Phosphorus-containing thyromimetics

• US 7,829,552 B2
• Filed: 11/19/2004
• Issued: 11/09/2010
• Est. Priority Date: 11/19/2003
• Status: Active Grant

• 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:
  US10/580,134
• Publication Number:
  US 20090118236A1
• Time in Patent Office: 2,181 Days
• Field of Search: 514/140, 558/70
• 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, 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 syndromex and diabetes.

Claims

1. A compound of Formula VIII:

2. A pharmaceutical compositions comprising a pharmaceutically acceptable amount of a compound of claim 1.

3. The compounds of claim 1, wherein:

G is selected from the group consisting of —

O— and

—

CH₂;

R⁵ is selected from the group consisting of —

OH or —

F; and

R⁶ and T may not be taken together along with the carbons they are attached to form a ring.

4. The compounds of claim 1, wherein:

G is selected from the group consisting of —

O— and

—

CH₂—

;

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R⁵ is selected from the group consisting of —

OH or —

F; and

R⁶, R⁷, R⁸, and R⁹ are hydrogen.

5. The compounds of claim 1, wherein:

G is selected from the group consisting of —

O— and

—

CH₂—

;

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R³ is selected from the group consisting of optionally substituted —

C₁-C₁₂ alkyl, optionally substituted —

C₂-C₁₂ alkenyl, and optionally substituted —

C₂-C₁₂ alkynyl,

R⁴ is hydrogen;

R⁵ is selected from the group consisting of —

OH or —

F; and

R⁶, R⁷, R⁸, and R⁹ are hydrogen.

6. The compounds of claim 1, wherein

G is selected from the group consisting of —

O— and

—

CH₂—

;

T is selected from the group consisting of —

(CR^a₂)_k—

, —

O(CR^b₂)(CR^a₂)_n—

,—

C(O)(CR^a₂)_m—

, —

(CR^a₂)C(O)—

, —

(CR^a₂)C(O)(CR^a)_n , —

(CR^a₂)_nC(O)(CR^a₂)— and

—

C(O)NH(CR^b₂)(CR^a₂)_p—

;

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R⁶, R⁷, R⁸, and R⁹ are hydrogen;

R³ is an optionally substituted —

C₁-C₁₂ alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group consisting of —

OH or —

F;

Y and Y′

are each independently selected from the group consisting of —

O—

, and —

NR^v—

;

when Y and Y′

are —

O—

, R¹¹ attached to —

O—

is independently selected from the group consisting of —

H, —

C(R^z)₂—

OC(O)R^y, and —

C(R^z)₂—

O—

C(O)OR^y;

when Y and Y′

are —

NR^v—

, then R¹¹ attached to —

NR^v—

is independently selected from the group consisting of —

H, —

C(R^x)₂COOR^y, and -cycloalkylene-COOR^y;

when Y is —

O— and

Y′

is NR^v, then R¹¹ attached to —

O—

is independently selected from the group consisting of —

H, and optionally substituted aryl; and

R¹¹ attached to —

NR^v—

is independently selected from the group consisting of H, —

C(R^x)₂COOR^y, and -cycloalkylene-COOR^y;

or when Y and Y′

are independently selected from —

O— and

—

NR^v—

, then together R¹¹ and R¹¹ are the group;

7. A compound of claim 1, wherein

G is —

CH₂—

;

T is selected from the group consisting of CH₂, CH₂CH₂, OCH₂, C(O)CH₂, and CH₂C(O);

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R⁶, R⁷, R⁸, and R⁹ are hydrogen;

R³ is an optionally substituted —

C₁-C₁₂ alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group consisting of —

OH or —

F;

Y and Y′

are each independently selected from the group consisting of —

O—

, and —

NR^v—

;

when Y and Y′

are —

O—

, R¹¹ attached to —

O—

is independently selected from the group consisting of —

H, —

C(R²)₂—

OC(O)R^y, and —

C(R^z)₂—

O—

C(O)OR^y;

when Y and Y′

are —

NR^v—

, then R¹¹ attached to —

NR^v—

is independently selected from the group consisting of —

H, —

C(R^x)₂COOR^y, and -cycloalkylene-COOR^y;

when Y is —

O— and

Y′

is NR^v, then R¹¹ attached to —

O—

is independently selected from the group consisting of —

H, and optionally substituted aryl; and

R¹¹ attached to —

NR^v—

is independently selected from the group consisting of H, —

C(R^x)₂COOR ^Y, and -cycloalkylene-COOR^y;

or when Y and Y′

are independently selected from —

O— and

—

NR^v—

, then together R¹¹ and R¹¹ are the group;

8. The compounds of claim 1 wherein:

G is —

CH₂;

R⁵ is selected from the group consisting of —

OH or —

F; and

R⁶ and T may not be taken together along with the carbons they are attached to form a ring.

9. The compounds of claim 1, wherein:

G is —

CH₂—

;

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R⁵ is selected from the group consisting of —

OH or —

F; and

R⁶, R⁷, R⁸, and R⁹ are hydrogen.

10. The compounds of claim 1, wherein:

G is —

CH₂—

;

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R³ is independently selected from the group consisting of optionally substituted —

C₁-C₁₂ alkyl, optionally substituted —

C₂-C₁₂ alkenyl, and optionally substituted —

C₂-C₁₂ alkynyl;

R⁴ is hydrogen;

R⁵ is selected from the group consisting of —

OH or —

F; and

R⁶, R⁷, R⁸, and R⁹ are hydrogen.

11. The compounds of claim 1, wherein

G is —

CH₂—

;

T is selected from the group consisting of —

(CR^a₂)_k—

, —

O(CR^b₂)(CR^a₂)_n—

,—

C(O)(CR^a₂)_m—

, —

(CR^a₂)_mC(O)—

, —

(CR^a₂)C(O)(CR^a₂)_n, —

(CR^a₂)_nC(O)(CR^a₂)— and

—

C(O)NH(CR^b₂)(CR^a₂)_p—

;

R¹ and R² are each independently selected from the group consisting of halogen, optionally substituted —

C₁-C₄ alkyl, and cyano;

R⁶, R⁷, R⁸, and R⁹ are hydrogen;

R³ is an optionally substituted —

C₁-C₁₂ alkyl;

R⁴ is hydrogen;

R⁵ is selected from the group consisting of —

OH or —

F;

Y and Y′

are each independently selected from the group consisting of —

O—

, and —

NR^v—

;

when Y and Y′

are —

O—

, R¹¹ attached to —

O—

is independently selected from the group consisting of —

H, —

C(R^z)₂—

OC(O)R^y, and —

C(R^z)₂—

O—

C(O)OR^y;

when Y and Y′

are —

NR^v—

, then R¹¹ attached to —

NR^v—

is independently selected from the group consisting of —

H, —

C(R^x)₂COOR^y, and -cycloalkylene-COOR^y;

when Y is —

O— and

Y′

is NR^v, then R¹¹ attached to —

O—

is independently selected from the group consisting of —

H, and optionally substituted aryl; and

R¹¹ attached to —

NR^v—

is independently selected from the group consisting of H, —

C(R^x)₂COOR ^y, and -cycloalkylene-COOR^y;

or when Y and Y′

are independently selected from —

O— and

—

NR^v—

, then together R¹¹ and R¹¹ are the group;

12. A compound of Formula VIII:

13. The compounds of claim 12, wherein R¹ and R² are each —

CH₃.

14. The compounds of claim 12, wherein V is phenyl substituted by one or two groups selected from fluoro and chloro.

15. The compounds of claim 12, wherein V is 3-chlorophenyl.

16. A compound having a structure: