FURANYL COMPOUNDS AND THE USE THEREOF

• US 20160024040A1
• Filed: 09/30/2015
• Published: 01/28/2016
• Est. Priority Date: 06/07/2010
• Status: Active Grant

• Current Assignee: Novomedix LLC
• Original Assignee: Novomedix LLC
• Inventors: Fung, Leah M., Chan, Kyle W.H., Swindlehurst, Cathy A.
• Granted Patent: US 9,663,483 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

Provided herein are substituted furanyl compounds, pharmaceutical compositions comprising the compounds, methods of their preparation, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or amelioration of various disorders, including cancer and proliferative disorders. In one embodiment, the compounds provided herein modulate eIF4E activity. In one embodiment, the compounds provided herein modulate the Hedgehog pathway activity. In one embodiment, the compounds provided herein are used in combination with surgery, radiation therapy, immuno therapy and/or one or more additional anticancer drugs for the treatment, prevention, and/or amelioration of cancer and proliferative disorders.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein L is S(O)₂.

3. The compound of claim 1, wherein L is C(O).

4. The compound of claim 3, wherein R₄ is

5. The compound of claim 3, wherein R₄ is

6. The compound of claim 5, having formula (V):

7. The compound of any one of claims 1 and 3-6, wherein the compound is:

8. A pharmaceutical composition comprising a compound of any one of claims 1-7, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and at least one pharmaceutically acceptable excipient or carrier.

9. The pharmaceutical composition of claim 8, further comprising one or more additional active agents.

10. A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by cap-dependent protein translation, comprising administering a compound of any one of claims 1-7, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 8 or 9.

11. A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by eIF4E, comprising administering a compound of any one of claims 1-7, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 8 or 9.

12. A method of treating, preventing, or ameliorating one or more symptoms of a disorder mediated by the Hedgehog pathway, comprising administering a compound of any one of claims 1-7, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 8 or 9.

13. The method of any one of claims 10-12, wherein the disorder is cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+ breast cancer, ER-breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors.

14. A method of treating, preventing, or ameliorating one or more symptoms of a disorder, comprising administering a compound of any one of claims 1-7, or an enantiomer, a mixture of enantiomers, or a mixture of two or more diastereomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, or a pharmaceutical composition of claim 8 or 9, wherein the disorder is cancer, a proliferative disorder, breast cancer, triple negative breast cancer, ER+ breast cancer, ER−

breast cancer, basal cell nevus syndrome (Gorlin syndrome), basal cell carcinoma, skin cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, brain cancer, medulloblastoma, glioblastoma, colorectal cancer, ovarian cancer, liver cancer, pancreatic cancer, pancreatic carcinoma, pancreatic angiosarcoma, pancreatic adenosarcoma, gastric cancer, gastroesophageal junction cancer, prostate cancer, cervical cancer, bladder cancer, head and neck cancer, lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, solid tumors that cannot be removed by surgery, locally advanced solid tumors, metastatic solid tumors, leukemia, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or recurrent or refractory tumors.

15. The method of any one of claim 13 or 14, wherein the cancer is resistant to conventional therapy.

16. The method of any one of claim 13 or 14, wherein the cancer is vincristine-resistant.

17. The method of any one of claim 13 or 14, wherein the cancer is taxol-resistant.

18. The method of any one of claim 13 or 14, wherein the cancer is cytarabine-resistant.

19. The method of any one of claim 13 or 14, wherein the cancer is doxorubicin-resistant.