US2018037581A1PendingUtilityA1
Heteroarylene-bridged benzodiazepine dimers, conjugates thereof, and methods of making and using
Est. expiryJan 14, 2035(~8.5 yrs left)· nominal 20-yr term from priority
Inventors:Ivar M. McdonaldNaidu S. ChowdariWalter Lewis JohnsonYong ZhangRobert M. BorzilleriSanjeev Gangwar
A61P 35/00A61P 11/00A61P 1/00C07D 487/04C07K 5/06052C07D 519/00A61K 47/6851A61K 47/6889C07D 471/04A61K 47/6803
58
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Claims
Abstract
Benzodiazepine dimers having a structure represented by wherein X comprises a heteroaromatic moiety and is as further defined in the application; R 1 is and the other variables in formulae (I), (Ia), and (Ib) are as defined in the application. Such dimers are useful as anti-cancer agents, especially when used in an antibody-drug conjugate (ADC).
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A benzodiazepine dimer having a structure represented by formula (I)
wherein
X is selected from the group consisting of
R 1 is according to formula (Ia) or formula (Ib):
each G and G′ is C or N, with the proviso that no more than two Gs or two G′s are N;
each R 2 is independently H or C 1 -C 5 alkyl;
each R 3 and R 4 is independently H, F, Cl, Br, OH, C 1 -C 3 alkyl, O(C 1 -C 3 alkyl), cyano, (CH 2 ) 0-5 NH 2, or NO 2 ;
each double line in a diazepine ring system independently represents a single bond or a double bond;
each R 5 is H if the double line to the N to which it is attached is a single bond and is absent if the double line is a double bond;
each R 6 is H, OH, SO 3 Na, or SO 3 K if the double line to the C to which it is attached is a single bond and is absent if the double line is a double bond;
each R 7 , R 8 , R 9 , and R 10 is independently H, C 1 -C 5 alkyl, C≡C(CH 2 ) 1-5 X 2 , OH, O(C 1 -C 5 alkyl), cyano, NO 2, F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ,
or where a R 7 , R 8 , R 9 , or R 10 is attached to a G or G′ that is N, such R 7 , R 8 , R 9 , or R 10 is absent;
the dotted lines in ring C of formula (Ib) indicate the optional presence of a C1-C2, C2-C3, or C2-R 11 double bond;
R 11 is H, ═O, ═CH 2 , ═CH(C 1 -C 5 alkyl), CH═CH(CH 2 ) 1-5 X 2 , C≡C(CH 2 ) 1-5 X 2 , C 1 -C 5 alkyl, OH, O(C 1 -C 5 alkyl), cyano, NO 2, F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , 4- to 7-membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ;
R 11 is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;
each X 2 is independently H, F, Cl, Br, OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 alkylene), CO 2 H, N 3, CN, NO 2, CO 2 (C 1 -C 3 alkyl), NH 2, NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2, SH, CHO, N(CH 2 CH 2 ) 2 N(C 1 -C 3 alkyl), NHNH 2, or C(═O)NHNH 2 ;
each Y is independently CH 2, C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl; and
Y′ and Y″ are independently CH 2, C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C1-C3 alkyl, with the proviso that at least one of Y′ and Y″ is present;
or a pharmaceutically acceptable salt thereof.
2 . A benzodiazepine dimer according to claim 1 , wherein X is
3 . A benzodiazepine dimer according to claim 1 , having a structure represented by formula (IIa):
4 . A benzodiazepine dimer according to claim 3 , wherein X is
5 . A benzodiazepine dimer according to claim 3 , having a structure represented by formula (IIa″)
wherein
R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond;
R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond;
each R 9 is independently H, OH, OMe, NH 2, NMe 2, O(CH 2 CH 2 O) 1-8 Me, OCH 2 CH 2 OH, or
and
X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me.
6 . A benzodiazepine dimer according to claim 5 , selected from the group consisting of
7 . A benzodiazepine dimer according to claim 1 , having a structure represented by formula (IIb)
8 . A benzodiazepine dimer according to claim 7 , wherein X is
9 . A benzodiazepine dimer according to claim 7 , having a structure represented by formula (IIb″)
wherein
R 9 is H, OH, OMe, NH 2, NMe 2, O(CH 2 CH 2 O) 1-8 Me, OCH 2 CH 2 OH, or
R 11 is H, ═CH 2, CH═CHMe, ═CHMe, C≡CCH 2 NH 2,
R 11 is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;
X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;
at least one of the double lines in a diazepine ring system is a double bond;
R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond; and
R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond.
10 . A benzodiazepine dimer according to claim 1 ,
wherein
one G′ is N and the others are C;
at least one of the double lines in a diazepine ring system is a double bond;
R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond; and
R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond.
11 . A benzodiazepine dimer according to claim 10 , wherein X is
12 . A benzodiazepine dimer-linker compound having a structure represented by formula (IIIa), (IIIb), (IIIc) or (IIIc′″):
wherein
T is a self-immolating group;
t is 0 or 1;
AA a and each AA b are independently selected from the group consisting of alanine, β-alanine, γ-aminobutyric acid, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine;
u is 0 or 1;
p is 1, 2, 3, or 4;
q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 (preferably 2, 3, 4, or 8);
r is 1, 2, 3, 4, or 5;
s is 0 or 1;
R 31 is
X 4 is S—S, O or NH;
R 1 is according to formula (Ia) or formula (Ib):
X is selected from the group consisting of
each G and G′ is C or N, with the proviso that no more than two Gs or two G's are N;
each R 2 is independently H or C 1 -C 5 alkyl;
each R 3 and R 4 is independently H, F, Cl, Br, OH, C 1 -C 3 alkyl, O(C 1 -C 3 alkyl), cyano, (CH 2 ) 0-5 NH 2, or NO 2 ;
each double line in a diazepine ring system independently represents a single bond or a double bond;
each R 5 is H if the double line to the N to which it is attached is a single bond and is absent if the double line is a double bond;
each R 6 is H, OH, SO 3 Na, or SO 3 K if the double line to the C to which it is attached is a single bond and is absent if the double line is a double bond;
each R 7 , R 8 , R 9 , and R 10 is independently H, C 1 -C 5 alkyl, C≡C(CH 2 ) 1-5 X 2 , OH, O(C 1 -C 5 alkyl), cyano, NO 2, F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ,
or where a R 7 , R 8 , R 9 , or R 10 is attached to a G or G′ that is N, such R 7 , R 8 , R 9 , or R 10 is absent;
the dotted lines in ring C of formula (Ib) indicate the optional presence of a C1-C2, C2-C3, or C2-R 11 double bond;
R 11 is H, ═O, ═CH 2 , ═CH(C 1 -C 5 alkyl), CH═CH(CH 2 ) 1-5 X 2 , C≡C(CH 2 ) 1-5 X 2 , C 1 -C 5 alkyl, OH, O(C 1 -C 5 alkyl), cyano, NO 2, F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , 4- to 7-membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ;
R 11 is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;
each X 2 is independently H, F, Cl, Br, OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 alkylene), CO 2 H, N 3, CN, NO 2, CO 2 (C 1 -C 3 alkyl), NH 2, NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2, SH, CHO, N(CH 2 CH 2 ) 2 N(C 1 -C 3 alkyl), NHNH 2, or C(═O)NHNH 2 ;
X 3 is H, OH, OMe, Me, or CH 2 OH;
each R 50 is independently H, O(C 1 -C 3 alkyl), O(C 2 -C 3 alkylene), O(C 2 -C 3 alkynyl), F, Cl, Br, or CN;
each Y is independently CH 2, C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl; and
Y′ and Y″ are independently CH 2, C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl, with the proviso that at least one of Y′ and Y″ is present.
