JP3290962B2 - CETP activity inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel CETP activity inhibitor comprising a compound having a bis- (2-aminophenyl) disulfide structure or a 2-aminophenylthio structure as an active ingredient, especially atherosclerosis or hyperlipidemia. The present invention relates to a therapeutic or prophylactic agent for the disease. The present invention also relates to a compound having a bis- (2-aminophenyl) disulfide structure or a 2-aminophenylthio structure, a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0002]

2. Description of the Related Art It has been considered that the relationship between arteriosclerosis and serum lipoprotein has a certain relationship from the results of many epidemiological studies. For example, Ba
dimon et al. (J. Clin. Invest., 85,
1234-1124 (1990)), when a fraction containing HDL (high-density lipoprotein) and VHDL (ultra-high-density lipoprotein) was intravenously injected into cholesterol-loaded rabbits, it prevented not only the progression of atherosclerotic lesions but also regression. It has been reported that HDL and VHDL have anti-atherosclerotic effects in relation to atherosclerotic diseases and serum lipoproteins.

In recent years, the existence of a protein that transfers lipids between blood lipoproteins, that is, CETP (cholesterol ester transfer protein) has been revealed. CETP is 1965
Nichols & Smith (J. Lipid R
es. , 6, 206, 1965) for the first time, and its cDNA was cloned in 1987 by Drayna et al. Its molecular weight is 74,000 Da as a glycoprotein, and when the sugar chain is completely cleaved, about 58,000
000 Da. The cDNA was composed of 1656 residues, followed by 476 following 17 signal peptides.
Of the amino acids, about 44% of which are hydrophobic amino acids, are extremely hydrophobic, and are easily deactivated by oxidation. In addition, CETP is synthesized in organs such as liver, spleen, adrenal gland, adipose tissue, small intestine, kidney, skeletal muscle, and myocardium. CaC
o2 cells, hepatocytes (for example, human hepatoma cell-derived strain H
(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 cultures, sheep choroid plexus, and the like.

[0004] It has been clarified that CETP is involved in the metabolism of all lipoproteins in vivo and plays a major role in the reverse cholesterol transfer system. That is, it has attracted attention as a mechanism for preventing the accumulation of cholesterol in peripheral cells and for 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 a reduction in CE (cholesterol ester) of HDL in blood is one of the risk factors for coronary artery disease. Also CE
TP activity differs depending on the animal species, and in animals with low activity,
Arteriosclerosis due to cholesterol load is hardly caused,
Conversely, it is easily induced in highly active animals, CET
In the case of P deficiency, it is evident that hyper-HDL and low LDL (low-density lipoprotein) blood are caused, and it becomes difficult to develop arteriosclerosis.
The importance of CETP in mediating the transfer of CE in L to blood LDL has been recognized.

[0005] By the way, free cholesterol (FC) synthesized and secreted in the liver is a very low density lipoprotein (VL).
DL). Next, VLDL is activated in the blood by the action of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) to produce intermediate-density lipoprotein (ID).
After L), it is metabolized to LDL. LDL is LD
It is taken into peripheral cells via the L receptor, and FC is supplied to the cells. Contrary to such a flow from the liver to peripheral cells, there is a flow of cholesterol from peripheral cells to the liver called a reverse cholesterol transfer system. That is, FC accumulated in peripheral tissues is extracted by HDL, further esterified on HDL by the action of LCAT (lecithin: cholesterol acyltransferase) to form CE, and migrates to the hydrophobic core of HDL. It matures into spherical HDL particles. CE in HDL is transferred to apoB-containing lipoproteins such as VLDL, IDL and LDL by CETP present in the blood, and TG is transferred to HDL at a molar ratio of 1: 1 in exchange for this. CE transferred to the apoB-containing lipoprotein is taken up by the liver via the liver LDL receptor,
Cholesterol is indirectly transferred to the liver. In addition, HDL takes in apoprotein E secreted from macrophages or the like and is HDL containing CE-rich apoprotein E.
There is also a mechanism in which this is directly taken into the liver via the LDL receptor or remnant receptor. Also, HD
There is also a pathway in which only CE in HDL is selectively taken up into hepatocytes without L particles being taken up by the liver. In addition, there are pathways by which HDL particles are taken up into hepatocytes via the so-called HDL receptor in the liver.

That is, in the state where the CETP activity is increased, since the CE transfer from the HDL increases, the HDL
CE in VLDL, IDL and C in LDL
E will increase. When the uptake of IDL and LDL into the liver increases, LDL receptors are down-regulated, and blood LDL increases. In contrast, in the CETP-deficient state,
HDL withdraws cholesterol from peripheral cells with the help of LCAT and gradually increases the size of ApoE
To win. Then, the HDL that has become apoE-rich is taken into the liver via the liver LDL receptor and is catabolized. However, in humans, this mechanism is not working well, and large HDL stagnates in the blood. As a result, the cholesterol pool in the liver shrinks and LDL decreases because of the up-regulation of the LDL receptor. Therefore, IDL, VLD that promote arteriosclerosis by selectively inhibiting CETP
L and LDL can be reduced, and HDL that acts suppressively can be increased, and it can be expected to provide an agent for preventing or treating arteriosclerosis or hyperlipidemia which has never been seen before.

[0007] Recently, there have been reports on compounds aimed at inhibiting such CETP activity. For example, Biochemical and
Biophysical Research Comm
communications 223, 42-47 (199
In 6), CE is modified by modifying a cysteine residue.
As compounds that inactivate TP, dithiodipyridine derivatives, substituted dithiodibenzene derivatives, and the like are disclosed. However, the document states that the compounds of the present invention include:
Bis- (2-aminophenyl) disulfide structure or 2
There is no description of a compound having an -aminophenylthio structure, or a description suggesting this.

[0008] WO 95/06626 discloses that
As a CETP activity inhibitor, Wiedendiol-A
And Wiedendiol-B are disclosed. However, no description suggesting the compound of the present invention is found in the publication.

Further, as compounds having an anti-atherosclerosis effect, Japanese Patent Publication No. 45-11132 and Japanese Patent Publication No. 45-2
No. 892, Japanese Patent Publication No. 45-2891, Japanese Patent Publication No. Sho 4
Japanese Patent Publication No. 5-2731 and Japanese Patent Publication No. 45-2730 disclose 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 supporting them, and no description that they have CETP activity inhibition. Further, there is no description suggesting the compound of the present invention.

[0010] On the other hand, bis-
A number of compounds having a (2-aminophenyl) disulfide structure or a 2-aminophenylthio structure have also been reported. For example, WO 96/09406 discloses a disulfide compound such as 2-acetylaminophenyl disulfide. However, the compound disclosed in the publication is a compound useful for retroviruses, that is, HIV-1, and there is no description suggesting that the compound is, of course, disclosed as useful for inhibiting CETP activity.

Japanese Patent Application Laid-Open No. Hei 8-253454 discloses 2,
Diphenyl disulfide compounds such as 2'-di (pyrimidylamino) -diphenyl disulfide are disclosed. However, the compound disclosed in the publication is a compound having an inhibitory action on IL-1β production and an inhibitory action on TNFα release, and of course, there is no disclosure of usefulness as CETP activity inhibition, and no description suggesting this.

JP-A-2-155937 discloses 2,
Bis- (acylaminophenyl) disulfide compounds such as 2'-diacetylaminodiphenyl disulfide are disclosed. However, the compound disclosed in the publication relates to a method for producing a vulcanized rubber filled with carbon black, and there is no description of usefulness as CETP activity inhibition, and no description suggesting this. In the claims of the publication, C ₅ -C ₁₂ cycloalkyl and cycloalkenyl are defined as R ⁹ and R ¹⁰ , and specific examples thereof include cyclohexyl and cyclohexenyl. There is no description in the text of the working examples supporting its use or its general production method.

JP-A-2-501772 discloses that o-
Acylaminophenyl disulfide derivatives such as pivaloylaminophenyl disulfide are disclosed as intermediates in the manufacture of pyrazolone photographic couplers. However,
The publication relates to a photographic element and does not suggest the invention of the present application. In addition, in the specification of this publication, a 2-cyclohexanecarbonylaminophenylthio group is described as an example of the coupling-off group of the coupler, but there is no description of Examples supporting the use thereof.

Japanese Patent Application Laid-Open No. 8-171167 discloses 2-
Thiophenol derivatives such as acetylaminothiophenol or disulfide derivatives are disclosed. However, the invention of this publication relates to a silver halide emulsion and does not suggest the present invention.

JP-A-4-233908 discloses disulfide derivatives such as bis (2-acetamidophenyl) disulfide. However, the compound in this publication is disclosed as a chain transfer agent,
It does not suggest the present invention. Further, although a cyclohexyl group is disclosed as a specific example of R ₃ in X and Y, there is no description of an example or a general production method supporting the use thereof.

JP-A-63-157150 discloses that o
Amidophenyl disulfide derivatives such as pivalamidophenyl disulfide are disclosed as stabilizer compounds. However, the invention of this publication relates to a photographic element and does not suggest the present invention. Also,
In the claims of the publication, a cycloalkyl group is defined as R in the substituent V or Y of the stabilizer compound, but there is no description of examples or general production methods supporting the use thereof.

Further, JP-A-8-59900, JP-A-7-258472, JP-A-7-224028, JP-A-7-49554 and JP-A-6-190
No. 37, JP-A-6-19024, JP-A-3-19024
226750, JP-A-2-284146,
JP-A-2-23338, JP-A-1-321432
Gazette, JP-A-1-278543 and JP-B-47
No. 3,357,786 also discloses bis- (amidophenyl).
Disulfide derivatives are disclosed, but all of them are CE
Of course, there is no description suggesting the usefulness as TP inhibitory activity.

[0018]

As described above, the present inventors have conducted intensive studies to provide a compound that selectively inhibits the activity of CETP, and as a result, have found an unprecedented mechanism of action, namely, an increase in HDL. At the same time, they have found a novel compound that can lower LDL and is useful as a preventive or therapeutic agent for arteriosclerosis or hyperlipidemia, and completed the present invention.

[0019]

That is, the present invention relates to compounds and medicaments having the following CETP activity inhibitory activities (1) to (7).

(1) General formula (I)

[0021]

Embedded image

[0022] In the formula, R is a linear or branched C _1-10 alkyl group; a linear or branched C _2-10 alkenyl group, halogenated C _1-4 lower alkyl group; C _{3- 10} cycloalkyl group;
C _5-8 cycloalkenyl group; C _3-10 cycloalkyl C
_1-10 alkyl group (where the cycloalkyl group, cycloalkenyl group or cycloalkylalkyl group is a linear or branched C _1-10 alkyl group; a linear or branched C _1-10 alkyl group;
_2-10 alkenyl; C _3-10 cycloalkyl group; C _5-8 cycloalkenyl group; C _3-10 cycloalkyl C _1-10 alkyl group; an aryl group; an amino group; C _1-4 lower alkylamino group; An acylamino group; an oxo group; an aralkyl group; and an arylalkenyl group, which may be substituted); an aryl group; an aralkyl group; or 5 to 6 having 1 to 3 nitrogen, oxygen, or sulfur atoms.
Membered heterocyclic group (where the aryl group, aralkyl group or heterocyclic group is a linear or branched C _1-10 alkyl group;
A linear or branched C _2-10 alkenyl group; a halogen atom;
Nitro group; amino group optionally substituted with a C _1-4 lower alkyl group or an acyl group; hydroxyl group; C _1-4 lower alkoxy group; C _1-4 lower alkylthio group; halogenated C _1-4 lower alkyl group An acyl group; and an oxo group), and X ₁ , X ₂ , X ₃ ,
X ₄ may be the same or different and are a hydrogen atom; a halogen atom; a C _1-4 lower alkyl group; a halogenated C _1-4 lower alkyl group; a C _1-4 lower alkoxy group; a cyano group; Or an aryl group, wherein Y is -CO-;
Or -SO ₂ - and and, Z is hydrogen atom; or dimeric a is group forming a disulfide body, C _1-4 lower alkoxymethyl group, C _{1 -4} lower alkylthiomethyl group, an aralkyloxy methyl group, aralkyl Thiomethyl group, C _3-10 cycloalkyloxymethyl group, C _5-8 cycloalkenyloxymethyl group, C _3-10 cycloalkyl C _1-10 alkoxymethyl group, aryloxymethyl group, arylthiomethyl group, acyl group , An acyloxy group, an aminocarbonyloxymethyl group, a thiocarbonyl group or a thio group.], A prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate thereof or CET containing solvate as active ingredient
P activity inhibitor.

(2) R is a linear or branched C _1-10 alkyl group; a linear or branched C _2-10 alkenyl group; 1 to 3 selected from a fluorine atom, a chlorine atom and a bromine atom Halogenated C _1-4 lower alkyl group substituted with two halogen atoms; C _3-10 cycloalkyl group _optionally substituted with one to four substituents selected from the following, C _5-8 cycloalkenyl A group or a C _3-10 cycloalkyl C _1-10 alkyl group;
Linear or branched C _1-10 alkyl group, linear or branched C _2-10 alkenyl group, C _3-10 cycloalkyl group, C _5-8
An aralkyl group having a cycloalkenyl group, a C _3-10 cycloalkyl C _1-10 alkyl group, an aryl group selected from phenyl, biphenyl and naphthyl, an oxo group or an aryl group selected from phenyl, biphenyl and naphthyl; An aryl group, an aralkyl group or a 5- or 6-membered heterocyclic group having 1 to 3 nitrogen, oxygen or sulfur atoms which may be substituted with 1 to 4 substituents; _1-10 alkyl group, straight or branched C _2-10 alkenyl group, halogen atom selected from fluorine atom, chlorine atom or bromine atom, nitro group or halogen atom selected from fluorine atom, chlorine atom or bromine atom Is a halogenated C _1-4 lower alkyl group having the formula: wherein Z is a hydrogen atom; a mercapto protecting group selected from the following group; A group to be formed, a C _1-4 lower alkoxymethyl group, a C _1-4 lower alkylthiomethyl group, an aralkyloxymethyl group having an aryl group selected from phenyl, biphenyl and naphthyl, an aryl group selected from phenyl, biphenyl and naphthyl. aralkylthio methyl group having, C _3-10 cycloalkyl oxymethyl group, C _5-8 cycloalkenyl oxymethyl group, C _3-10 cycloalkyl C _1-10 alkoxymethyl group, phenyl, biphenyl, aryl group selected from naphthyl (1) which is an aryloxymethyl group having an aryl group selected from phenyl, biphenyl and naphthyl, an acyl group, an acyloxy group, an aminocarbonyloxymethyl group, a thiocarbonyl group and a thio group. Compounds, their prodrug compounds, their physicians Salts that may be above acceptable, or CETP activity inhibitor comprising as an active ingredient a hydrate or solvate thereof.

(3) General formula (I-1)

[0025]

Embedded image

Wherein R, X ₁ , X ₂ , X ₃ , X ₄ and Y are the same as those in the above (2), and Z ₁ is a hydrogen atom;

[0027]

Embedded image

(Where R, X₁, X_Two, X_Three, X_FourAnd Y are
Each is as described above);₁R₁ [Where Y
₁Is -CO-; or -CS-;₁Is linear or branched
C_1-10An alkyl group (where the alkyl group is
_1-4Lower alkoxy group; C_1-4Lower alkyl group, acyl group
Or an amino group optionally substituted with a hydroxyl group; C_1-4Low
Primary alkylthio group; carbamoyl group; hydroxyl group; halogen
An atom; an acyloxy group; a carboxy group; an acyl group;
C_1-10Substituted with an alkyl, halogen or nitro group
By a group selected from an optionally substituted aryloxy group
Optionally substituted); C_1-4Lower alkoxy group; C
_1-4Lower alkylthio group; amino group; ureido group (here
And these amino or ureido groups are C_1-4Low-grade alk
A hydroxyl group; an acyl group; and C_1-4Lower alkoxy group
With a group selected from an aryl group which may be substituted with
May be substituted); C_3-10Cycloalkyl group;
C_3-10Cycloalkyl C_1-10An alkyl group (where
A cycloalkyl group or a cycloalkylalkyl group
Chain or branched C_1-10Alkyl group; linear or branched C
_2-10Alkenyl group; C_3-10Cycloalkyl group; C_5-8Shi
Chloroalkenyl group; C_3-10Cycloalkyl C_1-10Archi
Aryl group; amino group; C_1-4Lower alkyl amine
An amino group; an oxo group; an aralkyl group;
Substituted by a group selected from arylalkenyl groups
Aryl group; aralkyl group; aryl group
Alkenyl group; arylthio group; nitrogen atom, oxygen atom or
A 5- or 6-membered heterocyclic group having 1 to 3 sulfur atoms;
Is a 5- or 6-membered heteroarylalkyl group (wherein
Aryl, aralkyl, arylalkenyl
Group, arylthio group, heterocyclic group or heteroaryl group
Linear or branched C_1-10Alkyl group; linear or branched
C_2-10Alkenyl group; halogen atom; nitro group; C_1-4
A which may be substituted with a lower alkyl group or an acyl group;
Amino group; hydroxyl group; C_1-4Lower alkoxy group; C_1-4Lower class
Alkylthio group; halogenated C_1-4Lower alkyl group; reed
Substituted by a group selected from the group consisting of
Or -SR._Two  [Where R_TwoIs C_1-4A lower alkyl group (where the lower alkyl group
Primary alkyl group is C_1-4Lower alkoxy group; C_1-4Low Al
An amino group optionally substituted with a kill group or an acyl group;
C_1-4Lower alkylthio group; carbamoyl group; hydroxyl group;
A group selected from a carboxy group; an acyl group; and a heterocyclic group
Or an aryl group (here,
And the aryl group is C_1-4Lower alkyl group; fluorine atom
A halogen atom selected from a hydrogen atom, a chlorine atom or a bromine atom;
Nitro group; hydroxyl group; C_1-4Lower alkoxy group; C_1-4Low grade
Alkylthio group; acyl group; C_1-4Lower alkyl group or
An amino group optionally substituted with an acyl group;
A halogen atom selected from a hydrogen atom, a chlorine atom or a bromine atom
Halogenated C having_1-4Groups selected from lower alkyl groups
Which may be replaced by a)]
Compound according to the above (2), and its prodrug compound
Or a pharmaceutically acceptable salt thereof, or a hydrate or
A CETP activity inhibitor comprising a solvate as an active ingredient.

