US2020093934A1PendingUtilityA1
Novel peptidic linkers and cryptophycin conjugates, their preparation and their therapeutic use
Est. expiryMay 10, 2037(~10.8 yrs left)· nominal 20-yr term from priority
C07D 405/14A61K 38/15C07K 11/00C07D 405/06A61K 47/10A61K 47/22A61K 47/65A61K 47/6889A61P 35/00A61K 47/64A61K 47/6829C07K 5/06052
63
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present disclosure relates to compounds of formula (I): RCG1-L-P (I) wherein RCG1 represents a reactive chemical group being reactive towards a chemical group present on a polypeptide such as an antibody; P represents H, OH or an activated O; and L represents a specific linker. The disclosure also relates to cryptophycin payloads, as well as to cryptophycin conjugates, to compositions containing them and to their therapeutic use, especially as anticancer agents. The disclosure also relates to the process for preparing these conjugates.
Claims
exact text as granted — not AI-modified1 . Compounds of formula (I):
RCG1-L-P (I)
wherein
RCG1 represents a reactive chemical group that is reactive towards a chemical group present on a polypeptide such as an antibody;
P represents a hydrogen atom, —OH or an activated O;
L represents a linker of formula (II):
wherein:
L1 is of formula (III):
wherein:
when P represents a hydrogen atom, then x=0 or 1 and y=1 and z=0;
when P represents —OH, then x=y=z=0;
when P represents an activated O, then x=1 and y=z=0, or x=y=z=1;
J 1 , J 2 , J 3 and J 4 are chosen, independently of each other, from CA 1 and N;
ALK represents a (C 1 -C 12 )alkylene group, for instance (C 1 -C 6 )alkylene, such as of the form —(CH 2 ) n —, n being an integer ranging from 1 to 12 and for example ranging from 1 to 6;
A 1 , A 2 , A 3 , A 4 , A 5 , and A 6 represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group, such as a hydrogen atom or a methyl group;
(AA)w represents a sequence of w substituted AA s or non-substituted amino acids AA ns connected together via peptide bonds;
w represents an integer ranging from 1 to 12, for instance from 1 to 6, such as 2 or 3;
if (AA)w contains at least one substituted amino acid AA s , then L2 represents a single bond, a (C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ), group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a (CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a CH(SO 3 H)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-CH(SO 3 H) group, a (C 1 -C 6 )alkyl-cyclohexyl group, a C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a C(═O)—(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—CH(SO 3 H)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-CH(SO 3 H) group, a C(═O)—(C 1 -C 6 )alkyl-cyclohexyl group, a NA 8 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a NA 8 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-CH(SO 3 H) group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —O(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-CH(SO 3 H) group, a NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 group, a NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 7 -aryl group, a NA 7 -heteroaryl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 group, a C(═O)—NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -aryl group, a C(═O)—NA 7 -heteroaryl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 —(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group or a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group;
if (AA)w represents a sequence of w non-substituted amino acids AA ns , then L2 represents a NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 group, a NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 7 -aryl group, a NA 7 -heteroaryl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ); group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 group, a C(═O)—NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -aryl group, a C(═O)—NA 7 -heteroaryl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ); group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ); group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group or a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group;
A 7 representing a straight or branched, saturated or unsaturated, optionally substituted C 1 -C 160 hydrocarbon chain wherein optionally at least one methylene unit is independently replaced by —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —CH(OH)—, —CH(SO 3 H)—, —O—, —C(═O)—, —S(═O)—, —S(═O) 2 —, —NHS(═O) 2 —, —N(alkyl)S(═O) 2 —, —S(═O) 2 NH—, —S(═O) 2 N(alkyl)-, —P(═O)(OH)—, —P(═O)(OH)O—, —O—P(═O)(OH)—, —O—P(═O)(OH)—O— or a heterocycloalkyl group optionally substituted with at least one substituent, identical or different, chosen from —OH, —Oalkyl, -alkyl, a halogen atom, —NH 2 , —NHalkyl, and —N(alkyl) 2 , being understood that each A 7 comprising a SO 3 H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO 3 −+ Na);
A 8 representing a hydrogen atom or a (C 1 -C 6 )alkyl group, for instance a hydrogen atom or a methyl group;
i representing an integer ranging from 1 to 50, for instance ranging from 1 to 35.
