WO2001027088A1

WO2001027088A1 - Lpl potentiators

Info

Publication number: WO2001027088A1
Application number: PCT/JP2000/007072
Authority: WO
Inventors: Hisashi Shinkai; Takahisa Motomura; Noriaki Hamakawa
Original assignee: Japan Tobacco Inc.
Priority date: 1999-10-12
Filing date: 2000-10-12
Publication date: 2001-04-19
Also published as: AU7684500A; JP2001226358A

Abstract

LPL potentiators containing as the active ingredient compounds of general formula (I), medicinally acceptable salts of the same, or hydrates or solvates thereof, wherein R is optionally substituted aryl; R1 is hydrogen, optionally substituted alkyl, or the like; R2 is hydrogen, halogeno, or the like; R3, R4, R5 and R6 are each independently hydrogen, halogeno, or the like; X is alkylene, -Z-O-Z1-, or the like; and Y is -O- or -NR8- (wherein R8 is hydrogen, lower alkyl, or halogenated lower alkyl).

Description

Specification

LPL activity enhancer

Technical field

The present invention relates to a novel LPL (lipoprotein lipase) activity enhancer comprising a compound having a 2-phenylbenzimidazole structure or a 2-phenylbenzoxazole structure as an active ingredient, It relates to therapeutic or prophylactic drugs. The present invention also relates to a novel compound having a 2-phenylbenzimidazole structure or a 2-phenylbenzoxazole structure, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

Background art

Conventionally, in arteriosclerotic diseases such as ischemic heart disease, hyperlipidemia is one of the risk factors for diabetes and hypertension. In particular, a number of epidemiological studies have clarified the causal relationship between hypercholesterolemia and ischemic heart disease and have established its position as an independent risk factor. On the other hand, hypertriglyceridemia was considered to be a risk factor, but was considered to be weak as an independent risk factor. This is because, in the case of cholesterol, there is LDL (low density lipoprotein), a typical lipoprotein that works on arteriosclerosis, whereas TG (tridali ceride), a major carrier of chylomicron and VLDL (ultra Low-density lipoprotein) was considered to be because there was no evidence of a contribution to arteriosclerosis. Therefore, cholesterol-lowering drugs have become the mainstay of treatment for hyperlipidemia.

However, recent epidemiological studies (Framingham Study: Am. Heart J., 112, 432, 1986; PROCAM Study: Am. J. Cardiol., 70, 733, 1992; Hels ink i Heart Study: N. Engl. J. Med., 317, 1237, 1987) revealed that hypertriglyceridemia was often present in the development of ischemic heart disease. That is, TG has come to attract attention as one of the independent risk factors. It has also been reported that the risk of developing ischemic heart disease is higher when low HDL (high density lipoprotein) monocholesterol is involved. Therefore, for the treatment or prevention of hyperlipidemia and the like, it is considered important not only to reduce TG but also to positively increase HDL-cholesterol.

By the way, lipid metabolism in a living body is as follows. That is, lipids taken in by the diet are absorbed in the small intestine and secreted into the blood as chylomicrons via lymphatic vessels. The secreted chylomicron is degraded into free fatty acids by the action of LPL (lipoprotein lipase) present in the capillary bed to form chylomicron remnants, which are transmitted to the liver via the chylomicron remnant receptor in the liver. It is captured. Further, in the liver, the incorporated chylomicron remnant and / or free fatty acid is converted into TG or the like by an enzyme such as acyl CoA synthetase, and is associated with apolipoprotein B to form VLDL. Secreted out. The secreted V.LDL becomes IDL (intermediate density lipoprotein) by the action of LPL, is converted to LDL by HTGL (hepatic lipase), and is distributed to peripheral tissues. When chylomicrons and ultra-low-density lipoproteins are converted by the action of LPL, their membrane parts (containing phospholipids and cholesterol as main components) are released as disc-shaped primitive HDL.

Thus, in the metabolism of lipids in the living body, lipoproteins in the blood are continually enzymatically acted upon.In particular, LFL binds to vascular endothelium and is a lipoprotein that is a neutral lipid-rich lipoprotein in the blood. It governs the hydrolysis of micron VLDL TG and is involved in the production of primitive HDL, which is important for cholesterol metabolism.

Recently, when LPL is overexpressed in mice, TG in the blood decreases, HDL-cholesterol increases, cholesterol levels decrease, and sclerotic lesions in the aorta are suppressed. (J.

Biol. Chem., 268, 17924-17929, 1993: J. Biol. Chem., 269, 11417-11424, 1994: Proc. Natl. Acad. Sci. USA, 93, 7242-7246, 1996). This is an important finding indicating the possibility of treating hyperlipidemia through the promotion of LPL activity. As described above, LPL plays an important role in lipid metabolism, and enhances or promotes the activity of LP, that is, promotes the production or release of LPL. By promoting or activating, TG can be reduced and HDL-cholesterol can be increased. Therefore, by increasing the activity of LPL, it is expected that hypertriglyceridemia and low HD L-cholesterolemia will be corrected and the occurrence of arteriosclerosis will be suppressed. Therefore, a compound that enhances or promotes LPL activity will show a low value for a new type of preventive or therapeutic drug for hyperlipidemia or arteriosclerosis, as well as for hypertriglyceridemia and other TGs It is also expected to be used as a therapeutic or preventive drug for diseases (eg, hypothyroidism, Cushing's syndrome, inflammation, nephrotic syndrome, etc.), hypercholesterolemia, and obesity. Recently, reports have been made on compounds having such LPL activity enhancing action.

For example, in modern medical care, Vol. 28, No. 7, pp. 31-317 (1996) and Japanese Patent Application Laid-Open No. 3-68592 (EP 402033), the LPL A carboxylic acid amide derivative such as 4-methoxyethoxyphenylmethyl-N- (4-bromo-12-cyanophenyl) benzamide is disclosed as a compound having an activating action. However, the literature and the publication do not disclose any compounds having a structure such as the compound of the present invention, nor do they mention any suggestion thereof. JP-A-2-76880 (US Pat. No. 5,554,795 and US Pat. No. 5,860,577) discloses 8-tert-butyltinole-7,8-dihydro-15-methyl as a compound capable of enhancing LPL activity. One 6H-pyro [3,2-e] [1,2,4] triazolo [1,5-a] pyrimidine and the like are disclosed. However, the compound in the publication is only described as a therapeutic agent for improving cachexia, and not only a compound having a structure such as the compound of the present invention is disclosed but also a description suggesting this is not found.

In addition, various compounds having a benzimidazole structure or a benzoxazole structure according to the present invention have been reported.

For example, Japanese Patent Application Laid-Open Nos. 56-8368 (GB2053912) and GB2053215 disclose lipids | hypoallergenic effects, such as TG and cholesterol in blood. Benzimidazole derivatives such as 2- (n-pentadecyl) benzimidazole-5-methyl methyl ribonate have been disclosed as compounds having an effect of lowering the concentration of benzene. However, the compound of the publication is characterized in that it has a linear or branched alkyl group having 7 to 2 ° carbon atoms at the 2-position of the benzimidazole ring and one CO OR ¹ at the 5- or 6-position. In addition to the disclosure of a compound having a structure such as the compound of the present invention, there is no description that it has an effect of promoting the activity of LPL, and further, there is no alertness that suggests them.

US Pat. No. 4,714,476 discloses that 2,2-dimethyl-5- [4- (5-monomethyl-1H-benzui) is a compound as an anti-atherosclerotic agent having an effect of increasing HDL and decreasing LDL. Midazono-2-yl) phenoxy] benzimidazo-l-u-2-enofoxy carboxylic acids such as methyl pentanoate have been disclosed. However, the compound disclosed in this publication has a phenoxy group at the 2-position of the benzimidazole ring, and an arnic acid is bonded to the oxygen atom of the phenoxy group. Of course, there is no description of a compound having such a function, or a description that it has an effect of promoting the activity of PL, and further no description that suggests such a function.

Japanese Patent Application Laid-Open No. Hei 2-306916 discloses a compound having a platelet adhesion inhibitory effect useful as a therapeutic or prophylactic agent for arteriosclerosis and the like, and a compound comprising 2- (2-methoxyphenyl) 16_ (triphneolomethyi). Nore) Benzimidazole and benzazonole compounds such as 6-chloro-2- (2- (3-piperidinopropyloxy) phenyl] benzothiazol are disclosed. However, the publication does not disclose a compound having a structure such as the compound of the present invention, but also mentions that it has an action of promoting the activity of LPL, and furthermore, does not disclose any description suggesting them.

Further, WO 99/116162 (US Pat. No. 5,924,332) discloses a compound having an antibacterial activity such as 6-amidino-2- [3- (4-methylphenoxy) phenyl] benzimidazo monole. —Substituted phenyrubenzimidazole has been disclosed. However, the compound disclosed in the publication is located at position 6 of the benzimidazole ring. It is characterized by having a toro group, an amidino group or a cyano group, and it does not disclose a compound having a structure such as the compound of the present invention, and of course does not find any description suggesting that.

EP 1 48431 and Japanese Patent Application Laid-Open No. 60-15676 disclose a compound having an effect on blood pressure and contractility of myocardium as' 2- (2-methoxy41-benzinoleoxy-1-pheninole)- Benzi midazoles such as 5-funoleo mouth venzi midazones are disclosed. However, the publication does not disclose any compound having a structure as in the present invention, nor does it mention any suggestion thereof.

Japanese Unexamined Patent Publication No. 6-510743 (US5446059) discloses a compound useful as a compound useful for the treatment of inflammatory and / or immunoallergic diseases and the like. (1-adamantyl) phenyl] Benzimidazole derivatives such as benzimidazole are disclosed. However, the compound of the publication is characterized by having a substituent on the benzimidazole ring via an oxygen atom, and of course not only disclose a compound having a structure such as the compound of the present invention but also suggesting that. Is not found.

Japanese Patent Application Laid-Open No. H8-501133 (US Pat. No. 5,814,465) discloses 2- [3-—4- [4-methoxyphene) as a compound having a selective inhibitory action on phosphodiesterase type IV. 2) Butoxy] 1-4-Methoxyphenyl] 1 1H-Venzimidazole-5-Rubonic acid and 2- [3- (benzyloxy)-4-methoxyphenyl] -1H-Venzimidazo Potassium mono-resin ethers such as olenoic acid are disclosed. However, the publication does not disclose a compound having a structure such as the compound of the present invention, but does not find any description suggesting this. Japanese Patent Application Laid-Open No. 8-134073 (US Pat. No. 5,563,143) discloses 2- [3- (2-indanyloxy) -14-methoxypheninole] as a compound that suppresses tumor necrosis factor. Cateconoresin ether compounds such as 1 H-benzimidazolone-5-potassolenoic acid have been disclosed. However, the publication does not disclose a compound having a structure such as the compound of the present invention, but also mentions a suggestion thereof. 5, No. 17, pp. 1969—19772 (19995) has selective inhibitor of phosphodiesterase type IV in B ioorganic & Medicinal Chemistry Letters, Vol. As a compound, catechol-benzimidazoles such as 2- [3- (pentinoleoxy) -14-methoxyphenyl] -1H-benzimidazono-5-potassic acid are disclosed. However, there is no mention in the literature of a compound having a structure such as the compound of the present invention, nor is there any description suggesting this.

Japanese Patent Application Laid-Open No. Hei 8-109169 (EP 694535) discloses a compound useful as a tachykinin receptor antagonist. WO 97Z31635 discloses a method for preventing sleep apnea or preventing sleep apnea. As a compound useful for the treatment, WO977333873 discloses a compound useful for the prevention or treatment of interstitial cystitis or urethral syndrome. US Pat. No. 5,552,426 discloses a compound useful for the treatment. Benzimidazole has been disclosed as a compound useful for treating or preventing amyloid peptide-related symptoms. However, these publications do not disclose any compounds having a structure such as the compound of the present invention, nor do they mention any suggestion thereof.

Japanese Unexamined Patent Publication (Kokai) No. 61-65848 (US Pat. No. 4,925,853) discloses 2- (4,1-methoxyphenyl) —4-hydroxy-17 as a compound having 5-lipoxygenase inhibitory activity. Methynobenzimidazonole hydrochloride: Benzimidazoles such as ethanol are disclosed. However, the publication does not disclose any compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof. JP-A-59-2785 (US Pat. No. 4,528,837 and US Pat. No. 4,696,931) discloses 2- (2′-methoxy) as a compound having an effect on myocardial contractility. An imidazole derivative such as 4′-pendinoleoxy-pheninole) -benzimidazole is disclosed. However, the publication does not disclose a compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.

Japanese Patent Application Laid-Open No. Sho 62-471 discloses a compound having an effect on blood pressure and myocardial contraction. For example, 2-arylimidazole derivatives such as 2- (2'-methoxy-4'-benzyloxy-phenyl) -15-methylmercaptobenzimidazole are disclosed. However, the publication does not disclose any compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.

Zechoslo v. Chem. Commun., Vol. 41, pp. 36 28-36 34 (1 978) shows that 2- [5-bromo- 2- (2-cyclobenzyloxy) phenyl] 2-phenylbenzimidazolones such as benzimidazole are disclosed. However, the document does not disclose a compound having a structure such as the compound of the present invention, nor does it mention any suggestion thereof.

WO 98Z50029 discloses compounds such as [4- (1H-benzimidazo-l-5-inolecanolepoxamine) _2_fe-norebenzoinole] methionine tri. I have. However, the publication relates to inhibitors of protein isoprenyltransferase and the oncogene protein Ras or other related small g-proteins, which inhibits pharmacosylation or geranylgeranylation, and discloses their usefulness as LPL activity enhancers. Of course, there is no mention to suggest it. Further, the claims of the publication include, for example, a hydrogen atom and a halogen atom as R, a heterocyclic ring as R ₂ (a covalent bond is defined as L _n ), and a force S and R ₃ as 1 to five § Norekokishi good Ariru group optionally substituted with a substituent such as group, hydrogen atom and halogen atom as a, 1 ^ as an L ₄ one _{_{N (R S) - L s}} -, one L ₄ —0— L _s — and — L ₄ — S (O). — ₂ — L _s — is absent as L ₄ and L _s , and an alkylene group having 1 to 10 carbon atoms is defined as a covalent bond as Z. Particularly, as a specific example of a complex ring, Although a benzoimidazole ring and a benzoxazole ring are described, no examples supporting the use of a compound having a structure such as the compound of the present invention and description of a general production method thereof can be found in the publication. Disclosure of the invention

The present inventors have conducted intensive studies as described above to provide a compound having an activity of enhancing LPL activity, that is, a compound having an activity-enhancing activity such as promoting or activating the production or release of LPL. That is, the present inventors have found a novel compound which can reduce triglyceride and increase HDL-cholesterol and which is useful as a preventive or therapeutic agent for hyperlipidemia or arterial dysplasia, thereby completing the present invention. .

That is, the present invention relates to compounds and medicaments having the LPL activating action shown in the following (1) to (28).

(1) General formula (I)

[Where R is

A linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a linear chain having 1 to 4 carbon atoms Or a branched lower alkoxy group, a cyano group, a nitro group, a carbamoyl group, a carbamoyl group substituted with a linear or branched lower alkyl group having 1 to 4 carbon atoms, and a 2 to 5 carbon atoms Aryl groups which may be substituted with 1 to 4 substituents selected from linear or branched lower alkanoyl groups,

Is

A hydrogen atom;

Selected from a halogen atom, a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms, a carboxy group and a linear or branched lower alkoxy carbonyl group having 2 to 5 carbon atoms. A linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 substituent groups; Aryl group; or

A 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom,

R ₂

A hydrogen atom;

A halogen atom; or

Selected from a halogen atom, a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms, a carboxy group and a linear or branched lower alkoxy carbonyl group having 2 to 5 carbon atoms 1 A linear or branched lower alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 3 substituents,

R ₃ , R ₄ , R ₅ and R ₆ may be the same or different,

A hydrogen atom;

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

Is a cyano group,

X is

A linear or branched alkylene group having 1 to 8 carbon atoms;

-Z Z,-;

— Z _ S— Z! —; Or

I Z—NR ₇ — Ζ, — (where R ₇ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms, and Z and may be the same or different. A straight-chain or branched lower alkylene group having 1 to 4 carbon atoms, or a single bond).

Y is

-0-; or - NR ₈ - (wherein, R ₈ is a hydrogen atom, a linear or branched祆状lower alkyl group having 1 to 4 carbon atoms, or having from 1 to 4 carbon straight or branched C port Gen Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient.

(2) — In general formula (I),

But

A linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a linear chain having 1 to 4 carbon atoms Or an aryl group which may be substituted with 1 to 3 substituents selected from a branched lower alkoxy group, a cyano group, a nitro group and a carbamoyl group;

R]

A linear or branched argyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 hydroxyl groups; or

Is a feninole group,

R ₂ force

A hydrogen atom; or

A halogen atom,

R ₃ and R ₄ may be the same or different,

A hydrogen atom; or

A halogen atom,

But

A hydrogen atom;

A halogen atom;

A straight or branched chain having 1 to 4 carbon atoms; ^ lower alkyl group;

A nitro group; or

Is a cyano group,

R ₆ A hydrogen atom,

X is

A linear or branched alkylene group having 1 to 8 carbon atoms;

--Z-;

One Z-o—;

― Is one Ζ [― ；

One Ζ— S—;

-ΝΗ- Ζ,; or

-Ζ -ΝΗ- (where Z and are as described in (1) above) and Υ is

-0-; or

— LPL activity enhancer according to the above (1), wherein NR ₈ ′-(where R ₈ ′ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms) .

(3) The compound represented by the general formula (I) is

General formula (I,)

(Wherein R, R, R ₂ , R ₃ , R ₅ , R ₆ , X and Y are each as described in the above (1)). The LPL activity enhancer according to 1).

(4) In the general formula (I '),

Length

A linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a linear chain having 1 to 4 carbon atoms Or from branched lower alkoxy, cyano, nitro, and carbamoyl groups A aryl group optionally substituted with 1 to 3 selected substituents,

A straight-chain or branched alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 hydroxyl groups; or

A phenyl group,

R ₂

A hydrogen atom; or

A halogen atom,

R ₃ and R ₄ may be the same or different,

A hydrogen atom; or

A halogen atom,

R ₅

A hydrogen atom;

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

Is a cyano group,

R ₆

A hydrogen atom,

X is

A linear or branched alkylene group having 1 to 8 carbon atoms;

-0- z,-;

One z—o—;

One s-z] one;

One Z—S—;

-NH- Ζ,-; or

-Ζ -ΝΗ- (where Ζ and Ζ, are as described in (1) above), Y is

One o-;

— NR ₈ ′ —where R ₈ , is as described in (2) above,

(3) The LPL activity enhancer according to the above.

(5) The LPL-active 增 potentiator according to the above (4), wherein Y is one NR _e '-(where R _s , is as described in the above (2)).

(6) The compound represented by the general formula (I) is

5—t e r t boutinole 1 2 _ (4—black mouth 1 3—benzinoleoxyphene) Benzi midazo monole;

5-t e rt-Puchinore 2- (4-kuroguchi 3-(2-kuroguchi benzoinoleoxy) fu-nore] Benzimidazolone;

5—t ert—butinole 1—2— [4—black mouth 1—3— (2-methylpentinoleoxy) pheninole] Benzui midazonole;

5-tert-butyl-1-2- [4-chloro-3- (2-cyanobenzyloxy) pheninole] Benzui midazo monole;

5—t e rt—Pininole 1—2— [4—one mouth 3— (2-canolebamoy / rependinoreoxy) feninole] Benzimidazo monole;

5-t e r t -butynole 2 -— [4-chloro-3- (2-methoxybenzinoreoxy) fueni / re] benzimidazonole;

5-tert-butynole 2- [4-black mouth 1-3-[2- (triphnolelomethinole) penzinoleoxy] feninole] benzimidazo monole;

5-tert-butynole 2— [4-Chloro-3-—3— (Trifluoromethionole) Benzinoleoxy] pheninole] Benzimidazolone;

5-ter t-butinone 2 -— [4-one-mouth-one 3 -— [4 -— (tri-no-noreo-methinole) benzyloxy] phenyl] benzii midazo-one:

5-tert-butynole 2- [4-chloro-3- [2- (triphnolelomethinole) benzinoleamino] phenyl] benzimidazonole; ₂ one _[4 - Black mouth - [2- (tri Furuoromechiru) Benjiruokishi] phenylene Le - 5 Hue Nino les benzimidazole;

5-t e rt—butinole 1—2— [4 1 black 1—3—2—funoleo 1—penzinoleoxy] feninole] Benzi midazo 1 / re;

5-tert-butyl-1-2- [4-chloro-3- [2- (trinoleo-methinole) fenii / reoxymethinole] feninole] benzii midazo / re;

5-tert-butyl-2- [4-chloro-1,3- [4-funoleol 2- (trif-noroleol-methyl) penzinoleoxy] pheninole] Benzimidazonole;

2— [4-Chloro—3— [2- (tri-frenoleolomethinole) penzinoleoxy] feninole] 1—5-propylbenzimidazolone;

5-butyl-2- [4-chloro-3- [2- (trifluoromethyl) benzyloxy] pheninole] benzimidazoinole;

5-tert-butyl-1-2- [4-chloro-1--3- (2,4-di (trifluoromethyl) benzyloxy] phenyl] benzimidazole;

5-tert-butynole 2-[4-bromo_ 3 _ [2- (trifunoleo methinole) penzinoleoxy] feninole] benzimidazonole;

5-t er t -butinole 2-[4 -funoleo mouth 3-[2-(trifunoleo mouth methyl) benzinoleoxy] feninole] benzui midazonole;

5-tert-butynole 2- [4-bromo-1-3- [4-fluoro-2- (trif-noreolomethyl) benzyloxy] phenyl] benzimidazonole;

2- [4-chloro-3- (2- (trifluoromethyl) benzyloxy] phenyl] benzimidazo;

2- [4-Chloro-3- [2- (trinoleolomethyl) pendinoleoxy] feninole] 1-5-methinolebenzimidazonole;

5-tert-butyl-1-2- [4-chloro mouth_3- [2- (trifluoromethyl) benzyloxy] phenyl] —1-methylbenzimidazole;

2-[4-—Mouth-one 3— [2 -— (trifluoromethyl) benzyloxy] Nore] I 5—'Echinorenbenzimidazonole;

2— [4-Chloro-3 -— [2- (tri-bnoroleolomethyl) penzinoleoxy] feninole] 1-5—Isopropi zlebenzi midazo monole;

5-tert-butyl-2- [4-chloro-3- (2-nitrate benzoinoleoxy) pheninole] benzii midazo monole;

5—tcr t-butyl-1-2- [3- [2- (trifluoromethyl) benzyloxy] pheninole] benzimidazo-one;

5-ΐ ert-butyl-2- [4-methyl-3- [2 _ (tri-norenomethyl) penzinoleoxy] pheninole] benzimidazole;

5-t e rt-butyl-2-[4-1-3-[2-(trifluoromethyl) pendinoleoxy] feninole] Benzimidazolone;

5—t ert butynole 1—2— [4-chloro-3- (2— (trifnorolelomethinole) benzinoleoxy] pheninole] benzoxazozinole;

5-tert-butyl-2- [4-cyano 3— [2- (trifluoromethyl) pendinoleoxy] pheninole] benzii midazo monole;

5-tert-butyl- 2 _ [2-chloro-5- [2- (triphnorelomethyl) benzyloxy] phenyl] benzimidazonole;

6-tert-butyl-1-2- [4-chloro-3- [2- (triphnolelomethinole) benzyloxy] pheninole] 1-methylbenzimidazolone;

5-t e r t boutinole 1 2-[4-chloro-3-(2-funoreo mouth benzoinoleoxy) feninole] benzui midazonole;

5-tert-butyl-1-2- [4-chloro-3- (2-bromobenzinoleoxy) phenyl] benzimidazonole;

6—t er t-butyl-2-[4-chloro-3 -— [2- (trifnorelomethyl) benzinoleoxy] pheninole] benzoxazozinole:

5-tert-Butyl-2- [3-chloro-5-C2- (trifluoromethyl) pendinoleoxy] pheninole] benzimidazolone; 5-tert-butynole 1-2-[4-black 1-3-[2-(tri-phenolic methinole) phenyloxy] phenyl] benzimidazonole;

5-t e r t-buchinore 1-[4-black mouth 1 3-[2-[2-(tri-no-no-me-no-me-no-no-)] gno] ethoxy] fueno-no] benzii midazono-le;

5-t e r t —butyl 1 2— [4—black mouth 3— (4-fluorobenzinoreoxy) fuinore] benzui midazo mono;

5-t e r t —Pininole 2— [4-Chloro 3— [5-F zleo 1 2— (Trifluoromethinole) Penzinoleoxy] Feninole] Benzi midazo 1;

5-tcrt-butyl-1-2- [4-chloro-1,3- [2- (2- (triphenyl) methyl] phenyl] ethyl] phenyl] benzimidazo;

5-t er Perbutyl 1 2 _ [4-black 1 3-[2-(trifluoromethyl) benzinorechi] feninole] benzimidazonole;

2- [4-chloro-1,3- [2- (trifluoromethyl) benzyloxy] phenyno] -5_ (1,1-dimethylpropyl) benzimidazole;

6-t ert-butynole 4-chloro-2- [4-chloro-3- [2- (trifolenormetinole) penzinoleoxy] feninole] Benzi midazo monole;

5-tert-butynole 2-[4-chloro-2-1- (2- (trifnoreomethine) benzyloxy] phenyl] benzimidazole;

5—t e rt one petit / ray 2-[4—black mouth 3— [4—promo 2— (trinooleolomethinole) benzinoreoxy] phenyl ^^] benzimidazo monole;

5-tert-butyl 2- [2,4-dichroic 5- (2- (triphenylenomethyl) benzinoleoxy] phenyl) benzimidazo;

5-tert-butyl-2- [4-cyano-3- (5-fluoro-2- (trifnorolemethinole) benzinoleoxy] pheninole] benzimidazonole;

5-tert-butynole 1-2-[4-cyano 1-3-[5-fluo-1-2-(tri-fluorenomethyl) penzinoleamino] feninole] benzimidazo / 1;

2— [4—Cyanone 3— [5—Funoleo mouth 1 2— [Phenyl]]-5- (1,1-dimethyl-2-hydroxyxethyl) benz imidazole, the LPL activity enhancer according to the above (1).

(7) A therapeutic drug for hypertriglyceridemia, comprising as an active ingredient the compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(8) A prophylactic or therapeutic drug for hyperlipidemia comprising the compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof as an active ingredient.

(9) A prophylactic or therapeutic drug for arteriosclerotic diseases, comprising as an active ingredient the compound according to any one of the above (1) to (6), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. .

(10) General formula (I ")

(Wherein, R, R ₂ , R ₃ , RR ₆ , X and Y are as described in the above (1), and R is

Selected from a halogen atom, a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms, a carboxy group and a linear or branched lower alkoxy carbonyl group having 2 to 5 carbon atoms 1 A straight-chain or branched alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 substituents;

Aryl group; or

R is A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

A pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(11) The compound according to the above (10), wherein Y is -NH-, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

( 12 is

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, a straight-chain or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a carbon number:! A phenyl group substituted by 1 to 2 substituents selected from 1 to 4 straight-chain or branched lower alkoxy groups, cyano groups, nitro groups and carbamoyl groups; and 1 to 3 hydroxyl groups. A linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted,

R ₅ 'force ^s

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms; or

Is a cyano group,

X is

-ο-ζ,-；

-s-ζ,-; or

(11) The compound according to the above (11), wherein the compound is (i) NH-Zi- (where, Z is a linear or branched lower alkylene group having 1 to 4 carbon atoms or a single bond), or a medicament thereof. Or a hydrate or solvate thereof.

(1 3) R ₂ , R ₃ and R ₆ are hydrogen atoms, and R ₄ is a hydrogen atom or a halogen atom The compound according to (12), a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof.

(14) R is a phenyl group substituted with one or two substituents selected from a halogen atom, a methyl group, a cyano group, a carbamoyl group, a methoxy group, a trifluoromethyl group, and a nitro group. A certain compound according to the above (13), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(15) R is an isopropyl group, a tert-butyl group, a 1,1-dimethylpropyl group or a 1,1-dimethyl-12-hydroxyxethyl group, and R ₅ ′ is a halogen atom, a methyl group or a cyano group. And R is 2— (trifluoromethyl) phenyl group, 3— (trifluoromethyl) phenyl group, 41- (trifluoronorethynole) phenyl group, 2-phenylene 6— (Trinooleolomethinole) Phenyl group, 4-funoleol 2- (triphenylolemethinole) Phenyl group, 4-bromo-2- (trif / leolomethyl) phenyl group, 2 The compound according to the above (11), which is a 4,4-di (trifluoromethyl) phenyl group or a 5-fluoro-2- (trifluoromethyl) phenyl group, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(16) R is 2 _ (trifluoromethyl) phenyl group, 4-phenolole 2-(triphenylolemethinole) phenyl group or 5-phenolyl _ 2-(trifluoromethyl) ) The compound according to the above (15), which is a phenyl group, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(1 7) 5-tert-butynole 2-[4-chloro-3- (2-chlorobenzenole) feninole] benzimidazonole;

5-tert butinolay 2-[4-black one 3-(2-methinolebenzyloxy) feninole] Benzi midazonole;

5-tert-butyl-1-2- [4-chloro-3- (2-cyanobenzyloxy) pheninole] benzimidazonole;

5-tert-butynole 2- [4-chloro-one 3- (2-force rubamoinolebenzyloxy) feninole] benzimidazole; 5-tert-butyl-2-[4 _ black mouth _ 3-(2-methoxypenzinoreoxy) feninole] Benzi midazonole;

5—t ert—Pininole 2 — [— Chloro_3— [2— (Trifunoleo methinole) Benzinoleoxy] pheninole] Benzimidazole;

5-tert-butyl-2- [4-chloro-3- [3- (trifluoromethyl) benzyloxy] pheninole] benzimidazole;

5-tert-butyl 2--[4-one mouth 3-[4-(trifluoromethyl) benzizureoxy] feninole] benzimidazono:

5-tert-butynone 2-[4-one-mouth 3- 3- [2- (trifluoromethyl) benzinoleamino] phenyl] benzimidazono;

5-tert-butynone 2- [4-chloro-3- [2-funoleo-6- (trif / reolomethyl) benzyloxy] pheninole] Benzi midazonole;

5-tert-butyl-1-2- [4-chloro-1-3- [2- (methyl trifnoreo) phenyloxymethinole] feninole] Benzui midazonole;

5-ter t 1-2-[4-black 1-3-4-funoreo 1-(trino oleolomethinole) Benzinoleoxy] feninole] Benzi midazo / 1;

2— [4-Chloro-3 -— [2- (trifluoromethyl) penzinoleoxy] phenylinole] — 5-propinolebenzi midazonole;

5—Pininole 1—2—4—Black 1—3—2— (Tri-Fonoleolomethinole) Benzinoleoxy] Feninole] Benzi Midazo—

5-tert-Butinolay 2-[4-Krollo 3-[2,4-G (tri-Fnoleo mouth Mechinore) Penzinoleoxy] feninole] Benzi midazonole;

5-tert-butynole 2-[4-bromo-3- (2-triphenylenoleoxymethyl) benzinoleoxy] pheninole] benzimidazonole;

5-tert-butyl-1-2- [4-fluoro-3- [2_ (trifluorometinole) penzinoleoxy] pheninole] benzii midazonole;

5-tert-butyl-2-[4-bromo-3-[4-phenololeol 2-(triflic ノレロメチノレ) Benzinoleoxy] Feninore] Benzimidazo monole;

2-[4-1-3-[2-(tri phneololomethyl) benzyloxy] phenyl] — 5-methinolebenzimidazonole;

5-t e rt—butinole 1—2— [4 1-black mouth 3— [2— (tri-funoleo methinole) benzyloxy] feninole] _1-methinolebenzi midazo 1;

2-[4-Chloro-3- [2- (trifluoromethyl) benzyloxy] pheno] 1 5-ethinolebenzimidazonole;

2-[4-1 _ 3-[2-(Trifluoromethinole) benzyloxy] feninole] 1-5-isopropinolebenzimidazole;

5-tert-butynole 2- [4-chloro-3- (2-2-pentopeninoleoxy) phenyl] benzimidazole;

5-tert-butyl-1-2- [4-methynole-3- [2- (trifluoromethylinole) benzinoleoxy] pheninole] benzimidazo-one;

5-tert-butyl-1-2-[4-3-[2-(trifluoromethylinole) pendinoleoxy] feninole] benzimidazonole;

5-tert-butyl-1-2- [4-chloro-1-3- [2- (methyl triphenylenobenzo) benzinoleoxy] pheninole] benzoxazozinole;

5-tert-Puchinore 2-[4-Cyanore 1-3-[2-(Trifluoromethinole) Penzinoleoxy] feninole] Benzimidazonole;

5—t e rt—butynole 2— [2-black mouth 5— [2— (tri fenoleo mouth methinole) penzinoleoxy] feninole] benzii midazonole;

6-t ert—butynole 2— [4—black mouth 3— [2— (trifluoromethyl) benzyloxy] pheninole] _1-methinolebenzi midazo;

5-t e r t -Pininole 2-[4-Chloro-3- (2-benoloxy) feninole] Benzimidazole;

5-tert-butyl-1-[4-chloro-3-(2-bromobenzinoleoxy) pheninole] benzi midazonole; 6-tert-petit / ret 2-[4-trimethyl-3- (2- (triphenol) methoxy] benzyloxy] pheninole] benzoxazozo;

5-tcrt-butyl-1-2- [3-chloro-1--5- [2- (trifluoromethyl) benzyloxy] pheninole] benzimidazonole;

5-tert-butyl 2- [4-chloro-one 3- [2- (trinoleo-methinole) pheninoleoxy] feninole] benzimidazo-one;

5-tert-butynole 2-[4-chloro-3- [2- [2- (trifnoreomethyl) phenyl / re] ethoxy] phenyl] benzimidazole;

5-t e r t -Pininole 1-2-[4-1 mouth 3-(4-Funoleo mouth penzinoreoxy) Feninole] Benzi midazonole;

5-tert-butyne 1-[4-chloro-3-] [5-funoleo-l- 2- (trif-norolelomethinole) penzinoleoxy] feninole] benzimidazonole;

5-t er t—butinole 2— [4—black mouth 3 _ [2— [2— (tri fenoleo mouth methyl) feninole] chininole] feninole] benzui midazonole;

5-tert-butynole 2-[4-black mouth 3-[2-(trifunoleo mouth methinole) benzylthio] feninole] benzimidazonole;

2— [4—Black mouth 1—3— [2- (Trifluoromethinole) benzyloxy] phenynole] — 5— (1,1-Dimethinolepropinole) Benzi midazonole;

6-tert-butynole 4-chloro-2- [4-chloro-3- (2- (trifnorolemethinole) penzinoleoxy] phenyl benzimidazonole;

5-ter ΐ -butynole 1-[4-Bromo 3-[4-bromo-2 _ (trifnorolemethinole) penzinoleoxy] feninole] Benzimidazonole;

5-t er t butylinole 2 -— [2,4-dichloro-5- [2- (trifnorolemethyl) penzinoleoxy] bueninole] benzimi.dazoinole;

5-tert-butyl-2- [4-cyano-3- [5-fluoro-2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole;

5-tert-butinolay 2-[4-cyano 3-[5-phenololeol 2-(trif Norelomethyl) penzinoleamino] feninole] benzii midazonole; and

2— [4—Cyanone 3— [5—Funoleo 1—2- (Trifluoromethyl) benzyl] phenyl] _5— (1,1-Dimethyl_2-Hydroxitytyl) Benzimidazole The selected compound according to (10), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(1 8) 5-tert-Petite / Lae 2— [4-Cro-one 3— [4-Fenoleo _ 2— (Triphnorelomethyl) benzyloxy] phenyl] Benzimidazonole;

5-tert-butyl-2- [4-bromo-1-3- [2- (methyl methyl trypnole) pendinoleoxy] pheninole] benzimidazo monole;

5-t e r t boutinole 1 2-[4-black mouth 3-[2-(trifnoreo mouth methinole) benzinoleamino] feninole] benzimidazonole;

5—t e r t —Finolone 2— [4—Black Mouth 3— [5—Funoleo Methylone 2— (Trif Norrelomethinole) Penzinoleoxy] Feninole] Benzi Midazonole;

5-tert-butyl-1-2- [4-cyano-3-[5-fluoro-2 _ (trif-noreolomethinole) penzinoleoxy] phenyl] benzimidazo-one;

5-tert-putinole 1-2-[4-cyano 1-3-[5-phneoreomethyl 1-2-(triphenylenolomethyl) benzylamino] phenyl] benzymidazonole; and

2— [4—1 cyano 1—3— [5—Funoleomethinole 2— (Trifnorolelomethinole) Benzinoleoxy] Phenyl] 1—5— (1,1, Dimethinole 2—Hydroxityl) Benzimidazole The compound according to the above (10), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(19) A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of (10) to (18), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

(20) A method for enhancing LPL activity, comprising administering an effective amount of the compound according to any one of (1) to (6).

(21) A method for treating hypertriglyceridemia, comprising administering to a patient an effective amount of the compound according to any one of (1) to (6). (22) A method for preventing or treating hyperlipidemia, comprising administering to a patient an effective amount of the compound according to any one of (1) to (6).

(23) A method for preventing or treating arteriosclerotic diseases, comprising administering to a patient an effective amount of the compound according to any one of (1) to (6).

(24) Use of the compound described in any one of (1) to (6) above for producing an LPL activity enhancer. .

(25) The method according to (1) to above, for producing a therapeutic agent for hypertriglyceridemia.

Use of the compound described in any of (6).

(26) Use of the compound described in any one of (1) to (6) above for producing a prophylactic or therapeutic drug for hyperlipidemia.

(27) Use of the compound according to any one of the above (1) to (6) for producing a prophylactic or therapeutic drug for atherosclerotic disease.

(28) The LPL activity enhancer according to any one of the above (1) to (6) and at least one of the hypertensives are at least one of hypertriglyceridemia, hyperlipidemia, and arteriosclerotic disease Commercial package containing documentation stating that it can or should be used for therapy.

Detailed description of the invention

Here, “a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms” means an alkyl group having 1 to 4 carbon atoms which may be straight-chain or branched. It means, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group.

“A straight-chain or branched alkyl group having 1 to 6 carbon atoms” means an alkyl group having 1 to 6 carbon atoms which may be straight-chain or branched. Specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1,1-dimethylpropyl, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl, hexyl group and the like. "A linear or branched lower alkylene group having 1 to 4 carbon atoms" means an alkylene group having 1 to 4 carbon atoms which may be linear or branched, Specific examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a propylene group, an ethylethylene group, and a dimethylmethylene group.

"A linear or branched alkylene group having 1 to 8 carbon atoms" means an alkylene group having 1 to 8 carbon atoms which may be linear or branched, Specific examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, an octamethylene group, a propylene group, an ethylethylene group, a dimethylmethylene group, and a dimethyltrimethylene group.

"Halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

"A straight-chain or branched halogenated lower alkyl group having 1 to 4 carbon atoms" means 1 to 3 straight-chain or branched lower alkyl groups having 1 to 4 carbon atoms. The same or different halogen atoms (described above) are substituted. Specifically, it is a fluoromethyl group, a chloromethyl group, a bromomethyl group, a difluoromethyl group, a dichloromethyl group, a trifluoromethyl group, a trichloromethyl group. Chloroethinole group, diphnoleolotineol group, triflenolelotinele group, pentachloroethenole group, bromopropinole group, dichloropropyl group, trifluorobutyl group and the like.

"A straight-chain or branched lower alkoxy group having 1 to 4 carbon atoms" means the alkoxy group having a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms described above. Specific examples include a methoxy group, an ethoxy group, a propoxy group, an i.sopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, and a tert-butoxy group.

"A carbamoyl group substituted by a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms" means a straight-chain or branched-chain having 1 to 4 carbon atoms as defined above for a carbamoyl group. Lower alkyl group is the same or different and is substituted by 1 or 2 lower alkyl groups, specifically, methylcarbamoyl group, ethynolecanolebamoyl group, propylcanolebamoyl group, isopropynolecarbamoinole group, Butinorecanorebamoinole group, Isobutinorecanolebamoinole group, sec —butylcarbamoinole group, tert —Butilecanolebamoyl group, dimethylca Norebamoyl group, getylcarbamoyl group, dipropyl-lubamoyl group, diisobutyl-l-pyruvamoyl group, dibutylcarbamoyl group, diisobutylphenylcarbamoyl group, di-sec-butylcarbamoyl group, di-tert-butylcarbamoyl group, N-ethylethyl-N —Methylcarbamoyl group, N-methyl-N-propylcanolebamoyl group, N-ethyl-N-propylcaproluvamoyl group and the like.

"A straight-chain or branched lower alkanoyl group having 2 to 5 carbon atoms" means an alkanoyl group having 2 to 5 carbon atoms which may be straight-chain or branched, Specific examples include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and vivaloyl groups.

“A straight-chain or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” means an alkoxycarbonyl group having 2 to 5 carbon atoms which may be straight-chain or branched. And specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, and a tert-butoxycarbonyl group. And the like.

“Aryl group” includes phenyl, naphthyl, biphenyl and the like.

“A 5- to 6-membered heterocyclic group having 1 to 3 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom” means 1 to 3 selected from an oxygen atom, a nitrogen atom or a sulfur atom A 5- or 6-membered aromatic or non-aromatic heterocyclic group having the following heteroatoms, specifically, oxadiazolyl, thiadiazolyl, triazolyl, oxazolyl, imidazolyl, pyrazolyl, and thiazolyl groups. , A pyrrolyl group, a furyl group, a phenyl group, a triazinyl group, a pyrazyl group, a pyridazinyl group, a pyrimidinyl group, an aromatic heterocyclic group such as a pyridyl group, etc .; , Thiadiazinyl, morpholino, morpholinyl, oxazinyl, thiazinyl, piperazinyl, piperidyl Piperidino group, Biraniru group, a like non-aromatic heterocyclic group such as Chiopiraniru group. Hereinafter, the present invention will be described in more detail, but is not necessarily limited to the following. The “aryl group” for R is preferably a phenyl group.

As the substituent of the aryl group in R, "a linear or branched lower alkyl group having 1 to 4 carbon atoms" is preferably a methyl group or an ethyl group, particularly preferably a methyl group.

As a substituent of Ariru group "linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms" of R, preferred substituents for Ariru group in _c R is a triflate Ruo b methyl The “halogen atom” is preferably a fluorine atom, a chlorine atom or a bromine atom, and particularly preferably a fluorine atom.

The straight-chain or branched lower alkoxy group having 1 to 4 carbon atoms, which is a substituent of the aryl group in R, is preferably a methoxy group or an ethoxy group, particularly preferably It is a methoxy group.

As the substituent of the aryl group in R, the "carbamoyl group substituted with a linear or branched lower alkyl group having 1 to 4 carbon atoms" is preferably a methylcarbamoyl group, an ethylcarbamoyl group or a dimethyl group. It is a carbamoyl group.

The “linear or branched lower alkanoyl group having 2 to 5 carbon atoms” which is a substituent of the aryl group in R is preferably an acetyl group.

As the "may be substituted with 1 to 4 substituents" of the aryl group in R, it is preferable that the aryl group may be substituted with 1 to 2 substituents.

The substituent of the aryl group in R is preferably a methyl group, a fluorine atom, a chlorine atom, a bromine atom, a trifluoromethyl group, a methoxy group, a cyano group, a nitro group or a rubamoyl group. It is an orthomethyl group or a fluorine atom.

Preferred are a phenyl group, a 2-chlorophenyl group, a 2-fluorophenyl group, a 2-bromophenyl group, a 4-phenololenophenyl group, a 2-methynolephenyl group, a 2-cyanophenyl group, 2-carbamoylphenyl, 2-methoxyphenyl, 2-nitrophenole, 2- (trinoleolomethinole) pheninole, 3-(triphenylolenomethinole) phen Dinore group, 4 1 (tri-noreolometinole) feninole Group, 2-phenololeol 6-(trinoleolomethynole) phenyl group, 4- phenole 1-(trifluoromethyl) phenyl group, 2,4-di (trinoleolomethyl) phenyl group, 5 —Fluoro-2 -— (trifluoromethyl) phenyl group or 4-bromo-2- (trifluoromethyl) phenyl group, particularly preferably 2- (trifluoromethyl) phenyl group, 4-fluoro-2 -— (trifluoro Phenyl) or 5-fluoro-2- (trifluoromethyl) phenyl.

The “straight or branched alkyl group having 1 to 6 carbon atoms” in 1 ^ is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group or a 1,1- It is a dimethylpropyl group, particularly preferably an isopropyl group, a tert-butyl group or a 1,1-dimethylpropyl group.

The “halogen atom” which is a substituent of the alkyl group in R 1, is preferably a fluorine atom or a chlorine atom.

The “linear or branched lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the alkyl group in is preferably a methoxy group or an ethoxy group.

The “linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” which is a substituent of the alkyl group in the above is preferably a methoxycarbonyl group or an ethoxycanoleboninole group.

As the “optionally substituted with 1 to 3 substituents” of the alkyl group for R 1, it is preferable that the alkyl group may be substituted with 1 substituent.

The substituent of the alkyl group in R 1 is preferably a hydroxyl group or a carboxy group.

In the above, the “aryl group” is preferably a phenyl group.

In the above, the "5- to 6-membered heterocyclic group having 1 to 3 complex atoms selected from oxygen atom, nitrogen atom and sulfur atom" is preferably a pyridyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group A pyrazolyl group, a morpholino group, a morpholinyl group, a piperazinyl group, a piperidino group, a piperidyl group or a pyrrolidinyl group. R is preferably a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a 1,1-dimethylpropyl group, a 1.1-dimethyl-2-hydroxyshethyl group or A phenyl group, particularly preferably an isopropyl group, a tert-butyl group, a 1,1-dimethylpropyl group, or a 1,1-dimethyl-2-hydroxyxethyl group.

As the “linear or branched alkyl group having 1 to 6 carbon atoms” for R, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group or a 1,1-dimethyl group And a propyl group, particularly preferably an isopropyl group, a tert-butyl group or a 1,1-dimethylpropyl group.

The “halogen atom” which is a substituent of the alkyl group in the above, is preferably a fluorine atom or a chlorine atom,

The “linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” as a substituent of alkyl S in the above is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

As the "optionally substituted with 1 to 3 substituents" of the alkyl group for R 1 and ', it is preferable that the alkyl group may be substituted with 1 substituent.

The substituent of the alkyl group in R is preferably a hydroxyl group or a carboxyl group.

In the above, the “aryl group” is preferably a phenyl group.

As the "5- to 6-membered heterocyclic group having 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur atoms" for R and ', preferably a pyridyl group, a thiazolyl group, an oxazolyl group, or a A midazolyl group, a pyrazolyl group, a morpholino group, a morpholinyl group, a piperazinyl group, a piperidino group, a piperidyl group or a pyrrolidinol group.

R is preferably methyl, ethyl, propyl, isopropyl A butyl group, a tert-butyl group, a 1,1-dimethylpropyl group, a 1,1-dimethyl-2-hydroxyshethyl group or a phenyl group, particularly preferably an isopropyl group, a tert-butyl group, It is a 1-dimethylpropyl group or a 1,1-dimethyl-12-hydroxyl group.

The “halogen atom” for R ₂ is preferably a chlorine atom.

The “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R ₂ is preferably a methyl group or an ethyl group.

The “halogen atom” as a substituent for the lower alkyl group in R ₂ is preferably a fluorine atom or a chlorine atom.

The “linear or branched lower alkoxy group having 1 to 4 carbon atoms” as a substituent of the lower alkyl group for R ₂ is preferably a methoxy group or an ethoxy group.

The “linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms” as a substituent of the lower alkyl group for R ₂ is preferably a methoxycarbonyl group or an ethoxycarbonyl group.

As the “may be substituted with 1 to 3 substituents” of the lower alkyl group for R _{2, it} is preferable that the lower alkyl group may be substituted with 1 substituent.

The substituent of the lower alkyl group for R ₂ is preferably a hydroxyl group or a carboxy group.

R ₂ is preferably a hydrogen atom or a chlorine atom.

The “halogen atom” in R ₃ , R ₄ , R _s or R ₆ is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, particularly preferably a chlorine atom or a bromine atom.

The “linear or branched lower alkyl group having 1 to 4 carbon atoms” in R ₃ , R _s or R ₆ is preferably a methyl group.

The “linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms” in R ₃ , R ₄ , R ₅ or R ₆ is preferably a trifluoromethyl group. The R _3, R have R _s or R _e, is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a nitro group or a Shiano group.

Here, specifically, R ₃ is particularly preferably a hydrogen atom or a chlorine atom. R is particularly preferably a hydrogen atom or a chlorine atom. R ₅ is particularly preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a nitro group or a cyano group, and more preferably a chlorine atom, a bromine atom or a cyano group. R ₆ is particularly preferably a hydrogen atom.

The “halogen atom” in R _s ′ is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and particularly preferably a chlorine atom or a bromine atom.

The “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R ₅ ′ is preferably a methyl group.

The “linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms” for R ₅ ′ is preferably a trifluoromethyl group.

R ₅ ′ is preferably a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, a nitro group or a cyano group, and particularly preferably a chlorine atom, a bromine atom or a cyano group.

The “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R ₇ is preferably a methyl group.

R ₇ is preferably a hydrogen atom.

The “linear or branched lower alkylene group having 1 to 4 carbon atoms” in Z or is preferably a methylene group or an ethylene group.

The “linear or branched alkylene group having 1 to 8 carbon atoms” in X is preferably an ethylene group.

As "linear or branched lower alkyl group having 1 to 4 carbon atoms" in R _B, is preferably a methyl group.

The “linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms” for R ₈ is preferably a chloromethyl group or a trifluoromethyl group. The “linear or branched lower alkyl group having 1 to 4 carbon atoms” for R ₈ ′ is preferably a methyl group.

More specifically, in the general formula (I) (or the general formula (1 ")), as X-R, a 2- (trifluoromethyl) benzyloxy group or a 4-fluoro-1--2 (Triphenylolemethinole) benzinoleoxy group, 5-funoleoleol 2- (trifluoromethyl) benzyloxy group, 2- (trifluoromethyl) benzylamino group is a tert-butyl group as R] (or R), 1.1 —Dimethyl 2 —Hydroxyshetyl group, R ₂ , R ₃ , R ₄ and R ₆ are hydrogen atoms, R _E (or R ₅ ) is chlorine, bromine or cyano group, and Y is one. NH— is most preferred.

In the present invention, the compound represented by the general formula (I) includes a known compound, and is preferably a compound represented by the general formula (1 ′). Among the compounds represented by the general formula (I), the compound represented by the general formula (Γ ') is a novel compound. Therefore, in the present specification, the term “compound represented by the general formula (I)” refers to a compound represented by the general formula (I)

(I ′) and the compound represented by the general formula (1 ″) are also included.

In the present invention, “: LPL activity is high” means that LPL activity is enhanced or promoted, and more specifically, LPL production or release is promoted, activated or its activity is sustained. I do.

The “pharmaceutically acceptable salt” may be any salt that forms a non-toxic salt with the compound represented by the above general formula (I). Examples thereof include hydrochloride and hydrogen bromide. Inorganic acid salts such as acid salts, hydroiodide salts, sulfates, nitrates, phosphates, carbonates, bicarbonates, and perchlorates; formates, acetates, trifluoroacetates, propionates, and oxalates Acid, glycolate, succinate, lactate, maleate, hydroxymaleate, methylmaleate, fumarate, adipate, tartrate, lingate, citrate, benzoate Organic acid salts such as acid salts, silicates, ascorbates, salicylates, 2-acetoxybenzoates, nicotinate, isonicotinate; methanesulphonate, ethanesulphonate, isethione Salt, benzene Sulfonates, p-sulfonates such as toluenesulfonate and naphthalenesulfonate; acidic amino acids such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; magnesium Alkaline earth metal salts such as salts and calcium salts; ammonium salts; organic bases such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N, Ν'-dibenzylethylenediamine salts Salts; examples include amino acid salts such as lysine salts and arginine salts. In some cases, it may be a hydrate or a solvate with an alcohol or the like.

INDUSTRIAL APPLICABILITY The compound of the present invention has an excellent LPL activity enhancing action, and is expected as a novel type of preventive or therapeutic agent for hyperlipidemia or arteriosclerotic disease.

When the compound of the present invention represented by the general formula U), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is used as a pharmaceutical preparation, a pharmaceutically acceptable carrier known per se is usually used. Excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffering agents, emulsifiers, fragrances, coloring agents, sweeteners, thickeners, corrigents, solubilizing agents, other additives, Specifically, carbohydrates such as water, vegetable oil, phenolic alcohol such as ethanol or benzyl alcohol, polyethylene glycol corn, glycerol triazetate gelatin, lactose, starch, etc., magnesium stearate, talc, lanolin, Tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, and pills mixed with petrolatum, etc. Sill, suspensions, emulsions, can be administered orally or parenterally depending on the form of such syrups. The compounds of the present invention can be used not only as human medicines but also as animal medicines.

The dose may vary depending on the type and degree of the disease, the compound to be administered, the administration route, the age, sex, weight and the like of the patient. In the case of oral administration, the compound (I) per adult per day is usually 1 to: It is preferred to administer 100 mg, especially 50 mg to 800 mg.

Production method The compound of the present invention can be produced, for example, by the following method, but it goes without saying that the method of producing the compound of the present invention is not limited thereto.

R ₁₀ is water »group, merbut group, -NHR _T

ω (Process 1)

This step is for introducing a protecting group into the carboxy group, and may be carried out as needed. The method is not particularly limited as long as it is a commonly used method. For example, the compound (III) R ₁₀ is a hydroxyl group, a mercapto group, (wherein, 1¾ ₇ are as described above) one NHR _7, a halogen atom or one CHO, R "is methylcarbamoyl group, a carboxy protecting group such as Echiru group or Ariru group Wherein R ₃ , R ₄ , RR _c and Z are as described above] is the compound (II) (wherein R ₃ , R ₄ , R _s , R ₆ , R, and Z are as defined above) the presence of an acid of the a) or the like sulfuric acid, hydrochloric acid, p- toluenesulfonic acid as a R _u OH (Shiki屮and R _u are defined as above), benzene optionally The reaction can be carried out in an organic solvent such as toluene or toluene or a mixed solvent thereof at room temperature or under heating.

(Process 2)

This step, R ,. There hydroxyl group, a process which we used when a mercapto group or one NHR _7, i.e., the compound (IV) _{_{(wherein, R, R 3, R 4}} , R 5, R 6, R u及beauty X is As described above) is a compound (III) wherein There hydroxyl, mercapto group or one NHR ₇ (where, R ₇ is as defined above) and, R _3, R _4, R have R _6, R _u and Z are as defined above] with the compound R ₁₂ — Ζ, — R (where R, ₂ are halogen atoms and R and Z, are as described above) and potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride, etc. The reaction is carried out under cooling or heating in an organic solvent such as dimethylformamide, acetone or toluene or a mixed solvent thereof in the presence of a base, or particularly when the compound (III) is used. Is a hydroxyl group, and the compound R ₁₂ — — When R ₁₂ of R is an iodine atom, pyridine or the like is added as necessary in the presence of a base such as potassium carbonate, and copper chloride or copper bromide is added. Dimethylformamide, toluene, dimethylsulfoxide, or other organic solvents, or a mixture thereof or without solvent, at room temperature or under heating with a catalyst such as copper iodide. Can be.

Also, R, of the compound (III). When is a hydroxyl group or a mercapto group, the compound (IV) is a compound of the formula (III) and the compound HO— — R (where R and Z are as defined above) Ether, tetrahydrofuran, dioxane, dichloromethane, dichloromethane, dichloromethane, clog form, benzene, toluene, dime It can also be synthesized by reacting in an organic solvent such as chillformamide or a mixed solvent thereof under cooling or heating.

Further, the compound (III) If a guard NHR _7, the compound (IV) is, I匕合compound (III) with the compound OHC- - R (wherein, R and Z _t are the aforementioned toe ) In an organic solvent such as dimethinoleformamide, dioxane, toluene, dimethylsnoreoxide, methanol, ethanol, or a mixture thereof, and then sodium borohydride, sodium borohydride, and hydrogen hydride. Organic solvents such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropinoleanolone, dimethoxetane, and toluene in the presence of reducing agents such as lithium borohydride, lithium aluminum hydride, trimethylsilane, and triethylsilane; It can also be synthesized by reacting in a mixed solvent under cooling or heating.

The above step 2 is X is - Z- O- Z, -, - Z- S- - and single Z- NR ₇ - - is particularly useful for synthesizing the compound (IV) is.

(Process 3)

This process involves: Is a step used when is a halogen atom, that is, the compound (IV) (wherein R, R ₃ , R ₄ , R ₅ , R ₆ , R „and X are as defined above) compound (III) (wherein, R,. is a halogen _{_{atom, R 3, R 4, R}} 5, R 6, R u and Z are as defined above) with a compound R ₁₃ - Z, - R [Wherein, R ₁₃ is a hydroxyl group, a mercapto group or one NHR ₇ (where R ₇ is as described above), and R and ₁ are as described above], and potassium carbonate, A compound capable of reacting under cooling or heating in an organic solvent such as dimethylformamide, acetone, toluene or a mixed solvent thereof in the presence of a base such as sodium carbonate, sodium hydrogen carbonate, sodium hydride or the like. III) and the compound R _l2 — 一 (wherein R and are as defined above) with tetrakis (triphene) Nylphosphine) In the presence of a catalyst such as palladium or bis (triphenylphosphine) palladium chloride, zinc or the like, in an organic solvent such as dimethoxetane, ether, tetrahydrofuran or a mixed solvent thereof under cooling or heating. It can be synthesized by reacting below.

(Process 4)

This process involves: Is the process used when is one CHO, that is, The compound (IV) (wherein R, R ₃ , R „, R ₅ , R ₆ , R„ and X are as described above) is a compound (III) (where R ₁₀ is is _{_{CHO, R 3, R 4,}} R s, R 6, R u and Z are as defined above) with a compound R ₇ HN- Z] in one R (wherein, R, R ₇及Pi is the aforementioned With dimethylformamide, dioxane, toluene, dimethylsulfoxide, methanol, ethanol and the like, or a mixed solvent thereof, and then sodium borohydride, sodium borohydride cyanide, hydrogen In the presence of reducing agents such as lithium borohydride, lithium aluminum hydride, trimethylsilane, and triethylsilane, methanol, ethanol, ether, dioxane, tetrahydrofuran, diinpropyl alcohol, dimethoxyethane, toluene, etc. Organic solvent or a mixed solvent thereof, in cowpea to react under cooling to under heating can be synthesized.

Since the above-mentioned step 4 is X is _Z- NR ₇ - is particularly useful for synthesizing the compound (IV) is a - Z _t.

(Process 5)

The compound (V) (wherein R, R ₃ , R ₄ , R _s , R ₆ and X are as described above) is obtained by preparing the compound (IV) (wherein R, R ₃ , R ₄ , R _s , R _e , R, and X are as described above), and sodium hydroxide, sodium hydroxide, sodium carbonate, carbonate base, etc. or hydrochloric acid, hydrobromic acid, etc. Organic solvents such as methanol, ethanol, tetrahydrofuran, dioxane, dimethoxetane, aethenole, diisopropinoleether, and ethylene glycol, water or a mixed solvent or a non-solvent thereof in the presence of It can be synthesized by reacting under cooling or heating.

(Step 6)

The compound (VI) (wherein R ₁₄ is a halogen atom, and R, R ₃ , R ₄ , R ₅ , R ₆ and X are as described above) is a compound (V) (wherein , R, R ₃ , RR _s , R ₆ and X are as described above) in the presence of an acid halide agent such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, etc. Organic solvents such as black form, dimethylformamide, dichloromethane, toluene, pyridine, etc. It can be synthesized by reacting in a mixed solvent under cooling or heating.

In the case of compound (V) in which X is —Z—NH—Z, —, the compound is protected by an amino-protecting group such as a benzyloxycarbonyl group or an acetyl group by a conventional method, and then subjected to this step. Can be synthesized. In addition, after performing the following step 7, the amino protecting group can be removed by a conventional method as necessary.

(Step 7)

Compound (VIII) (wherein, R ₁₅ is an amino group, a hydroxyl group or a nitro group protected by an amino protecting group such as tert-butoxycarbonyl, and R, R, R ₂ , R ₃ , R ₄ , R _s , R ₆ , R ₈ and X are as defined above, and compound (VI) (wherein R, R ₃ , R or R _s , _RG , _RM and X are as defined above) and Compound (VII)

(Wherein, R, R ₂ , R _s and R _1S are as described above), and in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylbiperidine, and the like, dichloromethane, The reaction is carried out under cooling or heating in an organic solvent such as Tonolen, Athenole, Tetrahydrofuran, Dishkisan, Diisopropylether, Dimethoxetane, Hexane, etc. or in a mixed solvent or without solvent, under cooling or heating. Can be synthesized.

(Step 8)

Compound (I) _{(wherein, R, R ,, R 2,} R 3, R, R s, R 6, X and Y are been as described above for) the compound (VIII) (wherein, R, R, R ₂ , R ₃ , R ₄ , R _s , R ₆ , R _e , R _1S and X are as described above), and tin chloride, zinc, iron, sodium nitrite, sodium sulfide, sodium sulfide, In the presence of a reducing agent such as sodium disulfide, etc., use ammonium chloride, hydrochloric acid, etc., as necessary, with ethyl acetate, acetic acid, methanol, ethanol, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxetane, toluene, etc. The reaction is carried out under cooling or heating in an organic solvent, water or a mixed solvent thereof or in a solvent-free condition, and if necessary, then benzene, tonylene and benzene, in the presence of an acid such as hydrochloric acid, acetic acid or p-toluenesulfonic acid. , Xylene, methanol, Data It can be synthesized by reacting under heating in an organic solvent such as knol, a mixed solvent thereof, or no solvent. This method is particularly effective when R _1S is a nitro group. In particular, when R _1S is a protected amino group or hydroxyl group, compound (VIII) is converted to methanol, ethanol, toluene, benzene, xylene in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, and camphorsulfonic acid. It can also be synthesized by reacting in an organic solvent such as above or a mixed solvent thereof under heating.

The salt addition compound of compound (I) or the hydrate or solvate of compound (I) obtained in the above step 8 can be synthesized by a conventional method after synthesizing compound (I). Can be synthesized as follows.

That is, compound (I) is prepared by subjecting compound (I) to the presence of hydrochloric acid, hydrogen chloride monoether, hydrogen chloride monoethyl acetate, hydrogen chloride-dioxane, or the like, in the presence of chloroform, dichloromethane, ethyl acetate, ethanolone, methanolone, acetone, tonorenene, tetranoine. It can be synthesized by reacting under cooling or heating in an organic solvent such as drofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or without solvent.

In the case of compound (I) in which R ₄ is a halogen atom, a cyano group, or the like, compound (IV) can be synthesized by the following method, and then synthesized by the method of steps 5 to 8 described above. .

(Step 9)

Compound (X) (wherein R ₃ , R or R ₆ , R „and Z are as described above) is compound (IX) (wherein R ₃ , R _s , R ₆ and Z are as defined above. Is processed in the same manner as in Step 1 described above.

(Step 10)

Compound (XI) (wherein R, R ₃ , R _s , R ₆ , and X are as described above) is a compound (X) (where R ₃ , R ₅ , R ₆ , R _n And Z are as described above) and the compound HO——R (where R and Z are as described above), carbonated sodium, sodium carbonate, sodium hydrogencarbonate, sodium hydride, etc. The reaction is carried out in an organic solvent such as dimethinolephonoremamide, acetone, dimethinolesnolefoxide, tetrahydrofuran, dimethoxetane, or a mixture thereof in the presence of a base of Can be.

(Process 1 1)

Compound (XII) _{(wherein, R, R 3, R s} , R 6, R " and X are Ru der as described above) is the compound (XI) _{_{(wherein, R, R 3, R 5}} , R ₆ and X are as described above) in the presence of an acid such as acetic acid, ammonium chloride, or hydrochloric acid with iron, zinc, or the like, an organic solvent such as methanol, ethanol, ether, or tetrahydrofuran, water, or a mixture thereof. It can be synthesized by reacting at room temperature or under heating in a solvent or without solvent.

(Process 1 2)

Compound (IV) (wherein R, R ₃ , R _s , R ₆ , R], and X are as described above) is compound (XII) (where R, R ₃ , R _s , R ₆ and X are as described above) in the presence of an acid such as hydrochloric acid or hydrobromic acid in sodium nitrite or the like, in an organic solvent such as acetic acid, water or a mixed solvent thereof. After reacting the mixture under cooling or heating, the reaction product is treated with CuR ₄ (wherein is the same as above) in the presence of hydrochloric acid, hydrobromic acid, sodium cyanide, sodium iodide, etc. However, in this case, a halogen atom or a cyano group is particularly preferred). The reaction can be carried out by reacting under cooling or heating in an organic solvent, water or a mixed solvent thereof, or no solvent.

Further, for example, in the case of the compound (I) in which R ₃ and R ₅ are both groups other than a hydrogen atom, particularly a halogen atom or a cyano group, the compound (V) is synthesized by the following method, Can be synthesized by the method of Steps 6 to 8.

(Process 15)

(Step 18)

(Process 13)

Compound (XIV) (wherein R ₁₃ ′ is a hydroxyl group or a mercapto group, and R ₃ , R ₄ , R _s , R ₆ and Z are as described above) are compound (XIII) (wherein R ₃ , R ₄ , R ₆ , ₁₃ ′ and Z are as described above) in the presence of an acid such as hydrochloric acid, hydrobromic acid or the like, with sodium nitrite or the like, an organic solvent such as acetic acid, water or a mixture thereof. After reacting in a solvent under cooling or heating, the reaction product is treated with CuR ₅ (where R ₅ is as described above) in the presence of hydrochloric acid, hydrobromic acid, sodium cyanide, or the like. In this case, a halogen atom or a cyano group is particularly preferred). It can be synthesized by reacting under cooling or heating in an organic solvent such as water, a mixed solvent thereof or no solvent.

(Process 14)

Compound (XV) (wherein, R _3, R have _{_{_{R s, R 6, R l3}}} ' and Z Ru der as described above), the I匕合compound (XIV) (wherein, R _3, R ₄ , R _s , R ₆ , R ₁₃ 'and Z are as described above) with iron, zinc, etc. in the presence of acetic acid, ammonium chloride, hydrochloric acid, etc., in the presence of methanol, ethanol, ether, It can be synthesized by reacting in an organic solvent such as tetrahydrofuran, water or a mixed solvent thereof or without solvent at room temperature or under heating.

(Process 15)

Compound (XV I) (wherein R ₃ , R ₄ , R ₅ , R ₆ , R ₁₃ ′ and Z are as described above) is a compound (XV) (where R ₃ , R ₄ , R _s , R ₆ , R ₁₃ 'and Z are as described above) in the presence of an acid such as hydrochloric acid or hydrobromic acid with sodium nitrite or the like, an organic solvent such as acetic acid, water or a mixture thereof. After reacting in a solvent under cooling or heating, the reaction product is cooled in the presence of sodium iodide or the like, in an organic solvent such as acetic acid, chloroform, water or a mixed solvent thereof or in a solvent-free state. Alternatively, it can be synthesized by reacting under heating.

(Process 16)

_{(Wherein, R, R 3, R,} ¾ R 5, R 6 and X are as defined above) Compound (XV II) may Ihigo compound (XV I) (wherein, R _3, R ₄ , R _s , R _e , R ₁₃ ′ and Z are as defined above) and compound Ru—Z, —R (where R, R ₁₂ and Z _t are as defined above) with potassium carbonate, In the presence of a base such as sodium carbonate or sodium hydrogen carbonate, the reaction is carried out under cooling or heating in an organic solvent such as dimethylformamide or acetone, or a mixed solvent thereof, or compound (XVI) and compound HO— A condensing agent obtained by combining Z, —R (wherein R and Z are as described above) with triphenylphosphine, trifluorobutylphosphine, etc., and diisopropyl azodicarboxylate, getyl azodicarboxylate, dicyclohexyl azodicarboxylate, etc. In the presence, ether, te It can be synthesized by reacting in an organic solvent such as trahydrofuran, dioxane, dichloromethane, dichloromethane, benzene, toluene, dimethylformamide or the like, or a mixed solvent thereof under cooling to heating.

(Process 17)

Compound (XV III) _{_{(wherein, R, R 3, R 4}} , R RN R 6 and X are as described above) is Ihigo compound (XV II) (wherein, R, R _3, R ₄ , R ₅ , R ₆ and X are as described above), if necessary, in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium chloride, and the like. The compound can be synthesized by reacting with copper cyanide or the like in an organic solvent such as dimethylformamide, pyridine or toluene, or a mixed solvent thereof at room temperature or under heating.

(Step 18)

Compound (V) (wherein, R, R ₃ , R ₄ , R _s , R ₆ and X are as described above) is compound (XV III) (wherein, R, R ₃ , R ₄ , R _s , R ₆ and X are as described above) in the presence of a base such as sodium hydroxide or potassium hydroxide, in an organic solvent such as ethylene dali alcohol, ethanol, toluene, xylene or a mixed solvent thereof. The reaction can be carried out at room temperature or under heating to complete the synthesis.

Compound (I) can also be synthesized by the following method.

CXXD

(xxiO

(Step 19)

Compound (XX) [wherein, R ₁₆ is a hydroxyl group, a mercapto group, _NHR ₇ (where R ₇ is as described above) or a nitro group, and R ₃ , R ₄ , R _s , R _c , R _M and Z are the same as described above.] Is a compound (XIX) (wherein R ₃ , R „R _s , R ₆ , R ₁₆ and Z are the same as those described above), and oxalyl chloride, thionyl chloride, In the presence of acid halides such as phosphorus chloride, phosphorus pentachloride, and oxychloride, in the presence of organic solvents such as chloroform, dimethylformamide, dichloromethane, and toluene; It can be synthesized by reacting under cooling or heating.

In the case of the compound (XIX) in which R ₁₆ is a hydroxyl group, a mercapto group or —NHR ₇ , the compound can be synthesized by carrying out this step after protecting with a protecting group by a conventional method in advance. In addition, these protective groups can be removed by a conventional method, if necessary, after performing Step 21 described below.

(Step 20)

Compound (XXI) (wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ R ₁₅ , R, ₆ and Z are as described above) are compound (XX) ( Where R ₃ , R ₄ , R ₅ , R ₆ , R _H , R, _fi and Z are as described above) and the compound (VII) (wherein R, R ₂ , R _s and R] ₅ are as described above), and pyridine, triethylamine, N— In the presence of a base such as methyl morpholine or N-methylbiperidine, an organic solvent such as dichloromethane, chloroform, tonoleene, ethere ^^, tetrahydrofuran, dioxane, diisopropinoleether, dimethoxetane, hexane, water or a mixture thereof. It can be synthesized by reacting under cooling or heating in a mixed solvent or without solvent.

