Small molecule inhibitors of N-terminus activation of the androgen receptor

Patent metadata

Field	Value
Publication number	US-9487479-B2
Application number	US-99903509-A
Country	US
Kind code	B2
Filing date	Aug 24, 2009
Priority date	Aug 22, 2008
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

Compounds having a structure of Formula (A) are provided. Uses of such compounds for treatment of various indications, including prostate cancer as well as methods of treatment involving such compounds are provided. Uses of compounds having a structure of Formula (F) 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 compound of the Formula (A):

or a salt thereof, wherein:
X is C or N;
Y is O or S;
R 1 is H, OH, J, OJ, SJ, or NJJ′, wherein J and J′ are each independently a one to ten carbon linear, branched, non-aromatic cyclic, or aromatic or partially aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, COOR, CONH 2 , CONHR, CONR 2 , 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 , and wherein R is a linear, or branched saturated and unsubstituted C 1 -C 10 alkyl;
R 2 is H, an amino acid side chain or a two to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, COOR, CONH 2 , CONHR, CONR 2 , 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 , and wherein R is a linear, or branched saturated and unsubstituted C 1 -C 10 alkyl, provided that R 2 is not a proline or phenylalanine side chain;
R 3 is H, OH, OG, SG, NGG′ or a one to ten carbon linear, branched, or non-aromatic cyclic, or aromatic or partially aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein G and G′ are each independently a one to ten carbon linear, branched, non-aromatic cyclic, or aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group and wherein the optional substituent is selected from one or more of: oxo, COOH, OH, COOR, CONH 2 , CONHR, CONR 2 , R, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 , wherein R is an unsubstituted C 1 -C 10 alkyl; and
R 4 and R 6 are each independently H, an amino acid side chain or a one to ten carbon linear, branched, aromatic or partially aromatic cyclic, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, OR, R, 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 , and wherein R is an unsubstituted C 1 -C 10 alkyl, provided that both R 4 and R 6 are not H and provided that neither R 4 or R 6 are:

and
provided that neither R 4 or R 6 is a proline side chain;
R 5 is H, an amino acid side chain or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, CONH 2 , OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 , provided that R 5 is not a proline or phenylalanine side chain; and
is a double bond;
and provided that the compound is not:

2. A compound having the following Formula (B):

or a salt thereof, wherein:
X is C or N;
Y is O or S;
R 1 is H, OH, J, OJ, SJ, or NJJ′, wherein J and J′ are each independently a one to ten carbon linear, branched, non-aromatic cyclic, or aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 ;
R 2 is H or a two to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, 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 , and wherein R is a linear, or branched saturated and unsubstituted C1-C10 alkyl;
R 3 is H, OH, OG, SG, NGG′ or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein G and G′ are each independently a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated alkyl group and wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 ; and
R 4 is H or a one to ten carbon linear, branched, aromatic cyclic, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, OR, R, 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 , and wherein R is an unsubstituted C 1 -C 10 alkyl, provided that R 4 is not:

R 5 is H or a one to ten carbon linear, branched, or non-aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 ;
Z is an optionally substituted Bu, Pr or Et, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , SO 3 H, and NO 2 ; and
is a single bond or a double bond,

provided that the compound is not,

3. The compound of claim 1 , wherein R 3 is H, OH, OG, or a one to ten carbon linear, or branched, saturated or unsaturated, optionally substituted alkyl group, wherein G is a one to ten carbon linear, or branched, saturated or unsaturated alkyl group and wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , CN, SH, SO 3 H, and NO 2 .

4. The compound of claim 1 , wherein R 3 is H, OH, OBu, OPr, OEt, or OMe.

5. The compound of claim 1 , wherein R 1 is H, OH, J, or OJ, wherein J is a one to ten carbon linear, branched, non-aromatic cyclic, or aromatic cyclic, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , and NO 2 .

6. The compound of claim 1 , wherein R 1 is H, OH, J, or OJ, wherein J is a one to four carbon linear, or branched, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, and NH 2 .

7. The compound of claim 1 , wherein R 1 is H, OH, OBu, OPr, OEt, OMe, Bu, Pr, Et, or Me.

8. The compound of claim 1 , wherein R 1 is OMe.

9. The compound of claim 2 , wherein is a double bond.

10. The compound of claim 1 , wherein R 2 is H or a two to ten carbon linear, or branched, saturated or unsaturated, optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, COOH, OH, F, Cl, Br, I, NH 2 , and NO 2 .

11. The compound of claim 1 , wherein R 2 is H or a two to four carbon linear, or branched, saturated optionally substituted alkyl group, wherein the optional substituent is selected from one or more of: oxo, OH, F, Cl, Br, I, and NH 2 .

12. The compound of claim 1 , wherein R 4 is H or a one to ten carbon linear, or branched,

Assignees

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P5/00

  Drugs for disorders of the endocrine system · CPC title

• 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