JP2001233767A - Apo ai expression sthenic agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide excellent apo AI expression sthenic agents since substances capable of activating apo AI are conceived to lead to the creation of entirely new medicaments for blood lipid. abnormalities, arteriosclerotic disorders and other various diseases involving HDL. SOLUTION: The apo AI expression sthenic agents include compounds each shown by the formula (I) (wherein, Y1 is O, S or NR1; Y2, Y3, Y4 and Y5 are CR2 or N, CR3 or N, CR4 or N, and CR5 or N, respectively; R1 is A1, Z-A2, H, a lower alkyl of the like; R2, R3, R4 and R5 are each A1, Z-A2, H, a halogen or the like; at least one arbitrarily selected from Y1, Y2, Y3, Y4 and Y5 has A1, either one of them has Z-A2; Z is a single bond, CR6=CR7 or the like; R6 and R7 are each H or a lower alkyl; and A1 and A2 are each an aryl, heterocyclic group or the like), prodrugs thereof, pharmaceutically acceptable salts thereof and solvates thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an apoAI expression enhancer.

[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. Western epidemiological studies, such as the Framingham Study and MRFIT (Multiple RiskFa
ctor Intervention Trial), it is reported that the lower the HDL-C, the higher the incidence of coronary artery disease. Another report shows that the risk of arteriosclerosis is also increased when total cholesterol and triglyceride are normal and only HDL-C shows a low level. Ie low HDL
-C blood (35-40 mg / dl or less) is independent CH
It is a risk factor for D, and the complication rate of coronary artery disease is rapidly increasing.

[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 (HDL ₃ ).
Mature HDL has various subfractions depending on the specific gravity.
These particles are further alternative to a collection HDL _2. 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.

A compound having an HDL elevating effect is described in WO97.
/ 19931, WO97 / 19932, US55998
29, EP796874 and the like, compounds having an action of increasing apo AI are disclosed in JP-A-5-221959 and JP-A-8-29.
1094, WO97 / 09048 and the like, but each has a different structure from the compound according to the present invention.

[0006]

An object of the present invention is to provide an excellent apoAI expression enhancer.

[0007]

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

Embedded image Wherein Y ¹ is O, S or NR ¹ and Y ² is CR
² or N, Y ³ is CR ³ or N, Y ⁴
Is CR ⁴ or N, Y ⁵ is CR ⁵ or N, R ¹ is A ¹ ; -ZA ² ; hydrogen; lower alkyl which may have a substituent; An optionally substituted acyl; an optionally substituted amino; a lower alkoxycarbonyl optionally substituted; or a carbamoyl optionally substituted; R ² , R ³ , R
⁴ and R ⁵ are each independently A ¹ ; -ZA ² ; hydrogen; halogen; hydroxy; lower alkyl optionally having substituents; lower alkoxy optionally having substituents; Acyl optionally having a substituent; amino optionally having a substituent; mercapto; lower alkylthio optionally having a substituent; carboxy; lower alkoxycarbonyl optionally having a substituent Or carbamoyl optionally having substituent (s), and Y ¹ , Y
^{2, Y} 3, ^{Y 4} and optionally at least one selected from ^{Y 5} is have ^{A 1,} one but has the ^{-Z-A 2,} -Z- represents a single bond, ^-CR 6 = CR ⁷ -Or -N-
R ⁶ and R ⁷ are each independently hydrogen or lower alkyl, and A ¹ and A ² are each independently a cycloalkyl optionally having a substituent, ApoAI expression enhancer comprising a compound represented by the formula (I): a good aryl or a heterocyclic group which may have a substituent), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. ,

2) A 5-membered ring consisting of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is 1,2,3-triazole, 1,2,2
4-triazole, 1,2,3-thiadiazole, 1,
2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,2
ApoAI expression enhancer according to 1), which is 5-oxadiazole, 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan or thiophene; 3) Y ^The 5-membered ring consisting of ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is 1,2,3-triazole, 1,2,4-triazole, 1,2,4-thiadiazole, 1,3,4- Thiadiazole, 1,2,4-oxadiazole, 1,3
ApoAI expression enhancer according to 2), which is 4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, furan or thiophene,

4) A ¹ and A ² are independently phenyl, pyridyl, pyrazinyl, furyl, thienyl, thiazolyl, pyrazolyl, isoxazolyl, benzofuryl or indolyl, each of which may have a substituent; 1) ApoAI expression enhancer according to any one of to 3), 5) amino wherein A ¹ and A ² are each independently substituted with halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkyl. Phenyl optionally substituted with phenyl, styryl or heteroaryl; thiazolyl optionally substituted with lower alkyl; pyrazolyl optionally substituted with lower alkyl; unsubstituted pyridyl; unsubstituted indolyl; unsubstituted benzofuryl; Unsubstituted thienyl; or unsubstituted furyl 4), wherein the Apo AI expression enhancer, 6) Z is a single bond, 1) to 5 apo AI expression enhancer according to any one of)

7) Y ¹ is O, S or NR ¹ ;
¹ is lower alkyl which may have a substituent or amino which may have a substituent, and Y ² , Y ³ , Y ⁴
And one or two of Y ⁵ are each independently CA ¹
, And the one is CA ^2, CH or N each independently otherwise, 1) to 6 apo AI expression enhancer according to any one of the) 8) blood lipid abnormalities or arteriosclerosis An agent for enhancing apoAI expression according to any one of 1) to 7), which is a prophylactic and / or therapeutic agent for sexual diseases.

Further, the above compound, a prodrug thereof,
A method for enhancing apoAI expression, and a method for treating and / or preventing abnormal blood lipids, arteriosclerotic disease or coronary artery disease, which comprises administering a pharmaceutically acceptable salt or a solvate thereof. I will provide a. In another embodiment, the above-mentioned compound or a prodrug thereof for producing a medicament for enhancing apoAI expression or a medicament for treating and / or preventing blood lipid abnormality, arteriosclerotic disease or coronary artery disease, The use of a pharmaceutically acceptable salt or a solvate thereof is provided.

In the compound of the present invention, two or more A
^{When 1} is present, they may each be the same or different. As used herein, "halogen" includes fluorine, chlorine, bromine and iodine. “Lower alkyl” means 1 to 6 carbon atoms, preferably 1 carbon atom.
-3 straight and branched alkyl, e.g., 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)" includes lower alkyl optionally substituted at any position by one or more substituents,
As the substituent, halogen, hydroxy, lower alkoxy, aryl, acyl, acyloxy, carboxy,
Lower alkoxycarbonyl, amino, lower alkylamino, nitro and heteroaryl, and the like. The alkyl moiety of “lower alkoxy”, “lower alkylthio” and “lower alkylamino” is the above “lower alkyl”
Is the same as Substituents of "lower alkoxy optionally having substituent (s)" and "lower alkylthio optionally having substituent (s)" are the same as the substituents of "lower alkyl optionally having substituent (s)" It is.

"Lower alkylenedioxy" specifically includes methylenedioxy, ethylenedioxy and the like. The lower alkyl portion of the “lower alkoxycarbonyl” is the same as the above “lower alkyl”, and the substituent of the “optionally substituted lower alkoxycarbonyl” is the above “lower optionally substituted” The same as the substituent for "alkyl". “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 aryl or heteroaryl. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, benzoyl, and the like, and preferably acetyl or benzoyl.

Examples of the substituent for the "optionally substituted acyl" include the same substituents as those for the above "optionally substituted lower alkyl". Aroyl is a lower alkyl. It may be substituted. One or more optional positions of the acyl may be substituted with these substituents.
The acyl moiety of “acyloxy” is the same as the above “acyl”. "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. Preferably it is unsubstituted amino, lower alkylamino, di-lower alkylamino, benzylamino or acylamino. The substituent of "carbamoyl optionally having substituent (s)" is the same as the substituent of "lower alkyl optionally having substituent (s)". Preferably it is unsubstituted carbamoyl or di-lower alkylcarbamoyl.

"Cycloalkyl" refers to C3-C1.
It includes an alicyclic carbocyclic group having 0, preferably 3 to 6 carbon atoms, and specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. The substituent of "cycloalkyl optionally having substituent (s)" is the above "lower alkyl optionally having substituent (s)"
And the same as the above.

"Aryl" includes, for example, phenyl, naphthyl, indanyl, indenyl, anthryl and the like. Preferably it is phenyl or naphthyl, most preferably phenyl. "Heteroaryl" includes mono- and bicyclic aromatic heterocyclic groups containing one or more heteroatoms arbitrarily selected from N, S and O in the ring. Specifically, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl,
Monocyclic groups such as pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; and indolyl, isoindolyl, indolizinyl, benzimidazolyl,
Indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxodiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl , Triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, quinoxalinyl, purinyl, pteridinyl, naphthyridinyl and pyrazinopyridazinyl. Preferably pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl,
It is oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, benzoxazolyl, benzofuryl or benzothienyl.

The term "heterocyclic group" refers to a monocyclic or bicyclic non-aromatic group containing one or more heteroatoms arbitrarily selected from the group consisting of the above "heteroaryl" and N, S and O. Includes cyclic groups. Specific examples of the `` non-aromatic heterocyclic group '' include, dioxanyl, dioxazinyl, dioxolanyl, dioxolyl, dithiazinyl, imidazolidinyl, imidazolinyl, morpholyl, morpholino, oxazinyl, oxadiazyl, furazalyl, oxathianyl, oxathiazinyl, oxathiolinyl, oxazolinyl, oxazolinyl, oxazolinyl, Piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, thiadiazolidinyl, thianyl, thiadinyl, thiadiazinyl,
Monocyclic groups such as thiiranyl and thiolanyl and chromanyl, 2H-chromenyl, coumarinyl, coumaranonyl, 1,3
-Dioxaindanyl, indolinyl, isoindolinyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, 6,7-dihydro-5H- [1] pyrimidinyl, benzothiazinyl, tetrahydroquinoxalyl, Cyclopentenopyridinyl, 4,5,
Includes bicyclic groups such as 6,7-tetrahydro-1H-indolyl, 4-oxochromenyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl and pyrrolidinyl.

The substituents of the "aryl which may have a substituent" and the "heterocyclic group which may have a substituent" in A ¹ and A ² are halogen; hydroxy; halogen, hydroxy Or lower alkyl optionally substituted with lower alkoxy; lower alkoxy optionally substituted with halogen, hydroxy, carboxy or lower alkoxycarbonyl; optionally substituted with halogen, hydroxy, carboxy, lower alkoxycarbonyl or phenyl Lower alkenyl; lower alkenyloxy optionally substituted with halogen or hydroxy; mercapto; lower alkylthio; cycloalkyl optionally substituted with halogen, hydroxy or lower alkyl; ; Acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl, lower alkyl or amino optionally substituted with acyl; hydrazino; carbamoyl which may be substituted by lower alkyl; lower alkylsulfonyl; nitro;
Cyano; aryl optionally substituted with halogen, hydroxy, lower alkyl or lower alkoxy; heterocyclic group; phenoxy optionally substituted with halogen, hydroxy or lower alkyl; monocyclic heteroaryloxy; halogen, hydroxy Or phenyl; which may be substituted with lower alkyl; oxo; and lower alkylenedioxy. One or more arbitrary positions may be substituted with these substituents.

The compounds according to the present invention include pharmaceutically acceptable salts that can be formed for each compound. “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; paratoluenesulfonic acid,
Salts of organic acids such as methanesulfonic acid, oxalic acid or citric acid; salts of organic bases such as ammonium, trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; halogens such as methyl iodide and ethyl iodide And quaternary salts with alkyl halides; and salts of alkaline earth metals such as calcium and magnesium. The compound according to the present invention may be coordinated with a suitable organic solvent and / or water to form a solvate. For example, hydrates and the like can be mentioned.

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 carboxy, an ester derivative produced by condensing carboxy with an appropriate alcohol [for example, COOR ^A (R ^A is, for example, a lower alkyl which may have a substituent, respectively) , Lower alkenyl or aryl (where the substituent is hydroxy, acyloxy, carboxy, sulfonic acid, amino, lower alkylamino, etc.)
Amide derivatives prepared by reacting carboxy with a suitable amine [eg CONR
^{B R C} (R ^B is, for example, hydrogen, lower alkyl, etc., ^{R C} is, for example, hydrogen, lower alkyl, amino, hydroxy, etc.), etc.]
Are exemplified. For example, when the compound according to the present invention has hydroxy, an acyloxy derivative produced by reacting hydroxy with a suitable acyl halide or a suitable acid anhydride [for example, -OCOR ^A ( ^RA is as defined above) Etc.] are exemplified. For example, when the compound according to the present invention has an amino, an amide derivative produced by reacting the compound having an amino with a suitable acid halide or a suitable mixed anhydride [for example, NHCOR
^A , NHCOOR ^A ( ^RA is as defined above) and the like.

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 is that all have an Apo AI expression enhancing effect, preferred compounds have one of A ¹ and one A ^2, the compounds below. In the formula (I), a five-membered ring composed of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ has 1,2,3 having ^one of A ¹ and A ² at the 1-position and the other at the 4-position. A 1,2,4-oxadiazole having one of A ¹ and A ² at the 3-position and the other at the 5-position (hereinafter referred to as Y-1). , Y-2), a 1,2,4-triazole having one of A ¹ and A ² at the 3-position and the other at the 5-position (hereinafter referred to as Y-3) ) compounds, in either the 2-position of the ^{a 1} and ^{a 2,} is a 1,3,4-oxadiazole with other 5-position (hereinafter, referred to as a Y-4) compounds, ^{a 1} and the 3-position of either one of a ^2, 1, 2,4-thiadiazole having the other to position 5 (hereinafter Y-5 to a) compounds, one of ^{A 1} and ^{A 2} in the 2-position, a 1,3,4-thiadiazole having the other to position 5 (hereinafter referred to as a Y-6) compound, one of ^{a 1} and ^{a 2} 2
Is a furan having the other in position 5 (hereinafter referred to as Y-7
A) is a compound having one of A ¹ and A ² at the 3-position and the other at the 5-position (hereinafter referred to as Y-8), A ¹ and A ²
Is an oxazole having one of the two at position 2 and the other at position 4 (hereinafter referred to as Y-9), A ¹
And one of A ² in the 2-position, oxazol having the other at the 5-position (hereinafter, referred to as a Y-10)
A compound which is a pyrazole having one of A ¹ and A ² at the 3-position and the other at the 5-position (hereinafter referred to as Y-11), and ^one of A ¹ and A ² being 2
Is a tetrazole having the other at the 5-position (hereinafter referred to as
A compound which is a thiazole having one of A ¹ and A ² at the 2-position and the other at the 4-position (hereinafter referred to as Y-13), A ¹ and A ^A compound having one of the two at position 2 and the other at position 5 (hereinafter referred to as Y-14);
Or 1,2,4-triazole having one of A ¹ and A ² at the first position and the other at the third position (hereinafter, referred to as “ ^1” and “ ^2” ).
Y-15) compound.

A ¹ or A ² is substituted with one or more groups selected from the group consisting of amino, halogen, phenyl and thiadiazolyl which may be substituted with hydroxy, lower alkoxy, lower alkyl, lower thioalkyl, lower alkyl. (Hereinafter referred to as A ¹
Or A ² is A-1), a lower alkyl wherein A ¹ or A ² is optionally substituted with halogen,
Lower alkylsulfonyl, lower alkylcarbamoyl,
Furyl, thiazolyl, thienyl or pyrazolyl which may be substituted with one or more groups selected from the group consisting of nitro, phenyl, benzoyl and thienyl (hereinafter A ¹ or A ² is A-2) A) a compound wherein A ¹ or A ² is pyridyl optionally substituted with halogen (hereinafter A ¹ or A ² is A-3); and A ¹ or A ² is benzofuryl or indolyl (Hereinafter, A ¹ or A ² is A-4)

A¹And A²Are both A-1 (hereinafter referred to as A-1).
Bottom, A¹And A²Is A-5) compound, A
¹And A²Is A-1 and the other is A
-2 (hereinafter A ¹And A²Is A-6
A) compound, A¹And A²One of A-1
And the other is A-3 (hereinafter A ¹And A²Is A
-7) compound A¹And A²Any of
One is A-1 and the other is A-4 (hereinafter A ¹
And A²Is A-8) compound, A¹and
A²Are both A-2 (hereinafter, A¹And A²Is A-
9) compound, A¹And A²Any one of
Is A-2 and the other is A-3 (hereinafter A ¹You
And A²Is A-10) compound,

A compound wherein Z is a single bond, a compound wherein Z is -N- or -HC = CH-

Z is a single bond, Y ¹ , Y ² , Y ³ , Y
The combination of ⁴ and ^{Y 5} consisting of 5-membered ring and A1 and A2 (Y, A) is the following compound. (Y-1, A
-5), (Y-2, A-5), (Y-3, A-5), (Y-4, A-5), (Y-5, A-5),
(Y-6, A-5), (Y-7, A-5), (Y-8, A-5), (Y-9, A-5), (Y-10,
(A-5), (Y-11, A-5), (Y-12, A-5), (Y-13, A-5), (Y-14, A-
5), (Y-1, A-6), (Y-2, A-6), (Y-3, A-6), (Y-4, A-6), (Y
-5, A-6), (Y-6, A-6), (Y-7, A-6), (Y-8, A-6), (Y-9, A-
6), (Y-10, A-6), (Y-11, A-6), (Y-12, A-6), (Y-13, A-
6), (Y-14, A-6), (Y-1, A-7), (Y-2, A-7), (Y-3, A-7),
(Y-4, A-7), (Y-5, A-7), (Y-6, A-7), (Y-7, A-7), (Y-8, A
-7), (Y-9, A-7), (Y-10, A-7), (Y-11, A-7), (Y-12, A-
7), (Y-13, A-7), (Y-14, A-7), (Y-1, A-8), (Y-2, A-8),
(Y-3, A-8), (Y-4, A-8), (Y-5, A-8), (Y-6, A-8), (Y-7, A
-8), (Y-8, A-8), (Y-9, A-8), (Y-10, A-8), (Y-11, A-
8), (Y-12, A-8), (Y-13, A-8), (Y-14, A-8), (Y-1, A-
9), (Y-2, A-9), (Y-3, A-9), (Y-4, A-9), (Y-5, A-9), (Y
-6, A-9), (Y-7, A-9), (Y-8, A-9), (Y-9, A-9), (Y-10, A-
9), (Y-11, A-9), (Y-12, A-9), (Y-13, A-9), (Y-14, A-
9), (Y-1, A-10), (Y-2, A-10), (Y-3, A-10), (Y-4, A-1
0), (Y-5, A-10), (Y-6, A-10), (Y-7, A-10), (Y-8, A-1
0), (Y-9, A-10), (Y-10, A-10), (Y-11, A-10), (Y-12, A-
10), (Y-13, A-10) or (Y-14, A-10).

Examples of the compound (I) according to the present invention are shown in the following table.

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

[0033]

[Table 6]

[0034]

[Table 7]

[0035]

[Table 8]

[0036]

[Table 9]

[0037]

[Table 10]

[0038]

[Table 11]

[0039]

[Table 12]

[0040]

[Table 13]

[0041]

[Table 14]

[0042]

[Table 15]

[0043]

[Table 16]

[0044]

[Table 17]

[0045]

[Table 18]

[0046]

[Table 19]

[0047]

[Table 20]

[0048]

[Table 21]

[0049]

[Table 22]

[0050]

[Table 23]

[0051]

[Table 24]

[0052]

[Table 25]

[0053]

[Table 26]

[0054]

[Table 27]

[0055]

[Table 28]

In the above table, the preferred compound is 123TA14-2, 1
23TD45-6, 124OD35-12, 124OD35-13, 124OD35-14, 124O
D35-15, 124TA35-17, 124TD35-6, 134OD25-9, 134OD25-
10, 134OD25-11, 134OD25-12, 134OD25-13, 134OD25-1
4, 134OD25-15, 134OD25-16, 134OD25-17, 134OD25-1
8, 134OD25-19, 134OD25-20, 134OD25-21, 134OD25-2
2, 134OD25-23, 134OD25-24, 134OD25-25, 134OD25-2
6, 134OD25-27, 134OD25-28, 134OD25-29, 134OD25-3
0, 134OD25-31, 134OD25-32, 134OD25-33, 134OD25-3
4, 134OD25-35, 134OD25-36, 134OD25-37, 134OD25-3
8, 134OD25-39, 134OD25-40, 134OD25-41, 134OD25-4
2, 134OD25-43, 134OD25-44, 134OD25-45, 134OD25-4
6, 134OD25-47, 134OD25-48, 134OD25-49, 134OD25-5
0, 134TD25-1, 134TD25-2, 134TD25-3, 134TD25-4, 134
TD25-5, 134TD25-6, F25-10, IM45-12, IM45-16, IX35-
1, IX35-8, IX35-9, IX35-12, IX35-13, OX24-5, OX24-
7, OX24-8, OX25-1, OX25-2, PZ35-4, PZ35-5, PZ35-
6, T25-1, TZ-1, TZ-2, TZ-3, TZ-4, TZ-5, TZ-6, TZ-
7, TZ24-2, TZ24-3, TZ24-4, TZ24-5, TZ24-6, TZ24-
7, TZ24-8, TZ24-9, TZ24-11, TZ24-12, TZ24-13, TZ2
4-14, TZ24-15, TZ24-16, TZ24-17, TZ24-18, TZ24-1
9, TZ24-20, TZ25-2 and TZ25-6.

