Oxamic acids and derivatives as thyroid receptor ligands

• US 6,326,398 B1
• Filed: 02/28/2000
• Issued: 12/04/2001
• Est. Priority Date: 03/01/1999
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Dow, Robert L., Chiang, Yuan-Ching Phoebe
• Primary Examiner(s): Davis, Zinna Northington
• Application Number:
  US09/514,862
• Time in Patent Office: 645 Days
• Field of Search: 514/535, 514/563, 514/617, 564/155, 562/433, 560/19, 560/143
• US Class Current: 514/535
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 3/04 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 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 5/16 for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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: C07C 235/74 of a saturated carbon skeleton
• 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 2602/08 : the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2602/10 : the other ring being six-membered, e.g. tetraline
• CPC Class Codes: C07C 2602/42 : the bicyclo ring system containing seven carbon atoms
• 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 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/16 : with acylated ring nitrogen atom
• CPC Class Codes: C07D 215/08 : with acylated ring nitrogen atom
• CPC Class Codes: C07D 215/20 : Oxygen atoms
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/06 : with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 217/08 : with a hetero atom directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/192 : from aromatic carboxylic acids
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 317/58 : Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 333/20 : by nitrogen atoms nitro, nitroso radicals C07D333/12

Abstract

The present invention provides novel compounds of the Formula

and prodrugs thereof, geometric and optical isomers thereof, and pharmaceutically acceptable salts of such compounds, prodrugs and isomers, wherein R¹-R⁸ and W are as described herein. Pharmaceutical compositions containing such compounds, prodrugs, isomers or pharmaceutically acceptable salts thereof, and methods, pharmaceutical compositions and kits for treating obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism and related disorders and diseases such as diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis are also provided.

Claims

1. A compound of the Formula

a prodrug thereof, a geometric or optical isomer thereof, or a pharmaceutically acceptable salt of said compound, said prodrug, or said isomer, wherein:

R¹ and R² are each independently hydrogen, halogen, C_1-6 alkyl, trifluoromethyl, —

CN, —

OCF₃ or —

OC_1-6 alkyl;

R³ and R⁴ may be taken together to form a carbocyclic ring A of the formula —

(CH₂)_b—

or a heterocyclic ring A selected from the group consisting of —

Q—

(CH₂)_c— and

—

(CH₂)_j—

Q—

(CH₂)_k—

wherein Q is O, S or NR¹⁷, wherein said carbocyclic ring A and said heterocyclic ring A are each independently optionally substituted with one or more substituents independently selected from C_1-4 alkyl, halide or oxo;

R⁵ is fluoro, hydroxy, C_1-4 alkoxy of OC(O)R⁹;

R⁶ is hydrogen, halogen, C_1-4 alkyl or trifluoromethyl;

R⁷ is hydrogen or C_1-6 alkyl;

R⁸ is —

OR⁹ or —

NR¹⁹R²⁰;

R⁹ for each occurrence is independently (A) hydrogen, (B) C_1-12 alkyl optionally substituted with one or more substituents independently selected from Group V, (C) C_2-12 alkenyl, (D) C_3-10 cycloalkyl optionally substituted with one or more substituents independently selected from C_1-6 alkyl, C_2-5 alkynyl, C_3-10 cycloalkyl, —

CN, —

NR¹³R¹⁴ oxo, —

OR¹⁸, —

COOR¹⁸ or aryl optionally substituted with X and Y, (E) aryl optionally substituted with X and Y, or (F) het optionally substituted with X and Y;

R¹³ and R¹⁴ for each occurrence are independently hydrogen, C_1-6 alkyl, C_2-6 alkenyl, —

(C_1-6 alkyl)-C_1-6 alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, —

(C_1-4 alkyl)-aryl optionally substituted with X and Y, —

(C_1-4 alkyl)-heterocycle optionally substituted With X and Y, —

(C_1-4 alkyl)-hydroxy, —

(C_1-4 alkyl)-halo, —

(C_1-4 alkyl)-poly-halo, —

(C_1-4 alkyl)-CONR¹⁵R¹⁶ or C_3-10 cycloalkyl;

R¹⁵ and R¹⁶ for each occurrence are independently hydrogen, C_1-6 alkyl, C_3-10 cycloalkyl or aryl optionally substituted with X and Y;

R¹⁷ is hydrogen, C_1-6 alkyl, —

COR⁹ or —

SO₂R⁹;

R¹⁸ is hydrogen, C_1-6 alkyl, C_2-6 alkenyl, —

(C_1-6 alkyl)-C_1-6 alkoxy, aryl optionally substituted with X and Y, het optionally substituted with X and Y, —

(C_1-4 alkyl)-aryl optionally substituted with X and Y, —

(C_1-4 alkyl)-heterocycle optionally substituted with X and Y, —

(C_1-4 alkyl)-hydroxy, —

(C_1-4 alkyl)-halo, —

(C_1-4 alkyl)-poly-halo, —

(C_1-4 alkyl)-CONR¹⁵R¹⁶, —

(C_1-4 alkyl)-(C_1-4 alkoxy) or C_3-10 cycloalkyl;

R¹⁹ is hydrogen or C_1-6 alkyl;

R²⁰ is hydrogen or C_1-6 alkyl;

W is O, S(O)_d, CH₂ or NR⁹;

Group V is halogen, —

NR¹³R¹⁴, —

OCF₃, —

OR⁹, oxo, trifluoromethyl, —

CN, C_3-10 cycloalkyl, aryl optionally substituted with X and Y, and het optionally substituted with X and Y;

het for each occurrence is a heterocyclic ring D selected from the group consisting of 4-, 5-, 6-, 7- and 8-membered partially and fully saturated, and unsaturated, heterocyclic rings containing from one to four heteroatoms independently selected from the group consisting of N, O and S, and including any bicyclic group in which said heterocyclic ring D is fused to a benzene ring or a heterocyclic ring E selected from the group consisting of 4-, 5-, 6-, 7- and 8-membered partially and fully saturated, and unsaturated, heterocyclic rings containing from one to four heteroatoms independently selected from the group consisting of N, O and S;

X and Y for each occurrence are independently (A) hydrogen, (B) halogen, (C) trifluoromethyl, (D) —

OCF₃, (E) —

CN, (F) C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —

OCF₃, —

CF₃ and phenyl, (G) C_1-6 alkoxy, (H) aryl optionally substituted with one or more substituents independently selected from the group consisting of halogen, —

OCF₃, —

CF₃, C_1-4 alkyl and C_1-4 alkoxy, (I) —

C(O)₂R¹³, (J) —

C(O)NR¹³R¹⁴, (K) —

C(O)R¹³, (L) —

NR¹³C(O)NR¹³R¹⁴ and (M) —

NR¹³C(O)R¹⁴;

or X and Y for any occurrence in the same variable may be taken together to form (a) a carbocyclic ring D of the formula —

(CH₂)_e—

or (b) a heterocyclic ring F selected from the group consisting of —

O(CH₂)_lO—

, (CH₂)_gNH— and

—

CH═

CHNH—

;

each d is independently 0, 1 or 2;

b is 3, 4, 5, 6 or 7;

c, f, g, j and k are each independently 2, 3, 4, 5 or 6; and

e is 3, 4, 5, 6 or 7.

2. A compound or pharmaceutically acceptable salt as defined in claim 1 wherein W is oxygen.

3. A compound or pharmaceutically acceptable salt as defined in claim 2 wherein R¹ is located at the 3 position, R² is located at the 5 position, R³ is located at the 2′

position, R⁴ is located at the 3′

position, R⁵ is located at the 4′

position, and R⁶ is located at the 5′

position.

4. A compound or pharmaceutically acceptable salt according to claim 3 wherein R³ and R⁴ are taken together to form a carbocyclic ring A of the formula —

(CH₂)_b—

or a heterocyclic ring A selected from the group consisting of —

Q—

(CH₂)_c and —

(CH₂)_j—

Q—

(CH₂)_k—

wherein Q is O, S or NR¹⁷, wherein said carbocyclic ring A and said heterocyclic ring A are each independently optionally substituted with one or more substituents independently selected from C_1-4 alkyl, halide or oxo, R⁵ is hydroxy, R⁶ is hydrogen and R⁷ is hydrogen.

5. A compound or pharmaceutically acceptable salt as defined in claim 4 wherein R¹ and R² are each independently methyl, bromo or chloro, and R⁸ is hydroxy, methoxy, ethoxy, isopropoxy, NH₂ or NH(CH₃).

6. A compound or pharmaceutically acceptable salt as defined in claim 5 wherein R³ and R⁴ are taken together to form said carbocyclic ring A or said heterocyclic ring A.

7. A compound or pharmaceutically acceptable salt as defined in claim 6 wherein R³ and R⁴ are taken together to form said carbocyclic ring A.

8. A compound or pharmaceutically acceptable group as defined in claim 7 wherein R³ and R⁴ are taken together to form —

(CH₂)₃—

, —

CH₂—

C(CH₃)₂—

CH₂—

or —

(CH₂)₄—

.

9. A compound or pharmaceutically acceptable salt as defined in claim 8 wherein R¹ is methyl, R² is methyl, R⁸ is hydroxy, and R³ and R⁴ are taken together to form —

(CH₂)₃—

.

10. A compound or pharmaceutically acceptable salt as defined in claim 8 wherein R¹ is methyl, R² is methyl, R⁸ is ethoxy, and R³ and R⁴ are taken together to form —

(CH₂)₃—

.

11. A compound or pharmaceutically acceptable salt as defined in claim 8 wherein R¹ is chloro, R² is methyl, R⁸ is hydroxy, and R³ and R⁴ are taken together to form —

(CH₂)₃—

.

12. A compound or pharmaceutically acceptable salt as defined in claim 8 wherein R¹ is chloro, R² is methyl, R⁸ is ethoxy, and R³ and R⁴ are taken together to form —

(CH₂)₃—

.

13. A compound or pharmaceutically acceptable salt as defined in claim 8 wherein R¹ is methyl, R² is methyl, R⁸ is hydroxy, and R³ and R⁴ are taken together to form —

(CH₂)₄—

.

14. A compound or pharmaceutically acceptable salt as defined in claim 8 wherein R¹ is methyl, R² is methyl, R⁸ is ethoxy, and R³ and R⁴ are taken together to form —

(CH₂)₄—

.

15. A compound or pharmaceutically acceptable salt as defined in claim 6 wherein R³ and R⁴ are taken together to form said heterocyclic ring A.

16. A compound or pharmaceutically acceptable salt as defined in claim 15 wherein said heterocyclic ring A is —

Q—

(CH₂)_c—

.

17. A compound or pharmaceutically acceptable salt as defined in claim 1 wherein R⁸ is —

OR⁹.

18. A compound or pharmaceutically acceptable salt as defined in claim 17 wherein R⁹ is C_1-12 alkyl.

19. A compound or pharmaceutically acceptable salt as defined in claim 18 wherein R⁹ is methyl.

20. A compound or pharmaceutically acceptable salt as defined in claim 18 wherein R⁹ is ethyl.

21. A compound or pharmaceutically acceptable salt as defined in claim 18 wherein R⁹ is isopropyl.

22. A pharmaceutically acceptable salt as defined in claim 1 wherein said salt is a potassium salt.

23. A pharmaceutically acceptable salt as defined in claim 1 wherein said salt is a sodium salt.

24. A compound in accordance with claim 1 which is:

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid.

25. The compound of claim 24 in the form of a potassium salt.

26. The compound of claim 24 in the form of a sodium salt.

27. A compound in accordance with claim 1 which is:

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid methyl ester.

28. A compound in accordance with claim 1 which is:

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester.

29. A compound in accordance with claim 1 which is:

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid isopropyl ester.

30. A compound in accordance with claim 1 which is:

N-[3-chloro-4-(7-hydroxy-2,2-dimethyl-indan-4-yloxy)-5-methyl-phenyl]-oxamic acid,

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid,

N-[3-chloro-4-(7-hydroxy-indan-4-yloxy)-5-methyl-phenyl]-oxamic acid,

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamic acid ethyl ester,

N-[4-(7-hydroxy-indan-4-yloxy)-3,5-dimethyl-phenyl]-oxamide,

N-[3-chloro-4-(7-hydroxy-indan-4-yloxy)-5-methyl-phenyl]-oxamide,

N-[3-chloro-4-(4-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-5-methyl-phenyl]-oxamic acid, or

N-[3-chloro-4-(4-hydroxy-5,6,7,8-tetrahydro-naphtalen-1-yloxy)-5-methyl-phenyl]-oxamide.

31. A compound or pharmaceutically acceptable salt as defined in claim 3 wherein R⁵ is fluoro.

32. A method of treating a condition selected from the group consisting of obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis, in a mammal which comprises administering to said mammal an effective treating amount of a compound, prodrug, isomer or pharmaceutically acceptable salt of claim 1.

33. A method as defined in claim 32 further including administering an anorectic agent.

34. A method as defined in claim 32 further including administering a lipase inhibitor.

35. A method as defined in claim 33 further including administering a lipase inhibitor.

36. A method as defined in claim 32 wherein said condition is obesity.

37. A method as defined in claim 33 wherein said condition is obesity.

38. A method as defined in claim 34 wherein said condition is obesity.

39. A method as defined in claim 35 wherein said condition is obesity.

40. A pharmaceutical composition comprising a compound, prodrug, isomer or pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable vehicle, diluent or carrier.

41. A pharmaceutical composition as defined in claim 40 further including an anorectic agent.

42. A pharmaceutical composition as defined in claim 40 further including a lipase inhibitor.

43. A pharmaceutical composition as defined in claim 41 further including a lipase inhibitor.

44. A pharmaceutical composition for treating a condition selected from the group consisting of obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, typothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis, in a mammal comprising a compound, prodrug, isomer or pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable vehicle, diluent or carrier.

45. A pharmaceutical composition as defined in claim 44 further including an anorectic agent.

46. A pharmaceutical composition as defined in claim 44 further including a lipase inhibitor.

47. A pharmaceutical composition as defined in claim 45 further including a lipase inhibitor.

48. A pharmaceutical composition as defined in claim 44 wherein said condition is obesity.

49. A pharmaceutical composition as defined in claim 45 wherein said condition is obesity.

50. A pharmaceutical composition as defined in claim 46 wherein said condition is obesity.

51. A pharmaceutical composition as defined in claim 47 wherein said condition is obesity.

52. A kit for the treatment of a condition selected from the group consisting of obesity, hyperlipidemia, glaucoma, cardiac arrhythmia, skin disorders, thyroid disease, hypothyroidism, diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, hypercholesteremia, depression and osteoporosis which comprises:

a first compound, said first compound being a compound, prodrug, isomer, or pharmaceutically acceptable salt as defined in claim 1, and a pharmaceutically acceptable vehicle, carrier or diluent, in a first unit dosage form;

a second compound, said second compound being an anorectic agent or a lipase inhibitor, and a pharmaceutically acceptable vehicle, carrier or diluent, in a second unit dosage form; and

a container.

53. A kit as defined in claim 52 wherein said condition is obesity.