JP2009001495A - 2-aryl-benzimidazole-5-carboxamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a 2-aryl-benzimidazole derivative which can inhibit an sEH (soluble epoxide hydrolase) activity to increase EETs (epoxyeicosatrienoic acids) and is expected as a medicine for circulatory organ diseases including hypertension, cerebral infarction, and renal diseases, based on a vasodilator action, a series of inflammatory diseases via an NFκB/IκB kinase activation, autoimmune diseases, endocrine metabolic diseases including hyperlipemia and diabetes, and adult respiratory distress syndromes. <P>SOLUTION: This compound is a 2-aryl-benzimidazole derivative represented by formula of Fig. a pharmaceutically acceptable salt or its hydrate. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to 2-aryl-benzimidazole-5-carboxamide derivatives that inhibit soluble epoxide hydrolase (hereinafter, sometimes abbreviated as sEH if necessary). The compound of the present invention inhibits sEH activity, thereby increasing epoxyeicosatrienoic acid (hereinafter sometimes abbreviated as EETs if necessary), hypertension based on vasodilatory effect, renal disease, Cardiovascular diseases including cerebral infarction, a series of inflammatory diseases through activation of NFκB / IκB kinase, or treatment of autoimmune diseases, as well as endocrine metabolic diseases including hyperlipidemia and diabetes, and treatment of adult respiratory distress syndrome Expected as an agent.

  EETs are vasoactive eicosanoids produced from arachidonic acid by the P450 metabolic pathway, but in mammals, depending on the position of the epoxy group, 5,6-EET, 8,9-EET, 11,12-EET, 14,15 -EET and other isomers are biosynthesized. Various physiological effects have been reported for these EETs (see Non-Patent Document 1).

  EETs are known as powerful vasodilators and dilate the isolated kidney, liver, or cerebral blood vessels in a physiologically present concentration range. Some EETs are produced in vascular endothelial cells and activate Ca2 + -activated K + -channels that are present in vascular smooth muscle cells, which is why vascular endothelial cell-derived hyperpolarization factor (EDHF) It is considered as one (see Non-Patent Document 2).

  EETs have been reported to inhibit VCAM-1 expression by TNFα stimulation by suppressing transcription of NFκB and IκB kinases (see Non-Patent Document 3). Since NFκB and IκB kinases play a central role in the inflammatory response, EETs increased in blood vessels or tissues are thought to have anti-inflammatory effects.

  In addition, it has been reported that metabolites (19 or 20-hydroxy EET) by EETs or CYP4A activate the transcription factor Peroxisome Proliferator-Activated Receptor (PPAR) α (see Non-Patent Document 4). Fibrates having PPARα activation action are used as blood lipid lowering agents because they promote the expression of lipid metabolism-related genes in the liver. Furthermore, 11,12-EET is also known to suppress the transcription factor forkhead transcription factor (FOXO) -1 in vascular endothelial cells (see Non-Patent Document 5). Since the activation of FOXO-1 suppresses the maturation of adipocytes, its relation to impaired glucose tolerance in diabetes has attracted attention (see Non-Patent Document 6). Experimentally, FOXO-1 knockout mice are also glucose-resistant. Abnormalities have improved (see Non-Patent Document 7). Therefore, EETs can be expected not only to be effective for vascular or inflammatory diseases, but also to be involved in the regulation of endocrine metabolism.

  Epoxide hydrolase is a generic name for a group of enzymes that hydrolyze by adding water molecules to epoxy groups or arene oxide groups. In mammals, it is thought to be responsible for the hydrolysis of foreign epoxides, mutagenic epoxides, etc., reported as soluble epoxide hydrolase (sEH), leukotriene A4 hydrolase, cholesterol epoxide hydrolase, or microsomal epoxide hydrolase (mEH) Has been. Of these, sEH is deeply involved in the metabolism of epoxide derived from long-chain unsaturated fatty acids such as arachidonic acid and linolenic acid. On the other hand, mEH also metabolizes epoxide derived from long-chain unsaturated fatty acid, but its reaction rate is thought to be low.

  sEH is active in almost all organs, and physiologically, it is responsible for converting EETs produced in cells into dihydroxyeicosatrienoic acid (DHET), an inactive substance. It has been reported that sEH is upregulated in the kidney of AgII-induced hypertension model (see Non-Patent Document 8) or spontaneous hypertension model (SHR) (see Non-Patent Document 9). These results suggest that sEH is involved in hypertension, and sEH knockout mice have been experimentally proven to have a lower average blood pressure than normal animals (see Non-Patent Document 10).

  To date, several sEH inhibitors have been reported. For example, the compound of formula 4.

Wherein Z is oxygen or sulfur, W is carbon, phosphorus or sulfur, X and Y are each independently nitrogen, oxygen or sulfur, and at least one of R _{a to} R _d is hydrogen when X is carbon , and the although R _b when X is a nitrogen is a hydrogen, X is absent when the oxygen or sulfur, Y is is R _d is hydrogen when nitrogen, when Y is oxygen or sulfur, R _a And R _c are each independently substituted or unsubstituted C ₁ -C ₂₀ alkyl, cycloalkyl, aryl, acyl, or heterocycle (see Patent Document 1).

  There is also a report on a pyrazolylphenyl derivative represented by Formula 5 (see Patent Document 2).

  In addition, its effectiveness has been reported in various model animals. In the Angiotensin II (Ag II) -induced hypertension model, N-cyclohexyl-N-dodecylurea, which is an sEH inhibitor, has a hypotensive effect (Non-patent Document 8). reference). Moreover, albuminuria, which is an indicator of decreased renal function, increases with hypertension, but 1-cyclohexyl-3-dodecylurea, another sEH inhibitor, markedly suppressed this (see Non-Patent Document 11). Also in SHR, N, N′-dicyclohexylurea decreases the amount of 14,15-DHET in urine, and accordingly has a hypotensive action (see Non-Patent Document 9). Furthermore, 1-cyclohexyl-3-dodecyl urea, which is an sEH inhibitor, suppresses proliferation of vascular smooth muscle cells associated with platelet-derived growth factor stimulation, and thus can be expected as a therapeutic agent for arteriosclerosis (see Non-Patent Document 12).

  On the other hand, sEH metabolites (leukotoxin-diol and isoleukotoxin-diol) of linolenic acid (or leukotoxin and isoleukotoxin) are causative agents of adult respiratory distress syndrome (ARDS), and sEH inhibitor 4-phenylchalcone improves mortality. It has been reported that it can be performed (see Non-Patent Document 13). In addition, another sEH inhibitor 1- (4-aminophenyl) pyrazoles has been reported to suppress IL-2 production from T lymphocytes, and is expected as a therapeutic agent for autoimmune diseases (see Patent Document 3). ).

  Against this background, sEH inhibitors are used for hypertension based on vasodilatory effects, renal diseases, cardiovascular diseases including cerebral infarction, a series of inflammatory diseases through NFκB / IκB kinase activation, or autoimmune diseases, Furthermore, it is expected as a therapeutic agent for endocrine metabolic diseases including hyperlipidemia and diabetes and adult respiratory distress syndrome.

  On the other hand, there was no report that a benzimidazole derivative having a substituted aryl or heteroaryl group at the 2-position and an N-alkylcarboxamide group at the 5-position, particularly an N-substituted aralkylcarboxamide derivative, showed sEH inhibitory activity.