2 . Compounds of formula (I) according to claim 1 , wherein said sequence (AA)w of non-substituted amino acids AA ns is selected from the following list: Gly-Gly, Phe-Lys, Val-Lys, Val-AcLys, Val-Cit, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Ala-Lys, Val-Ala, Phe-Cit, Phe-Gly, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Ala-Phe, Gly-Gly-Gly, Gly-Ala-Phe, Gly-Phe-Gly, Gly-Val-Cit, Gly-Phe-Leu-Cit, Gly-Phe-Leu-Gly, and Ala-Leu-Ala-Leu, such as Val-Ala and Val-Cit, for instance Val-Ala.
3 . Compounds of formula (I) according to claim 1 , wherein said substituted amino acids AA s have the formula (VI):
wherein:
T represents a saturated or unsaturated, linear or branched, (C 1 -C 8 ) trivalent alkyl group, preferably T is
U group represents a single bond, —NHC(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-, —NHC(═O)NH—, —NHC(═NH)NH—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —S—, —Se—, —O—, —NH—, —N(alkyl)-, —C(═O)—, —OP(═O)—, —S(═O)—, —S(═O) 2 —, —NHS(═O) 2 —, —N(alkyl)S(═O) 2 —, —S(═O) 2 NH—, —S(═O) 2 N(alkyl)-, —P(═O)(OH)—, —P(═O)(OH)O—, —O—P(═O)(OH)—, or —O—P(═O)(OH)—O, such as U group represents —NH—C(═O)—, or —C(═O)NH—;
A 9 represents a straight or branched, saturated or unsaturated, optionally substituted C 1 -C 160 hydrocarbon chain wherein optionally at least one methylene unit is independently replaced by —NH—C(═O)—, —N(alkyl)C(═O)—, —C(═O)NH—, —C(═O)N(alkyl)-, —NHC(═O)NH—, —NHC(═NH)NH—, —OC(═O)—, —C(═O)O—, —OC(═O)O—, —CH(OH)—, —CH(SO 3 H)—, —CH(Oalkyl)-, —CHF—, —CF 2 —, —S—, —Se—, —O—, —NH—, —N(alkyl)-, —N + H(alkyl)-, —N+(alkyl) 2 -, —C(═O)—, —OP(═O)—, —S(═O)—, —S(═O) 2 —, —NHS(═O) 2 —, —N(alkyl)S(═O) 2 —, —S(═O) 2 NH—, —S(═O) 2 N(alkyl)-, —P(═O)(OH)—, —P(═O)(OH)O—, —O—P(═O)(OH)—, —O—P(═O)(OH)—O— or a heterocycloalkyl group optionally substituted with at least one substituent, identical or different, chosen from —OH, —Oalkyl, -alkyl, a halogen atom, —NH 2 , —NHalkyl, and —N(alkyl) 2 , for instance A 9 is [(CH 2 ) 2 —O] 4 —CH 3 , —[(CH 2 ) 2 —O] 24 —CH 3 ,
or —[(CH 2 ) 2 —O)] 4 —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H;
being understood that each A 9 comprising a SO 3 H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO 3 −+ Na).
4 . Compounds of formula (I) according to claim 1 , wherein the substituted amino acids AA s have the formula (VI) as defined in claim 3 in which;
T represents
U group represents —NH—C(═O)—, or —C(═O)NH—;
A 9 represents [(CH 2 ) 2 —O] b —CH 3 wherein b represents an integer ranging from 1 to 50, for instance ranging from 1 to 24, such as 4, 7 and 24, for instance 4 and 24.
