Utilities of olefin derivatives

• US 20040242615A1
• Filed: 04/19/2004
• Published: 12/02/2004
• Est. Priority Date: 09/14/2001
• Status: Active Grant

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Nagata, Kiyoshi, Ishizuka, Natsuki, Hayashi, Kunio, Yamamori, Teruo
• Granted Patent: US 8,124,625 B2
• Time in Patent Office: Days
• US Class Current: 514/277
• 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 of them; are disclosed.

Claims

1. A method of enhancing the expression of apoAI, which comprises administrating a therapeutically effective amount of 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 5, in which Y¹, Y², Y³, and Y⁴ in formula (I) is a hydrogen.

7. The method according to any one of claims 1 to 6, in which Z¹, and Z² in formula (I) is a hydrogen.

8. The method according to any one of claims 1 to 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.

9. The method according to any one of claims 1 to 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

10. The method according to any one of claims 1 to 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.

11. The method according to any one of claims 1 to 7, in which m and n in formula (I) are 1, and —

X—

is -β

-.

12. A method of prevention or treatment of dyslipidemia or arteriosclerotic diseases, which comprises administrating a therapeutically effective amount of a compound of formula (I) as defined in claim 1, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient suspected to have dyslipidemia or arteriosclerotic diseases.

13. A compound of formula (II):

14. The compound according to claim 13, in which the group:

15. The compound according to claim 13 or 14, in which Ar² is 3-pyridyl, 3-furyl, 3-thienyl, or 1,3-thiazol-2-yl;

a prodrug thereof, a pharmaceutically acceptable salt or solvate of them.

16. A pharmaceutical composition, which comprises the compound according to any one of claims 13 to 15, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them, together with a pharmaceutically acceptable additive.

17. The pharmaceutical composition according to claim 16, which is used to enhance the expression of apoAI.

18. The pharmaceutical composition according to claim 16, which is used for prevention and/or treatment of dyslipidemia or arteriosclerotic diseases.