nitrobutanoate (lc)
  • Catalytic amount 1.1.3,3-tetramethyl guanidine was added to a stirring mixture of ethyl (2/r)-3-
  • the reaction was allowed to cool at room temperature and excess of nitro methane was removed under reduced pressure and resultant residue was extracted with ethyl acetate.
  • the organic layer was washed with water, brine, dried over anhydrous sodium sulphate and concentrated to obtain crude product which was purified by column chromatography to obtain desired product (yield 55 %).
  • Step-4 ( ⁇ )3-[6-(Difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]-4-nitrobutanoic acid (Id)
  • Aqueous sodium hydroxide (100 mmol) solution was added to a solution of ethyl 3-[6- (difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]-4-nitrobutanoate (50.0 mmol) in methanol and resultant mixture was heated to reflux for lhr. The excess of solvent was reduced under vacuum and resultant residue was acidified with 10 % aqueous acetic acid solution and further extracted with ethyl acetate.
  • Step-5 (-)-3-[6-(Difluoromethoxy)[l] benzofuro [3, 2-c] pyridin-9-yl-N-(l -phenyl ethyl)-4- nitrobutanamide and (+)-3-[6-(difiuoromethoxy)[l] benzofuro [3, 2-c] pyridin-9-yl-/V-(l- phenyl ethyl)-4-nitrobutanamide
  • ' 3,2-c]pyridin-9-yl]-4- nitrobutanoic acid (0.450 g, 1.23 mmol).
  • Step-6a (-)-4-[6-(Dif]uoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]pyrro]idin-2-one
  • (-)-3-[6-(difluoromethoxy)[l] benzofuro [3,2-c] pyridin-9-yl-N-(l -phenyl ethyl)-4-nitrobutanamide (diastereomer 5) (50.0 mmol) in acetic acid was heated at 60-70 °C.
  • zinc dust 500 mmol
  • Step-6b (+)-4-[6-(Difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]pyrrolidin-2-one
  • Example-5 to Example-53 mentioned in below Table-I were prepared using ( ⁇ )-4-[6- (difluoromethoxy)[ ] ]benzofuro[3,2-c]pyridin-9-yl]pyrrolidin-2-one (Example-3) and appropriate alkyl/aryl halide having formula R-L-Lev (wherein Lev is halogen e.g Br, CI. or 1, Table I), by following the similar procedure as described in Example-4.
  • Table- 1 Structural details of Example-5 to 53 and R-L-Lev
  • Step-1 ( ⁇ ) 4-[6-(Difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]-l-(2-nuoro-4- iodobenzyl) pyrrolidin-2-one (54a)
  • Step-2 ( ⁇ ) 4-(6-Difluoromethoxy[l]benzofuro[3,2-c]pyridin-9-yl)-l-(2-fluoro-4-phenyl benzyl )pyrrolidin-2-one:
  • Tetrakistriphenylphosphine Pd (0) (5.0 mol, catalytic amount), aqueous sodium carbonate (0.027g, 0.253 mmol) and phenyl boronic acid (0.023 g, 0.190 mmol) was added in a stimng degassed solution of ( ⁇ )-4-f6-(difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]-l-(2-fluoiO- 4-iodobenzyl)pyrrolidin-2-one (step-1 product) (0.070 g, 0.126 mmol) in 1 ,2-dimethoxy ethane (5 ml) and resultant mixture was refluxed for 48 hours.
  • Example-1 The title compound was prepared by following the similar procedure described in Example-4, by using (-) 4-[6(difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]pyrrolidin-2-one (Example-1, 0.100 g, 0.314 mmol), sodium hydride (0.015 g.0.625 mmol), 4-chloro benzyl bromide (0.07 lgm.
  • Example-2 The title compound was prepared by following the similar procedure as described in Example-4 by using (+)-4-[6-(difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]pyrrolidin-2- one (Example-2, 0.100 g, 0.314 mmol), sodium hydride (0.015 g, 0.625 mmol), 4-chloro benzyl bromide (0.071 g, 0.345 mmol) and dimethyl formide to obtain desired product (yield 50 %); ⁇ NMR (300 MHz, CDC1 3 ): ⁇ 2.76-2.81 (m, 1H), 3.05-3.13 (m.1H), 3.37-3.40 (m, 1H), 3.86-3.90 (m.
  • Step- 1 (+)-4-[6-(Difluorornethoxy)[l]benzofuro[3.2-c]pyridin-9-yl]-l-(2-iluoro-4-iodo benzyl) pyrrolidin-2-one:
  • Step -2 (+)-4-(6-Difluoromethoxy[l]benzofuro[3,2-c]pyridin-9-yl)-l-(2-fluoro-4-pyridin-3- ylbenzyl) pyrrolidin-2-one
  • Step-1 - l-(5-Bromo-2-fluorobenzyl)-4-[6-(difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9- yl]pyrrolidin-2-one (63a)
  • Step-2 4-[6-(Difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]-l-[2-nuoro-5-(pyridine-3- yl)]pyrrolidin-2-one
  • This compound was prepared by following same procedure as described for Example-4 by using (+) 4-[6-(difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]pyrrolidin-2-one (Example- 2, 0.080 g, 0.251 mmol) and 5-[4-(bromomethyl)phenyI]pyrimidine (Intermediate- L 0.070 g, 0.281 mmol) to obtain desired product (yield 30 %).
  • This compound was prepared by following same procedure as described for Example-4 by using (+) 4-[6-(difluoromethoxy)[l]benzofuro[3,2-c]pyridin-9-yl]pyrrolidin-2-one (Example- 2, 0.050 g, 0.157 mmol) and 4-chloro-2-fluorobenzyl bromide (0.053 g, 0.235 mmol) and (60%) sodium hydride (0.009 g, 0.392 mmol) to get desired product. (28 %).
  • Step- 1 4-Methoxy-3-[(4-nitropyridin- -oxide-3-yl)oxy]benzaldehyde (68a)
  • Step-2 4-Methoxy-3-[(4-aminopyridin-3-yl)oxy]benzaldehyde (68b)
  • Step-3 - 8-Methoxy[ ] ]benzofuro[2,3-c]pyridine-5-carbaldehyde (68c)
  • sulphuric acid 45 mL
  • sodium nitrite 32.0 mmol
  • Reaction mixture was then stirred at -5 to 0 °C for 2 more hours and then heated to 70-80 °C for 1-2 hour.
  • the reaction mixture was then cooled to ambient temperature and diluted with water.
  • Step-6 ( ⁇ )-Ethyl 3-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)-4-nitro butanoate (68f)
  • the title compound was prepared by following the similar procedure as described in step - 3 of Example-1 by using ethyl (2 )-3-(8-methoxy[l]benzofuro[2,3-i , ]pyridin-5-yl) acrylate (0.7 mmol), Catalytic amount 1,1,3,3-tetramethyl guanidine and nitro methane to obtain desired product (60 %).
  • Step-7 - ( ⁇ )-3-(8-Methoxy[l]benzofuro[2,3-c]pyridin-5-yl)-4-nitrobutanoic acid (68g)
  • the title compound was prepared by following the similar procedure as described in step - 4 of Example- 1 by using ( ⁇ )-Ethyl 3-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)-4-nitro butanoate (2.10 g, 5.865 mmol), aqueous solution of sodium hydroxide (0.426 g.10.65 mmol in 10 mL of water) and methanol to get desired product.(71%).
  • Step- 8 - (-) 3-(8-Methoxy[l]benzofuro[2,3-c]pyridin-5-yl)-N-(l-phenylethyl)-4-nitro butanamide and (+) 3-(8-Methoxy[l]benzofuro[2,3-c]pyridin-5-yl)-N-(l-phenylethyl)-4- nitrobutanamide.
