Compositions and Their Use

Abstract

The present invention relates to therapeutic compositions comprising a PDE10A inhibitor for use in the prevention, management and / or treatment of inflammatory bowel disease, in particular for use in individuals suffering from ulcerative colitis.

Description

Technical Field

[0001] The present invention relates to compositions and methods for the prevention, management and / or treatment of inflammatory bowel disease. More specifically, the present invention relates to, but is not limited to, the treatment of ulcerative colitis.

Background Art

[0002] Inflammatory bowel disease (IBD) is a chronic, unremitting inflammation that affects the gastrointestinal tract and results in multiple symptoms such as weight loss, abdominal pain, recurrent diarrhea, and bleeding. The prevalence of IBD is approximately 1 in 1000 people in Europe, and higher prevalence and incidence rates are observed in industrialized Western countries (Loftus EV, Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences, Gastroenterology. 2004, 126(6):1504-17). The peak incidence occurs between 10 and 39 years of age.

[0003] The two main forms are ulcerative colitis (UC) and Crohn's disease (Ramos et al., Mechanisms of Disease: Inflammatory Bowel Diseases, Mayo Clin Proc. 2019, 94(1):155-165). Ulcerative colitis is a chronic lifelong disorder characterized by diffuse mucosal inflammation of the colon. The etiology of UC is unknown, but available evidence suggests that both dysregulated innate and adaptive immune pathways contribute to abnormal intestinal inflammation (Geremia et al., Innate and adaptive immunity in inflammatory bowel disease. Autoimmun Rev. 2014 13(1):3-10).

[0004] Currently, there is no treatment for UC. Treatment strategies include lifestyle interventions as well as medical and surgical procedures. Pharmacological management includes corticosteroids, immunosuppressants, and anti-tumor necrosis factor (TNF)-α biologics (Baumgart et al., Inflammatory bowel disease: clinical aspects and established and evolving therapies, Lancet. 2007 369(9573):1641-57).

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

[0006] Therefore, the treatment of IBD, particularly UC, remains an urgent need. The object of the present invention is to provide a treatment method that can be used in various IBD states. Such a treatment method would be beneficial if it could be used to treat IBD, including (but not limited to) UC.

Summary of the Invention

Means for Solving the Problems

[0007] According to one aspect of the present invention, there is provided a composition comprising a PDE10A inhibitor for use in the prevention, management and / or treatment of inflammatory bowel disease.

[0008] According to a related but alternative aspect of the present invention, there is provided an inhibitor of PDE10A for use in the prevention, management and / or treatment of inflammatory bowel disease.

[0009] Preferably, the prevention, management and / or treatment of inflammatory bowel disease comprises administering a therapeutically effective amount of a PDE10A inhibitor to a patient in need thereof.

[0010] According to a related but further aspect of the present invention, there is provided a method for the prevention, management and / or treatment of inflammatory bowel disease, the method comprising administering a therapeutically effective amount of a PDE10A inhibitor to an individual in need of such prevention, management and / or treatment.

[0011] According to a related but further alternative aspect of the present invention, there is provided the use of an inhibitor of PDE10A in the manufacture of a medicament for the prevention, management and / or treatment of inflammatory bowel disease in an individual.

[0012] According to a related but still alternative aspect of the present invention, there is provided a pharmaceutical composition comprising a PDE10A inhibitor and a pharmaceutically acceptable carrier, excipient or diluent.

[0013] In the search for novel mechanisms to inhibit inflammation, the inventors have surprisingly and advantageously found that selective inhibition of PDE10A by small molecule inhibitors helps to restore cGMP signaling to normal levels in in vitro assays of IL-8 neutrophil activation, and thus this represents an unexpected and promising treatment for inflammatory bowel disease, particularly ulcerative colitis.

[0014] Cyclic nucleotide phosphodiesterases (PDEs) are a family of enzymes that catalyze the breakdown of the cyclic nucleotide second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). The intracellular levels of cAMP and cGMP are regulated by both their rates of synthesis (by adenylate cyclase and guanylate cyclase, respectively) and their hydrolysis by phosphodiesterases. By regulating the duration and amplitude of cAMP and cGMP second messenger signals, PDEs play an important regulatory role in signal transduction.

[0015] There are 11 different PDE subtypes (PDE1 - 11), each encoding a PDE with unique substrate specificity, kinetics, allosteric regulators, tissue expression profiles, and pharmacological sensitivities. PDE10A can hydrolyze both cAMP and cGMP. PDE10A hydrolyzes cAMP with a K m of 0.05 μM and cGMP with a K m of 3 μM. PDE10A has a lower K m for cAMP, but the V max cGMP / cAMP ratio is 4.7, indicating a higher specific activity for cGMP. Overall, this suggests that PDE10A is a cAMP-inhibited cGMP phosphodiesterase.

[0016] In contrast, PDE4 is known to hydrolyze cAMP, and thus inhibitors of PDE4 may increase the level of cAMP without significantly affecting the cGMP level. Such increased levels of cAMP may have anti-inflammatory effects.

[0017] In normal tissues, PDE10A has a restricted expression pattern. High PDE10A RNA levels are detected only in the striatum (caudate nucleus and putamen) of the brain and in the testis (Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem. 1999;274:18438-18445). To date, inhibitors of PDE10A have been mainly investigated for neurological conditions including schizophrenia and Parkinson's disease (Geerts H, Spiros A, Roberts P. Phosphodiesterase 10 inhibitors in clinical development for CNS disorders. Expert Rev Neurother. 2017, 17(6):553-560). PDE10A has not been extensively investigated for inflammation. A search of the literature identified one paper (Garcia AM et al., Targeting PDE10A GAF Domain with Small Molecules: A Way for Allosteric Modulation with Anti-Inflammatory Effects. Molecules. 2017, 22(9)) that described the inhibition of LPS-induced nitrite release from the Raw264.7 macrophage cell line, i.e., a transformed mouse cell line rather than human primary cells, by a PDE10 inhibitor. The authors attributed the observed effect to the cAMP hydrolytic activity of PDE10A rather than its cGMP activity.

[0018] The inventors have surprisingly found that the PDE10A inhibitors described herein can provide a beneficial anti-inflammatory effect in patients suffering from an inflammatory bowel disease, such as ulcerative colitis, through selective inhibition of cGMP hydrolysis, can increase the level of cGMP, and can help restore cGMP signaling to normal levels.

[0019] As used herein, the terms "treating", "treatment", "treat", "treating", etc. refer to obtaining a desired pharmacological and / or physiological effect. This effect can be prophylactic in terms of completely or partially preventing a disease or its symptoms, and / or therapeutic in terms of partial or complete cure of a disease and / or adverse effects caused by the disease. "Treatment" and "treating" as used herein encompass any treatment of a disease in a mammal, particularly a human, and include: (a) preventing a disease from occurring in a subject who may be susceptible to the disease but has not yet been diagnosed as having the disease; (b) inhibiting the disease, i.e., preventing or delaying its onset; (c) alleviating the disease, i.e., causing regression of the disease.

[0020] As used herein, the term "subject" or "individual" includes any human or non-human animal. The term "non-human animal" includes all mammals such as non-human primates, sheep, dogs, cats, cows, horses, etc.

[0021] Inflammatory bowel disease may include ulcerative colitis or Crohn's disease. Preferably, the inflammatory bowel disease includes ulcerative colitis.

[0022] The present invention provides a PDE10A inhibitor for use in the prevention, management and / or treatment of inflammatory bowel disease. Suitably, the inflammatory bowel disease is selected from ulcerative colitis and / or Crohn's disease. Suitably, the inflammatory bowel disease is ulcerative colitis.

[0023] In some embodiments, the PDE10A inhibitor is a small molecule. Any inhibitor of PDE10A may be suitable for use in any one of the aspects of the present invention. Examples of PDE10A inhibitors may include, but are not limited to, one or more of the following: PF-02545920, TAK-063, papaverine, RG7203, JNJ-42314415, AMG-579, PG-10, BMS-843496, PDM-042, and derivatives thereof. It will be apparent to those skilled in the art that one or more combinations of PDE10A inhibitors or one or more PDE10A inhibitors may be used to provide a suitable therapy.

[0024] In some embodiments, the PDE10A inhibitor may be as described in US Patent Application Publication No. 2010 / 0197651A1 and may be suitably selected from Examples 1 to 195 described therein.

[0025] In such embodiments, the PDE10A inhibitor preferably has the formula (I),

Chemical formula

[0026] Preferably, R 1 represents a phenyl group optionally substituted by 1 to 5 substituents selected from a halogen atom, a C 1~10 alkyl group, and a C 1~10 alkoxy group.

[0027] Preferably, R 2is a C optionally substituted by one or more substituents selected from a halogen atom, C 1~10 alkoxy group, and C 3~7 cycloalkyl group, which represents an C 1~10 alkoxy group.

[0028] Preferably, R 3 represents a hydrogen atom or a C 1~10 alkoxy group.

