Pyrrolobenzodiazepines

Patent metadata

Field	Value
Publication number	US-9321774-B2
Application number	US-201314397843-A
Country	US
Kind code	B2
Filing date	Apr 30, 2013
Priority date	Apr 30, 2012
Publication date	Apr 26, 2016
Grant date	Apr 26, 2016

Abstract

A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; R 2 is selected from —H, —OH, ═O, ═CH 2 , —CN, —R, OR, halo, dihalo, ═CHR, ═CHRR′, —O—SO 2 —R, CO 2 R and COR; R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo; where R and R′ are independently selected from optionally substituted C 1-7 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; R 10 and R 11 either together form a double bond, or are selected from H and QR Q respectively, where Q is selected from O, S and NH and R Q is H or C 1-7 alkyl or H and SO x M, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where X 1 and Y 1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; X 2 and Y 2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Z 1 is selected from O and S; Z 2 is selected from CH and N; F is selected from a single bond and -(E-F 1 ) m —; each E is independently selected from a single bond, and —C(═O)—NH—; each F 1 is independently a C 3-20 heteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —(CH 2 ) n —C 3-20 heterocycloalkyl, and —O—(CH 2 ) n —C 3-20 heterocycloalkyl group; each n is 0-4; provided that A2 is not A2′, where X 1 and Y 1 of A2′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3′, where X 2 and Y 2 of A3′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and R 1 is C 1-4 alkyl.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
the dotted double bond indicates the presence of a single or double bond between C2 and C3;
R 2 is selected from —H, —OH, =0, ═CH 2 , —CN, —R, OR, halo, dihalo, ═CHR, ═CHRR′, —O—SO 2 —R, CO 2 R and COR;
R 7 is selected from H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
where R and R′ are independently selected from optionally substituted C 1-7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-20 heterocyclyl and C 5-20 aryl groups, wherein the optional substituents are selected from

—F, —Cl, —Br, —I, —OH, —OR 24 , —CH(OR 21 )(OR 21 ), —CH(OH)(OR 21 ), —CR(OR 21 )(OR 21 ), ═O, ═S, ═NR 22 , —C(═O)R 21 , —C(═O)OH, —C(═S)SH, —C(═O)SH, —C(═S)OH, —C(═NH)OH, —C(═NOH)OH, —C(═O)OR 21 , —OC(═O)R 21 , —OC(═O)OR 21 , —NR 23 R 23 , —C(═O)NR 23 R 23′ , —C(═S)NR 23 R 23′ , —NR 22 C(═O)R 21 , —OC(═O)NR 23 R 23′ , —N(R 22 )CONR 23 R 23′ , —NH—C(═NH)NH 2 , ═NR 22 , —C(═NR 22 )N(R 22 ) 2 , —NO 2 , —NO, —N 3 , —CN, —NC, —OCN, —NCO, —SCN, —NCS, —SH, —SR 21 , —SS—R 21 , —S(═O)R 21 , —S(═O)R 21 , —S(═O)OH, —S(═O) 2 OH, —S(═O)OR 21 , —S(═O) 2 OR 21 , —OS(═O)R 21 , —OS(═O)R 21 , —OS(═O) 2 OR 21 , —S(═O)NR 23 R 23′ , —S(═O) 2 NR 23 R 23′ , —NR 22 S(═O) 2 OH, —NR 22 S(═O) 2 R 21 , —NR 22 S(═O)R 21 , —PR 22 2 , —P(═O) 2 , —P(═O)(R 21 ) 2 , —P(═O)(OH) 2 , —P(═O)(OR 22 ) 2 , —OP(═O)(OH) 2 , —OP(═O)(OR 22 ) 2 , —OP(OH) 2 , —OP(OR 22 ) 2 , —OP(OR 22 )—N(R 22 ) 2 ; and —OP(═O)(OR 22 )—N(R 22 ) 2 wherein
each R 21 is independently selected from C 1-7 alkyl, a C 3-20 heterocyclyl, or a C 5-20 aryl;
each R 22 is independently selected from hydrogen C 1-7 alkyl, a C 3-20 heterocyclyl or a C 5-20 aryl;
each R 23 is independently selected from hydrogen C 1-7 alkyl a C 3-20 heterocyclyl a C 5-20 or, in the case of a “cyclic” amino group, R 23 and R 23′ , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms;
each R 24 is independently alkyl; and
each R 25 is independently selected from optionally substituted C 1-7 alkyl a C 3-20 heterocyclyl, or a C 5-20 aryl;
R 10 and R 11 either together form a double bond, or are selected from H and QR Q respectively, where Q is selected from O, S and NH and R Q is H or C 1-7 alkyl or H and SO X M, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation;
A is selected from A1, A2, A3, A4 or A5:

Where
X 1 and Y 1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively;
X 2 and Y 2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S;
N and S; N and O; and CH and O, respectively;
Z 1 is selected from O and S;
Z 2 is selected from CH and N;
F is selected from a single bond and -(E-F 1 ) m —;
each E is independently selected from a single bond, and —C(═O)—NH—;
each F 1 is independently a C 5-20 heteroarylene group;
m is 1, 2 or 3;
G is selected from hydrogen, C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —(CH 2 ) n —C 3-20 heterocyclyl, and —O—(CH 2 ) n —C 3-20 heterocyclyl group;
each n is 0-4;
wherein C 3-20 heterocyclyl pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 rings atoms, of which 1 to 10 are ring heteroatoms selected from N, O and S;
wherein C 5-20 heteroarylene pertains to a divalent moiety obtained by removing a hydrogen atom from each of two ring atoms of a heteroaromatic compound, which moiety has from 3 to 20 rings atoms, of which 1 to 10 are ring heteroatoms selected from N, O and S;
provided that A2 is not A2:

where X 1 and Y 1 of A2′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and
provided that A3 is not A3′:

where X 2 and Y 2 of A3′ are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively;
B is either a single bond or:

where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and
R 1 is C 1-4 alkyl.

2. A compound according to claim 1 , wherein R 7 is OR 7A , where R 7A is optionally substituted C 1-7 alkyl.

3. A compound according to claim 2 , wherein R 7A is selected from Me, CH 2 Ph and allyl.

4. A compound according to claim 1 , wherein R 10 and R 11 form a double bond together.

5. A compound according to claim 1 , wherein R 1 is C 1-2 alkyl.

6. A compound according to claim 5 , wherein R 1 is methyl.

7. A compound according to claim 1 , wherein R 2 is selected from —H, ═CH 2 , —R, ═CHR, and ═CRR′.

8. A compound according to claim 1 , wherein R 2 is of the configuration C1:

9. A compound according to claim 1 , wherein R 2 is selected from optionally substituted phenyl, optionally substituted napthyl, optionally substituted pyridyl, optionally substituted quinolinyl or isoquinolinyl.

10. A compound according to claim 9 , wherein R 2 is selected from 4-methoxy-phenyl, 3-methoxyphenyl, 4-ethoxy-phenyl, 3-ethoxy-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 3,4-bisoxymethylene-phenyl, 4-methylthienyl, 4-cyanophenyl, 4-phenoxyphenyl, quinolin-3-yl and quinolin-6-yl, isoquinolin-3-yl and isoquinolin-6-yl, 2-thienyl, 2-furanyl, methoxynaphthyl, and naphthyl.

11. A compound according to claim 1 , wherein R 2 is selected from:
(a) C 1-5 saturated aliphatic alkyl;
(b) C 3-6 saturated cycloalkyl;
(c)

wherein each of R 21 , R 22 and R 23 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 12 group is no more than 5;
(d)

wherein one of R 25a and R 25b 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
(e)

where R 24 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.

12. A compound according to claim 1 , wherein if R 2 is selected from ═O, ═CH 2 , ═CHR, ═CHRR′, there is a single bond between C2 and C3.

13. A compound according to claim 1 , wherein there is no double bond between C2 and C3 and R 2 is H.

14. A compound according to claim 1 , wherein X 1 and Y 1 are selected from N a

Assignees

• Medimmune Ltd

Inventors

• Howard Philip Wilson
• Thurston David Edwin
• Rahman Khondaker Mirazur
• Taylor Peter William

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title