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US 8,952,147 B2Granted
Conjugates, preparation thereof, and therapeutic use thereof
AssigneeSanofi
InventorsHervé Bouchard, Marie-Priscille Brun, Alain Commercon, Jidong Zhang
Life of this patent
Estimating the term…
Abstract
Provided herein are cryptophycin conjugates and compositions containing them. Methods of making and using such compounds also are provided.
Claims39
A compound of formula (II):
- in which:
- R1 represents a halogen atom and R2 represents an —OH, an acyl group derived from an amino acid AA, or a (C1-C4)alkanoyloxy group
- or alternatively R1 and R2 form an epoxide unit;
- AA denotes a natural or unnatural amino acid;
- R3 represents a (C1-C6)alkyl group;
- R4 and R5 both represent H or together form a double bond CH═CH between C13 and C14;
- R6 and R7 represent, independently of each other, H or a (C1-C6)alkyl group;
- R8 and R9 represent, independently of each other, H or a (C1-C6)alkyl group;
- R10 represents at least one substituent of the phenyl nucleus chosen from:
- H, an OH, (C1-C4)alkoxy, a halogen atom, —NH2, —NH(C1-C6)alkyl or —N(C1-C6)alkyl2;
- R11 represents at least one substituent of the phenyl nucleus chosen from H and a (C1-C4)alkyl group;
- L represents a linker in the ortho (O), meta (m) or para (p) position of the phenyl nucleus bearing the unit RCG1 chosen from:
- -G′ X (CR13R14)t(OCH2CH2)y(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t(OCH2CH2)y—Y′—(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t(CR17═CR18)(CR15R16)u(OCH2CH2)y Q RCG1;
- -G′ X (CR13R14)t(OCH2CH2)y(CR17═CR18)(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-phenyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-furyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-oxazolyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-thiazolyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-thienyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-imidazolyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-piperazinyl-CO(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-piperidyl-methyl-NR12—CO(CR15R16), Y′ Q RCG1;
- -G′ X (CR13R14)t-piperidyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-piperidyl-NR12—(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-triazolyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-triazolyl-(CR15R16)u Y′ Q RCG1;
- -G′ X (CR13R14)t-phenyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-furyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-oxazolyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-thiazolyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-thienyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-imidazolyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-piperazinyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-piperidyl-(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-piperidyl-methyl-NR12—(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-piperidyl-NR12—(CR15R16)u Q RCG1;
- -G′ X (CR13R14)t-triazolyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t(OCH2CH2)y(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t(OCH2CH2)y—Y′—(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t(CR17═CR18)(CR15R16)u(OCH2CH2)y Q RCG1;
- -G″ Y (CR13R14)t(OCH2CH2)y(CR17═CR18)(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-phenyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-furyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-oxazolyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-thiazolyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-thienyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-imidazolyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-piperazinyl-CO(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-piperidyl-methyl-NR12—CO(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-piperidyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-piperidyl-NR12—(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-triazolyl-(CR15R16)u Y′ Q RCG1;
- -G″ Y (CR13R14)t-phenyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-furyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-oxazolyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-thiazolyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-thienyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-imidazolyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-piperazinyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-piperazinyl-(CR15R16)u Q CCR1;
- G″ Y (CR13R14)t-piperidyl-(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-piperidyl-methyl-NR12—(CR15R16)u Q RCG1;