Further preferred compounds are 123TA14-2 and 124OD.
35-12, 124OD35-13, 124OD35-14, 124OD35-15, 124TA35
-17, 124TD35-6, 134OD25-9, 134OD25-10, 134OD25-1
1, 134OD25-12, 134OD25-13, 134OD25-14, 134OD25-1
5, 134OD25-16, 134OD25-17, 134OD25-19, 134OD25-2
0, 134OD25-23, 134OD25-25, 134OD25-27, 134OD25-2
8, 134OD25-30, 134OD25-32, 134OD25-33, 134OD25-3
4, 134OD25-35, 134OD25-36, 134OD25-37, 134OD25-3
8, 134OD25-40, 134OD25-41, 134OD25-42, 134OD25-4
3, 134OD25-46, 134OD25-49, 134TD25-1, 134TD25-2, 1
34TD25-4, 134TD25-5, 134TD25-6, F25-10, IX35-1, IX
35-8, IX35-9, IX35-12, IX35-13, OX24-5, OX24-7, OX
24-8, OX25-1, OX25-2, PZ35-4, PZ35-5, PZ35-6, TZ-
1, TZ-2, TZ-3, TZ-4, TZ-5, TZ-6, TZ-7, TZ24-2, TZ2
4-3, TZ24-5, TZ24-6, TZ24-7, TZ24-9, TZ24-11, TZ24
-12, TZ24-13, TZ24-14, TZ24-16, TZ25-2 and TZ25-6
It is.

Particularly preferred compounds are 123TA14-2, 124OD35
-12, 124OD35-15, 124OD35-13, 124TD35-6, 134OD25-
9, 134OD25-10, 134OD25-11, 134OD25-15, 134OD25-1
4, 134OD25-23, 134OD25-28, 134OD25-27, 134OD25-3
2, 134OD25-40, 134OD25-46, 134TD25-1, 134TD25-4, 1
34TD25-5, F25-10, IX35-1, IX35-13, IX35-8, IX35-
9, OX24-5, OX24-8, PZ35-4, PZ35-5, TZ-1, TZ-2, TZ-
3, TZ-4, TZ-7, TZ24-3, TZ24-6 and TZ24-11.

The compound (I) according to the present invention can be synthesized, for example, by the following method. It is available as a commercially available reagent or can be synthesized by applying literature methods described in Tables 1-28. Unless otherwise specified, for example, it can be synthesized by the following method.

1) Synthesis of pyrazole derivative (PZ35)

Embedded image (Wherein each symbol is as defined above) 1,3-diketone (1) and hydrazine are heated in a solvent to obtain a pyrazole derivative (PZ35). As the solvent, alcohol or the like may be used. The reaction temperature may be from room temperature to the reflux temperature of the solvent.

2) Synthesis of oxazole derivative (OX25)

Embedded image (In the formula, Hal represents a halogen, and other symbols are as defined above.) For example, Synthesis, 112 (1990) or Tetrahedron Let
First, chloroacetophenone (2) is converted to aminoacetophenone (4) by the method described in T., 30, 5285 (1989). (4) after acylation with an acid halide, phosphorus oxychloride,
The oxazole derivative (OX25) can be obtained by ring closure with polyphosphoric acid, phosphorus trichloride, dimethyldichlorosilane, or the like. No solvent is used, or acetonitrile, dimethylformamide, toluene, or the like may be used, and the reaction may be carried out at room temperature to the reflux temperature of the solvent.

3) Synthesis of thiazole derivative (TZ24)

Embedded image (In the formula, X is halogen or toluenesulfonyloxy (hereinafter referred to as OTs), and other symbols are as defined above.) For example, according to the method described in J. Heterocycl. Chem., 28, 673 (1991), Haloacetophenone (2) (for example, 2
Directing bromoacetophenone) and thioamide (7), an alcohol, in a solvent such as dimethylformamide, thiazole derivatives (TZ24) having A ¹ and A ² in 2 and 4 positions is reacted at the reflux temperature of room temperature to the solvent - I can do things.

The compound can be synthesized by the following method. Synth. Commu
According to the method described in n., 28, 2371 (1998), acetophenone is converted into a tosylate (2: X = OTs) and reacted with thioamide (7). As the solvent, methylene chloride, methanol, ethanol or the like may be used.

Embedded image Wherein each symbol is as defined above. Thiazole derivatives (TZ25) having A ¹ and A ² at the 2- and 5-positions are described, for example, in Collect. Czech. Chem, 58, 2720.
According to the method described in (1993), the ketoamide derivative (6) can be reacted with the Lawesson's reagent for synthesis. As the solvent, benzene, toluene, xylene, dioxane or the like may be used, and the reaction is carried out at room temperature to the reflux temperature of the solvent.

4) 1,2,4-oxadiazole derivative
Synthesis of (124OD35)

Embedded image (Wherein each symbol is as defined above) For example, according to the method described in Tetrahedron 46, 3941 (1990), in the presence of zinc chloride, amide oxime (9) and nitrile (8)
Thus, 1,2,4-oxadiazole (124OD35) can be synthesized. Ethyl acetate, butyl acetate and the like are used as the solvent. The reaction is carried out at room temperature to the reflux temperature of the solvent.

5) 1,3,4-oxadiazole derivative
Synthesis of (134OD25)

Embedded image (In the formula, Hal is a halogen, n is 0 or 1, and other symbols are as defined above.) [Method A] (10 → 5 → 11 → 134OD25) The compound (134OD25) is synthesized by, for example, J Org. Chem., 58,
2628 (1993). First step: When the raw material is a carboxylic acid, it is first converted to an acid halide (5) with thionyl chloride, oxalyl chloride or the like. Second step: When hydrazine monohydrate is reacted with (5),
The intermediate 1,2-bisbenzoylhydrazine (11) is obtained. The reaction is preferably performed in a methylene chloride solvent at an ice-cooled temperature or at a reflux temperature of the solvent. Third step: Ring closure of (11) with phosphorus oxychloride, polyphosphoric acid, phosphorus trichloride and dimethyldichlorosilane to give 134OD25. No solvent may be used, or acetonitrile, dimethylformamide, toluene or the like may be used, and the reaction temperature is preferably from room temperature to 150 ° C.

[Method B] (12 + 13 → 14 → 134OD25) The method B is synthesized, for example, according to the method of Synthesis, 946 (1979). That is, phenyltrichloromethane (12) and hydrazide (13) are heated and refluxed in an alcohol solvent in the presence of a base to obtain 134OD25. In this reaction, sodium carbonate and pyridine may be used as the base, and alcohols such as methanol and ethanol may be used as the solvent. When the ring-closed intermediate (14) remains, it can be converted to 134OD25 by heating at 130 ° C. in a dimethylformamide solvent under an acid catalyst such as paratoluenesulfonic acid.

[Method C] (15 + 16 or 17 → 134OD25) According to the method described in J. Gen. Chem. USSR., 1125 (1992), tetrazole (15) and acid chloride (16) or acid anhydride ( 1
By heating 7), 134OD25 can be obtained. No solvent is used, or acetonitrile, dimethylformamide, pyridine or toluene may be used,
The reaction temperature is preferably from 50 to 150 ° C. The raw material tetrazole (15) can be obtained by using a commercially available reagent or by the method described in, for example, J. Org. Chem., 58, 4139 (1993).

[Method D] (13 + 16 → 18 → 134OD25) Intermediate (18) can be obtained, for example, by the method described in Khim. Geterotsikl. Soedin., 333 (1996). The ring closure reaction of (18) may be performed in the same manner as in the third step of Method A.

6) 1,2,4-triazole derivative (124
Synthesis of TA35)

Embedded image (Wherein each symbol is as defined above) 1,3,4-oxadiazole (134OD25) is sealed with thiourea and tetrahydrofuran solvent in a sealed tube at 100 to 150.
It can be converted to 124TA35 by heating at ° C.

7) 1,3,4-thiadiazole derivative 13
Synthesis of 4TD25

Embedded image (In the formula, Hal is a halogen, and each symbol is as defined above.) [Method A] (5 + 19 → 18 → 134TD25) 1,3,4-thiadiazole derivative (134TD25) is described in, for example, J. Prakt. Chem. , 322, 933 (1980) by reacting the above-mentioned intermediate (18) with phosphorus pentasulfide.

[Method B] (13 + 20 → 21 → 22 + 23 → 134TD25) For example, J. Chem. Soc. C., 1986 (1971) or J. Chem. S
According to the method described in oc. Perkin Trans 1, 9, 1987 (1982), an intermediate (22) is obtained, and further condensed with a thioamide (23) to form a 1,3,4-thiadiazole derivative (134TD25). .

8) Synthesis of isoxazole derivative (IX35)

Embedded image (In the formula, R is lower alkyl, and other symbols are as defined above.) For example, it can be synthesized by the method described in Organic Synthesis Col. Vol. 6, 278 (1988). That is, the oxime (24), which can be easily synthesized from the corresponding ketone body by a conventional method, is converted into a dianion with n-butyllithium in THF under ice-cooling in THF, and then condensed with the ester (25) at the same temperature. (IX35).

The apoAI expression enhancer of the present invention activates HDL's reverse cholesterol transfer action, anti-inflammatory action, anticoagulant action and the like. 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.

An effective amount of the compound according to the present invention may be supplemented with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like which are suitable for the dosage form. 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.

[0077]

EXAMPLES Reference Example 1 2-amino-3'-methoxyacetophenone hydrochloride (4-1)

Embedded image 2-bromo-3'-methoxyacetophenone (2.291 g, 1
0.00mmol), sodium diformylimide (1.102 g, 11.6
(0 mmol) and acetonitrile (5 ml) were stirred at room temperature for 2 hours and further at 60 ° C. for 2 hours. The insolubles in the reaction solution were removed by filtration, the solvent was distilled off under reduced pressure from the filtrate, and the residue was added with 5% hydrochloric acid ethanol (25 ml) without purification, and allowed to stand at room temperature for 24 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the precipitated crystals obtained were washed with isopropyl ether and then with ethyl acetate to obtain crude crystals 4-1 (1.869 g, 92.7%). NMR (DMSO d-6): 3.85 (3H, s), 4.59 (2H, s), 7.27-7.35
(1H, m), 7.45-7.56 (2H, m), 7.58-7.65 (1H, m), 8.42
(3H, br)

Reference Example 2 3-Floyl chloride (5-1)

Embedded image Thionyl chloride (14.5 ml, 20.0 mmol) was added to 3-furancarboxylic acid (11.21 g, 10.0 mmol), and the mixture was stirred at 40 ° C for 2 hours 30 minutes. The reaction product was purified by distillation under reduced pressure to obtain colorless crystals of 3-furoyl chloride 5-1 (11.89 g, 91.0%). (Caution: 5-1 has strong pungent odor) Boiling point 68-72 ° C (3325 Pa)

Reference Example 3 N- (3'-methoxyphenacyl) -3-furanamide (6-1)

Embedded image 5-1 (0.685 g, 5.25 mmol) was added dropwise to a solution of 4-1 (1.008 g, 5.00 mmol) in pyridine (4 ml) under ice-cooling.
And stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure,
Ice and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The crude crystals were recrystallized from ethyl acetate-hexane to give pale yellow prism crystals 6-1 (970 mg, 74.8%). Melting point 86-88 ° C Elemental analysis C ₁₄ H ₁₃ NO ₄ -0.1H ₂ O Calculated C, 64.41; H, 5.10;
N, 5.37: Found C, 64.50; H, 4.99; N, 5.45 NMR (CDCl 3): 3.88 (3H, s), 4.90 (2H, d, J = 4.2), 6.73
(1H, dd, J = 0.9 and 2.1), 6.90 (1H, br), 7.15-7.22 (1
H, m), 7.43 (1H, t, J = 7.8), 7.48 (1H, t, J = 1.8), 7.5
3 (1H, t, J = 1.8), 7.61 (1H, d, J = 7.5), 8.00-8.05 (1H,
m)

Reference Example 4 2-furylyl- (3-methoxybenzylidene) hydrazide (21-1)

Embedded image To a solution of 2-furylylhydrazide (2.522 g, 20.00 mmol) in ethanol (20 ml) was added m-anisaldehyde (2.43 ml, 1
9.97 mmol) was added dropwise at room temperature, stirred for 4 hours, and left overnight. Crystals precipitated from the reaction solution were collected by filtration and washed with 95% ethanol to obtain colorless prism crystals 21-1 (4.436 g, 90.8%). Mp 156-157 ° C. Elemental Analysis C ₁₃ H ₁₂ N ₂ O ₃ Calculated C, 63.93; H, 4.95; N, 11.
47: Found C, 63.69; H, 4.98; N, 11.41 NMR (CDCl ₃ ): 3.87 (3H, s), 6.58 (1H, dd, J = 1.5 and 3.
3), 6.94-7.01 (1H, m), 7.24-7.44 (4H, m), 7.47-7.57
(1H, m), 8.24 (1H, s), 9.39 (1H, br)

Reference Example 5 3-acetamidobenzonitrile

Embedded image Acetic anhydride (10 ml, 105.98 mmol) was added to 3-aminobenzonitrile (2.50, 21.16 mmol) at room temperature, the mixture was stirred at the same temperature for 1 hour, and the remaining reagent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The extract was washed with isopropyl ether to obtain pale brown crystals (3.266 g, 96.3%). Melting point 120-12
3 ° C Elemental analysis C ₉ H ₈ N ₂ O Calculated C, 67.49; H, 5.03; N, 17.49:
Found C, 67.47; H, 5.01; N, 17.57 NMR (CDCl 3): 2.21 (3H, s), 7.35-7.47 (3H, m), 7.67-7.
75 (1H, m), 7.92 (1H, br)

Reference Example 6 N- [3- (5-tetrazoylphenyl)] acetamide (15-1)

Embedded image 3-acetamidobenzonitrile (2.883 g, 18.00 mmol)
Trimethylsilyl azide (4.8m
l, 36.16 mmol) and di-n-butyltin oxide (0.448 g, 1.80 mmo
l) was added and the mixture was heated under reflux for 16 hours. The solvent was distilled off under reduced pressure,
Methanol was added to the residue, and the mixture was further distilled under reduced pressure. The residue was extracted with saturated aqueous sodium hydrogen carbonate (1.81 g, 21.55 mmol) in water and washed with ethyl acetate. The aqueous alkaline solution was acidified with hydrochloric acid.
The precipitated crystals were collected by filtration and washed with ethanol.15-1 (2.033 g, 55.6
%). Melting point 250-260 ° C (dec) Elemental analysis C ₉ H ₉ N ₅ O Calculated C, 53.20; H, 4.46; N, 34.46:
Found C, 53.25; H, 4.40; N, 33.52 NMR (DMSO d-6): 2.09 (3H, s), 5.20 (1H, t, J = 7.8), 7.
62-7.78 (2H, m), 8.39 (1H, t, J = 1.8), 10.20 (1H, s)

Reference Example 7 1,2-bis (3-methylphenyl) hydrazine (11-1)

Embedded image Thionyl chloride (18.0) was added to m-toluic acid (10.89 g, 80.0 mmol).
ml, 248.1 mmol) and stirred at 40 ° C. for 3 hours.
Excess thionyl chloride was removed under reduced pressure. To a solution of crude m-toluic acid chloride in dry methylene chloride (44 ml) was added hydrazine monohydrate (11.5 ml, 237.08 mmol) for 1 hour 30 at room temperature.
Then, the mixture was stirred for 1 hour. Add water to the reaction solution,
The precipitated crystals were collected by filtration and washed with water and methanol to obtain colorless powdery crystals 11-1 (10.06 g, 93.8%). Melting point 220-22
3 ° C Elemental analysis C ₁₆ H ₁₆ N ₂ O ₂ Calculated C, 71.62; H, 6.01; N, 10.
44: Found C, 71.27; H, 5.77; N, 10.61 NMR (DMSO d-6): 2.39 (6H, s), 7.37-7.45 (4H, m), 7.68
-7.78 (4H, m), 10.29 (2H, br)

Reference Example 8 Bis [(3-furoyl)-(3
-Methoxybenzoyl)] hydrazine (18-1)

Embedded image m-anisic acid hydrazide (1.255 g, 7.552 mmol) pyridine
After 5-1 (1.035 g, 7.929 mmol) was added dropwise to the (4 ml) solution under ice cooling, the mixture was stirred at the same temperature for 4 hours and further at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with ethyl acetate and then with isopropyl ether, and then recrystallized from isopropanol to give colorless needles 18-1 (1.578 g, 80.3%)
I got Mp 211-212 ° C. Elemental Analysis _{C 13 H 12 N 2 O 4} -0.5H 2 O Calculated C, 57.99; H, 4.87;
N, 10.40: Found C, 57.79; H, 4.83; N, 10.61 NMR (DMSO d-6): 3.82 (3H, s), 6.93 (1H, d, J = 1.8), 7.
11-7.23 (1H, m), 7.38-7.56 (3H, m), 7.80 (1H, d, J = 1.
8), 8.30 (1H, d, J = 0.9), 10.23 (1H, br), 10.42 (1H, b
r)

Reference Example 9 1- (3-methoxyphenyl)
Etanone oxime (24-1) 3-methoxyacetophenone (10 g), hydroxylamine hydrochloride (5.1 g), 4M aqueous sodium hydroxide solution (18 m
L), water (30 mL) and ethanol (50 mL) were refluxed for 2 hours. The solvent was distilled off under reduced pressure, and the aqueous layer was extracted with ether. The organic layer was washed with water and saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the oil was azeotropically dehydrated twice with toluene, and used for the subsequent reaction without further purification.

Example 1 3,5-di (4-methoxyphenyl) -1-methylpyrazole (PZ35-4)

Embedded image To a solution of 1,3-bis (4-methoxyphenyl) -1,3-propanedione (14.2 g, 5.0 mmol) in ethanol (10 ml) was added sodium hydrogencarbonate (1.68 g, 20.0 mmol) and methylhydrazine sulfate (1.44 g). g, 10.0 mmol) and heated under reflux for 3 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in chloroform. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol, and colorless prism crystals of PZ35-4 (1.4
2g, 96.6%). Melting point 107-108 ° C

Example 2 2- (3-furyl) -5- (3
-Methoxyphenyl) oxazole (OX25-2)

Embedded image 6-1 (778mg, 3.00mmol) and phosphorus oxychloride (7.8ml, 83.68m
mmol) was stirred at 100 ° C. for 1 hour. After phosphorus oxychloride was distilled off under reduced pressure, ice was added to the residue, neutralized with concentrated aqueous ammonia, and extracted with ethyl acetate. The extraction layer is water,
After washing with saturated saline, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane (1: 3)) and recrystallized from isopropyl ether to give pale yellow prism crystals OX25.
-2 (662 mg, 85.9%) was obtained. Melting point 88-90 ° C

Example 3 2- (4-methoxyphenyl)
-4-phenylthiazole (TZ24-5)

Embedded image α-bromoacetophenone (3.981 g, 20.00 mmol), 4-
A suspension of methoxythiobenzamide (3.345 g, 20.00 mmol) and dry ethanol (40 ml) was stirred at 50 ° C. for 2 hours. After evaporating the solvent under reduced pressure, ice was added to the residue and the mixture was made weakly alkaline with 4N-sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform), and further recrystallized from ethyl acetate-hexane to obtain a pale yellow prism crystal TZ24-5 (4.786 g, 89.5%). Melting point 98.5-100 ° C

Example 4 4- (2-furyl) -2- (4
-Methoxyphenyl) thiazole (TZ24-6)

Embedded image 2-acetylfuran (0.661 g, 6.00 mmol), hydroxy (tosyloxy) iodobenzene (Koser's Reagent, 2.
A suspension of 35 g (6.00 mmol) and dry methylene chloride (12 ml) was stirred at room temperature for 16 hours, and the solvent was distilled off under reduced pressure. 4- in the residue
Methoxythiobenzamide (1.00 g, 6.00 mmol) and dry ethanol (24 ml) were added, and the mixture was heated under reflux for 4 hours. After the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The ether layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was eluted by silica gel chromatography (toluene), and the crude crystals were recrystallized from isopropyl ether-hexane to give light brown crystals.
TZ24-6 (668 mg, 43.4%) was obtained. 77-78 ° C

Example 5 2- (3-furyl) -5- (3
-Methoxyphenyl) thiazole (TZ25-6)

Embedded image 6-1 (1.063 g, 4.00 mmol), Lawson's reagent (2.10 g, 5.19 mmol)
l) and a suspension of dry xylene (20 ml) were heated at reflux for 1 hour and 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was chromatographed on neutral alumina and silica gel, eluted with ethyl acetate-hexane (1: 4), and further recrystallized from isopropyl ether to give light brown prism crystals.
TZ25-6 (681 mg, 66.1%) was obtained. 61-62 ° C

Example 6 5- (4-methoxyphenyl)
-3-phenyl-1,2,4-oxadiazole (124O
D35-12)

