Compounds and methods for the treatment of ERB B2/NEU positive diseases
Disclosed herein are anti-ERB B2/NEU antibodies conjugated with maytansinoid drugs for targeted delivery to disease tissues. Methods relating to the preparation and uses of such drug conjugates to treat ERB B2/NEU positive cells in cancers are provided.
1. A method of treating HER2 expressing breast cancer or HER2 expressing gastric cancer in a patient in need thereof comprising administering an effective amount of a compound of Formula 1a:
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; and
Anti-HER2 is an anti-ERB B2/NEU (HER2) antibody.
2. A method of treating HER2 expressing breast cancer or HER2 expressing gastric cancer in a patient in need thereof comprising administering an effective amount of a compound of Formula 1a:
or a salt thereof,
wherein
X is Cl;
Y is C 1 -C 6 alkyl;
R 1 is hydrogen;
R 2 is C 1 -C 6 alkyl;
R 3 is methyl;
R 4 is —OH;
R 7 is C 1 -C 6 alkyl; and
R 8 is C 1-6 alkyl;
n is 0, 1, 2, 3, 4, 5, 6, 7 or 8;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10; and
Anti-HER2 is an anti-ERB B2/NEU (HER2) antibody.