JP2008214305A - Substituted amine derivative and pharmaceutical composition containing the same as active ingredient - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel compound excellent in CNT2 inhibition activity and excellent in vivo stability and physicochemical stability, to provide a pharmaceutical composition containing the compound as an active ingredient, and to provide a drug for treating hyperuricemia containing the compound. <P>SOLUTION: Disclosed is a compound represented by formula (I) [wherein --- denotes a single bond or a double bond; n and w are each 0-5; L is -NH-, an alkenylene group, or the like; and A and B are specified substituents], a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof. A pharmaceutical composition containing it as an active ingredient is also disclosed. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to novel substituted amine derivatives. The present invention also relates to a composition comprising this substituted amine derivative as an active ingredient, particularly a pharmaceutical composition used for the prevention or treatment of diseases caused by abnormal plasma uric acid levels.

Ventilation (gout) is an abnormality of purine metabolism accompanied by hyperuricemia and urate deposits, joint disorders, renal disorders, urolithiasis, and cardiovascular disorders. Unexplained primary (narrow ventilation) and innate metabolism Some are secondary due to hyperuricemia during chemotherapy for abnormal or malignant tumors. Uric acid is derived from the purine of nucleic acid synthesis in the diet and in vivo, and is excreted in the urine from the kidney as its final product. Hyperuricemia is caused by excessive intake of these purines, increased synthesis of uric acid, or decreased urinary excretion. Therapeutic drugs for hyperuricemia have been broadly divided into uric acid synthesis inhibitors that block uric acid synthesis and uric acid excretion promoters that promote the excretion of uric acid, and various drugs have been reported, but problems remain. Therefore, it is desired to develop a therapeutic agent for hyperuricemia with higher efficacy and fewer side effects. In recent years, an association between hyperuricemia and metabolic syndrome has also been reported. (Non-Patent Document 1)

Nucleic acid digestion and absorption pathways in humans are as follows: ingested food-derived nucleic acids and nucleoproteins are released in the intestine, and these released nucleic acids are converted into mononucleotides by ribonuclease, deoxyribonuclease, etc., and nucleotidase and phosphatase Is broken down into nucleosides and absorbed by the involvement of membrane proteins called nucleoside transport carriers. With regard to research on nucleoside transport carriers, it has been reported that purine nucleosides are taken up by a subtype called CNT2 mainly distributed in the small intestine (Non-patent Document 2).

Based on this report, inhibition of CNT2 can prevent purine nucleoside absorption in the small intestine, thereby reducing uric acid levels in plasma and treating hyperuricemia. Based on this idea, an agent that inhibits CNT2, that is, a CNT2 inhibitor has been proposed. As CNT2 inhibitors, compounds represented by the following general formulas of Chemical Formula 1, Chemical Formula 2 and Chemical Formula 3 have been proposed (Patent Documents 1 to 3).

Although these compounds exhibit uric acid inhibitory action, the compounds reported here cannot be said to have sufficient activity, nor are in vivo stability or physicochemical stability sufficient.
J. Am. Soc. Nephrol., 2006; 17: S165, Arterioscler. Thromb. Vasc. Biol., 2005; 25: 1038, Hypertension, 2006; 48: 1031 Ho-Chul Shin, Jin-Suk Kim, Balvinder Singh Vig, Xueqin Song, John Charles Drach and Gordon Lewis Amidon, Biol. Pharm. Bull. 29, (2) 247 International Publication No. 2005/063788 Pamphlet International Publication No. 2006/030803 Pamphlet International Publication No. 2006/115137 Pamphlet

The present invention provides a compound having excellent CNT2 inhibitory activity, good in vivo stability, and excellent physicochemical stability, and also has good medicinal properties and few side effects by utilizing this CNT2 inhibitory action. The object is to provide a therapeutic drug for hyperuricemia.

The present inventor considers that the compounds of Patent Literature 1 and Patent Literature 2 having a natural sugar residue in the compound are inferior in stability to ribonuclease and deoxyribonuclease present physically and in the intestine, and thus have CNT2 inhibitory activity. As a result of various studies on compounds having excellent stability and good stability, as a result of various experiments using residues of unnatural sugars in which the conformation of the ribose moiety is fixed instead of the residues of natural sugars, the general formula (I The compound represented by (2) has an excellent CNT2 inhibitory action and the absorption of purine nucleosides in the body is suppressed, and the present invention has been completed.
That is, the present invention provides a general formula (I):

[式中、n及びwは0〜5である。---は一重結合又は二重結合である。
Ｌは、N−R¹、CR¹R²、分岐してもよいアルケニレン(炭素数2〜5)、分岐してもよいアルキニレン(炭素数2〜5)、又はS(O)_vで表される基である。ここでR¹及びR²は、同一又は異なってもよく水素原子、低級アルキル基(炭素数1〜5) 又は低級ハロアルキル基(炭素数1〜5)である。vは0〜2である。
Ａは、下記の一般式

[Wherein, n and w are 0 to 5. --- is a single bond or a double bond.
L is represented by N—R ¹ , CR ¹ R ² , alkenylene (2 to 5 carbon atoms) that may be branched, alkynylene (2 to 5 carbon atoms) that may be branched, or S (O) _v. It is a group. Here, R ¹ and R ² may be the same or different and each represents a hydrogen atom, a lower alkyl group (1 to 5 carbon atoms) or a lower haloalkyl group (1 to 5 carbon atoms). v is 0-2.
A is the following general formula

｛式中、mは0〜1であり、---は一重結合又は二重結合である。
Xは、CH、CH₂、O、S、N−R¹、CF₂又は−(=CH₂)−である。ここでR³、R⁴、R⁵、R⁶、R⁷、R⁸及びR⁹は、同一又は異なってもよく水素原子、水酸基、-(CH₂)_u-低級アルコキシ基(炭素数1〜5)、ハロゲン原子、ハロアルキル基(炭素数1〜5)、低級アルキル基(炭素数1〜5)、低級アルケニル基(炭素数2〜5)、又は低級アルキニル基(炭素数2〜5)である。但し、XがO、--- が一重結合の時は、R³、R⁴、R⁶とR⁸は水素原子、R⁵とR⁷は水酸基ではない。R⁹は水酸基又はハロゲン原子である。uは0〜5である。
R³、R⁴、R⁵、R⁶、R⁷、R⁸及びR⁹は環を形成してもよい。｝
で表される基である。
Ｂは、下記一般式

{In the formula, m is 0 to 1, and --- is a single bond or a double bond.
X _{is, CH, CH 2, O,} S, N-R 1, CF 2 or - (= CH ₂₎ - a. Here, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may be the same or different, and may be a hydrogen atom, a hydroxyl group, a — (CH ₂ ) _u -lower alkoxy group (having 1 to 5) a halogen atom, a haloalkyl group (C1-5), a lower alkyl group (C1-5), a lower alkenyl group (C2-5), or a lower alkynyl group (C2-5) is there. However, when X is O and --- is a single bond, R ³ , R ⁴ , R ⁶ and R ⁸ are not hydrogen atoms, and R ⁵ and R ⁷ are not hydroxyl groups. R ⁹ is a hydroxyl group or a halogen atom. u is 0-5.
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may form a ring. }
It is group represented by these.
B is the following general formula

｛式中、i及びkは0〜5である。--- は一重結合又は二重結合である。
Z¹、Z²、Z³、Z⁴、Z⁵、Z⁶、Z⁷、Z⁸、Z⁹、Z¹⁰、Z¹¹、Z¹²、Z¹³、Z¹⁴、Z¹⁵及びZ¹⁶は、同一又は異なってもよくCH、 CH₂、O、S、N又はNHである。
R¹⁰とR¹¹は、同一又は異なってもよく、水素原子、ハロゲン原子、低級アルキル基(炭素数1〜5)、置換基を有してもよいシクロアルキル基(炭素数3〜8)、置換基を有してもよいヘテロシクロアルキル基、低級ハロアルキル基(炭素数1〜5)、低級アルケニル基(炭素数2〜5)、低級アルキニル基(炭素数2〜5)、水酸基、低級アルコキシ基(炭素数1〜5)、低級ハロアルコキシ基(炭素数1〜5)、低級アルコキシカルボニル基(炭素数1〜5)、カルボキシル基、ニトロ基、シアノ基、置換基を有してもよい単環あるいは二環性芳香環(炭素数5〜10)、置換基を有してもよい単環あるいは二環性複素芳香環(炭素数1〜10)、置換基を有してもよいベンジル基、置換基を有してもよいアミノ基(4級化されてもよい)、−CONR¹²R¹³、−NHCOR¹⁵、−(CH₂)_o−R¹⁵−(CH₂)_p−R¹⁶、−低級アルケニレン(炭素数2〜5) −R¹⁵、−低級アルキニレン(炭素数2〜5) −R¹⁵、−(CH₂)_o−シクロアルキル基(炭素数3〜8)−(CH₂)_p−R¹⁵、−(CH₂)_o−ヘテロシクロアルキル基−(CH₂)_p−R¹⁵、−(CH₂)_o−NHC(=NH)−NH₂、−(CH₂)_o−C(=NH)−NH₂、-(CH₂)_o-D-(CH₂)_t-E-(CH₂)_p-R¹⁵、

{Wherein i and k are 0-5. --- is a single bond or a double bond.
^{Z 1, Z 2, Z 3} , Z 4, Z 5, Z 6, Z 7, Z 8, Z 9, Z 10, Z 11, Z 12, Z 13, Z 14, Z 15 and Z ¹⁶ are the same or better _{CH, CH 2, O, S} , N or NH or different.
R ¹⁰ and R ¹¹ may be the same or different, a hydrogen atom, a halogen atom, a lower alkyl group (1 to 5 carbon atoms), an optionally substituted cycloalkyl group (3 to 8 carbon atoms), Optionally substituted heterocycloalkyl group, lower haloalkyl group (1 to 5 carbon atoms), lower alkenyl group (2 to 5 carbon atoms), lower alkynyl group (2 to 5 carbon atoms), hydroxyl group, lower alkoxy Group (1 to 5 carbon atoms), lower haloalkoxy group (1 to 5 carbon atoms), lower alkoxycarbonyl group (1 to 5 carbon atoms), carboxyl group, nitro group, cyano group, may have a substituent Monocyclic or bicyclic aromatic ring (5 to 10 carbon atoms), optionally substituted monocyclic or bicyclic heteroaromatic ring (1 to 10 carbon atoms), optionally substituted benzyl group, an optionally substituted amino group (which may be ^{quaternized), - CONR 12 R 13,} -NHCOR 15, - (CH 2) o -R 15 - (CH 2) p -R 16 , -Low Alkenylene (C2-5) -R ^15, - lower alkynylene (2-5 carbon _{^{atoms) -R 15, - (CH 2}} ) o - cycloalkyl group (3 to 8 carbon atoms) - (CH _{2) p} - R ¹⁵ ,-(CH ₂ ) _o -heterocycloalkyl group-(CH ₂ ) _p -R ¹⁵ ,-(CH ₂ ) _o -NHC (= NH) -NH ₂ ,-(CH ₂ ) _o -C (= _{NH) -NH 2, - (CH} 2) o -D- (CH 2) t -E- (CH 2) p -R 15,

It is.
Here, in the formula, o and p may be the same or different, 0 to 15, t is 1 to 5, q is 0 to 2, d, k, and j are 0 to 5. D and E may bond be the same or different ^{(-), - CONR 12 -} , - NR 12 CO -, - O -, - NR 12 -, - S (O) q -, - NR 12 S (O ) _q −, —S (O) _q NR ¹² —, —NHC (═O) NH—.
R ¹² , R ¹³ and R ¹⁴ may be the same or different and are a hydrogen atom, a carbonyl group, a carboxyl group, a lower alkyl group (C1-5) or a hydroxy lower alkyl group (C1-5). A ring may be formed.
R ¹⁵ , R ¹⁶ and R ¹⁷ have a hydrogen atom, a halogen atom, a lower alkyl group (1 to 5 carbon atoms), an optionally substituted cycloalkyl group (3 to 8 carbon atoms), or a substituent. Heterocycloalkyl group, lower haloalkynylene group (1 to 5 carbon atoms), lower alkenylene group (2 to 5 carbon atoms), lower alkynyl group (2 to 5 carbon atoms), hydroxyl group, lower alkoxy group (1 carbon atom) -5), lower haloalkoxy group (C1-5), lower alkoxycarbonyl group (C1-5), carboxyl group, nitro group, cyano group, aminosulfonic acid group, may have a substituent Monocyclic or bicyclic aromatic ring (5 to 10 carbon atoms), optionally substituted monocyclic or bicyclic heteroaromatic ring (1 to 10 carbon atoms), optionally substituted benzyl Group, -S (O) _q -lower alkyl group (1 to 5 carbon atoms), -CONR ¹⁸ R ¹⁹ , an optionally substituted amino group (which may be quaternized), Mino acid residue, sugar residue,

It is.
Here, in the formula, R ¹⁸ and R ¹⁹ are a hydrogen atom, a lower alkyl group (C1-5), a lower alkylcarbonyl group (C1-5), a lower alkylsulfonyl group (C1-5), Benzenesulfonyl group which may have a substituent, lower alkoxycarbonyl group (1 to 5 carbon atoms), lower hydroxyalkyl group (1 to 5 carbon atoms), hydroxyethoxy group, alkoxyethoxy group, having a substituent It may be an aminoethoxy group, or — (CH ₂ ) _o —CONH ₂ .
R ²⁰ , R ²¹ and R ²² have a hydrogen atom, a halogen atom, a lower alkyl group (1 to 5 carbon atoms), a cycloalkyl group (3 to 8 carbon atoms) which may have a substituent, or a substituent. Heterocycloalkyl group, lower haloalkynylene group (1 to 5 carbon atoms), lower alkenylene group (2 to 5 carbon atoms), lower alkynyl group (2 to 5 carbon atoms), hydroxyl group, lower alkoxy group (1 carbon atom) -5), lower haloalkoxy group (C1-5), lower alkoxycarbonyl group (C1-5), carboxyl group, nitro group, cyano group, aminosulfonic acid group, may have a substituent Monocyclic or bicyclic aromatic ring (5 to 10 carbon atoms), optionally substituted monocyclic or bicyclic heteroaromatic ring (1 to 10 carbon atoms), optionally substituted benzyl Group, -S (O) _q -lower alkyl group (C1-5), optionally substituted amino group (may be quaternized)
R ²³ is a lower alkyl group (having 1 to 5 carbon atoms)}
It is group represented by these.
Y ¹ , Y ² , Y ³ , Y ⁴ may be the same or different CH ₂ , CH, O, S, N—R ²⁴ , CH ₂ —NH ₂ , CH ₂ —OH, CH ₂ —SH, —CH _2- or a halogen atom, and R ²⁴ is a hydrogen atom, a lower alkyl group (having 1 to 5 carbon atoms), or a lower haloalkyl group (having 1 to 5 carbon atoms). ]
Or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof.
In the above general formula (I) compound, A represents the general formula:

{Wherein X is O and --- is a single bond.
R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ may be the same or different from each other, and may be a hydrogen atom, a hydroxyl group, a — (CH ₂ ) _u -lower alkoxy group (having 1 to 5 carbon atoms), a halogen atom, or a haloalkyl group. (C1-5), lower alkyl group (C1-5), lower alkenyl group (C2-5) or lower alkynyl group (C2-5).
R ⁵ is a hydroxyl group, a halogen atom, a haloalkyl group (1 to 5 carbon atoms), a lower alkyl group (1 to 5 carbon atoms), a lower alkenyl group (2 to 5 carbon atoms), or a lower alkynyl group (2 to 5 carbon atoms). ). R ⁹ is a hydroxyl group or a halogen atom. u is 0-5.
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may form a ring. } And pharmaceutically acceptable salts, or prodrugs thereof are preferred. Also,
In the above general formula (I) compound, A represents the general formula

{In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different, and are a hydrogen atom, a hydroxyl group, a-(CH ₂ ) _u -lower alkoxy group (C 1-5), A halogen atom, a haloalkyl group (having 1 to 5 carbon atoms), a lower alkyl group (having 1 to 5 carbon atoms), a lower alkenyl group (having 2 to 5 carbon atoms), or a lower alkynyl group (having 2 to 5 carbon atoms). R ⁹ is a hydroxyl group or a halogen atom. u is 0-5.
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁹ may form a ring. }
And a pharmaceutically acceptable salt thereof, or a prodrug thereof is preferable.

In addition, in the above-mentioned general formula (I) compound, a compound in which A is a five-membered ring capable of taking a Northern-lock conformation, a pharmaceutically acceptable salt thereof or a prodrug thereof is preferable. In the above general formula (I) compound, a compound wherein Y is CH, a pharmaceutically acceptable salt thereof or a prodrug thereof is preferred. In the compound of the general formula (I), a compound in which L is N—R ¹ and R ¹ is a hydrogen atom, a pharmaceutically acceptable salt thereof, or a prodrug thereof is preferable.

The present invention also provides a pharmaceutical composition comprising the above compound, a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient. This pharmaceutical composition is used as a prophylactic or therapeutic drug for diseases caused by abnormal plasma uric acid levels. The disease caused by this abnormal plasma uric acid level is a disease selected from ventilation, high uric acid plasma, urolithiasis, hyperuric acid nephropathy and acute uric acid nephropathy. The present invention also includes at least one selected from the group consisting of the above pharmaceutical composition and colchicine, a nonsteroidal anti-inflammatory drug, a corticosteroid, a uric acid synthesis inhibitor, a uric acid excretion promoter, a urinary alkalinizing drug, and an acid oxidase group. It is a pharmaceutical composition comprising a combination of one kind of drug.

Furthermore, the present invention provides a pharmaceutical composition as described above, an antihypertensive agent, a hypoglycemic agent, an anti-obesity agent, an anti-nucleic acid antimetabolite, an antihypertensive diuretic, an antituberculosis agent, an anti-inflammatory analgesic, a hyperlipidemic agent, an asthma therapeutic agent. , Lipid lowering agent, cholesterol synthesis inhibitor, cholesterol absorption inhibitor, immunosuppressant, intravascular pressure disorder therapeutic agent, ischemic heart disease therapeutic agent, β-3 adrenergic receptor agonist, cannabinoid agonist or antagonist, neuropeptide Y5 receptor antagonist, apo-B / MTP inhibitor, 11β hydroxysteroid dehydrogenase-1 inhibitor, peptide YY _3-36 agonist, MCR4 agonist, CCK-A agonist, monoamine reuptake inhibitor, sympathomimetic drug, dopamine agonist, melanocyte stimulating hormone receptor Agonist, leptin receptor agonist, galanin antagonist, instep Gland stimulant, glucocorticoid receptor antagonist, orexin receptor antagonist, epiandrosterone dehydrogenase drug, histamine-3 receptor antagonist, lipase inhibitor, PPAR ligand modulator, insulin secretagogue, sulfonylurea, α-glucosidase inhibitor, insulin Sensitizing drugs, hepatic glucose output lowering drugs, non-thiazolidinone compounds, protein tyrosine phosphatase-B inhibitors, dipeptidyl peptidase IV inhibitors, glucagon antagonists, HMG-CoA reductase inhibitors, sterol esters, cholesterol absorption inhibitors, ACAT inhibition Agent, bile acid reuptake inhibitor, microsomal triglyceride transporter inhibitor, fibric acid derivative, β-blocker, ACE inhibitor, calcium channel blocker Car, diuretics, renin inhibitors, pharmaceutical compositions comprising a combination of at least one agent of AT-1 receptor antagonists, ET receptor antagonists, metabolic syndrome therapeutic agent selected from the AII receptor antagonists.

  A of the compound represented by the general formula (I) of the present invention is a residue of an unnatural sugar. The compound in which A is a residue of a natural sugar is easily decomposed because the sugar moiety is natural ribose with a high degree of freedom. In the present invention, A is a non-natural sugar residue. Also, the conformation of the furanose ring was fixed. By immobilizing this conformation, the compound becomes difficult to hydrolyze, becomes physicochemically stable, and increases the CNT2 inhibitory activity. In particular, when this fixation is fixed to Northern, stability against hydrolysis, physicochemical stability, and CNT2 inhibitory activity are further increased. The compound represented by the general formula (I) of the present invention has an excellent CNT2 inhibitory action, suppresses in vivo absorption of purine nucleosides, and is useful as a plasma uric acid level lowering agent.

The compound of the present invention represented by the general formula (I) will be described in detail.
L is N-R ¹ , CR ¹ R ² , an alkenylene which may be branched (for example,-(CH = CH)-, --CH ₂ (CH = CH)-,-(CH = CH) CH _2- , -(CH ₂ ) ₂ (CH = CH)-,-(CH = CH) (CH ₂ ) ₂ -,-(CHCH ₃ ) (CH = CH)-,-(CH = CH) (CHCH ₃ )-, etc. ), Which may be branched (e.g., ethylene, propene, isopropene, butene, isobutene, pentene, isopentene, 2,2-dimethylpropene, etc.) is S (O) _v ( Group, sulfoxide group, sulfonic acid group, etc.).
A is a group represented by the following formula.

The five-membered ring that forms the skeleton of A is known to take many conformations. All these conformations are represented as angle P on the pseudorotational cycle. As a representative example, conformations of P = 0 °, P = 90 °, P = 180 °, P = 270 ° are called Northern, Eastern, Southern, Western (C. Altona, MJ Sundaralingham, J. Am Chem. Soc., 1972, 94, 8205). The following formula is an example of ribose. In the formula, Ar is purine or uracil.

Compounds that can predominate the northern and southern conformations of nucleosides that take many conformations have been reported in areas such as antiviral agents (Jonathan K. Watts, Kashinath Sadalapure, Niloufar Choubdar, B. Mario Pinto, Masad J. Damha, J. Org. Chem., 2006, 71, 921, Victor E. Marquez, Maqbool A. Siddiqui, Abdallah Ezzitouni, Pamela Russ, Jianying Wang, Richard W. Wagner, Mark D. Matteucci, J. Med Chem., 1996, 39, 3739). However, for CNT2 inhibitors, no compound has been reported that fixes the stable conformation of nucleosides. It is difficult to predict which of the conformations of Northern, Eastern, Southern, and Western is in the active conformation, but the compounds in the Northern-lock conformation are compared to the conventionally known compounds, The CNT2 inhibitory activity was remarkably increased, and it was difficult to hydrolyze and was stable physicochemically.

R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ in the above formula A may be the same or different, and may be a hydrogen atom, a hydroxyl group, a — (CH ₂ ) _u -lower alkoxy group (for example, methoxy Group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, etc.), halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom), lower alkyl group (for example, methyl group, ethyl group, propyl) Group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, neopentyl group, etc.), cycloalkyl group (for example, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.), lower haloalkyl group ( For example, trifluoromethyl group, 2,2,2-trifluoroethyl group, 4-bromobutane group, 5-chloropropane group, etc.), lower alkenyl group (for example, ethylene group, propene) , Isopropene group, butene group, etc.), lower alkynyl group (e.g., ethynyl group, propargyl group). R ⁹ includes a hydroxyl group and a halogen atom (for example, fluorine atom, chlorine atom, bromine atom, iodine atom).

