Pyrrolobenzodiazepines and conjugates thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/5517
C07D-519/00
C07D-487/04
A61K-047/68
출원번호
US-0510397
(2014-09-10)
등록번호
US-10188746
(2019-01-29)
국제출원번호
PCT/EP2014/069248
(2014-09-10)
국제공개번호
WO2016/037644
(2016-03-17)
발명자
/ 주소
Howard, Philip Wilson
출원인 / 주소
MEDIMMUNE LIMITED
대리인 / 주소
Kolom, Melissa E.
인용정보
피인용 횟수 :
0인용 특허 :
38
초록▼
A conjugate of formula (A): Wherein Y is selected from formulae A1 and A2: Z1 is a C1-3 alkylene group; Z2 is a C1-3 alkylene group; Q is: where QX is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue; L is a linker connected to a cell binding agent; CBA is the cell b
A conjugate of formula (A): Wherein Y is selected from formulae A1 and A2: Z1 is a C1-3 alkylene group; Z2 is a C1-3 alkylene group; Q is: where QX is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue; L is a linker connected to a cell binding agent; CBA is the cell binding agent; and n is an integer between 0 and 48.
대표청구항▼
1. A conjugate of formula (A): and salts and solvates thereof, wherein:D represents either group D1 or D2: the dotted line indicates the optional presence of a double bond between C2 and C3;when there is a double bond present between C2 and C3, R2 is selected from the group consisting of:(ia) C5-10
1. A conjugate of formula (A): and salts and solvates thereof, wherein:D represents either group D1 or D2: the dotted line indicates the optional presence of a double bond between C2 and C3;when there is a double bond present between C2 and C3, R2 is selected from the group consisting of:(ia) C5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, 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;(id) wherein each of R31, R32 and R33 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; (ie) wherein one of R35a and R35b 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 (if) where R34 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; (ig) halo;when there is a single bond present between C2 and C3,R2 is where R36a and R36b 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; R6 and R9 are independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, SnMe3 and halo;either (a) R10 is H, and R11 is OH or ORA, where RA is C1-4 alkyl; or(b) R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or(c) R10 is H and R11 is OSOZM, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation; or(d) R11 is OH or ORA, where RA is C1-4 alkyl and R10 is selected from: where Rz is selected from: (z-i) (z-ii) OC(═O)CH3;(z-iii) NO2;(z-iv) OMe;(z-v) glucoronide;(z-vi) —C(═O)—X1—NHC(═O)X2—NH—RZC, where —C(═O)—X1—NH— and —C(═O)—X2—NH— represent natural amino acid residues and Rzc is selected from Me, OMe, OCH2CH2OMe;Y is selected from formulae A1 and A2: Z1 is a C1-3 alkylene group;Z2 is a C1-3 alkylene group;Q is: where QX is such that Q is an amino-acid residue, a dipeptide residue or a tripeptide residue; L is a linker connected to a cell binding agent;CBA is the cell binding agent;n is an integer between 0 and 48;R and R′ are each independently selected from optionally substituted C1-12 alkyl, C3-20 heterocyclyl and C5-20 aryl groups, and optionally in relation to the group NRR′, R and R′ together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered heterocyclic ring;R8 is either:(a) independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, SnMe3 and halo; or(b) of formula A*: wherein: D′ represents either group D′1 or D2: wherein the dotted line indicates the optional presence of a double bond between C2′ and C3′;R17 is independently selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR′, NO2, SnMe3 and halo;R″ is a C3-12 alkylene group, which chain may be interrupted by one or more heteroatoms, e.g. O, S, N(H), NMe and/or aromatic rings, e.g. benzene or pyridine, which rings are optionally substituted; andX and X′ are independently selected from O, S and N(H); andR22, R16, R19, R20 and R21 are as defined for R2, R6, R9, R10 and R11 respectively. 2. The conjugate according to claim 1, wherein R9 is H and R6 is H. 3. The conjugate according to claim 1, wherein D is D1, there is a double bond between C2 and C3, and R2 is: a C5-7 aryl group which bears one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methylthiophenyl; or(b) a C1-5 saturated aliphatic alkyl group; or(c) a C3-6 saturated cycloalkyl group; or(d) a group of formula: wherein the total number of carbon atoms in the R2 group is no more than 4; or(e) or (f) a group of formula: wherein R34 is selected from H, methyl, ethyl, ethenyl and ethynyl. 4. The conjugate according to claim 1, wherein D is D1, there is a double bond between C2 and C3, and R2 is and: (a) R36a and R36b are both H; or(b) R36a and R36b are both methyl; or(c) R36a and R36b is H, and the other is selected from C1-4 saturated alkyl, C2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted. 5. The conjugate according to claim 1, wherein R10 is H, and R11 is OH. 6. The conjugate according to claim 1, wherein R10 and R11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound. 7. The conjugate according to claim 1, wherein R11 is OH or ORA and R10 is selected from: wherein —C(═O)—X1—NHC(═O)X2—NH—, selected from: -Phe-Lys-, -Val-Ala- -Val-Lys-, -Ala-Lys- and -Val-Cit-. 8. The conjugate according to claim 1, wherein R8 is OR8A, where R8A is optionally substituted C1-4 alkyl. 9. The conjugate according to claim 1, wherein R8 is of formula A*. 10. The conjugate according to claim 9, wherein X and X′ are O, R″ is C3-7 alkylene and R17 is OR17A, where R17A is optionally substituted C1-4 alkyl. 11. The conjugate according to claim 9, wherein R16, R19, R20, R21 and D′ are the same as R6, R9, R10, R11 and D respectively. 12. The conjugate according to claim 1, wherein L is of formula: -LA-(CH2)m-ehere m is from 0 to 6; andLA is selected from: where Ar represents a C5-6 arylene group. 13. The conjugate according to claim 1, wherein Q is selected from: NH-Phe-Lys-C═O,NHVal-Ala-C═O,NHVal-Lys-C═O,NHAla-Lys-C═O,NH-Val-Cit-C═O,NH-Phe-Cit-C═O,NH-Leu-Cit-C═O,NH-Ile-Cit-C═O,NH-Phe-Arg-C═O, andNH-Trp-Cit-C═O; where Cit is citrulline. 14. A pharmaceutical composition comprising the conjugate of claim 1 a pharmaceutically acceptable diluent, carrier or excipient. 15. A compound of formula (B): wherein: YL is selected from formulae B1 and B2: G is a linker for connecting to a cell binding agent; andD, R6, R8, R9, R10, R11, Z1 and Z2, Q and n are as defined in claim 1. 16. The compound according to claim 15, wherein G is of formula: GA-(CH2)m-where m is from 0 to 6; andGA is selected from: where Ar represents a C5-6 arylene group. 17. A compound of formula (C): wherein Yc is selected from formulae C1 and C2: and D, R6, R8, R9, R10, R11, Z1 and Z2 are as defined in claim 1.
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