US 12,246,196 B2
Antibody-drug conjugates comprising substituted benzo[e]pyrrolo[1,2-a][1,4]diazepines
Narihiro Toda, Tokyo (JP); Yusuke Ota, Tokyo (JP); Fuminao Doi, Tokyo (JP); Masaki Meguro, Tokyo (JP); Ichiro Hayakawa, Tokyo (JP); Shinji Ashida, Tokyo (JP); Takeshi Masuda, Tokyo (JP); Takashi Nakada, Tokyo (JP); Mitsuhiro Iwamoto, Tokyo (JP); Naoya Harada, Tokyo (JP); Tomoko Terauchi, Tokyo (JP); Daisuke Okajima, Tokyo (JP); Kensuke Nakamura, Tokyo (JP); Hiroaki Uchida, Tokyo (JP); and Hirofumi Hamada, Tokyo (JP)
Assigned to DAIICHI SANKYO COMPANY, LIMITED, Tokyo (JP)
Filed by DAIICHI SANKYO COMPANY, LIMITED, Tokyo (JP)
Filed on Jun. 26, 2022, as Appl. No. 17/849,688.
Application 17/849,688 is a division of application No. 16/651,501, granted, now 11,628,223, previously published as PCT/JP2018/036252, filed on Sep. 28, 2018.
Claims priority of application No. 2017-190713 (JP), filed on Sep. 29, 2017.
Prior Publication US 2022/0395579 A1, Dec. 15, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 487/04 (2006.01); A61K 47/68 (2017.01); A61P 35/00 (2006.01); C07D 487/20 (2006.01); C07K 16/30 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 47/68035 (2023.08); A61P 35/00 (2018.01); C07K 16/30 (2013.01)] 34 Claims
 
1. An antibody-drug conjugate represented by [Formula 1]:
Ab-[-L-D]m1  [Formula 1]
wherein:
Ab represents an immunoglobulin G (IgG) antibody or a functional fragment of the immunoglobulin G (IgG) antibody;
wherein the immunoglobulin G (IgG) antibody optionally has a remodeled glycan; and
wherein the immunoglobulin G (IgG) antibody may bond to L directly via its amino acid residue, via a glycan, or via a remodeled glycan;
L represents the following formula:
-Lb-La-Lp-NH—B—CH2—OC(O)—*
wherein:
Lb represents a spacer bonding La and a glycan or remodeled glycan of Ab represented by the following [Formula 5], [Formula 6], [Formula 7], or [Formula 67]:

OG Complex Work Unit Chemistry
wherein:
custom character represents bonding to a glycan or remodeled glycan of Ab; and
* represents bonding to La;
La represents —C(O)—(CH2CH2)n2—C(O)—, —C(O)—(CH2CH2)n2—C(O)—NH—(CH2CH2)n3—C(O)—, —C(O)—(CH2CH2)n2—C(O)—NH—(CH2CH2O)n3—CH2—C(O)—, —C(O)—(CH2CH2)n2—NH—C(O)—(CH2CH2O)n3—CH2CH2—C(O)—, —(CH2)n4—O—C(O)—, —(CH2)n9—C(O)—, or —(CH2CH2)n10—C(O)—NH—(CH2CH2O)n11—CH2CH2—C(O)—;
n2 represents 1, 2, or 3;
n3 represents 1, 2, 3, 4, or 5;
n4 represents 0, 1, or 2;
n9 represents 2,3,4,5,6,or 7;
n1° represents 1, 2, or 3;
n″ represents 6, 7, 8, 9, or 10;
Lp represents an amino acid residue consisting of two, three, four, five, six, or seven amino acids selected from the group consisting of alanine (A), arginine (R), asparagine (N), aspartic add (D), citrulline (Cit), cysteine (C), glutamic acid (E), glutamine (Q), glycine (G), histidine (H), isoleucine (I), leucine (L), lysine (K), methionine (M), phenylalanine (F), proline (P), selenocysteine (U), serine (S), threonine (T), tryptophan (W), tyrosine (Y), and valine (V);
B represents phenylene or heteroarylene; and
* represents bonding to D;
D represents a drug represented by the following [Formula 2]:

OG Complex Work Unit Chemistry
wherein:
X represents —NH—, —O—, or —S—;
Y represents —NH—, —O—, or —S—;
R1 represents H, halogen, C is alkyl, NR′R″, OH, OC is alkyl, SH, or SC is alkyl;
R2 represents H, halogen, C is alkyl, NR′R″, OH, OC is alkyl, SH, or SC is alkyl;
(i) R3 represents H; and
R° and R3, taken together with the carbon atom to which they are bound, form ═CH2 or a saturated 3- to 5-membered spirocyclyl; or
(ii) R3 and R°, taken together with the carbon atoms to which they are bound, form —CR5═CH; and
R5 represents C1-6 alkyl, aryl, or heteroaryl;
wherein the Cis alkyl Is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, and OC1-6 alkyl;
wherein the aryl or heteroaryl Is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-6 alkyl, C(NR′)NR″R″, NR′R″, NHC(NR′)NR″R″, NHC(O)R′, OH, OC1-6 alkyl, SC is alkyl, and C3-5 cycloalkoxy;
wherein each Cis alkyl substituent is optionally and Independently substituted with one, two, or three substituents Independently selected from the group consisting of halogen, C(NR′)NR″R″, NR′R″, NHC(NR′)NR″R″, OH, and OC(O)R′; and
wherein each OC is alkyl substituent Is optionally and independently substituted with one, two, or three independently selected halogen substituents; or
(iii) R3, W, and R3, taken together with the carbon atoms to which they are bound, form a 1,2-phenylene or 6-membered heterocyclylene;
wherein the 1,2-phenylene or 6-membered heterocyclylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Cis alkyl, and OC is alkyl; and
wherein each C1-4 alkyl and OC1-4 alkyl substituent Is optionally and independently substituted with one, two, or three Independently selected halogen substituents;
each R′ independently represents H or Cis alkyl;
each R″ independently represents H or Cis alkyl;
each R″ independently represents H or Cis alkyl;
R6 represents H;
R7 represents H; or
R6 and R′, taken together with the carbon atom and nitrogen atom to which they are bound, form —CH═N—;
R8 represents OH or OC1-3 alkyl;
ring A represents a saturated 3- to 5-membered spirocyclyl, wherein the 3- to 5-membered spirocyclyl is optionally substituted with one, two, three, or four independently selected halogen substituents;
n1 represents 2, 3, 4, 5, 6, 7, or 8;
* represents bonding to L; and
m1 represents 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
 
25. The antibody-drug conjugate according to claim 1, wherein the average number of conjugated drug molecules per immunoglobulin G (IgG) in the antibody-drug conjugate is in the range of 1 to 3 or in the range of 3 to 5.