JP2003221376A - Cept activity inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a new compound which selectively inhibits CEPT (cholesterol ester-transferring protein) activity. <P>SOLUTION: This CETP inhibitor contains a compound represented by formula (I) or its salt [wherein each of X<SB>1</SB>-X<SB>4</SB>and Y<SB>1</SB>-Y<SB>5</SB>is hydrogen atom or an optional substituent; Z is represented by the formula (II): -Z<SB>1</SB>-Z<SB>2</SB>(wherein Z<SB>1</SB>is CO or the like; Z<SB>2</SB>is hydrogen atom, methoxy group, methyl group, amino group, or the like); A is (a) a di-substituted amino group; X<SB>2</SB>and X<SB>3</SB>, X<SB>3</SB>and X<SB>4</SB>or X<SB>4</SB>and A jointly form a homo- or hetero-cyclic group which may have a substituent]. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel CETP activity inhibitor, particularly a therapeutic or prophylactic agent for arteriosclerosis or hyperlipidemia.

[0002]

2. Description of the Related Art It has long been considered that a relationship between arteriosclerotic diseases and serum lipoprotein has a certain relationship from the results of many epidemiological studies. For example, Ba
dimon et al. (J. Clin. Invest., 85,
1234-1241 (1990)), when a fraction containing HDL (high-density lipoprotein) and VHDL (ultra-high density lipoprotein) was intravenously injected into cholesterol-loaded rabbits, it not only prevented the development of arteriosclerotic lesions but also caused regression. It has been reported that it was observed, and HDL and VHDL are considered to have anti-atherogenic effects in the relationship between arteriosclerotic diseases and serum lipoprotein.

In recent years, the presence of a protein that transfers lipid between blood lipoproteins, namely CETP (cholesterol ester transfer protein), has been revealed. CETP is 1965
Nichols & Smith (J. Lipid R
es. , 6,206, 1965), and its existence was first pointed out, and then in 1987, cDNA cloning was carried out by Drayna et al. Its molecular weight is 74,000 Da as a glycoprotein, and when the sugar chain is completely cleaved it is about 58,
It is 000 Da. In addition, its cDNA consists of 1656 residues and is composed of 17 signal peptides followed by 476.
Although it encodes individual amino acids, about 44% of them are hydrophobic amino acids, and therefore have extremely high hydrophobicity and are easily deactivated by oxidation. CETP is synthesized in organs such as liver, spleen, adrenal gland, adipose tissue, small intestine, kidney, skeletal muscle, and myocardium, and cell types include human monocyte-derived macrophages, B lymphocytes, adipocytes, small intestinal epithelial cells, CaC
o2 cells, hepatocytes (for example, human hepatoma cell-derived strain H
It has been confirmed to be synthesized in cells such as epG2 cells). In addition to the above tissues, it is also present in cerebrospinal fluid and semen, and its presence has been confirmed in human neuroblastoma and neuroglioma cell culture fluids, sheep choroid plexus, and the like.

It has been clarified that CETP is involved in metabolism of all lipoproteins in the living body and has a great role in the reverse cholesterol transfer system. That is, it has come into the spotlight as a mechanism for preventing the accumulation of cholesterol in peripheral cells and preventing arteriosclerosis. In fact, H plays an important role in this reverse cholesterol transfer system.
With respect to DL, numerous epidemiological studies have shown that the reduction of CE (cholesterol ester) of HDL in blood is one of the risk factors for coronary artery disease. Also, CE
TP activity varies depending on the animal species, and in animals with low activity,
Atherosclerosis due to cholesterol load is less likely to be induced,
Conversely, it is easily induced in highly active animals, CET
In the case of P deficiency, it has been clarified that hyper HDL and low LDL (low density lipoprotein) emia are caused, and it becomes difficult to become arteriosclerosis.
The importance of CETP mediating the transfer of CE in L to blood LDL has become recognized.

By the way, free cholesterol (FC) synthesized and secreted in the liver is very low density lipoprotein (VL).
DL). Next, VLDL is activated by the action of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in the blood, thereby causing an intermediate-density lipoprotein (ID
After going through L), it is metabolized to LDL. LDL is LD
It is taken up by peripheral cells via the L receptor and FC is supplied to the cells. Contrary to the flow from the liver to the peripheral cells, there is a flow of cholesterol from the peripheral cells to the liver called the cholesterol reverse transfer system. That is, FC accumulated in peripheral tissues is extracted by HDL, and further esterified on HDL by the action of LCAT (lecithin: cholesterol acyltransferase) to form CE, which is transferred to the hydrophobic core of HDL, and HDL is It matures into spherical HDL particles. CE in HDL is transferred to apo B-containing lipoprotein such as VLDL, IDL, and LDL by CETP existing in blood, and in exchange for this, TG is transferred to HDL at a molar ratio of 1: 1. CE transferred to the apo B-containing lipoprotein is taken up by the liver via the LDL receptor of the liver,
Cholesterol is indirectly transferred to the liver. In addition, HDL incorporates apoprotein E secreted from macrophages and the like and is rich in CE-rich apoprotein E-containing HDL.
There is also a mechanism in which this is directly taken up by the liver via the LDL receptor and the remnant receptor. Also, HD
There is also a pathway in which L particles are not taken up by the liver and only CE in HDL is selectively taken up by hepatocytes. Furthermore, there is also a pathway in which HDL particles are taken up by hepatocytes via the so-called HDL receptor in the liver.

That is, in the state where CETP activity is increased, CE transfer from HDL is increased, so that HDL is increased.
In CE decreased and C in VLDL, IDL and LDL
E will increase. Then, when the uptake of IDL and LDL into the liver increases, the LDL receptor is down-regulated, and the LDL in blood increases. On the other hand, in the CETP deficiency state,
HDL extracts cholesterol from the peripheral cells with the help of LCAT and gradually increases its size.
To win. Then, the HDL that has become rich in apoE is taken up by the liver via the LDL receptor in the liver and is catabolized. However, in humans, this mechanism does not work well, resulting in the retention of large HDL in the blood. As a result, the liver cholesterol pool shrinks and upregulates the LDL receptor, resulting in a decrease in LDL. Therefore, IDL and VLD that promote arteriosclerosis by selectively inhibiting CETP
It is expected that L and LDL can be reduced and HDL acting suppressively can be increased, and that a preventive or therapeutic drug for arteriosclerosis or hyperlipidemia that has never been provided can be provided.

[0007] Recently, there have been reports on compounds aimed at inhibiting such CETP activity. For example, Biochemical and B
iophysical Research Commun
ications 223, 42-47 (1996) discloses dithiodipyridine derivatives, substituted dithiodibenzene derivatives, and the like as compounds that inactivate CETP by modifying cysteine residues. However, in the document, neither the description of the compound of the present invention nor the description suggesting it is found.

Further, in WO95 / 06626,
As a CETP activity inhibitor, Wiedendiol-A
And Wiedendiol-B are disclosed. However, there is no description suggesting the compound of the present invention in the publication. Further, as compounds having an arteriosclerosis-preventing action, JP-B-45-11132, JP-B-45-2892, and JP-B-45-2891,
Japanese Patent Publication No. 45-2731 and Japanese Patent Publication No. 45-2730.
The publication discloses mercaptoanilides substituted with higher fatty acids such as o-isostearoylaminothiophenol. However, these publications only describe that they have an arteriosclerosis-preventing action, and there is no description of test examples that support them, nor that there is inhibition of CETP activity. Further, there is no description suggesting the compound of the present invention.

Japanese Patent Publication No. 2001-512416 (WO
98/04528) discloses biaryl compounds that inhibit CETP. However, there is no description suggesting the compound of the present invention in the publication. WO 00/17164, WO
In 00/17166 and WO 01/40190, 4-carboxyamino-2-substituted-1,2,
3,4-Tetrahydroquinoline is disclosed as a CETP inhibitor. However, there is no description suggesting the compound of the present invention in the publication. WO 00
/ 18721, WO 00/18723 and WO 00/18724 disclose 3- [N- (3-fluorophenyl) methyl-N- (4-trifluoromethylphenyl) as a CETP activity inhibitor. Tertiary-heteroalkylamine compounds such as methylamino] -1,1,1-trifluoro-2-propanol are disclosed. However, the compound of the publication is, for example,
It is characterized in that the terminal thereof is substituted with a halogen atom, such as 1,1-trifluoro-2-propanol, and not only the disclosure of the structure of the compound of the present invention but also the description to suggest it. I can't find it.

On the other hand, various compounds having a structure such as the compound of the present invention have been reported. For example, JP 20
01-106666 and WO 01/10825
The publication discloses a carbamate derivative having an oxime ether group in the phenyl group. However, the compound of the publication is a compound useful as a fungicide for agricultural and horticultural use, and neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found. In WO 00/69810, 3- (4
Compounds such as-{[N- [3- (2,6-dichlorophenyl) acryloyl] -N- (4-tert-butylbenzyl) amino] methyl} benzoylamino) propionic acid are disclosed. However, the compound of the publication is
A compound useful as a glucagon antagonist,
There is no disclosure of utility as a CETP activity inhibitor, nor is there any description suggesting it. WO 99/67
No. 204 discloses 1- [N- (4-chlorobenzyl).
Compounds such as -N- (N, N-dimethylcarbamoyl) aminomethyl] -4-guanidinomethylbenzene are disclosed. However, the compound of the same publication is a compound useful as an analgesic, and neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found.

WO 99/44987 and US
6,218,426 discloses N-useful gonadotropin-releasing hormone antagonists / agonists.
Compounds such as (4-tert-butylbenzyl) -N- [4- (guanidinomethyl) benzyl] benzamide are disclosed. However, in the publication, neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found. US Pat. No. 5,834,514 and Japanese Patent Publication No. 9-512556 (WO95 / 2).
9672), N-benzyl-N- (2,4-
It is disclosed that halomethylamide compounds such as dichlorobenzyl) chloroacetamide are useful as inhibitors of IL-1β protease activity. However, in the publication, neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found. WO9
No. 7,24,328 discloses N, N-bis (2,4-dimethoxybenzyl) -N ′-(4-methoxyphenyl).
2-Amino-heterocyclic compounds such as urea are disclosed. However, the compound of the same publication is a compound useful as a leukotriene synthesis inhibitor, and neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found.

In WO 96/10559, 1-
Urea derivatives such as benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- (2,4,6-trimethylphenyl) urea are disclosed. However, the compound of the same publication is a compound useful as an acyl-CoA: cholesterol / acyltransferase inhibitor, and is a CETP.
Neither the disclosure of the usefulness as an activity inhibitor nor the suggestion thereof is found. US 4,623,662
In the publication, urea compounds such as 1-benzyl-1- (2,4-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea are useful as acyl-CoA: cholesterol / acyltransferase inhibitors. It is disclosed to be a compound. However, in the publication, neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found. US Pat. No. 4,473,579 discloses urea compounds such as 1,1-dibenzyl-3- (2,4-dimethylphenyl) -3-phenylurea. However, the compound of the same publication is a compound useful as an acyl-CoA: cholesterol-acyltransferase inhibitor, and neither the utility as a CETP activity inhibitor is disclosed nor the description suggesting it is found.

US Pat. No. 4,122,255, US
No. 4,064,125, US Pat. No. 4,151,354 and US Pat. No. 4,127,606.
[[2- [3- (Dimethylamino) propoxy] phenyl] methyl] -3-phenyl-N- (phenylmethyl)
Compounds such as -2-propenamide are disclosed. However, the compound of the same publication is a compound useful as an anti-inflammatory agent, and neither the disclosure of the usefulness as a CETP activity inhibitor nor the description suggesting it is found. WO
99/18066 discloses 2-butyl-3- [4- [2- [N-benzyl- (4-pyridin-2-yl) amino] ethoxy] phenyl] propion having usefulness such as lipid lowering action. Amidocarboxylic acid compounds such as ethyl acid are disclosed. However, in the same publication, CE
There is no disclosure of utility as a TP activity inhibitor, of course, there is no description suggesting it, and further, there is no disclosure of structure such as the compound of the present invention or description suggesting it.

[0014]

The object of the present invention is to provide a novel compound which selectively inhibits the activity of CETP. The present invention also increases LDL by selectively inhibiting CETP activity, while at the same time increasing LDL.
It is also an object to provide a compound useful as a prophylactic or therapeutic agent for arteriosclerosis or hyperlipidemia, which can lower the blood pressure.

[0015]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that the following (1) to (1)
The compound shown in 1) has an activity of selectively inhibiting the activity of CETP (hereinafter referred to as CETP inhibitory activity), and is useful as a drug, particularly as a prophylactic or therapeutic drug for arteriosclerosis or hyperlipidemia. I found out. Further, among the compounds shown in the following (1) to (11), the present inventors
It was found that the compounds described in 5) to (22) are novel compounds. The present inventors have made further studies and completed the present invention.

That is, the present invention is (1) General formula (I);

[Chemical 10] [In the formula, X _{1 to} X ₄ and Y _{1 to} Y ₅ are the same or different and each represent a hydrogen atom or an arbitrary substituent. Z is the formula (I
I); -Z ₁ -Z ₂ (In the formula, Z ₁ is -CO-, -CS-.
Or represents —SO ₂ —, Z ₂ is a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted amino group, an optionally substituted alkoxy group or a substituted Represents an optionally substituted alkylthio group. ) Is represented. A represents a disubstituted amino group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or an optionally substituted hydrocarbon group having 1 to 20 carbon atoms. Further, X ₂ and X ₃ , X ₃ and X ₄ or X ₄ and A are taken together to form a homocyclic group which may have a substituent or a heterocyclic group which may have a substituent. May be formed. ] The CETP activity inhibitor characterized by containing the compound shown by these, or its salt,

(2) (a) X ₁ , X ₂ , X ₃ and X ₄
Are the same or different, (1) hydrogen atom, (2) halogen atom, (3) nitro group, (4) hydroxyl group, (5) mercapto group, (6) cyano group, (7) carboxyl group, ( 8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) C _1-6 alkylthio group, (11) C _1-6 alkylsulfinyl group, (12)
C _1-6 alkylsulfonyl group, (13) amino group, (14) mono- or di-C _1-4 alkylamino group, (15) C _1-6 alkanoyl group, (16) C _1-6 alkanoyloxy group , (17) a carbamoyl group optionally substituted by a C _1-6 alkyl group, (18)
C _1-6 alkyl group optionally substituted aminosulfonyl group, (19) optionally substituted C _1-2 also be ₀ hydrocarbon group or (20) an optionally substituted C _1-10 alkoxy group Or (b) X ₂ and X ₃ , X ₃ and X ₄ or X ₄ and A together have a homocyclic group or a substituent which may have a substituent. An optionally substituted heterocyclic group is formed, and X ₁ , X ₂ , X ₃ or X ₄
Of the above, groups that do not form a ring group are the same or different, (1) hydrogen atom, (2) halogen atom, (3) nitro group,
(4) hydroxyl group, (5) mercapto group, (6) cyano group, (7) carboxyl group, (8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) C _1-6 alkylthio group , (11)
C _1-6 alkylsulfinyl group, (12) C _1-6 alkylsulfonyl group, (13) amino group, (14) mono- or di-C _1-4 alkylamino group, (15) C _1-6 alkanoyl group , (16) C _1-6
Alkanoyloxy group, (17) carbamoyl group optionally substituted with C _1-6 alkyl group, (18) aminosulfonyl group optionally substituted with C _1-6 alkyl group, (19) substituted A C _1-20 hydrocarbon group or a (20) optionally substituted C _1-10 alkoxy group, wherein the CETP activity inhibitor according to the above (1),

(3) The homocyclic group is a homocyclic group consisting of 3 to 8 member carbon atoms, and the heterocyclic group is carbon atom and 1
A CETP activity inhibitor according to the above (1) or (2), which is a 5- to 8-membered heterocyclic group consisting of 4 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen; (4) Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, Y ₂ is a hydrogen atom, a halogen atom, a nitro group or an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, and Y ₄ Is a halogen atom, a nitro group, a cyano group, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, or 1 carbon atom To a carbamoyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, an aminosulfonyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, or an aromatic heterocyclic group, (1) CE described in TP activity inhibitor,

(5) A has 1 to 6 carbon atoms which may be substituted with (a) a cycloalkyl group having 3 to 8 carbon atoms.
Two substituents selected from the group consisting of an alkyl group having 7 to 16 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms and an alkanoyl group having 1 to 6 carbon atoms. An amino group substituted with, (b) a cyclic amino group, (c) an optionally substituted alkoxy group having 1 to 10 carbon atoms, (d) an optionally substituted alkyl group having 1 to 15 carbon atoms And (e) an optionally substituted alkenyl group having 2 to 10 carbon atoms or (f) an optionally substituted alkynyl group having 2 to 10 carbon atoms. C
An ETP activity inhibitor, (6) Z ₁ is -CO-,
Z ₂ is a hydrogen atom, an optionally substituted alkoxy group having 1 to 10 carbon atoms, an optionally substituted alkyl group having 1 to 15 carbon atoms, an optionally substituted alkenyl having 2 to 10 carbon atoms Group, optionally substituted carbon number 2
To 10 alkynyl groups, amino groups or mono- or di-C _1-4 alkylamino groups, the CETP activity inhibitor according to the above (1),

(7) Hydrocarbon group having 1 to 20 carbon atoms which may be substituted, alkoxy group having 1 to 10 carbon atoms which may be substituted, and C 1 which may be substituted.
To 15 alkyl groups, optionally substituted carbon atoms 2
To 10 alkenyl groups and optionally substituted alkynyl groups having 2 to 10 carbon atoms are (1) nitro group, (2) hydroxyl group, (3) mercapto group, (4) cyano group, ( 5) Carbamoyl group, (6) Carboxyl group, (7)
C _1-6 alkoxycarbonyl group, (8) a sulfo group, (9) a halogen atom, (10) C _1-6 alkoxy group, (11) C _1-6 alkylthio group, (12) C _{1 -6} alkylsulfinyl group , (13) C _1-6
From the group consisting of an alkylsulfonyl group, (14) amino group, (15) mono- or di-C _1-4 alkylamino group, (16) C _1-6 alkanoyl group and (17) C _1-6 alkanoyloxy group. (1), (2), (4), characterized by being selected
A CETP activity inhibitor according to (5) or (6),

(8) The substituents on the homocyclic ring which may have a substituent and the heterocyclic ring which may have a substituent (1) have 1 carbon atom which may be substituted with a halogen atom.
To 20 hydrocarbon groups, (2) nitro groups, (3) hydroxyl groups, (4) mercapto groups, (5) cyano groups, (6) carbamoyl groups, (7) carboxyl groups, (8) C _1-6 Alkoxycarbonyl group, (9) sulfo group, (10) halogen atom, (11) C _1-6 alkoxy group, (12) C _1-6 alkylthio group, (13) C _1-6 alkylsulfinyl group, (14) A C _1-6 alkylsulfonyl group,
(15) amino group, (16) mono- or di-C _1-4 alkylamino group, (17) C _1-6 alkanoyl group and (18) C _1-6 alkanoyloxy group. A CETP activity inhibitor according to the above (1) or (2),

(9) (a) X ₁ and X ₄ are hydrogen atoms, and X ₂ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or a halogen atom. An alkoxy group having 1 to 6 carbon atoms which may be substituted with, X ₃ is a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or ( b) X ₁ is a hydrogen atom, and X ₂ and X ₃ or X ₃ and X ₄ together may be substituted with an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom. Good carbon number 3
Or forms a 8 cyclic hydrocarbon or an aryl group having 6 to 14 carbon atoms, groups that do not form a ring group of X _2, X ₃ or X ₄ are the same or different, a hydrogen atom, a halogen Atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom, wherein Y ₁ , Y ₃ and Y ₅ are hydrogen. Is an atom and Y ₂ is
A hydrogen atom, a halogen atom, a nitro group or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, and Y ₄ may be substituted with a halogen atom, a nitro group, a cyano group or a halogen atom. Good alkyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, alkoxycarbonyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
A carbamoyl group optionally substituted with an alkyl group,
An aminosulfonyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms or an aromatic heterocyclic group,
Is a formula (a); -N (R <^101> ) < ₂ >, -N (R <^101> ).
(R ¹⁰² ), -N (R ¹⁰¹ ) (R ¹⁰³ ), -N
(R ¹⁰¹ ) (R ¹⁰⁴ ) or -N (R ^{10 1} )
(R ¹⁰⁵ ) (In the formula, R ¹⁰¹ has 1 to 6 carbon atoms which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms.
R ¹⁰² is an aralkyl group having 7 to 16 carbon atoms, R ¹⁰³ is an alkenyl group having 2 to 6 carbon atoms, R ¹⁰⁴ is an alkoxycarbonyl group having 1 to 6 carbon atoms, and R ¹⁰⁵ is 1 carbon atom. And alkanoyl groups of 6 to 6. ), A (b) 5- to 7-membered cyclic amino group, (c) an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom, or (d) a halogen atom. A good alkyl group having 1 to 15 carbon atoms, Z ₁ is —CO—, Z ₂ is a hydrogen atom,
1 to 10 carbon atoms which may be substituted with a halogen atom
The alkoxy group, an alkyl group having 1 to 15 carbon atoms which may be substituted with a halogen atom, an amino group or a mono- or di-C _1-4 alkylamino group. CETP activity inhibitor of

(10) X ₁ and X ₄ are hydrogen atoms, (a) X ₂ is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a trifluoromethyloxy group, and , X ₃ is a hydrogen atom, a chlorine atom or a methyl group, or (b) X ₂ and X
₃ together form cyclopentane, cyclohexane, cycloheptane, dimethylcyclopentane or benzene, Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, and Y ₂ is hydrogen atom, chlorine atom. , A nitro group or a trifluoromethyl group, Y ₄ is a hydrogen atom,
Chlorine atom, bromine atom, nitro group, cyano group, methyl group,
A trifluoromethyl group, a methylsulfonyl group or a methoxycarbonyl group, wherein A is the following formula

[Chemical 11] A substituent selected from Z ₁ is —CO—,
CETP according to (1) above, wherein Z ₂ is a hydrogen atom, a methoxy group, a methyl group or an amino group.
Activity inhibitors,

(11) (3-Cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N-ethylamino) indan-5-ylmethyl]-
Carbamic acid methyl ester, [6- (N-butyl-N
-Ethylamino) indan-5-ylmethyl]-(3-
Cyano-5-trifluoromethylbenzyl) -carbamic acid methyl ester, (3-nitro-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl)
-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, [6- (N-butyl-N-
Ethylamino) indan-5-ylmethyl]-(3,5
-Dichlorobenzyl) -carbamic acid methyl ester,
[6- (N-butyl-N-ethylamino) indan-5
-Ylmethyl]-(3-chloro-5-trifluoromethylbenzyl) -carbamic acid methyl ester,

(3-Bromo-5-trifluoromethylbenzyl)-[6- (N-butyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, [6- (N-butyl-N -Ethylamino) indan-5-ylmethyl]-(3-methyl-5-trifluoromethylbenzyl) -carbamic acid methyl ester, [6
-(N-Butyl-N-ethylamino) indan-5-ylmethyl]-(3-nitro-5-trifluoromethylbenzyl) -carbamic acid methyl ester, [6- (N-
Cyclopentylmethyl-N-ethylamino) tetralin-5-ylmethyl]-(3-methylsulfonyl-5-trifluoromethylbenzyl) -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester,

(3-Cyano-5-trifluoromethylbenzyl)-[6- (N-cyclobutylmethyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano-5- Trifluoromethylbenzyl)-[6- (N-cyclopropylmethyl-
N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopropylethyl-N-ethylamino) tetralin-5-ylmethyl ] -Carbamic acid methyl ester, (3-cyano-5
-Trifluoromethylbenzyl)-[6- (N-2-methylpropyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6 -(N-
Cyclopentylmethyl-N-ethylamino) -6,7,
8,9 tetrahydro 5H benzocyclohepten-2-ylmethyl] -carbamic acid methyl ester,

(3,5-bistrifluoromethylbenzyl)-[2,2-dimethyl-6- (N-butyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistri) Fluoromethylbenzyl)-[6- (N-propyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-butyl-N -Ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester,
(3,5-bistrifluoromethylbenzyl)-[6-
(N, N-Dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-butyl-N
-Propylamino) indan-5-ylmethyl] -carbamic acid methyl ester,

(3,5-bistrifluoromethylbenzyl)-[6- (N-3-methylbutyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl) )-[6- (N-3,3-Dimethylbutyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-cyclopentyl) Methyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-3-butylenyl-N-ethylamino) indan-5-ylmethyl ] -Carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-ben Dil-N-propylamino)
Indan-5-ylmethyl] -carbamic acid methyl ester,

(3,5-bistrifluoromethylbenzyl)-[6- (N-1-methylethyl-N-propylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethyl) Benzyl)-(6-piperidylindan-5-ylmethyl)-
Carbamic acid methyl ester, benzyl- [6- (N,
N-dipropylamino) indan-5-ylmethyl]-
Carbamic acid methyl ester, [6- (N, N-dipropylamino) indan-5-ylmethyl]-(3-trifluoromethylbenzyl) -carbamic acid methyl ester, [6- (N, N-dipropylamino) Indan-5
-Ylmethyl]-(3-methylbenzyl) -carbamic acid methyl ester,

(3-chlorobenzyl)-[6- (N, N
-Dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester, [6- (N, N-dipropylamino) indan-5-ylmethyl]-(3-nitrobenzyl) -carbamic acid methyl ester, (3 -Cyanobenzyl)-[6- (N, N-dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester, [6- (N, N-dipropylamino) indan-5
-Ylmethyl]-(3-methoxycarbonylbenzyl)
-Carbamic acid methyl ester, (3,5-dinitrobenzyl)-[6- (N, N-dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester,

(3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5-methylbenzyl)
-Carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5)
-Chlorobenzyl) -carbamic acid methyl ester,
(3,5-bistrifluoromethylbenzyl)-(2-
Dipropylamino-5-methoxybenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5-trifluoromethyloxybenzyl) -carbamic acid methyl ester, [2- (N-butyl-N-ethylamino) -5-
Trifluoromethyloxybenzyl]-(3-nitro-
5-trifluoromethylbenzyl) -carbamic acid methyl ester,

(3-Cyano-5-trifluoromethylbenzyl)-[2- (N-butyl-N-ethylamino)-
5-Trifluoromethyloxybenzyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-4,5-dimethylbenzyl) -carbamic acid methyl ester, (3,5
-Bistrifluoromethylbenzyl)-[6- (N-dipropylamino) indan-5-ylmethyl] -acetamide, (3,5-bistrifluoromethylbenzyl)
-[6- (N-dipropylamino) indan-5-ylmethyl] -urea, (3,5-bistrifluoromethylbenzyl)-[6- (N-dipropylamino) indan-
5-ylmethyl] -formamide,

(3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5-trifluoromethylbenzyl) -carbamic acid methyl ester, (3,5
-Bistrifluoromethylbenzyl)-(2-dipropylaminobenzyl) -carbamic acid methyl ester,
(3,5-bistrifluoromethylbenzyl)-(2-
Dipropylamino-4,5-dichlorobenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-4-chloro-5-trifluoromethyloxybenzyl) -carbamic acid Methyl ester, [3- (N-butyl-N-ethylamino) naphthalen-2-ylmethyl]-(3-cyano-5-trifluoromethylbenzyl) -carbamic acid methyl ester,

(3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-4-methyloxybenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N- Propionyl-N-propylamino) indan-5-ylmethyl] carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-ethoxycarbonyl-N-propylamino) indan-5-ylmethyl] carbamic acid Methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (1-propylbutoxy) indan-5-ylmethyl] carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (1 -Ethylpropyloxy) indan-
5-ylmethyl] carbamic acid methyl ester, (3,
5-bistrifluoromethylbenzyl)-[4,5-dimethyl-2- (1-propylbutyl) benzyl] carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6- (1-propyl Butyl) indan-5-ylmethyl] -carbamic acid methyl ester, a CETP activity inhibitor,

(12) The CETP activity inhibitor according to the above (1) to (11), which is a preventive or therapeutic drug for hyperlipidemia,
(13) The above (1) which is a preventive or therapeutic drug for arteriosclerosis
~ CETP activity inhibitor according to (11),

(14) Formula (I ');

[Chemical 12] [Wherein (a) X₁’And X_Four′ Is a hydrogen atom, X
_Two’Is replaced by a hydrogen atom, a halogen atom, or a halogen atom.
Optionally substituted alkyl group having 1 to 6 carbon atoms or ha
C 1-6 carbon atoms which may be substituted with a rogen atom
Rucoxy group, X_Three'Is also a hydrogen atom or a halogen atom
Preferably 1 carbon atom which may be substituted with a halogen atom
An alkyl group of 6 to 6 or (b) X₁’Is hydrogen
A child, X_Two’And X_Three’Or X_Three’And X_Four’
Taken together may be substituted with a halogen atom
Charcoal optionally substituted with an alkyl group having 1 to 6 carbon atoms
A cycloalkane ring or benzene ring with a prime number of 3 to 8
Forming, X_Two’, X_Three’Or X_FourRing of '
The groups not forming a group are the same or different, a hydrogen atom,
Halogen atom, charcoal optionally substituted with halogen atom
Substitute with an alkyl group having a prime number of 1 to 6 or a halogen atom
An optionally substituted alkoxy group having 1 to 6 carbon atoms
R, Y₁’, Y_Three’And Y₅'Is a hydrogen atom,
Y_TwoIs a halogen atom, a nitro group or a halogen atom.
An optionally substituted alkyl group having 1 to 6 carbon atoms
R, Y_Four'Is a halogen atom, nitro group, cyano group, halo
Alkyl having 1 to 6 carbon atoms which may be substituted with a gen atom.
Kill group, alkylsulfonyl group having 1 to 6 carbon atoms, carbon
Alkoxycarbonyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
A carbamoyl group optionally substituted with an alkyl group,
An optionally substituted alkyl group having 1 to 6 carbon atoms
A minosulfonyl group or an aromatic heterocyclic group, A ′
Is the formula (a); -N (R¹⁰¹)_Two, -N (R¹⁰¹)
(R¹⁰²), -N (R^{10 1}) (R¹⁰³), -N
(R¹⁰¹) (R¹⁰⁴) Or -N (R¹⁰¹)
(R¹⁰⁵) (Where R is¹⁰¹Is a C3-8 carbon
C1-C6 optionally substituted with a low alkyl group
An alkyl group, R¹⁰²Is aralkyl having 7 to 16 carbon atoms
R group, R¹⁰³Is an alkenyl group having 2 to 6 carbon atoms,
R¹⁰⁴Is an alkoxycarbonyl group having 1 to 6 carbon atoms,
R¹⁰⁵Represents an alkanoyl group having 1 to 6 carbon atoms
You ), And (b) a 5- to 7-membered cyclic amino
Group, formula (c); -C (R¹⁰⁶) (R¹⁰⁷) (Where
R¹⁰⁶And R¹⁰⁷May be the same or different
C 1 to C which may be substituted with a halogen atom
6 represents an alkyl group. ) Group or
(D) Formula; -OC (R¹⁰⁶) (R¹⁰⁷) (Where
R¹⁰⁶And R¹⁰⁷Is the same as defined above. ) Indicated by
Z'is a group of formula; -Z₁’-Z_Two’(In the formula,
Z₁'Is -CO- or -CS- and Z _Two’Is hydrogen
Child, a carbon atom which may be substituted with a halogen atom, from 1 to
10 alkoxy groups, even if substituted with halogen atoms
Good C1 to C15 alkyl, amino or mono
-Or Di-C_1-4It is an alkylamino group. )so
It is a group shown. ] The compound or its salt shown by these,

(15) The compound or salt thereof according to the above (14), wherein Z ₁ ′ is —CO—.
(16) The compound or salt thereof according to the above (14), wherein Z ₂ 'is a methoxy group, (17)
X ₁ 'is a hydrogen atom, and X ₂ ' and X ₃ 'or X
₃ ′ and X ₄ ′ together form a cycloalkane ring or benzene ring having 3 to 8 carbon atoms which may be substituted with a halogen atom and may be substituted with an alkyl group having 1 to 6 carbon atoms. The groups which do not form a ring group among X ₂ ', X ₃ ' or X ₄ 'are the same or different, and have a carbon atom of 1 to 1 which may be substituted with a hydrogen atom, a halogen atom or a halogen atom. (6) an alkyl group having 6 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or a salt thereof, (18) X ₁ 'and X ₄ 'Is a hydrogen atom, and X ₂ ' and X ₃ 'together form a cycloalkane ring having 3 to 8 carbon atoms, or the compound or salt thereof according to (17) above. ,

(19) X ₁ 'and X ₄ ' are hydrogen atoms, and X ₂ 'is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or a halogen atom. substituted alkoxy group having 1 to 6 carbon atoms, which may, and wherein the X 3 _'is a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom (20) The compound or salt thereof according to the above (16)
Y ₁ ′, Y ₃ ′ and Y ₅ ′ are hydrogen atoms, Y ₂ ′ is a halogen atom, a nitro group or a trifluoromethyl group, and Y ₄ ′ is a halogen atom, a methyl group, a nitro group, a cyano group or methyl. A sulfonyl group, a trifluoromethyl group or a methoxycarbonyl group,
7) to the compound according to any one of (19) or a salt thereof,
(21) Y ₂ 'is a trifluoromethyl group,
Y ₄ ′ is a nitro group, a cyano group or a trifluoromethyl group, or a compound or salt thereof according to the above (20),

(22) A'is the following formula

[Chemical 13] Wherein the substituent is selected from the above (1
4) to the compound or salt thereof according to any one of (21),
(23) A drug comprising the compound according to (14) to (22) or a pharmaceutically acceptable salt thereof,

(24) Formula (III);

[Chemical 14] (In the formula, Y _{1 to} Y _{5 each} represent a hydrogen atom or any substituent.) Or a salt thereof, and a compound represented by the general formula (I
V);

[Chemical 15] (In the formula, X _{1 to} X ₄ represent a hydrogen atom or an arbitrary substituent, and A is a disubstituted amino group, an optionally substituted alkoxy group, an optionally substituted alkylthio group or a substituted group. Optionally represents a hydrocarbon group having 1 to 20 carbon atoms, and X ₂ and X ₃ , X ₃ and X ₄ or X ₄ and A, taken together, may have a substituent. A ring group or a heterocyclic group which may have a substituent may be formed), or a compound represented by the formula (V);

[Chemical 16] (In the formula, Y _{1 to} Y ₅ are as defined above.) Or a salt thereof, and a general formula (VI);

[Chemical 17] (In the formula, X _{1 to} X ₄ and A have the same meanings as described above.) And the compound represented by the general formula (VI
I);

[Chemical 18] (In the formula, X₁~ X_Four, Y₁~ Y₅And A agree with the above
Righteousness. ), A compound represented by
To the amino group of the compound represented by formula (VII), the formula (II); -Z₁-Z_Two (In the formula, Z₁Is -CO-, -CS- or -SO_Two-Show
I, Z_TwoIs a hydrogen atom, optionally substituted carbon atom 1
To 20 hydrocarbon groups, optionally substituted amino
Group, optionally substituted alkoxy group or substituted
It represents an optionally substituted alkylthio group. ) Group Z represented by
The compound according to (1) above, wherein
The manufacturing method of.

[0041]

BEST MODE FOR CARRYING OUT THE INVENTION The definitions of terms used in the present specification are as follows. The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. The term "alkyl group" refers to a straight chain or branched chain alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, te group.
rt-butyl group, pentyl group, isopentyl group, ter
t-pentyl group, neopentyl group, hexyl group, isohexyl group, 3,3-dimethylbutyl group, heptyl group, 1
-Propylbutyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group and the like, and the number of carbon atoms is 1
To 15, more preferably 1 to 10, and still more preferably 1 to 6. The "alkenyl group" represents a linear or branched alkenyl group, and examples thereof include a vinyl group, an allyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a butadienyl group, 2 -Methylallyl group, hexatrienyl group, 3-octenyl group and the like are mentioned, and the carbon number is 2 to 10, more preferably 2 to 6.

The term "alkynyl group" means a straight chain or branched chain alkynyl group, and examples thereof include an ethynyl group, a 2-propynyl group, an isopropynyl group, a butynyl group, a t-butynyl group and a 3-hexynyl group. The carbon number is 2 to 1
It is 0, more preferably 2 to 6. The "aryl group" is, for example, a phenyl group, a 1- or 2-naphthyl group,
Biphenyl group, 1-, 2- or 9-anthryl group, 1
Examples thereof include a-, 2-, 3-, 4- or 9-phenanthryl group, an acenaphthyl group, an anthracenyl group and an azulenyl group. The “cyclic hydrocarbon group” is, for example, a C _3-10 cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group or a cyclononyl group (among others, a C _3-10 cycloalkyl group).
_{A 3-6} cycloalkyl group is preferred. ); For example, a C _3-10 cycloalkenyl group such as a cyclopropenyl group, a cyclopentenyl group, a cyclohexenyl group (among others, a C _3-6 cycloalkenyl group is preferable) and the like.

The "hydrocarbon group" means a group having 1 to 20 carbon atoms.
Hydrocarbon groups are preferred, eg (1) C as described above.
_1-15An alkyl group, (2) C as described above_2-10Alkenyl
Group, (3) C as described above_2-10Alkynyl groups, (4) above
C like_3-10A cycloalkyl group, (5) as described above
Na C_3-10A cycloalkenyl group, (6) C as described above
_6-14Aryl group, (7) C_7-20Aralkyl groups (for example,
Benzyl group, phenethyl group, benzhydryl group, triti
Group, etc., among which benzyl group and phenethyl group
Is preferred. ) And the like.

The term "alkoxy group" refers to a straight or branched chain alkoxy group such as methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, tert.
Examples include -butoxy group, 1-ethylpropoxy group, pentyloxy group, tert-pentyloxy group, 1-ethylbutoxy group, hexyloxy group and the like. 1 carbon
To 10 and more preferably 1 to 6. The "alkylthio group" represents a linear or branched alkylthio group,
For example, methylthio group, ethylthio group, propylthio group,
Examples thereof include an isopropylthio group, a butylthio group, a tert-butylthio group, a pentylthio group, a tert-pentylthio group and a hexylthio group. Carbon number is 1 to 1
It is 0, more preferably 1 to 6.

