Inhibitors of CYP17A1

Patent metadata

Field	Value
Publication number	US-9611270-B2
Application number	US-201514815686-A
Country	US
Kind code	B2
Filing date	Jul 31, 2015
Priority date	Aug 1, 2014
Publication date	Apr 4, 2017
Grant date	Apr 4, 2017

Abstract

Compounds according to formula I or II are provided. Such compounds are useful in treating cancers, such as leukemia, colon cancer, breast cancer, or prostate cancer by beneficially inhibiting CYP17A1. Pharmaceutical compositions and methods including the compounds are also provided.

First claim

What is claimed is:

1. A compound according to formula I or II

or a salt thereof, or a tautomer thereof, or a solvate thereof, wherein
Q 1 is

Q 2 is

R 1 and R 2 are each independently H, OH, C(O)NR 27 R 5 , C(O)OR 6 , NR 7 R 8 , trifluoromethyl, trifluoromethoxy, halo, nitro, cyano, or a substituted or unsubstituted alkoxy, aryloxy, arylalkoxy, or alkanoyloxy group provided that R 1 and R 2 are not both H, or R 1 and R 2 together are ═O, ═N—OH, or ═N—NHR 9 ;
R 3 is H, or R 1 and R 3 together are O, NR 9 , S, S(O), S(O) 2 , or a bond, provided that when R 1 and R 3 together are not NR 9 or a bond then R 2 is not NR 7 R 8 ;
R 4 is H, or R 1 and R 4 together are O, NR 10 , S, S(O), S(O) 2 , or a bond, provided that when R 1 and R 3 together are not NR 10 or a bond then R 2 is not NR 7 R 8 ;
Z 1 and Z 2 are each independently CH or N;
R 27 , R 5 , R 7 , R 8 , R 9 , and R 10 are each independently H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group;
R 6 is independently at each occurrence H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group;
R 11 is H or a substituted or unsubstituted cycloalkyl, cycloalkylalkyl, alkanoyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group; and
R 12 and R 13 are each H or together are ═O, provided that R 12 and R 13 together are not ═O when R 11 is H;
or R 11 , R 1-2 , and R 13 together are —N═N—N═;
with the proviso that where Z 1 is N, R 1 and R 3 together are a bond, and R 4 is H, then R 2 is not H.

2. The compound of claim 1 , wherein Z 1 and Z 2 are each N.

3. The compound of claim 1 , wherein the compound of formula I is a compound of formula III, IV, or V

or a salt thereof, or a tautomer thereof, or a solvate thereof, wherein
X 1 and X 2 are each independently H, C(O)NR 16 R 17 , C(O)OR 18 , NR 19 R 20 , trifluoromethyl, halo, nitro, or cyano;
Y 1 and Y 2 are each independently O, NR 21 , S, S(O), S(O) 2 , or a bond, provided that when Y 1 and Y 2 are not NR 21 or a bond then X 1 and X 2 are not NR 19 R 20 ,
Z 3 , Z 4 , and Z 5 are each independently CH or N;
R 14 and R 15 are each independently H, OH, NR 22 R 23 , trifluoromethoxy, or a substituted or unsubstituted alkoxy, aryloxy, arylalkoxy, or alkanoyloxy, group provided that R 14 and R 15 are not both H;
or R 14 and R 15 together are ═O, ═N—OH, or ═N—NHR 24 ;
R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group; and
R 18 is H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group;
with the proviso that when Z 3 is N and Y 1 is a bond then X 1 is not H.

4. The compound of claim 3 , wherein Z 3 , Z 4 , and Z 5 are each independently N.

5. The compound of claim 3 , wherein
Y 1 is O or a bond;
Y 2 is a bond; and
X 1 and X 2 are each independently C(O)NR 16 R 17 , C(O)OR 18 , nitro, or cyano.

6. The compound of claim 3 , wherein R 1A and R 15 are each independently H, OH, NR 22 R 23 , or trifluoromethoxy; or R 14 and R 15 together are ═O or ═N—OH.

7. The compound of claim 1 , wherein the compound of formula II is a compound of formula VI, VII, or VIII

or a salt thereof, or a tautomer thereof, or a solvate thereof, wherein
Z 6 , Z 7 , and Z 8 are each independently CH or N;
R 25 is H or a substituted or unsubstituted cycloalkyl, cycloalkylalkyl, alkanoyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group; and
R 26 is a substituted or unsubstituted cycloalkyl, cycloalkylalkyl, alkanoyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group.

8. The compound of claim 7 , wherein the compound of formula II is a compound according to formula VI.

9. The compound of claim 1 , wherein the compound is

or a salt thereof, or a tautomer thereof, or a solvate thereof.

10. A pharmaceutical composition, comprising an effective amount of the compound of claim 2 and a pharmaceutically acceptable carrier.

11. A method comprising inhibiting CYP17A1 by administration of the compound of claim 2 .

12. The method of claim 11 , comprising inhibiting CYP17A1 by administration of a pharmaceutical composition wherein the pharmaceutical composition comprises an effective amount of the compound and a pharmaceutically acceptable carrier.

13. The method of claim 11 , wherein administration of the compound selectively inhibits CYP17A1.

14. The method of claim 13 , wherein administration of the compound selectively inhibits CYP17A1 over CYP21A2.

15. The method of claim 11 , wherein the compound is of formula III or V

or a salt thereof, or a tautomer thereof, or a solvate thereof, wherein
X 1 is H, C(O)NR 16 R 17 , C(O)OR 18 , NR 19 R 20 , trifluoromethyl, halo, nitro, or cyano;
Y 1 is O, NR 21 , S, S(O), S(O) 2 , or a bond, provided that when Y 1 is not NR 21 or a bond then X 1 is not NR 19 R 20 ;
Z 3 and Z 5 are each independently N;
R 14 and R 15 are each independently H, OH, NR 22 R 23 , trifluoromethoxy, or a substituted or unsubstituted alkoxy, aryloxy, arylalkoxy, or alkanoyloxy, group provided that R 14 and R 15 are not both H;
or R 14 and R 15 together are ═O, ═N—OH, or ═N—NHR 24 ;
R 16 , R 17 , R 19 , R 20 , R 21 , R 22 , R 23 , and R 24 are each independently H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group; and
R 18 is H or a substituted or unsubstituted alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, or heteroaralkyl group;
with the proviso that when Z 1 is N and Y 1 is a bond then X 1 is not H.

16. A method of treating a biological condition comprising administering to a subject suffering from a biological condition selected from leukemia, colon cancer, breast cancer, or prostate cancer, an effective amount of the compound of claim 2 .

17. The method of claim 16 , wherein the method comprises administering a pharmaceutical composition, wherein the

Assignees

• Univ Kansas

Inventors

• Aube Jeffrey
• Scott Emily E
• Fehl Charlie

Classifications

• C07J31/006

  not covered by C07J31/003 · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07J71/001

  Oxiranes · CPC title

• C07J73/005

  by nitrogen as hetero atom · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title