R ¹⁰ and R ^{11 in} the formula B may be the same or different, and are a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a lower alkyl group (for example, a methyl group, Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, pentyl group, neopentyl group, etc.), cycloalkyl group (for example, cyclopentyl group, cyclohexyl group, cycloheptyl group) Etc.), heterocycloalkyl groups (eg morpholine, piperidine, piperazine, tetrahydrofuran, dioxane, dithiane, etc.), lower haloalkyl groups (eg trifluoromethyl group, 2,2,2-trifluoroethyl group etc.), lower alkenylene groups (E.g., ethylene group, propene group, isopropene group, butene group, etc.), lower alkynyl group (e.g. Nyl group, propargyl group, etc.), hydroxyl group, optionally substituted amino group (for example, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group) , Diisopropylamino group, acetylamino group, methylsulfonylamino group, methoxycarbonylamino group, t-butoxycarbonylamino group, etc.), lower alkoxy group (for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group) Group), lower haloalkoxy group (for example, chloromethoxy group, bromomethoxy group, dichloromethoxy group, iodopropoxy group, 4,4-difluorobutoxy group, etc.), lower alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, Propoxyca (Bonyl group, isopropoxycarbonyl group etc.), carboxyl group, nitro group, cyano group, monocyclic or bicyclic aromatic ring which may have a substituent (for example, phenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group) A methoxyphenyl group, an aminophenyl group, a cyanophenyl group, a thiomethylphenyl group, a methylsulfonylphenyl group, a naphthalene ring, an azulene ring, etc.), a monocyclic or bicyclic heteroaromatic ring that may have a substituent (for example, Pyridine ring, furan ring, thiophene ring, imidazole ring, thiazole ring, benzofuran ring, benzothiophene ring, benzimidazole ring, benzothiazol ring, etc.).

R ¹² , R ¹³ and R ¹⁴ may be the same or different and may be a hydrogen atom, a carbonyl group, a carboxyl group, or a lower alkyl group that may form a ring (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group). Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, pentyl group, neopentyl group, etc.).

R ¹⁵ , R ¹⁶ and R ¹⁷ are a hydrogen atom, a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a lower alkyl group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, pentyl group, neopentyl group, etc.), cycloalkyl group (for example, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.), heterocycloalkyl group (for example, morpholine, piperidine, etc.) , Piperazine, tetrahydrofuran, dioxane, dithiane, etc.), lower haloalkyl groups (eg, trifluoromethyl group, 2,2,2-trifluoroethyl group, etc.), lower alkenylene groups (eg, ethylene group, propene group, isopropene group, Butene group), lower alkynyl group (eg, ethynyl group, propargyl group, etc.), An acid group, an amino group which may have a substituent (for example, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group, diisopropylamino group) Acetylamino group, methylsulfonylamino group, methoxycarbonylamino group, t-butoxycarbonylamino group, etc.), lower alkoxy group (eg, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butoxy group, pentyloxy group) , Cyclopentyloxy group, etc.), lower haloalkoxy group (eg, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, etc.), lower alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbo Nyl group, etc.), carboxyl group, nitro group, cyano group, monocyclic or bicyclic aromatic ring optionally having a substituent (e.g. phenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, methoxyphenyl group, Aminophenyl group, cyanophenyl group, thiomethylphenyl group, methylsulfonylphenyl group, naphthalene ring, azulene ring, etc.), monocyclic or bicyclic heteroaromatic ring (for example, pyridine ring, furan ring) which may have a substituent Thiophene ring, imidazole ring, thiazole ring, benzofuran ring, benzothiophene ring, benzimidazole ring, benzothiazol ring, etc.). Optionally substituted benzyl group (eg, chlorobenzyl group, bromobenzyl group, nitrobenzyl group, ethylbenzyl group, isopropylbenzyl group), —S (O) _q -lower alkyl group (eg, methyl group, Ethyl group, propyl group, isopropyl group, butyl group, pentyl group, cyclopentyl group, etc.)-CONR ¹⁷ R ¹⁸ , amino group which may have a substituent (for example, amino group, methylamino group, dimethylamino group, ethyl group) Amino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group, diisopropylamino group, acetylamino group, methylsulfonylamino group, methoxycarbonylamino group, t-butoxycarbonylamino group, etc.), amino acid residue ( For example, glycine, alanine, valine, leucine, isoleucine, phenylalanine , Asparagine, glutamine, tryptophan, proline, serine, threonine, tyrosine, cysteine, cystine, methionine, aspartic acid, glutamic acid, lysine, arginine, histidine, 2-aminoadipic acid, 2-aminoisobutyric acid, 3-aminoadipic acid, 3-aminoisobutyric acid, β-alanine, 2-aminopimenic acid, 2-aminobutyric acid, 2,4-diaminobutyric acid, 4-aminobutyric acid, desmosine, piperidinecarboxylic acid, 2,2-diaminopimenic acid, 6- Aminocaproic acid, 2,3-diaminopropionic acid, 2-aminoheptanoic acid, N-ethylglycine, 2- (2-thienyl) glycine, 3- (2-thienyl) alanine, penicillamine, sarcosine, N-ethylasparagine, N-methylisoleucine, hydroxy Resin, 6-N-methyllysine, Allo-hydroxylysine, N-methylvaline, 3-hydroxyproline, norvaline, 4-hydroxyproline, norleucine, isodesmosine, ornithine, Allo-isoleucine and derivatives thereof, etc. Glucose derived from ketose, including amino sugar, amino alcohol, sugar acid, mannose, fructose, galactose, ribose, erythrose, glyceraldehyde, sedoheptulose, glucosamine, galactosamine, glucuronic acid, galactonic acid, mannonic acid, glucamine, 3- Amino-1,2-propanediol, glucaric acid, galactaric acid and other O-glycosides, N-glycosides, C-glycosides, etc.)

R ¹⁸ and R ¹⁹ are a hydrogen atom, a lower alkyl group (for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, cyclopentyl group, etc.), lower alkylcarbonyl group (for example, methyl ketone group, ethyl ketone group) Propyl ketone group, butyl ketone group, pentyl ketone group), lower alkylsulfonyl group (for example, methyl sulfonic acid, ethyl sulfonic acid, propyl sulfonic acid, butyl sulfonic acid, pentyl sulfonic acid), benzene which may have a substituent A sulfonyl group (for example, methylbenzenesulfonic acid, ethylbenzenesulfonic acid, chlorobenzenesulfonic acid, bromobenzenesulfonic acid), a lower alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, (Butoxycarbonyl group, pentoxycarbonyl group), hydroxyethoxy group, alkoxyethoxy group (for example, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group, butoxyethoxy group, pentoxyethoxy group), may have a substituent Aminoethoxy group (for example, aminoethoxy group, methylaminoethoxy group, dimethylaminoethoxy group, ethylaminoethoxy group, propylaminoethoxy group, butylaminoethoxy group, pentylaminoethoxy group), — (CH ₂ ) _o —CONH ₂ Is mentioned. R ²⁰ , R ²¹ and R ²² are a hydrogen atom, a halogen atom (eg, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom), a lower alkyl group (eg, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, pentyl group, neopentyl group, etc.), cycloalkyl group (for example, cyclopentyl group, cyclohexyl group, cycloheptyl group, etc.), heterocycloalkyl group (for example, morpholine, piperidine, etc.) , Piperazine, tetrahydrofuran, dioxane, dithiane, etc.), lower haloalkyl groups (eg, trifluoromethyl group, 2,2,2-trifluoroethyl group, etc.), lower alkenylene groups (eg, ethylene group, propene group, isopropene group, Butene group), lower alkynyl group (eg, ethynyl group, propargyl group, etc.), An acid group, an amino group which may have a substituent (for example, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, dipropylamino group, isopropylamino group, diisopropylamino group) Acetylamino group, methylsulfonylamino group, methoxycarbonylamino group, t-butoxycarbonylamino group, etc.), lower alkoxy group (eg, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butoxy group, pentyloxy group) , Cyclopentyloxy group, etc.), lower haloalkoxy group (eg, trifluoromethoxy group, 2,2,2-trifluoroethoxy group, etc.), lower alkoxycarbonyl group (eg, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, Isopropoxycarbo Nyl group, etc.), carboxyl group, nitro group, cyano group, monocyclic or bicyclic aromatic ring optionally having a substituent (e.g. phenyl group, fluorophenyl group, chlorophenyl group, methylphenyl group, methoxyphenyl group, Aminophenyl group, cyanophenyl group, thiomethylphenyl group, methylsulfonylphenyl group, naphthalene ring, azulene ring, etc.), monocyclic or bicyclic heteroaromatic ring (for example, pyridine ring, furan ring) which may have a substituent Thiophene ring, imidazole ring, thiazole ring, benzofuran ring, benzothiophene ring, benzimidazole ring, benzothiazol ring, etc.). Optionally substituted benzyl group (eg, chlorobenzyl group, bromobenzyl group, nitrobenzyl group, ethylbenzyl group, isopropylbenzyl group), —S (O) _q -lower alkyl group (eg, methyl group, An ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a cyclopentyl group, etc.) and an amino group which may have a substituent (for example, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group) Propylamino group, dipropylamino group, isopropylamino group, diisopropylamino group, acetylamino group, methylsulfonylamino group, methoxycarbonylamino group, t-butoxycarbonylamino group, etc.), R ²² is a lower alkyl group (for example, Methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, Cyclopentyl group, etc.). R ²⁴ represents a hydrogen atom, a lower alkyl group (for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a cyclopentyl group, etc.) or a lower haloalkyl group (for example, a trifluoromethyl group, 2, 2, 2-trifluoroethyl group, 4-bromobutane group, 5-chloropropane group, etc.).

  The compound of the present invention contains any stereoisomer, optical isomer, tautomer and any mixture thereof. Further, the compounds of the present invention include all compounds that are metabolized in vivo and converted to the general formula (I) and compounds that are converted into salts, so-called prodrugs. Examples of the group that forms the prodrug of the present invention include those described in Prog. Med., 5, 2157, 1985. and those described in Hirokawa Shoten 1990, “Development of Drugs”, Vol. Group.

  The term “pharmaceutically acceptable salt” is a compound of the invention that retains the biological effectiveness and properties of the compound of the invention and is not biologically or otherwise inconvenient. Examples of the addition salt of the compound of the present invention include those described in WILEY-VCH publication “Handbook of Pharmaceutical Salts (2002)”. For example, acid addition salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, It is derived from citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, glutamic acid, aspartic acid and the like. Base addition salts are lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, ammonia, isopropylamine, diethylamine, triethylamine, ethanolamine, piperidine, pyridine, tris (hydroxymethyl) methylamine, tris ( Derived from hydroxyethyl) methylamine, lysine, arginine, choline and the like.

Specific examples of the compound represented by the general formula (I) are shown below.
(1) 2- (6-Amino-8-{[2- (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino} purin-9-yl) -5-hydroxymethyl-3-methyltetrahydrofuran-3,4 -Diol (2) 2- (6-hydroxy-8-{[2- (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino} purin-9-yl) -5-hydroxymethyl-3-methyltetrahydrofuran-3 , 4-diol (3) acetic acid 4- (4-{[1- (3,4-dibenzoyloxy-5-benzoyloxymethylbicyclo [3.1.0] hex-2-yl) -1H-benzimidazo-2 -Ilamino] methyl} biphenyl-2-yloxy) butyl ester (4) 2- [4- (4-{[1- (3,4-dibenzoyloxy-5-benzoyloxymethylbicyclo [3.1.0] hexyl- 2-yl) -1H-benzimidazol-2-ylamino] methyl} biphenyl-2-yloxy) butyl] isoindole-1,3-dione (5) 4- (2-{[2- (4-chlorobutoxy) Biphenyl-4-ylmethyl ] Amino} benzimidazol-1-yl) -1-benzoyloxymethylbicyclo [3.1.0] hexane-2,3-dibenzoyloxyether (6) 4- (2-{[2- (4-dimethylaminobutoxy) ) Biphenyl-4-ylmethyl] amino} benzoimidazol-1-yl) -1-benzoyloxymethylbicyclo [3.1.0] hexane-2,3-benzoyloxyether (7) acetic acid-4- (4-{[1 -(3,4-Dibenzoyloxyether-5-benzoyloxymethyl-3-methyltetrahydrofuran-2-yl) -1H-benzimidazol-2-ylamino] -methyl} biphenyl-2-yloxy) butyl ester (8) 2- (2-{[2- (4-Chlorobutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -5-benzoyloxymethyl-3-methyltetrahydrofuran-3,4-benzoyloxyether ( 9) 2- (2-{[2- (4-Hydroxybutoxy) biphenyl-4-ylmethyl] a No} benzimidazol-1-yl) -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (10) 5- (2-{[2- (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino } Benzimidazol-1-yl) -3-hydroxymethylcyclopent-3-ene-1,2-diol

(11) 3- (2-{[2- (4-Hydroxybutoxy) biphenyl-4-ylmethyl] amino} benzoimidazol-1-yl) -5-hydroxymethylcyclopentane-1,2-diol (12) 4 -(2-{[2- (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -1-hydroxymethylbicyclo [3.1.0] hexane-2,3-diol (13) 4- (2-{[2- (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) cyclopentane-1,2,3-triol (14) 1- [3- (3 -{[1- (3,4-Dihydroxy-5-hydroxymethylbicyclo [3.1.0] hex-2-yl) -1H-benzoimidazol-2-ylamino] methyl} phenoxy) propyl] piperidine-4-carboxylic acid Amide (15) 3- (4-{[1- (3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) -1H-benzimidazol-2-ylamino] me Til} phenyl) acetic acid ethyl ester (16) 3- (4-{[1- (3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) -1H-benzimidazol-2-ylamino] Methyl} phenyl) acrylic acid (17) 2- {2- [3- (4-hydroxybutoxy) -4-thiophen-3-ylbenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyl Tetrahydrofuran-3,4-diol (18) 2- [2- (4-bromobenzylamino) benzimidazol-1-yl] -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (19) 2- (2-{[2 '-(4-Hydroxybutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (20) 2- (2-{[2,3′-bis (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino} benzimidazole-1- Le) -5-hydroxymethyl-3-methyl-3,4-diol

(21) 4- (4-{[1- (3,4-Dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) -1H-benzimidazol-2-ylamino] methyl} biphenyl-2-yloxy ) Butyronitrile (22) N- [4- (4-{[1- (3,4-dihydroxy-5-hydroxymethyl-3-methyltetrahydrofuran-2-yl) -1H-benzimidazol-2-ylamino] methyl} Biphenyl-2-yloxy) butyl] methanesulfonamide (23) 2- (2-{[2- (4-hydroxybutylsulfanyl) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -5-hydroxymethyl -3-methyltetrahydrofuran-3,4-diol (24) 3-ethyl-2- (2-{[2- (4-hydroxybutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -5 -Hydroxymethyltetrahydrofuran-3,4-diol (25) 2- {2-[(3a, 7a-dihydrobenzo [b] thiof N-3-ylmethyl) amino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (26) 2- (2- {3- [2- (4-hydroxybutoxy) ) Biphenyl-4-yl] propylamino} benzoimidazol-1-yl) -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (27) 2- [4- (4-{[1- (3 , 4-Dihydroxy-5-hydroxymethylbicyclo [3.1.0] hex-2-yl) -1H-benzimidazol-2-ylamino] methyl} biphenyl-2-yloxy) butyl] isoindole-1,3-dione ( 28) 4- (2-{[2- (4-Aminobutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -1-hydroxymethylbicyclo [3.1.0] hexane-2,3-diol (29) 4- {2- [3- (3-Aminopropoxy) benzylamino] benzimidazol-1-yl} -1-hydroxymethylbicyclo [3.1.0] hexane-2,3- Diol (30) 2- (2-{[2- (4-Aminobutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol

(31) 4- (2-{[2- (4-Dimethylaminobutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -1-hydroxymethylbicyclo [3.1.0] hexane-2,3 -Diol (32) 1-hydroxymethyl-4- {2- [3- (3-methylaminopropoxy) benzylamino] benzimidazol-1-yl} bicyclo [3.1.0] hexane-2,3-diol (33 ) 1-hydroxymethyl-4- (2-{[2- (4-methylaminobutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) bicyclo [3.1.0] hexane-2,3-diol (34) 4- (2-{[2- (4-Dimethylaminobutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -1-hydroxymethylbicyclo [3.1.0] hexane-2,3 -Diol (35) 4- {2- [3- (3-dimethylaminopropoxy) benzylamino] benzimidazol-1-yl} -1-hydroxymethylbicyclo [3.1.0] he Xan-2,3-diol (36) 2- {2- [3- (4-dimethylaminobutoxy) -4-methylbenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran- 3,4-diol (37) 2- {2- [3- (4-dimethylaminobutoxy) -4-ethylbenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3, 4-diol (38) 2- {2- [3- (4-dimethylaminobutoxy) -4-vinylbenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4- Diol

(39) 2- {2- [3- (4-Dimethylaminobutoxy) -4-isopropoxybenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol ( 40) 2- {2- [4-cyclohexyl-3- (4-dimethylaminobutoxy) benzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (41) 2- {2- [4-Benzyloxy-3- (4-dimethylaminobutoxy) benzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (42) 2 -{2- [3- (4-Dimethylaminobutoxy) -4-hydroxybenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (43) 2- { 2- [3- (4-Dimethylaminobutoxy) -4-methoxybenzylamino] benzimidazole 1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (44) 2- {2- [3- (4-dimethylaminobutoxy) -4-isopropoxybenzylamino] benzo Imidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (45) 2- {2- [4-cyclohexyloxy-3- (4-dimethylaminobutoxy) benzylamino] benzimidazole -1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (46) 2- {2- [3- (4-dimethylaminobutoxy) -4-phenoxybenzylamino] benzimidazole-1 -Yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (47) 2- {2- [3,4-bis (4-dimethylaminobutoxy) benzylamino] benzimidazol-1-yl} -5-Hydroxymethyl-3-methyltetrahydrofuran-3,4-diol (48) 2- {2- [3- ( 4-Dimethylaminobutoxy) -4-morpholin-4-ylbenzylamino] benzimidazol-1-yl} -5-hydroxymethyl-3-methyltetrahydrofuran-3,4-diol

The compounds of the above (1) and (2) --- (48) will be referred to below as compound (1) and compound (2) --- compound (48), respectively.
The production method of the compound represented by the general formula (I) of the present invention will be described.
The compound of the present invention can be produced by the following method. Examples of the protective group used in the production include the protective groups described in “Protective Groups in Organic Synthesis (1999)” published by WILEY-Interscience.
An outline of a method for producing a compound when the L group of the general formula (I) is N—R ¹ and R ¹ is a hydrogen atom is shown below.

The actual steps 1 to 7 for producing the above compound are shown below.

Process 1
The compound represented by general formula 2 and the compound represented by general formula 3 are reacted in the absence of solvent or in an inert solvent to give imine 4. Examples of the solvent used in the reaction include toluene, benzene, xylene, N, N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, chloroform, dichloroethane, and mixed solvents thereof. The reaction temperature is usually from room temperature to reflux temperature. If necessary, water generated by the reaction is removed using Dean-Stark. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is several hours to several days. The obtained imine is reduced to an amine in an inert solvent using a reducing agent such as sodium borohydride, potassium borohydride, sodium cyanide borate, sodium triacetoxyborate. Examples of the solvent used for the reaction include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloroethane, toluene and a mixed solvent thereof. The reaction temperature is usually from ice-cold temperature to reflux temperature, preferably room temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 30 minutes to several days.

In this step, reduction may be performed after purifying and isolating the imine, but reduction may also be performed without purifying the imine. The compound represented by the general formula 2 used as a starting material in this step is either a commercially available product or a known method (for example, J. Org. Chem., 1981, 46 (13) 2891-2823. Chem. Pharm. Bull., 1977, 25 (4), 575-578., Tetrahedron, 1970, 26, 4251-4259., Etc.) or a method based thereon.
The compound represented by the general formula 3 can be purchased as a commercial product, or can be produced by a known method or a method based thereon, and an example process is shown in the following figure.

Process 2
The compound represented by the general formula 5 is reacted with sodium azide in an inert solvent to synthesize the compound represented by the general formula 6. Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloroethane, toluene and a mixed solvent thereof, and preferably N, N-dimethylformamide. The reaction temperature is usually from ice-cold temperature to reflux temperature, preferably 150 ° C. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 1 hour to several days.

The compound represented by the general formula 6 is reduced using a general azide reduction method. In the method using a hydrogenation reaction, catalytic reduction is performed using a metal catalyst such as palladium carbon and platinum oxide in an inert solvent. In this reaction, an acid such as hydrochloric acid may be present. Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloroethane, toluene and a mixed solvent thereof, and tetrahydrofuran is preferred. The reaction temperature is usually from ice-cooling temperature to solvent reflux temperature, preferably room temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 1 hour to several days.

Process 3
The compound represented by formula 5 is reacted with the compound represented by formula 7 in the presence of a base in an inert solvent to synthesize the compound represented by formula 1. Examples of the base used include triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, sodium hydroxide, sodium methoxide and the like. Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloroethane, toluene and a mixed solvent thereof, and N, N-dimethylformamide is preferable. The reaction temperature is usually from ice-cooling temperature to reflux temperature, preferably 100 ° C. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 1 hour to several days.

Process 4
A compound represented by the general formula 8 (for example, 2-chlorobenzimidazole) and a sugar derivative compound represented by the general formula 9 (for example, J. Org. Chem., 1999, 64, 4172-4178., Bioorg. Med. Chem. Lett., 2006, 16, 285-287., J. Med. Chem., 2001, 44, 3985-3993., Tetrahedron Lett., 1997, 38, 4207-4210., Tetrahedron Lett., 2005, 46 , 8913-8915., Tetrahedron Lett., 2004, 8981-8982., J. Org. Chem., 2004, 69, 3993-3996., Tetrahedron Lett., 1997, 38, 6189-6192, J. Med. Chem ., 2006, 49, 273-281., J. Org. Chem., 2006, 71, 921-925., J. Med. Chem., 2006, 49, 1140-1148., Org. Lett., 2001, 3, 597-599., NUCLEOSIDE & NUCLEOTIDE, 1994, 13, 2035-2050, J. Org. Chem., 1997, 62, 1754-1759. The compound represented by the general formula 7 is synthesized according to the conditions of various Mitsunobu reactions.

The reaction is carried out using a carboxamide such as diethyldicarboxamide, diisopropylcarboxamide, dicyclohexylcarboxamide or the like in the presence of a phosphine reagent such as triphenylphosphine or tributylphosphine. Examples of the solvent used in the reaction include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloroethane, toluene and a mixed solvent thereof. The reaction temperature is usually from ice-cooling temperature to solvent reflux temperature, preferably room temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 30 minutes to several days. In addition, the same reaction can be carried out using phospholanes such as cyanomethylenetributylphosphorane and cyanomethylenetrimethylphosphorane even in the absence of a phosphine reagent. Examples of the solvent used in the reaction include benzene and toluene. The reaction temperature is usually from room temperature to the solvent reflux temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 30 minutes to several days.

Process 5
The compound represented by the general formula 7 includes a compound represented by the general formula 5 and a sugar derivative represented by the general formula 9 in which R is a leaving group (for example, Tetrahedron Lett., 1997, 38, 4207-4210., Tetrahedron Lett., 1999, 40, 3309-3312., J. Org. Chem., 1997, 62, 1754-1759., J. Med. Chem., 2001, 44, 3985-3993., J. Org. Chem. , 2006, 71, 4018-4020., WO 2004/002422 WO 03/068162. And the like) can also be coupled. The compound represented by the general formula 5 is pretreated with a silylating agent such as N, O-bis (trimethylsilyl) acetamide, N, N′-bis (trimethylsilyl) urea, trimethylsilyl chloride, hexamethyldisilazane, etc. It can be coupled to the presence of a Lewis acid such as trimethylsilyl trifluoromethanesulfonate or tin tetrachloride in an active solvent.

Examples of the solvent used in the reaction include acetonitrile, tetrahydrofuran, dichloroethane, N, N-dimethylacetamide, N, N-dimethylformamide, dimethyl sulfoxide and a mixed solvent thereof, and acetonitrile is preferable. The reaction temperature is usually from ice-cooling temperature to solvent reflux temperature, preferably room temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually 1 hour to 1 day.
The compound represented by the general formula 3 can be purchased as a commercial product, or can be produced by a known method or a method based thereon, and an example is shown in the following figure.

Step 6
The compound represented by the general formula 3 is synthesized by reduction of a general nitrile. For the reduction, diisopropylaluminum hydride or the like is used in an inert solvent, and then hydrolyzed using hydrochloric acid or the like. Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran, dichloromethane, toluene, hexane and a mixed solvent thereof, and preferably dichloromethane. The reaction temperature is usually from ice-cooling temperature to solvent reflux temperature, preferably room temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 1 hour to several days.

Step 7
The compound represented by the general formula 7 is synthesized by reduction of a general nitrile. The reduction is performed using lithium aluminum hydride, sodium borohydride, lithium borohydride or the like in an inert solvent. Examples of the solvent used in the reaction include diethyl ether, tetrahydrofuran, dichloromethane, toluene, methanol, ethanol and a mixed solvent thereof. The reaction temperature is usually from ice-cooling temperature to solvent reflux temperature, preferably room temperature. The reaction time varies depending on the raw materials and the solvent reaction temperature, but is usually from 1 hour to several days.

  The present invention is a pharmaceutical composition comprising the compound represented by the above general formula (I), a pharmaceutically acceptable salt thereof or a prodrug thereof as an active ingredient. This pharmaceutical composition is an anti-steroidal inflammation which is a disease caused by abnormal plasma uric acid abnormalities, such as the prevention or treatment of ventilation and colchicine, such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoroxixib or tenoxicam Drugs such as allopurinol, oxypurinol, febuxostat, FYX-051 or Y-700 uric acid synthesis inhibitors such as probenecid, bucolome or benzbromarone, uric acid excretion promoters such as sodium bicarbonate, potassium citrate Or a urinary alkalinizing agent that is sodium citrate, such as an antihypertensive diuretic that is chlorothiazide, trichloromethiazide, furosemide or triamterene, such as an AT-1 receptor antagonist that is losartan or irbesartan, Calcium channel blockers, for example diltiazem, verapamil or amlodipine, for example ACE inhibitors which are captopril or silazopril, for example biguanide antihyperglycemic agents which are metformin or phenformin, for example rosiglitazone, troglitazone, pioglitazone, ONO-5129, K-111 Or a PPAR ligand agonist or antagonist that is MCC-555, for example an α-glucosidase inhibitor that is miglitol, acarbose or voglibose, such as dipeptidyl peptidase 4 inhibitor that is sitagliptin, TS-021, SYR-322, TA-6666 or vildagliptin An insulin secretagogue such as chlorpromazine, glimeprid or tolbutamide, for example a lipase inhibitor such as orelstat or cetiristat, such as β which is CL316243 3 in combination with at least one drug selected from an adrenergic receptor agonist, for example a cannabinoid antagonist which is rimonabant, for example an AII receptor antagonist which is losartan, candesartan or telmisartan, for example an anti-obesity drug which is sibutramine or S-2367 be able to.

  As solid components for oral administration of the compound of the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or more active substances are present in at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid. Mixed with magnesium aluminate. The composition is prepared according to conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium calcium glycolate, stabilizers such as lactose, glutamic acid or aspartic acid. A solubilizing agent or a solubilizing agent such as Tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate or the like, or a gastric or enteric film, if necessary.

  Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents such as purified water. , Including ethyl alcohol. In addition to the inert diluent, the composition may contain solubilizers, solubilizers, wetting agents, suspending agents and other adjuvants, sweeteners, flavoring agents, fragrances and preservatives.

  Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension dilution include distilled water for injection and physiological saline. Examples of diluents for water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil; alcohols such as ethyl alcohol; polysorbate 80 (trade name).

  These compositions may further contain additives such as isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers or solubilizers. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation. These can also be used by producing a sterile solid composition and dissolving it in sterile water or a sterile solution for injection before use.

Next, the pharmacological test and the results of the compound represented by the general formula (1) of the present invention will be described.
[Test Example 1]
Measurement of inhibition of adenosine uptake via human CNT2 `` Uptake buffer '' is 140 mL sodium chloride, 2 mM potassium chloride, 1 mM calcium chloride, 1 mM magnesium chloride, 10 mM hepes (HEPES) 2- [4- (2-hydroxyethyl)- 1-piperazinyl] ethanesulfonic acid, 5 mM Tris (hydroxymethyl) aminomethane, and 5 mM glucose in a pH 7.4 buffer solution, adenosine non-radioactive label (Sigma) and ³ H label (GE Healthcare Bio (Made by Science Co., Ltd.) was mixed and added so that the final concentration of adenosine was 10 μM. For measurement of basal uptake, a “basic uptake measurement buffer” containing 140 mM choline chloride was prepared instead of sodium chloride. At the time of measurement, NBPPR was added to the uptake buffer solution and the basal uptake measurement buffer solution so that the final concentration was 10 μM.

When measuring the inhibitory activity of a compound, the compound was dissolved in dimethyl sulfoxide, and then appropriately diluted with an uptake buffer to obtain a measurement buffer. The medium of human CNT2 transiently expressing cells was removed, 500 μL of pretreatment buffer (basic uptake measurement buffer not containing adenosine and glucose) was added per well, and the mixture was allowed to stand at 37 ° C. for 10 minutes. After repeating the same operation once more, the pretreatment buffer was removed, 300 μL 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 buffer for measurement and the buffer for basal uptake were removed, and the plate was washed twice with 500 μL of washing buffer (basic uptake measurement buffer containing 10 μL of non-radiolabeled adenosine) per well. Cells were lysed with 200 μL of 0.5 mol / L sodium hydroxide per well and transferred to a 100 μL glass vial. 5 mL of liquid scintillator ACS-II (GE Healthcare Bioscience) was added and mixed, and the radioactivity was measured with a scintillation counter (Aloka). The amount of adenosine uptake at each concentration of the test compound was calculated by taking the value obtained by subtracting the basal uptake from the uptake of the control group as 100%. The concentration at which the test compound inhibited adenosine uptake by 50% (IC ₅₀ value) was calculated by a regression linear equation. The results are shown in the following table. The comparative compound is a compound having a natural sugar residue.

Results and Discussion Compound (9) and compound (12) having a non-natural sugar residue had a higher CNT2 inhibitory effect than a comparative compound having a natural sugar residue.
[Test Example 2]
Four-week-old male SD rats (Nippon Charles River Co., Ltd.) were purchased, and animals that had passed a quarantine period of 1 week or longer were used for the experiments. The body weight of rats fasted for about 24 hours from the day before the test was measured, and grouped using grouping software (Stat Light # 11, manufactured by Yukkusu). The test substance and [ ³ H] adenosine solution (4 μCi / mL) were each orally administered in a volume of 2 mL / kg, and about 500 μL of blood was collected from the orbital venous plexus 15 minutes later. Centrifuge the blood at 3000 rpm for 10 minutes, add 13 μL of 30% hydrogen peroxide to 100 μL of the resulting serum, leave it for about 10 minutes, and then add 5 liquid scintillation cocktail (ACS-II, manufactured by GE Healthcare Biosciences). After adding mL and mixing well, the radioactivity was measured with a liquid scintillation counter (manufactured by Aloka).
The inhibition rate of adenosine absorption was calculated from the following equation, a regression line was calculated from the inhibition rate and the logarithmic dose at that time, and the dose of the test substance that inhibits adenosine absorption by 50% (ED ₅₀ value) was calculated from the regression linear equation.
Inhibition rate (%) = {1−Radioactivity in serum of rats administered with test substance (dpm) / Radioactivity in serum of rats administered with solvent (dpm)} × 100

Results and Discussion The compound (9) having a non-natural sugar residue showed a higher ED ₅₀ value than the comparative compound having a natural sugar residue.
[Test Example 3]
Stability of nucleic acid transporter inhibitors in solution
0.02 mL of a ^10-3 M methanol solution of a comparative compound, compound (9) or compound (12) was added to 1.98 mL of pH 3, 4 and 5 acetate buffer or pH 6, 7 and 8 phosphate buffer. . (The final concentration was 10 ⁻⁵ M) After completion of incubation at 25 ° C. for 24 hours, 0.5 mL of the reaction solution was neutralized to 1 mL. To this, 0.01 mL of a methanol solution of 10 ⁻³ M 4-hydroxybenzoic acid n-propyl ester as an internal standard substance was added. HPLC measurement was performed under the measurement conditions shown below, and the ratio (IS ratio) between the amount of the internal standard substance and the amount of the compound was calculated. The residual rate (%) of the test drug was determined by comparison with the IS ratio obtained by the same operation as described above before incubation.

HPLC measurement conditions-Column used: Inertsil ODS-2 (φ4.6 × 150 mm)
・ Eluent: 20 mM phosphate buffer (pH 6) / CH ₃ CN = 7/3 (w / w)
・ Detection wavelength: 250 nm
・ Flow rate: 1 mL / min
・ Injection volume: 0.02 mL
・ Measurement time: 20 min

Results and Discussion The compound (9) or compound (12) having a non-natural sugar residue has improved stability in a solution at pH 3 as compared with a comparative compound having a natural sugar residue.
Next, reference examples and examples are shown. A reference example is an example which showed the manufacturing method of the raw material compound used in the Example which is a manufacture example of the compound represented by General formula (1) of this invention.
Reference example 1

Diethyl zinc (1.0 M, n-hexane solution) 16.2 mL of methylene chloride in 30 mL was added with an ice-cooled solution of 5.62 g of alcohol in 30 mL of methylene chloride. Diiodomethane 2.9mL was dripped at the reaction liquid over 10 minutes, and it stirred at room temperature for 21 hours. The reaction mixture was ice-cooled, water was added, and the mixture was stirred for 2 hr. The treatment solution was filtered, and the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 3.83 g of the title compound as a colorless amorphous product.
¹ H-NMR (CDCl ₃ ) δ = 0.58 (dd, J = 5.2Hz, 8.8Hz, 1H), 1.13 (t, J = 5.2Hz, 1H) 1.31 (s, 3H), 1.53 (s, 3H), 1.71 (m, 1H), 2.36 (d, J = 9.2Hz, 1H), 2.85 (d, J = 10.0Hz, 1H), 3.43 (d, J = 10.0Hz, 1H), 4.54-4.59 (m, 2H ), 5.00 (d, J = 6.4Hz, 1H), 7.20-7.30 (m, 9H), 7.39-7.42 (d, J = 8.0Hz, 6H).
Reference example 2

