JP2022137234A - Prophylactic and/or therapeutic agent for neurodegenerative disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel medicine having the a prophylactic and/or therapeutic activity for a neurodegenerative disease selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration, and α-synucleinopathy.

SOLUTION: The present invention provides a prophylactic and/or therapeutic agent for a neurodegenerative disease selected from the group consisting of frontotemporal lobar degeneration and α-synucleinopathy, the agent containing a tyrosine kinase inhibitor. Preferably, the tyrosine kinase inhibitor is bosutinib or its analog.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2022,JPO&INPIT

Description

TECHNICAL FIELD The present invention relates to preventive and/or therapeutic agents for neurodegenerative diseases. More particularly, it relates to a prophylactic and/or therapeutic agent for neurodegenerative diseases selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration and α-synucleinopathy.

Alzheimer's disease (hereinafter sometimes abbreviated as AD) is a brain degenerative disease representative of dementia, and the number of patients with it is steadily increasing. The decline in quality of life associated with the deterioration of cranial nerve function in AD patients has a great impact on not only the patients themselves but also their families and others around them, and has become a serious problem facing modern society. As of 2010, the annual medical costs for 35 million AD patients were 604 billion dollars, and it is predicted that the number of AD patients will increase to 114 million in 2050, further increasing medical costs. Under these circumstances, drug repositioning (DR), that is, diversion of existing drugs, is being emphasized for AD treatment (Non-Patent Document 1). The safety of existing drugs has already been established with a vast amount of clinical information on their safety and pharmacokinetics (Chembl database, etc.). Therefore, it is expected that intervention as a preemptive treatment for the pre-AD group with no clinical symptoms but positive amyloid test can be expected.

Similar to Alzheimer's disease, frontotemporal lobar degeneration (FTLD) is known as a disease exhibiting progressive neurodegenerative disorders. Frontotemporal lobar degeneration is the second or third most common early-onset neurodegenerative dementia, after Alzheimer's disease, and presents with symptoms of marked behavioral and personality changes, often accompanied by language impairment. This will gradually develop into cognitive impairment and dementia. In addition, similar to Alzheimer's disease, research is underway, but the full picture of the onset mechanism has not yet been elucidated.

Parkinson's disease is a typical neurodegenerative disease along with Alzheimer's disease, and it is known that Lewy bodies appear in the substantia nigra in the brain of patients. Lewy bodies are protein aggregates consisting of 140 amino acid residues called α-synuclein, and are called Lewy body diseases such as Parkinson's disease, Lewy body dementia, multiple system atrophy, etc. It is also known to appear in the brains of diseased patients, and diseases associated with accumulation of α-synuclein in the brain are called α-synucleinopathies. Aggregation of α-synuclein, that is, α-synuclein fibril formation, is thought to play an important role in the progression of α-synucleinopathy. is underway.

However, although research on these neurodegenerative diseases is being vigorously pursued, the full picture of the onset mechanism is not clear, and the present situation is that no radical drug has been developed yet.

By the way, the disease-causing cells that are induced to differentiate from patient-derived iPS cells (disease iPS cells) are expected to reproduce the patient's pathology in vitro, so they are expected to be a powerful drug efficacy evaluation system. there is Recent reports on human iPS cell-derived neurons emphasize the importance of human neurons as a tool for evaluating drug responsiveness (Non-Patent Documents 2-4).

Front. Biosci. (Schol. Ed). 7, 184-8 (2015) PLoS One 6, e25788 (2011) JAMA Neurol. 71, 1481-9 (2014) Stem Cell Reports 1,491-498 (2013)

An object of the present invention is to provide a novel drug having preventive and/or therapeutic activity for neurodegenerative diseases selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration and α-synucleinopathy, and to It is to accelerate the development of preventive and/or therapeutic agents for such neurodegenerative diseases as pharmaceuticals.

The present inventors used neuronal cells derived from diseased iPS cells to find anti-amyotrophic lateral sclerosis (ALS) activity from a known compound library containing drugs already on the market as pharmaceuticals. Compounds were screened. As a result, we found that inhibitors of the tyrosine kinase Src/c-Abl improved the survival of ALS motor neurons. Furthermore, the Src/c-Abl inhibitor and kenpaullone, which is already known to have anti-ALS activity (Cell Stem Cell, 2013; 12(6):713-726), are also effective against other neurodegenerative diseases. As a result, they found that the survival of cortical neurons derived from patients with specific neurodegenerative diseases was improved, and completed the present invention.