[0029] Preferably, ring A is (1) a halogen atom, (2) a C 1~10 alkyl group optionally substituted by 1 to 3 halogen atoms, (3) a C 1~10 alkoxy group optionally substituted by 1 to 3 halogen atoms, (4) a C 3~7 cycloalkyl group, (5) a halogenoalkylsulfonyloxy group, (6) a C 3~7 cycloalkyl-C 2~6 alkynyl group, and (7) a benzene ring optionally substituted by 1 to 5 substituents selected from a halogen atom, a hydroxy group, an oxo group, a C 1~10 alkoxycarbonyl group, a C 1~10 alkoxy group optionally substituted by a halogen, and a C 1~10 alkyl group optionally substituted by a halogen, and containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms, which is a 4- to 6-membered heterocyclic group represented by a benzene ring optionally substituted by 1 to 5 substituents selected from the group consisting of.

[0030] Preferably, ring B represents a pyrazole ring optionally further substituted by 1 to 3 substituents selected from a halogen atom and a C 1~10 alkyl group optionally substituted by a halogen.

[0031] Preferably, R 1 represents a phenyl group optionally substituted by 1 to 5 halogen atoms, R 2 represents a hydrogen atom or a C 1~10 alkoxy group, and R 3 represents a hydrogen atom, and ring A is a 4- to 6-membered heterocyclic group containing 0 to 1 oxygen atoms and 1 to 3 nitrogen atoms as heteroatoms, optionally substituted with 1 to 4 substituents selected from a halogen atom, a hydroxy group, an oxo group, a halogeno C 1~10 alkoxy group, a C 1~10 alkoxycarbonyl group, and a C 1~10 alkyl group which may be further substituted with 1 or 2 substituents selected from a halogen atom and a C 1~10 alkoxy group, and is represented by a benzene ring which may be further substituted with 1 or 2 substituents selected from a halogen atom and a C ring B represents a pyrazole ring.

[0032] Preferably, the 4- to 6-membered heterocyclic group of ring A containing 0 or 1 oxygen atom and 1 to 3 nitrogen atoms as heteroatoms is a morpholino group, a pyrrolyl group, a dihydropyrrolyl group, a pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl group, an imidazolyl group or an imidazolidinyl group.

[0033] In one embodiment, the PDE10A inhibitor is preferably 1-[2-fluoro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0034] In one embodiment, the PDE10A inhibitor is preferably 1-[2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0035] In one embodiment, the PDE10A inhibitor is preferably 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0036] In one embodiment, the PDE10A inhibitor is preferably 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0037] In one embodiment, the PDE10A inhibitor is preferably 1-[4-(4-chloro-1H-pyrazol-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0038] In one embodiment, the PDE10A inhibitor is preferably 1-[2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0039] In one embodiment, the PDE10A inhibitor is preferably 3-[1-(2-fluorophenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one, or a salt thereof.

[0040] In one embodiment, the PDE10A inhibitor is preferably 3-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxypyridazin-4(1H)-one, or a salt thereof.

[0041] In one embodiment, the PDE10A inhibitor is preferably 1-[4-(4,4-dimethyl-2-oxopyrrolidin-1-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0042] In one embodiment, the PDE10A inhibitor is preferably 1-[4-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-2-fluorophenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0043] In one embodiment, the PDE10A inhibitor is preferably 5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, or a salt thereof.

[0044] In some embodiments, the above PDE10A inhibitor may be as described in US Patent Application Publication No. 2013 / 150344A1, and may suitably be selected from Examples 1 to 102.

[0045] In such an embodiment, the PDE10A inhibitor preferably has the formula (II),

Chemical formula

Chemical formula

Chemical formula

[0046] Preferably, R 3 is a substituted pyridine ring or a substituted pyrazole ring.

[0047] In one embodiment, the PDE10A inhibitor is preferably 5-{3-[1-(3-chlorophenyl)-1H-pyrazol-5-yl]-5-methoxy-4-oxopyridazin-1(4H)-yl}-4-fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one or a salt thereof.

[0048] In one embodiment, the PDE10A inhibitor is preferably 1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]-3,3-dimethyl-1,3-dihydro-2H-indol-2-one or a salt thereof.

[0049] In one embodiment, the PDE10A inhibitor is preferably 1-[1-(1-cyclopropylethyl)-1H-pyrazol-4-yl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt thereof.

[0050] In one embodiment, the PDE10A inhibitor is preferably 5-methoxy-1-[2-methoxy-6-(3,3,4,4-tetrafluoropyrrolidin-1-yl)pyridin-3-yl]-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt thereof.

[0051] In one embodiment, the PDE10A inhibitor is preferably 1-[6-(3,4-difluoro-1H-pyrrol-1-yl)-2-methoxypyridin-3-yl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one or a salt thereof.

[0052] In some embodiments, the PDE10A inhibitor may be as described in US Patent Application Publication No. 2014 / 0178304A1.

[0053] In such an embodiment, the PDE10A inhibitor is preferably TAK-063. TAK-063 (valpodect) has the IUPAC formula 1-(2-fluoro-4-pyrazol-1-ylphenyl)-5-methoxy-3-(2-phenylpyrazol-3-yl)pyridazin-4-one (CAS number: 1238697-26-1) and has the following structure.

Chemical formula

[0054] TAK-063 has been studied in a Phase 2 clinical trial for the treatment of people with schizophrenia. TAK-063 was administered at 20 mg once daily, but may be reduced to 10 mg once daily if higher doses are not tolerated.

[0055] In some embodiments, the PDE10A inhibitor is papaverine. Papaverine has the IUPAC formula 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxyisoquinoline (CAS number: 58-74-2) and has the following structure.

Chemical formula

[0056] Papaverine is an alkaloid found in opium, but is not closely related to other opium alkaloids in its structure or pharmacological action. It is a direct-acting smooth muscle relaxant used in the treatment of impotence and as a vasodilator, especially for cerebral vasodilation. Papaverine is currently administered to patients for the treatment of cerebral ischemia and peripheral ischemia associated with arterial spasm and myocardial ischemia associated with arrhythmia. The dosage is 150 mg orally every 12 hours.

[0057] In some embodiments, the PDE10A inhibitor is RG7203. RG7203 is a small molecule inhibitor of PDE10 for the treatment of schizophrenia that has previously undergone clinical trials.

[0058] In some embodiments, the PDE10A inhibitor may be as described in WO 2006 / 072828 A2 and may be appropriately selected from Examples 1 to 85 described therein.

[0059] In such embodiments, the PDE10A inhibitor preferably has formula (III),

Chemical formula

[0060] Preferably, HET 1 is a 5-membered heteroaromatic ring appropriately selected from the group consisting of pyrazole, isoxazole, triazole, oxazole, thiazole and imidazole.

[0061] Preferably, HET 2 is selected from the group consisting of 4-pyridyl, 4-pyridazine and isoxazole. Preferably, HET 2 is 4-pyridyl.

[0062] Preferably, Y is selected from the group consisting of carbon and nitrogen, provided that no more than one Y is nitrogen. Preferably, all Ys are carbon.

[0063] Preferably, X 1 is carbon and X is oxygen.

[0064] Preferably, the PDE10A inhibitor is appropriately selected from the following group. 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Methyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Ethyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(1-Ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, Dimethyl-(2-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)-amine, Dimethyl-(2-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-ethyl)-amine, 1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol, 1-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol, 2-[4-(2-Isopropyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(4-pyridin-4-yl-isoxazol-5-yl)-phenoxymethyl]-quinoline, 2-[4-(5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Methyl-5-pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Methyl-6-pyridin-4-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Methyl-6-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)-phenoxymethyl]-quinoline, 2-[4-(4-pyridazin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(1-Methyl-4-pyridazin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Methyl-4-pyridazin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(4-Pyrimidin-4yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(4-Pyridazin-3-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-{4-[4-(3-Methyl-isoxazol-5-yl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{4-[2-Methyl-4-(3-Methyl-isoxazol-5-yl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{4-[1-Methyl-4-(3-Methyl-isoxazol-5-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{4-[2-Methyl-5-(3-Methyl-isoxazol-5-yl)-pyrimidin-4-yl]-phenoxymethyl}-quinoline, 2-[4-(2-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(3-Methyl-5-pyridin-4-yl[1,2,4]triazol-4-yl)-phenoxymethyl]-quinoline, 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoxaline, 7-Chloro-2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline hydrochloride, 6-Fluoro-2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline hydrochloride, 2-[2-Fluoro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[2-Fluoro-4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[2,3-difluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[3-fluoro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline, 2-[4-(1-methyl-5-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline, 2-[4-(1-methyl-3-pyridin-4-yl-1H-pyrazol-4-yl)-phenoxymethyl]-quinoline, 2-methyl-1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol, 2-methyl-1-{4-pyridin-4-yl-5-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol, (R)-1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol, (S)-1-{4-pyridin-4-yl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-pyrazol-1-yl}-propan-2-ol, 2-[4-(1-isopropyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(1-isobutyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-[1.8]naphthyridine, 2-{2-[4-(4-pyridin-4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline, 2-{2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline, 2-{4-[4-(2-Chloro-pyridin-4-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{4-[1-Methyl-4-(2-methyl-pyridin-4-yl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline, Dimethyl-(4-{1-methyl-3-[4-(quinolin-2-ylmethoxy)-phenyl]-1H-pyrazol-4-yl}-pyrido[1,2-a]pyridin-2-yl)-amine, 2-[4-(5-Pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline, 2-[4-(3-Methyl-5-pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-quinoline, 2-[2-Chloro-4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[2-Chloro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline, 2-[4-(3-Methyl-5-pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline, 2-[4-(2-Pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(5-Methyl-2-pyridin-4-yl-2H-[1,2,4]triazol-3-yl)-phenoxymethyl]-quinoline, 8-Methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-pyrido[1,2-a]pyrimidinone, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinazoline, 2-[3-fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 4-chloro-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, 4-methoxy-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline, dimethyl-{2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinolin-4-yl}-amine, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-benzyloxy]-quinoline disuccinate, 2-((4-(5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline, 2-((4-(2-methyl-5-(pyridin-4-yl)oxazol-4-yl)phenoxy)methyl)quinoline, 2-((4-(3-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline, 2-((4-(1,3-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline, 2-((4-(1,5-dimethyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)quinoline, 2-(1-(4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)ethyl)quinoline, 2-((4-(5-(Pyridin-4-yl)-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline, 2-((4-(2-Methyl-5-(pyridin-4-yl)-2H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline, 2-((4-(3-Methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenoxy)methyl)quinoline, 2-((4-(1-(Pyridin-4-yl)-1H-imidazol-2-yl)phenoxy)methyl)quinoline, 2-((4-(5-(Pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline, 2-((4-(2-Methyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline, 2-((4-(2-Ethyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline, 2-((4-(2-(Pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)quinoline, and pharmaceutically acceptable salts thereof.

