JP2004323504A - Dibenzylamine compound and its pharmaceutical use - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound selectively inhibiting the activity of a CETP. <P>SOLUTION: This CETP activity inhibitor is a compound expressed by general formula (1) [wherein, R<SP>1</SP>, R<SP>2</SP>are each a 1-6C alkyl which many be substituted by a halogen atom, or the like; R<SP>3</SP>, R<SP>4</SP>and R<SP>5</SP>are each H, or R<SP>3</SP>and R<SB>4</SB>together with a carbon atom to which R<SP>3</SP>, R<SB>4</SB>bond, may form a homocyclic or heterocyclic ring which may have a substituent; A is N(R<SP>7</SP>)(R<SP>8</SP>) or the like; ring B is an aryl or a heterocyclic residue; R<SP>6</SP>is H , a halogen, nitro, a 1-6C alkyl or the like; and (n) is 1-3 integer], or its prodrug or pharmaceutically acceptable salt, or includes these compounds. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

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

  For some time, the relationship between atherosclerotic disease and serum lipoproteins has been considered to have a certain relationship from the results of many epidemiological studies. For example, according to Badimon et al., When a fraction containing HDL (high-density lipoprotein) and VHDL (ultra-high-density lipoprotein) was intravenously injected into a cholesterol-loaded rabbit, not only the prevention of the progression of atherosclerotic lesions but also regression was observed. It has been reported that HDL and VHDL have an anti-atherosclerotic effect in relation to atherosclerotic disease and serum lipoprotein (see Non-Patent Document 1).

  In recent years, the existence of a protein that transfers lipids between blood lipoproteins, that is, CETP (cholesterol ester transfer protein) has been revealed. The existence of CETP was first pointed out by Nichols & Smith in 1965, and then cDNA cloned by Drayna et al. In 1987 (see Non-Patent Document 2). Its molecular weight is 74,000 Da as a glycoprotein, and about 58,000 Da when sugar chains are completely cleaved. In addition, the cDNA is composed of 1656 residues and encodes 476 amino acids following 17 signal peptides. Of these, about 44% are hydrophobic amino acids, and therefore have extremely high hydrophobicity. In addition, it is 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. As cell types, human monocyte-derived macrophages, B lymphocytes, adipocytes, intestinal epithelial cells, It has been confirmed that it is synthesized in cells such as CaCo2 cells and hepatocytes (for example, human hepatoma cell-derived strain HepG2 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.

  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, with respect to HDL, which plays an important role in this reverse cholesterol transfer system, a number of epidemiological studies have shown that reduction of CE (cholesterol ester) of HDL in blood is one of the risk factors for coronary artery disease. I have. In addition, CETP activity differs depending on the animal species. In animals with low activity, arteriosclerosis due to cholesterol load is less likely to be induced, and in animals with high activity, it is easily induced. In the case of CETP deficiency, hyperHDLemia is high. It has also been shown that they cause low LDL (low density lipoprotein) blood and become less susceptible to arteriosclerosis, and mediate the transfer of CE in HDL to blood LDL together with the importance of blood HDL. The importance of CETP has been recognized.

  By the way, free cholesterol (FC) synthesized and secreted in the liver is taken up by very low density lipoprotein (VLDL). Next, VLDL is metabolized into LDL after passing through intermediate-density lipoprotein (IDL) by the action of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) in blood. LDL is taken up into peripheral cells via the LDL 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 migrated 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. The CE transferred to the apoB-containing lipoprotein is taken up by the liver via the liver LDL receptor, whereby cholesterol is indirectly transferred to the liver. In addition, HDL takes in apoprotein E secreted from macrophages and the like to become CE-rich HDL containing apoprotein E, and there is also a mechanism in which HDL is directly taken into the liver via LDL receptor or remnant receptor. There is also a pathway in which only CE in HDL is selectively taken up into hepatocytes without the HDL particles being taken up into the liver. In addition, there are routes through 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, the CE transfer from the HDL increases, so that the CE in the HDL decreases and the CE in the VLDL, IDL and LDL increases. When the uptake of IDL and LDL into the liver increases, LDL receptors are down-regulated, and blood LDL increases. In contrast, in a CETP-deficient state, HDL extracts cholesterol from peripheral cells with the help of LCAT and gradually increases in size to acquire apoE. Then, the HDL that has become apoE-rich is taken into the liver via the LDL receptor of the liver and is catabolized. However, in humans, this mechanism is not working well, resulting in large HDL stagnation in the blood. As a result, LDL decreases because the liver cholesterol pool shrinks and is up-regulated for the LDL receptor. Therefore, by selectively inhibiting CETP, IDL, VLDL and LDL which promote arteriosclerosis can be reduced, and HDL which acts suppressively can be increased. It can be expected to provide a prophylactic or therapeutic drug.
In recent years, many drugs have been developed to inhibit the activity of CETP, but a compound having a satisfactory activity has not yet been developed.

  By the way, many reports on compounds aimed at inhibiting the activity of CETP have recently come to be seen. For example, dithiodipyridine derivatives and substituted dithiodibenzene derivatives have been disclosed as compounds that inactivate CETP by modifying cysteine residues. However, the present invention is, of course, suggested. No description is found (see Non-Patent Document 3).

In addition, as a CETP activity inhibitor, Wiedendiol-A and Wiedendiol-B are disclosed, but there is no description suggesting the compound of the present invention (see Patent Document 1).
Further, as a compound having an anti-arteriosclerosis effect, mercaptoanilides substituted with a higher fatty acid such as o-isostearoylaminothiophenol are disclosed. There is no description of supporting test examples nor description of CETP activity inhibition (see Patent Documents 2 to 6). Further, there is no description suggesting the compound of the present invention.

Further, although a biaryl compound that inhibits CETP is disclosed, there is no description suggesting the compound of the present invention (see Patent Document 7).
Further, 4-carboxyamino-2-substituted-1,2,3,4-tetrahydroquinoline is disclosed as a CETP activity inhibitor, but there is no description suggesting the compound of the present invention (Patent Documents 8 to 9). 10).

On the other hand, various reports have been made on compounds having a structure similar to the compound of the present invention. For example, carbamate derivatives characterized by having an oxime ether group in the phenyl group are disclosed, but are compounds useful as agricultural and horticultural fungicides, and of course, they disclose their usefulness as CETP activity inhibitors. Is not found (see Patent Documents 11 and 12).
Also disclosed are compounds such as 3- (4-{[N- [3- (2,6-dichlorophenyl) acryloyl] -N- (4-tert-butylbenzyl) amino] methyl} benzoylamino) propionic acid. However, the compound disclosed in the publication is a compound useful as a glucagon antagonist, and of course, it does not disclose its usefulness as a CETP activity inhibitor, nor is there any description suggesting this (see Patent Document 13).
Furthermore, compounds such as 1- [N- (4-chlorobenzyl) -N- (N, N-dimethylcarbamoyl) aminomethyl] -4-guanidinomethylbenzene are disclosed, but are compounds useful as analgesics. There is, of course, no disclosure of usefulness as a CETP activity inhibitor, nor is there any description suggesting this (see Patent Document 14).

On the other hand, compounds such as N- (4-tert-butylbenzyl) -N- [4- (guanidinomethyl) benzyl] benzamide, which is useful as a gonadotropin releasing hormone antagonist / agonist, are disclosed. There is no description that suggests this, as well as the usefulness of the agent (see Patent Documents 15 and 16).
It is also disclosed that halomethylamide compounds such as N-benzyl-N- (2,4-dichlorobenzyl) chloroacetamide are useful as IL-1β protease activity inhibitors (see Patent Documents 17 and 18). . However, the publication does not disclose any usefulness as a CETP activity inhibitor, nor does it mention any suggestion thereof.
Furthermore, 2-amino-heterocyclic compounds such as N, N-bis (2,4-dimethoxybenzyl) -N '-(4-methoxyphenyl) urea are disclosed, but compounds useful as leukotriene synthesis inhibitors. In addition, there is no description of the usefulness as a CETP activity inhibitor, and no description suggesting this is found (see Patent Document 19).

On the other hand, urea derivatives such as 1-benzyl-1- [3- (pyrazol-3-yl) benzyl] -3- (2,4,6-trimethylphenyl) urea are disclosed, but acyl-CoA: cholesterol. -It is a compound useful as an acyltransferase inhibitor, and there is no description of its usefulness as a CETP activity inhibitor, of course, nor is there any description suggesting this (see Patent Document 20).
Also, urea compounds such as 1-benzyl-1- (2,4-dichlorobenzyl) -3- (2,4-dimethylphenyl) urea are useful compounds as acyl-CoA: cholesterol acyltransferase inhibitors. However, there is no disclosure of usefulness as a CETP activity inhibitor, nor is there any description suggesting this (see Patent Document 21).
Further, urea compounds such as 1,1-dibenzyl-3- (2,4-dimethylphenyl) -3-phenylurea are disclosed, but acyl-CoA: a compound useful as a cholesterol acyltransferase inhibitor. There is, of course, no disclosure of usefulness as a CETP activity inhibitor, nor is there any description suggesting this (see Patent Document 22).

Also disclosed are compounds such as N-[[2- [3- (dimethylamino) propoxy] phenyl] methyl] -3-phenyl-N- (phenylmethyl) -2-propenamide, And usefulness as a CETP activity inhibitor is not disclosed, nor is there any description suggesting that (see Patent Documents 23 to 26).
Furthermore, amide carboxyls such as ethyl 2-butyl-3- [4- [2- [N-benzyl- (4-pyridin-2-yl) amino] ethoxy] phenyl] propionate having utility such as lipid lowering action. Although an acid compound is disclosed, there is no description that suggests that the compound is useful as a CETP activity inhibitor, of course. Is not found (see Patent Document 27).

  On the other hand, a compound having a structure similar to the present invention and having CETP inhibitory activity has been disclosed (see Patent Document 28). Specifically, the following general formula is disclosed.

Here, when R ₂ and R ₃ together form a heterocycle or cycloalkenyl, they are structurally similar to the present invention. However, there is no specific disclosure (Example) of ring B as shown in the present invention in the present invention. In addition, the present invention differs from the present invention in that the present invention always has R ₁ (haloalkyl, haloalkenyl, haloalkoxyalkyl or haloalkenyloxyalkyl).
That is, the invention does not disclose specific structures such as the compound of the present invention, nor does it mention any suggestion thereof.
International Publication No. 95/06626 pamphlet Japanese Patent Publication No. 45-11132 Japanese Patent Publication No. 45-2892 JP-B-45-2891 Japanese Patent Publication No. 45-2731 Japanese Patent Publication No. 45-2730 WO 98/04528 pamphlet International Publication No. 00/17164 pamphlet WO 00/17166 pamphlet WO 01/40190 pamphlet JP 2001-106666 A WO 01/10825 pamphlet WO 00/69810 pamphlet International Publication No. 99/67204 pamphlet International Publication No. 99/44987 pamphlet U.S. Pat. No. 6,218,426 U.S. Pat. No. 5,834,514 WO 95/29672 pamphlet WO 97/24328 pamphlet WO 96/10559 pamphlet U.S. Pat. No. 4,623,662 U.S. Pat. No. 4,473,579 U.S. Pat.No. 4,122,255 US Patent No. 4064125 U.S. Pat. No. 4,151,354 U.S. Pat. No. 4,127,606 WO 99/18066 pamphlet WO 00/18724 pamphlet The Journal of Clinical Investigation, 1990, Vol. 85, p. 1234-1241. Journal of Lipid Research, 1965, Volume 6, p. 206. Biochemical and Biophysical Research Communications, 1996, Vol. 223, p. 42-47.

  An object of the present invention is to provide a novel compound that selectively inhibits the activity of CETP. In addition, the present invention can increase HDL cholesterol and lower LDL cholesterol and triglyceride simultaneously by selectively inhibiting the activity of CETP, and furthermore, atherosclerosis or hyperlipidemia without CYP inhibitory action. It is another object of the present invention to provide a compound useful as a prophylactic or therapeutic agent for the disease.

The present inventors have conducted intensive studies to achieve the above object, and as a result, the compounds shown in the following [1] to [13] have the activity of selectively inhibiting CETP activity (hereinafter referred to as CETP inhibitory activity). And found to be useful as a medicament, particularly as a preventive or therapeutic agent for arteriosclerosis or hyperlipidemia. Furthermore, they have found that a compound having a structure as represented by the general formula (1) has strong CETP inhibitory activity, and have completed the present invention. More specifically, it is as shown in the following [1] to [74].
[1] General formula (1)

(In the formula,
R ¹ and R ² are the same or different and are a halogen atom, a nitro group, a cyano group, or a C _1-6 alkyl group _optionally substituted with a halogen atom;
R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, a C _1-6 alkylthio group optionally substituted with a halogen atom, or A C _1-6 alkoxy group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may have a substituent together with a carbon atom to which R ³ and R ⁴ or R ⁴ and R ⁵ are bonded; May form an elementary ring or a heterocyclic ring which may have a substituent;
A is -N (R ⁷ ) (R ⁸ ) (where R ⁷ and R ⁸ are the same or different and are each a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or -(CH ₂ ) _m -COOR ⁹ (where R ⁹ is a hydrogen atom or a C _1-6 alkyl group, and m is 0 or an integer of 1 to 5), or C _4-10 cycloalkylalkyl group (wherein _{C 4-10} cycloalkylalkyl group, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl _{group, C 1-6 alkoxy, C 1-6} alkyl group ( the _{C 1-6} alkyl group, a hydroxyl _group, may be substituted with _{C 1-6} alkoxy group or phosphono ^{_{group), - (CH 2) q}} -CON (R 20) (R 21) ( ^{wherein, R 20} and ^{R 21} are the same or different and each represents a hydrogen atom or a C _-6 alkyl group, q is 0 or an integer of 1 to 5) or ^{_{- (CH 2) r -COOR 10}} ( ^{wherein, R 10} is a hydrogen atom or a _{C 1-6} alkyl group, r Is 0 or an integer of 1 to 5) and may be substituted by 1 to 3)), -C (R ¹¹ ) (R ¹² ) (R ¹³ ) (where R ¹¹ , R ¹² and R ¹³ is the same or different and is substituted by a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or —COOR ⁹ (where R ⁹ is the same as described above)) Or a C _4-10 cycloalkylalkyl group (the C _4-10 cycloalkylalkyl group may be a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group, a C _{1 -6} alkyl group (the _{C 1-6} alkyl group, Group _may be substituted with _{C 1-6} alkoxy group or phosphono ^{_{group), - (CH 2) q}} -CON (R 20) (R 21) ( ^wherein, R ^{20, R 21} and q are the Or — (CH ₂ ) _r —COOR ¹⁰ (wherein R ¹⁰ and r may be the same as defined above) or may be substituted with 1 to 3), or —O—C ( R ¹¹ ) (R ¹² ) (R ¹³ ), wherein R ¹¹ , R ¹² and R ¹³ are the same as above;
Ring B is an aryl group or a heterocyclic residue;
R ⁶ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group or a C _1-6 alkyl group (C _1-6 The alkyl group is a hydroxyl group or —COOR ¹⁴ (where R ¹⁴ is a hydrogen atom or a C _1-6 alkyl group);
and n is an integer of 1 to 3.], a prodrug thereof, or a pharmaceutically acceptable salt thereof.

^{[2] R} 3, R ⁴ and ^{R 5} are the same or different and represent a hydrogen atom, halogen atom, optionally substituted with also a _{C 1-6} alkyl group or a halogen atom substituted by a halogen atom _{C 1-6} An alkoxy group, or an optionally substituted homocyclic ring or a substituted or unsubstituted heterocycle together with the carbon atom to which R ³ and R ⁴ or R ⁴ and R ⁵ are bonded; May form a ring;
R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or —COOR ⁹ (where R ⁹ is a hydrogen atom or C _{1- 6} alkyl group) or a C _4-10 cycloalkylalkyl group (the C _4-10 cycloalkylalkyl group is a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group) , A C _1-6 alkoxy group, a C _1-6 alkyl group or —COOR ¹⁰ (where R ¹⁰ is a hydrogen atom or a C _1-6 alkyl group). ;
R ¹¹ , R ¹² and R ¹³ may be the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or —COOR ⁹ (where R ⁹ is Or a C _4-10 cycloalkylalkyl group (the C _4-10 cycloalkylalkyl group may be a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _{1 -6 alkoxy, C 1-6} alkyl group or -COOR ^{10 (wherein, R 10} is same as that defined above) Yes 1 at the 3-substituted may be) in;
R ⁶ is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group or a C _1-6 alkyl group (the C _1-6 alkyl group is a hydroxyl group or —COOR ¹⁴ wherein R ¹⁴ may be substituted with a hydrogen atom or a C _1-6 alkyl group, or the dibenzylamine compound or a prodrug thereof or the pharmaceutically acceptable salt thereof according to the above [1]. Salt.

[3] The dibenzylamine compound according to the above [1] or [2], wherein R ¹ is a C _1-6 alkyl group substituted with a halogen atom, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[4] The dibenzylamine compound of the above-mentioned [3], wherein R ¹ is a trifluoromethyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[5] ring B and (R ⁶ ) _n are

(Where R ⁶⁰ , R ⁶¹ and R ⁶² are the same or different and are each a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl The above [1] that is a group or a C _1-6 alkyl group, wherein the C _1-6 alkyl group is a hydroxyl group or —COOR ¹⁴ (where R ¹⁴ may be the same as described above); ], The dibenzylamine compound according to [3] or [4], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[6] ring B and (R ⁶ ) _n are

(Wherein R ⁶⁰ , R ⁶¹ and R ⁶² are as defined above), or a dibenzylamine compound or a prodrug thereof or a pharmaceutically acceptable salt thereof according to the above [5].
[7] ring B and (R ⁶ ) _n are

Wherein R ⁶⁰ and R ⁶¹ are the same as described above, or a dibenzylamine compound or a prodrug thereof or a pharmaceutically acceptable salt thereof according to the above [6].
[8] Any of the above [1] or [3] to [7] wherein A is —N (R ⁷ ) (R ⁸ ) (where R ⁷ and R ⁸ are the same as the above [1]). A dibenzylamine compound or a prodrug thereof or a pharmaceutically acceptable salt thereof according to any one of the above.
[9] The dibenzylamine compound of the above-mentioned [8], wherein R ⁷ is a C _1-6 alkyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[10] The dibenzylamine compound of the above-mentioned [9], wherein R ⁶ is a C _1-6 alkyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[11] N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl ) Benzyl]-(2-methyl-2H-tetrazol-5-yl) amine;
3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H-tetrazole- 5-yl) amino] methyl} -5-trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine hydrochloride,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2H-tetrazol-5-yl)-[3,5-bis (trifluoromethyl) benzyl] Amine,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) amine hydrochloric acid salt,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(5-methyl-1H-pyrazole- 3-yl) amine,
5- {N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylaminopentanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylate,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 -Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-ethyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H- [1 , 2,4] triazol-3-yl) amine,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N-phenylamino} methyl) -5-trifluoromethylbenzonitrile,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4,5-dimethylthiazol-2-yl) amino] methyl} -5- Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(thiazol-2-yl) amine hydrochloride salt,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (thiazol-2-yl) amino} methyl) -5-trifluoromethylbenzonitrile Hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(oxazol-2-yl) amine hydrochloric acid salt,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4,5-dimethylthiazole-2 -Yl) amine hydrochloride,

3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (5-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methyloxazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisothiazole-5- Il) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylisoxazole-3 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisoxazole-5 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 3-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 4-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] thiadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] oxadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-3-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-2-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl]-(2-methyl-2H- Tetrazol-5-yl) amine hydrochloride,
3-{[N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 Ylmethyl) -N-ethylamino] pentanoic acid methyl chloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,

5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methyl hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methyl hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,2 , 4] oxadiazol-3-yl) amine hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylate hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylate,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} indane- 5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methyl-isoxazol-5-yl) amino] methyl} indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3 -Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,

N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methyl- [1,2 , 4] thiadiazol-5-yl) amine,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) amino ] Methyl {indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5 Methyl 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoate hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl chloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3 -Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} -methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
2- (5- {N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] amino} tetrazole- 2-yl) ethanol hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) Amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) amino ] Methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl chloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) Amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) amino ] Methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} -5,6 7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,

5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3 -Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (2-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4-tri Fluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- {N- [6-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] amino} Methyl) indan-5-yl] -N-ethylamino} pentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -2,2-dimethylpentanoic acid hydrochloride,
6- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 Il) -N-ethylamino] hexanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
(1- {2- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {Indan-5-yl) -N-ethylamino] ethyl {cyclopentyl) acetic acid hydrochloride,
trans-4-({N- [6-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] ] Amino {methyl) indan-5-yl] -N-ethylamino {methyl) cyclohexanecarboxylic acid,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethylphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
(1- {2- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] ethyl {cyclopentyl) acetic acid,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,

trans-4-({N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] ] Amino {methyl) -5,6,7,8-tetrahydronaphthalen-2-yl] -N-ethylamino {methyl) cyclohexanecarboxylic acid hydrochloride,
1- {3- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] propyl} cyclohexanecarboxylic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -3,3-dimethylpentanoic acid;
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3 -Yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] hexanoic acid hydrochloride,
trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {Indan-5-yl) -N-ethylamino] methyl} cyclohexyl) acetic acid hydrochloride,
6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -3,3-dimethylhexanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -4,4-dimethylpentanoic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,

6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -5,5-dimethylhexanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-propylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-isobutylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid amide,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methylamide,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid dimethylamide,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-chlorophenyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(p-tolyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(m-tolyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-(3,5-dichlorobenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoro Methoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N-ethyl-N- (2-{[N '-(2-methyl-2H-tetrazol-5-yl) -N'-(3-methyl-5-trifluoromethylbenzyl) amino] ] Methyl {-4-trifluoromethoxyphenyl) amino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-(3-chloro-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}-] 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N-ethyl-N- (2-{[N '-(2-methyl-2H-tetrazol-5-yl) -N'-(3-nitro-5-trifluoromethylbenzyl) amino] ] Methyl {-4-trifluoromethoxyphenyl) amino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2-difluorobenzo [1,3] dioxol-5-yl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2-difluorobenzo [1,3] dioxol-5-yl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-3- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] ] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) propionic acid hydrochloride,
trans- (4-{[N- (7-} [N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (7-} [N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-2- (4-{[N- (7-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino ] Methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) acetamide hydrochloride,
trans-N- [3,5-bis (trifluoromethyl) benzyl] -N- {2- [N'-ethyl-N '-(4- (methoxymethyl) cyclohexylmethyl) amino] -5-trifluoromethoxy Benzyl}-(2-methyl-2H-tetrazol-5-yl) amine hydrochloride,

trans-2- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino ] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) ethanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexylmethyl) phosphonic acid,
trans-4-{[N- (2-{[N '-(3-bromo-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-bromophenyl) -N-ethylamino] methyl} cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-bromophenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-chloro-5-ethylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-methoxyphenyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methoxy-4-methylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4,5-dimethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylthiophenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-chloro-5-ethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methoxy-4-methylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-4-({N- [2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -4- (2,2,2-trifluoroethyl) phenyl] -N-ethylaminodimethyl) cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-ethylphenyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,

trans-4-{[N- (2-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}-] 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-isopropenylphenyl) amino] methyl} -4-trifluoromethoxy Phenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(p-tolyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl {cyclohexyl) acetic acid dihydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl} cyclohexyl) acetic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid methanesulfonate,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) ethyl acetate and trans- (4-{[N- (2-{[N '-[3,5-bis (Trifluoromethyl) benzyl] -N '-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) The dibenzylamine compound according to the above [1], a prodrug thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of acetic acid.

[12] trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) Amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl} cyclohexyl) acetic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid, and trans- (4-{[N- (2-{[N '-[3,5-bis ( Trifluoromethyl) benzyl] -N '-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid The dibenzylamine compound according to the above [1], a prodrug thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of methanesulfonates.

[13] N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl ) Benzyl]-(2-methyl-2H-tetrazol-5-yl) amine;
3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H-tetrazole- 5-yl) amino] methyl} -5-trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine hydrochloride,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2H-tetrazol-5-yl)-[3,5-bis (trifluoromethyl) benzyl] Amine,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) amine hydrochloric acid salt,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(5-methyl-1H-pyrazole- 3-yl) amine,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 -Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-ethyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H- [1 , 2,4] triazol-3-yl) amine,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N-phenylamino} methyl) -5-trifluoromethylbenzonitrile,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4,5-dimethylthiazol-2-yl) amino] methyl} -5- Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(thiazol-2-yl) amine hydrochloride salt,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (thiazol-2-yl) amino} methyl) -5-trifluoromethylbenzonitrile Hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(oxazol-2-yl) amine hydrochloric acid salt,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4,5-dimethylthiazole-2 -Yl) amine hydrochloride,

3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (5-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methyloxazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisothiazole-5- Il) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylisoxazole-3 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisoxazole-5 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 3-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 4-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] thiadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] oxadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-3-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-2-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl]-(2-methyl-2H- Tetrazol-5-yl) amine hydrochloride and 3-{[N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl] -N- (2-methyl-2H -Tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile hydrochloride, the dibenzylamine compound according to the above [2], a prodrug thereof, or a pharmaceutically acceptable salt thereof. .

[14] A medicament comprising the dibenzylamine compound according to any one of [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Composition.
[15] A CETP activity inhibitor comprising, as an active ingredient, the dibenzylamine compound according to any one of the above [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
[16] A therapeutic drug for hyperlipidemia comprising the dibenzylamine compound according to any one of the above [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient or Prophylactic drug.
[17] Hyperlipidemia, comprising administering the dibenzylamine compound according to any one of the above [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal. For treating or preventing the disease.
[18] A therapeutic or prophylactic agent for arteriosclerosis comprising the dibenzylamine compound according to any one of the above [1] to [13], a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient. .
[19] administering at least one of the dibenzylamine compound according to any one of the above [1] to [13], a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal; Treatment or prevention method.

[20] The pharmaceutical composition of the above-mentioned [14], which is used in combination with another therapeutic agent for hyperlipidemia.
[21] The pharmaceutical composition of the above-mentioned [20], wherein the other therapeutic agent for hyperlipidemia is a statin drug.
[22] The pharmaceutical composition of the above-mentioned [21], wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.

[23] The pharmaceutical composition of the above-mentioned [14], which is used in combination with another therapeutic agent for obesity.
[24] The pharmaceutical composition of the above-mentioned [23], wherein the other therapeutic agent for obesity is mazindol.

[25] The pharmaceutical composition of the above-mentioned [14], which is used in combination with another drug for treating diabetes.
[26] The other antidiabetic agent is one or more agents selected from the group consisting of an insulin preparation, a sulfonylurea agent, an insulin secretagogue, a sulfonamide agent, a biguanide agent, an α-glucosidase inhibitor and an insulin sensitizer. A certain pharmaceutical composition according to the above [25].
[27] The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. The pharmaceutical composition according to the above [26], which is one or more selected drugs.

[28] The pharmaceutical composition of the above-mentioned [14], which is used in combination with another therapeutic drug for hypertension.
[29] The other therapeutic agent for hypertension is selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers. The pharmaceutical composition according to the above [28], which is one or more drugs.
[30] Other therapeutic agents for hypertension include furosemide sustained-release agent, captopril, captopril sustained-release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril , Perindopril erbumin, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release, nilvadipine, nifedipine, nifedipine sustained release, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release, nisoldipine, nitrendipine, manidipine hydrochloride, Barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride Pindolol, Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Hydrochloric acid Chilisolol, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent [29] The pharmaceutical composition according to the above [29], which is one or more drugs selected from the group consisting of urapidil and phentolamine mesylate.

[31] The therapeutic or prophylactic agent according to the above-mentioned [16], wherein the target of treatment or prevention is hyperlipidemia and used in combination with another therapeutic agent for hyperlipidemia.
[32] The therapeutic or prophylactic agent according to [31], wherein the other therapeutic agent for hyperlipidemia is a statin drug.
[33] The therapeutic or prophylactic agent according to the above [32], wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.

[34] The therapeutic or prophylactic agent according to the above-mentioned [16], wherein the target for treatment or prevention is hyperlipidemia and used in combination with another therapeutic agent for obesity.
[35] The therapeutic or prophylactic agent according to the above [34], wherein the other therapeutic agent for obesity is mazindol.

[36] The therapeutic or prophylactic agent according to the above-mentioned [16], wherein the target for treatment or prevention is hyperlipidemia and used in combination with another therapeutic agent for diabetes.
[37] The other antidiabetic drug is one or more drugs selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. A certain therapeutic or prophylactic agent according to the above [36].
[38] The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. The therapeutic or prophylactic agent according to the above [37], which is one or more selected drugs.

[39] The therapeutic or prophylactic agent according to the above-mentioned [16], wherein the target for treatment or prevention is hyperlipidemia and used in combination with another therapeutic agent for hypertension.
[40] The other therapeutic agent for hypertension is selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers. The therapeutic or prophylactic agent according to the above [39], which is one or more drugs.
[41] Other therapeutic agents for hypertension include furosemide sustained release, captopril, captopril sustained release, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril , Perindopril erbumin, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release, nilvadipine, nifedipine, nifedipine sustained release, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release, nisoldipine, nitrendipine, manidipine hydrochloride, Barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride Pindolol, Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Hydrochloric acid Chilisolol, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent The therapeutic or therapeutic agent according to [40], which is one or more drugs selected from the group consisting of urapidil, phentolamine mesylate. Medicine.

[42] The method of the above-mentioned [17], wherein the target of treatment or prevention is hyperlipidemia, and the subject is used in combination with another therapeutic agent for hyperlipidemia.
[43] The method of the above-mentioned [42], wherein the other therapeutic agent for hyperlipidemia is a statin drug.
[44] The method of the above-mentioned [43], wherein the statin drug is at least one drug selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.

[45] The treatment or prevention method of the above-mentioned [17], wherein the target of treatment or prevention is hyperlipidemia, and the combination is used with another therapeutic agent for obesity.
[46] The method of the above-mentioned [45], wherein the other therapeutic agent for obesity is mazindol.

[47] The method of the above-mentioned [17], wherein the subject of treatment or prevention is hyperlipidemia, and is used in combination with another therapeutic agent for diabetes.
[48] The other antidiabetic drug is one or more drugs selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. A certain therapeutic or preventive method according to the above [47].
[49] The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. The treatment or prevention method according to the above [48], which is one or more selected drugs.

[50] The treatment or prevention method of the above-mentioned [17], wherein the target of treatment or prevention is hyperlipidemia, and the combination is used in combination with another therapeutic agent for hypertension.
[51] The other therapeutic agent for hypertension is selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers. The treatment or prevention method according to the above [50], which is one or more drugs.
[52] Other therapeutic agents for hypertension include furosemide sustained-release agent, captopril, captopril sustained-release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril , Perindopril erbumin, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release, nilvadipine, nifedipine, nifedipine sustained release, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release, nisoldipine, nitrendipine, manidipine hydrochloride, Barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride Pindolol, Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Hydrochloric acid Chilisolol, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent Or the drug of the above [51], which is one or more drugs selected from the group consisting of urapidil and phentolamine mesylate. Law.

[53] The therapeutic or prophylactic agent according to the above [18], wherein the target for treatment or prevention is arteriosclerosis and used in combination with another therapeutic agent for hyperlipidemia.
[54] The therapeutic or prophylactic agent according to the above [53], wherein the other therapeutic agent for hyperlipidemia is a statin drug.
[55] The therapeutic or preventive drug according to the above [54], wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.

[56] The therapeutic or prophylactic agent according to [18], wherein the target for treatment or prevention is arteriosclerosis, and the subject is used in combination with another therapeutic agent for obesity.
[57] The therapeutic or prophylactic agent according to the above [56], wherein the other therapeutic agent for obesity is mazindol.

[58] The therapeutic or prophylactic agent according to [18], wherein the target for treatment or prevention is arteriosclerosis, and the subject is used in combination with another therapeutic agent for diabetes.
[59] The other antidiabetic drug is one or more drugs selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. A certain therapeutic or prophylactic agent according to the above [58].
[60] The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. The therapeutic or prophylactic agent according to the above [59], which is one or more drugs selected.

[61] The therapeutic or prophylactic agent according to the above-mentioned [18], wherein the target for treatment or prevention is arteriosclerosis and used in combination with another therapeutic agent for hypertension.
[62] The other therapeutic agent for hypertension is selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers. The therapeutic or prophylactic agent according to the above [61], which is one or more drugs.
[63] Other antihypertensive agents are furosemide sustained release agent, captopril, captopril sustained release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril , Perindopril erbumin, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release, nilvadipine, nifedipine, nifedipine sustained release, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release, nisoldipine, nitrendipine, manidipine hydrochloride, Barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride Pindolol, Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Hydrochloric acid Chilisolol, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent The therapeutic or prophylactic agent according to [62], which is one or more drugs selected from the group consisting of urapidil and phentolamine mesylate. Medicine.

[64] The method of the above-mentioned [19], wherein the target of treatment or prevention is arteriosclerosis, and the subject is used in combination with another therapeutic agent for hyperlipidemia.
[65] The method of the above-mentioned [64], wherein the other therapeutic drug for hyperlipidemia is a statin drug.
[66] The method of the above-mentioned [65], wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.

[67] The method of the above-mentioned [19], wherein the subject to be treated or prevented is arteriosclerosis, and is used in combination with another therapeutic agent for obesity.
[68] The method of the above-mentioned [67], wherein the other therapeutic agent for obesity is mazindol.

[69] The method of the above-mentioned [19], wherein the subject to be treated or prevented is arteriosclerosis, and the subject is used in combination with another drug for treating diabetes.
[70] The other antidiabetic drug is one or more drugs selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. A certain therapeutic or preventive method according to the above [69].
[71] The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. The treatment or prevention method according to the above [70], which is one or more selected drugs.

[72] The treatment or prevention method of the above-mentioned [19], wherein the target for treatment or prevention is arteriosclerosis, and the combination is used in combination with another therapeutic agent for hypertension.
[73] The other therapeutic agent for hypertension is selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers. The treatment or prevention method according to the above [72], which is one or more drugs.
[74] Other antihypertensive agents include furosemide sustained release agent, captopril, captopril sustained release agent, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril , Perindopril erbumin, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release, nilvadipine, nifedipine, nifedipine sustained release, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release, nisoldipine, nitrendipine, manidipine hydrochloride, Barnidipine hydrochloride, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride Pindolol, Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Hydrochloric acid Chilisolol, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained release agent Or the treatment or prevention according to the above [73], which is one or more drugs selected from the group consisting of urapidil and phentolamine mesylate. Law.

The definition of each substituent used in this specification is as follows.
“Halogen atom” means a chlorine atom, a bromine atom, a fluorine atom and the like. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁶⁰ , R ⁶¹ and R ⁶² are preferably a chlorine atom or a fluorine atom, and R ⁷ , R ⁸ , R ¹¹ , R ¹² and R Preferred halogen atoms as substituents of the C _4-10 cycloalkylalkyl group in ¹³ are a chlorine atom and a fluorine atom.

The “C _2-6 alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, for example, an ethenyl group (vinyl group), a 1-propenyl group, a 2-propyl group. Benzyl group (allyl group), isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2 -Methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,2-dimethyl-1-propenyl group, 2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1-ethyl-2-propenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group , 2-methyl-1-butenyl group, 1-isopropylvinyl group, 2,4- Pentadienyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2,4-hexadienyl group and 1-methyl-1-pentenyl group And is preferably a linear or branched alkenyl group having 2 to 4 carbon atoms. Particularly preferred are an ethenyl group, an isopropenyl group and a 2-methyl-2-propenyl group.

The “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and an isobutyl group. , A sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group or a hexyl group, preferably a straight-chain or branched alkyl having 1 to 4 carbon atoms. Group. Particularly preferred are a methyl group, an ethyl group and an isopropyl group. R ²⁰ and R ²¹ are preferably a methyl group. R ⁶ , R ⁶⁰ , R ⁶¹ and R ⁶² are preferably a methyl group or an ethyl group, and R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ are preferably an ethyl group, a propyl group or a butyl group. R ⁹ and R ¹⁰ are preferably a methyl group or an ethyl group. A preferred C _1-6 alkyl group as a substituent of the C _4-10 cycloalkylalkyl group in R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ is a methyl group or an ethyl group. R ¹⁴ is preferably a methyl group or an ethyl group.

The “C _1-6 alkyl group _optionally substituted with a halogen atom” is a group in which the above C _1-6 alkyl group may be substituted with the above halogen atom, for example, a methyl group, an ethyl group, a propyl group, Isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, trifluoromethyl group, 1- or 2-chloroethyl group, 1 -Or 2-bromoethyl group, 1- or 2-fluoroethyl group, 1-, 2- or 3-chloropropyl group, 1-, 2- or 3-bromopropyl group, 1-, 2- or 3-fluoropropyl Group, 1-, 2-, 3- or 4-chlorobutyl group, 1-, 2-, 3- or 4-bromobutyl group, 1-, 2-, 3- or 4-fluorobutyl group, etc. Ri is preferably methyl group, ethyl group or trifluoromethyl group. R ¹ , R ² , R ³ , R ⁴ and R ⁵ are preferably a methyl group, an ethyl group or a trifluoromethyl group.

The “C _1-6 alkoxy group” represents a linear or branched alkoxy group having 1 to 6 carbon atoms, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group. Pentyloxy, tert-pentyloxy or hexyloxy, preferably methoxy, ethoxy, isopropoxy, butoxy and tert-butoxy having 1 to 4 carbon atoms. Particularly preferred is a methoxy group or an ethoxy group. R ⁶ , R ⁶⁰ , R ⁶¹ and R ⁶² are preferably methoxy groups, and preferred C ₁ as a substituent of a C _4-10 cycloalkylalkyl group in R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ . _{The -6} alkoxy group is a methoxy group or an ethoxy group.

The "be a C _1-6 alkoxy group substituted by a halogen atom", said C _1-6 alkoxy group with the aforementioned halogen atoms are those which may be substituted, such as methoxy group, an ethoxy group, a propoxy group, Isopropoxy, butoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy, trifluoromethoxy, 1- or 2-chloroethoxy, 1- or 2-bromoethoxy, 1 -Or 2-fluoroethoxy group, 1-, 2- or 3-chloropropoxy group, 1-, 2- or 3-bromopropoxy group, 1-, 2- or 3-fluoropropoxy group, 1-, 2-, 3- or 4-chlorobutoxy group, 1-, 2-, 3- or 4-bromobutoxy group, 1-, 2-, 3- or 4-fluorobutoxy group, etc. Ku is a methoxy group, an ethoxy group or a trifluoromethoxy group. R ³ , R ⁴ and R ⁵ are preferably a methoxy group, an ethoxy group or a trifluoromethoxy group.

The "a C _1-6 alkylthio group optionally substituted by a halogen atom", the C _1-6 alkylthio group with a halogen atom are those that may be substituted, such as methylthio group, ethylthio group, propylthio group, isopropylthio Thio group, butylthio group, tert-butylthio group, pentylthio group, tert-pentylthio group, hexylthio group, trifluoromethylthio group, 1- or 2-chloroethylthio group, 1- or 2-bromoethylthio group, 1- or 2-fluoroethylthio group, 1-, 2- or 3-chloropropylthio group, 1-, 2- or 3-bromopropylthio group, 1-, 2- or 3-fluoropropylthio group, 1-2 -, 3- or 4-chlorobutylthio group, 1-, 2-, 3- or 4-bromobutylthio group, 1-, 2-, 3- or 4-fluobium A thio group and the like, preferably methylthio group, ethylthio group or trifluoromethylthio group. R ³ , R ⁴ and R ⁵ are preferably a methylthio group, an ethylthio group or a trifluoromethylthio group.

The “C _4-10 cycloalkylalkyl group” is a C _3-7 cycloalkyl group in which a C _1-3 alkyl group has been substituted. Here, the “C _3-7 cycloalkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a cycloheptyl group. . Preferable is a cycloalkyl group having 3 to 6 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. The “C _1-3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, such as a methyl group, an ethyl group, a propyl group, and an isopropyl group, and is preferably These are a methyl group, an ethyl group, and a propyl group.

Specific examples of the “C _4-10 cycloalkylalkyl group” include, for example, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethyl group, a cyclopentylethyl group (1- or 2- ( Cyclopentyl) ethyl group), cyclohexylethyl group (1- or 2- (cyclohexyl) ethyl group), cyclopentylpropyl group (1-, 2- or 3- (cyclopentyl) propyl group) or cyclohexylpropyl group ( 1-, 2- or 3- (cyclohexyl) propyl group). Preferable is a cycloalkylalkyl group having 3 to 7 carbon atoms, specifically, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group. Preferred C _4-10 cycloalkylalkyl groups for R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ are a cyclopentylmethyl group, a cyclohexylmethyl group, and a 2- (cyclopentyl) ethyl group.

An "acyl group" is an alkylcarbonyl group such as an acetyl group, a propionyl group, a butyryl group, a pivaloyl group and the like; an arylcarbonyl group such as a benzoyl group and a naphthoyl group. Preferably it is an acetyl group. R ⁶ , R ⁶⁰ , R ⁶¹ and R ⁶² are preferably acetyl groups, and preferred acyl groups as substituents of C _4-10 cycloalkylalkyl groups in R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹³ . Is an acetyl group.

  The “aryl group” is a phenyl group, a naphthyl group, a biphenyl group, or the like, and is preferably a phenyl group.

  The term "heterocyclic residue" refers to a 5- to 8-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like in addition to a carbon atom, and condensed thereto. Examples thereof include a bicyclic or tricyclic fused heterocyclic group. For example, a pyrrolyl group (1-, 2- or 3-pyrrolyl group), a furyl group (2- or 3-furyl group), a thienyl group (2- or 3-thienyl group), an imidazolyl group (1-, 2-, 4- -Or 5-imidazolyl group), oxazolyl group (2-, 4- or 5-oxazolyl group), thiazolyl group (2-, 4- or 5-thiazolyl group), pyrazolyl group (1-, 3-, 4- or 5-pyrazolyl group), isoxazolyl group (3-, 4- or 5-isoxazolyl group), isothiazolyl group (3-, 4- or 5-isothiazolyl group), oxadiazolyl group (1,2,4-oxadiazole-3) Or 5-yl group, 1,3,4-oxadiazol-2-yl group, 1,2,5-oxadiazol-3-yl group), thiadiazolyl group, (1,2,4-thiadiazole-3) Or 5-yl 1,3,4-thiadiazol-2-yl group, 1,2,5-thiadiazol-3-yl group), triazolyl group (1,2,4-triazol-1,3,4 or 5-yl group, 1,2,3-triazol-1, 2 or 4-yl group), indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group), benzofuryl group (2- , 3-, 4-, 5-, 6- or 7-benzofuryl group), benzothienyl group (2-, 3-, 4-, 5-, 6- or 7-benzothienyl group), benzimidazolyl group (1 -, 2-, 4-, 5-, 6- or 7-benzimidazolyl group), benzoxazolyl group (2-, 4-, 5-, 6- or 7-benzoxazolyl group), benzothiazolyl group (2-, 4-, 5-, 6- or 7-benzothiazolyl group), pyridyl group (2- 3- or 4-pyridyl group), pyridine-1-oxide group (2-, 3- or 4-pyridine-1-oxide group), pyrimidinyl group (2-, 4- or 5-pyrimidinyl group), tetrazolyl group ( 1H-tetrazol-1 or 5-yl group, 2H-tetrazol-2 or 5-yl group), quinolyl group (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group) or Isoquinolyl group (1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl group) and the like.

As the “homocycle”, for example, C _6-10 arene (C _6-10 aryl) (eg, benzene (phenyl), naphthalene (naphthyl), etc.), C _3-7 cycloalkane (C _3-7 cycloalkyl) (eg, cyclopropane (cyclopropyl), cyclobutane (cyclobutyl), cyclopentane (cyclopentyl), cyclohexane (cyclohexyl), cycloheptane (cycloheptyl) _{etc.), C 3-7} cycloalkene _{(C 3-7} cycloalkenyl) ( For example, a 3- to 7-membered carbon ring which may be condensed, such as cyclopropene (cyclopronil), cyclobutene (cyclobutenyl), cyclopentene (cyclopentenyl), cyclohexene (cyclohexenyl), cycloheptene (cycloheptenyl) and the like, is used. In addition, the parenthesis attached to each homocyclic ring indicates an homocyclic group corresponding to the homocyclic ring.

Examples of the substituent which may be possessed by the above homocyclic, for example, (1) optionally substituted with halogen C _1-6 alkyl group (particularly, a C _1-6 alkyl group is preferably substituted by halogen ), (2) _C3-10 cycloalkyl group, (3) _C2-10 alkenyl group, (4) _C2-10 alkynyl group, (5) _C6-10 aryl group, (6) _C7-20 aralkyl group, (7) nitro group, (8) hydroxy group, (9) mercapto group, (10) oxo group, (11) thioxo group, (12) cyano group, (13) carbamoyl group, 14) carboxyl group, (15) C _1-6 alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, etc.), (16) sulfo, (17) halogen atom, (18) C _1-6 alkoxy group, 19) C _6-10 aryloxy group (eg, phenoxy group etc.), (20) C _1-6 acyloxy group (eg, acetoxy, propionyloxy), (21) C _1-6 alkylthio group (eg, methylthio group, Ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, tert-butylthio group, etc.), (22) C _6-10 arylthio group (eg, phenylthio group, etc.), (23) C _1-6 alkylsulfinyl Group (eg, methylsulfinyl) , Etc. ethylsulfinyl group), (24) C _6-10 arylsulfinyl group (e.g., such as phenylsulfinyl group), (25) C _1-6 alkylsulfonyl group (e.g., methylsulfonyl group, ethylsulfonyl group etc.), ( 26) C _6-10 arylsulfonyl group (e.g., such as phenylsulfonyl group), (27) amino group, (28) C _1-6 acylamino group (e.g., acetylamino group, propionylamino group, etc.), (29) mono -Or di-C _1-4 alkylamino group (eg, methylamino group, ethylamino group, n-propylamino group, isopropylamino group, n-butylamino group, dimethylamino group, diethylamino group, etc.), (30) _C3-8 cycloalkylamino group (eg, cyclopropylamino group, cyclobutylamino group, cyclopentylamino group, cyclohexylamino group, etc.), (31) _{C6- 10} arylamino group (eg, anilino, etc.), (32) C _1-6 alkanoyl group (eg, formyl group, acetyl group, hexanoyl group, etc.), (33) C _6-10 arylcarbonyl group (eg, benzoyl group, etc.) ), (34) a 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms (eg, 2- or 3-thienyl group, 2- or 3- Furyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl group, 2-, 4- or 5-imidazolyl group, 1,2,3- or 1,2,4-triazolyl (1,2,4-triazole-1,3,4 or 5- Yl group, 1,2,3-triazol-1,2 or 4-yl group 1H or 2H-tetrazolyl (1H-tetrazol-1 or 5-yl group, 2H-tetrazol-2 or 5-yl group), 2-, 3- or 4-pyridyl group, 2-, 4- or 5-pyrimidyl Group, 3- or 4-pyridazinyl group, quinolyl group (2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl group), isoquinolyl group (1-, 3-, 4-, 5- -, 6-, 7- or 8-isoquinolyl group), an indolyl group (1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl group), and the like. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

Preferred examples of the "homocyclic ring optionally having substituent (s)" which may be formed together with the carbon atom to which R ³ and R ⁴ or R ⁴ and R ⁵ are bonded include C _3-7 cyclo Alkane or benzene, more preferably cyclopentane or cyclohexane.

  As the “heterocycle”, a 5- to 8-membered heterocycle containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to a carbon atom, and a bicyclic or tricyclic condensed thereto And heterocycles. Specific examples of the heterocyclic ring include, for example, (1) thiophene (thienyl group), furan (furyl group), pyrrole (pyrrolyl group), pyrroline (pyrrolinyl group), pyrrolidine (pyrrolidinyl group), 1,3-dioxole ( 1,3-dioxolyl group), oxazole (oxazolyl group), thiazole (thiazolyl group), pyrazole (pyrazolyl group), imidazole (imidazolyl group), imidazoline (imidazolinyl group), isoxazole (isoxazolyl group), isothiazole (isothiazolyl group) , Furazane (furazanyl group), 1,2,3-thiadiazole (1,2,3-thiadiazolyl group), 1,2,5-thiadiazole (1,2,5-thiadiazolyl group), 1,2,3-triazole (1,2,3-triazolyl group), 1,2,3-triazolidine (triazolidinyl )), A 5-membered heterocyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to carbon atoms; (2) pyridine (pyridyl group), pyrimidine (pyrimidinyl group), thiomorpholine ( Thiomorpholinyl group), morpholine (morpholinyl group), 1,2,3-triazine, 1,2,4-triazine (triazinyl group), piperidine (piperidinyl group), pyran (pyranyl group), thiopyran (thiopyranyl group), 1, 4-oxazine (1,4-oxazinyl group), 1,4-dioxane (1,4-dioxanyl group), 1,4-thiazine (1,4-thiazinyl group), 1,3-thiazine (1,3- Thiazinyl group), piperazine (piperazinyl group), oxotriazine (oxotriazinyl group), pyridazine (pyridazinyl group), pyrazine (pyrazinyl group), etc. Oxygen atom in addition to carbon atoms, a sulfur atom, such as 6-membered heterocyclic ring containing 1 to 4 hetero atoms selected from nitrogen atom, and the like. Examples of the bicyclic or tricyclic fused heterocycle include benzofuran (benzofuryl group), benzothiazole (benzothiazolyl group), benzoxazole (benzoxazolyl group), tetrazolo [1,5-b] pyridazine (tetrazolo [1, 5-b] pyridazinyl group), triazolo [4,5-b] pyridazine (triazolo [4,5-b] pyridazinyl group), benzimidazole (benzimidazolyl group), quinoline (quinolyl group), isoquinoline (isoquinolyl group), cinnoline (Cinnolinyl group), phthalazine (phthalazinyl group), quinazoline (quinazolinyl group), quinoxaline (quinoxalinyl group), indolizine (indolidinyl group), indole (indolyl group), quinolizine (quinolizinyl group), 1,8-naphthyridine (1, 8-naphthyridinyl group), Teridine (pteridinyl group), dibenzofuran (dibenzofuranyl group), carbazole (carbazolyl group), acridine (acridinyl group), phenanthridine (phenanthridinyl group), chroman (chromanyl group), benzoxazine (benzoxazinyl group) Group), a phenazine (phenazinyl group), a phenothiazine (phenothiazinyl group), a phenoxazine (phenoxazinyl group), and other carbon atoms, and a bicyclic ring containing 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like. And tricyclic fused heterocyclic rings. The parentheses attached to each heterocyclic ring indicate a heterocyclic group corresponding to the heterocyclic ring.

Examples of the heterocyclic substituent which may be possessed by, for example, _{(1) C 1-6} alkyl group, _{(2) C 2-6} alkenyl group, _{(3) C 2-6} alkynyl group, (4) _{C 3 -6} cycloalkyl group, (5) cycloalkenyl group, _{(6) C 7-11} aralkyl group, _{(7) C 6-14} aryl group, _{(8) C 1-6} alkoxy group, _{(9) C 6-14} Aryloxy group (eg, phenoxy group, etc.), (10) C _1-6 alkanoyl group (eg, formyl group, acetyl group, propionyl group, n-butyryl group, iso-butyryl group, etc.), (11) C _{6- 14} arylcarbonyl group (eg, benzoyl group, etc.), (12) C _1-6 alkanoyloxy group (eg, formyloxy group, acetyloxy group, propionyloxy group, n-butyryloxy group, iso-butyryloxy group, etc.), 13) _{C 6-14} arylcarbonyloxy group (e.g., benzoyloxy group ), (14) carboxyl group, (15) C _1-6 alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, n- propoxycarbonyl group, iso- propoxycarbonyl group, n- butoxycarbonyl group, isobutoxycarbonyl Group, tert-butoxycarbonyl group, etc.), (16) carbamoyl group, (17) N-mono-C _1-4 alkylcarbamoyl group (eg, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group , N- isopropylcarbamoyl group, N- butylcarbamoyl group etc.), (18) N, N- di -C _1-4 alkylcarbamoyl group (e.g., N, N- dimethylcarbamoyl group, N, N- diethylcarbamoyl group, (N, N-dipropylcarbamoyl group, N, N-dibutylcarbamoyl group, etc.), (19) cyclic aminocarbonyl group (eg, 1-aziridinylcarbonyl group, 1-A Substituted with a (20) halogen atom, a (21) halogen atom, a thidinylcarbonyl group, a 1-pyrrolidinylcarbonyl group, a 1-piperidinylcarbonyl group, an N-methylpiperazinylcarbonyl group, a morpholinocarbonyl group, and the like. A C _1-6 alkyl group (eg, chloromethyl group, dichloromethyl group, trifluoromethyl group, trifluoroethyl group, etc.), (22) oxo group, (23) amidino group, (24) imino group, (25) amino group, (26) mono- or di-C _1-4 alkylamino group (eg, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, dimethylamino group, diethylamino group , Dipropylamino, diisopropylamino, dibutylamino, etc.), (27) Hetero selected from oxygen, sulfur, nitrogen, etc. in addition to carbon and one nitrogen A 3- to 6-membered cyclic amino group optionally containing 1 to 3 atoms (eg, aziridinyl group, azetidinyl group, pyrrolidinyl group, pyrrolinyl group, pyrrolyl group, imidazolyl group, bilazolyl group, imidazolidinyl group, piperidino group, morpholino group Group, dihydropyridyl group, pyridyl group, N-methylpiperazinyl group, N-ethylpiperazinyl group, etc.), (28) C _1-6 alkanoylamino group (eg, formamide group, acetamido group, trifluoroacetamido group , Propionylamide group, butyrylamide group, isobutyrylamide group, etc., (29) benzamide group, (30) carbamoylamino group, (31) N- _C1-4 alkylcarbamoylamino group (eg, N-methylcarbamoylamino Group, N-ethylcarbamoylamino group, N-propylcarbamoylamino group, N-isopropylcarba Ylamino group, such as N- butylcarbamoyl amino group), (32) N, N- di -C _1-4 alkylcarbamoyl group (eg, N, N- dimethylcarbamoyl group, N, N- diethylcarbamoyl group, N, N-dipropylcarbamoylamino group, N, N-dibutylcarbamoylamino group, etc., (33) _C1-3 alkylenedioxy group (eg, methylenedioxy group, ethylenedioxy group, etc.), (34) -B (OH) ₂ , (35) hydroxy group, (36) epoxy group (-O-), (37) nitro group, (38) cyano group, (39) mercapto group, (40) sulfo group, (41) ) Sulfino group, (42) phosphono group, (43) sulfamoyl group, (44) C _1-6 alkylsulfamoyl group (eg, N-methylsulfamoyl group, N-ethylsulfamoyl group, N-propyl Sulfamoyl group, N-isopropylsulfamoyl group, N-butylsulfamoyl group, etc.), (45) di-C _1-6 alkylsulfamoyl group (eg, N, N-dimethylsulfamoyl group, N, N-diethylsulfamoyl group, N, N-dipropylsulfamoyl group, N, N -Dibutylsulfamoyl group, etc.), (46) C _1-6 alkylthio group (eg, methylthio group, ethylthio group, propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group, tert-butylthio group, etc.) , (47) phenylthio group, (48) C _1-6 alkylsulfinyl group (e.g., methylsulfinyl group, ethylsulfinyl group, propyl sulfinyl group, butylsulfinyl group etc.), (49) phenylsulfinyl group, (50) C _{1 -6} alkylsulfonyl group (eg, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, butylsulfonyl group, etc.), and (51) phenylsulfonyl group. The number of substitutions is 1 to 6, preferably 1 to 3, and more preferably 1 to 2.

Preferred examples of the “heterocyclic ring optionally having substituent (s)” which may be formed together with the carbon atom to which R ³ and R ⁴ or R ⁴ and R ⁵ bind, include thiophene, furan, pyrrole, Pyrroline, oxazole, thiazole, pyrazole, imidazole, imidazoline, isoxazole, isothiazole, furazane, 1,2,3-thiadiazole, 1,2,5-thiadiazole, 1,2,3-triazole, 1,2,3-triazine 1,2,4-triazine, 1,2,3-triazolidine, 2,2-difluoro-1,3-dioxole, and 2,2,3,3-tetrafluoro-1,4-dioxane.

In the above embodiment, the substituent in the `` homocyclic ring which may have a substituent '' and the substituent in the `` heterocyclic ring which may have a substituent '' may be substituted with (1) a halogen atom. a C _1-6 alkyl group, (2) nitro group, (3) hydroxy group, (4) mercapto group, (5) cyano group, (6) carbamoyl group, (7) carboxyl group, (8) C _{1- 6} alkoxycarbonyl, (9) sulfo group, (10) a halogen atom, (11) _{C 1-6} alkoxy group, (12) _{C 1-6} alkylthio group, _{(13) C 1-6} alkylsulfinyl group, (14 ) C _1-6 alkylsulfonyl group, (15) amino group, (16) mono- - or di _{-C 1-4} alkylamino group, _{(17) C 1-6} alkanoyl group and (18) _{C 1-6} alkanoyloxy It is preferably selected from the group consisting of groups.

  The “pharmaceutically acceptable salt” may be any salt that forms a non-toxic salt with the compound represented by the above general formula (1). Examples thereof include hydrochloride and bromide. Various inorganic acid salts such as hydrochloride, hydroiodide, sulfate, nitrate, phosphate, carbonate, bicarbonate, perchlorate; formate, acetate, trifluoroacetate, propionic acid Salt, oxalate, glycolate, succinate, lactate, maleate, hydroxymalate, methylmaleate, fumarate, adipate, tartrate, malate, citrate, Organic acid salts such as benzoate, cinnamate, ascorbate, salicylate, 2-acetoxybenzoate, nicotinate, isonicotinate; methanesulfonate, ethanesulfonate, isethionate , Benzenesulfonate Sulfonates such as p-toluenesulfonate and naphthalenesulfonate; acidic amino acids such as aspartate and glutamate; alkali metal salts such as sodium and potassium; alkaline earths such as magnesium and calcium Metal salts; ammonium salts; organic base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt; amino acid salts such as lysine salt and arginine salt; However, the present invention is not limited to these. Further, depending on the case, a hydrate, a hydrate or a solvate with an alcohol or the like may be used.

  Further, in the compound represented by the general formula (1), various isomers may exist. For example, when an E-form and a Z-form are present as geometric isomers, and when an asymmetric carbon atom is present, enantiomers and diastereomers are present as stereoisomers based on these, and tautomers are provided. Can exist. Accordingly, the scope of the present invention includes all these isomers and mixtures thereof.

  Here, the compound of the present invention includes a prodrug compound and a metabolite.

  A “prodrug compound” is a derivative of a compound of the present invention that has a group that can be chemically or metabolically degraded and that, after being administered to a living organism, reverts to the original compound and exhibits its original efficacy. Includes complexes and salts not due to binding.

  As the prodrug compound of the compound represented by the general formula (1) of the present invention, the carboxyl group of the compound represented by the general formula (1) is an ethyl group, a pivaloyloxymethyl group, a 1- (acetyloxy ) Ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, carboxymethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group A compound modified with a phenyl group, an o-tolyl group, or the like; a hydroxyl group of the compound represented by the general formula (1) is an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a benzoyl group, a 4-methylbenzoyl group; A compound modified with a dimethylcarbamoyl group or a sulfo group; the amino group of the compound represented by the general formula (1) is a hexylcarbamoyl group 3-methylthio-1- (acetylamino) propylcarbonyl group, 1-sulfo-1- (3-ethoxy-4-hydroxyphenyl) methyl group, (5-methyl-2-oxo-1,3-dioxole-4- Il) Compounds modified with a methyl group or the like.

  The compound according to the present invention or a salt thereof has an excellent CETP activity inhibitory action. Therefore, IDL, VLDL and LDL which promote arteriosclerosis can be reduced, and HDL which acts suppressively can be increased. As a result, it is useful as a preventive or therapeutic agent for hyperlipidemia. It is also useful as a prophylactic or therapeutic drug for arteriosclerotic diseases and the like.

  Furthermore, the combined use of the compound of the present invention with another therapeutic agent for hyperlipidemia (statin drug) promotes an increase in HDL cholesterol, remarkably lowers the arteriosclerosis index, and exhibits an extremely excellent synergistic effect. Is expected. This indicates that the compound of the present invention can be used in combination with other drugs, particularly other drugs for treating hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension.

Next, various substituents or substitution positions will be described in more detail.
R ¹ is preferably a C _1-6 alkyl group which may be substituted with a halogen atom, and more preferably a trifluoromethyl group.

R ² is preferably a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom or a cyano group, and more preferably a trifluoromethyl group or a cyano group.

R ³ and R ⁴ are preferably a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, a C _1-6 alkoxy group optionally substituted with a halogen atom, or a substituent substituted with a halogen atom. C _1-6 alkylthio group or a carbon atom to which R ³ and R ⁴ are bonded to form a homocyclic ring.

R ⁵ is preferably a hydrogen atom.
R ⁶ is preferably a hydrogen atom or a C _1-6 alkyl group, and more preferably a hydrogen atom, a methyl group or an ethyl group.
n is preferably 0, 1 or 2.

Preferably in ring B and (R ⁶ ) _n ,

(Where R ⁶⁰ , R ⁶¹ and R ⁶² are the same as described above), and more preferably

(Where R ⁶⁰ and R ⁶¹ are the same as described above).
Preferably in A, it is ^-N (R 7) ^{(R 8),} further preferably a ^{R 7} is _{C 1-6} alkyl group, and ^{R 8} is ^{_{- (CH 2) r -COOR 10}} ( wherein, r and R ¹⁰ are the same as described above), and are a C _4-10 cycloalkylalkyl group which may be substituted or a C _1-6 alkyl group substituted with a carboxyl group.

Preferred specific examples of the compound (1) of the present invention are listed below:
1． N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl] -(2-methyl-2H-tetrazol-5-yl) amine,
2.3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H- Tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile,
3． N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine,
Four. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine hydrochloride,
Five. N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2H-tetrazol-5-yl)-[3,5-bis (trifluoromethyl) benzyl] Amine,
6． N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) amine hydrochloric acid salt,
7． N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(5-methyl-1H-pyrazole- 3-yl) amine,
8.5- {N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3- Yl) amino] methyl} indan-5-yl) -N-ethylaminopentanoic acid hydrochloride,
9． trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylate,
10.3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile,
11． N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-ethyl-2H-tetrazole- 5-yl) amine,
12． N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H- [1 , 2,4] triazol-3-yl) amine,
13. 3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N-phenylamino} methyl) -5-trifluoromethylbenzonitrile,
14.3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4,5-dimethylthiazol-2-yl) amino] methyl}- 5-trifluoromethylbenzonitrile,
15． N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(thiazol-2-yl) amine hydrochloride salt,
16.3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (thiazol-2-yl) amino} methyl) -5-trifluoromethyl Benzonitrile hydrochloride,
17． N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(oxazol-2-yl) amine hydrochloric acid salt,
18． N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylthiazol-2-yl ) Amine hydrochloride,
19. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methylthiazol-2-yl ) Amine hydrochloride,
20. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4,5-dimethylthiazole-2 -Yl) amine hydrochloride,

21.3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (5-methylthiazol-2-yl) amino] methyl} -5 Trifluoromethylbenzonitrile hydrochloride,
22.3-{[N- [6- (N′-cyclopentylmethyl-N′-ethylamino) indan-5-ylmethyl] -N- (4-methylthiazol-2-yl) amino] methyl} -5 Trifluoromethylbenzonitrile hydrochloride,
twenty three. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methyloxazol-2-yl ) Amine hydrochloride,
twenty four. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisothiazole-5- Il) amine hydrochloride,
twenty five. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylisoxazole-3 -Yl) amine hydrochloride,
26. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisoxazole-5 -Yl) amine hydrochloride,
27. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 3-yl) amine hydrochloride,
28. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 4-yl) amine hydrochloride,
29. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] thiadiazol-2-yl) amine hydrochloride,
30. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] oxadiazol-2-yl) amine hydrochloride,
31. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-3-ylamine hydrochloride;
32. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-2-ylamine hydrochloride;
33. N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl]-(2-methyl-2H- Tetrazol-5-yl) amine hydrochloride,
34.3-{[N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] Methyl} -5-trifluoromethylbenzonitrile hydrochloride,
35.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
36. 5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane- Methyl 5-ylmethyl) -N-ethylamino] pentanoate hydrochloride,
37. 5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
38. 5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] pentanoic acid hydrochloride,
39. 5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane- 5-yl) -N-ethylamino] pentanoic acid hydrochloride,
40. 5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} indane- 5-yl) -N-ethylamino] pentanoic acid hydrochloride,

41. 5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] pentanoic acid hydrochloride,
42. trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methyl hydrochloride,
43. trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methyl hydrochloride,
44. trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
45. trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
46. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,2 , 4] oxadiazol-3-yl) amine hydrochloride,
47. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylate hydrochloride,
48. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
49. trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylate,
50. trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
51. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
52. trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
53. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
54. trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} indane- 5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
55.5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane- Methyl 5-yl) -N-ethylamino] pentanoate hydrochloride,
56.5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methyl-isoxazol-5-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,
57.5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane- 5-yl) -N-ethylamino] pentanoic acid hydrochloride,
58. 5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl} indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
59. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3 -Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
60. trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,

61. N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methyl- [1,2 , 4] thiadiazol-5-yl) amine,
62.5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl ) Amino] methyl {indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
63.5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
64.5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl chloride,
65.5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
66.5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
67. trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
68. trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
69. trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3 -Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
70. trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
71. trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} -methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
72. trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
73.2- (5- {N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] amino} Tetrazol-2-yl) ethanol hydrochloride,
74.5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl chloride,
75.5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl ) Methyl amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoate hydrochloride,
76.5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
77.5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl ) Amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
78.5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
79. 5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} -5 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
80.5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,

81.5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
82. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3 -Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
83.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] pentanoic acid hydrochloride,
84.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 4-trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
85.5- [N- (2-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4 -Trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
86.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
87.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] pentanoic acid hydrochloride,
88.5- {N- [6-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] [Amino {methyl) indan-5-yl] -N-ethylamino} pentanoic acid hydrochloride,
89.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] pentanoic acid hydrochloride,
90.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] -2,2-dimethylpentanoic acid hydrochloride,
91.6- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane- 5-yl) -N-ethylamino] hexanoic acid hydrochloride,
92.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
93. trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
94. (1- {2- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {Indan-5-yl) -N-ethylamino] ethyl {cyclopentyl) acetic acid hydrochloride,
95. trans-4-({N- [6-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] ] Amino {methyl) indan-5-yl] -N-ethylamino {methyl) cyclohexanecarboxylic acid,
96. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethylphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
97. (1- {2- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] ethyl {cyclopentyl) acetic acid,
98. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
99. trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,

100. trans-4-({N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] ] Amino {methyl) -5,6,7,8-tetrahydronaphthalen-2-yl] -N-ethylamino {methyl) cyclohexanecarboxylic acid hydrochloride,
101.1- {3- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] Methyl {indan-5-yl) -N-ethylamino] propyl} cyclohexanecarboxylic acid hydrochloride,
102.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] -3,3-dimethylpentanoic acid,
103.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3- Yl) amino] methyl {indan-5-yl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
104.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
105.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethylphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
106. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
107.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
108.5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3- Yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
109. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3 -Yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
110.6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] hexanoic acid hydrochloride,
111. trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {Indan-5-yl) -N-ethylamino] methyl} cyclohexyl) acetic acid hydrochloride,
112. 6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
113.6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] -3,3-dimethylhexanoic acid hydrochloride,
114.5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] -4,4-dimethylpentanoic acid hydrochloride,
115. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
116.6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
117.6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethylphenyl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
118. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
119. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,

120.6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] -5,5-dimethylhexanoic acid hydrochloride,
121. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-propylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
122. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-isobutylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
one two Three. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid amide,
124. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methylamide,
125. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid dimethylamide,
126. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-chlorophenyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
127. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(p-tolyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
128. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(m-tolyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
129. trans-4-{[N- (2-{[N '-(3,5-dichlorobenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoro Methoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
130. trans-4-{[N-ethyl-N- (2-{[N '-(2-methyl-2H-tetrazol-5-yl) -N'-(3-methyl-5-trifluoromethylbenzyl) amino] ] Methyl {-4-trifluoromethoxyphenyl) amino] methyl} cyclohexanecarboxylic acid hydrochloride,
131. trans-4-{[N- (2-{[N '-(3-chloro-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}-] 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
132. trans-4-{[N-ethyl-N- (2-{[N '-(2-methyl-2H-tetrazol-5-yl) -N'-(3-nitro-5-trifluoromethylbenzyl) amino] ] Methyl {-4-trifluoromethoxyphenyl) amino] methyl} cyclohexanecarboxylic acid hydrochloride,
133. trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2-difluorobenzo [1,3] dioxol-5-yl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
134. trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2-difluorobenzo [1,3] dioxol-5-yl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
135. trans-3- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] ] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) propionic acid hydrochloride,
136. trans- (4-{[N- (7-} [N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
137. trans- (4-{[N- (7-} [N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
138. trans-2- (4-{[N- (7-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino ] Methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) acetamide hydrochloride,
139. trans-N- [3,5-bis (trifluoromethyl) benzyl] -N- {2- [N'-ethyl-N '-(4- (methoxymethyl) cyclohexylmethyl) amino] -5-trifluoromethoxy Benzyl}-(2-methyl-2H-tetrazol-5-yl) amine hydrochloride,

140. trans-2- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino ] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) ethanol hydrochloride,
141. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
142. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
143. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
144. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexylmethyl) phosphonic acid,
145. trans-4-{[N- (2-{[N '-(3-bromo-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
146. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-bromophenyl) -N-ethylamino] methyl} cyclohexyl) methanol hydrochloride,
147. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-bromophenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
148. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-chloro-5-ethylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
149. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-methoxyphenyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
150. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methoxy-4-methylphenyl) -N-ethylamino] methyl {cyclohexyl] methanol hydrochloride,
151. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4,5-dimethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
152. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylthiophenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
153. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-chloro-5-ethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
154. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
155. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methoxy-4-methylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
156. trans-4-({N- [2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -4- (2,2,2-trifluoroethyl) phenyl] -N-ethylaminodimethyl) cyclohexanecarboxylic acid hydrochloride,
157. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
158. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
159. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-ethylphenyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,

160. trans-4-{[N- (2-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}-] 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
161. trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-isopropenylphenyl) amino] methyl} -4-trifluoromethoxy Phenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
162. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(p-tolyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl {cyclohexyl) acetic acid dihydrochloride,
163. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
164. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
165. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
166. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl} cyclohexyl) acetic acid,
167. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid,
168. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid methanesulfonate,
169. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) ethyl acetate
170. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid,
171. trans- (4-{[N- (2-{[N '-(3-methyl-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid,
172.trans- (4-{[N- (2-{[N '-(3-methyl-5-trifluoromethylbenzyl) -N'-(5-methyl- [1,2,4] oxadiazole -3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid,
173. cis- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) ethyl acetate
174. {4- [2- (2-{[N- [3,5-bis (trifluoromethyl) benzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5-methyl -4-trifluoromethylphenyl) butyl] cyclohexyldiacetic acid, and
175.5- [2-({N- [3,5-bis (trifluoromethyl) benzyl] -N- [2-methyl-2H-tetrazol-5-yl] amino} methyl) -5-methyl-4 -Trifluoromethylphenoxy] heptanoic acid.

Of the compounds listed above, the following compounds are particularly preferred.
115. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
118. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
142. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
143. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
154. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
157. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
158. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
166. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl} cyclohexyl) acetic acid,
167. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid, and
168. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-Methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid methanesulfonate.

  The compound of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof has excellent CETP activity inhibition in mammals (eg, human, monkey, cow, horse, dog, cat, rabbit, rat, mouse, etc.). It has an effect and can be used as a CETP activity inhibitor. In addition, the compound of the present invention, a prodrug thereof, or a pharmaceutically acceptable salt thereof utilizes a superior CETP activity inhibitory action, and is useful for diseases involving CETP (eg, hyperlipidemia, arteriosclerosis, atherosclerosis). Sclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial hypercholesterolemia, cardiovascular disorders, angina, emptiness Medicines that are effective in the prevention and treatment of blood, cardiac ischemia, thrombosis, myocardial infarction, reperfusion injury, angiogenic restenosis, hypertension, vascular complications of diabetes, obesity or endotoxemia, especially high fat It is useful as a prophylactic or therapeutic agent for blood or arteriosclerotic diseases.

  When the compound of the present invention represented by the general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof is used as a pharmaceutical preparation, it is usually known as a pharmacologically acceptable carrier or excipient. Agents, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, corrigents, solubilizers, and other additives, specifically Tablets, pills by mixing with water, vegetable oil, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triazetate gelatin, lactose, starch, etc., carbohydrates, magnesium stearate, talc, lanolin, petrolatum, etc. , Powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups It can be administered by the form orally or parenterally.

  The dosage of the medicament according to the present invention may vary depending on the type and degree of the disease, the compound to be administered and the administration route, the age, sex, body weight, etc. of the patient. In the case of oral administration, the general formula (1) per adult per day is usually used. ), The compound of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof is preferably administered at about 1 to 1000 mg, particularly about 50 to 800 mg.

  The medicament according to the present invention may be administered alone, or may be used in combination with another preventive or therapeutic agent for hyperlipidemia, and / or a preventive or therapeutic agent for arteriosclerotic disease, It may be used in combination with a medicament (for example, a therapeutic agent for obesity, a therapeutic agent for diabetes, a therapeutic agent for hypertension, a therapeutic agent for arteriosclerosis, a therapeutic agent for coronary artery disease, etc.). In particular, when used in combination with another therapeutic drug for hyperlipidemia (statin-based drug), an extremely excellent synergistic effect that blood cholesterol is particularly markedly suppressed is expected.

  Here, the `` combination '' means that the compound of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof is used in combination with another drug such as a therapeutic drug for hyperlipidemia, The form of use is not particularly limited. For example, administration as a pharmaceutical composition containing the compound of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof together with another medicament, or separately formulating without mixing, and simultaneously or at a time interval And both administrations.

  The dose of the other concomitant drug may vary depending on the type and degree of the disease, the administration route, the age, sex, weight, etc. of the concomitant drug used, but in the case of oral administration, it is usually about 1 to 1 per adult per day. It is preferred to administer about 1000 mg, especially about 50 mg to 800 mg.

  Examples of the therapeutic drug for hyperlipidemia used in combination with the medicament according to the present invention include statins such as lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or cerivastatin.

  Examples of the therapeutic agent for obesity used in combination with the medicament according to the present invention include mazindol.

  Examples of the antidiabetic drug used in combination with the medicament according to the present invention include insulin preparations, sulfonylurea drugs (eg, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, etc.), insulin secretagogues (eg, , Nateglinide, etc.), sulfonamides (eg, glibazole), biguanides (eg, metformin hydrochloride, buformin hydrochloride, etc.), α-glucosidase inhibitors (eg, voglibose, acarbose, etc.) or insulin sensitizers (eg, hydrochloric acid Pioglitazone) and the like.

  The antihypertensive agent used in combination with the medicament according to the present invention includes loop diuretics (eg, furosemide sustained release agent, etc.), angiotensin converting enzyme inhibitors (eg, captopril, captopril sustained release agent, enalapril maleate, alacepril, hydrochloric acid Delapril, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril erbumin, etc.), angiotensin II receptor antagonist (eg, losartan potassium, candesartan cilexetil etc.), Ca antagonist (Examples: Nicardipine hydrochloride, Nicardipine hydrochloride sustained release agent, Nilvadipine, Nifedipine, Nifedipine sustained release agent, Benidipine hydrochloride, Diltiazem hydrochloride, Diltiazem hydrochloride sustained release agent, Nisoldipine, Nitrendipine, Manidipine hydrochloride, Hydrochloride Lunidipine, efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, etc., beta-blockers (eg, propranolol hydrochloride, sustained-release propranolol hydrochloride, pindolol, pindolol sustained-release agent, indenolol hydrochloride, carteolol hydrochloride, carteolol hydrochloride, sustained release) Release agent, bunitrolol hydrochloride, sustained release of bunitrolol hydrochloride, atenolol, acebutolol hydrochloride, metoprolol tartrate, sustained release of metoprolol tartrate, nipradilol, penbutolol, tilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, malonic acid Bopindolol, bevantol hydrochloride, etc.), α, β blockers (eg, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, etc.) or α blockers (eg, , Prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride sustained-release agent, urapidil, phentolamine mesilate, etc.).

  Further, the medicament according to the present invention can be administered not only to humans but also to other mammals (for example, monkeys, cows, horses, dogs, cats, rabbits, rats, mice, etc.).

Next, an example of a method for producing the dibenzylamino compound represented by the compound (1) will be described, but the production method of the present invention is not limited thereto.
In performing the reaction described below, the functional group other than the site may be protected in advance if necessary, and may be deprotected at an appropriate stage.
Furthermore, in each step, the reaction may be carried out by a usual method, and the isolation and purification may be carried out by appropriately selecting or combining conventional methods such as crystallization, recrystallization, column chromatography, and preparative HPLC. Just do it.

General Production Method A method for producing the compound represented by the general formula (1) is illustrated below.

(Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶⁰ , A, rings B and n are as defined above, X is a halogen atom, and Ph is a phenyl group.)

Manufacturing method 1
Step 1-1
General reductive amination. The compound represented by the general formula (3) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (3) in a solvent in the presence of a reducing agent. .
Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; dichloromethane and chloroform , Carbon tetrachloride, halogen solvents such as 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; Polar solvents such as N-dimethylformamide and the like can be mentioned, and these can be used alone or in combination. A preferred solvent in this reaction is chloroform or dichloromethane.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and the like. A preferable reducing agent in this reaction is sodium triacetoxyborohydride.

Step 1-2
General alkylation. One of the target compounds represented by the general formula (1-a) by reacting the compound represented by the general formula (4) with a compound represented by the general formula (5) in a solvent in the presence of a base Can be obtained.
Examples of the solvent used in the reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane and diglyme; hydrocarbon solvents such as benzene, toluene, hexane and xylene; methanol and ethanol Isopropyl alcohol, tert-butanol and the like; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as acetone, N, N-dimethylformamide, dimethyl sulfoxide and the like. Or they can be used together. A preferred solvent in this reaction is N, N-dimethylformamide.
Examples of the base include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal alkoxides such as sodium ethoxide, sodium methoxide and potassium tert-butoxide; alkyl lithiums such as n-butyllithium and sec-butyllithium Alkali metal amides such as lithium diisopropylamide, sodium amide, lithium bistrimethylsilylamide; alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. Alkali metal hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; organic bases such as triethylamine, pyridine and N-methylmorpholine; and preferably sodium hydride or It is a potassium tert- butoxide.
In addition, a desired salt can be obtained by performing a salt-forming operation on the obtained target compound.

Manufacturing method 2
Step 2-1
This is a general reductive amination reaction. The compound represented by the general formula (7) can be obtained by reacting the compound represented by the general formula (6) with the compound represented by the general formula (3) in a solvent in the presence of a reducing agent. .
Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chloroform, carbon tetrachloride, and the like. Halogen solvents such as 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as N, N-dimethylformamide And these can be used alone or in combination. A preferred solvent in this reaction is dichloromethane or toluene.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, lithium hydride, aluminum hydride, and the like.A preferable reducing agent in this reaction is sodium borohydride. .
Alternatively, after the general formula (6) and the general formula (3) are reacted to form a Schiff base, a reduction reaction can be performed. The reaction for generating a Schiff base is carried out by azeotropic dehydration in a solvent such as benzene, toluene or ethanol in the absence of a catalyst or in the presence of an acid catalyst such as hydrochloric acid or acetic acid, or a non-proton such as methylene chloride or toluene. There is a method using a dehydrating agent such as molecular sieves in a neutral solvent.

Step 2-2
The compound represented by the general formula (8) obtained by treating the general formula (2) by a usual reduction reaction is reacted with thionyl chloride in a solvent such as toluene, tetrahydrofuran or chloroform to obtain a compound represented by the general formula ( The compound (8) in which the hydroxyl group is chlorinated can be obtained. Further, by performing the same reaction as in Step 1-2 using the obtained compound and the compound represented by the general formula (7), one of the target compounds represented by the general formula (1-a) is obtained. be able to.

Manufacturing method 3
Step 3-1
General reductive amination. The compound represented by the general formula (10) can be obtained by reacting the compound represented by the general formula (2) with the compound represented by the general formula (9) in a solvent in the presence of a reducing agent. .
Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chloroform, carbon tetrachloride, and the like. Halogen solvents such as 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as N, N-dimethylformamide And these can be used alone or in combination. A preferred solvent in this reaction is dichloromethane.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, and the like. A preferable reducing agent in this reaction is sodium triacetoxyborohydride.

Step 3-2
This is a general nucleophilic substitution reaction. The target compound represented by the general formula (1-a) is obtained by reacting the compound represented by the general formula (11) with the compound represented by the general formula (10) in the same manner as in Step 1-2. You can get one.
In addition to the method of directly reacting the compound represented by the general formula (11) having the ring B, there is a method of constructing the ring B on the nitrogen atom of the compound (10) by a known method. As an example of this method, the following manufacturing method 3 ′ and manufacturing method 3 ″ are given.
Manufacturing method 3 '

Step 3'-1
The compound represented by the general formula (10) is reacted with the compound (12) in a solvent. Further, the obtained residue is reacted with hydrazine hydrate in a solvent in the presence of an acid to obtain a compound represented by the general formula (1-b), which is one of the target compounds.
Examples of the solvent used in the first reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chloroform, Halogen solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as N, N-dimethylformamide; these may be used alone or in combination. be able to. A preferred solvent in this reaction is dichloromethane.
Examples of the solvent used in the next reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chloroform, Halogen solvents such as carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; N, N-dimethyl Examples thereof include polar solvents such as formamide and dimethyl sulfoxide, which can be used alone or in combination. A preferred solvent in this reaction is 1,2-dimethoxyethane.
Examples of the acid used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; organic acids such as trifluoroacetic acid, trichloroacetic acid, acetic acid, methanesulfonic acid, and p-toluenesulfonic acid, and mixtures thereof; Methanesulfonic acid.
Manufacturing method 3 "

Step 3 ″ -1
After reacting the compound represented by the general formula (10) with bromocyanide in the presence of a base in a solvent, the obtained residue is reacted with hydroxylamine in a solvent. Further, the obtained residue is reacted with an acylating agent such as an acid chloride represented by the general formula (13) in a solvent to give a compound represented by the general formula (1-c), which is one of the target compounds Can be obtained.
Examples of the solvent used for the first reaction include alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; benzene, Hydrocarbon solvents such as toluene, hexane and xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; N, N-dimethyl Examples thereof include polar solvents such as formamide and the like, and these can be used alone or in combination. A preferred solvent in this reaction is methanol.
Similarly, the base used in the first reaction includes, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; alkali metal phosphates such as sodium phosphate and potassium phosphate; triethylamine, pyridine, Organic bases such as N-methylmorpholine can be mentioned, and preferred is sodium hydrogen carbonate.

  Examples of the solvent used in the next reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chloroform, Halogen solvents such as carbon tetrachloride and 1,2-dichloroethane; alcohol solvents such as methanol, ethanol, isopropyl alcohol and tert-butanol; and polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide. Can be used alone or in combination. The preferred solvent in this reaction is dioxane.

  Examples of the solvent used in the last reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; hydrocarbon solvents such as benzene, toluene, hexane, and xylene; dichloromethane, chloroform, Halogen solvents such as carbon tetrachloride and 1,2-dichloroethane; ester solvents such as ethyl acetate, methyl acetate and butyl acetate; polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide; Or they can be used together. A preferred solvent in this reaction is pyridine.

Further, after synthesizing the compound (1) by the above-mentioned production method, the functional groups of the portions A, B and R ^{1 to} R ⁶ may be further converted by a known method.
As the functional group conversion reaction, for example, when the terminal of the substituent A is an ester, the resulting compound (1-a) is subjected to a usual ester hydrolysis reaction, so that the terminal of the substituent A is a carboxyl. The substrate can be easily obtained. Examples of the solvent used in the ester hydrolysis reaction include ether solvents such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, and diglyme; alcohol solvents such as methanol, ethanol, isopropyl alcohol, and tert-butanol; Or water, and these can be used alone or in combination. Similarly, examples of the base used in the ester hydrolysis reaction include metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.
Further, there is a method in which a protected hydroxyl group at the terminal of the substituent A is deprotected and then converted into a cyano group, a carboxyl group or the like.

  The compound represented by the general formula (2), which is a raw material of the above production method, can be produced by a conventionally known method. Hereinafter, some examples will be described.

(In the formula, R ³ , R ⁴ , R ⁵ and R ⁷ are the same as described above, and —CH ₂ R ^8a is a group corresponding to R ^8. )
Manufacturing method 4
The aniline represented by the general formula (15) is reacted with an acid halide or the like in the presence or absence of a base in an organic solvent, water, or a solvent-free under cooling or heating, to thereby be represented by the general formula (16). A compound can be synthesized (Step 4-1). The compound represented by the general formula (17) is reacted with a compound represented by the general formula (16) and a reducing agent such as lithium aluminum hydride, Red-Al, and sodium borohydride in an organic solvent under cooling or heating. The compound can be synthesized (Step 4-2). The compound represented by the general formula (18) is reacted with the compound represented by the general formula (17) and an alkyl halide or the like in the presence or absence of a base in an organic solvent, water or a solvent without cooling or heating. The compound can be synthesized (Step 4-3). By reacting the compound represented by the general formula (18) with an organic solvent or no solvent under cooling to heating using a Vilsmeier reagent prepared from phosphorus oxychloride and N, N-dimethylformamide or the like, A compound represented by the general formula (2-a), which is one of the starting materials, can be synthesized (Step 4-4).

(In the formula, R ³ , R ⁴ , R ⁵ , R ¹¹ , R ¹² and R ¹³ are the same as described above.)
Manufacturing method 5
A phenol represented by the general formula (19) and an alcohol represented by the formula: (R ¹¹ ) (R ¹² ) (R ¹³ ) COH (wherein R ¹¹ , R ¹² and R ¹³ are the same as above), The compound represented by the general formula (20) is synthesized by reacting in the presence of phenylphosphine with a condensing agent such as diethyl azodicarboxylate in an organic solvent, water or no solvent under cooling or heating. (Step 5-1). The compound represented by the general formula (20) is reacted with a Vilsmeier reagent prepared from phosphorus oxychloride and N, N-dimethylformamide or the like in an organic solvent or without a solvent under cooling or heating to obtain a desired compound. A compound represented by the general formula (2-b), which is one of the starting materials, can be synthesized (step 5-2).

(In the formula, R ³ , R ⁴ , R ⁵ , R ¹¹ and R ¹² are the same as described above, and X is a halogen atom.)
Manufacturing method 6
A lithio compound generated by reacting halobenzene represented by the general formula (21) with butyllithium in an organic solvent under cooling to room temperature is treated with a ketone, aldehyde, or the like, to thereby be represented by the general formula (22). A compound can be synthesized (Step 6-1). Synthesis of the compound represented by the general formula (23) by hydrogenating the compound represented by the general formula (22) in an organic solvent or water at room temperature to under heating in the presence of a catalyst such as palladium hydroxide. (Step 6-2). By reacting the compound represented by the general formula (23) with a brominating agent such as bromosuccinimide under cooling or heating in an organic solvent or without solvent, the compound represented by the general formula (24) is obtained. A compound can be synthesized (Step 6-3). A lithiated product generated by reacting the compound represented by the general formula (24) with butyllithium in an organic solvent under cooling to room temperature is treated with N, N-dimethylformamide or the like to obtain a desired raw material. The compound represented by the general formula (2-c) can be synthesized (Step 6-4).

(In the formula, R ³ , R ⁴ , R ⁵ , R ⁷ and R ⁸ are the same as described above.)
Manufacturing method 7
By treating a lithio compound generated by reacting a fluorobenzene compound represented by the general formula (25) with LDA or butyllithium or the like in an organic solvent under cooling to room temperature, and treating with N, N-dimethylformamide or the like. The compound represented by the general formula (26) can be synthesized (Step 7-1). A compound represented by the general formula (26) and an amine represented by the formula; (R ₇ ) (R ₈ ) NH are dissolved in an organic solvent or without solvent under cooling or heating in the presence of a base such as potassium carbonate. By reacting, a compound represented by the general formula (2-d), which is one of the desired raw materials, can be synthesized (Step 7-2).

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by these.

Example 1
N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl] -(2-methyl-2H-tetrazol-5-yl) amine

a) N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl) Amine 3- (N-cyclopentylmethyl-N-ethylamino) -5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (333 mg) and 5-amino-2-methyltetrazole (231 mg) in chloroform solution (10 ml) ) Was added with sodium triacetoxyborohydride (745 mg) under stirring at room temperature, followed by acetic acid (13 μl). After stirring the reaction solution overnight, sodium borohydride (50 mg) and methanol (3 ml) were added, and the mixture was further stirred for 2 hours. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated saline, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the residue was concentrated by column chromatography (n-hexane). : Ethyl acetate = 6: 1 → 3: 1) to give the title compound (254 mg, 59%).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 1.01 (t, J = 7.1 Hz, 3H), 1.10-1.30 (m, 2H), 1.30-1.62 (m, 4H), 1.67-1.82 (m, 6H), 1.93 -2.10 (m, 1H), 2.63-2.77 (m, 4H), 2.81 (d, J = 7.1Hz, 2H), 2.94 (q, J = 7.1Hz, 2H), 4.14 (s, 3H), 4.51 ( d, J = 5.8Hz, 2H), 5.35-5.50 (brs, 1H), 6.87 (s, 1H), 7.03 (s, 1H).

b) N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl) Benzyl]-(2-methyl-2H-tetrazol-5-yl) amine N- [3- (N′-cyclopentylmethyl-N′-ethylamino) -5,6, obtained in a) of Example 1. Hydrogenation of a solution of (7,8-tetrahydronaphthalen-2-ylmethyl)-(2-methyl-2H-tetrazol-5-yl) amine (121 mg) in N, N-dimethylformamide (DMF) (2 ml) at room temperature with stirring. Sodium (16 mg) was added. After stirring the reaction solution for 1 hour, 3,5-bis (trifluoromethyl) benzyl bromide (73 μl) was added, and the mixture was further stirred overnight. Water was added to the reaction solution, extracted with ethyl acetate, and washed sequentially with water and saturated saline. After the organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue was concentrated. The residue was purified by column chromatography (n-hexane: ethyl acetate = 10: 1) to give the title compound (102 mg, 52 mg). %) (See Table 1).

Example 2
3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H-tetrazole- 5-yl) amino] methyl} -5-trifluoromethylbenzonitrile a) 3-bromomethyl-5-trifluoromethylbenzonitrile 3-hydroxymethyl-5-trifluoromethylbenzonitrile (1.00 g) and tetrabromide Triphenylphosphine (1.37 g) was added to a dichloromethane solution (10 ml) of carbon (1.81 g) under ice-cooling and stirring, and the mixture was stirred for 30 minutes. The residue obtained by concentrating the reaction solution was subjected to column chromatography. The title compound (1.11 g, 84%) was obtained by purifying with (n-hexane: ethyl acetate = 9: 1).
_{^{1 HNMR (CDCl 3, 400MHz)}} δ: 4.50 (s, 2H), 7.85 (s, 1H), 7.87 (s, 2H).

b) 3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H- Tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6 obtained in a) of Example 1. To a solution of 2,7,8-tetrahydronaphthalen-2-ylmethyl]-(2-methyl-2H-tetrazol-5-yl) amine (132 mg) in DMF (2 ml) was added sodium hydride (17 mg) with stirring at room temperature. . After stirring the reaction solution for 1 hour, 3-bromomethyl-5-trifluoromethylbenzonitrile (114 mg) obtained in b) of Example 2 was added, and the mixture was further stirred overnight.
Water was added to the reaction solution, extracted with ethyl acetate, and washed sequentially with water and saturated saline. The organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 6: 1) to give the title compound (86 mg, 44 mg). %) (See Table 1).

Example 3
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine The title compound was obtained in the same manner as in Example 1 (see Table 1).

Example 4
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine hydrochloride

  N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2 To a solution of -methyl-2H-tetrazol-5-yl) amine (550 mg) in n-hexane (12 ml) was added dropwise 1N hydrochloric acid-diethyl ether (0.76 ml) with stirring at room temperature. The precipitated solid was collected by filtration and dried to give the title compound (332 mg) (see Table 1).

Example 5
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2H-tetrazol-5-yl)-[3,5-bis (trifluoromethyl) benzyl] Amine

  Compound N- [6- (N′-cyclopentylmethyl-N′-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) obtained in the same manner as in Example 1. To a solution of benzyl]-(2-triphenylmethyl-2H-tetrazol-5-yl) amine (75 mg) in ethyl acetate (1 ml) was added dropwise 4N hydrochloric acid-ethyl acetate (3 ml) while stirring at room temperature. After stirring at room temperature for 1.5 hours, 1N aqueous sodium hydroxide and then an aqueous citric acid solution were added, followed by extraction with ethyl acetate and washing with water and saturated saline in this order. After the organic layer was dried over sodium sulfate, the sodium sulfate was filtered off and concentrated, and the resulting residue was purified on a preparative TLC plate (n-hexane: ethyl acetate = 2: 1) to give the title compound (24 mg). , 46%) (see Table 1).

Example 6
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) amine hydrochloric acid salt

a) N-cyclopentylmethyl-N- {6-[[3,5-bis (trifluoromethyl) benzylamino] methyl] indan-5-yl} -ethylamine 6- (N-cyclopentylmethyl-N-ethylamino) Sodium triacetoxyborohydride (1.70 g) was added to a dichloromethane solution (20 ml) of indane-5-carbaldehyde (1.09 g) and 3,5-bis (trifluoromethyl) benzylamine (1.26 g) at room temperature with stirring. ) Was added and the reaction was stirred overnight. The reaction solution was washed sequentially with saturated aqueous sodium hydrogen carbonate, water and saturated saline, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the residue was concentrated by column chromatography (n-hexane). : Ethyl acetate = 6: 1) to give the title compound (1.65 g, 83%).
¹ H NMR (CDCl ₃ , 300 MHz) δ: 0.95 (t, J = 7.1 Hz, 3H), 1.04-1.22 (m, 2H), 1.35-1.78 (m, 6H), 1.90-2.17 (m, 3H), 2.78 (d, J = 7.4Hz, 2H), 2.75-2.95 (m, 6H), 3.84 (s, 2H), 3.88 (s, 2H), 7.07 (s, 1H), 7.12 (s, 1H), 7.75 ( s, 1H), 7.83 (s, 2H).

b) N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) Amine N-cyclopentylmethyl-N- {6-[[3,5-bis (trifluoromethyl) benzylamino] methyl] indan-5-yl} -ethylamine (150 mg) obtained in a) of Example 6 and Triethylamine (0.17 ml) was added to a toluene solution (3 ml) of 2-chloropyrimidine (69 mg) with stirring at room temperature, and the reaction solution was refluxed overnight. The reaction solution was concentrated and purified on a preparative TLC plate (n-hexane: ethyl acetate = 6: 1) to obtain the title compound (68 mg, 39%).
¹ H NMR (CDCl ₃ , 400 MHz) δ: 0.92 (t, J = 7.1 Hz, 3H), 0.97-1.12 (m, 2H), 1.30-1.60 (m, 6H), 1.83-2.08 (m, 3H), 2.80 -2.93 (m, 8H), 4.86 (s, 2H), 5.06 (s, 2H), 6.59 (t, J = 4.7Hz, 1H), 6.91 (s, 1H), 7.04 (s, 1H), 7.66 ( s, 2H), 7.71 (s, 1H), 8.36 (d, J = 4.7Hz, 2H).

c) N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) Amine hydrochloride N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) obtained in Example 6b) ) Benzyl]-(pyrimidin-2-yl) amine (68 mg) was obtained in the same manner as in Example 4 to give the title compound (50 mg) (see Table 2).

Example 7
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(5-methyl-1H-pyrazole- 3-yl) amine

  N-cyclopentylmethyl-N- {6-[[3,5-bis (trifluoromethyl) benzylamino] methyl] indan-5-yl} -ethylamine (500 mg) obtained in a) of Example 6 in dichloromethane Diketene (85 μl) was added to the solution (20 ml) under ice-cooling and stirring, and stirring was continued for 2 hours. A part (250 mg) of the residue obtained by concentrating the reaction solution was dissolved in dimethoxyethane (0.7 ml), methanesulfonic acid (0.56 ml) was added dropwise under ice cooling and stirring, and then hydrazine hydrate ( 0.21 ml) was added dropwise. After the reaction solution was stirred at room temperature for 5 days, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine in that order, and the organic layer was dried over sodium sulfate. After removing sodium sulfate by filtration, the residue obtained by concentration was purified by preparative thin-layer chromatography (TLC) plate (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (58 mg). (See Table 2).

Example 8
5- {N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylaminopentanoic acid hydrochloride

a) 5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3- Yl) amino] methyl {indan-5-yl) -N-ethylamino] pentanoic acid methyl 5- (N- {6- [N '-(3,5) obtained in the same manner as in Example 6 a). 5-bis (trifluoromethyl) benzylamino) methyl] indan-5-yl {-N-ethylamino) methylpentanoate (500 mg) and sodium bicarbonate (160 mg) in methanol suspension (10 ml) at room temperature. Below, bromocyan (165 mg) was added and stirring was continued for 2 hours.
The reaction solution was diluted with ethyl acetate, washed with water and saturated saline in this order, and the organic layer was dried over sodium sulfate. After removing sodium sulfate by filtration, the residue obtained by concentration was dissolved in 1,4-dioxane (5 ml), a hydroxylamine aqueous solution (50%, 0.14 ml) was added, and the mixture was stirred at room temperature for 5 hours. The residue obtained by concentrating the reaction solution was dissolved in pyridine (10 ml), and acetyl chloride (0.1 ml) was added with stirring under ice cooling. After stirring at room temperature for 30 minutes, the mixture was stirred at 130 ° C. for 3 hours. The reaction solution was concentrated, and the obtained residue was purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to give the title compound (178 mg, 31%).
¹ H NMR (CDCl ₃ , 300 MHz) δ: 0.88 (t, J = 7.0 Hz, 3H), 1.25-1.60 (m, 4H), 1.95-2.10 (m, 2H), 2.20 (t, J = 7.3 Hz, 2H ), 2.49 (s, 3H), 2.70-2.90 (m, 8H), 4.56 (s, 2H), 4.72 (s, 2H), 6.99 (s, 1H), 7.02 (s, 1H), 7.65 (s, 2H), 7.72 (s, 1H).
b) 5- {N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3- Yl) amino] methyl {indan-5-yl) -N-ethylaminopentanoic acid hydrochloride 5- [N- (6-{[N '-[3,5]) obtained in Example 8a). -Bis (trifluoromethyl) benzyl] -N '-(5-methyl- [1,2,4] oxadiazol-3-yl) amino] methyl {indan-5-yl) -N-ethylamino]} To a tetrahydrofuran-methanol (THF-MeOH) solution (4: 1, 5 ml) of methyl tannate (178 mg) was added an aqueous sodium hydroxide solution (4N, 2 ml) at room temperature with stirring. After the reaction solution was stirred overnight, water was added, extracted with ethyl acetate, and washed sequentially with water and saturated saline. After the organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 2: 1). 1N hydrochloric acid-diethyl ether (0.3 ml) was added dropwise to a n-hexane solution (7 ml) of the obtained compound while stirring at room temperature. The precipitated solid was collected by filtration and dried to give the title compound (158 mg, 86%) (see Table 2).

Example 9
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylate

a) 5-{[3,5-bis (trifluoromethyl) benzyl] amino} -2-methyl-2H-tetrazole 3,5-bis (trifluoromethyl) benzaldehyde (6.71 g) and 5-amino-2 A toluene solution (70 ml) of -methyltetrazole (3.30 g) was heated to reflux for 4 hours. The residue obtained by concentrating the reaction solution was dissolved in ethanol (70 ml), and sodium borohydride (2.10 g) was added with stirring at room temperature. After the reaction solution was stirred at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The sodium sulfate was removed by filtration, and the residue obtained by concentration was recrystallized from isopropanol-water (3: 7.50 ml) to obtain the title compound.
¹ H NMR (CDCl ₃ , 300 MHz) δ: 4.16 (s, 3 H), 4.66 (d, J = 6.3 Hz 2 H), 4.92 (brs, 1 H), 7.79 (s, 1 H), 7.83 (s, 2 H).
b) trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl methylcyclohexanecarboxylate trans-4-{[N-ethyl-N- (2-hydroxymethyl-4-trifluoromethoxyphenyl) amino] methyl Thionyl chloride (0.074 ml) was added to a chloroform solution (5 ml) of methyl cyclohexylcarboxylate (330 mg) under ice-cooling and stirring, and stirring was continued for 10 minutes. The reaction solution was treated with aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed sequentially with water and saturated saline, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the residue obtained by concentration was dissolved in DMF (3 ml). This solution was treated with 5-[[3,5-bis (trifluoromethyl) benzyl] amino] -2-methyl-2H-tetrazole (331 mg) obtained in Example 9a) and sodium hydride (51 mg). The mixture was added dropwise to a DMF solution (3 ml) at room temperature with stirring. After stirring was continued for 15 minutes, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate, washed sequentially with water and saturated saline, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (366 mg, 62%) (see Table 2). ).

Example 169
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) ethyl acetate

a) 2-Fluoro-4-methyl-5-trifluoromethylbenzaldehyde To a suspension of 5-fluoro-2-iodotoluene (110.6 g) and copper iodide (76.2 g) in N-methylmorpholine (200 ml). Under stirring at 120 ° C., methyl fluorosulfonyl (difluoro) acetate (150 g) was added dropwise over 2 hours. After continuing stirring at the same temperature for 3.5 hours, the reaction solution was distilled under normal pressure to obtain a yellow liquid. This was diluted with hexane (300 ml), washed with saturated saline, and the organic layer was dried over sodium sulfate. The hexane solution obtained by removing sodium sulfate by filtration was added dropwise over 1.5 hours to a solution obtained by cooling and stirring tetrahydrofuran (300 ml) and a 1.0 M s-butyllithium / hexane solution (600 ml) at -78 ° C. . After stirring was further continued for 1 hour, N, N-dimethylformamide (57 ml) was added dropwise. After completion of the dropwise addition, 2N hydrochloric acid solution (600 ml) was added, and the temperature was returned to room temperature. This was extracted with hexane, washed with water and saturated saline, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration and concentrated to obtain the title compound (61.54 g, 52%).
_{^{1 HNMR (CDCl 3, 300MHz)}} δ: 2.56 (s, 3H), 7.14 (d, J = 10.7Hz, 1H), 8.15 (d, J = 6.8Hz, 1H), 10.32 (s, 1H).

b) Ethyl trans-8 {4-[(N-ethylamino) methyl] cyclohexyl} acetate b-1) Ethyl solution of trans-4- (ethoxycarbonylmethyl) cyclohexanecarboxylic acid ethyl 4-oxocyclohexanecarboxylate (150 g) (600 ml), sodium hydroxide (38.8 g) was added with stirring at room temperature. After stirring the reaction solution for 1 hour, ethyl diethylphosphonoacetate (192 ml) was added. To this reaction solution, a 21% sodium ethoxide / ethanol solution (363 ml) was added dropwise over 1 hour under ice-cooling and stirring. After stirring was continued for 1 hour, acetic acid (126 ml) was added, then ammonium formate (111 g) and palladium carbon (5%, 15 g) were added, and the mixture was heated and stirred at 60 ° C. for 6 hours. After the temperature of the reaction solution was returned to room temperature, insolubles were removed by filtration through Celite, and the residue obtained by concentration was diluted with ethyl acetate, and washed sequentially with 2N hydrochloric acid, water and saturated saline. After the organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration and concentrated to obtain a crude product of the title compound (180.4 g).

b-2) Ethyl trans- [4- (N-ethylcarbamoyl) cyclohexyl] acetate Tetrahydrofuran of a crude product of trans-4- (ethoxycarbonylmethyl) cyclohexanecarboxylic acid (180.4 g) obtained in b-1) Thionyl chloride (74 ml) was added to the solution (200 ml) with stirring at room temperature. After stirring the reaction solution for 3 hours, it was concentrated to obtain an acid chloride. A solution of the above acid chloride in tetrahydrofuran (80 ml) was added dropwise to tetrahydrofuran (250 ml) and 70% ethylamine water (250 ml) with ice cooling and stirring. After the reaction solution was stirred for 30 minutes, water (800 ml) was added, extracted with ethyl acetate, and washed sequentially with water and saturated saline. After the organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the residue obtained was concentrated. The residue obtained was recrystallized from hexane-ethyl acetate to give the title compound (78.9 g, yield from ethyl 4-oxocyclohexanecarboxylate). 37%).
¹ H NMR (CDCl ₃ , 300 MHz) δ: 0.90-1.10 (m, 2H), 1.13 (t, J = 7.3 Hz, 3H), 1.25 (t, J = 7.1 Hz, 3H), 1.40-1.60 (m, 2H ), 1.72-1.95 (m, 5H), 1.99 (m, 1H), 2.19 (d, J = 6.8Hz, 2H), 3.28 (m, 2H), 4.13 (q, J = 7.1Hz, 2H), 5.39 (brs, 1H).

b-3) trans-8 {4-[(N-ethylamino) methyl] cyclohexyl} ethyl acetate trans- [4- (N-ethylcarbamoyl) cyclohexyl] ethyl acetate (100 g) and sodium borohydride (75.2 g) Acetic acid (114 ml) was added dropwise to the suspension of tetrahydrofuran (800 ml) over 1 hour with stirring under reflux, and the reaction solution was further stirred for 2 hours. The reaction solution was quenched by dropwise addition of water (200 ml) under ice-cooling and stirring. After adding 1.5N aqueous sodium hydroxide (1000 ml), the mixture was extracted with ethyl acetate, and washed sequentially with water and saturated saline. After the organic layer was dried over sodium sulfate, sodium sulfate was removed by filtration, and the residue obtained by concentration was dissolved in ethanol (500 ml), and 4N hydrochloric acid-ethyl acetate (125 ml) was added dropwise with stirring at room temperature. After continuing stirring for further 20 hours, the mixture was diluted with ethyl acetate and washed sequentially with 2N aqueous sodium hydroxide, water and saturated saline. After the organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration and concentrated to obtain the title compound (81.9 g, 87%).
_{^{1 HNMR (CDCl 3, 300MHz)}} δ: 0.82-1.08 (m, 4H), 1.10 (t, J = 7.1Hz, 3H), 1.25 (t, J = 7.1Hz, 3H), 1.37 (m, 1H), 1.66-1.88 (m, 5H), 1.99 (m, 1H), 2.18 (d, J = 6.8Hz, 2H), 2.44 (d, J = 6.6Hz, 2H), 2.62 (q, J = 7.1Hz, 2H ), 4.12 (q, J = 7.1Hz, 2H).

c) trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] ] Methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) ethyl acetate c-1) trans- (4-{[N-ethyl-N- (2-hydroxymethyl- 5-methyl-4-trifluoromethylphenyl) amino] methyl {cyclohexyl) ethyl acetate p-toluenesulfonate 2-fluoro-4-methyl-5-trifluoromethylbenzaldehyde (47.03 g), trans- {4- [(N-ethylamino) methyl] cyclohexyl ヘ ethyl acetate (57.05 g) and potassium carbonate (94.5 g) in toluene (470 l) was heated to reflux for 48 hours. The reaction solution was returned to room temperature, washed successively with water, aqueous potassium hydrogen sulfate and saturated saline, and the organic layer was dried over magnesium sulfate. Ethanol (100 ml) was added to the solution obtained by filtering off magnesium sulfate, and sodium borohydride (4.31 g) was added with stirring at room temperature. After the reaction solution was stirred for 1 hour, aqueous ammonium chloride (200 ml) was added and the layers were separated. The organic layer was washed sequentially with water and saturated saline, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the residue obtained by concentration was dissolved in diethyl ether (1060 ml). Under stirring at room temperature, p-toluenesulfonic acid hydrate (43.4 g) was added, and stirring was continued for 2 hours. The precipitated crystals were collected by filtration and dried to give the title compound (120 g, 32%).
¹ HNMR (CDCl ₃ , 300MHz) δ: 0.70-1.14 (m, 4H), 1.21 (t, J = 7.1Hz, 3H), 1.23 (t, J = 7.1Hz, 3H), 1.42 (m, 1H), 1.50-1.78 (m, 4H), 1.93 (m, 1H), 2.09 (d, J = 6.7Hz, 2H), 2.36 (s, 3H), 2.54 (s, 3H), 3.10-4.15 (m, 4H) , 4.09 (q, J = 7.1Hz, 2H), 4.85-5.25 (m, 2H), 7.07 (d, J = 8.0Hz, 2H), 7.33 (s, 1H), 7.54 (s, 1H), 7.77 ( d, J = 8.0Hz, 2H), 11.57 (brs, 1H).

c-2) trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) ) Amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) ethyl acetate trans- (4-{[N-ethyl-N- (2-hydroxymethyl-5- Methyl-4-trifluoromethylphenyl) amino] methyl {cyclohexyl) ethyl acetate A toluene-water solution (480-480 ml) of p-toluenesulfonic acid salt (120 g) and sodium hydrogencarbonate (32.3 g) was stirred at room temperature for 30 minutes. After that, the layers were separated. The organic layer was washed successively with water and saturated saline, and dried over magnesium sulfate. The solution obtained by filtering off magnesium sulfate was added dropwise to a place where a toluene solution (360 ml) of thionyl chloride (17.65 ml) was stirred under ice-cooling. Stirring was continued at room temperature for 30 minutes, pyridine (33 ml) was added to the reaction solution, and the mixture was washed sequentially with water and saturated saline, and the organic layer was dried over sodium sulfate. The sodium sulfate was filtered off, the residue obtained by concentration and 5-{[3,5-bis (trifluoromethyl) benzyl] amino} -2-methyl-2H-tetrazole (69) obtained in Example 9a). 0.7 g) of N, N-dimethylformamide solution (900 ml) was added with potassium t-butoxy (27.5 g) under stirring at room temperature. After stirring was continued for 2 hours, a saturated aqueous ammonium chloride solution was added, extraction was performed with ethyl acetate, and the extract was washed with water and saturated saline sequentially, and the organic layer was dried over sodium sulfate. The sodium sulfate was removed by filtration, and the residue obtained by concentration was purified by column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (118 g, 80%) (see Table-34). .

Example 170
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl} cyclohexyl) acetic acid

  trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl A 4N aqueous sodium hydroxide solution (163 ml) was added to an ethanol solution (326 ml) of ethyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetate (118 g) with stirring at room temperature. Was. After stirring the reaction solution at 60 ° C. for 2 hours, the mixture was neutralized by adding aqueous citric acid under ice-cooling and stirring, then extracted with ethyl acetate, and washed sequentially with water and saturated saline. After the organic layer was dried over sodium sulfate, the sodium sulfate was removed by filtration, and the residue was purified by column chromatography (n-hexane: ethyl acetate = 2: 1) to give the title compound (104 g, 92%). Was obtained (see Table 34).

Example 142
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride

  trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl An ether solution (1.5 ml) of {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid (130 mg) was stirred at room temperature, and 1N hydrochloric acid-ether (0.20 ml). Was added. The precipitated solid was collected by filtration and dried to give the title compound (128 mg, 94%) (see Table 29).

Example 168
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid methanesulfonate

  trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl To a solution of {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl} cyclohexyl) acetic acid (96.3 g) in ethyl acetate (580 ml) was added methanesulfonic acid (13.56 ml) at room temperature while stirring. added. After stirring was continued for 15 hours, the precipitated solid was collected by filtration and dried to obtain a methanesulfonate ethyl acetate hydrate. This was suspended in heptane-ethyl acetate (3: 1, 990 ml), heated and stirred at 80 ° C. for 20 hours, returned to room temperature, collected by filtration, and dried to give the title compound (91.0 g, 83%). (See Table 34).

  The compounds of Examples 10 to 141 and 143 to 167 were obtained in the same manner as in Examples 1 to 9, 142, 168, 169 and 170. These are shown in Tables 1 to 34 together with Examples 1 to 9, 142, 168, 169 and 170.

  Similarly, the compounds shown in Table 35 can be produced.

(Test example)
Next, the following test was performed for the CETP activity inhibitory effect of the compound of the present invention.

(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) was performed. A fraction of> 1.125 g / mL (HDL ₃ fraction) was collected. The obtained fraction was dialyzed against a PBS solution [10 mmol / L Na ₂ HPO ₄ ; 10 mmol / L NaH ₂ PO ₄ ; 0.15 mol / L NaCl; 1 mol / L EDTA (pH 7.4)]. Then, tritium-labeled cholesterol (37 MBq) was dissolved in 95% ethanol was added slowly with stirring to the above HDL ₃ fraction, by 18 h incubation the [this operation 37 ° C., tritium-labeled cholesterol to HDL ₃ surface It is esterified by the action of existing lecithin acyltransferase (LCAT) and incorporated into HDL ₃ as tritium-labeled cholesteryl ester ([ ³ H] CE)]. After the incubation, KBr was added, the specific gravity was adjusted to d = 1.21 g / mL, density gradient centrifugation (227,000 × g, 4 ° C., 17 hours) was performed, and fractionation with specific gravity d <1.21 g / mL was performed. Was collected. The resulting fractions were dialyzed against the PBS solution, _^[3 H] HDL ³ incorporating ^{CE ([3 H] CE-} HDL 3, specific gravity: 1.125 <d <1.21, specific activity: 1, 000 dpm / μL) to obtain a donor lipoprotein.

(Test Example 1: CETP activity inhibitory action in whole plasma in vitro)
Was added donor lipoprotein obtained above in healthy human plasma was prepared _^[3 H] CE-HDL ³ containing plasma (1,000dpm / μL). The compound was dissolved in dimethylformamide. Was added 2μL and _^[3 H] CE-HDL ³ containing plasma 100μL only compound solution or solvent in a microtube and incubated for 4 hours at 37 ° C. or 4 ° C.. After ice-cooling, 100 μL of a TBS solution containing 1 mol / L magnesium chloride and 2% dextran sulfate [20 mmol / L Tris; 0.15 mol / L NaCl (pH 7.4)] is added to each microtube, and the mixture is thoroughly stirred. did. After standing at 4 ° C. for 30 minutes, centrifugation (10,000 × g, 4 ° C., 10 minutes) was performed, and the radioactivity of the obtained centrifugal supernatant (HDL fraction) was measured using a scintillation counter. The difference between the measured values incubated at 4 ° C. and 37 ° C. with the solvent alone was defined as the 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. The concentration of the compound that inhibits CETP activity by 50% was calculated as an IC ₅₀ value. The results are shown below.

(Test Example 2: Inhibition of CETP activity in whole plasma of normal hamster in ex vivo)
The compound of the present invention was suspended in a 0.5% methylcellulose solution, and then orally administered once to normal hamsters using a plastic sonde. Blood was collected 2 or 4 hours after administration, and CETP activity in plasma was measured according to the following method.
Hamsters plasma (100 [mu] L), was added donor lipoprotein obtained above was prepared _^[3 H] CE-HDL ³ containing plasma (about 1,000dpm / μL). _^[3 H] CE-HDL ³ aliquoted containing plasma to two microtubes by 25μL min at 37 ° C. The one, respectively and incubated for 4 hours at 4 ° C. The one. After cooling on ice, 50 μL of a TBS solution containing 1 mol / L magnesium chloride and 2% dextran sulfate was added to each microtube, followed by thorough stirring. After standing at 4 ° C. for 30 minutes, centrifugation (10,000 × g, 4 ° C., 20 minutes) was performed, and the radioactivity of the obtained supernatant (HDL fraction) was measured with a liquid scintillation counter. Further, the radioactivity of ^{_[3 H]} CE-HDL ³ containing plasma was measured with a liquid scintillation counter, which was used as a total radioactivity. From the total radioactivity (Totalcount), the radioactivity in the 37 ° C incubation (37 ° C count), and the radioactivity in the 4 ° C incubation (4 ° C count) in each individual sample, the transfer rate of [ ³ H] CE was calculated by the following equation. This was defined as CETP activity.
CETP activity (transfer rate%) = {[(4 ° C. count) − (37 ° C. count)] / (Totalcount)} × 100
Next, the CETP activity inhibition rate of each compound administration group, assuming that the CETP activity of the solvent administration group was 100%, was calculated by the following formula, and expressed as%.
CETP activity inhibition rate (%) = 100 − [(CETP activity of each compound administration group) / (CETP activity of solvent administration group) × 100]

  The results are shown below.

(Test Example 3: Blood HDL cholesterol increasing effect in normal hamster)
In the above animals, 40 μL of a 15% polyethylene glycol solution was added to 40 μL of plasma collected 4 or 8 hours after administration, and the mixture was stirred well. After standing at room temperature for 10 minutes, centrifugation (10,000 × g, 4 ° C., 20 minutes) was performed, and the cholesterol content (HDL cholesterol content) of the obtained supernatant (HDL fraction) was measured. The HDL cholesterol increase rate in each compound administration group when the HDL cholesterol amount in the solvent administration group was set to 100% was calculated by the following formula, and is shown in%.
HDL cholesterol increase rate (%) = [(HDL cholesterol amount of each compound administration group / HDL cholesterol amount of solvent administration group) × 100] −100
The results are shown below.

(Test Example 4: Combination test)
For the experiment, a 10-week-old male Japanese white rabbit (Kitayama Labes) was used. The animals acclimated under the normal feed (RC-4, manufactured by Oriental Bioservice) were fasted for 24 hours, and then fed a high cholesterol diet (RC-4 with 0.25% cholesterol, manufactured by Oriental Bioservice). Each bird was fed 100 g per day for 3 days (preliminary feeding). On the day following the third day of preliminary feeding, blood was collected from the auricular artery before feeding, and the animals were divided into groups of 6 animals per group based on the parameters (HDL cholesterol, total cholesterol, triglyceride) and body weight as indices.

Prepare a feed in which simvastatin (0.002%), the compound of Example 168 (0.2%), simvastatin (0.002%) + the compound of Example 168 (0.2%) are added to a high cholesterol diet ( Oriental Bioservice Co., Ltd.), and the animals to which each feed was divided were fed 100 g per bird for 15 days. Eight hours after feeding on the 15th day after administration, whole blood was collected from the carotid artery under anesthesia, and the amount of HDL cholesterol, total cholesterol, and ApoA-I in plasma were measured. The arteriosclerosis index was calculated as [(total cholesterol amount-HDL cholesterol amount) / HDL cholesterol amount]. Further, the HDL ₃ fraction was separated from the plasma by ultracentrifugation, and the amount of cholesterol in the fraction was measured. The table shows the arteriosclerosis index, the amount of ApoA-I, and the amount of HDL ₃ cholesterol when the value of the control group is 100%.

Claims (74)

General formula (1)

(In the formula,
R ¹ and R ² are the same or different and are a halogen atom, a nitro group, a cyano group, or a C _1-6 alkyl group _optionally substituted with a halogen atom;
R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted with a halogen atom, a C _1-6 alkylthio group optionally substituted with a halogen atom, or A C _1-6 alkoxy group which may be substituted with a halogen atom, or a C _1-6 alkoxy group which may have a substituent together with a carbon atom to which R ³ and R ⁴ or R ⁴ and R ⁵ are bonded; May form an elementary ring or a heterocyclic ring which may have a substituent;
A is -N (R ⁷ ) (R ⁸ ) (where R ⁷ and R ⁸ are the same or different and are each a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or -(CH ₂ ) _m -COOR ⁹ (where R ⁹ is a hydrogen atom or a C _1-6 alkyl group, and m is 0 or an integer of 1 to 5), or C _4-10 cycloalkylalkyl group (wherein _{C 4-10} cycloalkylalkyl group, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl _{group, C 1-6 alkoxy, C 1-6} alkyl group ( the _{C 1-6} alkyl group, a hydroxyl _group, may be substituted with _{C 1-6} alkoxy group or phosphono ^{_{group), - (CH 2) q}} -CON (R 20) (R 21) ( ^{wherein, R 20} and ^{R 21} are the same or different and each represents a hydrogen atom or a C _-6 alkyl group, q is 0 or an integer of 1 to 5) or ^{_{- (CH 2) r -COOR 10}} ( ^{wherein, R 10} is a hydrogen atom or a _{C 1-6} alkyl group, r Is 0 or an integer of 1 to 5) and may be substituted by 1 to 3)), -C (R ¹¹ ) (R ¹² ) (R ¹³ ) (where R ¹¹ , R ¹² and R ¹³ is the same or different and is substituted by a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or —COOR ⁹ (where R ⁹ is the same as described above)) Or a C _4-10 cycloalkylalkyl group (the C _4-10 cycloalkylalkyl group may be a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group, a C _{1 -6} alkyl group (the _{C 1-6} alkyl group, Group _may be substituted with _{C 1-6} alkoxy group or phosphono ^{_{group), - (CH 2) q}} -CON (R 20) (R 21) ( ^wherein, R ^{20, R 21} and q are the Or — (CH ₂ ) _r —COOR ¹⁰ (wherein R ¹⁰ and r may be the same as defined above) or may be substituted with 1 to 3), or —O—C ( R ¹¹ ) (R ¹² ) (R ¹³ ), wherein R ¹¹ , R ¹² and R ¹³ are the same as above;
Ring B is an aryl group or a heterocyclic residue;
R ⁶ represents a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl group or a C _1-6 alkyl group (C _1-6 The alkyl group is a hydroxyl group or —COOR ¹⁴ (where R ¹⁴ is a hydrogen atom or a C _1-6 alkyl group);
and n is an integer of 1 to 3.], a prodrug thereof, or a pharmaceutically acceptable salt thereof. R ³ , R ⁴ and R ⁵ are the same or different and are a hydrogen atom, a halogen atom, a C _1-6 alkyl group optionally substituted by a halogen atom or a C _1-6 alkoxy group optionally substituted by a halogen atom; Or together with the carbon atom to which R ³ and R ⁴ or R ⁴ and R ⁵ are attached, form a homocyclic ring which may have a substituent or a heterocyclic ring which may have a substituent May be;
R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or —COOR ⁹ (where R ⁹ is a hydrogen atom or C _{1- 6} alkyl group) or a C _4-10 cycloalkylalkyl group (the C _4-10 cycloalkylalkyl group is a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group) , A C _1-6 alkoxy group, a C _1-6 alkyl group or —COOR ¹⁰ (where R ¹⁰ is a hydrogen atom or a C _1-6 alkyl group). ;
R ¹¹ , R ¹² and R ¹³ may be the same or different and each represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group is a phenyl group or —COOR ⁹ (where R ⁹ is Or a C _4-10 cycloalkylalkyl group (the C _4-10 cycloalkylalkyl group may be a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _{1 -6 alkoxy, C 1-6} alkyl group or -COOR ^{10 (wherein, R 10} is same as that defined above) Yes 1 at the 3-substituted may be) in;
R ⁶ is a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group or a C _1-6 alkyl group (the C _1-6 alkyl group is a hydroxyl group or —COOR ¹⁴ wherein R ¹⁴ may be substituted with a hydrogen atom or a C _1-6 alkyl group, or a dibenzylamine compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Salt obtained. The dibenzylamine compound according to claim 1 or 2, or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a C _1-6 alkyl group substituted with a halogen atom. The dibenzylamine compound according to claim 3, wherein R ¹ is a trifluoromethyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof. Ring B and (R ⁶ ) _n are

(Where R ⁶⁰ , R ⁶¹ and R ⁶² are the same or different and are each a hydrogen atom, a halogen atom, a nitro group, an amino group, a hydroxyl group, a cyano group, an acyl group, a C _1-6 alkoxy group, a C _2-6 alkenyl A group or a C _1-6 alkyl group, wherein the C _1-6 alkyl group is a hydroxyl group or a —COOR ¹⁴ (where R ¹⁴ may be the same as described above). 5. The dibenzylamine compound according to 3, or 4, or a prodrug thereof, or a pharmaceutically acceptable salt thereof. Ring B and (R ⁶ ) _n are

(Wherein R ⁶⁰ , R ⁶¹ and R ⁶² are the same as described above), or a dibenzylamine compound or a prodrug thereof or a pharmaceutically acceptable salt thereof. Ring B and (R ⁶ ) _n are

(Wherein R ⁶⁰ and R ⁶¹ are the same as described above), or a dibenzylamine compound or a prodrug thereof or a pharmaceutically acceptable salt thereof. A is ^-N (R 7) ^(R 8) (wherein, ^{R 7} and ^{R 8} are the same as Claim 1) dibenzylamine according to any one of claims 1 or 3 to 7 is A compound or a prodrug thereof or a pharmaceutically acceptable salt thereof. The dibenzylamine compound according to claim 8, wherein R ⁷ is a C _1-6 alkyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof. The dibenzylamine compound according to claim 9, wherein R ⁶ is a C _1-6 alkyl group, a prodrug thereof, or a pharmaceutically acceptable salt thereof. N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl] -(2-methyl-2H-tetrazol-5-yl) amine,
3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H-tetrazole- 5-yl) amino] methyl} -5-trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine hydrochloride,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2H-tetrazol-5-yl)-[3,5-bis (trifluoromethyl) benzyl] Amine,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) amine hydrochloric acid salt,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(5-methyl-1H-pyrazole- 3-yl) amine,
5- {N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylaminopentanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylate,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 -Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-ethyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H- [1 , 2,4] triazol-3-yl) amine,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N-phenylamino} methyl) -5-trifluoromethylbenzonitrile,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4,5-dimethylthiazol-2-yl) amino] methyl} -5- Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(thiazol-2-yl) amine hydrochloride salt,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (thiazol-2-yl) amino} methyl) -5-trifluoromethylbenzonitrile Hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(oxazol-2-yl) amine hydrochloric acid salt,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4,5-dimethylthiazole-2 -Yl) amine hydrochloride,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (5-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methyloxazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisothiazole-5- Il) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylisoxazole-3 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisoxazole-5 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 3-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 4-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] thiadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] oxadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-3-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-2-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl]-(2-methyl-2H- Tetrazol-5-yl) amine hydrochloride,
3-{[N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 Ylmethyl) -N-ethylamino] pentanoic acid methyl chloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methyl hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methyl hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,2 , 4] oxadiazol-3-yl) amine hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylate hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylate,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} indane -5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} indane- 5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methyl-isoxazol-5-yl) amino] methyl} indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3 -Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methyl- [1,2 , 4] thiadiazol-5-yl) amine,
5- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) amino ] Methyl {indan-5-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5 Methyl 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoate hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl chloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazole-3 -Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazole-3- Yl) amino] methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} -methyl}- 5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} -5 , 6,7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
2- (5- {N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] amino} tetrazole- 2-yl) ethanol hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) Amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) amino ] Methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid methyl chloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) Amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H- [1,2,4] triazol-3-yl) amino ] Methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(3-methylisoxazol-5-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(3-methylisoxazol-5-yl) amino] methyl} -5,6 7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (3-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -5,6 , 7,8-Tetrahydronaphthalen-2-yl) -N-ethylamino] pentanoic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3 -Yl) amino] methyl {indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (2-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4-tri Fluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] pentanoic acid hydrochloride,
5- {N- [6-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] amino} Methyl) indan-5-yl] -N-ethylamino} pentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] pentanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -2,2-dimethylpentanoic acid hydrochloride,
6- [N- (6-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 Il) -N-ethylamino] hexanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
trans-4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
(1- {2- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {Indan-5-yl) -N-ethylamino] ethyl {cyclopentyl) acetic acid hydrochloride,
trans-4-({N- [6-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] ] Amino {methyl) indan-5-yl] -N-ethylamino {methyl) cyclohexanecarboxylic acid,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethylphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
(1- {2- [N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] ethyl {cyclopentyl) acetic acid,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (3-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-ethyl-2H-tetrazol-5-yl) amino] methyl} methyl} -5,6,7,8-tetrahydronaphthalen-2-yl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-({N- [3-({N '-[3,5-bis (trifluoromethyl) benzyl] -N'-[2- (2-hydroxyethyl) -2H-tetrazol-5-yl] ] Amino {methyl) -5,6,7,8-tetrahydronaphthalen-2-yl] -N-ethylamino {methyl) cyclohexanecarboxylic acid hydrochloride,
1- {3- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} Indan-5-yl) -N-ethylamino] propyl} cyclohexanecarboxylic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -3,3-dimethylpentanoic acid;
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {indan-5-yl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(1-methyl-1H-pyrazol-3-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
5- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazol-3-yl) Amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] -3,3-dimethylpentanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole-3 -Yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] hexanoic acid hydrochloride,
trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {Indan-5-yl) -N-ethylamino] methyl} cyclohexyl) acetic acid hydrochloride,
6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -3,3-dimethylhexanoic acid hydrochloride,
5- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -4,4-dimethylpentanoic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethoxyphenyl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
6- [N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4- Trifluoromethylphenyl) -N-ethylamino] -4,4-dimethylhexanoic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
6- [N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} indane-5 -Yl) -N-ethylamino] -5,5-dimethylhexanoic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-propylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-isobutylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid amide,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid methylamide,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid dimethylamide,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-chlorophenyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(p-tolyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(m-tolyl) amino] methyl} -4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-(3,5-dichlorobenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} -4-trifluoro Methoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N-ethyl-N- (2-{[N '-(2-methyl-2H-tetrazol-5-yl) -N'-(3-methyl-5-trifluoromethylbenzyl) amino] ] Methyl {-4-trifluoromethoxyphenyl) amino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-(3-chloro-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}-] 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N-ethyl-N- (2-{[N '-(2-methyl-2H-tetrazol-5-yl) -N'-(3-nitro-5-trifluoromethylbenzyl) amino] ] Methyl {-4-trifluoromethoxyphenyl) amino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2-difluorobenzo [1,3] dioxol-5-yl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (6-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2-difluorobenzo [1,3] dioxol-5-yl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-3- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] ] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) propionic acid hydrochloride,
trans- (4-{[N- (7-} [N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (7-} [N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-2- (4-{[N- (7-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino ] Methyl {-2,2,3,3-tetrafluoro-2,3-dihydrobenzo [1,4] dioxin-6-yl) -N-ethylamino] methyl {cyclohexyl) acetamide hydrochloride,
trans-N- [3,5-bis (trifluoromethyl) benzyl] -N- {2- [N'-ethyl-N '-(4- (methoxymethyl) cyclohexylmethyl) amino] -5-trifluoromethoxy Benzyl}-(2-methyl-2H-tetrazol-5-yl) amine hydrochloride,
trans-2- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino ] Methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) ethanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexylmethyl) phosphonic acid,
trans-4-{[N- (2-{[N '-(3-bromo-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}- 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-bromophenyl) -N-ethylamino] methyl} cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-bromophenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-chloro-5-ethylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-methoxyphenyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methoxy-4-methylphenyl) -N-ethylamino] methyl {cyclohexyl) methanol hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4,5-dimethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylthiophenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-chloro-5-ethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methoxy-4-methylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-4-({N- [2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl} methyl} -4- (2,2,2-trifluoroethyl) phenyl] -N-ethylaminodimethyl) cyclohexanecarboxylic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-ethylphenyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-(3-cyano-5-trifluoromethylbenzyl) -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl}-] 4-trifluoromethoxyphenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid hydrochloride,
trans-4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(4-isopropenylphenyl) amino] methyl} -4-trifluoromethoxy Phenyl) -N-ethylamino] methyl} cyclohexanecarboxylic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(p-tolyl) amino] methyl} -4-trifluoromethoxyphenyl ) -N-ethylamino] methyl {cyclohexyl) acetic acid dihydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] -N'-(5-methyl- [1,2,4] oxadiazole- 3-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl} cyclohexyl) acetic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid methanesulfonate,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetate and trans- (4-{[N- (2-{[N '-[3,5-bis (Trifluoromethyl) benzyl] -N '-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) The dibenzylamine compound according to claim 1, which is selected from the group consisting of acetic acid, a prodrug thereof, or a pharmaceutically acceptable salt thereof. trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-trifluoromethoxyphenyl) -N-propylamino] methyl {cyclohexyl) acetic acid hydrochloride,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-propylamino] methyl} cyclohexyl) acetic acid,
trans- (4-{[N- (2-{[N '-[3,5-bis (trifluoromethyl) benzyl] benzyl] -N'-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-4-methyl-5-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid, and trans- (4-{[N- (2-{[N '-[3,5-bis ( Trifluoromethyl) benzyl] -N '-(2-methyl-2H-tetrazol-5-yl) amino] methyl {-5-methyl-4-trifluoromethylphenyl) -N-ethylamino] methyl {cyclohexyl) acetic acid The dibenzylamine compound according to claim 1, which is selected from the group consisting of methanesulfonic acid salts, a prodrug thereof, or a pharmaceutically acceptable salt thereof. N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl] -(2-methyl-2H-tetrazol-5-yl) amine,
3-{[N- [3- (N'-cyclopentylmethyl-N'-ethylamino) -5,6,7,8-tetrahydronaphthalen-2-ylmethyl] -N- (2-methyl-2H-tetrazole- 5-yl) amino] methyl} -5-trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-methyl-2H-tetrazole- 5-yl) amine hydrochloride,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2H-tetrazol-5-yl)-[3,5-bis (trifluoromethyl) benzyl] Amine,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(pyrimidin-2-yl) amine hydrochloric acid salt,
N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- [3,5-bis (trifluoromethyl) benzyl]-(5-methyl-1H-pyrazole- 3-yl) amine,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (2-methyl-2H-tetrazol-5-yl) amino] methyl} -5 -Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(2-ethyl-2H-tetrazole- 5-yl) amine,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H- [1 , 2,4] triazol-3-yl) amine,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N-phenylamino} methyl) -5-trifluoromethylbenzonitrile,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4,5-dimethylthiazol-2-yl) amino] methyl} -5- Trifluoromethylbenzonitrile,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(thiazol-2-yl) amine hydrochloride salt,
3-({N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (thiazol-2-yl) amino} methyl) -5-trifluoromethylbenzonitrile Hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(oxazol-2-yl) amine hydrochloric acid salt,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methylthiazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4,5-dimethylthiazole-2 -Yl) amine hydrochloride,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (5-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
3-{[N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -N- (4-methylthiazol-2-yl) amino] methyl} -5-trifluoro Methylbenzonitrile hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(4-methyloxazol-2-yl ) Amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisothiazole-5- Il) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methylisoxazole-3 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(3-methylisoxazole-5 -Yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 3-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(1-methyl-1H-pyrazole- 4-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] thiadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl]-(5-methyl- [1,3 , 4] oxadiazol-2-yl) amine hydrochloride,
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-3-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [6- (N'-cyclopentylmethyl-N'-ethylamino) indan-5-ylmethyl] -pyridin-2-ylamine hydrochloride;
N- [3,5-bis (trifluoromethyl) benzyl] -N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl]-(2-methyl-2H- Tetrazol-5-yl) amine hydrochloride and 3-{[N- [2- (N'-cyclopentylmethyl-N'-ethylamino) -5-trifluoromethylbenzyl] -N- (2-methyl-2H The dibenzylamine compound according to claim 2, which is selected from the group consisting of -tetrazol-5-yl) amino] methyl} -5-trifluoromethylbenzonitrile hydrochloride, a prodrug thereof, or a pharmaceutically acceptable salt thereof.   A pharmaceutical composition comprising the dibenzylamine compound according to any one of claims 1 to 13, a prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  A CETP activity inhibitor comprising, as an active ingredient, the dibenzylamine compound according to any one of claims 1 to 13, a prodrug thereof, or a pharmaceutically acceptable salt thereof.  A therapeutic or prophylactic agent for hyperlipidemia comprising the dibenzylamine compound according to any one of claims 1 to 13, a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.  14. The treatment or prevention of hyperlipidemia, comprising administering the dibenzylamine compound according to any one of claims 1 to 13, a prodrug thereof, or a pharmaceutically acceptable salt thereof to a mammal. Method.  A therapeutic or prophylactic agent for arteriosclerosis, comprising as an active ingredient the dibenzylamine compound according to any one of claims 1 to 13, a prodrug thereof, or a pharmaceutically acceptable salt thereof.  14. A method for treating or preventing arteriosclerosis, comprising administering to a mammal the dibenzylamine compound according to any one of claims 1 to 13, a prodrug thereof, or a pharmaceutically acceptable salt thereof.   The pharmaceutical composition according to claim 14, which is used in combination with another therapeutic agent for hyperlipidemia.   21. The pharmaceutical composition according to claim 20, wherein the other therapeutic agent for hyperlipidemia is a statin drug.   22. The pharmaceutical composition according to claim 21, wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin.   15. The pharmaceutical composition according to claim 14, which is used in combination with another therapeutic agent for obesity.   24. The pharmaceutical composition according to claim 23, wherein the other therapeutic agent for obesity is mazindol.   The pharmaceutical composition according to claim 14, which is used in combination with another drug for treating diabetes.   The other diabetes therapeutic agent is one or more agents selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. 26. The pharmaceutical composition according to 25, wherein   The other therapeutic agent for diabetes is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride. 27. The pharmaceutical composition according to claim 26, which is the above drug.   15. The pharmaceutical composition according to claim 14, which is used in combination with another therapeutic agent for hypertension.   One or more other antihypertensive drugs selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers 29. The pharmaceutical composition according to claim 28, which is a medicament.   Other antihypertensive drugs include furosemide sustained release, captopril, captopril sustained release, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril eb Min, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release agent, nisoldipine, nitrendipine, manidipine hydrochloride, balunidipine hydrochloride, Efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride, pindo , Pindolol sustained release agent, indenolol hydrochloride, carteolol hydrochloride, carteolol hydrochloride sustained release agent, bunitrolol hydrochloride, bunitrolol hydrochloride sustained release agent, atenolol, acebutolol hydrochloride, metoprolol tartrate, metoprolol tartrate sustained release agent, nipradilol, penbutolol sulfate, Chilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride 30. The pharmaceutical composition according to claim 29, which is one or more drugs selected from the group consisting of a drug, urapidil, and phentolamine mesylate.   17. The therapeutic or prophylactic agent according to claim 16, wherein the subject to be treated or prevented is hyperlipidemia and used in combination with another therapeutic agent for hyperlipidemia.   32. The therapeutic or prophylactic agent according to claim 31, wherein the other therapeutic agent for hyperlipidemia is a statin drug.   33. The therapeutic or prophylactic agent according to claim 32, wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.   17. The therapeutic or prophylactic agent according to claim 16, wherein the subject to be treated or prevented is hyperlipidemia and is used in combination with another therapeutic agent for obesity.   35. The therapeutic or prophylactic agent according to claim 34, wherein the other therapeutic agent for obesity is mazindol.   17. The therapeutic or prophylactic agent according to claim 16, wherein the subject to be treated or prevented is hyperlipidemia and is used in combination with another antidiabetic agent.   The other diabetes therapeutic agent is one or more agents selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. 36. The therapeutic or prophylactic agent according to 36.   The other therapeutic agent for diabetes is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride. The therapeutic or prophylactic agent according to claim 37, which is the above drug.   17. The therapeutic or prophylactic agent according to claim 16, wherein the subject to be treated or prevented is hyperlipidemia, and is used in combination with another therapeutic agent for hypertension.   One or more other antihypertensive drugs selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers The therapeutic or prophylactic agent according to claim 39, which is a drug.   Other antihypertensive drugs include furosemide sustained release, captopril, captopril sustained release, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril eb Min, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release agent, nisoldipine, nitrendipine, manidipine hydrochloride, balunidipine hydrochloride, Efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride, pindo , Pindolol sustained release agent, indenolol hydrochloride, carteolol hydrochloride, carteolol hydrochloride sustained release agent, bunitrolol hydrochloride, bunitrolol hydrochloride sustained release agent, atenolol, acebutolol hydrochloride, metoprolol tartrate, metoprolol tartrate sustained release agent, nipradilol, penbutolol sulfate, Chilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride 41. The therapeutic or prophylactic agent according to claim 40, which is one or more drugs selected from the group consisting of a drug, urapidil and phentolamine mesylate.   18. The method according to claim 17, wherein the subject to be treated or prevented is hyperlipidemia and used in combination with another therapeutic agent for hyperlipidemia.   43. The method according to claim 42, wherein the other therapeutic drug for hyperlipidemia is a statin drug.   44. The method according to claim 43, wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin.   18. The method according to claim 17, wherein the subject to be treated or prevented is hyperlipidemia and is used in combination with another therapeutic agent for obesity.   46. The method according to claim 45, wherein the other therapeutic agent for obesity is mazindol.   18. The method according to claim 17, wherein the subject to be treated or prevented is hyperlipidemia and used in combination with another drug for treating diabetes.   The other diabetes therapeutic agent is one or more agents selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. 47. The treatment or prevention method according to 47.   The other therapeutic agent for diabetes is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose and pioglitazone hydrochloride. 49. The treatment or prevention method according to claim 48, which is the above drug.   18. The method according to claim 17, wherein the subject to be treated or prevented is hyperlipidemia and used in combination with another therapeutic agent for hypertension.   One or more other antihypertensive drugs selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers 51. The method according to claim 50, which is a medicament.   Other antihypertensive drugs include furosemide sustained release, captopril, captopril sustained release, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril eb Min, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release agent, nisoldipine, nitrendipine, manidipine hydrochloride, balunidipine hydrochloride, Efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride, pindo , Pindolol sustained release agent, indenolol hydrochloride, carteolol hydrochloride, carteolol hydrochloride sustained release agent, bunitrolol hydrochloride, bunitrolol hydrochloride sustained release agent, atenolol, acebutolol hydrochloride, metoprolol tartrate, metoprolol tartrate sustained release agent, nipradilol, penbutolol sulfate, Chilisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride 52. The method according to claim 51, which is one or more drugs selected from the group consisting of a drug, urapidil, and phentolamine mesylate.   19. The therapeutic or prophylactic agent according to claim 18, wherein the subject to be treated or prevented is arteriosclerosis and used in combination with another therapeutic agent for hyperlipidemia.   54. The therapeutic or prophylactic agent according to claim 53, wherein the other therapeutic agent for hyperlipidemia is a statin drug.   55. The therapeutic or prophylactic agent according to claim 54, wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and cerivastatin.   19. The therapeutic or prophylactic agent according to claim 18, wherein the subject to be treated or prevented is arteriosclerosis and is used in combination with another therapeutic agent for obesity.   57. The therapeutic or prophylactic agent according to claim 56, wherein the other therapeutic agent for obesity is mazindol.   19. The therapeutic or prophylactic agent according to claim 18, wherein the subject to be treated or prevented is arteriosclerosis and used in combination with another therapeutic agent for diabetes.   The other diabetes therapeutic agent is one or more agents selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. 58. The therapeutic or prophylactic agent according to 58.   The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. 60. The therapeutic or prophylactic agent according to claim 59, which is the above agent.   19. The therapeutic or prophylactic agent according to claim 18, wherein the subject to be treated or prevented is arteriosclerosis, and is used in combination with another therapeutic agent for hypertension.   One or more other antihypertensive drugs selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers 63. The therapeutic or prophylactic agent according to claim 61, which is a drug.   Other antihypertensive drugs are furosemide sustained release, captopril, captopril sustained release, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril elb Min, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release agent, nisoldipine, nitrendipine, manidipine hydrochloride, balunidipine hydrochloride, Efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride, pindo , Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Chillisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride 63. The therapeutic or prophylactic agent according to claim 62, which is one or more drugs selected from the group consisting of a drug, urapidil and phentolamine mesylate.   20. The method according to claim 19, wherein the subject to be treated or prevented is arteriosclerosis and used in combination with another therapeutic agent for hyperlipidemia.   65. The method according to claim 64, wherein the other therapeutic drug for hyperlipidemia is a statin drug.   66. The method according to claim 65, wherein the statin drug is one or more drugs selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cerivastatin.   20. The method according to claim 19, wherein the subject to be treated or prevented is arteriosclerosis and used in combination with another therapeutic agent for obesity.   68. The method according to claim 67, wherein the other therapeutic agent for obesity is mazindol.   20. The method according to claim 19, wherein the subject to be treated or prevented is arteriosclerosis, and the subject is used in combination with another drug for treating diabetes.   The other diabetes therapeutic agent is one or more drugs selected from the group consisting of an insulin preparation, a sulfonylurea drug, an insulin secretagogue, a sulfonamide drug, a biguanide drug, an α-glucosidase inhibitor and an insulin sensitizer. 69. The method for treatment or prevention according to 69.   The other antidiabetic agent is selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybusol, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, and pioglitazone hydrochloride. 71. The treatment or prevention method according to claim 70, which is the above drug.   20. The method according to claim 19, wherein the subject to be treated or prevented is arteriosclerosis and is used in combination with another drug for treating hypertension.   One or more other antihypertensive drugs selected from the group consisting of loop diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, Ca antagonists, β-blockers, α, β-blockers and α-blockers 73. The treatment or prevention method according to claim 72, which is a drug.   Other antihypertensive drugs are furosemide sustained release, captopril, captopril sustained release, enalapril maleate, alacepril, delapril hydrochloride, cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril elb Min, losartan potassium, candesartan cilexetil, nicardipine hydrochloride, nicardipine hydrochloride sustained release agent, nilvadipine, nifedipine, nifedipine sustained release agent, benidipine hydrochloride, diltiazem hydrochloride, diltiazem hydrochloride sustained release agent, nisoldipine, nitrendipine, manidipine hydrochloride, balunidipine hydrochloride, Efonidipine hydrochloride, amlodipine besylate, felodipine, cilnidipine, alanidipine, propranolol hydrochloride, sustained-release propranolol hydrochloride, pindo , Pindolol sustained release agent, Indenolol hydrochloride, Carteolol hydrochloride, Carteolol hydrochloride sustained release agent, Bunitrolol hydrochloride, Bunitrolol hydrochloride sustained release agent, Atenolol, acebutolol hydrochloride, Metoprolol tartrate, Metoprolol tartrate sustained release agent, Nipradilol, Penbutolol sulfate, Chillisolol hydrochloride, carvedilol, bisoprolol fumarate, betaxolol hydrochloride, ceriprolol hydrochloride, bopindolol malonate, bevantolol hydrochloride, labetalol hydrochloride, arotinolol hydrochloride, amosulalol hydrochloride, prazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, bunazosin hydrochloride, bunazosin hydrochloride 74. The method according to claim 73, which is one or more drugs selected from the group consisting of a drug, urapidil and phentolamine mesylate.