Malonamic acids and derivatives thereof as thyroid receptor ligands

• US 6,924,310 B2
• Filed: 10/10/2003
• Issued: 08/02/2005
• Est. Priority Date: 03/31/2000
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Original Assignee: Pfizer Inc., Pfizer Products Incorporated (Pfizer Inc.)
• Inventors: Aspnes, Gary E., Estep, Kimberly G., Chiang, Yuan-Ching P.
• Primary Examiner(s): Zucker, Paul A.
• Application Number:
  US10/683,372
• Publication Number:
  US 20040077694A1
• Time in Patent Office: 662 Days
• Field of Search: 560/13, 514/563
• US Class Current: 514/563
• 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 compound of formula A

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

wherein R¹ and R² are each independently —

CH₃ or —

Cl;

R⁴ is —

SO₂—

NH-cyclopropyl, —

SO₂—

NH-cyclobutyl, —

SO₂—

NH-cyclopentyl, —

SO₂—

NH-cyclohexyl, —

SO₂—

NH—

(C₁-C₈)alkyl or —

SO₂—

NH-phenyl optionally substituted with fluoro;

R⁸ and R⁹ are each independently hydrogen or methyl; and

R¹⁰ is —

C(O)OH, —

C(O)OCH₃ or —

C(O)OCH₂CH₃.

2. A compound of claim 1 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 —

(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-cyclopropyl;

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-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—

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;

R⁴ is —

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.

3. A compound of claim 1 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-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

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

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

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

5. A pharmaceutical composition comprising an effective amount of a compound of claim 1, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug in admixture with at least one pharmaceutically carrier.

6. A pharmaceutical composition comprising a compound of claim 1, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug;

and an additional compound useful to treat a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorder, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesteremia, depression, osteoporosis and hair loss.

7. A composition of claim 6 wherein the condition is obesity.

8. A composition of claim 7 wherein the additional compound is a lipase inhibitor.

9. A composition of claim 8 wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastin, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers.

10. A composition of claim 7 wherein the additional compound is an anorectic agent.

11. A composition of claim 8 wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.

12. A composition of claim 6 wherein the condition is hair loss.

4. A compound 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-cyclobutylsulfamoyl-4-hydroxy-phenoxy)-phenyl]-malonamic acid;

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

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

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