[0065] Preferably, the PDE10A inhibitor is preferably 2-{4-[-Pyridin-4-yl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{4-[-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline, 2-{3-Fluoro-4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline, 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-quinoxaline, and is selected from the group consisting of pharmaceutically acceptable salts thereof.

[0066] In some embodiments, the PDE10A inhibitor may be as described in WO 2007 / 077490 A2, and may be appropriately selected from Examples 1 to 37 described in the specification thereof.

[0067] In such embodiments, the PDE10A inhibitor preferably has the formula (IV), [Chemical formula] In formula (IV), HET 1 is selected from the group consisting of monocyclic heteroaryl and bicyclic heteroaryl, and this HET 1 may optionally be substituted with at least one R 4 ; HET 2 is monocyclic heteroaryl, and this HET 2 may optionally be substituted with at least one R 5 ; HET 3 is 8- or 9-membered bicyclic heteroaryl, and this HET 3 may optionally be substituted with at least one R 6 ; R 1 is halogen, hydroxyl, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, C1-C8 alkylthio, -NR 3 R 3 , -OCF3, -S(O) n -R 3 , -C(O)-NR 3 R 3and selected from the group consisting of C1-C8 alkyl substituted with a heteroatom, said heteroatom being selected from the group consisting of nitrogen, oxygen and sulfur, said heteroatom being further substituted with one or more substituents selected from the group consisting of hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C1-C8 haloalkyl, each R 2 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl-C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkenyl, C1-C8 haloalkyl and C3-C8 cycloalkyl, each R 3 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, each R 4 is independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 alkylthio, C1-C8 haloalkyl, and -OR 8 ,-NR 8 R 8 and -SR 8 and is selected from the group consisting of C1-C8 alkyl substituted with one or more substituents selected from the group consisting of, R 5 is independently selected from the group consisting of halogen, hydroxyl, cyano, -NR 8 R 8 C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C1-C8 alkylthio, and C1-C8 haloalkyl, B 1 and B 2 are independently adjacent atoms in HET selected from the group consisting of carbon and nitrogen, 1 in B 3 and B 4 are adjacent atoms in HET, B 3 in3 is carbon, and B 4 is nitrogen, and X and X 1 are each independently selected from the group consisting of oxygen, sulfur, -C(R 2 )2, and -NR2, provided that at least one of X or X 1 is -C(R 2 )2, each R 6 is independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkoxy, C1-C8 cycloalkyl, C1-C8 alkylthio, C3-C8 haloalkyl, NR 7 R 7 , -O-CF3, -S(O) m -R 7 , and -C(O)NR 7 R 7 , and C1-C8 alkyl substituted with a heteroatom, the heteroatom being selected from the group consisting of nitrogen, oxygen, and sulfur, the heteroatom being optionally further substituted with a substituent selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, and C1-C8 haloalkyl, or two Rs 6 may optionally, together with the atom to which they are attached, form a C4-C 10 cycloalkyl, C4-C 10 cycloalkenyl, (4-10 membered) heterocycloalkyl ring, or (4-10 membered) heterocycloalkenyl ring, each R 7 is independently selected from the group consisting of hydrogen and C1-C8 alkyl, each R 8 is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C2-C8 alkenyl, and C2-C8 alkynyl, n is 0, 1, or 2, m is 0, 1, or 2, and p is 0, 1, 2, 3, or 4.

[0068] Preferably, HET 1is a 5-membered heteroaryl appropriately selected from the group consisting of pyrazolyl, isoxazolyl, triazolyl, oxazolyl, thiazolyl and imidazolyl.

[0069] Preferably, HET 2 is selected from the group consisting of 4-pyridyl, 4-pyridazinyl and isoxazolyl, and is preferably 4-pyridyl.

[0070] Preferably, the PDE10A inhibitor is preferably 1-methyl-2-[4-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 2-[4-(1-ethyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1-methyl-1H-benzimidazole, 1-{3-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)-phenyl]-4-pyridin-4-yl-pyrazol-1-yl}-propan-2-ol, 1-methyl-2-[4-(4-pyridin-4-yl-isoxazol-5-yl)-phenoxymethyl]-1H-benzimidazole, 1-methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 1-methyl-2-[4-(2-methyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 1-fluoromethyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 1-isopropyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 1-cyclopropyl-2-(4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 1-(2-Methoxy-ethyl)-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-imidazo[1,2-a]pyridine, 2-[4-(2-methyl-4-pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl]-imidazo[1,2-a]pyridine, 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-[1,2,4]triazolo[1,5-a]-pyridine, 2-{4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-[1,2,4]triazolo[1,5-a]pyridine, 2-{4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl)]-phenoxymethyl}-imidazo[1,2-a]pyridine, 1-methyl-2-{4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-1H-benzimidazole, 1-fluoromethyl-2-{4-[4-pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-1H-benzimidazole, 1-methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-imidazo[4,5-b]pyridine, 1-methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-imidazo[4,5-c]pyridine, 5,6-difluoro-1-methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-benzothiazole, 2-{4-[4-Pyridin-4-yl-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-3-yl]-phenoxymethyl}-benzothiazole, 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline, 3-Methyl-2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-imidazo[1,2-a]pyridine, 2-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1-(2,2,2-trifluoro-ethyl)-1H-benzimidazole, 1-Methyl-2-[4-(5-pyridin-4-yl-pyrazol-1-yl)-phenoxymethyl]-1H-benzimidazole, 1-Methyl-2-{2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenyl]-ethyl}-1H-benzimidazole, 1-Methyl-2-[4-(4-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenoxymethyl]-1H-benzimidazole, 2-Methyl-7-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-thiazolo[3,2-a]pyrimidin-5-one, 7-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-thiazolo[3,2-a]pyrimidin-5-one, 2-[3-Fluoro-4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-1-methyl-1H-benzimidazole, 6-[4-(1-Methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-imidazo[2,1-b]thiazole, 2-((4-(5-(Pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)-1-methyl-1H-benzo[d]imidazole, 2-((4-(5-(Pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)-1H-benzo[d]imidazole, 2-((4-(2-Methyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)-1-methyl-1H-benzo[d]imidazole, 2-((4-(2-Ethyl-5-(pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)-1-methyl-1H-benzo[d]imidazole, 2-((4-(2-(Pyridin-4-yl)-1H-imidazol-1-yl)phenoxy)methyl)-1-methyl-1H-benzo[d]imidazole, and is selected from the group consisting of its pharmaceutically acceptable salts.

[0071] In some embodiments, the PDE10A inhibitor may be as described in WO 2008 / 001182 A1 and may be appropriately selected from the examples described in the specification thereof.

[0072] In such embodiments, the PDE10A inhibitor preferably has formula (V),

Chemical formula

[0073] Preferably, HET 3 is selected from the group consisting of the following. [Chemical formula]

[0074] Preferably, Ring 2 is selected from the group consisting of phenyl, 4-pyridyl, 4-pyridazinyl and isoxazolyl, and appropriately 4-pyridyl.

[0075] Preferably, X 1 is C(R 2 )2 and X is oxygen.

[0076] Preferably, both m and n are 1.

[0077] Preferably, A and A 1 are oxygen and C(R 9 )2 respectively.

[0078] Preferably, the PDE10A inhibitor is 1-pyridin-4-yl-8-(quinolin-2-ylmethoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-pyridin-4-yl-8-((1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-pyridin-4-yl-8-((H-imidazo[1,2-a]pyridin-2-yl)methoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-Pyridin-4-yl-8-([1,2,4]triazolo[1,5-a]pyridin-2-ylmethoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-Pyridin-4-yl-8-(quinazolin-2-ylmethoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-Pyridin-4-yl-8-(imidazo[2,1-b]thiazol-6-ylmethoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-Phenyl-4-yl-8-(quinolin-2-ylmethoxy)-4,5-dihydro-6-oxa-3,3a-diaza-benzazulene, 1-Pyridin-4-yl-8-(quinolin-2-ylmethoxy)-4,5,6-dihydro-3,3a-diaza-benzazulene, and is appropriately selected from the group consisting of its pharmaceutically acceptable salts.

