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WO2014078214A1 - Azétidine benzimidazoles utilisables en tant qu'inhibiteurs de pde10 - Google Patents

Azétidine benzimidazoles utilisables en tant qu'inhibiteurs de pde10 Download PDF

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Publication number
WO2014078214A1
WO2014078214A1 PCT/US2013/069372 US2013069372W WO2014078214A1 WO 2014078214 A1 WO2014078214 A1 WO 2014078214A1 US 2013069372 W US2013069372 W US 2013069372W WO 2014078214 A1 WO2014078214 A1 WO 2014078214A1
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WIPO (PCT)
Prior art keywords
methyl
azetidin
imidazol
benzo
pyrimidin
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Ceased
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PCT/US2013/069372
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English (en)
Inventor
Douglas C. Beshore
Chris Culberson
Adam W. JOHNSON
Scott D. Kuduk
Thomas S. Reger
Justin T. SHEEN
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Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Publication of WO2014078214A1 publication Critical patent/WO2014078214A1/fr
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    • 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
    • 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
    • C07D413/14—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

  • Schizophrenia is debilitating disorder affecting the psychic and motor functions of the brain. It is typically diagnosed in individuals in their early to mid-twenties and symptoms include hallucinations and delusions or at the other extreme, anhedonia or social withdrawal. Across the spectrum, the symptoms are indicative of cognitive impairment and functional disabilities. Notwithstanding improvements in antipsychotic treatments, current therapies, including typical (haloperidol) and atypical (clozapine or olanzapine) antipsychotics, have been less than acceptable and result in an extremely high rate of noncomplicance or discontinuation of medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and unacceptable side affects. The side effects have been associated with significant metabolic, extrapyramidal, prolactic and cardiac adverse events. See, Lieberman et al, N. Engl. J. Med. (2005) 353 : 1209-1223.
  • PDEs 3', 5'-cyclic nucleotide specific phosphodiesterases
  • families are further subdivided based on catalytic domain homology and substrate specificity and include the 1) cAMP specific, PDE4A- D, 7A and 7B, and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C, and 9A, and 3) those that are dual substrate, PDE 1A-C, 2A, 3A and 3B, 10A, and 1 1A.
  • the homology between the families ranging from 20% to 45% suggests that it may be possible to develop selective inhibitors for each of these subtypes.
  • PDE 10 The identification of PDE 10 was reported by three groups independently and was distinguished from other PDEs on the basis of its amino acid sequence, functional properties, and tissue distribution (Fujishige et al, J. Biol. Chem. (1999) 274: 18438-18445; Loughney et al, Gene (1999) 234: 109-1 17; Soderling et al, PNAS, USA (1999) 96: 7071-7076).
  • the PDE10 subtype at present consists of a sole member, PDEIOA, having alternative splice variants at both the N-terminus (three variants) and C-terminus (two variants), but that does not affect the GAF domain in the N-terminus or the catalytic site in C-terminus.
  • PDEIOA is unique relative to other PDE families also having the conserved GAF domain in that its ligand is cAMP, while for the other GAF-domain PDEs the ligand is cGMP (Kehler et al, Expert Opin. Ther. Patents (2007) 17(2): 147-158).
  • PDEIOA has limited but high expression in the brain and testes. The high expression in the brain and, in particular, the neurons of the striatum, unique to PDE 10, suggests that inhibitors thereto may be well suited from treating neurological and psychiatric disorders and conditions.
  • PDE 10 compounds see US Serial Numbers
  • PDE10 Inhibition of PDE10 is believed to be useful in the treatment of schizophrenia and a wide variety of conditions or disorders that would benefit from increasing levels of cAMP and/or cGMP within neurons, including a variety neurological, psychotic, anxiety and/or movement disorders. Accordingly, agents that inhibit PDE 10 and especially PDEIOA may be desirable as therapeutics for neurological and psychiatric disorders.
  • the present invention is directed to substituted azetidine benzimidazole compounds which may be useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDE10).
  • PDE10 phosphodiesterase 10
  • the present invention also relates to the use of such compounds for treating neurological and psychiatric disorders, such as schizophrenia, psychosis or Huntington's disease, and those associated with striatal hypofunction or basal ganglia dysfunction.
  • the present invention is directed to compounds of the formula I:
  • R represents H, or C l -6alkyl
  • R1 and R3 are independently selected from the group consisting of H, Ci-6alkyl, Ci-6alkenyl, OR, C(0)R, (CH2) n C6-10 aryl, C3-I0 cycloalkyl, (CH2) n C5-lO heterocyclyl, said alkyl, alkenyl, aryl, cycloalkyl, and heterocyclyl optionally is substituted with 1 to 3 groups of R a ; or
  • R1 and R3 can be combined combined with the atoms to which they are attached to form a 4 to 7 membered saturated or unsaturated heterocyclic group, said group optionally having 1 to 2 additional heteroatoms selected from the group consisting of O, N, and S, and optionally substituted with 1 to 3 groups of R a ;
  • R2 is selected from the group consisting of H, O-R, CN, 0(CH2) n OR, OCHR(CH2) n OR, SR, SO2R, S(0)R, N(R)2, C(0)N(R)2, Ci-3 haloalkyl, 0(CH2) n Cl-3haloalkyl, 0(CH2) n C3- 6cycloalkyl, (CH2)nC5-10heterocycle, Cl-6alkyl, and C3-I0cycloalkyl, said alkyl, cycloalkyl, and heterocycle is unsubstituted or substituted with 1 to 3 groups of R a ;
  • R a is selected from the group consisting of:
  • An embodiment of the present invention includes compounds wherein R is hydrogen.
  • An embodiment of the present invention includes compounds wherein R is Cl-6 alkyl.
  • a subembodiment of this invention is realized when R is methyl.
  • An embodiment of the present invention includes compounds wherein Rl is optionally substituted Cl-6 alkyl.
  • a subembodiment of this invention is realized when Rl is optionally substituted methyl, ethyl or propyl.
  • a further embodiment is realized when Rl is optionally substituted methyl or ethyl.
  • An embodiment of the present invention includes compounds wherein Rl is hydrogen.
  • An embodiment of the present invention includes compounds wherein Rl is (CH2)nC6-10 ar y optionally subsituted with 1 to 3 groups of R a .
  • An embodiment of the present invention includes compounds wherein Rl is optionally substituted C2-6 alkenyl.
  • R2 is selected from the group consisting of H, O-R, and Ci-6alkyl, said alkyl unsubstituted or substituted with 1 to 3 groups of R a .
  • R2 is Cl-6alkyl, said alkyl unsubstituted or substituted with 1 to 3 groups of R a .
  • R2 is methyl.
  • An embodiment of the present invention includes compounds wherein R3 is C 1-6 alkyl.
  • a subembodiment of this invention is realized when R3 is methyl, ethyl or propyl.
  • An embodiment of the present invention includes compounds wherein R3 is hydrogen.
  • An embodiment of the present invention includes compounds wherein R3 is optionally substituted C3-10 cycloalkyl.
  • a subembodiment of this aspect of the invention is realized when R3 is optionally substituted cyclohexyl.
  • An embodiment of the present invention includes compounds wherein R3 is optionally substituted C5-I0 heterocyclyl.
  • a subembodiment of this aspect of the invention is realized when R3 is optionally substituted piperidinyl, tetrahydropyranyl, or oxazolyl.
  • An embodiment of the present invention includes compounds wherein R3 is optionally substituted (CH2)nC6-10 arvl - A subembodiment of this aspect of the invention is realized when R3 is optionally substituted phenyl.
  • An embodiment of the present invention includes compounds wherein R3 is OR.
  • An embodiment of the present invention includes compounds wherein Rl is hydrogen and R3 is hydrogen or optionally substituted C1 -6 alkyl.
  • a subembodiment of this invention is realized when Rl is hydrogen and R3 is optionally substituted methyl, ethyl or propyl.
  • Another embodiment of the present invention includes compounds wherein Rl and R3 are combined with the atoms to which they are attached to form a 4 to 7 membered heterocyclic group, said group optionally having 1 to 2 additional heteroatoms selected from the group consisting of O, N, and S, and optionally substituted with 1 to 3 groups of R a .
  • a sub- embodiment of this aspect of the invention invention is realized when Rl and R3 combine to form an optionally substituted 4 to 7 membered heterocyclic group selected from the group consisting of azetidinone, pyrrolidinone, piperidinone, azepanone, imidazolidinone,
  • Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted pyrrolidinone. Another sub- embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted imidazolidinone. Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted oxazolidinone. Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted hydantoin.
  • Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted azetidinone. Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted piperidinone. Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted azepanone. Another sub-embodiment of this invention is realized when Rl and R3 combine to form an optionally substituted imidazolidinedione.
  • R 1 and R 3 are as originally described.
  • a sub-embodiment of the invention of formula la is realized when R 1 is hydrogen, optionally substituted Cl-6 alkyl, optionally substituted C2-6 alkenyl, and optionally substituted C6-10 ar yl-
  • Another subembodiment of the invention of forumula la is realized when R 1 is hydrogen, optionally substituted methyl, ethyl, or ethenyl, or optionally substituted phenyl.
  • Still another subembodiment of the invention of formula la is realized when R 3 is optionally substituted Cl-6 alkyl, C3-I0 cycloalkyl, (CH2)nC5-lO heterocyclyl, or (CH2)nC6-10 ar yl-
  • R 3 is optionally substituted methyl, ethyl, proypl, isopropyl, cyclohexyl, oxazolyl, (CH2)nphenyl, tetrahydropyranyl, or piperidinyl.
  • R 1 is hydrogen, optionally substituted methyl, ethyl, or ethenyl, or optionally substituted phenyl
  • R 3 is optionally substituted methyl, ethyl, proypl, isopropyl, cyclohexyl, oxazolyl, (CH2)nphenyl, tetrahydropyranyl, or piperidinyl.
  • Still another subembodiment of the invention of formula la is realized when R 1 is hydrogen, and R 3 is optionally substituted methyl, ethyl, proypl, isopropyl, cyclohexyl, oxazolyl, (CH2)nphenyl, tetrahydropyranyl, or piperidinyl.
  • An embodiment of the present invention includes compounds represented by structural formula lb:
  • a sub-embodiment of the invention of formula lb is realized when m is 1. Another sub-embodiment of the invention of formula lb is realized when m is 2. Another sub-embodiment of the invention of formula lb is realized when m is 3. A sub-embodiment of the invention of formula lb is realized when m is 4.
  • Still another sub-embodiment of the invention of formula lb is realized when m is 1 and there is one R a selected from the group consisting of C 1-6 alkyl, C02R, -(CH2)nO-R, (CH2)nCl-3 haloalkyl; (CH2)n C6-10aryl, (CH2)nC5-lO heterocycle, C3-6cycloalkyl, (CH2)nCN, hydroxyl, and (CH2)nN(R)2.
  • Still another sub-embodiment of the invention of formula lb is realized when m is 2 and there one R a selected from the group consisting of C 1-6 alkyl, CO2R, -(CH2)nO-R, (CH2)nCl-3 haloalkyl; (CH2)n C6-10aryl, (CH2)nC5- 10 heterocycle, C3-6cycloalkyl,
  • Still another sub- embodiment of the invention of formula lb is realized when m is 4 and there is one R a selected from the group consisting of C 1-6 alkyl, CO2R, -(CH2) n O-R, (CH2) n Cl-3 haloalkyl; (CH2) n C6-10aryl, (CH2)nC5-10 heterocycle, C3-6cycloalkyl, (CH2)nCN, hydroxyl, and (CH2)nN(R)2.
  • Still another embodiment of the invention of formula lb is realized when m is 1, 2, 3, or 4 and R a is selected from the group consisting of methyl, ethyl, propyl, optionally substituted phenyl, optionally substituted pyridyl, C(0)Omethyl, CH 2 OH, CF 3 , (CH2) n CN, OH, and H 2 .
  • R a is as originally described.
  • a sub- embodiment of the invention of formula Ibb is realized when R a is selected from the group consisting of methyl, ethyl, propyl, optionally substituted phenyl, optionally substituted pyridyl, C(0)Omethyl, CH 2 OH, CF 3 , (CH2) n CN, OH, and NH 2 .
  • R a is as originally described.
  • a sub- embodiment of the invention of formula Ic is realized when R a is selected from the group consisting of methyl, ethyl, propyl, optionally substituted phenyl, optionally substituted pyridyl, C(0)Omethyl, CH 2 OH, CF 3 , (CH2) n CN, OH, and NH 2 .
  • R x is selected from the group consisting hydrogen, methyl, ethyl, propyl, butyl, t-butyl, cyclopropyl, optionally substituted phenyl, optionally substituted pyridyl, C(0)R, C(0)Omethyl, CH 2 OR, CF 3 , (CH2) n CN, OH, and NH 2 .
  • An embodiment of the present invention includes compounds represented by structural formula Ie:
  • R x is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, t-butyl, cyclopropyl, optionally substituted phenyl, optionally substituted pyridyl, C(0)R, C(0)Omethyl, CH 2 OR, CF 3 , (CH2) n CN, OH, and NH 2 .
  • Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein and pharmaceutically acceptable salts thereof and individual enantiomers and diastereomers thereof.
  • variable e.g. aryl, heterocycle, R1 , R ⁇ etc.
  • its definition on each occurrence is independent at every other occurrence.
  • combinations of substituents/or variables are permissible only if such combinations result in stable compounds.
  • alkyl encompasses groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, and alkynyl and means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, and heptyl.
  • alkenyl refers to a
  • alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.
  • alkenyl is C2-C6 alkenyl.
  • Preferred alkynyls are C2-C6 alkynyl.
  • Alkenyl “alkynyl” and other like terms include carbon chains containing at least one unsaturated C-C bond.
  • haloalkyl refers to an alkyl substituent as described herein containing at least one halogen substituent.
  • cycloalkyl refers to a saturated hydrocarbon containing one ring having a specified number of carbon atoms.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • alkoxy or "0-alkyl”as used herein, alone or in combination, includes an alkyl group connected to the oxy connecting atom.
  • alkoxy also includes alkyl ether groups, where the term 'alkyl' is defined above, and 'ether' means two alkyl groups with an oxygen atom between them. Examples of suitable alkoxy groups include methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.
  • heterocycle, heterocyclyl, or heterocyclic represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, and S, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heterocycle or heterocyclic includes heteroaryl moieties.
  • heterocyclic elements include, but are not limited to, azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxolanyl, furyl,
  • heteroaryl represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
  • heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole,
  • heteroatom means O, S or N, selected on an independent basis.
  • a moiety that is substituted is one in which one or more hydrogens have been independently replaced with another chemical substituent.
  • substituted phenyls include 2-flurophenyl, 3, 4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2,4 fluor-3-propylphenyl.
  • substituted n-octyls include 2, 4 dimethyl-5-ethyl-octyl and 3-cyclopentyloctyl. Included within this definition are methylenes (- CH 2 -) substituted with oxygen to form carbonyl (-CO-).
  • Suitable substituents include, without limitation, halo, hydroxy, oxo (e.g., an annular -CH- substituted with oxo is -C(O)-), nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy, amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl, carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
  • Preferred substituents, which are themselves not further substituted are:
  • Halogen or "halo"refer to fluorine, chlorine, bromine and iodine.
  • mammal “mammalian” or “mammals” includes humans, as well as animals, such as dogs, cats, horses, pigs and cattle.
  • racemic mixtures of the compounds may be separated so that the individual enantiomers or diastereomers are isolated.
  • the separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or
  • any enantiomer or diastereomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (III) and deuterium (2H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • references to the compounds of present invention are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or in other synthetic manipulations.
  • the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
  • Salts derived from such inorganic bases include aluminum, ammonium, calcium, cupric, cuprous, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like salts. Particular embodiments include the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
  • the subject compounds may be useful in a method of treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • a neurological or psychiatric disorder associated with PDE10 dysfunction in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • a variety of other mammals may be treated according to the method of the present invention.
  • the subject compounds may be useful in a method of inhibiting PDE10 activity in a patient such as a mammal in need of such inhibition comprising the administration of an effective amount of the compound.
  • the present invention is directed to a compound of the present invention or a pharmaceutically acceptable salt thereof for use in medicine.
  • the present invention is further directed to a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a neurological or psychiatric disorder associated with PDE10 dysfunction in a mammalian patient in need thereof.
  • the present invention is further directed to a use of a compound of the present invention or a
  • the subject treated in the present methods is generally a mammal, in particular, a human being, male or female, in whom therapy is desired.
  • the term "therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. It is recognized that one skilled in the art may affect the neurological and psychiatric disorders by treating a patient presently afflicted with the disorders or by prophylactically treating a patient afflicted with such disorders with an effective amount of the compound of the present invention.
  • the enzyme and the substrate were then added to the assay plates in two consecutive additions of 10 ⁇ and then shaken to mix.
  • the reaction was allowed to proceed at room temperature for 60 minutes.
  • a binding solution was then made from the kit components, comprised of 80% Solution A, 20% Solution B and binding reagent at a volume of 1/600 the total binding solution.
  • the enzymatic reaction was stopped by addition of 60 ⁇ of the binding solution to each well of the assay plate.
  • the plates were sealed and shaken for 10 seconds.
  • the plates were incubated at room temperature for one hour, then the parallel and perpendicular fluorescence was measured using a Tecan Genios Pro plate reader (Tecan, Switzerland).
  • the compound of the present invention and other active agents may be administered separately or in conjunction.
  • the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • butyrophenone, diphenylbutylpiperidine and indolone classes of neuroleptic agent Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is molindolone.
  • the compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • the compounds of the invention are effective for use in humans.
  • administration of and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • Compositions for oral use may also be presented as hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • the subject compounds may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the dosage of active ingredient in the compositions of this invention may be varied, however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the active ingredient may be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • the dose will vary from patient to patient depending upon the nature and severity of disease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which those skilled in the art will recognize.
  • the following table shows representative data for the compounds of the Examples as PDEIO inhibitors as determined by the foregoing assays.
  • the PDEIO 3 ⁇ 4 is a measure of the ability of the test compound to inhibit the action of the PDEIO enzyme.

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Abstract

La présente invention concerne des composés de type azétidine benzimidazole substitué pouvant être utilisés en tant qu'agents thérapeutiques en vue du traitement d'affections du système nerveux central associées à la phosphodiestérase 10 (PDE10). La présente invention concerne également l'utilisation desdits composés en vue du traitement d'affections neurologiques et psychiatriques, comme la schizophrénie, la psychose ou la chorée de Huntington, ainsi que d'affections associées à un hypofonctionnement striatal ou à un dysfonctionnement des noyaux gris centraux.
PCT/US2013/069372 2012-11-15 2013-11-11 Azétidine benzimidazoles utilisables en tant qu'inhibiteurs de pde10 Ceased WO2014078214A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478519A (zh) * 2016-10-10 2017-03-08 上海再启生物技术有限公司 一种2‑甲基‑4‑氨基‑6‑氯嘧啶的制备方法
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
CN117295731A (zh) * 2021-03-17 2023-12-26 默沙东有限责任公司 Pde10化合物的前药

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110160206A1 (en) * 2008-09-04 2011-06-30 Eiji Kawanishi Tri-substituted pyrimidine compounds and their use as pde10 inhibitors
US20110166135A1 (en) * 2008-09-10 2011-07-07 Hiroshi Morimoto Aromatic nitrogen-containing 6-membered ring compounds and their use
US20110306590A1 (en) * 2010-05-13 2011-12-15 Allen Jennifer R Aryl- and heteroaryl- nitrogen-heterocyclic compounds as pde10 inhibitors
WO2012054366A2 (fr) * 2010-10-21 2012-04-26 Merck Sharp & Dohme Corp. Amino-triazolyles inhibiteurs de ped10

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110160206A1 (en) * 2008-09-04 2011-06-30 Eiji Kawanishi Tri-substituted pyrimidine compounds and their use as pde10 inhibitors
US20110166135A1 (en) * 2008-09-10 2011-07-07 Hiroshi Morimoto Aromatic nitrogen-containing 6-membered ring compounds and their use
US20110306590A1 (en) * 2010-05-13 2011-12-15 Allen Jennifer R Aryl- and heteroaryl- nitrogen-heterocyclic compounds as pde10 inhibitors
WO2012054366A2 (fr) * 2010-10-21 2012-04-26 Merck Sharp & Dohme Corp. Amino-triazolyles inhibiteurs de ped10

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106478519A (zh) * 2016-10-10 2017-03-08 上海再启生物技术有限公司 一种2‑甲基‑4‑氨基‑6‑氯嘧啶的制备方法
CN106478519B (zh) * 2016-10-10 2018-12-11 上海再启生物技术有限公司 一种2-甲基-4-氨基-6-氯嘧啶的制备方法
US11351149B2 (en) 2020-09-03 2022-06-07 Pfizer Inc. Nitrile-containing antiviral compounds
US11452711B2 (en) 2020-09-03 2022-09-27 Pfizer Inc. Nitrile-containing antiviral compounds
US11541034B2 (en) 2020-09-03 2023-01-03 Pfizer Inc. Nitrile-containing antiviral compounds
CN117295731A (zh) * 2021-03-17 2023-12-26 默沙东有限责任公司 Pde10化合物的前药

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