(4) R₁Is one to three selected from the following
Linear or branched C which may be substituted with a substituent
_1-10Alkyl group: fluorine atom, chlorine atom or bromine atom
A halogen atom selected from C_1-4Lower alkoxy group, C
_1-4Substituted with a lower alkyl group, an acyl group or a hydroxyl group
Optionally amino group, C_1-4Lower alkylthio group, cal
Reeds having a bamoyl, hydroxyl, acyl, or acyl group
Ruoxy group, carboxy group, fluorine atom, chlorine atom or
Even when substituted with a halogen atom selected from a bromine atom
Good aryloxy group C_1-4Lower alkoxy group; C_1-4Low
Lower alkylthio group; one or two substituents selected from the following
An amino group or a ureido group optionally substituted with a group; C
_1-4Lower alkyl group, hydroxyl group, acyl group, C_1-4Low Al
Aryl group optionally substituted by a oxy group C optionally substituted by a substituent selected from the following_3-10
Cycloalkyl group or C _3-10Cycloalkyl C_1-10Al
Kill group; straight-chain or branched C_1-10Alkyl group, C_3-10Shi
Chloroalkyl group, C_5-8Cycloalkenyl group, aryl
Group, amino group, C_1-4C having a lower alkyl group_1-4Low grade
Alkylamino group, acylamino group having an acyl group, which is substituted with 1 to 4 substituents selected from the following:
Aryl, aralkyl, arylalkenyl
Group or arylthio group; C_1-10Alkyl group, fluorine source
, A halogen atom selected from a chlorine atom or a bromine atom,
Nitro group, hydroxyl group, C_1-4Lower alkoxy group, C_1-4Low grade
Alkylthio group, acyl group halogen atom selected from fluorine atom, chlorine atom or bromine atom
C having halogen atom_1-4Lower alkyl group, C_1-4
A which may be substituted with a lower alkyl group or an acyl group;
Mino group substituted with 1 to 4 substituents selected from
1 to 3 nitrogen, oxygen or sulfur atoms
5- or 6-membered heterocyclic group
Alkyl group; linear or branched C_1-10Alkyl group,
Halogen selected from nitrogen, chlorine or bromine
Atom, acyl group, oxo group halogen atom selected from fluorine atom, chlorine atom or bromine atom
C having halogen atom_1-4A lower alkyl group
R_TwoIs substituted with 1 to 3 substituents selected from
C that may be_1-4Lower alkyl group; C_1-4Low Al
Coxy group, C_1-4Substituted with a lower alkyl group or an acyl group
An optionally substituted amino group, C_1-4Lower alkylthio group,
Carbamoyl, hydroxyl, carboxy, acyl, nitrogen
5-amino having 1 to 3 elementary, oxygen or sulfur atoms
6 to 6 membered heterocyclic group substituted with 1 to 4 substituents selected from
A good aryl group; C_1-4Lower alkyl group, fluorine atom
, A halogen atom selected from a chlorine atom or a bromine atom,
Nitro group, hydroxyl group, C_1-4Lower alkoxy group, C_1-4Low grade
Alkylthio group, acyl group C_1-4Even if substituted with a lower alkyl group or an acyl group
From good amino, fluorine, chlorine or bromine atoms
Halogenated C having selected halogen atom_1-4Lower class
A compound according to the above (3), which is
Compound, a pharmaceutically acceptable salt thereof, or a hydrate thereof
Alternatively, CETP activity inhibition using a solvate as an active ingredient
Harmful agents.

(5) Bis- [2- (pivaloylamino)
Phenyl] disulfide; bis- [2- (2-propylpentanoylamino) phenyl] disulfide; bis-
[2- (1-methylcyclohexanecarbonylamino)
Phenyl] disulfide; bis- [2- (1-isopentylcyclopentanecarbonylamino) phenyl] disulfide; bis- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] disulfide; N-
(2-mercaptophenyl) -2,2-dimethylpropionamide; N- (2-mercaptophenyl) -1-isopentylcyclohexanecarboxamide; N- (2-
N- (2-mercaptophenyl) -1-isopentylcyclopentanecarboxamide; N- (2-mercaptophenyl) -1-methylcyclohexanecarboxamide;
Mercaptophenyl) -1-isopropylcyclohexanecarboxamide; N- (4,5-dichloro-2-mercaptophenyl) -1-isopentylcyclohexanecarboxamide; N- (4,5-dichloro-2-mercaptophenyl) -1-iso Pentylcyclopentanecarboxamide; N- (2-mercapto-5-methylphenyl) -1-isopentylcyclohexanecarboxamide; N- (2-mercapto-4-methylphenyl) -1
-Isopentylcyclohexanecarboxamide; S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] thioacetate; S- [2- (1-Methylcyclohexanecarbonylamino) phenyl] 2,2-dimethylthiopropionate Phenylthioacetic acid S- [2- (pivaloylamino) phenyl]
Ester; 2,2-dimethylthiopropionic acid S-
[2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2-acetylamino-3-
Phenylthiopropionic acid S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 3-pyridinethiocarboxylic acid S- [2- (1-
Isopentylcyclohexanecarbonylamino) phenyl] ester; S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] chlorothioacetate
Esters: S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] methoxythioacetate; S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] thiopionate; S- [2] phenoxythioacetate -(1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2-methylthiopropionic acid S- [2- (1-
Isopentylcyclohexanecarbonylamino) phenyl] ester; 4-chlorophenoxythioacetic acid S-
[2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester of cyclopropanethiocarboxylic acid; 2-acetylamino-4-carbamoylthiobutyric acid S- [2-
(1-Isopentylcyclohexanecarbonylamino)
Phenyl] ester; 2-hydroxy-2-methylthiopropionic acid S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2
-Dimethylthiopropionic acid S- [2- (1-isopentylcyclopentanecarbonylamino) phenyl] ester; thioacetic acid S- [2- (1-isopentylcyclopentanecarbonylamino) phenyl] ester;
2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2 -(1-
Isopentylcyclopentanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S
-[2- (1-Isopentylcyclohexanecarbonylamino) -4-trifluoromethylphenyl] ester; O-methyl thiocarbonate S- [2- (1-
Isopentylcyclohexanecarbonylamino) phenyl] ester; S- [2- (1-methylcyclohexanecarbonylamino) phenyl] dithiocarbonate
S-phenyl ester; N-phenylthiocarbamic acid S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [2- (pivaloylamino) -4
-Trifluoromethylphenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2
-(1-cyclopropylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (2-cyclohexylpropionylamino) phenyl] ester;
2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-pentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1 -Cyclopropylmethylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S
-[4,5-dichloro-2- (1-cyclohexylmethylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5
-Dichloro-2- (1-isopropylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2-
(1-Isopentylcycloheptanecarbonylamino)
Phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-isopentylcyclobutanecarbonylamino) phenyl] ester;
2,2-dimethylthiopropionic acid S- [2- (1-
Isopentylcyclohexanecarbonylamino) -4-
Nitrophenyl] ester; 2,2-dimethylthiopropionic acid S- [4-cyano-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4-chloro- 2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [5-chloro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethyl Thiopropionic acid S- [4-
Fluoro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-difluoro-2-
(1-Isopentylcyclohexanecarbonylamino)
Phenyl] ester; 2,2-dimethylthiopropionic acid S- [5-fluoro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; bis- [4,5-dichloro-2- (1-isopentyl) Cyclohexanecarbonylamino) phenyl] disulfide; 2-tetrahydrofurylmethyl 2- (1-isopentylcyclohexanecarbonylamino) phenyl disulfide; N- (2-mercaptophenyl) -1-ethylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-propylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-butylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-isobutylcyclohexanecarboxamide; cyclohexanethio Acid S- [2- (1
-Isopentylcyclohexanecarbonylamino) phenyl] ester; S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] thiobenzoate
Ester; 5-carboxythiopentanoic acid S- [2-
(1-Isopentylcyclohexanecarbonylamino)
Phenyl] ester; thioacetic acid S- [2- (1-isopentylcyclohexanecarbonylamino) -4-methylphenyl] ester; bis- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] disulfide; N -(2-mercaptophenyl)-
1- (2-ethylbutyl) cyclohexanecarboxamide; 2-methylthiopropionic acid S- [2- [1-
(2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 2-methylthiopropionic acid S- [2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester; 1-acetylpiperidine-4-thiocarboxylic acid S- [2- [ 1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] thioacetate; 2,2-dimethylthiopropionic acid S
-[2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; methoxythioacetic acid S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 2-hydroxy-2-methylthio Propionic acid S- [2- [1
-(2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 4-chlorophenoxythioacetic acid S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 4-chlorophenoxythioacetic acid S- [ 2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester;
1-acetylpiperidine-4-thiocarboxylic acid S-
The compound according to the above (1), a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which is selected from the group consisting of [2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester. A CETP activity inhibitor comprising, as an active ingredient.

(6) Prevention of hyperlipidemia comprising the compound according to (1) to (5) above, a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. Or therapeutic drugs.

(7) Prevention or treatment of arteriosclerosis comprising a compound according to the above (1) to (5), a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. medicine.

Here, the term "linear or branched C _1-10 alkyl group" means an alkyl group having 1 to 10 carbon atoms which may be linear or branched. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylbutyl, 2-
Ethylbutyl group, 1-propylbutyl group, 1,1-dimethylbutyl group, 1-isobutyl-3-methylbutyl group,
1-ethylpentyl group, 1-propylpentyl group, 1-
Isobutylpentyl group, 2-ethylpentyl group, 2-isopropylpentyl group, 2-tert-butylpentyl group, 3-ethylpentyl group, 3-isopropylpentyl group, 4-methylpentyl group, 1,4-dimethylpentyl group, 2,4-dimethylpentyl group, 1-ethyl-4-methylpentyl group, hexyl group, 1-ethylhexyl group,
1-propylhexyl group, 2-ethylhexyl group, 2
-Isopropylhexyl group, 2-tert-butylhexyl group, 3-ethylhexyl group, 3-isopropylhexyl group, 3-tert-butylhexyl group, 4-ethylhexyl group, 5-methylhexyl group, heptyl group, 1-
Ethylheptyl group, 1-isopropylheptyl group, 2-
Ethylheptyl group, 2-isopropylheptyl group, 3-
Propylheptyl group, 4-propylheptyl group, 5-ethylheptyl group, 6-methylheptyl group, octyl group,
Examples thereof include a 1-ethyloctyl group, a 2-ethyloctyl group, a nonyl group, a 1-methylnonyl group, a 2-methylnonyl group, and a decyl group. Preferably, it is a linear or branched alkyl group having 1 to 8 carbon atoms.

The term "C _1-4 lower alkyl group" means an alkyl group having 1 to 4 carbon atoms which may be straight or branched, and specifically, a methyl group, Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
Examples are a sec-butyl group and a tert-butyl group.

"Linear or branched C _2-10 alkenyl group"
Means an alkenyl group having at least one double bond having 2 to 10 carbon atoms which may be linear or branched, and specifically, an allyl group, a vinyl group,
Isopropenyl group, 1-propenyl group, 1-methyl-2
-Propenyl group, 2-methyl-2-propenyl group, 1-
Methyl-1-butenyl group, crotyl group, 1-methyl-3
-Butenyl group, 3-methyl-2-butenyl group, 1,3-
Dimethyl-2-butenyl group, 1-pentenyl group, 1-methyl-2-pentenyl group, 1-ethyl-3-pentenyl group, 4-pentenyl group, 1,3-pentadienyl group,
2,4-pentadienyl group, 1-hexenyl group, 1-methyl-2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 1-butyl-5-hexenyl group, 1,3-hexadienyl group, 2,4 -Hexadienyl group, 1-heptenyl group, 2-heptenyl group, 3-heptenyl group, 4-
Heptenyl group, 5-heptenyl group, 6-heptenyl group,
1,3-heptadienyl group, 2,4-heptadienyl group, 1-octenyl group, 2-octenyl group, 3-octenyl group, 4-octenyl group, 5-octenyl group, 6-octenyl group, 7-octenyl group, 1 -Nonenyl group, 2-
A nonenyl group, a 3-nonenyl group, a 4-nonenyl group, a 5-nonenyl group, a 6-nonenyl group, a 7-nonenyl group, an 8-nonenyl group, a 9-decenyl group and the like. Preferably, it is a linear or branched alkenyl group having 2 to 8 carbon atoms.

The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom or the like.

The term "halogenated C _1-4 alkyl group" means the above-mentioned C _1-4 lower alkyl group substituted with 1 to 3 identical or different halogen atoms. Methyl group, chloromethyl group, bromomethyl group,
Difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, chloroethyl group, difluoroethyl group, trifluoroethyl group, pentachloroethyl group, bromopropyl group, dichloropropyl group, trifluorobutyl group and the like. Preferred are a trifluoromethyl group and a chloroethyl group.

The term "C _1-4 lower alkoxy group" means an alkoxy group having the aforementioned C _1-4 lower alkyl group,
Specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec
-Butoxy group, tert-butoxy group and the like.

The term "C _1-4 lower alkylthio group" means an alkylthio group having the above-mentioned C _1-4 lower alkyl group, and specifically includes a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group. Group, isobutylthio group, sec-butylthio group, tert-butylthio group and the like.

“C _3-10 cycloalkyl group” refers to a monocyclic or polycyclic C _3-10 cycloalkyl group.
And specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, octahydroindenyl, decahydronaphthyl, bicyclo [2.2 .1] heptyl group, adamantyl group and the like. Preferred are cyclopentyl, cyclohexyl, and cycloheptyl having 5 to 7 carbon atoms.

The "C _5-8 cycloalkenyl group" means a cycloalkenyl group having one or more double bonds on the ring and having 5 to 8 carbon atoms, specifically, a cyclopentenyl group, a cyclopentenyl group and a cyclopentyl group. Hexenyl group, cycloheptenyl group, cyclooctenyl group, cyclopentadienyl group, cyclohexadienyl group, cycloheptadienyl group, cyclooctadienyl group and the like. Preferred are a cyclopentenyl group, a cyclohexenyl group and a cycloheptenyl group having 5 to 7 carbon atoms.

"C_3-10Cycloalkyl C_1-10Alkyl
"Group" means the above-mentioned straight-chain or branched C _1-10To the alkyl group
The above C_3-10Means substituted with cycloalkyl group
And specifically, a cyclopropylmethyl group, a cyclopentene
Methyl group, cyclohexylmethyl group, cyclohexyl
Cyclopentylmethyl group, dicyclohexylmethyl group,
1-cyclopentylethyl group, 1-cyclohexylethyl
Group, 2-cyclopropylethyl group, 2-cyclopentyl
Ethyl group, 2-cyclohexylethyl group, 2-cyclo
Heptylethyl group, 1-cyclohexyl-1-methyle
Tyl group, 1-cyclohexylpropyl group, 2-cyclope
Ethylpropyl group, 3-cyclobutylpropyl group, 3-
Cyclopentyl propyl group, 3-cyclohexyl propyl
Group, 3-cycloheptylpropyl group, 1-cyclopro
Pill-1-methylpropyl group, 1-cyclohexyl-2
-Methylpropyl group, 1-cyclopentylbutyl group, 1
-Cyclohexylbutyl group, 3-cyclohexylbutyl
Group, 4-cyclopropylbutyl group, 4-cyclobutylbutyl
Tyl group, 4-cyclopentylbutyl group, 1-cyclohexyl
Sil-1-methylbutyl group, 1-cyclopentyl-2-
Ethylbutyl group, 1-cyclohexyl-3-methylbutyi
Group, 1-cyclopentylpentyl group, 1-cyclohexyl
Silpentyl group, 1-cyclohexylmethylpentyl
Group, 2-cyclohexylpentyl group, 2-cyclohexyl
Methylpentyl group, 3-cyclopentylpentyl group,
1-cyclohexyl-4-methylpentyl group, 5-cycl
Lopentylpentyl group, 1-cyclopentylhexyl
Group, 1-cyclohexylhexyl group, 1-cyclopentene
Methylhexyl group, 2-cyclopentylhexyl group,
2-cyclopropylethylhexyl group, 3-cyclopen
Tylhexyl group, 1-cyclohexylheptyl group, 1-
Cyclopentyl-1-methylheptyl group, 1-cyclohexyl
Xyl-1,6-dimethylheptyl group, 1-cyclohep
Tyloctyl group, 2-cyclopentyloctyl group, 3-
Cyclohexyloctyl group, 2-cyclopentylmethyl
Octyl group, 1-cyclopentylnonyl group, 1-cyclo
Hexylnonyl group, 3-cyclopropylnonyl group, 1-
Cyclopentyl decyl group, 1-cyclohexyl undeci
Group, 1-cyclopentyltridecyl group, 2-cyclo
A xyltridecyl group and the like.

