WO2012020726A1 - カゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害剤 - Google Patents
カゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害剤 Download PDFInfo
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- WO2012020726A1 WO2012020726A1 PCT/JP2011/068034 JP2011068034W WO2012020726A1 WO 2012020726 A1 WO2012020726 A1 WO 2012020726A1 JP 2011068034 W JP2011068034 W JP 2011068034W WO 2012020726 A1 WO2012020726 A1 WO 2012020726A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to a casein kinase 1 ⁇ and casein kinase 1 ⁇ inhibitor containing an oxazolone derivative, a salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient.
- the present invention relates to a medicament for the treatment of diseases in which the activation of casein kinase 1 ⁇ or casein kinase 1 ⁇ is associated with the pathological condition.
- diseases in which the activation of casein kinase 1 ⁇ or casein kinase 1 ⁇ is related to its pathological condition, it is particularly useful for the treatment and / or prevention of circadian rhythm cycle disorders (including sleep disorders), central neurodegenerative diseases, and cancer.
- the present invention relates to a medicament comprising a useful casein kinase 1 ⁇ and a casein kinase 1 ⁇ inhibitor.
- Casein kinase 1 belongs to serine threonine kinase (which also phosphorylates tyrosine residues in some cases), and its isoforms in mammals are 7 of ⁇ , ⁇ , ⁇ 1, ⁇ 2, ⁇ 3, ⁇ and ⁇ . The seed is known. These isoforms are involved in the regulation of various different biological functions by phosphorylating a variety of different substrate proteins and activating, deactivating, stabilizing or destabilizing the function of the protein.
- Mammalian casein kinase 1 ⁇ or casein kinase 1 ⁇ has a kinase domain similar in structure to other isoforms, but differs from other isoforms in the N-terminal and C-terminal domains. That is, the C terminal domain has multiple autophosphorylation sites and is considered to be involved in the regulation of autoenzyme activity.
- the kinase domain has a sequence (NLS: nuclear location signal) and a kinesin-like domain (KHD) that are thought to be involved in nuclear translocation.
- Casein kinase 1 ⁇ and casein kinase 1 ⁇ are involved in circadian rhythm disorders, casein kinase 1 ⁇ and casein kinase 1 ⁇ are involved in central neurodegenerative diseases, and casein kinase 1 ⁇ and casein kinase 1 ⁇ are involved in cancer.
- the details of their involvement in pathological conditions are known in the study of the interaction between the target protein such as substrate protein for casein kinase 1 ⁇ and casein kinase 1 ⁇ , and casein kinase 1 ⁇ and casein kinase 1 ⁇ . It's getting on.
- Specific examples of substrate proteins phosphorylated by casein kinase 1 ⁇ and casein kinase 1 ⁇ include period protein (Per), tau protein (tau), p53, and beta-catenin ( ⁇ -catenin). .
- the central core clock (the core core of the circadian core rhythm) is the core core clock (the core core of the clock), which is today made up of a network of about 10 so-called clock genes (clock genes). It is considered. Of these 10 gene groups, Per1, 2, 3 (Period 1, 2, 3) and Cry 1, 2 (cryptochrome 1, 2) and Bmal 1 (brain and muscle ARNT-like 1) and Clock (circadian locomotor output) cycles kaput) encodes transcription factors, and CK1 ⁇ and ⁇ encode casein kinase 1 ⁇ and casein kinase 1 ⁇ that phosphorylate these transcription factors. It is known that the functional abnormality of these clock genes affects the circadian rhythm phenotype of various animals including humans.
- Clock controls the pathway that generates an activation signal in the biological clock interaction network, and activates Per, Cry, and other downstream target genes.
- Per and Cry which are responsible for the pathway that emits regulatory signals, act to suppress Clock activity.
- Casein kinase 1 ⁇ and casein kinase 1 ⁇ promote Per-cytoplasmic degradation by phosphorylating Per and Cry.
- the results of these phosphorylations are involved in the nuclear translocation of these transcription factors and the control of their stability in the nucleus.
- the central biological clock in mammals is in the suprathalamic nucleus (SCN), but this SCN biological clock is linked to the gene expression biological clock in the central and peripheral tissues other than SCN.
- SCN suprathalamic nucleus
- Per is known as a circadian rhythm regulating protein in vivo. Per mRNA and protein levels oscillate in response to circadian rhythms and are closely involved in the control of the circadian clock. For example, it is known that a genetic disorder with a human Per2 phosphorylation site mutation (S662G) results in familial sleep advanced syndrome (FASPS: familial advanced sleep phase syndrome) due to a decrease in phosphorylation by casein kinase 1 ⁇ or casein kinase 1 ⁇ . This indicates that Per plays an important role in sleep regulation. It is known that the change in the intracellular protein amount of Per is controlled by phosphorylation by casein kinase 1 ⁇ or casein kinase 1 ⁇ . That is, it is known that when Per is phosphorylated by these kinases, the stability of the protein is significantly reduced.
- S662G human Per2 phosphorylation site mutation
- FASPS familial advanced sleep phase syndrome
- PF-670462 By shifting or resetting the phase of the circadian rhythm, it can be expected to contribute to the treatment of circadian rhythm disorders including various sleep disorders.
- conventional inhibitors such as PF-670462 have not been completed as pharmaceuticals because they also show an inhibitory action on kinases (eg, p38 ⁇ , etc.) for which side effects are a concern.
- casein kinase 1 ⁇ or casein kinase 1 ⁇ and central neurodegenerative diseases, particularly Alzheimer's disease will be described.
- tau protein aggregation at the site of Alzheimer's disease is an important marker of disease state.
- excessive phosphorylation of this tau protein plays an important role in aggregation. Therefore, the casein kinase 1 family, which is an enzyme overexpressed at the lesion site, can be considered as a candidate kinase that phosphorylates this tau protein.
- Li, Guibon, etc. of casein kinase 1 ⁇ are HEK-293 cells. We are conducting research using expression systems.
- casein kinase 1 ⁇ and tau protein associate in situ, and casein kinase 1 ⁇ directly phosphorylates tau protein, and overexpression of casein kinase 1 ⁇ causes phosphorylation of tau protein in vitro.
- non-selective casein kinase 1 inhibitor compound 3-[(2,3,6-trimethoxyphenyl) methylidenyl] -indolin-2-one (IC261), etc. Non-Patent Document 6
- insoluble tau PHF-tau (paired helical filaments-tau) obtained from a lesion site of an Alzheimer's disease patient and a phosphorylation site with that of a normal human. Mass spectrometry to identify specific phosphorylation sites in the lesions of Alzheimer's disease patients, and from the characteristics of the phosphorylation sites, casein kinase together with glycogen synthase kinase 3 ⁇ as a candidate kinase This suggests that 1 ⁇ is likely to be involved in the lesion development process (Non-patent Document 7).
- PHF-tau paired helical filaments-tau
- casein kinase 1 ⁇ or casein kinase 1 ⁇ and central neurodegenerative diseases, particularly Alzheimer's disease, will be further described.
- Alzheimer's disease the accumulation of amyloid-beta (A ⁇ ), which is toxic to neurons, is thought to be involved in the lesion.
- a ⁇ amyloid-beta
- the expression of casein kinase 1 is increased at the lesion site of Alzheimer's disease patients.
- a ⁇ is thought to be formed by cleaving APP (amyloid precursor protein) with beta-secretase (aspartyl protease ⁇ -secretase) and gamma-secretase (presenin-dependent protease ⁇ -secretase), Flajolet, Marc et al. The sites that are commonly phosphorylated by casein kinase 1, which is considered to exist in the subunit sequences of APP, beta-secretase, and gamma-secretase by in silico analysis, were examined.
- Non-Patent Documents 6, 7 and 8 show that casein kinase 1, particularly casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in the development of Alzheimer's disease, and the inhibition of the enzyme activity enables treatment of Alzheimer's disease. It greatly suggests the possibility of being done.
- Down syndrome is also a study of the genetic background or development of Alzheimer's disease because chromosome 21, which is assumed to have a causative gene for Alzheimer's disease, is trisomy (triploid) in somatic cells of patients with Down syndrome. It has been thought that it can become a model.
- the abnormal accumulation of a specific protein commonly seen in both is considered to be one of the important pathological and biochemical indicators related to the pathogenesis.
- casein kinase 1 ⁇ or casein kinase 1 ⁇ contributes to the regulation of various important physiological activities in cells, and its substrate proteins that are phosphorylated vary widely.
- the tumor suppressor p53 and the oncogene mdm2 are both important proteins that control carcinogenesis and at the same time are substrates for casein kinase 1.
- casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in a centrosome during cell division, a regulatory protein involved in spindle formation, or TRAIL (tumor necrosis factor-related apoptosis inducing factor) and Fas. It is also known to be involved in mediated apoptosis.
- pancreatic ductal adenocarcinoma PDACs
- PDACs pancreatic ductal adenocarcinoma
- No drug is known as an anticancer agent based on inhibition of casein kinase 1 ⁇ or casein kinase 1 ⁇ in the prior art, and in particular, pharmacological treatment of intractable pancreatic cancer based on this mechanism in the prior art has not been completed.
- An object of the present invention is to provide a casein kinase 1 ⁇ and a casein kinase 1 ⁇ inhibitor containing an oxazolone derivative, a salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient.
- the present invention also includes the selective inhibitor of casein kinase 1 ⁇ and casein kinase 1 ⁇ of the present invention as a pharmaceutically active ingredient to regulate the function of casein kinase 1 ⁇ or casein kinase 1 ⁇ in vivo.
- diseases in which the activation of casein kinase 1 ⁇ or casein kinase 1 ⁇ is related to the pathogenesis circadian rhythm cycle disorders (including sleep disorders), central neurodegenerative diseases, cancer treatment and / or prevention It aims at providing a useful medicine.
- an object of the present invention is to provide a method for the treatment and / or prevention of circadian rhythm cycle disorders (including sleep disorders), central neurodegenerative diseases, and cancer using the above medicament.
- this invention aims at provision of the novel oxazolone derivative and its pharmaceutically acceptable salt, and those hydrates.
- Non-Patent Document 13 That is, until now, as in the present inventors, it has a highly selective inhibitory action on casein kinase 1, and the selective inhibitory action of casein kinase 1 ⁇ and casein kinase 1 ⁇ has been selected for the selectivity of isoform inhibition. Focusing on the fact that possession is therapeutically significant, there is no known fact that diligent studies have been conducted to search for the target compound.
- the present inventors have included three-dimensional structure information of other similar proteins including casein kinase 1 ⁇ for the purpose of finding various compounds having an inhibitory action on the phosphorylation ability of casein kinase 1 ⁇ and casein kinase 1 ⁇ .
- a virtual screening using DOCK4 in which a consensus score was introduced into a commercially available compound database was performed (the 3D structure information of casein kinase 1 ⁇ was registered in the Protein Data Bank).
- Non-Patent Document 14 compounds were narrowed down. These compounds were purchased or newly synthesized and actually screened for biological activity.
- the compound represented by the following general formula (1) has an inhibitory action on the phosphorylating ability of casein kinase 1 ⁇ and casein kinase 1 ⁇ . Furthermore, it has been found that the compound has an inhibitory action with a selectivity that is not known to date. Therefore, it was clarified that the compound is useful as an active ingredient of a medicine for the treatment of the above-mentioned diseases.
- the present invention has been completed based on these findings.
- the present invention is an oxazolone derivative represented by the general formula (1) having an inhibitory action on casein kinase 1 ⁇ and casein kinase 1 ⁇ , a pharmaceutically acceptable salt thereof, and a solvate or hydrate thereof.
- X represents a halogen atom (any of a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom)]
- the present invention relates to casein kinase 1 ⁇ and casein kinase 1 ⁇ inhibition comprising as an active ingredient an oxazolone derivative represented by the above general formula (1), or a pharmaceutically acceptable salt or solvate or hydrate thereof. It is an agent.
- the present invention also provides casein kinase 1 ⁇ or casein comprising an oxazolone derivative represented by the above general formula (1), or a pharmaceutically acceptable salt thereof, a solvate thereof, or a hydrate thereof as an active ingredient. It is a pharmaceutical useful for the treatment and / or prevention of diseases in which the enzyme activation of kinase 1 ⁇ is associated with the pathogenesis of the disease state.
- the present invention also provides a circadian rhythm cycle disorder comprising an oxazolone derivative represented by the above general formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof or a hydrate thereof as an active ingredient. It is a medicament for the treatment and / or prevention of central nervous degenerative diseases (including sleep disorders), cancer. Furthermore, the present invention is a method for treating a disease in which the enzyme activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in a disease state, which comprises administering the above-mentioned medicine to a patient.
- the compound of the present invention can inhibit the activity of casein kinase 1 ⁇ and casein kinase 1 ⁇ . As a result, diseases in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in the disease state can be cured.
- the compound of the present invention and a medicament containing this as a pharmaceutically active ingredient can be used for the treatment of diseases in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in the pathological state.
- the compound of the present invention and a medicament containing the same as a pharmaceutically active ingredient have higher selectivity for casein kinase 1 ⁇ and casein kinase 1 ⁇ than the conventional compounds having casein kinase 1 inhibitory activity. Yes.
- the compound of the present invention and the medicament containing this as a pharmaceutically active ingredient are compared with existing compounds for the treatment of diseases in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in the pathology. More clinical efficacy can be expected, and at the same time higher safety compared to existing compounds can be expected.
- a preferred embodiment of the present invention is an oxazolone derivative represented by the general formula (1) and a pharmaceutically acceptable salt thereof and a solvate or hydrate thereof.
- the compound has an inhibitory action on casein kinase 1 ⁇ and casein kinase 1 ⁇ .
- the compound represented by the general formula (1) is newly synthesized in the present invention. Furthermore, it is disclosed for the first time by the present invention that the compound represented by the general formula (1) has an inhibitory activity on casein kinase 1 ⁇ and casein kinase 1 ⁇ activities.
- the novel oxazolone derivative represented by the general formula (1) of the present invention can be produced by using a chemical synthesis method shown in Examples described later.
- the oxazolone derivative represented by the general formula (1) contained as the casein kinase 1 ⁇ or casein kinase 1 ⁇ inhibitor and the pharmaceutical active ingredient according to the present invention includes its tautomers and geometric isomers unless otherwise specified.
- E body, Z body, etc. are also included.
- enantiomers, if present, are included in the scope of the present invention.
- casein kinase comprising an oxazolone derivative represented by the general formula (1), or a pharmaceutically acceptable salt thereof or a solvate or hydrate thereof as an active ingredient. 1 ⁇ and casein kinase 1 ⁇ inhibitors are provided. Further, according to a further preferred embodiment of the present invention, a disease in which the activation of casein kinase 1 ⁇ or casein kinase 1 ⁇ is related to the pathological condition, particularly circadian rhythm, containing the compound as a pharmacologically effective component. Provided are medicaments for the treatment of cycle disorders (including sleep disorders), central nervous degenerative diseases, and cancer.
- Casein kinase 1 ⁇ in the present invention means “casein kinase 1 delta”, “Casein Kinase 1 delta”, “Casein kinase 1 isoform delta”, CK1 ( ⁇ ) delta ”,“ CK1d ”,“ HCKID ”,“ Casein Kinase 1 ⁇ ”.
- NCBI Reference Sequences published by the National Center for Biotechnology Information (NCBI), sometimes referred to by relative names or aliases such as “,” “Casein kinase 1 isoform ⁇ ”, “CK1 (-) ⁇ ”
- the protein having the same or substantially the same amino acid sequence as the NP_001884.2, NP_620693.1, NP_620690.1, and NP_082150.1 registered as the amino acid sequence.
- the “protein containing substantially the same amino acid sequence” means about 60% or more, preferably about about the amino acid sequence represented by the above RefSeq numbers NP_001884.2, NP_620693.1, NP_620690.1, NP_082150.1.
- a protein containing an amino acid sequence substantially identical to the amino acid sequence represented by RefSeq numbers NP_001884.2, NP_620693.1, NP_620690.1, NP_082150.1, RefSeq numbers NP_001884.2, NP_620693.1, NP_620690 as a protein containing an amino acid sequence substantially identical to the amino acid sequence represented by RefSeq numbers NP_001884.2, NP_620693.1, NP_620690.1, NP_082150.1, RefSeq numbers NP_001884.2, NP_620693.1, NP_620690.
- amino acids in the amino acid sequence represented by NP_082150.1 are deleted or substituted Alternatively, it is a protein consisting of an added amino acid sequence and having protein kinase activity.
- Casein kinase 1 ⁇ in the present invention means “casein kinase 1 epsilon”, “Casein Kinase 1 epsilon”, “Casein kinase 1 isoform epsilon”, “CK1 ( ⁇ ) epsilon”, “CK1e”, “HCKIE”, “Casein Kinase 1”.
- the “protein containing substantially the same amino acid sequence” means about 60% or more, preferably about 70% or more, of the amino acid sequence represented by the above RefSeq numbers NP_001885.1, NP_689407.1, NP_038795.3, More preferably about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95 %, 96%, 97%, 98%, and most preferably a protein having an amino acid sequence having about 99% amino acid identity and having protein kinase activity.
- a protein containing an amino acid sequence substantially the same as the amino acid sequence represented by RefSeq numbers NP_001885.1, NP_689407.1, NP_038795.3 is represented by RefSeq numbers NP_001885.1, NP_689407.1, NP_038795.3 It consists of an amino acid sequence in which one or several amino acids in the amino acid sequence (preferably about 1 to 30, more preferably about 1 to 10 and even more preferably 1 to 5) are deleted, substituted or added. And a protein having protein kinase activity.
- Examples of diseases in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is related to the pathology include, but are not limited to, circadian rhythm cycle disorders (including sleep disorders), neurodegenerative diseases, and cancers. Can be mentioned.
- circadian rhythm cycle disorder includes, but is not limited to, mood disorder and sleep disorder
- the sleep disorder is circadian rhythm sleep disorder
- circadian rhythm sleep disorder is shift work sleep disorder A disease selected from the group consisting of jet lag syndrome, advanced sleep phase syndrome and delayed sleep phase syndrome.
- the sleep disorder includes a disease selected from the group consisting of insomnia, sleep-related breathing disorder, central hypersomnia, parasomnia, sleep-related movement disorder.
- the mood disorder described above is selected from depression disorder or bipolar disorder
- the depression disorder is major depressive disorder
- the mood disorder is selected from depression disorder or bipolar disorder
- bipolar disorder is bipolar I A disease selected from the group consisting of type disorder and bipolar type II disorder.
- insomnia, sleep-related breathing disorder, central hypersomnia, circadian rhythmic sleep disorder, sleep-related comorbidity, sleep-related movement disorder, and sleep disorder due to other causes can be mentioned.
- insomnia includes psychophysiological insomnia due to stress and the like, and insomnia due to medical diseases.
- sleep-related breathing disorders include central sleep apnea syndrome, obstructive sleep apnea syndrome, sleep-related hypoventilation / hypoxemia syndrome, and the like.
- central hypersomnia include narcolepsy, idiopathic hypersomnia, recurrent hypersomnia and the like.
- the circadian rhythm sleep disorder includes shift work sleep disorder, jet lag syndrome, sleep phase advance syndrome, sleep phase delay syndrome, and the like.
- sleep comorbidities include sleep aggression and REM sleep behavior disorder.
- sleep-related movement disorders include restless leg syndrome and periodic limb movement disorders.
- the neurodegenerative disease is not limited, but for example, the central neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, neurodegenerative disease against Down's syndrome, nerve physical damage (cerebral contusion etc. Neurodegeneration caused by brain tissue damage, nerve damage caused by head trauma, etc., nerve damage after ischemia or ischemia reperfusion (stroke, cerebral infarction, cerebral hemorrhage, cerebral ischemia, subarachnoid hemorrhage, aneurysm hemorrhage) , Neurodegeneration caused by myocardial infarction, hypoxia, an exacerbation due to anoxia / cerebral ischemia, etc.).
- the central neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, neurodegenerative disease against Down's syndrome, nerve physical damage (cerebral contusion etc. Neurodegeneration caused by brain tissue damage, nerve damage caused by head trauma, etc., nerve damage after ischemia or ischemia reperfusion (stroke, cerebral infarction, cerebral hemorrhage, cerebral
- cancers arising from the pancreas include, but are not limited to, pancreatic duct cancer and invasive pancreatic duct cancer, pancreatic endocrine tumor, intraductal papillary mucinous tumor, mucinous cystic tumor, acinar cell cancer, metastatic pancreatic cancer Etc.
- physiologically acceptable salts thereof may be used.
- the salt include alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, and calcium; ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris ( A salt of an amine such as hydroxymethyl) aminomethane, N, N-bis (hydroxyethyl) piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, L-glucamine; or lysine; Salts with basic amino acids such as ⁇ -hydroxylysine and arginine can be formed.
- salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; methanesulfonic acid, benzenesulfonic acid, paratoluenesulfonic acid, acetic acid, propionate, tartaric acid , Fumaric acid, maleic acid, malic acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid and other organic acids Salts; or salts with acidic amino acids such as aspartic acid and glutamic acid.
- a solvate or hydrate of the compound represented by the general formula (1) or a salt thereof can also be used as the active ingredient of the medicament of the present invention.
- the medicament of the present invention may be administered with an active ingredient compound represented by the general formula (1) and a pharmacologically acceptable salt thereof, or a solvate thereof or a hydrate thereof.
- an active ingredient compound represented by the general formula (1) a pharmaceutical composition containing the above-mentioned substance as an active ingredient, one or more pharmaceutical additives, and a pharmacologically acceptable carrier.
- the active ingredient of the medicament of the present invention two or more of the above substances can be used in combination.
- the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is related to its pathological condition.
- the type of pharmaceutical composition is not particularly limited, and dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, ointments, creams, gels, patches, inhalants, An injection agent etc. are mentioned. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or other appropriate solvent at the time of use. Tablets and granules may be coated by a known method. In the case of injection, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution as necessary, and a buffer or preservative may be added. Good. It is provided in any dosage form for oral or parenteral administration.
- a pharmaceutical composition for oral administration in the form of granules, fine granules, powders, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, for intravenous administration, for intramuscular administration
- it can be prepared as a pharmaceutical composition for parenteral administration in the form of injections, drops, transdermal absorbents, transmucosal absorbents, nasal drops, inhalants, suppositories, etc. for subcutaneous administration.
- Injections, infusions, and the like can be prepared as powdered dosage forms such as freeze-dried forms, and can be used by dissolving in an appropriate aqueous medium such as physiological saline at the time of use. It is also possible to administer a sustained release preparation coated with a polymer directly into the brain.
- a person skilled in the art can appropriately select the type of pharmaceutical additive used for the production of the pharmaceutical composition, the ratio of the pharmaceutical additive to the active ingredient, or the method for producing the pharmaceutical composition depending on the form of the composition. It is.
- an inorganic or organic substance, or a solid or liquid substance can be used, and generally it can be blended in an amount of 1 to 90% by weight based on the weight of the active ingredient.
- examples of such substances are lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium.
- Ion exchange resin methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, bee gum, titanium oxide, sorbitan fatty acid ester, Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polyso Bate, macrogol, vegetable oils, waxes, liquid paraffin, white petrolatum, fluorocarbons, nonionic surfactants, propylene glycol, water and the like.
- an active ingredient and excipient components such as lactose, starch, crystalline cellulose, calcium lactate, anhydrous silicic acid and the like are mixed to form a powder, or if necessary, sucrose, Add a binder such as hydroxypropylcellulose and polyvinylpyrrolidone, a disintegrant such as carboxymethylcellulose and carboxymethylcellulose calcium, and wet or dry granulate to form granules.
- these powders and granules may be tableted as they are or after adding a lubricant such as magnesium stearate or talc.
- granules or tablets should be coated with an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer and coated with an enteric solvent preparation, or ethylcellulose, carnauba wax, hardened oil, etc. You can also.
- an enteric solvent base such as hydroxypropylmethylcellulose phthalate or methacrylic acid-methyl methacrylate polymer
- enteric solvent preparation or ethylcellulose, carnauba wax, hardened oil, etc.
- active ingredients such as hydrochloric acid, sodium hydroxide, lactose, lactic acid, sodium, sodium monohydrogen phosphate, sodium dihydrogen phosphate, etc. It can be dissolved in distilled water for injection together with an isotonic agent, filtered aseptically and filled into ampoules, or further lyophilized by adding mannitol, dextrin, cyclodextrin, gelatin, etc. .
