Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation

Patent metadata

Field	Value
Publication number	US-9745303-B2
Application number	US-201314434830-A
Country	US
Kind code	B2
Filing date	Oct 11, 2013
Priority date	Oct 12, 2012
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

A method of synthesing a compound of formula (I) from a compound of formula (III).

First claim

The invention claimed is:

1. A method of synthesizing a compound of formula III:,

from a compound of formula VI:

which proceeds via a compound of formula VIIa or VI lb:

wherein:
R 2 is selected from a group of:
(a) formula IIa:

where A is a phenyl or C 5-7 heteroaryl group, and either:
(i) Q 1 is a single bond, and Q 2 is selected from a single bond and —Z—(CH 2 ) n —, where Z is selected from a single bond, O, S and NH and n is from 1 to 3, or
(ii) Q 1 is —CH═CH—, and Q 2 is a single bond;
(b) formula IIb:

R C1 , R C2 and R C3 are independently selected from H and unsubstituted C 1-2 alkyl;
(c) formula IIc:

L 2 is selected from a single bond and a group of:
(a)

wherein n is 0 to 3;
(b)

 wherein n is as defined above;
(c)

 wherein n is as defined above; and
(d)

 wherein n is as defined above, E is O, S or NR, D is N, CH, or CR, and F is N, CH, or CR;

L 1 is:

 where X is such that L 1 is an amino-acid residue, a dipeptide residue or a tripeptide residue;
Prot is selected from Fmoc (fluorenylmethyloxycarbonyl), Teoc (2-(trimethylsilyl)ethoxycarbonyl) and Boc (t-butoxycarbonyl);
R 12 is selected from:
(a) C 5-10 heteroaryl, phenyl, or naphthyl group, optionally substituted by one or more substituents selected from the group consisting of: halo, nitro, cyano, C 1-7 alkoxy, C 3-20 heterocyclyloxy, phenoxy, naphthyloxy, C 5-20 heteroaryloxy, C 1-7 alkyl, C 3-7 heterocyclyl and bis-oxy-C 1-3 alkylene;
(b) C 1-5 saturated aliphatic alkyl;
(c) C 3-6 saturated cycloalkyl;
(d)

 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;
(e)

 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
(f)

 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;

R 6 , R 6 ′ , R 9 and R 9′ are H;
R 7 is C 1-7 , alkoxy;
R″ is a C 3-12 alkylene group, which chain may be interrupted by one or more heteroatoms selected from O, S, NR N2 (where R N2 is H or C 1-4 alkyl), and/or aromatic rings selected from benzene and pyridine;
Y and Y′ are selected from O, S, and NH;
SEM is 2-((trimethylsilyl)ethoxy)methyl;
OTf is CF 3 SO 3 ;
C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms selected from O, S, and N;
C 3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms selected from O, S, and N;
C 5-20 heteroaryl is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a heteroaromatic compound, which moiety has from 5 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms selected from O, S, and N;
C 5-10 heteroaryl is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a heteroaromatic compound, which moiety has from 5 to 10 ring atoms, of which from 1 to 4 are ring heteroatoms selected from O, S, and N;
C 5-7 heteroaryl is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of a heteroaromatic compound, which moiety has from 5 to 20 ring atoms, of which from 1 to 4 are ring heteroatoms selected from O, S, and N; and
R 7′ is selected from the same groups as R 7 ;
wherein the R 2 group is introduced by coupling a compound of formula XIa, XIb or XIc:

(a)

(b)

(c)

wherein the R 12 group is introduced by coupling a derivative comprising R 12 which, when R 12 is

 is

 or otherwise the derivative is R B′ —R 12 , where R B represents boronic acid or a boronate and R B′ represents boronic acid or a boronate.

2. The method according to claim 1 , wherein Y and Y′ are O and R″ is a C 3-7 alkylene group with no substituents.

3. The method according to claim 2 , wherein R″ is a C 3 , C 5 or C 7 alkylene group.

4. The method according to claim 1 , wherein R 7 is methoxy.

5. The method according to claim 1 , wherein R 12 is selected from:
(a) phenyl;
(b) methyl, ethyl or propyl;
(c)

(d)

 wherein one of R 25a and R 25b is H and the other is phenyl; and
(e)

 wherein R 24 is selected from H and methyl.

6. The method according to claims 1 , wherein R 2 is a group of formula IIa, and Q 1 is a single bond.

7. The method according to claim 6 , wherein Q 2 is a single bond.

8. The method according to claim 6

Assignees

• Spirogen Sàrl
• Medimmune Ltd

Inventors

• Howard Philip Wilson

Classifications

• 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

• C07K5/06139

  with the first amino acid being heterocyclic · CPC title

• C07K5/06043

  Leu-amino acid · CPC title

• A61K47/65

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title