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

Patent metadata

Field	Value
Publication number	US-10201614-B2
Application number	US-201414776654-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 15, 2013
Publication date	Feb 12, 2019
Grant date	Feb 12, 2019

Abstract

Compounds having cytotoxic and/or anti-mitotic activity are disclosed. 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 cytotoxic and/or anti-mitotic activity.

First claim

What is claimed is:

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

wherein:
R 1 and R 2 are independently H or optionally substituted alkyl, wherein the carbon atoms are optionally substituted with: —OH, —I, —Br, —Cl, —F, —CN, —CO 2 H, —CHO, —COSH, or —NO 2 ; or R 2 and R 5 are fused and form a ring;
R 3 and R 4 are independently H or R; or R 3 and R 4 are joined to form a ring, wherein the ring formed by joining R 3 and R 4 is a three- to seven-member cycloalkyl within the definition of R;
R 5 is R or Ar; or R 5 and R 2 are fused and form a ring;
R 6 is H or R;
R 7 and R 8 are independently H or R; and
R 9 is:

R is a saturated or unsaturated linear or branched alkyl containing one to ten carbon atoms, or a cycloalkyl or heterocyclyl containing three to ten carbon atoms and zero to four nitrogen atoms, and the carbon atoms are optionally independently substituted with: ═O, ═S, OH, —OR 10 , —O 2 CR 10 , —SH, —SR 10 , —SOCR 10 , —NH 2 , —NHR 10 , —N(R 10 ) 2 , —NHCOR 10 , —NR 10 COR 10 , —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R 10 , —CHO, —COR 10 , —CONH 2 , —CONHR 10 , —CON(R 10 ) 2 , —COSH, —COSR 10 , —NO 2 , —SO 3 H, —SOR 10 , or —SO 2 R 10 , wherein R 10 is a linear or branched one to ten carbon saturated or unsaturated alkyl or a three to ten carbon cycloalkyl;
Y is a linear, saturated or unsaturated, one to six carbon alkyl group, optionally substituted with R, or X;
X is selected from the group consisting of: —OH, —OR, ═O, ═S, —O 2 CR, —SH, —SR, —SOCR, —NH 2 , —NHR, —N(R) 2 , —NHCOR, —NRCOR, —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R, —CHO, —COR, —CONH 2 , —CONHR, CON(R) 2 , —COSH, —COSR, —NO 2 , —SO 3 H, —SOR, and —SO 2 R;
R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR 24 , —CSR 24 , —OR 24 , and —NHR 24 , wherein each R 24 is, independently, alkyl optionally substituted with halogen, —OH or —SH;
or a stereoisomer or pharmaceutically acceptable salt thereof.

2. A compound having the following structure (Ia):

wherein:
R 14 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR 24 , —CSR 24 , —OR 24 , and —NHR 24 , wherein each R 24 is, independently, alkyl optionally substituted with halogen, —OH or —SH;
R 15 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 16 is selected from the group consisting of H and C 1-6 alkyl;
R 17 is selected from the group consisting of H and C 1-6 alkyl;
R 18 and R 30 are independently selected from the group consisting of H, C 1-6 alkyl and —SH, with the proviso that R 18 and R 30 cannot both be H;
R 19 , R 20 , R 21 and R 22 are each independently H or C 1-6 alkyl, wherein at least one of R 19 and R 20 is H; or R 20 and R 21 form a double bond, R 19 is H, and R 22 is H or C 1-6 alkyl; and
R 23 is selected from the group consisting of H and C 1-6 alkyl;
or a stereoisomer or pharmaceutically acceptable salt thereof.

3. A compound having the following structure (Ib):

wherein:
R 26 is selected from the group consisting of optionally substituted alkyl and optionally substituted aryl;
R 27 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 16 is selected from the group consisting of H and C 1-6 alkyl;
R 17 is selected from the group consisting of H and C 1-6 alkyl; and
R 18 is selected from the group consisting of C 1-6 alkyl and —SH,
or a stereoisomer or pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 or 3 , 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 24 , —O 2 CR 24 , —SH, —SR 24 , —SOCR 24 , —NH 2 , —N 3 , —NHR 24 , —N(R 24 ) 2 , —NHCOR 24 , —NR 24 COR 24 , —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R 24 , —CHO, —COR 24 , —CONH 2 , —CONHR 24 , —CON(R 24 ) 2 , —COSH, —COSR 24 , —NO 2 , —SO 3 H, —SOR 24 or —SO 2 R 24 , wherein each R 24 is, independently, alkyl optionally substituted with halogen, —OH or —SH.

5. The compound according to claim 2 or 3 , 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.

6. The compound according to claim 2 , wherein R 15 is selected from one of the following structures (II), (III), (IV) and (V):

wherein:
Q is CR 25 or N;
Z is C(R 25 ) 2 , NR 25 , S, or O;
wherein in structure (V), one instance of Z is CR 25 or N, and the other instance is (CR 25 ) 2 , NR 25 , S or O; and
each R 25 is, independently, selected from the group consisting of H, —OH, —R 24 , —OR 24 , —O 2 CR 24 , —SH, —SR 24 , —SOCR 24 , —NH 2 , —N 3 , —NHR 24 , —N(R 24 ) 2 , —NHCOR 24 , —NR 24 COR 24 , —R 24 NH 2 , —I, —Br, —Cl, —F, —CN, —CO 2 H, —CO 2 R 24 , —CHO, —COR 24 , —CONH 2 , —CONHR 24 , —CON(R 24 ) 2 , —COSH, —COSR 24 , —NO 2 , —SO 3 H, —SOR 24 and —SO 2 R 24 , wherein each R 24 is, independently, alkyl optionally substituted with halogen, —OH or —SH.

7. The compound according to claim 6 , wherein R 15 is selected from the group consisting of:

8. The compound according to claim 7 , wherein R 15 is:

9. The compound according to claim 3 , wherein R 27 is selected from one of the following structures (II), (III), (IV) and (V):

Assignees

• Zymeworks Inc

Inventors

• Winters Geoffrey C
• Mandel Alexander Laurence
• Rich James R
• Hedberg Bradley John
• Hsieh Tom Han Hsiao
• Bourque Elyse Marie Josée
• Babcook John

Classifications

• C07K16/32

  against translation products of oncogenes · CPC title

• A61K47/6855

  the tumour determinant being from breast cancer cell · CPC title

• C07K5/06078

  and aromatic or cycloaliphatic · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K47/6415

  Toxins or lectins, e.g. clostridial toxins or Pseudomonas exotoxins · CPC title