Protein folding agent, compound, protein folding method, pharmaceutical composition, and agent for suppressing cytotoxicity by transition metal

A protein folding method, comprising incubating a protein folding agent comprising at least one or more compounds selected from the group consisting of the following (A) to (E):

• (A) a cyclic polyamine that contains one or more thiol groups or disulfide bonds, is bindable to a transition metal ion, and is a compound represented by General Formula (A-1) or (A-2),
• wherein, Rx2 and Rx3 each independently represent a hydrogen atom or a monovalent hydrocarbon group that may have a substituent that is a substituent which substitutes a hydrogen atom of the monovalent hydrocarbon group to a thiol group, a hydroxy group, an amino group, a halogen atom, an alkoxy group, or an acyl group or that is a substituent which substitutes a methylene group of the monovalent hydrocarbon group to a ether bond, a carbonyl group, or an ester bond, Y1 to Y3 each independently represent an alkylene group having 1 to 5 carbon atoms, Lx1 and Lx2 each independently represent an alkylene group having 1 to 10 carbon atoms, which may contain at least one selected from the group consisting of an oxygen atom and a nitrogen atom, m0 represents an integer of 1 to 3, and when m0 is an integer of 2 or more, two or more Rx3's may be the same as or different from each other, and two or more Y3's may be the same as or different from each other,
• (B) a compound in which two or more of the cyclic polyamines (A) are bonded through a disulfide bond between the thiol groups;
• (C) a complex of the cyclic polyamine (A) or the compound (B) with a transition metal ion;
• (D) a salt of the cyclic polyamine (A) or the compound (B);
• and
• (E) a solvate of the cyclic polyamine (A) or the compound (B).

A compound represented by General Formula (B-1), (A-1-2), or (A-2),

• wherein, in General Formula (B-1), Rx12, Rx13, Rx22, and Rx23 each independently represent a hydrogen atom or a monovalent organic group, Y11, Y12, Y13, Y21, Y22, and Y23 each independently represent an alkylene group having 1 to 5 carbon atoms, Lx1 and Lx2 each independently represent an alkylene group having 1 to 10 carbon atoms, which may contain at least one selected from the group consisting of an oxygen atom and a nitrogen atom, m01 and m02 each independently represent an integer of 1 to 3, when m01 is an integer of 2 or more, two or more Rx13's may be the same as or different from each other, and two or more Y13's may be the same as or different from each other, and when m02 is an integer of 2 or more, two or more Rx23's may be the same as or different from each other, and two or more Y23's may be the same as or different from each other;
• in General Formula (A-1-2), Y1 to Y3 each independently represent an alkylene group having 1 to 5 carbon atoms, R's each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and L represents an alkylene group having 1 to 10 carbon atoms, which may contain at least one selected from the group consisting of an oxygen atom and a nitrogen atom;
• in General Formula (A-2), Rx3 represents a hydrogen atom or a monovalent organic group, Y1 to Y3 each independently represent an alkylene group having 1 to 5 carbon atoms, Lx1 and Lx2 each independently represent an alkylene group having 1 to carbon atoms, which may contain at least one selected from the group consisting of an oxygen atom and a nitrogen atom, m0 represents an integer of 1 to 3, and when m0 is an integer of 2 or more, two or more Rx3's may be the same as or different from each other, and two or more Y3's may be the same as or different from each other.

A method for treating or preventing a disease caused by aggregation of proteins, comprising administering to a subject a protein folding agent comprising at least one or more compounds selected from the group consisting of the following (A) to (E):

• (A) a cyclic polyamine that contains one or more thiol groups or disulfide bonds, is bindable to a transition metal ion, and is a compound represented by General Formula (A)
• wherein Rx1 to Rx3 each independently represent a hydrogen atom or a monovalent hydrocarbon group that may have a substituent that is a substituent which substitutes a hydrogen atom of the monovalent hydrocarbon group to a thiol group, a hydroxy group, an amino group, a halogen atom, an alkoxy group, or an acyl group, or that is a substituent which substitutes a methylene group of the monovalent hydrocarbon group to a ether bond, a carbonyl group, or an ester bond, provided that at least one of Rx1 to Rx3 contains one or more thiol groups, when Rx1 to Rx3 contain two or more thiol groups in total, the thiol groups may be bonded to each other to form a disulfide bond, Y1 to Y3 each independently represent an alkylene group having 1 to 5 carbon atoms, m0 represents an integer of 1 to 3, when m0 is an integer of 2 or more, two or more Rx3's may be the same as or different from each other, and two or more Y3's may be the same as or different from each other:
• (B) a compound in which two or more of the cyclic polyamines (A) are bonded through a disulfide bond between the thiol groups;
• (C) a complex of the cyclic polyamine (A) or the compound (B) with a transition metal ion;
• (D) a salt of the cyclic polyamine (A) or the compound (B);
• and
• (E) a solvate of the cyclic polyamine (A) or the compound (B)

A method for treating or preventing a disease caused by aggregation of proteins, comprising administering to a subject a protein folding agent comprising at least one or more compounds selected from the group consisting of the following (A) to (E):

• (A) a cyclic polyamine that contains one or more thiol groups or disulfide bonds, is bindable to a transition metal ion, and is a compound represented by General Formula (A-1) or (A-2),
• wherein, Rx2 and Rx3 each independently represent a hydrogen atom or a monovalent hydrocarbon group that may have a substituent that is a substituent which substitutes a hydrogen atom of the monovalent hydrocarbon group to a thiol group, a hydroxy group, an amino group, a halogen atom, an alkoxy group, or an acyl group, or that is a substituent which substitutes a methylene group of the monovalent hydrocarbon group to a ether bond, a carbonyl group, or an ester bond, Y1 to Y3 each independently represent an alkylene group having 1 to 5 carbon atoms, Lx1 and Lx2 each independently represent an alkylene group having 1 to 10 carbon atoms, which may contain at least one selected from the group consisting of an oxygen atom and a nitrogen atom, m0 represents an integer of 1 to 3, and when m0 is an integer of 2 or more, two or more Rx3's may be the same as or different from each other, and two or more Y3's may be the same as or different from each other;
• (B) a compound in which two or more of the cyclic polyamines (A) are bonded through a disulfide bond between the thiol groups;
• (C) a complex of the cyclic polyamine (A) or the compound (B) with a transition metal ion;
• (D) a salt of the cyclic polyamine (A) or the compound (B);
• and
• (E) a solvate of the cyclic polyamine (A) or the compound (B).