- reticine, polysorbate 80, polyoxyethylene hydrogenated castor oil and the like can be added to the active ingredient and emulsified in water to give an emulsion for injection.
- the active ingredient is moistened with a suppository base material such as cacao butter, fatty acid tri, di- and monoglycerides, polyethylene glycol, etc., dissolved, poured into a mold and cooled, or the active ingredient is made of polyethylene. What is necessary is just to coat
- the active ingredient is added to white petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., and if necessary, moistened and kneaded to make an ointment, or rosin, alkyl acrylate polymer After being kneaded with an adhesive such as polyalkyl, it is spread on a non-woven fabric such as polyalkyl to obtain a tape.
- the dose and frequency of administration of the medicament of the present invention are not particularly limited, and depending on conditions such as prevention of worsening / development of the disease to be treated and / or purpose of treatment, type of disease, patient weight and age, etc. It is possible to select appropriately according to the judgment.
- the dose per day for an adult in oral administration is about 0.01 to 1000 mg (weight of active ingredient), and can be administered once or several times a day or every few days. it can.
- daily dosages of 0.001 to 100 mg (active ingredient weight) are preferably administered continuously or intermittently to adults.
- the medicament of the present invention can be prepared as a sustained-release preparation such as a delivery system encapsulated in implantable tablets and microcapsules, using a carrier that can prevent immediate removal from the body.
- a carrier that can prevent immediate removal from the body.
- biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such materials can be readily prepared by those skilled in the art.
- Liposome suspensions can also be used as pharmaceutically acceptable carriers.
- Useful liposomes are prepared as a lipid composition comprising, but not limited to, phosphatidylcholine, cholesterol and PEG-derivatized phosphatidylethanol (PEG-PE) through a filter of appropriate pore size so as to be of a size suitable for use. Purified by evaporation.
- PEG-PE PEG-derivatized phosphatidylethanol
- the medicament of the present invention can be included in the form of a kit as a pharmaceutical composition together with instructions for administration in containers and packs.
- a kit When the pharmaceutical composition according to the present invention is supplied as a kit, different constituents of the pharmaceutical composition are packaged in separate containers and mixed immediately before use. The reason why the components are packaged separately in this way is to enable long-term storage without losing the function of the active component.
- a sealed glass ampoule includes a buffer packaged under a neutral and non-reactive gas such as nitrogen gas.
- Ampoules are composed of glass, polycarbonate, organic polymers such as polystyrene, ceramics, metals, or any other suitable material commonly used to hold reagents.
- suitable containers include simple bottles made from similar materials such as ampoules, and packaging materials that are internally lined with foil such as aluminum or an alloy.
- Other containers include test tubes, vials, flasks, bottles, syringes, or the like.
- the container has a sterile access port such as a bottle having a stopper that can be penetrated by a hypodermic needle.
- kits for use are attached to the kit.
- Instructions for using the kit comprising the pharmaceutical composition are printed on paper or other material and / or floppy disk, CD-ROM, DVD-ROM, Zip disk, video tape, audio tape, etc. It may be supplied as an electrically or electromagnetically readable medium. Detailed instructions for use may be actually attached to the kit, or may be posted on a website designated by the manufacturer or distributor of the kit or notified by e-mail or the like.
- the present invention relates to a medicament or medicament comprising the compound represented by the general formula (1) of the present invention and a pharmacologically acceptable salt thereof, or an active ingredient thereof, or a solvate or hydrate thereof.
- a therapeutic method is provided for treating a disease of interest by administering the composition to a patient.
- the therapeutic method of the present invention includes a therapeutic method relating to a disease in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ develops in relation to the disease state or a mammal suffering from the disease.
- “treatment” means to prevent or alleviate the progression and worsening of the disease state in a mammal that is likely to suffer from or suffers from the disease. Used to mean therapeutic treatment aimed at preventing or alleviating progression and worsening.
- disease means any disease in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is involved in the pathology, and is not particularly limited.
- insomnia sleep-related respiratory disorder , Central hypersomnia, circadian rhythm sleep disorder, sleep-related comorbidity, sleep-related movement disorder, etc., circadian rhythm cycle disorder sleep circadian rhythm sleep disorder, shift work sleep disorder Circadian rhythm disorder, including jet lag syndrome, advanced sleep phase syndrome and late sleep phase syndrome, include depression disorder or bipolar disorder, and in addition to Alzheimer's disease, Parkinson's disease, Down syndrome Neurodegenerative diseases that occur, central neurodegenerative diseases caused by cerebrovascular disorders, cancers that do not specify any cancer type, and especially cancers derived from the pancreas such as pancreatic duct cancer, invasive pancreatic duct cancer, pancreas Secreting tumor, intraductal papillary mucinous neoplasm is a concept including mucinous cystic tumor, acinar cell carcinoma,
- the subject of treatment is a “mammal”, which means any animal classified as a mammal, and is not particularly limited.
- pet animals such as dogs, cats, rabbits, cows, pigs, It refers to livestock animals such as sheep and horses.
- livestock animals such as sheep and horses.
- Particularly preferred “mammals” are humans.
- Example 1 4-((6-Methoxy-3-pyridinyl) methylene) -2- (5-fluoro-2-thienyl) -5 (4H) -oxazolone Since it is generally very difficult to introduce a fluoro group into the thiophene ring, the process shown in the following scheme 1 including many synthesis steps as compared to the synthesis method exemplified in the examples of Japanese Patent Application No. 2009-245477 is performed. As a result of trying to synthesize the compound represented by the formula (2), it was successfully produced. Note that the method for synthesizing the compound represented by the formula (2) is not limited to the process shown in Scheme 1.
- ⁇ Third step> Compound 5 (100 mg, 0.68 mmol), thionyl chloride (3 ml) and formamide (50 ⁇ l) were added to an eggplant-shaped flask, and the mixture was heated and stirred at an external temperature of 100 ° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, thionyl chloride was removed under reduced pressure, and azeotroped with toluene twice to obtain 112 mg of Compound 6 quantitatively.
- ⁇ Fifth step> 21.7 mg (0.107 mmol) of Compound 7, 200 ⁇ l of acetic anhydride and 65 ⁇ l of pyridine were added to an eggplant-shaped flask, and the mixture was heated and stirred at an external temperature of 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the residue was purified by preparative thin-layer chromatography (toluene / diethyl ether 5/1) to obtain 14 mg (0.046 mmol, total yield 0.3%) of Compound 2. Obtained.
- Example 2 4-((6-Methoxy-3-pyridinyl) methylene) -2- (5-chloro-2-thienyl) -5 (4H) -oxazolone Manufacture was performed also about the compound which introduce
- Example 3 4-((6-Methoxy-3-pyridinyl) methylene) -2- (5-bromo-2-thienyl) -5 (4H) -oxazolone
- the compound introduced with the bromo group represented by the formula (14) was also produced. Note that the method for synthesizing the compound into which the bromo group represented by the formula (14) is introduced is not limited to the process shown in Scheme 4.
- the HPLC purity (254 nm absorption wavelength) of Compound 14 was 95.8%.
- the peak observed as a result of measuring Compound 14 using a nuclear magnetic resonance apparatus AV-500 (500 MHz) manufactured by Burka is shown below.
- the compound of formula (2) and the compounds of formula (11) and formula (14) were readily dissolved at final concentrations of 35 mM, 10 mM and 20 mM, respectively.
- compounds having no halogen group introduced into the thiophene ring were dissolved by vigorous stirring at a final concentration of 10 mM. This shows that the compounds of formula (2), formula (11), and formula (14) have improved solubility compared to the prior art casein kinase 1 ⁇ or casein kinase 1 ⁇ selective inhibitor. I was able to. *
- Casein Kinase 1 ⁇ and Casein Kinase 1 ⁇ Inhibitory Action of Oxazolone Derivatives Casein kinase 1 ⁇ and casein kinase 1 ⁇ inhibitory activity of the compound is human recombinant casein kinase 1 ⁇ (INVITROGEN Cat No. PV3665) or human recombinant casein kinase 1 ⁇ (INVITROGEN Cat. No. PV3500) was used as an enzyme source, and Z′-LYTE Ser / Thr 11 Peptide (Catalog No. PV3671 from INVITROGEN) was used as a phosphorylated substrate.
