JP2001139550A - New use of amide compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound having excellent apo AI expression accelerating actions and useful as a medicine. SOLUTION: This apo AI expression accelerator comprises a compound represented by the formula (I) (wherein the ring A and Ar1 are each a monocyclic or a bicyclic aromatic hydrocarbon cyclic group or an aromatic heterocyclic group or the like which may respectively have a substituent group; R is hydrogen or the like; Z is oxygen or the like; Y1 and Y2 are each hydrogen, a lower alkyl or the like; (n) is an integer of 0-2; the broken line indicates the presence or absence of a bond; and the wavy line indicates the cis- or trans- geometrical isomerism related to the double bond), its prodrug, a phemaceutically acceptable salt thereof and a hydrate thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to apolipoprotein A.
The present invention relates to an I expression enhancer and a novel compound having the action.

[0002]

2. Description of the Related Art The involvement of cholesterol as a major cause of arteriosclerosis, which causes severe heart disease, is widely known. In particular, hyper-LDL blood in which the density of low-density lipoprotein (LDL) is increased is coronary artery disease (CHD: co
ronary heart diseases)
Using statins, LDL cholesterol (L
The LDL-C lowering therapy for lowering DL-C) has a remarkable clinical effect on the development of CHD and improvement of the disease state and survival rate in hypercholesterolemia patients. However, about 40% of CHD patients have normal LDL-C levels, and LDL-C lowering therapy is not always effective for these patients. On the other hand, half of the patients with normal LDL-C values have high density lipoprotein (HDL) cholesterol (HDL-
C) The value is said to be low. In recent years, this low HDL-C
It is becoming clear that bloodemia is another risk factor for the onset and recurrence of CHD.

[0003] HDL plays an important role in a reverse cholesterol transfer system known as a biological mechanism for recovering excess cholesterol in cells to the liver and maintaining normal cholesterol levels in the living body. Lipoproteins such as HDL are generally composed of lipids and a protein component called apoprotein. In HDL, an apoprotein called apolipoprotein AI (hereinafter abbreviated as apoAI) is a main component. The released apoAI binds to a specific site of the cell, extracts and binds excess cholesterol (FC) and phospholipid from the cell, and binds to preβ-H
It becomes a lipoprotein called DL. preβ-HDL
FC incorporated in a large amount into the inside is converted into cholesteryl ester (CE) by lecithin: cholesterol acyltransferase (LCAT), and the particle size increases to mature into spherical HDL (HDL3).
Mature HDL has various subfractions depending on the specific gravity.
These particles collect further and displace HDL2. Under the action of cholesteryl ester transfer protein (CETP) present in blood, CE is transferred to VLD and LDL. These lipoproteins that have taken up CE are eventually taken up by the liver via receptors. In this process, apoAI is regenerated, and cholesterol extraction and preβ-HDL regeneration are repeated again by interaction with peripheral cells.

HDL plays a central role in the reverse cholesterol transfer system, and it is now widely recognized that HDL is one of the protective factors of arteriosclerosis. That is, a drug that enhances HDL function is expected to play an extremely important clinical role as a therapeutic drug for arteriosclerotic diseases, and research on substances that increase HDL levels in plasma is being conducted from various angles. One of the most effective methods among them is a method of increasing the concentration of blood apoAI, which is a major component of HDL. Although an increase in HDL does not necessarily mean an increase in apoAI, an increase in apoAI would directly contribute to the enhancement of HDL function. it is obvious. In fact, it has been shown that there is a direct correlation between liver mRNA levels of apoAI and blood apoAI protein and HDL levels. Therefore, by enhancing apoAI gene expression,
It is thought that if the blood apoAI concentration can be increased, the HDL function will eventually be improved, leading to activation of the cholesterol reverse transfer system. In fact, anti-atherosclerotic effects have been shown in apoAI transgenic mice and rabbit pathological models administered with apoAI. From these facts, it is considered that the substance that activates apoAI leads to the creation of a completely new drug for blood lipid abnormalities, arteriosclerotic diseases, and various other diseases involving HDL.

Compounds having a similar structure to the compound according to the present invention are described in GB 2327675, WO 99/07669,
WO 99/24404, US 5670066, DE19
744438, JP-A-6-41118, JP-A-3-14
568, JP-A-4-253974, JP-A-11-147
874, Journal of Pharmaceutical Sciences vol. 68,
Nos. 7, 827-832, etc., all of which have completely different functions. Several compounds that have a similar structure to the compound according to the present invention and are considered to be effective for hyperlipidemia, arteriosclerosis, visceral fat syndrome and the like are already known. JP-A-3-68592 describes a compound that lowers triglyceride in plasma and consequently raises HDL-C level, but its action is lipoprotein lipase activation (Chem. Pharm. Bull. , 44
(3), 547 (1996)). Compounds described in WO98 / 39280 and WO98 / 02412 are acyl CoA
Cholesterol acyltransferase (ACAT)
To inhibit cholesterol accumulation in macrophages. The compounds described in JP-A-11-171848 inhibit acetyl-CoA carboxylase and suppress the biosynthesis of triglyceride. WO 99/07382
Have macrophage scavenger receptor antagonism. The compounds described in JP-A-11-158133 have LDL oxidation inhibitory and ACAT inhibitory effects. However, these all have completely different mechanisms of action from the compounds according to the present invention. Compounds having an action of increasing apo AI are described in JP-A-5-221959, JP-A-8-291904, WO97 / 09048, and the like, all of which differ in structure from the compounds according to the present invention.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an excellent apoAI expression enhancer and a novel compound having the action.

[0007]

According to the present invention, there is provided 1) a compound of formula (I):

Embedded image (Wherein ring A is Ar ² or

Embedded image And Ar ¹ and Ar ² are each independently a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent or a monocyclic or bicyclic ring which may have a substituent And ring B is a monocyclic non-aromatic hydrocarbon group which may have a substituent or a monocyclic non-aromatic heterocyclic group which may have a substituent. A cyclic group, R is hydrogen or lower alkyl optionally having substituent (s),
Z is oxygen or sulfur; Y ¹ and Y ² are each independently hydrogen, halogen, lower alkyl optionally having substituent (s), carboxy, lower alkoxycarbonyl optionally having substituent (s), cyano A phenyl which may have a substituent or a monocyclic aromatic heterocyclic group which may have a substituent, wherein two or more Y ¹ and two or more Y ² are different Often, n is an integer from 0 to 2,
Dashed lines independently indicate the presence or absence of a bond, and wavy lines indicate cis or trans geometric isomerism with respect to the double bond), a prodrug thereof, a pharmaceutically acceptable salt thereof or a water thereof. An apoAI expression enhancer containing a Japanese product,