That is, the present invention is as follows.
[1] Prevention and/or treatment of neurodegenerative diseases selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration and α-synucleinopathy, containing one or more Src/c-Abl pathway inhibitors agent.
[2] The agent according to [1], wherein the Src/c-Abl pathway inhibitor is bosutinib or an analogue thereof, imatinib or an analogue thereof, nilotinib or an analogue thereof, or kenpaullone or an analogue thereof.
[3] The agent of [2], wherein the Src/c-Abl pathway inhibitor is bosutinib or an analogue thereof.
[4] The agent according to any one of [1] to [3], wherein the Alzheimer's disease has a mutation in the amyloid precursor protein gene.
[5] The agent according to any one of [1] to [3], wherein the frontotemporal lobar degeneration is FTLD-Tau.
[6] The agent according to [5], wherein the FTLD-Tau has a mutation in the MAPT gene.
[7] The agent according to any one of [1] to [3], wherein the α-synucleinopathy is dementia with Lewy bodies.
[8] Alzheimer's disease, frontotemporal lobar degeneration and α-synucleinopathy in a mammal, characterized by administering to the mammal an effective amount of one or more Src/c-Abl pathway inhibitors. A method for the prevention and/or treatment of a neurodegenerative disease selected from the group consisting of pathies.
[9] one or more Src/c-Abl pathways for use in the prevention and/or treatment of a neurodegenerative disease selected from the group consisting of Alzheimer's disease, frontotemporal lobar degeneration and alpha-synucleinopathy inhibitor.

According to the present invention, it is possible to prevent and/or treat neurodegenerative diseases such as Alzheimer's disease, frontotemporal lobar degeneration, and α-synucleinopathy. In particular, in the present invention, there is little concern about side effects when an existing drug whose safety has been confirmed is used as an active ingredient.

Figure 1. Cortices derived from iPS cells from patients with Alzheimer's disease (APP E693Δ), frontotemporal lobar degeneration (MAPT R406W or MAPT Intron 10+14 C→T) or dementia with Lewy bodies (SNCA A53T). FIG. 4 shows the protective effects of bosutinib, imatinib, nilotinib, kenpaullone on neuronal survival. A bar graph in each cortical neuron column shows 0.1 µM addition, 1 µM addition, 1 µM addition, and 10 µM addition from the left (n = 6; one-way ANOVA, *: p<0.05; post hoc test.). Bars indicate mean ± standard deviation.

The present invention provides compounds from Alzheimer's disease, frontotemporal lobar degeneration and alpha-synucleinopathy containing one or more Src/c-Abl pathway inhibitors (these compounds are also referred to as "compounds of the invention"). A preventive and/or therapeutic agent for neurodegenerative diseases selected from the group consisting of (hereinafter also referred to as "preventive/therapeutic agent of the present invention") is provided.

Src/c-Abl pathway inhibitor means an agent that inhibits the pathway involving receptor tyrosine kinase (RTK), Src, c-Abl and protein kinase C (PKC), and the inhibitor includes these Included are agents that inhibit at least one activity and/or expression of a protein. Examples include tivozanib, pazopanib, sunitinib, BMS777607, CYC116, axitinib, KW2449, VX-680, crizotinib, MGCD-265, bosutinib, imatinib, nilotinib, dasatinib, sarakatinib, enzastaurin, bisindolylmaleimide I, kenpaullone, and analogs thereof. be done. Among them, bosutinib, imatinib, nilotinib, kenpaullone or analogs thereof are preferred, and bosutinib or analogs thereof are particularly preferred. Agents that inhibit expression include RTK, Src, c-Abl, or antisense nucleic acids against PKC, siRNA, shRNA, miRNA, ribozymes, and the like. These expression-inhibiting substances can be appropriately designed using known design software based on the nucleotide sequence of the gene, easily synthesized using an automatic DNA/RNA synthesizer, or commercially available drugs. can also be used. For example, Src siRNA (siRNA ID: s13414, s13413, etc.), c-Abl siRNA (siRNA ID: s866, s864, etc.) and the like can be obtained from Life Technologies.

In the present invention, Alzheimer's disease (AD) to be treated includes both sporadic and familial AD. In the case of familial AD, the causative gene is not particularly limited, and any gene including amyloid precursor protein (APP), presenilin 1 (Presenilin 1; PSEN1), presenilin 2 (Presenilin 2; PSEN2), etc. It can be a known causative gene. In one embodiment, in the case of familial AD with APP mutations, the APP gene mutations include dup APP mutation, APP KM670/671NL mutation, APP D678N mutation, APP E682K mutation, APP A692G mutation, APP E693K mutation, APP E693Q mutation, APP E693G mutation, APP E693del(APP E693Δ) mutation, APP D694N mutation, APP L705V mutation, APP A713T mutation, APP T714A mutation, APP T714I mutation, APP V715M mutation, APP V715A mutation, APP I716V mutation, APP I716F mutation, Examples include, but are not limited to, the APP I716T mutation and the APP V717I mutation. Here, for example, APP E693Δ means a deletion mutation of E693 in APP.