  • Example-68 4-(8-Methoxy-benzofuro[2,3-c]pyridin-5-yl)-pyrrolidin-2-one
  • Example-68 The title compound (example-68) was prepared by following the similar procedure as described in step - 6 of Example- 1 by using (-) 3-(8-methoxy[l]benzofuro[2,3-c]pyridin-5- yl)-N-(l-phenylethyl)-4-nitrobutanamide (Diastereomer-7, 0.600 g, 1.385 mmol), zinc powder, acetic acid (20 mL) to get desired product. (30%).
  • Step-9b - (+) 4-(8-Methoxy-benzofuro[2,3-c]pyridin-5-yl)-pyrrolidin-2-one (Example-69)
  • the title compound (example-69) was prepared by following the similar procedure as described in step - 6 of Example-1 by using (+) 3-(8-methoxy[l]benzofuro[2,3-c]pyridin-5- yl)-/V,(l-phenylethyl)-4-nitrobutanamide (Diastereomer -8, 0.600 g, 1.385 mmol), acetic acid (20 mL) to get desired product. (25%).
  • the title compound was prepared by following the similar procedure as described in Example-3 by using ( ⁇ _) 3-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)-4-nitiO butanoate (10 mmol), raney nickel (catalytic amount) and ammonium hydroxide solution to obtain the desired product (25 %).
  • Example-70 The title compound was prepared by following the similar procedure as described in Example-4 by using 4-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)pynOlidin-2-one (Example-70, 0.177 mmol) and 4-chloro2-fluorobenzylbromide (0.059 g, 0.265 mmol), sodium hydride (0.014 g, 0.354 mmol) and DMF to obtain desired product.
  • Step- 1 - ( ⁇ ) l-(2-Fluoro-4-iodobenzyl)-4-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl) pyrrolidin-2-one (72a)
  • the title compound was prepared by following the similar procedure as described in Example-4 by using ( ⁇ ) 4-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)pyrrolidin-2-one (0.150 g, 0.539 mmol, Example-70), sodium hydride (0.028 g, 0.694 mmol), N,N-dimethyl formamide (5 mL) and 2-fluoro-4-iodo benzyl bromide (0.201 g, 0.638 mmol) to obtain desire product.(l 33%).
  • Step-2 - ( ⁇ ) l-(2-Fluoro-4-pyridin-3-yIbenzyl)-4-(8-methoxy[l]benzofuro[2,3- ⁇ :]pyridin-5- yl)pyrrolidin-2-one (example-72)
  • the title compound was prepared by following the similar procedure as described in step-2 of Example-54 by using l-(2-fluoro-4-iodobenzyl)-4-(8-methoxy[l]benzofuro[2,3-c]pyridin-5- yl)pyrrolidin-2-one (Step-1, 0.200 g, 0.387 mmol), 1,2-dimethoxy ethane (5 ml), tetrakis triphenyl phosphine Pd (0) (0.020g), potassium carbonate (0.071 g, 0.581 mmol) and 3- pyridyl boronic acid (0.071 g, 0.581 mmol) to obtain desired product (35 %).
  • Step- 1 ( ⁇ )1 -(4-Iodobenzyl)-4-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)pyrrolidin-2-one
  • Example-4 The title compound was prepared by following the similar procedure as described in Example-4 by using 4-(8-rnethoxy[l]benzofuro[2,3-c]pyridin-5-yl)pyrrolidin-2-one (0.150 g, 0.531 mmol, Example-70), sodium hydride (0.028 g, 0.694 mmol) N,N-dimethyl formamide (5 mL) and 4-iodo benzyl bromide (0.190 g, 0.638 mmol) to get 0.150 g of desire product.
  • ⁇ NMR (DMSO) : ⁇ 2.74-2.82 (m, 1H), 2.99-3.08 (m. 1H), 3.39-3.44 (m.
  • Step-2 - ( ⁇ )-l-(4-Pyridin-3-ylbenzyl)-4-(8-methoxy[I]benzofuro[2,3-c]pyridin-5- yl)pyrrolidin-2-one (Example-73)
  • Example- 126 (+)-l-(2-fluoro-4-iodobenzyl)-4-(8-methoxy[l]benzofuro[2,3- c]pyridin-5-yl)pyrrolidin-2-one (Example- 126), (0.060 g, 0.116 mmol), tetrakis triphenyl phosphine Pd (0) (catalytic amount), sodium carbonate (0.025 g, 0.232 mmol) and 3-pyridyl boronic acid (0.021 g, 0.174 mmol), 1,2-dimethoxy ethane (5 ml) toobtain desired product (36%).
  • Example- 1257 The title compound was prepared by following the similar procedure as described in Step-2 of Example-54 by using (+)-l-(4-iodobenzyl)-4-(8-methoxy[l]benzofuro[2,3-c]pyridin-5- l)pyrrolidin-2-one (Example- 127) (0.090 g, 0.180 mmol), tetrakis triphenyl phosphine Pd (0) (catalytic amount), sodium carbonate (0.038 g, 0.360 mmol) and 3-pyridyl boronic acid (0.033 g, 0.270 mmol), 1,2-dimethoxy ethane (5 ml) to obtain desired product (38 %).
  • Example 76 to 98 mentioned in Table-II below were prepared using an appropriate (-)/(+)/( ⁇ ) 4-(8-methoxy-benzofuro[2,3-c]pyridin-5-yl)pyrrolidin-2-one and appropriate alkyl/aryl halides ( R-L-Lev, wherein Lev is halogen e.g CI, Br or I), by following the similar procedure as described in Example-4.
  • Step- 1 4-Methoxy-3-[(3-nitropyridin-2-yl)oxy]benzaldehyde (99a)
  • Step-2 4-Methoxy-3-[(3-aminopyridin-2-yl)oxy]benzaldehyde (99b)
  • Step-6 Ethyl 3-(8-methoxy[l]benzofuro[2,3-6]pyridin-5-yl) acrylate (99f)
  • Step-7 - ( ⁇ )-Ethyl 3-(8-methoxy[l]benzofuro[2,3-6]pyridin-5-yl)-4-nitro butanoate (99g)
  • Step-8 - ( ⁇ )-4-(8-Methoxy[l]benzofuro[2,3-6]pyridin-5-yl)pyrrolidin-2-one (Example-99)
  • the title compound was prepared by following the similar procedure as described in Example-3 by using ( ⁇ )-Ethyl 3-(8-methoxy[l]benzofuro[2,3- ⁇ ]pyridin-5-yl)-4-nitro butanoate (10 mmol), raney nickel (catalytic amount) and few drops of ammonium hydroxide to obtained the desired product (35 %).
  • Example-99 The title compound was prepared by following the similar procedure as described in Example-4 by using 4-(8-methoxy[l]benzofuro[2,3-i>]pyridin-5-yl)pyrrolidin-2-one (Example-99, 50 mmol) and 4-chloro-2-fluorobenzylbromide (60 mmol) to obtain desired product (25 %).
  • Step- 1 6-Methoxy[l ]benzofuro[3,2-i/]pyrimidine ( 101 a)
  • Step-2 9-Iodo-6- methoxy [1 ] benzofuro [3,2- ⁇ ] pyrimidine (101b)
  • Step-3 Methyl 3-(6-methoxy [1 ] benzofuro [3,2-d] pyrimidin-9-yl ) acrylate ( 101 c)
  • Step-4 ( ⁇ )-Methyl 3-(6-methoxy[ 1 ]benzofuro[3,2-i/]pyrimidin-9-yl)-4-nitrobutanoate( 101 d)
  • the title product was prepared by following the similar procedure as described in Step-3 of Example-1 by using methyl 3-(6-mefhoxy [1] benzofuro [3,2-d] pyrimidin-9-yl )acrylate (1.0 mmol), Catalytic amount 1,1,3,3-tetramethyl guanidine and nitro methane.
  • the crude product obtained was purified by using silica gel column chromatography technique with 15-16% acetone and pet.
  • Step-5 ( ⁇ )-4-(6-Methoxy[l]benzofuro[3,2-i/]pyrimidin-9-yl)pyrrolidin-2-one (example- 101)
  • the title product (example-101 ) was prepared by following the similar procedure as described in Example 3 by using methyl 3-(6-methoxy[l]benzofuro[3,2-d]pyrimidin-9-yl)-4- nitrobutanoate [step-4 product] (1.0 mmol) to obtain desired product (yield 60 %);
  • Example 102 to 104 mentioned in Table-Ill below were prepared using Example-101 and alkyl halide (R-L-Lev) by following the similar procedure as described in Example-4
  • Step - 2 - 8-(Difluoromethoxy)[l]benzofuro[2,3-c]pyridine-5-carbaldehyde (105b)
  • potassium carbonate 4.53 g, 0.0328 mmol
  • Step - 4 - Ethyl (2E)-3-[8-(difluoromethoxy)[l]benzofuro[2,3-c]pyridin-5-yl]acrylate (105d)
  • the title compound was prepared by following the similar procedure as described in step - 2 of Example-1 by using (2E)-3-(8-methoxy[l]benzofuro[2,3-c]pyridin-5-yl)acrylic acid (1.400 g, 4.59 mmol.), con. sulphuric acid (0.5 mL) and ethanol (10 mL) to obtain desired product (60 %).
  • Step-6 3-(8-Difluoromethoxy-benzo[4,5]furo[2,3-c]pyridin-5-yl)-4-nitro-butyric acid (105f)
  • the title compound was prepared by following the similar procedure as described in step - 4 of Example-1 by using ethyl 3-[8-(difluoromethoxy)[l]benzofuro[2,3-c]pyridin-5-yl]-4- nitrobutanoate (2.000 g, 5.076 mmol), aqueous solution of sodium hydroxide (0.406 g, 10.15 mmol) and methanol to obtain desired product (95 %).
  • the title compound was prepared by following the similar procedure as described in Example-3 by using ( ⁇ ) ethyl 3-[8-(difluoromethoxy)[l ]benzofuro[2,3-c]pyridin-5-yl]-4- nitrobutanoate (0.500 g, 1.26 mmol), triethylamine (1 mL) and raney nickel (catalytic amount) and methanol (10 mL) to obtain desired product (26 %).
  • Example- 107 to 112 mentioned in Table-IV below were prepared using an appropriate 4-(8- difluoromethoxy[l]benzofuro[2,3-c]pyridin-5-yl)pyrrolidin-2-one and appropriate alkyl/ aryl halides (R-L-Br) by following the similar procedure as described in Example-4.
  • Example-105 0.150 g, 0.476 mmol
  • N,N-dimethyl formamide 5.0 mL
  • sodium hydride 0.028 g, 0.707 mmol
  • l-Bromomethyl-2-fluoro-4-iodo-benzene 0.178 g, 0.566 mmol
  • Example - 113 The title compound was prepared by following the similar procedure as described in step - 2 of Example-54 by using (+) 4-(8-difluoromethoxy-benzo[4,5]furo[2,3-c]pyridin-5-yl)-l-(2- fluoro-4-iodo-benzyl)-pyrrolidin-2-one (Example - 113), 0.060 g, 0.108 mmol), tetrakis triphenyl phosphine Pd (0) (0.0 lOg, 0.0086 mmol), sodium carbonate (0.023 g, 0.217 mmol) and 1 -methyl- 1H- pyrazole-4-boronc acid pinacol ester (0.034 g, 0.163 mmol) to get desired product.
  • Step - 2 4-(8-Difluoromethoxy-benzo[4,5]furo[2,3-c]pyridin-5-yl)-l -(2,6-difluoro-4- pyrimidin-5-yl-benzyl)-pyrrolidin-2-one (Example- 1 17)
  • the title compound was prepared by following the similar procedure as described in step - 2 of Example-54 by using l -(4-Bromo-2,6-difluoro-benzyl)-4-(8-difluoromethoxy- benzo[4,5]furo[2,3-c]pyridin-5-yl)-pyrrolidin-2-one (0.040 g, 0.076 mmol), tetrakis triphenyl phosphine Pd (0) (0.01 Og, 0.0086 mmol), sodium carbonate (0.016 g, 0.152 mmol) and pyrimidine-5-boronic acid (0.014 g, 0.1 14 mmol) to get desired product. (0.015 g).
  • Step 1 - 3-[(3-Bromopyridin-N-oxide-4-yl)oxy]-4-methoxy-benza]dehyde (118a)

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Abstract

La présente invention a pour objet des inhibiteurs de la phosphodiestérase-10. En particulier, la présente invention concerne des dérivés tricycliques qui sont utiles en tant qu'inhibiteurs de la phosphodiestérase-10. La présente invention concerne aussi des procédés de préparation des composés selon la présente invention, des intermédiaires utilisés dans leur synthèse, des compositions pharmaceutiques, et des méthodes de traitement ou de prévention de maladies, d'états pathologiques et/ou de troubles modulés par la phosphodiestérase-10. (Formule I) (I)
PCT/IB2011/000846 2010-04-19 2011-04-18 Composés tricycliques en tant qu'inhibiteurs de la phosphodiestérase-10 Ceased WO2011132051A2 (fr)

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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)
CN103755715A (zh) * 2013-12-26 2014-04-30 武汉理工大学 苯并呋喃并[2,3-c]吡啶化合物及其合成方法
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)
CN108892616A (zh) * 2018-08-31 2018-11-27 凯莱英生命科学技术(天津)有限公司 制备苯甲醛类中间体的连续化装置及其应用
CN110003227A (zh) * 2019-04-26 2019-07-12 新乡市润宇新材料科技有限公司 一种2-甲基-8-甲氧基苯并呋喃[2,3-b]吡啶的合成方法
WO2019166822A1 (fr) * 2018-03-01 2019-09-06 The University Of Sussex Composés permettant de moduler la fonction du récepteur ampa
CN111499540A (zh) * 2020-04-22 2020-08-07 中南民族大学 氨氧化法制备2,4,6-三氯苯腈的方法和专用催化剂及制备方法
US11186567B2 (en) 2017-02-10 2021-11-30 University College Cardiff Consultants Limited AMPA receptor potentiators
CN115677637A (zh) * 2022-09-27 2023-02-03 萍乡学院 一种1-溴二苯并呋喃的简易制备方法
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AU2004228453B2 (en) * 2003-04-11 2010-08-19 Glenmark Pharmaceuticals S.A. Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
WO2006011024A2 (fr) * 2004-07-19 2006-02-02 Glenmark Pharmaceuticals Ltd. Nouveaux composes tricycliques utilises dans le traitement de troubles inflammatoires et allergiques, procede de preparation associe, et compositions pharmaceutiques les contenant
PL1831227T3 (pl) * 2004-12-17 2013-10-31 Glenmark Pharmaceuticals Sa Nowe związki heterocykliczne użyteczne w leczeniu stanów zapalnych i dolegliwości alergicznych
MX2009002657A (es) * 2006-09-11 2009-08-18 Matrix Lab Ltd Derivados dibenzofurano como inhibidores de pde-4 y pde-10.
WO2009081222A1 (fr) * 2007-12-21 2009-07-02 Glenmark Pharmaceuticals, S.A. Pyrimidines ou pyridines tricycliques substituées ligands des récepteurs des vanilloïdes

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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)
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)
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)
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WO2019166822A1 (fr) * 2018-03-01 2019-09-06 The University Of Sussex Composés permettant de moduler la fonction du récepteur ampa
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