Utilities of olefin derivatives

• US 20090036457A1
• Filed: 09/09/2008
• Published: 02/05/2009
• Est. Priority Date: 09/14/2001
• Status: Active Grant

• Current Assignee: Kiyoshi Nagata, Kunio Hayashi, Natsuki Ishizuka, Teruo Yamamori
• Original Assignee: Kiyoshi Nagata, Kunio Hayashi, Natsuki Ishizuka, Teruo Yamamori
• Inventors: Nagata, Kiyoshi, Ishizuka, Natsuki, Hayashi, Kunio, Yamamori, Teruo
• Granted Patent: US 8,053,445 B2
• Time in Patent Office: Days
• US Class Current: 514/249
• 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

1-18. -18. (canceled)

19. A method of enhancing the expression of apoAI, which comprises administrating a therapeutically effective amount of a compound of formula (I):

in which

Ar¹ and Ar² are independently a phenyl that may be optionally substituted, a naphthyl that may be optionally substituted, or a monocyclic or bicyclic aromatic heterocyclic group that may be optionally substituted;

—

X—

is a group of formula (α

);

wherein

the broken line is the presence or absence of a bond;

-Q= is a group of

when the broken line is the presence of a bond;

-Q- is —

CY²Y³- or —

NY⁴—

when the broken line is the absence of a bond;

Y² and Y³ are independently a hydrogen, a halogen, a lower alkyl that may be optionally substituted, a carboxy, a lower alkoxycarbonyl that may be optionally substituted, a cyano, a monocyclic carbocyclic group that may be optionally substituted, or a monocyclic heterocyclic group that may be optionally substituted,

Y⁴ is a hydrogen or a lower alkyl;

Z² is a linker group comprising 1 to 2 atoms that combines with the constituent atoms of the ring Ar¹ that are bonded to Z² via the two atoms to form a condensed ring;

m is 1;

n is 0;

provided that, when both Ar¹ and Ar² are a phenyl that may be optionally substituted, then Y² is not a phenyl that may be optionally substituted;

a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient expected to enhance the expression of apoAI.

20. The method according to claim 19, 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.

21. The method according to claim 19, in which at least one of Ar¹ and Ar² in formula (I) is 2-pyridyl, 2-quinolyl, 2-quinoxaloyl, 2-benzisoxazolyl, 2-benzothiazolyl, or 2-benzimidazolyl, each of which may be optionally substituted.

22. The method according to claim 20 or 21, in which one of Ar¹ and Ar² in formula (I) is a group as defined in claim 20 or 21, and the other is a phenyl that may be optionally substituted, or a monocyclic or bicyclic aromatic heterocyclic group that may be optionally substituted.

23. The method according to claim 20 or 21, in which one of Ar¹ and Ar² in formula (I) is a group as defined in claim 20 or 21, 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 naphthylthio;

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.

24. The method according to any one of claims 19 to 23, in which Y², Y³, and Y⁴ in formula (I) is a hydrogen.

25. 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 any one of claims 19-24, a prodrug thereof, a pharmaceutically acceptable salt or solvate of them to a patient suspected to have dyslipidemia or arteriosclerotic diseases.