Method of enhancing the expression of apolipoprotein AI using olefin derivatives

• US 8,124,625 B2
• Filed: 09/14/2001
• Issued: 02/28/2012
• Est. Priority Date: 09/14/2001
• Status: Expired due to Fees

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Yamamori, Teruo, Nagata, Kiyoshi, Ishizuka, Natsuki, Hayashi, Kunio
• Primary Examiner(s): Weddington, Kevin E
• Application Number:
  US10/489,365
• Publication Number:
  US 20040242615A1
• Time in Patent Office: 3,819 Days
• Field of Search: 514/310
• US Class Current: 514/318
• CPC Class Codes: A61K 31/215 of carboxylic acids
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• 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 213/06 containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
• CPC Class Codes: C07D 213/16 containing only one pyridine ring
• CPC Class Codes: C07D 213/26 Radicals substituted by halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/55 Acids; Esters
• CPC Class Codes: C07D 213/57 Nitriles
• CPC Class Codes: C07D 215/04 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
• CPC Class Codes: C07D 215/14 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 263/57 Aryl or substituted aryl radicals
• CPC Class Codes: C07D 277/66 with aromatic rings or ring systems directly attached in position 2
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Compounds having an activity to enhance the expression of apoAI are provided. Compounds of formula (I):

in which Ar¹ and Ar² are independently a phenyl, naphthyl, or monocyclic or bicyclic aromatic heterocyclic group, which may be optionally substituted; —X— is —N═CZ²—, —CY²═CZ²—, —CY²Y³—CHZ²—, —S—, —O—, or the like; Y¹, Y², Y³, Z¹ and Z² are independently a hydrogen, a halogen, a lower alkyl, a phenyl, or the like; Z¹ and Z² may be independently a linker group that may combine with Ar² and Ar¹ to form a condensed ring; m is 0 or 1, and n is 0 to 2; a prodrug thereof, a pharmaceutically acceptable salt or solvate thereof; are disclosed.

Claims

1. A method of enhancing the expression of apoAI, which comprises administrating a compound of formula (I):

2. The method according to claim 1, in which at least one of Ar¹ and Ar² in formula (I) is a monocyclic or bicyclic aromatic heterocyclic group that may be optionally substituted, and that contains a nitrogen atom at the position adjacent to the constituent atom of the ring that has a binding bond.

3. The method according to claim 1, in which at least one of Ar¹ and Ar² in formula (I) is 2-pyridyl, 2-quinolyl, 2-quinoxalyl, 2-benzisoxazolyl, 2-benzothiazolyl, or 2-benzimidazolyl, each of which may be optionally substituted.

4. The method according to claim 2 or 3, in which one of Ar¹ and Ar² in formula (I) is a group as defined in claim 2 or 3, and the other is a phenyl that may be optionally substituted, or a monocyclic or bicyclic aromatic heterocyclic group that may be optionally substituted.

5. The method according to claim 2 or 3, in which one of Ar¹ and Ar² in formula (I) is a group as defined in claim 2 or 3, and the other is a phenyl or a monocyclic or bicyclic aromatic heterocyclic group, each of which may be optionally substituted, wherein the substituent is a halogen;

a lower alkyl optionally substituted by a halogen or a lower alkoxy;

a hydroxy;

a lower alkoxy;

a phenyloxy;

a naphtylthio;

an acyloxy;

a carboxy;

a lower alkoxycarbonyl;

an amino optionally substituted by a lower alkyl or a lower acyl;

a phenyl that may be optionally substituted by a lower alkoxy;

a nitro;

a lower alkylthio;

a cyano;

a monocyclic heterocyclic group;

or an alkylenedioxy that may be substituted by a lower alkyl, a lower alkoxy or phenyl.

6. The method according to any one of claims 1 to 3, in which Y¹, Y², Y³, and Y⁴ in formula (I) is a hydrogen.

7. The method according to any one of claims 1 to 3, in which Z¹, and Z² in formula (I) is a hydrogen.

8. The method according to any one of claims 1 to 3, in which m in formula (I) is 1, —

X—

is a group of formula (α

), the broken line is the presence of a bond, -Q= is a group of

9. The method according to any one of claims 1 to 3, in which m and n in formula (I) are 1, and —

X—

is -β

-.

10. The method according to claim 4, in which Y¹, Y², Y³, and Y⁴ in formula (I) is a hydrogen.

11. The method according to claim 5, in which Y¹, Y², Y³, and Y⁴ in formula (I) is a hydrogen.

12. The method according to claim 4, in which Z¹, and Z² in formula (I) is a hydrogen.

13. The method according to claim 5, in which Z¹, and Z² in formula (I) is a hydrogen.

14. The method according to claim 6, in which Z¹, and Z² in formula (I) is a hydrogen.

15. The method according to claim 4, in which Z¹ in formula (I) is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar² that are bonded to Z¹ via the two atoms to form a condensed ring.

16. The method according to claim 5, in which Z¹ in formula (I) is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar² that are bonded to Z¹ via the two atoms to form a condensed ring.

17. The method according to claim 6, in which Z¹ in formula (I) is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar² that are bonded to Z¹ via the two atoms to form a condensed ring.

18. The method according to claim 4, in which m in formula (I) is 1, —

X—

is a group of formula (α

), the broken line is the presence of a bond, -Q= is a group of

19. The method according to claim 5, in which m in formula (I) is 1, —

X—

is a group of formula (α

), the broken line is the presence of a bond, -Q= is a group of

20. The method according to claim 6, in which m in formula (I) is 1, —

X—

is a group of formula (α

), the broken line is the presence of a bond, -Q= is a group of

21. The method according to claim 7, in which m in formula (I) is 1, —

X—

is a group of formula (α

), the broken line is the presence of a bond, -Q= is a group of

22. The method according to claim 4, in which m in formula (I) is 1, —

X—

is a group of formula (α

), and Z² is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar¹ to form a condensed ring.

23. The method according to claim 5, in which m in formula (I) is 1, —

X—

is a group of formula (α

), and Z² is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar¹ to form a condensed ring.

24. The method according to claim 6, in which m in formula (I) is 1, —

X—

is a group of formula (α

), and Z² is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar¹ to form a condensed ring.

25. The method according to claim 4, in which m and n in formula (I) are 1, and —

X—

is -β

-.

26. The method according to claim 5, in which m and n in formula (I) are 1, and —

X—

is -β

-.

27. The method according to claim 6, in which m and n in formula (I) are 1, and —

X—

is -β

-.

28. The method according to claim 7, in which m and n in formula (I) are 1, and —

X—

is -β

-.