Targeted pyrrolobenzodiazapine conjugates
View Patent ↗Provided are Conjugate comprising PBDs conjugated to a targeting agent and methods of using such PBDs.
1. A Conjugate having formula I:
L-(LU-D)p (I)
or a pharmaceutically acceptable salt thereof;
wherein L is a Ligand Unit selected from the group consisting of a full length antibody and an antigen binding fragment of a full length antibody;
LU is a Linker unit of formula X:
wherein E is of formula:
the asterisk indicates the point of attachment to a Drug Unit and the wavy line indicates the point of attachment to the Ligand Unit, and
wherein:
-A 1 - is selected from the group consisting of:
wherein n is 0 to 6;
wherein n is 0 to 6;
wherein n is 0 or 1, and m is 0 to 30; and
wherein n is 0 or 1, and m is 0 to 30;
wherein the asterisk indicates the point of attachment to the nitrogen atom of Formula X, and the wavy line indicates the point of attachment to the Ligand unit;
p is 1 to 20; and
D is a Drug unit, wherein the Drug Unit is a PBD dimer of formula I:
wherein:
R 2 is of formula II:
wherein A is a C 5-7 aryl group, X is attached to the carbonyl carbon of Formula X and is selected from the group consisting of: —O—, —S—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , wherein m is 1 to 3; and either:
(i) Q 1 is a single bond and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of 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;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 1-7 alkyl, C 3-7 heterocyclyl, dimethyl-aminopropyloxy, piperazinyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; and either:
(a) R 10 is H, and R 11 is OH or OR A , wherein R A is C 1-4 alkyl,
(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 SO z M, wherein z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms that are selected from the group consisting of O, S, and NH, or by an aromatic ring;
Y and Y′ are selected from the group consisting of O, S, and NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 , respectively, and R 10′ and R 11′ are the same as R 10 and R 11 , respectively, wherein if R 11 and R 11′ are SO z M, then each M is a monovalent pharmaceutically acceptable cation or together is a divalent pharmaceutically acceptable cation;
wherein C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S; and
wherein C 3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.
2. The Conjugate according to claim 1 wherein -LU-D is
wherein the wavy line indicates covalent attachment to the Ligand unit.
3. The Conjugate according to claim 2 wherein the Ligand unit is an antibody or an antigen-binding fragment thereof.
4. The Conjugate according to claim 3 wherein the monoclonal antibody is a humanized 1F6 antibody.
5. A compound having formula:
G 1 -L 1 -L 2 -D,
or a pharmaceutically acceptable salt thereof,
wherein -L 1 -L 2 - has the structure of formula X′:
wherein E is of formula:
the asterisk indicates the point of attachment to a Drug Unit, and the way line indicates the point of attachment to G 1 , wherein:
G 1 - is selected from the group consisting of:
wherein n is 0 to 6;
wherein n is 0 to 6;
wherein n is 0 or 1, and m is 0 to 30;
wherein n is 0 or 1, and m is 0 to 30; and
wherein the asterisk indicates the point of attachment to the nitrogen atom of Formula X′, and D is a Drug unit, wherein the Drug Unit is a PBD dimer having formula I:
wherein:
R 2 is of formula II:
wherein A is a C 5-7 aryl group, X is attached to the carbonyl carbon of Formula X and is selected from the group consisting of: —O—, —S—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , wherein m is 1 to 3; and either:
(i) Q 1 is a single bond and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of 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;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, ether, C 1-7 alkoxy, C 3-7 heterocyclyl, dimethyl-aminopropyloxy, piperazinyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR', nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; and either:
(a) R 10 is H, and R 11 is OH or OR A , where R A is C 1-4 alkyl,
(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 SO z M, wherein z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms that are selected from the group consisting of O, S, and NH, and/or by an aromatic ring;
Y and Y′ are selected from the group consisting of O, S, and NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 , respectively, and R 10′ and R 11′ are the same as R 10 and R 11 , respectively, wherein if R 11 and R 11′ are SO z M, then each M is a monovalent pharmaceutically acceptable cation, or together is a divalent pharmaceutically acceptable cation;
wherein C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S; and
wherein C 3-7 heterocyclyl is a monovalent moiet obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.
6. The compound according to claim 5 wherein the compound is
7. A compound having the structure of
or a pharmaceutically acceptable salt thereof,
wherein L 1 is a Specificity unit, wherein the Specificity unit is an amino acid sequence and is cleavable by the action of an enzyme;
D is a Drug unit, wherein the Drug unit is a PBD dimer of formula I:
wherein:
R 2 is of formula II:
wherein A is a C 5-7 aryl group, X is attached to the amino acid sequence of L 1 through the carbonyl carbon of it C-terminal amino acid residue and is selected from the group consisting of —O—, —S—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , wherein m is 1 to 3; and either:
(i) Q 1 is a single bond and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of 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;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 1-7 alkyl, C 3-7 heterocyclyl, dimethyl-aminopropyloxy, piperazinyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; and either:
(a) R 10 is H, and R 11 is OH or OR A , where R A is C 1-4 alkyl,
(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 SO z M, where z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms that are selected from the group consisting of O, S, and NH, and/or by an aromatic ring;
Y and Y′ are selected from the group consisting of O, S, and NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 , respectively, and R 10′ and R 11′ are the same as R 10 and R 11 , respectively, wherein if R 11 and R 11′ are SO z M, then each M is a monovalent pharmaceutically acceptable cation, or together is a divalent pharmaceutically acceptable cation;
wherein C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S; and
wherein C 3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.
