Branched hydrazone linkers

• US 5,824,805 A
• Filed: 12/19/1996
• Issued: 10/20/1998
• Est. Priority Date: 12/22/1995
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: King, Dalton, Trail, Pamela, Firestone, Raymond A.
• Primary Examiner(s): CEPERLEY, MARY
• Application Number:
  US08/770,614
• Time in Patent Office: 670 Days
• Field of Search: 564/34, 564/310, 564/35, 564/37, 564/151, 548/546, 548/547, 548/548
• US Class Current: 548/546
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/6889 Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07C 281/02 Compounds containing any of the groups , e.g. carbazates
• CPC Class Codes: C07D 207/452 with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07H 15/252 Naphthacene radicals, e.g. daunomycins, adriamycins

Abstract

Branched hydrazone linkers for linking a targeting ligand such as an antibody to a therapeutically active drug. The point of branching is at a polyvalent atom and the number of drugs increases by a factor of two for each generation of branching. A preferred drug is doxorubicin.

Claims

1. Having the formula ##STR44## wherein A is a thiol acceptor;

Q is a bridging group;

b is an integer of 0 or 1;

W is a spacer moiety;

m is an integer of 0 or 1;

a is an integer of 2, 3 or 4; and

X is a moiety of the formula --NH--NH₂ or ##STR45## or a moiety of the formula ##STR46## wherein W, a, b and m are as defined hereinbefore, and

X¹ is a moiety of the formula --NH--NH₂ or ##STR47## or a moiety of the formula ##STR48## wherein W, a, b, and m are defined hereinbefore, and

X² is a moiety of the formula NH--NH₂ or ##STR49## or a moiety of the formula ##STR50## 10 wherein W, a, b, and m are as defined hereinbefore, and

X³ is a moiety of the formula --NH--NH₂ or ##STR51## or a moiety of the formula ##STR52## wherein W, a, b and m are as defined hereinbefore, and

X⁴ is a moiety of the formula --NH--NH₂ or ##STR53##

2. The branched linker of claim 1 wherein X is --NH--NH₂ or ##STR54##

3. The branched linker of claim 1 wherein X¹ is --NH--NH₂ or ##STR55##

4. The branched linker of claim 1 wherein A is a Micheal Addition acceptor.

5. The branched linker of claim 1 wherein W is of the formula ##STR56## wherein g is an integer of 1 to 6.

6. The branched linker of claim 1 wherein W is of the formula ##STR57##

7. The branched linker of claim 1 wherein b is 0 and a is 2.

8. The branched linker of claim 6 wherein b is 0 and a is 2.

9. The branched linker of claim 1 wherein Q is of the formula

10. The branched linker of claim 9 wherein f is 1 or 2, h is 1 or 2, g is 1, and Z is phenyl, pyridyl, or a cycloaliphatic hydrocarbon ring containing 3 to 6 carbon atoms.

11. The branched linker of claim 10 wherein Z is phenyl or cyclohexyl.

12. The branched linker of claim 9 wherein g is 0 and f+h is an integer of 1 to 4.

13. The branched linker of claim 9 wherein g is 0 and f+h is an integer of 2.