Phosphorus-containing thyromimetics

• US 7,514,419 B2
• Filed: 05/26/2005
• Issued: 04/07/2009
• Est. Priority Date: 11/19/2003
• Status: Expired due to Fees

• Current Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Boyer, Serge H., Jiang, Hongjian, Erion, Mark D.
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US11/137,773
• Publication Number:
  US 20060046980A1
• Time in Patent Office: 1,412 Days
• Field of Search: 558/70, 514/140
• US Class Current: 514/140
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 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 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 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07F 9/301 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/306 Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
• CPC Class Codes: C07F 9/3808 Acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/3882 Arylalkanephosphonic acids C07F9/3839 takes precedence
• CPC Class Codes: C07F 9/4006 : Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4056 : Esters of arylalkanephosphonic acids C07F9/4025 takes precedence
• CPC Class Codes: C07F 9/4075 : Esters with hydroxyalkyl compounds
• CPC Class Codes: C07F 9/4407 : Amides of acyclic saturated acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4465 : of aliphatic amines
• CPC Class Codes: C07F 9/5728 : condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/58 : Pyridine rings
• CPC Class Codes: C07F 9/65517 : condensed with carbocyclic rings or carbocyclic ring systems
• 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

Abstract

The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.

Claims

1. A compound of Formula VIII:

2. The compound of claim 1, wherein R¹ and R² are each —

CH₃.

3. The compound of claim 1, wherein Y and Y′

are each —

NH—

.

4. The compound of claim 3, wherein R¹¹ attached to —

NH—

is —

C(R^x)₂—

COOR^y.

5. The compound of claim 1, wherein Y and Y′

are —

O—

.

6. The compound of claim 5, wherein R¹¹ attached to —

O—

is —

H or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, wherein R¹¹ attached to —

O—

is selected from the group consisting of —

C(R^z)₂—

OC(O)R^y and —

C(R^z)₂—

O—

C(O)OR^y.

13. A pharmaceutical composition comprising a compound of any one of claims 1-12 and a pharmaceutically acceptable excipient, carrier, or diluent.

14. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition in a form selected from the group consisting of a controlled release composition, transdermal patch, tablet, hard capsule, and soft capsule.

15. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition comprises a crystalline form of said compound.

16. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition comprises a salt form of said compound.

17. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition is administered orally in a unit dose of about 0.375 μ

g/kg to 3.75 mg/kg.

18. The new pharamaceutical compostion of claim 13 wherein said pharmaceutical composition is administered orally in a total daily dose of about 0.375 μ

g/kg/day to about 3.75 mg/kg/day, equivalent of the free acid.

8. A compound selected from the group consisting of:

9. A compound:

10. A compound:

11. A compound selected from the group consisting of:

12. A compound selected from the group consisting of: