Diglycidic ether derivative therapeutics and methods for their use

Patent metadata

Field	Value
Publication number	US-9862667-B2
Application number	US-99903709-A
Country	US
Kind code	B2
Filing date	Jul 2, 2009
Priority date	Jul 2, 2008
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

This invention provides compound having a structure of Formula I or Formula II. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are also provided.

First claim

What is claimed is:

1. A method for modulating androgen receptor (AR) activity for treatment of at least one indication selected from the group consisting of: prostate cancer, breast cancer, ovarian cancer, endometrial cancer, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, and age-related macular degeneration;
wherein, the method comprises administering to a mammalian cell a compound having a structure of Formula II:

wherein:
J and J′ are each independently H or a moiety selected from:

L is O, S, NH, NG, N + H 2 , or N + HG;
X is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 I, CHI 2 , CI 3 , CH 2 OJ′″, CH 2 OG, CH 2 OGOG′, GOG′, GOG′OG″, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 ;
Q is G, O, CH 2 , CHG, CG 2 , S, NH or NG;
each Z is independently N, CH, COH, C—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), C—(C 1 -C 10 substituted or unsubstituted unsaturated), CO—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), CO—(C 1 -C 10 substituted or unsubstituted unsaturated),CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;
R 1 and R 2 are each independently H, or a branched or unbranched, substituted or unsubstituted C 1 -C 10 alkyl or together form a substituted or unsubstituted, saturated, aromatic cyclic or non-aromatic cyclic C 3 -C 10 alkyl;
each G, G′ and G″ is independently a branched, unbranched, or aromatic cyclic or non-aromatic cyclic, substituted or unsubstituted, saturated or unsaturated C 1 -C 10 alkyl;
J′″ is H or a moiety selected from:

L′ is O, S, NH, NG, N + H 2 , or N + HG;
each Z′ is independently N, CH, C—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), C—(C 1 -C 10 substituted or unsubstituted unsaturated), CO—(C 1 -C 10 aromatic cyclic or non-aromatic cyclic), CO—(C 1 -C 10 substituted or unsubstituted unsaturated),CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;
Q′ is G, O, CH 2 , CHG, CG 2 , S, NH or NG;
X′ is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , CBr 3 , CH 2 I, CHI 2 , CI 3 , G, CH 2 OG, or CH 2 OGOG′;
wherein the optional substituent is selected from the group consisting of: oxo, OJ′″, COOH, R, OH, OR, F, Cl, Br, I, NH 2 , NHR, NR 2 , CN, SH, SR, SO 3 H, SO 3 R, SO 2 R, OSO 3 R, and NO 2 wherein R is an unsubstituted C 1 -C 10 alkyl.

2. The method of claim 1 , wherein X is CH 2 F, CH 2 Br, CH 2 I, CH 2 OG, CH 2 OGOG′, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 ; and
each Z is independently N, CH, or COH and each Z′ is independently N or CH.

3. The method of claim 1 , wherein each Z and Z′ is CH.

4. The method of claim 1 , wherein each of Q and Q′ are O.

5. The method of claim 1 , wherein each of R 1 and R 2 are independently H, or a branched or unbranched, substituted or unsubstituted, C 1 -C 10 alkyl.

6. The method of claim 1 , wherein each R 1 and R 2 is CH 3 .

7. The method of claim 1 , wherein X is H, CH 3 , CH 2 F, CH 2 Br, CH 2 I, CH 2 OJ′″, CH 2 OG, or CH 2 OGOG′.

8. The method of claim 1 , wherein X is CH 2 F, CH 2 I, CH 2 Br, CH 2 OH, CH 2 OCH 3 , or CH 2 O(isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 .

9. The method of claim 1 , wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OG, CH 2 OGOG′, GOG′, GOG′OG″, CH 2 SG, CH 2 NH 2 , CH 2 NHG, or CH 2 NG 2 .

10. The method of claim 1 , wherein X′ is H, CH 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OG, or CH 2 OGOG′.

11. The method of claim 1 , wherein X′ is CH 2 Cl, CH 2 F, CH 2 I, CH 2 Br, CH 2 OCH 3 , CH 2 O(isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 .

12. The method of claim 1 , wherein each J, J′, and J′″, when present is

13. The method of claim 1 , wherein each J, J′ J′″, when present, is H.

14. The method of claim 1 , wherein each L and L′, when present, is independently O, or S.

15. The method of claim 1 , wherein each L and L′, when present, is O.

16. The method of claim 1 , wherein the compound is selected from one or more of the following:

17. The method of claim 1 , wherein the mammalian cell is a human cell.

18. The method of claim 1 , wherein the modulating AR activity is for inhibiting AR N-terminal domain activity.

19. The method of claim 1 , wherein the modulating is in vivo.

20. The method of claim 1 , wherein the indication is prostate cancer.

21. The method of claim 20 , wherein the prostate cancer is androgen-independent prostate cancer.

22. The method of claim 20 , wherein the prostate cancer is androgen-dependent prostate cancer.

23. The method of claim 1 , wherein:
L is O, NH, NG, N + H 2 , or N + HG; and
L′ is O, NH, NG, N + H 2 , or N + HG.

24. The method of claim 1 , wherein X′ is CH 3 , CH 2 F, CH 2 Cl, CH 2 Br, CH 2 I, CH 2 OCH 3 , CH 2 O(isopropyl), or CH 2 OC 2 H 4 OC 4 H 9 .

25. The method of claim 1 , wherein each L and L′, when present, is independently O, NH or N+H 2 .

26. A compound having a structure of Formula II

wherein
each J and J′ is independently H or a moiety selected from:

each L and L′ is independently O, NH, NG, N + H 2 or N + HG;
each Q and Q′ is independently G, O, CH 2 , CHG, CG 2 , S, NH or NG;
each Z and Z′ is independently N, CH, COH, CF, CCl, CBr, CI, CNH 2 , CNHG, CNG 2 , COSO 3 H, COPO 3 H 2 ; CSG, CSOG, or CSO 2 G;
R 1 and R 2 are each independently H; or a branched or unbranched, substituted or unsubstituted C 1 -C 10 alkyl or together form a substituted or unsubstituted, saturated, aromatic cyclic or non-aromatic cyclic C 3 -C 10 alkyl;
X is CH 2 O(isopropyl), CH 2 OC 2 H 4 OC 4 H 9 , CH 2 SG, CH 2 NH 2 , CH 2 NHG, CH 2 I, CH 2 Br, CH 2 F, or CH 2 NG 2 ;
X′ is H, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CHI 2 , CI 3 , CH 2 F, CHF 2 , CF 3 , CH 2 OJ′″, CH 2 OG, GOG′, CH 2 SG, CH 2 NH 2 , CH 2 NHG or CH 2 NG 2 ;
J′″ is independently H or a moiety selected from:

each G and G′ is independently, a branched or unbranched, non-aromatic cyclic, substituted or unsubstituted, saturated C 1 -C 10 alkyl;
wherein the optional substituent is selected from the group consisting of: oxo, OJ′″, COOH,

Assignees

• Sadar Marianne D
• Mawji Nasrin R
• Wang Jun
• Andersen Raymond J
• Williams David E
• Leblanc Mike
• Univ British Columbia
• British Columbia Cancer Agency Branch

Inventors

• Sadar Marianne D
• Mawji Nasrin R
• Wang Jun
• Andersen Raymond J
• Williams David E
• Leblanc Mike

Classifications

• A61P5/28

  Antiandrogens · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/24

  of the sex hormones · CPC title

• A61P27/02

  Ophthalmic agents · CPC title