To a suspension of 2-chlorobenzimidazole (714 mg) in acetonitrile (25 mL) was added N, O-bis (trimethylsilyl) acetamide (3.1 mL), and the mixture was stirred at 120 ° C. for 1 hour, and then allowed to cool to room temperature. To the reaction solution, add 2,47 g of 1,2,3,5-tetra-O-benzoyl-2-C-methyl-D-ribofuranose in 20 mL of acetonitrile, add dropwise 1.5 mL of trimethylsilyl triflate, and then at 120 ° C. for 10 hours. Stir. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 1.46 g of the title compound as a colorless amorphous product.
¹ H-NMR (CDCl ₃ ) δ = 1.71 (s, 3H), 4.73-4.77 (m, 1H), 4.92 (dd, J = 4.4Hz, 12.4Hz, 1H), 5.03 (dd, J = 3.2Hz, 12.4Hz, 1H), 5.87 (d, J = 5.6Hz, 1H), 6.79 (s, 1H), 7.06 (t, J = 7.6Hz, 1H), 7.22-7.29 (m, 3H), 7.41-7.52 ( m, 5H), 7.57-7.62 (m, 2H), 7.68 (d, J = 8.0Hz, 1H), 7.75 (d, J = 8.4Hz, 1H), 8.04 (dd, J = 1.2Hz, 8.4Hz, 2H), 8.14 (d, J = 8.0Hz, 2H).
The following compounds were synthesized in the same manner.
Reference example 3

¹ H-NMR (CDCl ₃ ) δ = 0.95-0.99 (m, 1H), 1.03 (t, J = 4.4Hz, 1H), 1.28 (s, 3H), 1.55 (s, 3H), 1.77 (dd, J = 4.8Hz, 8.8Hz, 1H), 3.00 (d, J = 10.0Hz, 1H), 3.83 (d, J = 10.0Hz, 1H), 4.83 (d, J = 7.2Hz, 1H), 5.03 (s, 1H), 5.44 (d, J = 8.0Hz, 1H), 6.74 (t, J = 7.6Hz, 1H), 7.17 (t, J = 8.0Hz, 1H), 7.22-7.31 (m, 9H), 7.44 ( dd, J = 1.2Hz, 8.0Hz, 6H), 7.66 (d, J = 8.0Hz, 1H), 7.87 (d, J = 8.4Hz, 1H).
Reference example 4

6-tert-Butoxymethyl-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta [1,3] dioxol-4-ol 1.10 g in tetrahydrofuran 40 mL solution under ice-cooling, triphenylphosphine 4.77 g, 2 After adding 2.08 g of -chlorobenzimidazole, 3.6 mL of diisopropyl azodicarboxylate was added and stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 1.01 g of the title compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 1.25 (s, 9H), 1.36 (s, 3H), 1.52 (s, 3H), 4.13-4.22 (m, 2H), 4.81 (d, J = 5.6Hz, 1H ), 5.38 (d, J = 5.2Hz, 1H), 5.67 (s, 1H), 5.79 (s, 1H), 7.19-7.27 (m, 3H), 7.67-7.70 (m, 1H).
Reference Example 5

To a solution of 1.46 g of 2- (2-chlorobenzimidazol-1-yl) -5-benzoyloxymethyl-3-methyl-tetrahydrofuran-3,4-dibenzoate in 15 mL of dimethylformamide was added 1.09 g of sodium azide, and 110 ° C. For 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 1.48 g of the title compound as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 1.68 (s, 3H), 4.69-4.72 (m, 1H), 4.85 (dd, J = 5.2Hz, 12.4Hz, 1H), 4.98 (dd, J = 3.6Hz, 12.4Hz, 1H), 5.98 (d, J = 6.8Hz, 1H), 6.60 (s, 1H), 7.11 (t, J = 7.6Hz, 1H), 7.22-7.65 (m, 12H), 7.97 (d, J = 7.2Hz, 2H), 8.08-8.11 (m, 4H).
The following compounds were synthesized in the same manner.
Reference Example 6

¹ H-NMR (CDCl ₃ ) δ = 1.25 (s, 9H), 1.36 (s, 3H), 1.50 (s, 3H), 4.16 (m, 2H), 4.76 (d, J = 6.0Hz, 1H), 5.36- 5.38 (m, 2H), 5.72 (s, 1H), 7.12-7.26 (m, 3H), 7.61 (d, J = 7.6Hz, 1H).
Reference Example 7

¹ H-NMR (CDCl ₃ ) δ = 0.97-0.99 (m, 2H), 1.26 (s, 3H), 1.56 (s, 3H), 1.71 (dd, J = 5.2Hz, 8.0Hz, 1H), 3.07 ( d, J = 9.6Hz, 1H), 3.75 (d, J = 10.0Hz, 1H), 4.76-4.78 (m, 2H), 5.38 (d, J = 7.6Hz, 1H), 6.77 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 8.0Hz, 1H), 7.21-7.30 (m, 9H), 7.44 (dd, J = 1.2Hz, 8.0Hz, 6H), 7.61 (d, J = 7.6Hz, 1H), 7.72 (d, J = 8.0Hz, 1H).
Reference Example 8

2- (2-azidobenzimidazol-1-yl) -5-benzoyloxymethyl-3-methyltetrahydrofuran-3,4-dibenzoate 1.48 g of methanol 15 mL, ethyl acetate 5 mL solution was added palladium-activated carbon 315 mg, Hydrogenated for 3 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 982 mg of the title compound as a colorless amorphous product.
¹ H-NMR (CDCl ₃ ) δ = 1.70 (s, 3H), 4.68-4.72 (m, 1H), 4.89 (m, 1H), 4.97 (dd, J = 2.4Hz, 12.4Hz, 1H), 5.40 ( br-s, 2H), 5.90 (m, 1H), 6.52 (s, 1H), 7.16 (t, J = 7.6Hz, 1H), 7.38-7.63 (m, 12H), 8.04 (m, 4H), 8.10 (dd, J = 1.2Hz, 8.4Hz, 2H).
The following compounds were synthesized in the same manner.
Reference Example 9

¹ H-NMR (CDCl ₃ ) δ = 1.26 (s, 9H), 1.35 (s, 3H), 1.49 (s, 3H), 4.12 (d, J = 14.0Hz, 1H), 4.19 (d, J = 14.4 Hz, 1H), 4.70 (d, J = 6.0Hz, 1H), 5.32-5.33 (m, 2H), 5.58 (br-s, 2H), 5.94 (s, 1H), 7.07 (t, J = 7.6Hz , 1H), 7.13-7.19 (m, 2H), 7.39 (d, J = 8.0Hz, 1H).
Reference Example 10

¹ H-NMR (CDCl ₃ ) δ = 1.31 (s, 3H), 1.45 (s, 3H), 1.50-1.75 (m, 2H), 3.88 (d, J = 14.4Hz, 1H), 3.99 (d, J = 14.4Hz, 1H), 4.58 (m, 1H), 4.72 (d, J = 6.0Hz, 1H), 5.26 (d, J = 6.0Hz, 1H), 5.31 (s, 1H), 6.18 (s, 1H ), 7.04 (t, J = 7.6Hz, 1H), 7.14 (t, J = 7.6Hz, 1H), 7.19 (d, J = 7.6Hz, 1H), 7.20-7.41 (m, 9H), 7.42-7.47 (m, 7H).
Reference Example 11

¹ H-NMR (CDCl ₃ ) δ = 0.84 (dd, J = 6.8Hz, 8.8Hz, 1H), 1.09 (t, J = 8.4Hz, 1H) 1.28 (s, 3H), 1.52 (s, 3H), 1.61 (dd, J = 4.0Hz, 9.2Hz, 1H), 2.71 (d, J = 10.4Hz, 1H), 4.16 (d, J = 10.8Hz, 1H), 4.70-4.78 (m, 2H), 5.43 ( d, J = 7.6Hz, 1H), 6.73 (br-s, 2H), 7.06 (t, J = 7.6Hz, 1H), 7.20 (t, J = 7.6Hz, 1H), 7.24-7.44 (m, 17H ).
Reference Example 12

Platinum-active in 2-azido-1- (2,2-dimethyl-6-trityloxymethyltetrahydrocyclopenta [1,3] dioxol-4-yl) -1H-benzimidazole 327 mg in 6 mL ethanol and 2 mL ethyl acetate 110 mg of carbon was added and hydrogenated at 60 ° C. for 79 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 297 mg of the title compound as a colorless amorphous.
¹ H-NMR (CDCl ₃ ) δ = 1.29 (s, 3H), 1.56 (s, 3H), 2.38-2.62 (m, 3H), 3.39 (m, 2H), 4.56-4.61 (m, 1H), 4.65 -4.68 (m, 1H), 4.90-4.95 (m, 1H), 7.00 (t, J = 7.6Hz, 1H), 7.11-7.51 (m, 18H).
Reference Example 13

1- (6-tert-butoxymethyl-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta [1,3] dioxol-4-yl) -1H-benzimidazol-2-ylamine 208 mg and acetic acid 4- A 5 mL toluene solution of 165 mg of (4-formylbiphenyl-2-yloxy) butyl ester was azeotroped for 2 hours, and then the reaction solution was concentrated under reduced pressure. To a 4 mL solution of the residue in tetrahydrofuran was added 225 mg of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 313 mg of the title compound as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 1.20 (s, 9H), 1.34 (s, 3H), 1.48 (s, 3H), 1.69-1.80 (m, 4H), 2.02 (s, 3H), 3.98 (t , J = 6.0Hz, 2H), 3.96-4.05 (m, 3H), 4.12-4.16 (m, 1H), 4.65-4.79 (m, 4H), 5.25-5.27 (m, 2H), 5.96 (s, 1H ), 7.02-7.06 (m, 3H), 7.12-7.17 (m, 2H), 7.30-7.33 (m, 2H), 7.39 (t, J = 7.6Hz, 1H), 7.50-7.52 (m, 3H).
Reference Example 14

¹ H-NMR (CDCl ₃ ) δ = 1.20 (s, 9H), 1.34 (s, 3H), 1.48 (s, 3H), 1.69-1.80 (m, 4H), 2.02 (s, 3H), 3.98 (t , J = 6.0Hz, 2H), 3.96-4.05 (m, 3H), 4.12-4.16 (m, 1H), 4.65-4.79 (m, 4H), 5.25-5.27 (m, 2H), 5.96 (s, 1H ), 7.02-7.06 (m, 3H), 7.12-7.17 (m, 2H), 7.30-7.33 (m, 2H), 7.39 (t, J = 7.6Hz, 1H), 7.50-7.52 (m, 3H).

4- (4-aminomethylbiphenyl-2-yloxy) butan-1-ol 429 mg in propanol 5 mL solution with diisopropylethylamine 0.39 mL, 2- (6-amino-8-bromopurin-9-yl) -5-hydroxymethyl 250 mg of -3-methyltetrahydrofuran-3,4-diol was added and refluxed for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 115 mg of a yellow oil. 2 mL of methanol and 159 mg of NH ₄ F were added to the obtained residue, and the mixture was stirred at 60 ° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol) to obtain 48 mg of the title compound 1 as a pale yellow amorphous.
¹ H-NMR (CD ₃ OD) δ = 0.90 (s, 3H), 1.55-1.60 (m, 2H), 1.68-1.73 (m, 2H), 3.48 (t, J = 6.4Hz, 2H), 3.86 ( dd, J = 1.2Hz, 12.0Hz, 1H), 3.92-3.98 (m, 1H), 3.96 (t, J = 6.4Hz, 2H), 4.03 (dd, J = 2.4Hz, 12.0Hz, 1H), 4.15 (m, 1H), 4.52 (d, J = 15.2Hz, 1H), 4.69 (d, J = 15.6Hz, 1H), 6.00 (s, 1H), 6.99-7.08 (m, 3H), 7.13 (s, 1H), 7.20-7.34 (m, 6H), 7.45 (dd, J = 1.2Hz, 8.0Hz, 2H).
The following compound 2 was synthesized in the same manner.
Compound 2

¹ H-NMR (CDCl ₃ ) δ = 0.95 (s, 3H), 1.54-1.61 (m, 2H), 1.69-1.75 (m, 2H), 3.50 (t, J = 6.0Hz, 2H), 3.87 (d , J = 10.8Hz, 1H), 3.97 (t, J = 6.4Hz, 2H), 3.95-3.98 (m, 1H), 4.03 (dd, J = 2.0, 12.0Hz, 1H), 4.22 (d, J = 9.2Hz, 1H), 4.49 (d, J = 15.2Hz, 1H), 4.67 (d, J = 15.2Hz, 1H), 6.22 (s, 1H), 7.01 (d, J = 7.6Hz, 1H), 7.11 (s, 1H), 7.19 (d, J = 7.6Hz, 1H), 7.24 (t, J = 7.6Hz, 1H), 7.32 (t, J = 8.0Hz, 2H), 7.44 (d, J = 7.2Hz , 2H), 7.89 (s, 1H).