In the present invention, the term "frontotemporal lobar degeneration (FTLD)" means degenerative dementia prototyped by classic Pick's disease having lesions in the frontal lobe and anterior temporal lobe, and pathological classification of FTLD. Examples include FTLD-tau (frontotemporal lobar degeneration tauopathy), FTLD-TDP, FTLD-FUS, FTLD-UPS, and FTLD-without inclusion. In the present invention, FTLD to be treated is not particularly limited, but FTLD-tau is preferred, and FTLD with MAPT gene mutation is particularly preferred. Among others, misfolded tau proteins due to MAPT intron mutations (e.g., 10+14C → T mutation) and MAPT exon mutations (e.g., R406W mutation, P301L mutation) Especially preferred is FTLD-Tau (FTDP-17), in which accumulation of is observed.

In the present invention, α-synucleinopathies to be treated include, for example, Parkinson's disease (PD), sporadic or hereditary Lewy body dementia (DLB), pure autonomic failure accompanied by α-synuclein deposition ( PAF), multiple system atrophy (MSA), hereditary neurodegeneration with iron accumulation in the brain, and occasional Lewy body disease in old age. Genetic evidence indicates that point mutations in the gene encoding alpha-synuclein are associated with early-onset, severe, dominantly inherited forms of PD (Krueger et al., (1997) Nat. Genet., 18, 106-108; Zarranz et al., (2004) Ann. Neurol., 55(2):164-73; Polymeropoulos et al., (1997) Science, 276:2045-7). The α-synuclein gene mutation is a mutation that causes an amino acid change in which the 30th alanine of α-synuclein becomes proline (A30P), the 46th glutamic acid becomes lysine (E46K), or the 53rd alanine becomes threonine (A53T). etc.

Analogs of the above "Bosutinib (SKI-606)" include the following formula (I):

[In the formula:
n is an integer from 1-3;
X is N, CH, provided that when X is N, n is 2 or 3;
R is alkyl consisting of 1 to 3 carbon atoms;
R ¹ is 2,4-dichloro and 5-methoxy, 2,4-dichloro, 3,4,5-trimethoxy, 2-chloro and 5-methoxy, 2-methyl and 5-methoxy, 2,4-dimethyl, 2,4-dimethyl and 5-methoxy, or 2,4-dichloro and 5-ethoxy;
R ² is alkyl of 1-2 carbon atoms]
The compound represented by is mentioned.

Each term described as a generic concept in the description of each group of the above formula (I) (“alkyl consisting of 1 to 3 carbon atoms” for R, “alkyl consisting of 1 to 2 carbon atoms” for R ² ) follows the definitions and explanations in WO 2005/046693 (Japanese translation of PCT publication No. 2007-533655).

Specific examples of bosutinib analogues include the following compounds.
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[3-(4-ethyl-1-piperazinyl)propoxy]-6-methoxy-3-quinolinecarbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]-3-quinolinecarbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[2-(4-ethyl-1-piperazinyl)ethoxy]-6-methoxy-3-quinolinecarbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]-3-quinolinecarbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[(1-ethylpiperidin-4-yl)methoxy]-6-methoxyquinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(4-ethylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[3-(1-methylpiperidin-4-yl)propoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(4-methyl-1-piperazinyl)ethoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-propyl-1-piperazinyl)propoxy]-3-quinolinecarbonitrile;
4-[(2,4-dichlorophenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-3-quinolinecarbonitrile;
6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-4-[(3,4,5-trimethoxyphenyl)amino]quinoline-3-carbonitrile;
4-[(2-chloro-5-methoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;
6-methoxy-4-[(5-methoxy-2-methylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;
4-[(2,4-dimethylphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;
6-methoxy-4-[(5-methoxy-2,4-dimethylphenyl)amino]-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile;
4-[(2,4-dichloro-5-ethoxyphenyl)amino]-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinoline-3-carbonitrile

Analogs of the above "imatinib" include the following formula (II):

