Bifunctional AKR1C3 Inhibitors/Androgen Receptor Modulators and Methods of Use Thereof

Patent metadata

Field	Value
Publication number	US-2016159731-A1
Application number	US-201614993742-A
Country	US
Kind code	A1
Filing date	Jan 12, 2016
Priority date	Apr 13, 2011
Publication date	Jun 9, 2016
Grant date	—

Abstract

The invention includes compositions comprising selective AKR1C3 inhibitors. The invention also includes compositions comprising bifunctional AKR1C3 inhibitors and selective androgen receptor modulators. The invention further includes methods of treatment using the compositions of the invention.

First claim

1 . At least one compound selected from the group consisting of:
(i) a compound of Formula (I) or a salt thereof:

wherein in Formula (I):
R 1 is selected from the group consisting of C 1 -C 6 alkyl, haloalkyl, halo, nitro, —CN, C 1 -C 6 alkoxy, —C(═O)H, —C(═O)OH, —C(═O)—(C 1 -C 6 alkyl), and —SO 3 H; and,
each occurrence of R 2 is independently selected from the group consisting of H, C 1 -C 6 alkyl, haloalkyl, halo, nitro, —CN, C 1 -C 6 alkoxy, —C(═O)H, —C(═O)OH, —C(═O)—(C 1 -C 6 alkyl), and —SO 3 H; and,
(ii) a compound of Formula (II) or a salt thereof where the naphthyl ring can be alpha or beta substituted:

wherein in Formula (II):
R 3 is selected from the group consisting of C 1 -C 6 alkyl, haloalkyl, halo, nitro, —CN, C 1 -C 6 alkoxy, —C(═O)H, —C(═O)OH, —C(═O)—(C 1 -C 6 alkyl), and —SO 3 H; and, each occurrence of R 4 and R 5 is independently selected from the group consisting of H, C 1 -C 6 alkyl, haloalkyl, halo, nitro, —CN, C 1 -C 6 alkoxy, —C(═O)H, —C(═O)OH, —C(═O)—(C 1 -C 6 alkyl), and —SO 3 H.

2 . The compound of claim 1 , wherein in Formula (I) R 1 is selected from the group consisting of methyl, tert-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro and acetyl.

3 . The compound of claim 1 , wherein each occurrence of R 2 in Formula (I) is independently selected from the group consisting of H, methyl, tert-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro and acetyl.

4 . The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of 3-[N-(4-nitrophenyl)amino]benzoic acid, 3-[N-(4-acetylphenyl)amino]benzoic acid, 3-[N-(4-trifluoromethylphenyl)amino]benzoic acid, 3-[N-(4-chlorophenyl)amino]benzoic acid, 3-[N-(4-bromophenyl)amino]benzoic acid, 3-[N-(4-tent-butylphenyl)amino]benzoic acid, 3-[N-(4-methoxyphenyl)amino]benzoic acid, 3-[N-(4-methylphenyl)amino]benzoic acid, mixtures thereof and salts thereof.

5 . The compound of claim 1 , wherein in Formula (II) R 3 is selected from the group consisting of methyl, tert-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro and acetyl.

6 . The compound of claim 1 , wherein each occurrence of R 4 in Formula (II) is independently selected from the group consisting of H, methyl, tert-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro and acetyl.

7 . The compound of claim 1 , wherein each occurrence of R 5 in Formula (II) is independently selected from the group consisting of H, methyl, tert-butyl, methoxy, fluoro, chloro, bromo, trifluoromethyl, nitro and acetyl.

8 . The compound of claim 1 , wherein the compound of Formula (II) is 3-((4-nitronaphthalen-1-yl)amino)benzoic acid or a salt thereof.

9 . A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.

10 . The pharmaceutical composition of claim 9 , further comprising at least one therapeutic agent selected from the group consisting of indomethacin, desatinib, selegiline, seliciclib, TOK-001, SAHA, docetaxel, bevacizumab, taxotere, thalidomide, prednisone, Sipuleucel-T, cabazitaxel, MDV3100, ARN-509, abiraterone, temozolomide, tamoxifen, anastrozole, letrozole, vorozole, exemestane, fadrozole, formestane, raloxifene, tamoxifen, anastrozole, letrozole, vorozole, exemestane, fadrozole, formestane, raloxifene, mixtures thereof and salts thereof.

11 - 38 . (canceled)

Assignees

• Univ Pennsylvania

Inventors

• Penning Trevor M
• Adeniji Adegoke O
• Burns Michael C
• Winkler Jeffrey
• Twenter Barry

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/195

  having an amino group · CPC title

• A61K31/405

  Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/196

  the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil · CPC title