Chem Biol Interact., 129, 41-59 (2000) Circ Res., 78, 415-423 (1996) Science. 285 (5431), 1276-1279 (1999) J Biol Chem., 277, 38, 35105-35112 (2002) J Biol Chem., 278, 32, 29619-29625 (2003) Dev Cell., 4, 119-129 (2003) Nat Genet., 32, 245-253. (2002) Hypertension, 39, 690-694 (2002) Circ Res., 87, 992-998 (2000) J Biol Chem., 275, 51, 40504-40510 (2000) J Am Soc Nephrol. 15, 1244-53 (2004) Proc Natl Acad Sci U S A. 99, 2222-7 (2002) Am J Respir Cell Mol Biol. 25, 434-8 (2001) US patent US6531506 International Publication No. WO03 / 00255 International Publication No. WO00 / 23060

  The present invention increases EETs by inhibiting sEH activity, and increases blood pressure based on vasodilatory effects, renal diseases, cardiovascular diseases including cerebral infarction, a series of inflammatory diseases via NFκB / IκB kinase activation or An object of the present invention is to provide a 2-aryl-benzimidazole-5-carboxamide derivative, which is expected as a therapeutic agent for autoimmune diseases, as well as for endocrine metabolic diseases including hyperlipidemia and diabetes, and adult respiratory distress syndrome And

  As a result of diligent search and research for the purpose of solving the above problems, the present inventors have found that 2-aryl-benzimidazole-5-carboxamide derivatives have excellent sEH inhibitory activity, and completed the present invention. did.

  That is, the present invention provides the following formula 1

[Where:
R ¹ is a C _1-6 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-18 cycloalkyl group which may be substituted with ¹ to 4 halogen atoms,
Formula _{- (CH 2) n-Q} 1
(In the formula, n represents an integer of 1 to 8, Q ¹ represents —CN, —COOH, —SO ₃ H, —SR ^a , —SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , — OH, —OR ^d , —COOR ^a , —CONR ^e R ^f , C _3-18 cycloalkyl group, optionally substituted phenyl group, optionally substituted heteroaryl group, or optionally substituted 4 to 8 members A heterocycloalkyl group,
R ^a is a C _1-6 alkyl group, an optionally substituted C _7-18 aralkyl group or — (CH ₂ ) p—OH (p is an integer of 1 to 4),
R ^b or R ^c is independently a hydrogen atom, a C _1-6 alkyl group, a C _2-10 alkanoyl group, —SO ₂ R ^a or — (CH ₂ ) p—OH,
R ^d is a C _1-18 alkyl group, a C _3-18 cycloalkyl group, a C _2-10 alkenyl group or a C _2-10 alkanoyl group which may be substituted with 1 to 4 halogen atoms,
R ^e or R ^f is independently a hydrogen atom or a C _1-18 alkyl group)
Indicate
R ² is
A hydrogen atom, a C _1-18 alkyl group, a C _3-18 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group;
R ³ and R ⁴ are independently
A hydrogen atom, a halogen atom; —OH; a C _1-6 alkoxy group; a benzyloxy group; ^a C _1-18 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of —SR ^a , C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-18 cycloalkyl group _optionally substituted with a hydroxyl group, aryl group optionally substituted, 4- to 8-membered heterocycloalkyl group optionally substituted An _optionally substituted C _7-18 aralkyl group,
Formula _{- (CH 2) m-Q} 2
(In the formula, m represents an integer of 1 to 8, and Q ² represents a C _3-18 cycloalkyl group, a C _2-10 cycloalkenyl group, a C _2-10 alkanoyl group, —CN which may be substituted with a hydroxyl group. , —COOH, —SO ₃ H, —SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , —O—CH ₂ ═CH ₂ , —O (CH ₂ ) p—OH, —COOR ^a , —CONR ^e R ^f , —NHCOR ^g , an optionally substituted heteroaryl group, an optionally substituted 4- to 8-membered heterocycloalkyl group, an optionally substituted phenoxy group or a benzoyl group,
(R ^g is a C _1-18 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom or a C _1-6 alkoxy group or an optionally substituted phenyl group). Show. ),
Formula —NR ⁵ —Q ³
Wherein R ⁵ is a hydrogen atom or a C _1-18 alkyl group,
(Q ³ is a C _1-18 alkyl group, an optionally substituted aryl group, an optionally substituted C _7-18 aralkyl group, an optionally substituted heteroaryl group or a C _3-18 cycloalkyl group,- COR ^g ). Or R ³ and R ⁴ together with the adjacent nitrogen atom represent a group which forms an optionally substituted 4- to 8-membered heterocycloalkyl group or heteroaryl group. ]
Or a pharmaceutically acceptable salt or hydrate thereof.

Alternatively, provided is the benzimidazole compound of the above formula 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, wherein R ² is an optionally substituted aryl group or an optionally substituted heteroaryl group. To do.

Preferably, R ³ is a halogen atom; —OH; C _1-6 alkoxy group; benzyloxy group; C _1-18 which may be substituted with 1 to 4 substituents selected from the group consisting of —SR ^a. An alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, an optionally substituted C _3-18 cycloalkyl group, an optionally substituted 4- to 8-membered heterocycloalkyl group, or a formula — (CH ₂ ) m-Q ²²
(In the formula, Q ²² is a C _3-18 cycloalkyl group, a C _2-10 cycloalkenyl group, a C _2-10 alkanoyl group, —CN, —COOH, —SO ₃ H, — SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , —O—CH ₂ ═CH ₂ , —O (CH ₂ ) p—OH, —COOR ^a , —CONR ^e R ^f , —NHCOR ^g or substituted 4 to 8 membered heterocycloalkyl group).
Provided is the above-mentioned benzimidazole compound or a pharmaceutically acceptable salt or hydrate thereof, wherein R ⁴ is a hydrogen atom or a C _1-18 alkyl group.

More preferably, R ² is of formula 2

(Wherein R ⁶ , R ⁷ and R ⁸ are the same or different and are a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, and the other R ⁶ , R ⁷ and R ⁸ are hydrogen atoms. Or R ⁶ and R ⁷ together form —O—CH ₂ —O—, and the other R ⁸ is a hydrogen atom.)
The above-mentioned benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof is a group represented by the formula:

According to an embodiment of the present invention, R ³ is optionally substituted C _7-18 aralkyl group or formula — (CH ₂ ) q-Ar.
(Wherein q represents an integer of 1 to 8, Ar is a heteroaryl group),
Provided is a benzimidazole compound of the above formula 1, wherein R ⁴ is a hydrogen atom or a C _1-18 alkyl group, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

Preferably R ² is of formula 2

(Wherein the symbols are as defined above)
The above-mentioned benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof is a group represented by the formula:

  More preferably, Formula 3

(Wherein R ¹ , R ⁶ , R ⁷ and R ⁸ are as defined above,
R ²¹ , R ²² and R ²³ are the same or different and are a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, a C _1-6 alkoxy group or —SMe, and the other R ²¹ , R ²² and R ²³ are hydrogen atoms, or adjacent R ²¹ and R ²² are combined to form —O—CH ₂ —O—, and R ²³ is a hydrogen atom. ) Or a pharmaceutically acceptable salt thereof or a hydrate thereof.

According to an embodiment of the present invention, R ³ is of the formula —NR ⁵ -Q ³ ,
(Wherein the symbols are as defined above),
There is provided a benzimidazole compound according to the above formula 1, wherein R ⁴ is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

Preferably R ² is of formula 2

(Wherein the symbols are as defined above)
The above-mentioned benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof is a group represented by the formula:

According to an embodiment of the present invention, the benzimidazole compound of the above formula 1, wherein R ³ and R ⁴ together with the adjacent nitrogen atom are an optionally substituted 4-8 membered heterocycloalkyl group or heteroaryl group Alternatively, a pharmaceutically acceptable salt or hydrate thereof is provided.

Preferably R ² is of formula 2

(Wherein the symbols are as defined above)
The above-mentioned benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof is a group represented by the formula:

In addition, specific compounds shown below, that is,
1-butyl-N ′-(4-cyanophenyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carbohydrazide 1-butyl-2- (3,4-dichlorophenyl) -N′- (4-Nitrophenyl) -1H-benzimidazole-5-carbohydrazide 1-butyl-2- (3,4-dichlorophenyl) -N- (3-phenylpropyl) -1H-benzimidazole-5-carboxamide 1-butyl 2- (3,4-dichlorophenyl) -N- (3-methylbutyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N-hexyl-1H-benzimidazole 5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N-heptyl-1H-benzimidazole-5-carboxamide 1-butyl- 2- (3,4-Dichlorophenyl) -N- (7-methyloctyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (6-hydroxyhexyl)- The benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 1, which is at least one compound selected from 1H-benzimidazole-5-carboxamide.

further,
2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (2-phenylethyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-Dimethoxybenzyl) -1- [2- (2-fluorophenyl) ethyl] -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl ) -1-pentyl-1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (methylthioethyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichloro Enyl) -N- (2,3-dimethoxybenzyl) -1-propyl-1H-benzimidazole-5-carboxamide 3- (2- (3,4-dichlorophenyl) -5-[[(2,3-dimethoxybenzyl ) Amino] carbonyl] -1H-benzimidazol-1-yl) propyl acetate 1-butyl-2- (3-ethoxy-4-methoxyphenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole -5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (thiophen-2-ylmethyl) -1H-benzimidazole-5-carboxamide 2- (3,4- Dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1-hexyl-1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzene) Dil) -2- (3,4-dimethylphenyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (3-methylbutyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3,4-dimethoxyphenyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- ( 2,3-dichlorobenzyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3,5-dimethoxyphenyl) ) -1H-benzimidazole-5-carboxamide)
1-cyclopropyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2 -(4-Methoxyphenyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (2-methylpropyl) -1H-benzimidazole -5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1-trifluoroethyl-1H-benzimidazole-5-carboxamide N- (2,3-dimethoxybenzyl)- 2- (3,4,5-Trimethoxyphenyl) -1-benzyl-1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-Dimethoxybenzyl) -1- (3-hydroxypropyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (5-nitrothiophene-2 -Yl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-difluorobenzyl) -1H-benzimidazole-5-carboxamide 2- (3, 4-Dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (tetrahydrofuran-2-ylmethyl) -1H-benzimidazole-5-carboxamide 2- (1,3-benzodioxol-5-yl) -1-butyl-N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2, -Dimethoxybenzyl) -1-isopropyl-1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3,4,5-trifluorophenyl) -1H-benzimidazole -5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3-methoxyphenyl) -1H-benzimidazole-5-carboxamide N- (2,3-dimethoxybenzyl) -1- ( Furan-2-ylmethyl) -2- (3,4,5-trimethoxyphenyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl)- 1- (4-Fluorobenzyl) -1H-benzimidazole-5-carboxamide 1-cyclohexylmethyl-2- (3,4-dichlorophenyl) -N- ( , 3-Dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2-methyl-3-chlorobenzyl) -1H-benzimidazole-5-carboxamide 2- (3,4-Dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (2,2-dimethylpropyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl)- N- (2,3-dimethoxybenzyl) -1- (2-pyrrolidin-1-ylethyl) -1H-benzimidazole-5-carboxamide)
N- (2,3-dimethoxybenzyl) -1- (methoxyethyl) -2- (3,4,5-trimethoxyphenyl) -1H-benzimidazole-5-carboxamide N- (1,3-benzodioxy Sole-5-ylmethyl) -1-butyl-2- (3,4,5-trimethoxyphenyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- ( 2-methylthiobenzyl) -1H-benzimidazole-5-carboxamide N- (2-bromobenzyl) -1-butyl-2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-N -(2,4-dichlorobenzyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- [[5-Methyl-2- (trifluoromethyl) -3-furyl] methyl] -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (4-morpholinobenzyl ) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2-bromo-3-thienylmethyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-2 -(3,4-dichlorophenyl) -N- (3-methoxybenzyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2-piperidin-1-ylbenzyl) ) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2-methylbenzyl) -1H-benzimi Zole-5-carboxamide, which is at least one compound selected from 1-butyl-2- (3,4-dichlorophenyl) -N- (3,3-diphenylpropyl) -1H-benzimidazole-5-carboxamide The described benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof is provided.

  According to another aspect of the present invention, there is provided a medicament comprising any one of the above benzimidazole compounds or a pharmaceutically acceptable salt or hydrate thereof.

  According to another aspect of the present invention, there is provided a soluble epoxide hydrolase inhibitor comprising any of the above benzimidazole compounds or a pharmaceutically acceptable salt or hydrate thereof.

  According to another aspect of the present invention, there is provided a therapeutic agent for hypertension, renal disease or cerebral infarction comprising any one of the above benzimidazole compounds or pharmaceutically acceptable salts or hydrates thereof.

  Definitions and examples of terms used in the present invention are provided to illustrate the specification and claims, and are provided without limitation.

  “Halogen atom” includes fluorine atom, chlorine atom, bromine atom or iodine atom.

The “C _1-18 alkyl group” means a linear or branched alkyl group having 1 to 18 carbon atoms, such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl. Group, isobutyl group, tert-butyl group, sec-butyl group, 3-methylbutyl group, 7-methyloctyl group, n-pentyl group, n-hexyl group, n-heptyl group, tert-amyl group, 3-methylbutyl Group, neopentyl group, octyl group, decyl group, dodecyl group, tetradecyl group, hexadecyl group, octadecyl group and the like. Among them, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, 3-methylbutyl group, 7-methyloctyl group, n-pentyl group, An n-hexyl group, an n-heptyl group and the like are preferable.

The “C _1-6 alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, 3-methylbutyl group, n-pentyl group, n-hexyl group, etc. Can be mentioned. Of these, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a group, and the like are preferable.

“C _1-18 alkyl group optionally substituted with 1 to 4 substituents selected from the group consisting of a halogen atom or a C _1-6 alkoxy group” means that a hydrogen atom on the group is 1 to 4 A C _1-18 alkyl group which may be substituted by one halogen atom or C _1-6 alkoxy group is shown. For example, 8-trifluorooctyl group, 2-methoxydodecanyl group, etc. are mentioned.

