Prodrug compounds and uses thereof

• US 10,150,788 B2
• Filed: 06/11/2018
• Issued: 12/11/2018
• Est. Priority Date: 07/02/2014
• Status: Active Grant

• Current Assignee: Ligand Pharmaceuticals, Inc.
• Original Assignee: Ligand Pharmaceuticals, Inc.
• Inventors: Zhi, Lin
• Primary Examiner(s): Rozof, Timothy R
• Application Number:
  US16/005,601
• Publication Number:
  US 20180291050A1
• Time in Patent Office: 183 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/6615 Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07F 9/657163 the ring phosphorus atom being bound to at least one carbon atom
• CPC Class Codes: C07F 9/657181 the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
• CPC Class Codes: C07F 9/65746 the molecule containing more than one cyclic phosphorus atom
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided herein are cyclic phosphorus-containing prodrug compounds, their preparation and their uses, such as treating diseases via modulating molecular targets in the liver.

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein M is a nucleoside antiviral or anticancer agent.

3. The compound of claim 1, wherein M is a lipid modulator.

4. The compound of claim 1, wherein M is a nuclear hormone receptor modulator.

5. The compound of claim 1, wherein M is at least one selected from the group consisting of:

a HCV polymerase inhibitor, a reverse transcriptase inhibitor, a DNA synthesis inhibitor, an RNA synthesis inhibitor, and an antimetabolic agent.

6. The compound of claim 1, having the structure:

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

8. A method of treating a disease, disorder or condition in the liver of a subject comprising:

administering an effective amount of a compound of claim 1 to a subject in need thereof.

9. A method of treating a disease, disorder or condition by intervening in a molecular pathway or target in the liver in a subject comprising:

administering an effective amount of a compound of claim 1 to a subject in need thereof.

10. A method of treating a disease, disorder or condition in the liver or a disease, disorder or condition in which the physiological or pathogenic pathways involve the liver in a subject, comprising:

administering an effective amount of a compound of claim 1 to the subject.

11. The method of claim 8, wherein the disease, disorder or condition is selected from the group consisting of hepatitis, liver cancer, liver fibrosis, malaria, viral infection, parasitic infection, cancer, fatty liver, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia and a hormonal condition.

12. The method of claim 8, further comprising administering an effective amount of an additional therapeutic agent to the subject in need thereof.

13. The method of claim 8, wherein the subject is a mammal.

14. The method of claim 8, wherein the subject is a human.

15. A method of intervening in a molecular pathway or modulating a target in a cell comprising contacting the cell with a compound of claim 1.

16. The method of claim 15, wherein the cell is in vivo.

17. The method of claim 15, wherein the cell is ex vivo.

18. The method of claim 15, wherein the cell is a hepatocyte.

19. The method of claim 15, wherein the cell is mammalian.

20. The method of claim 15, wherein the cell is human.