WO2010138585A1 - Pyrimidinones constituant des inhibiteurs de pde10 - Google Patents

Pyrimidinones constituant des inhibiteurs de pde10 Download PDF

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WO2010138585A1
WO2010138585A1 PCT/US2010/036195 US2010036195W WO2010138585A1 WO 2010138585 A1 WO2010138585 A1 WO 2010138585A1 US 2010036195 W US2010036195 W US 2010036195W WO 2010138585 A1 WO2010138585 A1 WO 2010138585A1
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Prior art keywords
oxo
ethyl
dione
isoindole
dihydroquinazolin
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PCT/US2010/036195
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English (en)
Inventor
Christopher D. Cox
Jaime Lynn Bunda
Broc A. Flores
William Shipe
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Merck Sharp & Dohme Corp.
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Publication of WO2010138585A1 publication Critical patent/WO2010138585A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms

Definitions

  • the invention relates generally to compounds which act as inhibitors of phosphodiesterase 10 (PDElO), compositions and therapeutic uses thereof.
  • PDElO phosphodiesterase 10
  • 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 noncompliance or discontinuation of medication. Dissatisfaction with therapy is attributed to lack of efficacy or intolerable and unacceptable side affects.
  • Cyclic AMP is thought to regulate the activity of cAMP-dependent protein kinase (PKLA), which in turns phosphorylates and regulates many types of proteins including ion channels, enzymes and transcription factors.
  • PKLA cAMP-dependent protein kinase
  • cGMP is also responsible for downstream regulation of kinases and ion channels.
  • 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, 7 A and 7B, and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C 5 and 9A, and 3) those that are dual substrate, PDE IA-C, 2A, 3 A and 3B, 1OA, and 1 IA.
  • 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.
  • PDElO The identification of PDElO 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: 109-117; Soderling et al., PNAS. USA (1999) 96: 7071-7076).
  • the PDElO subtype at present consists of a sole member, PDElOA, 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.
  • the N-terminus splice variants, PDElOAl and PDE10A2 differ in that the A2 variant has a PICA phosphorylation site that upon activation, i.e. PKA phosphorylation in response to elevated cAMP levels, results in intracellular changes to the localization of the enzyme.
  • PDEl OA is unique relative to other PDE families also having the conserved GAF domain in that its Iigand is cAMP, while for the other GAF-domain PDEs the Iigand is cGMP (Kehler et al., Expert Opin. Ther. Patents (2007) 17(2): 147-158).
  • PDElOA 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 PDElO, suggests that inhibitors thereto may be well suited from treating neurological and psychiatric disorders and conditions.
  • the present invention is directed to pyrimidinone compounds that are useful as therapeutic agents for the treatment of central nervous system disorders associated with phosphodiesterase 10 (PDElO).
  • This invention also provides pharmaceutical compositions comprising a PDElO inhibitor, either alone or in combination, with one or more therapeutically active compounds and a pharmaceutically acceptable carrier.
  • This invention also comprises methods of treating neurological and psychiatric disorders and, in particular, schizophrenia, Huntington's disease, or psychosis associated with striatal hypofunction or basal ganglia dysfunction, with the PDElO inhibitors herein.
  • the present invention is directed to PDElO inhibitors and derivatives of structural formula I:
  • A is selected from the group consisting of (1) C3_io cycloalkyl, (2) C6-l ⁇ aryl,
  • R is selected from the group consisting of
  • R2 and R3 are each independently selected from the group consisting of (1) hydrogen,
  • R a is selected from the group consisting of
  • R a is selected from the group consisting of
  • R a is selected from the group consisting of (1) fluorine, (2) chlorine,
  • aryl optionally substituted with 1 to 3 groups of R a and all other variables are as previously described.
  • Another embodiment of this invention is when said aryl is phenyl.
  • An embodiment of the present includes compounds where A is -(CH2)nC5 ⁇ 10 heteroaryl optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Another embodiment of this invention is when said heteroaryl is pyridyl.
  • An embodiment of the present invention includes compounds where Ar is (CH2)nC6-10 ar yl optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Another embodiment of this invention is when said aryl is phenyl.
  • An embodiment of the present invention includes compounds where Ar is -(CH2)nC5-10 heterocyclyl optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Another embodiment of this invention is when said heterocyclyl is selected from the group consisting of indole and indazole.
  • An embodiment of the present invention includes compounds where R is -(CH2)nC5-l ⁇ heterocyclyl optionally substituted with 1 to 3 groups of R a and all other variables are as previously described.
  • Another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of (a) indole, and
  • An embodiment of the present invention includes compounds where R is -(CH2)nNR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described. Another embodiment of this invention is when R2 is hydrogen and R3 is -Cg-Cio a*yl- Another embodiment of this invention is when said -Cg-Cio aryl is biphenyl.
  • An embodiment of the present invention is where A and Ar is -(CH2)nC6-10 aryl, each optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described.
  • An embodiment of this invention is where A and Ar is phenyl and R is -(CH2)nC5-10 heterocyclyl, each optionally substituted with 1 to 3 groups of R a and all other variables are as previously described.
  • Another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Ar is selected from the group consisting of
  • biphenyl where each is optionally substituted with 1 to 3 groups of R a and all other variables are as previously described.
  • R is -(CH2)nC5-10 heterocyclyl or -(CH2) n NR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described.
  • n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • phthalimidyl Another embodiment of the compound of formula Ha is where Ar is phenyl and R is -(CH2) n C5-10 heterocyclyl or -(CH2)nNR 2 C(O)NR.2R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of (1) indole, and
  • Ax is indole and R is -(CH2)nC5-10 heterocyclyl or -(CH2) ⁇ NR2C(O)NR2R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described.
  • Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Another embodiment of the compound of formula Ha is where Ar is indazole and R is -(CH2)nC5-l 0 heterocyclyl or -(CH2) n NR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Another embodiment of the compound of formula Ha is where Ar is biphenyl and R is -(CH2) n C5- 10 heterocyclyl or -(CH2) n NR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when ⁇ is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • R a is selected from the group consisting of
  • Ra is selected from the group consisting of
  • Ar is selected from the group consisting of
  • R is -(CH2)nC5-10 heterocyclyl or -(CH2)nNR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of Ra and all other variables are as previously described.
  • n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Another embodiment of the compound of formula lib is where Ar is phenyl and R is -(CH2)nC5-10 heterocyclyl or -(CH2)nNR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Another embodiment of the compound of formula lib is where Ar is indole and R is -(CH2) n C5-10 heterocyclyl or -(CH2) n NR 2 C(O)NR 2 R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Another embodiment of the compound of formula lib is where Ar is indazole and R is -(CH2) n C5-10 heterocyclyl or -(CH2) ⁇ NR 2 C(O)NR2R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • Another embodiment of the compound of formula Hb is where Ar is biphenyl and R is -(CH2)nC5-10 heterocyclyl or -(CH2)nNR 2 C(O)NR 2 R3 optionally substituted with 1 to 3 groups of R a and all other variables are as previously described. Still another embodiment of this invention is when n is 1 to 3, preferably 2, and said heterocyclyl is selected from the group consisting of
  • R a is selected from the group consisting of (1) halogen, (2) hydroxy.
  • R a is selected from the group consisting of
  • R a is selected from the group consisting of
  • Ar is selected from the group consisting of (1) phenyl
  • R a is selected from the group consisting of
  • 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.
  • any variable e.g. aryl, heterocycle, Ra 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.
  • R a When R a is -O- and attached to a carbon it is referred to as a carbonyl group and when it is attached to a nitrogen (e.g., nitrogen atom on a pyridyl group) or sulfur atom it is referred to a N-oxide and sulfoxide group, respectively.
  • 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 hydrocarbon radical straight, branched or cyclic containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.
  • Preferred 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.
  • fluoroalkyl refers to an alkyl substituent as described herein containing at least one fluorine 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.
  • Ci-g includes alkyls containing 6, 5, 4, 3, 2, or 1 carbon atoms.
  • alkoxy 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.
  • suitable alkoxy groups include methoxy, ethoxy, n- propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, methoxymethane (also referred to as 'dimethyl ether'), and methoxyethane (also referred to as 'ethyl methyl ether').
  • aryl is intended to mean any stable monocyclic or bicycHc 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, benzof ⁇ ryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, c ⁇ nnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, 1,3-dioxoIanyl, ftuyl, imidazolidinyl, iniidazolinyl, imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl, isoqulnolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl, morpholin
  • the heterocyclic group is a heteroaryl group.
  • heteroaryl refers to groups having 5 to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, between one and about three heteroatoms selected from the group consisting of N, 0, and S heteroaryl groups include, without limitation, thienyl, benzothienyl, furyl, benzofuryl, dibenzofuryl, pyrrolyl, imidazolyl, pyrazoiyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazolyl, oxazolyl, thiazolyl, and isoxazolyl.
  • the heterocyclic group is fused to an aryl or heteroaryl group.
  • fused heterocycles include, without limitation, tetrahydroquinolinyl and dihydrobenzofuranyl.
  • 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 5 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, benzoth ⁇ azole, 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
  • heterocycloalkyls examples include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
  • Heleroalom 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 5 carboxy, hydroxyalkyl, , alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, and ureido groups.
  • Preferred substituents, which are themselves not further substituted are:
  • Halogen refers to fluorine, chlorine, bromine and iodine. Compounds described herein may contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers. The present invention includes all such possible isomers as well as mixtures of such isomers unless specifically stated otherwise.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. Any formulas, structures or names of compounds described in this specification that do not specify a particular stereochemistry are meant to encompass any and all existing isomers as described above and mixtures thereof in any proportion.
  • stereochemistry is meant to encompass that particular isomer in pure form or as part of a mixture with other isomers in any proportion.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein.
  • Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers 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 chromatography.
  • the coupling reaction is often the formation of salts using an enantiomerically pure acid or base.
  • the diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue.
  • the racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.
  • any enantiomer 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 singular forms "a,” “an” and “the” include plural references unless the content clearly dictates otherwise.
  • reference to “a primer” includes two or more such primers
  • reference to “an amino acid” includes more than one such amino acid, and the like.
  • references to the compounds of structural formulas I, Ha, lib, IHa, and HIb 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.
  • inorganic bases and organic bases include aluminum, ammonium, calcium, copper (cupris and cuprous), ferric, ferrous, lithium, magnesium, manganese (manganic and 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.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as argmine, betaine, caffeine, choline, N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol 5 ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamme, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins
  • the compound of the present invention When the compound of the present invention is basic, its corresponding salt may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandeiic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • composition as used herein is intended to encompass a product comprising specified ingredients in predetermined amounts or proportions, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • compositions in relation to pharmaceutical compositions is intended to encompass a product comprising one or more active ingredients, and an optional carrier comprising inert ingredients, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions of the present invention encompass any composition made by combining a compound of the present invention and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions of the present invention comprise compounds of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • additional therapeutic agents can include, for example, i) opiate agonists or antagonists, ii) calcium channel antagonists, iii) 5HT receptor agonists or antagonists, iv) sodium channel antagonists, v) NMDA receptor agonists or antagonists, vi) COX-2 selective inhibitors, vii) NKl antagonists, viii) non-steroidal anti-inflammatory drags ("NSAID”), ix) selective serotonin reuptake inhibitors ("SSRI”) and/or selective serotonin and norepinephrine reuptake inhibitors (“SSNRI”), x) tricyclic antidepressant drugs, xi) norepinephrine modulators, xii) lithium, xiii) valproate, xiv) neurontin (gab
  • compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Exemplifying the invention are the specific compounds disclosed in the Examples and herein that can be used for treating a disease state or condition associated with a neurological or psychiatric disorder.
  • Treating" or “treatment of a disease state includes: 1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; 2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; 3) or relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • 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.
  • treatment refers to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of the neurological and psychiatric disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms, as well as the prophylactic therapy to retard the progression or reduce the risk of the noted conditions, particularly in a patient who is predisposed to such disease or disorder.
  • the compounds of the invention are useful in methods of treating a neurological or psychiatric disorder associated with PDElO 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 can be treated according to the method of the present invention.
  • the subject compounds are useful in a method of inhibiting PDEl 0 activity 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 can be treated according to the method of the present invention.
  • Applicants propose that inhibitors of PDElO and, in particular inhibitors of PDElOA. will provide therapeutic benefit to those individuals suffering from psychiatric and cognitive disorders.
  • the unique and exclusive distribution of PDElOA in the medium spiny projection neurons of the striatum, which form the principle site for cortical and dopaminergic input within basal ganglia, suggests that it may be possible and desirable to identify inhibitors of PDElO to ameliorate or eliminate unwanted cellular signaling within this site.
  • compounds of the invention provide a method for treating or ameliorating diseases or conditions in which striatal hypofunction is a prominent feature or ones in which basal ganglia dysfunction plays a role, such as, Parkinson's disease, Huntington's disease, schizophrenia, obsessive-compulsive disorders, addiction and psychosis.
  • Other conditions for which the inhibitors described herein may have a desirable and useful effect include those requiring a reduction in activity and reduced response to psychomotor stimulants or where it would be desirable to reduce conditional avoidance responses, which is often predictive of clinical antipsychotic activity.
  • a selective PDElO inhibitor refers to an organic molecule that effectively inhibits an enzyme from the PDElO family to a greater extent than enzymes from the PDE 1-9 or PDEIl families.
  • a selective PDElO inhibitor is an organic molecule having a Ki for inhibition of PDElO that is less than or about one-tenth that for a substance that is an inhibitor for another PDE enzyme.
  • the organic molecule inhibits PDElO activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme.
  • a selective PDEl 0 inhibitor is an organic molecule, having a Ki for inhibition of PDElO that is less than or about one-hundredth that for a substance that is an inhibitor for another PDE enzyme.
  • the organic molecule inhibits PDElO activity to the same degree at a concentration of about one- hundredth or less than the concentration required for any other PDE enzyme.
  • a "selective PDElO inhibitor" can be identified, for example, by comparing the ability of an organic molecule to inhibit PDElO activity to its ability to inhibit PDE enzymes from the other PDE families.
  • an organic molecule may be assayed for its ability to inhibit PDElO activity, as well as PDElA, PDElB, PDElC, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A, PDE8B, PDE9A, and/or PDEl IA.
  • compounds of the present invention provide a method for treating schizophrenia or psychosis comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders.
  • DSM-IV-TR The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorders.
  • the term "schizophrenia or psychosis” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources.
  • Disorders and conditions encompassed herein include, but are not limited to, conditions or diseases such as schizophrenia or psychosis, including schizophrenia (paranoid, disorganized, catatonic, undifferentiated, or residual type), schizophreniform disorder, schizoaffective disorder, for example of the delusional type or the depressive type, delusional disorder, psychotic disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition and substance-induced or drug-induced (for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, phencyclidine, ketamine and other dissociative anaesthetics, and other psychostimulants), psychosispsychotic disorder, psychosis associated with affective disorders, brief reactive psychosis, schizoaffective psychosis, "schizophrenia-spectrum" disorders such as schizoid or schizotypal personality disorders, personality disorder of the paranoid type, personality disorder of the schizo
  • the compounds of the present invention provide a method for treating cognitive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • the DSM-IV-TR also provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline.
  • cognitive disorders includes the diagnosis and classification of these disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources.
  • disorders and conditions encompassed herein include, but are not limited to, disorders that comprise as a symptom a deficiency in attention and/or cognition, such as dementia (associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke, alcoholic dementia or other drug-related dementia, AIDS, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal dementia, delirium, amnestic disorders or age related cognitive decline.
  • dementia associated with Alzheimer's disease, ischemia, multi-infarct dementia, trauma, intracranial tumors, cerebral trauma, vascular problems or stroke
  • alcoholic dementia or other drug-related dementia AIDS
  • HIV disease Parkinson's disease
  • Huntington's disease Huntington's disease
  • Pick's disease Creutzfeldt Jacob disease
  • compounds of the present invention provide a method for treating anxiety disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • the D SM-IV-TR also provides a diagnostic tool that includes anxiety disorders as generalized anxiety disorder, obsessive- compulsive disorder and panic attack.
  • anxiety disorders includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources.
  • Disorders and conditions encompassed herein include, but are not limited to, anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.
  • anxiety disorders such as, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attack, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobia, substance-induced anxiety disorder and anxiety due to a general medical condition.
  • compounds of the present invention provide a method for treating substance-related disorders and addictive behaviors comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • the DSM-IV-TR also provides a diagnostic tool that includes persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder induced by substance abuse, and tolerance of, dependence on or withdrawal from substances of abuse.
  • the term "substance-related disorders and addictive behaviors” includes the diagnosis and classification of these mental disorders as described in DSM-IV-TR and the term is intended to include similar disorders described in other sources.
  • Disorders and conditions encompassed herein include, but are not limited to, substance-related disorders and addictive behaviors, such as substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.
  • substance-related disorders and addictive behaviors such as substance-induced delirium, persisting dementia, persisting amnestic disorder, psychotic disorder or anxiety disorder, drug addiction, tolerance, and dependence or withdrawal from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics.
  • compounds of the present invention provide a method for treating obesity or eating disorders associated with excessive food intake, and complications associated therewith, comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • obesity is included in the tenth edition of the International Classification of Diseases and Related Health Problems (ICD- 10) (1992 World Health Organization) as a general medical condition.
  • the DSM-IV-TR also provides a diagnostic tool that includes obesity in the presence of psychological factors affecting medical condition.
  • the term "obesity or eating disorders associated with excessive food intake” includes the diagnosis and classification of these medical conditions and disorders described in ICD-IO and DSM-IV-TR and the term is intended to include similar disorders described in other sources. Disorders and conditions encompassed herein include, but are not limited to, obesity, bulimia nervosa and compulsive eating disorders.
  • compounds of the present invention provide a method for treating mood and depressive disorders comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • mood and depressive disorders includes the diagnosis and classification of these medical conditions and disorders described in the DSM-IV-TR and the term is intended to include similar disorders described in other sources.
  • disorders and conditions encompassed herein include, but are not limited to, bipolar disorders, mood disorders including depressive disorders, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode, a depressive episode with atypical features, a depressive episode with melancholic features, a depressive episode with catatonic features, a mood episode with postpartum onset, post-stroke depression; major depressive disorder, dysthymic disorder, minor depressive disorder, premenstrual dysphoric disorder, post-psychotic depressive disorder of schizophrenia, a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia, a bipolar disorder, for example, bipolar I disorder, bipolar II disorder, cyclothymic disorder, depression including unipolar depression, seasonal depression and post-partum depression, premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PDD), mood disorders due to a general medical condition, and substance-induced mood disorders.
  • a bipolar disorder
  • compounds of the invention provide methods for treating other types of cognitive, learning and mental related disorders including, but not limited to, learning disorders, such as a reading disorder, a mathematics disorder, or a disorder of written expression, attention-deficit/hyperactivity disorder, age-related cognitive decline, pervasive developmental disorder including autistic disorder, attention disorders such as attention-deficit hyperactivity disorder (ADHD) and conduct disorder; an NMDA receptor- related disorder, such as autism, depression, benign forgetfulness, childhood learning disorders and closed head injury; a neurodegenerative disorder or condition, such as neurodegeneration associated with cerebral trauma, stroke, cerebral infarct, epileptic seizure, neurotoxin poisoning, or hypoglycemia-induced neurodegeneration; multi-system atrophy; movement disorders, such as akinesias and akinetic-rigid syndromes (including, Parkinson's disease, drug-induced parkinsonism, postencephalitic parkinsonism, progressive supranuclear palsy, multiple system atrophy, corticobas
  • compounds of the present invention provide a method for treating pain comprising administering to a patient in need thereof an effective amount of a compound of the present invention.
  • pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.
  • schizophrenia bipolar disorder
  • depression including unipolar depression, seasonal depression and post-partum depression
  • premenstrual syndrome PMS
  • premenstrual dysphoric disorder PDD
  • learning disorders pervasive developmental disorders, including autistic disorder, attention disorders including Attention-Deficit/Hyperactivity Disorder, autism, tic disorders including Tourette's disorder, anxiety disorders including phobia and post traumatic stress disorder, cognitive disorders associated with dementia, AIDS dementia, Alzheimer's, Parkinson's, Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus and hearing impairment and loss are of particular importance.
  • the present invention is further directed to a method for the manufacture of a medicament for treating neurological or psychiatric disorders associated with PDElO dysfunction, including those disorders and conditions listed above, in humans and animals comprising combining a compound of the present invention with one or more additional therapeutic agents, carriers, or diluents.
  • the present invention is also directed to compounds of the invention for use in the treatment of neurological or psychiatric disorders associated with PDElO dysfunction, including those disorders and conditions listed above, in humans and animals comprising combining a compound of the present invention with one or more additional therapeutic agents, carriers, or diluents.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents.
  • the compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of the present invention or the other drugs may have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • 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.
  • a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention may be desirable.
  • the combination therapy may also includes therapies in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules.
  • the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
  • compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful.
  • Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of the present invention.
  • the weight ratio of the compound of the present invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used.
  • the weight ratio of the compound of the present invention to the other agent will generally range from about 1000:1 to about 1 : 1000, such as about 200:1 to about 1 :200.
  • Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • 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).
  • the subject compounds may be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the present invention.
  • the subject compound and the other agent may be co-administered, either in concomitant therapy or in a fixed combination.
  • the subject compound may be employed in combination with anti- Alzheimer' s agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID 's including ibuprofen, vitamin E, and anti-amyloid antibodies.
  • the subject compound may be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, iniidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptylme, amobarbital, amoxapine, aripiprazole, atypical antipsychotics, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperi
  • the subject compound may be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole.
  • levodopa with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide
  • anticholinergics such as biperi
  • the dopamine agonist may be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.
  • the subject compound may be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine and ⁇ ndolone classes of neuroleptic agent.
  • Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenaz ⁇ ne, 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.
  • Other neuroleptic agents include loxapine, sulpiride and risperidone.
  • the neuroleptic agents when used in combination with thesubject compound may be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride.
  • a pharmaceutically acceptable salt for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothix
  • Perphenazine, chlorprothixene, clozapine, haloperidolj pimozide and risperidone are commonly used in a non-salt form.
  • the subject compound may be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, ris
  • the subject compound may be employed in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, ⁇ -adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HT 1A agonists or antagonists, especially 5-HT IA partial agonists, and corticotropin releasing factor (CRF) antagonists.
  • norepinephrine reuptake inhibitors including tertiary amine tricyclics and secondary amine tricyclics
  • Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable sails thereof.
  • 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.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant
  • inhalation spray nasal, vaginal, rectal, sublingual, or topical routes of administration
  • nasal, vaginal, rectal, sublingual, or topical routes of administration 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
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • 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
  • an oil medium for example peanut oil, liquid paraffin, or olive oil
  • Aqueous suspensions, oily suspensions, dispersible powders or granules, oil-in-water emulsions, and sterile injectable aqueous or oleagenous suspension may be prepared by standard methods known in the art.
  • the subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein.
  • the dose of the active ingredient in the composition 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 being adhered to by the patient, concurrent medication, and other factors which those skilled in the art will recognize.
  • dosage levels between 0.01 to 10 mg/kg of body weight daily are administered to the patient, e.g., humans and elderly humans.
  • the dosage range will generally be about 0.5 mg to 1.0 g per patient per day which may be administered in single or multiple doses.
  • the dosage range will be about 0.5 mg to 500 mg per patient per day; in another embodiment about 0.5 mg to 200 mg per patient per day; and in yet another embodiment about 5 mg to 50 mg per patient per day.
  • Pharmaceutical compositions of the present invention may be provided in a solid dosage formulation such as comprising about 0.5 mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg active ingredient.
  • the pharmaceutical composition may be provided in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient.
  • the compositions may be provided in the form of tablets containing 1.0 to 1000 mg of the active ingredient, such as, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 20O 5 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably in a regimen of once or twice per day.
  • the compounds of the invention had activity in inhibiting the human PDElO enzyme as described in the biological assay that follows, generally with a Ki of less than about 1 ⁇ M. Many of the compounds within the present invention had activity in inhibiting the human PDElO enzyme in the aforementioned assay, generally with a Ki of less than about 0.1 ⁇ M. Such a result is indicative of the intrinsic activity of the compounds in use as inhibitors of the PDElO enzyme. In general, one of ordinary skill in the art would appreciate that a substance is considered to effectively inhibit PDElO activity if it has a Ki of less than or about 1 ⁇ M, preferably less than or about 0.1 ⁇ M.
  • the present invention also includes compounds within the generic scope of the invention which possess activity as inhibitors of other phosphodiesterase enzymes.
  • the PDElO Ki is a measure of the ability of the test compound to inhibit the action of the PDEl 0 enzyme.
  • the Ki of the compound was determined for PDEs 1-5, 7-9, and 11.
  • the selectivity is defined as the Ki of the test compound for the most potently inhibited PDE other than PDElO, divided by the Ki for PDElO.
  • the PDE enzyme most potently inhibited other than PDElO is listed.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the schemes and examples herein, in addition to other standard manipulations such as ester hydrolysis, cleavage of protecting groups, etc., as may be known in the literature or exemplified in the experimental procedures. Starting materials are made according to procedures known in the art or as illustrated herein.
  • the final product may be further modified, for example, by manipulation of substituents.
  • substituents may include, but are not limited to, reduction, oxidation, alkylation, acylat ⁇ on, and hydrolysis reactions which are commonly known to those skilled in the art.
  • the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products.
  • the following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way.
  • anthranilic acid (or alternatively a l-amino-2- carboxy-heterocycle) can be coupled in one pot to an aliphatic carboxylic acid with triphenylphosphite, followed by addition of aniline (or an amino-substituted heterocycle) to provide compounds A-I of the current invention.
  • R group of A-I contains a phthalimide
  • it can be removed by refluxing in EtOH with hydrazine to provide primary amine B-I.
  • This can be converted to substituted phthalimide B-2 by refluxing in dioxane with the appropriate phthalic anhydride.
  • B-2 contains a nucleophilic group (such as a phenol), it can be further functionalized by alkylation to provide B-3.
  • B-2 contains an arylbromide, it can be reacted under Suzuki or Stille conditions to provide B-4.
  • D-3 (835 g, 2.50 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) and stirred at room temperature for 2 hours. Solvents were removed and the residue azeotroped with toluene. This provided D-4 (690 g, 100%) as an off-white solid. Data for D-4: LRMS: calculated M + H for C14H15NO5: 278.27; Found: 278.62.
  • 2-Amino-4-methylbenzoic acid 150 mg, 0.99 mmol
  • D-4 275 mg, 0.99 mmol
  • triphenylphosphite 286 ⁇ L, 1.1 mmol
  • 6- aminoindazole 132 mg, 0.99 mmol
  • heating at 100 0 C was resumed for 4 hours.
  • the reaction was partitioned between EtOAc and saturated NaHC ⁇ 3. After separation, the organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated by rotary evaporation.
  • the activity of the compounds in accordance with the present invention as PDElO inhibitors may be readily determined without undue experimentation using a fluorescence polarization (FP) methodology well known in the art (Huang, W., et al., J, Biomol Screen, 2002, 7: 215).
  • FP fluorescence polarization
  • the compounds of the Examples had activity in reference assays by exhibiting their ability to inhibit the hydrolysis of the phosphate ester bond of a cyclic nucleotide. Any compound exhibiting a Ki (inhibitory constant) below 1 ⁇ M would be considered a PDElO inhibitor as defined herein.
  • PDE10A2 was amplified from human fetal brain cDNA (Clontech, Mountain View, CA) using a forward primer corresponding to nucleotides 56-77 of human PDEl 0A2 (Accession No. AFl 27480, Genbank Identifier 4894716), containing a Kozak consensus sequence, and a reverse primer Corresponding to nucleotides 2406-2413 of human PDE10A2 (Accession No. AF 127480, Genbank Identifier 4894716).
  • Amplification with Easy-A polymerase (Stratagene, La Jolla, CA) was 95 0 C for 2 minutes followed by thirty three cycles of 95°C for 40 seconds, 55 0 C for 30 seconds, and 72 0 C for 2 minutes 48 seconds. Final extension was 72 0 C for 7 minutes.
  • the PCR product was TA cloned into pcDNA3.2-TOPO (Invitrogen, Carlsbad, CA) according to standard protocol.
  • AD293 cells with 70-80% confluency were transiently transfected with human PDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to manufacturer specifications (Invitrogen, Carlsbad, CA). Cells were harvested 48 hours post-transfection and lysed by sonication (setting 3, 10 X 5 sec pulses) in a buffer containing 20 mM HEPES, 1 mM EDTA and protease inhibitor cocktail (Roche). Lysate was collected by centrifugation at 75,000 xg for 20 minutes. Supernatant containing the cytoplasmic fraction was used for evaluation of PDE10A2 activity.
  • the fluorescence polarization assay for cyclic nucleotide phosphodiesterases was performed using an MAP® FP kit supplied by Molecular Devices, Sunnyvale, CA (product # R8139). IMAP® technology has been applied previously to phosphodiesterase assays (Huang, W., et al., J. Biomol Screen, 2002, 7: 215). Assays were performed at room temperature in 384- well microliter plates with an incubation volume of 20.2 ⁇ L. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 8 ⁇ L of each of 10 solutions differing by 3-fold in concentration, at 32 serial dilutions per plate.
  • PDElO inhibitor can be any compound that is present at 5,000 times its Ki value in the assay described as follows, such as papaverine (see Siuciak, et al. Neuropharmacology (2006) 51 :386-396; Becker, et al.
  • a Labcyte Echo 555 (Labcyte, Sunnyvale, CA) is used to dispense 200 nL from each well of the titration plate to the 384 well assay plate.
  • a solution of enzyme (1/1600 dilution from aliquots; sufficient to produce 20% substrate conversion) and a separate solution of FAM- labeled cAMP PDE from Molecular Devices (product # R7506), at a final concentration of 50 nM are made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl2, 0.05% NaN3 0.01% Tween-20, and 1 mM DTT).
  • the enzyme and the substrate are then added to the assay plates in two consecutive additions of 10 ⁇ L, and then shaken to mix.
  • the reaction is allowed to proceed at room temperature for 30 minutes.
  • a binding solution is 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 is stopped by addition of 60 ⁇ L of the binding solution to each well of the assay plates and the plates are sealed and shaken for 10 seconds.
  • the plate was incubated at room temperature for at least one hour prior to determining the fluorescence polarization (FP).
  • FP fluorescence polarization
  • the parallel and perpendicular fluorescence of each well of the plate was measured using a Perkin Elmer En VisionTM plate reader (Waltham, MA).
  • Fluorescence polarization was calculated from the parallel (S) and perpendicular (P) fluorescence of each sample well and the analogous values for the median control well, containing only substrate (So and Po), using the following equation:
  • Dose-inhibition profiles for each compound were characterized by fitting the mP data to a four-parameter equation given below.
  • the median signal of the "0% inhibition controls” (0%mP) and the median signal of the "100% inhibition controls” (100%mP) are constants determined from the controls located in columns 1-2 and 23-24 of each assay plate.