5 . Compounds of formula (I) according to claim 1 , wherein the sequence (AA s )w containing at least one substituted amino acid AA s , is selected from the list:
6 . Compounds of formula (I) according to claim 1 , wherein (AA)w contains at least one substituted amino acid AA s and L2 represents:
a (C 1 -C 6 )alkyl group, such as a (CH 2 ) 3 — group; a —C(═O)—(C 1 -C 6 )alkyl group, such as a —C(═O)—(CH 2 ) 3 — group; or a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, such as a —(CH 2 ) 2 —NA 7 -(CH 2 ) 2 — group in which A 7 is a —C(═O)—(CH 2 ) 2− C(═O)—NH—(CH 2 ) 2− SO 3 H group;
being understood that each A 7 comprising a SO 3 H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO 3 −+ Na).
7 . Compounds of formula (I) according to claim 1 , wherein (AA)w contains w non-substituted amino acid AA ns and L2 represents:
a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, such as a —(CH 2 ) 2 —NA 7 -(CH 2 ) 2 — group in which A 7 represents:
a —C(═O)—[(CH 2 ) 2 —O] a —CH 3 group wherein “a” represents an integer ranging from 1 to 50, such as ranging from 1 to 24, for instance 4, 7 and 24, such as A 7 is a —C(═O)—[(CH 2 ) 2 —O] 4 —CH 3 group, a —C(═O)—[(CH 2 ) 2− O] 7 —CH 3 group, or a —C(═O)—[(CH 2 ) 2 —O] 24 —CH 3 group;
a —C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2− SO 3 H group; or
a —C(═O)—(CH 2 ) 2 —C(═O)—NH—[(CH 2 ) 2 —O] a —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group wherein “a” represents an integer ranging from 1 to 50, such as ranging from 1 to 24, for instance 4, such as A 7 is —C(═O)—(CH 2 ) 2 —C(═O)—NH—[(CH 2 ) 2 —O] 4 —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group;
being understood that each A 7 comprising a SO 3 H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO 3 −+ Na).
8 . Compounds of formula (I) according to claim 1 , wherein A 7 represents
a —C(═O)—[(CH 2 ) 2 —O] 4 —CH 3 group; a —C(═O)—[(CH 2 ) 2 —O] 7 —CH 3 group, a —C(═O)—[(CH 2 ) 2 —O] 24 —CH 3 group; a —C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; a —C(═O)—(CH 2 ) 2 —C(═O)—NH—[(CH 2 ) 2 —O—] 4 —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; being understood that each A 7 comprising a SO 3 H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO 3 −+ Na).
9 . Compounds of formula (I) according to claim 1 , wherein (AA)w contains at least one substituted amino acid AA s and/or w non-substituted amino acid AA ns and L2 represents:
a NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 group, a NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a NA 7 -aryl group, a NA 7 -heteroaryl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a (C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a (C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 group, a C(═O)—NA 7 -(CH 2 CH 2 O) i (C 1 -C 6 )alkyl group, a C(═O)—NA 7 -aryl group, a C(═O)—NA 7 -heteroaryl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 C(═O)—(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-C(═O)NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl group, a C(═O)—NA 8 -(C 1 -C 6 )alkyl-NA 7 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ), group or a C(═O)—NA 8 -(C 1 -C 6 )alkyl-(OCH 2 CH 2 ) i —NA 7 -(C 1 -C 6 )alkyl group.
10 . Compounds of formula (I) according to claim 1 , wherein (AA)w contains at least one substituted amino acid AA s and/or w non-substituted amino acid AA ns and L2 represents:
11 . Compounds of formula (I) according to claim 1 , wherein (AA)w contains at least one substituted amino acid AA s and/or w non-substituted amino acid AA ns and L2 comprises a A 7 representing:
a C(═O)—[(CH 2 ) 2 —O] 4 —CH 3 group; a C(═O)—[(CH 2 ) 2 —O] 7 —CH 3 group; a C(═O)—[(CH 2 ) 2 —O] 24 —CH 3 group; a C(═O)—(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; a C(═O)—(CH 2 ) 2 —C(═O)—NH—[(CH 2 ) 2 —O] 4 —(CH 2 ) 2 —C(═O)—NH—(CH 2 ) 2 —SO 3 H group; being understood that each A 7 comprising a SO 3 H function can be under salt forms such as alkali metal salts, for instance sodium salts (SO 3 −+ Na).
12 . Compounds of formula (I) according to anyone of claims 1 to 11 , wherein said linker L is selected from the following list:
13 . Compounds of formula (I) according to anyone of claims 1 to 12 , wherein RCG1 is selected from the following list:
(i) a RaZa-C(═O) reactive group for which Z a represents a single bond, —O— or —NH—, for instance —O—, and R a represents a hydrogen atom, a (C 1 -C 6 )alkyl group, a (C 3 -C 7 )cycloalkyl group, an alkenyl group, an aryl group, a heteroaryl group or a (C 3 -C 7 )heterocycloalkyl group, the aryl group, the heteroaryl group and/or the (C 3 -C 7 )heterocycloalkyl group being optionally substituted by 1 to 5 atoms/groups chosen from a halogen atom, for instance a fluorine atom, an alkyl group, an alkoxy group, a hydroxyl group, an oxo group, a nitro group and a cyano group;
(ii) one of the following reactive groups: a maleimido
group; a haloacetamido Cl, Br or
group with R 21 representing a hydrogen atom or a (C 1 -C 6 )alkyl group, such as Me; Cl—; N 3 —; HO—; HS—; an activated disulfide such as H or
H 2 N—; HC≡C— group or an activated C≡C group such as a cyclooctyne moiety for instance a
an O-alkyl hydroxylamine or a Pictet-Spengler reaction substrate such as
for instance RCG1 is selected from the following list:
14 . Cryptophycin payloads of formula (IV):
wherein:
R 1 represents a (C 1 -C 6 )alkyl group;
R 2 and R 3 represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group;
or alternatively R 2 and R 3 form together with the carbon atom to which they are attached a (C 3 -C 6 )cycloalkyl or a (C 3 -C 6 )heterocycloalkyl group;
R 4 and R 5 represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkyl-NH(R12) group or a (C 1 -C 6 )alkyl-OH group or a (C 1 -C 6 )alkyl-SH group or a (C 1 -C 6 )alkyl-CO 2 H group;
or alternatively R 4 and R 5 form together with the carbon atom to which they are attached a (C 3 -C 6 )cycloalkyl or a (C 3 -C 6 )heterocycloalkyl group;
X represents O or N(R 6 );
R 6 represents a hydrogen atom or a (C 1 -C 6 )alkyl group;
R 7 and R 8 represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkyl-CO 2 H group or a (C 1 -C 6 )alkyl-N(C 1 -C 6 )alkyl 2 group;
or alternatively R 7 and R 8 form together with the carbon atom to which they are attached a (C 3 -C 6 )cycloalkyl group or a (C 3 -C 6 )heterocycloalkyl group;
R 9 represents at least one substituent of the phenyl nucleus chosen, independently of each other, from: a hydrogen atom, —OH, (C 1 -C 4 )alkoxy, a halogen atom, —NH 2 , —NH(C 1 -C 6 )alkyl or —N(C 1 -C 6 )alkyl 2 or —NH(C 1 -C 6 )cycloalkyl or (C 3 -C 6 )heterocycloalkyl group;
R 10 represents at least one substituent of the phenyl nucleus chosen from a hydrogen atom and a (C 1 -C 4 )alkyl group;
Y represents
—NR 11 —(C 1 -C 6 )alkyl-, such as —NR 11 —(CH 2 ) n — like
—O—(C 1 -C 6 )alkyl-, such as —O—(CH 2 ) n — like
—S—(C 1 -C 6 )alkyl-, such as —S—(CH 2 ) n — like
Y being positioned in an ortho (o), meta (m) or para (p) position of the phenyl nucleus;
R 11 and R 12 represent, independently of each other, a hydrogen atom or (C 1 -C 5 )alkyl, such as a hydrogen atom or a methyl group;
n represents an integer ranging from 1 to 6;
L is defined as in formula (I) according to claim 1 and represents a linker of formula (II) as defined in any one of claims 1 to 12 ;
RCG1 represents a reactive chemical group present at the end of the linker L, RCG1 being reactive towards a chemical group present on a polypeptide such as an antibody.
15 . Cryptophycin payloads of formula (IV) according to claim 14 , having the following structure:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, RCG 1 , X, Y and L are as defined in formula (IV) according to claim 14 .
16 . Cryptophycin payloads of formula (IV) according to claim 14 which are selected from the following list:
17 . Conjugate of formula (V):
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, X, Y and L are as defined in formula (IV) according to claim 14 or 15 ;
G represents the product of reaction between RCG1 as defined in claim 13 , a reactive chemical group present at the end of the linker L of formula (II) as defined in claim any one of claims 1 to 12 , and RCG2, an orthogonal reactive chemical group present on a polypeptide such as the antibody (Ab); and
Ab represents an antibody.
18 . Conjugates of formula (V) according to claim 17 , having the following structure:
wherein:
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , n, X, Y, L, G, RCG1, RCG2 and Ab are as in formula (V) according to claim 17 .
19 . Conjugates of formula (V) according to claim 17 or 18 , wherein RCG2 is selected from:
(i) ε-amino groups of lysines borne by the side chains of the lysine residues that are present at the surface of an antibody;
(ii) α-amino groups of N-terminal amino acids of antibody heavy and light chains;
(iii) the saccharide groups of the hinge region;
(iv) the thiols of cysteines generated by reducing intra-chain disulfide bonds or the thiols of engineered cysteines;
(v) amide groups borne by the side chains of some glutamine residues that are present at the surface of an antibody; and
(vi) aldehyde groups introduced using formylglycine generating enzyme.
20 . Conjugates of formula (V) according to claim 17 or 18 , wherein:
when RCG1 represents a N-hydroxysuccinimidyl ester, RCG2 represents a NH 2 group;
when RCG1 represents a maleimido function, a haloacetamido function, a chlorine atom or an activated disulfide, RCG2 represents a —SH group;
when RCG1 represents a N3 group, RCG2 represents a C≡CH group or an activated C≡C group such as a cyclooctyne moiety;
when RCG1 represents a OH or NH 2 group, RCG2 represents a carboxylic acid or amide function;
when RCG1 represents a SH group, RCG2 represents a maleimido function, a haloacetamido function or an activated disulfide function;
when RCG1 represents a C≡CH group or an activated C≡C group, RCG2 represents a N3 group;
when RCG1 represents a O-alkyl hydroxylamine function or a Pictet-Spengler reaction substrate, RCG2 represents an aldehyde or ketone function.
21 . Conjugates of formula (V) according to any one of claims 17 to 20 , wherein G is selected from:
for instance, G represents the following groups:
22 . Conjugates of formula (V) according to claim 17 , which is selected from the following list:
wherein Ab represents an antibody.
23 . Process for preparing a conjugate of formula (V) as defined in any one of claims 17 to 22 comprising at least the steps of:
(i) placing in contact and leaving to react:
an optionally buffered aqueous solution of an antibody, optionnally modified by means of a modifying agent,
and
a solution of a cryptophycin payload of formula (IV) as defined in any one of claims 14 to 16 ,
the chemical group RCG1 of the cryptophycin payload of formula (IV) being reactive towards the chemical groups RCG2 present on the polypeptide such as the antibody especially towards the amino groups present on antibodies, the said chemical groups RCG2 having been introduced, where appropriate, by the modifying agent, so as to attach the cryptophycin payload of formula (IV) to the antibody by formation of a covalent bond;
(ii) and then optionally to separate the conjugate formed in step (i) from the cryptophycin payload of formula (IV) and/or from the unreacted antibody and/or from any aggregates that may have formed.
24 . Medicament, wherein it comprises at least one conjugate of formula (V) according to any one of claims 17 to 22 .
25 . Pharmaceutical composition, wherein it comprises at least one conjugate of formula (V) according to any one of claims 17 to 22 , and also at least one pharmaceutically acceptable excipient.
26 . Use of the conjugates of formula (V) according to any one of claims 17 to 22 as anticancer agents.
27 . Conjugates of formula (V) according to any one of claims 17 to 22 for use in the treatment of cancer.Join the waitlist — get patent alerts
Track US2020093934A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.