In the “C _1-6 alkyl group _optionally substituted with 1 to 4 halogen atoms”, a hydrogen atom on the group may be substituted with 1 to 4 halogen atoms (preferably a fluorine atom). A C _1-6 alkyl group is shown. For example, a trifluoromethyl group, 1,1,1-trifluoroethyl group, 1,1,1-trifluoropropyl group, 1,1,1-trifluorobutyl group and the like can be mentioned. Of these, a trifluoromethyl group and a 1,1,1-trifluoroethyl group are preferable.

The "halogen atom; -OH; C _1-6 alkoxy group; a benzyloxy group 1-4 may be substituted with a substituent C _1-18 alkyl group selected from the group consisting of -SR ^a 'is A hydrogen atom on the group is substituted by at least one of 1 to 4 halogen atoms (preferably a fluorine atom), —OH, C _1-6 alkoxy group, benzyloxy group, —SR ^a . And C _1-18 alkyl groups which may be _substituted . For example, 2-methoxyethyl group, 2-propyloxyethyl group, 3-methoxypropyl group, 3-butoxypropyl group, 2-ethylhexyloxypropyl group, 3-isopropyloxypropyl group, 3-ethoxypropyl group, 2- ( Methoxymethyl) propyl group, 2-methylthioethyl group, 2-ethylthioethyl group, 2- (2-hydroxyethylthio) ethyl group, 2- (hydroxymethyl) -3- (methylthio) propyl group, 3-hydroxypropyl Group, 2-hydroxypropyl group, 5-hydroxypentyl group, 6-hydroxyhexyl group, 2-benzyloxy-1-hydroxymethylpropyl group, and the like are preferable.

The “C _2-10 alkenyl group” means an alkenyl group having at least one double or straight chain having 2 to 10 carbon atoms, such as a vinyl group, a propenyl group, a butenyl group, A hexenyl group, an allenyl group, an octenyl group, a decanyl group, etc. are mentioned.

The “C _2-10 alkynyl group” refers to an alkynyl group containing a linear or branched triple bond having 2 to 10 carbon atoms, such as ethynyl group, propynyl group, hexynyl group, octynyl. Group, decynyl group and the like. Of these, an ethynyl group and a propynyl group are preferable.

The “C _3-18 cycloalkyl group” includes a cyclic alkyl group having 3 to 18 carbon atoms and a bicyclic hydrocarbon. Examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, bicyclo [2.2.1] heptanyl group, bicyclo [3.2.1] octanyl group, adamantyl group. . Of these, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group are preferable.

The "which may C _3-18 cycloalkyl group substituted with a hydroxyl group" refers to an optionally substituted C _3-18 cycloalkyl group hydrogen atoms by hydroxyl groups on the base. For example, 2-hydroxycyclooctyl group etc. are mentioned.

The “C _2-10 cycloalkenyl group” refers to a cyclic alkenyl group having 2 to 10 carbon atoms, and examples thereof include a cyclopentenyl group and a cyclohexenyl group.

The “C _2-10 alkanoyl group” has a form in which a linear or branched alkyl group having 1-10 carbon atoms and one carbonyl group (—CO—) are combined. _{A 26} alkanoyl group is preferred. As the C ₂₆ alkanoyl group, for example, acetyl group, propionyl group, n-butyryl group, isobutyryl group, pivaloyl group, n-pentanoyl group, 4-methylpentanoyl group and n-hexanoyl group are preferable.

The “C _1-6 alkoxy group” means a linear or branched alkoxy group having 1-6 carbon atoms, and a C _1-4 alkoxy group is preferable. Examples of the C _1-4 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, and a tert-butoxy group.

The “optionally substituted phenyl group” refers to a substituted or unsubstituted phenyl group. The substituent in the phenyl group is one or more selected from the group consisting of a halogen atom, a hydroxyl group, —NO ₂ , a C _1-18 alkyl group which may be substituted with 1 to 4 halogen atoms, and an alkoxy group. Show. Preferred substituents are a halogen atom, a C _1-4 alkyl group, a methoxy group or an ethoxy group. Examples of such an optionally substituted phenyl group include a 2-fluorophenyl group, a 4-fluorophenyl group, a 4-methylphenyl group, a 2-chlorophenyl group, and a 4-methoxyphenyl group.

  The “aryl group” refers to a monocyclic or condensed polycyclic aromatic hydrocarbon group having 6 to 15 carbon atoms, such as a phenyl group, a naphthyl group (including a 1-naphthyl group and a 2-naphthyl group), Examples include a pentarenyl group, an indenyl group, an indanyl group, a heptaenyl group, a fluorenyl group, and a 1,2,3,4-tetrahydronaphthalenyl group. Preferred are a phenyl group, a naphthyl group, an indenyl group, an indanyl group, and a 1,2,3,4-tetrahydronaphthalenyl group, and a naphthyl group and a phenyl group are more preferred.

The “aryl group that may be substituted” refers to a substituted or unsubstituted aryl group. The substituent in the aryl group is a halogen atom, a C _1-18 alkyl group which may be substituted with 1 to 4 halogen atoms, a C _3-18 cycloalkyl group, —NO ₂ , —COOH, —SO ₃ H. , -SR ^a , -SOR ^a , -SO ₂ R ^a , -NR ^b R ^c , -OR ^d , -COOR ³ , -CONR ^e R ^f , -NHC (= O) H, -OR ^d , -O- (CH ₂ ) t—O— (t is 1 or 2), one or more selected from the group consisting of C _2-10 alkanoyl groups. Preferred substituents are a halogen atom, a C _1-4 alkyl group, a methoxy group or an ethoxy group. Examples of such an optionally substituted aryl group include a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 3,4-dimethoxyphenyl group, a 3,5-dimethoxyphenyl group, a 3,4,5-trimethyl group, and the like. Methoxyphenyl group, 2,4,5-trimethoxyphenyl group, 3-ethoxy-4-methoxyphenyl group, piperonyl group, 3,4,5-trifluorophenyl group, 3,4-dichlorophenyl group, 3,4- A dimethylphenyl group is more preferred.

  The “heteroaryl group” is a monocyclic or condensed aromatic heterocyclic group containing one or more heteroatoms selected from O, S and N. In the case where the aromatic heterocyclic group is a condensed ring, those having a partially hydrogenated monocycle are also included. Examples of such heteroaryl groups include pyrazolyl group, thiazolyl group, isothiazolyl group, thiadiazolyl group, imidazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, pyrrolyl group, imidazolyl group, (1,2,3 )-And (1,2,4) -triazolyl group, tetrazolyl group, pyranyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, quinolyl group, isoquinolyl group, benzofuranyl group, isobenzofuranyl group, indolyl group, Isoindolyl group, indazolyl group, benzimidazolyl group, benztriazolyl group, benzoxazolyl group, benzothiazolyl group, benzo [b] thiophenyl group, (1,2)-and (1,3) -benzooxathiol group, Chromenyl group, 2-oxochromenyl group, ben Thiadiazolyl group, quinolizinyl group, phthalazinyl group, naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, cinnolinyl group, and a carbazolyl group. Among them, pyridyl group, imidazolyl group, pyrazinyl group, furyl group, thienyl group, indolyl group, benzimidazolyl group, thiazolyl group, pyrrolyl group, benzo [b] thiophenyl group, 2,3-dihydrobenzofuranyl group, 2,3 -A dihydroisoindolyl group, etc. are preferred.

