US 12,312,419 B2
Hemiasterlin derivative having cysteine residue
Atsushi Suwa, Osaka (JP)
Assigned to Sumitomo Pharma Co., Ltd., Osaka (JP)
Appl. No. 17/429,429
Filed by Sumitomo Pharma Co., Ltd., Osaka (JP)
PCT Filed Feb. 12, 2020, PCT No. PCT/JP2020/005307
§ 371(c)(1), (2) Date Aug. 9, 2021,
PCT Pub. No. WO2020/166600, PCT Pub. Date Aug. 20, 2020.
Claims priority of application No. 2019-023960 (JP), filed on Feb. 13, 2019.
Prior Publication US 2022/0144889 A1, May 12, 2022
Int. Cl. A61K 38/00 (2006.01); A61K 47/68 (2017.01); A61P 35/00 (2006.01); C07K 5/08 (2006.01); C07K 5/10 (2006.01)
CPC C07K 5/08 (2013.01) [A61K 47/6811 (2017.08); A61P 35/00 (2018.01); C07K 5/10 (2013.01); A61K 38/00 (2013.01)] 26 Claims
 
1. A compound represented by formula (1) or (1′):

OG Complex Work Unit Chemistry
wherein
b represents an integer of 1 to 5;
X represents —NH— or —CO—;
Z represents a group represented by formula (Z-1), formula (Z-2), formula (Z-3), formula (Z-4), formula (Z-5), formula (Z-6), formula (Z-7), formula (Z-8), formula (Z-9), formula (Z-10) or formula (Z-11):

OG Complex Work Unit Chemistry

OG Complex Work Unit Chemistry
where
n represents an integer of 0 to 2;
p represents an integer of 1 to 3;
AA represents a glutamic acid residue (Glu), an aspartic acid residue (Asp) or a lysine residue (Lys), and when there is a plurality of AAs, each AA may be the same as or different from each other and AAs are bonded to each other via an amide bond, and an N-terminal nitrogen atom of (AA)n or (AA)p forms an amide bond together with carbonyl group (a);
G represents —O— or —NH—; and
W represents a group represented by formula (W-1) or formula (W-2):

OG Complex Work Unit Chemistry
where
R6a and R6b each independently represent a hydrogen atom or a methyl group;
R7 represents a C1-6 alkyl group; and
Q represents a group represented by formula (Q-1), formula (Q-2), formula (Q-3), formula (Q-4), formula (Q-5), formula (Q-6) or formula (Q-7):

OG Complex Work Unit Chemistry
where
R8a and R8b each independently represent a hydrogen atom, a halogen atom, a C1-6 alkyl group or a C1-6 alkoxy group; and
R8c, R8d and R8e each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, an amino group, a carboxyl group, a phenyl group, or a C1-6 alkyl group, a C1-6 alkoxy group or a C1-6 alkyl ester group optionally substituted with 1 to 3 fluorine atoms;
R3 represents —(CH2)u—COR9;
u represents 1 or 2;
R4 and R9 each independently represent a hydroxy group or AD;
AD represents Glu, Asp or Lys, and an N-terminal nitrogen atom of AD forms an amide bond together with a neighboring carbonyl group;
with a proviso that when R4 or R9 is AD, n is 0 or 1; and
R5a and R5b each independently represent a hydrogen atom or a methyl group;
with a proviso that when X is —NH—, Z is formula (Z-1), formula (Z-2), formula (Z-3), formula (Z-4) or formula (Z-5), and when X is —CO—, Z is formula (Z-6), formula (Z-7), formula (Z-8), formula (Z-9), formula (Z-10) or formula (Z-11);
R1 represents a hydrogen atom or (AB)m;
AB represents an alanine residue (Ala), an arginine residue (Arg), an asparagine residue (Asn), an aspartic acid residue (Asp), a cysteine residue (Cys), a glutamine residue (Gln), a glutamic acid residue (Glu), a glycine residue (Gly), a histidine residue (His), an isoleucine residue (Ile), a leucine residue (Leu), a lysine residue (Lys), a methionine residue (Met), a phenylalanine residue (Phe), a proline residue (Pro), a serine residue (Ser), a threonine residue (Thr), a tryptophan residue (Trp), a tyrosine residue (Tyr) or a valine residue (Val), and when there is a plurality of ABs, each AB may be the same as or different from each other and ABs are bonded to each other via an amide bond;
m represents an integer of 1 to 9;
R2 represents a hydroxy group or (AC)g;
AC represents an alanine residue (Ala), an arginine residue (Arg), an asparagine residue (Asn), an aspartic acid residue (Asp), a cysteine residue (Cys), a glutamine residue (Gln), a glutamic acid residue (Glu), a glycine residue (Gly), a histidine residue (His), an isoleucine residue (Ile), a leucine residue (Leu), a lysine residue (Lys), a methionine residue (Met), a phenylalanine residue (Phe), a proline residue (Pro), a serine residue (Ser), a threonine residue (Thr), a tryptophan residue (Trp), a tyrosine residue (Tyr) or a valine residue (Val), and when there is a plurality of ACs, each AC may be the same as or different from each other and ACs are bonded to each other via an amide bond; and
g represents an integer of 1 to 9;
with a proviso that when R1 is (AB)m and R2 is (AC)g, a sum of m and g is an integer of 2 to 10, or a salt thereof.