2) Ar ¹ is a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and is adjacent to a ring-constituting atom having a bond, which is a nitrogen atom; 3) 2-pyridyl, 2-quinolyl, 2-quinoxalyl, 2-benzisoxazolyl, 2-benzothiazolyl or 2-benzopyridyl, wherein Ar ¹ may have a substituent. 1) The apoAI expression enhancer according to 1), which is benzoimidazolyl, 4) a benzene ring which may be substituted with Ar ² condensed with ring B or a monocyclic ring which may have a substituent An apo AI expression enhancer according to any one of 1) to 3), which is an aromatic heterocyclic ring; 5) phenyl or an optionally substituted phenyl ring A may be substituted. A) an aromatic heterocyclic group represented by any one of (1) to (3); Of apo AI expression enhancer,

6) Ring A is phenyl or a monocyclic aromatic heterocyclic group, each of which may have a substituent (substituent is a halogen; a lower optionally substituted by halogen or lower alkoxy) Alkyl; hydroxy; lower alkoxy; phenoxy; naphthyloxy; acyloxy; carboxy; lower alkoxycarbonyl; amino optionally substituted by lower alkyl or lower acyl; phenyl optionally substituted by lower alkoxy;
Nitro; lower alkylthio, cyano, monocyclic heterocyclic group; or alkylenedioxy), 5) Apo AI expression enhancer according, 7) Y ¹ and / or Y ² is hydrogen, 1) - 6) The apo AI expression enhancer according to any of 8), 8) Z is oxygen, 1) the apo AI expression enhancer according to any of 1) to 7), 9) n is 1 or 2, and a dashed line ApoAI expression enhancer according to any one of 1) to 8), wherein all indicate the presence of a bond; 10) when n is 1 and the dashed line indicates the presence of a bond, the wavy line indicates NRCZ and ring A Indicates that the relationship is a trans configuration, and when n is 2 and each broken line indicates the presence of a bond, the wavy line indicates NRCZ and CY ^2.
And / or the relationship between CY ¹ and ring A is trans-configuration, 9) the apoAI expression enhancer according to 9), 11) a prophylactic and / or therapeutic agent for abnormal blood lipid or arteriosclerotic disease, ApoAI expression enhancer according to any of 1) to 10),

12) Formula (II):

Embedded image Wherein Het ¹ is pyridyl, furyl, 3-thienyl or pyrrolyl, R is hydrogen or lower alkyl, W ¹ is CR ³ or N, R ¹ , R ² , R ³ , R ⁴ and R ⁵ is each independently hydrogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino or acyl), a prodrug thereof, or a pharmaceutically acceptable salt thereof. Or their hydrates,

13) Formula (III):

Embedded image Wherein Het ² is pyridyl, furyl, thienyl or pyrrolyl, R is hydrogen or optionally substituted lower alkyl, W ² is CR ⁸ or N;
Y ¹ and Y ² are each independently hydrogen, halogen, a lower alkyl optionally having a substituent, carboxy, a lower alkoxycarbonyl optionally having a substituent, cyano,
A phenyl which may have a substituent or a monocyclic aromatic heterocyclic group which may have a substituent, and R ⁶ ,
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), carboxy, substituent A lower alkoxycarbonyl optionally having a substituent, an amino optionally having a substituent or an acyl optionally having a substituent, wherein any two of R ⁶ , R ⁷ and R ⁸ are And m is 1 or 2, each dashed line independently indicates the presence or absence of a bond, and each wavy line indicates cis or trans geometric isomerism with respect to the double bond. 14) W ² is CH, R is hydrogen or lower alkyl, and all dashed lines indicate the presence of a bond. ) Described compounds, Prodrug provides their pharmaceutically acceptable salt or a hydrate thereof.

Further, the above compound, a prodrug thereof,
It is intended to provide a method for enhancing apoAI expression and a method for treating and / or preventing blood lipid abnormality or arteriosclerotic disease, which comprises administering a pharmaceutically acceptable salt or a hydrate thereof. . In another embodiment, the above-mentioned compound, a prodrug thereof, or a pharmaceutical thereof for producing a medicament for enhancing apoAI expression or a medicament for treating and / or preventing blood lipid abnormalities or arteriosclerotic diseases. Provide use of acceptable salts or hydrates thereof.

In the present specification, when n is 2, two Y1 and two Y2 may be different from each other. "Halogen" includes fluorine, chlorine, bromine and iodine. “Lower alkyl” refers to a group having 1 to 6 carbon atoms;
It preferably includes straight-chain and branched alkyl having 1 to 3 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl and the like. "Lower alkyl optionally having substituent (s)"
It includes lower alkyl which may be substituted at any position by one or more substituents, and the substituent includes halogen, hydroxy, lower alkoxy, monocyclic or bicyclic hydrocarbon cyclic group, acyl, acyloxy, Examples include carboxy, lower alkoxycarbonyl, amino, lower alkylamino, nitro, and monocyclic or bicyclic heterocyclic groups. The alkyl part of “lower alkoxy”, “lower alkylthio” and “lower alkylamino” is the same as the above “lower alkyl”.

The "alkylenedioxy" specifically includes methylenedioxy, ethylenedioxy and the like. The substituent of "lower alkoxy optionally having substituent (s)" is the above "lower alkyl optionally having substituent (s)"
And the same as the above. "Lower alkoxycarbonyl"
The lower alkyl moiety is the same as the above “lower alkyl”, and the substituent of the “optionally substituted lower alkoxycarbonyl” is the substituent of the “optionally substituted lower alkyl” Is the same as “Acyl” includes aroyl and aliphatic acyl having 1 to 7 carbon atoms. Here, “aroyl” means a group in which a carbonyl group is bonded to an aromatic hydrocarbon cyclic group or an aromatic heterocyclic group. Specifically, formyl, acetyl, propionyl,
Butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl and the like.
The same applies to the acyl moiety of “acyloxy”.

Examples of the substituent of "acyl optionally having substituent (s)" include the same as the above-mentioned "lower alkyl optionally having substituent (s)", wherein aroyl is substituted with lower alkyl. You may. One or more optional positions of the acyl may be substituted with these substituents. "Amino optionally having a substituent" includes unsubstituted, monosubstituted or disubstituted amino, and the substituent of the above-mentioned "lower alkyl optionally having a substituent" and Lower alkyl and the like.

"Monocyclic non-aromatic hydrocarbon cyclic group"
It is a cyclic group having 3 to 10 carbon atoms, preferably 5 to 8 carbon atoms, and includes a non-aromatic cyclic group which may have one or more double bonds at any position. Specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,
And cyclononyl and cyclodecyl. The “monocyclic hydrocarbon cyclic group” is a cyclic group having 3 to 10 carbon atoms, preferably 5 to 8 carbon atoms, and includes the above “monocyclic non-aromatic hydrocarbon cyclic group” and phenyl. I do. “Monocyclic aromatic hydrocarbon cyclic group” means phenyl (or benzene ring).

"Monocyclic aromatic heterocyclic group" refers to N, S
And an aromatic cyclic group containing one or more heteroatoms arbitrarily selected from O in the ring, specifically, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, triazolyl, triazinyl , Tetrazolyl, isoxazolyl, oxazolyl,
Examples include oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl.
The “monocyclic non-aromatic heterocyclic group” means that one or more substitutable carbon atoms of the above “monocyclic non-aromatic hydrocarbon cyclic group” are arbitrarily selected from N, S and O It includes a non-aromatic cyclic group substituted with a hetero atom. Specifically, dioxanyl, dioxazinyl, dioxolanyl, dioxolyl, dithiazinyl, imidazolidinyl, imidazolinyl, morpholyl, oxazinyl, oxadiazyl, furazalyl, oxathianyl, oxathiazinyl, oxathiolanyl, oxazolidinyl, oxazolinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyrazinyl, pyridinyl, pyrazinyl, pyrazinyl, pyrazinyl , Tetrahydropyranyl, thiadiazolidinyl, thianyl, thiadinyl, thiadiazinyl, thiiranyl, thiolanyl and the like. "Monocyclic heterocyclic group" refers to the "monocyclic aromatic heterocyclic group" and "monocyclic non-aromatic heterocyclic group"
And is preferably pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl or thiazolyl. The heterocyclic part of the “monocyclic aromatic heterocyclic oxy” is the same as the above-mentioned aromatic heterocyclic group.

The "bicyclic hydrocarbon cyclic group" includes an aromatic or non-aromatic cyclic group having 6 to 12 carbon atoms in which two rings are fused. Specifically, it includes naphthyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl and the like. Preferably it is naphthyl. “Bicyclic aromatic hydrocarbon cyclic group” means naphthyl (or naphthalene ring). The “bicyclic heterocyclic group” refers to a cyclic ring in which one or more substitutable carbon atoms of the above “bicyclic hydrocarbon cyclic group” are substituted with a heteroatom arbitrarily selected from N, S and O. Compounds. For example, in drills,
Isoindolyl, indolizinyl, benzimidazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxaziazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, Benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl,
Aromatic heterocyclic groups such as isoquinolyl, quinoxalinyl, purinyl, pteridinyl, naphthyridinyl and pyrazinopyridazinyl and chromanyl, 2H-chromenyl, coumarinyl, coumaranonyl, 1,3-dioxaindanyl, indolinyl, isoindolinyl, dihydro Quinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 6,7-dihydro-5H- [1] pyrimidinyl, benzothiazinyl, tetrahydroquinoxalyl, cyclopentenopyridinyl, 4,5,6 And non-aromatic heterocyclic groups such as 7,7-tetrahydro-1H-indolyl, 4-oxochromenyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl and pyrrolidinyl. Preferably in drills,
Benzimidazolyl, benzoxazolyl, benzoxiadiazolyl, benzothiazolyl, benzthiadiazolyl, benzofuryl, benzothienyl, imidazopyridyl, triazolopyridyl, quinolyl, isoquinolyl and quinoxalinyl. The “bicyclic heterocyclic group” includes only the aromatic heterocyclic group among the above “bicyclic heterocyclic groups”.

"A monocyclic or bicyclic hydrocarbon group which may have a substituent", "a monocyclic hydrocarbon group which may have a substituent", " Substituents of "optionally possessed phenyl" and "optionally substituted monocyclic or bicyclic aromatic hydrocarbon cyclic group" include halogen; hydroxy; halogen, hydroxy or lower alkoxy. Lower alkyl which may be substituted; lower alkoxy which may be substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl;
Lower alkenyl optionally substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl; lower alkenyloxy optionally substituted with halogen or hydroxy; lower alkylthio; non-alkyl optionally substituted with halogen, hydroxy or lower alkyl Acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl; amino optionally substituted with lower alkyl or acyl; hydrazino; nitro; cyano; halogen, hydroxy, lower alkyl or lower; A monocyclic or bicyclic aromatic hydrocarbon cyclic group optionally substituted by alkoxy; a monocyclic or bicyclic heterocyclic group; phenoxy optionally substituted by halogen, hydroxy or lower alkyl ; Monocyclic aromatic heterocycle-oxy; oxo; and lower alkylenedioxy, and the like, one or more optional positions may be substituted with these substituents. Preferably halogen; hydroxy; lower alkyl optionally substituted with halogen or hydroxy; lower alkoxy optionally substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl; substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl Lower alkenyl optionally; lower alkylthio; acyl; acyloxy;
Carboxy; lower alkoxycarbonyl; amino optionally substituted with lower alkyl or acyl; hydrazino; nitro; cyano; phenyl; monocyclic or bicyclic heterocyclic group; oxo; and lower alkylenedioxy.

"A monocyclic aromatic heterocyclic group which may have a substituent", "a monocyclic non-aromatic heterocyclic group which may have a substituent", " A monocyclic heterocyclic group which may be substituted ", a" monocyclic aromatic heterocyclic group which may have a substituent "," a monocyclic or bicyclic group which may have a substituent " Cyclic aromatic heterocyclic group "," 2-pyridyl optionally substituted ", and" 2-pyridyl, 2-quinolyl, 2-quinoxalyl, 2- The substituent of "benzoisoxazolyl, 2-benzothiazolyl or 2-benzimidazolyl" is the same as the substituent of the above-mentioned "monocyclic or bicyclic hydrocarbon cyclic group which may have a substituent". Preferably a halogen; a hydroxy; a lower alkyl optionally substituted with a lower alkoxy; a lower alkoxy; a lower alkenyl; a lower alkylthio; an acyl; an acyloxy; a carboxy; a lower alkoxycarbonyl; an amino optionally substituted with a lower alkyl; And phenyl and a monocyclic heterocyclic group which may be substituted.

The “monocyclic or bicyclic aromatic heterocyclic group in which the adjacent position of the ring-constituting atom having a bond is a nitrogen atom” is a bond with NRCZ at the ortho position of the N atom constituting the ring. Having the above "monocyclic or bicyclic aromatic heterocyclic group"
Is included. Specific examples include 2-pyridyl, 2- or 4-pyrimidinyl, 3-pyridazinyl, 2-pyrazinyl, 1,3,5-triazin-2-yl, 2-pyrrolyl, 1- or 3-pyrazolyl, 2- or 4-imidazolyl, 2- or 4-oxazolyl, 3-isoxazolyl, 1,3,4-oxadiazol-2-yl,
1,3-thiazol-2-yl, 1,3-thiazol-
4-yl, 1,2,5-thiadiazol-3-yl,
1,2,3-thiadiazol-4-yl, 1,3,4-
Thiadiazol-2-yl, 3-isothiazolyl, 1,
Monocyclic aromatic heterocyclic groups such as 2,3-triazol-4-yl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl and 2-benzimidazolyl;
Benzisothiazolyl, 3-benzisoxazolyl, 2
-Benzoxazolyl, 2-benzothiazolyl, 1-benzotriazolyl, 1- or 3-indazolyl, 3-
Cinnolinyl, 2-indolyl, 1- or 3-isoindolyl, 2-naphthyridinyl, 2-, 4-, 6- or 7-pteridinyl, 2-, 6 or 8-purinyl, 1
Includes bicyclic aromatic heterocyclic groups such as-or 3-isoquinolyl, 2-quinolyl, 2- or 4-quinazolinyl, 2-quinoxalinyl and the like. These may be substituted at any position with one or more substituents similar to those described above for the “optionally substituted monocyclic or bicyclic hydrocarbon cyclic group”.

