Classifications

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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
  • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
• • 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
  • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
  • A61P25/16—Anti-Parkinson drugs
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/24—Antidepressants
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms 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
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• pyrazine compounds that are PDE 10 inhibitors, pharmaceutical compositions containing such compounds, and processes for preparing such compounds.
• Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDElO, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.
• cAMP and cGMP cyclic nucleotide monophosphates
• PKA cAMP-dependent protein kinase
• Downstream mediators of cGMP signaling also include kinases and ion channels. In addition to actions mediated by kinases, cAMP and cGMP bind directly to some cell proteins and directly regulate their activities.
• Cyclic nucleotides are produced from the actions of adenylyl cyclase and guanylyl cyclase, which convert ATP to cAMP and GTP to cGMP. Extracellular signals, often through the actions of G protein-coupled receptors, regulate the activities of the cyclases. Alternatively, the amount of cAMP and cGMP may be altered by regulating the activities of the enzymes that degrade cyclic nucleotides. Cell homeostasis is maintained by the rapid degradation of cyclic nucleotides after stimulus-induced increases. The enzymes that degrade cyclic nucleotides are called 3 ',5 '-cyclic nucleotide-specific phosphodiesterases (PDEs).
• PDEs 3 ',5 '-cyclic nucleotide-specific phosphodiesterases
• PDE-PDEl 1 Eleven PDE gene families (PDEl-PDEl 1) have been identified based on their distinct amino acid sequences, catalytic and regulatory characteristics, and sensitivity to small molecule inhibitors. These families are coded for by 21 genes; and further multiple splice variants are transcribed from many of these genes. Expression patterns of each of the gene families are distinct. PDEs differ with respect to their affinity for cAMP and cGMP. Activities of different PDEs are regulated by different signals. For example, PDEl is stimulated by Ca 2+ /calmodulin. PDE2 activity is stimulated by cGMP. PDE3 is inhibited by cGMP. PDE4 is cAMP specific and is specifically inhibited by rolipram. PDE5 is cGMP-specif ⁇ c. PDE6 is expressed in retina.
• PDE 10 sequences were identified by using bioinformatics and sequence information from other PDE gene families (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999; Loughney et al., Gene 234: 109-117, 1999; Soderling et al., Proc. Natl. Acad. ScL USA 96:7071-7076, 1999).
• the PDElO gene family is distinguished based on its amino acid sequence, functional properties and tissue distribution.
• the human PDE 10 gene is large, over 200 kb, with up to 24 exons coding for each of the splice variants.
• the amino acid sequence is characterized by two GAF domains (which bind cGMP), a catalytic region, and alternatively spliced N and C termini. Numerous splice variants are possible because at least three alternative exons encode N termini and two exons encode C-termini.
• PDElOAl is a 779 amino acid protein that hydrolyzes both cAMP and cGMP. The K m values for cAMP and cGMP are 0.05 and 3.0 micromolar, respectively.
• PDE 10 RNA transcripts were initially detected in human testis and brain.
• the tissue distribution of PDE 10 indicates that PDE 10 inhibitors can be used to raise levels of cAMP and/or cGMP within cells that express the PDElO enzyme, for example, in neurons that comprise the basal ganglia and therefore would be useful in treating a variety of neuropsychiatric conditions involving the basal ganglia such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive compulsive disorder, and the like.
• the present invention comprises a new class of pyrazine compounds useful in the treatment of diseases, such as PDE 10 -mediated diseases and other maladies, such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder.
• diseases such as PDE 10 -mediated diseases and other maladies, such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder.
• the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of PDE 10-mediated diseases and other maladies, such as schizophrenia, bipolar disorder, or obsessive-compulsive disorder, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
• X 5 , X 7 , X 8 , X 9 , X 10 , X 11 , Y and Z are defined below.
• Each of X 1 , X 2 , X 3 , X 4 , and X 5 is independently N or C; wherein no more than two of X 1 ,
• X 2 , X 3 and X 4 are N;
• Each of X 6 , X 7 , X 9 , and X 10 is independently N or C; each of X 8 and X 11 is C; wherein no more than three of X 6 , X 7 , X 9 , and X 10 are N;
• Z is NH, NR 6 , S, SO, SO 2 , O, or C; wherein Z is only C when X s is N; m is O, 1, 2, 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2;
• R 1 is selected from the group consisting of
• R 2 is, independently in each instance, F, Cl, Br, CN, OH, OCi_ 4 alk, Ci- 4 alk or Ci_ 4 haloalk
• R 3 is, independently in each instance, F, Cl, Br, CN, OH, OCi_ 4 alk, Ci- 4 alk, or -NR a Ci_ 4 alk
• R 4 is independently in each instance, F, Cl, CH 3 , CN, CF 3 , CHF 2 , CH 2 F, OR a , or NR a R a ;
• R a is independently, at each instance, H or R b ;
• R d is a nitrogen-linked saturated, partially-saturated, or unsaturated 5-, 6- or 7-membered ring heterocycle containing the linking nitrogen and 0, 1 or 2 additional nitrogen atoms and containing 0 or 1 sulfur or oxygen atom, the heterocycle being substituted by 0, 1 , 2 or 3 substituents selected from oxo, halo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -NH 2 , -NHCi_ 4 alk, and [0016]
• the group: is selecte from the group consisting of ;
• Y is NH
• Y is -N-CH 2 -C 6 C 5 -F.