(Step 2 1)

Compound (XXII) (wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₃ , Y and Z are as described above) is compound (XXI) (wherein _{_{R ,, R 2, R 3,}} R 4, R 5,

R ₆ , R ₈ , R, R ₁₆ and Z are as described above) in the presence of a reducing agent such as tin chloride, zinc, iron, sodium dithionite, sodium sulfide or sodium disulfide. If necessary, use ammonium chloride, hydrochloric acid, or the like, an organic solvent such as ethyl acetate, acetic acid, methanol, ethanol, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxetane, or toluene, water, or a mixed solvent thereof. The reaction is carried out in a medium, cooled or heated state, and then, if necessary, in the presence of an acid such as hydrochloric acid, acetic acid, p-toluene-nolefonic acid, or an organic solvent such as benzene, toluene, xylene, methanol, ethanol, or the like. It can be synthesized by reacting the mixture in a mixed solvent or a non-solvent with heating. This method is particularly effective when R ₁₅ is a nitro group. In particular, when R ₁₅ is a protected amino group or hydroxyl group, compound (XXI) can be prepared by reacting compound (XXI) with methanol, ethanol, toluene, benzene or benzene in the presence of an acid such as hydrochloric acid, p-toluenesulfonic acid, and camphorsulfonic acid. It can also be synthesized by reacting in an organic solvent such as xylene or a mixed solvent thereof under heating.

(Step 22)

Compound (I) (wherein, R, R !, R ₂ , R ₃ , R ₄ , R _s , R ₆ , X and Y are as described above) is a compound (XXII) ( Where R ₁ R ₂ , R ₃ , R ₄ , R _s , R ₆ , R ₁₃ , Y and Z are as described above) and compound R ₁₂ — Zi—R (where R, R ₁₂ and Z, are as described above) and potassium carbonate, sodium carbonate, carbonate The ability to react under cooling or heating in an organic solvent such as dimethylformamide, acetate, toluene, or a mixture thereof in the presence of a base such as hydrogen sodium or sodium hydride, or, particularly, R ₁₃ of compound (XX II) is a hydroxyl group, the compound R ₁₂ - Z, - if R ₁₂ in R is combinations are ® © atom is the presence of a base such as carbonate force Riumu, if necessary Add pyridine, etc., and use a catalyst such as copper chloride, copper bromide, copper iodide, etc., in an organic solvent such as dimethylformamide, toluene, dimethylsulfoxide, or a mixed solvent thereof or without a solvent, at room temperature or under heating. Can be synthesized by reacting . '

When R _{13 of} compound (XXII) is a hydroxyl group or a mercapto group, compound (I) is compound (XXII) and compound HO—Z! —R (where R and are as described above). Ether, tetrahydrofuran, dichloroxane, dichloromethane in the presence of a condensing agent combining triphenylphosphine, triptylphosphine, etc. with diisopropyl azodicarboxylate, getyl azodicarboxylate or dicyclohexyl azodicarboxylate. It can also be synthesized by reacting under cooling or heating in an organic solvent such as chlorophonolem, benzene, tonolene or dimethylformamide or a mixed solvent thereof.

Further, when R ₁₃ of compound (XXII) is —NHR ₇ , compound (I) is a compound (XXII) and compound OHC——R, wherein R and are as defined above. ) With dimethylformamide, dioxane, toluene, dimethylsulfoxide, methanol, ethanol or other organic solvent or a mixture thereof, and then sodium borohydride, sodium cyanoborohydride, lithium borohydride, hydride In the presence of a reducing agent such as lithium aluminum, trimethylsilane or triethylsilane, in an organic solvent such as methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropinoleanolone, dimethoxetane, or tonoleene, or a mixed solvent thereof. To react under cooling or heating Therefore, they can be synthesized.

The salt addition compound of compound (I) or the hydrate or solvate of compound (I) obtained in step 22 can be synthesized by a conventional method after synthesizing compound (I). For example, they can be synthesized as follows.

That is, compound (I) is prepared by treating compound (I) in the presence of hydrochloric acid, hydrogen chloride-ether, ethyl chloride-hydrogen monoxide, hydrogen chloride-dioxane, etc., in the presence of chloroform, dichloromethane, ethyl acetate, ethanol, methanol, acetone, toluene, tetrahydrochloride. It can be synthesized by reacting under cooling or heating in an organic solvent such as drofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or without solvent.

Further, compound (I) can also be synthesized by synthesizing compound (VIII) by the following method and then performing step 8 described above.

(Step 23)

Compound (XX ′) (wherein R ″ R ₄ , R ₅ , R ₆ , R ₁₃ , R ₁₄ and Z are as described above) is compound (XIX ′) (wherein R ₃ , R ₃ ₄ , R _s , R ₆ , R ₁₃ and Z are as described above) in the presence of an acid halide such as oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, etc. Form, dimethylformamid It can be synthesized by reacting under cooling or heating in an organic solvent such as solvent, dichloromethane, toluene, pyridine or the like or a mixed solvent thereof.

The compound (XX ′) can also be synthesized by, if necessary, protecting R ₁₃ of the compound (XIX ′) with a protecting group by a conventional method and then performing this step. Further, after performing the following step 24, this protecting group can be removed by a conventional method as necessary.

(Step 24)

The compound (XXI,) (wherein R ₂ , R ₃ , R ₅ , R ₆ , R ₁₃ , R _15, and Z are as described above) is a compound (XX ′) (formula , R ₃ , R ₄ , R _s , R _fi , R ₁₃ , R ₁₄ and Z are as described above) and compound (VII) (where R !, R ₂ , R ₈ and R _1S are as described above). And in the presence of a base such as pyridine, triethylamine, N-methylmorpholine, N-methylbiperidine, dichloromethane, chloroform, toluene, ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethoxetane, It can be synthesized by reacting under cooling or heating in an organic solvent such as xan, water or a mixed solvent thereof, or without solvent.

(Step 25)

The compound (VIII) (wherein R, R or R ₂ , R ₃ , R or R _s , R ₆ , R ₈ , R] ₅ and X are the same as the compound (XX I,) Wherein R, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₈ , R ₁₃ , R ₁₅ and Z are as described above) and the compound R _{I2 —Z} , —R (wherein , R, R, ₂ and are as described above) and an organic solvent such as dimethylformamide, acetone or toluene in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydrogencarbonate or sodium hydride. during these Namiai solvents are R, ₃ by hydroxyl is reacted under cooling乃under optimum warming, or in particular compounds (XX I '), it匕合compound R ₁₂ - Zeta, - R ₁₂ of R is In the case of a combination of iodine atoms, pyridine or the like is added as necessary in the presence of a base such as potassium carbonate, and a catalyst such as copper chloride, copper bromide, or copper iodide is used. Dimethylformamidine de, toluene, dimethyl sulfoxide and the like The reaction can be carried out in an organic solvent, a mixed solvent thereof or in a non-solvent at room temperature to under heating.

When R _{13 of} compound (XXI,) is a hydroxyl group or a mercapto group, compound (VIII) is compound (XXI ′) and compound HO—Z, —R (where R and Z, Are as described above) and ether, tetrahydrofuran in the presence of a condensing agent obtained by combining triphenylphosphine, tributylphosphine, etc. with diinpropyl azodicarboxylate, getyl azodicarboxylate, dicyclohexyl azodicarboxylate, etc. , Dioxane, dichloromethane, chlorophonolem, benzene, tonoleene, dimethylformamide, and the like, or a mixed solvent thereof, or by reacting the mixture under cooling or heating.

Furthermore, Compound (XX I ') when R ₁₃ of an NHR _7, the' compound (VIII), the compound (XX I ') and compound OHC- Z _t - R (wherein, R and Z _t Is as described above) in an organic solvent such as dimethylformamide, dioxane, toluene, dimethylsulfoxide, methanol, ethanol or a mixture thereof, and then sodium borohydride and sodium borohydride. Methanol, ethanol, ether, dioxane, tetrahydrofuran, diisopropyl alcohol, dimethoxetane, toluene, etc. in the presence of reducing agents such as lithium, lithium borohydride, lithium aluminum hydride, trimethylsilane, triethylsilane, etc. Synthesized by reacting under cooling or heating in an organic solvent or a mixed solvent of these Rukoto can.

Meanwhile, for the compound (I) in which R, for example, in the general formula (I) is an aryl group or a heterocyclic group, the compound obtained in the above step 8 or step 22 is reacted as follows. Can also be synthesized.

(xxnD ω

(Step 26)

The compound (I) (wherein R, R, R ₂ , R ₃ , RR _s , R ₆ , X and Y are as described above) is the compound (XX III) (formula Wherein R, R ₂ , R ₃ , R ₄ , R _s , R _e , R _l2 , X and Y are as described above, and a compound R, B (OH) ₂ (where R is With a catalyst such as tetrakis (triphenylphosphine) palladium or bis (triphenylphosphine) palladium chloride, and a base such as sodium carbonate, triethylamine, sodium hydrogencarbonate or the like. It can be synthesized by reacting in the presence of an organic solvent such as methanol, ethanol, toluene or dimethylformamide, water or a mixed solvent thereof under cooling or heating. In the general formula (I), the compound (I) in which the substituent at R is, for example, a carbamoyl group or a carbamoyl group substituted with a lower alkyl group is a corresponding compound wherein the substituent at R is a cyano group. After synthesizing (I) by the above step 8 or step 22, it can also be synthesized by the following method (for convenience, in compound (Ia) and compound (XXIV), R is a phenyl group). Shown).

0)

(Step 2 7)

Compound (XX IV) (wherein, R, R ₂ , R ₃ , R ₄ , R _s , R ₆ , X and Y are as described above) is compound (la) (where R !, R ₂ , R ₃ , R ₄ , R _s , R ₆ , X and Y are the same as described above) in the presence of a base such as sodium hydroxide and potassium hydroxide, and an organic solvent such as ethylene glycol, ethanol and toluene. It can be synthesized by reacting in a solvent, water or a mixed solvent thereof under heating.

(Step 28)

Compound (I) (where R, R or R ₂ , R ₃ , R or R _s , R ₆ , X and Y are as described above) is a compound (XX IV) (where R is in _{_{_{R 2, R 3, R 4}}} , R s, R 6, X及Pi Y are as described above) chloride Anmoniumu or NHR ₁₇ R ₁₈ (wherein, R _l7 and R ₁₈ are identical or different A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, or a hydrogen atom) to 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride Condensation agents such as xylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole, etc., if necessary, can be used for 1-hydroxybenzotriazole, hydroxysuccinimide, N-hydroxy- Activator such as 5-norbornene 1,2,3-dicarboxylic acid imide The reaction is carried out under cooling or heating in an organic solvent such as dimethylformamide, dichloromethane, chlorohonolem, acetonitrile, tetrahydrofuran, dimethylsulfoxide, carbon tetrachloride, toluene, or a mixed solvent thereof. Can be synthesized. If necessary, this reaction may be performed in the presence of a base such as triethylamine, N-methylmorpholine, or 4-dimethylaminopyridine.

Further, in the general formula (I), the compound (I) in which R _s is, for example, a cyano group is obtained by synthesizing the corresponding compound (I) in which R _{s is a} halogen atom by the aforementioned step 8 or step 22, It can also be synthesized by the following method.

(lb) ω

(Step 29)

Compound (I) (wherein, R, R, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , X and Y are as described above) is a compound (I b) ( In the formula, R, R 1 _¾ R ₂ , R ₃ , R ₄ , R _e , R ₁₂ , X and Y are the same as described above, and if necessary, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) ) In the presence of a catalyst such as palladium chloride, zinc cyanide, copper cyanide, etc., in an organic solvent such as dimethylformamide, pyridine, toluene or a mixed solvent thereof at room temperature or under heating. Can be synthesized. This step can also be performed on the corresponding compound (XXII) synthesized in step 21 described above. In this case, compound (I) is obtained by converting the compound synthesized in this step into the above-described step. It can be synthesized by processing at 22.

In addition, the salt addition compound of the compound (I) obtained in the above step 26, 28 or 29 The compound or and the hydrate or solvate can be synthesized by a conventional method after synthesizing the compound (I) if necessary. For example, the compound (I) can be synthesized as follows.

That is, compound (I) was prepared by treating compound (I) in the presence of hydrochloric acid, hydrogen chloride-ether, ethyl chloride-ethyl acetate, hydrogen chloride-dioxane, etc., in the presence of chloroform, dichloromethane, ethyl acetate, ethanolanol, methanolol, acetone, tonoren, It can be synthesized by reacting under cooling or heating in an organic solvent such as trahydrofuran, dioxane, hexane or the like, water or a mixed solvent thereof, or no solvent.

The substituents of the compounds used in the above steps 1 to 29 may be protected with a protecting group by a conventional method or may be subjected to each step after protecting with a protecting group, if necessary. The protecting group may be removed by a conventional method as necessary, or may be removed by a conventional method in the final step.

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

Embodiment of the Invention

Next, the present invention will be specifically described with reference to Production Examples, Examples, and Test Examples, but the present invention is not limited thereto. The numbers of each step described in the examples and the symbols described after each compound correspond to the numbers and symbols used in the description of the above-mentioned production method.

Example

Production Example 1

Synthesis of 4-bromo-3-hydroxybenzoic acid

48% Hydrobromic acid (100 ml) was added to 4-amino-3-hydroxybenzoic acid (50.0 g), and the mixture was dissolved by heating at 55 ° C. Then, sodium nitrite (22 6 g) in water (50 ml) was added dropwise over 1 hour.

Then, the reaction solution was mixed with copper (I) bromide (25.8 g) and 48% hydrobromic acid. (50 ml) of suspension in black form (200 ml) was added under stirring at 40 ° C. over 30 minutes, followed by stirring at 50 ° C. for 3.5 hours. After cooling, 1N hydrochloric acid (500 ml) was added, and the mixture was extracted twice with ethyl acetate (500 ml), and washed sequentially with water (500 ml) and saturated saline (500 ml). After drying over sodium sulfate, the solvent was distilled off to obtain the title compound (64.8 g) as yellow crystals.

Production Example 2

Synthesis of 2-chloro-5-hydroxybenzoic acid

1) A solution of 4-chloro-m-creso-mono (10. Og) in acetone (100 ml) was dissolved in lithium carbonate (19.4 g) and methyl iodide (6.55 m l) was added, and the mixture was stirred overnight at room temperature. The insoluble material was removed by filtration, the solvent was distilled off, water (50 ml) was added, and the mixture was extracted twice with ether (50 ml). After drying over sodium sulfate, the solvent was distilled off to obtain colorless oily 4-methyl-13-methylaniline (10.7 g).

2) To a solution of the compound (10.7 g) obtained in 1) above in water (200 ml) was added tetrabutylammonium bromide (1.13 g) and potassium permanganate.

(21.5 g) was added, and the mixture was heated under reflux at 110 ° C overnight. After cooling, insolubles were removed by filtration through celite and washed twice with hot water (50 ml). The obtained aqueous layer was washed twice with ether (10 Oml) and neutralized with concentrated hydrochloric acid. The precipitated crystals were collected by filtration to obtain 2-chloro-5-methoxybenzoic acid (2.06 g) as white crystals.

3) Compound (2.06 g) obtained in 2) above and 48% hydrobromic acid (2 1.

A solution of Oml) in acetic acid (10 ml) was heated to reflux at 130 ° C for 21 hours. After allowing to cool, the solvent was distilled off to obtain the title compound as a crude product.

Production Example 3

4-—Mouth—Synthesis of 3-mercaptobenzoic acid

1) To a solution of 60% sodium hydride (0.880 g) in dimethylformamide (20 ml) was added 4-ethyl-1-ethylhydroxybenzoate (3.99 g) under stirring at room temperature. It was added little by little and stirred for 30 minutes. Furthermore, dimethylthio force is applied to this reaction solution. Rubamoyl chloride (2.71 g) was added, and the mixture was stirred at 80 for 3 hours. After cooling, add 1N hydrochloric acid (60ml), extract twice with ethyl acetate (60ml), twice with water (20ml) and twice with 1N aqueous sodium hydroxide solution (5ml). Then, it was washed successively with saturated saline (20 ml). After the solvent was distilled off, the resulting residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 85:15) to give a colorless oil, 4 ^ chloro-3- ( Ethyl (dimethylamino) thiocarbonyloxybenzoate (4.11 g) was obtained. .

2) A solution of the compound (4.11 g) obtained in 1) above in phenyl ether (5 ml) was ripened and stirred at 220 under an argon atmosphere for 4 hours. After allowing to cool, the reaction solution is purified by silica gel column chromatography (developing solvent; hexane to hexane: ethyl acetate = 8: 2) to give a colorless oil, 4-chloro-3- (dimethylamino) carboxyltyoxybenzoate. Ethyl acid (3.60 g) was obtained.

3) To a solution of the compound (3.25 g) obtained in 2) above in ethanol (30 ml) was added potassium hydroxide (2.04 g), and the mixture was heated and stirred at 50 ° C for 2 hours. After stirring, acetic acid (5.80 ml) and water (60 ml) were sequentially added dropwise, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to give the title compound (1.45 g) as white crystals.

Production Example 4

4 Synthesis of monochloro-3- (bromomethyl) ethyl benzoate

1) Concentrated sulfuric acid (2.00 ml) was added to a solution of 3-methylaminobenzoic acid (11.9 g) in ethanol (100 ml), and the mixture was heated under reflux for 4 hours. After cooling, the solvent was distilled off, water (50 ml) was added to the residue, and the mixture was extracted twice with ether (80 ml). The organic layer was washed twice with water (50 ml), twice with saturated aqueous sodium hydrogen carbonate (50 ml), and then with saturated saline (50 ml). After drying over sodium sulfate, the solvent was distilled off to obtain ethyl 4-ethyl-1-methylbenzoate (12.4 g) as a colorless oil.

2) A solution of the compound (5.995 g) obtained in 1) above in carbon tetrachloride (60 ml) N-bromosuccinimide (5.87 g) was added to the mixture, and 2,2′-azobisisobutyronitrile (20 mg) was further added 5 times every 5 minutes while heating under reflux. After cooling, insolubles were removed by filtration, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 98: 2) to give the title compound (5.87 g) as a colorless oil.

Production Example 5

Synthesis of 3-acetoxoxy 4-cyclobenzoic acid

4 To a solution of monochloro-3-hydroxybenzoic acid (17.3 g) in acetic acid (20 ml), add acetic anhydride (18.9 ml) and sodium acetate (4.10 g), and add 13 Heated to reflux overnight at 0. After adding water (60 ml), the mixture was allowed to cool and stirred for another hour. The precipitated crystals were collected by filtration to give the title compound (20.5 g) as white crystals.

Production Example 6

Synthesis of 4-Funoleo mouth 1 2- (trifluoromethyl) benzinole bromide 1) Tetrahydrofuran of 4-fluoro-2- (trifluoromethyl) benzoic acid (55.0 g) and triethylamine (40. Oml) To a solution of (400 ml) was added dropwise a solution of ethyl ethyl formate (27.7 ml) in tetrahydrofuran (100 ml) under ice-cooling over 20 minutes. The mixture was stirred for 3 hours under ice cooling, and the precipitated crystals were removed by filtration. The obtained filtrate was added dropwise to a suspension of sodium borohydride (11.Og) in tetrahydrofuran (10 Om 1) over 15 minutes under ice-cooling with stirring over 1.5 minutes. Stirred. Further, after stirring at 4 O 4C for 4 hours, 6 、 hydrochloric acid (30 ml) was added dropwise under ice cooling. After adding water (500 ml) and extracting twice with ethyl acetate (500 ml), the mixture is extracted twice with water (500 ml) and saturated aqueous sodium hydrogen carbonate (500 ml), and then with saturated saline (500 ml). Washed sequentially. After drying over sodium sulfate, the solvent was distilled off to give 4-fluoro-2- (trifluoromethyl) benzylanolenocore (49.4 g) as a yellow oil.

2) To a solution of the compound (42.7 g) obtained in 1) above in toluene (80 ml), Under ice cooling and nitrogen atmosphere, phosphorus tribromide (8.30 ml) was added dropwise over 1 hour, and the mixture was stirred for 30 minutes. After further stirring at room temperature for 1.5 hours, saturated carbonated aqueous sodium hydroxide solution (400 ml) was gradually added under ice-cooling, and the mixture was extracted twice with ether (300 ml). The extract was washed successively with saturated aqueous sodium bicarbonate (200 ml) and saturated saline (200 tnl), dried over sodium sulfate, and then the solvent was distilled off. The obtained residue was distilled (boiling point: 84-85 at 27 mmHg) to give a colorless oil (38.0 g). Production Example 7

Synthesis of 5-bromo-1 2- (bromomethyl) benzotri phenololeide

1) To a mixture of 2-methylbenzotrifluoride (19.0 g) and concentrated sulfuric acid (10 Om 1) was added 70% nitric acid (7.90 ml) at 16 ° C for 1 hour. And dropped. After stirring for another hour, the reaction solution was poured into ice (700 g). After stirring for 1 hour, the mixture was extracted twice with ether (100 ml), washed twice with water (100 ml), and successively with saturated saline (100 ml). After drying over sodium sulfate, the solvent was distilled off, and ethanol (200 ml) and 5% Pd—C (2.36 g) were added. Stirred for hours. After stirring, the reaction solution was filtered through celite, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate 82) to give 5-amino-2-methylbenzotrifluoride (9.53 g) as a colorless oil. Obtained.

2) To a solution of the compound (4.50 g) obtained in 1) above in water (10 ml) was added 48% hydrobromic acid (10 ml), and while stirring under ice-cooling, nitrous acid was added. A solution of sodium (1.86 g) in water (5 ml) was added dropwise. The mixture was further stirred for 30 minutes, and the reaction solution was added with copper (I) bromide (2.03 g) and 48% hydrobromic acid (5 ml) at 40 ° C. (20 ml) was added slowly to the solution. After stirring at 4 for 1 hour, the mixture was allowed to cool and extracted twice with ethyl acetate (50 ml). The extract was washed twice with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated saline (100 ml) in that order, dried over sodium sulfate, and then the solvent was distilled off. The resulting residue was distilled (6. Om mHg, boiling point: 57) to give 5-bromo-2-methylbenzene as a colorless oil. Zotrifluoride (4.17 g) was obtained.

3) N-bromosuccinimide (2.58 g) was added to a solution of the compound (3.14 g) obtained in 2) above in carbon tetrachloride (30 ml), and the mixture was heated and stirred for 100 minutes. Below, 2,2'-azobisisobutyronitrile (20 mg) was added 10 times every 5 minutes. After cooling, insoluble materials were removed by filtration, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 98: 2) to give the title compound (1.73 g) as a colorless oil.

Production Example 8

4-t e r t Synthesis of aniline

1) 4-tert-Butylaniline (88.0 g) was added dropwise to acetic anhydride (400 ml) at room temperature over 15 minutes, and the mixture was stirred for 30 minutes. Next, 70% nitric acid (56. Oml) was added dropwise to the reaction solution over 40 minutes under ice cooling, and the mixture was stirred for 1 hour. Water (800 ml) was added, the mixture was stirred at room temperature for 4 hours, and the precipitated crystals were collected to obtain N- (4-tert-butynole). Cetamide (13] .g) was obtained.

2) A 4N aqueous sodium hydroxide solution (200 ml) was added to a solution of the compound (131 g) obtained in 1) above in ethanol (400 ml), and the mixture was added to 100. The mixture was stirred at C for 2 hours. Then, acetic acid (140 ml) and water (770 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration to give the title compound (103 g) as orange needle crystals.

Production Example 9

Synthesis of 4-tert-butyl-N-methyl-2-nitroaniline

1) The toluene (30 ml) solution of N— (4- -ert-butyl-2-dinitrophenyl) acetamide (5.00 g) obtained in 1) of Production Example 8 described above was Under ice cooling and stirring, slowly add 60% sodium hydride (0.890 g), and after stirring for 15 minutes, add methyl iodide (2.00 ml) and add 130 ° C And heated to reflux overnight. After cooling, water (60 ml) was added, and the mixture was extracted twice with ethyl acetate (50 ml). Distilled off. The resulting residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1) to give a yellow solid of N- (4-tert-butylinole-2-nitropheninole) -1-N-methylacetate. Toamide (4.49 g) was obtained.

2) To a solution of the compound (4.49 g) obtained in 1) above in ethanol (30 ml) was added a 4 N aqueous solution of potassium hydroxide (13.O ml), and the mixture was heated and returned with lO Ot for 6 hours Shed. After allowing to cool, the solvent was distilled off, water (200 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml). The extract was washed successively with water (100 ml) and saturated saline (100 ml), dried over sodium sulfate, and evaporated to remove the title compound as a reddish-brown oil (3.66). g) was obtained.

Production Example 10

5—tert—butynole 2— (tert—butoxycarboninoleamino) aniline synthesis

1) A mixture of 4-tert-butyl-2-nitro-2-arylene (4.00 g) and di-tert-butyl dicarbonate (4.49 g) was stirred at 80 for 6 hours. After cooling, the residue is purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 20: 1 to 10: 1) to give an orange oil N- (tert-butoxycanoleboninole). There was obtained tert-butynole 2--2-atrolin (4.13 g).

2) To a solution of the compound (4.13 g) obtained in 1) above in ethanol (40 ml) was added 5% Pd-C (1.50 g), and the mixture was stirred at room temperature under a hydrogen atmosphere. Stirred for hours. After the reaction solution was filtered through celite, the solvent was distilled off to obtain the title compound (3.64 g) as a white solid.

Production example 1 1

5-tert Butynole 2-(t tert Butoxycanolepo-Noleamino) Synthesis of N-methylaniline

5-tert-butyl-2- (tert-butoxy) obtained in Production Example 10 described above Triethylamine (0.767 ml) was added to a solution of cicarbonylamino (aniline) (1.32 g) in ether (70 ml), and then dimethyl sulfate (0.520 ml) was added dropwise at room temperature. Stirred. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 6: 1) to give the title compound (0.62 lg) as a white solid. Obtained.

Production example 1 2

Synthesis of 5-tert-butyl-2-aminophenol hydrochloride

1) A mixture of 3-tert-butylphenol (7.51 g) and acetic anhydride (30 ml) was stirred at 115, and 70% nitric acid (3.50 ml) was added dropwise over 30 minutes. After the addition, the mixture was stirred at 115 for 1 hour, water (30 ml) and ethanol (30 ml) were added, and the mixture was further stirred at room temperature for 30 minutes. The solvent was distilled off, ethyl acetate (80 ml) was added, and the solvent ( _c ) washed with water (40 ml) and saturated saline (40 ml) in that order was distilled off. The obtained residue was subjected to silica gel column chromatography ( Purification with a developing solvent; hexane: ethyl acetate = 98: 2) gave 5-tert-butyl-l2-nitrophenol (2.72 g) as a yellow oil.

2) To a solution of the compound (2.72 g) obtained in 1) above in ethanol (25 ml), add 6N hydrochloric acid (3.50 ml) and 5% Pd-C (0.540 g), and add room temperature. The mixture was stirred under a hydrogen atmosphere for 4 hours. After the reaction solution was filtered through celite, the solvent was distilled off. The obtained residue was azeotroped twice with toluene (20 ml) to give the title compound (2.71 g) as a white solid.

Production example 1 3

Synthesis of 4-tert-Aminole-2-nitroaline

1) 70% nitric acid (3.22 ml) was added dropwise to a mixture of tert-amylbenzene (5.0.00 g) and acetic anhydride (30 ml) under ice cooling, and the mixture was stirred for 2 hours. Water (100 ml) was added, the mixture was stirred at room temperature for 1 hour, and extracted twice with ethyl acetate (5 Om 1). The extract was washed twice with saturated aqueous sodium hydrogen carbonate (50 ml) and sequentially with saturated saline (50 ml), dried over sodium sulfate, and the solvent was distilled off. Then, ethanol (5 0ιτι 1) of 5% P d _C to the resulting residue (2. 0 0 g) was added, under a gas of hydrogen at room temperature棼囲After stirring 6 h, _c solvent was filtered through Celite Bok After distilling off the residue, the resulting residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1) to obtain a colorless oil, 4-tert-amylaniline (4.08). g) was obtained.

2) Using the compound (4.08 g) obtained in 1) above, the title compound (3.76 g) was obtained in the same manner as in the above-mentioned Preparation Example 8.

Production example 1 4

4-Tertop, Chinole 2-Cross mouth 6-Nitroaniline synthesis

4-tert e-butyrinol 2-nitronitrin (1.94 g) of acetonitrile

To the (20 ml) solution was added N-mouth rosuccinimide (1.34 g), and the mixture was stirred at 100 for 2 hours. After allowing to cool, the solvent was distilled off, ether (15 ml) was added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 95: 5) to give an orange oily substance. The compound (1.27 g) was obtained.

Production example 1 5

4-Synthesis of 1-bromo-2-nitroaniline

2 To a solution of 1-troaniline (13.8 g) in 90% acetic acid (100 ml) was added lithium bromide (11.9 g) and sodium molybdate (1.20 g). And 30% aqueous hydrogen peroxide (11.9 ml) was added dropwise over 15 minutes while stirring at room temperature. After stirring for 1 hour, water (100 ml) was added, and the mixture was further stirred at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (21.3 g) as orange needles.

Production Example 1 6

5-Funolero 2- (tri-Funolelomethinole) Synthesis of benzinole bromide

1) To a suspension of 5-fluoro-2- (trifluoromethyl) benzoic acid (81.3 g) in mouth-mouth form (400 ml) and dimethylformamide (0.1 ml) at room temperature Then, oxalyl chloride (42.O ml) was added dropwise, and the mixture was stirred for 3 hours. Evaporate the solvent After that, the obtained residue was added dropwise to methanol (400 tnl) at room temperature and stirred for 1 hour. After evaporating the solvent, water (100 ml) was added, and the mixture was extracted twice with ether (200 ml). Water (100 ml), a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and saturated saline (l) were added. Washed sequentially with O Om l). After drying over magnesium sulfate, the solvent was distilled off to obtain a yellow oily compound (92.3 g).

Then, a solution of the above yellow oil (47.9 g) in tetrahydrofuran (100 ml) was added to a suspension of lithium aluminum hydride (7.59 g) in tetrahydrofuran (450 ml). Below, dripped. After stirring at the same temperature for 2 hours, water (7.60 ml), 15% sodium hydroxide (7.60 ml) and water (22.8 ml) were sequentially added, and the mixture was returned to room temperature and stirred for 1 hour. After filtering off the insoluble matter, the solvent was distilled off to obtain 5-fluoro-2- (trifluoromethyl) benzyl alcohol (37.8 g) as white crystals.

2) Phosphorus tribromide (6.10 ml) was added dropwise to a solution of the compound (31.1 g) obtained in 1) above in a chloroform (90 ml) solution under ice-cooling. Stirred for 2 hours. After stirring, saturated sodium hydrogencarbonate (300 ml) was added, and the mixture was extracted three times with black-mouthed form (100 ml). After drying over magnesium sulfate, the solvent was distilled off. The obtained residue was distilled (boiling point 90-91 ° C at 30 mmHg) to give the title compound (26.0 g) as a pale yellow oil.

Production Example 1 7

Synthesis of 4-cyano 3-ethyl benzoate

Zinc cyanide (8.62 g) and tetrakis (triphenylphosphine) palladium (7.07) were added to a solution of 4-bromo-3-hydroxyethyl benzoate (30.0 g) in dimethylformamide (180 ml). g) was added, and the mixture was heated and refluxed at 180 for 2 hours. After cooling, ethyl acetate (600 ml) was added, and the mixture was washed twice with water (500 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol = 98: 2-95: 5) to give the title compound (19.9 g) as a brown solid. Production example 1 8

Synthesis of 4 _bromo-3-nitrobenzoic acid

1) A solution of 70% nitric acid (29.7 ml) and concentrated sulfuric acid (30 ml) was added dropwise to a solution of ethyl 4-bromobenzoate (77.0 g) in concentrated sulfuric acid (100 ml) under ice-cooling. And stirred for 1 hour. After stirring, the reaction solution was poured into ice (lOOOg) and extracted twice with ethyl acetate (1 000 ml). The obtained organic layer was washed sequentially with water (500 ml), a saturated aqueous solution of sodium hydrogen carbonate (500 ml) and a saturated saline solution (500 ml). After drying over sodium sulfate, the solvent was distilled off to obtain ethyl ethyl 4-bromo-3-nitrobenzoate (92.0 g).

2) To a solution of the compound (92.0 g) obtained in 1) above in ethanol (400 ml) was added a 4 N aqueous sodium hydroxide solution (125 ml), and the mixture was heated under reflux for 1 hour, and then treated with acetic acid (12 5 ml) and water (600 ml) were added sequentially. After cooling, the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (74.3 g) as pale yellow crystals.

Production example 1 9

5—Funoleolo 2— (Trifnorolelomethinole) Synthesis of benzaldehyde

Manganese dioxide (I 78 g) was added to a solution of 5-fluoro-2- (trifluoromethinole) benzyl alcohol (33.1 g) obtained in the above-mentioned Production Example 16-1) in ethyl acetate (330 ml). Was added and the mixture was refluxed for 30 hours. After cooling, insolubles were removed by filtration, and the solvent was distilled off. The obtained residue was distilled (boiling point: 75 ° C at 45 mmHg) to give the title compound (23.1 g) as a colorless oil.

Production Example 20

4-1- (2-Acetoxy-1,1-dimethylethyl) — Synthesis of 2-nitroaniline

1) In an atmosphere of anoregone, a suspension of magnesium (1.34 g) in anhydrous ethanol (40 m 1) was heated at 50 with 1-chloro-2-methyl-2-phenylpropane (8.43 g). )) In anhydrous ether (10 ml) was added dropwise over 20 minutes and stirred for 3 hours. I did. Furthermore, after stirring in an oxygen atmosphere under ice cooling for 3 hours, water (40 ml) and sodium hydrogen sulfite (10 g) were added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, extraction was performed three times with ether (40 ml), and the organic layer was washed twice with water (30 ml) and saturated saline (30 ml). The solvent was distilled off to obtain 2-methyl-12-pheninole-1-propanole (7.64 g) as a crude product as a colorless oil.

2) To a solution of the crude product (6.74 g) obtained in 1) above in pyridine (35 ml) was added dropwise acetic anhydride (8.50 ml) at room temperature, and the mixture was stirred for 3.5 hours. , water

(50 ml) was added, and the mixture was further stirred for 30 minutes. Extracted twice with diisopropyl ether (60 in 1), and the obtained organic layer was successively extracted with 3N hydrochloric acid (50 ml), water (50 ml), a saturated aqueous solution of sodium hydrogencarbonate (50 ml), and water (50 ml). After washing and drying over sodium sulfate, the solvent was distilled off.

Then, acetic anhydride (40 ml) was added to the residue, 70% nitric acid (5.70 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 16 hours. Water (120 ml) was added, and the mixture was further stirred at room temperature for 2 hours, and then extracted twice with diisopropyl ether (50 ml). The obtained organic layer was extracted with water (50 ml) and a saturated aqueous solution of sodium hydrogen carbonate (50 ml). Washing was performed three times at 50 ml). After drying over sodium sulfate, the solvent was distilled off to obtain a crude product of yellow oil, 4- (2-acetoxy-1,1-dimethylethyl) nitrobenzene (9.81 g).

3) A suspension of the crude product (7.12 g) obtained in 2) above, ethanol (7 Om 1), 5% Pd—C (3.50 g) was added at room temperature under atmospheric The mixture was stirred for 4 hours in a hydrogen atmosphere. After removing the insoluble matter, the solvent was distilled off to obtain crude 4- (2-acetoxy-dimethylethyl) aniline (3.997 g) as a yellow oily product.

4) To the crude product (4.44 g) obtained in 3) above, add acetic anhydride (25 ml), stir at room temperature for 1 hour, and then add 70% nitric acid (2.56 ml) under ice-cooling. ) Was added dropwise, and the mixture was further stirred for 1 hour. Water (75 ml) was added, the mixture was returned to room temperature, stirred for 1 hour, and then the solvent was distilled off. Further, add water (100 ml) and add ethyl acetate (50 ml). After extraction twice, the mixture was washed three times with a saturated aqueous solution of sodium hydrogencarbonate (5.0 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 3) to give N-

There was obtained [4 -— (2-acetoxy-1,1,1-dimethylether) -12-nitrophenyl] acetamide (4.40 g).

5) To a solution of the compound (4.40 g) obtained in 4) above in ethanol (22 ml) was added a 4N aqueous sodium hydroxide solution (11.2 ml), and the mixture was stirred at room temperature overnight, and then stirred at room temperature for 6N. Hydrochloric acid (8 ml) was added, and the solvent was distilled off. Add water (50 ml), extract twice with ethyl acetate (50 ml), wash with saturated aqueous sodium bicarbonate solution (50 ml) and saturated saline (50 ml) sequentially, and evaporate the solvent. did. Chloroform (30 ml) and pyridine (1.73 ml) were added to the obtained residue, and anhydrous acetic acid (1.62 ml) was further added at room temperature. Stirred for a while. After adding methanol and evaporating the solvent, 1N hydrochloric acid (50 ml) was added, and the mixture was extracted twice with ethyl acetate (40 ml). The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and a saturated saline solution (50 ml), dried over sodium sulfate, and evaporated to remove the solvent to give 4- (2-acetoxoxy-1,1-dimethylethyl) as a yellow oil. ) — 2-Nitroaniline (3.80 g) was obtained.

As described above, the compounds produced in Production Examples 1 to 20 are shown in Table 1 below. In Table 1, Me represents a methyl group, Et represents an ethyl group, Ac represents an acetyl group, and Boc represents a tert-butoxycarbonyl group.

Example 1

5-tert e-butynole 2 -— [4-chloro-3 -— [4-funoleolole 2 -— (trinoolenomethinole) benzinoleoxy] feninole] Benzimidazonole hydrochloride-hydrate synthesis

Process 1) 4-Mouth-to-mouth 3- 3-Diethylhydroxybenzoate (III) _To a solution of _4- chloro- ₃ -hydroxybenzoic acid (28.0 g) in ethanol (280 ml) was added concentrated sulfuric acid (2.80 ml), and the mixture was stirred at 100 ° C for 19 hours. After the solvent was distilled off, 20 ° / ₀ ethanol water (100 ml) was further added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected to give the title compound (31.2 g) as white needles.

Step 2) 4-Chloro-3— [4-Funoleomethinole) Benziroxy] Ethyl benzoate (IV)

A mixture of the compound (27.9 g) obtained in the above step 1), dimethylformamide (30 Oml) and potassium carbonate (38.6 g) was obtained at room temperature in the above-mentioned Production Example 6. Then, 4-fluoro-2- (trifluorenomethyl) benzyl bromide (37.6 g) was added thereto, and the mixture was stirred for 12 hours. After stirring, water (900 ml) was added to the reaction solution, and the mixture was extracted twice with ethyl acetate (500 ml). The organic layer was washed four times with water (300 ml), then with saturated saline (300 ml), dried over sodium sulfate, and evaporated to remove the solvent to give the title compound (52.6 g) as white crystals. ).

Step 5) 4- (4-fluoro-2- (trifluoromethylinole) benzoyloxy) benzoic acid (V)

To a solution of the compound (52.6 g) obtained in the above step 2) in ethanol (150 ml) was added 4N aqueous sodium hydroxide solution (52.5 ml), and the mixture was stirred at 100 ° C for 2.5 hours. Stirred. Thereafter, acetic acid (36 ml) was added dropwise to the reaction solution, water (30 Oml) was further added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration to give the title compound (47.5 g) as white crystals.

Step 6) 4-Chloro-3 -— [4-Fnoroleol 2- (trifluoromethyl) benzyloxy] benzoyl chloride (VI)

To a mixed solution of the compound (47.5 g) obtained in the above step 5) and a mixture of chloroform (500 ml) and dimethylformamide (0.500 ml) was added oxalinole chloride (18. ) Was added dropwise over 40 minutes, and the mixture was stirred at room temperature for 1 hour. After stirring, The solvent was distilled off, then toluene (250 ml) was added, and the insoluble matter was removed by filtration. The title compound (50.0 g) as white crystals was obtained by evaporating the solvent of the obtained residue.

Step 7) N- (4-tert-Petit / Lee 2-two-That Phenyl) 1-4-Chloro-Three- [4-Fhenooleol 2- (Triphnorelomethinole) Benzinoleoxy] benzamide (VIII)

In a pyridine (260 ml) solution of 4-tert-butyl-2-nitroaniline (26.5 g) obtained in Production Example 8 described above, while stirring at room temperature, the compound obtained in the above step 6> ( 47.7 g) was added little by little, and then stirred at 40 ° C for 3.5 hours. Further, water (300 ml) was added, and the mixture was stirred under ice cooling for 30 minutes. The precipitated crystals were collected by filtration to give the title compound (63.87 g) as yellow crystals.

Step 8) 5-tert-butynol 2- [4-chloro-3- [4-funoleomethyl-2- (triphnorelomethyl) benzyloxy] phenyl] benzimidazo-monole hydrochloride hydrate (I)

A mixture of the compound (63.9 g) obtained in the above step 7), acetic acid (650 ml) and reduced iron (23.6 g) was stirred at 130 for 1.5 hours. After allowing to cool, water (2000 ml) was added, and the mixture was extracted three times with ethyl acetate (1500 ml). The organic layer was washed twice with water (500 ml), then with an aqueous potassium carbonate solution (300 ml), and dried over sodium sulfate. The solvent was distilled off to obtain light yellow crude crystals (60.6 g).

Then, ethanol (400 ml) was added to the crude crystals (40.0 g), dissolved by heating at 100, and 6N hydrochloric acid (2.10 ml) and water (130 ml) were sequentially added dropwise. Then, the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (40.3 g) as white crystals.

Example 2

5-tert-Butyl-1-2- [4-bromo-1--3- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride.Synthesis of hydrate Step 1) Ethyl 4-bromo-3-hydroxybenzoate (III) Ethanol (650 ml) of 4-bromo-13-hydroxybenzoic acid (64.8 g) obtained in the above Preparation Example 1 Concentrated sulfuric acid (6.5 ml) was added to the solution, and the mixture was stirred at 100 for 4 hours. After cooling, the solvent was distilled off, and then 20% aqueous ethanol (200 ml) was added, followed by stirring overnight. The precipitated crystals were collected by filtration to give the title compound (68.7 g) as brown crystals.

Step 2) 4-Bromo-1- 3- [2- (trifluoromethyl) benzyloxy] ethyl benzoate (IV)

To a solution of the compound (39.2 g) obtained in step 1) above in acetone (400 ml) was added potassium carbonate (66.4 g), and the mixture was stirred at room temperature under stirring for 2- (trifluoromethyl) benzyl bromide. A solution of (38.3 g) in acetone (40 Om 1) was added dropwise, and the mixture was stirred at 60 ° C. for 4.5 hours. After cooling, 1 N hydrochloric acid (1 000 ml) was added, and the mixture was extracted twice with ethyl acetate (1 000 ml). The organic layer was washed successively with water (500 ml) and saturated saline (500 ml), and dried over sodium sulfate. The solvent was distilled off to obtain the title compound (65.0 g) as orange crystals.

Step 5) 4-Bromo-3- [2- (trifluoromethyl) benzyloxy] benzoic acid (V)

To a solution of the compound (65.0 g) obtained in the above step 2) in ethanol (120 ml) was added 4 N sodium hydroxide (120.Oml), and the mixture was stirred at 100 ° C for 30 minutes. . Acetic acid (82.4 ml) and water (120 m) were sequentially added dropwise, followed by stirring at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (57.5 g) as pale yellow crystals.

Step 6) 4-Bromo-3- [2- (trifluoromethyl) benzyloxy] benzoyl chloride (VI)

To a mixed solution of the compound (57.5 g) obtained in the above step 5) in a mixture of chloroform (570 ml) and dimethylformamide (0.500 ml) was added oxalyl chloride (20. After l) was added dropwise over 30 minutes, the mixture was stirred at 40 for 1 hour. Dissolution The solvent was distilled off, then toluene was added, and the insolubles were removed by filtration. The solvent was distilled off to obtain crude yellow crystals (61.1 g).

Step 7) N- (4-tert-butyl-l-2-nitrophenole) -14-bromo-13- [2- (trifluoromethyl) benzyloxy] benzamide (VIII) Obtained in Production Example 8 described above. 4 To a solution of 1-tert-butyl-2--2-troaniline (28.6 g) in pyridine (300 ml) was added the compound (55.1 g) obtained in the above step 6) at room temperature with stirring. Stirred for 13 hours. After evaporating the solvent, 3N hydrochloric acid (400 ml) was added, and the mixture was extracted twice with ethyl acetate (800 ml). The organic layer was washed successively with 1 N hydrochloric acid (300 ml), saturated aqueous sodium hydrogen carbonate (300 ml) and saturated saline (300 ml), and dried over sodium sulfate. Further, the solvent was distilled off, and ethyl acetate (80 ml) and hexane (320 ml) were added, followed by stirring at room temperature for 1 hour. The precipitated crystals were collected to give the title compound (65.7 g) as yellow crystals.

Step 8) 5-tert-butyl-2- [4-bromo-3- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazonole hydrochloride ■ Hydrate (I)

To a solution of the compound (65.0 g) obtained in the above step 7) in acetic acid (650 ml) was added reduced iron (23.0 g), and the mixture was stirred at 120 for 5 hours. After allowing to cool, water (2000 ml) was added to the reaction solution, and extracted three times with ethyl acetate (1 000 ml). The organic layer was washed sequentially with water (500 ml) and saturated saline (500 ml), dried over sodium sulfate, and the solvent was distilled off. The obtained residue was azeotropically distilled with toluene (300 ml) to obtain pale yellow crude crystals (61.8 g).

Then, ethanol (390 ml) was added to the crude crystals (39.0 g), and 10

The mixture was dissolved by heating at 0 ^, and 6N hydrochloric acid (19.3 ml) and water (200 ml) were sequentially added dropwise, followed by stirring at room temperature overnight. The precipitated compound was collected by filtration to give the title compound (68.0 g) as white crystals.

Example 3 5-tert-Butyl-2— [4-chloro-1-3- (2— (trifluoromethine)> Penzinoleoxy] pheninole] Synthesis of benzoxazonole

Step 2) 4-Chloro-3- [2- (triphenyloleomethyl) benzyloxy] ethyl benzoate (IV)

To a solution of the compound (10. Og) obtained in the above step 1) of Example 1 in dimethylformamide (100 ml) was added lium carbonate (13.8 g). , 2- (Trifluoromethyl) benzyl chloride (7.62 g) was added, and the mixture was heated and stirred at 60 C for 2 hours. After allowing to cool, water (300 ml) was added to the reaction solution, extracted twice with ethyl acetate (200 ml), four times with water (200 ml), and saturated saline (200 ml). Was sequentially washed. After drying over sodium sulfate, the solvent was distilled off to obtain the title compound (17.9 g) as white crystals.

Step 5) 4- [1- (2- (trifluoromethyl) benzyloxy] benzoic acid (V)

To a solution of the compound (17.89 g) obtained in step 2) above in ethanol (75 ml) was added 4 N sodium hydroxide (25 ml), and the mixture was heated at 100 ° C for 1 hour. After refluxing, acetic acid (25 ml) was added. After allowing to cool, the mixture was further stirred for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (14.6 g) as white crystals.

Step 6) 4-—Mouth-3— [2- (Trifnoroleromethyl) pendinoreoxy] benzoyl mouth mouth (VI)

Oxalyl chloride was added to a mixed solution of the compound (12.Og) obtained in the above step 5) in a mixture of chloroform (120 ml) and dimethylformamide (0.10 ml) at room temperature with stirring. (4.75 ml) was added dropwise, and the mixture was stirred for 4 hours, and the solvent was distilled off. Toluene (50 ml) was added to the obtained residue, the insolubles were removed by filtration, and the solvent was distilled off to obtain the title compound (12.6 g) as white crystals.

Step 7) N— (5-tert-butyl-2-hydroxyphenyl) 1-41-chloro mouth 1-3- [2- (trifluoromethyl) pendinoleoxy] benzamide (VIII) To a solution of 4-amino-tetrafluoroethylene / lephenone (0.330 g) in 5 ml of pyridine (5 ml) was added pyridine (0.1 80 ml), and then the mixture was allowed to stand at room temperature. Under stirring, the compound (0.698 g) obtained in the above step 6) was slowly added, and the mixture was stirred at room temperature overnight. Ethyl acetate (20 ml) was added, and the mixture was washed sequentially with 1 N hydrochloric acid (20 ml), water (20 ml), and saturated saline (20 ml), and the solvent was distilled off to give the title compound as a crude product. I got

Step 8) 5-tert-butyl-2- [4-chloro-3- [2- (trifluoromethyl) benzinoleoxy] pheninole] benzoxazonole (I)

To a solution of the crude product obtained in the above step 7) in toluene (10 ml) was added p-toluenesulfonic acid monohydrate (0.400 g), and the mixture was heated under reflux at 130 ° C for 3 hours. After cooling, ethyl acetate (20 ml) was added, and the mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate (20 ml) and saturated saline (20 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: 1) to give the title compound (0.382 g) as white crystals.

Example 4

5 -t ert petit; ret 2— [4—black mouth 3— [2— (trifluoromethyl) phenyloxymethyl] pheninole] benzimidazole hydrochloride 'hydrate

Step 3) 4-chloro-3- [2- (trifluoromethyl) phenyloxymethyl] ethyl benzoate (IV)

2- (Trifluoromethyl) phenol was added to an acetone (5 Gm 1) solution of 4-cyclo-3- (bromomethyl) benzoyl benzoate (5.87 g) obtained in Production Example 4 described above. (4.86 g) and lithium carbonate (8.28 g) were added, and the mixture was stirred at room temperature overnight. The insoluble material was filtered off and the solvent was distilled off, the obtained residue was purified by silica gel column inlet Mato chromatography (developing solvent: hexane: acetic acid Echiru = ⁹ 5: 5) white solid of the title by the purification child in The compound (6.60 g) was obtained.

Then, using the compound obtained in the above step 3), the above-mentioned Example 1 or Example 2 was used. Step 5) to Step 8> above) to give the title compound 5-tert-butynole 2- [4-chloro-3- [2- (trifluoromethylinole) phenyloxymethyl] phenyl] benzimidazo Le hydrochloride hydrate was obtained.

Example 5

5-tert-butynole 2- (4-chloro-3- [2- (triphenylolenomethylen) phenyloxy] phenyl] benzimidazole hydrochloride 'Hydrate Step 2) .4—Cross 1-3- [2— ( Trifluoromethyl) phenyloxy] ethyl benzoate (IV)

To a solution of the compound (3.99 g) obtained in Step 1> of Example 1 above in pyridine (40 ml) was added lithium carbonate (13.8 g) and copper chloride (I) (1.98 g). 1) Addition of potassium chloride and notrifluoride (6.53 g) were added, and the mixture was stirred overnight at 140 ° C under an argon atmosphere. After release, ethyl acetate (5 Om) was added to the reaction solution, and neutralized with 6N hydrochloric acid (100 ml). After filtering off the insoluble matter, the solution was extracted twice with ethyl acetate (50 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 9: 1) to give the title compound (0.876 g) as a yellow solid.

Then, using the compound obtained in the above step 2), the reaction is carried out in the same manner as in the steps 5) to 8) of the above-mentioned Example 1 or Example 2, whereby the title compound 5-tert-butyl-1-2- is obtained. [4-Chloro-1- [2- (trifluoromethyl) phenyl] phenyl] benzimidazole hydrochloride hydrate was obtained.

Example 6

5-tert-butyl-1 2 -— [4-chloro-3 -— [2- [2- (methyl triphenyl) phenyl] ethoxy] phenyl] benzimidazole hydrochloride 'hydrate

Step 2) 4-chloro-3- [2- [2- (trifluoromethyl) phenyl] ethoxy] ethyl benzoate (IV)

The compound (0.798 g) obtained in step 1) of Example 1 described above was treated with anhydrous tetrahydrofuran. To a solution of drofuran (5 ml) was added 2- (trifluoromethyl) phenethyl alcohol (0.762 ml) and triphenylphosphine (1.36 g). To this reaction solution, acetyl dicarboxylate (0.818 ml) was added dropwise while stirring under ice cooling, and the mixture was stirred for 1 hour. The mixture was further stirred at room temperature overnight, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate 9: 1) to give the title compound (0.80 lg) as a colorless oil. Then, the compound obtained in the above step 2) is reacted in the same manner as in the steps 5) to 8) of the above-mentioned Example 1 or Example 2 to give the title compound 5-tert-butynole 2- [ 4-Chloro-3- [2- [2- (triphenylolemethinole) phenyl] ethoxy] phenyl] benzimidazole hydrochloride 'hydrate was obtained. Example 7

5—tert-butynole 2 -— [4-chloro-3— [2-—2— (tri-norole methinole) pheninole] ethyl] phenyl] benzimidazonole hydrochloride Step 3) 4-chloro-3 — [2-— [2 -— (trifluoromethyl) furyl] ethyl] ethyl benzoate (IV)

Tetrakis (triphenylphosphine) palladium (0.139 g) was added to a solution of zinc powder (0.785 g) in dimethoxetane (20 ml), and the mixture was stirred at room temperature with stirring as described above. The dimethoxetane of 4-chloro-3- (promomethyl) benzoyl benzoate (1.67 g) and 2- (trinoleolomethyl) benzinole bromide (1.44 g) obtained in Production Example 4 ( 10 ml) The solution was added dropwise. After stirring for 2 hours, the reaction solution was filtered through celite, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: hexane ethyl acetate == 15: 1) to give the title compound (0.895 g) as a colorless oil.

Next, the compound obtained in the above step 3) is reacted in the same manner as in steps 5) to 8) of the above-mentioned Example 1 or Example 2 to give the title compound, 5-tert-butynole 2- 1- [2- [2- (triphenylenomethinophenyl) phenyl] ethyl] phenyl] benzimidazole hydrochloride was obtained. Example 8

5-tert-petit / lae 2-[3-chloro-1-5-[2-(trifnoreomethyl) benzyloxy, n] phenyl] benzimidazole hydrochloride-hydrate Step 10 0) 3-d Toro 5— [2— (Trifluoromethinole) penzinoleoxy] ethyl benzoate (XI)

To a solution of ethyl 3,5-dinitrobenzoate (4.00 g) in dimethylformamide (3 Oml) was added potassium carbonate (4.60 g) and 2- (trifluoromethyl) benzyl alcohol (2. .2 1 ml) was added, and the mixture was heated and stirred at 120 ° C. for 8 hours. After cooling, water was added, and the mixture was extracted twice with ethyl acetate (40 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 9: 1) ′ to give the title compound (3.28 g) as a pale-yellow oil.

Step 1 1) 3-Amino-5- [2- (Trifluoromethyl) benzyloxy] ethyl benzoate (XTI)

To a mixed solution of the compound (3.28 g) obtained in the above step 10) in ethanol (20 ml), tetrahydrofuran (10 ml) and water (5 ml) was added reduced iron (1.98 g) and ammonium chloride. (1.90 g) was added, and the mixture was heated and refluxed at 100 for 4 hours. After cooling, insolubles were removed by filtration, water (40 ml) was added to the filtrate, and the mixture was extracted twice with ethyl acetate (40 ml). After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 3) to give the title compound (2.79 g) as yellow crystals. Obtained.

Step 1 2) 3-Chloro-5- [2- (trifluoromethyl) benzyloxy] ethyl benzoate (IV)

Concentrated hydrochloric acid (10 ml) was added to a solution of the compound (2.45 g) obtained in the above step 11) in acetic acid (30 ml), and then sodium nitrite (0.548 g) was added under ice cooling. After a water (5 ml) solution was added dropwise, the mixture was stirred for 1 hour. Then, the reaction solution was slowly added to a suspension of copper (I) chloride (1.07 g) and concentrated hydrochloric acid (10 ml) under ice-cooling. After stirring for 1 hour, the mixture was further stirred at room temperature for 1 hour. The reaction solution was extracted twice with ethanol acetate (40 ml), and the organic layer was extracted twice with water (40 ml), saturated aqueous sodium hydrogen carbonate (40 ml), and saturated saline (40 ml). It was washed successively and dried over sodium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate 9: 1) to give the title compound (1.44 g) as a yellow oil. Obtained.

Next, the compound obtained in the above step 12) is reacted in the same manner as in steps 5) to 8) of the above-mentioned Example 1 or Example 2 to give the title compound 5-tert-butynol 2- 3- [1- (triphenylenolomethinole) benzoyloxy] phenyl] benzimidazole hydrochloride .hydrate was obtained.

Example 9

5-tert-butyl-1 2- [2,4-dichloro-5- [2- (triphenylenomethyl) benzyloxy] phenyl] benzimidazole hydrochloride -hydrate

Step 1 3) 2,4-Dichloro-5--2 trophenol (XIV)

Concentrated hydrochloric acid (20 ml) was added to a solution of 2-amino-4-chloro-5-nitrophenol (10. Og) in water (40 ml), and sodium nitrite (3.84 g) was stirred under ice-cooling. ) In water (10 ml) was added dropwise and stirred for 30 minutes. Next, the reaction solution was slowly added to a solution of copper chloride (I) (2.89 g) and concentrated hydrochloric acid (10 ml) in a mouthpiece (40 ml) at 40 ° C and stirred for 1 hour. did. After allowing to cool, extract twice with ethyl acetate (50 ml), wash three times with water (100 ml), wash with saturated aqueous sodium hydrogen carbonate (100 ml) and saturated saline (100 ml) sequentially And dried over sodium sulfate. The title compound (10.6 g) was obtained as a brown solid by evaporating the solvent. Process 1 4) 5-Amino-2,4-dichlorophenol (XV)

Step: The compound (10.6 g) obtained in 13) was reduced (11.4 g) in a mixed solution of ethanol (100 ml), tetrahydrofuran (50 ml) and water (25 ml). ) And ammonium chloride (10.9 g), and heat at 100 for 1 hour under reflux. did. After cooling, insolubles were removed by filtration, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 2: 1) to give the title compound (6.53 g) as an orange solid.

Process 1 5) 2,4-Dichloro-5-odophenol (XVI)

To a mixture of the compound (5.00 g) obtained in the above step 14) and 6N hydrochloric acid (50 ml) was added sodium nitrite (2.03 g) in water (6 ml) while stirring under ice-cooling. ) After the solution was dropped, the mixture was stirred for 1 hour. Further, a solution of sodium iodide (4.42 g) in water (6 ml) was added dropwise, and the mixture was stirred at 4 for 1 hour. After cooling, an aqueous solution of sodium bisulfite was added until the brown color disappeared, and the mixture was extracted twice with ethyl acetate (50 ml). The organic layer was washed with water (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml), and saturated saline (50 ml) in that order, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give the title compound (4.97 g) as a yellow solid.

Step 1 6) 2 — [(2,4-Dichloro-5-phosphorinyloxy) methyl] benzotrifluoride (XVI I)

To the dimethylformamide (20 ml) of the compound (2.00 g) obtained in the above step 15) was added potassium carbonate (1.91 g) and 2- (trifluoromethyl) benzyl chloride (1 .06ml) and stirred at 60 for 1 hour. After cooling, water (60 ml) was added, and the mixture was extracted twice with ethyl acetate (50 ml), washed three times with water (50 ml), and washed successively with saturated saline (50 ml). After drying over sodium sulfate, the solvent was distilled off to obtain the title compound (2.92 g) as a yellow solid.

Step 17) 2,4-Dichroic 5- (2- (trifluoromethyl) benzyloxy) benzonitrile (XVI I I)

To a solution of the compound (2.93 g) obtained in the above step 16) in dimethylformamide (30 ml) was added zinc cyanide (0.500 g) and tetrakis (triphenylphosphine) palladium (0.378). g) was added, and the mixture was stirred overnight at 120 under an argon atmosphere. After cooling, add water (90 ml), and add ethyl acetate (50 ml) twice. Extracted. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ether acetate-15: 1: 1 to 9: 1) to give the title compound (1, 4) as a yellow solid. 8 g) were obtained.

Step 1 8) 2,4-Dichloro-5- [2- (trifluoromethyl) benzyloxy] benzoic acid (V).

To a solution of the compound (0.780 g) obtained in step 17) above in ethylene glycol (8 ml) was added a 4 N aqueous sodium hydroxide solution (2. For 4 hours. After cooling, 1N hydrochloric acid (20 ml) was added, and the mixture was extracted twice with ethyl acetate (50 ml). After evaporating the solvent, the obtained residue was suspended in 20% aqueous ethanol (20 ml), and the insoluble material was collected by filtration to obtain the title compound (0.752 g) as a white solid. Was.

Next, the compound obtained in the above step 18) is reacted in the same manner as in steps 6) to 8) of Example 1 or Example 2 described above to give the title compound 5-tert-butyl-1-2. — [2,4-Dichloro-5- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride 'hydrate was obtained.

5-tert-butyl 1-butyl 2- [2-chloro-5- [2- (trifluoromethyl) benzyloxy] f; t-nyl] benzimidazole Synthesis of hydrochloride

Process 1) 2—Chloro-5—Ethyl hydroxybenzoate (I I I)

To a solution of the crude product obtained in Production Example 2 above in ethanol (20 ml) was added concentrated sulfuric acid (0.200 ml), and the mixture was heated and refluxed at 100 for 5 hours. After cooling, the solvent was distilled off, a saturated aqueous sodium hydrogen carbonate solution (20 ml) was added, and the mixture was extracted twice with ether (20 ml). The organic layer was washed successively with water (20 ml) and saturated saline (20 ml), and dried over sodium sulfate. The title compound (1.61 g) was obtained as a pale yellow solid by distilling off the solvent.

Next, the compound obtained in the above step 1) is reacted in the same manner as in the step 2) and the steps 5) to 8) of the above-mentioned Example 1 or Example 2 to thereby give the title compound ' 5-tert-butyl-2- [2-chloro-5- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride was obtained.

Example 1 1

5-tert-Butynole 2-[4-1-3-[2-(trifluoromethyl) benzylthio] phenyl] Synthesis of benzimidazole hydrochloride

Using the compound obtained in the above-mentioned Production Example 3, and reacting in the same manner as in the above-mentioned Example 1 or Example 2, the title compound 5-tert-butyl-2- [4-chloro-1- [2- — (Trinorelomethinole) ben. Dinorethio] phenyl] benzimidazole hydrochloride was obtained.

Example 1 2

6-tert-Butyl-2- [4-chloro-3_ [2- (trifluoromethynorole) benzyloxy] phenyl] -11-methylbenzimidazole hydrochloride 'Hydrate synthesis

Step 7) 1 ^ _ (2—1 6 1 "1: —Butoxycarburylamino 5—tert—Butylphenyl) -14-Chloro-N-Methylenol 3 -— [2- (Trifluoromethyl) benzyloxy) benzami De (VIII)

Pyridine (10 ml) was added to a solution of 5-tert-butyl-2- (tert-butoxycarbo-lamino) -N-methinorea diline (0.621 g) in toluene (10 ml) obtained in Production Example 11 described above. After adding the compound (0.778 g) obtained in the above-mentioned step 6) of Example 3 under stirring at room temperature, the mixture was stirred for 5 hours. 'Ethyl acetate (30 ml) was added, washed with water (20 ml) and saturated saline (20 tn 1) sequentially, dried over sodium sulfate, and the solvent was distilled off. Hexane (10 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (1.30 g) as white crystals.

Step 8) 6-tert-butyl-2- [4-chloro-3- [2- (trifluoromethyl) benzyloxy] phenyl] -111-methylbenzimidazole hydrochloride monohydrate (I) To a solution of the compound (1.30 g) obtained in the above step 7) in ethanol (6 ml) was added 6 N hydrochloric acid (13 ml), and the mixture was heated under reflux at 100 ° C. for 1 hour. After water (6 ml) was added dropwise, the mixture was allowed to cool and stirred for 1 hour. The precipitated crystals were collected by filtration to give the title compound (0.980 g) as white crystals.

Example 13

6-tert—butynole 2— [4—black mouth 3— [2— (trifluorometinole) penzinoleoxy] pheninole] Benzoxazo monole

Using the compound obtained in step 6) of Example 3 and the 5-tert-butyl-2-aminophenol hydrochloride obtained in Production Example 12 described above, Step 7) to Step 8 of Example 3 described above were performed. ) To give the title compound, 6-tert-butynole-l 2- [4-chloro-3- [2- (trifnorelomethinole) benzyloxy] phenyl] benzoxazole.

Example 14

5 -t e r t —Butyl-2 -— [4-trimethyl-3- (2- (trifluoromethyl) benzyloxy] phenyl) -11-Methylbenzimidazole hydrochloride · hydrate

The compound obtained in the step 6) of the above-mentioned Example 3 and the 4-tert-butyl-N-methyl-2-nitro-2-line obtained in the above-mentioned Production Example 9 were used. By reacting in the same manner as in Steps 7) to 8) of Example 2, the title compound 5-tert-butyl-2- [4-chloro-3- [2- (trifluoromethylinole) benzyloxy] phenyl] —1-methinole Benzimidazonole hydrochloride 'hydrate was obtained.

Example 15

5- (1,1-Dimethylpropyl) 1-2- [4-chloro-3_ [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride 'Hydrate

The compound obtained in Step 6 of Example 3 described above and the compound 4 obtained in Production Example 13 described above -The reaction was carried out in the same manner as in Steps 7) to 8) of Example 1 or Example 2 using ertamoyl-2-nitroaniline, to give the title compound 5- (1,1, -dimethylpropyl) -1-amine. 2- [4-Chloro-3- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazol hydrochloride 'hydrate was obtained.

Example 16

6-tert-butynole-1-chloro-2-[[4-chloro-3-] [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride.Synthesis of hydrate

Using the compound obtained in Step 6 of Example 3 and 4-tert-butyl-2-chloro-6-nitroaniline obtained in Production Example 14 described above, Example 1 or Example By reacting in the same manner as in Steps 7) to 8) of Step 2), the title compound, 6-tert-butynole-1,4-chloro-2- [4-chloro-3- [2- (triphenylenoleomethyl) benzyloxy] phenole, is obtained. A benzimidazo monohydrochloride hydrate was obtained.

Example 17

5-tert-Butyl-2- [4-chloro-3- (4-bromo-12- (trifluorophenol) -benzyloxy] pheninole] benzimidazolone hydrochloride hydrate

A reaction was conducted in the same manner as in Example 1, except that 5-bromo-12- (bromomethyl) benzotrifluoride was used in place of the 4-phnoleo-1- (trifluoromethyl) benzinolepromide in Example 1 described above. Thus, the title compound, 5-tert-butynole 2- [4-chloro-1--3- [4-bromo-12- (triphenylenomethyl) benzyloxy] phenyl] benzimidazol hydrochloride.hydrate was obtained. Example 18

5-tert-Butyl-2- [4-chloro-3- (2-cyanobenzyloxy) fuunil] benzimidazole hydrochloride.Synthesis of hydrate Using 2-cyanobenzyl bromide instead of 4-fluoro-2- (trifluoromethyl) benzyl bromide in Example 1 described above, the reaction was carried out in the same manner as in Example 1 to give the title compound, 5-tert-butyl butyl. 2- [4-Chloro-3- (2-cyanobenzyloxy) phenyl] benzimidazole hydrochloride monohydrate was obtained.

Example 19

5-tert-butyl-1-2- [4-cyano-3- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazol hydrochloride 'Hydrate synthesis process 2 9〉 5-tert-butyl-1-2- 4-cyano-3- (2- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride hydrate (I)

Zinc cyanide (0.140 g) and tetrakis (tripheninolephosphine) were added to dimethylformamide (1 O ml) of the compound (1.0 g) obtained in Example 2 described above. Palladium (0.115 g) was added, and the mixture was heated under reflux at 160 under an argon atmosphere for 5 hours. After cooling, water (20 ml) was added, and the mixture was extracted twice with ethyl acetate (20 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 7: 3), and the precipitated crystals were dissolved by heating in ethanol (14 ml), and then dissolved in 6N hydrochloric acid (0. 40 ml) and water (2.8 ml) were sequentially added dropwise. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration to give the title compound (0.558 g) as white crystals.

Example 20

5 -t ert—butynole 2 -— [4-chloro-1--3-(, 2-rubamoylbenzinoleoxy) phenyl] benzimidazole hydrochloride hydrate

Step 2 7) 5-tert-butyl-2- [4-chloro-3- (2-carboxybenzyloxy) phenyl] benzimidazole (XXIV)

To a solution of the compound (0.400 g) obtained in Example 18 above in ethylene glycol (6 ml) was added a 4N aqueous sodium hydroxide solution (2 ml). The mixture was heated to reflux for some time. After cooling, 6N hydrochloric acid (2 ml) and water (5 ml) were sequentially added, and the mixture was further stirred for 30 minutes. The precipitated crystals were collected by filtration to give the title compound (0.420 g) as white crystals.

Step 28) 5-tert-Butyl-2-[[4-chloro-3- (2-force rubamoylbenzyloxy) phenyl] benzimidazole hydrochloride 'hydrate (I) The compound obtained in the above step 27) (0. 400 g) in a solution of dimethylformamide (5 ml) in 1-hydroxybenzotriazole (0.130 g), ammonium chloride (0.064 g), 1-ethyl-3- (3 —Dimethylaminopropinole) Carbodiimide hydrochloride (0.168 g) and triethylamine (0.334 ml) were added, and the mixture was stirred at room temperature for 10 hours. Water (20 ml) was added, and the mixture was extracted three times with ethyl acetate (20 ml), washed successively with water (20 ml) and saturated aqueous sodium hydrogen carbonate (2 Oml), and then the solvent was distilled off. . Ethanol (4 ml) was added to the obtained residue, the mixture was heated to 100, and 6 N hydrochloric acid (0.22 ml) and water (1.2 ml) were sequentially added dropwise. After cooling, the mixture was stirred for 1 hour, and the precipitated crystals were collected by filtration to obtain the title compound (0.319 g) as white crystals.

Example 2 1

2 -— [4-one-mouth-one 3 -— [2- (tri-frenoleolomethinole) pendinoleoxy] phenyl] -1-5-furbenzimidazole hydrochloride

Step 7) N— (4-Bromo-2-nitrophenyl) 1-4-Chloro-3 -— [2- (trifluoromethyl) benzyloxy] benzamide (V I I)

In a pyridine (100 ml) solution of 4-bromo-2-nitroaniline (4.99 g) obtained in Production Example 15 described above, the mixture was obtained in Step 6) of Example 3 described above under stirring at room temperature. The obtained compound (7.99 g) was added little by little. After stirring at room temperature overnight, water (200 ml) was added, and the mixture was further stirred for 1 hour. The precipitated crystals were collected by filtration to give the title compound (10.9 g) as yellow crystals.

Step 8) 5-bromo-1- [4-chloro-3- [2- (trifluoromethyl) benzyloxy] phenyl] benzimidazol (XX III) To a solution of the compound (10.9 g) obtained in the above step 7) (10.9 g) in ethyl acetate (400 ml) was added tin (II) chloride dihydrate (18.6 g), and the mixture was stirred at 80 ° C overnight. Stirred. After cooling, add 1N aqueous sodium hydroxide (400 ml), extract twice with ethyl acetate (30 Oml), wash twice with water (200 ml), and then with saturated saline (200 ml). did. After drying over sodium sulfate, the solvent was distilled off, acetic acid was added, and the mixture was stirred at 100 ° C for 1 hour. After cooling, the solvent was distilled off and azeotroped twice with toluene (100 ml). Hexane (100 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (9.18 g) as white crystals.

Step 26) 2- [4-Chloro-3 -_ [2- (trifluoromethyl) benzyloxy] phenyl] -1-5-phenylbenzimidazole hydrochloride (I)

To a mixed solution of the compound (2.50 g) obtained in the above step 8) in ethanol (25 ml) and toluene (50 ml) was added a 2 M aqueous sodium carbonate solution (6.90 ml), phenylboronic acid (0.84). 3 g) and tetrakis (triphenylphosphine) palladium (0.266 g) were added, and the mixture was stirred overnight at 110 ° C under an argon atmosphere. After allowing to cool, ethyl acetate (200 ml) was added, and the mixture was washed twice with water (100 ml) and sequentially with saturated saline (100 ml), and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography; 7- 1 (developing solvent; hexane: ethyl acetate = 7: 3) to obtain a white solid (2.09 g).

Next, the obtained white solid was dissolved by heating in ethyl acetate (100 ml), 4N ethyl monoacetate hydrochloride (5 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to give the title compound (1.97 g) as white crystals.

Example 22 to Example 45

Compounds in Tables 7 to 13 were obtained in the same manner as in Example 1 or Example 2 described above.

Example 46

5-tert-Petit / Ray 2— [4 B) Phenyl] Synthesis of benzimidazole hydrochloride 'hydrate

Step 2 3) 3-Acetoxy-l 4-cyclobenzoyl alkyd (XX ') The 3-acetoxy-4-l-chlorobenzoic acid (9.44 g) obtained in Production Example 5 above was obtained. To a dichloromethane (50 ml) solution was added a solution of oxalyl chloride (5.23 ml) in dimethylformamide (0.04 OmU), and the mixture was stirred at room temperature for 3 hours, and the solvent was distilled off. l) was added, and the insoluble material was filtered off. The solvent was distilled off to obtain the title compound (10.3 g) as white crystals.

Step 24) N— (2-tert ebut—butoxycanoleponinoleamino-5-tert—butyl phenol) · ~ 4-chloro-3-hydroxyhydroxybenzamide (XXI ')

In a toluene (10mi) solution of the compound (1.16 g) obtained in the above step 23), 5-tert-butyl 2- (tert-butoxycarbonylamino) obtained in Production Example 10 described above was added. Add aniline (1.32 g) and pyridine (0.808 ml), stir at room temperature for 30 minutes, add water (20 ml), extract twice with ethyl acetate (30 ml), and add water (20 ml). After washing sequentially with 20 ml) and saturated saline (20 ml), the mixture was dried over sodium sulfate, and the solvent was distilled off.

Next, methanol (25 ml) and potassium carbonate (1.38 g) were added to the obtained residue, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off, saturated aqueous ammonium chloride (50 ml) was added, and the mixture was extracted twice with ethyl acetate (50 ml), and dried over sodium sulfate. The solvent was distilled off to obtain the title compound (2.05 g) as a white solid.

Step 25) N- (2-tert-butoxycanolebonylamine) 5-tert-butynolephen-2-ole-4-chloro-3- (2-2-trobenzinoleoxy) benzamide (VIII)

To a solution of the compound (2.05 g) obtained in the above step 24) in acetone (20 ml) was added potassium carbonate (1.35 g) and 2-nitrobenzyl bromide (1.05 g). The mixture was stirred overnight. After the solvent was distilled off, water (40 ml) was added, extracted twice with ethyl acetate (40 ml), and dried over sodium sulfate. Evaporate the solvent The title compound (2.32 g) was obtained as a white solid.

Step 8) 5-tert-butyl-1-2- [4-chloro-3- (2--2-trobenzyldioxy) phenyl] benzimidazole hydrochloride.hydrate (I)

6N hydrochloric acid (3.00 ml) was added to a solution of the compound (1.00 g) obtained in the above step 25) in ethanol (10 ml), and the mixture was heated under reflux at 100 for 2 hours, and then added with water ( 2.0 ml) was added dropwise. After allowing to cool, the mixture was further stirred for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (0.75 g) as white crystals.

Example 4 7

5-tert-Butyl-2-[4-chloro-one 3-] [2- (tri-phenolic-methyl) -benzylamino] phenyl] benzimidazonole hydrochloride.Synthesis of hydrate Step 1 9) 4 3-Nitrobenzoyl chloride (XX)

To a mixed solution of 4-chloro-3-nitrobenzoic acid (40.3 g) in clonor honolem (400 ml) and dimethylformamide (0.400 ml) was added oxalyl chloride (26.2 m After l) was added dropwise over 15 minutes, the mixture was stirred overnight. The solvent was distilled off, toluene (200 ml) was added, the insoluble material was removed by filtration, and the solvent was distilled off. Thus, the title compound (44.7 g) was obtained as a crude yellow product.

Step 20) N— (4-tert ebutynole 2--2-trophenyl) 1-41-black mouth—3-nitrobenzamide (XXI)

In a pyridine (400 ml) solution of 4-tert-butyl-2-nitroaniline (40.8 g) obtained in Production Example 8 described above, it was obtained in the above step 19) under stirring at room temperature. The compound (44.7 g) was added, and the mixture was stirred for 3 hours. After the solvent was distilled off, ethyl acetate (1500 ml) was added, and the mixture was washed twice with 1 N hydrochloric acid (500 ml), sequentially with water (500 ml) and saturated saline (500 ml), and then washed with sulfuric acid. Dried with sodium. The solvent was distilled off, and ethyl acetate (60 ml) and hexane (240 ml) were added. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (61. 6 g) was obtained.

Step 2 1) 5-tert-Butyl-1- (3-amino-4-monophenyl) Benzi Midazonole (XX II)

To a solution of the compound (61.6 g) obtained in the above step 20) in acetic acid (70 Om〗), add reduced iron (54.6 g), and heat at 130 ^: for 1.5 hours. Stirred. After allowing to cool, water (350 ml) was added, extracted twice with ethyl acetate (150 ml), twice with water (700 ml) and carbonated water (5 ml). 00ml) and a saturated saline solution (500 ml). After drying over sodium sulfate, the solvent was distilled off to obtain the title compound (49.8 g) as pale yellow crystals.

Step 2 2) 5-tert-butyl-1-2- [4-chloro-1-3- (2- (trifnorolomethyl) benzylamino] phenyl] benzimidazole hydrochloride 'hydrate (I)

To a solution of the compound (49.8 g) obtained in the above step 21) in toluene (500 ml) was added 2- (trifluoromethyl) benzaldehyde (57.8 g), and 13 The mixture was refluxed with O ^ C for 48 hours. After allowing to cool, the solvent was distilled off, methanol (500 ml) was added, and the mixture was further stirred at room temperature overnight. The precipitated crystals were collected by filtration and dissolved in a mixed solvent of tetrahydrofuran (800 ml) and methanol (200 ml). To this reaction solution, sodium borohydride (8.90 g) was added little by little over 20 minutes under ice-cooling, followed by stirring at room temperature for 2 hours. Saturated saline (300 ml) was added, extracted twice with ethyl acetate (500 ml), and washed twice with saturated saline (500 ml). After drying over sodium sulfate, the solvent was distilled off to obtain a yellow amorphous solid (56.6 g).

Then, a solution of the obtained solid (35.0 g) in ethanol (350 ml) was heated to 100, and 6N hydrochloric acid (19.1 ml) and water (70 ml) were successively added. After the dropwise addition, the mixture was stirred at room temperature overnight. The precipitated crystals were collected by filtration to give the title compound (30.4 g) as pale yellow crystals.

Example 4 8

5-tert-butino! ^ I 2— [4-Chloro-3 -— [5-Funoleolol 2 -— (Trifluoromethinole) benzyloxy] phenyl] Benzimidazol hydrochloride 'Water Synthesis of Japanese

Step 2) 4-—Port 3— [5-Funoleo-methyl 2 (tri-Fnoroleolomethyl) benzoyloxy] Ethyl benzoate (IV)

A mixture of the compound (18.1 g) obtained in the step 1) of Example 1 described above, dimethylformamide (20 Om 1), and potassium carbonate (24.8 g) was added at room temperature to the above mixture. 5-Fluoro-2- (trifluoromethyl) benzyl bromide (24.2 g) obtained in Production Example 16 was added thereto, and the mixture was stirred overnight. After stirring, water (400 ml) was added to the reaction solution, and extracted twice with ethyl acetate (150 ml). The organic layer was washed with water (200 ml) three times, dried over sodium sulfate, and evaporated to give the title compound (36.9 g) as a yellow oil.

Step 5) 4-Black 3-[5-Funoleol 2- (triphenylolemethyl) benzoyloxy] Benzoic acid (V)

To a solution of the compound (36.9 g) obtained in the above step 2) in ethanol was added a 4 N aqueous sodium hydroxide solution (34. Oml), and the mixture was heated under reflux for 1.5 hours. Thereafter, acetic acid (23.5 ml) and water (280 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration to give the title compound (30.9 g) as white crystals.

Step 6) 4-—Mouth 3— [5-Fluoro-2 _ (trifluoromethyl) benzyloxy] benzoyl chloride (VI)

To a mixed solution of the compound (30.7 g) obtained in the above step 5) in a mixture of chloroform (150 ml) and dimethylformamide (0.1 lm) was added oxalyl chloride (9.21 ml) at room temperature. ) Was added dropwise and stirred for 1.5 hours. After stirring, the solvent was distilled off, toluene (300 ml) was added, and the insoluble matter was removed by filtration. The title compound (32.3 g) was obtained as white crystals by evaporating the solvent of the obtained residue.

Step 7) N— (4-tert e-t-butyrezii 2-nitropheninole) 1-41-chloro-

3-[5-Funoleolo 2-(Triphnoreolomethinole) Penzinoleoxy] benzamide (VIII) In a pyridine (200 ml) solution of 4-tert-butyl-2-tronitrolin (16.9 g) obtained in Production Example 8 described above, it was obtained in the above step 6) at room temperature. The compound (31.9 g) was added, and the mixture was stirred at room temperature for 2 hours. Further, water (40 Om〗) was added, and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to give the title compound (43.2 g) as yellow crystals.

Step 8) 5-tert-butyl-2- [4-chloro-3- [5-funoleolor 21- (trifluoromethyl) benzyloxy] phenyl] benzimidazole hydrochloride-hydrate (I)

A mixture of the compound (43.Og), acetic acid (450m) and reduced iron (16.Og) obtained in the above step 7) was heated under reflux at 13 for 3 hours. After allowing to cool, water (200 ml) was added, and the mixture was extracted twice with ethyl acetate (100 ml). After the obtained organic layer was washed twice with water (500 ml), the solvent was distilled off.

Then, ethanol (400 ml) was added to the residue, dissolved by heating, and 6 N hydrochloric acid (27.3 ml) and water (120 ml) were sequentially added dropwise. After cooling, the mixture was stirred at room temperature for 3 hours, and the precipitated crystals were collected by filtration to give the title compound (41.3 g) as white crystals.

Example 4 9

5-tert-butyl-1-2- [4-cyano-3- (5-fluoro-2- (trifluoromethyl) benzylamino] phenyl] benzimidazole hydrochloride

Step 1 9) 4-Bromo-3-nitrobenzoyl chloride (XX)

A mixed solution of 4-promo-3-nitrobenzoic acid (61.5 g) obtained in the above-mentioned Production Example 18 (500 ml) and dimethylformamide (0.5 ml) of 3-nitrobenzoic acid (61.5 g) To the mixture, oxalyl chloride (48. 2 ml) was added dropwise at room temperature, and the mixture was stirred overnight. The solvent was distilled off, toluene (300 ml) was added, the insolubles were filtered off, and the solvent was distilled off to obtain the title compound (64.4 g) as yellow crystals.

Step 20) 4-Bromo-N- (4-tert-butynole 2-nitole mouth) One 3-nitto vent (XX I)

The compound (64) obtained in the above-mentioned step 19) was added at room temperature to a solution of 4-tert-butyl-2-nitroaniline (42.7 g) obtained in Production Example 8 above in pyridine (400 ml). .0 g) was added and stirred for 2 hours. Further, water (800 ml) was added, and the mixture was stirred for 1 hour. The precipitated crystals were collected by filtration to obtain the title compound (73.9 g) as yellow crystals.

Step 2 1) 5-tert-Butyl-1- (3-amino-4-bromophenyl) benzimidazole (XXII)

To a solution of the compound (71.8 g) obtained in the above step 20) in acetic acid (700 ml) was added reduced iron (66.4 g), and the mixture was heated under reflux for 2 hours. After allowing to cool, add water (3500 ml), extract with ethyl acetate (1 000 ml), extract 2 冋, water (1 000 ml), carbonated water (500 ml), water (1 000 ml) , And washed successively with saturated saline (1 000 ml). After drying over magnesium sulfate, the solvent was distilled off to obtain a purple amorphous title compound (69.0 g).

Process 29) 5-tert-butyl-2- (3-amino-4-cyanophenyl) benzimidazo

To the compound (69.0 g) obtained in the above step 21), zinc cyanide (12.0 g) and tetrakis (triphenylphosphine) palladium (3.93) were added to dimethylformamide (400 ml). g) was added, and the mixture was stirred at 180 with stirring for 15 hours. After cooling, insoluble materials were removed by filtration, water (1000 ml) was added, and the mixture was extracted three times with ethyl acetate (500 ml). The obtained organic layer was washed three times with water (500 ml) and sequentially with saturated saline (500 ml), dried over magnesium sulfate, and the solvent was distilled off. Ether (200 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (37.5 g) as a pale yellow crystal.

Step 22) 5-tert-butyl-2- [4-cyano-1- [5-fluoro-2- (triphenylenomethino) penzinoleamino] fenii / le] benzii midazo monole hydrochloride (I) W

In a solution of the compound (29.0 g) obtained in the above step 29) in toluene (50 Om 1), the 5-fluoro-2- (trifluoromethyl) benzylaldehyde obtained in the above-mentioned Preparation Example 19 was added. (23.1 g) was added, and the mixture was heated under reflux for 12 hours. After cooling, the solvent was distilled off, the residue under ice-cooling, tetra Bidorofuran sodium borohydride (7. 5 7 g) (30 O m 1) and methanol (5 Om 1) was added to a mixed solution . After stirring for 1 hour, water (500 ml) was added, and the mixture was extracted twice with ethyl acetate (500 ml). The organic layer was washed three times with a saturated saline solution (500 ml), dried over sodium sulfate, and the solvent was distilled off.

Next, ethanol (460 ml) was added to the obtained residue, and the mixture was heated and dissolved. Then, 6N hydrochloric acid (34. Oml) and water (135 ml) were sequentially added dropwise. After cooling, the mixture was stirred overnight, and the precipitated crystals were collected by filtration to give the title compound (37.5 g) as yellow crystals.

Example 50

5-tert-Butyl-2-[4-Cyan-3-3- [5-Fluoro-2- (tri-frenoleolomethinole) penzinoleoxy] pheninole] Benzimidazole Hydrate '

Step 2) 4-cyano 3- [5-fluoro-2- (trifluoromethyl) benzyloxy] ethyl benzoate (IV)

Of 4-cyano 3-hydroxyethyl benzoate (19.9 g), dimethylformamide (20 Ora 1) and lithium carbonate (28. 1 g) obtained in Production Example 17 described above. To the suspension was added 5-fluoro-2- (trifluoromethyl) benzyl bromide (26.0 g) obtained in Production Example 16 above at room temperature, and the mixture was stirred overnight. After stirring, water (600 ml) was added, and the mixture was extracted twice with ethyl acetate (500 ml), washed three times with water (500 ml) and sequentially with saturated saline (500 ml). After drying over sodium sulfate, the solvent was distilled off. Ethyl acetate (40 ml) and hexane (320 ml) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour, and the precipitated crystals were collected by filtration to give the title compound (31. 2 g) was obtained. Step 5) 4-cyano 3- [5-fluoro-2- (trifluoromethyl) benzyloxy] benzoic acid (V)

To a solution of the compound (31.2 g) obtained in the above step 2) in ethanol (128 ml) was added a 4 N aqueous sodium hydroxide solution (32 ml), and the mixture was heated under reflux for 1 hour. Thereafter, acetic acid (32 ml) and water (96 ml) were sequentially added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration to give the title compound (26.9 g) as white crystals.

Process 6) 4-cyano 3- [5-fluoro-2- (trifluoromethyl) benzyloxy] benzoyl chloride (VI)

A solution of the compound (26.9 g) obtained in the above step 5) in a mixed solution of chloroform (270 ml) and dimethylformamide (0.27 ml) was mixed at room temperature with oxalinole chloride (10.3 ml). l) was added dropwise and stirred for 2 hours. After stirring, the solvent was distilled off, toluene (300 ml) was added, and the insoluble matter was removed by filtration. The title compound (27.6 g) was obtained as a white solid by evaporating the solvent of the obtained residue.

Process 7) N- (4-tert-butyl-2-nitrophen-2-ole)

3— [5-Henooleol 2— (trifluoromethyl) benzyloxy] benzamide (V I I I)

The compound obtained in the above step 6) was added at room temperature to a solution of 4-tert-butyl-2-nitroaniline (16.1 g) obtained in Production Example 8 above in pyridine (270 ml) at room temperature. (27.6 g) was added and stirred for 2 hours. Furthermore, water (540 ml) was added, and the mixture was stirred overnight, and the precipitated crystals were collected to give the title compound (36.1 g) as a yellow solid.

Step 8) 5-tert-Butyl-2- [4-cyano-3- [5-fluoro-21- (trifluoromethyl) benzinoleoxy] pheninole] benzimidazo / le hydrate (I)

A suspension of the compound (36.1 g) obtained in the above step 7), acetic acid (360 ml) and reduced iron (13.7 g) was heated under reflux at 130 for 1 hour. After cooling, water (1 500 ml), and extracted twice with ethyl acetate (700 ml). The organic layer was washed twice with water (3 50 m l), the solvent was distilled off, and _c to give a pale yellow residue (34. 5 g), the residue (2. 00 g) and acetone (1 4m was dissolved in l), stirring at 40 ° C, water (4. dropwise Om l), 2 hours at the same temperature, the title of the white crystals collected by filtration to crystals which stirred _c precipitated overnight at room temperature compound _c example 5 1 was obtained (1. 56 g)

5-tert-butyl-1-2- [4-cyano-3- [5-fluoro-2- (trifluoromethyl) benzyloxy] phenyl] benzimidazol hydrochloride 'Hydrate synthesis

Ethanol (525 ml) was added to the pale yellow residue (34.5 g) obtained in step 8) of Example 50, and the mixture was dissolved by heating. Then, 6N hydrochloric acid (17.3 ml) and water (1 0.5 ml) was sequentially added dropwise. After cooling, the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration to give the title compound (27.1 g) as white crystals.

Example 52

2 -— [4-Cyanone 1—3— [5-Fluoro-2- (triphenyloleomethyl) benzyloxy] phen 2 / re] 1—5— (1,1-Dimethinole 1—2-hydroxyxetinole) Synthesis of benzimidazole hydrochloride

Step 7) N— [4 -— (2-acetoxy—1.1-dimethylethyl) 1—2—2—2 mouth mouth—2— (5—funoleo mouth 1—— B) Penzinoleoxy] benzamide (VIII)

At room temperature, a solution of 4- (2-acetoxy-1,1-dimethylethyl) —2-nitro-2-arine (1.27 g) obtained in Production Example 20 described above in pyridine (10 ml) was added at room temperature. The compound (1.43 g) obtained in step 6) of Example 50 described above was added, and the mixture was stirred overnight. Further, water (40 ml) was added, and the mixture was stirred for 1 hour, and the precipitated crystals were collected by filtration to obtain the title compound (2.09 g) as yellow crystals.

Step 8) 2- [4-Cyan-1-3- [5-fluoro-2- (trifluoromethyl) benzyloxy] phenyl] -1-5- (1,1-dimethyl-2-hydroxy) Chill) benzimidazole hydrochloride (I)

A suspension of the compound (2.09 g) obtained in the above step 7), acetic acid (20 ml) and reduced iron (0.711 g) was stirred at 130 ° C for 4 hours. After cooling, water (100 ml) was added, and the mixture was extracted twice with ethyl acetate (40 ml). The organic layer was washed successively with water (50 ml), aqueous carbonated aqueous solution (50 ml), water (50 ml), and a saturated saline solution (50 ml), dried over sodium sulfate, and then the solvent was distilled off. I left. '

Then, to the residue were added ethanol (8 ml) and a 4 N aqueous solution of sodium hydroxide (2 ml), and the mixture was stirred at room temperature for 2 hours. The temperature was raised to 100¾, 6N hydrochloric acid (3 ml), Water (3 ml) was sequentially added dropwise. After cooling, the mixture was stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration to give the title compound (1.63 g) as a white solid.

As described above, the compounds produced in Examples 1 to 52 are shown in Tables 2 to 14.

OAV

Spirit O-AV

Next, the results of tests performed on the LPL activating action of the compound of the present invention are shown.

(Test example)

Test Example 1: LPL activating effect using 3T3-L1 cells

3T3_L1 cells obtained from the Human Science Research Resource Bank were suspended in DMEM-low glucose medium containing 10% fetal bovine serum, and placed in a 96-well plate at 4 × 10 ⁴ ce 11 s Zwell. (200 // 1 / well). After 2 S, this medium was removed and replaced with a DMEM-high glucose medium containing 10% fetal bovine serum containing or not containing a test compound prepared so that the final dimethylsulfoxide concentration was 0.1% (200 lZwe 11) . On the next day, remove the culture medium, and add phenolic-free DMEM containing low-glucose medium containing 100 μl of Zinc to a final concentration of 10 UZm and 0.1% bovine serum albumin, respectively. After culturing and incubating at 37 for 40 minutes, the supernatant was recovered. The solution containing the above cleansed 25 n substrate solution prepared pre Me in 1 [1 0% intralipid (P harmacia Co.) 1 ml per ^{l X 1 0 e d pm [} 3 H] triolein (manufactured Am Ersham Co.): Rat blood that had been fasted for 24 hours was treated with 56 for 30 minutes and dialyzed against physiological saline. The obtained solution was: 6 ° / ₀ bovine serum albumin, 0.1% parin and 0.1%. A solution obtained by mixing 0.15M Tris C1 buffer (pH 8.5) containing 1M NaCl in a ratio of 1: 0.5: 13.5] [75 µl] and adding 2 µl Incubated at 5 ° C for 2 hours. Methanol: Chlorohonolem: Heptane = 1.41: 1.25: 1 Add a mixed solution of 1.625 τη1 to stop the reaction, and add 0.1 Μ sodium carbonate buffer (ρΗ10.5) After adding 0.5 ml and stirring, the mixture was centrifuged at 3000 rpm for 10 minutes. 750 1 of the supernatant was collected, 3 ml of U1 TIMAGOLD XR (manufactured by Packard) was added, and the radioactivity was measured. The LPL activating effect was calculated by the following equation, and the results are shown in Tables 15 to 16. (Radioactivity using a test compound-containing medium)

X 100

(Radioactivity using a test compound-free medium) Test example 2: Effect on serum parameters (TG, total cholesterol (TC) and HDL-cholesterol) of normal rats

Administer 0.5% methylcellulose or a 0.5% methylcellulose suspension of test compound (30 mg kg) to a 9-week-old SD rat manufactured by Nippon Charles River Co., Ltd. with a habituation period of 10 days or more. After 6 hours, blood was collected from the tail vein. The obtained blood was centrifuged at 12000 rpm for 5 minutes to collect serum, and TG, TC and HDL-cholesterol in the serum were measured with a measurement kit using an automatic blood analyzer. The effects of the test compound on each serum parameter were calculated by the following formulas, and the results are shown in Tables 15 to 16.

(Serum parameters at 0.5% methylcellulose suspension of test compound)

― X 100

(Serum parameter values after administration of 0.5% methylcellulose only)

Table 15

Table 16

50 is the number; ** is lOmg kg As is clear from the field of industrial application and the above test results, the compound (I) according to the present invention has an excellent LPL activity enhancing action. Therefore, it is expected to be a new type of prophylactic or therapeutic drug for hyperlipidemia or arteriosclerotic disease, which can lower triglyceride in blood, as well as increase HDL-cholesterol. This application is based on Japanese Patent Application No. 289 187 filed in Japan, Japanese Patent Application No. 351645, and Japanese Patent Application No. 2000-304587 filed in Japan. They are all included in the description.