"Any two of R ⁶ , R ⁷ and R ⁸ together form a ring" means that any two of R ⁶ , R ⁷ and R ⁸ are bonded to a pyridine ring or It means forming a non-aromatic hydrocarbon cyclic group, a benzene ring or a heterocyclic group together with the ring-constituting atoms of the pyrimidine ring. Specifically, when forming a quinolyl, isoquinolyl, quinazolinyl, pteridinyl, purinyl, pyridoxazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl or tetrahydroquinazolinyl and the like together with the pyridine ring or pyrimidine ring bonded thereto. Include.

[0023]

Embedded image Means a bicyclic or tricyclic group in which Ar ² and ring B are fused, preferably a bicyclic group. Ring B is a 4- to 7-membered non-aromatic hydrocarbon cyclic group or non-aromatic heterocyclic group,
It may have one or more double bonds at any position. The ring-constituting atoms of each of ring B and Ar ² may be any of carbon, nitrogen, oxygen and sulfur. As ring B, preferably

Embedded image Wherein W ³ is CR ¹¹ R ¹² , O, NR ¹³ or S, and R ¹¹ , R ¹² and R ¹³ are each independently hydrogen; halogen; hydroxy; optionally substituted with halogen or hydroxy. Lower alkyl; halogen, hydroxy,
Lower alkoxy optionally substituted by carboxy or lower alkoxycarbonyl; lower alkenyl optionally substituted by halogen, hydroxy, carboxy or lower alkoxycarbonyl; lower alkylthio; acyl; acyloxy; carboxy; lower alkoxycarbonyl; Amino optionally substituted with acyl; hydrazino; nitro; cyano; phenyl; or a heterocyclic group, wherein R ¹¹ and R ¹² may together form oxo. A broken line indicates the presence or absence of a bond).

Ar ² to which ring B is condensed includes, for example, a benzene ring. Specific examples of ring A in that case include 1-, 2-, 3- or 4-dihydronaphthalenyl, 1-, 2- or 3-indolinyl, 1- or 2
-Indanyl, 1-, 2- or 3-indenyl, 1-
Or 2-tetrahydronaphthalenyl, 2-, 3- or 4-1,2-dihydroquinolinyl, 3- or 4-isochromanyl, 2-, 3- or 4-chromanyl, 2-3,
-Or 4-chromenyl, 2-, 3- or 4-thiochromenyl, 2-, 3- or 4-benzothiopyranyl,
2- or 3-dihydrobenzothienyl, 2- or 3
-Dihydrobenzofuryl, 2-benzo [1,3] dioxolyl, 2-2,3-dihydrobenzo [1,4] dioxonyl, 2-
Or 3-3,4-dihydro-2H-benzo [1,4] oxazinyl, 8- or 9-6,7-dihydro-5H-benzocycloheptenyl and 2-, 3- or 4-oxo-4H-chromenyl And the like. Examples of Ar ² to which ring B is condensed include a benzene ring and a 5-membered ring such as a pyridine ring, a pyrazine ring and a pyrimidine ring, and a 6-membered ring such as a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, and a thiazole ring. Ring and a bicyclic aromatic ring such as a quinoline ring, an isoquinoline ring and an indole ring;
It is possible to replace the benzene ring in the specific examples of the ring A with these rings. Ring B and Ar ² may have the same substituent at any position as in the above “optionally substituted monocyclic or bicyclic hydrocarbon cyclic group” and the like.

The compounds according to the present invention include the pharmaceutically acceptable salts from which each compound can be formed. "Pharmaceutically acceptable salts" include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; quaternary salts with alkyl halides such as methyl iodide, ethyl iodide;
And salts of alkaline earth metals such as calcium and magnesium. The compound according to the present invention includes a hydrate thereof, and one molecule of compound (I) may be coordinated with an arbitrary number of water molecules.

The compounds according to the present invention also include prodrugs thereof. A prodrug is a derivative of the compound of the present invention having a group that can be chemically or metabolically degraded, and a compound that exhibits a pharmacological action by being converted to the compound of the present invention in a metabolic process in a living body. It is. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs,
Elsevier, Amsterdam 1985. For example, when the compound according to the present invention has a carboxy, a prodrug such as an ester derivative produced by reacting carboxy with a suitable alcohol or an amide derivative produced by reacting carboxy with a suitable amine. Drag is exemplified. For example, when the compound according to the present invention has hydroxy, a prodrug such as an acyloxy derivative produced by reacting hydroxy with a suitable acyl halide or a suitable acid anhydride is exemplified.

For example, when the compound according to the present invention has an amino, a prodrug such as an amide derivative produced by reacting the amino-containing compound with a suitable acid halide or a suitable mixed anhydride. Is exemplified. When the compound (I) according to the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers and all diastereomers. When the compound (I) according to the present invention has a double bond, the substituent arrangement of the double bond includes any of geometric isomers, if any.

The compounds according to the present invention all have an apoAI expression-enhancing effect. Particularly preferred compounds include
The following compounds are mentioned. In the formula (I), 1) Ar ¹ is a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent or a monocyclic or bicyclic aromatic ring which may have a substituent A heterocyclic group (where the substituent is halogen, lower alkyl optionally substituted with halogen, hydroxy, lower alkoxy, aryloxy, acyloxy, carboxy, lower alkoxycarbonyl, lower alkyl or lower acyl; Amino, phenyl, nitro, lower alkylthio,
Cyano, a monocyclic heterocyclic group or lower alkylenedioxy) (hereinafter, Ar ¹ is Ar1-a)
The compound, Ar ¹ may have a substituent, and a monocyclic or bicyclic aromatic heterocyclic group in which the adjacent ring-constituting atom having a bond is a nitrogen atom (here, the substituent is Ar above
1-a) (hereinafter, Ar ¹ is Ar1-b);

Ar ¹ may be substituted with lower alkyl or amino, and is a monocyclic or bicyclic aromatic heterocyclic group in which the adjacent ring-constituting atom having a bond is a nitrogen atom (hereinafter referred to as Ar ¹ ). , Ar ¹ is Ar ¹ -c), and Ar ¹ is an unsubstituted monocyclic or bicyclic aromatic heterocyclic group in which a ring-constituting atom having a bond is a nitrogen atom. (Hereinafter, Ar ¹ is Ar1-d) compound, Ar ¹ is 2-quinolyl, 2-quinoxalyl, 2-
Benzimidazolyl, 2-thiazolyl, 2-benzothiazolyl, 2-oxazolyl, 2-benzoxazolyl,
2-oxadiazolyl, 2-pyridyl, 2-pyrimidyl or 2-imidazolyl (hereinafter, Ar ¹ is Ar1
-E) compound,