• Y is -CH 2 -.
• Y and R 3 form a 5- to 6- membered ring fused to the ring containing both said Y and R 3 ; wherein Y is NH, and R 3 is Ci- 4 alk or -NR a Ci_ 4 alk.
• X 1 is N or C
• each of X 2 , X 3 , X 4 , and X 5 is C.
• X 5 is N.
• X 5 is C .
• m is 0 or 1.
• n is 0 or 1.
• p is 0 or 1.
• R 1 is selected from the group consisting of H, F, Cl, Br, I,
• R 1 is selected from the group consisting of H, F, Cl, Br,
• R 1 is selected from the group consisting of a saturated, partially-saturated or unsaturated 4-, 5-, 6-, or 7-membered monocyclic ring, wherein each said ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 O atoms, and wherein each said ring is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, Ci_6alk, Ci_4haloalk, -OR a ,
• R 1 is selected from the group consisting of a saturated, partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 O atoms, and wherein each said ring is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, Ci_ ⁇ alk, Ci_ 4 haloalk, -OR a ,
• R 1 is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl, pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl, oxaspiro[3.5]nonyl, azepanyl, oxepanyl, quinolinyl, dihydrotriazolo[4,3-a]pyrazinyl, pyrrolo[2,3-b]pyridinyl, all of which are substituted by 0, 1, 2 or 3 groups selected from all of
• R 1 is -L-R 7 wherein L is -CH 2 -.
• R 1 is selected from the group consisting of: Cl, Br, I,
• R 1 is selected from the group consisting of:
• R 2 is, independently in each instance, F, Cl, Br, CN, OH,
• R 3 is, independently in each instance, F, Cl, Br, CN, OH,
• R 4 is F .
• R 5 is methyl
• R 6 is methyl
• R 8 is Ci_6alk substituted by 0 or 1 -OR a .
• R a is H or Ci_ 6 alk substituted by 0 or 1 -OH, -OCi_ 4 alk, -
• R c is a Co- 4 alk-linked saturated, partially-saturated or unsaturated 3-, 5-, or 6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected from O and S, which is substituted by 0 or 1 groups selected from F, Ci_ ⁇ alk,
• Ci_ 4 haloalk, -OR a , R 7 , or R 8 are Ci_ 4 haloalk, -OR a , R 7 , or R 8 .
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDElO inhibitors comprising the step of administering a compound of formula (I) of the present invention.
• Another aspect of the invention relates to a method wherein said condition that may be treated with PDElO inhibitors is selected from the group consisting of psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention def ⁇ cit/hyperactivity disorder
• ADHD Alzheimer's disease
• Another aspect of the invention relates to a method wherein said condition that may be treated with PDElO inhibitors is selected from the group consisting of schizophrenia, bipolar disorder, and obsessive-compulsive disorder.
• Another aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically-acceptable diluent or carrier.
• Another aspect of the current invention relates to compounds having the general structure of formula (II):
• Z is NH, NR 6 , S or O; m is 0, 1, 2, 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; y is O, 1, 2, 3 or 4;
• X 1 is N or C
• X 5 is N or C
• Ring A is a carbon-linked-saturated, carbon-lmked-partially-saturated, or carbon-lmked- unsaturated A-, 5-, 6-, 7-, 8-, 9-, 10-, 1 X-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom; or a nitrogen-linked-saturated, nitrogen-linked- partially-saturated, or nitrogen- linked-unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, H-, or 12-membered ring heterocycle containing the linking nitrogen and 0, 1 or 2 additional N atoms and containing 0 or 1 S or O atom;
• R 2 is, independently in each instance, F, Cl, Br, CN, OH, OCi 4 alk, Ci 4 alk or Ci 4 haloalk;
• R 3 is, independently in each instance, F, Cl, Br, CN, OH, Ci- 4 alk or Ci_ 4 haloalk;
• R 4 is independently in each instance, F, Cl, CH 3 , CN, CF 3 , CHF 2 , CH 2 F, OR a , or NR a R a ;
• R a is independently, at each instance, H or R b ;
• Z is NH, N-C 1-4 alk or S.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp2 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp2 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp2 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp2 hybridization.
• ring A is a carbon- linked-saturated, partially-saturated, or unsaturated A-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is a carbon-linked-saturated A-, 5-, 6-, 7-, 8-, 9-,
• ring A is a nitrogen-linked-saturated A-, 5-, 6-, 7- membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is a nitrogen-linked-partially-saturated 4-, 5-, 6-, 7-
• ring A is a nitrogen-linked-unsaturated 4-, 5-, 6-, 8-, 10-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.
• ring A is selected from the group consisting of azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl, pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, and tetrahydrothiopyranyl.
• ring A is selected from the group consisting of oxaspiro[3.5]nonyl, azepanyl, oxepanyl, and quinolinyl.
• ring A is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl, pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl, oxaspiro[3.5]nonyl, azepanyl, oxepanyl, quinolinyl, dihydrotriazolo[4,3-a]pyrazinyl, pyrrolo[2,3-b]pyridinyl, all of which are substituted by 0, 1, 2 or 3 groups selected from all
• ring A is selected from the group consisting of [00102] In another embodiment, ring A is selected from the group consisting of:
• m is 0 or 1.
• n is 0 or 1.
• p is 0 or 1.
• y is 0, 1 , 2, or 3.
• R 9 is selected from the group consisting of H, F, Cl, Br,
• R 2 is, independently in each instance, F, Cl, Br, CN, OH,
• R 3 is, independently in each instance, F, Cl, Br, CN, OH,
• R 4 is F.
• R 6 is methyl
• R 8 is Ci_6alk substituted by 0 or 1 -OR a .
• R a is H or d_ 6 alk substituted by 0 or 1 -OH, -OCi_ 4 alk,
• R c is a Co- 4 alk-linked saturated, partially-saturated or unsaturated 3-, 5-, or 6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected from O and S, which is substituted by 0 or 1 groups selected from Ci_6alk, R 7 , or -OR a .
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDElO inhibitors comprising the step of administering a compound of formula (II).
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDE 10 inhibitors comprising the step of administering a compound of formula (II); wherein said condition is selected from the group consisting of psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
• a compound of formula (II) wherein said condition is selected from the group consisting of psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention deficit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDE 10 inhibitors comprising the step of administering a compound of formula (II); wherein said condition is selected from the group consisting of schizophrenia, bipolar disorder, and obsessive-compulsive disorder.
• Another aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (II) and a pharmaceutically-acceptable diluent or carrier.
• Another aspect of the current invention relates to compounds having the general structure of formula (III):
• Z is NH, NR 6 , S or O; m is O, 1, 2, 3 or 4; n is 0, 1 or 2; p is 0, 1 or 2; y is O, 1, 2, 3 or 4;
• X 1 is N or C
• X 5 is N or C
• Ring A is a carbon-linked-saturated, carbon-linked-partially-saturated, or carbon-linked- unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom; or a m ' trogen-linked-saturated, nitrogen-linked- partially-saturated, or nitrogen- linked-unsaturated 4-, 5-, 6-, 7-, 8-, 9-, 10-, H-, or 12-membered ring heterocycle containing the linking nitrogen and 0, 1 or 2 additional N atoms and containing 0 or 1 S or O atom;
• R 2 is, independently in each instance, F, Cl, Br, CN, OH, OCi_ 4 alk, Ci_ 4 alk or Ci_ 4 haloalk;
• R 3 is, independently in each instance, F, Cl, Br, CN, OH, OCi_ 4 alk, Ci_ 4 alk or Ci_ 4 haloalk;
• R 4 is independently in each instance, F, Cl, CH 3 , CN, CF 3 , CHF 2 , CH 2 F, OR a , or NR a R a ;
• R a is independently, at each instance, H or R b ;
• Z is NH, N-C 1-4 alk or S.
• Another aspect of the current invention relates to compounds having the general structure of formula (Ilia):
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp2 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp2 hybridization.
• Another aspect of the current invention relates to compounds having the general structure of formula (HIb): or a pharmaceutically acceptable salt thereof, wherein m, n, p, y, R 2 , R 3 , R 4 , and R 9 are as defined in compounds of formula (III), and any other embodiments below.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp2 hybridization.
• ring A is bonded to the pyrazinyl ring via a carbon atom having an sp hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp3 hybridization.
• ring A is bonded to the pyrazinyl ring via a nitrogen atom having an sp2 hybridization.
• ring A is a carbon- linked-saturated, partially-saturated, or unsaturated A-, 5-, 6-, 7-, 8-, 9-, 10-, 1 X-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is a carbon-linked-saturated A-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is a nitrogen-linked-saturated 4-, 5-, 6-, 7- membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is a nitrogen-linked-partially-saturated 4-, 5-, 6-, 7-
• ring A is a nitrogen-linked-unsaturated 4-, 5-, 6-, 8-, 10-, or 12-membered carbocycle ring containing 0, 1 or 2 N atoms and containing 0 or 1 S or O atom.
• ring A is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.
• ring A is selected from the group consisting of azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl, pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridinyl, and tetrahydrothiopyranyl.
• ring A is selected from the group consisting of oxaspiro[3.5]nonyl, azepanyl, oxepanyl, and quinolinyl.
• ring A is selected from the group consisting of cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl, phenyl, 2-pyridyl,
• ring A is selected from the group consisting of:
• n is 0 or 1.
• p is 0 or 1.
• y is 0, 1 , 2, or 3.
• R 2 is, independently in each instance, F, Cl, Br, CN, OH, OCi_ 4 alk, Ci_ 4 alk or d_ 4 haloalk.
• R 3 is, independently in each instance, F, Cl, Br, CN, OH, OCi_ 4 alk, Ci_ 4 alk or Ci_ 4 haloalk.
• R 4 is F.
• R 6 is methyl.
• R 8 is d_ 6 alk substituted by 0 or 1 -OR a .
• R a is H or Ci_ 6 alk substituted by 0 or 1 -OH, -OCi_ 4 alk, -
• R c is a Co_ 4 alk-linked saturated, partially-saturated or unsaturated 3-, 5-, or 6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 atom selected from O and S, which is substituted by 0 or 1 groups selected from Ci_ 6 alk, R 7 , or -OR a .
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDE 10 inhibitors comprising the step of administering a compound of formula
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDE 10 inhibitors comprising the step of administering a compound of formula
• said condition is selected from the group consisting of psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention def ⁇ cit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
• ADHD attention def ⁇ cit/hyperactivity disorder
• Another aspect of the invention relates to a method of treating conditions that may be treated with PDElO inhibitors comprising the step of administering a compound of formula
• Another aspect of the invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (III) and a pharmaceutically-acceptable diluent or carrier.
• X 1 is N or C
• X 2 is N or C;
• X 3 is N or C;
• X 4 is N or C; wherein no more than two of X 1 , X 2 , X 3 and X 4 are N;
• Z is NH, NR 6 , S or O; m is 0, 1 or 2; n is independently in each instance 0, 1 or 2;
• R 2 is, independently in each instance, F, Cl, Br, CN, OH, OCi- 4 alk, Ci- 4 alk or Ci_ 4 haloalk;
• R 3 is, independently in each instance, F, Cl, Br, CN, OH, Ci- 4 alk or Ci_ 4 haloalk;
• R 4 is independently in each instance, F, Me or CN;
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_6alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -NH 2 , -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk;
• R d is a nitrogen-linked saturated, partially-saturated or unsaturated 5-, 6- or 7-membered ring heterocycle containing the linking nitrogen and 0, 1 or 2 additional nitrogen atoms and containing 0 or 1 sulfur or oxygen atoms, the heterocycle being substituted by 0, 1, 2 or 3 substituents selected from oxo, halo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -NH 2 , -NHCi_ 4 alk, and
• n 0.
• Another aspect of the invention relates to a method of treating schizophrenia, bipolar disorder, or obsessive-compulsive disorder using an effective amount of a compound of formula (IV).
• Another aspect of the invention relates to a method of treating a disorder treatable by inhibition of PDElO in a patient which method comprises administering to the patient a pharmaceutical composition comprising an effective amount of a compound of formula (IV).
• Another aspect of the invention relates to a pharmaceutical composition comprising a compound of fomula (IV) and a pharmaceutically-acceptable diluent or carrier.
• Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.
• Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of schizophrenia, bipolar disorder, or obsessive-compulsive disorder.
• Another aspect of the invention relates to compounds of selected from the group consisting of:
• the compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diasteromers.
• the present invention includes all pharmaceutically acceptable isotopically- labelled compounds of the present invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
• isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 38 Cl, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
• isotopes of hydrogen such as 2 H and 3 H
• carbon such as 11 C, 13 C and 14 C
• chlorine such as 38 Cl
• fluorine such as 18 F
• iodine such as 123 I and 125 I
• nitrogen such as 13 N and 15 N
• oxygen such as 15 O, 17 O and 18 O
• phosphorus such as 32 P
• sulphur such as 35 S.
• Certain isotopically-labelled compounds of the present invention are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
• Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
• Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non- labeled reagent previously employed.
• Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d ⁇ -acetone, d 6 -DMSO.
• C ⁇ _ ⁇ alk means an alkyl group comprising a minimum of ⁇ and a maximum of ⁇ carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein ⁇ and ⁇ represent integers.
• the alkyl groups described in this section may also contain one or two double or triple bonds.
• a designation of Coalk indicates a direct bond. Examples of
• Ci_ 6 alkyl include, but are not limited to the following:
• Halo or "halogen” means a halogen atoms selected from F, Cl, Br and I.
• C ⁇ - ⁇ haloalk means an alk group, as described above, wherein any number ⁇ at least one— of the hydrogen atoms attached to the alk chain are replaced by F, Cl, Br or I.
• the group N(R a )R a and the like include substituents where the two R a groups together form a ring, optionally including a N, O or S atom, and include groups such as:
• N(C ⁇ _ ⁇ alk) C ⁇ _palk wherein ⁇ and ⁇ are as defined above, include substituents where the two C a _palk groups together form a ring, optionally including a N, O or S atom, and include groups such as:
• Carbocycle means a ring comprising by itself or in combination with other terms, represents, unless otherwise stated, cyclic version of "C ⁇ _palk". Thus, the term “carbocycle” is meant to be included in the terms “C a _palk”. Examples of carbocycle include cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene, cyclohexylene and the like. [00220] "Heterocycle” means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
• “Pharmaceutically-acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
• the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
• suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
• pharmaceutically acceptable salts see infra and Berge et al, J. Pharm. Sci. 66: 1 (1977).
• Saturated, partially-saturated or unsaturated includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
• leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
• Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like.
• Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
• aralkyl examples include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
• aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9- phenylfluorenyl), phenanthrenyl, durenyl and the like.
• cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
• Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
• a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
• Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1 ,2-bis(methylene)benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
• the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
• Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
• an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
• Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
• aralkyl groups For example, aralkyl groups.
• Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
• Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups.
• Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1 ,2- bis(dimethylsilyl)benzene, 1 ,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl.
• Silylation of an amino groups provide mono- or di-silylamino groups. Silylation of aminoalcohol compounds can lead to a N,N,O-trisilyl derivative.
• silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
• Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
• Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
• Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
• Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogeno lysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogeno lysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can readily be neutralized to yield the free amine. Carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
• Y' O, S, NR
• a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
• the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
• prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
• Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989
• drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). Hydroxy groups have been masked as esters and ethers.
• EP 039,051 (Sloan and Little, 4/11/81) discloses Mannich- base hydroxamic acid prodrugs, their preparation and use.
• the methods in general, comprises the step of administering a therapeutically effective amount of a compounds of the present invention, or an individual stereoisomer, a mixture of stereoisomers, or a pharmaceutically acceptable salt or solvate thereof, to a patient in need thereof to treat the disorder or disease.
• this invention provides a use of a compound as described herein in the manufacture of a medicament for treating a disorder or disease treatable by inhibition of PDElO.
• the compounds of the present invention inhibit PDElO enzyme activity, and hence raise the levels of cAMP or cGMP within cells that express PDElO. Accordingly, inhibition of PDElO enzyme activity would be useful in the treatment of diseases caused by deficient amounts of cAMP or cGMP in cells. PDElO inhibitors would also be of benefit in cases wherein raising the amount of cAMP or cGMP above normal levels results in a therapeutic effect. Inhibitors of PDElO may be used to treat disorders of the peripheral and central nervous system, cardiovascular diseases, cancer, gastro-enterological diseases, endocrinological diseases and uro logical diseases.
• Indications that may be treated with PDE 10 inhibitors include, but are not limited to, those diseases thought to be mediated in part by the basal ganglia, prefrontal cortex, and hippocampus. These indications include psychoses, Parkinson's disease, dementias, obsessive compulsive disorder, tardive dyskinesia, choreas, depression, mood disorders, impulsivity, drug addiction, attention def ⁇ cit/hyperactivity disorder (ADHD), depression with parkinsonian states, personality changes with caudate or putamen disease, dementia and mania with caudate and pallidal diseases, and compulsions with pallidal disease.
• ADHD attention def ⁇ cit/hyperactivity disorder
• Psychoses are disorders that affect an individual ' s perception of reality. Psychoses are characterized by delusions and hallucinations. The compounds of the present invention are suitable for use in treating patients suffering from all forms of psychoses, including, but not limited to, schizophrenia, late-onset schizophrenia, schizoaffective disorders, prodromal schizophrenia, and bipolar disorders. Treatment can be for the positive symptoms of schizophrenia as well as for the cognitive deficits and negative symptoms. Other indications for PDElO inhibitors include psychoses resulting from drug abuse (including amphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus, sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewy bodies, or hypoglycemia.
• Obsessive-compulsive disorder has been linked to deficits in the frontal- striatal neuronal pathways (Saxena et al., Br. J. Psychiatry Suppl, 35:26-37, 1998). Neurons in these pathways project to striatal neurons that express PDElO. PDElO inhibitors cause cAMP to be elevated in these neurons; elevations in cAMP result in an increase in CREB phosphorylation and thereby improve the functional state of these neurons.
• the compounds of the present invention are therefore suitable for use in the indication of OCD.
• OCD may result, in some cases, from streptococcal infections that cause autoimmune reactions in the basal ganglia (Giedd et al., Am J Psychiatry. 157:281-283, 2000). Because PDElO inhibitors may serve a neuroprotective role, administration of PDElO inhibitors may prevent the damage to the basal ganglia after repeated streptococcal infections and thereby prevent the development of OCD. [00236] In the brain, the level of cAMP or cGMP within neurons is believed to be related to the quality of memory, especially long term memory.
• cAMP phosphodiesterase PDE
• PDE protein kinase that phosphorylates a transcription factor
• the phosphorylated transcription factor then binds to a DNA promoter sequence to activate genes that are important in long term memory. The more active such genes are, the better is long-term memory. Thus, by inhibiting a phosphodiesterase, long term memory can be enhanced.
• Dementias are diseases that include memory loss and additional intellectual impairment separate from memory.
• the compounds of the present invention are suitable for use in treating patients suffering from memory impairment in all forms of dementia.
• Dementias are classified according to their cause and include: neurodegenerative dementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease, Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiac disorders), mixed vascular and Alzheimer's, bacterial meningitis, Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subdural hematoma or traumatic brain injury), infectious (e.g., HIV), genetic (down syndrome), toxic (e.g., heavy metals, alcohol, some medications), metabolic (e.g., vitamin B 12 or folate deficiency), CNS hypoxia, Cushing's disease, psychiatric (e.g., depression and schizophrenia), and hydrocephalus.
• neurodegenerative dementias e
• the condition of memory impairment is manifested by impairment of the ability to learn new information and/or the inability to recall previously learned information.
• the present invention includes methods for dealing with memory loss separate from dementia, including mild cognitive impairment (MCI) and age-related cognitive decline.
• MCI mild cognitive impairment
• the present invention includes methods of treatment for memory impairment as a result of disease.
• Memory impairment is a primary symptom of dementia and can also be a symptom associated with such diseases as Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, HIV, cardiovascular disease, and head trauma as well as age-related cognitive decline.
• the compounds of the present invention are suitable for use in the treatment of memory impairment due to, for example, Alzheimer's disease, multiple sclerosis, amylolaterosclerosis (ALS), multiple systems atrophy (MSA), schizophrenia, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeld- Jakob disease, depression, aging, head trauma, stroke, spinal cord injury, CNS hypoxia, cerebral senility, diabetes associated cognitive impairment, memory deficits from early exposure of anesthetic agents, multiinfarct dementia and other neurological conditions including acute neuronal diseases, as well as HIV and cardiovascular diseases.
• Alzheimer's disease multiple sclerosis
• ALS amylolaterosclerosis
• MSA multiple systems atrophy
• schizophrenia Parkinson's disease
• Huntington's disease Huntington's disease
• Pick's disease Creutzfeld- Jakob disease
• depression head trauma
• stroke spinal cord injury
• CNS hypoxia CNS hypoxia
• cerebral senility diabetes associated cognitive impairment
• the compounds of the present invention are also suitable for use in the treatment of a class of disorders known as polyglutamine-repeat diseases. These diseases share a common pathogenic mutation.
• the expansion of a CAG repeat, which encodes the amino acid glutamine, within the genome leads to production of a mutant protein having an expanded polyglutamine region.
• Huntington's disease has been linked to a mutation of the protein huntingtin. In individuals who do not have Huntington's disease, huntingtin has a polyglutamine region containing about 8 to 31 glutamine residues. For individuals who have Huntington's disease, huntingtin has a polyglutamine region with over 37 glutamine residues.
• DRPLA dentatorubral-pallidoluysian atrophy
• DRPLA dentatorubral-pallidoluysian atrophy
• ataxin-1 spinocerebellar ataxia type-1
• ataxin-2 spinocerebellar ataxia type-2
• ataxin-3 also called Machado-Joseph disease or MJD
• ataxin-3 spinocerebellar ataxia type-6 (alpha la- voltage dependent calcium channel); spinocerebellar ataxia type-7 (ataxin-7); and spinal and bulbar muscular atrophy (SBMA, also know as Kennedy disease).
• SBMA spinal and bulbar muscular atrophy
• the basal ganglia are important for regulating the function of motor neurons; disorders of the basal ganglia result in movement disorders. Most prominent among the movement disorders related to basal ganglia function is Parkinson's disease (Obeso et al, Neurology. 62(1 Suppl l):S17-30, 2004). Other movement disorders related to dysfunction of the basal ganglia include tardive dyskinesia, progressive supranuclear palsy and cerebral palsy, corticobasal degeneration, multiple system atrophy, Wilson disease, dystonia, tics, and chorea. The compounds of the invention are also suitable for use to treat movement disorders related to dysfunction of basal ganglia neurons.
• PDE 10 inhibitors are useful in raising c AMP or cGMP levels and prevent neurons from undergoing apoptosis.
• PDElO inhibitors may be anti-inflammatory by raising cAMP in glial cells.
• Autoimmune diseases or infectious diseases that affect the basal ganglia may result in disorders of the basal ganglia including ADHD, OCD, tics, Tourette's disease, Sydenham chorea.
• any insult to the brain can potentially damage the basal ganglia including strokes, metabolic abnormalities, liver disease, multiple sclerosis, infections, tumors, drug overdoses or side effects, and head trauma.
• the compounds of the invention can be used to stop disease progression or restore damaged circuits in the brain by a combination of effects including increased synaptic plasticity, neurogenesis, anti-inflammatory, nerve cell regeneration and decreased apoptosis.
• cAMP and cGMP The growth of some cancer cells is inhibited by cAMP and cGMP.
• cells may become cancerous by expressing PDElO and reducing the amount of cAMP or cGMP within cells.
• inhibition of PDElO activity inhibits cell growth by raising cAMP.
• PDElO may be expressed in the transformed, cancerous cell but not in the parent cell line.
• PDElO is expressed and PDElO inhibitors reduce the growth rate of the cells in culture.
• breast cancer cells are inhibited by administration of PDElO inhibitors.
• Many other types of cancer cells may also be sensitive to growth arrest by inhibition of PDElO.
• the compounds of the invention are also suitable for use in the treatment of diabetes and related disorders such as obesity, by focusing on regulation of the cAMP signaling system.
• PDE-10 especially PDE-IOA
• intracellular levels of cAMP are increased, thereby increasing the release of insulin-containing secretory granules and, therefore, increasing insulin secretion.
• WO 2005/012485 which is hereby incorporated by reference in its entirety.
• the compounds of Formula (I) can also be used to treat diseases disclosed in US Patent application publication No. 2006/019975, the disclosure of which is incorporated herein by reference in its entirety.
• PDE 10 inhibitory activities of the compounds of the present invention can be tested, for example, using the in vitro and in vivo assays described in the Biological Examples below.
• the compounds of this invention can be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities.
• the actual amount of a compound of this invention, i.e., the active ingredient depends upon numerous factors, such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
• Therapeutically effective amounts of compounds of formula (I) may range from approximately 0.1-1000 mg per day; preferably 0.5 to 250 mg/day, more preferably 3.5 mg to 70 mg per day.
• compounds of this invention can be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• routes e.g., oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration.
• the preferred manner of administration is oral using a convenient daily dosage regimen, which can be adjusted according to the degree of affliction.
• Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
• formulations depend on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
• pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area, i.e., decreasing particle size.
• U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules.
• compositions are comprised of, in general, a compounds of the present invention in combination with at least one pharmaceutically acceptable excipient.
• Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compounds of the present invention.
• excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
• Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like.
• Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc.
• Preferred liquid carriers, particularly for injectable solutions include water, saline, aqueous dextrose, and glycols.
• Compressed gases may be used to disperse a compound of this invention in aerosol form.
• Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
• Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, Gennaro, A. R. (Mack Publishing Company, 18th ed., 1995).
• the level of the compound in a formulation can vary within the full range employed by those skilled in the art.
• the formulation contains, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compounds of the present invention based on the total formulation, with the balance being one or more suitable pharmaceutical excipients.
• the compound is present at a level of about 1-80 wt %.
• the compounds can be administered as the sole active agent or in combination with other pharmaceutical agents such as other agents used in the treatment of psychoses, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, cognitive impairment and/or memory loss, e.g., nicotinic ⁇ -7 agonists, PDE4 inhibitors, other PDElO inhibitors, calcium channel blockers, muscarinic ml and m2 modulators, adenosine receptor modulators, ampakines, NMDA-R modulators, mGluR modulators, dopamine modulators, serotonin modulators, canabinoid modulators, and cholinesterase inhibitors (e.g., donepezil, rivastigimine, and galanthanamine).
• other pharmaceutical agents such as other agents used in the treatment of psychoses, especially schizophrenia and bipolar disorder, obsessive-compulsive disorder, Parkinson's disease, Alzheimer's disease, cognitive impairment and/or memory loss
• Drugs suitable in combination with the compounds of the present invention include, but are not limited to, other suitable schizophrenia drugs such as Clozaril, Zyprexa, Risperidone, and Seroquel; bipolar disorder drugs, including, but not limited to, Lithium, Zyprexa, and Depakote; Parkinson's disease drugs, including, but not limited to, Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane, and Cogentin; agents used in the treatment of Alzheimer's disease, including, but not limited to, Reminyl, Cognex, Aricept, Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol; agents used in the treatment of dementia, including, but not limited to, Thioridazine, Halope
• agonists, antagonists such as Rosiglitazone, Troglitazone and Pioglitazone
• insulin secretagogues e.g., sulfonylurea drugs, such as Glyburide, Glimepiride, Chlorpropamide, Tolbutamide, and Glipizide, and non-sulfonyl secretagogues
• ⁇ -glucosidase inhibitors such as Acarbose, Miglitol, and Voglibose
• insulin sensitizers such as the PPAR- ⁇ agonists, e.g., the glitazones; biguanides, PTP-IB inhibitors, DPP-IV inhibitors, and 1 lbeta-HSD inhibitors
• hepatic glucose output lowering compounds such as glucagon antagonists and metaformin, e.g., Glucophage and Glucophage XR
• insulin and insulin derivatives both long and short acting forms and formulations of insulin
• the compounds of the invention along with their definitions, such as m, n, p, R 1 , R 2 , R 3 , R 4 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X ⁇ ,Y and Z, are as described above.
