2-beta-naphthyl-acetic acid analogs as AKR1C3 inhibitors and methods of using same

Patent metadata

Field	Value
Publication number	US-11459295-B2
Application number	US-201615769565-A
Country	US
Kind code	B2
Filing date	Oct 21, 2016
Priority date	Oct 22, 2015
Publication date	Oct 4, 2022
Grant date	Oct 4, 2022

Abstract

The invention includes 2-β-naphthyl-acetic acid derivatives, which are selective AKR1C3 inhibitors. In certain embodiments, the compounds of the invention are (R)-naproxen analogs. The invention further includes methods of treating cancer, such as prostate cancer and/or castration-resistant prostate cancer, using at least one compound of the invention.

First claim

What is claimed is:

1. A (R)-enantiomer compound of formula (Ia), or a salt or solvate thereof:

wherein:
R 1 is selected from the group consisting of OH, —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkoxy,
wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted aryl, OH, C 1 -C 6 alkoxy, halogen, and —CN;

R 2 is ethyl; and
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, —S(C 1 -C 6 alkyl), —S(C 3 -C 8 cycloalkyl), —S(═O)(C 1 -C 6 alkyl), —S(═O)(C 3 -C 8 cycloalkyl), —S(═O) 2 (C 1 -C 6 alkyl), and —S(═O) 2 (C 3 -C 8 cycloalkyl);

wherein the compound is free of the corresponding (S)-enantiomer.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of OH and C 1 -C 6 alkoxy, wherein the alkoxy group is optionally substituted with at least one substitutent selected from the group consisting of C 1 -C 6 alkyl, optionally substituted aryl, OH, C 1 -C 6 alkoxy, halogen, and —CN.

3. The compound of claim 1 , wherein R 1 is OH, methoxy, ethoxy, i-propoxy, n-propoxy, n-butoxy, i-butoxy, sec-butoxy, or t-butoxy.

4. The compound of claim 1 , wherein R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —S(C 1 -C 6 alkyl), —S(═O)(C 1 -C 6 alkyl), and —S(═O) 2 (C 1 -C 6 alkyl).

5. The compound of claim 1 , wherein R 4 is methyl, methoxy, ethyl, ethoxy, —S(═O)CH 3 , —S(═O) 2 CH 3 , —S(═O)CH 2 CH 3 , or —S(═O) 2 CH 2 CH 3 .

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

7. The pharmaceutical composition of claim 6 , further comprising at least one additional agent that treats or ameliorates cancer.

8. The compound selected from the group consisting of:
2(R)-(6-ethylnaphthalen-2-yl)propanoic acid;
2(R)-(6-ethoxynaphthalen-2-yl)propanoic acid;
2(R)-(6-(methylsulfinyl)naphthalen-2-yl)propanoic acid;
2(R)-(6-methoxynaphthalen-2-yl)-N-(methylsulfonyl)butanamide; and
2(R)-(6-methoxynaphthalen-2-yl)butanoic acid;
or a salt or solvate thereof, or any mixtures thereof;
wherein the compound is free of the corresponding (S)-enantiomer.

9. The compound 2(R)-(6-methoxynaphthalen-2-yl) butanoic acid

or a salt or solvate thereof, or any mixtures thereof;
wherein the compound is free of the corresponding (S)-enantiomer.

10. A method of treating or ameliorating prostate cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of at least one compound of formula (Ia), or a salt or solvate thereof:

wherein:
R 1 is selected from the group consisting of OH, —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkoxy,
wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted aryl, OH, C 1 -C 6 alkoxy, halogen, and —CN;

R 2 is ethyl; and
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, —S(C 1 -C 6 alkyl), —S(C 3 -C 8 cycloalkyl), —S(═O)(C 1 -C 6 alkyl), —S(═O)(C 3 -C 8 cycloalkyl), —S(═O) 2 (C 1 -C 6 alkyl), and —S(═O) 2 (C 3 -C 8 cycloalkyl);

wherein the compound is free of the corresponding (S)-enantiomer.

11. The method of claim 10 , wherein the cancer comprises castration-resistant prostate cancer.

12. The method of claim 10 , the method further comprising administering to the subject 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, enzalutamide, ARN-509, abiraterone, temozolomide, any salt thereof, any solvates thereof, and any mixtures thereof.

13. The method of claim 10 , wherein the compound promotes analgesia in the subject suffering from prostate cancer.

14. A method of inhibiting aldo-keto reductase family 1, member C3 (AKR1C3) in a mammalian cell, the method comprising contacting the cell with an effective amount of at least one compound of formula (Ia), or a salt or solvate thereof:

wherein:
R 1 is selected from the group consisting of OH, —NHSO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkoxy, and C 3 -C 8 cycloalkoxy,
wherein the alkyl, alkoxy or cycloalkoxy group is optionally substituted with at least one substituent selected from C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, optionally substituted aryl, OH, C 1 -C 6 alkoxy, halogen, and —CN;

R 2 is ethyl; and
R 4 is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkoxy, —S(C 1 -C 6 alkyl), —S(C 3 -C 8 cycloalkyl), —S(═O)(C 1 -C 6 alkyl), —S(═O)(C 3 -C 8 cycloalkyl), —S(═O) 2 (C 1 -C 6 alkyl), and —S(═O) 2 (C 3 -C 8 cycloalkyl);

wherein the compound is free of the corresponding (S)-enantiomer.

15. The method of claim 14 , wherein the cell comprises a prostate cell.

16. The method of claim 15 , wherein the cell comprises a prostate cancer cell or a castration-resistant prostate cancer cell.

17. The method of claim 14 , wherein the cell is in vivo in the mammal.

Assignees

• Univ Pennsylvania
• Univ Vanderbilt

Inventors

• Penning Trevor M
• Adeniji Adegoke
• Marnett Lawrence J

Classifications

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• A61K31/131

  acyclic · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4166

  having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin · CPC title

• C07C323/62

  having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton · CPC title