Aromatic amine derivative and use thereof

• US 20090325956A1
• Filed: 10/12/2007
• Published: 12/31/2009
• Est. Priority Date: 10/13/2006
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Matsui, Junji, Miyata, Kenichi, Taniguchi, Takahiko, Kubo, Osamu
• Application Number:
  US12/311,776
• Publication Number:
  US 20090325956A1
• Time in Patent Office: Days
• US Class Current: 514/235.5
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/40 Acylated on said nitrogen atom
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 241/22 Benzenesulfonamido pyrazines
• CPC Class Codes: C07D 249/14 Nitrogen atoms
• CPC Class Codes: C07D 261/14 Nitrogen atoms
• CPC Class Codes: C07D 275/02 not condensed with other rings
• CPC Class Codes: C07D 277/20 having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 277/32 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 277/46 : by carboxylic acids, or sulfur or nitrogen analogues thereof
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The present invention provides a novel SCD inhibitor. An SCD inhibitor containing a compound represented by the formula [I]

wherein ring A is an optionally substituted aromatic ring, ring B is an optionally substituted ring, ring C is an optionally substituted aromatic ring, R is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and X is a spacer having 1 to 5 atoms in the main chain, or a salt thereof, or a prodrug thereof.

Claims

1. An SCD inhibitor comprising a compound represented by the formula [I]

wherein

ring A is an optionally substituted aromatic ring,

ring B is an optionally substituted ring,

ring C is an optionally substituted aromatic ring,

R is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and

X is a spacer having 1 to 5 atoms in the main chain,

or a salt thereof, or a prodrug thereof.

2. The agent of claim 1, wherein the ring A is an optionally substituted aromatic cyclic hydrocarbon or an optionally substituted 5- or 6-membered monocyclic aromatic heterocycle.

3. The agent of claim 1, wherein the ring B is an optionally substituted aromatic cyclic hydrocarbon or an optionally substituted 5- or 6-membered nitrogen-containing heterocycle.

4. The agent of claim 1, wherein the ring C is an optionally substituted 6-membered aromatic ring.

5. The agent of claim 1, wherein X is the formula —

(CH₂)_m—

Y—

(CH₂)_n—

wherein m and n are each an integer of 0 to 4 (total of m and n does not exceed

     4), and Y is a bond (when Y is a bond, m is not

     0), —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

or —

N(R¹)—

(wherein R¹ is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group).

6. The agent of claim 1, wherein X is —

CH₂—

O—

.

7. The agent of claim 1, wherein R is a hydrogen atom.

8. The agent of claim 1, which is an agent for the prophylaxis or treatment of hyperlipidemia.

9. The agent of claim 8, which further comprises a drug having a blood lipid improving effect.

10. The agent of claim 1, which is an agent for the prophylaxis or treatment of diabetes or obesity.

11. A method for the prophylaxis or treatment of hyperlipidemia or obesity in a mammal, which comprises administering the agent of claim 1 to the mammal.

12. A method for the prophylaxis or treatment of diabetes or obesity in a mammal, which comprises administering the agent of claim 1 to the mammal.

13-14. -14. (canceled)

15. A compound represented by the formula [II]

wherein

ring A′

is a further optionally substituted pyrazole ring,

ring B′

is an optionally substituted ring,

R² is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,

ring C is an optionally substituted aromatic ring,

R is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and

Y¹ is —

C(R³)(R⁴)—

X¹—

(R³ and R⁴ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, a cyano group, a nitro group, an optionally substituted acyl group or a halogen atom, and X¹ is a spacer having 1 to 4 atoms in the main chain,

provided that ring B′

is not a furan ring, R² is not a methyl group, and one of ring B′ and

ring C is a heterocycle,

or a salt thereof.

16. The compound of claim 15, wherein ring A′

is a pyrazole ring.

17. The compound of claim 15, wherein ring B′

is benzene, piperidine, morpholine, pyrrolidine or pyridine.

18. The compound of claim 15, wherein R² is an optionally substituted C_1-6 alkyl group, an optionally substituted C_7-12 aralkyl group, optionally substituted C_6-10 aryl group or an optionally substituted 5- or 6-membered nitrogen-containing heterocyclic group.

19. The compound of claim 15, wherein ring C is an optionally substituted 6-membered aromatic ring.

20. The compound of claim 15, wherein R is a hydrogen atom.

21. The compound of claim 15, wherein Y¹ is —

CH₂O—

, —

CH₂CH₂—

or —

CH₂CH₂O—

.

23. A prodrug of the compound of claim 15.

24. A pharmaceutical agent comprising the compound of claim 15 or a prodrug thereof.

25. The pharmaceutical agent of claim 24, which is an SCD inhibitor.

26. The pharmaceutical agent of claim 24, which is an agent for the prophylaxis or treatment of hyperlipidemia.

27. The pharmaceutical agent of claim 26, further comprising a drug having a blood lipid improving effect.

28. The pharmaceutical agent of claim 24, which is an agent for the prophylaxis or treatment of diabetes or obesity.

29. A method for the prophylaxis or treatment of hyperlipidemia in a mammal, which comprises administering the compound of claim 15 or a prodrug thereof to the mammal.

30. A method for the prophylaxis or treatment of diabetes or obesity in a mammal, which comprises administering the compound of claim 15 or a prodrug thereof to the mammal.

22. 3-[(2-Chlorophenoxy)methyl]-N-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]pyrrolidine-1-carboxamide;

4-[(2-chlorophenoxy)methyl]-N-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide;

4-[(2-chloro-5-fluorophenoxy)methyl]-N-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide;

N-[1-(4-fluorobenzyl)-1H-pyrazol-4-yl]-4-{[2-fluoro-5-(trifluoromethyl)phenoxy]methyl}pyridine-2-carboxamide;

4-[(2,5-dichlorophenoxy)methyl]-N-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxamide;

or a salt thereof.

31-32. -32. (canceled)

33. A compound represented by the formula [III]

wherein

ring A″

is an optionally substituted aromatic heterocycle,

is a ring selected from

each of which is optionally substituted,

ring C is an optionally substituted aromatic ring,

R is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group,

Y² is —

C(R³)(R⁴)—

X²—

wherein R³ and R⁴ are each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, a cyano group, a nitro group, an optionally substituted acyl group or a halogen atom, and

X² is a spacer having 1 to 4 atoms in the main chain,

ring A″

is not pyrazol-4-yl having a substituent at the 1-position,

X² is not —

NH—

,

or a salt thereof.

34. The compound of claim 33, wherein ring A″

is an optionally substituted 5- or 6-membered nitrogen-containing aromatic heterocycle.

35. The compound of claim 33, wherein ring B″

is unsubstituted.

36. The compound of claim 33, wherein ring C is an optionally substituted 6-membered aromatic ring.

37. The compound of claim 33, wherein R is a hydrogen atom.

38. The compound of claim 33, wherein Y² is —

CH₂O—

, —

CH₂CH₂—

or —

CH₂CH₂O—

.

40. A prodrug of the compound of claim 33.

41. A pharmaceutical agent comprising the compound of claim 33 or a prodrug thereof.

42. The pharmaceutical agent of claim 41, which is an SCD inhibitor.

43. The pharmaceutical agent of claim 41, which is an agent for the prophylaxis or treatment of hyperlipidemia.

44. The pharmaceutical agent of claim 43, further comprising a drug having a blood lipid improving effect.

45. The pharmaceutical agent of claim 41, which is an agent for the prophylaxis or treatment of diabetes or obesity.

46. A method for the prophylaxis or treatment of hyperlipidemia in a mammal, which comprises administering the compound of claim 33 or a prodrug thereof to the mammal.

47. A method for the prophylaxis or treatment of diabetes or obesity in a mammal, which comprises administering the compound of claim 33 or a prodrug thereof to the mammal.

39. N-(4,6-Dimethylpyridin-2-yl)-2-[(2-fluorophenoxy)methyl]morpholine-4-carboxamide;

N-(4,6-dimethylpyridin-2-yl)-2-{[2-(trifluoromethyl)phenoxy]methyl}morpholine-4-carboxamide;

2-[(2-chloro-5-fluorophenoxy)methyl]-N-(4,6-dimethylpyridin-2-yl)morpholine-4-carboxamide;

2-[(2-chloro-5-fluorophenoxy)methyl]-N-(6-ethylpyridin-2-yl)morpholine-4-carboxamide;

2-[(2-chloro-5-fluorophenoxy)methyl]-N-[5-(hydroxymethyl)pyridin-2-yl]morpholine-4-carboxamide;

or a salt thereof.

48-49. -49. (canceled)