[0079] In some embodiments, the PDE10A inhibitor may be as described in US Patent Application Publication No. 20140148461A1, and may be appropriately selected from Examples 1 to 32 described in that specification.

[0080] In such embodiments, the PDE10A inhibitor is preferably 4-(1-Methyl-3-(4-((1-methyl-1H-imidazol-5-yl)ethynyl)phenyl)-1H-pyrazol-4-yl)pyridine, 2-((4-(1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)pyridine, 5-Methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)pyridine, 4-(1-Methyl-3-(4-((1-propyl-1H-pyrazol-4-yl)ethynyl)phenyl)-1H-pyrazol-4-yl)pyridine, 5-Fluoro-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)pyridine, 3-Methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)pyridine, 4-(1-Methyl-3-(4-((1-methyl-1H-imidazol-2-yl)ethynyl)phenyl)-1H-pyrazol-4-yl)pyridine, 4-Methyl-2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)pyridine, 2-Methyl-6-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)pyridine, 4-(1-Methyl-3-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)phenyl)-1H-pyrazol-4-yl)pyridine, 4-(3-(4-((1H-pyrazol-4-yl)ethynyl)phenyl)-1-methyl-1H-pyrazol-4-yl)pyridine, 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenyl)ethynyl)quinoline, 2-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]-1,5-naphthyridine, 2-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]imidazo[1,2-a]pyridine, 6-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]-1H-pyrrolo[2,3-b]pyridine, 4-Methyl-2-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]quinoline, 2-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]thiazole, 2-[2-[4-[1-Methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]quinoxaline, 3-[2-(6-Methyl-2-pyridyl)ethynyl]-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, 2-Methoxy-6-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]pyridine, 3-Methoxy-2-[2-[4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]pyridine, 4-[1-Methyl-3-[4-(2-phenylethynyl)phenyl]pyrazol-4-yl]pyridine, 3-[4-[2-(6-Methyl-2-pyridyl)ethynyl]phenyl]-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole, 5-[1-Methyl-3-[4-[2-(6-methyl-2-pyridyl)ethynyl]phenyl]pyrazol-4-yl]pyrimidine, 2-Methyl-6-[2-[4-[1-methyl-4-(1H-pyrazol-4-yl)pyrazol-3-yl]phenyl]ethynyl]pyridine, 2-Methyl-6-[2-[4-[2-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]pyridine, 2-Methyl-6-[2-[4-[1-methyl-4-(2-methylpyrazol-3-yl)pyrazol-3-yl]phenyl]ethynyl]pyridine, 4-[1-Methyl-3-[4-[2-(6-methyl-2-pyridyl)ethynyl]phenyl]pyrazol-4-yl]pyridazine, 2-Methyl-6-[2-[4-[1-methyl-4-(3-pyridyl)pyrazol-3-yl]phenyl]ethynyl]pyridine, 2-[2-[4-[4-(4-Fluorophenyl)-1-methyl-pyrazol-3-yl]phenyl]ethynyl]-6-methyl-pyridine, 2-[2-[4-[4-(4-methoxyphenyl)-1-methyl-pyrazol-3-yl]phenyl]ethynyl]-6-methyl-pyridine, 2-[2-[2-methoxy-4-[1-methyl-4-(4-pyridyl)pyrazol-3-yl]phenyl]ethynyl]-6-methyl-pyridine, and may be selected from the group consisting of pharmaceutically acceptable salts thereof.

[0081] In some embodiments, the PDE10A inhibitor may be as described in WO 2012133607A1, and may be appropriately selected from Examples 1 to 418 described in the specification thereof.

[0082] In such embodiments, the PDE10A inhibitor preferably has the formula (VI),

Chemical formula

[0083] In such embodiments, the PDE10A inhibitor is suitably 8-[4-({[1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline, 1-Methyl-5-(1-methyl-3-yl){[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 1-Methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 1-Methyl-5-(1-methyl-)3-{[4-(1-methyl-1H-benzimidazol-4-yl)benzyl]oxy}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 2-(3-{[1-Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}prop-1-yn-1-yl)quinoline, 1-Methyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)piperidin-2-one, 4-(3-{[4-(6-Fluoro-3-methylquinolin-)2-yl)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridin-2(1H)-one, 5-(3-{[4-(6-Methoxy-3-methylquinolin-2-yl)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridin-2(1H)-one, 1-Methyl-4-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 5-(3-{[4-(3-Ethylquinolin-2-yl)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridin-2(1H)-one, 3-Methyl-2-(4-{[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 3-Methyl-2-[4-({[1-methyl-4-(pyridazin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline, 2-(4-{[(1,1’-Dimethyl-1H,1’H-4,4’-bipyrazol-3-yl)oxy]methyl}phenyl)-3-methylquinoline, 1-Methyl-5-(1-methyl-3-{[4-(quinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 1-Ethyl-5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 5-(1-methyl-3-{[4-(3-methylquinolin-2-yl)benzyl]oxy}-1H-pyrazol-4-yl)-1-propylpyridin-2(1H)-one, 5-(3-{[4-(6-Fluoro-3-methylquinolin-2-yl)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)-1-methylpyridin-2(1H)-one, 1-Methyl-5-(2-methyl-5-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-2H-1,2,3-triazol-4-yl)pyridin-2(1H)-one, 3-Methyl-2-(4-{[1-methyl-4-(2-methylpyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)quinoline, 2-(4-{[4-(2,6-Dimethylpyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]methoxy}phenyl)-3-methylquinoline, 1-Methyl-4-(1-methyl-3-{2-[4-(3-methylquinolin-2-yl)phenyl]ethyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 1-Methyl-4-(1-methyl-3-{[4-(3-methylquinolin-2-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 1-Methyl-4-(4-{[1-methyl-4-(2-methyl-1-oxidopyridin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-Methyl-4-(4-{[1-methyl-4-(pyridazin-4-yl)-1H-pyrazol-3-yl]methoxy}phenyl)-1H-benzimidazole, 1-Methyl-4-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyrazol-4-yl)pyridin-2(1H)-one, 1'-Ethyl-1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H,1'H-4,4'-bipyrazole, and may be selected from the group consisting of pharmaceutically acceptable salts thereof.

[0084] In some embodiments, the PDE10A inhibitor may be as described in US Patent Application Publication No. 2013343992A1, and may be appropriately selected from Examples 1 to 19 described therein.

[0085] In such embodiments, the PDE10A inhibitor preferably has formula (VII),

Chemical Formula

Chemical formula

[0086] Preferably, HetAr is selected from the group consisting of the following. [Chemical formula] In the above formula, Z 1 , Z 8 , Z 13 , and R 1 are as defined above.

[0087] In some embodiments, the PDE10A inhibitor is preferably PF-02545920. PF-02545920 (mardepodect, MP-10) has the IUPAC formula 2-[[4-(1-methyl-4-pyridin-4-ylpyrazol-3-yl)phenoxy]methyl]quinolone (CAS number: 898562-94-2) and has the following structure. [Chemical formula]

[0088] PF-02545920 is a potent and selective cyclic nucleotide PDE10 competitive inhibitor with a reported IC 50 value of 1.26 nM. PF-02545920 is being investigated in clinical trials for the treatment of Huntington's disease. Patients were given 5 mg or 20 mg of PF-02545920 twice daily.

[0089] In some embodiments, the PDE10A inhibitor is JNJ-42314415. JNJ-42314415 has the IUPAC formula 3-[6-(2-methoxyethyl)pyridin-3-yl]-2-methyl-8-morpholin-4-ylimidazo[1,2-a]pyrazine (CAS number: 1334165-90-0) and has the following structure. [Chemical formula]

[0090] JNJ-42314415 is a potent and selective centrally active PDE10 inhibitor with a Ki of 35 nM against human recombinant PDE10, showing more than 100-fold selectivity against other PDE families.

[0091] In some embodiments, the PDE10A inhibitor is AMG-579. AMG-579 has the IUPAC formula 1-[4-[3-[4-(1H-benzimidazole-2-carbonyl)phenoxy]pyrazin-2-yl]piperidin-1-yl]ethanone (CAS number: 1227067-61-9) and has the following structure.

Chemical formula

[0092] AMG-579 is a potent and selective CNS-penetrant, orally bioavailable PDE10 inhibitor with an IC 50 . AM-579 shows high selectivity with an IC 50 > 30 μM against all other PDE isoforms.

[0093] In some embodiments, the PDE10A inhibitor is PQ-10. PQ-10 has the IUPAC formula 6,7-dimethoxy-4-[(3R)-3-(quinoxalin-2-yloxy)pyrrolidin-1-yl]quinazoline (CAS number: 927691-21-2) and has the following structure.

Chemical formula

[0094] PQ-10 is a potent and selective inhibitor of PDE10, and significantly enhances basic auditory information processing in rats. PQ-10 was orally administered to rodents with induced memory impairment. The dosage was in the range of 0.1 - 3 mg / kg. PQ-10 was found to be highly brain-penetrant and to reverse the induced memory impairment.

[0095] In some embodiments, the PDE10A inhibitor is BMS-843496. BMS-843496 has the IUPAC formula 2-((4-chloro-6-((pyridin-3-ylmethyl)amino)pyrimidin-2-yl)amino)-N-ethyl-4-methylthiazole-5-carboxamide (CAS number: 2044975-69-9) and has the following structure.

Chemical formula

[0096] BMS-843496 is a potent and selective PDE10A inhibitor with a binding affinity (Kd) of 0.15 nM and an IC 50 of 2.11 nM and >100-fold selectivity against other PDE family members. Studies in animals have found that administration of BMS-843496 correlates with an antipsychotic effect measured using a conditioned avoidance response model.

[0097] In some embodiments, the PDE10A inhibitor is PDM-042. PDM-042 has the IUPAC formula (E)-4-(2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6-(pyrrolidin-1-yl)pyrimidin-4-yl)morpholine (CAS number: ) and has the following structure.

Chemical formula

[0098] PDM-042 shows potent inhibitory activity against human and rat PDE10, with an IC 50 value of less than 1 nmol / L and >1000-fold selectivity against other phosphodiesterases. In behavioral studies using a rat model related to schizophrenia, PDM-042 administered between 0.1 - 0.3 mg / kg significantly antagonized MK-801-induced hyperlocomotion without affecting spontaneous locomotor activity and attenuated the conditioned avoidance response.

[0099] The PDE10A inhibitor may be selected from PF-02545920 or TAK-063.

[0100] The PDE10A inhibitor may be a selective inhibitor of PDE10A. Suitably, the PDE10A inhibitor has an IC 50 against PDE10A less than 5 nM. Suitably, the PDE10A inhibitor has an IC 50 against PDE10A less than 5 nM and an IC 50 against other PDE family members greater than 1 μM. Suitable assays for measuring the IC 50 of inhibitors against PDE10A and other PDE family members are known in the art.

[0101] Preferably, the PDE10A inhibitor selectively inhibits cGMP hydrolysis in the intestinal tissue of a patient suitably having inflammatory bowel disease. Preferably, the PDE10A inhibitor selectively inhibits cGMP hydrolysis over cAMP hydrolysis.

[0102] Preferably, the prevention, management and / or treatment of inflammatory bowel disease of the present invention provided by the PDE10A inhibitor includes increasing cGMP signaling in the intestinal tissue of the patient.

[0103] Preferably, the prevention, management and / or treatment of inflammatory bowel disease of the present invention provided by the PDE10A inhibitor includes increasing cGMP signaling and cAMP signaling in the intestinal tissue of the patient.

[0104] Preferably, the prevention, management and / or treatment of inflammatory bowel disease of the present invention provided by the PDE10A inhibitor includes reducing the level of inflammatory cytokines in the intestinal tissue of the patient.

[0105] For use in accordance with any aspect of the present invention, a therapeutic component(s), such as an inhibitor, referred to herein may be provided as any pharmaceutically acceptable derivative selected from, but not limited to, one or more of pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable hydrates, pharmaceutically acceptable polymorphs, pharmaceutically acceptable esters, and pharmaceutically acceptable prodrugs.

[0106] For use in accordance with any one of the aspects of the present invention, a therapeutic component(s), such as an inhibitor, referred to herein may be administered in any suitable pharmacological dosage, and it is understood that the exact amount (i.e., therapeutically effective amount) will depend on the nature of the inhibitor and the condition being treated. For example, a suitable dosage may include a daily dosage of about 0.1 milligram to about 100 milligrams per kilogram of body weight of an animal, preferably given as a single daily dose or as divided doses two to six times a day, or in a sustained release form.

[0107] For most large mammals, the total daily dosage is preferably about 1 milligram to about 1000 milligrams, more preferably about 1 milligram to about 350 milligrams, especially about 1 mg to about 100 mg. In the case of a 70 kg adult, the total daily dosage is preferably in the range of about 7 milligrams to about 350 milligrams. Typically, such dosages may be in the range of about 50 to 500 mg per day, for example about 240 mg per day or about 100 mg per day. This dosing regimen may be adjusted to provide an optimal therapeutic response, as is known to those skilled in the art.

[0108] Accordingly, the present invention further provides a use or method as described herein, wherein one or more therapeutic components comprising an inhibitor referred to herein may optionally be included in a pharmaceutical formulation together with one or more pharmaceutically acceptable carriers therefor. The one or more pharmaceutically acceptable carriers for each therapeutic component may be the same or different.

[0109] Optionally, other therapeutic components may be included in the pharmaceutical formulations of the invention described herein.

[0110] For example, according to any one of the aspects of the invention described herein, this pharmaceutical formulation may further comprise an inhibitor of inflammatory signaling, including those described below. Thus, according to any one of the aspects of the invention described herein, the PDE10A inhibitor may be for administration separately, sequentially, or simultaneously with one or more pharmaceutically active ingredients.

[0111] The formulation comprises a composition suitable for oral administration, rectal administration, topical administration, parenteral administration (including subcutaneous administration, intramuscular administration, and intravenous administration), ocular administration (ophthalmic), pulmonary administration (nasal inhalation or oral inhalation), or nasal administration (e.g., in the form of droplets or sprays, etc.). However, the most appropriate route in any given case will depend on the nature and severity of the condition being treated, as well as the nature of the therapeutic component, e.g., the nature of the PDE10A inhibitor and / or other active ingredients present.

[0112] In actual use, therapeutic component(s) such as the inhibitor(s) referred to herein can be made into a close physical mixture with one or more pharmaceutical carriers according to conventional pharmaceutical formulation techniques. This carrier may take a wide variety of forms depending on the form of the preparation desired for administration, e.g., oral or parenteral (including intramuscular and intravenous).

[0113] In the preparation of the formulation / composition in a dosage form for administration, any of the usual pharmaceutical excipients such as diluents of solid or liquid nature, flavoring agents, preservatives, coloring agents, etc. may be used. Liquid preparations may be, for example, in the form of suspensions, elixirs, and solutions.

[0114] Such liquid preparations may contain one or more of the following: sucrose as a sweetening agent, methylparaben and / or propylparaben as preservatives, dyes, and flavoring agents. Oral solid preparations are more preferred than oral liquid formulations, and are preferably in the form of, for example, powders, hard capsules, soft capsules, and tablets. In the case of a solid form, the one or more pharmaceutical carriers may include one or more of starch, sugar, microcrystalline cellulose, solid diluents or liquid diluents, granulating agents, lubricants, binders, disintegrants, etc.

[0115] Tablets, pills, capsules, etc. may also contain one or more of the following: binders such as tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweetening agents such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain a liquid carrier such as fatty oil in addition to the materials of the above types.

[0116] Tablets and capsules represent advantageous oral unit dosage forms because they are easy to administer. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques. For example, the tablets may be coated with shellac, sugar, or both.

[0117] Such formulations, compositions, and preparations preferably contain at least 0.1% of a therapeutic component such as an inhibitor (e.g., a PDE10A inhibitor) mentioned herein. The proportion of the therapeutic component(s) such as an inhibitor mentioned herein in these formulations / compositions may of course vary, and may conveniently be between about 2% and about 60% by weight of the unit dose. The amount of the therapeutic component(s) such as an inhibitor mentioned herein in such a therapeutically useful composition is an amount such that an effective dosage (i.e., a therapeutically effective amount) is obtained.

[0118] Various other materials may be present to act as coatings or to modify the physical form of the dosage unit.

[0119] For parenteral administration, pharmaceutical forms include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. Solutions or suspensions of these active inhibitors can be prepared in water for injection and, if desired, mixed with surfactants such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils.

[0120] Accordingly, the pharmaceutical carrier(s) can be, for example, water, an alcohol (e.g., ethanol), a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils, and a solvent or dispersion medium containing these combinations. In all cases, the above forms must be sterile and fluid to enable administration by syringe. The above forms must be stable under the conditions of manufacture and storage. Under normal conditions of storage and use, these preparations contain preservatives to prevent the growth of microorganisms.

[0121] In any one of the treatment methods of the present invention, a "therapeutically effective amount" refers to an amount of a PDE10A inhibitor sufficient to effect the desired treatment (e.g., of a disease) when administered to a subject for prophylactic or therapeutic treatment. The "therapeutically effective amount" varies, for example, depending on the inhibitor used, as described above, the state and severity of the disease, and the age, weight, etc. of the subject being treated.

[0122] In any one of the methods for the prevention, management, and / or treatment of inflammatory bowel disease in a subject according to the present invention, the above PDE10A inhibitor or its formulation may be administered to the subject using any one of the available methods and routes suitable for drug delivery described herein.

[0123] The PDE10A inhibitor or its formulation may be administered in a single dose or multiple doses. Appropriate dosing frequencies may be at least once a day, every other day, once a week, once every two weeks, three weeks, or four weeks, once a month, once every two months, or once every three to six months. The PDE10A inhibitor may be administered over a period of at least one week, at least one month, at least three to six months, at least one year, two years, three years, four years or five years, or over the course of the disease or the lifetime of the subject.

[0124] Preferably, the subject referred to in any one of the aspects of the present invention is a mammal, preferably a human. However, both humans and veterinary subjects are within the scope of the present invention. For veterinary applications, the age of the animal is estimated (increased or decreased) from the human situation using the average lifespan for calibration.

[0125] The inhibitor may be artificially produced. That is, the inhibitor does not exist naturally. However, the inhibitor may be a molecule that exists naturally, but by its concentration and formulation in a pharmaceutical or pharmaceutical preparation, it becomes possible to be used for the prevention, improvement or treatment of inflammatory bowel disease, otherwise it may have no efficacy or limited efficacy.

[0126] In an embodiment, the inhibitor comprises a small molecule. This small molecule may be any suitable organic molecule that inhibits PDE10A.

[0127] The inhibitor may comprise an antibody or a mixture of antibodies. Such antibodies (multiple types possible) may be polyclonal or monoclonal.

[0128] The monoclonal antibody may be obtained by any suitable method. Suitable methods are known to those skilled in the art. For example, the monoclonal antibody may be obtained using hybridoma technology such as fusing antibody-producing cells of an antigen-immunized mammal with mammalian myeloma cells to produce a hybridoma cell line. Preferably, the hybridoma cell line is first produced by immunizing a mammal with an immunizing antigen and generating the immunized mammal. Suitable immunizing antigens are as defined above. The mammal may be immunized by any suitable method such as intraperitoneal, subcutaneous, intravascular, intramuscular or splenic injection, or oral administration. Preferably, the immunizing antigen may be administered, optionally together with an adjuvant such as Freund's complete adjuvant, as a suspension or solution in a buffer such as phosphate buffered saline (PBS). Any suitable mammal, such as a mouse, rat, rabbit, sheep or goat, may be used. It will be understood by those skilled in the art that the mammal should typically be selected to be compatible with the myeloma cells to be used in the subsequent cell fusion step. Preferably, the immunizing antigen is administered to the mammal several times, for example 2, 3, 4 or more times, at intervals of 4 to 21 days.

[0129] Typically, the antibody-producing cells of the immunized mammal may be spleen cells. Preferably, spleen cells of the immunized mammal may be recovered and fused with mammalian myeloma cells. The mammalian myeloma cells may be derived from any suitable source such as a mouse, rat or rabbit. Preferably, the mammalian myeloma cells may be derived from the same mammalian source as the mammal immunized with the immunizing antigen. Preferably, the myeloma cells may be of mouse origin. Preferably, the mammalian myeloma cells are hypoxanthine-guanine-phosphoribosyl transferase deficient (HGPRT - ) and / or thymidine kinase deficient (TK -) is selected to have. For example, mammalian myeloma cells may be mouse P3 / NS1 / 1-Aq4-1 cells. Splenocytes may be fused to mammalian myeloma cells by any suitable method. Suitable methods are known to those skilled in the art. For example, splenocytes may optionally be fused to mammalian myeloma cells using electrofusion in the presence of a fusion promoter such as polyethylene glycol (PEG) or Sendai virus (HVJ). Preferably, splenocytes and mammalian myeloma cells may be mixed at a ratio of 1:1 to 10:1.

[0130] Typically, the fused cells may be cultured and screened to selectively obtain hybridomas. The fused cells may be cultured in any suitable medium. The fused cells may be screened for hybridomas by any suitable method. Suitable methods are known to those skilled in the art. For example, the fused cells may be screened for hybridomas using immunoenzymatic assays such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or surface plasmon resonance (SPR). Preferably, the fused cells may be screened for hybridomas using enzyme-linked immunosorbent assay (ELISA). It will be understood by those skilled in the art that typically screened is the supernatant of the culture of the fused cells. Preferably, the fused cells may be screened for hybridomas by screening for binding to PDE10A. More preferably, the fused cells may be screened for hybridomas by screening for binding to PDE10A using enzyme-linked immunosorbent assay (ELISA).

[0131] The monoclonal antibody produced by the cultured hybridoma may be obtained by any suitable method. Suitable methods are known to those skilled in the art. For example, the monoclonal antibody produced by the cultured hybridoma may be obtained by centrifugation of the supernatant of the culture.

[0132] In certain alternative embodiments, when a monoclonal antibody is produced by culturing the obtained hybridoma intraperitoneally in a suitable mammal, such as a mouse, etc., the obtained hybridoma may be administered intraperitoneally to a mammal, such as a mouse, etc. The monoclonal antibody produced by culturing in the peritoneal cavity of a suitable mammal, such as a mouse, etc., may then be obtained by collecting the fluid in the peritoneal cavity.

[0133] The monoclonal antibody produced by culturing the obtained hybridoma in a suitable medium or intraperitoneally in a suitable mammal, such as a mouse, etc., may be used directly or may be purified. Preferably, this monoclonal antibody may be purified. The monoclonal antibody may be purified by any suitable method. Suitable methods are known to those skilled in the art. For example, the monoclonal antibody may be purified by ammonium sulfate precipitation, ion exchange chromatography or an anti-IgG antibody column.

[0134] When a monoclonal antibody having binding to PDE10A (or its ligand) is used, such an antibody may be used in combination with (or co-administered with) a small molecule inhibitor of PDE10A.

[0135] In certain embodiments, the antibodies of the present invention may be polyclonal. The polyclonal antibody may be produced by any suitable method. Suitable methods are known to those skilled in the art. For example, the polyclonal antibody may be produced by immunizing a mammal with an immunizing antigen and inducing the production of antibodies specific for the immunizing antigen. Suitable immunizing agents are as defined above. Any suitable mammal, such as a mouse, rat or rabbit, may be used. The polyclonal antibody produced by the immunized mammal may be obtained by any suitable method. Suitable methods are known to those skilled in the art. For example, the polyclonal antibody may be obtained by collecting the serum of the immunized mammal.

[0136] Polyclonal antibodies generated by immunizing a mammal with an immunizing antigen and collecting the serum of the immunized mammal may be used directly or may be purified. Preferably, the monoclonal antibody may be purified. The polyclonal antibody may be purified by any suitable method. Suitable methods are known to those skilled in the art. For example, the polyclonal antibody may be purified by ammonium sulfate precipitation, ion exchange chromatography, or an anti-IgG antibody column.

[0137] The polyclonal antibody may be screened for binding to PDE10A using any suitable method. Suitable methods are known to those skilled in the art. For example, the polyclonal antibody may be screened for binding to PDE10A using immunoassays such as enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or surface plasmon resonance (SPR). Preferably, the polyclonal antibody may be screened for binding to PDE10A using enzyme-linked immunosorbent assay (ELISA).

[0138] The antibody of the present invention may be of any suitable isotype. Preferably, the antibody is of isotype IgG. To avoid misunderstanding, an antibody of isotype IgG typically contains four peptide chains, two of which are heavy chains and two of which are light chains, and has two antigen-binding fragment (Fab) regions. The Fab region contains the complementarity-determining region (CDR), which is the part of the antibody that binds to the antigen.

[0139] The inhibitor(s) may contain whole antibodies (the entire antibody) or multiple whole antibodies, but the inhibitor may also contain antibody fragments or modified forms thereof. Suitable examples of whole antibodies include, but are not limited to, monovalent or divalent antibodies. Suitable examples of antibody fragments include, but are not limited to, Fab, F(ab’)2, Fv, Fab / c having one Fab and a complete Fc, and single-chain Fv (scFv) having a heavy chain (H) or light chain (L) Fv linked by a suitable linker. Other antibody scaffold proteins may be used, examples of which include Nanobodies® (registered trademark) containing a synthetic single immunoglobulin variable heavy chain domain derived from camelid antibodies (e.g., camel or llama), Domain Antibodies (commercially available from Domantis (Belgium)) containing affinity matured single immunoglobulin variable heavy chain domains or immunoglobulin variable light chain domains, UniBodies (commercially available from Genmab, and UniBodies are modified full human IgG4 antibodies with the hinge region of the antibody removed), Trifunctional Antibodies (monoclonal antibodies having binding sites for two different antigens), Affibodies (sold by Affibody, and Affibodies are 58 amino acid residue protein domains derived from one of the IgG-binding domains of staphylococcal protein A, based on a three-helix bundle domain), Anticalin (antibody mimetics synthesized from human lipocalins that can also be formatted as so-called Duocalin, a dual-targeting protein), or DARPin (Designed Ankyrin Repeat Proteins, another example of antibody mimetics based on repetitive proteins such as ankyrin repeat proteins or leucine-rich repeat proteins, which are ubiquitous binding molecules).

[0140] In certain embodiments, the antibody may be optimized or humanized. "Optimized" and similar terms used herein mean that the amino acid sequence of the antibody is adapted, by mutation or modification including, for example, glycosylation, to be suitable for use in the patient to whom it is administered. "Humanized" and similar terms used herein mean that the amino acid sequence of the antibody is adapted, by mutation or modification including, for example, glycosylation, to reduce the composition of non-human amino acid sequences in the antibody.

[0141] When the antibody is humanized, it may be partially humanized or substantially fully humanized. "Partially humanized" means that a portion of the amino acid sequence of the antibody is adapted, by mutation or modification including, for example, glycosylation, to be the same as the amino acid sequence of a human antibody. When the antibody is partially humanized, it may be partially humanized in any region of the antibody. Preferably, when the antibody is partially humanized, it may be partially humanized in one or more of the variable antigen-binding fragment (Fab) regions of the antibody. "Substantially fully humanized" means that substantially all of the amino acid sequence of the antibody is adapted, by mutation or modification including, for example, glycosylation, to be the same as the amino acid sequence of a human antibody. Preferably, the antibody is substantially fully humanized.

