WO2006115137A1

WO2006115137A1 - 2-aminobenzimidazole derivative and use of the same for medical purposes

Info

Publication number: WO2006115137A1
Application number: PCT/JP2006/308177
Authority: WO
Inventors: Kazuo Shimizu; Takashi Miyagi; Norihiko Kikuchi
Original assignee: Kissei Pharmaceutical Co., Ltd.
Priority date: 2005-04-22
Filing date: 2006-04-19
Publication date: 2006-11-02
Also published as: JPWO2006115137A1

Abstract

Disclosed is a 2-aminobenzimidazole derivative which is effective for a disease cause by abnormal serum uric acid level. A 2-aminobenzimidazole derivative represented by the general formula (I) or a prodrug thereof or a pharmacologically acceptable salt of the compound or prodrug or the like; or a pharmaceutical composition comprising the compound, prodrug or salt as the active ingredient; or the like. (I) wherein R1 represents a halogen atom or the like; m is an integer of 0 to 2; n is an integer of 1 to 2; R2 represents OH or the like; R3 and R4 dependently represent H or OH; the ring Q represents a heterocyclic ring or a bicyclic hydrocarbon group; R5 and R6 independently represent a cyano group, -AH, -A-D-E-G or the like (where A represents a single bond, O, S, NR8 or the like; D represents an alkylene or alkenylene group which may be substituted or the like; E represents a single bond, O, S, NR9 (where R8 and R9 independently represent H or an alkyl group which may be substituted), a (hetero)cycloalkylene or (hetero)arylene group which may be substituted or the like; G represents H, an alkyl or alkenyl group which may be substituted or the like); R7 represents H, a halogen atom, a (hetero)aryl group which may be substituted or the like.

Description

Specification

2-Aminobenzimidazole derivatives and their pharmaceutical uses

Technical field

[0001] The present invention relates to a 2-aminobenzimidazole derivative useful as a pharmaceutical product.

[0002] More specifically, the present invention has a sodium-dependent nucleoside transporter (hereinafter referred to as CNT) inhibitory activity and is useful as a preventive or therapeutic agent for diseases caused by abnormal plasma uric acid levels. The present invention relates to an aminobenzimidazole derivative or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof.

Background art

[0003] Uric acid is the end product of purines in humans. Regardless of gender and age, uric acid solubility in plasma is 7. OmgZdL, the upper limit of normal, and those exceeding this are clinically hyperuricemia. Defined. Hyperuricemia is thought to result from a combination of genetic factors involved in purine metabolism, which are more common in adult males, and secondary factors such as the intake of high-tech energy and high nucleic acid diets. If hyperuricemia persists, the risk of developing arthritis increases due to the deposition of urate crystals in or around the joint. Such symptoms of arthritis are called gout, and arthritis is called gout attack. The types of hyperuricemia are broadly classified into uric acid overproduction, where uric acid production increases, uric acid excretion, where uric acid excretion decreases in the urine, and mixed types where both are mixed (for example, (See Non-Patent Documents 1 and 2).

[0004] In preventing or treating hyperuricemia and gout, it is fundamental to prevent the development of gout arthritis by controlling the plasma uric acid level below a certain level. The incidence is said to be the lowest when 4.6 to 6.6 mgZdL is controlled. Conventionally, for the treatment of hyperuricemia and gout, plasma uric acid levels have been improved using the urate synthesis inhibitor aloprinor or the uric acid excretion promoters probenecid, bucolome, and benzbromarone. In the treatment of gout attacks, analgesic treatment drugs such as colchicine, nonsteroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, and oxaprozin and corticosteroids are included. It is used. Alopurinol, a uric acid synthesis inhibitor, has side effects such as poisoning syndrome (hypersensitivity vasculitis), Stevens' Johnson syndrome, exfoliative dermatitis, aplastic anemia, and impaired liver function. In addition, there is a restriction that uric acid excretion-promoting drugs cannot be used in patients with renal failure, and probenecid, bucolome and venesbromarone develop side effects such as gastrointestinal disorders and urinary tract stones. In patients with idiosyncratic cases, fulminant hepatitis may occur (see Non-patent Document 1, for example).

[0005] New U, preventive treatment drugs with few side effects that can solve the problems of conventional treatment drugs, especially in terms of expanding the options for treatment methods, There is a need for new and different preventive drugs.

[0006] Hyperuricemia is caused by lifestyle habits such as overeating, high purine / high fat, high protein diet preference, habitual drinking, lack of exercise, and is also deeply associated with obesity, high blood pressure, and abnormal glucose and lipid metabolism. Because of this, the role of life guidance as a non-drug therapy aimed at correcting lifestyle habits is great! Of these, diets that limit purine overdose occupy an important position, but these diets and lifestyle improvements are difficult to sustain and often unsuccessful.

[0007] Purine digestion / absorption regulators have been proposed as different from conventional uric acid synthesis inhibitors or uric acid excretion promoters and used as part of or instead of diet therapy (for example, (See Patent Document 1). The invention described in Patent Document 1 is a purine digestion / absorption regulator for humans containing chitosan, but the dosage is relatively high at 2 to 2000 mgZkgZ days, and it is administered in the form of a beverage or food. As it is said, it is mainly for the auxiliary use of dietary therapy. In addition to Patent Document 1, a hyperuricemia-improving agent and food for improvement containing chitosan or dietary fiber as an active ingredient have also been developed (for example, see Patent Document 2). Although the action of chitosan or dietary fiber described in Patent Document 1 or 2 is not clear, the purine body is bound or adsorbed to chitosan or dietary fiber, which is a polymer, so that purine body absorption is suppressed and uric acid is not absorbed. Production is expected to decrease.

[0008] Regarding the digestion and absorption pathway of nucleic acids in humans, ingested nucleic acids and nucleoprotein strength are released in the intestinal tract, and the nucleic acid strength ribonuclease, deoxyribonuclease It is broken down into mononucleotides by creatase and polynucleotides. Furthermore, the main pathway is considered to be a pathway in which mononucleotides are decomposed into nucleosides and absorbed by nucleotidase and phosphatase. Of these, the absorbed purine nucleoside is considered to be converted to uric acid (see, for example, Non-Patent Document 3). In addition to this route, there are other routes that can be absorbed after purine nucleosides are decomposed to produce purine bases, or routes in which purine bases in food are directly absorbed. The details have not yet been elucidated.

[0009] The uptake of nucleosides in the intestine involves a membrane protein called a nucleoside transporter. For mammalian cells, this transport carrier includes an equilibrative transporter (hereinafter ENT and!), Which is taken up by the difference in nucleoside concentration, and a sodium-dependent nucleoside transporter that utilizes a difference in ion concentration inside and outside the cell ( (Referred to as non-patent document 4). As for human nucleoside transport carriers, two types of ENTs, type 1 (hereinafter referred to as ENT1) and type 2 (hereinafter referred to as ENT2), have been identified and cloned (for example, Non-Patent Documents 5 and 6). (See) In addition, three types of CNT, Type 1 (hereinafter referred to as CNT1), Type 2 (referred to as CNT2 above), and Type 3 (hereinafter referred to as CNT3) have been identified and cloned (for example, see Non-Patent Documents 7 to 9). .

[0010] The distribution and characteristics of these transport carriers are confirmed to some extent. ENT is widely expressed in normal human tissues, both ENT1 and ENT2, and transports both purines and pyrimidine nucleosides. Functionally, the sensitivity to inhibition by nitrobenzylthioinosine (hereinafter referred to as NBMPR) is different, ENT1 is also significantly inhibited by low concentrations of NBMPR (IC <5 nM), and ENT2 is blocked by NBMPR.

50

It is inhibited only by high concentrations of NBMPR (IC> 1 M), which are difficult to harm. (For example,

50

(See Non-Patent Document 10)

[0011] On the other hand, regarding CNT, CNT1 takes in pyrimidine nucleosides and adenosine, and in rats, expression of messenger RNA (hereinafter referred to as mRNA) is observed in the jejunum and kidney. CNT2 takes in purine nucleosides and uridine, and in humans, many types of mRNA are expressed in organs including heart, liver, skeletal muscle, kidney, intestine, etc. ing. Recently cloned CNT3 incorporates both purine and pyrimidine nucleosides, and in humans, mRNA expression has been confirmed in bone marrow, spleen, intestine and mammary gland. Functionally, it has been confirmed that all CNTs are not affected by NBMPR. (For example, see Non-Patent Documents 9 and 11)

[0012] In addition, to study the transport mechanism in the intestinal tract so far, mucosa via CNT

It has been shown that nucleosides are taken in from the (mucosal) side, and nucleosides are absorbed from the serosal side via ENT (see, for example, Non-Patent Document 12). However, the role of transport carriers in nucleoside absorption in the human intestinal tract, especially in the small intestine, has been elucidated in detail!

[0013] On the other hand, Patent Documents 1 and 2 show that the plasma uric acid level is decreased by suppressing the absorption of purine bodies. It has also been confirmed that the plasma uric acid level is reduced by restricting the intake of the human body, and the uric acid produced from the purine nucleoside absorbed from the intestinal tract is reflected in the plasma uric acid concentration (for example, non-patent literature). 13). Therefore, it is possible to adjust the uric acid level in plasma by effectively suppressing purine nucleoside absorption, which is an intestinal force.

[0014] To date, it has been reported that it is useful for the prevention or treatment of viral infections caused by certain 2-aminobenzimidazole derivatives, herpesviruses, and the prevention or treatment of restenosis of coronary arteries. There is no report or suggestion that it is useful for the prevention or treatment of diseases caused by abnormal plasma uric acid levels such as gout and hyperuricemia (see Patent Documents 3 to 6).

