Hindered disulfide drug conjugates
AssigneeGenentech, Inc.
InventorsPeter Dragovich, Zhonghua Pei, Thomas Pillow, Jack Sadowsky, Jinhua Chen, John Wai
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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.
Claims22
A linker-drug compound of structure (I):
- wherein:
- X is a leaving group selected from the group consisting of;
- wherein the sulfur atom of leaving group, X, and the sulfur atom, S, of Structure (I) are bound via a sulfur-sulfur bond;
- R1 and R2 are independently selected from —CH3 and —CH2CH3, or R1 and R2 together with the carbon atom to which they are bound form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran and tetrahydropyran;
- Sp is a spacer wherein n is 0 or 1;
- and
- D is a drug moiety selected from a maytansine, an auristatin, a dolastatin, a pyrrolobenzodiazepine (PBD) monomer or dimer having the structure:
- wherein n in the structure of the pyrrolobenzodiazepine (PBD) dimer is 0 or 1, a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) monomer or dimer, and a CBI-PBD dimer.
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 together with the carbon atom to which they are bound form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran and tetrahydropyran;
- Sp is a spacer wherein n is 0 or 1;
- and
- D is a drug moiety selected from a maytansine, an auristatin, a dolastatin, a pyrrolobenzodiazepine (PBD) monomer or dimer having the structure:
- wherein n in the structure of the pyrrolobenzodiazepine (PBD) dimer is 0 or 1, a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) monomer or dimer, and a CBI-PBD dimer.
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 selected from the group consisting of;
- wherein the sulfur atom of leaving group, X, and the sulfur atom, S, of Structure (I) are bound via a sulfur-sulfur bond;
- R1 and R2 are independently selected from —CH3 and —CH2CH3, or R1 and R2 together with the carbon atom to which they are bound form a ring selected from cyclobutyl, cyclopentyl, cyclohexyl, oxetane, tetrahydrofuran and tetrahydropyran;
- Sp is a spacer wherein n is 0 or 1;
- and
- D is a drug moiety selected from a maytansine, an auristatin, a dolastatin, a pyrrolobenzodiazepine (PBD) dimer having the structure:
- wherein n in the structure of the pyrrolobenzodiazepine (PBD) dimer is 0 or 1, a 1-(chloromethyl)-2,3-dihydro-1H-benzo[e]indole (CBI) monomer or dimer, and a CBI-PBD dimer;
- 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.
Dependencies are inferred from the claim text.