- -G″ Y (CR13R14)t-piperidyl-NR12—(CR15R16)u Q RCG1;
- or -G″ Y (CR13R14)t-triazolyl-(CR15R16)u Q RCG1;
- in which formulae:
- G′ represents a —CH═CH— or —(CH2)n— group;
- G″ represents a —(CH2)n— group;
- n represents an integer ranging from 1 to 6;
- X represents a single bond or a —CO—, —COO— or —CONR12—, wherein the CO is attached to G′;
- Y represents a —O—, —OCO—, —OCOO—, —OCONR12—, —NR12—, —NR12CO—, —NR12CONR′12—, —NR12COO— or —S(O)q—, wherein the O and the NR12 are attached to G″;
- q represents an integer that may be 0, 1 or 2;
- Y′ represents a —O—, —OCO—, —OCOO—, —OCONR12—, —NR12—, —NR12CO—, —NR12CONR′12—, —NR12COO—, —S(O)q—, —CO—, —OCO—, or —CONR12—;
- R12, R′12, R13, R14, R15, R16, R17 and R18 represent, independently of each other, H or a (C1-C6)alkyl group;
- t, u and y represent integers that may range from 0 to 20 and such that t+u+y is greater than or equal to 1;
- in the case of the linker of formula -G″Y(CR13R14)t(OCH2CH2)y—Y′—(CR15R16)u Q RCG1, if y is 0 and Q represents a single bond, then u cannot be 0;
- Q represents a single bond, a (C1-C10)alkylene group or a (OCH2CH2)l group, wherein i is an integer ranging from 1 to 20;
- RCG1 represents —SZa, —C(═O)—ZbRb,
- with R12 representing H or (C1-C6)alkyl;
- or L is chosen from:
- in which formulae:
- represents one of the following 9 groups:
- n represents an integer ranging from 1 to 6;
- ALK represents a group (C1-C12)alkylene;
- R12 and R′12 represent, independently of each other, H or a group (C1-C6)alkyl;
- i represents an integer ranging from 1 to 20;
- or alternatively L is a linker of formula (IV):
- in which:
- (AA)w represents a sequence of w amino acids AA connected together via peptide bonds;
- w represents an integer ranging from 1 to 12;
- n represents an integer ranging from 1 to 6;
- D represents one of the following units:
- for which:
- R12 represents H or a (C1-C6)alkyl group;
- R19, R20, R21 and R22 represent, independently of each other, H, a halogen atom, —OH, CN or a (C1-C4)alkyl group;
- T attached to (CH2), represents NR12 or O;
- V1 represents O, S or NR12;
- V2 represents CR22 or N;
- V3, V4 and V5 are chosen, independently of each other, from CR22 and N;
- Za represents H or the group —SRa, wherein Ra represents a (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl or (C3-C7)heterocycloalkyl;
- Zb represents a single bond, —O— or —NH—, wherein Rb represents H, (C1-C6)alkyl, (C3-C7)cycloalkyl, aryl, heteroaryl or (C3-C7)heterocycloalkyl.
99 more elements
A compound of formula (III):
- in which:
- R1 represents a halogen atom and R2 represents an —OH, an acyl group derived from an amino acid AA, or a (C1-C4)alkanoyloxy group;
- or alternatively R1 and R2 form an epoxide unit;
- AA denotes a natural or unnatural amino acid;
- R3 represents a (C1-C6)alkyl group;
- R4 and R5 both represent H or together form a double bond CH═CH between C13 and C14;
- R6 and R7 represent, independently of each other, H or a (C1-C6)alkyl group;
- R8 and R9 represent, independently of each other, H or a (C1-C6)alkyl group;
- R10 represents at least one substituent of the phenyl nucleus chosen from:
- H, an OH, (C1-C4)alkoxy, a halogen atom, —NH2, —NH(C1-C6)alkyl or —N(C1-C6)alkyl2;
- R11 represents at least one substituent of the phenyl nucleus chosen from H and a (C1-C4)alkyl group;
- and
- G represents a group —(CH2)nY, which is in an ortho (o), meta (m) or para (p) position on the phenyl nucleus bearing the unit CR1,
- n is an integer ranging from 1 to 6, and Y denoting Cl, —N3, OH, NH2, —NR12—CH2—C≡CH in which R12 represents H;
- (C1-C6)alkyl;
- —OMs;
- —OC(═O)—O-(4-nitrophenyl);
- wherein R12 represents H or (C1-C6)alkyl.
15 more elements
A compound of formula:
- in which:
- R1 represents a halogen atom and R2 represents an —OH, an acyl group derived from an amino acid AA, or a group (C1-C4)alkanoyloxy;
- or alternatively R1 and R2 form an epoxide unit;
- AA denotes a natural or unnatural amino acid;
- R3 represents a (C1-C6)alkyl group;
- R4 and R5 both represent H or together form a double bond CH═CH between C13 and C14;
- R6 and R7 represent, independently of each other, H or a (C1-C6)alkyl group;
- R8 and R9 represent, independently of each other, H or a (C1-C6)alkyl group;
- R10 represents at least one substituent of the phenyl nucleus chosen from:
- H, an OH, (C1-C4)alkoxy, a halogen atom, —NH2, —NH(C1-C6)alkyl or —N(C1-C6)alkyl2;
- R11 represents at least one substituent of the phenyl nucleus chosen from H and a (C1-C4)alkyl group;
- and
- n is an integer ranging from 1 to 6.
10 more elements
Dependencies are inferred from the claim text.