The "aryl group" includes a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group and the like. Preferred are a phenyl group, a naphthyl group and a biphenyl group.

The "aralkyl group" means a group in which one or more of the above-mentioned aryl groups are substituted with the above-mentioned C _1-4 lower alkyl groups, and specifically, a benzyl group, a benzhydryl group,
Trityl group, phenethyl group, 3-phenylpropyl group,
Examples thereof include a 2-phenylpropyl group, a 4-phenylbutyl group, a naphthylmethyl group, a 2-naphthylethyl group, a 4-biphenylmethyl group, and a 3- (4-biphenyl) propyl group.

The term "arylalkenyl group" means an alkenyl group having 2 to 4 carbon atoms which is substituted by the above-mentioned aryl group, specifically, 2-phenylvinyl group,
3-phenyl-2-propenyl group, 3-phenyl-2-
Examples thereof include a methyl-2-propenyl group, a 4-phenyl-3-butenyl group, a 2- (1-naphthyl) vinyl group, a 2- (2-naphthyl) vinyl group, and a 2- (4-biphenyl) vinyl group.

The "arylthio group" means an arylthio group having the above-mentioned aryl group, and specifically includes a phenylthio group, a naphthylthio group and the like.

The term "heterocyclic group" means at least one or more selected from a nitrogen atom, an oxygen atom and a sulfur atom, specifically 5 to 5 having 1 to 4, preferably 1 to 3 heteroatoms. It means a 6-membered aromatic or non-aromatic heterocyclic group, specifically, a thiatriazolyl group, a tetrazolyl group, a dithiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, an oxazolyl group, a pyrazolyl group, a pyrrolyl group, and a furyl group. , Thienyl group, tetrazinyl group, triazinyl group, pyrazinyl group, pyridazinyl group,
Pyrimidinyl group, aromatic heterocyclic group such as pyridyl group, and dioxolanyl group, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, dithiadiazinyl group,
A non-aromatic heterocyclic group such as thiadiazinyl group, morpholino group, morpholinyl group, oxazinyl group, thiazinyl group, piperazinyl group, piperidyl group, piperidino group, pyranyl group, thiopyranyl group; Preferable is an aromatic heterocyclic (heteroaryl) group such as a furyl group, a thienyl group, a pyrrolyl group, and a pyridyl group, and at least one nitrogen atom such as a pyrrolidinyl group, a tetrahydrofuryl group, a piperazinyl group, a piperidyl group, and a piperidino group. Is a non-aromatic heterocyclic group.

The term "heteroarylalkyl group" means a group in which the above-mentioned 5- to 6-membered aromatic heterocyclic (heteroaryl) group is substituted for the above-mentioned C _1-4 lower alkyl group. 2-thienylmethyl group, 2-furylmethyl group,
2-pyridylmethyl group, 3-pyridylmethyl group, 2-thienyl-2-ethyl group, 3-furyl-1-ethyl group, 2
-Pyridyl-3-propyl group and the like.

The term "acyl group" specifically means a formyl group, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaler group, a pivaloyl group,
Hexanoyl group, acryloyl group, propioloyl group,
Methacryloyl group, crotonoyl group, benzoyl group, naphthoyl group, toluoyl group, hydroatropoyl group, atropoyl group, cinnamoyl group, furoyl group, tenoyl group, nicotinoyl group, isonicotinoyl group, glycoloyl group, lactoyl group, glyceroyl group, tropoyl group ,
Benzyloyl group, salicyloyl group, anisoyl group, vanilloyl group, veratroyl group, piperoniroyl group, protocatechuyl oil group, galloyl group, cyclopentanecarbonyl group, cyclohexanecarbonyl group, cycloheptanecarbonyl group, 1-methylcyclohexanecarbonyl group,
Examples thereof include a 1-isopentylcyclopentanecarbonyl group, a 1-isopentylcyclohexanecarbonyl group, a tert-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, and a 2- (1-isopentylcyclohexanecarbonylamino) phenylthiocarbonyl group. Preferably, an acetyl group, a tert-butoxycarbonyl group, a benzoyl group, a 1-methylcyclohexanecarbonyl group, a 1-isopentylcyclopentanecarbonyl group, a 1-isopentylcyclohexanecarbonyl group,
-(1-Isopentylcyclohexanecarbonylamino) phenylthiocarbonyl group.

[0050] R, "optionally substituted C _3-10 cycloalkyl group" for R ₁ and the like, which may be "optionally substituted C _5-8 cycloalkenyl group" and "substituted C _{3 The} " _optionally substituted" in the " _-10 cycloalkyl C _1-10 alkyl group" means that it may be substituted with 1 to 4 substituents, and the substituents may be the same or different. And the position of the substituent is arbitrary and not particularly limited. Specifically linear or branched C _1-10 alkyl group described above in; a linear or branched C _2-10 alkenyl group described above; C _3-10 cycloalkyl group above; aforementioned C _{5 - 8} cycloalkenyl group; the above-mentioned C _3-10
A cycloalkyl C _1-10 alkyl group; the aforementioned aryl group;
Amino group; C _1-4 such as methylamino group, ethylamino group, etc.
Lower alkylamino group; acylamino group such as acetylamino group, propionylamino group and benzylamino group; oxo group; aralkyl group described above; arylalkenyl group described above. The above substituents are mainly recommended as substituents for R. In the case of R ₁ ,
Among them, the aforementioned linear or branched C _1-10 alkyl group; the aforementioned C _3-10 cycloalkyl group; the aforementioned C _5-8 cycloalkenyl group; the aforementioned aryl group; preferable.

"Optionally substituted aryl group", "optionally substituted 5- or 6-membered heterocyclic group having 1 to 3 nitrogen, oxygen or sulfur atoms" for R, R _{1 and the} like , "Optionally substituted aralkyl group", "optionally substituted arylalkenyl group", "optionally substituted arylthio group", and "optionally substituted 5- or 6-membered heteroarylalkyl group""May be substituted" in "" means that it may be substituted by 1 to 4, preferably 1 to 3 substituents, and the substituents may be the same or different ,
The position of the substituent is arbitrary and not particularly limited. Specifically, the above-mentioned straight-chain or branched C _1-10 alkyl group, preferably a straight-chain or branched C _1-6 alkyl group; the above-mentioned straight-chain or branched C _2-10 alkenyl A group, preferably a linear or branched C _2-6 alkenyl group; the aforementioned halogen atom; a nitro group; an amino group optionally substituted with the aforementioned C _1-4 lower alkyl group or the aforementioned acyl group. ;
A hydroxyl group; the above-mentioned C _1-4 lower alkoxy group; the above-mentioned C _1-4 lower alkylthio group; the above-mentioned halogenated C _1-4 lower alkyl group; the above-mentioned acyl group; The above substituents are mainly recommended as substituents for R ₁ , and in the case of R, particularly the above-mentioned straight-chain or branched C _1-6 alkyl group; the above-mentioned halogen atom; Is preferred.

The “optionally substituted” in the “optionally substituted linear or branched C _1-10 alkyl group” for R ₁ or the like is the same as the above. And the substituents may be the same or different, and the position of the substituent is arbitrary and not particularly limited. Specifically, the aforementioned C _1-4 lower alkoxy group; the aforementioned C _1-4 lower alkyl group, the aforementioned amino group optionally substituted with an acyl group or a hydroxyl group; the aforementioned C _1-4 lower alkylthio group; A carbamoyl group; a hydroxyl group; the above-mentioned halogen atom; the above-mentioned acyloxy group having an acyl group; the carboxy group; the above-mentioned acyl group; and the above-mentioned aryloxy group having an optionally substituted aryl group.

In R ₂ or the like, “optionally substituted C
The `` optionally substituted '' in the `` _1-4 lower alkyl group '' means that it may be substituted by 1 to 3 substituents, and the substituents may be the same or different, Further, the position of the substituent is arbitrary and is not particularly limited. Specifically, the above-mentioned C _1-4 lower alkoxy group; the above-mentioned C _1-4 lower alkyl group or the amino group optionally substituted with the above-mentioned acyl group; the above-mentioned C _1-4 lower alkylthio group; a carbamoyl group A hydroxyl group; a carboxy group;
The aforementioned acyl group; the aforementioned heterocyclic group (especially an aromatic bicyclic group such as a thienyl group or a non-aromatic heterocyclic group such as a tetrahydrofuryl group) and the like.

The "optionally substituted" in the "optionally substituted amino group" and the "optionally substituted ureido group" for R _{1 and the} like may be one or more, preferably one to two. Means that the substituent may be the same or different,
The position of the substituent is arbitrary and not particularly limited. Specific examples include the aforementioned C _1-4 lower alkyl groups; hydroxyl groups; the aforementioned acyl groups; and the aforementioned aryl groups that may be substituted with the aforementioned C _1-4 lower alkoxy groups.

The "mercapto protecting group" in Z means a commonly used mercapto protecting group, and is not particularly limited as long as it is an organic residue which is eliminated in a living body. Also,
A disulfide which is a dimer may be formed. Specifically, a C _1-4 lower alkoxymethyl group;
_1-4 lower alkylthiomethyl group; aralkyloxy methyl; aralkylthio methyl group; C _3-10 cycloalkyloxy methyl; C _5-8 cycloalkenyl oxymethyl group; C _3-10 cycloalkyl C _1-10 alkoxymethyl Group;
Aryloxymethyl group; arylthiomethyl group; acyl group; acyloxy group; aminocarbonyloxymethyl group; thiocarbonyl group; That is, more specifically, a C _1-4 lower alkoxymethyl group having the aforementioned C _1-4 lower alkoxy group; a C _1-4 lower alkylthiomethyl group having the aforementioned C _1-4 lower alkylthio group; An aralkyloxymethyl group having an aralkyl group; an aralkylthiomethyl group having an aralkyl group as described above;
_3-10 cycloalkyl C _3-10 cycloalkyloxy methyl group having a group; C _5-8 cycloalkenyl oxymethyl group having a C _5-8 cycloalkenyl group described above; the aforementioned C
Arylthio methyl group having the aforementioned arylthio group; aryloxy methyl group having the aforementioned aryl group; C _3-10 cycloalkyl C _1-10 alkoxymethyl group having _3-10 cycloalkyl C _{1-1 0} alkyl group; The aforementioned linear or branched C _1-10 alkyl group which may be substituted, the aforementioned halogenated C _1-4 lower alkyl group, the aforementioned C _1-4 lower alkoxy group, the aforementioned C _1-4 A lower alkylthio group, the above-mentioned optionally substituted amino group, the above-mentioned optionally substituted ureido group, the above-mentioned optionally substituted C _3-10
Cycloalkyl group, the above-mentioned _optionally substituted C _3-10
A cycloalkyl C _1-10 alkyl group, the above-mentioned _optionally substituted aryl group, the above-mentioned optionally substituted aralkyl group, the above-mentioned optionally substituted arylalkenyl group, the above-mentioned optionally substituted A good arylthio group,
Having the above-mentioned optionally substituted 5- or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms or the above-mentioned optionally substituted 5- or 6-membered heteroarylalkyl group acyl group; the aforementioned optionally substituted straight or branched C _1-10 alkyl group, a halogenated C _1-4 lower alkyl group described above, C _1-4 lower alkoxy group described above, the aforementioned C _1-4 lower alkylthio groups, the above-mentioned optionally substituted amino groups, the above-mentioned optionally substituted ureido groups, the above-mentioned optionally substituted C _3-10 cycloalkyl groups, the above-mentioned substituted An _optionally substituted C _3-10 cycloalkyl C _1-10 alkyl group, the aforementioned _optionally substituted aryl group, the aforementioned optionally substituted aralkyl group, the aforementioned optionally substituted aryl alkenyl group, Was replaced by A good arylthio group, an optionally substituted 5- to 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms, or an optionally substituted 5- or 6-membered heteroaryl acyloxy group having an alkyl group; the aforementioned optionally substituted straight or branched C _1-10 alkyl group, a halogenated C _1-4 alkyl group above, C _{1 -4} lower alkoxy group described above, The aforementioned C _1-4 lower alkylthio group, the aforementioned optionally substituted C _3-10 cycloalkyl group, the aforementioned optionally substituted C _3-10 cycloalkyl C _1-10 alkyl group,
The above-mentioned optionally substituted aryl group, the above-mentioned optionally substituted aralkyl group, the above-mentioned optionally substituted arylalkenyl group, and the above-mentioned 1 to 3 nitrogen, oxygen or sulfur atoms An optionally substituted 5- or 6-membered heterocyclic group or an aminocarbonyloxymethyl group optionally substituted with the aforementioned optionally substituted 5- or 6-membered heteroarylalkyl group; A linear or branched C _1-10 alkyl group which may be
The aforementioned halogen C _1-4 lower alkyl group, the aforementioned C _1-4 lower alkoxy group, the aforementioned C _1-4 lower alkylthio group, the aforementioned optionally substituted amino group, the aforementioned optionally substituted amino group Ureido group, the above-mentioned optionally substituted C
_3-10 cycloalkyl group, the above-mentioned _optionally substituted C
_3-10 cycloalkyl C _1-10 alkyl group, the above-mentioned _optionally substituted aryl group, the above-mentioned optionally substituted aralkyl group, the above-mentioned optionally substituted arylalkenyl group, the above-mentioned substituted An arylthio group which may be optionally substituted, 1 to 3
An optionally substituted 5- or 6-membered heterocyclic group or a thiocarbonyl group having an optionally substituted 5- or 6-membered heteroarylalkyl group; the aforementioned optionally substituted C _{1 -4} is a thio group having a lower alkyl group or an aryl group.

More specifically, the “linear or branched C _1-10 alkyl group” for R includes a methyl group, an ethyl group, an isopropyl group, a butyl group, an isobutyl group and a tert-butyl group. , A heptyl group, a 1-propylbutyl group and a 1-isobutyl-3-methylbutyl group are preferred.

The "linear or branched C _2-10 alkenyl group" for R includes allyl, vinyl, isopropenyl, 1-methyl-2-propenyl, 2-methyl-
A 2-propenyl group, a 1-methyl-1-butenyl group, a crotyl group, a 1,3-dimethyl-2-butenyl group, a 1-pentenyl group, and a 1-methyl-2-pentenyl group are preferred.

The “halogenated C _1-4 lower alkyl group” for R is a C _1-4 lower alkyl group (particularly preferably methyl group) substituted by the above-mentioned halogen atom (particularly preferably fluorine atom or chlorine atom). ), And is preferably a trifluoromethyl group.