- the composition (final concentration) at the time of the assay activity measurement assay is as follows.
- casein kinase 1 ⁇ and casein kinase 1 ⁇ inhibitory compounds against various kinases can be examined using a Profiler Pro kit (manufactured by Caliper Life Sciences) according to the method of the attached document.
- the compounds represented by the formulas (2), (11) and (14) were reacted with various kinases for 15 minutes so that the final concentration was 10 ⁇ M, 1 ⁇ M or 0.1 ⁇ M. After the reaction, the enzyme activity was examined.
- the compound is an inhibitory compound with higher selectivity for casein kinase 1 ⁇ and casein kinase 1 ⁇ .
- the compounds represented by the formulas (2), (11) and (14) have a weak inhibitory effect as compared with casein kinase 1 ⁇ and casein kinase 1 ⁇ by using the method of Profiler Pro kit (manufactured by Caliper Life Science).
- Profiler Pro kit manufactured by Caliper Life Science
- DYRK1A is known as a candidate kinase that phosphorylates tau protein and a kinase that controls circadian rhythm cycle.
- the compound can be a more effective circadian rhythm disorder drug and neurodegenerative disease drug.
- casein kinase 1 ⁇ and casein kinase 1 ⁇ -inhibiting compounds for treating circadian rhythm cycle disorders can be demonstrated by the following animal model. That is, rats are acclimated to light / dark (LD) conditions for 12 hours light period: 12 hours dark period for one week or longer. Immediately before the dark period, the compound represented by the formula (11) was mixed with a solubilizing agent and administered intraperitoneally at a dose of 60 mg / kg. In rats to which the compound represented by formula (11) was administered immediately after administration, a statistically significant decrease in behavioral amount and increase in non-REM sleep amount were observed compared to the compound-untreated rats.
- LD light / dark
- the compound represented by the formula (11) is a compound in which a halogen group or the like is not introduced into the thiophene ring ((4-((6- The medicinal effect was significantly improved compared to methoxy-3-pyridinyl) methylene) -2- (2-thienyl) -5 (4H) -oxazolone)). It has been shown that the compound represented by the formula (11) is effective for treating circadian rhythm cycle disorders.
- the casein kinase 1 ⁇ inhibitory activity of the compound using tau as a substrate is determined by using human recombinant casein kinase 1 ⁇ (Carna Biosciences Cat No. 03-103) as an enzyme source and human recombinant tau (Sigma Aldrich Cat No. T0576). As a phosphorylated substrate.
- the composition (final concentration) in the inhibition activity detection assay is as follows.
- the compound and enzyme are reacted in advance for 15 minutes at room temperature, and then tau is added to perform phosphorylation for 2 hours.
- Western blotting was performed using the reaction solution after phosphorylation, and phosphorylation of human recombinant tau transferred onto the PVDF membrane was performed using a chemiluminescence method (ECL Plus) using Phos-tag (Nard Cat No.
- Typhoon (Amersham Biosciences, Model 9400) and Odyssey (LI-COR, Model 9120) were used to detect phosphorylation by chemiluminescence and total tau protein by infrared fluorescence, respectively.
- the ratio of the signal intensity of phosphorylated tau to the signal intensity of the tau is determined and this is used as the phosphorylation rate of tau.
- significant phosphorylation of the substrate was inhibited. I was able to observe. This indicates that the compounds represented by the formulas (2) and (11) may inhibit the pathological excess of tau phosphorylation in central neurodegenerative diseases (such as Alzheimer's disease).
- Inhibitory compounds are administered for a long time by feeding or drinking water using transgenic mice that overexpress mutant tau proteins that exhibit neurofibrillary tangles in the brain. It can be proved by pathological examination that the degree of synapse loss and nerve loss decreases compared to the non-administered group.
- casein kinase 1 ⁇ and casein kinase 1 ⁇ -inhibiting compounds in pancreatic cancer can be demonstrated in the following animal models. Specifically, about 5 million cell lines of human pancreatic cancer are cultured in vitro, and then subcutaneously injected into the back of SCID mice. After 14 days, the inhibitory compound is mixed with a solubilizing agent (such as carboxymethylcellulose) and administered orally or intraperitoneally. Subcutaneous tumor size is observed daily. Further, on the 10th day after administration, the effectiveness of the inhibitor can be proved by removing the tumor subcutaneously and measuring the tumor weight.
- solubilizing agent such as carboxymethylcellulose