The “optionally substituted heteroaryl group” refers to a substituted or unsubstituted heteroaryl group. The substituent in the heteroaryl group is a halogen atom, a C _1-18 alkyl group which may be substituted with 1 to 4 halogen atoms, a C _3-18 cycloalkyl group, —NO ₂ , —COOH, —SO _3. H, —SR ^a , —SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , —OR ^d , —COOR ^a , —CONR ^e R ^f , —NHC (═O) H, —OR ^d , —O One or more selected from the group consisting of — (CH ₂ ) t—O— (t is 1 or 2), a phenyl group, a heteroaryl group, and a C _2-10 alkanoyl group are shown. Preferred substituents are a halogen atom, —NO ₂ , C _1-4 alkyl group, methoxy group or ethoxy group. For example, 2-nitrothiophen-5-yl group, 2-methylpyrazin-4-yl group, 1,2,5-trimethylpyrazolyl group, 2-methyl-5-trifluoromethylfuran-4-yl group and the like can be mentioned. It is done.

  The “4- to 8-membered heterocycloalkyl group” refers to a 4- to 8-membered heterocycloalkyl group containing at least one hetero atom (oxygen atom, nitrogen atom or sulfur atom) in the ring. And a cyclic amino group which has one or more nitrogen atoms and may contain one or more oxygen atoms or sulfur atoms. For example, morpholino group, thiomorpholino group, piperidyl group, piperazinyl group, 1-pyrrolidinyl group, 2-oxopyrrolidinyl group, 1,3-dioxolanyl group, 2-oxoindazolidinyl group, perhydroazepinyl group Perhydro-1,4-diazepinyl group, and the like.

The “optionally substituted 4- to 8-membered heterocycloalkyl group” refers to a substituted or unsubstituted heterocycloalkyl group. The substituent in the heterocycloalkyl group is a halogen atom, —OH, a C _1-6 alkyl group which may be substituted with 1 to 4 halogen atoms, —COOR ^a , — (CH ₂ ) p—OH, — One or more selected from the group consisting of CONR ^e R ^f , a phenyl group, a heteroaryl group, an optionally substituted C _7-18 aralkyl group and a C _2-10 alkanoyl group are shown. Examples include 4-methylpiperazinyl group, 4-acetylpiperazinyl group, 4-phenylpiperazinyl group, 4- (pyridin-2-yl) piperazinyl group, 4-carbamoylpiperidino group and the like.

The “C _7-18 aralkyl group” refers to an arylalkyl group having 7 to 10 carbon atoms, such as benzyl group, phenylethyl group, 3-phenylpropyl group, 3-phenyl-1-methylpropyl group, naphthyl. A methyl group is mentioned.

The “ _optionally substituted C _7-18 aralkyl group” refers to a substituted or unsubstituted C _7-18 aralkyl group. The substituent in the C _7-18 aralkyl group is a halogen atom, a C _1-18 alkyl group which may be substituted with 1 to 4 halogen atoms, a C _3-18 cycloalkyl group, —OH, —NO ₂ , ^{_{-COOH, -SO 3 H, -SR a}} , -SOR a, -SO 2 R a, -SO 2 NH 2, -NR b R c, -OR d, -COOR 3, -CONR e R f, -NHC (═O) H, —OR ^d , —O— (CH ₂ ) t—O— (t is 1 or 2), C _2-10 alkanoyl group, heteroaryl group, heterocycloalkyl group 1 or more. For example, 2,3-dimethoxybenzyl group, 2,3-dimethylbenzyl group, 2,3-dichlorobenzyl group, 1- (4-bromophenyl) ethyl group, 4-chlorophenylethyl group, 3-phenylpropyl group, 2 -Piperidinophenylmethyl group, 4-morpholinophenylmethyl group, 3,3-diphenylpropyl group and the like can be mentioned.

The “optionally substituted phenoxy group” refers to a substituted or unsubstituted phenoxy group. The substituent in the phenoxy group is one or more selected from the group consisting of a halogen atom, a C _1-18 alkyl group which may be substituted with 1 to 4 halogen atoms, —NR ^b R ^c and —OR ^d. Indicates.

  In addition, the “pharmaceutically acceptable salt” is a salt with an alkali metal, an alkaline earth metal, ammonium, alkylammonium, or the like, a salt with a mineral acid or an organic acid, such as a sodium salt, Potassium, calcium, ammonium, aluminum, triethylammonium, acetate, propionate, butyrate, formate, trifluoroacetate, maleate, tartrate, citrate, stearate, Succinate, ethyl succinate, lactobionate, gluconate, glucoheptonate, benzoate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, benzenesulfonate, paratoluenesulfone Acid salt, lauryl sulfate, malate, aspartate, glutamate, adipate, cysteine Salt with N-acetylcysteine, hydrochloride, hydrobromide, phosphate, sulfate, hydroiodide, nicotinate, oxalate, picrate, thiocyanate, Mention may be made of undecanoic acid salts, salts with acrylic acid polymers, salts with carboxyvinyl polymers.

  Various production methods for the compound of formula 1, which is the compound of the present invention, will be described in detail below, but are not particularly limited to those exemplified.

(Production method 1)
(Wherein the symbols are as defined above)
Compound Ic can be obtained by reacting commercially available compound Ia with amine Ib. Examples of the solvent used in this reaction include dioxane, acetonitrile, toluene, dimethoxyethane, tetrahydrofuran, N, N-dimethylformamide and the like. The reaction temperature is 0 ° C to 150 ° C, preferably 25 ° C to 100 ° C.

  Next, the nitro group of Ic can be reduced to obtain compound Id. Nitro group reducing agents include palladium activated carbon / hydrogen atmosphere, palladium activated carbon / hydrazine hydrate, palladium activated carbon / ammonium formate, tin (II) chloride monohydrate, iron / ammonium chloride, rane-nickel / hydrazine Hydrates, etc., preferably palladium on activated carbon / hydrogen atmosphere or iron / ammonium chloride. Examples of the solvent used for this reaction include methanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene, methylene chloride, chloroform, acetonitrile, ethyl acetate and the like. The reaction temperature is desirably adjusted as appropriate depending on the reducing conditions, and is preferably 25 ° C to 100 ° C.

  Next, aldehyde Ie and compound Id can be reacted to obtain benzimidazole derivative Ig. Examples of the solvent used in this reaction include methanol, ethanol, propanol, tetrahydrofuran, dioxane, toluene, and acetic acid. Among them, acetic acid is preferable. The reaction temperature is preferably 0 ° C to 150 ° C. Compound Ig can also be obtained from acid chloride If and Id.

  Next, the ester of Compound Ig can be hydrolyzed to obtain a carboxylic acid derivative. Examples of the base used at this time include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, and water, methanol, ethanol, propanol, tetrahydrofuran, dioxane and a mixed solvent thereof are used as the solvent. It is done.

  Next, the compound 1 of the present invention can be obtained by condensing an amine or hydrazine Ih with a carboxylic acid derivative. Condensation reagents for amide bonds include N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), carbonyldiimidazole, benzotriazole-N-hydroxytrisdimethyl. Aminophosphonium hexafluorophosphoric acid (Bop reagent), diphenylphosphoryl azide (DPPA) and the like are used. Of these, DCC and EDC are preferable. Moreover, the target product may be obtained in high yield by adding N-hydroxysuccinimide or 1-hydroxybenzotriazole (HOBt) to DCC or EDC. Examples of the solvent used for the reaction include chloroform, dichloromethane, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, diethyl ether and the like. The reaction temperature is -20 ° C to 100 ° C, preferably 0 ° C to 40 ° C.

