US2015320879A1PendingUtilityA1
Self-stabilizing linker conjugates
Est. expiryMay 15, 2032(~5.8 yrs left)· nominal 20-yr term from priority
C07D 207/36C07D 207/40C07K 5/06052A61K 47/65C07K 7/02A61K 47/48338A61K 47/68031
55
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention provides Ligand-Drug Conjugates, Drug-Linkers, Linkers, and Ligand-Linker Conjugates comprising a self-stabilizing linker assembly component.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having the formula:
or a suitably protected form and/or salt thereof, wherein
D′ is a Drug unit, Detection unit or Stability unit;
L O is an optional secondary linker assembly that is present; and
BU is a Basic unit;
HE is a hydrolysis enhancer unit comprising an electron withdrawing group;
the circle represents a scaffold, wherein the scaffold is a C 1-8 alkylene, C 1-8 heteroalkylene, C 6-10 arylene, or C 4-10 heteroarylene, and optionally having a functional group from a reactive site suitable for attachment to L O ;
the subscripts m, q and r are each 0 or 1, provided the sum of m+q+r is 0, 1 or 2, and provided that if m+q+r is 0, the scaffold is a C 6-10 arylene or C 4-10 heteroarylene;
the subscripts a and b are each 0 or 1, provided the sum of a+b is 1; and
Q and Z are hydrogen or halogen provided at least one of Q and Z is halogen,
or having the formula:
or a suitably protected form and/or salt thereof, wherein
BU is a Basic unit;
HE is a hydrolysis enhancer unit comprising an electron withdrawing group;
the circle represents a scaffold, wherein the scaffold is a C 1-8 alkylene, C 1-8 heteroalkylene, C 6-10 arylene, or C 4-10 heteroarylene, optionally having a functional group from a reactive site suitable for attachment to A, W, or Y;
the subscripts m, q and r are each 0 or 1, provided the sum of m+q+r is 0, 1 or 2, and provided that if m+q+r is 0, the scaffold is a C 6-10 arylene or C 4-10 heteroarylene;
the subscript a and b are each 0 or 1, provided the sum of a+b is 1;
—W— is an optional Cleavable unit,
the subscript w′ is 0 or 1;
—Y— is an optional Spacer unit,
the subscript y′ is 0 or 1;
-A- is a Stretcher unit;
-A′-is an optional Stretcher unit component at the terminus of A,
the subscript a′ is 0 or 1;
and each subscript u independently ranges from 1 to 20, wherein when u ranges from 2 to 20, A is present, and when u is 1, A is present or absent; and
Q and Z are hydrogen or halogen, provided at least one of Q and Z is halogen.
2 . The compound of claim 1 , wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein
D′ is a Drug unit;
L O is a secondary linker assembly; and
BU is a Basic unit;
HE is a hydrolysis enhancer unit comprising an electron withdrawing group;
the circle represents a scaffold, wherein the scaffold is a C 1-8 alkylene, C 1-8 heteroalkylene, C 6-10 arylene, or C 4-10 heteroarylene, and optionally having a functional group from a reactive site suitable for attachment to L O ;
the subscript r is 1; and
the subscript a is 1,
or has the formula of:
or a suitably protected form and/or salt thereof, wherein
the subscript a is 1;
—W— is an optional Cleavable unit,
the subscript w′ is 0 or 1;
—Y— is an optional Spacer unit,
the subscript y′ is 0 or 1;
-A- is a Stretcher unit;
-A′-is an optional Stretcher unit component at the terminus of A,
the subscript a′ is 0 or 1;
the subscript u ranges from 1 to 20, wherein when u ranges from 2 to 20, A is present, and when u is 1, A is present or absent; and
BU, HE, the subscripts a and r and the circle are as previously defined.
3 . The compound of claim 1 , wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein a is 1,
or has the formula of:
or a suitably protected form and/or salt thereof, wherein u ranges from 1 to 8,
and wherein
T is —(C(R 9 )(R 10 ))—, and the subscript c is 1, 2, 3 or 4, wherein
R 9 and R 10 are, in each occurrence, independently selected from the group consisting of H and C 1-3 alkyl;
R 11 and R 12 are independently selected from the group consisting of H, C 1-6 alkyl and a suitable protecting group, or taken together are a suitable protecting group, or taken together with the nitrogen atom to which they are attached define a C 3 -C 6 heterocycloalkyl; and
the subscript a is 1, and the subscript u ranges from 1 to 8.
4 . The compound of claim 3 wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein
the subscript u is 1, 2, 3 or 4.
5 . The compound of claim 3 or 4 , wherein at least one of R 11 and R 12 is a suitable acid-labile protecting group.
6 . The compound of claim 5 wherein the acid-labile protecting group is t-butyloxycarbonyl (BOC).
7 . The compound of claim 4 wherein the compound has the structure of:
or a suitably protected form and/or salt thereof, wherein M is a suitable counteranion and D′ is a Drug unit.
8 . The compound of claim 7 wherein —W— is -Val-Cit-, -Phe-Lys- or Val-Ala-.
9 . The compound of claim 7 wherein the subscript y is 1 and —Y— has the formula of:
wherein the wavy line adjacent to the nitrogen atom indicates covalent binding of that heteroatom to W and the # adjacent to the carbonyl indicates covalent binding of its carbon atom to RG or adjacent to the oxygen atom indicates covalent binding of that heteroatom atom to D′.
10 . The compound of claim 7 wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein D′ is a Drug Unit.
11 . The compound of claim 10 wherein the Drug unit D′ is an auristatin drug.
12 . The compound of claim 11 wherein the compound has the formula of:
13 . The compound of claim 7 wherein the subscript w is 1 and the subscript y is 0 (i.e., Y is absent), W is Val-Cit-, -Phe-Lys- or Val-Ala- and D′ is a Drug unit.
14 . A compound having the formula:
or a suitably protected form and/or salt thereof, wherein
RG is a reactive group comprising a reactive site at the terminus of L O that is suitable for attaching L O to a Drug unit, Detection unit or Stability unit;
L O is an optional secondary linker assembly that is present;
BU is a Basic unit;
HE is a hydrolysis enhancer unit comprising an electron withdrawing group;
the circle represents a scaffold, wherein the scaffold is a C 1-8 alkylene, C 1-8 heteroalkylene, C 6-10 arylene, or C 4-10 heteroarylene, and optionally having a functional group from a reactive site suitable for attachment to L O ;
the subscripts m, q and r are each 0 or 1, provided the sum of m+q+r is 0, 1 or 2, and provided that if m+q+r is 0, the scaffold is a C 6-10 arylene or C 4-10 heteroarylene;
the subscripts a and b are each 0 or 1, provided the sum of a+b is 1; and
Q and Z are hydrogen or halogen provided at least one of Q and Z is halogen,
or having the formula of:
or a suitably protected form and/or salt thereof, wherein
RG is a reactive group comprising a reactive site at the terminus of
that is suitable for attaching a Drug unit, Detection unit or Stability unit to one of Y, W and A/A′, depending on the presence or absence of Y and/or W;
BU is a Basic unit;
HE is a hydrolysis enhancer unit comprising an electron withdrawing group;
the circle represents a scaffold, wherein the scaffold is a C 1-8 alkylene, C 1-8 heteroalkylene, C 6-10 arylene, or C 4-10 heteroarylene, optionally having a functional group from a reactive site suitable for attachment to A, W, or Y;
the subscripts m, q and r are each 0 or 1, provided the sum of m+q+r is 0, 1 or 2, and provided that if m+q+r is 0, the scaffold is a C 6-10 arylene or C 4-10 heteroarylene;
the subscript a and b are each 0 or 1, provided the sum of a+b is 1;
—W— is an optional Cleavable unit,
the subscript w′ is 0 or 1;
—Y— is an optional Spacer unit,
the subscript y′ is 0 or 1;
-A- is a Stretcher unit;
-A′-is an optional Stretcher unit component at the terminus of A,
the subscript a′ is 0 or 1;
and each subscript u independently ranges from 1 to 20, wherein when u ranges from 2 to 20, A is present, and when u is 1, A is present or absent; and
Q and Z are hydrogen or halogen, provided at least one of Q and Z is halogen.
15 . The compound of claim 14 , wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein
RG is a reactive group comprising a reactive site at the terminus of L O that is suitable for attaching L O to a Drug unit;
L O is an optional secondary linker assembly that is present; and
BU is a Basic unit;
HE is a hydrolysis enhancer comprising an electron withdrawing group;
the circle represents a scaffold, wherein the scaffold is a C 1-8 alkylene, C 1-8 heteroalkylene, C 6-10 arylene, or C 4-10 heteroarylene, and optionally having a functional group from a reactive site suitable for attachment to L O ;
the subscript r is 1; and
the subscript a is 1,
or has the formula:
or a suitably protected form and/or salt thereof, wherein
the subscript a is 1;
—W— is an optional Cleavable unit,
the subscript w′ is 0 or 1;
—Y— is an optional Spacer unit,
the subscript y′ is 0 or 1;
-A- is a Stretcher unit;
-A′-is an optional Stretcher unit component at the terminus of A,
the subscript a′ is 0 or 1; and
the subscript u ranges from 1 to 20, wherein when u ranges from 2 to 20, A is present, and when u is 1, A is present or absent.
16 . The compound of claim 15 wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein a is 1,
or has the formula
or a suitably protected form and/or salt thereof, wherein u ranges from 1 to 8,
and wherein
T is —(C(R 9 )(R 10 ))—, and the subscript c is 1, 2, 3 or 4, wherein
R 9 and R 10 are, in each occurrence, independently selected from the group consisting of H and C 1-3 alkyl;
R 11 and R 12 are independently selected from the group consisting of H, C 1-6 alkyl and a suitable protecting group, or taken together are a suitable protecting group, or taken together with the nitrogen atom to which they are attached define a C 3 -C 6 heterocycloalkyl.
17 . The compound of claim 16 wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein
u is 1, 2, 3 or 4.
18 . The compound of claim 15 or 16 wherein at least one of R 11 and R 12 is a suitable acid-labile protecting group.
19 . The compound of claim 18 wherein the acid-labile protecting group is t-butyloxycarbonyl (BOC).
20 . The compound of claim 17 wherein the compound has the structure of:
or a suitably protected form and/or salt thereof, wherein M is a suitable counteranion.
21 . The compound of claim 20 wherein the subscript w is 1 and —W— is -Val-Cit-,-Phe-Lys- or Val-Ala-.
22 . The compound of claim 20 wherein the subscript y is 1 and —Y— has the formula of:
wherein the wavy line adjacent to the nitrogen indicates covalent binding of that heteroatom to W and the # adjacent to the carbonyl indicates covalent binding of its carbon atom to RG.
23 . The compound of claim 20 wherein the compound has the formula of:
24 . The compound of claim 20 wherein the compound has the formula of:
25 . A compound having the formula of:
or a suitably protected form and/or salt thereof,
and wherein
T is —(C(R 9 )(R 10 ))—, and the subscript c is 1, 2, 3 or 4, wherein
R 9 and R 10 are, in each occurrence, independently selected from the group consisting of H and C 1-3 alkyl; and
R 11 and R 12 are independently selected from the group consisting of H, C 1-6 alkyl and a suitable protecting group, or taken together form a suitable protecting group, or taken together with the nitrogen atom to which they are attached define a C 3 -C 6 heterocycloalkyl.
26 . The compound of claim 25 , wherein the compound has the formula of:
or a suitably protected form and/or salt thereof, wherein the subscript c is 1 or 2.
27 . The compound of claim 26 , wherein T is —CH 2 —.
28 . The compound of claim 26 , wherein the compound has the formula of:
or a suitably protected form and/or salt thereof.
29 . The compound of claim 25 , 26 , 27 or 28 , wherein at least one of R 11 and R 12 is a suitable acid-labile protecting group.
30 . The compound of claim 29 , wherein the acid-labile protecting group is t-butyloxycarbonyl (BOC).
31 . The compound of claim 28 , wherein the compound has the formula of:
32 . The compound of claim 28 , wherein the compound has the formula of:Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.