JPWO2020180158A5

JPWO2020180158A5 -

Info

Publication number: JPWO2020180158A5
Application number: JP2021553322A
Authority: JP
Publication date: 2023-08-16

Description

前記化学式（ＩＩ）の化合物は、具体的に、次の化学式で表示され得る：
The compound of formula (II) can be specifically represented by the following formula:

Claims

A compound represented by the following chemical formula (I), or a pharmaceutically acceptable salt or solvate thereof:

In the above chemical formula,
R ¹ is D-galactose β-pyranose or D-galactose α-pyranose;
R ² is Cl or Br;
R ³ is a single bond, -O- or -NH-.

A compound represented by the following chemical formula (II), or a pharmaceutically acceptable salt or solvate thereof:

In the above chemical formula,
R ¹ is D-galactose β-pyranose or D-galactose α-pyranose;
R ² is Cl or Br;
R ³ is a single bond, -O- or -NH-;
W is a spacer;
^L1 is a linker.

The W is
—R ⁴ —A—R ⁵ —, —R ⁴ —A—, —(CH ₂ CH ₂ R ⁶ ) _x —, —(CH ₂ ) _r (R ⁷ (CH ₂ ) _p ) _q —, —(( CH ₂ ) _p R ⁷ ) _q —, —(CH ₂ ) _r (R ⁷ (CH ₂ ) _p ) _q R ⁸ —, —((CH ₂ ) _p R ⁷ ) _q (CH ₂ ) _r —, —R ⁸ ((CH ₂ ) _p R ⁷ ) _q —, or —(CH ₂ ) _r (R ⁷ (CH ₂ ) _p ) _q R ⁸ CH ₂ —,
wherein R ⁴ and R ⁵ are each independently —(CH ₂ ) _r (V(CH ₂ ) _x ) _p (CH ₂ ) _q , A is a direct bond or a peptide bond, V is a single a bond, O or S;
R ⁶ is —O—, C ₁ -C ₈ alkylene, —NR ⁹ — or —C(O)NR ¹³ —;
R ⁷ and R ⁸ are each independently a single bond, —O—, —NR ¹⁰ —, —C(O)NR ¹¹ —, —NR ¹² C(O)— or C ₃ -C ₂₀ heteroaryl; ,
R ⁹ to R ¹³ are each independently hydrogen, C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkyl)C ₆ -C ₂₀ aryl, or (C ₁ -C ₆ alkyl)C ₃ -C ₂₀ hetero is aryl,
x is an integer from 1 to 5, r is an integer from 0 to 10, p is an integer from 0 to 10, q is an integer from 0 to 20,
3. A compound according to claim 2, wherein 1-10 hydrogens in said W can be replaced by hydroxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, amino, ONH ₂ or oxo. above acceptable salts or solvates.

The ^L1 is
hydroxy, aldehyde, ONH ₂ , NH ₂ , or 4- to 7-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, said heteroaryl being hydroxy, aldehyde, Substitutable by 1 to 5 substituents independently selected from C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, amino, ONH ₂ or oxo, or formula (Ia) below or having the structure (Ib):

wherein Q ¹ is cyclooctynyl or heterocyclooctynyl, said cyclooctynyl or heterocyclooctynyl optionally selected from C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ aryl and C ₃ -C ₁₂ heteroaryl fused with 1 or 2 independently selected rings, optionally substituted with hydroxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, amino, ONH ₂ or oxo,
R ¹³ is C ₁ -C ₂₄ alkyl, C ₃ -C ₂₄ cycloalkyl, C ₃ -C ₂₄ aryl, C ₃ -C ₂₄ heteroaryl, C ₃ -C ₂₄ alkylaryl, C ₃ -C ₂₄ alkylheteroaryl, selected from C ₃ -C ₂₄ arylalkyl and C ₃ -C ₂₄ heteroarylalkyl, said heteroaryl comprising a heteroatom selected from O, S and NR ¹⁴ wherein R ¹⁴ is hydrogen or C ₁ _—C4 alkyl group,
Sp ¹ , Sp ² , Sp ³ and Sp ⁴ are spacer moieties each independently a single bond or linear or branched C ₁ -C ₂₀₀ alkylene, C ₂ -C ₂₀₀ alkenylene , C ₂ -C ₂₀₀ alkynylene, C ₃ -C ₂₀₀ cycloalkylene, C ₅ -C ₂₀₀ cycloalkenylene, C ₈ -C ₂₀₀ cycloalkynylene, C ₇ -C ₂₀₀ alkylarylene, C ₇ -C ₂₀₀ arylalkylene, C selected from ₈ -C ₂₀₀ arylalkenylene and C ₉ -C ₂₀₀ arylalkynylene, said alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, alkylarylene, arylalkylene, arylalkenylene and arylalkynylene are optionally substituted with or containing a heteroatom selected from O, S and NR ¹⁴ ;
Z ¹ and Z ² are each independently selected from O, C(O) and N(R ¹³ );
each a is independently 0 or 1;
each b is independently 0 or 1;
c is 0 or 1,
d is 0 or 1;
e is 0 or 1,
f is an integer from 0 to 150,
g is 0 or 1,
3. The compound, a pharmaceutically acceptable salt or solvate thereof, according to claim 2, wherein i is 0 or 1.

A compound, a pharmaceutically acceptable salt or a solvate thereof, according to claim 2, characterized in that it comprises a compound represented by the following chemical formula:

An antibody-drug conjugate comprising a compound represented by formula (III), or a pharmaceutically acceptable salt or solvate thereof:

In the above chemical formula,
R ¹ is D-galactose β-pyranose or D-galactose α-pyranose;
R ² is Cl or Br;
R ³ is a single bond, -O- or -NH-;
W is a spacer;
^L2 is a linker;
Abs are antibodies or antigen-binding fragments thereof.

The W is
—R ⁴ —A—R ⁵ —, —R ⁴ —A—, —(CH ₂ CH ₂ R ⁶ ) _x —, —(CH ₂ ) _r (R ⁷ (CH ₂ ) _p ) _q —, —(( CH ₂ ) _p R ⁷ ) _q —, —(CH ₂ ) _r (R ⁷ (CH ₂ ) _p ) _q R ⁸ —, —((CH ₂ ) _p R ⁷ ) _q (CH ₂ ) _r —, —R ⁸ ((CH ₂ ) _p R ⁷ ) _q —, or —(CH ₂ ) _r (R ⁷ (CH ₂ ) _p ) _q R ⁸ CH ₂ —,
wherein R ⁴ and R ⁵ are each independently —(CH ₂ ) _r (V(CH ₂ ) _x ) _p (CH ₂ ) _q , A is a direct bond or a peptide bond, V is a single bond, O or S,
R ⁶ is —O—, C ₁ -C ₈ alkylene, —NR ⁹ — or —C(O)NR ¹³ —;
R ⁷ and R ⁸ are each independently a single bond, —O—, —NR ¹⁰ —, —C(O)NR ¹¹ —, —NR ¹² C(O)— or C ₃ -C ₂₀ heteroaryl; ,
R ⁹ to R ¹³ are each independently hydrogen, C ₁ -C ₆ alkyl, (C ₁ -C ₆ alkyl)C ₆ -C ₂₀ aryl or (C ₁ -C ₆ alkyl)C ₃ -C ₂₀ heteroaryl and
x is an integer from 1 to 5, r is an integer from 0 to 10, p is an integer from 0 to 10, q is an integer from 0 to 20,
8. The antibody-drug conjugate of claim 7, wherein 1-10 hydrogens in W can be replaced by hydroxy, _C1 - _C8 alkyl, _C1 - _C8 alkoxy, amino, _ONH2 or oxo. Gate.

The ^L2 is
-CH ₂ NH-, -ON=C(CH ₃ )-, -ON=, -CH=, CH=N- or containing 1 to 3 heteroatoms selected from N, O and S 4- to 7-membered heterocycle, wherein said heterocycle is 1-5 independently selected from hydroxy, aldehyde, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, amino, ONH ₂ or oxo or having the structure of the following chemical formula (II-a) or (II-b):

wherein ^Q2 is cyclooctenyl fused with triazole or heterocyclooctenyl fused with triazole;
said cyclooctenyl or heterocyclooctenyl is optionally further fused with 1 or 2 rings each independently selected from C ₃ -C ₁₂ cycloalkyl, C ₃ -C ₁₂ aryl and C ₃ -C ₁₂ heteroaryl optionally substituted with hydroxy, C ₁ -C ₈ alkyl, C ₁ -C ₈ alkoxy, amino, ONH ₂ or oxo, said Q ² being linked to Ab through a nitrogen atom contained in the triazole,
Sp ¹ , Sp ² , Sp ³ and Sp ⁴ are spacer moieties each independently a single bond or linear or branched C ₁ -C ₂₀₀ alkylene, C ₂ -C ₂₀₀ alkenylene, C ₂ -C ₂₀₀ alkynylene, C ₃ -C ₂₀₀ cycloalkylene, C ₅ -C ₂₀₀ cycloalkenylene, C ₈ -C ₂₀₀ cycloalkynylene, C ₇ -C ₂₀₀ alkylarylene, C ₇ -C ₂₀₀ arylalkylene, C ₈ —C ₂₀₀ arylalkenylene and C ₉ -C ₂₀₀ arylalkynylene, wherein said alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene, alkylarylene, arylalkylene, arylalkenylene and arylalkynylene are optionally is substituted with or contains a heteroatom selected from O, S and NR ¹⁴ in
Z ¹ and Z ² are each independently selected from O, C(O) and N(R ¹³ );
each a is independently 0 or 1;
each b is independently 0 or 1;
c is 0 or 1,
d is 0 or 1;
e is 0 or 1,
f is an integer from 0 to 150,
g is 0 or 1,
8. The antibody-drug conjugate of claim 7, wherein i is 0 or 1.

A conjugate according to claim 7, characterized in that it comprises a compound of the formula:

The conjugate according to claim 7, characterized in that the linker is linked to the antibody via a cysteine, lysine, azide group, ketone group introduced into the antibody or the N-terminus of the antibody protein.

8. The conjugate of claim 7, wherein said antibody is selected from the group consisting of anti-BCMA antibody, anti-ROR1 antibody, anti-Her2 antibody, anti-NaPi2b antibody and anti-CLL1 antibody.

A pharmaceutical composition for the prevention or treatment of proliferative diseases, comprising the conjugate according to any one of claims 7-12.