- casein kinase 1 ⁇ and casein kinase 1 ⁇ inhibitor of the present invention and a medicament containing the inhibitor as an active ingredient are used to treat and / or treat diseases in which the activation mechanism of casein kinase 1 ⁇ or casein kinase 1 ⁇ is related to the pathological condition. It greatly contributes to the development of medicines useful for prevention. Above all, it greatly contributes to the development of medicines useful for the treatment and / or prevention of circadian rhythm cycle disorders (including sleep disorders), central neurodegenerative diseases, and cancer.
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Abstract
Description
アルツハイマー病病変部位におけるタウタンパク質の凝集は病態の重要なマーカーであることはよく知られている。且つこのタウタンパク質の過剰なリン酸化が凝集に重要な関与をしていることもよく知られている。そこで、このタウタンパク質をリン酸化する候補キナーゼとして当該病変部位に過剰に発現している酵素であるカゼインキナーゼ1ファミリーが考えられるため、そのうち、カゼインキナーゼ1δについてLi, Guibon等は、HEK-293細胞発現系を用いた研究を行っている。その結果、まず、カゼインキナーゼ1δとタウタンパク質とはin situで会合し直接カゼインキナーゼ1δがタウタンパク質をリン酸化すること、そして、カゼインキナーゼ1δの過剰発現により、タウタンパク質のin vitroでリン酸化される部位と同じ部位のリン酸化が増加することなどを、非選択的カゼインキナーゼ1阻害化合物3-[(2,3,6-trimethoxy phenyl) methylidenyl] -indolin-2-one (IC261)を用いるなどして示している(非特許文献6)。他方、Hanger, Diane P.等は、アルツハイマー病患者の病変部位より得られた極めてリン酸化され凝集した、いわゆる不溶性タウ:PHF-tau(paired helical filaments-tau)及び正常ヒトのそれとのリン酸化部位を質量分析により比較を行い、アルツハイマー病患者の病変部位に特有のリン酸化部位を同定するとともに、そのリン酸化部位の特徴から、対象候補キナーゼとしてグリコーゲンシンターゼキナーゼ3β(glycogen synthase kinase 3β)とともにカゼインキナーゼ1δが病変発生過程に関与している可能性の高さを示唆している(非特許文献7)。
アルツハイマー病においては、神経細胞に毒性を示すアミロイドベータ(amyloid-β: Aβ)の蓄積がその病変に関与すると考えられている。他方、同時にアルツハイマー病患者の病変部位にはカゼインキナーゼ1の発現が増加している事実が知られている。AβはAPP(amyloid precursor protein) がベータセクレターゼ(aspartyl protease β-secretase)及びガンマセクレターゼ(presenin-dependent protease γ-secretase)によって切断されて形成されると考えられているため、Flajolet, Marc等は、in silico解析によってこれらAPP、ベータセクレターゼ、ガンマセクレターゼのサブユニットの配列の中に存在すると考えられるカゼインキナーゼ1によって共通にリン酸化される部位を検討した。次に、これらの結果を参考にして、APPを安定に発現しているN2A細胞(N2A- APP695 cells)に対して常時安定に活性な(constitutively active)カゼインキナーゼ1εを過剰発現したところ、Aβ40及びAβ42の量が対照に比して、夫々約2倍と2.5倍となったと報告している。更に、この系に、非選択的カゼインキナーゼ1阻害化合物IC261を添加した際にAβ40及びAβ42の量が低下したとされ、更に、別の2種の非選択的カゼインキナーゼ1阻害化合物、CKI-7及びD4476によっても同様の結果が得られたと報告をしている(非特許文献8)。
これらの報告(非特許文献6、7及び8)は、アルツハイマー病の発症にカゼインキナーゼ1、特にカゼインキナーゼ1δあるいはカゼインキナーゼ1εが関与しており、その酵素活性の阻害によりアルツハイマー病の治療が為される可能性を大きく示唆するものである。
また、アルツハイマー病の原因遺伝子が存在すると想定される第21染色体がダウン症患者の体細胞でトリソミー(3倍体)になっていることなどから、ダウン症は、アルツハイマー病の遺伝的背景あるいは発症の研究などのモデルになりうると考えられてきた。特に、両者に共通して見られる特定のタンパク質の異常蓄積は、その発症機序に関係する重要な病理学的、生化学的指標の一つであると考えられ研究されてきた。実際に、ダウン症患者では中年期(35歳前後)以降にアルツハイマー様脳病変が多発することが知られている。これらの事実は、ダウン症を背景とする神経変性疾患に関しても、カゼインキナーゼ1、特にカゼインキナーゼ1δあるいはカゼインキナーゼ1εの酵素活性の阻害により、ダウン症を背景とする神経変性疾患の治療が為される可能性を大きく示唆するものである。
カゼインキナーゼ1ファミリーは細胞内の様々な重要な生理活性の調整に与っており、そのリン酸化される基質タンパク質は多岐にわたっている。例えば、癌抑制因子p53及び癌遺伝子mdm2は何れも癌化を制御する重要なタンパク質であり同時にカゼインキナーゼ1の基質でもある。これらのリン酸化の状況により細胞の癌化が亢進されると考えられているが、カゼインキナーゼ1のアイソフォームのうち、中でもカゼインキナーゼ1εあるいはカゼインキナーゼ1δによるp53のリン酸化、及びその結果としてのp53とmdm2との相互作用の変化及びp53の安定化と活性化などについて大いに注目されている。更には、カゼインキナーゼ1εあるいはカゼインキナーゼ1δが、細胞分裂の際の中心体、紡錘体形成の際に関与する調整タンパク質に関与する事実、あるいはTRAIL(tumor necrosis factor-related apoptosis inducing factor)及びFasを介するアポトーシスに関与することも知られている。
また、本発明は、本発明のカゼインキナーゼ1δ及びカゼインキナーゼ1εの選択的阻害剤を医薬上の有効性成分として含む、カゼインキナーゼ1δあるいはカゼインキナーゼ1εの生体内での機能を調節することにより、カゼインキナーゼ1δあるいはカゼインキナーゼ1εの酵素活性化が病態の発生過程に関連している疾患の治療及び/又は予防に有用な医薬を提供することを目的とする。カゼインキナーゼ1δあるいはカゼインキナーゼ1εの酵素活性化が病態の発生過程に関連している疾患のうち、概日リズム周期障害(睡眠障害を含む)、中枢神経変性疾患、癌の治療及び/又は予防に有用な医薬を提供することを目的とする。さらに、本発明は、上記医薬を用いた概日リズム周期障害(睡眠障害を含む)、中枢神経変性疾患、癌の治療及び/又は予防方法を提供することを目的とする。
さらに、本発明は、新規オキサゾロン誘導体及びその薬剤上許容される塩並びにそれらの水和物の提供を目的とする。
その結果、下記の一般式(1)で表される化合物がカゼインキナーゼ1δ及びカゼインキナーゼ1εのリン酸化能に対する阻害作用を有することを見出した。さらに、該化合物はこれまでに知られていない程度に選択性の高い阻害作用を有することを見出した。よって該化合物が上記の疾患の治療のための医薬の有効成分として有用であることを明らかにした。本発明はこれらの知見を基にして完成されたものである。
[式(1)中、Xはハロゲン原子(フッ素原子、塩素原子、臭素原子、又はヨウ素原子のいずれでもよい)を表す]
また、本発明は、上記一般式(1)で表されるオキサゾロン誘導体、またはその薬剤上許容される塩もしくはそれらの溶媒和物もしくはそれらの水和物を有効成分として含む、カゼインキナーゼ1δあるいはカゼインキナーゼ1εの酵素活性化が病態の発生過程に関連している疾患の治療及び/又は予防に有用な医薬である。また本発明は、上記一般式(1)で表されるオキサゾロン誘導体、またはその薬剤上許容される塩もしくはそれらの溶媒和物若もしくはそれらの水和物を有効成分として含む、概日リズム周期障害(睡眠障害を含む)、中枢神経変性疾患、癌の治療及び/又は予防のための医薬である。
さらに、本発明は、上記医薬を患者に投与することを含む、カゼインキナーゼ1δあるいはカゼインキナーゼ1εの酵素活性化機序が病態に関与する疾患の治療方法である。
一般式(1)で表される化合物は、本発明において新規に合成されたものである。さらに、一般式(1)で表される化合物がカゼインキナーゼ1δ及びカゼインキナーゼ1ε活性の阻害活性を有することは、本発明により初めて開示される。本発明の一般式(1)で表される新規オキサゾロン誘導体は、後述の実施例で示す化学的合成方法を用いて製造することができる。
本発明に係るカゼインキナーゼ1δあるいはカゼインキナーゼ1ε阻害剤及び医薬の有効成分として含まれる一般式(1)で表されるオキサゾロン誘導体には、特に断らない限り、その互変異性体、幾何異性体(例えば、E体、Z体など)も含まれる。また、鏡像異性体についても、存在する場合には、本発明の範囲に含まれる。
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-フルオロ-2-チエニル)-5(4H)-オキサゾロン及びその許容される塩並びに水和物、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-クロロ-2-チエニル)-5(4H)-オキサゾロン及びその許容される塩並びに水和物、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-ブロモ-2-チエニル)-5(4H)-オキサゾロン及びその許容される塩並びに水和物、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-ヨード-2-チエニル)-5(4H)-オキサゾロン及びその許容される塩並びに水和物。
ここで、「実質的に同一のアミノ酸配列を含むタンパク質」とは、上記RefSeq番号NP_001884.2、NP_620693.1、NP_620690.1、NP_082150.1で表わされるアミノ酸配列と約60%以上、好ましくは約70%以上、より好ましくは約80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,最も好ましくは約99%のアミノ酸同一性を有するアミノ酸配列を含み、かつ、タンパク質リン酸化酵素活性を有するタンパク質である。