Patent Document 1: Japanese Patent Laid-Open No. 2001-163788

Patent Document 2: Japanese Patent No. 2632577

Patent Document 3: International Publication No. 97Z25337 Pamphlet

Patent Document 4: U.S. Pat.No. 6,204,249

Patent Document 5: U.S. Pat.No. 6,617,315

Patent Document 6: International Publication No. 01Z77083 Pamphlet

Non-patent document 1: Hyperuricemia · Gout treatment guidelines, Japanese gout · Nuclear Nucleic Acid Metabolism Society, 1st edition, 2002, p. 12-45 Non-Patent Document 2: Taniro Ikuo, 1 other, “Diagnosis and Treatment”, 2002, No. 90, No. 2, p. 186-191

Non-Patent Document 3: "Harper, Biochemistry Original, 25th Edition", Hayato Kamishiro, published by Maruzen Co., Ltd., January 30, 2001, p. 417

Non-Patent Document 4: Carol E. Cass, 11 others, “Membrane Transporters as Drug Targets”, 1999, p. 318—32 Non-Patent Document 5: Mark Griffiths, 10 Name, “NATURE MEDICIN E”, January 1997, No. 3, IV, p. 89- 93

Non-Patent Document 6: Charles R. Crawford and three others, “The Journal of Biological Chemistry”, 1998, No. 273, No. 9, p. 528 8-5293

Non-Patent Document 7: \ 1 & 61 \ ^ 丄 .1¾261, 5 others, "American Journal of Physiology", 1997, 272th, Cell Physiology, 41卷, p. C707-C714

Non-Patent Document 8: Juan Wang and five others, “American Journal of Physiology J, 1997, 273th, Ren al Physiology, 42nd, p. F1058— F1065

Non-Patent Document 9: \ 1 & 61 \ ^ 丄 .1¾261, 14 others, “The Journal of Biological Chemistry J, 2001, 276 卷, No. 4, p. 291 4 -2927

Non-Patent Document 10: Carol E. Cass, 11 others, “Membrane Transporters as Drug Targets”, 1999, p. 316— 3 18

Non-Patent Document 11: Carol E. Cass, 11 others, “Membrane Transporters as Drug Targets”, 1999, p. 327-3 32

Non-Patent Document 12: James D. Young, 4 others, “Gastrointestinal Transport Molekiyura ¹ ~~ Fiji Sairon ~~ (Gastrointestinal transport, molecular physiology), 2 001, p. 334- 337

Non-Patent Document 13: N. Zollner, "Proceedings of the Nutrition Society J, 1982, 41st, p. 329-342 Disclosure of the Invention

Problems to be solved by the invention

[0015] An object of the present invention is to provide a 2-aminobenzimidazole derivative useful for the prevention or treatment of a disease caused by an abnormal plasma uric acid level.

Means for solving the problem

As a result of intensive studies to solve the above-mentioned problems, the present inventors have demonstrated a certain 2-aminobenzimidazole derivative having a CNT inhibitory activity represented by the following general formula (I), and an excellent plasma. The inventor has obtained the knowledge that it exerts an inhibitory effect on the increase in uric acid level, and has reached the present invention.

[0017] The present invention is a novel 2-aminobenzimidazole derivative or a prodrug thereof or a pharmacologically acceptable salt thereof that has excellent CNT inhibitory activity and remarkably suppresses an increase in plasma uric acid level. Or a hydrate thereof, and a pharmaceutical composition containing the same and a pharmaceutical use thereof.

That is, the present invention relates to a 2-aminobenzimidazole derivative represented by the following general formula (I), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof, or The present invention relates to a pharmaceutical composition containing it as an active ingredient.

[Chemical 1]

[Where, R ¹ is a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group; m is an integer of 0 to 2;

R ² is a hydroxyl group or a fluorine atom;

R ³ and R ⁴ are independently a hydrogen atom or a hydroxyl group;

n is 1 or 2;

Ring Q is a heterocyclic group or a bicyclic hydrocarbon group;

One of R ⁵ and R ⁶ is a cyano group or an —A—D—E—G group.

{A is a single bond, −0 −, 1 S −, 1 NR ⁸ −, 1 COO −, 1 CONR ⁸ −, NR ⁸ CO − or — NR ⁸ COO— (R ⁸ is independently a hydrogen atom Or a substitutable lower alkyl group);

D represents a substitutable lower alkylene group, a substitutable lower alkene group, or a substitutable lower alkenylylene group;

E represents a single bond, over 0 - one S - one NR ⁹ -, One COO - one CONR ⁹ - one NR ⁹ CO ^{one, - NR 9 COO -, -} N + R 9 R 1C) - ( R ⁹ and R ¹⁰ are each independently a hydrogen atom or a substitutable lower alkyl group), a substitutable (hetero) cycloalkylene group, a substitutable (hetero) alkylene group, or a substitutable nitrogen-containing heterocycloalkyl group. Quaternary salts or quaternary salts of substituted nitrogen-containing heteroaryl groups;

G represents a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkenyl group, or a substitutable lower alkynyl group.

(However, A and E are not a single bond at the same time! / ヽ)}

The other is a hydrogen atom, halogen atom, cyano group, -AH group or -A-D-E-G group {A, D, E and G are as defined above. It may be)}. ]

The present invention also includes a 2-aminobenzimidazole derivative represented by the following general formula (Γ), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof as an effective component. Containing CNT inhibitor, gout, hyperuricemia, urinary calculus, hyperuric acid nephropathy, pharmaceutical composition for prevention or treatment of diseases caused by abnormal plasma uric acid level such as acute uric acid nephropathy Ingredients selected from the group of colchicine, non-steroidal anti-inflammatory drugs, corticosteroids, uric acid synthesis inhibitors, uric acid excretion promoters, urinary alkalinizing drugs and uric acid oxidase The pharmaceutical composition comprising a combination of at least one drug.

[Chemical 2]

[Where,

R ¹ is a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group; m is an integer of 0 to 2;

R ² is a hydroxyl group or a fluorine atom;

R ³ and R ⁴ are independently a hydrogen atom or a hydroxyl group;

n is 1 or 2;

Ring Q is a heterocyclic group or a bicyclic hydrocarbon group;

R ⁵ and R ⁶ are independently a hydrogen atom, a halogen atom, a cyano group, a −811 group or a −8-0 E—G group.

{A is a single bond, over 0 - one S - one NR ⁸ -, one COO - one CONR ⁸ -, NR ⁸ CO - or - NR ^⁸ COO- (R ⁸ is a hydrogen atom or an optionally substituted lower Alkyl group);

E represents a single bond, over 0 - one S - one NR ⁹ -, One COO - one CONR ⁹ - one NR ⁹ CO ^{one, NR 9 COO -, - N} + R 9 R 1C) - (R ⁹ and R ¹⁰ are each independently a hydrogen atom or a substitutable lower alkyl group), a substitutable (hetero) cycloalkylene group, a substitutable (hetero) alkylene group, or a substitutable nitrogen-containing heterocycloalkyl group. A quaternary salt or a quaternary salt of a substituted nitrogen-containing heteroaryl group; G is a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkenyl group or a substitutable lower alkyl group};

R ⁷ is a hydrogen atom, a halogen atom, a cyan group, a substitutable (hetero) aryl group or a substitutable (hetero) cycloalkyl group. ]

In the general formulas (I) and (Γ), the term “substitutable” means that 1 to 3 different or similar substituents may be present. Examples of the substituent that may have a halogen atom, cyan group,

— NW ² COO W ³ , —NHC (= NH) —NH, — CONW ² W ³ , — NW ² CONW ³ W ⁴ , —SO NW ² W

twenty two

³ or N + W ⁵ W ⁶ W ⁷ , and are each independently a hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group, or an aryl lower alkyl group, or W ² and W 3, W ³ And W ⁴ may form a cycloaliphatic amino group ring structure including a nitrogen atom bonded thereto, and w ^{5 to} w ⁷ are each independently a lower alkyl group, a hydroxy lower alkyl group, or A force that is an aryl lower alkyl group, or w ⁵ , w ^6, and w ⁷ may include a nitrogen atom to form a ring structure.

[0021] The meanings of the terms in this specification are as follows.

A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

Lower alkyl is linear or branched having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s ec butinole, tert butinole, pentinole, isopentinole, neopentinole, tert pentyl, hexyl, etc. Of alkyl. The lower alkenyl refers to a linear or branched alkenyl having 2 to 6 carbon atoms such as vinyl, aryl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 2-methylaryl and the like. Lower alkynyl refers to straight-chain or branched alkynyl having 2 to 6 carbon atoms such as ethynyl and 2-propynyl. Lower alkylene refers to linear or branched alkylene having 1 to 6 carbon atoms. Lower alkylene refers to straight or branched alkylene having 2 to 6 carbon atoms. Lower alkylene is straight-chain or branched alkynylene having 2 to 6 carbon atoms.

[0022] Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Heterocycloalkyl is aziridinyl , Azetidinyl, morpholinylated 2-morpholinyl, thiomorpholinyl, pyrrolidino, piperidinylated 4-piperidyl, 1-piperazil, 2-oxopyrrolidine 1-yl, etc., from oxygen, sulfur and nitrogen atoms in the ring It contains 1 to 2 selected heteroatoms, has 1 to 2 oxo groups, and may be a 3- to 10-membered monocyclic, polycyclic or bridged heterocycloalkyl (for example, 1, 3-dioxoisoindoline and 2-yl group). (Hetero) cycloalkyl refers to cycloalkyl or heterocycloalkyl. (Hetero) cycloalkylene is a divalent group obtained by removing one hydrogen atom bonded to an atom other than the above-mentioned free valence of cycloalkyl or heterocycloalkyl.

[0023] The aryl refers to an aromatic cyclic hydrocarbon group having 6 or 10 carbon atoms such as phenyl and naphthyl (for example, examples of the aryl lower alkyl group include benzyl, phenyl, naphthylmethyl, naphthylethyl and the like). ). Heteroaryl refers to thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiazole, triazole, tetrazole, and furazane. Atoms, sulfur atoms and nitrogen atomic energy 5- to 6-membered aromatic heterocyclic groups containing 1 to 4 selected heteroatoms, or indoles, isoindoles, benzofurans, isobenzofurans, benzothiols Fen, Benzoxazonole, Benzothiazonore, Benzoisoxazozole, Benzoisothiazole, Indazole, Benzimidazole, Pyrrolo-Pyridine, Purine, Quinoline, Isoquinoline, Phthalazine, Quinoxaline, Quinazoline, Shinori A 5- or 6-membered ring and a 6-membered ring containing 1 to 4 arbitrary heteroatoms selected from oxygen, sulfur and nitrogen atoms in the ring, such as N, indolizine, naphthyridine, and pteridine An aromatic heterocyclic group. Nitrogen-containing heteroaryl refers to a heteroaryl containing at least one nitrogen atom in the ring. (Hetero) aryl refers to aryl or heteroaryl. (Hetero) arylene refers to a divalent group that is bonded to atoms other than those with free valence of aryl or heteroaryl! /, Except for one hydrogen atom.

[0024] Lower alkoxy is carbon number such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc. 1-6 straight chain Or branched alkoxy. Hydroxy lower alkyl refers to lower alkyl substituted with a hydroxyl group.

[0025] The alicyclic amino group ring structure is selected from oxygen atom, sulfur atom and nitrogen atom such as aziridinyl, azetidinyl, morpholy-containing thiomorpholyl, 1-pyrrolidi-containing piperidinized 1-piperaduryl, 1-pyrrolyl Containing a hetero atom in the ring other than the nitrogen atom of the binding site! /, But a cyclic amino group! Uh.

[0026] Examples of the quaternary salt include a quaternary ammonium salt, a pyridinium salt, and a piperageum salt. Examples of the anionic ligand include fluoride, chloride, promide, iodide, hydroxide, acetate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, sulfate, tetrafluoroborate, and chromate chromate. Preferred examples include azide, hydroxide, acetate, methanesulfonate, sulfate and the like.

[0027] In ring Q, a heterocycle refers to a heterocycle in which one of the heteroaryl or the bicyclic heteroaryl is hydrogenated (for example, indoline, isoindoline, chroman, tetrahydropyrrolopyridine, benzodi). Oxol, 1, 4 benzodioxane, ノ, idroquinoline, etc.). Preferably, heteroaryl such as indole, benzothiazole, benzimidazole, benzofuran, benzothiophene, benzoxazole and the like can be mentioned. The bicyclic hydrocarbon group is a bicyclic aromatic hydrocarbon having 8 to 10 carbon atoms such as naphthalene or a hydrocarbon ring in which one of the rings is hydrogenated (for example, indene, dihydronaphthalene, tetrahydronaphthalene). Etc.). Preferably, naphthalene etc. are mentioned.

[0028] In the present invention, m is preferably 0. R ⁵ and R ⁶ are preferably A—D—E—G (wherein A, D, E, G have the same meaning as described above, but preferably A is —O—; D is a hydroxyl group. , -NW lower alkylene group having ² W ³ or ^{^{^{N + W 5 W 6 W 7}}} (W 2, W 3 and W ⁵ ~ ⁷ are the same as defined above); E is a single bond, heterocyclo to substitutable An alkylene group, a quaternary salt of a substituted nitrogen-containing heterocycloalkyl and a quaternary salt of a substituted nitrogen-containing heteroaryl; G is a hydrogen atom and a substitutable lower alkyl group).

[0029] The 2-aminobenzimidazole compound represented by the general formula (I) of the present invention is produced, for example, according to the following [Method 1] to [Method 3] or a method analogous thereto. It is possible The

[Method 1]

[0031] [Chemical 3]

[In the formula, X is a halogen atom; L is a leaving group such as a halogen atom or an acetoxy group; R′—R ⁷ , mn, and ring Q have the same meaning as described above.)

[0033] The o-phenylenediamine compound () is subjected to a cyclization reaction with phosgene, carbodiimidazole or the like to obtain a urea compound (), which is halogenated to give a 2-halobenzimidazole compound. (4). Alternatively, the o-phenylenediamine compound) can be subjected to a cyclization reaction with cyanogen bromide or the like to obtain a 2-neck benzimidazole compound (4). Next, the compound (4) is glycosylated with a sugar donor () to give a saccharified 2-Haben Benzimidazole compound (day) and condensed with the amine compound (Z). Accordingly, the compound represented by the general formula (I) of the present invention can be produced by removing a protecting group such as a sugar moiety.

[0034] The cyclization reaction is!, Even in the case of deviation, in the presence or absence of a base such as sodium carbonate, triethylamine, pyridine, tetrahydrofuran, dichloromethane, acetic acid, toluene, N, N-dimethylformamide, acetonitrile, etc. In an inert solvent such as a mixed solvent, the mixture is usually mixed at 0 ° C. to reflux temperature for 10 minutes to 1 day. [0035] The halogenation reaction may be carried out using an acid halogen reagent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, fluorosulfuric acid or the like without solvent or in toluene, dichloromethane, Mixing in an inert solvent such as a mixed solvent usually at -78 ° C to reflux temperature for 30 minutes to 1 day can be performed.

In the glycosylation reaction, when the leaving group L of the sugar donor () is a halogen atom such as a bromine atom, the leaving group L is a cetoxy group in the presence of a base such as sodium hydride or potassium carbonate. In such a case, after pretreating the 2-Haguchi Benzimidazole compound (4) with a silylating agent such as N, O-bis (trimethylsilyl) acetamide trimethylsilyl chloride, hexamethyldisilazane, etc. N, N-dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidinone, dimethyl in the presence of Lewis acids such as trimethylsilyl trifluoromethanesulfonate, tin tetrachloride, boron trifluoride, etc. Mix in an inert solvent such as sulfoxide, acetonitrile, 1,2-dichloroethane, tetrahydrofuran, or a mixed solvent thereof, usually at 0 ° C to reflux temperature for 30 minutes to 1 day. It is possible to carry out that 〖Koyori.

[0037] The condensation reaction is carried out in the presence or absence of a base such as sodium hydride, potassium carbonate, triethylamine, diisopropylethylamine, toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, ethanol, isobutanol. In an inert solvent such as water or a mixed solvent thereof, the reaction can be carried out usually by mixing at room temperature to reflux temperature for 1 hour to 3 days.

[0038] When a protecting group is required, the procedures for introduction and desorption can be appropriately combined according to conventional methods. For example, a protecting group such as a sugar moiety can be removed according to a method generally used in organic synthesis such as alkaline hydrolysis as necessary (hereinafter the same).

[Method 2]

[0040] [Chemical 4]

[0041] (! ~~, m, n, ring Q, L have the same meaning as above)

[0042] A 2-aminominobenzimidazole compound (dan) is subjected to a condensation reaction with an aldehyde compound (£) and then reduced to an N-substituted 2-aminoaminobenzimidazole compound (i And a sugar donor () can be used to obtain a compound represented by the general formula (I) of the present invention.

[0043] The condensation reaction is carried out in the presence or absence of a base such as sodium acetate, sodium carbonate, sodium ethoxide, or an acid such as acetic acid or methanesulfonic acid, toluene, tetrahydrofuran, dichloromethane, N, N dimethylformamide, Mixing in an inert solvent such as ethanol, water, or a mixed solvent thereof, usually at room temperature to reflux temperature, for 10 minutes to 1 day can be performed.

[0044] The reduction reaction uses a reducing agent such as lithium aluminum hydride and sodium borohydride in an inert solvent such as toluene, tetrahydrofuran, dichloromethane, and a mixed solvent thereof, usually at 78 ° C to reflux temperature. Can be done by mixing for 30 minutes to 1 day

[0045] The glycosylation reaction can be carried out in the same manner as in [Method 1].

[Method 3]

[0047] [Chemical 5]

[0048] (in the formula! ^ ~, M, n, ring Q, X have the same meaning as above)

[0049] Saccharification 2-Haguchi Benz-imidazole compound (day) is azide converted to azide compound (11), and saccharification 2-amaminobenzimidazole compound (!) Obtained by reduction is converted to aldehyde compound (£). After the condensation reaction, it is reduced to produce the compound represented by the general formula (I) of the present invention.

[0050] The azidation reaction is carried out by using an azide reagent such as sodium azide or lithium azide, using toluene, tetrahydrofuran, dichloromethane, N, N-dimethylformamide, ethanol, isobutanol, water, or a mixed solvent thereof. In an inert solvent such as the above, mixing can be performed usually at room temperature to reflux temperature for 1 hour to 3 days.

[0051] The reduction reaction is carried out by using a metal catalyst such as palladium carbon powder and platinum oxide in the presence or absence of an acid such as hydrochloric acid, and using methanol, ethanol, tetrahydrofuran, ethyl acetate, acetic acid, a mixed solvent thereof or the like. Preference is given to catalytic reduction by mixing in an inert solvent, usually from room temperature to reflux temperature for 30 minutes to 1 day.

[0052] The condensation reaction and the reduction reaction can be carried out in the same manner as in [Method 2].

[0053] In addition, the compound represented by the general formula (I) of the present invention can be produced, for example, by the following method or a method according to them, or by appropriately combining them.

[0054] At least one of R ^{5 to} R ⁷ is a substituted alkoxy group, a substituted thioalkyl group, or a substituted group. The compound represented by the general formula (I) which is a substituent having an alkylamino group or a quaternary ammonium group is a compound having a hydroxyl group, a thiol group or an amino group corresponding to the group. It can also be produced by alkylation using an alkylating agent such as an alkylated compound.

[0055] The alkylation reaction is carried out in the presence of a base such as sodium hydroxide, potassium carbonate, triethylamine, diisopropylpropylamine or the like, and optionally in the presence of sodium iodide, methanol, ethanol, tetrahydrofuran, N, N-dimethylformamide, water. The reaction can be carried out by mixing in an inert solvent such as a mixed solvent, usually at room temperature to reflux temperature for 10 minutes to 1 day.

[0056] The compound represented by the general formula (I), in which at least one of R ^{5 to} R ⁷ is a substituent having a substituted alkoxy group or a substituted carboxyalkyl group, has a hydroxyl group or a carboxy group corresponding to the group. It can be produced by subjecting a compound having a reaction to a condensation reaction with a corresponding alcohol compound.

[0057] The condensation reaction is carried out in the presence of a Mitsunobu reagent such as jetyl diazo azodicarboxylate or diisopropyl azodicarboxylate, and an organic phosphorus reagent such as triphenylphosphine, toluene, tetrahydrofuran, N, N-dimethylformamide, a mixed solvent thereof or the like. In an inert solvent, the mixture can be mixed usually at room temperature to reflux temperature for 10 minutes to 1 day.

[0058] The compound represented by the general formula (I) in which at least one of R ^{5 to} R ⁷ is a substituent having a strong rubamoyl group is obtained by converting a compound having a carboxy group corresponding to the group into a corresponding amine compound It can be produced by subjecting it to a condensation reaction with, and further subjecting it to an amidy reaction if necessary.

[0059] The condensation reaction can be carried out in a conventional manner in an inert solvent using a condensing agent such as diphenylphosphoryl azide and dicyclohexylcarbodiimide.

[0060] In the presence of an active ester reagent such as 1-hydroxybenzotriazole, the amidy reaction is usually performed at room temperature to reflux temperature in an inert solvent such as toluene, tetrahydrofuran, N, N-dimethylformamide, or a mixed solvent thereof. And mixing for 10 minutes to 1 day.

[0061] At least one of R ^{5 to} R ⁷ is a lower alkyl group, a lower alkyl group, or a cycloalkyl group. The compound represented by the general formula (I), which is a substituent having a group or a (hetero) aryl group, is a compound in which a group corresponding to the group is a halogen atom, a corresponding alkene compound, an alkyne compound, or It can also be produced by subjecting it to a condensation reaction with a boric acid compound.

[0062] The condensation reaction may be carried out using palladium catalysts such as palladium acetate and tetrakis (triphenylphosphine) palladium, organic phosphorus such as triphenylphosphine, 2,2,1bis (diphenylphosphino) 1,1,1, binaphthyl and the like. In the presence of a ligand and a base such as cesium carbonate, sodium tert-butoxide, etc., in an inert solvent such as toluene, tetrahydrofuran, N, N-dimethylformamide, or a mixed solvent thereof, usually at room temperature to reflux temperature, 10 This can be done by mixing for 1 minute to 1 day.

[0063] The compound represented by the general formula (I), wherein at least one of R ^{5 to} R ⁷ is a substituent having an acylamino group, an alkoxycarbolamino group, a sulfo-lumino group or a ureido group, A compound having a corresponding amino group can also be produced by subjecting it to an acylation, force rubamination, sulfolation or ureido reaction.

[0064] The acylation, force rubamination, sulfonylation, and ureido reaction are carried out by using a corresponding acylating agent such as an acyl halide derivative, a strong rubamatizing agent such as a chloroformate compound, and a sulfonolide compound. In the presence or absence of a base such as sodium hydroxide, pyridine, triethylamine, diisopropylethylamine, tetrahydrofuran, N, and the like using a sulfating agent such as , N-dimethylformamide, water, in an inert solvent such as a mixed solvent thereof, usually at room temperature to reflux temperature for 10 minutes to 1 day.

[0065] Next, production methods of various raw material compounds (β), (Ζ) and () used in [Method 1] to [Method 3] are exemplified below.

[Production method 1]

Each kind of saccharified 2-haguchi benzimidazole compound (day) can be produced by the following method.

[0067] [Chemical 6]

17

[In the formula, R ^a is a hydrogen atom or a protecting group for a hydroxyl group;

m and X have the same meaning as above. )

[0069] D-ribose form (IS) of glycated 2-haguchi benzimidazole compound (β) is appropriately converted to a compound of general formula (14) (for example, Chemical & Ph armaceutical Bulletin, 51 (4) 399-403 (2003); and hemical & Pharmaceutical Bulletin, ό 6 (3) 945-953 (1988)), 2,, 3, deoxy (1≤) (eg, J Chem. Soc, Perkin Trans. 1, 298-304 (2001); J. Heterocyclic Chem., 38, 1297 (2001)), 2, —deoxy (l ^) (eg, The Journal of Antibiotics, 37 , 941-942 (1984); European Journal of Organic Chemistry, 3997—4002 (2003); Journal of Medicinal Chemistry, 46 (22), 4 776-4789 (2003)), 5, —fluoride () (eg Angew. Chem. Int. Ed "41, No. 20, 3913-3915 (2002); Nucleosides & Nucleotide, 14 (9 & 10), 1831-1852 (1995); Journal of Organic Chemistry, 53, 5046-5050 (1988) )) And 3, deoxy (l ^) (eg, T etrahedron Letters, 7941-7943 (2003); Journal of Organic Chemist ry, 66, 7469-747 7 (2001); Journal of the American Chemical Society, 123 (5), 870-874 (2001)).

[0070] [Production method 2]

The amine compound (1) can also be produced by the following method.

[0071] [Chemical 7]

[0072] (wherein R ^{5 to} R ⁷ , n, and X have the same meaning as described above).

[0073] The aldehyde compound (S) can be converted into an oxime compound (IS) by oximation, and subjected to a reduction reaction to produce the amine compound (1). In addition, a nitrile compound () is subjected to a reduction reaction, a carbamoyl compound (22) obtained by reacting an acid chloride compound (21) with ammonia, or a halogenated compound. Even if the phthalimide compound () obtained by phthalimidizing the compound is subjected to a deprotection reaction, or the azide compound obtained by azidating the halogenated compound (2 3) is subjected to a reduction reaction, the amine Compound).

[0074] The oximation reaction is performed by reacting hydroxylamine with an inert solvent such as toluene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof, usually at 78 ° C to reflux temperature for 30 minutes to 1 day. It can be carried out.

[0075] The reaction with ammonia is carried out by mixing in an inert solvent such as no solvent or toluene, dichloromethane, or a mixed solvent thereof, usually at 78 ° C to reflux temperature, usually for 30 minutes to 1 day. Can do.

[0076] The reduction reaction of the strong rubermoire compound can be carried out according to a general reduction method of strong ruberamoyl. That's fine. For example, using a reducing agent such as borane-dimethylsulfide complex, borane-tetrahydrofuran complex, lithium aluminum hydride, diisobutylaluminum hydride, etc. in an inert solvent such as toluene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof.

Usually, it can be performed at 78 ° C to reflux temperature for 30 minutes to 1 day.

[0077] The phthalimidation reaction is carried out in the presence or absence of a base such as sodium hydride, sodium carbonate, potassium hydroxide, phthalimide or a salt thereof, toluene, tetrahydrofuran, dichloromethane, N, N dimethylformamide, ethanol, The reaction can be carried out in an inert solvent such as a mixed solvent usually at room temperature to reflux temperature for 10 minutes to 1 day.

[0078] The deprotection reaction of phthalimide may be performed in accordance with a general deprotection reaction of phthalimide. For example, methylamine, hydrazine, etc. can be used in an inert solvent such as toluene, tetrahydrofuran, or a mixed solvent thereof, usually at 78 ° C. to reflux temperature for 30 minutes to 1 day.

[0079] The azidation reaction and the subsequent reduction reaction can be carried out in the same manner as in [Method 3]. [0080] The reduction reaction of the oxime compound (! £), the nitrile compound and the azide compound can be carried out using oxime or- What is necessary is just to follow the general reduction method of tolyl. For example, using a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in an inert solvent such as toluene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof, usually at a temperature of from 78 ° C to the reflux temperature for 30 minutes. It can be mixed for 1 day or can be carried out by the same method as the catalytic reduction described in [Method 3].

[0081]

[0082] (wherein R ^{5 to} R ⁷ , rings Q, and X have the same meanings as described above).

[0083] Further, the benzyl halide compound (23a) in which n is 1 is obtained by converting the methylbenzene compound () to Can be obtained by halogenation. Halogenation reaction can be carried out by using a reaction initiator such as benzoyl peroxide, α, α, azobisisobutyrate-tolyl, etc. as necessary. Using a halogenated reagent such as acid imide, in an inert solvent such as tetrahydrofuran, dichloromethane, acetic acid, toluene, Ν, Ν-dimethylformamide, or a mixed solvent thereof, usually at 0 ° C to reflux temperature for 10 minutes to 1 This can be done by mixing for a day.

[Production method 3]

The aldehyde compound (£) can also be produced by the following method.

[0085] [Chemical 9]

[0086] (In the formula, it is a halogen halide ion; IT to R ⁷ , ring Q, and X have the same meaning as above)

[0087] In the aldehyde compound (£), the aldehyde compound () in which n is 1 is produced by hydrolyzing the methyl compound () into a halogenated compound (2Z). be able to. Next, it is subjected to a condensation reaction with a triphenylphosphine compound to obtain an olefin compound (2), and then hydrolyzed to produce an aldehyde compound () in which n is 2. Can do.

[0088] The halogenation reaction is carried out by using a reaction initiator such as benzoyl peroxide, α, α'-azobisisobutyryl-tolyl as required. Using a halogenating reagent such as bromosuccinic acid imide, tetrahydrofuran, dichloromethane, acetic acid, toluene, , N-dimethylformamide, in an inert solvent such as a mixed solvent thereof, usually by mixing at 0 ° C. to reflux temperature for 10 minutes to 1 day. The subsequent hydrolysis reaction can be carried out by reacting with a reagent such as silver nitrate in methanol, usually at room temperature to reflux temperature for 1 hour to 1 day, and then treating with hydrochloric acid or sulfuric acid aqueous solution.

[0089] The condensation reaction is carried out in the presence of a base such as sodium hydride, potassium tert-butoxide, n-butyllithium, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, sodium hydroxide, tetrahydrofuran, dimethyl In an inert solvent such as sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidinone, 1,3-dimethyl-2-imidazolidinone, acetonitrile, mixed solvents thereof, etc. Mixing can be carried out for 30 minutes to 1 day at ° C to reflux temperature.

[0090] The hydrolysis reaction of olefin is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium, tetrahydrofuran, acetone, acetonitrile, water, Mixing in a solvent such as a mixed solvent, usually at 0 ° C to reflux temperature, for 30 minutes to 1 day can be carried out.

[0091] [Chemical 10]

[In the formula, Ar is a substitutable (hetero) aryl group; R ⁵ , R °, R ^a , n, ring Q, and X have the same meaning as described above.]

[0093] In the aldehyde compound (S), for example, an aldehyde compound () in which R ⁷ is a substitutable (hetero) aryl group is subjected to a condensation reaction of the corresponding halogenated compound with a boric acid compound. Can be manufactured.

[0094] The condensation reaction is carried out by using a catalyst such as tris (dibenzylideneacetone) dipalladium, Sufine, 2, 2, 1bis (diphenylphosphino) 1 1, 1 — In the presence of organic phosphorus ligands such as binaphthyl and bases such as cesium carbonate, sodium tert-butoxide, toluene, tetrahydrofuran, N, N— It can be carried out by mixing for 1 hour to 1 day, usually at room temperature to reflux temperature, in an inert solvent such as dimethylformamide or a mixed solvent thereof.

[0095] In the aldehyde compound (£), the condensed aldehyde compound (H ^) represented by the following general formula can also be produced by the method exemplified below.

[0096] [Chemical 11]

[0097] (In the formula, Y is NH, O or S; Z is N or CH; R ^{5 to} R ′ have the same meaning as described above.)

[0098] [Chemical 12]

[0099] (wherein R ^{5 to} R ⁷ , X, Y, and Ζ have the same meaning as described above.)

[0100] The benzaldehyde compound (ai) is subjected to a substitution reaction using the ester compound (22), and then a condensed ring ester compound () is obtained by a cyclization reaction, and subjected to a reduction reaction to form a condensed ring alkyl. A dehydride compound () can be produced. In addition, the aminobenzene compound (^) is subjected to a cyclization reaction to obtain a dicarboxyl compound (), which is treated with a halogenating agent such as thioyl chloride or phosphorus oxychloride as necessary, and then condensed. The condensed aldehyde compound (2 ^) can also be produced by subjecting the condensed ester compound (az) obtained by the above to a reduction reaction.

[0101] The substitution reaction is usually performed at 0 ° C in an inert solvent such as tetrahydrofuran, methanol, N, N dimethylformamide, or a mixed solvent thereof using a base such as triethylamine or potassium carbonate as necessary. It can be carried out by mixing at a reflux temperature for 10 minutes to 1 day.

[0102] The cyclization reaction may be carried out using a base such as triethylamine or potassium carbonate and a reagent such as Z or jetyl oxalate or oxalyl chloride, if necessary, in tetrahydrofuran, methanol, N, N dimethylformamide, or a mixture thereof. It can be performed by mixing in an inert solvent such as a solvent, usually at 0 ° C. to reflux temperature for 10 minutes to 1 day (for example, Tetrahedr on Letters, 41 (28), 5415-5418 (2000); Synlett, (5), 670-672 (2001)).

[0103] The ring condensation reaction is carried out in the presence of a base such as sodium hydrogen carbonate in an inert solvent such as tetrahydrofuran, methanol, N, N-dimethylformamide, or a mixed solvent thereof, usually at room temperature to reflux temperature for 1 hour to 3 hours. (For example, refer to Heterocycles, 24 (10), 2803-2807 (1986); Journal of Heterocyclic Chemistry, 24 (6), 1683-1684 (198 7)).

[0104] The reduction reaction to aldehyde may be carried out according to a general reduction method to ester strength aldehyde. For example, using a reducing agent such as diisobutylaluminum hydride and mixing in an inert solvent such as toluene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof, usually at -78 ° C to reflux temperature for 30 minutes to 1 day. You can do it from Tsujiko.

[0105] The condensed ring aldehyde compound () can also be produced by reducing the condensed ring ester compound () or to an alcohol and then acidifying the aldehyde.

[0106] The reduction reaction to an alcohol is usually performed at 78 ° C in an inert solvent such as toluene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof using a reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride. C to reflux temperature, 30 minutes to 1 day Mixing can be done from the top.

[0107] The oxidation reaction is carried out in an inert solvent such as toluene, tetrahydrofuran, dichloromethane, or a mixed solvent thereof using an oxidizing agent such as manganese dioxide, usually at -78 ° C to reflux temperature. Mixing for 1 minute for 1 minute can be done.

[0108] As the protecting group used in the above method or production method, various protecting groups generally used in organic synthesis reactions can be used. For example, hydroxyl-protecting groups include p-methoxybenzyl group, benzyl group, methoxymethyl group, acetyl group, bivalol group, benzoyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, aryl group, etc. In addition, when two hydroxyl groups are adjacent to each other, an isopropylidene group, a cyclobenzylidene group, a cyclohexylidene group, and the like can be given. Examples of the protective group for thiol group include ρ-methoxybenzyl group, benzyl group, acetyl group, pivaloyl group, benzoyl group, benzyloxycarbol group and the like. Examples of the protecting group for an amino group include a benzyloxycarbonyl group, a tert-butoxycarbol group, a benzyl group, a p-methoxybenzil group, a trifluoroacetyl group, an acetyl group and a phthaloyl group. Examples of the protecting group for carboxy group include benzyl group, tert-butyldimethylsilyl group, and aryl group.

[0109] The compound represented by the general formula (I) of the present invention obtained in the production method is a fractional recrystallization method which is a conventional separation means, a purification method using chromatography, a solvent extraction method, a solid phase extraction. It can be isolated and purified by a method or the like.

[0110] The 2-aminobenzimidazole derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt thereof by a conventional method. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-Toluenesulfonic acid, propionic acid, citrate, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, aspartic acid and other organic acids Salts with acid bases, sodium salts, potassium salts and other inorganic bases, N-methyl-D-dalkamine, N, N, monodibenzylethylenediamine, 2-aminoethanol, tris (hydroxymethyl) Examples thereof include addition salts with organic bases such as aminomethane, arginine and lysine. [0111] The 2-aminobenzimidazole derivative represented by the general formula (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt thereof is a solvent acceptable as a pharmaceutical such as water or ethanol. And solvates thereof.

[0112] Among the 2-aminobenzimidazole derivatives represented by the general formula (I) of the present invention, the compound having an unsaturated bond includes two geometric isomers, a cis (Z) compound and There are compounds in trans (E) form, but in the present invention, those compounds may be used.

[0113] Among the 2-aminobenzimidazole derivatives represented by the general formula (I) of the present invention, the compound having an asymmetric carbon atom except the sugar residue is two kinds of optical isomers. There are R-configuration compounds and S-configuration compounds. In the present invention, these optical isomers may be used or a mixture of these optical isomers.

Various tautomers exist in the 2-aminobenzimidazole derivative represented by the general formula (I) of the present invention, and the compounds of the present invention also include these tautomers.

[0115] Further, in the present invention, various prodrugs of the 2-aminobenzimidazole derivative represented by the general formula (I) can also be used. A prodrug is a compound obtained by modifying a parent compound with a group used in a normal pharmacologically acceptable prodrug, and imparts characteristics such as, for example, improved stability and durability. In addition, it can be expected to be converted into the parent compound in the intestinal tract and the like to exert its effect. The 2-daminobenzimidazole derivative prodrug represented by the general formula (I) is represented by the general formula (I) by a conventional method using a corresponding prodrug reagent such as a halogenated compound. —Aminobenzimidazole derivatives in hydroxyl groups, amino groups, and other possible prodrugs of prodrugs. After one or more arbitrary groups are selected, the groups constituting the prodrugs are appropriately introduced according to conventional methods, and then desired. If necessary, it can be manufactured by isolation and purification according to conventional methods (“Monthly Pharmacy Clinical Pharmacokinetics for Proper Use of Drugs”, March 2000 Extra Special Issue, No. 42, No. 4, p. 669-707, “New 'Drag Delivery System”, published by CMC Corporation, January 31, 2000, p. 67-17 3). Examples of the group constituting the prodrug used in the hydroxyl group amino group include, for example, lower alkyl CO—, lower alkyl O, lower alkyl CO—, lower alkyl—OCO—lower alkyl—CO, lower alkyl—OCO, and lower alkyl. Alkyl— o-lower alkyl-OCO- and the like.

[0116] When the pharmaceutical composition of the present invention is used for prevention or treatment, the ability to use various dosage forms orally or parenterally depending on the usage, for example, powders, fine granules, granules, Oral preparations such as tablets, capsules and dry syrups are preferred.

[0117] These pharmaceutical compositions are mixed with pharmaceutical additives such as excipients, disintegrants, binders, lubricants, etc., as appropriate according to the dosage form, in accordance with ordinary pharmaceutical methods. It can be manufactured according to the formula.

[0118] For example, if necessary, powders may be added to the active ingredient by adding appropriate excipients, lubricants, etc., and mixed well to obtain a powder. For tablets, add appropriate excipients, disintegrants, binders, lubricants, etc. as necessary to the active ingredients, and tablet into tablets according to conventional methods. Further, if necessary, apply tablets as needed. Film coated tablets, sugar-coated tablets, enteric-coated skin tablets, etc. Capsules are prepared by adding appropriate excipients and lubricants as necessary to the active ingredients and mixing well, or after granulating or granulating according to conventional methods, filling into appropriate capsules And Further, in the case of such an orally administered preparation, it can be an immediate release or sustained release preparation depending on the prevention or treatment method.

[0119] The 2-aminobenzimidazole derivative represented by the general formula (I) of the present invention exhibits a CNT inhibitory action and can suppress an increase in plasma uric acid level. Therefore, the pharmaceutical composition of the present invention is useful as a preventive or therapeutic agent for diseases caused by abnormal plasma uric acid levels. Examples of diseases caused by abnormal plasma uric acid levels include gout, hyperuricemia, urolithiasis. In particular, there may be mentioned diseases such as hyperuric acid nephropathy and acute uric acid nephropathy, and particularly gout and hyperuricemia.

[0120] When the medicinal thread composition of the present invention is used for actual prevention or treatment, the compound represented by the above general formula (I), a prodrug thereof or a pharmacologically acceptable compound thereof, which is an active ingredient thereof The dose of salt or its hydrate is appropriately determined depending on the patient's age, sex, body weight, disease and degree of treatment, etc.For example, in the case of oral administration, it is generally in the range of 1 to 2 OOOmg per day for adults. It can be appropriately administered once or divided into several times.

[0121] In addition to the 2-aminobenzimidazole derivative of the present invention, it does not substantially inhibit nucleoside absorption !, and can be used in combination with a therapeutic agent for hyperuricemia or a therapeutic agent for gout. The Examples of therapeutic agents for hyperuricemia that can be used in the present invention include uric acid excretion promoters such as probenecid, bucolome, and benzbromarone, uric acid synthesis inhibitors such as aloprinol, oxypurinol, and febuxostat, sodium bicarbonate, Examples include urinary alkaline glazes such as potassium citrate and sodium citrate, uric acid oxidases such as raspricase, uricase-PEG-20, and gene recombinant urate oxidase (uricase). Examples of gout treatments include colchicine, non-steroidal anti-inflammatory drugs such as indomethacin, naproxen, fenbufen, pranoprofen, and oxaprozin, as well as corticosteroids. In the present invention, in addition to the effective component of the present invention, it can be used in combination with at least one of these drugs. However, the pharmaceutical composition formed by combining at least one of these drugs is The dosage form is not limited to a single pharmaceutical composition formulated at the same time as the active ingredient of the invention, but can also be used as a pharmaceutical composition produced separately from the pharmaceutical composition containing the active ingredient of the present invention, simultaneously or at different intervals. Including. In addition, when used in combination with a drug other than the active ingredient of the present invention, the dose of the compound of the present invention can be reduced according to the dose of the other drug used in combination. It is possible to obtain an advantageous effect that is more than an additive effect in terms of prevention or treatment, and to avoid or reduce the side effects of other drugs used in combination. The invention's effect

[0122] The 2-aminobenzimidazole derivative represented by the general formula (I) of the present invention, a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof has excellent CNT inhibitory activity. It is expressed and inhibits the in vivo absorption of purine nucleosides in the intestinal tract, thereby significantly suppressing the increase in plasma uric acid levels.