The above alkyl group, alkenyl group, alkynyl group
Group, hydrocarbon group, alkoxy group and alkylthio group
Substituents include (1) halogen, (2) nitro, (3) nitro
So, (4) cyano, (5) substituent {eg, (i) C_1-6Alkyl (the
C_1-6Alkyl is a hydroxyl group, C _1-6Alkoxy, C_1-3A
Lucoxy-C_1-3Alkoxy, C_1-3Alkylthio, hydr
Roxy-C_1-3Alkoxy, C_1-6Alkyl-carboni
Le, carboxy, carbamoyl, C_1-6Alkyl-cal
Vamoyl, nitrogen-containing 5- to 7-membered heterocyclic group or halogen substituted
You may have as a group. ), (Ii) C_1-4Acyl, (ii
i) C_7-20Aralkyl (the C_7-20The aralkyl group is a halogen
N, C_1-3Alkoxy or C_1-4Alkyl as a substituent
You may have), (iv) C_6-14Aryl (the C_6-14A
The reel may have halogen as a substituent.
I), (v) C_2-6Alkenyl, (vi) C_3-7Cycloalk
Le, (vii) C_1-3Alkoxy-carbonyl, (viii) mono-
Or di-C_{1- 6}Alkylamino, (ix) C_2-6Alkenylia
Mino, (x) C_1-3Alkoxy-carbonyl, (xi) C_1-6A
Lukyrcarbonyl, (xii) C_3-6Cycloalkyl oxyca
Rubonyl or (xiii) trifluoromethylsulfonyl}
Optionally possessed hydroxyl, (6) mercapto group
Kuha formula-S (O) f-R^{twenty one}{In the formula, f is an integer of 1 or 2
To R^{twenty one}Is a substituent (eg halogen, nitro, cyano,
Droxy, oxo, thioxo, carboxy, cyano-C
_6-14Aryl, halogeno C_6-14Have aryl etc.
Also includes a hydrocarbon group, and the hydrocarbon group may be C
_1-20Hydrocarbon radicals, especially C_1-6Alkyl, C_6-14Ally
Le, C_7-20Aralkyl is preferred. )}, (7) replaced
Optionally an amino group {eg, formula-NR^{twenty two}R^{twenty three}(In the formula, R
^{twenty two}And R^{twenty three}Are the same or different and are a hydrogen atom, C_1-6A
Rukiru, C_1-6Acyl or a 5- to 8-membered heterocyclic group is shown. )
Via the amino group represented by or the above nitrogen atom
Group}, the formula (8) -CO-R^{twenty four}{In the formula, R^{twenty four}Is (i) hydrogen source
Child, (ii) hydroxy, (iii) C_1-10Alkyl, (iv) C_1-6
Alkoxy (This alkoxy is halogen, nitro, etc.
C which may have a substituent_6-14Substituted with aryl
May be. ), (V) C_3-6Cycloalkyl, (vi) C
_6-14Aryl, (vii) C_6-14Aryl-oxy, (viii)
C_7-20Aralkyl, (ix) formula-NR^{twenty two}R^{twenty three}(In the formula, R^{twenty two}Over
And R^{twenty three}Has the same meaning as above. ) Is substituted
Is an amino group or (x) a 5- to 8-membered heterocyclic group. }so
The groups represented, among them, C_1-10Acyl is preferred,
(9) One selected from nitrogen atom, oxygen atom and sulfur atom
5 to 8 membered heterocycle containing 4 heteroatoms
A group (the heterocyclic group is (i) a halogen atom, (ii) C_1-4Archi
Le, (iii) C_{1 -3}Alkoxy, (iv) C_1-4Alkylthio,
(v) Substituted with phenoxy which may be substituted with halogen
It may have been done. }, (10) Sulfo, (11) C_6-14Ally
Le (the C _6-14The aryl group includes (a) hydroxyl and (b) amine.
No, (c) mono- or di-C_1-6Alkylamino (eg, methyl
Luamino, ethylamino, propylamino, dimethylamino
Mino, diethylamino, etc.), (d) C_1-6Alkoxy and
(e) Substitute with 1 to 4 substituents selected from halogen etc.
It may be replaced. ), (12) C_3-7Cycloalkyl,
(13) C_1-6Alkylenedioxy (eg methylene dioxy)
Ci, ethylenedioxy, propylenedioxy, 2,2-
Dimethylenedioxy, etc.), (14) oxo, (15) thioxo,
(16) C_2-4Alkynyl, (17) C_3-10Cycloalkyl group,
(18) C_2-10Alkenyl group (among others, C_2-6Alkenyl
Groups are preferred. ), (19) C_7-20Aralkyl, (20) Amidi
No., (21) azide and the like. The number of substituents is 1
~ 6, but preferably 1-5, more 1-3
Is preferred, and 1-2 is most preferred.

Alkyl groups having the above substituents,
Lucenyl group, alkynyl group, hydrocarbon group, alkoxy group
And the substituent on the alkylthio group further has a substituent
May be. Examples of the substituent which may further have:
For example, (1) hydroxyl, (2) amino, (3) mono- or
The-C_1-4Alkylamino (eg, methylamino, ethyl
Amino, propylamino, dimethylamino, diethyla
Mino etc.), (4) C_1-4Alkoxy, (5) halogen and (6) di
1 to 4 groups selected from Toro and the like, more preferably
Is 1 to 2 groups. The hydrocarbon group is
Alkyl group, cycloalkenyl group, aryl group or aryl group
When it is a aralkyl group, it has C as a substituent. _1-6Alkyl
1 to 3 may be included, and this C_1-6Alkyl is
Furthermore, 1 to 3 hydroxy, oxo, C_1-3Arco
Kish, C_1-3Alkylthio, halogen, carbamoyl, etc.
May be replaced with. The substituted C_1-6Al
As a formyl (methyl is replaced by oxo
), Carboxyl (methyl is oxo and hydroxy)
Replaced by Si), C_1-6Alkoxy Carboni
Ru (methyl substituted by oxo and alkoxy)
Of) (eg, methoxycarbonyl, ethoxycarbonyl,
C such as t-butoxycarbonyl_1-6Alkoxy Carboni
), Hydroxy C_1-6Alkyl (eg, hydroxymethyi)
Hydroxyethyl, hydroxybutyl, hydroxy
Propyl), C_1-3Alkoxy-C_1-6Alkyl (eg,
Methoxymethyl, ethoxymethyl, ethoxybutyl,
Ropoxymethyl, propoxyhexyl, etc.)
Be done. The number of substituents that the substituent may further have
1 to 3 are preferable, and 1 to 2 is particularly preferable.
Good

The "alkylsulfonyl group having 1 to 6 carbon atoms" refers to a straight chain or branched alkylsulfonyl group having 1 to 6 carbon atoms, for example, methylsulphonyl group, ethylsulfonyl group, propylsulfonyl group. , Isopropylsulfonyl group, butylsulfonyl group, tert-butylsulfonyl group, pentylsulfonyl group, tert-pentylsulfonyl group, hexylsulfonyl group and the like. “C _1-6 alkylsulfinyl” refers to a linear or branched alkylsulfinyl group having 1 to 6 carbon atoms, and examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, and a butylsulfinyl group. To be

The "alkoxycarbonyl group having 1 to 6 carbon atoms" is the one in which the C _1-6 alkoxy moiety is the same as the above-mentioned "C _1-6 alkoxy group" and includes, for example, methoxycarbonyl group, ethoxycarbonyl group and propoxy group. Examples thereof include a carbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group and a pentyloxycarbonyl group. The “C _1-6 alkylcarbonyl group” refers to the one in which the C _1-6 alkyl part is the above-mentioned “C _1-6 alkyl group”, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, Examples thereof include an isopropylcarbonyl group, a butylcarbonyl group, an isobutylcarbonyl group, a tert-butylcarbonyl group and a pentylcarbonyl group.

The substituent of the amino group is as described above.
A hydrocarbon group having 1 to 20 carbon atoms, C _1-6Alkanoyl group
Or C_1-6Examples thereof include an alkylsulfonyl group. Up
The number of the above substituents is 1 to 2. In particular, the number of substituents is 2
The case of is referred to as "disubstituted amino group". "Disubstituted amino
The "group" also includes a cyclic amino group. Here, "ring
The "mino group" represents a cyclic amino group, and
More preferably, it is a 4- to 8-membered amino group, for example, azetidi
Nyl, pyrrolidinyl, piperidino, hetero
Moles with oxygen atom, sulfur atom, nitrogen atom as atoms
Holino group, thiomorpholino group, piperazinyl group, etc.
A lower alkyl group at the 4-position nitrogen atom of the piperazinyl group
Alternatively, an aryl group or the like may be substituted.

The above-mentioned "C _1-6 alkanoyl group" means an alkanoyl group having 1 to 6 carbon atoms, for example, a formyl group, an acetyl group, a propionyl group, a butyryl group or a pivaloyl group having 1 to 6 carbon atoms. Alkanoyl groups. A formyl group, an acetyl group or a pivaloyl group is preferable. In the present specification, other than the formyl group is also referred to as “alkylcarbonyl group”. Further, the above-mentioned “C _1-6 alkylsulfonyl group” represents a straight chain or branched chain alkylsulfonyl group having 1 to 6 carbon atoms as described above.

Examples of the “homocyclic group” include C _6-10 aryl group (eg, phenyl, naphthyl, etc.), C _3-7 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) ),
An optionally condensed 3- to 7-membered carbocyclic group such as a C _3-7 cycloalkenyl group (eg, cyclopronyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.) and the like are used.

Examples of the substituent which the above homocyclic group may have include (1) C which may be substituted with halogen.
_1-15 alkyl (among them, C _1-6 alkyl _optionally substituted with halogen is preferable), (2) C _3-10 cycloalkyl, (3) C _2-10 alkenyl, (4) C _{2 -10} alkynyl,
(5) C _3-10 cycloalkyl, (6) C _6-10 aryl, (7) C
_7-20 aralkyl, (8) nitro, (9) hydroxyl, (10) mercapto, (11) oxo, (12) thioxo, (13) cyano, (1
4) carbamoyl, (15) carboxyl, (16) C ₁₆ alkoxy - carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), (17) sulfo, (18) halogen, (19) C
_1-6 alkoxy, (20) C _6-10 aryloxy (eg, phenoxy, etc.), (21) C _1-6 acyloxy (eg, acetoxy, propionyloxy), (22) C _1-6 alkylthio (eg, methylthio) , ethylthio, n- propylthio, isopropylthio, n- butylthio, t-butylthio, etc.), (23) C _{6- 10} arylthio (e.g., phenylthio, etc.), (24) C _1-6 alkylsulfinyl (e.g., methylsulfinyl, Ethylsulfinyl, etc.), (25) C _6-10 arylsulfinyl (eg, phenylsulfinyl, etc.), (2
6) C _1-6 alkylsulfonyl (eg, methylsulfonyl,
Ethylsulfonyl etc.), (27) C _6-10 arylsulfonyl (eg, phenylsulfonyl etc.), (28) amino, (29) C
_1-6 acylamino (eg, acetylamino, propionylamino, etc.), (30) mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino) , Dimethylamino, diethylamino, etc.), (31) C _3-8 cycloalkylamino (eg, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), (32) C _6-10 arylamino (eg, anilino) etc),
(33) C _1-6 alkanoyl (eg, formyl, acetyl, hexanoyl, etc.), (34) C _1-6 alkanoyloxy (eg,
Acetyloxy, propionyloxy, etc.), (35) C _6-10
Aryl-carbonyl (eg, benzoyl, etc.), 5- to 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, etc. in addition to the (36) carbon atom (eg, 2- or 3-) Thienyl, 2- or 3-furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3
-, 4- or 5-isothiazolyl, 2-, 4- or 5-
Oxazolyl, 3-, 4- or 5-isoxazolyl,
2-, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-
Pyrimidyl, 3- or 4-pyridanidyl, quinolyl, isoquinolyl, indolyl, etc.) and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

As the "heterocyclic group", a 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atom, and bicyclic condensed with it Alternatively, a tricyclic fused heterocyclic group and the like can be mentioned.
Specific examples of the heterocyclic group include, for example, (1) thienyl group, furyl group, pyrrolyl group, pyrrolinyl group, oxazolyl group, thiazolyl group, pyrazolyl group, imidazolyl group,
Imidazolinyl group, isoxazolyl group, isothiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-oxadiazolyl group, flazanyl group, 1,2,4-thiadiazolyl group, 1,2,3-thiadiazolyl group, 1, 2,5-thiadiazolyl group, 1,2,3-triazolyl group, 1,2,4-
5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom, etc. in addition to carbon atoms such as triazolyl group, triazinyl group, triazolidinyl group, 1H- or 2H-tetrazolyl group; ) Pyridyl group, pyrimidinyl group, thiomorpholinyl group, morpholinyl group, triazinyl group, pyrrolidinyl group, piperidinyl group, pyranyl group, thiopyranyl group, 1,4-oxazinyl group, 1,4-thiazinyl group, 1,3-thiazinyl group, piperazinyl group Group, triazinyl group, oxotriazinyl group, pyridazinyl group, pyrazinyl group, etc., and 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like. To be
Examples of the bicyclic or tricyclic fused heterocyclic group include a benzofuryl group, a benzothiazolyl group, a benzoxazolyl group, a tetrazolo [1,5-b] pyridazinyl group, a triazolo [4,
5-b] pyridazinyl group, benzimidazolyl group, quinolyl group, isoquinolyl group, cinnolinyl group, phthalazinyl group, quinazolinyl group, quinoxalinyl group, indolizinyl group, indolyl group, quinolidinyl group, 1,8-naphthyridinyl group, purinyl group, pteridinyl group, In addition to carbon atoms such as dibenzofuranyl group, carbazolyl group, acridinyl group, phenanthridinyl group, chromanyl group, benzoxazinyl group, phenazinyl group, phenothiazinyl group, phenoxazinyl group, oxygen atom, sulfur atom, nitrogen atom, etc. And a bicyclic or tricyclic fused heterocyclic group containing 1 to 4 heteroatoms selected from

The "aromatic heterocyclic group" means a substituent having an aromatic property among the above-mentioned heterocyclic groups, for example, a pyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, Pyrazolyl group, isoxazolyl group, isothiazolyl group, oxadiazolyl group, triazolyl group, indolyl group, benzofuryl group, benzothienyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, pyridyl group, pyridine-1-
Examples thereof include an oxide group, a pyrimidinyl group, a tetrazolyl group, a quinolyl group and an isoquinolyl group.

Examples of the group which may be substituted on the above heterocyclic group include (1) C _1-6 alkyl, (2) C _2-6 alkenyl,
(3) C _2-6 alkynyl, (4) C _3-6 cycloalkyl, (5) C
_5-7 cycloalkenyl, (6) C _7-11 aralkyl, (7) C
_6-14 aryl, (8) C _1-6 alkoxy, (9) C _6-14 aryloxy (eg, phenoxy, etc.), (10) C _1-6 alkanoyl (eg, formyl, acetyl, propionyl, n-butyryl) , Iso-butyryl etc.), (11) C _6-14 aryl-carbonyl (eg benzoyl etc.), (12) C _1-6 alkanoyloxy (eg formyloxy, acetyloxy, propionyloxy, n-butyryloxy, iso) -Butyryloxy, etc.), (13) C _6-14 aryl-carbonyloxy (eg, benzoyloxy etc.), (14) carboxyl, (15) C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, iso- propoxycarbonyl, n- butoxycarbonyl, isobutoxycarbonyl, tert- butoxycarbonyl, etc.), (16) carbamoyl group, (17) N-mono--C _1-4 alkylcarbamoyl (e.g. N- methylcarbamoyl, N- ethylcarbamoyl, N- propylcarbamoyl, N- isopropylcarbamoyl, N- butylcarbamoyl, etc.), (18) N, N- di -C
_1-4 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, etc.), (19) cyclic aminocarbonyl (eg, 1- Aziridinyl carbonyl, 1-azetidinyl carbonyl, 1-pyrrolidinyl carbonyl, 1-
Piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.), (20) halogen, (21)
Mono-, di- or tri-halogeno-C _1-4 alkyl (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), (22) oxo, (23) amidino, (24) imino, ( 25) amino, (26) mono- or di-C
_1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, etc.), (27)
In addition to carbon atom and one nitrogen atom, oxygen atom, sulfur atom,
3- to 6-membered cyclic amino group optionally containing 1 to 3 hetero atoms selected from nitrogen atom (eg, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, vilazolyl, imidazolidinyl, piperidino, morpholino, Dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.), (28) C _1-6 alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide) Etc.), (29) benzamide, (30) carbamoylamino, (3
1) N—C _1-4 alkylcarbamoylamino (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino,
N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), (32)
N, N-di-C _1-4 alkylcarbamoylamino (eg,
N, N-dimethylcarbamoylamino, N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N,
N-dibutylcarbamoylamino, etc.), (33) C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (34) -B (OH) ₂ , (35) hydroxyl, (36) epoxy (-O-), (37) nitro, (38) cyano, (39) mercapto, (40) sulfo, (41) sulfino, (42) phosphono, (4)
3) Dihydroxyboryl, (44) sulfamoyl, (45) C
_1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (46) DiC _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), (47) C _1-6 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.), (48) phenylthio, (49) C _1-6 alkylsulfinyl (eg , methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl etc.), (50) phenylsulfinyl, (51) C _1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, Ropirusuruhoniru, butylsulfonyl, etc.), (52)
Phenyl sulfonyl etc. are mentioned. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

The compound according to the present invention has the general formula (I):

[Chemical 19] Indicated by. In the above formula, the substituents represented by X _{1 to} X ₄ , Y _{1 to} Y ₅ , Z and A will be described in detail below.

In the above general formula (I), X _{1 to} X ₄ and Y ₁
The substituents represented by ~ Y ₅ may be the same or different and may be a hydrogen atom or any substituent. More specifically, X
₁ , X ₂ , X ₃ and X ₄ are the same or different and are (1) hydrogen atom, (2) halogen atom, (3) nitro group, (4) hydroxyl group, (5) mercapto group, (6) Cyano group, (7) carboxyl group, (8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) C _1-6 alkylthio group, (11) C _1-6 alkylsulfinyl group, (12) A C _1-6 alkylsulfonyl group,
(13) Amino group, (14) Mono- or di-C _1-4 alkylamino group, (15) C _1-6 alkanoyl group, (16) C _1-6 alkanoyloxy group, (17) C _1-6 A carbamoyl group optionally substituted with an alkyl group, (18) an aminosulfonyl group optionally substituted with a C _1-6 alkyl group, (19) an optionally substituted C _{1-2 0} hydrocarbon group or (20) It is preferably an optionally substituted C _1-10 alkoxy group.

The substituents in the above-mentioned "hydrocarbon group having 1 to 20 carbon atoms which may be substituted" and "alkoxy group having 1 to 10 carbon atoms which may be substituted" are (1) nitro group, ( 2) hydroxyl group, (3) mercapto group, (4) cyano group, (5) carbamoyl group, (6) carboxyl group, (7)
C _1-6 alkoxycarbonyl group, (8) sulfo group, (9) halogen atom, (10) C _1-6 alkoxy group, (11) C _1-6 alkylthio group, (12) C _1-6 alkylsulfinyl group , (13) C _1-6
Alkylsulfonyl group, (14) amino group, (15) mono- - or di -C _1-4 alkylamino group, from the group consisting of (16) C _1-6 alkanoyl group and (17) C ₁₆ alkanoyloxy It is preferably selected.

Among them, X ₁ and X ₄ are hydrogen atoms,
X ₂ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom, and X ₃ is It is more preferably a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom.

Further, X ₁ and X ₄ are hydrogen atoms, X ₂ is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a trifluoromethyloxy group, and X ₃ Is particularly preferably a hydrogen atom, a chlorine atom or a methyl group.

In another embodiment, X ₂ and X ₃ , X
₃ and X ₄ or X ₄ and A may be joined together to form an allocyclic group which may have a substituent or a heterocyclic group which may have a substituent. In such a case, further, the groups not forming a ring group among X ₁ , X ₂ , X _{3 and} X ₄ are the same or different, and (1) a hydrogen atom,
(2) halogen atom, (3) nitro group, (4) hydroxyl group, (5) mercapto group, (6) cyano group, (7) carboxyl group, (8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) C _1-6 alkylthio group, (11) C _1-6 alkylsulfinyl group, (12) C _{1 -6} alkylsulfonyl group, (13)
Amino group, (14) mono- - or di -C _1-4 alkylamino group, (15) C _1-6 alkanoyl group, (16) C _1-6 alkanoyloxy group, with (17) C ₁₆ alkyl group Optionally substituted carbamoyl group, (18) _optionally substituted aminosulfonyl group with a C _1-6 alkyl group, (19) optionally substituted C _1-20 hydrocarbon group or (20) substituted It is preferably an optionally _substituted C _1-10 alkoxy group.

In the above embodiment, the homocyclic group is a homocyclic group consisting of 3 to 8 member carbon atoms, and the heterocyclic group is
It is preferably a 5- to 8-membered heterocyclic group consisting of carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen.

In the above embodiment, the substituent in the "homocyclic ring optionally having substituent (s)" and the substituent in the "heterocycle optionally having substituent (s)" are substituted with a halogen atom (1). Optionally substituted hydrocarbon group having 1 to 20 carbon atoms, (2) nitro group, (3) hydroxyl group, (4) mercapto group, (5) cyano group, (6) carbamoyl group, (7) carboxyl group , (8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) halogen atom, (11) C _1-6 alkoxy group, (12)
C _1-6 alkylthio group, (13) C _1-6 alkylsulfinyl group, (14) C _1-6 alkylsulfonyl group, (15) amino group,
(16) mono - or di -C _{1 -4} alkyl amino group, (17) C _1-6
It is preferably selected from the group consisting of alkanoyl groups and (18) C _1-6 alkanoyloxy groups.

Among them, X ₁ is a hydrogen atom, and X ₂ and X ₃ or X ₃ and X ₄ together are substituted with an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom. An optionally substituted cyclic hydrocarbon having 3 to 8 carbon atoms or an aryl group having 6 to 14 carbon atoms, X
_{Among 2} , ₂ , X _{3 and} X _4, the groups not forming a ring group are the same or different and are a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or a halogen atom. More preferably, it is an alkoxy group having 1 to 6 carbon atoms which may be substituted with.

Further, X ₁ and X ₄ are hydrogen atoms, and X ₂ and X ₃ are taken together to form cyclopentane,
More preferably, it forms cyclohexane, cycloheptane, dimethylcyclopentane or benzene, especially cyclopentane.

In the above general formula (I), the substituent represented by A is, together with X ₄ , a homocyclic group or a substituent which may have a substituent, as described above. It may form a heterocyclic group which may have. In another embodiment, the substituent represented by A is a disubstituted amino group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or an optionally substituted C1-20 group. The case where it is a hydrocarbon group is mentioned.

In the above embodiment in which the substituent represented by A does not form a ring group together with X ₄ , the substituent represented by A is (a) a cycloalkyl having 3 to 8 carbon atoms. A C1 to C6 alkyl group which may be substituted with a group, a C7 to C16 aralkyl group, a C2 to C6 alkenyl group, a C1 to C6 alkoxycarbonyl group and a C1 to C6 An amino group substituted with two substituents selected from the group consisting of alkanoyl groups, (b) cyclic amino groups, and (c) optionally substituted carbon atoms of 1 to 1
0 alkoxy group, (d) optionally substituted alkyl group having 1 to 15 carbon atoms, (e) optionally substituted alkenyl group having 2 to 10 carbon atoms, or (f) optionally substituted. It is preferably an alkynyl group having 2 to 10 carbon atoms.

The above-mentioned "hydrocarbon group having 1 to 20 carbon atoms which may be substituted", "carbon atom which may be substituted 1
To 15 alkyl group "," optionally substituted alkenyl group having 2 to 10 carbon atoms "," optionally substituted alkynyl group having 2 to 10 carbon atoms "," optionally substituted alkoxy group " And a substituent in the "optionally substituted alkoxy group having 1 to 10 carbon atoms" is
(1) nitro group, (2) hydroxyl group, (3) mercapto group,
(4) cyano group, (5) carbamoyl group, (6) carboxyl group, (7) C _1-6 alkoxycarbonyl group, (8) sulfo group,
(9) Halogen atom, (10) C _1-6 alkoxy group, (11) C _{1-6
Alkylthio} group, (12) C _1-6 alkylsulfinyl group,
(13) C _1-6 alkylsulfonyl group, (14) amino group, (15)
It is preferably selected from the group consisting of mono- or di-C _1-4 alkylamino groups, (16) C _1-6 alkanoyl groups and (17) C _1-6 alkanoyloxy groups.

In the above aspect, among others, the substituent represented by A is represented by the formula (a); -N (R ^{10 1} ) ₂ , -N (R
¹⁰¹ ) (R ¹⁰² ), -N (R ¹⁰¹ ).
(R ¹⁰³ ), —N (R ¹⁰¹ ) (R ¹⁰⁴ ), or —N (R ¹⁰¹ ) (R ¹⁰⁵ ), (wherein, R ¹⁰¹ may be substituted with a cycloalkyl group having 3 to 8 carbon atoms). R ¹⁰² represents an alkyl group having 1 to 6 carbon atoms, and R ¹⁰² has 7 carbon atoms.
An aralkyl group having from 16 to 16 and R ¹⁰³ has from 2 to 6 carbon atoms.
R ¹⁰⁴ represents an alkoxycarbonyl group having 1 to 6 carbon atoms, and R ¹⁰⁵ represents an alkanoyl group having 1 to 6 carbon atoms. ), A (b) 5- to 7-membered cyclic amino group, (c) an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom, or (d)
1 to 15 carbon atoms which may be substituted with a halogen atom
More preferably, it is an alkyl group.

Particularly, the substituent represented by A is represented by the following formula:

[Chemical 20] Particularly preferred is a substituent selected from

Among the above-listed substituents, the substituent represented by A is represented by the following formula:

[Chemical 21] Group represented by, or the following formula

[Chemical formula 22] The group represented by is more preferable.

In the above general formula (I), the substituents represented by Y _{1 to} Y ₅ may be the same or different and may be hydrogen atoms or arbitrary substituents. Specifically, the substituents represented by Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, and the substituent represented by Y ₂ may be a hydrogen atom, a halogen atom, a nitro group or may be substituted. A hydrocarbon group having 1 to 20 carbon atoms, wherein the substituent represented by Y ₄ is a halogen atom, a nitro group, a cyano group, or an optionally substituted carbon atom having 1 to 20 carbon atoms.
Hydrocarbon group, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a carbamoyl group optionally substituted by an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms It is preferably an aminosulfonyl group which may be substituted with a group or an aromatic heterocyclic group.

"C1-C20 which may be substituted
Substituents in "hydrocarbon group" are (1) nitro group, (2) hydroxyl group, (3) mercapto group, (4) cyano group, (5) carbamoyl group, (6) carboxyl group, (7) C _1-6 alkoxycarbonyl group, (8) sulfo group, (9) halogen atom, (10)
C _1-6 alkoxy group, (11) C _1-6 alkylthio group, (12) C
_1-6 alkylsulfinyl group, (13) C _1-6 alkylsulfonyl group, (14) amino group, (15) mono- or di-C _1-4 alkylamino group, (16) C _1-6 alkanoyl group and (17) C _1-6
It is preferably selected from the group consisting of alkanoyloxy groups.

Among them, Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, and Y ₂ is a hydrogen atom, a halogen atom, a nitro group or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom. And Y ₄ is a halogen atom, a nitro group,
A cyano group, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms,
More preferably, it is a carbamoyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, an aminosulfonyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, or an aromatic heterocyclic group.

Further, Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, Y ₂ is a hydrogen atom, a chlorine atom, a nitro group or a trifluoromethyl group, and Y ₄ is a hydrogen atom, a chlorine atom or bromine. Particularly preferred is an atom, a nitro group, a cyano group, a methyl group, a trifluoromethyl group, a methylsulfonyl group or a methoxycarbonyl group, especially a trifluoromethyl group.

In the compound represented by the general formula (I), the substituent represented by Z is represented by the formula (II): -Z ₁ -Z
₂ (In the formula, Z ₁ represents —CO—, —CS— or —SO ₂ —, Z ₂ is a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, or an optionally substituted one. Represents a good amino group, an optionally substituted alkoxy group or an optionally substituted alkylthio group).

Specifically, Z ₁ is -CO-, and Z _1
2 is a hydrogen atom, optionally substituted carbon atoms 1 to 1
0 alkoxy group, optionally substituted alkyl group having 1 to 15 carbon atoms, optionally substituted alkenyl group having 2 to 10 carbon atoms, optionally substituted alkynyl group having 2 to 10 carbon atoms, It is preferably an amino group or a mono- or di-C _1-4 alkylamino group.

The above-mentioned "hydrocarbon group having 1 to 20 carbon atoms which may be substituted" and "carbon atom which may be substituted 1"
To 15 alkyl group "," optionally substituted alkenyl group having 2 to 10 carbon atoms "," optionally substituted alkynyl group having 2 to 10 carbon atoms "and" optionally substituted carbon number " Substituents in "1 to 10 alkoxy groups" include (1) nitro group, (2) hydroxyl group, (3) mercapto group, (4) cyano group, (5) carbamoyl group, (6) carboxyl group, (7) ) C _1-6 alkoxycarbonyl group, (8) sulfo group, (9) halogen atom, (10) C _1-6 alkoxy group, (1
1) C _1-6 alkylthio group, (12) C _1-6 alkylsulfinyl group, (13) C _1-6 alkylsulfonyl group, (14) amino group, (15) mono- or di-C _1-4 alkyl Amino group, (16)
It is preferably selected from the group consisting of C _1-6 alkanoyl group and (17) C _1-6 alkanoyloxy group.

Among them, Z ₁ is --CO--
₂ is (a) an alkoxy group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, which may be substituted with a halogen atom, and (b) an alkoxy group having 1 to 15 carbon atoms which may be substituted with a halogen atom. More preferably, it is an alkyl group, (c) amino group or (d) mono- or di-C _1-4 alkylamino group.

Further, it is particularly preferable that Z ₁ is —CO— and Z ₂ is a hydrogen atom, a methoxy group, a methyl group or an amino group, especially a methoxy group.

Specific examples of the compound represented by the above general formula (I) include the compounds described above.

Among the compounds represented by the above general formula (I), the compounds represented by the following general formula (I ') are novel compounds. That is, the general formula (I ′)

[Chemical formula 23] [Wherein (a) X₁’And X_Four′ Is a hydrogen atom, X
_Two’Is replaced by a hydrogen atom, a halogen atom, or a halogen atom.
Optionally substituted alkyl group having 1 to 6 carbon atoms or ha
C 1-6 carbon atoms which may be substituted with a rogen atom
Rucoxy group, X_Three'Is also a hydrogen atom or a halogen atom
Preferably 1 carbon atom which may be substituted with a halogen atom
An alkyl group of 6 to 6 or (b) X₁’Is hydrogen
A child, X_Two’And X_Three’Or X_Three’And X_Four’
Taken together may be substituted with a halogen atom
Charcoal optionally substituted with an alkyl group having 1 to 6 carbon atoms
A cycloalkane ring or benzene ring with a prime number of 3 to 8
Forming, X_Two’, X_Three’Or X_FourRing of '
The groups not forming a group are the same or different, a hydrogen atom,
Halogen atom, charcoal optionally substituted with halogen atom
Substitute with an alkyl group having a prime number of 1 to 6 or a halogen atom
An optionally substituted alkoxy group having 1 to 6 carbon atoms
R, Y₁’, Y_Three’And Y₅'Is a hydrogen atom,
Y_TwoIs a halogen atom, a nitro group or a halogen atom.
An optionally substituted alkyl group having 1 to 6 carbon atoms
R, Y_Four'Is a halogen atom, nitro group, cyano group, halo
Alkyl having 1 to 6 carbon atoms which may be substituted with a gen atom.
Kill group, alkylsulfonyl group having 1 to 6 carbon atoms, carbon
Alkoxycarbonyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
A carbamoyl group optionally substituted with an alkyl group,
An optionally substituted alkyl group having 1 to 6 carbon atoms
A minosulfonyl group or an aromatic heterocyclic group, A ′
Is the formula (a); -N (R¹⁰¹)_Two, -N (R¹⁰¹)
(R¹⁰²), -N (R^{10 1}) (R¹⁰³), -N
(R¹⁰¹) (R¹⁰⁴) Or -N (R¹⁰¹)
(R¹⁰⁵) (Where R is¹⁰¹Is a C3-8 carbon
C1-C6 optionally substituted with a low alkyl group
An alkyl group, R¹⁰²Is aralkyl having 7 to 16 carbon atoms
R group, R¹⁰³Is an alkenyl group having 2 to 6 carbon atoms,
R¹⁰⁴Is an alkoxycarbonyl group having 1 to 6 carbon atoms,
R¹⁰⁵Represents an alkanoyl group having 1 to 6 carbon atoms
You ), And (b) a 5- to 7-membered cyclic amino
Group, formula (c); -C (R¹⁰⁶) (R¹⁰⁷) (Where
R¹⁰⁶And R¹⁰⁷May be the same or different
C 1 to C which may be substituted with a halogen atom
6 represents an alkyl group. ) Group or
(D) Formula; -OC (R¹⁰⁶) (R¹⁰⁷) (Where
R¹⁰⁶And R¹⁰⁷Is the same as defined above. ) Indicated by
Z'is a group of formula; -Z₁’-Z_Two’(In the formula,
Z₁'Is -CO- or -CS- and Z _Two’Is hydrogen
Child, a carbon atom which may be substituted with a halogen atom, from 1 to
10 alkoxy groups, even if substituted with halogen atoms
Good C1 to C15 alkyl, amino or mono
-Or Di-C_1-4It is an alkylamino group. )so
It is a group shown. ] It is a compound shown by these.

In the compound represented by the above general formula (I '), X ₁ ' is a hydrogen atom, and X ₂ 'and X ₃ '
Alternatively, X ₃ ′ and X ₄ ′ together form a cycloalkane ring or benzene ring having 3 to 8 carbon atoms which may be substituted with an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom. forms a, _{X 2} ',
A group which does not form a ring group in X ₃ 'or X ₄ ' is the same or different and is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom or a halogen atom; It is preferably an optionally substituted alkoxy group having 1 to 6 carbon atoms. Among them, it is more preferable that X ₁ ′ and X ₄ ′ are hydrogen atoms and that X ₂ ′ and X ₃ ′ together form a cycloalkane ring having 3 to 8 carbon atoms.

[0084] As another embodiment of the _{X 1 '~X 4',} a _{X 1} 'and _{X 4'} is a hydrogen atom, _{X 2} 'is a hydrogen atom, a halogen atom, optionally substituted by halogen atom A good C1 to C6 alkyl group or a C1 to C6 alkoxy group which may be substituted with a halogen atom, and X ₃ 'is a hydrogen atom, a halogen atom or a carbon which may be substituted with a halogen atom. It is also preferable that it is an alkyl group of the numbers 1 to 6.

In the compound represented by the general formula (I ′), Y ₁ ′, Y ₃ ′ and Y ₅ ′ are hydrogen atoms, and Y ₂ ′ is a halogen atom, a nitro group or a trifluoromethyl group. Y ₄ ′ is preferably a halogen atom, a methyl group, a nitro group, a cyano group, a methylsulfonyl group, a trifluoromethyl group or a methoxycarbonyl group. Among them, Y ₂ 'is a trifluoromethyl group,
More preferably, Y ₄ ′ is a nitro group, a cyano group or a trifluoromethyl group.

In the compound represented by the above general formula (I '), A'is represented by the following formula:

[Chemical formula 24] It is preferably a substituent selected from

In the compound represented by the above general formula (I ′), Z ₁ ′ is preferably —CO—. Further, Z ₂ ′ is preferably a methoxy group.

The above-mentioned compound of the present invention may optionally form a salt. The salt of the compound according to the present invention is preferably a pharmaceutically acceptable salt.
Here, the "pharmaceutically acceptable salt" may be any salt as long as it forms a non-toxic salt with the compound represented by the general formula (I). Inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, hydrogencarbonate, perchlorate; formate, acetate, trifluoro Acetate, propionate,
Oxalate, glycolate, succinate, lactate, maleate, hydroxymaleate, methylmaleate, fumarate, adipate, tartrate, malate, citrate, benzoic acid. Salt, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate,
Organic acid salts such as nicotinate and isonicotinate; methanesulfonate, ethanesulfonate, isethionate,
Sulfonates such as benzenesulfonate, p-toluenesulfonate and naphthalenesulfonate; acidic amino acid salts such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; magnesium salt,
Alkaline earth metal salts such as calcium salts; ammonium salts; trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,
Organic base salts such as N′-dibenzylethylenediamine salt;
Examples thereof include amino acid salts such as lysine salt and arginine salt. In addition, in some cases, it may be a hydrate or a solvate with an alcohol or the like. The same applies to the compound represented by the above general formula (I ′). When the compound of the present invention is obtained as a free form, the salt of the compound of the present invention can be converted into a salt by a method known per se or a method analogous thereto, and conversely, when obtained as a salt. Can be converted into a free form or other salt by a method known per se or a method analogous thereto.

When the compound according to the present invention has n (n is a natural number) asymmetric carbon, it has 2 ⁿ optical isomers. The compound according to the present invention or a salt thereof may be an optical isomer or a racemate. When the compound of the present invention or a salt thereof is an optically active substance, it can be separated by a usual optical resolution means. Furthermore, the compounds according to the present invention also include prodrug compounds of the compounds described above. The “prodrug compound” is a compound of the present invention which has a group capable of being chemically or metabolically decomposed, and which has pharmaceutically activity by hydrolysis or solvolysis or by decomposition under physiological conditions. Is a derivative of.

The compound of the present invention or a salt thereof has excellent CET.
It has a P activity inhibitory action and can be used as a CETP activity inhibitor. In addition, the compound of the present invention or a salt thereof,
Utilizing its excellent CETP activity inhibitory action, it is useful as a drug, particularly as a preventive or therapeutic drug for hyperlipidemia or arteriosclerotic disease. However, among the compounds of the present invention or salts thereof, the use of the novel compounds represented by the general formula (I ′) or salts thereof is not limited to the above applications. However, the novel compound represented by the general formula (I ′) or a salt thereof is also
It is preferably used as a medicine, particularly as a prophylactic or therapeutic agent for hyperlipidemia or arteriosclerotic disease.

When the compound of the present invention represented by the general formula (I) or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is usually a pharmacologically acceptable carrier known per se,
Excipients, diluents, fillers, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, corrigents, solubilizers, other additives, etc. Water, vegetable oils, alcohols such as ethanol or benzyl alcohol, carbohydrates such as polyethylene glycol, glycerol triazetate gelatin, lactose, starch, magnesium stearate, talc, lanolin,
Mixed with petrolatum etc., tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches,
It can be administered orally or parenterally in the form of an aerosol, elixir, suspension, emulsion, syrup and the like. The same applies when the novel compound represented by the general formula (I ′) or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation.

The dose of the drug according to the present invention may vary depending on the kind and degree of the disease, the compound to be administered and the administration route, the age, sex, body weight of the patient, etc. The compound of the present invention represented by the formula (I) or a pharmaceutically acceptable salt thereof is added in an amount of about 1 to 1000.
It is preferable to administer about mg, particularly about 50 mg to 800 mg. The dose of the novel compound represented by the general formula (I ′) or a pharmaceutically acceptable salt thereof is also about 1 to 1000 mg, particularly about 50 mg to 800 mg.
About mg is preferable. The medicament according to the present invention may be administered alone, may be used in combination with other prophylactic or therapeutic agents for hyperlipidemia, and / or prophylactic or therapeutic agents for arteriosclerotic diseases, or other You may use together with a medicine. Further, the medicament according to the present invention can be administered not only to humans but also to other mammals (for example, monkeys, cows, horses, dogs, cats, rabbits, rats, mice, etc.).

The compound of the present invention can be produced, for example, by the following (Method 1), but it goes without saying that the production method of the compound of the present invention is not limited thereto.

[Chemical 25] (In the formula, X _{1 to} X ₄ , Y _{1 to} Y ₅ , A and Z have the same meanings as described above.)

Benzaldehyde represented by the general formula (III) and benzylamine represented by the general formula (IV), or benzylamine represented by the general formula (V) and the general formula (VI)
Benzaldehyde represented by, is mixed in an organic solvent, water, or no solvent, and using a reducing agent such as sodium triacetoxyborohydride, sodium cyanotrihydroborohydride, or sodium borohydride under cooling or heating. By reacting, the compound represented by the general formula (VII) can be synthesized. This general formula (VII) and acid halide, isocyanate, carbonic acid halide, sulfonic acid halide, thiocarbonic acid halide, etc. in the presence or absence of a base,
The general formula (I) can be synthesized by reacting in an organic solvent, water or a solvent-free under cooling or heating.
Further, by reacting the general formula (VII) with a formate ester such as methyl formate in formic acid at room temperature or under heating,
A compound represented by the general formula (I) in which the Z group is a formyl group can be synthesized. More specifically, the methods described in Examples 1 to 51 and 54 to 57 below can be mentioned.

In the above method, the compound represented by the general formula (III) and the compound represented by the general formula (V) can be synthesized from generally commercially available compounds or, if necessary, from commercially available raw materials. More specifically, the following Example 1
The method described in (a) of is mentioned.

In the above method, the compound represented by the general formula (IV) and the compound represented by the general formula (VI) can also be synthesized from commercially available compounds or, if necessary, from commercially available raw materials. The compound represented by the general formula (IV-1) among the compounds represented by the general formula (IV) and the compound represented by the general formula (VI-1) among the compounds represented by the general formula (VI) are For example, it can be synthesized by the following (Method 2).

[Chemical formula 26] (In the formula, X _{1 to} X ₄ have the same meanings as described above. R ₁ and R 2
Represents a substituent of an amino group. Preferably, (a) R1
Is an alkyl group having 1 to 6 carbon atoms which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms, and 7 to 1 carbon atoms.
An aralkyl group having 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, R2 may be the same as or different from R1, and a carbon which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms. Alkyl group having 1 to 6 carbon atoms, 7 to 1 carbon atoms
An aralkyl group having 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms or an alkylcarbonyl group having 1 to 6 carbon atoms, or (b)
R1 and R2 together form a cyclic amino group. )

That is, by reacting the aniline represented by the general formula (VIII) with an acid halide or the like in the presence or absence of a base under cooling or heating in an organic solvent, water, or a solvent-free system, The compound represented by IX) can be synthesized. The compound represented by the general formula (IX) is reacted with a reducing agent such as lithium aluminum hydride, Red-Al or sodium borohydride in an organic solvent under cooling or heating to obtain the compound represented by the general formula (X). The compound can be synthesized. By reacting the compound represented by the general formula (X) with an alkyl halide or the like in the presence or absence of a base under cooling to heating in an organic solvent, water, or a solvent-free form,
The compound represented by the general formula (XI) can be synthesized. Vilsmeier prepared from a compound represented by the general formula (XI) from phosphorus oxychloride and N, N-dimethylformamide
The compound represented by the general formula (VI-1) can be synthesized by reacting with a reagent in an organic solvent or without solvent under cooling or heating.

By reacting the synthesized compound represented by the general formula (IV-1) with hydroxylamine hydrochloride in the presence of a base at room temperature to under heating in an organic solvent, water or a solvent-free system, The compound represented by XII) can be synthesized. The compound represented by the general formula (XII) is hydrogenated in an organic solvent or water at room temperature or under heating in the presence of a catalyst such as palladium carbon, or lithium aluminum hydride, Red-Al, hydrogenated The compound represented by the general formula (IV-1) can be synthesized by reacting a reducing agent such as sodium borohydride in an organic solvent with cooling or heating. More specifically, the methods described in Examples 1 to 45 below can be mentioned.

Among the compounds represented by the general formula (VI), the compound represented by the general formula (VI-1) can also be synthesized by, for example, the following (method 3).

[Chemical 27] (In the formula, X _{1 to} X ₄ , R ₁ and R 2 are as defined above.
holo represents halogen. )

That is, the compound formula represented by the general formula (XIV) can be synthesized from the halogenoaniline represented by the general formula (XIII) by the same method as the above (method 2). Further, the halogenoaniline represented by the general formula (XIII) and an alkyl halide in the presence or absence of a base,
The compound represented by the general formula (XIV) can also be synthesized by reacting in an organic solvent, water or a solvent-free under cooling to heating. The thio compound formed by reacting the compound represented by the general formula (XIV) with butyllithium in an organic solvent under cooling to room temperature is treated with N, N-dimethylformamide or the like to give the general formula (VI- The compound shown in 1) can be synthesized. More specifically, the methods described in Examples 46 to 49 below can be mentioned.

The compound represented by the general formula (IV-1) among the compounds represented by the general formula (IV) can also be synthesized by, for example, the following (method 4).

[Chemical 28] (In the formula, X _{1 to} X ₄ , R ₁ and R 2 are as defined above.)

That is, a compound represented by the general formula (XV) and a compound of the formula; R1-CHO (wherein R1 has the same meaning as described above).
The aldehyde represented by is mixed in an organic solvent, water, or no solvent, and reacted with a reducing agent such as sodium triacetoxyborohydride, sodium cyanotrihydroborohydride, sodium borohydride under cooling or heating. By doing so, the compound represented by the general formula (XVI) can be synthesized. A compound represented by the general formula (XVI),
Formula; R3-CHO (In the formula, R3 has 1 to 6 carbon atoms which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms.)
And an aralkyl group having 7 to 16 carbon atoms or an alkenyl group having 1 to 6 carbon atoms. By reacting the aldehyde represented by
A compound represented by the general formula (XVII), which is CH ₂ R3, can be synthesized. By reacting the compound represented by the general formula (XVII) with a reducing agent such as lithium aluminum hydride, Red-Al and sodium borohydride in an organic solvent under cooling or heating, the general formula (IV- The compound shown in 1) can be synthesized. More specifically, the methods described in Examples 50 to 51 below can be mentioned.

Among the compounds represented by the general formula (VI), the compound represented by the general formula (VI-2) can also be synthesized by, for example, the following (method 5).

[Chemical 29] (In the formula, X _{1 to} X ₄ have the same meanings as described above. V represents an oxygen atom or a sulfur atom. R 4 represents an optionally substituted carbon atom of 1 to 10, preferably 1 to 6 carbon atoms. Indicates an alkyl group.)

That is, a phenol or thiophenol represented by the general formula (XX) and a formula; R4OH (in the formula, R4OH
4 has the same meaning as above. ) In the presence of triphenylphosphine, using a condensing agent such as diethyl azodicarboxylate, under cooling or heating an organic solvent, water,
Alternatively, the compound represented by the general formula (XXI) can be synthesized by reacting in the absence of a solvent. General formula (XX
A compound represented by the general formula (VI) The compound represented by -2) can be synthesized. More specifically, the following Examples 54 to 5
The method described in 5 can be mentioned.

Among the compounds represented by the general formula (VI), the compound represented by the general formula (VI-3) can also be synthesized by, for example, the following (method 6).

[Chemical 30] (In the formula, X _{1 to} X ₄ and halo have the same meanings as described above. R 5 or R 6 are the same or different and may be an alkyl group which may be substituted, preferably C 3-8. Represents a good alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group.)

That is, by treating a lithio compound generated by reacting a halobenzene represented by the general formula (XXII) with butyllithium in an organic solvent under cooling to room temperature with a ketone, an aldehyde or the like, The compound represented by XXIII) can be synthesized. General formula (XXII
The compound represented by the general formula (XXIV) can be synthesized by hydrogenating the compound represented by I) in the presence of a catalyst such as palladium hydroxide at room temperature or under heating in an organic solvent or water. Using a brominating agent such as bromosuccinimide for the compound represented by the general formula (XXIV),
The compound represented by the general formula (XXV) can be synthesized by reacting in an organic solvent or without a solvent under cooling or heating. By treating a lithio compound generated by reacting a compound represented by the general formula (XXV) with butyllithium in an organic solvent under cooling to room temperature by treating with N, N-dimethylformamide or the like, the general formula (VI- The compound represented by 3) can be synthesized. More specifically, the methods described in Examples 56 to 57 below can be mentioned.

In addition, among the compounds represented by the general formula (I),
The compound represented by the formula (I-1) can also be synthesized by the method described in (Method 7) below.

[Chemical 31] (In the formula, X _{1 to} X ₄ , R ₁ , R 2, Y _{1 to} Y ₅ and Z
Has the same meaning as above. )

That is, the compound represented by the general formula (XVIII) is synthesized by hydrogenating the formula (Ia) in the presence of a catalyst such as palladium carbon at room temperature to under heating in an organic solvent or water. can do. A compound represented by the general formula (XVIII) and a compound represented by the formula; R1-CHO (wherein R1 has the same meaning as described above), an organic solvent, water,
Alternatively, by mixing in a solvent-free and reacting with a reducing agent such as sodium triacetoxyborohydride, sodium cyanotrihydroborohydride, sodium borohydride under cooling or heating, the general formula (XIX) is obtained. The compounds shown can be synthesized. The compound represented by the general formula (XIX) and an acid halide, an isocyanate, a carbonic acid halide, a sulfonic acid halide, a thiocarbonic acid halide in the presence or absence of a base, an organic solvent under cooling or heating,
Formula (I-1) can be synthesized by reacting in water or without solvent. More specifically, Example 52 below
~ 53.

[0109]

EXAMPLES [Example 1] (3-Cyano-5-trifluoromethylbenzyl)-
[6- (N-Cyclopentylmethyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester ((3-Cyano-5-trifluoromethylbenzyl)-[6- (N
-cyclopentylmethyl-N-ethylamino) indan-5-ylmethyl]-
Synthesis of carbamic acid methyl ester (a) Synthesis of 3-formyl-5-trifluoromethylbenzonitrile (a-1) 3-Nitro-5-trifluoromethylbenzenemethanol (3) -Nitro-5-trifluoromethylbenzenemethano
l) Synthesis of 3-formyl-5-trifluoromethylbenzoic acid (3-Ni
tro-5-trifluoromethylbenzoic acid) (50 g) in tetrahydrofuran solution (300 ml) under ice-cooling with stirring, borane-tetrahydrofuran complex, tetrahydrofuran solution (1.04M, 300m
l) was added dropwise. After completion of the dropping, warm the reaction solution to 75 ° C. 1.
Stirring was continued for 5 hours. The reaction solution was returned to room temperature and tetrahydrofuran was distilled off under reduced pressure to about 1/4, diluted with ethyl acetate, and washed successively with 1N hydrochloric acid water, water, and saturated brine. The organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, and concentrated to dryness to obtain the desired product (45.23 g, 96%).
¹ HNMR (CDCl ₃ , 300MHz) δ: 2.13 (brs, 1H), 4.92 (s, 2H), 7.99
(s, 1H), 8.41 (s, 1H), 8.45 (s, 1H)

(A-2) 3-amino-5-trifluoromethylbenzenemethanol (3-Amino-5-trifluoromethylben)
3-Nitro-5-trifluoromethylbenzenemethanol (45.
23 g) in methanol (500 ml) in 5% palladium-carbon (4.5
g) was added and hydrogenated over 3.5 hours with stirring at room temperature.
After the catalyst was filtered off, the product was concentrated and dried to obtain the desired product (38.22g, 98%). ¹ H NMR (CDCl ₃ , 300 MHz) δ: 1.83 (brs, 1H), 3.88 (brs, 2H), 4.
66 (s, 2H), 6.81 (s, 1H), 6.84 (s, 1H), 6.98 (s, 1H)

(A-3) 3-Bromo-5-trifluoromethylbenzene (3-Bromo-5-trifluoromethylben)
A solution of synthetic copper (II) bromide (53.6 g) in acetonitrile (500 ml) was added dropwise to tert-butyl nitrite (35.7 ml) with stirring under ice cooling. After stirring for 5 minutes, 3-amino-5-trifluoromethylbenzenemethanol
A solution of (38.22 g) in acetonitrile (200 ml) was added dropwise over 40 minutes, the ice bath was removed, and stirring was continued at room temperature for 3.5 hours. 1N Hydrochloric acid was added to the reaction solution, the mixture was extracted with ethyl acetate, and washed successively with 1N hydrochloric acid water, water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the desired product (40.09g, 79%). )
Got ¹ H NMR (CDCl ₃ , 300 MHz) δ: 2.08 (brs, 1 H), 4.75 (s,
2H), 7.56 (s, 1H), 7.68 (s, 1H), 7.70 (s, 1H) mp: 47.5-49 ℃

(A-4) 3-Hydroxymethyl-5-trifluoromethylbenzonitrile (3-Hydroxymethyl-5-trif
Synthesis of luoromethylbenzonitrile) 3-Bromo-5-trifluoromethylbenzenemethanol (40.
09 g), zinc cyanide (19.38 g), and tetrakis (triphenylphosphine) palladium (10 g) in N, N-dimethylformamide suspension (500 ml) were heated to 120 ° C. and stirred for 3 hours.
The insoluble matter was removed by filtration through Celite, the filtrate was concentrated, diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was subjected to column chromatography (n-
Purify with hexane: ethyl acetate = 2: 1) to obtain the desired product (25.85
g, 82%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 2.12 (brs, 1H), 4.84 (s, 2H), 7.83
(s, 1H), 7.87 (s, 2H)

(A-5) 3-Formyl-5-trifluoromethylbenzonitrile
Nitrile) synthesis Dimethyl sulfoxide (27.4 ml) in dichloromethane (4
(00 ml) was cooled to -78 ° C under stirring, and oxalyl chloride (16.8 ml) was added.
It was added dropwise over 15 minutes. After stirring for 15 minutes, 3-hydroxymethyl-5-trifluoromethylbenzonitrile (3-Hy
droxymethyl-5-trifluoromethylbenzonitrile) (25.85
g) dichloromethane solution (100 ml) was added dropwise over 30 minutes,
After stirring for another 30 minutes, triethylamine (89.6 ml) was added over 10 minutes. The reaction solution was returned to room temperature, the insoluble material was removed by filtration, the filtrate was concentrated, diluted with ethyl acetate, and washed successively with water, 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying the organic layer with sodium sulfate,
The sodium sulfate was filtered off and the residue obtained by concentration was washed with isopropyl ether with stirring to obtain the desired product (23.51 g, 92%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 8.17 (s, 1H), 8.37 (s, 2H), 10.12
(s, 1H) mp: 73-74 ℃

(B) (3-Cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N
-Ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester ((3-Cyano-5-trifluoromethylbe
nzyl)-[6- (N-cyclopentylmethyl-N-ethylamino) indan-
Synthesis of 5-ylmethyl] -carbamic acid methyl ester) (b-1) Synthesis of N-Indan-5-ylcyclopentanecarboxyamide (5-Aminoindan) (60.96) Cyclopentanecarbonyl chloride (52.9 ml) was added dropwise to a pyridine solution (500 ml) of g) under ice-cooling, the reaction solution was returned to room temperature, and stirring was continued for 1 hour. The reaction solution was concentrated, water was added, and the precipitated crude solid was collected by filtration and washed with isopropyl ether to obtain the desired product (90.66 g, 86%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 1.60-2.12 (m, 10H), 2.66 (quin
tet, J = 7.9Hz, 1H), 2.77-2.92 (m, 4H), 7.05-7.25 (m, 3H), 7.
49 (s, 1H) mp: 155-156 ℃

(B-2) (N-Cyclopentylmethyl) indan-5-ylamine ((N-Cyclopentylmethyl) indan-5
N-Indan-5-ylcyclopentanecarboxamide (N-Indan-5-ylcyclamide) was added to a suspension of lithium aluminum hydride (15g) in tetrahydrofuran (500ml) under stirring at 70 ° C.
A tetrahydrofuran solution (500 ml) of opentanecarboxyamide (45.0 g) was added dropwise over 1 hour. After continuing stirring for an additional 1 hour, the reaction solution was stirred with ice cooling, water (15 ml), 4N aqueous sodium hydroxide (15 ml) and water (30 ml) were added dropwise in this order, and the produced insoluble matter was removed by filtration through Celite. The filtrate was concentrated and dried to obtain the target product (35.04g, 83%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 1.10-2.24 (m, 11H), 2.70-2.9
0 (m, 4H), 3.00 (d, J = 6.9Hz, 2H), 3.52 (brs, 1H), 6.42 (dd, J =
2.1,8.1Hz, 1H), 6.53 (s, 1H), 7.01 (d, J = 7.8Hz, 1H)

(B-3) (N-cyclopentylmethyl-N-
Ethyl) indan-5-ylamine ((N-Cyclopentylme
thyl-N-ethyl) indan-5-yl-amine) (N-Cyclopentylmethyl) indan-5-yl-amine (76.24 g),
A suspension of ethyl iodide (85 ml) and potassium carbonate (150 g) in N, N-dimethylformamide (700 ml) was heated to 70 ° C. and stirred for 2 hours. The reaction mixture was concentrated, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the filtrate was concentrated and dried to obtain the desired product (81.99g, 95%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 1.11 (t, J = 7.0Hz, 3H), 1.10-2.3
5 (m, 11H), 2.73-2.90 (m, 4H), 3.14 (d, J = 7.3Hz, 2H), 3.37
(q, J = 7.0Hz, 2H), 6.52 (dd, J = 2.4,8.3Hz, 1H), 6.61 (s, 1H),
7.06 (d, J = 8.3Hz, 1H)

(B-4) 6- (N-cyclopentylmethyl-
N-ethylamino) indan-5-ylmethyl} -carbaldehyde oxime (6- (N-Cyclopentylmethyl-N-eth
ylamino) indan-5-carbaldehyde oxime) synthesis N, N-dimethylformamide (500 ml) was added dropwise with stirring under ice-cooling phosphorus oxychloride (70 ml) over 40 minutes, followed by (N-cyclopentylmethyl-N-ethyl). ) Indan-5-ylamine ((N-Cyclopentylmethyl-N-ethyl) indan-5-yl-amin
e) (91.55 g) of N, N-dimethylformamide solution (300 ml)
It was added dropwise over 2 hours. The reaction mixture was further stirred for 1 hour, poured into cold 5N aqueous sodium hydroxide (1500 ml), extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, filtered to remove sodium sulfate, concentrated and dried to give 6- (N-cyclopentylmethyl-
N-ethylamino) indan-5-ylmethyl-carbaldehyde (6- (N-Cyclopentylmethyl-N-ethylamino) in
A crude product of dan-5-carbaldehyde) was obtained. Hydroxylamine hydrochloride was added to an ethanol solution (600 ml) of this crude product.
(52g) and sodium acetate (82g) were added and heated to 100 ° C.
It was stirred for 0 minutes. The reaction mixture was concentrated, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off,
The residue obtained by concentration is subjected to column chromatography (n-
Purify with hexane: ethyl acetate = 10: 1 → 4: 1) to obtain the desired product (3
8.51 g, 36%) was obtained. ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.95 (t, J = 7.1Hz, 3H), 1.10-2.1
2 (m, 11H), 2.80-3.00 (m, 8H), 7.06 (s, 1H), 7.59 (s, 1H), 7.
66 (brs, 1H), 8.58 (s, 1H) mp 92-93 ℃

(B-5) {N-[(6-aminomethyl) indan-5-yl]} (N-cyclopentylmethyl) ethylamine ({N-[(6-Aminomethyl) indan-5-yl]} ( N-cyclopen
tylmethyl) ethylamine) 6- (N-cyclopentylmethyl-N-ethylamino)
Indan-5-ylmethyl} -carbaldehyde oxime (6- (N-Cyclopentylmethyl-N-ethylamino) indan-5-c
arbaldehyde oxime) (38.51g) in acetic acid solution (250ml) 10%
Palladium-carbon (5 g) was added, and the mixture was stirred at room temperature, pressurized to 3 atm and hydrogenated for 48 hours. The catalyst was filtered off, concentrated, diluted with ethyl acetate, and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off and concentrated to obtain the desired product (3
4.85 g, 95%) was obtained. ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.99 (t, J = 7.1Hz, 3H), 1.07-2.
12 (m, 13H), 2.73-2.95 (m, 8H), 3.86 (s, 2H), 7.06 (s, 1H),
7.15 (s, 1H)

(B-6) 3-{[6- (N-cyclopentylmethyl-N-ethylamino) indan-5-ylmethyl]
Aminomethyl} -5-trifluoromethylbenzonitrile (3- [6- (N-Cyclopentylmethyl-N-ethylamino) indan-
5-ylmethyl] aminomethyl} -5-trifluoromethylbenzonitr
ile) synthesis {N- [6-aminomethyl] indan-5-yl]}
(N-cyclopentylmethyl) ethylamine ({N-[(6-A
minomethyl) indan-5-yl]} (N-cyclopentylmethyl) ethyla
mine) (39.34 g), 3-formyl-5-trifluoromethylbenzonitrile (3-Formy obtained in (a) of Example 1)
A chloroform solution (350 ml) of l-5-trifluoromethylbenzonitrile) (23.5 g) was stirred at room temperature, sodium triacetoxyborohydride (33 g) was added, and then acetic acid (1.3 ml) was added. The reaction mixture was stirred for 2 hours and then washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the desired product (47.61 g, 89
%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.96 (t, J = 7.1Hz, 3H), 1.02-2.1
2 (m, 11H), 2.79 (d, J = 7.4Hz, 2H), 2.68-2.98 (m, 6H), 3.82
(s, 2H), 3.86 (s, 2H), 7.07 (s, 1H), 7.11 (s, 1H), 7.78 (s, 1
H), 7.87 (s, 1H), 7.88 (s, 1H)

(B-7) (3-Cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-
N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester ((3-Cyano-5-trifluoromethyl
benzyl)-[6- (N-cyclopentylmethyl-N-ethylamino) inda
n-5-ylmethyl] -carbamic acid methyl ester) 3-{[6- (N-cyclopentylmethyl-N-ethylamino) indan-5-ylmethyl] aminomethyl}-
5-trifluoromethylbenzonitrile (3- [6- (N-Cyc
lopentylmethyl-N-ethylamino) indan-5-ylmethyl] amino
A chloroform solution (500 ml) of methyl} -5-trifluoromethylbenzonitrile) (47.61 g) was added with dropwise addition of methyl chlorocarbonate (12.1 ml) and pyridine (25.4 ml) under ice cooling and stirring. The reaction solution
After stirring for 1 hour, the mixture was concentrated, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off,
The residue obtained by concentration is subjected to column chromatography (n-
Hexane: ethyl acetate = 15: 1) and the desired product (49.33g,
92%). ¹ H NMR (CDCl ₃ , 300MHz) δ: 0.82-0.92 (m, 3H), 0.92-1.10
(m, 2H), 1.30-1.60 (m, 6H), 1.80-2.12 (m, 3H), 2.69-2.90
(m, 8H), 3.82 (brs, 3H), 4.35-4.73 (m, 4H), 6.88-7.08 (m, 2
H), 7.47-7.80 (m, 3H) mp 90-92 ℃

(Example 2) [6- (N-butyl-N-ethylamino) indan-5
-Ylmethyl]-(3-cyano-5-trifluoromethylbenzyl) -carbamic acid methyl ester ((3-Cyano
-5-trifluoromethylbenzyl)-[6- (N-butyl) -N- thylami
no) indan-5-ylmethyl] carbamic acid methyl ester)
Synthesis of (1) N-Indan-5-ylacetamide (N-Indan-
5-ylacetamide) Synthesis of 5-Aminoindan (50.0 Aminoindan) (40.0 g) in chloroform (200 ml) was added with stirring under ice-cooling, acetic anhydride (31 ml) was added dropwise, and the reaction mixture was allowed to warm to room temperature for 2 hours. Stirring was continued.
Isopropyl ether (300 ml) was added to the crude solid obtained by concentrating the reaction solution, and the mixture was washed with stirring to obtain the desired product (49.69 g, 94%).
Got ¹ HNMR (CDCl ₃ , 400 MHz) δ2.06 (quintet, J = 7.4Hz, 2H), 2.
15 (s, 3H), 2.82-2.95 (m, 4H), 7.07 (brs, 1H), 7.14 (s, 2H),
7.43 (s, 1H) mp: 104-105 ℃

(2) Synthesis of (N-ethyl) indan-5-ylamine ((N-Ethyl) indan-5-ylamine) A suspension of lithium aluminum hydride (22.4 g) in tetrahydrofuran (700 ml) was stirred at 70 ° C. Below, N-Indane-5
Ileacetamide (N-Indan-5-ylacetamide) (51.61g)
Tetrahydrofuran solution (300 ml) was added dropwise over 1 hour. After continuing stirring for a further 1 hour, the reaction solution was stirred with ice cooling, water (22.5 ml), 4N aqueous sodium hydroxide (22.5 ml),
Water (67.5 ml) was added dropwise in this order, the generated insoluble matter was filtered off with Celite, and the filtrate was concentrated and dried to obtain the desired product (44.75 g, 94%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 1.24 (t, J = 7.0Hz, 3H), 2.03 (qu
intet, J = 7.3Hz, 2H), 2.81 (q, J = 7.3Hz, 4H), 3.14 (q, J = 7.0H
z, 2H), 3.40 (brs, 1H), 6.43 (dd, J = 2.6,8.1Hz, 1H), 6.53 (s,
1H), 7.02 (d, J = 7.7Hz, 1H)

(3) (N-Butyl-N-ethyl) indan-5-yl-am
ine) synthesis (N-ethyl) indan-5-ylamine ((N-Ethyl) in
dan-5-yl-amine) (24.14 g), butyl iodide (32 ml), potassium carbonate (41.18 g) in N, N-dimethylformamide suspension (350
(ml) was heated to 100 ° C. and stirred for 6 hours. The reaction mixture was concentrated, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off, and the product was concentrated and dried (31.23 g,
96%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.94 (t, J = 7.3Hz, 3H), 1.13 (t, J
= 7.0Hz, 3H), 1.25-1.60 (m, 4H), 1.97-2.10 (m, 2H), 2.76-2.
90 (m, 4H), 3.16-3.25 (m, 2H), 3.32 (q, J = 7.0Hz, 2H), 6.50
(d, J = 8.0Hz, 1H), 6.59 (s, 1H), 7.05 (d, J = 8.4Hz, 1H)

(4) 6- (N-Butyl-N-ethylamino) indan-5-carbaldehyd
Synthesis of N, N-dimethylformamide (180 ml) was added dropwise with phosphorus oxychloride (39.6 ml) over 30 minutes while stirring with ice cooling, followed by (N-butyl-N-ethyl) indan-5-ylamine. ((N-But
A N, N-dimethylformamide solution (180 ml) of yl-N-ethyl) indan-5-yl-amine) (30.8 g) was added dropwise over 1 hour. The reaction solution was further stirred for 1 hour, poured into cold 3.5N aqueous sodium hydroxide (930 ml), extracted with ethyl acetate, and washed successively with water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off, concentrated and dried, and 6-
(N-Butyl-N-ethylamino) indan-5-ylmethyl-carbaldehyde (6- (N-Butyl-N-ethylamino)
indan-5-carbaldehyde) was obtained as a crude product. Hydroxylamine hydrochloride (19.7 g) and sodium acetate (34.9 g) were added to an ethanol solution (500 ml) of this crude product, and the mixture was heated to 100 ° C. and stirred for 30 minutes. The reaction mixture was concentrated, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine.
The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 8: 1 → 4: 1) to obtain the desired product (11.69. g, 32%) was obtained. ¹ HNMR (CDCl ₃ , 400MHz) δ: 0.86 (t, J = 7.3Hz, 3H), 0.96 (t, J
= 7.1Hz, 3H), 1.23-1.41 (m, 4H), 2.04-2.13 (m, 2H), 2.82-3.
09 (m, 8H), 7.03 (s, 1H), 7.21 (brs, 1H), 7.59 (s, 1H), 8.56
(s, 1H) mp: 65-69 ℃

(5) {N-[(6-aminomethyl) indan-5-yl]} (N-butyl) ethylamine ({N-
[(6-Aminomethyl) indan-5-yl]} (N-Butyl) ethylamine)
Synthesis of 6- (N-butyl-N-ethylamino) indan-5
Ilmethyl-carbaldehyde oxime (6- (N-Butyl-N
10% Palladium-carbon (512 mg) was added to an acetic acid solution (15 ml) of -ethylamino) indan-5-carbaldehyde oxime) (1.37 g), and the mixture was stirred at room temperature, pressurized to 3 atm and hydrogenated for 15 hours. The catalyst was filtered off, concentrated, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine.
The organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the mixture was concentrated to give the desired product (1.15 g, 89%). ¹ HNMR (CDCl ₃ , 400MHz) δ: 0.87 (t, J = 7.3Hz, 3H), 0.99 (t, J
= 7.1Hz, 3H), 1.23-1.45 (m, 4H), 2.01-2.12 (m, 2H), 2.25 (brs, 2H), 2.82-
2.97 (m, 8H), 3.86 (s, 2H), 7.04 (s, 1H), 7.13 (s, 1H)

(6) 3-{[6- (N-butyl-N-ethylamino) indan-5-ylmethyl] aminomethyl} -5-trifluoromethylbenzonitrile (3- {6-
[(N-Butyl-N-ethylamino) indan-5-ylmethyl] aminometh
yl} -5-trifluoromethylbenzonitrile) synthesis {N- [6-aminomethyl] indan-5-yl]}
(N-Butyl) ethylamine ({N-[(6-Aminomethyl) ind
an-5-yl]} (N-butyl) ethylamine) (37.4 g), from Example 1.
3-Formyl-5-trifluoromethylbenzonitr obtained in (a)
ile) (23.0 g) in chloroform (350 ml) with stirring at room temperature,
Sodium triacetoxyborohydride (29.4g) was added, followed by acetic acid (1.3ml). The reaction mixture was stirred for 2 hours and then washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. After drying the organic layer with sodium sulfate,
Column chromatography (n-hexane: ethyl acetate = 3: 1) of the residue obtained by removing sodium sulfate by filtration and concentration.
And the desired product (45.08 g, 91%) was obtained. ¹ H NMR (CDCl ₃ , 400M
Hz) δ: 0.84 (t, J = 7.2Hz, 3H), 0.96 (t, J = 7.1Hz, 3H), 1.20-
1.40 (m, 4H), 2.01-2.13 (m, 2H), 2.81-2.97 (m, 8H), 3.80 (s,
2H), 3.83 (s, 2H), 7.06 (s, 1H), 7.09 (s, 1H), 7.77 (s, 1H), 7.
86 (s, 1H), 7.87 (s, 1H)

(7) [6- (N-butyl-N-ethylamino) indan-5-ylmethyl]-(3-cyano-5)
-Trifluoromethylbenzyl) -carbamic acid methyl ester ([6- (N-butyl) -N-thylamino) indan-5-ylmeth
yl]-(3-Cyano-5-trifluoromethylbenzyl) carbamic ac
Synthesis of id methyl ester 3-{[6- (N-butyl-N-ethylamino) indan-5-ylmethyl] aminomethyl} -5-trifluoromethylbenzonitrile (3- {6-[(N-Butyl -N-ethylamin
o) indan-5-ylmethyl] aminomethyl} -5-trifluoromethyl
Chloroform solution (450 ml) of benzonitrile) (45.08 g) was stirred under ice cooling and methyl chlorocarbonate (12.2 ml) and pyridine (25.
5 ml) was added dropwise. The reaction mixture was stirred for 1 hr, concentrated, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the residue obtained by concentration was subjected to column chromatography (n-hexane: ethyl acetate =
8: 1) to obtain the desired product (49.57 g, 97%). ¹ HNMR (CDCl ₃ , 400MHz) δ: 0.81 (t, J = 7.2Hz, 3H), 0.90 (t, J
= 7.1Hz, 3H), 1.10-1.33 (m, 4H), 1.99-2.11 (m, 2H), 2.72-2.
90 (m, 8H), 3.81 (brs, 3H), 4.31-4.70 (m, 4H), 6.90-7.14 (m,
2H), 7.48-7.70 (m, 2H), 7.76 (s, 1H) mp: 66-69 ℃

(Examples 3 to 45) Using the same method as in Example 1 or 2, the compounds of Examples 3 to 45 shown in the following table were obtained.

(Example 46) (3,5-bistrifluoromethylbenzyl)-(2-
Dipropylamino-5-trifluoromethylbenzyl)
-Carbamic acid methyl ester ((3,5-Bistrifluoromet
hylbenzyl)-(2-dipropylamino-5-trifluoromethylbenzy
l) Synthesis of (carbamic acid methyl ester) (1) [(N- (2-Bromo-4-trifluoromethylphenyl)] dipropylamine ([N- (2-Bromo-4-triflu
oromethylphenyl)] dipropylamine) 2-bromo-4-trifluoromethylaniline (2-Brom
o-4-trifluoromethylaniline) (490mg), propyl iodide
(1.95 ml) and potassium carbonate (2.77 g) in N, N-dimethylformamide suspension (8 ml) were heated to 80 ° C. and stirred for 15 hours. Water was added to the reaction solution, extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, sodium sulfate was filtered off, and the residue obtained by concentration was subjected to column chromatography (n-hexane: ethyl acetate =
It was purified by 50: 1) to obtain the desired product (150 mg, 23%).

(2) 2-dipropylamino-5-trifluoromethylbenzaldehyde
Synthesis of ifluoromethylbenzaldehyde) [(N- (2-Bromo-4-trifluoromethylphenyl)] dipropylamine ([N- (2-Bromo-4-trifluoromet
A tetrahydrofuran solution (3 ml) of hylphenyl)] dipropylamine) (150 mg) was cooled to −78 ° C., and t-butyllithium and an n-pentane solution (1.51 mol / l, 0.4 ml) were added dropwise thereto. After the reaction solution was stirred for 30 minutes, N, N-dimethylformamide was added, the temperature was returned to room temperature, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue was concentrated and purified by column chromatography (n-hexane: ethyl acetate = 15: 1) to obtain the desired product (46 mg, 36%). Got

(3) (3,5-Bistrifluoromethylbenzyl)-(2-dipropylamino-5-trifluoromethylbenzyl) -carbamic acid methyl ester ((3,5-Bistrifluoromethylbenzyl)-(2-dipropylamino-
5-trifluoromethylbenzyl) carbamic acid methyl este
r) Synthesis of 2-dipropylamino-5-trifluoromethylbenzaldehyde
ldehyde) (46 mg), 3,5-bistrifluoromethylbenzylamine (3,5-Bistrifluoromethylbenzylamine)
A dichloromethane solution (1 ml) of (52 mg) was stirred at room temperature, sodium triacetoxyborohydride (49 mg) was added, and then acetic acid (11 μl) was added. The reaction mixture was stirred for 2 hours, diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the residue was concentrated and the resulting dichloromethane solution (1 ml) was added dropwise with methyl chlorocarbonate (18 μl) and pyridine (19 μl) under ice-cooling stirring. The reaction solution was stirred for 1 hour, water was added, and the mixture was extracted with ethyl acetate,
It was washed successively with water and saturated saline. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 8: 1) to obtain the desired product (76 mg, 83%). Got ¹ HNMR (DMSO-d ₆ , 400MHz) δ: 0.72 (t, J = 7.3Hz, 6H), 1.20-
1.40 (m, 4H), 2.72-2.90 (m, 4H), 3.70 (brs, 3H), 4.60 (s, 2
H), 4.62 (s, 2H), 7.05-7.35 (m, 1H), 7.28 (d, J = 8.4Hz, 1H),
7.48 (d, J = 8.4Hz, 1H), 7.77 (brs, 2H), 7.94 (s, 1H)

(Examples 47 to 49) The compounds of Examples 47 to 49 were obtained in the same manner as in Example 46.

(Example 50) [3- (N-butyl-N-ethylamino) naphthalene-
2-ylmethyl]-(3-cyano-5-trifluoromethylbenzyl) -carbamic acid methyl ester ([3- (NB
utyl-N-ethylamino) naphthalen-2-ylmethyl]-(3-Cyano
-5-trifluoromethylbenzyl) carbamic acid methyl est
(1) Synthesis of 3-Butylaminonaphthalene-2-carboxamide 3-aminonaphthalene-2-carboxamide (3-Amio
naphthalene-2-carboxyamide) (250 mg) and butyraldehyde (0.16 ml) in dichloromethane (10 ml) with stirring at room temperature, sodium triacetoxyborohydride (371 mg) was added and the reaction mixture was stirred for 2 hours, and then with ethyl acetate. The mixture was diluted and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the residue was concentrated and purified by column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the desired product (296 mg, 91%). Got

(2) 3- (N-butyl-N-ethylamino) naphthalene-2-carboxamide (3- (N-Butyl-N
3-ethylamino) naphthalene-2-carboxyamide) 3-butylaminonaphthalene-2-carboxyamide (3-Butylamionaphthalene-2-carboxyamide) (296 mg),
Acetaldehyde (0.29 ml) in dichloromethane (10 ml)
Under stirring at room temperature, sodium triacetoxyborohydride
(837 mg) was added and the reaction mixture was stirred for 2 hours, diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. After drying the organic layer with sodium sulfate,
Column chromatography (n-hexane: ethyl acetate = 2: 1) of the residue obtained by removing sodium sulfate by filtration and concentration.
And purified to give the desired product (196 mg, 59%).

(3) Synthesis of [N- (3-aminomethylnaphthalen-2-yl)]-(N-butyl) ethylamine A suspension of lithium aluminum hydride (55 mg) in tetrahydrofuran (2 ml) was stirred at 70 ° C. , 3- (N-butyl) ethylaminonaphthalene-2-carboxamide (3- (N-But
A solution of (yl) -ethylaminonaphthalene-2-carboxyamide) in tetrahydrofuran (1 ml) was added dropwise. After continuing stirring for 3 hours, the reaction solution was stirred under ice-cooling, water (55 μl), 4N aqueous sodium hydroxide (55 μl), and water (0.16 ml) were added dropwise in this order, and the produced insoluble matter was removed by filtration through Celite. Concentrate and dry the filtrate and
72 mg, 93%) was obtained.

(4) 3-{[3- (N-butyl-N-ethylamino) naphthalen-2-ylmethylamino] methyl} -5-trifluoromethylbenzonitrile (3-{[3-
(N-Butyl-N-ethylamino) naphthalen-2-ylmethylamino] m
ethyl} -5-trifluoromethylbenzonitrile) synthesis [N- (3-aminomethylnaphthalen-2-yl)]-
(N-Butyl) ethylamine ([N- (3-Aminomethylnaph
thalen-2-yl)]-(N-butyl) ethylamine) (120 mg), 3-formyl-5-trifluoromethylbenzonitrile (3-Formyl-5-trifluoromethylben obtained in (a) of Example 1)
zonitrile) (103 mg) in dichloromethane (3 ml) with stirring at room temperature, sodium triacetoxyborohydride (149 mg)
Was added and the reaction mixture was stirred for 2 hours, diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the residue was concentrated and purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to give the desired product (115 mg, 56%). Got

(5) [3- (N-butyl-N-ethylamino) naphthalen-2-ylmethyl]-(3-cyano-
Synthesis of 5-trifluoromethylbenzyl) -carbamic acid methyl ester 3-{[3- (N-butyl-N-ethylamino) naphthalen-2-ylmethylamino] methyl} -5-trifluoromethylbenzonitrile (3 -{[3- (N-Butyl-N-ethylam
ino) naphthalen-2-ylmethylamino] methyl} -5-trifluoro
Methylbenzonitrile) (115mg) in dichloromethane (2m
l) with stirring under ice cooling, methyl chlorocarbonate (0.10 ml), pyridine
(0.13 ml) was added dropwise. The reaction mixture was stirred for 30 minutes, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the desired product (112 mg, 96%). Got ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.82 (t, J = 7.3Hz, 3H), 0.97 (t, J
= 6.9Hz, 3H), 1.10-1.45 (m, 4H), 2.90-3.10 (m, 4H), 3.86 (br
s, 3H), 4.35-4.85 (m, 4H), 7.30-7.80 (m, 9H)

Example 51 The compound of Example 51 was obtained in the same manner as in Example 50.

(Example 51) (3,5-bistrifluoromethylbenzyl)-[6-
(N-propionyl-N-propylamino) indan-
5-ylmethyl] carbamic acid methyl ester ((3,5-B
istrifluoromethylbenzyl)-[6- (N-propionyl-N-propyl
amino) indan-5-ylmethyl] carbamic acid methyl este
Synthesis of r) (1) (6-aminoindan-5-ylmethyl)-
(3,5-bistrifluoromethylbenzyl) carbamic acid methyl ester ((6-Aminoindan-5-ylmethyl)-(3,5
-bistrifluoromethylbenzyl) carbamic acid methyl es
(3,5-bistrifluoromethylbenzyl)-(6-dibenzylaminoindan-5-ylmethyl) -carbamic acid methyl ester ((3,5-Bistrifluoromethylbenzyl)-synthesized in the same manner as in Example 1. (6-dibenzylaminoi
ndan-5-ylmethyl) -carbamic acid methyl ester) (700m
g) in methanol solution (15 ml) with 10% palladium-carbon (175 m
g) was added and hydrogenated for 4.5 hours with stirring at room temperature. The catalyst was filtered off, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the desired product (43
3 mg, 87%) was obtained.

(2) (3,5-bistrifluoromethylbenzyl)-(6-propylaminoindan-5-ylmethyl) -carbamic acid methyl ester ((3,5-Bistri
fluoromethylbenzyl)-(6-propylaminoindan-5-ylmethy
l) Synthesis of (carbamic acid methyl ester) (6-aminoindan-5-ylmethyl)-(3,5-
Bistrifluoromethylbenzyl) carbamic acid methyl ester ((6-Aminoindan-5-ylmethyl)-(3,5-bistrifl
uoromethylbenzyl) carbamic acid methyl ester) (1.5
g), propionyl aldehyde (0.36 ml) in dichloromethane (30 ml) was stirred at room temperature, sodium triacetoxyborohydride (1.42 g) was added and the reaction mixture was stirred for 2 hours, diluted with ethyl acetate and saturated sodium hydrogen carbonate. It was washed successively with water, water and saturated saline. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 5: 1) to obtain the desired product (1.23 g, 75%). ) Got.

(3) (3,5-bistrifluoromethylbenzyl)-[6- (N-propionyl-N-propylamino) indan-5-ylmethyl] carbamic acid methyl ester ((3,5-Bistrifluoromethylbenzyl)-[6 -(N-
propionyl-N-propylamino) indan-5-ylmethyl] carbamic
acid methyl ester) synthesis (3,5-bistrifluoromethylbenzyl)-(6-
Propylaminoindan-5-ylmethyl) -carbamic acid methyl ester ((3,5-Bistrifluoromethylbenzyl)
-(6-propylaminoindan-5-ylmethyl) carbamic acid meth
yl ester) (100 mg) in pyridine (2 ml) with stirring at room temperature.
Propionyl chloride (54 μl) was added dropwise. The reaction mixture was stirred for 1 hr, concentrated, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate = 3: 1) to obtain the desired product (102 mg, 91%). ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.84 (t, J = 7.2Hz, 3H), 0.98 (t, J
= 7.2Hz, 3H), 1.35-2.05 (m, 4H), 2.05-2.20 (m, 2H), 2.60-3.
00 (m, 5H), 3.81 (brs, 3H), 3.92-4.08 (m, 1H), 4.15-4.80 (m,
4H), 6.93 (s, 1H), 6.90-7.20 (brs, 1H), 7.45-7.70 (brs, 2
H), 7.79 (s, 1H)

Example 53 The compound of Example 53 was obtained in the same manner as in Example 52.

(Example 54) (3,5-bistrifluoromethylbenzyl)-[6-
(1-Propylbutoxy) indan-5-ylmethyl]
Carbamic acid methyl ester ((3,5-Bistrifluoromethy
lbenzyl)-[6- (1-propylbutoxy) indan-5-ylmethyl] carba
Synthesis of mic acid methyl ester (1) 5- (1-propylbutoxy) indane (5- (1-P
ropylbutoxy) indan) 5-hydroxyindan (1.16 g), 4
-Heptanol (1.00 g), triphenylphosphine (2.25
g) and a tetrahydrofuran solution (20 ml) of diethyl azodicarboxylate (1.36 ml) were stirred at room temperature for 12 hours. The reaction mixture was concentrated and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the desired product (888 mg, 51%)
Got

(2) Synthesis of (3,5-bistrifluoromethylbenzyl)-[6- (1-propylbutoxy) indan-5-ylmethyl] amine N, N-dimethylformamide (5 ml) was stirred under ice-cooling. Phosphorus oxychloride (1.4 ml) was added dropwise, followed by 6- (1-Propylbutoxy) indan (888 mg).
N, N-dimethylformamide solution (5 ml) was added dropwise. The reaction solution was stirred at 100 ° C. for 5 hours, poured into cold 1N sodium hydroxide aqueous solution, extracted with ethyl acetate, and washed successively with water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated and dried to give 6- (1-propylbutoxy) indan-5-carbaldehyde (6-
A crude product of (1-Propylbutoxy) indan-5-carbaldehyde) was obtained. A solution of this crude product in dichloromethane (10 ml),
3,5-bistrifluoromethylbenzylamine (3,5-
Bistrifluoromethylbenzylamine) (485 mg) and sodium triacetoxyborohydride (680 mg) were added, the reaction mixture was stirred at room temperature for 2 hr, diluted with ethyl acetate, and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine.
The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the desired product (3
44 mg, 18%) was obtained.

(3) Synthesis of (3,5-bistrifluoromethylbenzyl)-[6- (1-propylbutoxy) indan-5-ylmethyl] carbamic acid methyl ester (3,5-bistrifluoromethylbenzyl)-[ 6-
(1-Propylbutoxy) indan-5-ylmethyl]
Amine ((3,5-Bistrifluoromethylbenzyl)-[6- (1-propy
lbutoxy) indan-5-ylmethyl] amine) (344 mg) in a dichloromethane solution (5 ml) under ice-cooling with stirring, and methyl chlorocarbonate (0.14
ml) and pyridine (0.23 ml) were added dropwise. The reaction mixture was stirred for 30 minutes, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the residue obtained by concentration was subjected to column chromatography (n-hexane: ethyl acetate =
7: 1) to obtain the desired product (371 mg, 96%). ¹ HNMR (CDCl ₃ , 400MHz) δ: 0.80-0.94 (m, 6H), 1.17-1.62
(m, 8H), 1.99-2.11 (m, 2H), 2.75-2.90 (m, 4H), 3.70 & 3.87
(s, 3H), 4.12-4.23 (m, 1H), 4.38-4.58 (m, 4H), 6.69 (s, 1H),
6.94 & 7.14 (brs, 1H), 7.51 & 7.59 (brs, 2H), 7.72 (s, 1H)

(Example 55) By a method similar to that in Example 54, the compound of Example 55 was obtained.

Example 56 (3,5-bistrifluoromethylbenzyl)-[4
5-dimethyl-2- (1-propylbutyl) benzyl]
Carbamic acid methyl ester ((3,5-Bistrifluoromethy
lbenzyl)-[4.5-dimethyl-2- (1-propylbutyl) benzyl] car
Synthesis of bamic acid methyl ester (1) 1,2-dimethyl-4- (1-propylbutyl)
Benzene (1,2-Dimethyl-4- (1-propylbutyl) benzene)
Synthesis of 4-Bromo-oxylene (1.85 g) in tetrahydrofuran (30 ml) was cooled to -78 ° C under stirring and t
-Butyllithium, n-pentane solution (1.51M, 13.2 ml) was added dropwise. After stirring the reaction solution for 30 minutes, 4-heptanone (1.82 m
l) was added to return to room temperature, water was added and extracted with ethyl acetate,
It was washed successively with water and saturated saline. After drying the organic layer with sodium sulfate, sodium sulfate was filtered off, 20% palladium hydroxide (250 mg) was added to the remaining methanol solution (10 ml) obtained by concentration, and the mixture was pressurized to 3 atm under room temperature stirring. 3.5
Hydrogenated for hours. The catalyst was filtered off and the residue obtained by concentration was purified by column chromatography (n-hexane) to obtain the desired product (820 mg, 40%).

(2) 4,5-Dimethyl-2- (1-propylbutyl) benzaldehyde (4,5-Dimethyl-2- (1-pr
1,2-Dimethyl-4- (1-propylbutyl) benzene (820m
g), a solution of bromosuccinimide (714 mg) in N, N-dimethylformamide (20 ml) was stirred at 50 ° C. for 12 hours. Water was added to the reaction solution, extracted with n-hexane, and washed successively with water and saturated brine. After the organic layer was dried over sodium sulfate, sodium sulfate was filtered off and concentrated to give 1-bromo-4,5-dimethyl-2- (1-propylbutyl) benzene (1-Bromo-
A crude product of 4,5-dimethyl-2- (1-propylbutyl) benzene was obtained. Tetrahydrofuran solution of this crude product (10 ml)
Was cooled to −78 ° C., and t-butyllithium and an n-pentane solution (1.51M, 3.3 ml) were added dropwise under stirring. After the reaction solution was stirred for 30 minutes, N, N-dimethylformamide was added to bring it to room temperature, water was added and the mixture was extracted with ethyl acetate and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the residue was concentrated and purified by column chromatography (n-hexane: ethyl acetate = 15: 1) to obtain the desired product (393 mg, 42%). Got

(3) (3,5-bistrifluoromethylbenzyl)-[4,5-dimethyl-2- (1-propylbutyl) benzyl] amine ((3,5-Bistrifluoromethylb
enzyl)-[4.5-dimethyl-2- (1-propylbutyl) benzyl] amin
Synthesis of e) 4,5-Dimethyl-2- (1-propylbutyl) benzalde
Hyde) (393mg) in dichloromethane solution (10ml)
-Bistrifluoromethylbenzylamine (3,5-Bistri
fluoromethylbenzylamine) (565 mg) and sodium triacetoxyborohydride (540 mg) were added, and the reaction solution was allowed to stand at room temperature for 2 hours.
After stirring for an hour, the mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. After drying the organic layer with sodium sulfate, the sodium sulfate was filtered off,
The residue obtained by concentration is subjected to column chromatography (n-
Hexane: ethyl acetate = 12: 1) and the desired product (463mg, 60
%).

(4) (3,5-bistrifluoromethylbenzyl)-[4,5-dimethyl-2- (1-propylbutyl) benzyl] carbamic acid methyl ester ((3,5
-Bistrifluoromethylbenzyl)-[4.5-dimethyl-2- (1-prop
ylbutyl) benzyl] carbamic acid methyl ester) (3,5-bistrifluoromethylbenzyl)-[4
5-dimethyl-2- (1-propylbutyl) benzyl]
Amine ((3,5-Bistrifluoromethylbenzyl)-[4.5-dimeth
A solution of yl-2- (1-propylbutyl) benzyl] amine) (463 mg) in dichloromethane (5 ml) was stirred with ice-cooling and methyl chlorocarbonate (0.
16 ml) and pyridine (0.25 ml) were added dropwise. The reaction mixture was stirred for 30 minutes, water was added, the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the residue was concentrated and purified by column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the desired product (458 mg, 88%). Got ¹ HNMR (CDCl ₃ , 300MHz) δ: 0.78 (t, J = 7.0Hz, 6H), 0.95-1.6
5 (m, 8H), 2.19 (s, 3H), 2.24 (s, 3H), 2.55-2.80 (m, 1H), 3.82
(s, 3H), 4.30-4.60 (m, 4H), 6.71 (s, 1H), 6.97 (s, 1H), 7.40-
7.65 (m, 2H), 7.77 (s, 1H)

Example 57 The compound of Example 57 was obtained in the same manner as in Example 56.

The structural formulas and NMR data of the compounds obtained in Examples 1 to 57 are shown in the following table. Compounds without melting points are oily compounds.

[0153]

[Table 1]

[0154]

[Table 2]

[0155]

[Table 3]

[0156]

[Table 4]

[0157]

[Table 5]

[0158]

[Table 6]

[0159]

[Table 7]

[0160]

[Table 8]

[0161]

[Table 9]

[0162]

[Table 10]

[0163]

[Table 11]

[0164]

[Table 12]

Test Example Next, the CETP of the compound of the present invention was tested.
The following tests were carried out for the activity inhibiting effect. (Preparation of Donor Lipoprotein) Potassium bromide (KBr) was added to plasma of healthy subjects (40 ml), and specific gravity d = 1.125 g /
Adjust to ml and perform density gradient centrifugation (227,000 x
g, 4 ° C., 17 hours) and specific gravity d> 1.125 g /
A fraction of ml (fraction of HDL ₃ ) was collected. The resulting fractions PBS solution [10 mM of Na ₂ HPO ₄ / 10mM of N
aH ₂ PO ₄ /0.15M NaCl / 1 mM EDTA
(PH 7.4)]. Then, 10 nM tritium-labeled cholesterol (50.3 Ci / mM) was added to the mixture.
It was dissolved in 5% ethanol, gradually added to the above HDL ₃ fraction with stirring, and incubated at 37 ° C. for 18 hours [This operation allowed tritium-labeled cholesterol to react with lecithin acyltransferase (LCAT) present on the HDL ₃ surface. It is esterified by the action, and is incorporated into HDL ₃ as a trityl-labeled cholesteryl ester ([ ³ H] CE)]. After incubation, K
Br was added to adjust specific gravity d = 1.21 g / ml, and density gradient centrifugation (227,000 × g, 4 ° C., 17 hours)
Was carried out and a fraction having a specific gravity d <1.21 g / ml was collected.
The obtained fraction was dialyzed against the above PBS solution to give [ ³ H] CE.
HDL ₃ ([ ³ H] CE-HDL ₃ , specific gravity:
1.125 <d <1.21, specific activity: 101,000d
pm / nM) to obtain donor lipoprotein.

(Test Example 1: In Vitro CETP Activity Inhibitory Action in Whole Plasma) [ ³ H] CE-HDL ₃ -containing plasma (1,000 dpm / μL) was prepared by adding the donor lipoprotein obtained above to normal human plasma. Was prepared. The sample is 1: N of N-methylpyrrolidone and polyethylene glycol 400.
One solution was used as a solvent to prepare a sample solution. Sample solution or solvent only 2 μL and [ ³ H] CE-H in a microtube
100 μL of DL ₃ -containing plasma was added and incubated at 37 ° C. or 4 ° C. for 4 hours. After cooling with ice, TBS solution containing 1M magnesium chloride and 2% dextran sulfate [20 m
M Tris / 0.15 M NaCl (pH 7.4)]
100 μl was added to each microtube and mixed well. After leaving at 4 ° C for 30 minutes, centrifuge (10,0
Radioactivity of the obtained centrifugal supernatant (HDL fraction) was measured using a scintillation counter. The CETP activity was defined as the difference between the measured values obtained by incubating the solvent alone at 4 ° C. and 37 ° C., and the reduction rate of the difference between the measured values depending on the sample was defined as the CETP activity inhibition rate.
The IC ₅₀ value of each sample was calculated from the inhibition rate of CETP activity. The results are shown below.

[0167]

[Table 13] The IC ₅₀ value in the table indicates the average value or the average value ± standard error.

[0168]

[Table 14] The IC ₅₀ value in the table indicates the average value or the average value ± standard error.

(Test Example 2: CETP activity inhibitory activity in normal hamster whole plasma in ex vivo) After suspending the compound of the present invention in a 0.5% methylcellulose solution, the normal hamster was treated with a plastic sonde once a day for 7 days. Repeated oral administration was performed daily. Blood was collected 4 hours after the administration on the first day and the seventh day, and CETP activity in plasma was measured according to the following method. The donor lipoprotein obtained above was added to hamster plasma (180 μL), and [ ³ H] CE-HDL ₃ -containing plasma (approximately
1,000 dpm / μL) was prepared. 50 [ ³ H] CE-HDL ₃ containing plasma
Dispense μL into 3 microtubes, 2 at 37 ℃
Each of them was incubated at 4 ° C for 4 hours. After ice-cooling, 50 μm of TBS solution containing 1 M magnesium chloride and 2% dextran sulfate (20 mM Tris / 0.15 M NaCl (pH 7.4))
L was added to each microtube and stirred well. 4 ° C
After leaving at room temperature for 30 minutes, centrifuge (10,000 xg, 4 ℃, 20
The resulting supernatant (HDL fraction) was measured for radioactivity with a liquid scintillation counter. Also, [ ³ H]
The radioactivity of the CE-HDL ₃ -containing plasma was measured with a liquid scintillation counter, and this was taken as the total radioactivity. Total radioactivity in each individual sample (Total count), radioactivity in 37 ° C incubation (37 ° C count) and 4 ° C
The transfer rate of [ ³ H] CE was calculated from the radioactivity (4 ° C. count) in the incubation by the following formula, and this was defined as the CETP activity. The CETP activity of the solvent-administered group was set to 100%, and the CETP activity of each compound-administered group was calculated by the following formula and expressed in%. CETP activity (%) = {[(4 ℃ count)-(37 ℃ count)] /
(Total count)} x 100

The results are shown below.

[Table 15] The CETP activity in the table shows the average value.

(Test Example 3: Blood in normal hamster)
HDL cholesterol increasing action) In the above animals,
60 μL of a commercially available HDL cholesterol separation reagent was added to 20 μL of plasma collected 4 hours after the administration on the day, and well stirred.
After leaving it at room temperature for 10 minutes, centrifuge (10,000 xg, 4 ° C,
After 20 minutes), the amount of cholesterol in the obtained supernatant (HDL fraction) was measured. The results are shown below. The HDL cholesterol amount in the table below is calculated by the following formula, assuming that the amount of HDL cholesterol in the solvent-administered group is 100%, and is shown in%. HDL cholesterol amount (%) = (HDL cholesterol amount of each compound administration group / solvent administration group HDL cholesterol amount)
× 100

[0172]

[Table 16] The amount of HDL cholesterol in the table shows the average value.

[0173]

[Table 17] The amount of HDL cholesterol in the table shows the average value.

[0174]

From the above test results and the like, the compound or salt thereof according to the present invention has an excellent CETP activity inhibitory action. Therefore, IDL and VLD that promote arteriosclerosis
It is possible to lower L and LDL and increase HDL acting suppressively, and as a result, it is useful as a preventive or therapeutic drug for hyperlipidemia. It is also useful as a preventive or therapeutic drug for arteriosclerotic diseases.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07C 271/16 C07C 271/16 271/20 271/20 271/22 271/22 317/32 317/32 (72) Invention Person Yasuki Suzuki No. 1-1 Murasaki-cho, Takatsuki-shi, Osaka Prefecture F-term (Reference) within the Pharmaceutical Research Institute, Japan Tobacco Inc. 4C206 AA01 AA02 AA03 AA04 HA22 MA01 MA04 NA14 ZA45 ZC33 ZC41 4H006 AA01 AA03 AB20 AB23 AB27 RA06

Claims (24)

[Claims] 1. A compound represented by the general formula (I): [In the formula, X _{1 to} X ₄ and Y _{1 to} Y ₅ are the same or different and each represent a hydrogen atom or an arbitrary substituent. Z is the formula (I
I); -Z ₁ -Z ₂ (In the formula, Z ₁ is -CO-, -CS-.
Or represents —SO ₂ —, Z ₂ is a hydrogen atom, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, an optionally substituted amino group, an optionally substituted alkoxy group or a substituted Represents an optionally substituted alkylthio group. ) Is represented. A represents a disubstituted amino group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, or an optionally substituted hydrocarbon group having 1 to 20 carbon atoms. Further, X ₂ and X ₃ , X ₃ and X ₄ or X ₄ and A are taken together to form a homocyclic group which may have a substituent or a heterocyclic group which may have a substituent. May be formed. ] The CETP activity inhibitor containing the compound shown by these or its salt. 2. (a) X ₁ , X ₂ , X ₃ and X ₄ are the same or different, and (1) a hydrogen atom, (2) a halogen atom, (3)
Nitro group, (4) hydroxyl group, (5) mercapto group,
(6) cyano group, (7) carboxyl group, (8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) C _1-6 alkylthio group, (11) C _1-6 alkylsulfinyl group, (12) C _1-6 alkylsulfonyl group, (13) amino group, (14) mono- or di-C _1-4 alkylamino group, (15) C _1-6 alkanoyl group,
(16) C _1-6 alkanoyloxy group, (17) carbamoyl group optionally substituted by C _1-6 alkyl group, (18) aminosulfonyl group optionally substituted by C _1-6 alkyl group,
(19) an optionally substituted C _1-20 hydrocarbon group or
(20) is an optionally substituted C _1-10 alkoxy group, or (b) X ₂ and X ₃ , X ₃ and X ₄ or X ₄ and A are taken together to form a substituent. A homocyclic group which may have or a heterocyclic group which may have a substituent is formed, and a group which does not form a ring group among X ₁ , X ₂ , X _{3 and} X _4. But the same or different,
(1) hydrogen atom, (2) halogen atom, (3) nitro group, (4)
Hydroxyl group, (5) mercapto group, (6) cyano group,
(7) Carboxyl group, (8) C _1-6 alkoxycarbonyl group, (9) sulfo group, (10) C _1-6 alkylthio group, (11) C
_1-6 alkylsulfinyl group, (12) C _1-6 alkylsulfonyl group, (13) amino group, (14) mono- or di-C _1-4 alkylamino group, (15) C _1-6 alkanoyl group, (16) C _1-6 alkanoyloxy group, (17) carbamoyl group optionally substituted by C _1-6 alkyl group, (18) aminosulfonyl group optionally substituted by C _1-6 alkyl group, (19) The CETP activity inhibitor according to claim 1, which is an optionally substituted C _1-20 hydrocarbon group or (20) an optionally substituted C _1-10 alkoxy group. 3. The homocyclic group is a homocyclic group consisting of 3 to 8 member carbon atoms, and the heterocyclic group is 1 to 4 carbon atoms.
3. A CETP activity inhibitor according to claim 1 or 2, which is a 5- to 8-membered heterocyclic group consisting of a hetero atom selected from the group consisting of oxygen, sulfur and nitrogen. 4. Y ₁ , Y ₃ and Y ₅ are hydrogen atoms,
Y ₂ is a hydrogen atom, a halogen atom, a nitro group or an optionally substituted hydrocarbon group having 1 to 20 carbon atoms,
Y ₄ represents a halogen atom, a nitro group, a cyano group, an optionally substituted hydrocarbon group having 1 to 20 carbon atoms, or 1 carbon atom
To C6 alkylsulfonyl group, C1 to C6 alkoxycarbonyl group, C1 to C6 alkyl group which may be substituted, carbamoyl group, and C1 to C6 alkyl group. The CETP activity inhibitor according to claim 1, which is an aminosulfonyl group or an aromatic heterocyclic group. 5. A is (a) an alkyl group having 1 to 6 carbon atoms, which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms, an aralkyl group having 7 to 16 carbon atoms, or an alkyl group having 2 to 6 carbon atoms. , An amino group substituted with two substituents selected from the group consisting of an alkenyl group, an alkoxycarbonyl group having 1 to 6 carbon atoms and an alkanoyl group having 1 to 6 carbon atoms, (b) a cyclic amino group, (c) An optionally substituted alkoxy group having 1 to 10 carbon atoms, (d) an optionally substituted alkyl group having 1 to 15 carbon atoms, (e) an optionally substituted alkenyl group having 2 to 10 carbon atoms Or (f) an optionally substituted alkynyl group having 2 to 10 carbon atoms, CET according to claim 1.
P activity inhibitor. 6. Z ₁ is —CO—, Z ₂ is a hydrogen atom, an optionally substituted alkoxy group having 1 to 10 carbon atoms, or an optionally substituted alkyl group having 1 to 15 carbon atoms. Group, an optionally substituted alkenyl group having 2 to 10 carbon atoms, an optionally substituted alkynyl group having 2 to 10 carbon atoms, an amino group or a mono- or di-C _1-4 alkylamino group. The CETP activity inhibitor according to claim 1, wherein 7. An optionally substituted carbon atom number of 1 to 20
Hydrocarbon group of 1 to 10 carbon atoms which may be substituted
An alkoxy group having 1 to 1 carbon atoms which may be substituted.
5 alkyl groups, optionally substituted carbon atoms 2 to 1
The substituent in the alkenyl group of 0 and the alkynyl group of 2 to 10 carbon atoms which may be substituted is (1) nitro group, (2) hydroxyl group, (3) mercapto group, (4) cyano group, (5 ) Carbamoyl group, (6) carboxyl group, (7) C _1-6
Alkoxycarbonyl group, (8) sulfo group, (9) halogen atom, (10) C _1-6 alkoxy group, (11) C _1-6 alkylthio group, (12) C _1-6 alkylsulfinyl group, (13) C _1-6 alkylsulfonyl group, (14) amino group, (15) mono- or di-
C _1-4 alkylamino group, (16) C _1-6 alkanoyl group and
(17) The CETP activity inhibitor according to claim 1, 2, 4, 5 or 6, which is selected from the group consisting of C _1-6 alkanoyloxy groups. 8. The substituent in the homocyclic ring which may have a substituent and the heterocyclic ring which may have a substituent is (1)
1 to 20 carbon atoms which may be substituted with a halogen atom
Hydrocarbon group, (2) nitro group, (3) hydroxyl group, (4)
Mercapto group, (5) cyano group, (6) carbamoyl group, (7)
Carboxyl group, (8) C _1-6 alkoxycarbonyl group,
(9) sulfo group, (10) a halogen atom, (11) C _1-6 alkoxy group, (12) C _1-6 alkylthio group, (13) C _1-6 alkylsulfinyl group, (14) C _1-6 Alkylsulfonyl group, (15) amino group, (16) mono- or di-C _1-4 alkylamino group,
(17) C _{1 -6} alkanoyl group and (18) C _1-6 CETP activity inhibitor according to claim 1 or 2, characterized in that selected from the group consisting of alkanoyloxy groups. 9. (a) X ₁ and X ₄ are hydrogen atoms,
X ₂ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom, and X ₃ is A hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or (b) X ₁ is a hydrogen atom, and X ₂ and X ₃ or X ₃ and X ₄ together, has 3 to 8 carbon atoms which may be substituted by a halogen atom and may be substituted by an alkyl group having 1 to 6 carbon atoms.
Which forms a cyclic hydrocarbon or an aryl group having 6 to 14 carbon atoms, and the groups not forming a ring group among X ₂ , X _{3 and} X ₄ are the same or different, and are a hydrogen atom, a halogen atom, An alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom,
Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, Y ₂ is a hydrogen atom, a halogen atom, a nitro group or an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom;
₄ is a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, an alkylsulfonyl group having 1 to 6 carbon atoms, or 1 carbon atom
To an alkoxycarbonyl group having 1 to 6 carbon atoms, a carbamoyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, an aminosulfonyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms or an aromatic heterocyclic group Yes, A
Formula (a); -N (R ¹⁰¹ ) ₂ , -N (R ¹⁰¹ ) (R
¹⁰² ), -N (R ¹⁰¹ ) (R ¹⁰³ ), -N (R
¹⁰¹ ) (R ¹⁰⁴ ) or -N (R ^{10 1} ) (R
¹⁰⁵ ) (in the formula, R ¹⁰¹ is an alkyl group having 1 to 6 carbon atoms which may be substituted with a cycloalkyl group having 3 to 8 carbon atoms, R ¹⁰² is an aralkyl group having 7 to 16 carbon atoms, R ¹⁰² is ¹⁰³ is an alkenyl group having 2 to 6 carbon atoms,
¹⁰⁴ is an alkoxycarbonyl group having 1 to 6 carbon atoms, R
¹⁰⁵ represents an alkanoyl group having 1 to 6 carbon atoms. )
A group represented by (b) a 5- to 7-membered cyclic amino group,
(C) an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom, or (d) an alkyl group having 1 to 15 carbon atoms which may be substituted with a halogen atom, and Z ₁ represents —CO And Z ₂ represents a hydrogen atom, an alkoxy group having 1 to 10 carbon atoms which may be substituted with a halogen atom, an alkyl group having 1 to 15 carbon atoms which may be substituted with a halogen atom, an amino group or The CETP activity inhibitor according to claim 1, which is a mono- or di-C _1-4 alkylamino group. 10. X ₁ and X ₄ are hydrogen atoms,
(A) whether X ₂ is a hydrogen atom, a chlorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a trifluoromethyloxy group, and X ₃ is a hydrogen atom, a chlorine atom or a methyl group, Or (b) X ₂ and X
₃ together form cyclopentane, cyclohexane, cycloheptane, dimethylcyclopentane or benzene, Y ₁ , Y ₃ and Y ₅ are hydrogen atoms, and Y ₂ is hydrogen atom, chlorine atom. , A nitro group or a trifluoromethyl group, Y ₄ is a hydrogen atom,
Chlorine atom, bromine atom, nitro group, cyano group, methyl group,
Is a trifluoromethyl group, a methylsulfonyl group or a methoxycarbonyl group, and A is the following formula: A substituent selected from Z ₁ is —CO—,
Z ₂ is a hydrogen atom, a methoxy group, CETP activity inhibitor according to claim 1, characterized in that a methyl group or an amino group. 11. (3-Cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N
-Ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, [6- (N-butyl-N-ethylamino) indan-5-ylmethyl]-(3-cyano-5-trifluoromethylbenzyl) -carbamine Acid methyl ester, (3-nitro-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N-
Ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, [6- (N-butyl-N-ethylamino) indan-5-ylmethyl]-(3,5-dichlorobenzyl) -carbamic acid methyl ester, [ 6-
(N-Butyl-N-ethylamino) indan-5-ylmethyl]-(3-chloro-5-trifluoromethylbenzyl) -carbamic acid methyl ester, (3-bromo-
5-trifluoromethylbenzyl)-[6- (N-butyl-N-ethylamino) indan-5-ylmethyl]-
Carbamic acid methyl ester, [6- (N-butyl-N
-Ethylamino) indan-5-ylmethyl]-(3-
Methyl-5-trifluoromethylbenzyl) -carbamic acid methyl ester, [6- (N-butyl-N-ethylamino) indan-5-ylmethyl]-(3-nitro-
5-trifluoromethylbenzyl) -carbamic acid methyl ester, [6- (N-cyclopentylmethyl-N-
Ethylamino) tetralin-5-ylmethyl]-(3-
Methylsulfonyl-5-trifluoromethylbenzyl)
-Carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano- 5-trifluoromethylbenzyl)-[6- (N-cyclobutylmethyl-N-ethylamino) tetralin-5
-Ylmethyl] -carbamic acid methyl ester, (3-
Cyano-5-trifluoromethylbenzyl)-[6-
(N-Cyclopropylmethyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)
-[6- (N-Cyclopropylethyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6- (N-2-methyl Propyl-N-ethylamino) tetralin-5-ylmethyl] -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-
N-ethylamino) -6,7,8,9 tetrahydro 5H
Benzocyclohepten-2-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[2,2-dimethyl-6- (N-butyl-
N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-propyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid Methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-butyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-
[6- (N, N-dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-
Bistrifluoromethylbenzyl)-[6- (N-butyl-N-propylamino) indan-5-ylmethyl]
-Carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-3-methylbutyl-N-ethylamino) indan-5-ylmethyl]-
Carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-3,3-dimethylbutyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5 -Bistrifluoromethylbenzyl)-[6- (N-cyclopentylmethyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N- 3-Butylenyl-N-ethylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-benzyl-
N-Propylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-1-methylethyl-
N-Propylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(6-piperidylindan-5-
Ilmethyl) -carbamic acid methyl ester, benzyl- [6- (N, N-dipropylamino) indan-5-
Ilmethyl] -carbamic acid methyl ester, [6-
(N, N-dipropylamino) indan-5-ylmethyl]-(3-trifluoromethylbenzyl) -carbamic acid methyl ester, [6- (N, N-dipropylamino) indan-5-ylmethyl]-( 3-methylbenzyl) -carbamic acid methyl ester, (3-chlorobenzyl)-[6- (N, N-dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester,
[6- (N, N-dipropylamino) indan-5-ylmethyl]-(3-nitrobenzyl) -carbamic acid methyl ester, (3-cyanobenzyl)-[6- (N,
N-dipropylamino) indan-5-ylmethyl]-
Carbamic acid methyl ester, [6- (N, N-dipropylamino) indan-5-ylmethyl]-(3-methoxycarbonylbenzyl) -carbamic acid methyl ester, (3,5-dinitrobenzyl)-[6- ( N, N-
Dipropylamino) indan-5-ylmethyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5-methylbenzyl) -carbamic acid methyl ester, (3,5
-Bistrifluoromethylbenzyl)-(2-dipropylamino-5-chlorobenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5-methoxybenzyl) -carbamine Acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-5-trifluoromethyloxybenzyl) -carbamic acid methyl ester, [2- (N-butyl-N-ethylamino)- 5-trifluoromethyloxybenzyl]-
(3-Nitro-5-trifluoromethylbenzyl) -carbamic acid methyl ester, (3-cyano-5-trifluoromethylbenzyl)-[2- (N-butyl-N-ethylamino) -5-trifluoromethyl Oxybenzyl] -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-4,5-dimethylbenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)
-[6- (N-dipropylamino) indan-5-ylmethyl] -acetamide, (3,5-bistrifluoromethylbenzyl)-[6- (N-dipropylamino) indan-5-ylmethyl] -urea, (3,5-bistrifluoromethylbenzyl)-[6- (N-dipropylamino) indan-5-ylmethyl] -formamide,
(3,5-bistrifluoromethylbenzyl)-(2-
Dipropylamino-5-trifluoromethylbenzyl)
-Carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylaminobenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-4) , 5-Dichlorobenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-(2-dipropylamino-4-chloro-5-trifluoromethyloxybenzyl) -carbamic acid methyl ester, [3 -(N-Butyl-N-ethylamino) naphthalen-2-ylmethyl]-(3-cyano-5-trifluoromethylbenzyl) -carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-
(2-dipropylamino-4-methyloxybenzyl)
-Carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (N-propionyl-N-propylamino) indan-5-ylmethyl] carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl) -[6- (N-Ethoxycarbonyl-N-propylamino) indan-5-ylmethyl] carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[6- (1-propylbutoxy) indan-5- Ilmethyl] carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-
[6- (1-Ethylpropyloxy) indan-5-ylmethyl] carbamic acid methyl ester, (3,5-bistrifluoromethylbenzyl)-[4,5-dimethyl-2- (1-propylbutyl) benzyl] carbamine A CETP activity inhibitor comprising an acid methyl ester and (3-cyano-5-trifluoromethylbenzyl)-[6- (1-propylbutyl) indan-5-ylmethyl] -carbamic acid methyl ester. 12. The CETP activity inhibitor according to claim 1, which is a prophylactic or therapeutic drug for hyperlipidemia. 13. The CETP activity inhibitor according to claim 1, which is a preventive or therapeutic drug for arteriosclerosis. 14. A compound represented by the general formula (I ′); [Chemical 3] [Wherein (a) X₁’And X_Four′ Is a hydrogen atom, X
_Two’Is replaced by a hydrogen atom, a halogen atom, or a halogen atom.
Optionally substituted alkyl group having 1 to 6 carbon atoms or ha
C 1-6 carbon atoms which may be substituted with a rogen atom
Rucoxy group, X_Three'Is also a hydrogen atom or a halogen atom
Preferably 1 carbon atom which may be substituted with a halogen atom
An alkyl group of 6 to 6 or (b) X₁’Is hydrogen
A child, X_Two’And X_Three’Or X_Three’And X_Four’
Taken together may be substituted with a halogen atom
Charcoal optionally substituted with an alkyl group having 1 to 6 carbon atoms
A cycloalkane ring or benzene ring with a prime number of 3 to 8
Forming, X_Two’, X_Three’Or X_FourRing of '
The groups not forming a group are the same or different, a hydrogen atom,
Halogen atom, charcoal optionally substituted with halogen atom
Substitute with an alkyl group having a prime number of 1 to 6 or a halogen atom
An optionally substituted alkoxy group having 1 to 6 carbon atoms
R, Y₁’, Y_Three’And Y₅'Is a hydrogen atom,
Y_TwoIs a halogen atom, a nitro group or a halogen atom.
An optionally substituted alkyl group having 1 to 6 carbon atoms
R, Y_Four'Is a halogen atom, nitro group, cyano group, halo
Alkyl having 1 to 6 carbon atoms which may be substituted with a gen atom.
Kill group, alkylsulfonyl group having 1 to 6 carbon atoms, carbon
Alkoxycarbonyl group having 1 to 6 carbon atoms, 1 to 6 carbon atoms
A carbamoyl group optionally substituted with an alkyl group,
An optionally substituted alkyl group having 1 to 6 carbon atoms
A minosulfonyl group or an aromatic heterocyclic group, A ′
Is the formula (a); -N (R¹⁰¹)_Two, -N (R¹⁰¹)
(R¹⁰²), -N (R^{10 1}) (R¹⁰³), -N
(R¹⁰¹) (R¹⁰⁴) Or -N (R¹⁰¹)
(R¹⁰⁵) (Where R is¹⁰¹Is a C3-8 carbon
C1-C6 optionally substituted with a low alkyl group
An alkyl group, R¹⁰²Is aralkyl having 7 to 16 carbon atoms
R group, R¹⁰³Is an alkenyl group having 2 to 6 carbon atoms,
R¹⁰⁴Is an alkoxycarbonyl group having 1 to 6 carbon atoms,
R¹⁰⁵Represents an alkanoyl group having 1 to 6 carbon atoms
You ), And (b) a 5- to 7-membered cyclic amino
Group, formula (c); -C (R¹⁰⁶) (R¹⁰⁷) (Where
R¹⁰⁶And R¹⁰⁷May be the same or different
C 1 to C which may be substituted with a halogen atom
6 represents an alkyl group. ) Group or
(D) Formula; -OC (R¹⁰⁶) (R¹⁰⁷) (Where
R¹⁰⁶And R¹⁰⁷Is the same as defined above. ) Indicated by
Z'is a group of formula; -Z₁’-Z_Two’(In the formula,
Z₁'Is -CO- or -CS- and Z _Two’Is hydrogen
Child, a carbon atom which may be substituted with a halogen atom, from 1 to
10 alkoxy groups, even if substituted with halogen atoms
Good C1 to C15 alkyl, amino or mono
-Or Di-C_1-4It is an alkylamino group. )so
It is a group shown. ] The compound or its salt shown by these. 15. The compound or a salt thereof according to claim 14, wherein Z ₁ ′ is —CO—. 16. The compound or salt thereof according to claim 15, wherein Z ₂ 'is a methoxy group. 17. X ₁ ′ is a hydrogen atom, and X ₂ ′ and X ₃ ′ or X ₃ ′ and X ₄ ′ are taken together and have 1 to 6 carbon atoms which may be substituted with a halogen atom. Forming a cycloalkane ring or benzene ring having 3 to 8 carbon atoms which may be substituted with an alkyl group,
X ₂ ', X ₃ ' or X ₄ 'have the same or different groups that do not form a ring group, and a hydrogen atom, a halogen atom,
The compound according to claim 16, which is an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom. Its salt. 18. X ₁ ′ and X ₄ ′ are hydrogen atoms,
18. The compound or a salt thereof according to claim 17, wherein X ₂ 'and X ₃ ' together form a cycloalkane ring having 3 to 8 carbon atoms. 19. X ₁ 'and X ₄ ' are hydrogen atoms,
X ₂ 'is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom, or an alkoxy group having 1 to 6 carbon atoms which may be substituted with a halogen atom, and X ₃ 'Is a hydrogen atom, a halogen atom or a carbon atom which may be substituted with a halogen atom 1
17. The alkyl group of 6 to 6
Or a salt thereof. 20. Y ₁ ′, Y ₃ ′ and Y ₅ ′ are hydrogen atoms, Y ₂ ′ is a halogen atom, a nitro group or a trifluoromethyl group, and Y ₄ ′ is a halogen atom, a methyl group,
20. A compound or a salt thereof according to claim 17, which is a nitro group, a cyano group, a methylsulfonyl group, a trifluoromethyl group or a methoxycarbonyl group. 21. The compound or salt thereof according to claim 20, wherein Y ₂ ′ is a trifluoromethyl group and Y ₄ ′ is a nitro group, a cyano group or a trifluoromethyl group. 22. A'is the following formula: 15. A substituent selected from
21. The compound or salt thereof according to any one of 21 to 21. 23. A medicine comprising the compound according to any one of claims 14 to 22 or a pharmaceutically acceptable salt thereof. 24. General formula (III); [Chemical 5] (In the formula, Y₁~ Y₅Represents a hydrogen atom or any substituent.
Forget ) Or a salt thereof and a compound represented by the general formula (I
V); [Chemical 6] (In the formula, X₁~ X_FourRepresents a hydrogen atom or any substituent.
Where A is a disubstituted amino group or an optionally substituted amino group.
Lucoxy group, optionally substituted alkylthio group, or
An optionally substituted hydrocarbon group having 1 to 20 carbon atoms
Represent. Also, X_TwoAnd X_Three, X_ThreeAnd X_FourOr X_Fouras well as
A homocyclic group which, together with A, may have a substituent
Or forming a heterocyclic group which may have a substituent
Good. ) Is reacted with a compound represented by
Or a general formula (V); [Chemical 7] (In the formula, Y₁~ Y₅Has the same meaning as above. )
Compound or salt thereof, and general formula (VI); [Chemical 8] (In the formula, X₁~ X_FourAnd A are as defined above. )
The compound represented by the general formula (VI
I); [Chemical 9] (In the formula, X₁~ X_Four, Y₁~ Y₅And A agree with the above
Righteousness. ), A compound represented by
To the amino group of the compound represented by formula (VII), the formula (II); -Z₁-Z_Two (In the formula, Z₁Is -CO-, -CS- or -SO_Two-Show
I, Z_TwoIs a hydrogen atom, optionally substituted carbon atom 1
To 20 hydrocarbon groups, optionally substituted amino
Group, optionally substituted alkoxy group or substituted
It represents an optionally substituted alkylthio group. ) Group Z represented by
Of the compound according to claim 1, characterized in that
Production method.