Pyrrolobenzodiazepines and conjugates thereof

Patent metadata

Field	Value
Publication number	US-2016144052-A1
Application number	US-201414774535-A
Country	US
Kind code	A1
Filing date	Mar 13, 2014
Priority date	Mar 13, 2013
Publication date	May 26, 2016
Grant date	—

Abstract

A conjugate of formula (A):

First claim

1 .- 96 . (canceled)

97 . A conjugate of formula (A):

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, R 2 is selected from the group consisting of:
(ia) C 5-10 aryl group, optionally substituted by one or more substituents selected from the group comprising: halo, nitro, cyano, ether, carboxy, ester, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(ib) C 1-5 saturated aliphatic alkyl;
(ic) C 3-6 saturated cycloalkyl;
(id)

wherein each of R 31 , R 32 and R 33 are independently selected from H, C 1-3 saturated alkyl, C 2-3 alkenyl, C 2-3 alkynyl and cyclopropyl, where the total number of carbon atoms in the R 2 group is no more than 5;
(ie)

wherein one of R 35a and R 35b 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 R 34 is selected from: H; C 1-3 saturated alkyl; C 2-3 alkenyl; C 2-3 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,
R 2 is

where R 36a and R 36b are independently selected from H, F, C 1-4 saturated alkyl, C 2-3 alkenyl, which alkyl and alkenyl groups are optionally substituted by a group selected from C 1-4 alkyl amido and C 1-4 alkyl ester; or, when one of R 16a and R 16b is H, the other is selected from nitrile and a C 1-4 alkyl ester;
D′ represents either group D′1 or D′2:

wherein the dotted line indicates the optional presence of a double bond between C2′ and C3′;
R 6 and R 9 are independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
R 7 is independently selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, NO 2 , Me 3 Sn and halo;
Y is selected from formulae A1, A2, A3, A4, A5 and A6:

L is a linker connected to a cell binding agent;
CBA is the cell binding agent;
n is an integer selected in the range of 0 to 48;
R A4 is a C 1-6 alkylene group;
either
(a) R 10 is H, and R 11 is OH, OR A , where R A is C 1-4 alkyl; or
(b) R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound; or
(c) R 10 is H and R 11 is OSO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R and R′ are each independently selected from optionally substituted C 1-12 alkyl, O 3-20 heterocyclyl and C 5-20 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;
wherein R 16 , R 17 , R 19 , R 20 , R 21 and R 22 are as defined for R 6 , R 7 , R 9 , R 10 , R 11 and R 2 respectively;
wherein Z is CH or N;
wherein T and T′ are independently selected from a single bond or a C 1-9 alkylene, which chain may be interrupted by one or more heteroatoms e.g. O, S, N(H), NMe, provided 4 that the number of atoms in the shortest chain of atoms between X and X′ is 3 to 12 atoms; and
X and X′ are independently selected from O, S and N(H);
except that there cannot be double bonds between both C2 and C3 and C2′ and C3′.

98 . The conjugate according to claim 97 , wherein R 9 is H and R 6 is H.

99 . The conjugate according to claim 97 , wherein R 7 is OR 7A , where R 7A is Me.

100 . The conjugate according to claim 97 , wherein X is O and T is selected from a single bond, C 1 , and a C 2 alkylene group.

101 . The conjugate according to claim 100 , wherein T is a C 1 alkylene group.

102 . The conjugate according to claim 97 , wherein D is D2.

103 . The conjugate according to claim 97 , wherein D is D1, there is a double bond between C2 and C3, and:
(a) R 2 is phenyl, optionally substituted by one to three substituent groups selected from methoxy, ethoxy, fluoro, chloro, cyano, bis-oxy-methylene, methyl-piperazinyl, morpholino and methyl-thiophenyl; (b) R 2 is methyl, ethyl or propyl; (c) cyclopropyl; (d) a group of formula:

wherein the total number of carbon atoms in the R 2 group is no more than 4;
(e) the group:

(f) a group of formula:

wherein R 34 is selected from H and methyl.

104 . The conjugate according to claim 97 , wherein D is D1, there is a single bond between C2 and C3, and R 2 is

wherein
(a) R 36a and R 36b are both H;
(b) R 36a and R 36b are both methyl; or
(c) one of R 36a and R 36b is H, and the other is selected from methyl and ethyl.

105 . The conjugate according to claim 97 , wherein R 10 and R 11 form a nitrogen-carbon double bond between the nitrogen and carbon atoms to which they are bound.

106 . The conjugate according to claim 97 , wherein R 16 , R 17 , R 19 , R 20 , R 21 , D′, X′ and T′ are the same as R 6 , R 7 , R 9 , R 10 , R 11 , D, X and T respectively.

107 . The conjugate according to claim 97 , wherein L is of formula:
(a) -L A -(CH 2 ) m — (L1) where m is from 0 to 6; and L A is selected from:

where Ar represents a C 5-6 arylene group;
(b) -LA-(CH 2 ) m —O— (L2)
Where m is from 0 to 6;
(c) -L A -(CH 2 ) q —O—C(═O)—NH—(CH 2 ) p — (L3)
Where q is from 1 to 3, and p is from 1 to 3; or
(d)

Where m is from 0 to 6;
X 1 and X 2 are amino acid groups, selected from natural amino acids, which may be modified.

108 . The conjugate according to claim 107 , wherein the group —X 1 —X 2 — is selected from:
-Phe-Lys-,
-Val-Ala-,
-Val-Lys-,
-Ala-Lys-,
-Val-Cit-.

109 . The conjugate accord

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Flygare John A
• Pillow Thomas
• Wei Binqing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07K16/40

  against enzymes · CPC title