BEST MODE FOR CARRYING OUT THE INVENTION

[0123] The contents of the present invention will be described in more detail with reference to the following Reference Examples, Examples and Test Examples, but the present invention is not limited to the contents.

[0124] Reference Example 1

6 (t-Butyldimethylsilyloxy) benzofuran 2 Ethyl carboxylate

6-Methoxybenzofuran-2-ethyl carboxylate (3. Og) is dissolved in dichloromethane (13 mL) and stirred with ice cooling. 1. OmolZL boron tribromide-dichloromethane solution (41 mL)

-^ w ^^-mw ^ ^ ^. · Η stop 縱 / —, d) ψ 呦

. · Η stop 纖 n ^ra os) Be Λ Λ, ^ (stop ^^

Ma ^ CT 峯氺

-Z-, 厶, ^ {^ Λ ((Λ (^^ Λ (^ 1

(ω 'Ηΐ) 00 "8-S6" Z' (ΖΗΖ · 8 = ί "'Ρ' Ηΐ) WL '(ω' Ηΐ) 0 £ 'L ~ Z'L' ^ ΗΖ'Ζ 'ΖΗΖ · 8 = ί "'ΡΡ

'Ηΐ) 96 ・ 9' ( ^Ζ ΗΓΖ = Γ 'b' ΗΖ) Wf '( ^Ζ ΗΓΖ = Γ Ήε) ZV \' ( ^s ' Η6) εθ · ΐ '( ^s ' Η9) 92

: 3ρ (t α) 丽 Ν— Η _τ ^ e 邈 be ^ / i S—bee ^ [q], be: ^ (, ^ / (, ^ ^: ichiichi 9 [8210]

(s' Ηΐ) WT8 '(ω' Ηΐ) SS "Z-

WL '(ω' Ηΐ) SS- -02 "'(ω' Ηΐ) 06 · 9— 08 · 9 '( ^s Ήε) WZ' ( ^s ' Η6) ΖΟ" ΐ '( ^s ' Η9) 82

: 3ρ (t α) Ν Ν— Η _τ ^ Rinse ^ 1 s — Bee ^ [q], Be: ^ (^^ / (, ^ ^: One -L [10]. , ¾ί¾ 呦

[92ΐθ]

(ω 'ΗΖ)' (ω 'Ηΐ) SO'-00 '(ω' HI

) 06 / 9- 08/9 '( ^Ζ ΗΓΖ = Γ' ΗΖ) ZVf '( ^Ζ ΗΓΖ = Γ Ήε) ΖΥ \' ( ^s ' Η6) 00 · ΐ '( ^s ' Η9) S2

: Radd g Ποαθ) HN -Η _χ [Ζ10

. (¾) ^ mm ^ m ^ = Be ^^ /

.辛爵

. · Η

m ^^ ^ n ^ m- ^ ^ · η # ι¾ 翻 w 、 ¾ 次 ι) 呦 ^

91 · Ζ) / — ^ 缀 ^

, Spicy stabbed S · Π! Ί

¾ 、 Ma / ^ mu 邈 ^ 氺雜 ^ ^ ^ m ^ mM ^ ^ m ^^

Iraoos 氺 ^ 呦 Learning ^ Stop If ^. · Η # ι¾ 翻 ττ

LLl80 £ / 900ZdT / 13d 63 .CTSll / 900Z OAV The solute was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate Z-hexane = 1Z1) to obtain the title compound (2.6 g).

[0130] 'H-NMR CCDCl) S ppm:

Three

0.25 (6H, s), 1.00 (9H, s), 6.85—6.95 (IH, m), 7.00-7.05 (IH, m), 7.45-7.60 (2H, m), 9.77 (IH, s)

[0131] In the same manner as in Reference Example 2, the following compounds were synthesized using the corresponding starting compounds.

7 (t-Butyldimethylsilyloxy) benzo [b] thiophene 2 carbaldehyde — NMR (CDC1) S ppm:

Three

0.28 (6H, s), 1.07 (9H, s), 6.85—6.95 (IH, m), 7.25-7.35 (IH, m), 7.50-7.60 (IH, m), 8.01 (IH, s), 10.10 ( IH, s)

[0132] 6- (tert-Butyldimethylsilyloxy) benzo [b] thiophene 2 carbaldehyde

[0133] Reference Example 3

6 Hydroxybenzofuran 1 Carvaldehydride

6- (tert-Butyldimethylsilyloxy) benzofuran 2 carbaldehyde (2.6 g) is dissolved in tetrahydrofuran (50 ml), and lmol / L tetraptylammonium fluoride-tetrahydrofuran solution (10.3 ml) is added to the reaction mixture. The mixture was further stirred at room temperature for 30 minutes. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Z-hexane = 1Z1) to obtain the title compound (1.12 g).

[0134] 'H-NMR CCDCl) S ppm:

Three

6.85-6.95 (IH, m), 7.00-7.10 (IH, m), 7.45-7.65 (2H, m), 9.76 (IH, s)

[0135] In the same manner as in Reference Example 3, the following compounds were synthesized using the corresponding starting compounds.

[0136] 6-Hydroxybenzo [b] thiophene 2 carbaldehyde

— NMR (DMSO— d6) S ppm:

6.99 (IH, dd, J = 8.8Hz, 2.2Hz), 7.35 (IH, d, J = 2.2Hz), 7.91 (IH, d, J = 8.8Hz), 8.25- 8.30 (IH, s), 10.00 ( IH, s), 10.30 (IH, s) [0137] 7-Hydroxybenzo [b] thiophene 2 carbaldehyde

[0138] Reference Example 4

6— (3 black propoxy) naphthalene-2 carbaldehyde

6 Hydroxynaphthalene 2-Carbaldehyde (2.04 g) and potassium carbonate (2. 95 g) are suspended in N, N dimethylformamide (50 mL), and 1-bromo-3 black mouth propan (2. l lmL) under ice-cooling. ) Was added dropwise and stirred at room temperature for 16 hours. 2 mol ZL hydrochloric acid was added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate Z-hexane = 1Z5) to obtain the title compound (2. Og).

[0139] 'H-NMR CCDCl) S ppm:

Three

2.27-2.38 (2H, m), 3.81 (2H, t, J = 6.4Hz), 4.29 (2H, t, J = 5.8Hz), 7.16-7.29 (2H, m)

, 7.75-7.98 (3H, m), 8.24—8.28 (IH, m), 10.10 (IH, s)

[0140] In the same manner as in Reference Example 4, the following compounds were synthesized using the corresponding starting compounds.

[0141] 7- (3 black propoxy) benzo [b] thiophene-2 carbaldehyde

— NMR (CDC1) S ppm:

Three

2.30-2.40 (2H, m), 3.82 (2H, t, J = 6.3Hz), 4.35 (2H, t, J = 5.7Hz), 6.90—7.00 (IH, m), 7.35-7.45 (IH, m) , 7.50-7.60 (IH, m), 8.02 (IH, s), 10.10 (IH, s)

[0142] 6- (3 black propoxy) benzofuran 2-carbaldehyde

— NMR (CDC1) S ppm:

Three

2.25-2.35 (2H, m), 3.70—3.85 (2H, m), 4.15—4.25 (2H, m), 6.95-7.10 (2H, m), 7.50 (IH, s), 7.55-7.65 (IH, m ), 9.76 (IH, s)

[0143] 6— (3 black propoxy) benzo [b] thiophene-2 carbaldehyde

— NMR (DMSO— d) S ppm:

6

2.15-2.30 (2H, m), 3.82 (2H, t, J = 6.5Hz), 4.22 (2H, t, J = 6.0Hz), 7.13 (IH, dd, J = 8.8 Hz, 2.3Hz), 7.70 (IH, d, J = 2.3Hz), 8.00 (IH, d, J = 8.8Hz), 8.30-8.35 (IH, m), 10.0 0 (IH, s)

[0144] Reference Example 5 I '(ω' ΗΖ) SS "-er '(ΖΗΖ · 9 = ί"' Ρ ΉΪ) 6S'S '(ΖΗΖ · 9'ZHS'9 = f 'PP' Ηΐ) OZ "S '(ZHS'9

.辛瀚缀

¾ 、 Ma / ^ mu 邈 ^ 氺雜 ^ ^ ^ m ^ mM ^ ^ m ^^

. : · Η # ι¾Translation. οοι 工 ^ Di ( ^s i

1 、 ^^ X

9p}% [9W0] (zw = f 'ρ' ΗΪ) u'z vL = i 'Ρ' Ηΐ) ΐ

9 "Ζ '(ω Ή2)

'PP' Ηΐ) S9 "S '(ΖΗ9 · 9

^<z Ho ^ = f 'pp' ΗΪ) is's '(ω Ήε) 09 οε ·' ( ^s Ήε) ζτζ '( ^s Ήε) LVZ' ( ^s Ήε) so

¾ 遨 ë 攝攝エ () ((HZ "[= Be ^^ Z 邈 4S: 瀚缀 ffl 瀚缀)

. Supreme Supreme S-sect, 粼 ¾ Mom

^ 氺雜 ^ ^ ^ m ^ mM ^ ^ m ^^ ^ wm ^^ ^ Π— a— ^ one o— s 'ε' z

^ ί (^ (1 ^ 6 · ζι) d / f, ^ (H

1 、 ^^ X

..T80C / 900Zdf / X3d 3ε .CTSll / 900Z OAV ) 08 "Z-S9" Z '(ω ΉΖ)' L-OVL '(ω' HS) ΖΊ-00Ί WL = i 'P' Ηΐ) W9 WL '