13 . A benzodiazepine dimer-linker compound according to claim 12 , having a structure represented by formula (IIIa′)
wherein
each R 9 is independently H, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-4 H, (CH 2 CH 2 O) 1-4 (C1-C 3 alkyl), OH, Cl, F, or Br;
R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond; and
R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond.
14 . A benzodiazepine dimer-linker compound according to claim 12 , having a structure represented by formula (IIIb) wherein u is 1 and X is
15 . A benzodiazepine dimer-linker compound according to claim 12 , having a structure represented by formula (IIIb″)
wherein
each R 9 is independently H, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-4 H, (CH 2 CH 2 O) 1-4 (C1-C 3 alkyl), OH, Cl, F, or Br;
X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;
R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond; and
R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond.
16 . A benzodiazepine dimer-linker according to claim 15 , selected from the group consisting of
17 . A benzodiazepine dimer-linker compound according to claim 12 , having a structure represented by formula (IIIc) wherein u is 1 and X is
18 . A benzodiazepine dimer-linker compound according to claim 17 , having a structure represented by formula (IIIc″)
wherein
X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;
at least one of the double lines in a diazepine ring system is a double bond;
R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond;
R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond; and
R 9 is H, O(CH 2 CH 2 O) 1-4 H, (CH 2 CH 2 O) 1-4 (C1-C 3 alkyl), OH, Cl, F, or Br.
19 . A benzodiazepine dimer-linker compound according to claim 17 , selected from the group consisting of
20 . A conjugate of a benzodiazepine dimer and an antibody, having a structure represented by formula (IVa), (IVb), (IVc) or (IVc′″):
wherein
Ab is an antibody;
R 40 is
where the open valence of R 40 that is bonded to Ab is denoted by an asterisk (*) and
the open valence of R 40 that is bonded to (CH 2 ) r is denoted by a wavy line ( );
m is 1, 2, 3, or 4;
T is a self-immolating group;
t is 0 or 1;
AA a and each AA b are independently selected from the group consisting of alanine, β-alanine, γ-aminobutyric acid, arginine, asparagine, aspartic acid, γ-carboxyglutamic acid, citrulline, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, norleucine, norvaline, ornithine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine;
u is 0 or 1;
p is 1, 2, 3, or 4;
q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 (preferably 2, 3, 4, or 8);
r is 1, 2, 3, 4, or 5;
s is 0 or 1;
X 3 is H, OH, OMe, Me, or CH 2 OH;
X 4 is S—S, O or NH;
R 1 is according to formula (Ia) or formula (Ib):
X is selected from the group consisting of
each G and G′ is C or N, with the proviso that no more than two Gs or two G's are N;
each R 2 is independently H or C 1 -C 5 alkyl;
each R 3 and R 4 is independently H, F, Cl, Br, OH, C 1 -C 3 alkyl, O(C 1 -C 3 alkyl), cyano, (CH 2 ) 0-5 NH 2, or NO 2 ;
each double line in a diazepine ring system independently represents a single bond or a double bond;
each R 5 is H if the double line to the N to which it is attached is a single bond and is absent if the double line is a double bond;
each R 6 is H, OH, SO 3 Na, or SO 3 K if the double line to the C to which it is attached is a single bond and is absent if the double line is a double bond;
each R 7 , R 8 , R 9 , and R 10 is independently H, C 1 -C 5 alkyl, C≡C(CH 2 ) 1-5 X 2 , OH, O(C 1 -C 5 alkyl), cyano, NO 2, F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ,
or where a R 7 , R 8 , R 9 , or R 10 is attached to a G or G′ that is N, such R 7 , R 8 , R 9 , or R 10 is absent;
the dotted lines in ring C of formula (Ib) indicate the optional presence of a C1-C2, C2-C3, or C2-R 11 double bond;