[In the formula:
R ₁ is 4-pyrazinyl, 1-methyl-1H-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl where the amino group in each case is free, alkylated or acylated, 5-membered ring or 1H-indolyl or 1H-imidazolyl attached at a carbon atom of a ring, or unsubstituted or lower alkyl attached at a ring carbon atom and substituted or unsubstituted by oxygen at the nitrogen atom substituted pyridyl, each of R ₂ and R ₃ is independently of the other hydrogen or lower alkyl, and one or two of the groups R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each is nitro, fluoro-substituted lower alkoxy, or a group of formula (III)

wherein R ₉ is hydrogen or lower alkyl, X is oxo, thio, imino, N-lower alkyl-imino, hydroxyimino or O-lower alkyl-hydroxyimino, Y is oxygen or the group NH , n is 0 or 1, and R ₁₀ is an aliphatic group having at least 5 carbon atoms, or an aromatic, aromatic-aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, hetero cyclic or heterocyclic-aliphatic groups] and the remaining groups R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are each independently of each other hydrogen, unsubstituted or free or lower alkyl substituted by alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl, or lower alkanoyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or is acylated amino, or free or esterified carboxy]
The compound represented by is mentioned.

Each term described as a generic concept in the description of each group of formula (II) above (e.g., “lower alkyl”, “aliphatic group having at least 5 carbon atoms”, “alkylated amino”, “lower alkanoyl ” etc.) and other terms conform to the definitions and explanations in JP-A-6-087834.

Specific examples of analogs of imatinib include the following compounds.
N-(3-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(4-chlorobenzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-(3-benzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(2-pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(3-pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(4-pyridyl)carboxamido-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-(3-pentafluoro-benzoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(2-carboxy-benzoylamido)phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-(3-n-hexanoylamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-(3-nitro-phenyl)-4-(2-pyridyl)-2-pyrimidine-amine;
N-(3-nitro-phenyl)-4-(4-pyridyl)-2-pyrimidine-amine;
N-[3-(2-Methoxy-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(4-fluoro-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(4-cyano-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(2-thienylcarboxamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-(3-cyclohexylcarboxamido-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(4-methyl-benzoylamido)-phenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[3-(4-chlorobenzoylamido)-phenyl]-4-(4-pyridyl)-2-pyrimidine-amine;
N-{3-[4-(4-methyl-piperazinomethyl)-benzoylamido]-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine;
N-(5-benzoylamido-2-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methyl-phenyl}-4-(3-pyridyl)-2-pyrimidine-amine;
N-[5-(4-methyl-benzoylamido)-2-methylphenyl]-4-(3-pyridyl)-2-pyrimidine-amine;
N-[5-(2-naphthoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidin-amine;
N-[5-(4-chloro-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidin-amine;
N-[5-(2-methoxy-benzoylamido)-2-methyl-phenyl]-4-(3-pyridyl)-2-pyrimidin-amine;
N-(3-trifluoro-methoxy-phenyl)-4-(3-pyridyl)-2-pyrimidin-amine;
N-(3-[1,1,2,2-tetrafluoro-ethoxy]-phenyl)-4-(3-pyridyl)-2-pyrimidine-amine;
N-(3-nitro-5-methyl-phenyl)-4-(3-pyridyl)-2-pyrimidin-amine;
N-(3-nitro-5-trifluoromethyl-phenyl)-4-(3-pyridyl)-2-pyrimidin-amine;
N-(3-nitro-phenyl)-4-(N-oxide-3-pyridyl)-2-pyrimidine-amine;
N-(3-benzoyl-amido-5-methyl-phenyl)-4-(N-oxide-3-pyridyl)-2-pyrimidine-amine

Analogs of the above "nilotinib" include the following formula (IV):