Claims

The scope of the claims

General formula (I)

[Where R is

A linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a linear chain having 1 to 4 carbon atoms Or a branched lower alkoxy group, a cyano group, a nitro group, a carbamoyl group, a carbamoyl group substituted with a linear or branched lower alkyl group having 1 to 4 carbon atoms, and a 2 to 5 carbon atoms Is a aryl group which may be substituted with 1 to 4 substituents selected from a plurality of linear or branched lower alkenyl groups,

R 'is

A hydrogen atom;

Aryl group; or

R ₂

A hydrogen atom;

A halogen atom; or

A halogen atom, a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms, a carboxy group and a linear or branched lower alkoxy carboxy group having 2 to 5 carbon atoms A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms which may be substituted with 1 to 3 substituents selected from

R ₃ , R or R ₅ and R ₆ may be the same or different,

Hydrogen atom;

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

Is a cyano group,

X is

A linear or branched alkylene group having 1 to 8 carbon atoms;

One Z—O—Z “;

— Z— S— Zi—; or

-Z -ΝΚ, -Ζ,-(where R ₇ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms, and Z and Z are the same or different. A straight-chain or branched lower alkylene group having 1 to 4 carbon atoms or a single bond).

Y is

-O-; or

-NR ₈ - (wherein, R ₈ is a hydrogen atom, a linear or branched lower alkyl group having 1 to 4 carbons, or having 1 to 4 straight-chain or branched halogenated lower carbon Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient.

2-In general formula (I),

R is

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms, a straight-chain or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a straight-chain or branched A chain or branched aryl group optionally substituted with 1 to 3 substituents selected from a lower alkoxy group, a cyano group, a nitro group and a carbamoyl group;

A linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted by 1 to 3 hydroxyl groups; or

A phenyl group,

R ₂

A hydrogen atom; or

A halogen atom,

R ₃ and R ₄ may be the same or different,

.Hydrogen atom; or

A halogen atom,

But

A hydrogen atom;

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

Is a cyano group,

R _e

A hydrogen atom,

X is

A linear or branched alkylene group having 1 to 8 carbon atoms;

-0- ζ,-；

—— Ζ— ο— ；

— S— Ζ, —;

One Ζ— S—;

-ΝΗ- Ζ,-; or (I) Z—NH— (where Z and Z are as defined in claim 1);

Y is

-0-; or

2. The LPL activity enhancer according to claim 1, wherein -NR ₈ ′-(where R _s ′ is a hydrogen atom or a linear or branched lower alkyl group having 1 to 4 carbon atoms). .

3. The compound represented by the general formula (I) is

General formula (I,) '

(Wherein, R, R 1, R ₂ , R ₃ , R ₄ , R _s , R ₆ , X and Y are each as described in claim 1). 2. The LPL activity enhancer according to 1.

4. —In the general formula (I '),

Length

A linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a linear chain having 1 to 4 carbon atoms Or an aryl group which may be substituted with 1 to 3 substituents selected from a branched lower alkoxy group, a cyano group, a nitro group, and a carbamoyl group;

A straight-chain or branched alkynole group having 1 to 6 carbon atoms which may be substituted by 1 to 3 hydroxyl groups; or

A phenyl group;

R ₂

A hydrogen atom; or A halogen atom,

R ₃ and R ₄ may be the same or different,

A hydrogen atom; or

A halogen atom,

R ₅

A hydrogen atom;

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

Is a cyano group,

But

A hydrogen atom,

X is

A linear or branched alkylene group having 1 to 8 carbon atoms;

-0- Ζ,-;

-ζ -0-;

-s-ζ,-;

— Ζ— S— ；

-Ν-Ζ,-; or

-Ζ -ΝΗ- (where Ζ and are as defined in claim 1),

Υ

One Ο—; or

The LPL active 增 potentiator according to claim 3, which is one NR — (where R ₈ ′ is as defined in claim 2).

5. The LPL activity enhancer according to claim 4, wherein Y is 1 NR ₈ , 1 (where R _s , is as described in claim 2).

6. The compound represented by the general formula (I) is

5—t ert—butynole 1— (4—black 3—pentinoleoxypheninole) benzimidazole;

5-t er t -butinore 2-[4-black mouth _ 3-(2- black mouth penzinoleoxy) feninole] Benzui midazo z;

5-tert-butyl-1-2- [4-chloro-3- (2-methylbenzyloxy) pheninole] benzmidazinole;

5-tert-butyl-2- [4-chloro-2-3- (2-cyanobenzyloxy) pheninole] benzimidazonole;

5-tert-butyl-1-2- [4-chloro-1--3- (2-potassium benzyloxy) pheninole] benzimidazo-one;

5-tert ebutinole 2 -— [4-chloro-3- (2-methoxybenzyloxy) feninole] benzimidazonole;

5-tert-butyl-1-2- [4-chloro-1-3- [2- (trifluoromethylinole) penzinoleoxy] phenyl] benzimidazole;

5-t e r t -butynole 2-[4-chloro-one 3- (3- (trif-noreo-methinole) benzyloxy] phenyl] benzimidazonole;

5-tert-butyl-2- [4-chloro-3- [4- (tri-phenolic methinole) benzyloxy] phenyl] benzimidazonole;

5-ter t 1-2-[4-black 3-[2-(trifnoreo methinole) penzinoreamino] feninore] benzui midazonole;

2-[4-1-3-[2-(trifluoromethyl) benzyloxy] fenino] 1-5 _ feninolebenzi midazo

5-tert-butyl-1-2- [4-chloro-3- (2-fluoro-6- (trif-noreolomethyl) benzyloxy] phenyl] benzimidazolone;

5-tert-butyl-2-[4-chloro-1-3-[2-(tri-phenolelomethyl) pheninoleoxymethyl] pheninole] benzimidazole; 5-tert-butyl-2-[4-chloro-3-[4-funoleo-1-2-(tri-fluorenomethinole) pendinoleoxy] phenyl] benzimidazole;

2- [4-chloro-one 3-] [2- (trifluoromethyl) benzyloxy] fenoni] -1-5-propinolebenzi midazonole;

5-butyl-2- [4-chloro-1,3- [2- (trifluoromethyl) benzyloxy] pheninole] benzimidazo //;

5-t er t-butynole 2— [4-black mouth 3— [2,4-di-1 (trifnoreo mouth methinole) penzinoleoxy] feninole] benzimidazo monole;

5-tert-butynole 2- [4-bromo-1-3- [2- (trifunoleo methinole) benzinoleoxy] feninole] benzimidazonole;

5-tert-butyl 2-[4-funoleo 1- 3- [2- (trifluoromethine) penzinoleoxy] fu: i-note] Benzi midazo-one;

5—t ert—butynole 2 _ [4-bromo-1- 3— [4-funoleo mouth 1-2— (trifluoromethyl) benzyloxy] phenyl] benzimidazole;

2- [4-Chloro-3- [2- (trifluoromethyl) benzyloxy] phenyno] benzimidazonole;

2 -— [4-chloro-1--3— [2- (Trifluoromethyl) benzyloxy] phene] —5-Methinorebenzi midazo;

5-tert-butynole 2-[4-black 1 3 _ [2-(trifnoreo methinole) benzyloxy] feninole]-1-methinorebenzi midazo 1;

2— [4—Black mouth _ 3— [2— (Trifluoromethinole) Benzinoleoxy] feninole 1-1-Echinolenebenzimidazonole;

2-[4-one mouth _ 3-[2- (triphnoleolomethinole) penzinoleoxy] fuen-5-isopropylbenzimidazolone;

5-t er t-putinole 1-[4-chloro-3-(2-nit benzyloxy) pheninole] benzii midazonole;

5 to tert-butyl-1- (3- (2- (trifluoromethyl) benzyloxy) [Shi] Hue / Le] Benzi Midazonole;

5-tert-butyl-2- [4-methyl-3- [2- (trifluoromethyl) pendinoleoxy] pheninole] benzii midazonole;

5-tert-butyl-l2- [4-l-odd-l 3- [2- (trifluoromethyl) benzinole] benzino midazonole;

5-t e rt-butyl-2-[4-black mouth _ 3-[2-(triphenylenomethyl) pendinoleoxy] feninole] benzoxazonole;

5-tert-butyl-1-2-1 [4-cyano-3- [2- (trifluoromethyl) benzinoleoxy] phenizole] benzimidazolone;

5-tert-butyl-1-2- [2-chloro-5- [2- (methyl triphenoleo) pendinoleoxy] phenyl] benzimidazonole;

6-t er t-butynone 2- [4-chloro-3- [2- (trifluoromethyl) penzinoleoxy] pheninole] 1-methinolebenzi midazo;

5—t ert—butynole 1—2— [4-chloro-3— (2-funoleo mouth penzinoreoxy) feninole] benzimidazonole;

5—t ert—butynole 2— [4-chloro-3- (2-bromobenzinoleoxy) pheninole] benzii midazonole;

6-t e rt petit / ray 2- [4-chloro-1-3- (2- (methyl triphnole) pentinoleoxy] pheninole] benzoxazonole;

5-t e rt -butyl 2- [3-chloro-one 5 _ [2- (trif-noreo-methinole) Benzinole-shiki] feninole] Benzimidazo-one;

5-tert-butyl-1-2_ [4-chloro-3- [2- (trifluoromethyl) phenyloxy] phenyl] benzimidazole;

5-tert-butyl-1-2- [4-chloro-3- (2- [2- (triphenylenomethyl) phenyl] ethoxy] phenyl] benzimidazole;

5-tert-buty-sole 2- [4-black-mouth-l-3- (4-funoleo-benzinoleoxy) feninole] benzimidazo-onele; 5-tert-butynole 2- [4-chloro-3- [5-funoleo-2- (trif-norolelomethinole) benzyloxy] phenyl] benzimidazonole;

5-tert-butyl-1-2- [4-chloro-1-3- [2- [2- (trifluoromethyl) phenyl] ethyl] phenyl] benzimidazonole;

5-t er t 1 ptinole 2-[4-black mouth 3-[2-(trifluoromethyl) benzinorethio] phenyl] benzii midazo 1;

2— [4—Black mouth 3— [2— (Triphnorelomethinole) benzyloxy] phenyl] — 5— (1,1—Dimethinolepropynole) Benzi midazo:

6—t er 't—butynole 4—black mouth 2— [4—black mouth 3— [2— (trifnolemethyl) benzyloxy] phenyl] benzimidazole;

5-tert-butyl-l2- [4-l-l-l-l- [2- (trif-noreo-l-methynole) benzyl] -phenyl] benzimidazo-l / l;

5-t e r t Butino 1 2 -— [4-Bromo 3— [4-Bromo 2 — (tri phenol olemethinole) Benzinoleoxy] feninole] Benzimidazo 1;

5-tert-butynole 2- [2,4-dichloro-5- [2- (trifnoreomethyl) benzinoleoxy] feninole]

5-tert -butynole 2-[4-cyanore 3-[5-fluone 2-(trifluoromethinole) penzinoleoxy] feninole] Benzimidazole;

5-tert-butynole 2-[4-cyano 1-3-[5-phenolic 1-2-(trifluoromethyl) benzylamino] phenyl] benzimidazole;

2— [4-Cyanol 3 _ [5-Fluoro-2- (trifluoromethyl) benzinoleoxy] feninole] 1 5— (1,1, Dimethinole 2-Hydroxicetil) Benzimidazole 2. The LPL active enhancer according to claim 1, wherein

7. A therapeutic agent for hypertriglyceridemia comprising the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

8. A preventive or therapeutic drug for hyperlipidemia comprising the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

9. A prophylactic or therapeutic drug for arteriosclerotic diseases, comprising the compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

(Wherein, R, R ₂ , R ₃ , R ₄ , R ₆ , X and Y are as described in Claim 1;

Is

Selected from a halogen atom, a hydroxyl group, a linear or branched lower alkoxy group having 1 to 4 carbon atoms, a carboxy group and a linear or branched lower alkoxycarbonyl group having 2 to 5 carbon atoms 1 A straight-chain or branched alkyl group having 1 to 6 carbon atoms which may be substituted with 1 to 3 substituents;

Aryl group; or

R ₅ 'is

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms;

A linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms;

A nitro group; or

A pharmaceutically acceptable salt or a hydrate thereof. Or solvates.

1 1. The compound according to claim 10, wherein Y is -NH-, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

1 2. R force;

A linear or branched lower alkyl group having 1 to 4 carbon atoms, a linear or branched halogenated lower alkyl group having 1 to 4 carbon atoms, a halogen atom, a linear chain having 1 to 4 carbon atoms Or a phenyl group substituted with one or two substituents selected from a branched lower alkoxy group, a cyano group, a nitro group, and a carbamoyl group, and may be substituted with one to three hydroxyl groups. A linear or branched alkyl group having 1 to 6 carbon atoms,

R ₅ '

A halogen atom;

A straight-chain or branched lower alkyl group having 1 to 4 carbon atoms; or

Is a cyano group,

X is

One O—Z] one;

-s-ζ,-; or

11. The compound according to claim 11, which is -ΝΗ-Ζ-(where, Ζ is a linear or branched lower alkylene group having 1 to 4 carbon atoms or a single bond), and a pharmaceutical thereof. A salt or a hydrate or solvate thereof that is acceptable.

13. The compound according to claim 12, wherein R ₂ , R ₃ and R ₆ are hydrogen atoms, and R ₄ is a hydrogen atom or a halogen atom, a pharmaceutically acceptable salt thereof or a hydrate thereof. Or solvates.

14.R is a phenyl group substituted with one or two substituents selected from a halogen atom, a methyl group, a cyano group, a carbamoyl group, a methoxy group, a trifluoromethyl group and a nitro group The compound according to claim 13, a pharmaceutically acceptable salt thereof. Or a hydrate or solvate thereof.

1 5. R, 'is an isopropyl group, tert-butyl group, 1,1-dimethylpropyl group, or 1,1-dimethinole-2-hydroxyshethyl group, and R _s , is a halogen atom, a methyl group or a cyano group. Wherein R is a 2- (trifluoromethyl) phenyl group, a 3- (trifluoromethyl) phenyl group, a 4- (trifluoromethyl) phenyl group, a 2-phenylenomethyl 6- (trifluoromethylol) phenyl group, 4-Funoleo mouth-2-(Trifnorolelomethinole) phenyl group, 4-promo- 1 2- (Trifnorolelomethyl) phenyl group, 2,4-di- (trifluoromethylenole) phenyl group or 5-Fl 12. The compound according to claim 11, which is a 2-fluoro (trifluoromethyl) phenyl group, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

1 6. R is 2— (tri phneololomethyl) pheninole group, 4—fn oleole methine phenyl group or 5—fluoro-2- (tri phenol oleolomethylinole) phenyl 16. The compound according to claim 15, which is a group, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

1 7.5—t ert—butynole 1—2— [4-chloro-3- (2-chlorobenzinoleoxy) feninole] benzimidazonole;

5-tert-butynole 2-[4-black mouth _ 3-(2-methylpenzinoleoxy) phenole] Benzi midazo monole;

5-tert-butynole 2-[4-chloro-3- (2-cyanopendinoleoxy) pheninole] benzii midazonole;

5-t er t -butinore 2-[4-black mouth 1-3-(2-force rubamoylbenzyloxy) feninole] benzui midazo 1 / re;

5-t e rt —butynole 2- [4-chloro-3- (2-methoxybenzyloxy) feninole] benzimidazonole;

5—t ert—butyl 2 -— [4—black mouth—3— [2- (methyl trifluoride) pendinoleoxy] feninole] benzimidazonole;

5-tert-butynole 2- (4-monochloro-3-[3- (tri-frenoleolomethyl) Benzinoleoxy] feninole] benzui midazonole;

5-ΐ ert-butyl-1-2- [4-chloro-3- (4- (methyl trifnoreo) benzinole] feninole] benzimi midazo;

5-t er t -butyl 2- [4-chloro-one 3- [2- (trifluoromethinole) penzinoleamino] feninole] benzii midazonole;

5-tert-butynole 2- [4-chloro-1-3- [2-fluoro-6- (trifluoromethyl) pendinoleoxy] phenyl] benzimidazole;

5-t e rt petit / ray 2— [4-—black mouth 3— [2— (tri-funoleolomethinole) pheninoleoxymethy / re] feninole] benzimidazonole;

5 ~ t er t buchinoray 2-[.4 1-chloro- mouth 3-[4- funoreo- 1-2- (trifluoromethyl) benzinoleoxy] feninole] Benzi midazo mono;

2-[4-Chloro-3-[2-(Trifnorelomethinole) penzinoleoxy] feninole] 1-5 _ propinolebenzi midazonole;

5-butynole 2— [4-chloro-one 3— [2- (trifnorelomethyl) benzyloxy] feninole] Benzi midazonole;

5-tert-butyl-1-2- [4-chloro-3- (2,4-di (trifluoromethyl) benzyloxy] phenyl] benzimidazole;

5-tert-butyl-1-2- [4-bromo-1--3- [2- (trifluoromethinole) benzinoleoxy] phen2 / re] benzimidazole;

5—t e rt—butynole 1—2— [4—funoleo mouth _3— [2— (tri-noreolomethine) benzyloxy] pheninole] benzii midazo monole;

5-tert-butyl-1 2 _ [4-bromo-1 3 _ [4-funoleomethyl 1 2-(trif noreolomethyl) benzyloxy] phenyl] benzimidazonole;

2-[4-1-3-[2-(Trifluoromethinole) penzinoleoxy] feninole] 1-5-methinolebenzimidazonole;

5-tert-butyl 2-[4-chloro-1-3- [2- (trinoleomethyl) pendinoleoxy] pheninole] _-1-methylbenzimidazonole: 2- [4-Chloro-3- [2- (trifnorolelomethinole) benzyloxy] pheninole] _5-Echinolenebenzimidazole;

2-[4-Black mouth 1-3-[2-(Triphnorelomethinole) penzinoleoxy] feninole] — 5-isopropinolebenzimidazonole;

5-tert-butynol 2- [4-chloro-3- (2-nitroxybenzyloxy) pheninole] zimidazole;

5-tert 1 petit / ray 2-[4-methinole 1-3-[2-(trifluoromethinole) benzinoleoxy] feninole] benzimidazonole;

5-ter t boutinole 2— [4-d-do 3— [2— (trif / leo mouth methinole) benzyloxy] feninole] benzui midazo monole;

5-tert-butynone 2- [4-chloro-3- [2- (trifluoromethinole) penzinoleoxy] pheninole] benzoxazonole;

5-tert-butyl-1-2- [4-cyano-3-[2- (trifluoromethyl) penzinoleoxy] phenyl] benzimidazonole;

5-tert-butyl 2- 2- [2-chloro-5- [2- (trifluoromethyl) benzyloxy] pheninole] benzimidazonole;

6-t er t-butynole 2-[4-chloro-1-3- (2- (triphnoleolomethinole) benzyloxy] phenyl) 1-11-methylbenzimidazole:

5-tert-butyl-1-2- [4-chloro-1-3- (2-funoleo benzene / reoxy) feninole] benzimidazoone;

5-t er t boutinole 1-[4-black mouth 3-(2-bromopendinoleoxy) pheninole] benzimita

6-t e rt 1-Pininole 2 -— [4-—Black mouth 3— [2- (Triphnorelomethinole) penzinoleoxy] phenyl] benzoxazozinole;

5-tert-butyl-1-2- [3-black-mouth-one 5- [2- (trifluorometinole) benzinole] feninole] benzimidazo;

5-tert-butynole 2— [4-chloro-3-—2— (tri phneoleolomethinole) Pheninoleoxy] feninole] benzui midazonole;

5-tert-butyl-2- [4-chloro-3- [2- [2- (trifluorometinole) pheninole] ethoxy] feninole] benzimidazonole;

5-t e rt—butinole 1-[4-one mouth 3 _ (4-fluorobenzyloxy) feninole] Benzi midazonole;

5-tert 1-1-2-[4-Chloro-3-[5-Fenole 1-2-(Trifnorrelomethinole) penzinoleoxy] phenyl] Benzimidazo-

5-tert-butyl-2- [4-chloro-3- [2- [2- (trifluoromethyl) phen-nore] ethynole] phenyl] benzimidazonole;

5—t ert—butynole 2-[4-black lip 3— [2— (trihnole methinole) benzylthio] pheninole] benzimidazo monole;

2- [4-chloro-3- [2- (trifluoromethyl) benzyloxy] phenyl] 1-5- (1,1-dimethylpropyl) benzimidazo;

6-t e rt—butinore 4-blot mouth 2— [4-blot mouth _3— [2— (trino funorole methinole) benzinoleoxy] feninole] benzimidazonole;

5-tert—Ptinole 1 2 -— [4-Chloro 3— [4-Bromo 1 2— (trifnorolemethyl) benzyloxy] phenyl] Benzimidazonole:

5-tert-butynole 2-[2,4-dichloro-1-5-[2-(tri-phenolic methyl) benzyloxy] phenyl] benzimidazole;

5-tert-butynole 2-[4- cyano 3-[5-fluoro 1-2-(trifluoronorelomethyl) benzyloxy] phenyl] benzimidazonole;

5-tert-butynole 2-[4-cyano 1-3-[5-funoreo-1-(trifluoromethyl) penzinoleamino] phenyl] benzimidazonole; and

2— [4—Cyanone 3— [5—Funoleomethyl 2— (Triphnorelomethyl) benzinoleoxy] Feninole] 1—5— (1,1,1-Dimethinole 1—2-Hydroxitytyl) Benzimidazole 10. The compound according to claim 10, which is selected from the group consisting of: a pharmaceutically acceptable salt thereof, and a hydrate or solvate thereof.

1 8.5-t ert —butynole 2— [4-chloro-one 3— [4-funoleo-l- 2- (triphnorelomethy / re) benzyloxy] phenyl] benzimidazo;

5-tert-butyl-2- [4-bromo-1-3- [2- (triphenololemethinole) benzyloxy] pheninole] benzii midazonole; ,,

5-tert-butyl-2- [4-chloro-1-3- [2- (trifluoromethyl) benzinoreamino] feninole] benzui midazonole;

5-tert-butynole 2- [4-chloro-3_ [5-funoleolomethinole 2- (trifnorolemethinole) penzinoleoxy] feninole] benzimidazo monole;

5-t e rt—butino 1 2— [4—cyan 1 3— [5-fluoro 1 2 _ (trif norolo methino) benzinoleoxy] feninole] benzimidazono;

5-ter t butyl 2-[4-1 cyano 3-[5-fluoro 1-2-(trif noreolomethyl) benzinoleamino] feninole] benzimidazonole; and

2— [4-cyanone 3-—5-fluoro-2- (trifluoromethyl) benzyloxy] phenyl] —5 -— (1,1-dimethyl-2-hydroxicetyl) benz imidazole Claims 1 The compound according to 0, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

1 9. A pharmaceutical composition comprising the compound according to any one of claims 10 to 18, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

20. A method for enhancing LPL activity, comprising administering an effective amount of the compound according to any one of claims 1 to 6.

2 1. A method for treating triglycerideemia, comprising administering to a patient an effective amount of the compound according to any one of claims 1 to 6.

2 2. A method for preventing or treating hyperlipidemia, comprising administering to a patient an effective amount of the compound according to any one of claims 1 to 6.

2 3. A method for preventing or treating atherosclerotic disease, comprising administering to a patient an effective amount of the compound according to any one of claims 1 to 6.

24. The method according to any one of claims 1 to 6 for producing an LPL activity enhancer. Use of listed compounds.

25. Use of the compound according to any one of claims 1 to 6 for producing a therapeutic agent for hypertriglyceridemia.

2.6. Use of the compound according to any one of claims 1 to 6 for producing a prophylactic or therapeutic agent for hyperlipidemia.

27. Use of the compound according to any one of claims 1 to 6 for producing a prophylactic or therapeutic drug for atherosclerotic disease.

28. The LPL activity enhancer according to any one of claims 1 to 6, and the enhancer is used for treating at least one of hypertriglyceridemia, hyperlipidemia, and atherosclerotic disease. A commercial package containing documentation stating that it can or should be used.