R 11 is H, ═O, ═CH 2 , ═CH(C 1 -C 5 alkyl), CH═CH(CH 2 ) 1-5 X 2 , C≡C(CH 2 ) 1-5 X 2 , C 1 -C 5 alkyl, OH, O(C 1 -C 5 alkyl), cyano, NO 2, F, Cl, Br, O(CH 2 CH 2 O) 1-8 (C 1-3 alkyl), (CH 2 ) 0-5 X 2 , 4- to 7-membered aryl, heteroaryl, cycloalkyl, or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 , O(CH 2 ) 2-5 X 2 , 3- to 7-membered cycloalkyl or heterocycloalkyl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 , 5- to 6-membered aryl or heteroaryl unsubstituted or substituted with (CH 2 ) 0-5 X 2 or O(CH 2 ) 2-5 X 2 ;
R 11 is absent if a C1-C2, C2-C3, or C2-R 11 double bond is present and otherwise is H;
each R 50 is independently H, O(C 1 -C 3 alkyl), O(C 2 -C 3 alkylene), O(C 2 -C 3 alkynyl), F, Cl, Br, or CN;
each X 2 is independently H, F, Cl, Br, OH, O(C 1 -C 3 alkyl), O(C 1 -C 3 alkylene), CO 2 H, N 3, CN, NO 2, CO 2 (C 1 -C 3 alkyl), NH 2, NH(C 1 -C 5 alkyl), N(C 1 -C 5 alkyl) 2, SH, CHO, N(CH 2 CH 2 ) 2 N(C 1 -C 3 alkyl), NHNH 2, or C(═O)NHNH 2 ;
each Y is independently CH 2, C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl; and
Y′ and Y″ are independently CH 2, C═O, or CHR 12 ; wherein each R 12 is independently F, Cl, Br, or C 1 -C 3 alkyl, with the proviso that at least one of Y′ and Y″ is present.
21 . A conjugate of a benzodiazepine dimer and an antibody according to claim 20 , having a structure represented by formula (IVa″)
wherein
R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond;
R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond; and
R 9 is H, OH, OMe, NH 2, NMe 2, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-8 Me, OCH 2 CH 2 OH, F, Cl, Br or
22 . A conjugate of a benzodiazepine dimer and an antibody according to claim 20 , having a structure represented by formula (IVb) wherein the subscript u is 1 and X is
23 . A conjugate of a benzodiazepine dimer and an antibody according to claim 22 , having a structure represented by formula (IVb″)
wherein
X 3 is H, OH, OMe, Me CH 2 OH, O(allyl), Cl, or CO 2 Me;
R 5 is H if the double line to the N to which it is bonded is a single bond and absent if the double line is a double bond;
R 6 is H if the double line to the C to which it is bonded is a single bond and absent if the double line is a double bond; and
R 9 is H, OH, OMe, NH 2, NMe 2, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-8 Me, OCH 2 CH 2 OH, F, Br, Cl, or
24 . A conjugate of a benzodiazepine dimer and an antibody according to claim 20 , having a structure represented by formula (IVc) wherein the subscript u is 1 and X is
25 . A conjugate of a benzodiazepine dimer and an antibody according to claim 24 , having a structure represented by formula (IVc″)
wherein
X 3 is H, OH, OMe, Me, CH 2 OH, O(allyl), Cl, or CO 2 Me;
at least one of the double lines in a diazepine ring system is a double bond;
R 5 is H if the double line to the N to which it is attached is a single bond and absent if the double line is a double bond;
R 6 is H if the double line to the C to which it is attached is a single bond and absent if the double line is a double bond; and
R 9 is H, OH, OMe, C 1 -C 3 alkyl, O(CH 2 CH 2 O) 1-8 Me, F, Cl, or Br.
26 . A conjugate of a benzodiazepine dimer and an antibody according to claim 20 , wherein the antibody is an anti-fucosyl GM1 or anti-mesothelin antibody.
27 . A pharmaceutical formulation comprising a conjugate according to claim 20 and a pharmaceutically acceptable excipient.
28 . A method of treating a cancer in a subject suffering from such cancer, comprising administering to the subject a therapeutically effective amount of a conjugate according to claim 20 .
29 . A method according to claim 28 , wherein the cancer is lung or gastric cancerJoin the waitlist — get patent alerts
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