In R, “optionally substituted C _3-10
The term "cycloalkyl group" refers to the aforementioned straight-chain or branched C
_1-10 alkyl group (particularly preferably methyl group, ethyl group,
C _1-8 alkyl groups such as propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2,2-dimethylpropyl, 4-methylpentyl, and 2-ethylbutyl. The aforementioned linear or branched C _2-10 alkenyl groups (particularly preferably C _2-8 alkenyl groups such as 1-methylvinyl group, 2-methylvinyl group and 3-methyl-3-propenyl group); The aforementioned C _3-10 cycloalkyl group (particularly preferably C _3-10 cycloalkyl, cyclopentyl, cyclohexyl, etc.
_3-7 cycloalkyl group), the above-mentioned C _5-8 cycloalkenyl group (particularly preferably, a C _5-6 cycloalkenyl group such as a cyclopentenyl group and a cyclohexenyl group), and the above-mentioned C _3-10
Cycloalkyl C _1-10 alkyl group (particularly preferably cyclopropylmethyl group, 2-cyclopropylethyl group,
-Cyclopentylethyl group, cyclohexylmethyl group,
A C _3-7 cycloalkyl C _1-4 alkyl group such as a 2-cyclohexylethyl group, the above-mentioned aryl group (particularly preferably a phenyl group), an oxo group, the above-mentioned aralkyl group (particularly preferably a benzyl group, a phenethyl group, etc.) Phenyl C _1-
C _3-10 cycloalkyl group (particularly preferably cycloalkyl group) which may be substituted with 1 to 4 substituents selected from the group consisting of ₄ lower alkyl groups) and the above-mentioned arylalkenyl group (particularly preferably 2-phenylvinyl group). Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydroindenyl, decahydronaphthyl, adamantyl, bicyclo [2.2.
1] heptyl group), preferably 2,2,3,3
-Tetramethylcyclopropyl group, 1-isopentylcyclobutyl group, 1-isopropylcyclopentyl group, 1
-Isobutylcyclopentyl group, 1-isopentylcyclopentyl group, 1-cyclohexylmethylcyclopentyl group, cyclohexyl group, 1-methylcyclohexyl group, 1-ethylcyclohexyl group, 1-propylcyclohexyl group, 1-isopropylcyclohexyl group, 1-
Butylcyclohexyl group, 1-isobutylcyclohexyl group, 1-pentylcyclohexyl group, 1-isopentylcyclohexyl group, 1- (2,2-dimethylpropyl) cyclohexyl group, 1- (4-methylpentyl) cyclohexyl group, 1- ( 2-ethylbutyl) cyclohexyl group, 4-tert-butyl-1-isopentylcyclohexyl group, 1-cyclopropylcyclohexyl group,
1-bicyclohexyl group, 1-phenylcyclohexyl group, 1-cyclopropylmethylcyclohexyl group, 1-
Cyclohexylmethylcyclohexyl group, 1- (2-cyclopropylethyl) cyclohexyl group, 1- (2-cyclopentylethyl) cyclohexyl group, 1- (2-cyclohexylethyl) cyclohexyl group, 4-methylcyclohexyl group, 4-propylcyclohexyl group , 4-
Isopropylcyclohexyl group, 4-tert-butylcyclohexyl group, 4-pentylcyclohexyl group, 4
-Bicyclohexyl group, 1-isopentylcycloheptyl group, 3a-octahydroindenyl group, 4a-decahydronaphthyl group, 1-adamantyl group, 7,7-dimethyl-1- (2-oxo) bicyclo [2. 2.1] heptyl group. Further, the substitution position is not particularly limited, but is particularly preferably the substitution at the 1-position, and the substituent may be any of the above-mentioned substituents, and particularly preferably is a linear or branched C _{1-. It is a 10} alkyl group.

In R, “optionally substituted C _5-8
The substituents in the “cycloalkenyl group” are exactly the same as those in the above-mentioned “optionally substituted C _3-10 cycloalkyl group”, and specifically, the straight-chain or branched C _1-10 alkyl group described above. Groups (particularly preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2,2-dimethylpropyl,
A C _1-8 alkyl group such as a 4-methylpentyl group), the above-mentioned linear or branched C _2-10 alkenyl group (particularly preferably a 1-methylvinyl group, a 2-methylvinyl group, a 3-methyl- A C _2-8 alkenyl group such as a 3-propenyl group) and the above-mentioned C _3-10 cycloalkyl group (particularly preferably a C _3-7 group such as a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group).
Cycloalkyl group), the above-mentioned C _5-8 cycloalkenyl group (particularly preferably, a C _5-6 cycloalkenyl group such as a cyclopentenyl group and a cyclohexenyl group), and the above-mentioned C _3-10 cycloalkyl C _1-10 alkyl group (Especially preferred are cyclopropylmethyl, 2-cyclopropylethyl, 2-
Cyclopentylethyl group, cyclohexylmethyl group, 2
-C _3-7 cycloalkyl C such as cyclohexylethyl group
_1-4 lower alkyl groups), the aforementioned aryl groups (particularly preferably phenyl groups), oxo groups, and the aforementioned aralkyl groups (particularly preferably phenyl groups such as benzyl and phenethyl groups).
Cycloalkenyl group (especially cyclopentenyl group, cyclopentenyl group, cycloalkyl group) which may be substituted with 1 to 4 substituents selected from _1-4 lower alkyl groups) and the aforementioned arylalkenyl group (particularly preferably 2-phenylvinyl group). Hexenyl group), preferably 1-isopropyl-2-cyclopentenyl group, 1-isopropyl-3-cyclopentenyl group, 1-isobutyl-2-cyclopentenyl group, 1
-Isobutyl-3-cyclopentenyl group, 1-isopentyl-2-cyclopentenyl group, 1-isopentyl-3
-Cyclopentenyl group, 1-cyclohexylmethyl-2
-Cyclopentenyl group, 1-cyclohexylmethyl-3
-Cyclopentenyl group, 1-cyclohexenyl group, 2-
Cyclohexenyl group, 3-cyclohexenyl group, 1-methyl-2-cyclohexenyl group, 1-methyl-3-cyclohexenyl group, 1-ethyl-2-cyclohexenyl group, 1-ethyl-3-cyclohexenyl group, 1-propyl-2-cyclohexenyl group, 1-propyl-3-cyclohexenyl group, 1-isopropyl-2-cyclohexenyl group, 1-isopropyl-3-cyclohexenyl group,
1-butyl-2-cyclohexenyl group, 1-butyl-3
-Cyclohexenyl group, 1-isobutyl-2-cyclohexenyl group, 1-isobutyl-3-cyclohexenyl group, 1-pentyl-2-cyclohexenyl group, 1-pentyl-3-cyclohexenyl group, 1-isopentyl-2
-Cyclohexenyl group, 1-isopentyl-3-cyclohexenyl group, 1- (2,2-dimethylpropyl) -2
-Cyclohexenyl group, 1- (2,2-dimethylpropyl) -3-cyclohexenyl group, 1- (4-methylpentyl) -2-cyclohexenyl group, 1- (4-methylpentyl) -3-cyclohexenyl Group, 1-cyclopropyl-2-cyclohexenyl group, 1-cyclopropyl-3
-Cyclohexenyl group, 1-cyclohexyl-2-cyclohexenyl group, 1-cyclohexyl-3-cyclohexenyl group, 1-phenyl-2-cyclohexenyl group, 1
-Phenyl-3-cyclohexenyl group, 1-cyclopropylmethyl-2-cyclohexenyl group, 1-cyclopropylmethyl-3-cyclohexenyl group, 1-cyclohexylmethyl-2-cyclohexenyl group, 1-cyclohexylmethyl-3 -Cyclohexenyl group, 1- (2-cyclopropylethyl) -2-cyclohexenyl group, 1-
(2-cyclopropylethyl) -3-cyclohexenyl group, 1- (2-cyclopentylethyl) -2-cyclohexenyl group, 1- (2-cyclopentylethyl) -3-
A cyclohexenyl group, a 1- (2-cyclohexylethyl) -2-cyclohexenyl group, and a 1- (2-cyclohexylethyl) -3-cyclohexenyl group. Furthermore,
The substitution position is not particularly limited, but is particularly preferably the substitution at the 1-position, and the substituent may be any of the substituents described above, but is particularly preferably a linear or branched C _1-10.
It is an alkyl group or a C _3-10 cycloalkyl C _1-4 alkyl group.

In R, “optionally substituted C _3-10
“Cycloalkyl C _1-10 alkyl group” refers to the aforementioned C _3-10 alkyl group.
A cycloalkyl group (particularly preferably a cyclopentyl group,
A C _3-7 cycloalkyl group such as a cyclohexyl group), the above-mentioned C _5-8 cycloalkenyl group (particularly preferably a C _5-7 cycloalkenyl group such as a cyclopentenyl group or cyclohexenyl group) and the above-mentioned aryl group (particularly, Preferably a phenyl group), wherein the C _1-10 alkyl group may be substituted with 1 to 4 substituents selected from the group _consisting of a linear or branched C _3-10 cycloalkyl C _1-10 alkyl group. (Especially preferred are cyclohexylmethyl, 1-cyclohexylethyl, 1-cyclohexyl-1-methylethyl, 1-cyclohexyl-2-methylpropyl, 1-cyclohexyl-3-methylbutyl, 1-cyclohexylhexyl, -Cyclohexyl-4-methylpentyl group, 1
-Cyclohexylheptyl group). The substitution position is not particularly limited, and may be a linear or branched C _1-10
The alkyl group may have the substituent. Preferably a cyclohexylmethyl group, 1-cyclohexylethyl group, cyclohexylcyclopentylmethyl group, dicyclohexylmethyl group, 1-cyclohexyl-1-methylethyl group, 1-cyclohexyl-2-methylpropyl group,
1-cyclohexyl-3-methylbutyl group, 1-cyclohexyl-4-methylpentyl group, 1-cyclohexylhexyl group, and 1-cyclohexylheptyl group.

The "optionally substituted aryl group" for R includes the above-mentioned linear or branched C _1-6 alkyl group (particularly preferably tert-butyl group) and the above-mentioned halogen atom (particularly preferable). Represents an aryl group (particularly preferably a phenyl group) which may be substituted with 1 to 4 substituents selected from a fluorine atom, a chlorine atom) and a nitro group, preferably a phenyl group, a 2-chlorophenyl group,
A 4-nitrophenyl group and a 3,5-di-tert-butylphenyl group.

The “optionally substituted aralkyl group” for R may be the above-mentioned halogen atom (particularly preferably a fluorine atom or a chlorine atom), a nitro group or a hydroxyl group. And the C _1-4 lower alkyl group means a linear or branched aralkyl group (particularly preferably a benzyl group, a benzhydryl group or a trityl group). The substitution position is not particularly limited, and the substituent may be present on a linear or branched C _1-4 lower alkyl group. Preferred are a benzyl group and a trityl group.

In R, “optionally substituted 5 or 6 having 1 to 3 nitrogen, oxygen or sulfur atoms”
The heterocyclic group "of members, straight-chain or branched C _1-6 alkyl group (particularly preferably tert- butyl group) described above, a halogen atom mentioned above (particularly preferably fluorine atom, chlorine atom) and nitro The heterocyclic group which may be substituted with 1 to 4 substituents selected from the groups is preferable, and an aromatic heterocyclic group is preferable. Particularly preferred are a furyl group, a thienyl group and a pyridyl group.

R₁In the "optionally substituted straight chain"
Or branched C_1-10"Alkyl group" refers to the aforementioned halogen
Atoms (particularly preferably fluorine atoms and chlorine atoms)
C_{1- Four}Lower alkoxy group (particularly preferably methoxy
Group), the aforementioned C_1-4Lower alkyl groups (particularly preferably
Acetyl group or the aforementioned acyl group (particularly preferably acetyl group)
Group) or an amino group which may be substituted with a hydroxyl group, as described above.
C_1-4Lower alkylthio groups (particularly preferably methylthio
Group), a carbamoyl group, a hydroxyl group, and the aforementioned acyl group.
Acyloxy group (especially preferably acetyloxy
Group), carboxy group, acyl group (particularly preferably
A cyclocarbonyl group) and the aforementioned optionally substituted aryl
Aryloxy group having a group (particularly preferably phenoxy group)
And a substituent selected from 4-chlorophenoxy group)
Optionally substituted straight-chain or branched C _1-10Alkyl
Group, preferably a methyl group, a chloromethyl group,
Tyl group, isopropyl group, 1-methyl-2-pentyl
Group, octyl group, methoxymethyl group, dimethylamino
Tyl group, acetylaminomethyl group, 1-acetylamino
Ethyl group, 1-acetylamino-2-methylpropyl
Group, 1-acetylamino-3-methylbutyl group, 1-A
Cetylamino-3-methylthiopropyl group, 1-acetyl
Rumin-3-carbamoylpropyl group, 1-hydroxy
C-1-methylethyl group, 1-acetyloxy-1-me
Tylethyl group, 4-carboxybutyl group, 2-methoxy
Carbonylethyl group, phenoxymethyl group, 4-chloro
It is a phenoxymethyl group.

The “C _1-4 lower alkoxy group” for R ₁ is preferably a methoxy group or a tert-butoxy group.

"C _1-4 lower alkylthio group" for R ₁
Is preferably a methylthio group.

The “amino group which may be substituted” in R ₁ includes the above-mentioned C _1-4 lower alkyl group (particularly preferably an ethyl group, an isopropyl group and a tert-butyl group), and the above-mentioned acyl group (particularly an amino group). Preferably an acetyl group or a benzoyl group) and a substituent selected from the aforementioned aryl groups (particularly preferably a phenyl group and a 4-methoxyphenyl group) which may be substituted with the aforementioned C _1-4 lower alkoxy group. An amino group which may be substituted, preferably an ethylamino group, an isopropylamino group,
A butylamino group, a phenylamino group, and a 4-methoxyphenylamino group.

The “ureido group which may be substituted” for R ₁ includes the above-mentioned C _1-4 lower alkyl group (particularly preferably a methyl group and an ethyl group), the above-mentioned acyl group (particularly preferably an acetyl group, Benzoyl group) and the aforementioned C _1-4
A ureido group which may be substituted with a substituent selected from the aforementioned aryl groups (particularly preferably phenyl group and 4-methoxyphenyl group) which may be substituted with a lower alkoxy group, preferably N, N '-Diphenylureido group.

The “optionally substituted C” in R _{1
The "3-10} cycloalkyl group" is the above-mentioned linear or branched C _1-10 alkyl group (particularly preferably, methyl group, tert-
-Butyl group, isopentyl group), amino group, C
_1-4 may be substituted with a substituent selected from lower alkyl or an amino group optionally substituted with the aforementioned acyl (particularly preferably a methylamino group, an ethylamino group, an acetylamino group or a benzylamino group). C _3-10 cycloalkyl group (particularly preferably a cyclopropyl group, a cyclohexyl group), preferably a cyclopropyl group, a cyclohexyl group, a 1-methylcyclohexyl group, a 1-isopentylcyclohexyl group, a 1-aminocyclohexyl group, 1-acetylaminocyclohexyl group, 4-te
rt-butylcyclohexyl group.

The “optionally substituted C” in R _{1
The "3-10} cycloalkyl C _1-10 alkyl group" means the above-mentioned C
_3-10 cycloalkyl group (particularly preferably, cyclopentyl group, cyclohexyl group), the above-mentioned C _5-8 cycloalkenyl group (particularly preferably, cyclopentenyl group, cyclohexenyl group) and the above-mentioned aryl group (particularly preferably, phenyl group) May be substituted with a substituent selected from
And, the C _1-10 alkyl group means a linear or branched C _3-10 cycloalkyl C _1-10 alkyl group (particularly preferably a cyclohexyl group). The substitution position is not particularly limited, and the linear or branched C _1-10 alkyl group may have the substituent. Preferably it is a cyclohexylmethyl group.

The “optionally substituted aryl group” for R ₁ includes the above-mentioned linear or branched C _1-6 alkyl group (particularly preferably methyl group and tert-butyl group).
The aforementioned halogen atom (particularly preferably, a fluorine atom or a chlorine atom), a nitro group, a hydroxyl group, the aforementioned C _1-4 lower alkoxy group (particularly preferably, a methoxy group) and the aforementioned acyl group (particularly preferably, 2- (1- Aryl group (particularly preferably a phenyl group or a naphthyl group) which may be substituted with a substituent selected from isopentylcyclohexanecarbonylamino) phenylthiocarbonyl group, and preferably a phenyl group, a 1-naphthyl group, -A naphthyl group,
2-chlorophenyl group, 2,6-dichlorophenyl group,
2,6-dimethylphenyl group, 2-methoxyphenyl group, 2-nitrophenyl group, 4-nitrophenyl group,
A 3,5-di-tert-butyl-4-hydroxyphenyl group and a 4- [2- (1-isopentylcyclohexanecarbonylamino) phenylthiocarbonyl] phenyl group.

The “optionally substituted aralkyl group” for R ₁ includes the aforementioned halogen atom (particularly preferably a fluorine atom or a chlorine atom), a nitro group, the aforementioned C _1-4 lower alkyl group or the aforementioned acyl group. A substituent selected from an amino group (particularly preferably an amino group, an acetylamino group, a pivaloylamino group, a 1-methylcyclohexanecarbonylamino group, a tert-butoxycarbonylamino group, a benzoylamino group) and a hydroxyl group which may be substituted with a group And a C _1-4 lower alkyl group which may be substituted with a linear or branched aralkyl group (particularly preferably a benzyl group, a phenethyl group, a 3-phenylpropyl group, a naphthylmethyl group, a biphenylmethyl group) Means The substitution position is not particularly limited, and the substituent may be present on a linear or branched C _1-4 lower alkyl group. Preferably, benzyl, phenethyl, 3-phenylpropyl, 2-naphthylmethyl, 4-biphenylmethyl, benzhydryl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2-nitro Phenylmethyl group, 4-nitrophenylmethyl group, 2-pivaloylaminophenylmethyl group, 2- (1-methylcyclohexanecarbonylamino) phenylmethyl group, 2-tert-butoxycarbonylaminophenylmethyl group, 3-acetylamino Phenylmethyl group, 3- (1-methylcyclohexanecarbonylamino) phenylmethyl group, α-aminobenzyl group, α-acetylaminobenzyl group, α- (1-methylcyclohexanecarbonylamino) benzyl group, α-benzoylaminobenzyl group α- aminophenethyl group,
α-acetylaminophenethyl group and 1-acetylamino-2- (4-hydroxyphenyl) ethyl group.