8. The compound according to claim 7 , wherein L 1 is —NH-X 1 -X 2 -CO— wherein -X 1 -X 2 - is selected from the group consisting of -Phe-Lys-, -Val-Ala-, -Val-Lys-, -Ala-Lys-, -Val-Cit-, -Phe-Cit-, -Leu-Cit-, -Ile-Cit-, -Phe-Arg-, and -Trp-Cit-, wherein —NH— of L 1 is the amino group of X 1 and CO of L 1 is the carbonyl group of X 2 .
9. The compound according to claim 7 , wherein L 1 is —NH-X 1 -X 2 -CO— wherein -X 1 -X 2 - is selected from the group consisting of -Gly-Gly-, -Pro-Pro-, and -Val-Glu-, wherein —NH— of L 1 is the amino group of X 1 and CO of L 1 is the carbonyl group of X 2 .
10. The compound according to claim 9 , wherein the compound has the structure of:
11. A method of preparing a compound having the structure of
G 1 -L 1 -L 2 -D
wherein -L 1 - is a Specificity unit, wherein the Specificity unit is an amino acid sequence and is cleavable by the action of an enzyme;
L 2 is a bond;
G 1 is selected from the group consisting of:
wherein n is 0 to 6; and
wherein n is 0 or 1, and m is 0 to 30;
and wherein the asterisk indicates the point of attachment to L 1 ;
D is a Drug unit, wherein the Drug unit is a PBD dimer of formula I:
wherein:
R 2 is of formula II:
wherein A is a C 5-7 aryl group, X is attached to the carbonyl carbon of Formula X and is selected from the group consisting of —O—, —S—, —NH(C═O)—, and —N(R N )—, wherein R N is selected from the group consisting of H, C 1-4 alkyl and (C 2 H 4 O) m CH 3 , wherein m is 1 to 3; and either:
(i) Q 1 is a single bond and Q 2 is selected from the group consisting of a single bond and —Z—(CH 2 ) n —, wherein Z is selected from the group consisting of 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;
R 12 is a C 5-10 aryl group, optionally substituted by one or more substituents selected from the group consisting of halo, nitro, cyano, C 1-7 alkoxy, C 1-7 alkyl, C 3-7 heterocyclyl, dimethyl-aminopropyloxy, piperazinyl and bis-oxy-C 1-3 alkylene;
R 6 and R 9 are independently selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo;
R 7 is selected from the group consisting of H, R, OH, OR, SH, SR, NH 2 , NHR, NRR′, nitro, Me 3 Sn and halo, wherein R and R′ are independently selected from the group consisting of optionally substituted C 1-12 alkyl, C 3-20 heterocyclyl and C 5-20 aryl groups; and either:
(a) R 10 is H, and R 11 is OH or OR A , wherein R A is C 1-4 alkyl,
(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 SO z M, wherein z is 2 or 3 and M is a monovalent pharmaceutically acceptable cation;
R″ is a C 3-12 alkylene group, which chain is optionally interrupted by one or more heteroatoms that are selected from the group consisting of O, S, and NH, and/or by an aromatic ring;
Y and Y′ are selected from the group consisting of O, S, and NH;
R 6′ , R 7′ , R 9′ are selected from the same groups as R 6 , R 7 and R 9 , respectively, and R 10′ and R 11′ are the same as R 10 and R 11 , respectively, wherein if R 11 and R 11′ are SO z M, then each M is a monovalent pharmaceutically acceptable cation, or together is a divalent pharmaceutically acceptable cation,
said method comprising the step of condensing a compound of formula L 1 -L 2 -D, suitably protected, with L 1 , L 2 and D as previously defined, with a precursor of G 1 having the structure selected from the group consisting of:
wherein n is 0 to 6; and
wherein n is 0 or 1, and m is 0 to 30; and
wherein from said condensation G 1 and L 1 are attached to each other through an amide bond;
wherein C 3-20 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 20 ring atoms, of which 1 to 10 are heteroatoms selected from the group consisting of N, O and S; and
wherein C 3-7 heterocyclyl is a monovalent moiety obtained by removing a hydrogen atom of a heterocyclic compound which has 3 to 7 ring atoms, of which 1 to 4 are heteroatoms selected from the group consisting of N, O and S.