4-(2-アミノベンゾイミダゾール-1-イル)-1-ヒドロキシメチルビシクロ[3.1.0]ヘキサン-2,3-ジオール208mgと酢酸4-(4-ホルミルビフェニル-2-イルオキシ)ブチルエステル165mgのトルエン5mL溶液を2時間共沸した後、反応液を減圧濃縮した。残渣のテトラヒドロフラン4mL溶液に、トリアセトキシ水素化ホウ素ナトリウム225mgを加え、室温で3時間撹拌した。反応液を水に注ぎ、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、ろ過し、ろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル/ヘキサン）に付し、表題化合物3を313mg 黄色油状物として得た。
¹H-NMR(CDCl₃)δ= 1.63-1.70(m, 4H), 1.75(s, 3H), 1.99(s, 3H), 3.87(br-s, 2H), 3.98(t, J=6.4Hz, 2H), 4.65- 4.93(m, 5H), 5.82(br-s, 1H), 6.27(br-s, 1H), 6.47(s, 1H), 6.99-7.95(m, 27H).
同様の方法で以下の化合物４〜８を合成した
化合物４

Of 208 mg 4- (2-aminobenzoimidazol-1-yl) -1-hydroxymethylbicyclo [3.1.0] hexane-2,3-diol and 165 mg acetic acid 4- (4-formylbiphenyl-2-yloxy) butyl ester After azeotroping the toluene 5 mL solution for 2 hours, the reaction solution was concentrated under reduced pressure. To a 4 mL solution of the residue in tetrahydrofuran was added 225 mg of sodium triacetoxyborohydride, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane) to give 313 mg of the title compound 3 as a yellow oil.
¹ H-NMR (CDCl ₃ ) δ = 1.63-1.70 (m, 4H), 1.75 (s, 3H), 1.99 (s, 3H), 3.87 (br-s, 2H), 3.98 (t, J = 6.4Hz , 2H), 4.65- 4.93 (m, 5H), 5.82 (br-s, 1H), 6.27 (br-s, 1H), 6.47 (s, 1H), 6.99-7.95 (m, 27H).
Compound 4 wherein the following compounds 4 to 8 were synthesized in the same manner

¹ H-NMR (CDCl ₃ ) δ = 1.64 (m, 4H), 1.76 (s, 3H), 3.60 (t, J = 6.4Hz, 2H), 3.88 (br-s, 2H), 4.67-4.93 (m , 5H), 5.84 (br-s, 1H), 6.28 (br-s, 1H), 6.49 (s, 1H), 7.01-7.59 (m, 23H), 7.66-7.68 (m, 2H), 7.78-7.82 (m, 2H), 7.94 (m, 4H).
Compound 5

¹ H-NMR (CDCl ₃ ) δ = 1.75-1.88 (m, 7H), 3.41-3.44 (m, 2H), 3.87 (br-s, 2H), 4.64-4.93 (m, 5H), 5.82 (br- s, 1H), 6.29 (br-s, 1H), 6.47 (s, 1H), 7.00-7.61 (m, 21H), 7.94-7.95 (m, 6H).
Compound 6

¹ H-NMR (CDCl ₃ ) δ = 1.75-1.88 (m, 7H), 3.41-3.44 (m, 2H), 3.87 (br-s, 2H), 4.64-4.93 (m, 5H), 5.82 (br- s, 1H), 6.29 (br-s, 1H), 6.47 (s, 1H), 7.00-7.61 (m, 21H), 7.94-7.95 (m, 6H).
Compound 7

¹ H-NMR (CDCl ₃ ) δ = 1.63-1.70 (m, 4H), 1.75 (s, 3H), 1.99 (s, 3H), 3.87 (br-s, 2H), 3.98 (t, J = 6.4Hz , 2H), 4.65- 4.93 (m, 5H), 5.82 (br-s, 1H), 6.27 (br-s, 1H), 6.47 (s, 1H), 6.99-7.95 (m, 27H).
Compound 8

¹ H-NMR (CDCl ₃ ) δ = 1.75-1.88 (m, 7H), 3.41-3.44 (m, 2H), 3.87 (s, 1H), 4.64-4.93 (m, 5H), 5.82 (m, 1H) , 6.29 (m, 1H), 6.47 (s, 1H), 7.00-7.61 (m, 2H), 7.94-7.95 (m, 6H).

2-(2-{[2-(4-アセチルブトキシ)ビフェニル-4-イルメチル]アミノ}ベンゾイミダゾール-1-イル)-5-アセトキシメチル-3-メチルテトラヒドロフラン-3,4-ジアセトキシ313mgのメタノール4mL溶液にナトリウムメトキシド8mgを加え、室温で6時間撹拌した。反応液を減圧濃縮した後、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール）に付し、表題化合物9を115mg 無色固体として得た。
¹H-NMR(CD₃OD)δ= 0.90(s, 3H), 1.55-1.60(m, 2H), 1.68-1.73(m, 2H), 3.48(t, J=6.4Hz, 2H), 3.86(dd, J= 1.2Hz, 12.0Hz, 1H), 3.92-3.98(m, 1H), 3.96(t, J=6.4Hz, 2H), 4.03(dd, J=2.4Hz, 12.0Hz, 1H), 4.15(m, 1H), 4.52(d, J=15.2Hz, 1H), 4.69(d, J=15.6Hz, 1H), 6.00(s, 1H), 6.99-7.08(m, 3H), 7.13(s, 1H), 7.20-7.34(m, 6H), 7.45(dd, J=1.2Hz, 8.0Hz, 2H).
同様の方法で以下の化合物を合成した。

2- (2-{[2- (4-acetylbutoxy) biphenyl-4-ylmethyl] amino} benzimidazol-1-yl) -5-acetoxymethyl-3-methyltetrahydrofuran-3,4-diacetoxy 313 mg of methanol 4 mL Sodium methoxide (8 mg) was added to the solution, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol) to give 115 mg of the title compound 9 as a colorless solid.
¹ H-NMR (CD ₃ OD) δ = 0.90 (s, 3H), 1.55-1.60 (m, 2H), 1.68-1.73 (m, 2H), 3.48 (t, J = 6.4Hz, 2H), 3.86 ( dd, J = 1.2Hz, 12.0Hz, 1H), 3.92-3.98 (m, 1H), 3.96 (t, J = 6.4Hz, 2H), 4.03 (dd, J = 2.4Hz, 12.0Hz, 1H), 4.15 (m, 1H), 4.52 (d, J = 15.2Hz, 1H), 4.69 (d, J = 15.6Hz, 1H), 6.00 (s, 1H), 6.99-7.08 (m, 3H), 7.13 (s, 1H), 7.20-7.34 (m, 6H), 7.45 (dd, J = 1.2Hz, 8.0Hz, 2H).
The following compounds were synthesized in the same manner.

25 μL of hydrazine monohydrate was added to a solution of compound 27 in 165 mg of ethanol in 5 mL, and the mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / 40% methylamine methanol solution) to give 97 mg of the title compound 28 as a pale yellow solid.
¹ H-NMR (CD ₃ OD) δ = (CD3OD) 1.67-1.81 (m, 4H), 4.04 (t, J = 6.4Hz, 2H), 4.33 (s, 2H), 4.48 (dd, J = 5.6Hz , 6.4Hz, 1H), 4.57 (d, J = 6.0Hz, 1H), 4.64 (d, J = 15.2Hz, 1H), 4.70 (d, J = 14.8Hz, 2H), 5.39 (m, 1H), 6.05 (d, J = 1.6Hz, 1H), 6.90-6.93 (m, 1H), 7.00-7.08 (m, 2H), 7.16-7.34 (m, 6H), 7.45-7.51 (m, 3H).
The following compounds 29 and 30 were synthesized in the same manner.
Compound 29

¹ H-NMR (CD ₃ OD) δ = 0.88 (dd, J = 5.2 Hz, 7.6 Hz, 1 H), 1.30 (m, 1 H), 1.72 (dd, J = 4.0 Hz, 8.8 Hz, 1 H), 1.91- 1.98 (m, 2H), 2.88 (t, J = 7.2Hz, 2H), 3.26 (d, J = 11.6Hz, 1H), 4.03 (t, J = 6.0Hz, 2H), 4.15 (dd, J = 4.0 Hz, 7.2Hz, 1H), 4.23 (d, J = 11.6Hz, 1H), 4.55 (d, J = 3.6Hz, 1H), 4.60 (q, J = 15.2Hz, 2H), 4.72 (d, J = 6.4Hz, 1H), 6.77 (m, 1H), 6.96-7.04 (m, 4H), 7.19 (t, J = 8.0Hz, 1H), 7.25 (dd, J = 1.2Hz, 6.8Hz, 1H), 7.37 (m, 1H).
Compound 30

¹ H-NMR (CD ₃ OD) δ = 0.90 (s, 3H), 1.48-1.53 (m, 2H), 1.65-1.70 (m, 2H), 2.55 (t, J = 7.2Hz, 2H), 3.86 ( dd, J = 2.0Hz, 12.0Hz, 1H), 3.93-3.97 (m, 3H), 4.03 (dd, J = 2.0Hz, 12.0Hz, 1H), 4.15 (d, J = 8.8Hz, 1H), 4.53 (d, J = 15.6Hz, 1H), 4.68 (d, J = 15.2Hz, 1H), 5.99 (s, 1H), 6.99-7.08 (m, 3H), 7.13 (s, 1H), 7.20-7.35 ( m, 6H), 7.45 (m, 2H).

135 mg of sodium iodide was added to a solution of compound 5 in 165 mg of dimethylformamide in 5 mL, and the mixture was heated to reflux for 5 hours. The reaction solution was allowed to cool, and 200 mg of potassium carbonate and 54 μL of dimethylamine were added and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / 40% methylamine methanol solution) to give 97 mg of the title compound 31 as a pale yellow solid.
¹ H-NMR (CD ₃ OD) δ = 0.91 (m, 1H), 1.31 (m, 1H), 1.58-1.60 (m, 2H), 1.69-1.72 (m, 3H), 2.34 (s, 3H), 2.58 (t, J = 7.6Hz, 2H), 3.27 (d, J = 11.2Hz, 1H), 3.98 (t, J = 6.0Hz, 2H), 4.17 (dd, J = 3.6Hz, 6.8Hz, 1H) , 4.26 (d, J = 11.2Hz, 1H), 4.58 (d, J = 3.2Hz, 1H), 4.66 (AB-q, J = 15.2Hz, 2H), 4.75 (d, J = 7.2Hz, 1H) , 6.99-7.06 (m, 3H), 7.13 (s, 1H), 7.20-7.39 (m, 6H), 7.45 (m, 2H).
The following compounds 32-48 were synthesized by the same method.

The following compounds can be synthesized in the same manner as in Example 3.

The following compounds can be synthesized in the same manner as in Example 5.