The “inhibitor of soluble epoxide hydrolase” in the present invention means a compound that inhibits the action of catalyzing the hydrolysis of a substrate by sEH. The activity of the inhibitor is, for example, by reacting human-derived sEH with its substrate EETs in the presence of a test compound and measuring the amount of dihydroxyeicosatrienoic acid (DHET) produced by the reaction. Can be confirmed. The inhibitor of the present invention may be any inhibitor as long as its production amount is reduced as compared with the production amount of DHET reacted in the absence of the test compound, but the sufficient effect of the present invention is obtained. For this purpose, the DHET production amount when no test compound is added is 100%, and the compound concentration (IC ₅₀ value) at which 50% production amount is inhibited in the presence of the test compound is preferably 10 μM or less. The following is more preferable. Specifically, it can be confirmed according to the description of Test Example 1, for example.

  Thus, since the compound of the present invention can inhibit the activity of sEH, it is useful for the treatment of a disease caused by the activity of sEH, particularly a disease caused by a decrease in EETs due to the activity of sEH.

  Examples of such diseases include hypertension, kidney disease, cardiovascular disease including cerebral infarction, a series of inflammatory diseases and autoimmune disease therapeutic agents through activation of NFκB / IκB kinase, hyperlipidemia and diabetes Examples include endocrine metabolic disorders and adult respiratory distress syndrome.

  In particular, since EETs are powerful vasodilators (Circ Res. 1996 78: 415-23), if the compound of the present invention that suppresses the hydrolysis action of the substrate by sEH is used, EETs in vivo It is possible to keep the concentration constant within the physiological concentration region. Therefore, it is possible to maintain a normal vasodilatory action, and it can be used as an excellent therapeutic agent for cardiovascular diseases.

  Furthermore, since the compound of the present invention suppresses hydrolysis of EETs, which are powerful vasodilators, it can be used as an excellent therapeutic agent for hypertension when used in combination with known antihypertensive agents. Known antihypertensive agents include, for example, β-blockers such as Seloken and Tenormin, α-blockers such as Cardura, calcium antagonists such as Norvasc and Adalat, antihypertensive diuretics such as Torasemide and Spironolactone, Prinivil, Vasotec and the like Angiotensin converting enzyme (ACE) inhibitors, Angiotensin II (A-II) antagonists such as Cozaar, Diovan and the like can be mentioned. An excellent antihypertensive action can be obtained by combining an antihypertensive agent having an action different from that of the compound of the present invention.

  The medicament of the present invention can be systemically or locally administered orally or parenterally such as rectal, subcutaneous, intramuscular, intravenous and transdermal.

  In order to use the compound of the present invention as a medicine, any form of a solid composition, a liquid composition and other compositions may be used, and the optimum one is selected as necessary. The medicament of the present invention can be produced by blending the compound of the present invention with a pharmaceutically acceptable carrier. Specifically, conventional excipients, extenders, binders, disintegrants, coating agents, sugar coatings, pH adjusting agents, solubilizers or aqueous or non-aqueous solvents are added, and tablets are prepared by conventional pharmaceutical techniques. Pills, capsules, granules, powders, powders, solutions, emulsions, suspensions, injections, and the like. Examples of excipients and extenders include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. it can.

  The compound of the present invention can be formulated by forming an inclusion compound with α, β, γ-cyclodextrin, methylated cyclodextrin or the like.

  The dose of the compound of the present invention varies depending on the disease, symptoms, body weight, age, sex, route of administration, etc., but is preferably 0.1 to 1000 mg / kg body weight / day for adults, more preferably 0. 1 to 200 mg / kg body weight / day, which can be administered once a day or in several divided doses.

  The compound of the present invention has an action of inhibiting the activity of sEH and is useful for the treatment of a disease caused by the activity of sEH, particularly a disease caused by a decrease in EETs due to the activity of sEH.

  Such diseases include, for example, hypertension, kidney disease, cardiovascular diseases including cerebral infarction, a series of inflammatory diseases and autoimmune diseases mediated by NFκB / IκB kinase activation, hyperlipidemia and diabetes Examples include endocrine metabolic disorders and adult respiratory distress syndrome.

  In particular, since it is possible to suppress the hydrolysis action of EETs having a strong vasodilatory effect, it is useful for cardiovascular diseases such as hypertension, kidney disease and cerebral infarction.

  EXAMPLES Next, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.

Example 1
Synthesis of 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 3-amino-4-butylaminobenzoic acid methyl ester (1.0 g, 4.50 mmol), A mixture of 3,4-dichlorobenzaldehyde (866 mg, 4.95 mmol) and acetic acid (12 mL) was stirred at 110 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1-3: 1) to give 1-butyl-2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxyl. Acid methyl ester (1.24 g, 73%) was obtained.

  1-butyl-2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxylic acid methyl ester (1.23 g, 3.26 mmol), methanol (5 mL), 1M sodium hydroxide (15 mL) Was stirred at 90 ° C. for 1 hour. After cooling to room temperature, the reaction solution was adjusted to pH 3.0 with 6M hydrochloric acid. The precipitate was filtered, washed with water and dried. The obtained residue was dissolved in tetrahydrofuran (10 mL), and 2,3-dimethoxybenzylamine (472 mg), 1-hydroxybenzotriazole (381 mg) and 1-ethyl-3- (3-dimethylaminopropyl) were added to the solution. Carbodiimide hydrochloride (540 mg) was added and stirred for 12 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 2: 1) to obtain the title compound (1.07 g) as a colorless amorphous substance. Further, 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide was dissolved in ethyl acetate, and this solution was added to the solution at 0 ° C. 4M hydrochloric acid was added. The precipitated crystals were filtered and dried to give 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide hydrochloride (880 mg) as colorless crystals. Got as.

ESI m / z = 534, 536 (M + Na), 510, 512 (MH). C ₂₇ H ₂₇ C _l2 N ₃ O ₃ HCl ・ H ₂ O Calc for C 57.20, H 5.17, N 7.41.Found C 57.55, H 5.20, N 7.28.

  The compounds of the present invention shown in the following table were obtained by carrying out the same operations as in the above Examples using the corresponding starting materials and reactants. The compounds of the present invention obtained in the above Examples are shown in Table 1-1 to Table 1-37.

Test example 1
Test drug solutions prepared in various concentrations with dimethyl sulfoxide are added to 10 mM Tris-HCl (pH 7.4) buffer containing 250 mM sucrose, 0.1 mM ethylenediaminetetraacetic acid, and 0.1 mM dithiothreitol. Minutes (Analytical Biological Services) and room temperature. As a substrate after 15 minutes ^{14,15- [5,6,8,9,11,12,14,15 (n) - 3} H] was added ^{epoxyeicosatrienoic acid ([3 H] 14,15} -epoxyeicosatrienoic acid), The reaction was allowed to proceed for an additional 60 minutes at room temperature. After stopping the reaction by adding methanol (final concentration 50%), the substrate ([ ³ H] 14,15-epoxyeicosatrienoic acid) and the reaction product ([ ³ H] 14,15-dihydroxyeicosatrienoic acid contained in the reaction solution) ) Was adsorbed on octadodecylsilane resin (Wakogel 50C18). After separating the substrate and the reaction product with a 60% methanol solution, the amount of [ ³ H] 14,15-dihydroxyeicosatrienoic acid produced when no test compound is added is taken as 100%. The inhibitory compound concentration (IC ₅₀ value) was calculated.