The “optionally substituted arylalkenyl group” for R ₁ is the same as the above-mentioned straight-chain or branched C
_1-6 lower alkyl group (particularly preferably methyl group, ter
t-butyl group), the aforementioned halogen atom (particularly preferably a fluorine atom or a chlorine atom), an arylalkenyl group (particularly a phenylvinyl group) which may be substituted with a substituent selected from a nitro group and a hydroxyl group, Preferably 2-
It is a phenylvinyl group.

The “optionally substituted arylthio group” for R ₁ includes the aforementioned halogen atom (particularly preferably a fluorine atom or a chlorine atom), a nitro group, the aforementioned C _1-4 lower alkyl group or the aforementioned acyl group. optionally substituted amino group optionally (particularly preferably amino, acetylamino group, pivaloylamino group, 1-methyl cyclohexane carbonyl group, a benzoylamino group) a group, hydroxyl group and a halogenated C _{1 4} lower alkyl group above (Particularly preferably, a trifluoromethyl group), which means an arylthio group (particularly preferably, a phenylthio group) which may be substituted with a substituent selected from a phenylthio group,
Pivaloylaminophenylthio group, 2- (1-methylcyclohexanecarbonylamino) phenylthio group, 2-
(1-methylcyclohexanecarbonylamino-4-trifluoromethyl) phenylthio group.

The “optionally substituted 5- or 6-membered heterocyclic group having 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms” in R ₁ is the above-mentioned linear or branched C _{1 -6}
It may be substituted with a substituent selected from an alkyl group (particularly preferably a methyl group), a halogen atom (particularly preferably a fluorine atom and a chlorine atom), the aforementioned acyl group (particularly preferably an acetyl group and a benzoyl group) and an oxo group. Good heterocyclic group (particularly preferably aromatic heterocyclic group such as pyridyl group or non-aromatic heterocyclic group such as piperidyl group and pyrrolidinyl group)
And preferably a 3-pyridyl group, 1-methyl-4
-Piperidyl group, 1-acetyl-4-piperidyl group, 5
-Oxo-2-pyrrolidinyl group, 1-acetyl-2-pyrrolidinyl group, 1-benzoyl-2-pyrrolidinyl group. Particularly preferred are 4-piperidyl groups such as a 1-methyl-4-piperidyl group and a 1-acetyl-4-piperidyl group.

The “optionally substituted 5- or 6-membered heteroarylalkyl group” for R ₁ includes the above-mentioned linear or branched C _1-6 alkyl group (particularly preferably a methyl group) and the aforementioned Means a heteroarylalkyl group (particularly preferably a 2-thenyl group) which may be substituted with a halogen atom (particularly preferably a fluorine atom or a chlorine atom), and is preferably a 2-thenyl group.

The “optionally substituted C _1-4 ” in R ₂
The lower alkyl group ", C _1-4 lower alkoxy group (particularly preferably a methoxy group) mentioned above, C _1-4 lower alkyl group or an amino group (particularly preferably be substituted with an acyl group of dimethyl above Amino group), the aforementioned C _1-4 lower alkylthio group (particularly preferably methylthio group), carbamoyl group, hydroxyl group, carboxy group, the aforementioned acyl group (particularly preferably methoxycarbonyl group) and the aforementioned heterocyclic group (particularly preferred) Is optionally substituted with 1 to 3 substituents selected from an aromatic heterocyclic group such as a thienyl group or a non-aromatic heterocyclic group such as a tetrahydrofuryl group.
_1-4 means a lower alkyl group (particularly preferably a methyl group), preferably a tetrahydrofurylmethyl group.

[0079] The "optionally substituted aryl group" for R ₂ are the same as in R _1. Preferred are a phenyl group, a halogen-substituted phenyl group and an acylamino-substituted phenyl group.

The “halogen atom” in X ₁ , X ₂ , X ₃ and X ₄ means a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, and is preferably a fluorine atom or a chlorine atom.

The “C _1-4 lower alkyl group” in X ₁ , X ₂ , X ₃ and X ₄ is preferably a methyl group.

The “halogenated C _1-4 lower alkyl group” in X ₁ , X ₂ , X ₃ and X ₄ is the same as the above-mentioned halogen atom (particularly preferably a fluorine atom or a chlorine atom).
_1-4 means a lower alkyl group (particularly preferably a methyl group), preferably a trifluoromethyl group.

The “C _1-4 lower alkoxy group” in X ₁ , X ₂ , X ₃ and X ₄ is preferably a methoxy group.

"Acyl group" in X ₁ , X ₂ , X ₃ and X ₄
Is preferably a benzoyl group.

The "aryl group" in X ₁ , X ₂ , X ₃ and X ₄ is preferably a phenyl group.

"1-substituted-C" in R "_3-10Cyclo
An “alkyl group” is a cycloalkyl group (eg, cyclopropyl
Ropyl, cyclobutyl, cyclopentyl, cyclo
Hexyl group, cycloheptyl group and the like;
_5-7A cycloalkyl group, particularly preferably a cycloalkyl group.
A straight-chain or branched C 1
_1-10Alkyl group (particularly preferably methyl group, ethyl group,
Propyl, isopropyl, butyl, isobutyl
Group, pentyl group, isopentyl group, 2,2-dimethyl
Propyl group, 4-methylpentyl group, 2-ethylbutyl group
Etc. C_1-8Alkyl group), the aforementioned linear or branched C
_2-10Alkenyl group (particularly preferably 1-methylvinyl
Group, 2-methylvinyl group, 3-methyl-3-propenyl
C such as a group_2-8Alkenyl group), the aforementioned C_3-10Cycloal
A kill group (particularly preferably a cyclopropyl group,
C such as tyl group and cyclohexyl group_3-7Cycloalkyl
Group), the aforementioned C_5-8Cycloalkenyl group (particularly preferred
Represents a C such as a cyclopentenyl group or a cyclohexenyl group._5-6
Cycloalkenyl group), the aforementioned C_3-10Cycloalkyl C
_1-10Alkyl group (particularly preferably cyclopropylmethyl
Group, 2-cyclopropylethyl group, 2-cyclopentyl
Ethyl group, cyclohexylmethyl group, 2-cyclohexyl
C such as ruethyl group_3-7Cycloalkyl C_1-4Lower alkyl
Group), the aforementioned aryl group (particularly preferably phenyl
Group), the aforementioned aralkyl group (particularly preferably benzyl group)
C, phenylethyl, etc._1-4Lower alkyl group)
And the aforementioned arylalkenyl group (particularly preferably 2-
Phenylvinyl group)
And preferably 1-isopentylcyclobut
Tyl group, 1-isopropylcyclopentyl group, 1-iso
Butylcyclopentyl group, 1-isopentylcyclopen
A tyl group, a 1-cyclohexylmethylcyclopentyl group,
1-methylcyclohexyl group, 1-ethylcyclohexyl
Group, 1-propylcyclohexyl group, 1-isopropyl
Rucyclohexyl group, 1-butylcyclohexyl group, 1
-Isobutylcyclohexyl group, 1-pentylcyclohexyl
Xyl group, 1-isopentylcyclohexyl group, 1-
(2,2-dimethylpropyl) cyclohexyl group, 1-
(4-methylpentyl) cyclohexyl group, 1- (2-
Ethylbutyl) cyclohexyl group, 1-cyclopropyl
Cyclohexyl group, 1-bicyclohexyl group, 1-
Nylcyclohexyl group, 1-cyclopropylmethylcycl
Rohexyl group, 1-cyclohexylmethylcyclohexyl
Group, 1- (2-cyclopropylethyl) cyclohexyl
Group, 1- (2-cyclopentylethyl) cyclohexyl
Group, 1- (2-cyclohexylethyl) cyclohexyl
And a 1-isopentylcycloheptyl group. 1st place
Particularly preferably, the substituent is a straight-chain or branched C_1-10A
Is a alkyl group.

The “1-substituted-C _5-8 cycloalkenyl group” for R ″ is a cycloalkenyl group (particularly preferably a cycloalkenyl group such as a cyclopentenyl group or a cyclohexenyl group).
_5-6 cycloalkenyl is a group) of 1-position on the above-mentioned straight-chain or branched C _1-10 alkyl group (particularly preferably methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, Pentyl group, isopentyl group, 2,
C such as 2-dimethylpropyl group and 4-methylpentyl group
_1-8 alkyl group), and the aforementioned linear or branched C _2-10 alkenyl groups (particularly preferably 1-methylvinyl group, 2-methylvinyl group, 3-methyl-3-propenyl group, etc.
_2-8 alkenyl group), the aforementioned C _3-10 cycloalkyl group (particularly preferably, a C _3-7 cycloalkyl group such as a cyclopropyl group, a cyclopentyl group, and a cyclohexyl group);
The aforementioned C _5-8 cycloalkenyl group (particularly preferably, a C _5-6 cycloalkenyl group such as a cyclopentenyl group and a cyclohexenyl group), and the aforementioned C _3-10 cycloalkyl C _1-10 alkyl group (particularly preferably, cycloalkyl) Propylmethyl group, 2
A C _3-7 cycloalkyl C _1-4 lower alkyl group such as -cyclopropylethyl group, 2-cyclopentylethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group),
The above-mentioned aryl group (particularly preferably phenyl group), the above-mentioned aralkyl group (particularly preferably phenyl C _1-4 lower alkyl group such as benzyl group and phenethyl group) and the above-mentioned arylalkenyl group (particularly preferably 2-phenylvinyl) Group), preferably 1-isopropyl-2-cyclopentenyl group, 1-isopropyl-3-cyclopentenyl group, 1
-Isobutyl-2-cyclopentenyl group, 1-isobutyl-3-cyclopentenyl group, 1-isopentyl-2-
Cyclopentenyl group, 1-isopentyl-3-cyclopentenyl group, 1-cyclohexylmethyl-2-cyclopentenyl group, 1-cyclohexylmethyl-3-cyclopentenyl group, 1-methyl-2-cyclohexenyl group, 1
-Methyl-3-cyclohexenyl group, 1-ethyl-2-
Cyclohexenyl group, 1-ethyl-3-cyclohexenyl group, 1-propyl-2-cyclohexenyl group, 1-propyl-3-cyclohexenyl group, 1-isopropyl-
2-cyclohexenyl group, 1-isopropyl-3-cyclohexenyl group, 1-butyl-2-cyclohexenyl group, 1-butyl-3-cyclohexenyl group, 1-isobutyl-2-cyclohexenyl group, 1-isobutyl- 3-
Cyclohexenyl group, 1-pentyl-2-cyclohexenyl group, 1-pentyl-3-cyclohexenyl group, 1-
Isopentyl-2-cyclohexenyl group, 1-isopentyl-3-cyclohexenyl group, 1- (2,2-dimethylpropyl) -2-cyclohexenyl group, 1- (2,2
-Dimethylpropyl) -3-cyclohexenyl group, 1-
(4-methylpentyl) -2-cyclohexenyl group, 1
A-(4-methylpentyl) -3-cyclohexenyl group,
1-cyclopropyl-2-cyclohexenyl group, 1-cyclopropyl-3-cyclohexenyl group, 1-cyclohexyl-2-cyclohexenyl group, 1-cyclohexyl-3-cyclohexenyl group, 1-phenyl-2-cyclohexenyl Group, 1-phenyl-3-cyclohexenyl group, 1-cyclopropylmethyl-2-cyclohexenyl group, 1-cyclopropylmethyl-3-cyclohexenyl group, 1-cyclohexylmethyl-2-cyclohexenyl group, 1-cyclohexyl Methyl-3-cyclohexenyl group, 1- (2-cyclopropylethyl) -2-cyclohexenyl group, 1- (2-cyclopropylethyl) -3-
Cyclohexenyl group, 1- (2-cyclopentylethyl) -2-cyclohexenyl group, 1- (2-cyclopentylethyl) -3-cyclohexenyl group, 1- (2-cyclohexylethyl) -2-cyclohexenyl group, 1 −
(2-cyclohexylethyl) -3-cyclohexenyl group. The 1-position substituent is particularly preferably a linear or branched C _1-10 alkyl group.

The term "prodrug compound" refers to a compound of the present invention that has a group that can be chemically or metabolically degraded and has pharmacological activity when hydrolyzed or solvolyzed or decomposed under physiological conditions. Is a derivative of

The “pharmaceutically acceptable salt” is not particularly limited as long as it forms a non-toxic salt with the compound represented by the above formula (I).
Inorganic salts such as hydrobromide, hydroiodide, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate;
Formate, acetate, trifluoroacetate, propionate, oxalate, glycolate, succinate, lactate, maleate, hydroxymalate, methylmaleate, fumarate, adipic acid Salt, tartrate,
Organic acid salts such as malate, citrate, benzoate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinate;
Sulfonates such as methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate and naphthalenesulfonate; acidic amino acid salts such as aspartate and glutamate; sodium salts Alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salts; trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt,
Organic base salts such as N, N'-dibenzylethylenediamine salt; and amino acid salts such as lysine salt and arginine salt. In some cases, a hydrate or a solvate with an alcohol or the like may be used.

More specifically, R in the general formula (I) is 1-isobutylcyclohexyl, 1- (2-ethylbutyl) cyclohexyl, 1
-Isopentylcyclohexyl group is represented by Y as -CO
-Is a hydrogen atom as X ₁ , X ₂ , X ₃ and X ₄ , and Z is an isobutyryl group, 1-acerytyl-4-.
Piperidinecarbonyl groups are particularly preferred.

The compound of the present invention has an excellent CETP activity inhibitory activity and is expected as a new type of preventive 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, excipient, diluent known per se, Bulking agents, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, corrigents, solubilizers, and other additives, specifically water, vegetable oils, Tablets, pills, powders, granules by mixing with alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triazetate gelatin, carbohydrates such as lactose, starch, etc., magnesium stearate, talc, lanolin, petrolatum, etc. , Suppositories, injections,
It can be administered orally or parenterally in the form of eye drops, liquids, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like.

The dose may vary depending on the type and degree of the disease, the compound to be administered and the route of administration, the age, sex, weight and the like of the patient. 1000 mg, especially 50 mg to 8
Preferably, 00 mg is administered.

The compound of the present invention can be produced, for example, by the following method, but the method of producing the compound of the present invention is, of course, not limited thereto.

[0094]

Embedded image

(Step 1) Compound (II-2) (wherein R,
X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above)
Compound (VI) (wherein X ₁ , X ₂ , X ₃ and X ₄ are as defined above) and Compound (XII) (where X is a halogen atom and R and Y are as defined above) In the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylpiperazine, methylene chloride, chloroform, toluene, ether, tetrahydrofuran,
It can be synthesized by reacting under cooling or heating in an organic solvent such as dioxane, diisopropyl ether, dimethoxyethane, hexane, or the like, water or a mixed solvent thereof, or no solvent.

The compound (III-2) can be synthesized from the compound (II-2) by the following step 2. (Step 2) The compound (III-2) (wherein R, X ₁ , X ₂ ,
X ₃ , X ₄ and Y are as defined above, and the compound (II)
-2) (in the formula, R, X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above) are converted to sodium borohydride, lithium borohydride, lithium aluminum hydride, triphenylphosphine, zinc , In the presence of a reducing agent such as tin, methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane,
It can be synthesized by reacting under cooling or heating in an organic solvent such as toluene, hexane, acetone or acetic acid, water or a mixed solvent thereof.

Compound (II-2) or compound (IV-
2) is a compound (III-
It can also be synthesized from 2). (Step 3) Compound (II-2) (wherein, R, X ₁ , X ₂ , X
₃ , X ₄ and Y are as described above), and compound (III)
-2) (wherein R, X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above) in the presence of an oxidizing agent such as iodine, hydrogen peroxide, potassium permanganate, dimethyl sulfoxide, etc. Organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene, hexane, dimethylformamide, acetic acid, etc. Can be synthesized.

(Step 4) Compound (IV-2) wherein R,
R ₁ , X ₁ , X ₂ , X ₃ , X ₄ , Y and Y ₁ are as described above, and the compound (III-2) (wherein R, X ₁ , X ₂ ,
X ₃ , X ₄ and Y are as described above) and acid halide R
_1- YX (wherein R ₁ , X and Y are as described above), isocyanate R ₁ -NY (wherein R ₁ and Y are as described above), carbonate halide R ₁ -O-YX (Wherein R ₁ , X and Y are as described above) or thiocarbonate halide R ₁ -S-YX (wherein R ₁ , X and Y are as described above) with pyridine, triethylamine, N
Organic solvents such as methylene chloride, chloroform, toluene, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, hexane, etc., in the presence of a base such as -methylmorpholine, N-methylpiperazine, water or a mixed solvent thereof or without solvent The reaction is carried out under cooling or heating, or the carboxylic acid R ₁ —COOH
(Wherein R ₁ is as described above) or thiocarboxylic acid R ₁ -YSH (wherein R ₁ and Y are as described above) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide With a condensing agent such as hydrochloride, dicyclohexylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole, etc., if necessary, 1-hydroxybenzotriazole, hydroxysuccinimide, N
Dimethylformamide in the presence of an activator such as -hydroxy-5-norbornene-2,3-dicarboxylic imide;
Dichloromethane, chloroform, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride,
The reaction is carried out in an organic solvent such as toluene or a mixed solvent thereof under cooling or heating (this reaction may be carried out in the presence of a base such as pyridine or triethylamine), or a carboxylic acid R ₁ − In the presence of COOH (wherein R ₁ is as described above) and a base such as triethylamine and pyridine and ethyl chlorocarbonate and the like, in an organic solvent such as ethyl acetate and tetrahydrofuran or a mixed solvent thereof,
It can be synthesized by reacting under cooling or heating. When R ₁ is a group having a carboxy group, the compound can be synthesized by performing this step using a corresponding ester and then hydrolyzing the acid by a known method using an acid. Here, the compound (IV-2) is obtained by performing the above-mentioned step 2, or the following step 7 or the following step 10 without isolating the compound (III-2), followed by step 4
Can also be synthesized.

