Heteroaryl sulfone-based conjugation handles, methods for their preparation, and their use in synthesizing antibody drug conjugates

Patent metadata

Field	Value
Publication number	US-11712480-B2
Application number	US-201716321695-A
Country	US
Kind code	B2
Filing date	Jul 31, 2017
Priority date	Aug 3, 2016
Publication date	Aug 1, 2023
Grant date	Aug 1, 2023

Abstract

The present invention is directed to novel heteroaryl sulfone-based conjugation handles of the formula:(wherein R1, R2, Het, D, E, X, Y, Z, m, n, p, q, r, s and t are as defined herein), methods for their preparation, their use in synthesizing antibody drug conjugates, and the resulting antibody drug conjugates made with components having heteroaryl sulfone-based conjugation handles.

First claim

We claim:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein:
Het is a mono-, bi-, or polycyclic heteroaryl ring system having 1-4 heteroatoms,
wherein a carbon atom on said ring system bound to —S(O 2 )— is adjacent to at least one heteroatom on said ring system, and wherein each heteroatom is independently selected from the group consisting of N, O, and S;
m is 0, 1, 2, 3, 4, or 5;
n is 0, 1, 2, 3, 4, or 5;
p is 0, 1, or 2;
q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
r is 0, 1, or 2;
s is 0, 1, or 2;
t is 0 or 1;
w is 1 or 2;
each E is independently selected from the group consisting of: —C(R 1 ) 2 —, —O—C(R 1 ) 2 —C(R 1 ) 2 — where r is 2, and —C(R 1 ) 2 —C(R 1 ) 2 —O— where s is 1 or 2;
each R 1 is independently selected from the group consisting of: H, C 1 -C 6 straight or branched alkyl, C 2 -C 6 straight or branched alkenyl, and C 2 -C 6 straight or branched alkynyl;
R 2 is C 1 -C 10 alkyl optionally substituted with a halogen or haloalkyl, or C 5 -C 12 aryl optionally substituted with a halogen or haloalkyl;
each X is an independently selected amino acid;
each Y is an independently selected amino acid;
each Z is an independently selected spacer element; and
D is dolastatin, MMAD, MMAE, MMAF, PF-06380101, an active agent, a moiety capable of binding to an active agent;
wherein

(a) D is selected from the group consisting of dolastatin, MMAD, MMAE, MMAF and PF-06380101; or
(b) Z is

2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein D is selected from the group consisting of dolastatin, MMAD, MMAE, MMAF, and PF-06380101.

3. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein:
Z is:

4. A pharmaceutical composition comprising a compound of any one of claims 1 , 2 , and 3 or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

5. A method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 , 2 , and 3 .

6. The method of claim 5 , wherein said cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, esophageal cancer, ovarian cancer, prostate cancer, pancreatic cancer, skin cancer, stomach (gastric) cancer, testicular cancer, leukemias, and lymphomas.

7. A method of treating cancer, the method comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition of claim 4 .

8. The method of claim 7 , wherein said cancer is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, kidney cancer, lung cancer, esophageal cancer, ovarian cancer, prostate cancer, pancreatic cancer, skin cancer, stomach (gastric) cancer, testicular cancer, leukemias, and lymphomas.

Assignees

• Pfizer

Inventors

• Dushin Russell George
• Uccello Daniel P
• Starr Jeremy
• Che Ye
• Flanagan Mark
• Casavant Jeffrey M
• O'Donnell Christopher John
• Filzen Gary Frederick
• Young Jennifer
• Abramite Joseph A
• Tumey Lawrence N
• Moine Ludivine
• Gilbert Adam Matthew
• Roberts Lee R

Classifications

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6855 Primary

  the tumour determinant being from breast cancer cell · CPC title

• A61K47/50

  the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K47/6867

  the tumour determinant being from a cell of a blood cancer · CPC title