  The results are shown in Table 2.

Test example 2
Sprague-Dawley rats (7 weeks old, male) were divided into 3 groups using systolic blood pressure as an index. Angiotensin II was dissolved in 0.01 M acetic acid-containing physiological saline (7.2 mg / ml), then filled into an osmotic pump (Alzet) and injected subcutaneously (■ and ▲). An osmotic pump filled with 0.01 M acetic acid-containing physiological saline was injected subcutaneously into the control group (●). ● and ■ groups were suspended in 10% hydroxypropyl-β-cyclodextrin solution, and in group ▲ Compound 62 was suspended in hydroxypropyl-β-cyclodextrin solution, and were orally administered twice a day for 11 consecutive days. (30 mg / kg body weight). Systolic blood pressure was measured by the tail-cuff method over time. The results are shown in FIG.

  By administering the compound of the present invention to angiotensin II-induced hypertension model rats, a significant blood pressure lowering effect could be confirmed.

  From these results, it is possible to obtain an excellent antihypertensive action by using the 2-aryl-benzimidazole-5-carboxamide derivative of the present invention having an sEH inhibitory action, and to provide an excellent therapeutic agent for hypertension. It will be possible.

  According to the present invention, a 2-aryl-benzimidazole-5-carboxamide derivative that inhibits sEH activity can be provided. As a result, EETs in the body are increased, and it is possible to provide a drug effective for cardiovascular diseases including hypotension, renal disease, and cerebral infarction based on vasodilatory action. Furthermore, it is possible to provide a series of inflammatory diseases or autoimmune disease therapeutic agents via NFκB / IκB kinase activation, or endocrine metabolic diseases including hyperlipidemia and diabetes and adult respiratory distress syndrome.

FIG. 1 shows the results of measuring the systolic blood pressure by administering the sEH activity inhibitor to angiotensin II-induced hypertensive rats by the tail-cuff method (Test Example 2).

Claims (16)

Formula 1

[Where:
R ¹ is a C _1-6 alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-18 cycloalkyl group which may be substituted with ¹ to 4 halogen atoms,
Formula _{- (CH 2) n-Q} 1
(In the formula, n represents an integer of 1 to 8, Q ¹ represents —CN, —COOH, —SO ₃ H, —SR ^a , —SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , — OH, —OR ^d , —COOR ^a , —CONR ^e R ^f , C _3-18 cycloalkyl group, optionally substituted phenyl group, optionally substituted heteroaryl group, or optionally substituted 4 to 8 members A heterocycloalkyl group,
R ^a is a C _1-6 alkyl group, an optionally substituted C _7-18 aralkyl group or — (CH ₂ ) p—OH (p is an integer of 1 to 4),
R ^b or R ^c is independently a hydrogen atom, a C _1-6 alkyl group, a C _2-10 alkanoyl group, —SO ₂ R ^a or — (CH ₂ ) p—OH,
R ^d is a C _1-18 alkyl group, a C _3-18 cycloalkyl group, a C _2-10 alkenyl group or a C _2-10 alkanoyl group which may be substituted with 1 to 4 halogen atoms,
R ^e or R ^f is independently a hydrogen atom or a C _1-18 alkyl group)
Indicate
R ² is
A hydrogen atom, a C _1-18 alkyl group, a C _3-18 cycloalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group;
R ³ and R ⁴ are independently
A hydrogen atom, a halogen atom; —OH; a C _1-6 alkoxy group; a benzyloxy group; ^a C _1-18 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of —SR ^a , C _2-10 alkenyl group, C _2-10 alkynyl group, C _3-18 cycloalkyl group _optionally substituted with a hydroxyl group, aryl group optionally substituted, 4- to 8-membered heterocycloalkyl group optionally substituted An _optionally substituted C _7-18 aralkyl group,
Formula _{- (CH 2) m-Q} 2
(In the formula, m represents an integer of 1 to 8, and Q ² represents a C _3-18 cycloalkyl group, a C _2-10 cycloalkenyl group, a C _2-10 alkanoyl group, —CN which may be substituted with a hydroxyl group. , —COOH, —SO ₃ H, —SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , —O—CH ₂ ═CH ₂ , —O (CH ₂ ) p—OH, —COOR ^a , —CONR ^e R ^f , —NHCOR ^g , an optionally substituted heteroaryl group, an optionally substituted 4- to 8-membered heterocycloalkyl group, an optionally substituted phenoxy group or a benzoyl group,
(R ^g is a C _1-18 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of a halogen atom or a C _1-6 alkoxy group or an optionally substituted phenyl group). Show. ),
Formula —NR ⁵ —Q ³
Wherein R ⁵ is a hydrogen atom or a C _1-18 alkyl group,
(Q ³ is a C _1-18 alkyl group, an optionally substituted aryl group, an optionally substituted C _7-18 aralkyl group, an optionally substituted heteroaryl group or a C _3-18 cycloalkyl group,- COR ^g ). Or R ³ and R ⁴ together with the adjacent nitrogen atom represent a group which forms an optionally substituted 4- to 8-membered heterocycloalkyl group or heteroaryl group. ]
Or a pharmaceutically acceptable salt or hydrate thereof. The benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 1, wherein R ² is an optionally substituted aryl group or an optionally substituted heteroaryl group. R ³ is a halogen atom; —OH; C _1-6 alkoxy group; benzyloxy group; C _1-18 alkyl group which may be substituted with 1 to 4 substituents selected from the group consisting of —SR ^a ; A C _2-10 alkenyl group, a C _2-10 alkynyl group, an optionally substituted C _3-18 cycloalkyl group, an optionally substituted 4-8 membered heterocycloalkyl group, or the formula — (CH ₂ ) m -Q ²²
(In the formula, Q ²² is a C _3-18 cycloalkyl group, a C _2-10 cycloalkenyl group, a C _2-10 alkanoyl group, —CN, —COOH, —SO ₃ H, — SOR ^a , —SO ₂ R ^a , —NR ^b R ^c , —O—CH ₂ ═CH ₂ , —O (CH ₂ ) p—OH, —COOR ^a , —CONR ^e R ^f , —NHCOR ^g or substituted 4 to 8 membered heterocycloalkyl group).
The benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein R ⁴ is a hydrogen atom or a C _1-18 alkyl group. R ² is formula 2

(Wherein R ⁶ , R ⁷ and R ⁸ are the same or different and are a halogen atom, a C _1-6 alkyl group or a C _1-6 alkoxy group, and the other R ⁶ , R ⁷ and R ⁸ are hydrogen atoms. Or R ⁶ and R ⁷ together form —O—CH ₂ —O—, and R ⁸ is a hydrogen atom.)
The benzimidazole compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. R ³ is optionally substituted C _7-18 aralkyl group, or a group of the formula - (CH ₂₎ q-Ar
(Wherein q represents an integer of 1 to 8, Ar is a heteroaryl group),
The benzimidazole compound or a pharmaceutically acceptable salt or hydrate thereof according to claim 1, wherein R ⁴ is a hydrogen atom or a C _1-18 alkyl group. R ² is formula 2