Further, compound (V-2) can be synthesized by the following step 5 or step 5 '. Here, step 5
Is particularly preferred when R ₂ is an optionally substituted lower alkyl group, and step 5 ′ is particularly preferred when R ₂ is an optionally substituted aryl group. (Step 5) Compound (V-2) (wherein, R, R ₂ , X ₁ , X
₂ , X ₃ , X ₄ and Y are as described above), R ₂ -X
(Wherein R ₂ and X are as described above) and a sulfur compound such as sodium thiosulfate in an organic solvent such as ethanol, methanol, tetrahydrofuran, dioxane, dimethoxyethane, acetone, acetonitrile, water or a mixed solution thereof. Compound (III-2) (in the formula, R, X ₁ , X ₂ , X ₃ , X _3)
4 and Y are as described above) and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
It can be synthesized by adding a basic aqueous solution such as sodium bicarbonate under ice cooling or heating and reacting.

(Step 5 ′) Compound (V-2) (wherein
R, R ₂ , X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above; R ₂ -SH (wherein R ₂ is as described above) is represented by carbon tetrachloride Compound (II-) was added to a solution reacted with trimethylsilane-imidazole under ice-cooling or room temperature.
2) wherein R, X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above, and sulfuryl chloride is triethylamine;
It can be synthesized by adding a solution reacted in carbon tetrachloride under ice-cooling to room temperature in the presence of a base such as pyridine, N-methylmorpholine, N-methylpiperazine and the like, followed by reaction.

The compound (III-2) can also be synthesized by the following route. (Step 6) Compound (XI) (wherein, R, X ₁ , X ₂ , X ₃ ,
X ₄ and Y are as described above), and compound (X)
(Wherein X ₁ , X ₂ , X ₃ and X ₄ are as described above)
And compound (XII) (wherein R, X and Y are as described above) in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylpiperazine, methylene chloride, chloroform, toluene and ether. It can be synthesized by reacting under cooling or heating in an organic solvent such as dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, hexane, etc., water or a mixed solvent thereof, or without solvent.

(Step 7) Compound (III-2) (wherein
R, X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above)
Is a compound (XI) (wherein R, X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above), sodium acetate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, It is synthesized by reacting under cooling or heating in an organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, ether, diisopropyl ether, water or a mixed solvent thereof in the presence of a base such as sodium hydrogen carbonate. be able to.

Compound (III-2) can also be synthesized by the following route. (Step 8) Compound (VIII) (wherein R ₁₁ and R ₁₂ may be the same or different and are a lower alkyl group such as methyl and ethyl, and X ₁ , X ₂ , X ₃ and X ₄ are as described above. Is a compound (VII) wherein X ₁ , X ₂ , X ₃ and X ₄
Is as described above) and compound (XIII) (wherein
R ₁₁ , R ₁₂ and X are as described above) and an organic solvent such as dimethylformamide, tetrahydrofuran, dioxane, dimethoxyethane or a mixed solvent thereof in the presence of a base such as sodium hydride, triethylamine, N-methylmorpholine or the like. The reaction can be carried out in a medium, under cooling or under heating, and then the product can be reacted under heating in an organic solvent such as phenyl ether or sulfolane or a mixed solvent thereof or without a solvent.

(Step 9) Compound (IX) (wherein R,
R ₁₁ , R ₁₂ , X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above, and the compound (VIII) (wherein R ₁₁ , R ₁₂ ,
X ₁ , X ₂ , X ₃ and X ₄ are as defined above), in the presence of a reducing agent such as tin chloride, zinc, iron, sodium dithionite, sodium sulfide, sodium disulfide, ethyl acetate,
After reacting in an organic solvent such as acetic acid, methanol, ethanol, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, toluene, water or a mixed solvent thereof under cooling or heating, the reactant and the compound (XII (Wherein R, X and Y are as described above) in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylpiperazine, chloroform, methylene chloride, tetrahydrofuran, ether, dioxane, diisopropyl It can be synthesized by reacting under cooling or heating in an organic solvent such as ether, dimethoxyethane, toluene, hexane, etc., water or a mixed solvent thereof or without solvent.

(Step 10) Compound (III-2) (wherein
R, X ₁ , X ₂ , X ₃ , X ₄ and Y are as described above)
Is a compound (IX) wherein R, R ₁₁ , R ₁₂ , X ₁ , X ₂ ,
X ₃ , X ₄ and Y are as described above) in the presence of a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, methanol,
It can be synthesized by reacting in an organic solvent such as ethanol, tetrahydrofuran, dioxane, dimethoxyethane, ether, diisopropyl ether, water or a mixed solvent thereof under cooling or heating.

On the other hand, compound (VI) can also be synthesized from compound (VIII) by the following step 11. (Step 11) Compound (VI) (wherein X ₁ , X ₂ , X ₃ and X ₄ are as described above) is synthesized with compound (VIII) (wherein R ₁₁ , R ₁₂ , X ₁ , X ₂ , X ₃ and X ₄ are as described above) in the presence of a reducing agent such as tin chloride, zinc, iron, sodium dithionite, sodium sulfide or sodium disulfide in ethyl acetate, methanol, ethanol or ether. , Tetrahydrofuran, dioxane, diisopropyl ether, dimethoxyethane, organic solvents such as toluene,
After reacting in water or a mixed solvent thereof under cooling or heating, the product is treated with methanol, tetrahydrofuran in the presence of a base such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate and the like. ,
After reacting under cooling or heating in an organic solvent such as ethanol, dioxane, ether, diisopropyl ether, dimethoxyethane, water or a mixed solvent thereof, the product is treated with iodine, hydrogen peroxide, potassium permanganate. ,
In the presence of an oxidizing agent such as dimethyl sulfoxide, methanol,
The reaction is carried out under cooling or heating in an organic solvent such as ethanol, ether, dioxane, tetrahydrofuran, diisopropyl ether, dimethoxyethane, acetone, toluene, hexane, dimethylfluamide, acetic acid, water or a mixed solvent thereof, or without a solvent. Can be synthesized.

The compound (I) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization or chromatography.

The compounds of the present invention include one or more stereoisomers based on asymmetric carbon, and all such isomers and mixtures thereof are included within the scope of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described specifically with reference to Examples and Test Examples, but the present invention is not limited to these.

EXAMPLES Example 1 Bis- [2- (pivaloylamino) phenyl] disulfide (Formula (I); R = t-butyl, X ₁ , X ₂ , X ₃ , X ₄
= Hydrogen atom, Y = carbonyl, Z = 2- (pivaloylamino) phenylthio) Step 1) Mixing of bis- (2-aminophenyl) disulfide (8.00 g), pyridine (6.5 ml) and chloroform (150 ml) The solution was stirred at 0 ° C., and pivaloyl chloride (83 ml) was added dropwise to the mixture. After the addition was completed, the organic layer was washed with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a solid. The obtained solid was washed with ether-hexane and collected by filtration to give the title compound (1).
1.15 g, 83% yield).

Example 2 bis- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] disulfide (formula (I); R = 1- (2-ethylbutyl) cyclohexyl, X ₁ , X ₂ , X ₃ , X ₄ = hydrogen atom, Y = carbonyl,
Synthesis of Z = 2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenylthio) i) A suspension of 60% sodium hydride (980 mg) in tetrahydrofuran (80 ml) was stirred at room temperature, and cyclohexanecarboxylic acid (3. 00g) in tetrahydrofuran (10 ml) was added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour, further cooled to 0 ° C, and a 1.5 M solution of lithium isopropylamide in cyclohexane (18.7 ml) was added dropwise. Thereafter, the mixture was stirred at room temperature for 1.5 hours, cooled again to 0 ° C, and 1-bromo-2-ethylbutane (4.64 g) was obtained.
Of tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred overnight while gradually warming to room temperature. Water and 10% hydrochloric acid were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After drying, the mixture was concentrated to obtain 1- (2-ethylbutyl) cyclohexanecarboxylic acid (3.17 g, yield 64%).

Ii) 1- (2-ethylbutyl) cyclohexanecarboxylic acid (1.50 g) obtained in i) above,
Oxalyl chloride (0.85 ml), methylene chloride (20
ml) and a small amount of a mixed solution of dimethylformamide were stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 1- (2-ethylbutyl) cyclohexanecarbonyl chloride as a crude product.

Step 1) A solution of bis- (2-aminophenyl) disulfide (825 mg) in pyridine (20 ml) was stirred at room temperature, and 1- (2-ethylbutyl) of the crude product obtained in ii) above was added to the solution. ) Cyclohexanecarbonyl chloride was added dropwise. After the addition, the mixture was stirred at 100 ° C. overnight. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 15: 1) to give the title compound (667 mg, yield 32%).

Examples 3 to 8 The compounds shown in Tables 1 and 2 were obtained in the same manner as in Examples 1 and 2.

[0114]

[Table 1]

[0115]

[Table 2]

Further, compounds 1-1 to 1-19 shown in Tables 3 and 4 were obtained in the same manner as in Example 1 or Example 2.

[0117]

[Table 3]

[0118]

[Table 4]

Example 9 N- (2-mercaptophenyl) -2,2-dimethylpropionamide (formula (I); R = t-butyl, X ₁ ,
Synthesis of X ₂ , X ₃ , X ₄ = hydrogen atom, Y = carbonyl, Z = hydrogen atom) Step 2) Methanol of bis- [2- (pivaloylamino) phenyl] disulfide (300 mg) obtained in Example 1 above (0.4 ml) -tetrahydrofuran (4 m
l) The mixed solution was stirred at room temperature, sodium borohydride (70 mg) was added, and the mixture was heated under reflux for 4 hours. After cooling down,
After adding 10% hydrochloric acid, the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After drying, the mixture was concentrated, and the obtained residue was separated and purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1) to give the title compound (84 mg, yield 28%).

Example 10 N- (2-Mercaptophenyl) -1- (2-ethylbutane)
Tyl) cyclohexanecarboxamide (formula (I);
1- (2-ethylbutyl) cyclohexyl, X ₁, X_Two,
X_Three, X_Four= Hydrogen atom, Y = carbonyl, Z = hydrogen atom)
Step 2) Bis- [2- [1-] obtained in Example 2 above
(2-ethylbutyl) cyclohexanecarbonylamido
No] phenyl] disulfide (667 mg), triphe
Nylphosphine (577 mg), dioxane (8 m
l), a mixture of water (4 ml) was stirred at 50 ° C for 1 hour.
Was. After cooling, add 1N aqueous sodium hydroxide solution
Was washed with hexane and neutralized with 10% aqueous hydrochloric acid. Acetic acid
After extraction with chill, the extract was washed with saturated saline and dried over anhydrous sodium sulfate.
Dried. After drying and concentration, the residue obtained is silica
Gel column chromatography (developing solvent; hexane:
The title compound was obtained by purification with ethyl acetate = 15: 1).
(378 mg, yield 56%) was obtained.

[0121]

[Table 5]

Example 11 N- (2-mercaptophenyl) -1-isopentylcyclohexanecarboxamide (formula (I); R = 1-isopentylcyclohexyl, X ₁ , X ₂ , X ₃ , X ₄ = hydrogen atom, Synthesis of Y = carbonyl, Z = hydrogen atom) Step 6) N- (2- (1-Isopentylcyclohexane) carbonylthiophenyl) -1-isopentylcyclohexanecarboxamide (Formula (XI); R = 1-Isopentylcyclohexyl) , X ₁ , X ₂ , X ₃ , X ₄ = hydrogen atom, Y = carbonyl) A solution of 2-aminothiophenol (15.8 g) in pyridine (500 ml) was stirred at room temperature, and 2 equivalents of 1-isopentyl Cyclohexanecarbonyl chloride was added dropwise. After completion of the dropwise addition, the mixture was stirred at 60 ° C. for 2 hours and allowed to cool. After pyridine was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, hydrochloric acid,
The extract was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude oil of the title compound (60 g).
I got

Step 7) The crude product (60 g) obtained in the above step 6) was treated with methanol (60 m
1) Dissolved in a mixed solvent of tetrahydrofuran (60 ml), added potassium hydroxide (24.2 g), and stirred at room temperature for 1 hour. After stirring, water (50 ml) was added, and the mixture was washed with hexane (50 ml × 3 times). The aqueous layer was acidified with potassium hydrogen sulfate, and extracted with chloroform. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystalline product was washed with pentane and collected by filtration to give the title compound (2
(3.1 g, yield 60%).

Examples 12 and 18 In the same manner as in Example 11, the compounds shown in Tables 6 and 7 were obtained.

[0125]

[Table 6]

[0126]

[Table 7]

In the same manner as in Example 11, compounds 11-1 and 11-2 shown in Table 8 were obtained.

[0128]

[Table 8]

Example 19 N- (2-mercapto-5-methoxyphenyl) -1-
Methylcyclohexanecarboxamide (formula (I); R =
1-methylcyclohexyl, X ₁ , X ₃ , X ₄ = hydrogen atom, X ₂ = methoxy, Y = carbonyl, Z = hydrogen atom)
Step 8) N, N-dimethylthiocarbamic acid S- (4
-Methoxy-2-nitrophenyl) ester (formula (VII)
I); R ₁₁ , R ₁₂ = methyl, X ₁ , X ₃ , X ₄ = hydrogen atom,
X ₂ = methoxy) A solution of 4-methoxy-2-nitrophenol (4.00 g) in dimethylformamide (20 ml) was stirred at 0 ° C. in a suspension of sodium hydride (1.04 g) in dimethylformamide (40 ml). Was added dropwise. After dropping,
The mixture was stirred at room temperature for 30 minutes, dimethylthiocarbamoyl chloride (3.65 g) was added, and the mixture was stirred at 80 ° C for 1 hour. After cooling, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid, water, and saturated saline, and dried over anhydrous sodium sulfate. Ether-hexane was added to the residue obtained by concentration, and the precipitated solid was collected by filtration to obtain a yellow solid (5.11 g, yield 84%). Phenyl ether (10 ml) was added to this product (3.50 g), and the mixture was stirred at 210 ° C. for 1 hour and then allowed to cool. The solution was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 7: 1 to 3: 2) to give the title compound (3.35 g, yield 96%).

Step 9) N, N-dimethylthiocarbamic acid S- [2- (1-methylcyclohexanecarbonylamino) -4-methoxyphenyl] ester (formula (I)
X); R = 1-methylcyclohexyl, R ₁₁ , R ₁₂ = methyl, X ₁ , X ₃ , X ₄ = hydrogen atom, X ₂ = methoxy, Y =
Carbonyl) The compound (2.00 g) obtained in the above step 8) and Sn
Cl · 2H ₂ O (3.65 g) in ethyl acetate (75 m
l) The solution was stirred at room temperature overnight. Ethyl acetate (100 ml) was further added to this solution, then an aqueous solution of sodium hydroxide was added, and magnesium sulfate was added, and the precipitated solid was filtered off. The filtrate was concentrated to give N, N-dimethylthiocarbamic acid S- (2-amino-4-methoxyphenyl) ester (1.64 g, yield 93%).
To this, pyridine (2.9 ml) and chloroform (20
ml), and 1-methylcyclohexanecarbonyl chloride (1.39 g) was added dropwise at room temperature with stirring, followed by stirring for 1 hour. Thereafter, the solvent was distilled off, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1) to give the title compound (2.41 g, yield 95%).

Step 10) The compound (250 mg) obtained in the above step 9) was added to potassium hydroxide (140 mg), methanol (1.5 ml) -tetrahydrofuran (0.5 m
l) The solution was heated under reflux for 30 minutes. After cooling down,
Water was added and the aqueous layer was washed with hexane. An aqueous solution of potassium hydrogen sulfate was added to make the mixture acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. The residue obtained by concentration was subjected to column chromatography (developing solvent; hexane: ethyl acetate = 4).
0: 1) to give the title compound (104m
g, yield 52%).

Examples 20 to 24 In the same manner as in Example 19, the compounds shown in Table 9 were obtained.

[0133]

[Table 9]

In the same manner as in Example 19, compounds 19-1 to 19-9 in Table 10 were obtained.