'PP' Ηΐ) T9 "S '(ω' ΗΖ) OS'S- OS'S 'P' ΗΖ) 06, '(ω' HS) Z 'f- £ V f' ( ^z H2-9 = f '' ΗΖ) 08 · ε '(ω' ΗΖ) ΙΖ'Ζ- τΖ '( ^s Ήε) 9Γ2' ( ^s Ήε) 66 · ΐ '( ^s Ήε) ΐ9 "ΐ

: ^ Dcjg OoaO) H NH _x [Ϊ3ΐ0]

. (Ε

¾-(i / x = Be ^ 邈: 瀚缀 ffl 缀)

^^ c ^-^. Tsutoku Ss ^ m ^ ^^^ m ^ ^ ^

^ ^ m ^ ^ ^ m ^^ ^ -i ^ w ^ ^ ^> n

· Ϊ́) Ma (H 峯峯氺 ^ (H Stop If

One ^^ χBe: ^ — m— (/ ίί— α— ϋ— ^^ One ο— fH—

8p}% [OS TO] ( ^z H8 "Z = f 'P' Ηΐ) ZVL

'P' Ηΐ) IZ'L 'P' HI) W9 '(ZHS "'zH9" 9 = f 'PP' Ηΐ) ZS "S '(ΖΗ9 · 9'zH" S = f 'PP' Ηΐ) £ V '(saq' H

Z0 "S '(ω' Ηΐ) 89 ^ -33 ^ '(ω' ΗΖ) ZV -LZ ^ '( ^s Ήε) LVZ' ( ^s Ήε) 9Γ2 '( ^s Ήε) 66 · ΐ

: 3ρ (one a) 丽 N— Η _τ [6]

° -Μ ( ^Sra 6) 呦 ^ ¾ 遨 e

a> M ^^ · η # ι¾ 翻 ττ エ ^ 蹈蹈 ^ w ^ ^

0 / οίΗΟ) 晷瀚 $ g, (Ύ ^ Ζ) — (Sraooi)

— M— (/ fi— a— — ^^ — o— fH— s 'ε' Z) -I- ^ .-Z

1 、 ^^ x

( ^z H0 "8 = f 'P' Ηΐ) S9" Z '(zH0 "8 = f' P 'Ηΐ) LV

LLl80 £ / 900ZdT / 13d εε .CTSll / 900Z OAV 3H, m)

[0152] In the same manner as in Reference Example 8, the following compounds were synthesized using the corresponding starting compounds.

[0153] 2— {[6— (3-Propoxy) benzofuran-2-ylmethyl] amino} —1— (2, 3,

5-tri-I-O-acetyl-β-D-ribofuranosyl) 1- 1H-benzimidazole

— NMR (CDC1) S ppm:

Three

1.97 (3H, s), 2.00 (3H, s), 2.16 (3H, s), 2.20-2.30 (2H, m), 3.70-3.80 (2H, m), 4.10 -4.20 (2H, m), 4.25- 4.40 (2H, m), 4.55—4.65 (IH, m), 4.75-4.95 (2H, m), 5.35-5.45 (IH, m), 5.50-5.70 (2H, m), 6.04 (IH, d, J = 7.7Hz), 6.63 (IH, s), 6.80—6.85 (IH, m), 6.95-7.20 (4H, m), 7.30-7.30 (IH, m), 7.45-7.55 (IH, m)

[0154] 2— {[7— (3-Clopropoxy) benzo [b] thiophene 2-ylmethyl] amino}-1-(2, 3, 5-tri-I O-acetyl 1-j8-D-ribofuranosyl) 1 1H-Benzimidazole — NMR (CDC1) S ppm:

Three

1.87 (3H, s), 1.99 (3H, s), 2.16 (3H, s), 2.25-2.40 (2H, m), 3.81 (2H, t, J = 6.4Hz), 4.20-4.40 (4H, m), 4.50-4.60 (IH, m), 4.95-5.10 (2H, m), 5.35-5.45 (IH, m), 5.50-5.70 (2H, m), 6.04 (IH, d, J = 7.4 Hz), 6.70-6.80 (IH, m), 7.00-7.40 (6H, m), 7.50-7.6 0 (IH, m)

[0155] 2— {[6— (3-Cloropropoxy) benzo [b] thiophene 2-ylmethyl] amino}-1-(2, 3, 5-tri-I O-acetyl 1-j8-D-ribofuranosyl) 1 1H-Benzimidazole — NMR (CDC1) S ppm:

Three

1.84 (3H, s), 1.98 (3H, s), 2.16 (3H, s), 2.20-2.30 (2H, m), 3.76 (2H, t, J = 6.4Hz), 4.16 (2H, t, J = 5.9Hz), 4.20-4.40 (2H, m), 4.50—4.60 (IH, m), 4.90—5.05 (2H, m), 5.3 5-5.45 (IH, m), 5.50-5.65 (2H, m ), 6.03 (IH, d, J = 7.8Hz), 6.95 (IH, dd, J = 8.7Hz, 2.2Hz), 7.05-7.40 (5H, m), 7.45-7.65 (2H, m)

[0156] Example 1

2 — {[6 -— (3-Dimethylaminopropoxy) naphthalene-2-ylmethyl] amino} —1— (β-D-ribofuranosyl) mono 1H-benzimidazole

[0157] [Chemical 13]

[0158] 2— {[6— (3-Propoxy) naphthalene-2-ylmethyl] amino} —1— (2, 3, 5-tri 0-acetyl 1 β-D-ribofuranosyl) 1 1H-benz Imidazole (0.12 g) and sodium iodide (0.09 g) were suspended in acetone (15 mL) and heated to reflux for 16 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue, 50% aqueous dimethylamine solution (0.14 ml) and potassium carbonate (0.10 g) were suspended in acetonitrile (5 mL) and stirred at 70 ° C. for 16 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 mL), 5 mol ZL aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid (1 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The resulting residue is purified by reverse-phase preparative column chromatography (CAPSELL PAC C18UG80, 5 m, 20 X 50 mm, flow rate 30 mLZ min linear gradient, water Z methanol = 70/30 ~: L0Z 90, manufactured by Shiseido) This gave the title compound (0.06 g).

[0159] — NMR (DMSO— d) S ppm:

6

1.80-1.96 (2H, m), 2.14 (6H, s), 2.38 (2H, t, J = 7.1Hz), 3.60-3.78 (2H, m), 3.95-4. 20 (4H, m), 4.40- 4.50 (1H, m), 4.60—4.80 (2H, m), 5.83 (1H, d, J = 7.2Hz), 6.80—7.0 0 (2H, m), 7.08-7.35 (4H, m), 7.43-7.60 (2H, m), 7.70-7.80 (3H, m)

[0160] Examples 2 to 17

The compounds of Examples 2 to 17 shown in Table 1 were synthesized using the corresponding starting compounds in the same manner as in Example 1.

[0161] [Table 1]

[0162] Example 18

2 — [(1H-Indole-5-ylmethyl) amino] -1- 1- (j8- D Ribofuranosyl) -1- 1 H benzimidazole

[0163] [Chem. 14]

[0164] 2-Amino 1- (2, 3, 5-Tri-O acetyl 1-j8- D Ribofuranosyl) 1 1H-Benzimidazole (0. lg) and 1H-Indole 1-Carbaldehyde (0.07 g) Was suspended in tetrahydrofuran (5 mL) and stirred at room temperature for 13 hours. To the reaction mixture was added sodium triacetoxyborohydride (0. l lg), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 mL), 5 mo 1ZL aqueous sodium hydroxide solution (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. Acetic acid (ImL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. By purifying the obtained residue by reverse-phase preparative column chromatography (CAPSELL PAC C18UG80, manufactured by Shiseido Co., Ltd., 5 m, 20 X 50 mm, flow rate 3 OmLZ minute linear gradient, water Z methanol = 70Z30 ~: L0Z90) The title compound (0. Olg) was obtained.

[0165] 'H-NMR CCD OD) S ppm:

Three

3.70-3.85 (2H, m), 4.05—4.25 (2H, m), 4.50—4.80 (3H, m), 5.94 (1H, d, J = 7.5Hz), 6.

80 (1H, d, J = 3.0Hz), 6.95—7.40 (7H, m), 7.55-7.60 (1H, m)

[0166] Examples 19-24

The compounds shown in Table 2 were synthesized in the same manner as in Example 18 using the corresponding starting compounds.

[0167] [Table 2] (3H,

(1 H, s),

m),

(3H, (1 H, s),

m), (1 H, d,

(5H, d, J = 1.7Hz) (1 H, d,

(3H, (3H, m), (2H, d, J = 7.2Hz), m), m), 8.50 4.05-4.15 2.3Hz), 4.58 H, d,

(4H, m)

[0168] According to Reference Examples and Examples, the compounds shown in Table 3 can be synthesized using the corresponding starting compounds.

[0169] [Table 3]

Test example 1

CDNA cloning and expression plasmid of human CNT2

Human CNT2 cDNA was obtained by PCR amplification using human kidney cDNA (CLONTECH). PCR reaction solution is 1 / Z LCDNA, 2 pcs platinum platinum DNA polymerase high fidelity (manufactured by Invitrogen), 1 μΜ primer (forward: 5 AGG AGC CAG AGG GAA TCA AT-3 ', reverse: 5 ACA TCT TGG TGA GTG AGT TG-3,). Amplification is 1 cycle after heating at 94 ° C for 2 minutes, 94 ° C for 30 seconds, 58 ° C for 30 seconds, 68 This was carried out at 32 ° C for 3 minutes at ° C, and incorporated into a PCR®-TOPO vector (manufactured by Invitrogen). Using the prepared plasmid as a saddle type, PCR reaction was performed using a primer added with a restriction enzyme. PCR reaction solution is lOOng plasmid, 2 pie pie best DNA polymerase (units Pyrobest DNA polymerase Z Takara), 33 OnM primer (forward: 5'—CCG CTC GAG AGG AGC CAG AGG GAA TCA AT-3 ', reverse: 5'- CGT CTA GAA CAT CTT GGT GAG TGA GTT G-3,). Amplification is heated at 95 ° C for 3 minutes, then 1 cycle, 98 ° C for 10 seconds, 60 ° C for 30 seconds, 72 ° C for 1 minute, 15 cycles, 72. C7 minutes, 1 cycle, PCI—Neo'Mammalian'Etasprendon hekta ~~ neo mammalian expression vector / Neguchi Mega (Promega): ^ The cloned human CNT2 amino acid sequence is P22L (codon CCG force CTG), S4 5C (codon AGC force TGC), I160M (codon ATA is ATG )! /!

