Pyrrolobenzodiazepines and conjugates thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-487/04
A61K-047/48
A61K-031/5517
출원번호
US-0654065
(2013-12-20)
등록번호
US-9562049
(2017-02-07)
국제출원번호
PCT/EP2013/077705
(2013-12-20)
국제공개번호
WO2014/096368
(2014-06-26)
발명자
/ 주소
Howard, Philip Wilson
출원인 / 주소
MEDIMMUNE LIMITED
대리인 / 주소
Michael Best & Friedrich LLP
인용정보
피인용 횟수 :
1인용 특허 :
55
초록
A compound with the formula I: and salts and solvates thereof.
대표청구항▼
1. A compound with the formula I: or a pharmaceutically acceptable salt thereof, wherein:when there is a double bond present between C2 and C3, R2 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl, or C5-10 heteroaryl, optionally substituted by one or more substituents selecte
1. A compound with the formula I: or a pharmaceutically acceptable salt thereof, wherein:when there is a double bond present between C2 and C3, R2 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl, or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl; wherein each of R13a, R13b and R13c are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5; wherein one of R15a and R15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and where R14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3,R2 is where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester; when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocycloxy, C5-20 aryloxy, carboxy, ester, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl; wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and where R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2′ and C3′,R12 is where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;R″ is a C3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from the group consisting of benzene and pyridine;Y and Y′ are selected from O, S, or NH;R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively;R20 is H or Me and R21a and R21b are both H or together form ═O;RL is the group where the asterisk indicates the point of attachment to the N10 position, G1 is a functional group to form a connection to a cell binding agent, L1 is a linker, L2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker, and L1 or L2 is a cleavable linker;R11b is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;the heterocyclyl group in C3-20 heterocycloxy contains 1 to 10 ring heteroatoms selected from N, O and S;the heteroaryl group in C5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;the heterocyclyl group in C3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S; andthe heterocyclyl group in C3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S. 2. A compound according to claim 1, wherein R7 is a C1-4 alkyloxy group. 3. A compound according to claim 1, wherein Y is O, and R″ is C3-7alkylene. 4. A compound according to claim 1, wherein R6 and R9 are H. 5. A compound according to claim 1, wherein there is a double bond between C2′ and C3′, and R12 is: (a) a C5-7 aryl group, which may bear one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or(b) methyl, ethyl or propyl; or(c) cyclopropyl;(d) a group of formula: wherein the total number of carbon atoms in the R12 group is no more than 4; or (e) the group; or (f) a group of formula: wherein R24 is selected from H and methyl. 6. A compound according to claim 1, wherein there is a single bond between C2′ and C3′, R12 is and: (a) R26a and R26b are both H; or(b) R26a and R26b are both methyl; or(c) one of R26a and R26b is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted. 7. A compound according to claim 1, wherein there is a double bond between C2 and C3, and R2 is (a) a C5-7 aryl group, which may bears one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; or(b) methyl, ethyl or propyl; or(c) cyclopropyl; or(d) a group of formula: wherein the total number of carbon atoms in the R2 group is no more than 4; or or wherein R14 is selected from H and methyl. 8. A compound according to claim 1, wherein there is a single bond between C2 and C3, R2 is and: (a) R16a and R16b are both H; or(b) R16a and R16b are both methyl; or(c) one of R16a and R16b is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted. 9. A compound according to claim 1, wherein R20 is H or Me and R21a and R21b are both H. 10. A compound according to claim 1, wherein R20 is H or Me and R21a and R21b together form ═O. 11. A compound according to claim 9, wherein R20 is H. 12. A compound according to claim 1, wherein R11b is OH. 13. A compound according to claim 1, wherein R11b is ORA. 14. A compound according to claim 1, wherein R11b is SOzM. 15. A compound according to claim 14, wherein M is Na+ and z is 3. 16. A conjugate comprising a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, linked to a targeting agent. 17. A conjugate of formula IV: L-(RL′-D)p (IV)or a pharmaceutically acceptable salt thereof, wherein L-RL′ is the group: where the asterisk indicates the point of attachment to the N10 position, CBA is an antibody or antibody fragment, L1 is a linker, A is a connecting group connecting L1 to the antibody or antibody fragment, L2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker, and L1 or L2 is a cleavable linker;and D is of formula II: where the wavy line indicates the attachment point of RL′, when there is a double bond present between C2 and C3, R2 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl or C5-10heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro cyano, C1-7 alkoxy, C3-20 heterocycloxy, C5-20 aryloxy, C1-7 alkyl, C3-7 heterocyclyl, and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl; wherein each of R13a, R13b and R13c are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5; wherein one of R15a and R15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and where R14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3,R2 is