[0135]

[Table 10]

Example 25 S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] thioacetic acid ester (formula (I);
R = 1-Isopentylcyclohexyl, X ₁ , X ₂ ,
X ₃ , X ₄ = hydrogen atom, Y = carbonyl, Z = acetyl)
Step 4) N- (2-mercaptophenyl) -1-iso obtained in the same manner as in Step 2) of Example 9 or Step 7) of Example 11 or Step 10) of Example 19 Pentylcyclohexanecarboxamide (600 mg) and pyridine (0.48 ml) in chloroform (10 ml)
The solution was stirred at room temperature with acetyl chloride (0.17
ml) was added dropwise and stirred for 1 hour. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 12: 1) to obtain the title compound (666 mg, yield 98%).

Example 26 2-methylthiopropionic acid S- [2- [1- (2-
Ethylbutyl) cyclohexanecarbonylamino] phenyl] ester (formula (I); R = 1- (2-ethylbutyl) cyclohexyl, X ₁ , X ₂ , X ₃ , X ₄ = hydrogen atom,
Synthesis of Y = carbonyl, Z = isobutyryl) Step 4) N- (2-mercaptophenyl) -1- (2-ethylbutyl) cyclohexanecarboxamide (43.72 g) obtained in Example 10 and pyridine (2
A solution of 7.7 ml) in chloroform (300 ml) was stirred at room temperature while stirring with isobutyryl chloride (15.0 ml).
Was added dropwise and stirred for 1 hour. After evaporating the solvent, hexane was added and the precipitated solid was filtered off. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 15: 1) to give the title compound (50.72 g, yield 95%).

Example 27 2-methylthiopropionic acid S- [2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester (formula (I); R = 1-isobutylcyclohexyl,
X ₁ , X ₂ , X ₃ , X ₄ = hydrogen atom, Y = carbonyl, Z =
Step 4) A chloroform (25 ml) solution of N- (2-mercaptophenyl) -1-isobutylcyclohexanecarboxamide (2.50 g) and pyridine (1.8 ml) obtained in Example 18 above was added at room temperature. Under stirring, isobutyryl chloride (0.92 ml) was added dropwise, and the mixture was stirred for 1 hour. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 15: 1) to give the title compound (2.
94 g, 95% yield).

Example 28 1-acetylpiperidine-4-thiocarboxylic acid S-
[2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester (formula (I); R = 1
-(2-ethylbutyl) cyclohexyl, X ₁ , X ₂ , X
₃ , Synthesis of X ₄ = hydrogen atom, Y = carbonyl, Z = 1-acetyl-4-piperidinecarbonyl) Step 4) N- (2-mercaptophenyl) -1- (2- Ethylbutyl) cyclohexanecarboxamide (933 mg) and pyridine (0.5
ml) in chloroform (10 ml) at room temperature.
Acetylisonipecotic acid (500 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (616 mg), and 1-hydroxybenzotriazole (435 mg) were added dropwise to a chloroform (10 ml) solution, and 1 Stirred for hours. After stirring, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1 to chloroform: methanol = 10: 1) to give the title compound (1.
08g, 79% yield).

Example 28 ′ The compound of Example 28 (formula (I); R = 1- (2-ethylbutyl) cyclohexyl, X ₁ , X ₂ , X ₃ , X ₄ = hydrogen atom, Y = carbonyl, Z = 1-acetyl-4-piperidinecarbonyl) was synthesized according to another synthetic method. Step 4) To a suspension of 1-acetylisonipecotic acid (331 g) in ethyl acetate (2 l) was added triethylamine (541 ml) under a stream of argon, and the mixture was stirred under ice-cooling. A solution of ethyl chlorocarbonate (185 ml) in ethyl acetate (400 ml) was added dropwise to the reaction solution, and the temperature was further increased by one hour.
Stirred for 00 minutes. After cooling on ice, the reaction solution was added to Example 1 above.
N- (2-mercaptophenyl) -1-
A solution of (2-ethylbutyl) cyclohexanecarboxamide (618 g) in ethyl acetate (2 l) was added dropwise, and the mixture was further stirred under ice-cooling for 15 minutes. After stirring, 1N hydrochloric acid (1.
3l) was added, and the organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate, water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in diisopropyl ether (2.5 L), and crude crystals were obtained by stirring crystallization. The obtained crude crystals were further dissolved by heating in diisopropyl ether (5.5 l), and the mixture was stirred and crystallized to give the title compound (505 g, yield 55%).

Examples 29 to 65 Compounds shown in Tables 11 to 17 were obtained in the same manner as in Examples 25, 26, 27, 28 and 28 '.

[0142]

[Table 11]

[0143]

[Table 12]

[0144]

[Table 13]

[0145]

[Table 14]

[0146]

[Table 15]

[0147]

[Table 16]

[0148]

[Table 17]

Further, compounds 25-1 to 25-10 shown in Tables 18 to 27 were prepared in the same manner as in Examples 25 to 28.
9 was obtained.

[0150]

[Table 18]

[0151]

[Table 19]

[0152]

[Table 20]

[0153]

[Table 21]

[0154]

[Table 22]

[0155]

[Table 23]

[0156]

[Table 24]

[0157]

[Table 25]

[0158]

[Table 26]

[0159]

[Table 27]

Example 66 S- [4,5-Dichloro-2- (1-isopropylcyclohexanecarbonylamino) phenyl] ester of 2,2-dimethylthiopropionic acid (formula (I); R = 1-
Isopropylcyclohexyl, X ₁ , X ₄ = hydrogen atom, X
₂ , X ₃ = chlorine atom, Y = carbonyl, Z = pivaloyl)
Step 4) N, N-dimethylthiocarbamic acid S- [4,5-, obtained in the same manner as in step 9) of Example 19 above.
Dichloro-2- (1-isopropylcyclohexanecarbonylamino) phenyl] ester (86 mg) and potassium hydroxide (50 mg) in tetrahydrofuran (0.
A mixed solution of 5 ml) and methanol (1 ml) was heated under reflux for 30 minutes. After cooling, water was added to the solution, and the aqueous layer was washed with hexane. Further, the aqueous layer was made acidic with an aqueous potassium hydrogen sulfate solution, and extracted with chloroform (10 ml). Pyridine (90 μl) was added to this extract, and pivaloyl chloride (41 μl) was added with stirring at room temperature, followed by stirring for 1 hour. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (developing solvent; hexane:
The title compound (24 mg, yield 27%) was obtained by purification with ethyl acetate = 20: 1).

Examples 67 to 81 In the same manner as in Example 66, the compounds shown in Tables 28 to 30 were obtained.

[0162]

[Table 28]

[0163]

[Table 29]

[0164]

[Table 30]

In the same manner as in Example 66, compounds 66-1 to 66-53 shown in Tables 31 to 35 were obtained.

[0166]

[Table 31]

[0167]

[Table 32]

[0168]

[Table 33]

[0169]

[Table 34]

[0170]

[Table 35]

Example 82 Bis- [4,5-dichloro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] disulfide (formula (I); R = 1-isopentylcyclohexyl,
X ₁ , X ₄ = hydrogen atom, X ₂ , X ₃ = chlorine atom, Y = carbonyl, Z = 4,5-dichloro-2- (1-isopentylcyclohexanecarbonylamino) phenylthio) Step 10) N- (4,5-dichloro-2-mercaptophenyl) -1-isopentylcyclohexanecarboxamide (Formula (III-2); R = 1-isopentylcyclohexyl, X ₁ , X ₄ = hydrogen atom, X ₂ , X ₃ = Chlorine atom, Y
= Carbonyl) N, N- obtained in the same manner as in Step 9 of Example 19
Dimethylthiocarbamic acid S- [4,5-dichloro-
2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester (400 mg) and potassium hydroxide (180 mg) in tetrahydrofuran (2 ml)
After heating and refluxing the mixed solution of methanol (1 ml) for 2 hours, the mixture was allowed to cool. Water was added to this solution, and the aqueous layer was washed with hexane. The aqueous layer was acidified with a saturated aqueous solution of potassium hydrogen sulfate and then extracted with chloroform. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After the anhydrous sodium sulfate was removed by filtration, the organic solvent was distilled off under reduced pressure to obtain a crude product of the title compound.

Step 3) A solution of the crude product obtained in the above step 10) in dimethyl sulfoxide (5 ml) was stirred at 130 ° C. for 2 hours and then allowed to cool. Water was added to this solution and extracted with chloroform. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. The residue obtained by concentration was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 30: 1) to give the title compound (200 mg, yield 60%).

[0173]

[Table 36]

In the same manner as in Example 82, compound 82-1 in Table 35 was obtained.

Example 83 2-Tetrahydrofurylmethyl 2- (1-isopentylcyclohexanecarbonylamino) phenyl disulfide (Formula (I); R = 1-isopentylcyclohexyl, X ₁ , X ₂ , X ₃ , X ₄ = Hydrogen atom, Y = carbonyl,
Synthesis of Z = 2-tetrahydrofurylmethylthio) Step 5) Tetrahydrofurfuryl chloride (3.0)
g) and a mixed solution of sodium thiosulfate (4.13 g) in ethanol (6 ml) -water (6 ml) was heated under reflux for 17 hours, allowed to cool, and ethanol was distilled off under reduced pressure to obtain an aqueous solution of Bundt salt. N- (2-mercaptophenyl) -1-isopentylcyclohexanecarboxamide (380 mg) and sodium hydroxide (50 mg) obtained in the same manner as in Example 11 above at 0 ° C. in this solution.
Aqueous solution (1 ml) was added dropwise, and the mixture was stirred for 1.5 hours. Ether was added, and the organic layer was washed successively with an aqueous sodium hydroxide solution, water and saturated saline, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 8: 1) to give the title compound (12
8 mg, yield 24%).

Example 84 Phenyl 2-pivaloylaminophenyl disulfide (Formula (I); R = t-butyl, X ₁ , X ₂ , X ₃ , X ₄ =
Synthesis of hydrogen atom, Y = carbonyl, Z = phenylthio) Step 5 ′) Trimethylsilane-imidazole (2) was added to a solution of thiophenol (159 mg) in carbon tetrachloride (5 ml).
After stirring for 2 hours at room temperature, the precipitated imidazole was filtered off to obtain a solution. Next, bis- [2- (pivaloylamino) phenyl] disulfide (300 mg) obtained in the same manner as in Step 1 of Example 1 above.
To sulfur tetrachloride (97 mg) and triethylamine (1 drop) were sequentially added to a solution of
Stir at the same temperature for 1.5 hours. This was added dropwise to the previous solution cooled in an ice-salt bath, and stirred for 2.5 hours as it was. After completion of the reaction, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 12: 1) to give the title compound (3
37 mg, yield 74%).

[0177]

[Table 37]

Next, the results of tests performed on the CETP activity inhibitory effect of the compound of the present invention will be shown. (Test Example) (1) Preparation of donor lipoprotein Potassium bromide (KBr) was added to healthy human plasma (40 ml), the specific gravity was adjusted to 1.125 g / ml, and density gradient centrifugation (227,000 × g, (4 ° C., 17 hours), and a fraction having a specific gravity d> 1.125 g / ml (HDL ₃ fraction) was collected. The obtained fraction is a PBS solution [10 mM
Na ₂ HPO4 / 10mM of NaH ₂ PO4 / 0.15M of
NaCl / 1 mM EDTA (pH 7.4)]. Then, 10 nM of tritium labeled cholesterol (50.3Ci / mM) was dissolved in 95% ethanol was added slowly with stirring to the above HDL ₃ fraction, 3
Incubated at 7 ° C. for 18 hours [this procedure
Tritiated cholesterol was esterified by the action of lecithin acyl transferase present in HDL ₃ surface (LCAT), it is taken into HDL ₃ as Torichirumu labeled cholesteryl ester ^{([3 H] CE)]} . After incubation, KBr was added and the specific gravity d =
Adjusted to 1.21 g / ml, density gradient centrifugation (22
7,000 × g, 4 ° C., 17 hours), and specific gravity d <
A fraction of 1.21 g / ml was collected. The obtained fraction was dialyzed against the above PBS solution, and HD containing [ ³ H] CE was taken up.
L ₃ ([ ³ H] CE-HDL ₃ , specific gravity: 1.125 <d <
1.21, specific activity: 101,000 dpm / nM) to obtain a donor lipoprotein.

(2) Preparation of acceptor lipoprotein Healthy plasma (100 ml) was added to physiological saline (specific gravity d = 1.
006 g / ml) and density gradient centrifugation (22
7,000 × g, 4 ° C., 4 hours), and specific gravity d> 1.
A 006 g / ml fraction was collected. In the obtained fraction, KB
Then, the specific gravity d was adjusted to 1.063 g / ml, and density gradient centrifugation was performed (227,000 × g, 4 ° C., 20 hours).
And fractions having a specific gravity d <1.063 g / ml were collected. The obtained fraction was dialyzed against the aforementioned PBS solution, and
And LDL (specific gravity: 1.006 <d <1.
063) was obtained and used as the acceptor lipoprotein.

[0180] Test Example 1: addition of donor lipoprotein obtained in the above (1) to the CETP activity inhibitory effect healthy human plasma in total plasma in ^{vitro, [3 H] CE-HDL} 3 containing plasma (600,000D
pm / ml). The sample was prepared using a 1: 1 solution of N-methylpyrrolidone and polyethylene glycol 400 as a solvent. Microtube only sample solution or solvent and ^{2μl [3 H] CE-HDL} 3 containing plasma 1
00 μl was added and incubated at 37 ° C. or 4 ° C. for 4 hours. After cooling with ice, 0.15M magnesium chloride and 0.1M magnesium chloride were added.
TBS solution containing 3% dextran sulfate [20 mM T
ris / 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, centrifugation (8,000 rpm)
m, 4 ° C, 10 minutes), and the resulting centrifuged supernatant (HD
L fraction) was measured using a scintillation counter. The difference between the measured values after incubation at 4 ° C. and 37 ° C. with the solvent alone was defined as CETP activity, and the rate of decrease in the difference between the measured values depending on the sample was defined as the CETP activity inhibition rate. CET
The IC ₅₀ value of each sample was calculated from the P activity inhibition rate. The results are shown in Tables 38 to 48.

Test Example 2: Inhibition of CETP activity in plasma of transgenic mice ex vivo A sample was suspended in a 0.5% methylcellulose solution.
Human CETP gene-introduced transgenic mice fasted overnight (hereinafter referred to as mice; Japanese Patent Application No. Hei 8-1306).
No. 60) was orally administered using a plastic sonde. Blood was collected before administration and 6 hours after administration, and the CETP activity in plasma was measured according to the following method.

The donor lipoprotein ([ ³ H] CE-HDL ₃ containing 0.21 μg of cholesterol) obtained in the above (1) and the acceptor lipoprotein (2) obtained in the above (2)
1 μg cholesterol) and mouse plasma 0.9
μl was added to the microtube, and the TBS solution [10 m
M Tris / 0.15 M NaCl (pH 7.4)]
The total volume was adjusted to 600 μl / tube. After incubating the microtube at 37 ° C. or 4 ° C. for 15 hours, an ice-cold TBS solution (400 μl / tube) and 0.1 μg / ml.
A 0.3% dextran sulfate solution containing 15 M magnesium chloride (100 μl / tube) was added and stirred well. After leaving at 4 ° C. for 30 minutes, centrifugation (8,
000 rpm, 4 ° C., 10 minutes), and the radioactivity of the obtained centrifugal supernatant (HDL fraction) was measured using a scintillation counter. The difference between the measured values obtained by incubating the plasma of each individual before sample administration at 4 ° C. and 37 ° C. was determined by CET.
P activity and the rate of decrease in the difference between the measured values due to sample administration as CE
The TP activity inhibition rate was used. The results are shown in Tables 38 to 48.