(Wherein the symbols are as defined above)
The benzimidazole compound according to claim 5 or a pharmaceutically acceptable salt thereof or a hydrate thereof. Formula 3

(Wherein R ¹ , R ⁶ , R ⁷ and R ⁸ are as defined above,
R ²¹ , R ²² and R ²³ are the same or different and are a halogen atom, a C _1-6 alkyl group which may be substituted with a halogen atom, a C _1-6 alkoxy group or —SMe, and the other R ²¹ , R ²² and R ²³ are hydrogen atoms, or adjacent R ²¹ and R ²² are combined to form —O—CH ₂ —O—, and R ²³ is a hydrogen atom. The benzimidazole compound according to claim 6 or a pharmaceutically acceptable salt or hydrate thereof. R ³ is of the formula —NR ⁵ —Q ³ ,
(Wherein the symbols are as defined above),
The benzimidazole compound or a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 1, wherein R ⁴ is a hydrogen atom. R ² is formula 2

(Wherein the symbols are as defined above)
The benzimidazole compound according to claim 8, or a pharmaceutically acceptable salt thereof, or a hydrate thereof. 2. The benzimidazole compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ and R ⁴ together with the adjacent nitrogen atom are an optionally substituted 4- to 8-membered heterocycloalkyl group or heteroaryl group. Salt or hydrate thereof. R ² is formula 2

(Wherein the symbols are as defined above)
The benzimidazole compound according to claim 10 or a pharmaceutically acceptable salt thereof or a hydrate thereof. 1-butyl-N ′-(4-cyanophenyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carbohydrazide 1-butyl-2- (3,4-dichlorophenyl) -N′- (4-Nitrophenyl) -1H-benzimidazole-5-carbohydrazide 1-butyl-2- (3,4-dichlorophenyl) -N- (3-phenylpropyl) -1H-benzimidazole-5-carboxamide 1-butyl 2- (3,4-dichlorophenyl) -N- (3-methylbutyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N-hexyl-1H-benzimidazole 5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N-heptyl-1H-benzimidazole-5-carboxamide 1-butyl- 2- (3,4-Dichlorophenyl) -N- (7-methyloctyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (6-hydroxyhexyl)- The benzimidazole compound or a pharmaceutically acceptable salt or hydrate thereof according to claim 1, which is at least one compound selected from 1H-benzimidazole-5-carboxamide. 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (2-phenylethyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-Dimethoxybenzyl) -1- [2- (2-fluorophenyl) ethyl] -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl ) -1-pentyl-1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (methylthioethyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichloro Enyl) -N- (2,3-dimethoxybenzyl) -1-propyl-1H-benzimidazole-5-carboxamide 3- (2- (3,4-dichlorophenyl) -5-[[(2,3-dimethoxybenzyl ) Amino] carbonyl] -1H-benzimidazol-1-yl) propyl acetate 1-butyl-2- (3-ethoxy-4-methoxyphenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole -5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (thiophen-2-ylmethyl) -1H-benzimidazole-5-carboxamide 2- (3,4- Dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1-hexyl-1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzene) Dil) -2- (3,4-dimethylphenyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (3-methylbutyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3,4-dimethoxyphenyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- ( 2,3-dichlorobenzyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3,5-dimethoxyphenyl) ) -1H-benzimidazole-5-carboxamide)
1-cyclopropyl-2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2 -(4-Methoxyphenyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (2-methylpropyl) -1H-benzimidazole -5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1-trifluoroethyl-1H-benzimidazole-5-carboxamide N- (2,3-dimethoxybenzyl)- 2- (3,4,5-Trimethoxyphenyl) -1-benzyl-1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-Dimethoxybenzyl) -1- (3-hydroxypropyl) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (5-nitrothiophene-2 -Yl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2,3-difluorobenzyl) -1H-benzimidazole-5-carboxamide 2- (3, 4-Dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (tetrahydrofuran-2-ylmethyl) -1H-benzimidazole-5-carboxamide 2- (1,3-benzodioxol-5-yl) -1-butyl-N- (2,3-dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2, -Dimethoxybenzyl) -1-isopropyl-1H-benzimidazole-5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3,4,5-trifluorophenyl) -1H-benzimidazole -5-carboxamide 1-butyl-N- (2,3-dimethoxybenzyl) -2- (3-methoxyphenyl) -1H-benzimidazole-5-carboxamide N- (2,3-dimethoxybenzyl) -1- ( Furan-2-ylmethyl) -2- (3,4,5-trimethoxyphenyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl) -N- (2,3-dimethoxybenzyl)- 1- (4-Fluorobenzyl) -1H-benzimidazole-5-carboxamide 1-cyclohexylmethyl-2- (3,4-dichlorophenyl) -N- ( , 3-Dimethoxybenzyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2-methyl-3-chlorobenzyl) -1H-benzimidazole-5-carboxamide 2- (3,4-Dichlorophenyl) -N- (2,3-dimethoxybenzyl) -1- (2,2-dimethylpropyl) -1H-benzimidazole-5-carboxamide 2- (3,4-dichlorophenyl)- N- (2,3-dimethoxybenzyl) -1- (2-pyrrolidin-1-ylethyl) -1H-benzimidazole-5-carboxamide)
N- (2,3-dimethoxybenzyl) -1- (methoxyethyl) -2- (3,4,5-trimethoxyphenyl) -1H-benzimidazole-5-carboxamide N- (1,3-benzodioxy Sole-5-ylmethyl) -1-butyl-2- (3,4,5-trimethoxyphenyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- ( 2-methylthiobenzyl) -1H-benzimidazole-5-carboxamide N- (2-bromobenzyl) -1-butyl-2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-N -(2,4-dichlorobenzyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- [[5-Methyl-2- (trifluoromethyl) -3-furyl] methyl] -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (4-morpholinobenzyl ) -1H-benzimidazole-5-carboxamide 1-butyl-N- (2-bromo-3-thienylmethyl) -2- (3,4-dichlorophenyl) -1H-benzimidazole-5-carboxamide 1-butyl-2 -(3,4-dichlorophenyl) -N- (3-methoxybenzyl) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2-piperidin-1-ylbenzyl) ) -1H-benzimidazole-5-carboxamide 1-butyl-2- (3,4-dichlorophenyl) -N- (2-methylbenzyl) -1H-benzimi Zole-5-carboxamide is at least one compound selected from 1-butyl-2- (3,4-dichlorophenyl) -N- (3,3-diphenylpropyl) -1H-benzimidazole-5-carboxamide Item 7. A benzimidazole compound or a pharmaceutically acceptable salt or hydrate thereof according to Item 7.   The pharmaceutical containing the benzimidazole compound of any one of Claims 1-13, its pharmaceutically acceptable salt, or its hydrate.   The medicament according to claim 14, which is a soluble epoxide hydrolase inhibitor.   The medicament according to claim 15, which is a therapeutic drug for hypertension, renal disease or cerebral infarction.

Images