あるいは、RefSeq番号NP_001884.2、NP_620693.1、NP_620690.1、NP_082150.1で表わされるアミノ酸配列と実質的に同一のアミノ酸配列を含むタンパク質としては、RefSeq番号NP_001884.2、NP_620693.1、NP_620690.1、NP_082150.1で表わされるアミノ酸配列中の1又は数個(好ましくは、1~30個程度、より好ましくは1~10個程度、さらに好ましくは1~5個)のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列からなり、かつ、タンパク質リン酸化酵素活性を有するタンパク質である。
ここで、「実質的に同一のアミノ酸配列を含むタンパク質」とは、上記RefSeq番号NP_001885.1、NP_689407.1 、NP_038795.3で表わされるアミノ酸配列と約60%以上、好ましくは約70%以上、より好ましくは約80%,81%,82%,83%,84%,85%,86%,87%,88%,89%,90%,91%,92%,93%,94%,95%,96%,97%,98%,最も好ましくは約99%のアミノ酸同一性を有するアミノ酸配列を含み、かつ、タンパク質リン酸化酵素活性を有するタンパク質である。
あるいは、RefSeq番号NP_001885.1、NP_689407.1 、NP_038795.3で表わされるアミノ酸配列と実質的に同一のアミノ酸配列を含むタンパク質としては、RefSeq番号NP_001885.1、NP_689407.1 、NP_038795.3で表わされるアミノ酸配列中の1又は数個(好ましくは、1~30個程度、より好ましくは1~10個程度、さらに好ましくは1~5個)のアミノ酸が欠失、置換若しくは付加されたアミノ酸配列からなり、かつ、タンパク質リン酸化酵素活性を有するタンパク質である。
さらに、本発明の医薬の有効成分として、一般式(1)で表される化合物又はその塩の溶媒和物若しくは水和物を用いることもできる。
本発明の治療方法には、カゼインキナーゼ1δあるいはカゼインキナーゼ1εの活性化機序がその病態に関連して発症する疾患又は疾病に罹患した哺乳動物の該疾患に関する治療方法が含まれる。
ここで「治療」とは、疾患に罹患するおそれがあるか又は罹患した哺乳動物において、該疾患の病態の進行及び悪化を阻止又は緩和することを意味し、これによって該疾患の諸症状等の進行及び悪化を阻止又は緩和することを目的とする治療的処置の意味として使用される。
チオフェン環にフルオロ基を導入することは一般には非常に困難であるため、特願2009-245477の実施例に例示した合成方法と比較して多くの合成段階を含む以下のスキーム1に示す工程で、式(2)で示される化合物の合成を試みた結果、製造することに成功した。なお、式(2)で示される化合物の合成方法は、スキーム1に示す工程に限定されるものではない。
MALDI-TOFF MS 計算値 C14H9FN2O3S,304.03,実測値,304.23
なお、化合物2を合成するための工程中、第一工程でのチオフェン環へのフルオロ基導入が極めて困難であり総収率および純度は低いものであった。その結果、最終生成物である化合物2の純度が低く確度が高いとは言えないが、ブルカ社製核磁気共鳴装置AV-500(500MHz)を用いてDMSO-d6に化合物2を溶解することにより観測されたピークについて以下に示す。
1H-NMR(500MHz,DMSO-d6,δ) 8.73(s,1H),8.19(d,1H),7.72(m,1H),7.36(d,1H),7.26(m,1H),7.19(s,1H),3.91(s,3H)
そこで、他の合成方法も検討した結果、以下に示すスキーム2の方法により、生成物の総収率及び純度を著しく改善することに成功した。
化合物2のHPLC純度(254nm吸収波長)は98.7%であった。化合物2をHPLC/ESI-LIT-TOF MS装置(NanoFrontier LD)を用いて測定した結果、m/z = 355.0, 356.0 [M + CH4O-H]- が確認された。また、化合物2をブルカ社製核磁気共鳴装置AV-500(500MHz)を用いて測定した結果観測されたピークについて以下に示す。
1H-NMR(CDCl3)δppm (500MHz): 4.02 (s, 3H), 6.63 (dd, 1H, JHH = 8.4 Hz, JHF = 1.4 Hz), 6.86 (d, 1H, JHH = 8.8 Hz), 7.13 (s, 1H), 7.55 (dd, 1H, JHH = 8.4 Hz, JHF = 4.1 Hz), 8.60 (dd, 1H, JHH = 8.8 Hz, JHH = 2.3 Hz), 8.67 (d, 1H, JHH = 2.3 Hz)
13C-NMR (CDCl3) δppm (125MHz): 53.9, 110.0, 110.1, 111.8, 117.4, 117.5, 123.5, 127.6, 130.6, 130.6, 131.7, 140.9, 152.1, 158.2, 165.3, 166.5, 169.4, 171.8
今回得られた化合物2はHPLC純度98.7%、質量分析およびNMRスペクトルパターンからも、化合物2の生成が支持される。
式(2)で示されるフルオロ基を導入した化合物とともに、式(11)で示されるクロロ基を導入した化合物についても製造を実施した。なお、式(11)で示されるクロロ基を導入した化合物の合成方法は、スキーム3に示す工程に限定されるものではない。
別途用意した三口フラスコにグリシン323.2mg(4.31mmol)、0.5N水酸化ナトリウム15mlを加え攪拌し、先に得た褐色油状物を加え、1時間室温で攪拌した。反応終了後氷浴で冷却し、6N塩酸1mlを加え、析出した固形物を濾取し、冷水30mlで洗浄した。固形物を室温で減圧乾燥し化合物13を386.2mg(1.76mmol,53%)淡黄色固体で得た。生成物のHPLC分析において溶離時間10.06分、純度は99.5%以上であった。
化合物11のHPLC純度(254nm吸収波長)は99.5%であった。化合物11をHPLC/ESI-LIT-TOF MS 装置(NanoFrontier LD)を用いて測定した結果、m/z = 351.0, 352.0 [M + CH4O-H]- が確認された。また、化合物11をブルカ社製核磁気共鳴装置AV-500(500MHz)を用いて測定した結果観測されたピークについて以下に示す。
1H-NMR(CDCl3)δppm (500MHz): 4.02 (s, 3H), 6.86 (d, 1H, JHH = 8.8 Hz), 7.03 (s, 1H), 7.65 (d, 1H, JHH = 4.1 Hz), 8.62 (dd, 1H, JHH = 8.7 Hz, JHH = 2.4 Hz), 8.67 (d, 1H, JHH = 2.4 Hz)
13C-NMR (CDCl3) δppm (125MHz): 54.0, 111.8, 123.6, 126.7,126.9, 128.0, 128.1, 131.7, 132.2, 140.9, 152.2, 157.7, 165.4, 166.5
今回得られた化合物11はHPLC純度99.5%以上、質量分析およびNMRスペクトルパターンからも、化合物2の生成が支持される。
式(2)で示されるフルオロ基を導入した化合物とともに、式(14)で示されるブロモ基を導入した化合物についても製造を実施した。なお、式(14)で示されるブロモ基を導入した化合物の合成方法は、スキーム4に示す工程に限定されるものではない。
別途用意した三口フラスコにグリシン412.9mg(5.80mmol)、6N水酸化ナトリウム5mlを加え攪拌し、先に得た褐色油状物を加え、1時間室温で攪拌した。反応終了後氷浴で冷却し、6N塩酸1mlを加え、析出した固形物を濾取し、冷水30mlで洗浄した。固形物中の水をアセトンで共沸除去した後、室温で減圧乾燥し化合物16を492.6mg(0.19mmol, 39.0%)淡黄色固体で得た。生成物のHPLC分析において溶離時間10.39分、純度は99.7%であった。
化合物14のHPLC純度(254nm吸収波長)は95.8%であった。化合物14をHPLC/ESI-LIT-TOF MS装置(NanoFrontier LD)を用いて測定した結果、m/z = m/z = 396.9, 397.9 [M + CH4O-H]- が確認された。また、化合物14をブルカ社製核磁気共鳴装置AV-500(500MHz)を用いて測定した結果観測されたピークについて以下に示す。
1H-NMR(CDCl3)δppm (500MHz): 4.02 (s, 3H), 6.86 (d, 1H, JHH = 8.8 Hz), 7.17 (s, 1H), 7.17 (d, 1H, JHH = 4.0 Hz), 7.60 (d, 1H, JHH = 4.0 Hz), 8.63 (dd, 1H, JHH = 8.8 Hz, JHH = 2.4 Hz), 8.67 (d, 1H, JHH = 2.4 Hz)
13C-NMR (CDCl3) δppm (125MHz): 54.0, 111.8, 121.5, 123.6, 128.2, 129.9, 131.7, 131.7, 132.8, 140.9, 152.2, 157.6, 165.4, 166.5
今回得られた化合物14はHPLC純度95.8%、質量分析およびNMRスペクトルパターンからも、化合物14の生成が支持される。
1.オキサゾロン誘導体のカゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害作用
当該化合物のカゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害活性は、ヒトリコンビナントカゼインキナーゼ1δ(INVITROGEN社Cat No.PV3665)もしくは、ヒトリコンビナントカゼインキナーゼ1ε (INVITROGEN社Cat No.PV3500) を酵素源として使用し、Z’-LYTE Ser/Thr 11 Peptide(INVITROGEN社Cat No.PV3671)をリン酸化基質として測定した。阻害活性測定アッセイ時の組成(最終濃度)は下記の通りである。
カゼインキナーゼ1δのアッセイ
カゼインキナーゼ1δ 3.0μg/ml、あるいは1.0μg/ml、当該化合物 0.3μg/ml、Peptide 1.0μM、ATP 20μM、HEPES(pH7.4) 50mM、MgCl2 10mM、Brij-35 0.01%、DMSO 0.5%
カゼインキナーゼ1εのアッセイ
カゼインキナーゼ1ε 0.5μg/ml、当該化合物0.3μg/ml、Peptide 1.0μM、ATP 20μM、HEPES(pH7.4) 50mM、MgCl2 10mM、Brij-35 0.01%、DMSO 0.5%
あらかじめ当該化合物と酵素を15分間室温で反応させたのち、2時間後の残存するリン酸化活性を、Z’-LYTE Kinase Assay Kit-Ser/Thr 11 Peptide(INVITROGEN社Cat No.PV3670)を用いて測定した。
一方、式(2)、(11)ならびに(14)で示される化合物は、Profiler Pro kit(キャリパーライフサイエンス社製)の方法を用いることで、カゼインキナーゼ1δ及びカゼインキナーゼ1εと比べ阻害効果は弱いものの、Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A)に対して化合物濃度1μMを添加することで、酵素活性をそれぞれ 65%、78%、85%阻害することを見出した。DYRK1Aは、カゼインキナーゼ1δと同様、タウタンパク質をリン酸化する候補キナーゼならびに概日リズム周期を制御するキナーゼとして知られている。カゼインキナーゼ1δ及びカゼインキナーゼ1εとDYRK1Aをそれぞれ阻害することで、当該化合物はより効果的な概日リズム周期障害治療薬、神経変性疾患治療薬となりうる。
カゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害化合物の概日リズム周期障害治療に対する有効性は、以下の動物モデルで証明することができる。すなわち、ラットを、12時間明期:12時間暗期の明暗(light/dark: LD)条件に1週間以上馴化させる。暗期直前に式(11)で示される化合物を、溶解補助剤と混合し、60mg/kgの用量で腹腔投与した。投与直後より式(11)で示される化合物を投与したラットでは、化合物未処置ラットと比較して、統計的有意な行動量の低下およびノンレム睡眠量の増加が観察された。一方、式(2)のチオフェン環にハロゲン基等を導入していない化合物((4-((6-メトキシ-3-ピリジニル)メチレン)-2-(2-チエニル)-5(4H)-オキサゾロン))についても同様の試験をおこなった。その結果、有意な行動量の低下およびノンレム睡眠量の増加が観察されたが、式(11)で示される化合物はチオフェン環にハロゲン基等を導入していない化合物((4-((6-メトキシ-3-ピリジニル)メチレン)-2-(2-チエニル)-5(4H)-オキサゾロン))よりもより飛躍的に薬効が向上した。式(11)で示される化合物は概日リズム周期障害治療に対して有効であることを示している。
カゼインキナーゼ1δ 25μg/ml、タウ 10μg/ml、当該化合物(25μM ~1μM)、ATP 200μM、HEPES(pH7.4) 50mM、MgCl2 10mM、Brij-35 0.01%、Na3VO4 200μM、DMSO 0.25%
あらかじめ当該化合物と酵素を15分間室温で反応させたのち、タウを加えて2時間リン酸化反応を行う。リン酸化反応後の反応液を用いてウエスタンブロットをおこない、PVDF膜上に転写したヒトリコンビナントタウのリン酸化をPhos-tag (ナード社 Cat No. BTL-104)を用いて化学発光法(ECL Plus、GEヘルスケア社 Cat No. RPN2132)により検出する。リン酸化反応検出後のPVDF膜は、Phos-tagのプロトコルにしたがって脱プローブをおこなったのち、抗体反応により全タウ蛋白質量を検出することができる。
一次抗体として抗タウ抗体(DAKO Cytomation社、Cat No. A0024)と反応させたのち、IR Dye 680LT標識ヤギ抗ウサギ二次抗体(LI-COR社、Cat No. 926-68021)との反応をおこない、赤外蛍光を検出して全タウ蛋白質のシグナルとする。
化学発光によるリン酸化反応検出と、赤外蛍光による全タウ蛋白質の検出には、それぞれTyphoon (アマシャムバイオサイエンス社、モデル9400)とOdyssey (LI-COR社、モデル9120)を使用し、全タウ蛋白質のシグナル強度に対するリン酸化タウのシグナル強度の比を求めてこれをタウのリン酸化率とする。
このリン酸化率を、当該化合物の非添加反応液と添加反応液で比較した結果、式(2)、(11)で示される化合物を添加した反応液において、基質のリン酸化に有意な阻害を観察することができた。式(2)、(11)で示される化合物が中枢神経変性疾患(アルツハイマー病など)における病的な過剰なタウのリン酸化を阻害する可能性があることを示している。
Claims (11)
- 一般式(1)で表される化合物が、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-フルオロ-2-チエニル)-5(4H)-オキサゾロン、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-クロロ-2-チエニル)-5(4H)-オキサゾロン、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-ブロモ-2-チエニル)-5(4H)-オキサゾロン、
4-((6-メトキシ-3-ピリジニル)メチレン)-2-(5-ヨード-2-チエニル)-5(4H)-オキサゾロン、
のいずれかである、請求項1に記載のオキサゾロン誘導体。 - 請求項1又は2に記載のオキサゾロン誘導体、若しくはその塩又はそれらの溶媒和物もしくはそれらの水和物を有効成分として含むカゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害剤。
- 請求項1又は2に記載のオキサゾロン誘導体、若しくはその塩又はそれらの溶媒和物もしくはそれらの水和物を有効成分とする、カゼインキナーゼ1δあるいは1εの酵素活性化機序が病態に関与する疾患の治療のための医薬組成物。
- 前記疾患が睡眠障害を含む概日リズム周期障害である、請求項4に記載の医薬組成物。
- 前記疾患が神経変性疾患である、請求項4に記載の医薬組成物。
- 前記疾患が癌である、請求項4に記載の医薬組成物。
- 請求項1又は2に記載のオキサゾロン誘導体、若しくはその塩又はそれらの溶媒和物もしくはそれらの水和物を有効成分とする医薬組成物を投与することにより、カゼインキナーゼ1δあるいは1εの酵素活性化機序が病態に関与する疾患を治療する方法。
- 前記疾患が睡眠障害を含む概日リズム周期障害である、請求項8に記載の方法。
- 前記疾患が神経変性疾患である、請求項8に記載の方法。
- 前記疾患が癌である、請求項8に記載の方法。
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AU2011290238A AU2011290238B8 (en) | 2010-08-09 | 2011-08-08 | Inhibitor of casein kinase 1delta and casein kinase 1E |
KR1020137005642A KR101856266B1 (ko) | 2010-08-09 | 2011-08-08 | 카세인 키나아제 1δ 및 카세인 키나아제 1ε 저해제 |
JP2012528666A JP5181156B2 (ja) | 2010-08-09 | 2011-08-08 | カゼインキナーゼ1δ及びカゼインキナーゼ1ε阻害剤 |
EP11816390.6A EP2604606B1 (en) | 2010-08-09 | 2011-08-08 | Inhibitor of casein kinase 1delta and casein kinase 1epsilon |
CN201180039427.7A CN103097380B (zh) | 2010-08-09 | 2011-08-08 | 酪蛋白激酶1δ及酪蛋白激酶1ε抑制剂 |
CA2807359A CA2807359C (en) | 2010-08-09 | 2011-08-08 | Inhibitor of casein kinase 1.delta. and casein kinase 1.epsilon. |
US13/816,180 US8710231B2 (en) | 2010-08-09 | 2011-08-08 | Inhibitor of casein kinase 1delta and casein kinase 1E |
RU2013107659/04A RU2562833C2 (ru) | 2010-08-09 | 2011-08-08 | Ингибитор казеинкиназы 1 дельта и казеинкиназы 1 е |
IL224612A IL224612A (en) | 2010-08-09 | 2013-02-07 | Inhibitor of xain kinase 1 delta and xain kinase 1 epsilon |
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- 2011-08-08 RU RU2013107659/04A patent/RU2562833C2/ru active
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Also Published As
Publication number | Publication date |
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JPWO2012020726A1 (ja) | 2013-10-28 |
RU2562833C2 (ru) | 2015-09-10 |
EP2604606A4 (en) | 2013-08-07 |
US20130137730A1 (en) | 2013-05-30 |
HK1183874A1 (en) | 2014-01-10 |
EP2604606A1 (en) | 2013-06-19 |
AU2011290238B8 (en) | 2015-09-03 |
KR20140000666A (ko) | 2014-01-03 |
HK1211926A1 (en) | 2016-06-03 |
KR101856266B1 (ko) | 2018-05-09 |
CN103097380B (zh) | 2015-06-03 |
EP2604606B1 (en) | 2014-10-08 |
RU2013107659A (ru) | 2014-09-20 |
CN104803997A (zh) | 2015-07-29 |
CA2807359C (en) | 2020-07-07 |
IL224612A (en) | 2016-05-31 |
JP5181156B2 (ja) | 2013-04-10 |
US8710231B2 (en) | 2014-04-29 |
CN103097380A (zh) | 2013-05-08 |
CA2807359A1 (en) | 2012-02-16 |
AU2011290238B2 (en) | 2014-07-17 |
AU2011290238A1 (en) | 2013-03-21 |
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