Malonamic acids and derivatives thereof as thyroid receptor ligands

• US 7,202,275 B2
• Filed: 05/10/2005
• Issued: 04/10/2007
• Est. Priority Date: 03/31/2000
• Status: Expired due to Fees

• Current Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company LLC (Pfizer Inc.)
• Inventors: Aspnes, Gary E., Chiang, Yuan-Ching P., Estep, Kimberly G.
• Primary Examiner(s): Zucker; Paul A.
• Application Number:
  US11/125,710
• Publication Number:
  US 20050209333A1
• Time in Patent Office: 700 Days
• Field of Search: None
• US Class Current: 514/530
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 235/16 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/80 having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2601/18 with a ring being at least seven-membered
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/22 with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07D 209/46 with an oxygen atom in position 1

Abstract

The present invention relates to novel thyroid receptor ligands and, more particularly, relates to malonamic acids and derivatives thereof of Formula I, which are useful in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss. The present invention also provides methods, pharmaceutical compositions and kits for treating such diseases and disorders

Claims

1. A method of treating hair loss in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of Formula A:

2. The method of claim 1 wherein said compound is selected from the group consisting of:

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-cyclopropyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃;

R² is CH₃ ;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is CH₃;

R⁴ is —

SO₂—

NH-cyclobutyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH—

CH(CH₃)₂;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH—

(CH₂)₃—

CH₃;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴ is —

SO₂—

NH—

(CH₂)₆—

CH₃;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is Cl;

R² is Cl;

R⁴is —

SO₂—

NH-(4-fluoro-phenyl);

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

a compound wherein R¹ is CH₃, R² is CH₃, R⁴ is —

SO₂—

NH-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH; and

a compound wherein R¹ is Cl, R² is Cl, R⁴ is —

SO₂—

NH-cyclohexyl;

R⁸ and R⁹ are each hydrogen; and

R¹⁰ is —

C(O)OH;

or an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.

3. The method of claim 1 wherein said compound is selected from the group consisting of:

N-[3,5-dichloro-4-(3-cyclopropylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(3-cyclobutylsulfamnoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

N-[3-chloro-4-(3-cycloburtylsulfamoyl-4-hydroxy-phenoxy)-5-methyl-phenyl]-malonamic acid;

N-[4-(3-cycloburtylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid and;

N-[4-(3-cycloburtylsulfamoyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid;

or an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug.

4. The method of claim 1 wherein said hair loss is male pattern baldness or female pattern baldness.

5. The method of claim 1 wherein said compound is administered topically.

6. The method of claim 1 wherein said compound is administered in combination with minoxidil.

7. The method of claim 1 wherein said compound is administered in combination with finasteride.

8. The method of claim 1 wherein said mammal is a human.