[0142] Optimized and / or humanized antibodies and derivatives may be produced by any suitable method. Suitable methods are known to those of skill in the art. For example, optimized and / or humanized antibodies and their derivatives may be made using genetic engineering techniques, chimeric techniques, CDR grafting or veneering.

[0143] In certain embodiments, when optimized and / or humanized antibodies and derivatives thereof are produced using genetic engineering techniques, the polynucleotide encoding the antibody may be isolated and cloned into an expression vector to obtain a recombinant plasmid, the obtained recombinant plasmid may be used to transform a host organism, the transformant may be cultured, and expression of the polynucleotide encoding the antibody may be induced. When multiple polynucleotides are used, each polynucleotide may be cloned into the same or different expression vectors. Any suitable host organism may be transformed with the obtained recombinant plasmid. For example, the host organism may be a prokaryote such as Escherichia coli (E. coli), a bacillus including Bacillus subtilis (Bacillus subtilis), and an Enterobacteriaceae including Salmonella typhimurium (Salmonella typhimurium), or a eukaryote such as a yeast including Saccharomyces cerevisiae (Saccharomyces cerevisiae). Those skilled in the art will understand that the step of cloning into an expression vector to generate a recombinant plasmid may be performed using standard methods in the same or a different organism as the host organism. Preferably, the step of cloning into an expression vector to generate a recombinant plasmid may be performed using standard methods in Escherichia coli.

[0144] The optimized and / or humanized antibody may bind to any suitable antigen. Preferably, the optimized and / or humanized antibody binds to PDE10A.

[0145] The antibody or antibody mixture may be present in the composition in any suitable amount. Preferably, the antibody may be present in an amount of about 0.1 nanogram (ng) to 100 milligrams (mg), more preferably about 1 ng to 50 mg, and most preferably about 10 mg to 50 mg.

[0146] In other embodiments, the inhibitor(s) comprises a peptide or peptidomimetic thereof, or a C-terminal amidated peptide thereof.

[0147] The term "peptide" includes compounds having amino acid residues (H-Cα-[side chain]) that may be linked by peptide (-CO-NH-) bonds or non-peptide bonds.

[0148] The peptide may be synthesized by the Fmoc-polyamide mode of solid-phase peptide synthesis. Reagents for peptide synthesis are readily available on the market.

[0149] Purification of the peptide may be performed by any one or a combination of techniques such as size-exclusion chromatography, ion-exchange chromatography, and (primarily) reverse-phase high-performance liquid chromatography. Analysis of the peptide may be performed using thin-layer chromatography, reverse-phase high-performance liquid chromatography, amino acid analysis after acid hydrolysis, and fast atom bombardment (FAB) mass spectrometry.

[0150] The peptide may contain at least one D-amino acid residue, for example 1, 2, 3, 4, 5, 6, 7, or 8 D-amino acids. Typically, the compositions of the present invention may contain 0, 1, 2, or 3 D-amino acids. The presence of D-amino acids in the compositions of the present invention may be useful for preventing degradation of the compound by proteases. Other methods for making peptides resistant to proteolysis include blocking the N-terminal and / or C-terminal amino acid residues. Thus, in some embodiments, the N-terminal and / or C-terminal amino acid residues are blocked. Suitable blocking methods include N-terminal acetylation or incorporation of a pyroglutamic acid residue at the N-terminus.

[0151] The above peptide may be a peptide aptamer. Peptide aptamers typically consist of short sequences of 5-20 amino acid residues that can bind to a specific target molecule.

[0152] There are several different approaches to the design and synthesis of peptide compositions that do not contain amide bonds. In one approach, one or more amide bonds are replaced in an essentially isoteric manner by various chemical functional groups.

[0153] Retro-inverso peptide mimics in which the peptide bond is reversed can be synthesized by methods known in the art. This approach involves creating pseudopeptides that contain changes in the backbone rather than in the orientation of the side chains. Retro-inverso peptides containing an NH-CO bond instead of the CO-NH peptide bond are more resistant to proteolysis.

[0154] The peptide may be linear. However, it may be advantageous to introduce a cyclic moiety into the peptide-based framework. The cyclic moiety restricts the conformational space of the peptide structure, which can lead to an increase in efficacy. An additional advantage of this strategy is that the introduction of a cyclic moiety into the peptide may also result in peptides that have a reduced sensitivity to cellular peptidases.

[0155] In some embodiments of the present invention, the peptide may be attached to another moiety. Convenient moieties to which the peptide may be linked include polyethylene glycol (PEG) and peptide sequences such as TAT and antennapedia, which enhance delivery to cells.

[0156] PEGylation is a method well known to those skilled in the art, in which a (peptide or other compound) is modified such that one or more polyethylene glycol (PEG) molecules covalently bind to the side chains of one or more amino acids. This is one of the most important molecule altering structural chemistry techniques (MASC). Other MASC techniques may be used, and such techniques may improve the pharmacodynamic properties of the compound, for example, by extending its serum half-life in vivo. The PEG-peptide conjugate is formed by first activating the PEG moiety such that the PEG moiety reacts and couples with the compound of the present invention. The PEG moieties vary considerably in molecular weight and conformation, with the early moieties (monofunctional PEG; mPEG) being linear with a molecular weight of 12 kDa or less, and the later moieties having an increased molecular weight. A recent innovation in PEG technology, PEG2, involves the coupling of mPEG of 30 kDa (or less) to lysine amino acids (however, PEGylation can be extended to the addition of PEG to other amino acids), and this lysine amino acid further reacts to form a branched structure that behaves like a much larger molecular weight linear mPEG. Methods that may be used to covalently attach PEG molecules to peptides. Potential advantages of PEGylation of the compounds of the present invention include a reduction in renal clearance, which for some products results in more sustained absorption and restricted distribution after subcutaneous administration, and presumably, a more constant and sustained plasma concentration, thus resulting in an increase in clinical efficacy. Further potential advantages include a reduction in the immunogenicity and toxicity of the therapeutic compound.

[0157] In some embodiments, the inhibitor(s) is a prodrug of a peptide. A prodrug is a compound that is metabolized in vivo to produce a molecule such as a protein. Those skilled in the art will be proficient in the preparation of prodrugs.

[0158] The peptide may be a peptidomimetic. A peptidomimetic is an organic compound having a geometric shape and polarity similar to those of the molecules defined herein and having substantially the same function. The mimetic may be a molecule in which the NH group of one or more peptide linkages is replaced by a CH2 group. The mimetic may be a molecule in which one or more amino acid residues are replaced by an aryl group such as a naphthyl group.

[0159] In other embodiments, the inhibitor(s) include a nucleic acid capable of binding to and inhibiting PDE10A, such as single-stranded DNA or RNA. The same targets on PDE10A that are suitable for targeting by peptides and peptide aptamers are considered to be suitable for targeting by RNA or modified RNA aptamers. Nucleic acids such as single-stranded DNA and single-stranded RNA that bind to PDE10A and inhibit PDE10A expression by binding to mRNA or DNA may be provided. Typically, this nucleic acid is single-stranded and has 100 to 5000 bases.

[0160] Features, integers, characteristics, compounds, molecules, chemical moieties or groups described in connection with specific aspects, embodiments or examples of the present invention are to be understood as applicable to any other aspect, embodiment or example described herein, unless otherwise stated. All of the features disclosed in this specification (including any accompanying patent claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of any of the above-described embodiments. The present invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying patent claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

Brief Description of the Drawings

[0161] Embodiments of the present invention are described below by way of example only with reference to the accompanying drawings.

[0162]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Example

[0163] Example 1 Evaluation of PDE10A inhibitors for use in the treatment of ulcerative colitis To investigate the role of PDE10A in ulcerative colitis (UC), the Genotype-Tissue Expression (GTEx) database was used to examine PDE10A RNA expression in normal and diseased tissues. In addition, the expression level of guanylate cyclase 2C (GUCY2C) was also evaluated. GUCY2C is an enzyme that synthesizes cGMP in response to endogenous peptides guanylin and uroguanylin and heat-stable enterotoxin of Escherichia coli.

[0164] As previously described in the literature, in normal tissues, PDE10A is expressed at low levels outside the brain (as shown in Figure 1). However, in colonic mucosa and colonic tissue from ulcerative colitis patients, the PDE10A expression level was significantly upregulated compared to normal controls (as shown in Figure 2). This is a finding that has not been previously described in the literature and emphasizes the potential undiscovered role of PDE10A in UC pathology.

[0165] GUCY2C has been found to be specifically expressed at high levels in the colon and small intestine (as shown in Figure 1), suggesting a role for this enzyme in normal intestinal homeostasis. In UC colon mucosa and the colon, GUCY2C is significantly downregulated (as shown in Figure 2), which is a previously described finding in the literature.

[0166] Guanylate cyclase C and cGMP signaling are downregulated in ulcerative colitis (Brenna et al., The guanylate cyclase-C signaling pathway is down-regulated in inflammatory bowel disease, Scand J Gastroenterol. 2015;50(10):1241-52), and decreased expression of guanylate cyclase 2C, guanylin, and uroguanylin correlates with disease severity (Lan et al., Expression of guanylate cyclase-C, guanylin, and uroguanylin is downregulated proportionally to the ulcerative colitis disease activity index Sci Rep. 2016;6:25034. Published online April 29, 2016, doi:10.1038 / srep25034). This suggests that decreased cGMP signaling plays a role in UC pathology. cGMP in the gastrointestinal tract has also been shown to play a role in fluid and electrolyte secretion, barrier function, inflammation, and proliferation (Waldman et al., Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders., Gut. 2018 67(8):1543-1552).