Embedded image Benzamidoxime (9.04 g, 66.40 mmol), zinc chloride (2
7.15 g, 199.22 mmol) and a suspension of butyl acetate (68 ml) were added with anisnitrile 8-1 (8.84 g, 66.39 mmol) and a hydrogen chloride-ethyl acetate solution (4 M, 17.1 ml, 68.40 mmol) and added at 130 ° C. And refluxed for 3 hours. Ice was added to the reaction mixture and extracted with ethyl acetate. The extract was 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 and eluted with ethyl acetate-hexane (1: 9) to obtain 124OD35-12. This was further recrystallized from isopropyl ether to obtain colorless prism crystals (3.7
79 g, 22.6%). Melting point 97-98 ° C

Example 7 2,5-bis (3-toluyl)
-1,3,4-oxadiazole (134OD25-40)

Embedded image 11-1 (5.37 g, 20.01 mmol) and phosphorus oxychloride (18.7 ml, 20
(0.6 mmol) was stirred at 130 ° C. for 30 minutes.
After phosphorus oxychloride was distilled off under reduced pressure, ice was added to the residue,
The mixture was neutralized with concentrated aqueous ammonia and extracted with chloroform. The chloroform layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform), and further purified with ethyl acetate.
Recrystallized from hexane and colorless prism crystals 134OD25-40 (2.9
96 g, 59.8%). 82-83 ° C

Example 8 2- (2-pyridyl) -5-phenyl-1,3,4-oxadiazole (134OD25-46)

Embedded image Phenyltrichloromethane (7.82 g, 40.00 mmol), α-
A suspension of picolinic acid hydrazide (5.48 g, 39.96 mmol), sodium carbonate (4.02 g, 37.93 mmol) and dry ethanol (100 ml) was heated under reflux for 6 hours. After the inorganic substance was removed from the reaction solution by filtration, the solvent was distilled off under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Paratoluenesulfonic acid hydrate (0.761 g, 4.00 mmol) and dry dimethylformamide (20 ml) were added to the intermediate crude product, and the mixture was heated and stirred at 130 ° C. for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution,
Extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on neutral alumina and silica gel (hexane-chloroform (1: 4)) and further recrystallized from ethyl acetate-hexane to give colorless prism crystals.
4OD25-46 (3.036 g, 36.1%) was obtained. Melting point 127-128
° C

Example 9 2- (4-dimethylaminophenyl) -5-phenyl-1,3,4-oxadiazole (1
34OD25-15)

Embedded image 4-dimethylaminophenylcarboxylic acid (1.652 g, 10.00
mmol), dry dimethylformamide (0.039 ml, 0.05 mmol)
And oxalyl chloride in a suspension of dry methylene chloride (5 ml)
(1.05 ml, 12.04 mmol) was added dropwise at room temperature in 10 minutes,
After stirring for 1 hour, the solvent was distilled off under reduced pressure. Dry pyridine (0.81 ml, 10.01 mmol), 5-phenyltetrazole (1.462 g, 10.00 mmol) and dry acetonitrile (5 ml) were added to the reaction product, and the mixture was heated under reflux for 2 hours and 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract layer was 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, eluted with ethyl acetate-chloroform (1:15), and further recrystallized from ethyl acetate-hexane to obtain pale yellow prism crystals 134OD25-15 (422 mg, 15.9%). Melting point 13
5-140 ° C

Example 10 2- [2- (2-furyl) vinyl] -5- [1,3,4] -oxadiazole (134OD25
-twenty three )

Embedded image 3- (2-furyl) acrylic acid (1.381 g, 10.00 mmol),
A suspension of thionyl chloride (0.80 ml, 11.03 mmol), dimethylformamide (0.039 ml, 0.50 mmol) and acetonitrile (1.4 ml) was stirred at room temperature for 3 hours. Immediately to the product was added 5-phenyltetrazole (1.462 g, 10.00 mmol), and the mixture was stirred at room temperature for 1 hour and further at 100 ° C for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane (1: 3)), and further recrystallized from 95% ethanol to obtain pale yellow prism crystals 134OD25-23 (653 mg, 27.4%). 131-132 ° C

Example 11 2- (3-furyl) -5
(3-methoxyphenyl)-[1,3,4] -oxadiazole (134OD25-32)

Embedded image 18-1 (5.04 g, 19.37 mmol) and phosphorus oxychloride (18.0 ml, 19
3.11 mmol) was stirred at 100 ° C. for 1 hour 30 minutes. After phosphorus oxychloride was distilled off under reduced pressure, ice was added to the residue, neutralized with concentrated aqueous ammonia, and extracted with ethyl acetate.
The organic layer was 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, and extracted with ethyl acetate-hexane (1: 3).
OD25-32 eluted. The crude crystals were recrystallized from isopropyl ether to give colorless prism crystals (4.34 g, 92.5%). 70-71 ° C

Example 12 3- (3-furyl) -5
(3-methoxyphenyl)-[1,2,4] -triazole (124TA35-17)

Embedded image 134OD25-32 (1.211mg, 5.00mmol) and thiourea (1.00g, 13.
14 mmol) in tetrahydrofuran (5 ml) in a sealed tube.
Heat at 0 ° C. for 24 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extraction layer is water,
After washing with saturated saline, drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, eluting 124TA35-17 with ethyl acetate-hexane (1: 1), and recrystallized from ethyl acetate (471 mg, 39.1%). Melting point 169-171 ° C

Example 13 2- (3-furyl) -5
(3-methoxyphenyl)-[1,3,4] -thiadiazole (134TD25-2)

Embedded image 18-1 (1.562 g, 6.00 mmol), phosphorus pentasulfide (1.80 g, 8.10 mm
ol) and a dry pyridine (12 ml) suspension were stirred at 100 ° C. for 9 hours. After evaporating the solvent under reduced pressure, add ice to the residue and add 4M
-The mixture was made weakly alkaline with sodium hydroxide and extracted with ethyl acetate. The organic layer was 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, and a mixture (2.529 g) containing an unclosed form eluted with ethyl acetate was dissolved in paratoluenesulfonic acid hydrate (0.395 g, 2.08 mmol) and dry toluene (25 ml).
Was added and heated under reflux for 30 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate-hexane (1: 3)) and recrystallized from 95% ethanol to obtain 134TD25-2 (0.82
0g, 52.9%). 75.5-76.5 ° C

Example 14 2- (2-furyl) -5
[1,3,4] -thiadiazole (134TD25-5)

Embedded image 21-1 (2.931 g, 12.00 mmol) in thionyl chloride (1.04 ml, 14.3
A suspension containing 4 mmol) and benzene (12 ml) was heated under reflux for 6 hours. The solvent was distilled off under reduced pressure, hot petroleum ether was added to the residue, only the dissolved portion was separated, and the solvent was distilled off under reduced pressure. Crude product (1.521 g), 4-methylthiobenzamide
(0.875 g, 5.786 mmol) and dry ethanol (20 ml) were stirred at room temperature for 30 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate-hexane (1: 5)).
34TD25-5 (670 mg, 23.0%) was obtained. Melting point 111-113
° C

Example 15 5-furan-3-yl-3-
(3-methoxyphenyl) isoxazole (IX35-9)

Embedded image 1- (3-methoxyphenyl) ethanone oxime (1.65
g, 0.01 mol) was dissolved in THF (55 mL), and n-butyllithium (1.6 M hexane solution, 14 mL) was added dropwise under ice cooling.
Then, after stirring at the same temperature for 30 minutes, a solution of ethyl furan-3-carboxylate (0.7 g, 5 mmol) in THF (10 mL) was used.
Was slowly added. After stirring at ice temperature for 1 hour, 5N hydrochloric acid (1
8 mL) was added in one portion and the mixture was refluxed for 1 hour. After allowing to cool, the reaction solution was poured into ice, made alkaline with sodium hydrogen carbonate, and extracted with ether. Silica gel chromatography (82 g, ethyl acetate-hexane =
At 1: 4), a mixture mainly containing IX35-9 was taken out.
The mixture is further purified by silica gel chromatography (90 g, toluene)
To give IX35-9 (480 mg) as colorless crystals. This was further recrystallized from acetone-hexane to give colorless crystals. 36-37 ° C

Hereinafter, other compounds (I) were synthesized in the same manner. The physical constants are shown below.

[0102]

[Table 29]

[0103]

[Table 30]

Test Example 1 Promoter function 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 second / well). It was 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 31.

[0105]

[Table 31]

From Table 31, it can be seen that the compound of the present invention is apoA
It can be seen that the compound has an I expression enhancing effect.

Formulation Example 1 Tablet Compound (134OD25-32) 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 (134OD25-40) 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 (124OD35-12) 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.

[0110]

As is clear from the above test examples, the compounds according to the present invention exhibit an apoAI expression enhancing action. Therefore, the compounds according to the present invention are very useful as agents for preventing and / or treating abnormal lipids in blood, arteriosclerotic diseases or coronary artery diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI Theme coat ゛ (Reference) A61K 31/4155 A61K 31/4155 4C063 31/4192 31/4192 4C069 31/42 31/42 4C086 31/421 31 / 421 31/422 31/422 31/4245 31/4245 31/425 31/425 31/426 31/426 31/427 31/427 31/433 31/433 31/4436 31/4436 31/4439 31/4439 31/506 31/506 31/5375 31/5375 A61P 3/06 A61P 3/06 9/10 101 9/10 101 43/00 111 43/00 111 // C07D 207/32 C07D 207/32 207/34 207 / 34 207/50 207/50 231/12 231/12 CZ 231/14 231/14 249/06 504 249/06 504 257/04 257/04 E 261/08 261/08 263/32 263/32 271 / 06 271/06 271/10 271/10 277/22 277/22 277/24 277/24 285/06 285/06 285/08 285/08 285/10 285/10 285/135 307/36 307/36 307/38 307/38 307/42 307/42 307/68 307/68 333/06 333/06 333 / 12 333/12 333/16 333/16 333/18 333/18 401/04 401/04 401/14 401/14 403/04 403/04 405/04 405/04 405/14 405/14 407/04 407/04 409/04 409/04 409/14 409/14 413/04 413/04 413/06 413/06 413/14 413/14 417/04 417/04 417/10 417/10 417/14 417 / 14 285/12 E (72) Inventor Teruo Yamamori 5-12-4 Sagishima, Fukushima-ku, Osaka City, Osaka Prefecture Inside Shionogi & Co., Ltd. (72) Inventor Katsunori Sakai 5-12-4, Sagisu, Fukushima-ku, Osaka-shi, Osaka No.Shinogi Pharmaceutical Co., Ltd. DD54 DD58 DD62 DD67 EE01 4C069 AC07 AC10 BA08 BB49 BC23 4C086 AA01 AA02 BA03 BA06 BC13 BC17 BC36 BC62 BC71 BC73 BC82 BC85 BC86 GA02 GA07 GA08 GA09 GA10 MA01 MA04 NA14 ZA45 ZC02 ZC33

Claims (8)

[Claims] (1) Formula (I): Wherein Y ¹ is O, S or NR ¹ and Y ² is CR
² or N, Y ³ is CR ³ or N, Y ⁴
Is CR ⁴ or N, Y ⁵ is CR ⁵ or N, R ¹ is A ¹ ; -ZA ² ; hydrogen; lower alkyl which may have a substituent; An optionally substituted acyl; an optionally substituted amino; a lower alkoxycarbonyl optionally substituted; or a carbamoyl optionally substituted; R ² , R ³ , R
⁴ and R ⁵ are each independently A ¹ ; -ZA ² ; hydrogen; halogen; hydroxy; lower alkyl optionally having substituents; lower alkoxy optionally having substituents; Acyl optionally having a substituent; amino optionally having a substituent; mercapto; lower alkylthio optionally having a substituent; carboxy; lower alkoxycarbonyl optionally having a substituent Or carbamoyl optionally having substituent (s), and Y ¹ , Y
^{2, Y} 3, ^{Y 4} and optionally at least one selected from ^{Y 5} is have ^{A 1,} one but has the ^{-Z-A 2,} -Z- represents a single bond, ^-CR 6 = CR ⁷ -Or -N-
R ⁶ and R ⁷ are each independently hydrogen or lower alkyl, and A ¹ and A ² are each independently a cycloalkyl optionally having a substituent, ApoAI expression enhancer comprising a compound represented by the formula (I): a good aryl or a heterocyclic group which may have a substituent), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. . 2. A 5-membered ring consisting of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is 1,2,3-triazole, 1,2,4-
Triazole, 1,2,3-thiadiazole, 1,2,3
4-thiadiazole, 1,2,5-thiadiazole,
1,3,4-thiadiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-
The apo AI expression enhancer according to claim 1, which is oxadiazole, 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan or thiophene. 3. A 5-membered ring consisting of Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ is 1,2,3-triazole, 1,2,4-
Triazole, 1,2,4-thiadiazole, 1,3
4-thiadiazole, 1,2,4-oxadiazole,
3. Apo AI according to claim 2, which is 1,3,4-oxadiazole, pyrazole, tetrazole, oxazole, isoxazole, thiazole, furan or thiophene.
Expression enhancer. Wherein A ¹ and A ² are each independently may have a substituent and a phenyl, pyridyl, pyrazinyl, furyl, thienyl, thiazolyl, pyrazolyl,
The apoAI expression enhancer according to any one of claims 1 to 3, which is isoxazolyl, benzofuryl or indolyl. 5. A ¹ and A ² each independently being substituted with halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, amino, phenyl, styryl or heteroaryl optionally substituted with lower alkyl. Phenyl which may be substituted with lower alkyl; pyrazolyl which may be substituted with lower alkyl; unsubstituted pyridyl; unsubstituted indolyl; unsubstituted benzofuryl; unsubstituted thienyl; or unsubstituted furyl. Item 4. The apoAI expression enhancer according to Item 4. 6. The apoAI expression enhancer according to claim 1, wherein Z is a single bond. 7. Y¹Is O, S or NR¹And R¹Is
A lower alkyl or a substituent which may have a substituent;
An amino which may have², Y³, Y ⁴And
And Y⁵One or two of each are independently CA¹In
One is CA²And the others are each independently CH
Or the apo according to any one of claims 1 to 6,
AI expression enhancer. 8. The apoAI expression enhancer according to any one of claims 1 to 7, which is an agent for preventing and / or treating blood lipid abnormalities or arteriosclerotic diseases.