Prodrug compounds and their uses

• US 10,449,210 B2
• Filed: 02/11/2015
• Issued: 10/22/2019
• Est. Priority Date: 02/13/2014
• Status: Active Grant

• Current Assignee: Ligand Pharmaceuticals, Inc.
• Original Assignee: Ligand Pharmaceuticals, Inc.
• Inventors: Zhi, Lin
• Primary Examiner(s): Lewis, Patrick T
• Application Number:
  US15/118,821
• Publication Number:
  US 20170056429A1
• Time in Patent Office: 1,714 Days
• Field of Search: None
• 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 31/661 Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
• 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 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07D 317/20 Free hydroxyl or mercaptan
• CPC Class Codes: C07D 317/24 esterified
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 9/091 with hydroxyalkyl compounds with further substituents on alkyl
• CPC Class Codes: C07F 9/098 Esters of polyphosphoric acids or anhydrides
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/657154 Cyclic esteramides of oxyacids of phosphorus
• 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 9/65744 : condensed with carbocyclic or heterocyclic rings or ring systems
• CPC Class Codes: C07F 9/65746 : the molecule containing more than one cyclic phosphorus atom
• CPC Class Codes: C07F 9/65842 : Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
• CPC Class Codes: C07F 9/65844 : the phosphorus atom being part of a five-membered ring which may be condensed with another ring system
• CPC Class Codes: C07F 9/65846 : the phosphorus atom being part of a six-membered ring which may be condensed with another ring system
• 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 prodrug compounds, their preparation and their uses, such as treating liver diseases or nonliver diseases via intervening in molecular pathways in the liver. Novel prodrug compounds of acid/alcohol derivatives such as phosphates, phosphonates, phosphonamidates, phosphoramidates, carboxylates, phenolates, and alkoxylates, their preparation and their uses are described. Some of the novel prodrug compounds described herein do not generate a vinyl keto reactive intermediate in the activation process. Another aspect includes the use of prodrugs to treat diseases that benefit from enhanced drug distribution to the liver and like tissues and cells.

Claims

1. A compound of Formula I:

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

6. A method of treating a disease, disorder or condition comprising administering an effective amount of the compound of claim 1 to a subject in need thereof;

wherein the disease, disorder or condition is a disease, disorder or condition of the liver.

7. The method of claim 6, wherein the disease, disorder or condition is a metabolic, cardiovascular or hormonal disease in which the liver is involved in the production and/or the homeostasis control of the biochemical end products of the disease, disorder or condition.

8. The method of claim 6, wherein the disease, disorder or condition is selected from the group consisting of hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia and a hormonal condition.

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

2. A compound of Formula Ib or Ic:

3. A compound of Formula III:

4. A compound selected from the group consisting of:

10. A method of treating a disease, disorder or condition comprising administering an effective amount of the compound of claim 4 to a subject in need thereof;

wherein the disease, disorder or condition is a disease, disorder or condition of the liver.

11. The method of claim 10, wherein the disease, disorder or condition is a metabolic, cardiovascular or hormonal disease in which the liver is involved in the production and/or the homeostasis control of the biochemical end products of the disease, disorder or condition.

12. The method of claim 10, wherein the disease, disorder or condition is selected from the group consisting of hepatitis, liver cancer, liver fibrosis, fatty liver, malaria, viral infection, parasitic infection, diabetes, hyperlipidemia, atherosclerosis, obesity, dyslipidemia, hyperglycemia and a hormonal condition.