[0171] Test Example 2

Human CNT2--preparing transiently expressed cells

Human CNT2 expression plasmid was introduced into COS-7 cells (RIKEN CELL BANK RCB0539) by the lipofusion method. Lipofuecamine 2000 (manufactured by LIPOFECTA MINE 2000Z Invitrogen) was used as the lipofusion reagent. COS- 7 cells were suspended in 10% so as to be 5Xl0 ⁵ pcs Ri per lmL a © Shi fetal serum (manufactured by Sanko Junyaku) containing D-MEM medium (vitro Rozhen (Invitrogen) Inc.), which collagen-coated 96 Dispense 100 L per well of hole plate (Iwaki Glass), and culture for 2 hours at 37 ° C, 5% CO

2

I got it. Dilute 0.6; z L Lipofuectamine 2000 with 25; z L OPTI—MEM (manufactured by Invitrogen) per well and let stand at room temperature for 7 minutes (hereinafter referred to as Lipo 2000 OP TI) . Dilute 0.3; zg plasmid with 25; z L of OPTI-MEM (Invitrogen) per well, mix gently with Lipo 2000-OPTI and let stand for 30 minutes After that, add 50 L per well to the cell culture medium, 37 ° C, 5% CO

2 Cultivated for 2 days and used for measurement of uptake inhibition activity.

[0172] Test Example 3

Measurement of inosine uptake inhibition activity The “uptake buffer” is 140 mM sodium chloride, 2 mM potassium chloride, ImM chloride chloride, ImM magnesium chloride, 10 mM hepes (HEPES) 2- [4- (2-hydroxychetyl)-1-piperaduryl] ethane. Inosin final concentration of non-radioactive label of inosine (manufactured by Wako Pure Chemical Industries) and ¹⁴ C label (Muromachi Yakuhin) in buffer solution 7.4 containing sulfonic acid, 5 mM Tris (hydroxymethyl) aminomethane, 5 mM glucose Was mixed and added so as to be 10 M. For basal uptake measurement, a “basic uptake measurement buffer solution” containing 140 mM salty cholin was prepared in place of sodium chloride. At the time of measurement, NBMPR was added to the uptake buffer and the basal uptake measurement buffer so that the final concentration was M. When measuring the inhibitory activity of a compound, it was dissolved in dimethyl sulfoxide, and then appropriately diluted with an uptake buffer to obtain a measurement buffer. Human CNT2—Transient expression Remove the cell culture medium, add 200 L of pretreatment buffer (basic uptake measurement buffer that does not contain inosine and glucose) per well, and leave at 37 ° C for 10 minutes. did. After repeating the same procedure once, the pretreatment buffer was removed, 75 L of measurement buffer and basal uptake measurement buffer were added per well, and the mixture was allowed to stand at 37 ° C. After 30 minutes, the measurement buffer and the basal uptake measurement buffer were removed and washed twice with 200 L of washing buffer (basic uptake measurement buffer containing 10 M non-radiolabeled inosine) per well. . Cells were lysed with 75 L of 0.2 mol ZL sodium hydroxide per well, and the solution was transferred to a picoplate (Perkin Elmer). 150 L of micro scinti 40 (Perkin Elmer) was added and mixed, and the radioactivity was measured with a scintillation counter (Perkin Elmer). The amount of inosine uptake at each concentration of the test compound was calculated by taking the uptake of the control group as 100% after subtracting the basic uptake. The concentration (IC value) that inhibits the uptake of test compound strength inosine by 50% was calculated by oral plot. The results are shown in Table 4.

50

[Table 4] I

Test compound c ₅₀ value

(n M)

Example 1 1 8 3

Example 2 4 2 0

Example 5 2 2 4

Example 7 3 1 4

Example] 3 1 5 6

Example 1 6 1 6 5

Example 1 9 1 4 4 9

Example 2 0 1 4 0 0

Example 2 1 2 2 0 0

Example 2 3 6 6 3

Example 2 4 1 3 3 9

Industrial applicability

The 2-aminobenzimidazole derivative represented by the general formula (I) of the present invention or a prodrug thereof or a pharmacologically acceptable salt exhibits excellent CNT inhibitory activity and significantly increases plasma uric acid level. Can be suppressed. Therefore, it is useful as a preventive or therapeutic agent for diseases caused by abnormal plasma uric acid levels.

Claims

Claims 2-Aminobenzimidazole derivative represented by the general formula (I), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof:

[Chemical 1]

[Where,

R ² is a hydroxyl group or a fluorine atom;

R ³ and R ⁴ are independently a hydrogen atom or a hydroxyl group;

n is 1 or 2;

Ring Q is a heterocyclic or bicyclic hydrocarbon group;

One of R ⁵ and R ⁶ is a cyano group or an —A—D—E—G group.

E represents a single bond, over 0 - one S - one NR ⁹ -, One COO - one CONR ⁹ - one NR ⁹ CO ^{one, - NR 9 COO -, -} N + R 9 R 1C) - ( R ⁹ and R ¹⁰ are each independently a hydrogen atom or a substitutable lower alkyl group), a substitutable (hetero) cycloalkylene group, a substitutable (hetero) alkylene group, or a substitutable nitrogen-containing heterocycloalkyl group. Quaternary salts or quaternary salts of substituted nitrogen-containing heteroaryl groups; G represents a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkenyl group, or a substitutable lower alkynyl group.

(However, A and E are not a single bond at the same time! / ヽ)}

The other is a hydrogen atom, halogen atom, cyano group, -AH group or -A-D-E-G group {A, D, E and G are as defined above. It may be)}.

[2] The 2-aminobenzimidazole derivative according to claim 1, wherein n is 1, or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof.

[3] Substituent

[Chemical 2]

2. The 2-aminobenzimidazole derivative or prodrug thereof or pharmacologically acceptable salt thereof or hydrate thereof according to claim 1, wherein is a D ribosyl group.

[4] A pharmaceutical composition comprising the 2-aminobenzimidazole derivative according to any one of claims 1 to 3, or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof as an active ingredient.

[5] A CNT inhibitor comprising, as an active ingredient, a 2-aminobenzimidazole derivative represented by the following general formula (I ′), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof Agent:

[Chemical 3]

[Where,

R ² is a hydroxyl group or a fluorine atom;

R ³ and R ⁴ are independently a hydrogen atom or a hydroxyl group;

n is 1 or 2;

Ring Q is a heterocyclic group or a bicyclic hydrocarbon group;

E represents a single bond, over 0 - one S - one NR ⁹ -, One COO - one CONR ⁹ - one NR ⁹ CO ^{one, NR 9 COO -, - N} + R 9 R 1C) - (R ⁹ and R ¹⁰ are each independently a hydrogen atom or a substitutable lower alkyl group), a substitutable (hetero) cycloalkylene group, a substitutable (hetero) alkylene group, or a substitutable nitrogen-containing heterocycloalkyl group. A quaternary salt or a quaternary salt of a substituted nitrogen-containing heteroaryl group;

G is a hydrogen atom, a substitutable lower alkyl group, a substitutable lower alkenyl group or a substitutable lower alkyl group};

R ⁷ is a hydrogen atom, a halogen atom, a cyan group, a substituted (hetero) aryl group or a substituted (hetero) cycloalkyl group].

[6] Plasma uric acid, which contains, as an active ingredient, a 2-aminobenzimidazole derivative represented by the above general formula (I ′), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof A pharmaceutical composition for preventing or treating a disease caused by an abnormal value.

[7] The disease according to claim 6, wherein the disease caused by an abnormal plasma uric acid level is a disease selected from gout, hyperuricemia, urolithiasis, hyperuric acid nephropathy, and acute uric acid nephropathy. Pharmaceutical composition.

8. The pharmaceutical composition according to claim 7, wherein the disease caused by an abnormal plasma uric acid level is gout.

[9] The pharmaceutical composition according to claim 7, wherein the disease caused by abnormal plasma uric acid level is hyperuricemia

[10] A combination of at least one drug selected from the group consisting of colchicine, non-steroidal anti-inflammatory drug, corticosteroid, uric acid synthesis inhibitor, uric acid excretion promoter, urinary alkalinizing drug and uric acid oxidase. Item 10. A pharmaceutical composition according to any one of Items 6 to 9.

[11] The nonsteroidal anti-inflammatory drug is indomethacin, naproxen, fenbufen, pranobrofen, oxaprozin, ketoprofen, etoroxixib or tenoxicam, and the uric acid synthesis inhibitor is alopurinol, oxiprinol, febuxostat or Y-700 Uric acid excretion promoter is probenecid, bucolome or venesbromarone, urinary alkalizing agent is sodium bicarbonate, potassium citrate or sodium citrate, urate oxidase is raspricase, uricasee PEG-20, recombinant uric acid 11. The pharmaceutical composition according to claim 10, which is an oxidase (uricase).

[12] The method comprises administering an effective amount of a 2-aminobenzimidazole derivative represented by the above general formula (I ′), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate thereof. A method for preventing or treating a disease caused by an abnormal plasma uric acid level.

[13] The prevention or the prevention according to claim 12, wherein the disease caused by an abnormal plasma uric acid level is a disease selected from gout, hyperuricemia, urolithiasis, hyperuric acid nephropathy and acute uric acid nephropathy Method of treatment.

[14] Effective amount of colchicine, non-steroidal anti-inflammatory drug, corticosteroid, uric acid synthesis inhibitor, uric acid excretion promoter, urinary alkalinizing agent and uric acid oxidase combined 14. The method for prevention or treatment according to claim 12 or 13, comprising administering the drug.

[15] A 2-aminobenzimidazole derivative represented by the above general formula (Γ) or a prodrug thereof or a drug thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of diseases caused by abnormal plasma uric acid levels Use of a physically acceptable salt or hydrate thereof.

[16] The use according to claim 15, wherein the disease caused by an abnormal plasma uric acid level is a disease selected from gout, hyperuricemia, urolithiasis, hyperuric acid nephropathy and acute uric acid nephropathy.