2) Ring A is a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent or a monocyclic or bicyclic aromatic heterocyclic ring which may have a substituent Formula group (where the substituent means halogen, lower alkyl optionally substituted by halogen, hydroxy, lower alkoxy,
Aryloxy, acyloxy, carboxy, lower alkoxycarbonyl, amino, phenyl, nitro, lower alkylthio, cyano, monocyclic heterocyclic group or lower alkylenedioxy optionally substituted with lower alkyl or lower acyl) ( Hereinafter, it is assumed that the ring A is Aa), and the ring A may have a monocyclic or bicyclic aromatic hydrocarbon cyclic group or a substituent which may have a substituent. A monocyclic or bicyclic aromatic heterocyclic group (here, the substituent is halogen, lower alkyl optionally substituted with halogen, acyloxy, lower alkoxy, alkylenedioxy or phenyl) A compound in which ring A is Ab); ring A is an unsubstituted monocyclic or bicyclic aromatic heterocyclic group (hereinafter, ring A is Ac) To) compounds, Ring A is phenyl, 2
-Naphthyl, 2- or 3-furyl, 2- or 3
-Thienyl, 2- or 3-pyrrolyl, 2-, 3- or 4-pyridyl, 2-indolyl, 2-benzofuryl, 6-quinolyl, 2- or 6-benzothienyl or 3-2H-chromenyl (hereinafter referred to as "3H-chromenyl"). Ring A is Ad
A) a compound,

Ring A is

Embedded image Wherein Ar ² is Aa (hereinafter, ring A is Ae);

Embedded image Wherein Ar ² is Ab (hereinafter, ring A is Af), and ring A is

Embedded image Wherein Ar ² is Ac (hereinafter, ring A is Ag), and ring A is

Embedded image Ar ² is a benzene ring, a pyridine ring, a pyrazine ring, a pyrimidine ring, a pyrrole ring, a furan ring, a thiophene ring, an oxazole ring, an isoxazole ring, a thiazole ring, a quinoline ring, an isoquinoline ring or an indole ring;

Embedded image Wherein W ³ is CR ¹¹ R ¹² , O, NR ¹³ or S, and R ¹¹ , R ¹² and R ¹³ are each independently hydrogen; halogen; hydroxy; optionally substituted with halogen or hydroxy. Lower alkyl; halogen, hydroxy,
Lower alkoxy optionally substituted by carboxy or lower alkoxycarbonyl; lower alkenyl optionally substituted by halogen, hydroxy, carboxy or lower alkoxycarbonyl; lower alkylthio; acyl; acyloxy; carboxy; lower alkoxycarbonyl; Amino optionally substituted with acyl; hydrazino; nitro; cyano; phenyl; or a heterocyclic group, and a dashed line indicates the presence or absence of a bond (hereinafter, ring A is Ah) Compound),

3) a compound wherein R is hydrogen; 4) a compound wherein Z is oxygen;

5) Y ¹ and Y ² are each independently hydrogen, halogen, lower alkyl or cyano (hereinafter referred to as Y ¹
And Y ² is Ya)) compounds Y ¹ and Y
² are each independently hydrogen or lower alkyl (hereinafter, Y ¹ and Y ² is assumed to be Y-b) Compound, Y ¹
And Y ² are hydrogen (hereinafter, Y ¹ and Y ² are Yc
6) a compound wherein n is 1 or 2 and all dashed lines indicate the presence of a bond, a compound wherein n is 1 and the dashed line indicates the presence of a bond,

7) R is hydrogen, Z is oxygen, n
Is 0, and a combination of Ar ¹ and ring A (Ar1,
Compounds in which A) is (Ar1, A) = (Ar1-a, Aa), (Ar1-a, Ab), (Ar1-a, Ac),
(Ar1-b, Aa), (Ar1-b, Ab), (Ar1-b, Ac), (Ar1-c, A
-a), (Ar1-c, Ab), (Ar1-c, Ac), (Ar1-d, Aa), (Ar
1-d, Ab), (Ar1-d, Ac), (Ar1-e, Aa), (Ar1-e, A-
b), (Ar1-e, Ac), (Ar1-a, Ae), (Ar1-a, Af), (Ar1
-a, Ag), (Ar1-b, Ae), (Ar1-b, Af), (Ar1-b, Ag),
(Ar1-c, Ae), (Ar1-c, Af), (Ar1-c, Ag), (Ar1-d,
Ae), (Ar1-d, Af), (Ar1-d, Ag), (Ar1-e, Ad), (A
r1-e, Ae), (Ar1-e, Af), (Ar1-e, Ag), (Ar1-e, A-
h)

8) R is hydrogen, Z is oxygen, n
Is 1 or 2, the dashed line indicates the presence of a bond,
a combination of r ¹ , Y ¹ and Y ² and ring A (Ar1,
A compound in which (Y, A) is (Ar1, Y, A) = (Ar1-a, Yc, Aa), (Ar1-a, Yc, Ab),
(Ar1-a, Yc, Ac), (Ar1-b, Yc, Aa), (Ar1-b, Yc,
Ab), (Ar1-b, Yc, Ac), (Ar1-c, Yc, Aa), (Ar1-c,
Yc, Ab), (Ar1-c, Yc, Ac), (Ar1-d, Yc, Aa),
(Ar1-d, Yc, Ab), (Ar1-d, Yc, Ac), (Ar1-e, Yc,
Aa), (Ar1-e, Yc, Ab), (Ar1-e, Yc, Ac), (Ar1-e,
(Yc, Ad), (Ar1-e, Yc, Ah) (Ar1-a, Yb, Aa), (A
r1-a, Yb, Ab), (Ar1-a, Yb, Ac) (Ar1-b, Yb, A-
a), (Ar1-b, Yb, Ab), (Ar1-b, Yb, Ac), (Ar1-c, Y
-b, Aa), (Ar1-c, Yb, Ab), (Ar1-c, Yb, Ac), (Ar
1-d, Yb, Aa), (Ar1-d, Yb, Ab), (Ar1-d, Yb, A-
c), (Ar1-e, Yb, Aa), (Ar1-e, Yb, Ab), (Ar1-e, Y
-b, Ac), (Ar1-a, Yc, Ae), (Ar1-a, Yc, Af), (Ar
1-a, Yc, Ag), (Ar1-b, Yc, Ae), (Ar1-b, Yc, A-
f), (Ar1-b, Yc, Ag), (Ar1-c, Yc, Ae), (Ar1-c, Y
-c, Af), (Ar1-c, Yc, Ag), (Ar1-d, Yc, Ae), (Ar
1-d, Yc, Af), (Ar1-d, Yc, Ag), (Ar1-e, Yc, A-
e), (Ar1-e, Yc, Af), (Ar1-e, Yc, Ag), (Ar1-a, Y
-b, Ae), (Ar1-a, Yb, Af), (Ar1-a, Yb, Ag), (Ar
1-b, Yb, Ae), (Ar1-b, Yb, Af), (Ar1-b, Yb, A-
g), (Ar1-c, Yb, Ae), (Ar1-c, Yb, Af), (Ar1-c, Y
-b, Ag), (Ar1-d, Yb, Ae), (Ar1-d, Yb, Af), (Ar
1-d, Yb, Ag), (Ar1-e, Yb, Ae), (Ar1-e, Yb, A-
f), (Ar1-e, Yb, Ag), a compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