[In the formula:
R ₁ represents hydrogen, lower alkyl, lower alkoxy-lower alkyl, acyloxy-lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl or phenyl-lower alkyl;
R ₂ is hydrogen, lower alkyl, cycloalkyl, benzcycloalkyl, heterocyclyl, aryl group optionally substituted by one or more identical or different residues R ₃ , or 0 ring nitrogen atoms , 1, 2 or 3 and monocyclic or bicyclic heteroaryl groups having 0 or 1 oxygen atoms and 0 or 1 sulfur atoms, wherein each group is unsubstituted or mono- or polysubstituted; and R ₃ is hydroxy, lower alkoxy, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amino, mono- or disubstituted amino, cycloalkyl, heterocyclyl, aryl groups, or monocyclic or bicyclic groups having 0, 1, 2 or 3 ring nitrogen atoms and 0 or 1 oxygen atoms and 0 or 1 sulfur atoms represents a heteroaryl group, wherein each group is either unsubstituted or mono- or polysubstituted; or R ₁ and R ₂ taken together are optionally lower alkyl, cycloalkyl, heterocyclyl, alkylene having 4, 5 or 6 carbon atoms optionally mono- or disubstituted with phenyl, hydroxy, lower alkoxy, amino, mono- or disubstituted amino, oxo, pyridyl, pyrazinyl or pyrimidinyl; benzalkylene having 4 or 5 atoms; or oxaalkylene having 1 oxygen and 3 or 4 carbon atoms; or nitrogen being unsubstituted or lower-alkyl, phenyl-lower-alkyl, lower-alkoxycarbonyl-lower substituted with alkyl, carboxy-lower alkyl, carbamoyl lower alkyl, N-mono- or N,N-disubstituted carbamoyl lower alkyl, cycloalkyl, lower alkoxycarbonyl, carboxy, phenyl, substituted phenyl, pyridinyl, pyrimidinyl or pyrazinyl, represents azaalkylene having 1 nitrogen and 3 or 4 carbon atoms; and _R4 represents hydrogen, lower alkyl or halogen]
The compound represented by is mentioned.

Each term described as a generic concept in the description of each group of the above formula (IV) (e.g., “lower alkyl”, “lower alkoxy”, “cycloalkyl”, “benzcycloalkyl”, “heterocyclyl”, “aryl group ", "monocyclic or bicyclic heteroaryl group", "halogen", etc.) and other terms follow the definitions and explanations in WO2004/005281 (PCT Publication No. 2005-533827).

Specific examples of nilotinib analogues include the following compounds.
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]]aminobenzanilide;
4-methyl-N-(3-pyridinyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
N-(4-chlorophenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
2(R)- and 2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]propanoic acid;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(8-quinolinyl)benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-[trifluoromethoxy]phenyl)benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidinoethyl)benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-pyrrolidinophenyl)benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(1-[2-pyrimidinyl]-4-piperidinyl])benzamide;
N-(4-di[2-methoxyethyl]amino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
N-(4-[1H-imidazolyl]-3-trifluoromethylphenyl])-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(2-pyrrolidino-5-trif N-(3,4-difluorophenyl)-4-methyl-3- [[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylphenyl)benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-(3-trifluoromethylphenyl)benzamide;
N-(3-chloro-5-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
N-(4-diethylaminobutyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-N-[4-(4-methyl-1-piperazinyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,2,2-trifluoroethoxy)-3-trifluoromethylphenyl]benzamide;
4-methyl-N-[4-(2-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-N-(4-phenyl-3-trifluoromethylphenyl)-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-N-[4-(4-methyl-1H-imidazolyl)-3-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
methyl 2(R)- and 2(S)-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoylamino]-3-[4-hydroxyphenyl]propanoate;
N-[2-(N-cyclohexyl-N-methylaminomethyl)phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
N-[3-[2-(1H-imidazolyl)ethoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-N-[3-morpholino-5-trifluoromethylphenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
N-(4-diethylamino-3-trifluoromethylphenyl)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(3-pyridinyl)-5-trifluorophenyl]benzamide;
N-[3-[3-(1H-1-imidazolyl)propoxy]phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(3-pyridinyl)-3-trifluorophenyl]benzamide;
4-methyl-N-[3-(4-methyl-1-piperazinyl)-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-N-[3-methylcarbamoyl-5-trifluorophenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-N-[3-methylcarbamoyl-5-morpholino]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[3-(1H-imidazol-1-yl)propoxy]phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[2-(1H-imidazol-1-yl)ethoxy]phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(ethylamino)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(diethylamino)-3-(trifluoromethyl)phenyl]benzamide;
(±)-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[(2-hydroxypropyl)amino]-3-(trifluoromethyl)phenyl ] benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-[bis(2-methoxyethyl)amino]-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-piperidinyl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1-pyrrolidinyl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-phenyl-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[4-(3-pyridinyl)-3-(trifluoromethyl)phenyl]methyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-(trifluoromethyl ) phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl ] benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[4-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl ] benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-morpholinyl)-5-[(methylamino)carbonyl]phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-[(methylamino)carbonyl]-5-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(3-pyridinyl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-morpholinyl)-3-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(2-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl ] benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl ] benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(5-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl ] benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[3-(4-methyl-1-piperazinyl)-5-(trifluoromethyl)phenyl]benzamide;
4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]benzamide

As analogues of the above "kenpaullone", the following formula (V):