  • An apparent (K 1n ) for FAM-labeled cAMP of 150 nM was determined in separate experiments through simultaneous variation of substrate and selected drug concentrations,
  • AH other PDE's were GST Tag human enzyme expressed in insect cells and were obtained from BPS Bioscience (San Diego, CA): PDElA (Cat# 60010), PDE3A (Cat# 60030), PDE4A1 A (Cat# 60040), PDE5A1 (Cat# 60050), PDE6C (Cat# 60060), PDE7A (CaI* 60070), PDE8A1 (Cat# 60080), PDE9A2 (Cat# 60090), PDEl 1 A4 (Cat# 60110).
  • Assays for PDE 1 through 11 were performed in parallel at room temperature in 384-well microtiter plates with an incubation volume of 20.2 ⁇ L. Solutions of test compounds were prepared in DMSO and serially diluted with DMSO to yield 30 ⁇ L of each often solutions differing by 3-fold in concentration, at 32 serial dilutions per plate. 100% inhibition was determined by adding buffer in place of the enzyme and 0% inhibition is determined by using DMSO (1% final concentrations). A Labcyte POD 810 (Labcyte, Sunnyvale, CA) was used to dispense 200 nL from each well of the titration plate to make eleven copies of the assay plate for each titration, one copy for each PDE enzyme.
  • a solution of each enzyme (dilution from aliquots, sufficient to produce 20% substrate conversion) and a separate solution of FAM- labeled cAMP or FAM-labeled cGMP from Molecular Devices ( Sunnyvale, CA 5 product # R7506 or cGMP#R7508), at a final concentration of 50 nM were made in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl 2 , 0.05% NaN 3 0.01% Tween-20, and 1 niM DTT). Note that the substrate for PDE2 is 50 nM FAM cAMP containing 1000 nM of cGMP.
  • the enzyme and the substrate were then added to the assay plates in two consecutive additions of 10 ⁇ L 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 ⁇ L 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

Abstract

La présente invention porte sur des composés de pyrimidinone de formule structurelle générale I qui sont utiles comme agents thérapeutiques pour le traitement de troubles du système nerveux central associés à la phosphodiestérase 10 (PDE10).
PCT/US2010/036195 2009-05-29 2010-05-26 Pyrimidinones constituant des inhibiteurs de pde10 WO2010138585A1 (fr)

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WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
WO2013000994A1 (fr) * 2011-06-30 2013-01-03 Abbott Gmbh & Co. Kg Nouveaux composés inhibiteurs de la phosphodiestérase de type 10a
US8691827B2 (en) 2009-08-17 2014-04-08 Merck Sharp & Dohme Corp. Amino tetrahydro-pyridopyrimidine PDE10 inhibitors
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors

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Cited By (14)

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Publication number Priority date Publication date Assignee Title
US8691827B2 (en) 2009-08-17 2014-04-08 Merck Sharp & Dohme Corp. Amino tetrahydro-pyridopyrimidine PDE10 inhibitors
US8772316B2 (en) 2011-02-18 2014-07-08 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE10A)
WO2012112946A1 (fr) 2011-02-18 2012-08-23 Allergan, Inc. Dérivés de 6,7-dialkoxy-3-isoquinolinol substitués en tant qu'inhibiteurs de la phosphodiestérase 10 (pde10a)
US9670181B2 (en) 2011-02-18 2017-06-06 Allergan, Inc. Substituted 6,7-dialkoxy-3-isoquinolinol derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9938269B2 (en) 2011-06-30 2018-04-10 Abbvie Inc. Inhibitor compounds of phosphodiesterase type 10A
WO2013000994A1 (fr) * 2011-06-30 2013-01-03 Abbott Gmbh & Co. Kg Nouveaux composés inhibiteurs de la phosphodiestérase de type 10a
JP2014518237A (ja) * 2011-06-30 2014-07-28 アッヴィ・ドイチュラント・ゲー・エム・ベー・ハー・ウント・コー・カー・ゲー 新規なホスホジエステラーゼ１０ａ型阻害剤化合物
CN103958504B (zh) * 2011-06-30 2016-10-12 艾伯维德国有限责任两合公司 10a型磷酸二酯酶抑制剂化合物
WO2014071044A1 (fr) 2012-11-01 2014-05-08 Allergan, Inc. Dérivés de 6,7-dialcoxy-3-isoquinoline substitués à titre d'inhibiteurs de phosphodiestérase 10 (pde10a)
US9200016B2 (en) 2013-12-05 2015-12-01 Allergan, Inc. Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US9902710B2 (en) 2013-12-05 2018-02-27 Exonhit Therapeutics, Sa Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A)
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors

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