Examples of particularly preferred compounds include the following. Ia-1, Ia-3, Ia-4, Ia-5, Ia-6, Ia-7, Ia-9, Ia-10, I
a-16, Ia-17, Ia-18, Ia-23, Ia-27, Ia-29, Ia-30, Ia
-37, Ia-38, Ia-39, Ia-42, Ia-44, Ia-45, Ia-46, Ia-
48, Ia-53, Ia-54, Ia-55, Ia-59, Ia-60, Ia-61, Ia-6
2, Ia-63, Ia-64, Ia-69, Ia-72, Ia-95, Ia-97, Ia-10
4, Ia-105, Ia-112, Ia-113, Ia-118, Ia-119, Ia-144,
Ia-145, Ia-146, Ia-150, Ia-152, Ia-153, Ia-156, I
a-161, Ia-162, Ia-177, Ia-204, Ib-01, Ib-3, Ib-4,
Ib-6, Ib-7, Ib-8, Ib-9, Ib-11, Ib-12, Ib-13, Ib-1
4, Ib-144, Ib-17, Ib-18, Ib-19, Ib-20, Ib-24, Ib-2
5, Ib-26, Ib-28, Ib-35, Ib-73, Ib-97, Ib-102, Ib-1
05, Ib-131, Ib-137, Id-1 and Id-11.

The compound (I) according to the present invention can be synthesized, for example, by any one of the following methods A to C. An example is described below, but for details, for example, "Organic Synthetic Chemistry VI Synthetic Edition 4 (1977) 6, 79" or "Fourth Edition Experimental Chemistry Course (1992) 22, 138" can be referred to. . [Method A] (A-1 + A-2 → I)

Embedded image (In the formula, Hal is a halogen, and other symbols are as defined above.) In this step, the amine (A-1) and the acid halide (A-
This is the reaction 2), and the compound (I) can be synthesized according to a conventional method. Generally, triethylamine, pyridine, excess (A-1) or dimethylaminopyridine can be used as a coexisting base, and methylene chloride or tetrahydrofuran can be used as a solvent. The reaction may be performed at a temperature between ice-cooling and the reflux temperature of the solvent.

[Method B] (B-1 + B-2 → I)

Embedded image (In the formula, each symbol is as defined above.) This reaction is also a conventional method for synthesizing amides. That is, dicyclohexylcarbodiimide or 1-ethyl-3-hydrochloric acid
Compound (I ′) is obtained by directly condensing amines (B-1) and carboxylic acid (B-2) in the presence of a dehydrating condensing agent such as (3-dimethylaminopropyl) carbodiimide. The reaction is dimethylformamide,
It may be carried out in a solvent such as methylene chloride or tetrahydrofuran from room temperature to the reflux temperature of the solvent.

[Method C] (C-1 + C-2 → I)

Embedded image (In the formula, each symbol is as defined above.) This reaction is also a condensation reaction of the amines (C-1) and the carboxylic acid (C-2) as described above, and is described in Eur. J. Med. Chem., (1
994) 29, 841. That is, the compound (I ′) is obtained by activating the carboxylic acid (C-2) using, for example, triphenylphosphine and bromotrichloromethane and then reacting the activated carboxylic acid with an amine. The solvent is
Methylene chloride or tetrahydrofuran can be used. The reaction may be performed at room temperature to the reflux temperature of the solvent.

The compound (I) wherein R is H obtained by the above method and an alkyl halide are reacted in dimethylformamide at room temperature to 80 ° C. in the presence of sodium hydride, whereby R is lower alkyl. Compound (I) can be obtained. Compound (I) wherein Z is sulfur is represented by Z
Can be obtained by heating compound (I) wherein is an oxygen together with phosphorus pentasulfide or Lawesson reagent in a solvent such as pyridine or toluene at the reflux temperature of the solvent.

The apoAI expression enhancer of the present invention activates HDL's reverse cholesterol transfer action, anti-inflammatory action and anticoagulant action. Therefore, it is useful for the prevention and / or treatment of blood lipid abnormalities caused by a decrease in serum HDL, arteriosclerotic diseases and various circulatory diseases associated therewith. Specific examples of applicable diseases include hypoHDLemia, hypercholesterolemia, hypertriglyceridemia, arteriosclerosis, myocardial infarction, hyperuricemia, coronary artery disease, ischemic heart disease, corneal opacity, and cerebrovascular disease. Disability, hereditary HD
L deficiency (Tangier disease, fisheye disease, etc.) and the like.

When the compound of the present invention is administered as an apoAI expression enhancer, it can be administered either orally or parenterally. Oral administration may be carried out according to a conventional method by preparing a tablet, granule, powder, capsule, pill, liquid, syrup, buccal, sublingual or the like into a commonly used dosage form. For parenteral administration, any commonly used dosage form, such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents, and inhalants, can be suitably administered.

If necessary, various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, and diluents may be added to the effective amount of the compound of the present invention. They can be mixed to form a pharmaceutical preparation. In the case of an injection, a preparation may be prepared by sterilizing with an appropriate carrier. Specifically, as an excipient, lactose, sucrose, glucose, starch,
Examples of binders such as calcium carbonate and crystalline cellulose include methyl cellulose, carboxymethyl cellulose,
Disintegrators such as hydroxypropylcellulose, gelatin and polyvinylpyrrolidone include carboxymethylcellulose, sodium carboxymethylcellulose,
Lubricants such as starch, sodium alginate, powdered agar or sodium lauryl sulfate include talc, magnesium stearate, and macrogol. As a suppository base, cocoa butter, macrogol, methyl cellulose or the like can be used. In addition, when prepared as a liquid or emulsion, a suspension-type injection, a solubilizing agent, a suspending agent, ordinarily used,
An emulsifier, a stabilizer, a preservative, an isotonic agent and the like may be appropriately added, and in the case of oral administration, a flavoring agent, an aromatic agent and the like may be added.

The dose of the compound of the present invention as an apoAI expression enhancer is preferably determined in consideration of the patient's age, body weight, type and degree of disease, administration route and the like. When administered, usually 1 to 100 mg / k
g / day, preferably in the range of 5-30 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the administration route, but is usually 0.1 to 10 mg / kg / day,
It is preferably in the range of 1 to 5 mg / kg / day. This may be administered once to several times a day. Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the present invention.

[0045]

EXAMPLES Example 1 4-Chloro-N- (4-tolyl) benzamide (Ib-17)

Embedded image [Method A]: To a solution of p-toluidine (1.07 g, 10.0 mmol) in chloroform (20 ml) was added pyridine (2.37 g, 30.0 g) under ice-cooling.
mmol) and then p-chlorobenzoyl chloride (2.63 g, 1
5.0 mmol) and stirred at room temperature for 5 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed successively with a saturated aqueous solution of sodium hydrogen carbonate, water and chloroform, and recrystallized from acetone to obtain Ib-17 (2.0 g, 81.6%).

Example 2 Thiophene-2-carboxylic acid pyridin-2-ylamide (Ib-122)

Embedded image [Method C]: 2-aminopyridine (376 mg, 3.99 mmol),
To a solution of triphenylphosphine (786 mg, 3.00 mmol) and bromotrichloromethane (990 mg, 4.99 mmol) in tetrahydrofuran (10 ml) was added 2-thiophenecarboxylic acid (256 mg).
mg, 2.00 mmol) and heated under reflux for 6 hours, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and the crystals eluted with ethyl acetate-hexane (1: 3) were recrystallized from 95% ethanol to give Ib-122 (342 mg, 8
3.8%).

Example 3 N-methyl-N-phenylbenzamide (Ib-27)

Embedded image Dimethylformamide of Ib-1 (180 mg, 0.91 mmol)
(3 ml) solution under ice-cooling, sodium hydride (60%, 40 mg,
1.00 mmol). After stirring at room temperature for 30 minutes, methyl iodide (213 mg, 1.50 mmol) was added and reacted for 5 hours. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography to obtain a colorless oily substance Ib-27 (180 mg, 85.3%) eluted with ethyl acetate-hexane (1: 1).

Example 4 3-Phenyl-N-quinoxalin-2-yl-acrylamide (Ia-9)

Embedded image [Method A]: 2-aminoquinoxaline (435 m
g, 3.00 mmol) in tetrahydrofuran (12 ml) solution.
Triethylamine (728 mg, 7.20 mmol) and cinnamoyl chloride (1.20 g, 7.20 mmol) were added, the mixture was reacted for 5 hours, and left overnight. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, eluted with ethyl acetate-hexane (1: 2), and recrystallized from ethyl acetate-hexane to obtain Ia-9 (128 mg, 15.5%).

Example 5 3-Pyridin-3-yl-N-
Pyridin-2-yl-acrylamide (Ia-112)

Embedded image [Method B]: 2-aminopyridine (0.986 g, 10.48 mmol)
And β- (3-pyridyl) acrylic acid (0.746 g, 5.00 m
mol) in tetrahydrofuran (10 ml).
Ethyl-3- (3-dimethylaminopropyl) carbodiimide (1.006 g, 5.25 mmol) was added, the mixture was stirred for 21 hours, and the solvent was distilled off under reduced pressure. 10% citric acid aqueous solution was added to the residue,
The mixture was extracted with chloroform, washed with water, a saturated aqueous solution of sodium hydrogencarbonate and then with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and ethyl acetate-chloroform (1: 1).
And then recrystallized from ethyl acetate to give Ia-112 (440 m
g, 39.0%).

Example 6 3-furan-2-yl-N-pyridin-2-yl-acrylamide (Ia-104)

Embedded image [Method C]: 2-aminopyridine (376 mg, 4.00 mmol),
In a solution of triphenylphosphine (786 mg, 3.00 mmol) and bromotrichloromethane (990 mg, 4.99 mmol) in tetrahydrofuran (10 ml), 2-furanacrylic acid (276 m
g, 2.00 mmol) and heated under reflux for 6 hours, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography to remove 95% of the crystals eluted with ethyl acetate-hexane (1: 2).
Recrystallized from ethanol, Ia-104 (243 mg, 56.8%)
I got Other compounds were synthesized in the same manner. The structural formula is shown below.

[0051]

[Table 1]

[0052]

[Table 2]

[0053]

[Table 3]

[0054]

[Table 4]

[0055]

[Table 5]

[0056]

[Table 6]

[0057]

[Table 7]

[0058]

[Table 8]

[0059]

[Table 9]

[0060]

[Table 10]

[0061]

[Table 11]

[0062]

[Table 12]

[0063]

[Table 13]

[0064]

[Table 14]

[0065]

[Table 15]

[0066]

[Table 16]

[0067]

[Table 17]

[0068]

[Table 18]

[0069]

[Table 19]

[0070]

[Table 20]

[0071]

[Table 21]

[0072]

[Table 22]

[0073]

[Table 23]

[0074]

[Table 24]

Test Example 1 Promoting action of human apoAI producing gene promoter function The promoter region of the human apoAI producing gene was isolated,
A reporter plasmid was constructed by connecting it immediately upstream of the firefly luciferase structural gene. In addition, a marker plasmid imparting neomycin resistance was co-transfected into HepG2 cells, a human liver cancer-derived cell line, and G418 was added to DMEM medium containing 10% fetal bovine serum.
By culturing the cells in a selective medium supplemented with a final concentration of 0.7 mg / ml, manufactured by Gibco, a stable expression strain of the reporter molecule was established. This cell line was seeded in a 96-well culture plate at 50,000 cells per well, and cultured for 48 hours at 37 ° C. under 5% CO 2 concentration. Thereafter, the compound of the present invention dissolved in DMSO was added to a final concentration of 0 to 10 μg / ml. After further culturing for 24 hours, a luciferase assay reagent (Picagene LT7.5 (registered trademark) manufactured by Toyo Ink Mfg. Co., Ltd.) was added to the cells, and the luciferase activity was measured using a luminometer (Wallac MicroBeta ^™ TRILUX, 1 sec / well). Measured. Control luciferase activity (no compound of the present invention added, only DMSO added)
The compound concentration that enhances 2-fold relative to the minimum effective dose (ME
D). The results are shown in Table 25.

[0076]

[Table 25]

From Table 25, it can be seen that the compound according to the present invention
It can be seen that the compound has an I expression enhancing effect.

Formulation Example 1 Tablet Compound (Ia-1) 15 mg Starch 15 mg Lactose 15 mg Crystalline cellulose 19 mg Polyvinyl alcohol 3 mg Distilled water 30 ml Calcium stearate 3 mg Components other than calcium stearate are uniformly mixed, crushed and granulated and dried. Granules of an appropriate size were obtained. Next, calcium stearate was added and compression molded to obtain tablets.

Formulation Example 2 Capsule Compound (Ia-7) 10 mg Magnesium stearate 10 mg Lactose 80 mg is uniformly mixed to prepare a powder as a powder or fine granules. It was filled in a capsule container to make a capsule.

Formulation Example 3 Granules Compound (Ia-1) 30 g Lactose 265 g Magnesium stearate 5 g After mixing well, compression molding, pulverizing, sieving, and sieving to obtain granules of an appropriate size.