[In the formula:
A is oxygen or sulfur bound to the right by a single or double bond; R ₂ is selected from the group consisting of hydrogen, aryl, lower aliphatic substituents, especially alkyl and lower alkyl _esters ; _R7 is alkoxy, amino, acyl, aliphatic substituents, especially alkyl, alkenyl and alkynyl substituents, aliphatic alcohols, especially alkyl alcohols, aliphatic nitriles, especially alkyl nitriles, cyano, nitro, carboxyl, halogen, hydrogen, hydroxyl , imino and α,β unsaturated ketones; R ₈ to R ₁₁ are aliphatic substituents, especially alkyl, alkenyl and alkynyl substituents, especially lower aliphatic substituents, aliphatic alcohols, especially independently selected from the group consisting of alkyl alcohols, alkoxy, acyl, cyano, nitro, epoxy, haloalkyl groups, halogen, hydrogen and hydroxyl; R ₁₂ is an aliphatic group, especially a lower alkyl group, an aliphatic alcohol, especially an alkyl alcohol , carboxylic acid, and hydrogen]
The compound represented by is mentioned.

In the description of each group of formula (V) above, each term described as a generic term (eg, "lower") and other terms follow the definitions and explanations in WO1999/065910 (PCT National Publication No. 2002-518395).

Specific examples of kenpaullone analogues include the following compounds.
7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
11-chloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
10-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
8-bromo-6,11-dihydro-thieno[3',2':2,3azepino[4,5-b]indol-5(4H)-one;
9-bromo-7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-4-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-2,3-dimethoxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one; 7,12-dihydro-2,3-dimethoxy-9-trifluoromethyl- Indolo[3,2-d][1]benzazepine-6(5H)-one;
2-bromo-7,12-dihydro-9-trifluoromethyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepine-6(5H)-thione;
9-bromo-5,12-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-12-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-5,7-bis-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-5,7,12-tri-(t-butyloxycarbonyl)-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-5-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-12-methyloxycarbonylmethyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-12-(2-hydroxyethyl)-indolo[3,2-d][1]benzazepin-6(5H)-one;
2,9-dibromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
8,10-dichloro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
5-benzyl-9-bromo-7,12-dihydro-5-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-12-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-12-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-9-methyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-9-methoxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-fluoro-7,12-dihydro-12-(2-propenyl)-indolo[3,2-d][1]benzazepin-6(5H)-one;
11-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-2-(methyliminoamine)-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-2-(carboxylic acid)-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-10-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-bromo-7,12-dihydro-11-hydroxymethyl-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-4-hydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-2,3-dihydroxy-indolo[3,2-d][1]benzazepin-6(5H)-one;
2,3-dimethoxy-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2,3-dimethoxy,9-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
9-Nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)-propionitrile;
2-bromo-9-nitro-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)-acrylonitrile;
2-(3-hydroxy-1-propynyl),9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2-iodo-9-bromo-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2-(3-oxo-1-butenyl),9-trifluoromethyl-7,12-tetrahydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
8-chloro-6,11-dihydro-thieno[3',2':2,3]azepino[4,5-b]indol-5(4H)-one;
2-iodo,9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
7,12-dihydro-pyrido[3',2':4,5]pyrrolo[3,2-d][1]benzazepin-6(5H)-one;
11-methyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2-[2-(1-hydroxycyclohexyl)-ethynyl],9-trifluoromethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2-cyano-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
2-iodo-7,12-dihydro-indolo[3,2-d][1]benzazepine-6(5H)-one;
11-ethyl-7,12-dihydro-indolo[3,2-d][1]benzazepin-6(5H)-one;
8-methyl-6,11-dihydro-thieno[3',2':2,3]azepino[4,5-b]indol-5(4H)-one;
3-(6-oxo-9-trifluoromethyl-5,6,7,12-tetrahydro-indolo[3,2-d][1]benzazepin-2-yl)acrylic acid methyl ester

As the compounds of the present invention, commercially available products can be used, or each compound can be produced by a method known per se.
Bosutinib or analogs thereof are disclosed, for example, in U.S. Pat. , Boschelli, DH et al., J med.chem., 44, 822 (2001), Boschelli, DH et al., Bioorg.med.chem.lett., 13, 3797 (2003) , J. med. chem., 47, 1599 (2004), and Ye, F. et al., 221th National Meeting of the American Chemical Society, San Diego, California (April, 2001). can do. Imatinib or analogs thereof can be produced, for example, according to the method described in JP-A-6-087834. Nilotinib or an analogue thereof can be produced, for example, according to the method described in WO2004/005281 (Japanese PCT National Publication No. 2005-533827). Kenpaullone or analogues thereof can be produced, for example, according to the method described in "Arch. Pharm. (Weinheim), 325:297-299 (1992)" or WO1999/065910 (Japanese Patent Publication No. 2002-518395).

