Multimeric chelator compounds for use in targeted radiotherapy

Patent metadata

Field	Value
Publication number	US-2024156999-A1
Application number	US-202218275375-A
Country	US
Kind code	A1
Filing date	Jan 31, 2022
Priority date	Feb 1, 2021
Publication date	May 16, 2024
Grant date	—

Abstract

The present invention covers compounds of general formula (I): [(C)n-L]-(V)m (I) where C is a chelator and n>1, L is a multi-functional linker moiety comprising multiple functional groups for the covalent attachment of chelator such as a polyamine or polyacid-containing backbone or amino acid containing polymer comprising side-chains with amino, thiol or carboxylic acid moieties such as lysine, cysteine or glutamic acid and V is a tissue targeting moiety where m=1-5 which preferentially coupled through a coupling moiety to either the multifunctional linker moiety L or directly to the chelator moiety C, and stereoisomers, tautomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.

First claim

1 . A compound of general formula (I):
[(C)n-L]-(V)m   (I),
in which: C represents the macrocyclic chelating agent macropa, L represents a multi-functional linker moiety comprising multiple functional groups for the covalent attachment of C, and V is a tissue-targeting moiety, and wherein n is a natural number selected from 2 to 32 and m is from 1 to 5, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

2 . The compound of claim 1 , wherein the compound further comprises an alpha-emitting radioisotope or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

3 . The compound of claim 2 , wherein the alpha-emitting radioisotope is selected from the group consisting of radium-223, radium-224, bismuth-212, bismuth-213 and actinium-225 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

4 . The compound of claim 1 , wherein the tissue-targeting moiety is a monoclonal antibody or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

5 . The compound of claim 1 , wherein L is a multi-functional linker moiety comprising multiple functional groups for the covalent attachment of a chelator such as a polyamine or polyacid-containing backbone or amino acid containing polymer comprising side-chains with amino, thiol or carboxylic acid moieties such as lysine, cysteine or glutamic acid.

6 . The compound of claim 1 , wherein L is

7 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (A) below:

and
wherein either the amino substituent group or the carboxylic acid groups are used to form amide bonds with either L or V, n is 2, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

8 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (A) and wherein either the amino substituent group or the carboxylic acid groups are used to form amide bonds with either L or V, n is 3, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

9 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (A) and wherein either the amino substituent group or the carboxylic acid groups are used to form amide bonds with either L or V, n is 4, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

10 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (A) and wherein either the amino substituent group or the carboxylic acid groups are used to form amide bonds with either L or V, n is 8 and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

11 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (B) below:

and
wherein the carboxylic acid groups are used to form amide bonds with either L or V, n is 2, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

12 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (B) and wherein the carboxylic acid groups are used to form amide bonds with either L or V, n is 3, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

13 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (B) and wherein the carboxylic acid groups are used to form amide bonds with either L or V, n is 4, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

14 . The compound of claim 1 , wherein C is the macrocyclic chelating agent macropa of formula (B) and wherein the carboxylic acid groups are used to form amide bonds with either L or V, n is 8, and V is a monoclonal antibody, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.

15 . The compound of claim 1 wherein the compound is selected from the group consisting of:
4,4′-[(9,13-bis{2-[2-(2-{[2-carboxy-6-({16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13 -tetraoxa-7,16-diazacyclooctadecan-7-yl}methyl)pyridin-4-yl]amino}-2-oxoethoxy)acetamido]ethyl}-1,5,17,21-tetraoxo-3,19-dioxa-6,9,13,16-tetraazahenicosane-1,21-diyl)diimino]bis[6-({16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl}methyl)pyridine-2-carboxylic acid] (Example 7; Tet2);
4,4′-[7,11-bis(2-{3-[2-carboxy-6-({16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13 -tetraoxa-7,16-diazacyclooctadecan-7-yl}methyl)pyridin-4-yl]propanamido}ethyl)-3,15-dioxo-4,7,11,14-tetraazaheptadecane-1,17-diyl]bis[6-({16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl}methyl)pyridine-2-carboxylic acid] (Example 10, Tet5); and
4-[3-[[6-[2-[3-[bis[2-[2,6-bis[3-[2-carboxy-6-[[16-[(6-carboxy-2-pyridyl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl]-4-pyridyl]propanoylamino]hexanoylamino]ethyl]amino]propyl-[2-[2,6-bis[3-[2-carboxy-6-[[16-[(6-carboxy-2-pyridyl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl]-4-pyridyl]propanoylamino]hexanoylamino]ethyl]amino]ethylamino]-5-[3-[2-carboxy-6-[[16-[(6-carboxy-2-pyridyl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl]-4-pyridyl]propanoylamino]-6-oxo-hexyl]amino]-3-oxo-propyl]-6-[[16-[(6-carboxy-2-pyridyl)methyl]-1,4,10,13-tetraoxa-7,16-diazacyclooctadec-7-yl]methyl]pyridine-2-carboxylic acid (Example 14, Oct2).

16 . A method of preparing a compound of claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, said method comprising: reacting an intermediate compound of general formula (II):
[(X)p′-C]n-L   (II),
in which C, L, n and m and m are as defined for the compound of general formula (I) according to claim 1 , with V; in which V is as defined for the compound of general formula (I) according to claim 1 , thereby giving a compound of general formula (I):
[(C)n-L]-(V)m   (I),

in which C, L, V, n and and m are as defined for the compound of general formula (I) according to claim 1 .

17 . (canceled)

18 . A pharmaceutical composition comprising a compound of claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, and one or more pharmaceutically acceptable excipients.

19 . A pharmaceutical combination comprising:
one or more first active ingredients, wherein the one or more first active ingredients comprises a compound of claim 1 , or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same, and one or more further active ingredients.

20 . A method for treatment or prophylaxis of a disease, the method comp

Assignees

• Bayer Ag
• Bayer As

Inventors

• Brumby Thomas
• Cuthbertson Alan
• Indrevoll Bård
• Rafique Waqas
• Krogstie Vilde Roko
• Cruciani Véronique
• Kristian Alexander

Classifications

• A61K51/1096 Primary

  radioimmunotoxins, i.e. conjugates being structurally as defined in A61K51/1093, and including a radioactive nucleus for use in radiotherapeutic applications · CPC title

• A61K51/0482

  chelates from cyclic ligands, e.g. DOTA · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title