[0081]

As is clear from the above test examples, the compounds according to the present invention exhibit an apoAI expression enhancing action. Therefore, the compound according to the present invention is very useful as an agent for preventing and / or treating blood lipid abnormalities or arteriosclerotic diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/404 A61K 31/404 4C056 31/4184 31/4184 4C062 31/421 31/421 4C063 31/422 31 / 422 4C065 31/423 31/423 4C086 31/4245 31/4245 4C206 31/428 31/428 31/433 31/433 31/436 31/436 31/437 31/437 31/44 31/44 31/443 31/443 31/4433 31/4433 31/4436 31/4436 31/444 31/444 31/4545 31/4545 31/47 31/47 31/4709 31/4709 31/4725 31/4725 31/496 31 / 496 31/498 31/498 31/506 31/506 31/538 31/538 C07D 213/81 C07D 213/81 215/38 215/38 215/48 215/48 235/30 235/30 A 241/44 241 / 44 263/58 263/58 285/06 285/06 311/58 311/58 401/12 401/12 405/12 405/12 409/12 409/12 413/04 413/04 413/12 413/12 417/04 417/04 417/12 417/12 471/04 104 471/04 104Z 108 1 08A 114 114A 491/052 491/052 // C07D 277/82 277/82 307/85 307/85 (72) Inventor Natsuki Ishizuka 5-12-4 Sagisu, Fukushima-ku, Osaka City, Osaka Shionogi & Co., Ltd. (72) Inventor Katsunori Sakai 5-12-4 Sagishima, Fukushima-ku, Osaka City, Osaka Prefecture F-term in Shionogi & Co., Ltd. (Reference) BA03 BA05 BA06 BA34 BA39 BA52 BA53 BA58 BB01 BB02 BB04 BB07 BB08 BB10 BB11 CA01 CA02 CA05 CA06 CA33 CA34 CA42 CB01 CB02 CB04 CB10 DA01 DA05 DA06 DA42 DB01 DB02 EA01 4C056 AA01 AB01 AC02 CC02 CC02 CC01 CC02 CC CC22 CC25 CC26 CC29 CC34 CC42 CC51 CC52 CC54 CC58 CC62 CC67 CC75 CC76 CC79 CC81 CC82 CC92 CC94 CC95 DD04 DD06 DD12 DD26 DD29 DD67 EE01 4C065 AA03 AA04 BB04 BB06 BB09 CC01 DD02 EE02 HH01 HH02 HH08 AJ0A01 BC01 A01BCA01 BC01 BC01 BC30 BC36 BC38 BC39 BC42 BC52 BC67 BC69 BC70 BC71 BC8 2 BC84 BC85 CB05 CB09 CB22 GA02 GA04 GA07 GA08 GA09 GA10 MA01 MA04 NA14 ZA33 ZA36 ZA40 ZA45 ZC33 4C206 AA01 AA02 AA03 GA07 GA08 GA09 GA31 MA01 MA04 NA14 ZA33 ZA36 ZA40 ZA45 ZC33

Claims (14)

[Claims] (1) Formula (I): (Wherein ring A is Ar ² or And Ar ¹ and Ar ² are each independently a monocyclic or bicyclic aromatic hydrocarbon cyclic group which may have a substituent or a monocyclic or bicyclic ring which may have a substituent And ring B is a monocyclic non-aromatic hydrocarbon group which may have a substituent or a monocyclic non-aromatic heterocyclic group which may have a substituent. A cyclic group, R is hydrogen or lower alkyl optionally having substituent (s),
Z is oxygen or sulfur; Y ¹ and Y ² are each independently hydrogen, halogen, lower alkyl optionally having substituent (s), carboxy, lower alkoxycarbonyl optionally having substituent (s), cyano A phenyl which may have a substituent or a monocyclic aromatic heterocyclic group which may have a substituent; n is an integer of 0 to 2; Containing a compound, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof. Expression enhancer. 2. The method according to claim 1, wherein Ar ¹ is a monocyclic or bicyclic aromatic heterocyclic group which may have a substituent and is adjacent to a ring-constituting atom having a bond, which is a nitrogen atom. Item 4. The apoAI expression enhancer according to Item 1. 3. A method according to claim 1, wherein Ar ¹ is optionally substituted with 2-pyridyl, 2-quinolyl, 2-quinoxalyl,
Apo A according to claim 1, which is -benzisoxazolyl, 2-benzothiazolyl or 2-benzimidazolyl.
I expression enhancer. 4. The method according to claim 1, wherein Ar ² condensed with ring B is a benzene ring which may have a substituent or a monocyclic aromatic hetero ring which may have a substituent. 3. The apoAI expression enhancer according to any of 3. 5. The method according to claim 1, wherein ring A is phenyl which may have a substituent or monocyclic aromatic heterocyclic group which may have a substituent. ApoAI expression enhancer. 6. A ring A is a phenyl or a monocyclic aromatic heterocyclic group, each of which may have a substituent (wherein the substituent is a halogen; a lower optionally substituted by halogen or lower alkoxy). Alkyl; hydroxy; lower alkoxy; phenoxy; naphthyloxy; acyloxy;
Carboxy; lower alkoxycarbonyl; amino optionally substituted by lower alkyl or lower acyl; phenyl optionally substituted by lower alkoxy; nitro; lower alkylthio; cyano; monocyclic heterocyclic group; 6. The apo AI expression enhancer according to claim 5, wherein 7. The apoAI expression enhancer according to claim 1, wherein Y ¹ and / or Y ² is hydrogen. 8. The apoAI expression enhancer according to claim 1, wherein Z is oxygen. 9. The apo AI according to claim 1, wherein n is 1 or 2, and all the broken lines indicate the presence of a bond.
Expression enhancer. 10. When n is 1 and the dashed line indicates the presence of a bond, the wavy line indicates that the relationship between NRCZ and ring A is in the trans configuration, n is 2 and each dashed line is apo AI expression enhancer squiggle is related trans arrangement of NRCZ and CY ² relationships and / or CY ¹ and ring a, according to claim 9, wherein in the case of indicating the presence of a coupling. 11. The apoAI expression enhancer according to any one of claims 1 to 10, which is an agent for preventing and / or treating blood lipid abnormalities or arteriosclerotic diseases. 12. A compound of formula (II): Wherein Het ¹ is pyridyl, furyl, 3-thienyl or pyrrolyl, R is hydrogen or lower alkyl, W ¹ is CR ³ or N, R ¹ , R ² , R ³ , R ⁴ and R ⁵ is each independently hydrogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino or acyl), a prodrug thereof, or a pharmaceutically acceptable salt thereof. Or their hydrates. 13. A compound of the formula (III): Wherein Het ² is pyridyl, furyl, thienyl or pyrrolyl, R is hydrogen or optionally substituted lower alkyl, W ² is CR ⁸ or N;
Y ¹ and Y ² are each independently hydrogen, halogen, a lower alkyl optionally having a substituent, carboxy, a lower alkoxycarbonyl optionally having a substituent, cyano,
A phenyl which may have a substituent or a monocyclic aromatic heterocyclic group which may have a substituent, and R ⁶ ,
R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently hydrogen, halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), carboxy, substituent A lower alkoxycarbonyl optionally having a substituent, an amino optionally having a substituent or an acyl optionally having a substituent, wherein any two of R ⁶ , R ⁷ and R ⁸ are May form a ring, m is 1 or 2, each dashed line independently represents the presence or absence of a bond, and each wavy line represents cis or trans geometric isomerism with respect to the double bond. Compounds, their prodrugs, their pharmaceutically acceptable salts or their hydrates. 14. The compound according to claim 13, wherein W ² is CH, R is hydrogen or lower alkyl, and all dashed lines indicate the presence of a bond, a prodrug thereof, a pharmaceutically acceptable salt thereof or Their hydrates.