The compounds of the present invention include not only free forms but also pharmacologically acceptable salts thereof. Although pharmacologically acceptable salts vary depending on the type of compound, examples include alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, etc.), aluminum salts, ammonium salts, etc. base addition salts such as inorganic base salts of and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, or hydrochloride, odorant Inorganic acid salts such as hydrohydride, sulfate, hydroiodide, nitrate, phosphate, citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetic acid salts, and acid addition salts such as organic acid salts such as maleates, tartrates, methanesulfonates, benzenesulfonates, and paratoluenesulfonates.

When the compound of the present invention has isomers such as optical isomers, stereoisomers, positional isomers and rotational isomers, any one isomer and mixture thereof are also included in the compound of the present invention. For example, when the compound of the present invention has an optical isomer, the optical isomer resolved from the racemate is also included in the compound of the present invention.
These isomers can be separated by known synthetic techniques, separation techniques (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution techniques (e.g., fractional recrystallization method, chiral column method, diastereomer method, etc.). ), etc., can be obtained as single items.
The compound of the present invention may be a crystal, and the compound of the present invention includes both a single crystal form and a mixture of crystal forms. Crystals can be produced by applying a crystallization method known per se to crystallize.
The compounds of the present invention may be solvates (eg, hydrates, etc.) or non-solvates (eg, non-hydrates, etc.), both of which are included in the compounds of the present invention. be.
Compounds labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also included in the compounds of the present invention.

The prophylactic/therapeutic agent of the present invention can be prepared by mixing the compound of the present invention, which is an active ingredient, alone or with a pharmacologically acceptable carrier, excipient, diluent, etc., and forming a pharmaceutical composition in an appropriate dosage form. It can be administered orally or parenterally as a substance.

Compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), and syrups. agents, emulsions, suspensions and the like. On the other hand, compositions for parenteral administration include, for example, injections and suppositories, and injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, and the like. It may also include dosage forms. These formulations contain excipients such as sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as maize starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate and magnesium aluminometasilicate; carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate), lubricants (e.g. stearic acid, metal stearates such as calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as beeswax, gay wax; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; Sulfate; silicic anhydride, silicic acid such as silicic acid hydrate; and the above starch derivatives), binders (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the above excipients) ), disintegrants (e.g., low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, cellulose derivatives such as internally cross-linked sodium carboxymethyl cellulose; carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone ), emulsifiers (e.g. bentonite, colloidal clays such as Veegum; metal hydroxides such as magnesium hydroxide, aluminum hydroxide; sodium lauryl sulfate, calcium stearate cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, sucrose fatty acid esters. ), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol, cresol phenols such as thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (for example, commonly used sweeteners, acidulants, flavors, etc.), diluents, etc. Manufactured by known methods.

The dosage of the compound of the present invention, which is the active ingredient of the prophylactic/therapeutic agent of the present invention, may vary depending on various conditions such as the type of compound, symptoms, age, body weight, and drug acceptability of the subject. In the case of parenteral administration, the lower limit is 0.1 mg (preferably 0.5 mg) and the upper limit is 1000 mg (preferably 500 mg). ), up to 100 mg (preferably 50 mg) can be administered to adults 1 to 6 times per day. The dose may be increased or decreased according to symptoms. In particular, when the compound of the present invention is already on the market as a drug for diseases other than the above diseases, the dose of each compound can be appropriately selected within the range of confirmed safety.

Furthermore, the prophylactic/therapeutic agents of the present invention may be used in combination with other drugs such as donepezil, rivastigmine, galantamine, donepezil, memantine, and the like. The prophylactic/therapeutic agents of the invention and these other agents can be administered simultaneously, sequentially or separately.

The present invention also includes therapeutic and/or prophylactic methods in which an effective amount of the compound of the present invention or the prophylactic/therapeutic agent of the present invention is administered to a mammal (an animal to be treated or prevented). The animals include mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys and humans, preferably humans.

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to these.

Method <Generation of iPS cells and cell culture>
iPS cells were produced according to the method described in “Imamura, K., et al. Sci Rep 6, 34904 (2016)”. Using episomal vectors harboring OCT3/4, Sox2, Klf4, L-Myc, Lin28, p53-shRNA, and EBNA1, fibroblasts or single cells of patients with Alzheimer's disease, frontotemporal lobar degeneration or dementia with Lewy bodies Human iPSCs with mutations in the APP gene, SNCA gene or MAPT gene were generated from nuclei, and human iPS cell medium (primate embryonic Stem cell medium; ReproCELL) was used to culture on SNL feeder layers.

<Preparation of piggyBac vector for expressing Ngn2 and introduction into iPS cells>
iPS cells with a tetracycline-inducible Ngn2 construct were established according to the method described in “Imamura, K., et al. Sci Rep 6, 34904 (2016)”. To ensure the generation of homogenous neurons from iPS cells, we introduced the Ngn2 transcription factor into mouse or human iPS cells using the piggyBac vector. This vector contains the Ngn2 and neomycin resistance genes under the control of the tetracycline operator rtTA and was generated from the KW110_PB_TA_ERN (Ef1a_rtTA_neo) vector backbone. The generated vector was then co-transfected into iPS cells together with the transposase-encoding pCyL43 vector using Lipofectamine LTX (Invitrogen). After clonal selection using neomycin, iPS cells with tetracycline-inducible Ngn2 constructs were established.

<Generation of iPS cell-derived cortical neurons by Ngn2 induction>
iPS cell-derived cortical neurons were generated according to the method described in “Imamura, K., et al. Sci Rep 6, 34904 (2016)”. iPS cells were dissociated into single cells using actinase and treated with 1 μg/ml doxycycline (Clontech) in a 1:1 ratio of DMEM/F12 (Life Technologies) and Neurobasal (Life Technologies), 1% N2 supplement, 2% B27 supplement, 10 ng/ml brain-derived neurotrophic factor (BDNF, R&D Systems), 10 ng/ml glial cell-derived neurotrophic factor (GDNF, R&D Systems) and 10 ng/ml neurotrophin-3 Neuronal medium containing (NT-3; R&D Systems) was used to plate onto Matrigel-coated 96-well plastic plates.

<Cell survival assay>
A cell survival assay was performed according to the method described in “Imamura, K., et al. Sci Rep 6, 34904 (2016)”. Ngn2-transduced iPSCs were dissociated into single cells and seeded at 5×10 ⁴ cells/well on Matrigel-coated 96-well plates (BD Bioscience) using neuronal medium containing 1 μg/ml doxycycline. did. Cells were fixed and stained on days 8 and 21. The number of surviving neurons stained with NeuN was quantified with an IN Cell Analyzer 6000 (GE Healthcare) and expressed as the number of neurons on day 21/the number of neurons on day 8. Bosutinib, Imatinib, Nilotinib, or Kenpaullone was added every 3 days from day 8 to day 21, and the number of surviving neurons was assessed on day 21. Results of the cell viability assay are shown in FIG.

Results From FIG. 1, it was shown that bosutinib is remarkably effective against Alzheimer's disease, frontotemporal lobar degeneration and dementia with Lewy bodies. Nilotinib has been shown to be highly effective in certain frontotemporal lobar degenerations. Kenpaullone has been shown to be highly effective in frontotemporal lobar degeneration and dementia with Lewy bodies.

This application is based on Japanese Patent Application No. 2017-102176 (filing date: May 23, 2017) filed in Japan, the contents of which are all incorporated herein.

The compounds of the invention are useful for the prevention and/or treatment of neurodegeneration. In particular, drugs that have already been marketed as drugs for other diseases have accumulated clinical and non-clinical data such as safety, and there is already a library of peripheral compounds, so they can be developed quickly and at low cost. , it may be possible to develop drugs that can prevent and/or treat neurodegeneration.

Claims (7)

A prophylactic and/or therapeutic agent for neurodegenerative diseases, which contains a tyrosine kinase inhibitor and is selected from the group consisting of frontotemporal lobar degeneration and α-synucleinopathy. 2. The agent according to claim 1, wherein the tyrosine kinase inhibitor is a Src/c-Abl pathway inhibitor. The tyrosine kinase inhibitor is bosutinib or analogues thereof, imatinib or analogues thereof, nilotinib or analogues thereof, kenpaullone or analogues thereof, or dasatinib or analogues thereof The agent according to claim 1, which is a body. 2. The agent of claim 1, wherein said tyrosine kinase inhibitor is bosutinib or an analogue thereof. The agent according to any one of claims 1 to 4, wherein the frontotemporal lobar degeneration is FTLD-Tau. 6. The agent according to claim 5, wherein the FTLD-Tau has a mutation in the MAPT gene. The agent according to any one of claims 1 to 4, wherein the α-synucleinopathy is dementia with Lewy bodies.

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