Graph showing the results of Pharmacological Test 3

Claims (11)

The following general formula (I):

[Wherein, n and w are 0 to 5. --- is a single bond or a double bond.
L is represented by N—R ¹ , CR ¹ R ² , alkenylene (2 to 5 carbon atoms) that may be branched, alkynylene (2 to 5 carbon atoms) that may be branched, or S (O) _v. It is a group. Here, R ¹ and R ² may be the same or different and each represents a hydrogen atom, a lower alkyl group (1 to 5 carbon atoms) or a lower haloalkyl group (1 to 5 carbon atoms). v is 0-2.
A is the following general formula

{In the formula, m is 0 to 1, and --- is a single bond or a double bond.
X _{is, CH, CH 2, O,} S, N-R 1, CF 2 or - (= CH ₂₎ - a. Here, R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may be the same or different, and may be a hydrogen atom, a hydroxyl group, a — (CH ₂ ) _u -lower alkoxy group (having 1 to 5) a halogen atom, a haloalkyl group (C1-5), a lower alkyl group (C1-5), a lower alkenyl group (C2-5), or a lower alkynyl group (C2-5) is there. However, when X is O and --- is a single bond, R ³ , R ⁴ , R ⁶ and R ⁸ are not hydrogen atoms, and R ⁵ and R ⁷ are not hydroxyl groups. R ⁹ is a hydroxyl group or a halogen atom. u is 0-5.
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may form a ring. }
It is group represented by these.
B is the following general formula

{Wherein i and k are 0-5. --- is a single bond or a double bond.
^{Z 1, Z 2, Z 3} , Z 4, Z 5, Z 6, Z 7, Z 8, Z 9, Z 10, Z 11, Z 12, Z 13, Z 14, Z 15 and Z ¹⁶ are the same or better _{CH, CH 2, O, S} , N or NH or different.
R ¹⁰ and R ¹¹ may be the same or different, a hydrogen atom, a halogen atom, a lower alkyl group (1 to 5 carbon atoms), an optionally substituted cycloalkyl group (3 to 8 carbon atoms), Optionally substituted heterocycloalkyl group, lower haloalkyl group (1 to 5 carbon atoms), lower alkenyl group (2 to 5 carbon atoms), lower alkynyl group (2 to 5 carbon atoms), hydroxyl group, lower alkoxy Group (1 to 5 carbon atoms), lower haloalkoxy group (1 to 5 carbon atoms), lower alkoxycarbonyl group (1 to 5 carbon atoms), carboxyl group, nitro group, cyano group, may have a substituent Monocyclic or bicyclic aromatic ring (5 to 10 carbon atoms), optionally substituted monocyclic or bicyclic heteroaromatic ring (1 to 10 carbon atoms), optionally substituted benzyl group, an optionally substituted amino group (which may be ^{quaternized), - CONR 12 R 13,} -NHCOR 15, - (CH 2) o -R 15 - (CH 2) p -R 16 , -Low Alkenylene (C2-5) -R ^15, - lower alkynylene (2-5 carbon _{^{atoms) -R 15, - (CH 2}} ) o - cycloalkyl group (3 to 8 carbon atoms) - (CH _{2) p} - R ¹⁵ ,-(CH ₂ ) _o -heterocycloalkyl group-(CH ₂ ) _p -R ¹⁵ ,-(CH ₂ ) _o -NHC (= NH) -NH ₂ ,-(CH ₂ ) _o -C (= _{NH) -NH 2, - (CH} 2) o -D- (CH 2) t -E- (CH 2) p -R 15,

It is.
Here, in the formula, o and p may be the same or different, 0 to 15, t is 1 to 5, q is 0 to 2, d, k, and j are 0 to 5. D and E may bond be the same or different ^{(-), - CONR 12 -} , - NR 12 CO -, - O -, - NR 12 -, - S (O) q -, - NR 12 S (O ) _q −, —S (O) _q NR ¹² —, —NHC (═O) NH—.
R ¹² , R ¹³ and R ¹⁴ may be the same or different and are a hydrogen atom, a carbonyl group, a carboxyl group, a lower alkyl group (C1-5) or a hydroxy lower alkyl group (C1-5). A ring may be formed.
R ¹⁵ , R ¹⁶ and R ¹⁷ have a hydrogen atom, a halogen atom, a lower alkyl group (1 to 5 carbon atoms), an optionally substituted cycloalkyl group (3 to 8 carbon atoms), or a substituent. Heterocycloalkyl group, lower haloalkynylene group (1 to 5 carbon atoms), lower alkenylene group (2 to 5 carbon atoms), lower alkynyl group (2 to 5 carbon atoms), hydroxyl group, lower alkoxy group (1 carbon atom) -5), lower haloalkoxy group (C1-5), lower alkoxycarbonyl group (C1-5), carboxyl group, nitro group, cyano group, aminosulfonic acid group, may have a substituent Monocyclic or bicyclic aromatic ring (5 to 10 carbon atoms), optionally substituted monocyclic or bicyclic heteroaromatic ring (1 to 10 carbon atoms), optionally substituted benzyl Group, -S (O) _q -lower alkyl group (1 to 5 carbon atoms), -CONR ¹⁸ R ¹⁹ , an optionally substituted amino group (which may be quaternized), Mino acid residue, sugar residue,

It is.
Here, in the formula, R ¹⁸ and R ¹⁹ are a hydrogen atom, a lower alkyl group (C1-5), a lower alkylcarbonyl group (C1-5), a lower alkylsulfonyl group (C1-5), Benzenesulfonyl group which may have a substituent, lower alkoxycarbonyl group (1 to 5 carbon atoms), lower hydroxyalkyl group (1 to 5 carbon atoms), hydroxyethoxy group, alkoxyethoxy group, having a substituent It may be an aminoethoxy group, or — (CH ₂ ) _o —CONH ₂ .
R ²⁰ , R ²¹ and R ²² have a hydrogen atom, a halogen atom, a lower alkyl group (1 to 5 carbon atoms), a cycloalkyl group (3 to 8 carbon atoms) which may have a substituent, or a substituent. Heterocycloalkyl group, lower haloalkynylene group (1 to 5 carbon atoms), lower alkenylene group (2 to 5 carbon atoms), lower alkynyl group (2 to 5 carbon atoms), hydroxyl group, lower alkoxy group (1 carbon atom) -5), lower haloalkoxy group (C1-5), lower alkoxycarbonyl group (C1-5), carboxyl group, nitro group, cyano group, aminosulfonic acid group, may have a substituent Monocyclic or bicyclic aromatic ring (5 to 10 carbon atoms), optionally substituted monocyclic or bicyclic heteroaromatic ring (1 to 10 carbon atoms), optionally substituted benzyl Group, -S (O) _q -lower alkyl group (C1-5), optionally substituted amino group (may be quaternized)
R ²³ is a lower alkyl group (having 1 to 5 carbon atoms)}
It is group represented by these.
Y ¹ , Y ² , Y ³ , Y ⁴ may be the same or different CH ₂ , CH, O, S, N—R ²⁴ , CH ₂ —NH ₂ , CH ₂ —OH, CH ₂ —SH, —CH _2- or a halogen atom, and R ²⁴ is a hydrogen atom, a lower alkyl group (having 1 to 5 carbon atoms), or a lower haloalkyl group (having 1 to 5 carbon atoms). ]
Or a pharmaceutically acceptable salt, prodrug, hydrate or solvate thereof. A is the general formula:

{Wherein X is O and --- is a single bond.
R ³ , R ⁴ , R ⁶ , R ⁷ and R ⁸ may be the same or different, and may be a hydrogen atom, a hydroxyl group, a — (CH ₂ ) _u -lower alkoxy group (having 1 to 5 carbon atoms), a halogen atom, a haloalkyl group ( C1-5), a lower alkyl group (C1-5), a lower alkenyl group (C2-5) or a lower alkynyl group (C2-5).
R ⁵ is a hydroxyl group, a halogen atom, a haloalkyl group (1 to 5 carbon atoms), a lower alkyl group (1 to 5 carbon atoms), a lower alkenyl group (2 to 5 carbon atoms), or a lower alkynyl group (2 to 5 carbon atoms). ). R ⁹ is a hydroxyl group or a halogen atom. u is 0-5.
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may form a ring. }
2. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, or a prodrug thereof. A is the general formula:

{In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ may be the same or different, and are a hydrogen atom, a hydroxyl group, a-(CH ₂ ) _u -lower alkoxy group (C 1-5), A halogen atom, a haloalkyl group (having 1 to 5 carbon atoms), a lower alkyl group (having 1 to 5 carbon atoms), a lower alkenyl group (having 2 to 5 carbon atoms), or a lower alkynyl group (having 2 to 5 carbon atoms). R ⁹ is a hydroxyl group or a halogen atom. u is 0-5.
R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁹ may form a ring. }
2. The compound according to claim 1 and a pharmaceutically acceptable salt thereof, or a prodrug thereof.   The compound according to any one of claims 1 to 3, wherein A is a five-membered ring capable of taking a Northern-lock conformation, a pharmaceutically acceptable salt thereof, or a prodrug thereof. Y is CH, The compound in any one of Claims 1-3, its pharmaceutically acceptable salt, or its prodrug. L is N-R ^1, the compounds according to any one of claims 1 to 4 R ¹ is a hydrogen atom, acceptable salt or prodrug thereof their pharmaceutically. The pharmaceutical composition which uses the compound in any one of Claims 1-6, its pharmaceutically acceptable salt, or its prodrug as an active ingredient. The pharmaceutical composition according to claim 7, which is a preventive or therapeutic agent for a disease caused by an abnormal plasma uric acid level. The pharmaceutical composition according to claim 8, wherein the disease caused by abnormal plasma uric acid level is a disease selected from ventilation, high uric acid plasma, urolithiasis, hyperuric acid nephropathy and acute uric acid nephropathy. A group consisting of the pharmaceutical composition according to any one of claims 7 to 9, and colchicine, a nonsteroidal anti-inflammatory drug, a corticosteroid, a uric acid synthesis inhibitor, a uric acid excretion promoter, a urinary alkalinizing drug, and an acid oxidase group A pharmaceutical composition comprising a combination of at least one drug selected from The pharmaceutical composition according to any one of claims 7 to 9, an antihypertensive agent, a hypoglycemic agent, an antiobesity agent, an anti-nucleic acid antimetabolite, an antihypertensive diuretic, an antituberculosis agent, an anti-inflammatory analgesic, and a hyperlipidemic agent , Asthma therapeutic agent, lipid lowering agent, cholesterol synthesis inhibitor, cholesterol absorption inhibitor, immunosuppressive agent, intravascular pressure disorder therapeutic agent, ischemic heart disease therapeutic agent, β-3 adrenergic receptor agonist, cannabinoid agonist or antagonist, neuropeptide Y5 receptor antagonist, apo-B / MTP inhibitor, 11β hydroxysteroid dehydrogenase-1 inhibitor, peptide YY _3-36 agonist, MCR4 agonist, CCK-A agonist, monoamine reuptake inhibitor, sympathomimetic drug, dopamine agonist, Melanocyte stimulating hormone receptor agonist, leptin receptor agonist, galanin antago Strike, thyroid stimulant, glucocorticoid receptor antagonist, orexin receptor antagonist, epiandrosterone dehydrogenase drug, histamine-3 receptor antagonist, lipase inhibitor, PPAR ligand modulator, insulin secretagogue, sulfonylurea, α-glucosidase inhibitor , Insulin sensitizer, hepatic glucose output lowering agent, non-thiazolidinone compound, protein tyrosine phosphatase-B inhibitor, dipeptidyl peptidase IV inhibitor, glucagon antagonist, HMG-CoA reductase inhibitor, sterol ester, cholesterol absorption inhibitor, ACAT inhibitor, bile acid reuptake inhibitor, microsomal triglyceride transporter inhibitor, fibric acid derivative, beta blocker, ACE inhibitor, calcium cha Channel blockers, diuretics, renin inhibitors, AT-1 receptor antagonists, ET receptor antagonists, pharmaceutical compositions comprising a combination of at least one agent for metabolic syndrome therapeutic agent selected from the AII receptor antagonists.

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