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EP-4741401-A1 - BENZOTHIAZOIMIDAZOLYL COMPOUND AND USE THEREOF

EP4741401A1EP 4741401 A1EP4741401 A1EP 4741401A1EP-4741401-A1

Abstract

A compound represented by General Formula (1) is useful for preventing, improving, or treating diseases caused by endoplasmic reticulum stress. In General Formula (1), R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a functional group represented by following General Formula (2), or a functional group represented by following General Formula (3), (In Formula (2), a represents an integer of 1-6.) (In Formula (3), b represents an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) R 2 represents a hydrogen atom, a halogen atom, a lower alkoxy group, a functional group represented by General Formula (2) above, a functional group represented by following General Formula (4), or a functional group represented by following General Formula (5), (In Formula (4), c and d independently represent an integer of 1-6.) (In Formula (5), e and f independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) R 3 represents a hydrogen atom or a halogen atom, R 4 represents a hydrogen atom, a halogen atom, a functional group of following General Formula (6), or a functional group of following General Formula (7), (In Formula (6), g, h, and i independently represent an integer of 1-6.) (In Formula (7), j, k, and l independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) R 5 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkyl group, a lower alkyl-substituted sulfonyl group, a lower alkoxy-substituted carbonyl group, a functional group represented by following General Formula (8), a functional group represented by General Formula (9), a functional group represented by General Formula (10), a functional group represented by General Formula (11), a functional group represented by General Formula (12), a functional group represented by General Formula (13), or a functional group represented by General Formula (14), (In Formula (8), m and n independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) (In Formula (9), o represents an integer of 1-6, and R represents an alkyl group having 1-6 carbon atoms.) (In Formula (10), p represents an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) (In Formula (11), q, r, and s independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) (In Formula (12), t and u independently represent an integer of 1-6.) (In Formula (13), v and w independently represent an integer of 1-6.) (In Formula (14), x, y, and z independently represent an integer of 1-6.) R 6 represents a hydrogen atom or a lower alkoxy group.

Inventors

  • OYADOMARI, Seiichi

Assignees

  • ER Stress Research Institute, Inc.

Dates

Publication Date
20260513
Application Date
20240703

Claims (10)

