Hindered disulfide drug conjugates
AssigneeGenentech, Inc.
InventorsPeter Dragovich, Zhonghua Pei, Thomas Pillow, Jack Sadowsky, Jinhua Chen, John Wai
Life of this patent
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Abstract
The invention relates generally to disulfide drug conjugates wherein a linker comprising a sulfur-bearing carbon atom substituted with at least one hydrocarbyl or substituted hydrocarbyl is conjugated by a disulfide bond to a cysteine sulfur atom of a targeting carrier, and wherein the linker is further conjugated to a drug moiety. The invention further relates to activated linker-drug conjugates suitable for conjugation to a targeting carrier by a disulfide bond. The invention further relates to methods for preparing hindered disulfide drug conjugates.
Claims33
A linker-drug compound of structure (I):
- wherein:
- X is a leaving group;
- the leaving group, X, and the sulfur atom, S, are bound via a disulfide bond;
- R1 and R2 are independently selected from H and C1-3 alkyl, wherein only one of R1 and R2 can be H, or R1 and R2 together with the carbon atom to which they are bound form a three- to six-membered ring or a four- to six-membered ring comprising an oxygen heteroatom;
- Sp is a spacer wherein n is 0 or 1;
- and
- D is a drug moiety.
6-15. (canceled)
A disulfide conjugate compound of structure (II):
- wherein
- the carrier comprises a cysteine sulfur atom SA;
- p is 1, 2, 3, 4, 5, 6, 7 or 8;
- R1 and R2 are independently selected from H and C1-3 alkyl, wherein only one of R1 and R2 can be H, or R1 and R2 together with the carbon atom to which they are bound form a three- to six-membered ring or a four- to six-membered ring comprising an oxygen heteroatom;
- Sp is a spacer wherein n is 0 or 1;
- and
- D is a drug moiety.
18-21. (canceled)
(canceled)
A method of preparing a disulfide conjugate compound of structure (II):
- the method comprising:
- (A) forming a reaction mixture comprising
- (i) a solvent system comprising water,
- (ii) a carrier comprising at least one cysteine having a sulfhydryl moiety having a sulfur atom SA capable of bonding to a linker sulfur atom to form the disulfide bond, and
- (iii) a stoichiometric excess of a linker-drug conjugate compound of structure (I):
- wherein:
- X is a leaving group;
- the leaving group and the linker are bound via disulfide bond;
- R1 and R2 are independently selected from H and C1-3 alkyl, wherein only one of R1 and R2 can H, or R1 and R2 together with the carbon atom to which they are bound form a three- to six-membered ring or a four- to six-membered ring comprising an oxygen heteroatom;
- Sp is a spacer wherein n is 0 or 1;
- and
- D is a drug moiety;
- and
- (B) reacting the reaction mixture to form a product mixture comprising the disulfide conjugate compound of structure (II) wherein p is 1, 2, 3, 4, 5, 6, 7 or 8, and wherein the average value of p for a plurality of formed disulfide conjugate compounds in the product mixture is from about 1 to about 5, from about 1.5 to about 3, from about 1.5 to about 2.5, from about 1.7 to about 2.3, from about 1.8 to about 2.2, or about 2.
35-42. (canceled)
The method of claim 42 wherein X is selected from:
47-56. (canceled)
(canceled)
60-62. (canceled)
Dependencies are inferred from the claim text.