[0183]

[Table 38]

[0184]

[Table 39]

[0185]

[Table 40]

[0186]

[Table 41]

[0187]

[Table 42]

[0188]

[Table 43]

[0189]

[Table 44]

[0190]

[Table 45]

[0191]

[Table 46]

[0192]

[Table 47]

[0193]

[Table 48]

[0194]

According to the above test results, the compound (I) according to the present invention has an excellent CETP activity inhibitory action. Therefore, it is useful as a novel or preventive or therapeutic agent for a new type of hyperlipidemia which can reduce IDL, VLDL and LDL which promote arteriosclerosis and increase HDL which acts suppressively. It is also useful as a prophylactic or therapeutic drug for arteriosclerotic diseases and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/401 A61K 31/401 31/4015 31/4015 31/4402 31/4402 31/4406 31/4406 31/4409 31/4409 31/445 31/445 A61P 9/10 A61P 9/10 43/00 111 43/00 111 (56) References JP-A-7-233069 (JP, A) JP-A-7-233052 (JP, A) Kaihei 7-112980 (JP, A) EGAN, Robert W. et al., Specific Inhibition and Oxidative Regulation of 5-lipoxygenase, Adv. Prostaglandin, Thromb oxane, Leukotriene Res. , Vol. 11, 151-157, 1983 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/167 A61K 31/18 A61K 31/255 A61K 31/341 A61K 31/381 A61K 31/401 A61K 31 / 4015 A61K 31/4402 A61K 31/4406 A61K 31/4409 A61K 31/445 A61P 9/10 A61P 43/00 CA (STN) EMBASE (STN) MEDLINE (STN)

Claims (6)

(57) [Claims] 1. A compound of the general formula (I) [Wherein R is a linear or branched C _1-10 alkyl group; a linear or branched C _2-10 alkenyl group; a halogenated C _1-4 lower alkyl group; C _3-10 cycloalkyl A C _5-8 cycloalkenyl group; a C _3-10 cycloalkyl C _1-10 alkyl group (where the cycloalkyl group, cycloalkenyl group or cycloalkylalkyl group is a straight-chain or branched C _{1- A} linear or branched C _2-10 alkenyl group; a C _3-10 cycloalkyl group; a C _5-8 cycloalkenyl group; a C _3-10 cycloalkyl C _1-10 alkyl group; an aryl group; An amino group;
A C _1-4 lower alkylamino group; an acylamino group; an oxo group; an aralkyl group; and an arylalkenyl group, which may be substituted); an aryl group; an aralkyl group; A 5- or 6-membered heterocyclic group having 1 to 3 (where the aryl group, aralkyl group or heterocyclic group is a linear or branched C _1-10 alkyl group; a linear or branched C _2-10 alkenyl group, a halogen atom, a nitro group, C _1-4 lower alkyl group or an acyl amino group which may be substituted with a group; a hydroxyl group; C _1-4 lower alkoxy groups; C _1-4 lower alkylthio group A halogenated C _1-4 lower alkyl group; an acyl group; and an oxo group, which may be substituted).
In _{and, X 1, X 2, X} 3, X 4 may be the same or different, a hydrogen atom; a halogen atom; C _1-4 lower alkyl group, halogenated C _1-4 lower alkyl group; C _{1- 4 a} lower alkoxy group; a cyano group; a nitro group; an acyl group; or an aryl group, Y is —CO—, or —SO ₂ —, and Z is a hydrogen atom; or a disulfide that is a dimer. Group, C _1-4 lower alkoxymethyl group, C _1-4 lower alkylthiomethyl group, aralkyloxymethyl group, aralkylthiomethyl group, C _3-10 cycloalkyloxymethyl group, C _5-8 cycloalkenyloxymethyl group, C _3-10 cycloalkyl C _1-10 alkoxymethyl group, aryloxymethyl group, arylthiomethyl group, acyl group, acyloxy group, aminocarbonyloxymethyl group, thiocarbonyl group or thio Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient. 2. R is a straight-chain or branched C _1-10 alkyl group; a straight-chain or branched C _2-10 alkenyl group; 1 to 3 selected from a fluorine atom, a chlorine atom and a bromine atom A halogenated C _1-4 lower alkyl group substituted with a halogen atom of the following: a C _3-10 cycloalkyl group, a C _5-8 cycloalkenyl group which may be substituted with 1 to 4 substituents selected from the following: Or a C _3-10 cycloalkyl C _1-10 alkyl group; a linear or branched C _1-10 alkyl group, a linear or branched C _2-10 alkenyl group, a C _3-10 cycloalkyl group, A C _5-8 cycloalkenyl group, a C _3-10 cycloalkyl C _1-10 alkyl group, an aryl group selected from phenyl, biphenyl and naphthyl, an oxo group or an aralkyl group having an aryl group selected from phenyl, biphenyl and naphthyl: From one to four selected from An aryl group which may be substituted with substituent, an aralkyl group or a nitrogen atom, an oxygen atom or sulfur atom of 1 to 5 or 6-membered having three heterocyclic group; a linear or branched C _1-10 alkyl Group, a linear or branched C _2-10 alkenyl group, a halogen atom having a halogen atom selected from a fluorine atom, a chlorine atom or a bromine atom, a nitro group or a halogen atom having a halogen atom selected from a fluorine atom, a chlorine atom or a bromine atom A C _1-4 lower alkyl group, Z is a hydrogen atom; a mercapto protecting group selected from the following group; a disulfide-forming dimer, a C _1-4 lower alkoxymethyl group, a C _1-4 lower group An aralkyloxymethyl group having an aryl group selected from an alkylthiomethyl group, phenyl, biphenyl, and naphthyl; an aryl group selected from phenyl, biphenyl, and naphthyl Aralkylthio methyl group, C _3-10 cycloalkyloxy methyl, C _5-8 cycloalkenyl oxymethyl group, C _3-10 cycloalkyl C _1-10 alkoxymethyl group, phenyl, biphenyl, an aryl group selected from naphthyl The compound according to claim 1, which is an aryloxymethyl group, an arylthiomethyl group having an aryl group selected from phenyl, biphenyl, and naphthyl, an acyl group, an acyloxy group, an aminocarbonyloxymethyl group, a thiocarbonyl group, and a thio group. A CETP activity inhibitor comprising the prodrug compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. 3. A compound of the general formula (I-1) In the formula, R, X ₁ , X ₂ , X ₃ , X ₄ and Y are the same as those in claim 2, and Z ₁ is a hydrogen atom; (Wherein, R, X ₁ , X ₂ , X ₃ , X ₄ and Y are each as described above); -Y ₁ R ₁ wherein Y ₁ is —CO—; or —CS— R ₁ is a linear or branched C _1-10 alkyl group wherein the alkyl group is substituted with a C _1-4 lower alkoxy group; a C _1-4 lower alkyl group, an acyl group or a hydroxyl group. Amino group; C _1-4 lower alkylthio group; carbamoyl group;
A hydroxyl group; a halogen atom; an acyloxy group; a carboxy group; an acyl group; and a C _1-10 alkyl group, which may be substituted with a group selected from an aryloxy group which may be substituted with a halogen atom or a nitro group); C _1-4 lower alkoxy group; C _1-4 lower alkylthio group; amino group; ureido group (wherein these amino groups or ureido groups are C _1-4 lower alkyl groups; hydroxyl groups; acyl groups; and C _1-4 A C _3-10 cycloalkyl group; a C _3-10 cycloalkyl C _1-10 alkyl group (wherein these may be substituted with a group selected from an aryl group which may be substituted with a lower alkoxy group) A cycloalkyl group or a cycloalkylalkyl group is a linear or branched C _1-10 alkyl group; a linear or branched C _1-10 alkyl group;
_2-10 alkenyl group; C _3-10 cycloalkyl group; C _5-8 cycloalkenyl group; C _3-10 cycloalkyl C _1-10 alkyl group; aryl group; amino group; C _1-4 lower alkylamino group; An arylamino group; an oxo group; an aralkyl group; and an arylalkenyl group, which may be substituted); an aryl group; an aralkyl group; an arylalkenyl group; an arylthio group; 5 with 3
Or a 6-membered heterocyclic group; or a 5- or 6-membered heteroarylalkyl group (where the aryl group, aralkyl group, arylalkenyl group, arylthio group, heterocyclic group or heteroaryl group is a straight-chain or branched linear or branched C _2-10 alkenyl group; a halogen atom; a nitro group; C _1-4 lower alkyl group or an acyl amino group which may be substituted with a group; hydroxyl C _1-10 alkyl group; C _1-4 lower alkoxy group; C _1-4 lower alkylthio group; halogenated C
_1-4 lower alkyl group; an acyl group; and optionally substituted by a group selected from oxo group is also be)]; or -S-R ₂ [wherein, R ₂ is C _1-4 lower alkyl group ( Here, the lower alkyl group is a C _1-4 lower alkoxy group; an amino group which may be substituted with a C _1-4 lower alkyl group or an acyl group;
C _1-4 lower alkylthio group; carbamoyl group; hydroxyl group;
A carboxy group; an acyl group; and a heterocyclic group, which may be substituted); or an aryl group (where the aryl group is a C _1-4 lower alkyl group; a fluorine atom, a chlorine atom or a bromine atom) A halogen atom selected from;
A nitro group; a hydroxyl group; a C _1-4 lower alkoxy group; a C _1-4 lower alkylthio group; an acyl group; an amino group optionally substituted with a C _1-4 lower alkyl group or an acyl group; a fluorine atom, a chlorine atom or Or a prodrug thereof.) A halogenated C _1-4 lower alkyl group having a halogen atom selected from a bromine atom, which may be substituted by a group selected from a halogen atom. A CETP activity inhibitor comprising a compound, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. 4. A linear or branched C _1-10 alkyl group, wherein R ₁ may be substituted by 1 to 3 substituents selected from the following; selected from a fluorine atom, a chlorine atom and a bromine atom A halogen atom, a C _1-4 lower alkoxy group, a C _1-4 lower alkyl group, an amino group optionally substituted with an acyl group or a hydroxyl group, a C _1-4 lower alkylthio group, a carbamoyl group, a hydroxyl group, an acyl group, acyloxy group having an acyl group, a carboxy group, a fluorine atom, a chlorine atom or an aryloxy group C _1-4 lower alkoxy group optionally substituted with a halogen atom selected from bromine atom; C _1-4 lower alkylthio group; below 1 or 2 substituents amino group which may be substituted with a group or ureido group selected from; C _1-4 lower alkyl group, a hydroxyl group, an acyl group, substituted with a C _1-4 lower alkoxy group Optionally substituted with a substituent group selected from an aryl group below with have C _3-10
A cycloalkyl group or a C _3-10 cycloalkyl C _1-10 alkyl group; a linear or branched C _1-10 alkyl group, a C _3-10 cycloalkyl group, a C _5-8 cycloalkenyl group, an aryl group, An amino group, a C _1-4 lower alkylamino group having a C _1-4 lower alkyl group, an acylamino group having an acyl group, an aryl group optionally substituted with 1 to 4 substituents selected from the following, an aralkyl group An arylalkenyl group or an arylthio group; a C _1-10 alkyl group, a halogen atom selected from a fluorine atom, a chlorine atom or a bromine atom, a nitro group, a hydroxyl group, a C _1-4 lower alkoxy group, a C _1-4 lower alkylthio group, Acyl group substituted with a halogenated C _1-4 lower alkyl group, a C _1-4 lower alkyl group or an acyl group having a halogen atom selected from a fluorine atom, a chlorine atom or a bromine atom. Amino group 5- to 6-membered heterocyclic group having 1 to 3 nitrogen, oxygen or sulfur atoms which may be substituted by 1 to 4 substituents selected from the following: Heteroarylalkyl group; linear or branched C _1-10 alkyl group, halogen atom selected from fluorine atom, chlorine atom or bromine atom, acyl group, oxo group halogen selected from fluorine atom, chlorine atom or bromine atom A halogenated C _1-4 lower alkyl group having an atom, wherein R ₂ is a C _1-4 lower alkyl group which may be substituted with one to three substituents selected from the following; C _1-4 lower alkoxy group, C _1-4 lower alkyl or acyl optionally substituted amino group with a group, C _1-4 lower alkylthio group, a carbamoyl group, a hydroxyl group, a carboxyl group, an acyl group, a nitrogen atom, an oxygen atom or a sulfur atom To 1 to 3 have a 5
A 6- to 6-membered heterocyclic group, an aryl group optionally substituted with 1 to 4 substituents selected from the following: a C _1-4 lower alkyl group, a halogen atom selected from a fluorine atom, a chlorine atom or a bromine atom, Nitro group, hydroxyl group, C _1-4 lower alkoxy group, C _1-4 lower alkylthio group, acyl group, amino group optionally substituted by C _1-4 lower alkyl group or acyl group, fluorine atom, chlorine atom or bromine 4. The compound according to claim 3, which is a halogenated _C1-4 lower alkyl group having a halogen atom selected from atoms, a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. A CETP activity inhibitor as a component. 5. Bis- [2- (pivaloylamino) phenyl] disulfide; bis- [2- (2-propylpentanoylamino) phenyl] disulfide; bis- [2- (1-methylcyclohexanecarbonylamino) phenyl] disulfide Bis- [2- (1-isopentylcyclopentanecarbonylamino) phenyl] disulfide; bis- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] disulfide; N- (2-mercaptophenyl) -2,2 -Dimethylpropionamide; N- (2-mercaptophenyl) -1-isopentylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-methylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-isopentylcyclo Emissions Tan carboxamide; N-(2-mercapto-phenyl) -1-isopropyl-cyclohexanecarboxamide; N-(4,5-dichloro-2-mercapto-phenyl) -
1-isopentylcyclohexanecarboxamide; N- (4,5-dichloro-2-mercaptophenyl)-
1-isopentylcyclopentanecarboxamide; N- (2-mercapto-5-methylphenyl) -1-isopentylcyclohexanecarboxamide; N- (2-mercapto-4-methylphenyl) -1-isopentylcyclohexanecarboxamide; thioacetic acid S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [2- (1-
Methylcyclohexanecarbonylamino) phenyl] ester; S- [2- (pivaloylamino) phenyl] phenylthioacetate; S- [2- (1- (2-dimethylthiopropionic) acid]
Isopentylcyclohexanecarbonylamino) phenyl] ester; 2-acetylamino-3-phenylthiopropionic acid
S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 3-pyridinethiocarboxylic acid S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; chlorothioacetic acid S- [2- (1 -Isopentylcyclohexanecarbonylamino) phenyl] ester; S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] methoxythioacetate; S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] thiopropionate Ester; phenoxythioacetic acid S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2-methylthiopropionic acid S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl Sulfonyl] ester; 4-chlorophenoxy thioacetate S- [2- (1- isopentyl cyclohexanecarbonyl amino) phenyl]
Ester; cyclopropanethiocarboxylic acid S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl]
Ester; 2-acetylamino-4-carbamoylthiobutyric acid S- [2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2-hydroxy-2-methylthiopropionic acid S-
[2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [2- (1-
Isopentylcyclopentanecarbonylamino) phenyl] ester; S- [2- (1-isopentylcyclopentanecarbonylamino) phenyl] thioacetate; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2 -(1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-isopentylcyclopentanecarbonylamino) phenyl] ester; 2,2 -Dimethylthiopropionic acid S- [2- (1-
Isopentylcyclohexanecarbonylamino) -4-
Trifluoromethylphenyl] ester; O-methylthiocarbonate S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl]
E; S- [2- (1-methylcyclohexanecarbonylamino) phenyl] dithiocarbonate S-phenyl ester; S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] N-phenylthiocarbamate
Ester; 2,2-dimethylthiopropionic acid S- [2- (pivaloylamino) -4-trifluoromethylphenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1- Cyclopropylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (2-cyclohexylpropionylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-pentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-cyclopropylmethylcyclohexanecarbonylamino) Phenyl] ester; 2,2-dimethylthiopropyl Acid S- [4,5-dichloro-2- (1-cyclohexylmethylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-isopropylcyclohexane) Carbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-isopentylcycloheptanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-dichloro-2- (1-isopentylcyclobutanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [2- (1-
Isopentylcyclohexanecarbonylamino) -4-
Nitrophenyl] ester; 2,2-dimethylthiopropionic acid S- [4-cyano-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4-chloro- 2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [5-chloro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethyl Thiopropionic acid S- [4-fluoro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; 2,2-dimethylthiopropionic acid S- [4,5-difluoro-2- (1-isopentylcyclohexane) Carbonylamino) phenyl] ester; 2 2-dimethylthiopropionic acid S- [5-fluoro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] ester; bis- [4,5-dichloro-2- (1-isopentylcyclohexanecarbonylamino) phenyl] Disulfide; 2-tetrahydrofurylmethyl 2- (1-isopentylcyclohexanecarbonylamino) phenyl disulfide; N- (2-mercaptophenyl) -1-ethylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-propylcyclohexanecarboxamide N- (2-mercaptophenyl) -1-butylcyclohexanecarboxamide; N- (2-mercaptophenyl) -1-isobutylcyclohexanecarboxamide; cyclohexanethiocarboxylic acid S- [ - (1-isopentyl cyclohexanecarbonyl amino) phenyl]
Ester; Thiobenzoic acid S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl] ester; 5-Carboxythiopentanoic acid S- [2- (1-Isopentylcyclohexanecarbonylamino) phenyl]
Ester; thioacetic acid S- [2- (1-isopentylcyclohexanecarbonylamino) -4-methylphenyl] ester; bis- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] disulfide; N- ( 2-mercaptophenyl) -1- (2-ethylbutyl) cyclohexanecarboxamide; 2-methylthiopropionic acid S- [2- [1- (2-
Ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 2-methylthiopropionic acid S- [2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester; 1-acetylpiperidine-4-thiocarboxylic acid S-
[2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] thioacetate; 2,2-dimethylthiopropionic acid S- [2- [1-
(2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; methoxythioacetic acid S- [2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 2-hydroxy-2-methylthiopropionic acid S-
[2- [1- (2-ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 4-chlorophenoxythioacetic acid S- [2- [1- (2
-Ethylbutyl) cyclohexanecarbonylamino] phenyl] ester; 4-chlorophenoxythioacetic acid S- [2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester; 1-acetylpiperidine-4-thiocarboxylic acid S-
The compound according to claim 1, which is selected from the group consisting of [2- (1-isobutylcyclohexanecarbonylamino) phenyl] ester, a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. A CETP activity inhibitor as an active ingredient. 6. A prophylactic or therapeutic agent for hyperlipidemia comprising the compound according to claim 1, a prodrug compound thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.