  1. A compound represented by General Formula (1). In General Formula (1), R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a functional group represented by following General Formula (2), or a functional group represented by following General Formula (3), (In Formula (2), a represents an integer of 1-6.) (In Formula (3), b represents an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) R 2 represents a hydrogen atom, a halogen atom, a lower alkoxy group, a functional group represented by General Formula (2) above, a functional group represented by following General Formula (4), or a functional group represented by following General Formula (5), (In Formula (4), c and d independently represent an integer of 1-6.) (In Formula (5), e and f independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) R 3 represents a hydrogen atom or a halogen atom, R 4 represents a hydrogen atom, a halogen atom, a functional group of following General Formula (6), or a functional group of following General Formula (7), (In Formula (6), g, h, and i independently represent an integer of 1-6.) (In Formula (7), j, k, and l independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) R 5 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkyl group, a lower alkyl-substituted sulfonyl group, a lower alkoxy-substituted carbonyl group, a functional group represented by following General Formula (8), a functional group represented by General Formula (9), a functional group represented by General Formula (10), a functional group represented by General Formula (11), a functional group represented by General Formula (12), a functional group represented by General Formula (13), or a functional group represented by General Formula (14), (In Formula (8), m and n independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) (In Formula (9), o represents an integer of 1-6, and R represents an alkyl group having 1-6 carbon atoms.) (In Formula (10), p represents an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) (In Formula (11), q, r, and s independently represent an integer of 1-6, and Rs independently represent an alkyl group having 1-6 carbon atoms.) (In Formula (12), t and u independently represent an integer of 1-6.) (In Formula (13), v and w independently represent an integer of 1-6.) (In Formula (14), x, y, and z independently represent an integer of 1-6.) R 6 represents a hydrogen atom or a lower alkoxy group.
  2. The compound according to claim 1, wherein R 1 is a hydrogen atom, a halogen atom (particularly a chlorine atom), a lower alkyl group (particularly a propyl group), a lower alkoxy group (particularly a methoxy group), a halogen-substituted lower alkyl group (particularly a fluorine-substituted lower alkyl group, specifically a trifluoromethyl group), or a functional group represented by General Formula (2) (particularly a functional group of General Formula (2) in which a is 1), R 2 is a hydrogen atom, a halogen atom (particularly a chlorine atom), a lower alkoxy group (particularly a methoxy group), a functional group represented by General Formula (2) (particularly a functional group of General Formula (2) in which a is 1), or a functional group represented by General Formula (4) (particularly a functional group of General Formula (4) in which c and d are each 2), R 3 is a hydrogen atom or a chlorine atom, R 4 is a hydrogen atom, R 5 is a hydrogen atom, a lower alkyl group (particularly a methyl group), a lower alkoxy group (particularly an ethoxy group), a hydroxy-substituted lower alkyl group (particularly a hydroxy-substituted methyl group), a lower alkyl-substituted sulfonyl group (particularly a methyl-substituted sulfonyl group), a lower alkoxy-substituted carbonyl group (particularly an ethoxy-substituted carbonyl group), a functional group represented by General Formula (8) (particularly a functional group of General Formula (8) in which m is 0 or 1, n is 3, and R is a methyl group), a functional group represented by General Formula (9) (particularly a functional group of General Formula (9) in which o is 2, and R is a methyl group), or a functional group represented by General Formula (10) (particularly a functional group of General Formula (10) in which p is 2, and two Rs are each an ethyl group), and R 6 is a hydrogen atom or a methoxy group.
  3. The compound according to any one of claims 1 to 3, wherein R 1 is a halogen-substituted lower alkyl group, R 2 is a lower alkoxy group, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen-substituted lower alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a halogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a hydrogen atom, R 2 is a lower alkoxy group, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a functional group of General Formula (9) in which o is 2, and R is a methyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a lower alkoxy group, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen-substituted lower alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a functional group of General Formula (9) in which o is 2, and R is a methyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen-substituted lower alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a functional group of General Formula (8) in which m is 0, n is 3, and R is a methyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen-substituted lower alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a functional group of General Formula (10) in which p is 2, and two Rs are each an ethyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen-substituted lower alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a hydrogen atom, and R 6 is a hydrogen atom; a compound in which R 1 is a functional group of General Formula (2) in which a is 1, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a lower alkoxy group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a hydrogen atom, R 3 is a halogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkoxy-substituted carbonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkoxy group, and R 6 is a hydrogen atom; a compound in which R 1 is a lower alkyl-substituted sulfonyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a functional group of General Formula (8) in which m is 1, n is 3, and R is a methyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a functional group of General Formula (2) in which a is 1, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a hydroxy-substituted lower alkyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a functional group of General Formula (2) in which a is 1, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a halogen atom, R 2 is a functional group of General Formula (4) in which c and d are each 2, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a lower alkyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom; a compound in which R 1 is a lower alkyl-substituted sulfonyl group, R 2 is a hydrogen atom, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl group, and R 6 is a hydrogen atom; or a compound in which R 1 is a hydrogen atom, R 2 is a functional group of General Formula (4) in which c and d are each 2, R 3 is a hydrogen atom, R 4 is a hydrogen atom, R 5 is a lower alkyl-substituted sulfonyl group, and R 6 is a hydrogen atom.
  4. The compound according to any one of claims 1 to 3, wherein R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a propyl group (particularly, an n-propyl group), a trifluoromethyl group, a methoxy group, an ethoxy group, a functional group of General Formula (2) in which a is 1, or a functional group of General Formula (3) in which b is 3 and the three Rs are methyl group; R 2 is a hydrogen atom, a chlorine atom, a fluorine atom, a methoxy group, a functional group of General Formula (2) in which a is 1, a functional group of General Formula (4) in which c and d are each 2, a functional group of General Formula (5) in which e is 2, f is 1, and three Rs are methyl group, or a functional group of General Formula (5) in which e is 2, f is 3, and three Rs are methyl group; R 3 is a hydrogen atom or a chlorine atom; R 4 is a hydrogen atom, a bromine atom, a functional group of General Formula (6) in which g, h, and i are each 2, or a functional group of General Formula (7) in which j, k, and l are each 2 and three Rs are methyl group; R 5 is a hydrogen atom, a methyl group, a methoxy group, a hydroxymethyl group, a methylsulfonyl group, a lower alkyl-substituted oxycarbonyl group, a functional group of General Formula (8) in which m is 0, n is 3, and R is a methyl group, a functional group of General Formula (8) in which m is 1, n is 3, and R is a methyl group, a functional group of General Formula (9) in which o is 2 and R is a methyl group, a functional group of General Formula (10) in which p is 1 and two R groups are ethyl group, a functional group of General Formula (11) in which q, r, and s are each 2 and three Rs are methyl group, a functional group of General Formula (12) in which t and u are each 2, a functional group of General Formula (13) in which v and w are each 2, or a functional group of General Formula (14) in which x, y, and z are each 2; R 6 is a hydrogen atom or a methoxy group.
  5. A chemical chaperone comprising the compound according to any one of claims 1 to 4.
  6. A cytoprotectant against endoplasmic reticulum stress comprising the compound according to any one of claims 1 to 4.
  7. An agent for alleviating or reducing endoplasmic reticulum stress comprising the compound according to any one of claims 1 to 4.
  8. an agent for preventing, improving, or treating a disease caused by endoplasmic reticulum stress comprising the compound accord ing to any one of claims 1 to 4.
  9. The agent according to claim 8, wherein the disease caused by endoplasmic reticulum stress is neurodegenerative diseases, diabetes mellitus, metabolic diseases, cardiovascular diseases, cancers, renal disorders, osteodystrophy, cartilage tissue diseases, or autoimmune diseases.
  10. The agent according to claim 8, wherein the disease caused by endoplasmic reticulum stress is central diabetes insipidus.

Description

Technical Field The present invention relates to a benzothiazoimidazolyl compound, a chemical chaperone comprising the compound, a cytoprotectant comprising the compound against endoplasmic reticulum stress, and a method of preventing, improving, or treating a neurodegenerative disease, diabetes mellitus, a metabolic disease, a cardiovascular disease, cancer, a renal disorder, osteodystrophy, a cartilage tissue disease, or an autoimmune disease, using the compound. Background Art The endoplasmic reticulum functions as the site for protein folding and post-translational modification, and about 30% of the protein biosynthesized in cells undergoes modification and maturation in the endoplasmic reticulum. Living organisms are constantly exposed to various stresses from the external environment, and the stresses at the cellular level include defective nutrition (including amino acids, sugars, and lipids), changes in intracellular calcium concentration, hypoxia, heat shock, oxidative stress, virus infection, and mutant protein expression. If cells are exposed to such stress, proteins fail to fold properly in the endoplasmic reticulum lumen, and misfolded proteins accumulate. The state is called endoplasmic reticulum stress. Upon endoplasmic reticulum stress, cells activate a series of adaptive response mechanisms collectively referred to as the unfolded protein response (UPR), also known as the endoplasmic reticulum stress response, to eliminate aberrant proteins and maintain endoplasmic reticulum function to maintain healthy conditions. The conditions of the endoplasmic reticulum lumen are sensed by membrane proteins on the endoplasmic reticulum membrane. Of the sensors, IRE1 (inositol requiring enzyme 1), PERK (PKR-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6) are expressed non-tissue-specifically. In the steady state, a molecular chaperone BiP/GRP78 binds to these sensor proteins. If misfolded proteins accumulate, BiP/GRP78 dissociates from the sensor proteins and mediates the folding of the misfolded proteins. Meanwhile, the sensor proteins become activated and induce endoplasmic reticulum stress response. In the endoplasmic reticulum stress response, the translation of new proteins is first suppressed to reduce the load on the endoplasmic reticulum. This is achieved by PERK that phosphorylates eIF2α (eukaryotic initiation factor 2α subunit), which is essential for translation initiation. PERK also targets a transcriptional regulator ATF4 and promotes the translation of ATF4. If the endoplasmic reticulum stress continues, the transcription of CHOP or GADD34 is induced at the downstream of ATF4. GADD34 functions to dephosphorylate the phosphorylated eIF2α for restoration from the protein translation inhibition. CHOP and GADD34 are involved in the induction of apoptosis under prolonged endoplasmic reticulum stress. Next, to increase the protein folding capacity in the endoplasmic reticulum, activated ATF6 induces molecular chaperones such as BiP/GRP78 and GRP94, which perform protein folding. The ATF6 also induces transcription of XBP-1 and CHOP. Such misfolded proteins as above try to refold with the help of molecular chaperones or folding enzymes. Many of the proteins that fail to refold are retrotranslocated to the cytoplasm and degraded by the ubiquitin-proteasome system, which is a process known as endoplasmic reticulum-associated degradation (ERAD) (Non-Patent Literature 1 (Medical science, Vol.55, No.5, October 15, 2004, 416-417)). ERAD is primarily induced when IRE1 selectively splices a transcription factor XBP-1 (X-box-binding protein 1) into the active form. Cells having defects of endoplasmic reticulum stress that are unable to be solved even by such adaptive responses are removed by apoptosis induced by the expression of a transcription factor CHOP or the like. If the endoplasmic reticulum stress response fails, proteins are improperly folded, or misfolded proteins further aggregate, resulting in the loss of protein functions essential to maintain life. This causes various diseases. By observing an increase in the expression of factors involved in endoplasmic reticulum stress response, or endoplasmic reticulum stress markers, it has been revealed that endoplasmic reticulum stress or the failure of the endoplasmic reticulum stress response is involved in the onset of various diseases. Typical examples include neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), polyglutamine diseases (such as Huntington's disease), Creutzfeldt-Jakob disease, and central diabetes insipidus (including familial neurogenic diabetes insipidus (FNDI), secondary diabetes insipidus, and idiopathic diabetes insipidus). These diseases share a feature of accumulation of misfolded proteins. Alzheimer's disease develops due to the accumulation of amyloid β and tau proteins; Parkinson's disease develops due to the accumulation of α-syn