where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester; when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, carboxy, —C(═O)OC1-7alkyl, —C(═O)OC3-20heterocyclyl, —C(═O)O5-20aryl, C1-7alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl; wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and where R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2′ and C3′,R12 is where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;wherein the heterocyclyl group in C3-20 heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S;R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NHRR′, nitro, Me3Sn and halo;R″ is a C3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from the group consisting of benzene and pyridine;Y and Y′ are selected from O, S, or NH;R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively;R20 is H or Me and R21a and R21b are both H or together form ═O;R11b is selected from OH, ORA, where RA is C1-4 alkyl, and SOzM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;wherein the heterocyclyl group in C3-20 heterocycloxy contains 1 to 10 ring heteroatoms selected from N, O and S;wherein the heteroaryl group in C5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;wherein the heterocyclyl group in —C(═O)OC3-20heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; andwherein the heterocyclyl group in C3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S. 18. The conjugate according to claim 17, wherein L-RL′ is a group: where the asterisk indicates the point of attachment to the N10 position, CBA is an antibody or antibody fragment, L1 is a cleavable linker comprises a dipeptide and the group —X1—X2— in dipeptide, —NH—X1—X2—CO—, is selected from: -Phe-Lys-,-Val-Ala-,-Val-Lys-,-Ala-Lys-,-Val-Cit-,-Phe-Cit-,-Leu-Cit-,-Ile-Cit-,-Phe-Arg-,-Trp-Cit-,A is a connecting group connecting L1 to the cell binding agent, L2 is a covalent bond or together with —OC(═O)— forms a self-immolative linker. 19. The conjugate according to claim 18, wherein C(═O)O and L2 together form the group: where the asterisk indicates the point of attachment to the N10 position, the wavy line indicates the point of attachment to the linker L1, Y is NH, O, C(═O)NH or C(═O)O, and n is 0 to 3. 20. The conjugate according to claim 18, wherein A is: where the asterisk indicates the point of attachment to L1, the wavy line indicates the point of attachment to the cell binding agent, and n is 0 to 6; or where the asterisk indicates the point of attachment to L1, the wavy line indicates the point of attachment to the cell binding agent, n is 0 or 1, and m is 0 to 30. 21. The conjugate according to claim 16, wherein the cell binding agent of R10 is an antibody or an active fragment thereof. 22. The conjugate according to claim 21, wherein the antibody or antibody fragment is an antibody or antibody fragment for a tumour-associated antigen. 23. A compound of formula A: and salts thereof, whereinwhen there is a double bond present between C2 and C3, R2 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl; wherein each of R13a, R13b and R13c are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R2 group is no more than 5; wherein one of R15a and R15b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and where R14 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2 and C3,R2 is where R16a and R16b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R16a and R16b is H, the other is selected from nitrile and a C1-4 alkyl ester; when there is a double bond present between C2′ and C3′, R12 is selected from the group consisting of:(ia) phenyl, naphthyl, azulenyl or C5-10 heteroaryl, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C1-7 alkoxy, C3-20 heterocyclyloxy, C5-20 aryloxy, carboxy, —C(═O)OC1-7alkyl, —C(═O)OC3-20heterocyclyl, —C(═O)OC5-20aryl, C1-7 alkyl, C3-7 heterocyclyl and bis-oxy-C1-3 alkylene;(ib) C1-5 saturated aliphatic alkyl;(ic) C3-6 saturated cycloalkyl; wherein each of R21, R22 and R23 are independently selected from H, C1-3 saturated alkyl, C2-3 alkenyl, C2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R12 group is no more than 5; wherein one of R25a and R25b is H and the other is selected from: phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; and where R24 is selected from: H; C1-3 saturated alkyl; C2-3 alkenyl; C2-3 alkynyl; cyclopropyl; phenyl, which phenyl is optionally substituted by a group selected from halo, methyl, methoxy; pyridyl; and thiophenyl; when there is a single bond present between C2′ and C3′,R12 is where R26a and R26b are independently selected from H, F, C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C1-4 alkyl amido and C1-4 alkyl ester; or, when one of R26a and R26b is H, the other is selected from nitrile and a C1-4 alkyl ester; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, nitro, Me3Sn and halo;where R and R′ are independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups;wherein the heterocyclyl group in C3-20 heterocyclyloxy contains 1 to 10 ring heteroatoms selected from N, O and S;R7 is selected from H, R, OH, OR, SH, SR NH2, NHR, NHRR′, nitro, Me3Sn and halo;R″ is a C3-12 alkylene group, which chain is interrupted by one or more aromatic rings selected from the group consisting of benzene and pyridine;Y and Y′ are selected from O, S, or NH;R6′, R7′, R9′ are selected from the same groups as R6, R7 and R9 respectively;R20 is H or Me and R21a and R21b are both H or together form ═O;wherein the heterocyclyl group in C3-20 heterocyclyloxy contains 1 to 10 ring heteroatoms selected from N, O and S;wherein the heteroaryl group in C5-10 heteroaryl contains 1 to 4 ring heteroatoms selected from N, O and S;wherein the heterocyclyl group in —C(═O)OC3-20heterocyclyl contains 1 to 10 ring heteroatoms selected from N, O and S; andwherein the heterocyclyl group in C3-7 heterocyclyl contains 1 to 4 ring heteroatoms selected from N, O and S.
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