Cytotoxic and anti-mitotic compounds, and methods of using the same

Inventors: Geoffrey C. Winters (Vancouver, CA); Alexander L. Mandel (Vancouver, CA); Bradley J. Hedberg (Vancouver, CA); John Babcook (Vancouver, CA); James R. Rich (Vancouver, CA); Tom Han Hsiao Hsieh (Vancouver, CA); Elyse Marie Josée Bourque (Blaine, WA)

Assignee: ZYMEWORKS INC.

C07C311/51 A61K31/445 A61K38/05 A61K38/06 A61K39/3955 A61K47/48261 A61K47/48415 C07C323/12 C07C323/67 C07C327/06 C07C381/08 C07D207/08 C07D207/452 C07D211/34 C07D211/60 C07D213/56 C07D213/71 C07D333/34 C07K5/0205 C07K5/06078 C07C317/28 C07C317/32 C07C317/50 C07C2101/02 C07C2101/08 C07C2101/14

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 9,522,876
App. No.: 14/213,504
Granted: Dec 20, 2016
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Compounds having cytotoxic and/or anti-mitotic activity are disclosed. The compounds have the following structure (I): including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed. Also disclosed are compositions having the structure: (T)-(L)-(D), wherein (T) is a targeting moiety, (L) is an optional linker, and (D) is a compound having structure (I).

Claims (85)

1. A compound having the following structure (I):

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R 2 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;

R 3 is selected from the group consisting of H and C 1-6 alkyl;

R 4 is selected from the group consisting of H and C 1-6 alkyl; and

R 5 is selected from the group consisting of C 1-6 alkyl and —SH.

2. The compound according to claim 1 , wherein each optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl is, independently, optionally substituted with ═O, ═S, —OH, —OR 6 , —O 2 CR 6 , —SH, —SR 6 , —SOCR 6 , —NH 2 , —N 3 , —NHR 6 , —N(R 6 ) 2 , —NHCOR 6 , —NR 6 COR 6 , —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R 6 , —CHO, —COR 6 , —CONH 2 , —CONHR 6 , —CON(R 6 ) 2 , —COSH, —COSR 6 , —NO 2 , —SO 3 H, —SOR 6 or —SO 2 R 6 , wherein each R 6 is, independently, alkyl optionally substituted with halogen, —OH or —SH.

3. The compound according to claim 1 , wherein each optionally substituted aryl and optionally substituted heteroaryl is, independently, selected from the group consisting of optionally substituted phenyl, optionally substituted naphthyl, optionally substituted anthracyl, optionally substituted phenanthryl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted thiophenyl, optionally substituted benzofuryl, optionally substituted benzothiophenyl, optionally substituted quinolinyl, optionally substituted isoquinolinyl, optionally substituted imidazolyl, optionally substituted thiazolyl, optionally substituted oxazolyl, and optionally substituted pyridinyl.

4. The compound according to claim 1 , wherein R 2 is selected from one of the following structures (III), (IV), (V), (VI):

wherein:

Q is CR 7 or N;

Z is C(R 7 ) 2 , NR 7 , S, or O;

wherein in structure (VI), one instance of Z is CR 7 or N, and the other instance is C(R 7 ) 2 , NR 7 , S, or O;

each R 7 is, independently, selected from the group consisting of H, —OH, —OR 6 , —O 2 CR 6 , —SH, —SR 6 , —SOCR 6 , —NH 2 , —N 3 , —NHR 6 , —N(R 6 ) 2 , —NHCOR 6 , —NR 6 COR 6 , —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R 6 , —CHO, —COR 6 , —CONH 2 , —CONHR 6 , —CON(R 6 ) 2 , —COSH, —COSR 6 , —NO 2 , —SO 3 H, —SOR 6 or —SO 2 R 6 , wherein each R 6 is, independently, alkyl optionally substituted with halogen, —OH or —SH.

5. The compound according to claim 4 , wherein R 2 is selected from the group consisting of:

6. The compound according to claim 5 wherein R 2 is:

7. The compound according to claim 1 , wherein R 3 , R 4 and R 5 are each methyl.

8. The compound according to claim 1 , wherein R 3 is H, R 4 is methyl, and R 5 is methyl.

9. The compound according to claim 1 , which is (S,E)-N-(benzylsulfonyl)-2,5-dimethyl-4-((S)—N,3,3-trimethyl-2-((S)-3-methyl-2-(methylamino)-3-phenylbutanamido)butanamido)hex-2-enamide, having the following structure: