JP2001335476A - New uses for tricyclic compounds - Google Patents

Abstract

(57) [Problem] To provide an apoAI expression enhancer as a therapeutic agent for cardiovascular diseases based on enhancement of HDL function. Kind Code: A1 Formula (I): (In the formula, X ¹ and X ² are each independently an optionally substituted aryl, heteroaryl, hydrogen, halogen, or the like, and ring A may be each condensed with another aromatic ring A benzene ring or a 6-membered aromatic hetero ring containing 1 to 3 N atoms, wherein R ^{1 to} R ⁴ are each independently hydrogen,
An apoAI expression enhancer comprising a compound represented by the formula (I): a halogen, a lower alkyl or a lower alkoxy, etc.), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to apolipoprotein A.
It relates to an I 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 (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 ultra-low density lipoprotein (VLDL) and LDL. These lipoproteins that have taken up CE are eventually taken up by the liver via receptors. Apo AI is regenerated during this process,
Again, cholesterol extraction and pre-β-HDL regeneration are repeated 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 hepatic mRNA levels of apoAI and blood apoAI and HDL levels. Therefore, by enhancing apoAI gene expression, blood apoA
It is thought that if the I concentration can be increased, the HDL function will eventually be improved, leading to activation of the reverse cholesterol transfer system. In fact, anti-atherosclerotic effects have been shown in apoAI transgenic mice and rabbit pathological models administered with apoAI. From these things, Apo AI
The substances that activate are blood lipid abnormalities, arteriosclerotic diseases,
It is thought to lead to the creation of a completely new drug for various other diseases involving HDL.

A compound having an HDL elevating effect is described in WO97.
/ 19931, WO97 / 19932, US55998
29, EP796874, JP-A-9-255574, etc., compounds having an apoAI increasing effect are disclosed in JP-A-5-5-2.
21959, JP-A-8-291094, WO97 / 09
048 etc.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an HD
ApoA as a therapeutic agent for cardiovascular diseases based on enhanced L function
An object of the present invention is to provide an I expression enhancer.

[0007]

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

Embedded image (Wherein X ¹ and X ² are each independently an aryl optionally having a substituent, a heteroaryl optionally having a substituent, a cycloalkyl optionally having a substituent, Aryloxy optionally having a group, heteroaryloxy optionally having a substituent, arylthio optionally having a substituent, heteroarylthio optionally having a substituent, hydrogen, Halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower optionally having substituent (s) Alkenyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted acyl, optionally substituted amino or optionally substituted Bamoyl, at least one of X ¹ and X ² is an aryl which may have a substituent or a heteroaryl which may have a substituent, and ring A is fused with another aromatic ring. A 6-membered aromatic hetero ring containing 1 to 3 N atoms which may be condensed with a benzene ring or another aromatic ring, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are Each independently represents hydrogen, halogen, hydroxy,
Lower alkyl which may have a substituent, lower alkenyl which may have a substituent, lower alkoxy which may have a substituent, lower alkenyloxy which may have a substituent, carboxy A lower alkoxycarbonyl which may have a substituent, an acyl which may have a substituent, an amino which may have a substituent or a carbamoyl which may have a substituent). An apoAI expression enhancer comprising a compound of formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;

2) ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring,
A quinoline ring, a quinoxaline ring or a phthalazine ring, X ¹ is phenyl which may have a substituent or heteroaryl which may have a substituent, and X ² is hydrogen, halogen, hydroxy, lower alkyl. , lower alkenyl, lower alkoxy or phenyl, 1) apo AI expression enhancer according, 3) X ¹ is attached to the 4 'position, 1) or 2) above, wherein the apo AI expression enhancer, 4) X ¹ is phenyl which may have a substituent, furyl which may have a substituent or thienyl which may have a substituent; An AI expression enhancer, 5) an apoAI expression enhancer according to any one of 1) to 4), wherein at least one of the 2-position and the 6-position of ring A is an N atom, 6) R ¹ , R ² , R ^3, R ⁴ and water R ⁵ are each independently , Hydroxy, lower alkyl or lower alkoxy, 1) to 5 apo AI expression enhancer according to any one of)

7) ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring; X ¹ is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy or phenyl; X ² is phenyl which may have a substituent or heteroaryl which may have a substituent,
1), wherein the Apo AI expression enhancer, 8) X ² is attached to the 4 position of the ring A, 1) to 7-) Apo AI expression enhancer according to any one of, 9) X ² is a substituted group Is phenyl optionally having
1), 7 apo AI expression enhancer according to any one of) or ^{8), 10) R 1,} R 2, R 3, R 4 and R ⁵ are all hydrogen, 7) to 9) either 11) An apoAI expression enhancer according to any one of 1) to 10), which is an agent for preventing and / or treating blood lipid abnormalities or arteriosclerotic diseases. I do.

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 present specification, “halogen” refers to fluorine,
Includes chlorine, bromine and iodine. "Lower alkyl"
Means linear and branched alkyl having 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as 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 one or more substituents, and the substituent is halogen, hydroxy, lower alkoxy, Acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, optionally substituted imino (substituents are hydroxy, lower alkyl optionally substituted heterocyclic groups, etc.), nitro , Aryl and heteroaryl. The alkyl part of “lower alkoxy”, “lower alkylthio” and “lower alkylamino” is the same as the above “lower alkyl”. The substituent of the “lower alkoxy optionally having a substituent” is the same as the substituent of the above “lower alkyl optionally having a substituent”.

The "lower alkylenedioxy" specifically includes methylenedioxy, ethylenedioxy and the like. Examples of the substituent of "lower alkylenedioxy optionally having substituent (s)" include the substituent of the above "lower alkyl" or lower alkenyl, lower alkynyl 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". “Lower alkenyl” refers to a group having 2 to 2 carbon atoms.
6, preferably 2 to 4 linear or branched alkenyl, specifically vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl , Isohexenyl, etc., having one or more double bonds at any position. As the substituent of the "optionally substituted lower alkenyl", hydroxy,
Examples include halogen, lower alkoxy, carboxy, acyl, acyloxy, cycloalkyl, lower alkoxycarbonyl, aryl and heteroaryl, and one or more arbitrary positions may be substituted with these substituents. The lower alkenyl part of "lower alkenyloxy" and "lower alkenyloxycarbonyl" and the substituent part of "lower alkenyloxy optionally having substituent (s)" may have the above "lower alkenyl" and "substituent". And lower alkenyl.

The term "lower alkynyl" means a linear or branched alkynyl having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and specifically includes ethynyl, propynyl, butynyl, pentynyl, Hexinyl, heptynyl, octynyl, noninyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and may further have a double bond. The substituent of the “optionally substituted lower alkynyl” is the same as the substituent of the “optionally substituted lower alkyl”. `` Lower alkynyloxy '', the lower alkynyl part and the substituent part of `` lower alkynyloxy optionally having substituents '' are the above-mentioned `` lower alkynyl '' and `` lower alkynyl optionally having substituents '', respectively. The same is true.

"Acyl" refers to aroyl and C1-C1.
7 aliphatic acyls. Here, “aroyl” means a group in which a carbonyl group is bonded to aryl or heteroaryl. Specific examples of "acyl" include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, benzoyl and the like, and preferably acetyl or benzoyl. Examples of the substituent of the “optionally substituted acyl” include the same substituents as the above-mentioned “optionally substituted lower alkyl”.
The aromatic ring portion of "aroyl" may be substituted with lower alkyl. One or more optional positions of the acyl may be substituted with these substituents. The acyl moiety of “acyloxy” and “halogenoacyl” is the same as the above “acyl”.

The term "amino optionally having substituent (s)" includes amino which may be substituted by 1 to 3 substituents, and the above-mentioned "amino which may have substituent (s)" Substituents of "good lower alkyl" and lower alkyl and the like. Amino substituted with three substituents means a quaternary salt. Preferably, it is unsubstituted or amino substituted with 1 to 2 alkyl and / or acyl. 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" is a compound having 3 to 1 carbon atoms.
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, anthryl and the like. Further, phenyl condensed with a non-aromatic carbon ring such as indanyl and indenyl is also included. Preferably it is phenyl or naphthyl, most preferably phenyl. "Heteroaryl" includes mono- and bicyclic aromatic heterocyclic groups containing one or more heteroatoms in the ring arbitrarily selected from N, S and O. Specifically, monocyclic heteroaryl and indolyl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl, and isoindolyl , Indolizinyl, benzimidazolyl, indazolyl, cinnolinyl, phthalazinyl, benzoxazolyl, benzisoxazolyl, benzoxdiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzo Triazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quina Encompasses Riniru, quinolyl, isoquinolyl, quinoxalinyl, purinyl, pteridinyl, a bicyclic heteroaryl, such as naphthyridinyl and pyrazino pyridazinyl.

"Aryl optionally having substituent (s)",
"Optionally substituted phenyl", "optionally substituted heteroaryl", "optionally substituted furyl", and "optionally substituted" Examples of the substituent of "thienyl" include halogen; hydroxy; lower alkyl which may be substituted with halogen, hydroxy or lower alkoxy; lower alkoxy which may have a substituent (where the substituent means halogen, hydroxy, Amino, imino, hydroxyimino, phenyl or a heterocyclic group imino optionally substituted with lower alkyl); lower alkenyl optionally substituted with halogen, hydroxy or lower alkoxy; substituted with halogen, hydroxy or lower alkoxy Optionally lower alkenyloxy; halogen, hydroxy or lower alkoxy Optionally substituted lower alkynyl; halogen, hydroxy or lower alkoxy optionally substituted lower alkynyloxy; halogen,
Cycloalkyl optionally substituted with hydroxy, lower alkyl or lower alkoxy; acyl; acyloxy; carboxy; lower alkoxycarbonyl; lower alkenyloxycarbonyl; amino optionally substituted with lower alkyl, acyl or halogenoacyl; hydrazino; Carbamoyl optionally substituted with alkyl; nitro; cyano; lower alkenyloxy optionally substituted with halogen, hydroxy or lower alkoxy; mercapto; lower alkylthio;
Aryl optionally substituted with hydroxy, lower alkyl or lower alkoxy; halogen, hydroxy,
Heteroaryl optionally substituted with lower alkyl or lower alkoxy; aryloxy optionally substituted with halogen, hydroxy, lower alkyl or lower alkoxy; optionally substituted with halogen, hydroxy, lower alkyl or lower alkoxy Heteroaryloxy; phenylamino optionally substituted with halogen, hydroxy, lower alkyl or lower alkoxy; and lower alkylenedioxy optionally having substituent (s) wherein the substituent is halogen, hydroxy, lower alkyl , Lower alkenyl, lower alkynyl,
Lower alkoxy and the like), and one or more arbitrary positions may be substituted with these substituents. Preferably halogen; hydroxy; lower alkyl; lower alkoxy; acyl; acyloxy; amino; acylamino; phenyl optionally substituted by lower alkyl or lower alkoxy;

The aryl part of "aryloxy" and "arylthio" is the same as the above "aryl".
The substituent part of the “aryloxy optionally having substituent (s)” and the “arylthio optionally having substituent (s)” is the same as the substituent of the above “aryl optionally having substituent (s)”. is there. The heteroaryl portion of "heteroaryloxy" and "heteroarylthio" is the same as the above "heteroaryl", and "heteroaryloxy optionally having substituent (s)" and " The substituent part of "good heteroarylthio" is the same as the substituent of the "optionally substituted heteroaryl" described above.

Specific examples of the "6-membered aromatic hetero ring containing 1 to 3 N atoms" include a pyridine ring, a pyrimidine ring, a pyridazine ring, a pyrazine ring and a triazine ring. "A benzene ring which may be condensed with another aromatic ring" and "a 6-membered aromatic hetero ring containing 1 to 3 N atoms which may be condensed with another aromatic ring" are each a benzene ring And a benzene ring which may be condensed with a monocyclic aromatic hetero ring and a 6-membered aromatic hetero ring containing 1 to 3 N atoms. The “monocyclic aromatic heterocycle” includes a monocyclic aromatic heterocycle containing one or more heteroatoms arbitrarily selected from N, S and O in the ring. Specifically, pyrrole ring, imidazole ring, pyrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazole ring, triazine ring, tetrazole ring, isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring, Includes thiazole ring, thiadiazole ring, furan ring, thiophene ring and the like.
Specific examples of the "benzene ring which may be condensed with another aromatic ring" include a naphthalene ring, a benzofuran ring, a benzimidazole ring, a benzothiazole ring, a benzisothiazole ring, a benzoxazole ring, a benzisoxazole ring, and benzotriazole. Ring, benzoxadiazole ring, benzopyrazole ring, benzothiophene ring, benzothiazole ring, cinnoline ring, indazole ring, indole ring, indoline ring, isobenzofuran ring, isoindole ring, isoindoline ring, quinoline ring, isoquinoline ring, A quinoxaline ring, a quinazoline ring and a phthalazine ring; Preferred are a quinoline ring, a quinoxaline ring and a phthalazine ring. Specific examples of the "6-membered aromatic hetero ring which may be condensed with another aromatic ring and contains 1 to 3 N atoms" include a quinoline ring, an isoquinoline ring,
Examples include a quinoxaline ring, a quinazoline ring, a phthalazine ring, a cinnoline ring, a naphthyridine ring, a pteridine ring, a purine ring, and a pyrazinopyridazine ring. Preferred are a quinoline ring, a quinoxaline ring and a phthalazine ring.

The phrase "at least one of the 2-position or 6-position of ring A is an N atom" means that ring A is specifically

Embedded image And the like. “Heterocyclic group” includes the above “heteroaryl” and non-aromatic heterocyclic groups. "Non-aromatic heterocyclic groups" include N, S and O
And monocyclic and bicyclic non-aromatic heterocyclic groups containing one or more heteroatoms in the ring arbitrarily selected from Specific examples include oxanyl, thiylanyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, and morpholinyl.

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.

Hereinafter, a method for producing the compound (I) will be described. Compound (I) can be easily synthesized by using an aryl-aryl direct bonding reaction using a palladium catalyst. For example, a compound represented by the formula (I) (hereinafter, compound (I)
A compound represented by the formula (II) (hereinafter referred to as compound (II)) and a compound represented by the formula (III) (hereinafter referred to as compound (III)) in catalytic amounts: It can be produced by direct binding in the presence of palladium. However, at this time, some variations on the selection of Z (or L) are possible. For example, Suzuki reaction (Che
medical Communication 1979,
866, Journal of Synthetic Organic Chemistry, 1993, Vol. 51,
No. 11, pages 91 to 100), Z (or L)
Is used as boron. Alkyl silicon, zinc halide, alkyl tin (Still reaction: C
hem. Int. Ed. , 1986, 25, 508) can be used in exactly the same way. The optimal metal reagent may be appropriately selected depending on the structure of the target compound and its starting material. Since each method is basically exactly the same as the Suzuki reaction, a method for producing compound (I) will be described below using the Suzuki reaction as a specific example.

Embedded image (Wherein one of L and Z is dihydroxyboryl (B
(OH) _2), a di-lower alkyl boryl (BR ₂₎ or di-lower Arukokishiboriru _{(B (OR) 2) (} R is lower alkyl), the other is halogen or -OSO ₂ (C _q F
_{2q + 1} ) (q is an integer of 0 to 4), and other symbols are as defined above. Compound (II) and compound (III) are dissolved in a suitable solvent (for example, benzene, toluene, N, N-dimethyl). In a formamide, dimethoxyethane, tetrahydrofuran, dioxane, ethanol or methanol, or a mixed solvent of these and water, a palladium catalyst (for example, Pd (P
Ph ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , PdCl ₂ (OA
c) ₂ or PdCl ₂ (CH ₃ CN) ₂ etc., preferably P
d (PPh ₃ ) ₄ ) in the presence of basic conditions (for example, bases such as K ₃ PO ₄ , NaHCO ₃ , NaOEt, Na ₂ CO
₃ , Et ₄ NCl, Ba (OH) ₂ , Cs ₂ CO ₃ , Cs
F, NaOH or Ag ₂ CO ₃ ) at room temperature to under heating for several tens minutes to several tens hours to obtain a compound (I) in which two rings are C—C bonded. One of the substituents L and Z is a boryl group (eg, dihydroxyboryl, di-lower alkylboryl or di-lower alkoxyboryl). The other is a leaving group (for example, halogen or -OSO
Is a _{2 (C q F 2q + 1} ) ( where q is an integer from 0 to 4)).
Particularly, halogen or trifluoromethanesulfonyloxy (hereinafter referred to as OTf) is preferable, and most preferable is bromine, iodine or OTf. X ¹ , X ² and R ^{1 to} R ⁵ in the compounds (II) and (III) are preferably groups which do not affect the Suzuki reaction. For example, when a functional group which can be a leaving group such as a halogen or a sulfonic acid ester coexists in a molecule, an undesired product may be obtained. If it is higher than this, the reaction can usually proceed without any problems.

When there is a substituent which hinders the molecule, it may be protected by a suitable protecting group in advance, if necessary, and eliminated at a suitable stage by a usual method. Specifically, Protective Group
in Organic Synthesis 3r
d. Ed. , John Wiley & Son
s, NY (1999) or the like. For example, when any of X ¹ , X ² , R ^{1 to} R ⁵ is hydroxy, methyl, methoxymethyl, methanesulfonyl, benzyl, tetrahydropyranyl or t
It may be protected with -butyldimethylsilyl or the like, and the protecting group may be removed at an appropriate time.

In the above, two cyclic compounds (II) and (I
The method of deriving from (II) to the cyclic compound (I) formed by combining both has been described as an example. By repeating exactly the same operation for compound (I) and still another aromatic ring, an arbitrary number of aromatic rings can be bonded to an arbitrary position. In addition, as described below, when X ¹ or X ² is an aryl which may have a substituent or a heteroaryl which may have a substituent, compound (IV) or (V) is Compound (I) can be obtained by reacting with (IV) or compound (VII).

Embedded image (Wherein the symbols are as defined above)

The above method is an example of a method for deriving the target compound (I) according to the present invention by sequentially and directly bonding a plurality of cyclic compounds that have been constructed in advance. This skeletal synthesis method is applicable to almost all preparations of compound (I) and is the most preferable preparation method. Compound (I) can also be produced by a method other than the above method. For example, in compound (I), X ² is an optionally substituted aryl or an optionally substituted heteroaryl, and the ring A
Is a nitrogen-containing 6-membered ring, a ring A is constructed using an appropriate nitrogen-containing 6-membered ring-forming reaction to obtain the compound (I)
It is also possible to guide to. Alternatively, when X ¹ or X ² contains a heteroatom, a predetermined ring structure can be formed by using a known ring construction reaction. These methods are, for example, C
omprehensive Heterocyclic
Chemistry, O .; M-Cohen, E
d. , PergamonOxford (1984)
And Comprehensive Heterocyc
like Chemistry II, A. R. Kat
Rizky, et al. , Ed. , Pergm
on Oxford (1996). However, in the production method using these heterocyclic rings, the types of compound (I) that can be produced are extremely limited as compared with the above-mentioned ring bonding method, and the generality is poor.

The compounds according to the present invention include their prodrugs. 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, E.
lsevier, Amsterdam 1985. For example, when the compound according to the present invention has a carboxy, an ester derivative (for example, COOR ^A (for example, each of R ^A having a substituent) may be produced by condensing a compound having a carboxy with an appropriate alcohol. Amides prepared by reacting a suitable lower alkyl, lower alkenyl or aryl (where the substituent is hydroxy, acyloxy, carboxy, sulfonic acid, amino, lower alkylamino, etc.), etc.) or carboxy with a suitable amine. derivatives (e.g., CONR ^B R ^C (R ^B is, for example, hydrogen, lower alkyl, etc., R ^C
Is, for example, hydrogen, lower alkyl, amino, hydroxy, etc.)
And the like. For example, when the compound according to the present invention has hydroxy, an acyloxy derivative (for example, -OCOR ^A (R ^A is the same as above) produced by reacting a compound having hydroxy with a suitable acyl halide or a suitable acid anhydride. Synonymous with)
And the like. For example, if a compound of the present invention has an amino, a compound having an amino and a suitable acid halide or a suitable amide derivative is prepared by the mixed acid anhydride is reacted (e.g. NHCOR ^A, NHCOOR ^A ( R ^A is the same 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.

All of the compounds according to the present invention have an apoAI expression promoting action, and preferred compounds include the following compounds. (A) When X ¹ is aryl optionally having substituent (s) or heteroaryl optionally having substituent (s) a-1) A substituent wherein X ¹ is bonded to the 4′-position A compound which is an aryl which may have or a heteroaryl which may have a substituent (hereinafter, X ¹ is X1-1), wherein X ¹ is bonded to the 4′-position, Phenyl which may have a group or monocyclic heteroaryl which may have a substituent (hereinafter, X ¹ is X1-2
Wherein X ¹ is attached at the 4 ′ position;
A compound which is phenyl which may have a substituent, furyl which may have a substituent, or thienyl which may have a substituent (hereinafter, X ¹ is X1-3); X ¹ is bonded to the 4′-position, optionally substituted phenyl (substituent means halogen, hydroxy, lower alkyl, optionally substituted lower alkoxy (here, substituent Are amino, hydroxyimino, lower alkylpiperazinyl imino, phenyl), lower alkylenedioxy optionally having a substituent (substituents are halogen, hydroxy, lower alkyl, lower alkenyl,
Lower alkynyl, lower alkoxy, etc.), acyloxy,
Acylamino), unsubstituted furyl or unsubstituted thienyl (hereinafter, X ¹ is X1-4), X ¹
Is a substituted phenyl bonded to the 4′-position (substituents are halogen, lower alkyl, lower alkoxy, lower alkylenedioxy, acyloxy or acylamino) (hereinafter, X ¹ is X ^1- 5) compound,

A-2) X ² may be phenyl, hydrogen, halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), or having substituent (s) Good lower alkoxy, lower alkenyloxy optionally having a substituent, carboxy, lower alkoxycarbonyl optionally having a substituent, acyl optionally having a substituent, having a substituent A compound which is an amino or a carbamoyl which may have a substituent (hereinafter, X ² is X2-1), X ² is phenyl, hydrogen, halogen, hydroxy, lower alkyl, halogeno lower alkyl, Hydroxy lower alkyl,
Lower alkoxy lower alkyl, acyl lower alkyl, lower alkenyl, lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, lower alkylamino or acylamino ( below, X ² is X2-2
To) compounds is, X ² is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl or lower alkoxy (hereinafter, X ² is assumed to be X2-3) compounds, X ² is hydrogen, halogen, lower Alkyl or lower alkoxy (hereinafter, X ² is X ^2-4 )
Compound,

A-3) A 6-membered aromatic heteroatom containing 1 to 3 N atoms which may be condensed with a benzene ring or other aromatic ring in which ring A may be condensed with another aromatic ring. A compound that is a ring (hereinafter, ring A is A-1), ring A may be condensed with a benzene ring or a benzene ring,
A compound containing three N atoms and being a 6-membered aromatic heterocyclic ring in which at least one of the 2- or 6-positions is an N atom (hereinafter, ring A is A-2); A compound having a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, a quinoline ring, a quinoxaline ring or a phthalazine ring (hereinafter, ring A is A-3);

Embedded image (Hereinafter, ring A is A-4),

A-4) R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, lower alkenyl, lower alkoxy, Compounds which are carboxy, lower alkoxycarbonyl, acyl, amino, lower alkylamino or acylamino (hereinafter, R ^{1 to} R ⁵ are R-1), R ¹ , R ² , R ³ , R ⁴ and R ⁵ Are each independently hydrogen, halogen, hydroxy, lower alkyl, lower alkoxy, acyl, amino, lower alkylamino or acylamino (hereinafter, R ^{1 to} R ⁵ are R-2), R ¹ , R ^2, R ^3, R ⁴ and R ⁵ are each independently hydrogen, halogen, lower alkyl or lower alkoxy (hereinafter, R ¹ to R ⁵ is assumed to be R-3) compounds, R ^{1, 2,} R ^3, R ⁴ and R ⁵ are all hydrogen (hereinafter, R ¹ to R ⁵ is assumed to be R-4) compound,

(B) When X ² is an aryl which may have a substituent or a heteroaryl which may have a substituent b-1) X ¹ is phenyl, hydrogen, halogen, hydroxy, substituted Lower alkyl which may have a group, lower alkenyl which may have a substituent, lower alkoxy which may have a substituent, lower alkenyloxy which may have a substituent, substituent Optionally substituted lower alkynyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted acyl, optionally substituted amino or substituent a carbamoyl which may have a (hereinafter, X ¹ is assumed to be X1-6) compounds, X ¹ is phenyl, hydrogen, halogen, hydroxy, lower alkyl, halogeno-lower alkyl, Dorokishi lower alkyl, lower alkoxy-lower alkyl, acyl-lower alkyl, lower alkenyl,
Lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl lower alkoxy, lower alkenyloxy, carboxy, lower alkoxycarbonyl, acyl, amino, lower alkylamino or acylamino (hereinafter, X ¹
Is a compound wherein X ¹ is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl or lower alkoxy (hereinafter, X ¹ is X 1-8), and X ¹ is hydrogen it is (or less, X ¹ is X1-9
A) a compound,

B-2) X ² is an optionally substituted aryl or an optionally substituted heteroaryl bonded to the 4-position of ring A (hereinafter referred to as X ² There is to be X2-5) compounds, X ² is bonded to position 4 of the ring a, which may have a substituent phenyl or heteroaryl optionally monocyclic be substituted (Hereinafter, X ² is X 2-6), X ² is bonded to the 4-position of ring A, optionally substituted phenyl, having a substituent Or a thienyl which may have a substituent (hereinafter, X ² is X 2
-7), a compound having X ² bonded to the 4-position of ring A and optionally having a substituent (substituents being hydroxy, lower alkyl, lower alkoxy, acyloxy, lower alkyl) Amino, acylamino or),
Unsubstituted furyl or unsubstituted thienyl (hereinafter referred to as X ²
There is to be X2-8) compounds, X ² is bonded to position 4 of the ring A, is unsubstituted phenyl (hereinafter, X ² is X
2-9) compound,

B-3) a compound in which ring A is a benzene ring or a 6-membered aromatic heterocycle containing 1 to 3 N atoms (hereinafter, ring A is A-5); 1-3 N
A compound which is a 6-membered aromatic hetero ring containing atoms (hereinafter, ring A is A-6), wherein ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring (Hereinafter, ring A is A-7),

B-4) A compound wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are R-1, a compound wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are R-2 A compound wherein R ¹ , R ¹ , R ² , R ³ , R ⁴ and R ⁵⁴ are R-3, a compound wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are R-4,

X ¹ , X ² , A of the compound represented by the formula (I)
Wherein the combination (X ¹ , X ² , A, R) of R and R is the following (X ¹ , X ² , A, R) = (X1-1, X2-1, A-1, R-1) ), (X
1-1, X2-1, A-1, R-2), (X1-1, X2-1, A-1, R-3), (X
1-1, X2-1, A-1, R-4), (X1-1, X2-1, A-2, R-1), (X
1-1, X2-1, A-2, R-2), (X1-1, X2-1, A-2, R-3), (X
1-1, X2-1, A-2, R-4), (X1-1, X2-1, A-3, R-1), (X1
-1, X2-1, A-3, R-2), (X1-1, X2-1, A-3, R-3), (X1
-1, X2-1, A-3, R-4), (X1-1, X2-1, A-4, R-1), (X1
-1, X2-1, A-4, R-2), (X1-1, X2-1, A-4, R-3), (X1
-1, X2-1, A-4, R-4), (X1-1, X2-2, A-1, R-1), (X1
-1, X2-2, A-1, R-2), (X1-1, X2-2, A-1, R-3), (X1
-1, X2-2, A-1, R-4), (X1-1, X2-2, A-2, R-1), (X1
-1, X2-2, A-2, R-2), (X1-1, X2-2, A-2, R-3), (X1
-1, X2-2, A-2, R-4), (X1-1, X2-2, A-3, R-1), (X1
-1, X2-2, A-3, R-2), (X1-1, X2-2, A-3, R-3), (X1
-1, X2-2, A-3, R-4), (X1-1, X2-2, A-4, R-1), (X1
-1, X2-2, A-4, R-2), (X1-1, X2-2, A-4, R-3), (X1-
1, X2-2, A-4, R-4), (X1-1, X2-3, A-1, R-1), (X1-
1, X2-3, A-1, R-2), (X1-1, X2-3, A-1, R-3), (X1-
1, X2-3, A-1, R-4), (X1-1, X2-3, A-2, R-1), (X1-
1, X2-3, A-2, R-2), (X1-1, X2-3, A-2, R-3), (X1-
1, X2-3, A-2, R-4), (X1-1, X2-3, A-3, R-1), (X1-
1, X2-3, A-3, R-2), (X1-1, X2-3, A-3, R-3), (X1-
1, X2-3, A-3, R-4), (X1-1, X2-3, A-4, R-1), (X1-
1, X2-3, A-4, R-2), (X1-1, X2-3, A-4, R-3), (X1-
1, X2-3, A-4, R-4), (X1-1, X2-4, A-1, R-1), (X1-
1, X2-4, A-1, R-2), (X1-1, X2-4, A-1, R-3), (X1-
1, X2-4, A-1, R-4), (X1-1, X2-4, A-2, R-1), (X1-
1, X2-4, A-2, R-2), (X1-1, X2-4, A-2, R-3), (X1-
1, X2-4, A-2, R-4), (X1-1, X2-4, A-3, R-1), (X1-
1, X2-4, A-3, R-2), (X1-1, X2-4, A-3, R-3), (X1-
1, X2-4, A-3, R-4), (X1-1, X2-4, A-4, R-1), (X1-
1, X2-4, A-4, R-2), (X1-1, X2-4, A-4, R-3), (X1-
1, X2-4, A-4, R-4),

(X1-2, X2-1, A-1, R-1), (X1-2, X2-1,
A-1, R-2), (X1-2, X2-1, A-1, R-3), (X1-2, X2-1,
A-1, R-4), (X1-2, X2-1, A-2, R-1), (X1-2, X2-1,
A-2, R-2), (X1-2, X2-1, A-2, R-3), (X1-2, X2-1, A
-2, R-4), (X1-2, X2-1, A-3, R-1), (X1-2, X2-1, A
-3, R-2), (X1-2, X2-1, A-3, R-3), (X1-2, X2-1, A-
3, R-4), (X1-2, X2-1, A-4, R-1), (X1-2, X2-1, A-
4, R-2), (X1-2, X2-1, A-4, R-3), (X1-2, X2-1, A-
4, R-4), (X1-2, X2-2, A-1, R-1), (X1-2, X2-2, A-
1, R-2), (X1-2, X2-2, A-1, R-3), (X1-2, X2-2, A-
1, R-4), (X1-2, X2-2, A-2, R-1), (X1-2, X2-2, A-
2, R-2), (X1-2, X2-2, A-2, R-3), (X1-2, X2-2, A-
2, R-4), (X1-2, X2-2, A-3, R-1), (X1-2, X2-2, A-
3, R-2), (X1-2, X2-2, A-3, R-3), (X1-2, X2-2, A-
3, R-4), (X1-2, X2-2, A-4, R-1), (X1-2, X2-2, A-
4, R-2), (X1-2, X2-2, A-4, R-3), (X1-2, X2-2, A-
4, R-4), (X1-2, X2-3, A-1, R-1), (X1-2, X2-3, A-
1, R-2), (X1-2, X2-3, A-1, R-3), (X1-2, X2-3, A-
1, R-4), (X1-2, X2-3, A-2, R-1), (X1-2, X2-3, A-
2, R-2), (X1-2, X2-3, A-2, R-3), (X1-2, X2-3, A-
2, R-4), (X1-2, X2-3, A-3, R-1), (X1-2, X2-3, A-
3, R-2), (X1-2, X2-3, A-3, R-3), (X1-2, X2-3, A-
3, R-4), (X1-2, X2-3, A-4, R-1), (X1-2, X2-3, A-
4, R-2), (X1-2, X2-3, A-4, R-3), (X1-2, X2-3, A-
4, R-4), (X1-2, X2-4, A-1, R-1), (X1-2, X2-4, A-
1, R-2), (X1-2, X2-4, A-1, R-3), (X1-2, X2-4, A-
1, R-4), (X1-2, X2-4, A-2, R-1), (X1-2, X2-4, A-
2, R-2), (X1-2, X2-4, A-2, R-3), (X1-2, X2-4, A-
2, R-4), (X1-2, X2-4, A-3, R-1), (X1-2, X2-4, A-
3, R-2), (X1-2, X2-4, A-3, R-3), (X1-2, X2-4, A-
3, R-4), (X1-2, X2-4, A-4, R-1), (X1-2, X2-4, A-
4, R-2), (X1-2, X2-4, A-4, R-3), (X1-2, X2-4, A-
4, R-4),

(X1-3, X2-1, A-1, R-1), (X1-3, X2-1,
A-1, R-2), (X1-3, X2-1, A-1, R-3), (X1-3, X2-1,
A-1, R-4), (X1-3, X2-1, A-2, R-1), (X1-3, X2-1,
A-2, R-2), (X1-3, X2-1, A-2, R-3), (X1-3, X2-1, A
-2, R-4), (X1-3, X2-1, A-3, R-1), (X1-3, X2-1, A
-3, R-2), (X1-3, X2-1, A-3, R-3), (X1-3, X2-1, A-
3, R-4), (X1-3, X2-1, A-4, R-1), (X1-3, X2-1, A-
4, R-2), (X1-3, X2-1, A-4, R-3), (X1-3, X2-1, A-
4, R-4), (X1-3, X2-2, A-1, R-1), (X1-3, X2-2, A-
1, R-2), (X1-3, X2-2, A-1, R-3), (X1-3, X2-2, A-
1, R-4), (X1-3, X2-2, A-2, R-1), (X1-3, X2-2, A-
2, R-2), (X1-3, X2-2, A-2, R-3), (X1-3, X2-2, A-
2, R-4), (X1-3, X2-2, A-3, R-1), (X1-3, X2-2, A-
3, R-2), (X1-3, X2-2, A-3, R-3), (X1-3, X2-2, A-
3, R-4), (X1-3, X2-2, A-4, R-1), (X1-3, X2-2, A-
4, R-2), (X1-3, X2-2, A-4, R-3), (X1-3, X2-2, A-
4, R-4), (X1-3, X2-3, A-1, R-1), (X1-3, X2-3, A-
1, R-2), (X1-3, X2-3, A-1, R-3), (X1-3, X2-3, A-
1, R-4), (X1-3, X2-3, A-2, R-1), (X1-3, X2-3, A-
2, R-2), (X1-3, X2-3, A-2, R-3), (X1-3, X2-3, A-
2, R-4), (X1-3, X2-3, A-3, R-1), (X1-3, X2-3, A-
3, R-2), (X1-3, X2-3, A-3, R-3), (X1-3, X2-3, A-
3, R-4), (X1-3, X2-3, A-4, R-1), (X1-3, X2-3, A-
4, R-2), (X1-3, X2-3, A-4, R-3), (X1-3, X2-3, A-
4, R-4), (X1-3, X2-4, A-1, R-1), (X1-3, X2-4, A-
1, R-2), (X1-3, X2-4, A-1, R-3), (X1-3, X2-4, A-
1, R-4), (X1-3, X2-4, A-2, R-1), (X1-3, X2-4, A-
2, R-2), (X1-3, X2-4, A-2, R-3), (X1-3, X2-4, A-
2, R-4), (X1-3, X2-4, A-3, R-1), (X1-3, X2-4, A-
3, R-2), (X1-3, X2-4, A-3, R-3), (X1-3, X2-4, A-
3, R-4), (X1-3, X2-4, A-4, R-1), (X1-3, X2-4, A-
4, R-2), (X1-3, X2-4, A-4, R-3), (X1-3, X2-4, A-
4, R-4),

(X1-4, X2-1, A-1, R-1), (X1-4, X2-1,
A-1, R-2), (X1-4, X2-1, A-1, R-3), (X1-4, X2-1,
A-1, R-4), (X1-4, X2-1, A-2, R-1), (X1-4, X2-1,
A-2, R-2), (X1-4, X2-1, A-2, R-3), (X1-4, X2-1, A
-2, R-4), (X1-4, X2-1, A-3, R-1), (X1-4, X2-1, A
-3, R-2), (X1-4, X2-1, A-3, R-3), (X1-4, X2-1, A-
3, R-4), (X1-4, X2-1, A-4, R-1), (X1-4, X2-1, A-
4, R-2), (X1-4, X2-1, A-4, R-3), (X1-4, X2-1, A-
4, R-4), (X1-4, X2-2, A-1, R-1), (X1-4, X2-2, A-
1, R-2), (X1-4, X2-2, A-1, R-3), (X1-4, X2-2, A-
1, R-4), (X1-4, X2-2, A-2, R-1), (X1-4, X2-2, A-
2, R-2), (X1-4, X2-2, A-2, R-3), (X1-4, X2-2, A-
2, R-4), (X1-4, X2-2, A-3, R-1), (X1-4, X2-2, A-
3, R-2), (X1-4, X2-2, A-3, R-3), (X1-4, X2-2, A-
3, R-4), (X1-4, X2-2, A-4, R-1), (X1-4, X2-2, A-
4, R-2), (X1-4, X2-2, A-4, R-3), (X1-4, X2-2, A-
4, R-4), (X1-4, X2-3, A-1, R-1), (X1-4, X2-3, A-
1, R-2), (X1-4, X2-3, A-1, R-3), (X1-4, X2-3, A-
1, R-4), (X1-4, X2-3, A-2, R-1), (X1-4, X2-3, A-
2, R-2), (X1-4, X2-3, A-2, R-3), (X1-4, X2-3, A-
2, R-4), (X1-4, X2-3, A-3, R-1), (X1-4, X2-3, A-
3, R-2), (X1-4, X2-3, A-3, R-3), (X1-4, X2-3, A-
3, R-4), (X1-4, X2-3, A-4, R-1), (X1-4, X2-3, A-
4, R-2), (X1-4, X2-3, A-4, R-3), (X1-4, X2-3, A-
4, R-4), (X1-4, X2-4, A-1, R-1), (X1-4, X2-4, A-
1, R-2), (X1-4, X2-4, A-1, R-3), (X1-4, X2-4, A-
1, R-4), (X1-4, X2-4, A-2, R-1), (X1-4, X2-4, A-
2, R-2), (X1-4, X2-4, A-2, R-3), (X1-4, X2-4, A-
2, R-4), (X1-4, X2-4, A-3, R-1), (X1-4, X2-4, A-
3, R-2), (X1-4, X2-4, A-3, R-3), (X1-4, X2-4, A-
3, R-4), (X1-4, X2-4, A-4, R-1), (X1-4, X2-4, A-
4, R-2), (X1-4, X2-4, A-4, R-3), (X1-4, X2-4, A-
4, R-4)

(X1-6, X2-5, A-5, X-6), (X1-6, X2-5,
A-5, X-7), (X1-6, X2-5, A-5, X-8), (X1-6, X2-5,
A-5, X-9), (X1-6, X2-5, A-6, X-6), (X1-6, X2-5,
A-6, X-7), (X1-6, X2-5, A-6, X-8), (X1-6, X2-5,
A-6, X-9), (X1-6, X2-5, A-7, X-6), (X1-6, X2-5,
A-7, X-7), (X1-6, X2-5, A-7, X-8), (X1-6, X2-5, A
-7, X-9), (X1-6, X2-6, A-5, X-6), (X1-6, X2-6, A
-5, X-7), (X1-6, X2-6, A-5, X-8), (X1-6, X2-6, A
-5, X-9), (X1-6, X2-6, A-6, X-6), (X1-6, X2-6, A-
6, X-7), (X1-6, X2-6, A-6, X-8), (X1-6, X2-6, A-
6, X-9), (X1-6, X2-6, A-7, X-6), (X1-6, X2-6, A-
7, X-7), (X1-6, X2-6, A-7, X-8), (X1-6, X2-6, A-
7, X-9), (X1-6, X2-7, A-5, X-6), (X1-6, X2-7, A-
5, X-7), (X1-6, X2-7, A-5, X-8), (X1-6, X2-7, A-
5, X-9), (X1-6, X2-7, A-6, X-6), (X1-6, X2-7, A-
6, X-7), (X1-6, X2-7, A-6, X-8), (X1-6, X2-7, A-
6, X-9), (X1-6, X2-7, A-7, X-6), (X1-6, X2-7, A-
7, X-7), (X1-6, X2-7, A-7, X-8), (X1-6, X2-7, A-
7, X-9), (X1-6, X2-8, A-5, X-6), (X1-6, X2-8, A-
5, X-7), (X1-6, X2-8, A-5, X-8), (X1-6, X2-8, A-
5, X-9), (X1-6, X2-8, A-6, X-6), (X1-6, X2-8, A-
6, X-7), (X1-6, X2-8, A-6, X-8), (X1-6, X2-8, A-
6, X-9), (X1-6, X2-8, A-7, X-6), (X1-6, X2-8, A-
7, X-7), (X1-6, X2-8, A-7, X-8), (X1-6, X2-8, A-
7, X-9), (X1-6, X2-9, A-5, X-6), (X1-6, X2-9, A-
5, X-7), (X1-6, X2-9, A-5, X-8), (X1-6, X2-9, A-
5, X-9), (X1-6, X2-9, A-6, X-6), (X1-6, X2-9, A-
6, X-7), (X1-6, X2-9, A-6, X-8), (X1-6, X2-9, A-
6, X-9), (X1-6, X2-9, A-7, X-6), (X1-6, X2-9, A-
7, X-7), (X1-6, X2-9, A-7, X-8), (X1-6, X2-9, A-
7, X-9),

(X1-7, X2-5, A-5, X-6), (X1-7, X2-5,
A-5, X-7), (X1-7, X2-5, A-5, X-8), (X1-7, X2-5,
A-5, X-9), (X1-7, X2-5, A-6, X-6), (X1-7, X2-5,
A-6, X-7), (X1-7, X2-5, A-6, X-8), (X1-7, X2-5, A
-6, X-9), (X1-7, X2-5, A-7, X-6), (X1-7, X2-5, A
-7, X-7), (X1-7, X2-5, A-7, X-8), (X1-7, X2-5, A-
7, X-9), (X1-7, X2-6, A-5, X-6), (X1-7, X2-6, A-
5, X-7), (X1-7, X2-6, A-5, X-8), (X1-7, X2-6, A-
5, X-9), (X1-7, X2-6, A-6, X-6), (X1-7, X2-6, A-
6, X-7), (X1-7, X2-6, A-6, X-8), (X1-7, X2-6, A-
6, X-9), (X1-7, X2-6, A-7, X-6), (X1-7, X2-6, A-
7, X-7), (X1-7, X2-6, A-7, X-8), (X1-7, X2-6, A-
7, X-9), (X1-7, X2-7, A-5, X-6), (X1-7, X2-7, A-
5, X-7), (X1-7, X2-7, A-5, X-8), (X1-7, X2-7, A-
5, X-9), (X1-7, X2-7, A-6, X-6), (X1-7, X2-7, A-
6, X-7), (X1-7, X2-7, A-6, X-8), (X1-7, X2-7, A-
6, X-9), (X1-7, X2-7, A-7, X-6), (X1-7, X2-7, A-
7, X-7), (X1-7, X2-7, A-7, X-8), (X1-7, X2-7, A-
7, X-9), (X1-7, X2-8, A-5, X-6), (X1-7, X2-8, A-
5, X-7), (X1-7, X2-8, A-5, X-8), (X1-7, X2-8, A-
5, X-9), (X1-7, X2-8, A-6, X-6), (X1-7, X2-8, A-
6, X-7), (X1-7, X2-8, A-6, X-8), (X1-7, X2-8, A-
6, X-9), (X1-7, X2-8, A-7, X-6), (X1-7, X2-8, A-
7, X-7), (X1-7, X2-8, A-7, X-8), (X1-7, X2-8, A-
7, X-9), (X1-7, X2-9, A-5, X-6), (X1-7, X2-9, A-
5, X-7), (X1-7, X2-9, A-5, X-8), (X1-7, X2-9, A-
5, X-9), (X1-7, X2-9, A-6, X-6), (X1-7, X2-9, A-
6, X-7), (X1-7, X2-9, A-6, X-8), (X1-7, X2-9, A-
6, X-9), (X1-7, X2-9, A-7, X-6), (X1-7, X2-9, A-
7, X-7), (X1-7, X2-9, A-7, X-8), (X1-7, X2-9, A-
7, X-9),

(X1-8, X2-5, A-5, X-6), (X1-8, X2-5,
A-5, X-7), (X1-8, X2-5, A-5, X-8), (X1-8, X2-5,
A-5, X-9), (X1-8, X2-5, A-6, X-6), (X1-8, X2-5,
A-6, X-7), (X1-8, X2-5, A-6, X-8), (X1-8, X2-5, A
-6, X-9), (X1-8, X2-5, A-7, X-6), (X1-8, X2-5, A
-7, X-7), (X1-8, X2-5, A-7, X-8), (X1-8, X2-5, A-
7, X-9), (X1-8, X2-6, A-5, X-6), (X1-8, X2-6, A-
5, X-7), (X1-8, X2-6, A-5, X-8), (X1-8, X2-6, A-
5, X-9), (X1-8, X2-6, A-6, X-6), (X1-8, X2-6, A-
6, X-7), (X1-8, X2-6, A-6, X-8), (X1-8, X2-6, A-
6, X-9), (X1-8, X2-6, A-7, X-6), (X1-8, X2-6, A-
7, X-7), (X1-8, X2-6, A-7, X-8), (X1-8, X2-6, A-
7, X-9), (X1-8, X2-7, A-5, X-6), (X1-8, X2-7, A-
5, X-7), (X1-8, X2-7, A-5, X-8), (X1-8, X2-7, A-
5, X-9), (X1-8, X2-7, A-6, X-6), (X1-8, X2-7, A-
6, X-7), (X1-8, X2-7, A-6, X-8), (X1-8, X2-7, A-
6, X-9), (X1-8, X2-7, A-7, X-6), (X1-8, X2-7, A-
7, X-7), (X1-8, X2-7, A-7, X-8), (X1-8, X2-7, A-
7, X-9), (X1-8, X2-8, A-5, X-6), (X1-8, X2-8, A-
5, X-7), (X1-8, X2-8, A-5, X-8), (X1-8, X2-8, A-
5, X-9), (X1-8, X2-8, A-6, X-6), (X1-8, X2-8, A-
6, X-7), (X1-8, X2-8, A-6, X-8), (X1-8, X2-8, A-
6, X-9), (X1-8, X2-8, A-7, X-6), (X1-8, X2-8, A-
7, X-7), (X1-8, X2-8, A-7, X-8), (X1-8, X2-8, A-
7, X-9), (X1-8, X2-9, A-5, X-6), (X1-8, X2-9, A-
5, X-7), (X1-8, X2-9, A-5, X-8), (X1-8, X2-9, A-
5, X-9), (X1-8, X2-9, A-6, X-6), (X1-8, X2-9, A-
6, X-7), (X1-8, X2-9, A-6, X-8), (X1-8, X2-9, A-
6, X-9), (X1-8, X2-9, A-7, X-6), (X1-8, X2-9, A-
7, X-7), (X1-8, X2-9, A-7, X-8), (X1-8, X2-9, A-
7, X-9),

(X1-9, X2-5, A-5, X-6), (X1-9, X2-5,
A-5, X-7), (X1-9, X2-5, A-5, X-8), (X1-9, X2-5,
A-5, X-9), (X1-9, X2-5, A-6, X-6), (X1-9, X2-5,
A-6, X-7), (X1-9, X2-5, A-6, X-8), (X1-9, X2-5, A
-6, X-9), (X1-9, X2-5, A-7, X-6), (X1-9, X2-5, A
-7, X-7), (X1-9, X2-5, A-7, X-8), (X1-9, X2-5, A-
7, X-9), (X1-9, X2-6, A-5, X-6), (X1-9, X2-6, A-
5, X-7), (X1-9, X2-6, A-5, X-8), (X1-9, X2-6, A-
5, X-9), (X1-9, X2-6, A-6, X-6), (X1-9, X2-6, A-
6, X-7), (X1-9, X2-6, A-6, X-8), (X1-9, X2-6, A-
6, X-9), (X1-9, X2-6, A-7, X-6), (X1-9, X2-6, A-
7, X-7), (X1-9, X2-6, A-7, X-8), (X1-9, X2-6, A-
7, X-9), (X1-9, X2-7, A-5, X-6), (X1-9, X2-7, A-
5, X-7), (X1-9, X2-7, A-5, X-8), (X1-9, X2-7, A-
5, X-9), (X1-9, X2-7, A-6, X-6), (X1-9, X2-7, A-
6, X-7), (X1-9, X2-7, A-6, X-8), (X1-9, X2-7, A-
6, X-9), (X1-9, X2-7, A-7, X-6), (X1-9, X2-7, A-
7, X-7), (X1-9, X2-7, A-7, X-8), (X1-9, X2-7, A-
7, X-9), (X1-9, X2-8, A-5, X-6), (X1-9, X2-8, A-
5, X-7), (X1-9, X2-8, A-5, X-8), (X1-9, X2-8, A-
5, X-9), (X1-9, X2-8, A-6, X-6), (X1-9, X2-8, A-
6, X-7), (X1-9, X2-8, A-6, X-8), (X1-9, X2-8, A-
6, X-9), (X1-9, X2-8, A-7, X-6), (X1-9, X2-8, A-
7, X-7), (X1-9, X2-8, A-7, X-8), (X1-9, X2-8, A-
7, X-9), (X1-9, X2-9, A-5, X-6), (X1-9, X2-9, A-
5, X-7), (X1-9, X2-9, A-5, X-8), (X1-9, X2-9, A-
5, X-9), (X1-9, X2-9, A-6, X-6), (X1-9, X2-9, A-
6, X-7), (X1-9, X2-9, A-6, X-8), (X1-9, X2-9, A-
6, X-9), (X1-9, X2-9, A-7, X-6), (X1-9, X2-9, A-
7, X-7), (X1-9, X2-9, A-7, X-8), (X1-9, X2-9, A-
7, X-9) or a pharmaceutically acceptable salt thereof, a solvent hydrate thereof or a prodrug thereof.

Many conventional drugs relatively increase HDL content by lowering LDL, but the apoAI expression enhancer of the present invention directly increases HDL content and reverses HDL cholesterol. It activates the transport, anti-inflammatory and anticoagulant effects. Therefore, H in serum
It is useful for the prevention and / or treatment of blood lipid abnormalities caused by a decrease in DL, 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. Disorders, hereditary HDL deficiency (Tangier's disease, fish-eye disease, etc.).

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. A drug is prepared by mixing an effective amount of the compound according to the present invention with various pharmaceutical additives such as an excipient, a binder, a wetting agent, a disintegrant, a lubricant, a diluent and the like which are suitable for the dosage form. It can be a formulation. 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 desirably 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.

[0048]

EXAMPLES Example 1 3- (4-biphenyl) -6-methoxypyridazine (I-27) 3-chloro-6-methoxypyridazine (2.02 g), 4-biphenylboric acid (3.32 g), Pd (PPh ₃ ) ₄ (485 mg) was added with aqueous sodium carbonate solution (2 M, 16.8 ml) and dimethoxyethane (28 ml),
Refluxed for hours. After cooling, water was added and extracted with chloroform. After the organic layer was dried over magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel (150 g), and recrystallized from ethyl acetate to give 2.98 g (81.3%) of the desired product.

Example 2 2- [4- (3-thienyl) phenyl] pyridine (I-36) A solution of 2-bromopyridine (2.0 g) in anhydrous THF (50 ml) was cooled to -78 ° C. in a nitrogen stream. Then, a tert-butyllithium pentane solution (1.64 M, 15.0 ml) was added dropwise. After stirring for 10 minutes,
A 1M zinc chloride ether solution was added dropwise over 10 minutes. Then 2
After returning to room temperature over time, Pd (PPh ₃ ) ₄ (71 mg) and 1-bromo-4
A solution of -iodobenzene (3.56 g) in anhydrous THF (20 ml) was added, and the mixture was stirred at room temperature for 3 days. A 10% aqueous ammonia solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (70 g, hexane-ethyl acetate = 4: 1) to obtain 2.37 g (79.9%) of 2- (4-bromophenyl) pyridine. To this 2- (4-bromophenyl) pyridine (702 mg), 3-thiophenboric acid (460 mg),
Pd (PPh ₃ ) ₄ (104mg), sodium carbonate (2M, 3.6ml), DME
(6 ml) was added and refluxed for 2 hours. After cooling, water was added, extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. The solvent was distilled off, the residue was purified by silica gel column chromatography (40 g, hexane-ethyl acetate = 4: 1), and further recrystallized from ethyl acetate to obtain 457 mg of the desired product (6 mg).
4.3%).

In the same manner, another compound (I) was synthesized. The structural formula and physical constants are shown below.

[Table 1]

[0051]

[Table 2]

[0052]

[Table 3]

[0053]

[Table 4]

[0054]

[Table 5]

[0055]

[Table 6]

Test Example 1 Promoting 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). 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). Table 7 shows the results.

[0057]

[Table 7]

From the results of Test Example 1, it can be seen that the compound of the present invention has an apoAI expression enhancing effect.

Formulation Example 1 Tablet Compound (I) 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. The granules were sized. Next, calcium stearate was added and compression molded to obtain tablets.

Formulation Example 2 Capsule 10 mg of compound (I), 10 mg of magnesium stearate, and 80 mg of lactose are 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 (I) 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.

[0062]

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 symbol FI theme coat ゛ (Reference) A61K 31/443 A61K 31/443 4C206 31/4436 31/4436 31/4439 31/4439 31/444 31/444 31/47 31/47 31/4965 31/4965 31/498 31/498 31/50 31/50 31/502 31/502 31/505 31/505 31/53 31/53 A61P 3/06 A61P 3/06 9/10 9/10 101 101 43/00 105 43/00 105 // C07D 213/16 C07D 213/16 213/30 213/30 213/38 213/38 213/40 213/40 213/64 213/64 215/04 215/04 237/08 237/08 237/30 237/30 239/26 239/26 241/12 241/12 241/42 241/42 251/16 251/16 B 257/04 257/04 A 277/22 277/22 277/24 277/24 295/22 295/22 A 319/20 319/20 401/10 401/10 405/10 405/10 409/04 409/04 409/10 409/10 ( 72) Inventor Kunio Hayashi 5-12-4 Sagisu, Fukushima-ku, Osaka-shi, Osaka Shionogi Pharmaceutical Co., Ltd. (Reference) 4C022 LA01 LA04 4C033 AD09 AD20 4C055 AA01 BA02 BA03 BA06 BA08 BA42 BB02 CA01 CA02 CA08 DA01 EA01 4C063 AA01 BB01 BB06 CC47 CC75 CC92 DD12 DD28 EE01 4C086 AA01 AA02 BA15 BC17 BC48 BC42 BC42 BC42 BC42 BC42 BC42 BC42 BC42 BC42 BC42 BC42 BC41 GA07 GA08 MA01 MA04 NA14 ZA40 ZA45 ZC33 ZC41 4C206 AA01 AA02 HA08 KA01 MA01 MA04 NA14 ZA40 ZA45 ZC33 ZC41

Claims (11)

[Claims] (1) Formula (I): (Wherein X ¹ and X ² are each independently an aryl optionally having a substituent, a heteroaryl optionally having a substituent, a cycloalkyl optionally having a substituent, Aryloxy optionally having a group, heteroaryloxy optionally having a substituent, arylthio optionally having a substituent, heteroarylthio optionally having a substituent, hydrogen, Halogen, hydroxy, lower alkyl optionally having substituent (s), lower alkenyl optionally having substituent (s), lower alkoxy optionally having substituent (s), lower optionally having substituent (s) Alkenyloxy, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted acyl, optionally substituted amino or optionally substituted Bamoyl, at least one of X ¹ and X ² is an aryl which may have a substituent or a heteroaryl which may have a substituent, and ring A is fused with another aromatic ring. A 6-membered aromatic hetero ring containing 1 to 3 N atoms which may be condensed with a benzene ring or another aromatic ring, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are Each independently represents hydrogen, halogen, hydroxy,
Lower alkyl which may have a substituent, lower alkenyl which may have a substituent, lower alkoxy which may have a substituent, lower alkenyloxy which may have a substituent, carboxy A lower alkoxycarbonyl which may have a substituent, an acyl which may have a substituent, an amino which may have a substituent or a carbamoyl which may have a substituent). ApoA comprising the compound shown, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof.
I expression enhancer. (2) ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, a quinoline ring, a quinoxaline ring or a phthalazine ring;
¹ is phenyl which may have a substituent or heteroaryl which may have a substituent, and X ² is hydrogen,
The apoAI expression enhancer according to claim 1, which is halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy or phenyl. 3. The apoAI expression enhancer according to claim 1, wherein X ¹ is bonded to the 4 ′ position. 4. The method according to claim 1, wherein X ¹ is phenyl which may have a substituent, furyl which may have a substituent or thienyl which may have a substituent. The apoAI expression enhancer according to any one of the above. 5. ApoA according to claim 1, wherein at least one of the 2-position and 6-position of the ring A is an N atom.
I expression enhancer. 6. The apo AI according to claim ¹ , wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are each independently hydrogen, hydroxy, lower alkyl or lower alkoxy.
Expression enhancer. 7. A ring A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring; X ¹ is hydrogen, halogen, hydroxy, lower alkyl, lower alkenyl, lower alkoxy or phenyl; The apoAI expression enhancer according to claim 1, wherein X ² is phenyl which may have a substituent or heteroaryl which may have a substituent. 8. The apoAI expression enhancer according to claim 1, wherein X ² is bonded to the 4-position of ring A. 9. The apoAI expression enhancer according to claim 1, wherein X ² is phenyl which may have a substituent. 10. The apoAI expression enhancer according to claim 7, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are all hydrogen. 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.