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CN-122028915-A - Frontotemporal lobar degenerative disease therapeutic agent and therapeutic composition

CN122028915ACN 122028915 ACN122028915 ACN 122028915ACN-122028915-A

Abstract

The present invention addresses the problem of providing a therapeutic agent for frontotemporal lobar degeneration (FTLD) or a composition for FTLD treatment, and a method for treating FTLD, which have not been developed to date. The inventors of the present invention have found that the pathological state of a prefrontal cortex neuron is improved by inducing the prefrontal cortex neuron by differentiation of an FTLD patient-derived iPS cell and administering a therapeutic agent for frontotemporal lobar degeneration disease (FTLD) comprising a compound represented by formula (1-1), a compound represented by formula (2-1) or a compound represented by formula (3-1), a pharmaceutically acceptable salt thereof or a solvate thereof to the prefrontal cortex neuron exhibiting the pathological state of FTLD.

Inventors

  • KOKUBUN TAKASHI

Assignees

  • 凯制药股份有限公司

Dates

Publication Date
20260512
Application Date
20241101
Priority Date
20231102

Claims (10)

  1. 1. A frontotemporal lobar degenerative disease (FTLD) therapeutic agent comprising: a compound represented by the following formula (1-1): In the formula (1-1), R 1 independently represents an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenylethyl group, and n represents an integer of 1 to 3; A compound represented by the following formula (2-1): in the formula (2-1), R 21 is selected from the group consisting of hydrogen, a fatty acid acyl group having 2 to 18 carbon atoms, and an aromatic carboxylic acid acyl group having 7 to 9 carbon atoms; a compound represented by the following formula (3): In the formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, alkyl of 1-6 carbon atoms, CF 3 , R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group, and an optionally substituted nitrogen-containing aromatic heterocycle, R 33 is selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 6 carbon atoms, R 34 is selected from the group consisting of carboxyl, cyano, 1H-tetrazolyl; Their pharmaceutically acceptable salts or their solvates.
  2. 2. The FTLD therapeutic agent of claim 1, wherein FTLD is 1 or more symptoms selected from behavioral variant frontotemporal dementia (bvFTD), semantic Dementia (SD), progressive non-fluency aphasia (PNFA).
  3. 3. The FTLD therapeutic agent of claim 1 or 2, wherein n is 2 in the formula (1-1).
  4. 4. The FTLD therapeutic agent of claim 1 or 2, wherein R 1 in the formula (1-1) is n-propyl.
  5. 5. The FTLD therapeutic agent of claim 3, wherein R 1 in the formula (1-1) is n-propyl.
  6. 6. The FTLD therapeutic agent according to claim 1 or 2, wherein the compound represented by the formula (1-1) is a compound represented by the following formula (1-2): i.e. 4- [2- (dipropylamino) ethyl ] -1, 3-dihydro-2H-indol-2-one.
  7. 7. The FTLD therapeutic agent according to claim 1 or 2, wherein the pharmaceutically acceptable salt of the compound represented by the formula (1-1) is a hydrochloride of the compound represented by the following formula (1-2): i.e. 4- [2- (dipropylamino) ethyl ] -1, 3-dihydro-2H-indol-2-one hydrochloride.
  8. 8. The FTLD therapeutic agent according to claim 1 or 2, wherein the compound represented by the formula (2-1) is a compound represented by the following formula (2-2): i.e. 4-amino-N- (3, 4-dimethyl-5-isoxazolyl) benzenesulfonamide.
  9. 9. The FTLD therapeutic agent according to claim 1 or 2, wherein the compound represented by the formula (3-1) is a compound represented by the following formula (3-2): I.e., 4' - [ [ 4-methyl-6- (1-methyl-1H-benzoimidazol-2-yl) -2-propyl-1H-benzoimidazol-1-yl ] methyl ] biphenyl-2-carboxylic acid.
  10. 10. A pharmaceutical composition for the treatment of frontotemporal lobar degenerative disease (FTLD) comprising as active ingredients: a compound represented by the following formula (1-1): In the formula (1-1), R 1 independently represents an alkyl group having 1 to 6 carbon atoms or a 4-hydroxyphenylethyl group, n represents an integer of 1 to 3, A compound represented by the following formula (2-1): In the formula (2-1), R 21 is selected from the group consisting of hydrogen, a fatty acid acyl group having 2 to 18 carbon atoms, and an aromatic carboxylic acid acyl group having 7 to 9 carbon atoms, A compound represented by the following formula (3-1): In the formula (3-1), R 31 is selected from the group consisting of hydrogen, halogen, alkyl of 1-6 carbon atoms, CF 3 , R 32 is selected from the group consisting of an alkoxy group having 1 to 6 carbon atoms substituted with an imidazolyl group, and an optionally substituted nitrogen-containing aromatic heterocycle, R 33 is selected from the group consisting of hydrogen, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl group having 3 to 6 carbon atoms, R 34 is selected from the group consisting of carboxyl, cyano, 1H-tetrazolyl; Their pharmaceutically acceptable salts or their solvates.

Description

Frontotemporal lobar degenerative disease therapeutic agent and therapeutic composition Technical Field The present invention aims to develop a therapeutic agent or a therapeutic composition for frontotemporal lobar degenerative disease (Frontotemporal Lobar Degeneration: FTLD). Background Frontotemporal lobar degeneration disease (FTLD) is a type of dementia in which the forehead and sideotemporal lobes are degenerated and in which symptoms such as behavioral disorders and language disorders are a major factor. In japan, it is designated as a designation of an problematic symptom (designation of problematic symptom 127), it is estimated that about 1 ten thousand and 2 thousand patients exist (non-patent document 1), 5 to 6 ten thousand patients exist in the united states, and 10 ten thousand or more patients exist in the entire europe. FTLD is classified into 3 subtypes based on its clinical symptoms, and has characteristics shown in the following table: behavior variant frontotemporal dementia (behavioral variant frontotemporal dementia, bvFTD) Semantic dementia (SEMANTIC DEMENTIA, SD) Progressive Non-fluency aphasia (Progressive Non-Fluent Aphasia, PNFA). TABLE 1 FTLD is a pathologically, genetically diverse disease, sometimes classified according to related proteins into FTLD-TAU with accumulation of TAU observed (45%), FTLD-TDP43 with accumulation of TDP-43 observed (45%), FTLD-FUS with accumulation of FUS observed (9%). In addition, from the viewpoint of genes, it is known that GRN gene, MAPT gene, C9ORF72 gene, TARDBP gene are representative mutant genes. The frontotemporal dementia (frontotemporal dementia: FTD) is a group of diseases which comprehensively summarizes non-Alzheimer type degenerative dementia mainly including motor system cerebral cortex lesions, and is known to involve TAU degeneration, TDP-43 and FUS as the causes. The diseases involving TDP-43 and FUS are classified into those accompanied by movement disorder (amyotrophic lateral sclerosis) (FTLD-MND) and those not accompanied by movement disorder (FTLD-nonMND), and those caused by TAU degeneration are classified into those mainly comprising 3R TAU degeneration, and those mainly comprising 4R TAU degeneration (corticobasal degeneration, progressive supranuclear palsy, and silver-philic particulate dementia). As a method for diagnosing based on a pathological state, in the bvFTD cases, diagnosis can be made by 3 or more of the following evaluation items a to F. A. De-inhibition behavior is satisfied with any 1 or more of the following 3 symptoms. 1) Loss of social behavior 2) Lack of etiquette and polite 3) Impulse and light rate, behavior without any concern B. Don't care or lose strength C. Lack of co-emotion and emotion substitution, and satisfies any 1 or more of the following 2 symptoms. 1) Demand and emotional deficit response to others 2) Interest in society, communication with others, or reduction of emotional resonance ability, loss of D. the solidity/notch symptoms are more than 1 of the following 3 symptoms. 1) Repetition of simple actions 2) Compulsive or ceremony behavior 3) Notch board speech E. Lip tendency and eating habit, satisfying any 1 or more of the following 3 symptoms. 1) Modification of dietary preferences 2) Increase in overeating, drinking and smoking behavior 3) Oral labial exploration or differential eating symptoms F. in neuropsychological examination, executive dysfunction is observed, although memory, visual space cognitive ability is relatively preserved. In the case of SD, at least 3 of 4 were observed, A. Impairment of knowledge of the object (particularly low frequency/low affinity impairment is significant), B. Loss of surface layer read/write, C. Duplication is maintained. D. vocalization (grammatical, spontaneous) of speech presenting fluency is maintained. Under present circumstances, a therapeutic method for the purpose of cure of FTLD (improvement of cognitive function) has not been established, and symptomatic therapy has been performed on some symptoms. As such symptomatic therapy, for example, it is reported that administration of a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) of an antidepressant is useful when a behavioral disorder is apparent, and in addition, an antipsychotic agent, an antiepileptic agent, is known to be potentially effective although still at the level of case report. However, none of these aims at improving cognitive function, and it is desired to develop a drug capable of improving cognitive function. Prior art literature Non-patent literature Non-patent literature 1：Wada-Isoe K., et al., Epidemiological Survey of Frontotemporal Lobar Degeneration in Tottori Prefecture, Japan., Dement. Geriatr. Cogn. Dis. Extra. 2 (1), 381-386, 2012 Non-patent literature 2：Imaizumi K., et al., Rostrocaudal Areal Patterning of Human PSC-Derived Cortical Neurons by FGF8 Signaling., eNeuro, 5 (2), 2018 Disclosure of Invention Problems to be solved by the invention The prese