Hemiasterlin derivatives and antibody-drug conjugates including same

Patent metadata

Field	Value
Publication number	US-12018093-B2
Application number	US-201816637097-A
Country	US
Kind code	B2
Filing date	Aug 10, 2018
Priority date	Aug 10, 2017
Publication date	Jun 25, 2024
Grant date	Jun 25, 2024

Abstract

A compound represented by formula (1):

wherein
AA represents a particular amino acid residue or a C 1-6 alkyl ester thereof, 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; an N-terminal nitrogen atom of (AA) m forms an amide bond together with carbonyl (a); Q represents an unsubstituted phenyl group, or a group represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7); R 1a and R 1b each independently represent a hydrogen atom or a C 1-6 alkyl group; and m represents an integer of 1 to 10,

or a salt thereof.

First claim

The invention claimed is:

1. A compound represented by formula (1):

wherein
AA represents a glutamic acid residue (Glu), an aspartic acid residue (Asp), a cysteine residue (Cys), or a C 1-3 alkyl ester thereof, 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;
an N-terminal nitrogen atom of (AA) m forms an amide bond together with carbonyl (a);
Q represents a group represented by formula (Q-1), formula (Qa-2), or formula (Qa-7):

where
R 2a and R 2e represent a hydrogen atom;
R 2b , R 2c , and R 2d each independently represent a hydrogen atom, a halogen atom, or a C 1-3 alkoxy group;
R 2f represents a methyl group or an ethyl group; and
R aa , R ab and R ac each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a carboxyl group, or a C 1-3 alkyl group, C 1-3 alkoxy group or C 1-4 alkyl ester group optionally substituted with 1 to 3 fluorine atoms;

R 1a and R 1b each independently represent a hydrogen atom or a C 1-3 alkyl group; and
m represents an integer of 1 to 10,

or a salt thereof;
wherein the compound excludes a compound in which AA represents an aspartic acid residue (Asp), Q represents an unsubstituted phenyl group, one of R1a and R1b represents a methyl group and the other represents a hydrogen atom, and m represents an integer of 1.

2. The compound according to claim 1 , represented by formula (1):

wherein
AA represents a glutamic acid residue (Glu), an aspartic acid residue (Asp) or a cysteine residue (Cys), or a C 1-3 alkyl ester thereof, 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;
an N-terminal nitrogen atom of (AA) m forms an amide bond together with carbonyl (a);
Q represents an unsubstituted phenyl group or a group represented by formula (Q-1):

where
R 2a and R 2e represent a hydrogen atom;
R 2b , R 2c , and R 2d each independently represent a hydrogen atom, a halogen atom, or a methoxy group; and
R 2f represents a methyl group;

R 1a and R 1b each independently represent a hydrogen atom, a methyl group, or an ethyl group; and
m represents an integer of 1 to 10,

or a salt thereof.

3. The compound according to claim 1 , wherein Q is a group represented by formula (Q-2):

where R 2b and R 2c each independently represent a hydrogen atom, a halogen atom, or a C 1-3 alkoxy group,

or a salt thereof.

4. The compound according to claim 1 , wherein Q is a group represented by formula (Q-2):

where R 2b and R 2c each independently represent a hydrogen atom, a fluorine atom or a methoxy group,

or a salt thereof.

5. The compound according to claim 3 , wherein R 2b and R 2c are each a hydrogen atom,
or a salt thereof.

6. The compound according to claim 1 , wherein R 1a is a methyl group and R 1b is a hydrogen atom,
or a salt thereof.

7. The compound according to claim 1 , wherein m is an integer of 1 to 5,
or a salt thereof.

8. The compound according to claim 1 , wherein m is an integer of 2 to 10; and
(AA) m is a linear peptide residue,

or a salt thereof.

9. The compound according to claim 1 , wherein m is an integer of 3 to 10; and
(AA) m is a branched peptide residue having 1 or 2 branching points,

or a salt thereof.

10. The compound according to claim 1 , wherein (AA) m is a group represented by formula (A-1):

where AA 1 , AA 2 and AA 3 each independently represent Glu or Asp,

or a salt thereof.

11. The compound according to claim 1 , wherein AA is D-Glu, L-Glu, D-Asp or L-Asp, and when there is a plurality of AAs, each AA may be the same as or different from each other, or a salt thereof.

12. The compound according to claim 1 , wherein
AA is D-Glu, L-Glu, D-Asp or L-Asp, 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;
an N-terminal nitrogen atom of (AA) m forms an amide bond together with carbonyl (a);
Q represents an unsubstituted phenyl group or a group represented by formula (Q-1):

where
R 2a and R 2e represent a hydrogen atom;
R 2b , R 2c and R 2d each independently represent a hydrogen atom, a halogen atom or methoxy group; and
R 2f represents a methyl group;
R 1a is a methyl group and R 1b is a hydrogen atom; and
m represents an integer of 1 to 5,

or a salt thereof.

13. The compound according to claim 1 , selected from the following compounds:

or a salt thereof.

14. The compound according to claim 1 , represented by a formula selected from the following compounds:

or a salt thereof.

15. The compound according to claim 1 represented by the following formula:

or a salt thereof.

16. A compound represented by formula (1):

wherein
AA represents a glutamic acid residue (Glu), an aspartic acid residue (Asp), a cysteine residue (Cys), or a C 1-3 alkyl ester thereof, 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;
an N-terminal nitrogen atom of (AA) m forms an amide bond together with carbonyl (a);
Q represents a group represented by formula (Q-1) or formula (Qa-2):

where
R 2a and R 2e represent a hydrogen atom,
R 2b , R 2c and R 2d each independently represent a hydrogen atom, a halogen atom, or a C 1-3 alkoxy group;
R 2f represents a methyl group or an ethyl group; and
R aa , R ab and R ac each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, a carboxyl group, or a C 1-3 alkyl group, C 1-3 alkoxy group or C 1-4 alkyl ester group optionally substituted with 1 to 3 fluorine atoms;
R 1a and R 1b each independently represent a hydrogen atom or a C 1-3 alkyl group; and
m represents an integer of 2 to 10,

or a salt thereof.

17. The compound according to claim 1

Assignees

• Sumitomo Pharma Co Ltd

Inventors

• Ban Hitoshi
• Nishio Yukihiro
• Suwa Atsushi

Classifications

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• A61K47/68

  the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• A61K2039/505

  comprising antibodies · CPC title