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 - 11 . (canceled)
12 . A compound of Formula Ia:
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.
13 . The compound of claim 12 , which is a compound of Formula Ib
or a pharmaceutically acceptable salt or solvate thereof.
14 . The compound of claim 12 , which is a compound of Formula Ic
or a pharmaceutically acceptable salt or solvate thereof,
wherein Anti-HER2 is an anti-ERB B2/NEU (HER2) antibody.
15 . The compound of claim 14 , wherein the compound connected to anti-ERB B2/NEU(HER2) antibody is N2′-deacetyl-N2′-(6-maleimido-1-oxo-hexyl) maytansine.
16 . The method of claim 12 , wherein the anti-Erb B2/neu antibody is an antibody comprising trastuzumab or pertuzumab or an equivalent thereof.
17 . A pharmaceutical composition comprising a compound of claim 12 .
18 . A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of claim 12 .
19 . A method of treating a proliferative, inflammatory or immunologic disease or condition characterized by Erb B2/neu positive cells in a patient in need thereof comprising administering an effective amount of a compound of Formula IVa:
or a salt thereof, wherein the compound of Formula IVa is generated as a result of a metabolic chemical reaction following administration of a compound of claim 12 , or a pharmaceutically acceptable salt thereof, to the patient, wherein AA is an amino acid or thiolated amino acid.
20 . A method of treating a proliferative, inflammatory or immunologic disease or condition characterized by Erb B2/neu positive cells in a patient in need thereof comprising administering an effective amount of a compound of Formula IVb:
or a salt thereof, wherein the compound of Formula IVb is generated as a result of a metabolic chemical reaction following administration of a compound of claim 13 , or a pharmaceutically acceptable salt thereof, to the patient, wherein AA is an amino acid or thiolated amino acid.
21 . A method of treating a proliferative, inflammatory or immunologic disease or condition characterized by Erb B2/neu positive cells in a patient in need thereof comprising administering an effective amount of a compound of Formula IVc:
or a salt thereof, wherein the compound of Formula IVc is generated as a result of a metabolic chemical reaction following administration of a compound of claim 14 , or a pharmaceutically acceptable salt thereof, to the patient, wherein AA is an amino acid or thiolated amino acid.
22 . The method of claim 19 , wherein AA is wherein represents point of connection to the rest of the molecule.
23 . The compound of claim 12 , wherein
X is halo;
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;
24 . The compound of claim 12 , 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;
25 . A pharmaceutical composition comprising a compound of claim 24 .
26 . A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of claim 24 .
27 . The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is suitable for injection or infusion.
28 . The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is suitable for injection or infusion.