[0167] Although cAMP has not been studied as extensively in inflammation as cGMP, decreased cGMP signaling has been shown to increase inflammation in other systems (Ahluwalia et al., Antiinflammatory activity of soluble guanylate cyclase:cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci USA. 2004 101(5):1386-91; Raposo et al., Role of iNOS-NO-cGMP signaling in modulation of inflammatory and myelination processes. Brain Res Bull. 2014 104:60-73).

[0168] In summary, in the UC colon and colonic mucosa, PDE10A-mediated cGMP hydrolysis activity is increased, guanylate cyclase 2C-mediated cGMP synthesis activity is decreased, resulting in a net decrease in cGMP levels and signaling.

[0169] Next, experiments were conducted to evaluate whether inhibition of PDE10A by a small molecule inhibitor could help restore cGMP signaling to normal levels and thus represent a useful treatment for ulcerative colitis.

[0170] The PDE10A-selective tool compound PF-02545920 was evaluated in an in vitro assay of IL-8 neutrophil activation. PF-02545920 inhibited IL-8-induced neutrophil activation in a dose-dependent manner (as shown in Figure 3). This is interesting because the role of PDE10A in neutrophil function has not been previously described and further suggests a role for PDE10A in the regulation of inflammation, indicating that PDE10A inhibitors may be suitable as therapeutic agents for inflammatory bowel disease, particularly ulcerative colitis.

[0171] The therapeutic potential of PDE10A inhibitors for treating ulcerative colitis was further evaluated using tissue samples derived from colonic mucosa inflamed from ulcerative colitis patients.

[0172] The effects of selective PDE10 inhibition were tested on colonic mucosa inflamed from ulcerative colitis patients taken during routine endoscopy (Method 1, detailed below). These samples retain the disease phenotype in ex vivo culture and secrete high basal levels of inflammatory cytokines. The effects of selective PDE10 inhibition on the levels of the inflammatory cytokines IL-8 and IL-6 released from these tissue samples were measured. Both IL-6 and IL-8 are important regulators in ulcerative colitis pathology, and their levels correlate with disease severity (Waldner MJ et al., Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol. 2014 26(1), 75-9; Bernardo D et al., IL-6 promotes immune responses in human ulcerative colitis and induces a skin-homing phenotype in the dendritic cells and T-cells they stimulate. Eur J Immunol. 2012, 42(5), 1337-53; Pearl DS, Cytokine mucosal expression in ulcerative colitis, the relationship between cytokine release and disease activity. J Crohns Colitis. 2013, 7(6), 481-9).

[0173] The structurally distinct PDE10A inhibitors PF-02545920 and TAK-063 were tested in colonic biopsy samples from two patients with ulcerative colitis, along with two positive control compounds, the steroid prednisolone and the Janus kinase inhibitor tofacitinib. These colonic biopsies retain an inflammatory phenotype in ex vivo culture and secrete high levels of inflammatory cytokines. Selective PDE10A inhibition significantly decreased the secretion levels of IL-6 and IL-8 compared to the DMSO vehicle (Figures 4 and 5). This decrease was equivalent to that seen with the positive controls. PF-02545920 was tested at concentrations of 0.1 μM and 1 μM. The tested doses of each inhibitor result in a more selective PDE10A inhibition than other PDE family members.

[0174] In isolated enzyme biochemical assays, PF-02545920 has an IC 50 <5 nM for PDE10A and IC 50 >1 μM for other PDE family members, indicating that it is a highly selective PDE10A inhibitor (Grauer SM et al., Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther. 2009 331(2), 574 - 90). Therefore, at test concentrations of 0.1 μM and 1 μM in ex vivo tissue assays, PF-02545920 will selectively inhibit PDE10A.

[0175] In isolated enzyme biochemical assays, TAK-063 has an IC 50 of 0.3 nM for PDE10A and IC 50It has been shown to be a highly selective PDE10A inhibitor with >5 μM (Kunitomo J et al., Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor. J Med Chem. 2014 57(22):9627-43). Therefore, at a test concentration of 1 μM in ex vivo tissue assays, TAK-063 will selectively inhibit PDE10A.

[0176] The effect of selective PDE10A inhibition was also tested on inflamed colonic mucosa from drug therapy-resistant ulcerative colitis patients taken during colectomy (Method 2, detailed below). The PDE10A inhibitor PF-02545920 (1 μM) was tested in colonic samples from two ulcerative colitis patients. The effect of selective PDE10A inhibition on the level of the inflammatory cytokine TNFα released from these tissue samples was measured. TNFα is an inflammation-inducing mediator that is highly expressed in the colonic mucosa of UC patients and is the target of anti-TNFα biologics that have shown efficacy in the treatment of UC (Pugliese D et al., Anti TNF-α therapy for ulcerative colitis: current status and prospects for the future., Expert Rev Clin Immunol. 2017 13(3):223-233). Selective PDE10A inhibition significantly reduced the secretion level of TNFα compared to the DMSO vehicle (Figure 6).

[0177] The ability of selective PDE10A inhibition to significantly reduce the level of inflammatory cytokines in colonic mucosa from UC patients demonstrates the therapeutic utility of PDE10A inhibitors for the treatment of UC.

[0178] Method 1 Biopsy tissues were obtained from the colonic mucosa inflamed in patients with ulcerative colitis during routine endoscopy. Ex vivo biopsy cultures for analysis of inflammatory cytokine biomarkers were performed as previously described (Vossenkaemper A. et al., A CD3-specific antibody reduces cytokine production and alters phosphoprotein profiles in intestinal tissues from patients with inflammatory bowel disease. Gastroenterology, 2014, 147, 172-183). Biopsies were incubated in organ culture for 24 hours with the addition of a positive control compound or the specific PDE10A inhibitor PF-02545920. The supernatant recovered at the end of the experiment was snap-frozen and stored at -70 °C. For cytokine measurement, the frozen culture supernatant was thawed and analyzed for the levels of inflammatory cytokines using a Luminex cytokine assay kit (R&D Systems) and an R&D Systems MAGPIX® analyzer. Mean values ± SD were calculated for the levels of spontaneous cytokine production measured in the biopsy culture supernatants from each treatment group.

[0179] Method 2 Ulcerative colitis donor samples were obtained with full ethical consent from patients undergoing therapeutic resection for ulcerative colitis. Tissues were placed on a Netwell filter with the apical (mucosal) side facing up. The biopsies were then cultured in an incubator at 37 °C and high O2atmosphere conditions in either control medium or medium containing the test compound. To minimize variability, the biopsies were also cultured in the presence of the inflammatory stimulant staphylococcal enterotoxin B (SEB) to aid in the normalization of cytokine levels. Approximately 18 hours after the start of the culture, medium samples were collected, protease inhibitor was added, and the samples were stored at -80 °C. Subsequently, the supernatant was subjected to ELISA analysis for cytokine measurement.

[0180] Example 2 Exemplary formulations and treatment methods for ulcerative colitis Some exemplary formulations are provided below, along with the proposed dosing regimens. These are for illustrative purposes and it will be understood that they may be optimized during further experimentation, which may include clinical trials. For simplicity, the formulations do not specify any inactive ingredients (such as pharmaceutically acceptable carriers or excipients, etc.).

[0181] [Table 1]

[0182] [Table 2]

[0183] [Table 3]

[0184] [Table 4]

[0185] [Table 5]

[0186] [Table 6]

[0187] [Table 7]

[0188] [Table 8]

[0189]

Table 9

[0190] Those skilled in the art will of course understand that alternative PDE10A inhibitors can also be employed in place of those outlined above. The therapeutically effective dose will of course depend on the activity and form of the inhibitor selected.

[0191] The above-described embodiments are not intended to limit the scope of protection given by the claims, but rather are intended to illustrate examples of how the present invention may be implemented in any manner.

Claims

1. Use of a PDE10A inhibitor in the manufacture of a medicament for the prevention, management and / or treatment of inflammatory bowel disease, wherein the PDE10A inhibitor is selected from one or more of PF-02545920, TAK-063, papaverine, JNJ-42314415, AMG-579, PQ-10, BMS-843496, and PDM-042.

2. The use according to claim 1, wherein the inflammatory bowel disease is ulcerative colitis.

3. The use according to claim 1 or claim 2, wherein the PDE10A inhibitor is a selective inhibitor of PDE10A.

4. The use according to any one of claims 1 to 3, wherein the PDE10A inhibitor is selected from PF-02545920 or TAK-063.

5. The use according to any one of claims 1 to 4, wherein the PDE10A inhibitor selectively inhibits cGMP hydrolysis rather than cAMP hydrolysis.

6. The use according to any one of claims 1 to 5, wherein the management and / or treatment of the inflammatory bowel disease comprises increasing cGMP signaling in the intestinal tissue of the patient.

7. The use according to any one of claims 1 to 6, wherein the management and / or treatment of the inflammatory bowel disease comprises reducing the level of inflammatory cytokines in the intestinal tissue of the patient.

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