• Mass spectral data was determined by electrospray ionization technique. All examples were purified to >90% purity as determined by high-performance liquid chromatography. Unless otherwise stated, reactions were run at room temperature.
• the crude product was chromatographed through a Redi-Sep ® pre-packed silica gel column (120 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide N-(4-(3-chloropyrazin-2- yloxy)phenyl)benzo[d]thiazol-2-amine as light-tan solid.
• EXAMPLE 58 N-(4-(3-(TETRAHYDRO-2H-PYRAN-3-YLAMINO)PYRAZIN-2- YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE
• EXAMPLE 60 1 - ⁇ - ⁇ -(BENZO ⁇ THIAZOL ⁇ -YLAMINO ⁇ HENOXY ⁇ YRAZIN ⁇ -YLH- METHYLPIPERIDIN-4-OL
• STEP 2 l-(3-(4-(BENZO[D]THIAZOL-2-YLAMINO)PHENOXY)PYRAZIN-2-YL)-4- METHYLPIPERIDIN-4-OL .
• EXAMPLE 104 (1 H-BENZO [D]IMIDAZOL-2-YL)(4-(3 -(2- (TRIFLUOROMETHYL)PYRIDIN-4-YL)PYRAZIN-2-YLOXY)PHENYL)METHANONE
• EXAMPLE 106 3 -(3 -(4-( 1 H-BENZO [D]IMIDAZOLE ⁇ -CARBONYL)PHENOXY)PYRAZIN- 2- YL)PYRIDIN-2( 1 H)-ONE
• EXAMPLE 135 N-(4-(3-(2-METHYLPYRIDIN-4-YL)PYRAZIN-2- YLOXY)PHENYL)BENZO[D]THIAZOL-2-AMINE.
• EXAMPLE 136 3-(3-(4-(BENZO[D]THIAZOL ⁇ -YLAMINO)-S- FLUOROPHENOXY)PYRAZIN-2-YL)CYCLOHEX-2-ENONE
• the reaction flask was flushed with nitrogen and capped. The reaction was heated to 100 0 C for 16 hours. The reaction was then cooled down to RT and partitioned with ethyl acetate (50 ml) and water (50 ml). The organic layer was washed (2x) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and then filtered. The volatile were reduced to a smaller volume and the solid that precipitated out was filtered off.
• reaction was cooled down to RT. An aliquot was analyzed via LC-MS showed the reaction was incomplete. The reaction was filtered through celite and the filtrate was transferred back to the reaction vessel. An additional 4.15 g of ammonium formate and 0.350 of 10% Pd/C was added to the reaction under nitrogen. The vessel capped again and heated to 75 0 C overnight. The reaction was cooled down and filtered through a pad of celite. The filtrate was reduced under vacuum. The residue obtained was portioned with DCM and water. The organic layer was washed (2x) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate reduced. The volatiles were removed under vacuum.
• EXAMPLE 186 lH-BENZIMIDAZOL-2-YL(4-((3-(TETRAHYDRO-2H-PYRAN-3-YL)-2- PYRAZINYL)OXY)PHENYL)METHANONE
• STEP 2 5 -(4,4,5 ,5 -TETRAMETHYL- 1 ,3 ,2-DIOXABOROLAN-2-YL)-3 ,4-DIHYDRO-2H- PYRAN.
• STEP 3 lH-BENZIMIDAZOL-2-YL(4-((3-(5,6-DIHYDRO-2H-PYRAN-3-YL)-2- PYRAZINYL)OXY)PHENYL)METHANONE .
• STEP 4 lH-BENZIMIDAZOL-2-YL(4-((3-(TETRAHYDRO-2H-PYRAN-3-YL)-2- PYRAZINYL)OXY)PHENYL)METHANOL.
• EXAMPLE 187 1 H-BENZIMIDAZOL-2- YL(4-((3 -(4-METHOXY- 1 -CYCLOHEXEN- 1 -YL)- 2-PYRAZINYL) OXY)PHENYL)METHANONE
• EXAMPLE 188 lH-BENZIMIDAZOL-2-YL(4-((3-(CIS-4-HYDROXYCYCLOHEXYL)-2- PYRAZINYL)OXY)PHENYL)METHANONE AND lH-BENZIMIDAZOL-2-YL(4-((3- (TRANS-4-HYDROXYCYCLOHEXYL)-2-PYRAZINYL)OXY)PHENYL)METHANONE
• EXAMPLE 193 N-(4-(3-(TETRAHYDRO-2H-PYRAN-3-YL)PYRAZIN-2- YL0XY)P ⁇ ENYL)BENZ0[D]T ⁇ IAZ0L-2-AMINE

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