(12) Patent Application Publication (10) Pub. No.: US 2010/0267821 A1 Terauchi Et Al

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US 2010O267821A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0267821 A1 Terauchi et al. (43) Pub. Date: Oct. 21, 2010

(54) PROPHYLACTIC OR THERAPEUTICAGENT Publication Classification FOR RRTABLE BOWEL, SYNDROME (51) Int. Cl. A6II 3/343 (2006.01) (75) Inventors: Jun Terauchi, Osaka-Shi (JP); C07D 307/77 (2006.01) Fumihiko Sato, Osaka-shi (JP); A6IPI/00 (2006.01) Nobuhiro Inatomi, Osaka-shi (JP) (52) U.S. Cl...... 514/468; 549/458 (57) ABSTRACT Correspondence Address: The present invention provides a prophylactic or therapeutic EDWARDS ANGELL PALMER & DODGE LLP agent for irritable bowel syndrome, which comprises a com P.O. BOX SS874 pound represented by formula (I): BOSTON, MA 02205 (US) R2 (73) Assignee: Takeda Pharmaceutical Company Limited, Osaka-Shi (JP) A cí6. (21) Appl. No.: 12/826,473 O Y. O (22) Filed: Jun. 29, 2010 X wherein, R' represents an optionally substituted hydrocarbon group, etc., R represents a hydrogen atom or an optionally Related U.S. Application Data substituted hydrocarbon group, R represents a hydrogen (63) Continuation of application No. 12/225,269, filed on atom, an optionally substituted hydrocarbon group, etc., X Sep. 17, 2008, now abandoned, filed as application No. represents CHR, NR, CO, O or S (wherein, R represents a PCT/JP2007/055526 on Mar. 19, 2007. hydrogenatom, an optionally Substituted hydrocarbon group, etc.), Y represents C, CH or N. ------represents a single bond or double bond, ring A rep resents an optionally substituted 5- to 7-membered oxygen (30) Foreign Application Priority Data containing heterocyclic ring, ring B represents an optionally Substituted benzene ring, and m represents an integer of 1 to Mar. 20, 2006 (JP) ...... JP 2006-076532 4, or a salt thereof. Patent Application Publication Oct. 21, 2010 Sheet 1 of 4 US 2010/0267821A1

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Normal Control 10 30 group 9 Melatonin (mg/kg, p.o.) US 2010/0267821 A1 Oct. 21, 2010

PROPHYLACTIC OR THERAPEUTICAGENT DISCLOSURE OF INVENTION FOR RRTABLE BOWEL, SYNDROME Problems to be Solved by the Invention RELATED APPLICATIONS 0014. The object of the present invention is to provide a 0001. This application is a continuation of U.S. patent prophylactic or therapeutic agent for irritable bowel syn application Ser. No. 12/225,269 filed on Sep. 17, 2008, which drome. claims priority to PCT/JP2007/055526, filed on Mar. 19, 2007, which claims the benefit of JP 2006-076532, filed Mar. Means of Solving the Problems 20, 2006. The contents of each of these applications is incor 0015 The present inventors found out that certain mela porated herein by reference in their entirety. tonin agonists are effective for a prevention or treatment of irritable bowel syndrome, and resulted in the completion of TECHNICAL FIELD the present invention. 0002 The present invention relates to a prophylactic or 0016 That is, the present invention provides: therapeutic agent for irritable bowel syndrome. 00.17 1 A pharmaceutical composition for a prevention or treatment of irritable bowel syndrome, which comprises BACKGROUND ART a compound represented by formula (I): 0003 Irritable bowel syndrome (IBS) is a disorder that shows dysfunction of lower bowel such as abnormal defeca R2 tion (diarrhea or constipation) and concomitant abdominal R1 symptoms of abdominal pain and discomfort lasting for sev 1. eral months. (CH2) 0004. The pathophysiology of irritable bowel syndrome is Y. O still unclear, but it is now that mental stress is closely involved in the development of symptom, and a high coincidence rate of mental disorder Such as depression and hysteria has been X made known. Sleep disorder is often observed in patients with irritable bowel syndrome, and it is reported recently that sleep wherein, R' represents an optionally substituted hydrocarbon disorder in patients with irritable bowel syndrome correlates group, an optionally Substituted amino group or an optionally with the degree of abdominal symptoms (see non-patent substituted heterocyclic group, R represents a hydrogen documents 1. atom oran optionally substituted hydrocarbon group, R rep 0005. In addition, there is a report that, compared to resents a hydrogen atom, an optionally Substituted hydrocar healthy individuals and patients with irritable bowel syn bon group or an optionally substituted heterocyclic group, X drome having no depressive symptoms, patients with irritable represents CHR, NR, CO, O or S (wherein, R represents a bowel syndrome having depressive symptoms show more hydrogenatom, an optionally Substituted hydrocarbon group severe abdominal symptoms and sleep disorders (see non or hydroxyl group), Y represents C, CH or N. patent document 2). represents a single bond or double bond, ring A repre 0006 Further, there is a report that melatonin, known as a sents an optionally substituted 5- to 7-membered heterocyclic hormone regulating sleep-wake cycle, improves significantly ring containing, an oxygen atom, the abdominal symptoms Such as abdominal pain, abdominal ring B represents an optionally Substituted benzene ring, and bloating and sense of urgency for defecation in female m represents an integer of 1 to 4, or a salt thereof; patients suffering from irritable bowel syndrome (see non 0018 (2 The pharmaceutical composition for a preven patent document 3). tion or treatment of irritable bowel syndrome according to 0007 Furthermore, there is a report that melatonin shows the above-mentioned 1, wherein the compound repre an inhibitory action on partial restraint stress-induced defeca sented by formula (I) or a salt thereof is (S) N-2-(1,6,7, tion which is an experimental model based on defecation 8-tetrahydro-2H-indeno5,4-bfuran-8-yl)ethylpropiona abnormality for irritable bowel syndrome (see non-patent document 4). mide; 0008. In addition, patent document 1 discloses that (S)- 0019. 3. A method for a prevention or treatment of irri N-2-(1,6,7,8-tetrahydro-2H-indeno5,4-bfuran-8-yl)ethyl table bowel syndrome, which comprises administering an propionamide (general name: Ramelteon) has a melatonin effective amount of a compound represented by formula receptor MT1/MT2 agonistic action. (I): 0009 patent document 1 U.S. Pat. No. 6,034,239 0010 non-patent document 1 Monica Jarrett et al., Digestive Diseases and Sciences, Vol. 45, No. 5 (May 2000), pp. 952-959 00.11 non-patent document 2 Jennifer J.T. Robert et. al., Digestive Diseases and Sciences, Vol. 49, Nos. 7/8 (August 2004), pp. 1250-1258 0012 non-patent document 3 W. Z. Luet. al., Aliment Pharmacol Ther 2005; 22: pp. 927-934 0013 non-patent document 4 G. S. Song et. al., Neuro gastroenterol Motil 2005; 17: pp. 744–750 US 2010/0267821 A1 Oct. 21, 2010

wherein, R' represents an optionally substituted hydrocarbon BEST MODE FOR CARRYING OUT THE group, an optionally Substituted amino group or an optionally INVENTION substituted heterocyclic group, R represents a hydrogen atom or an optionally substituted hydrocarbon group, R rep 0027. Examples of melatonin agonists to be used for a resents a hydrogen atom, an optionally Substituted hydrocar preventive or therapeutic agent for irritable bowel syndrome bon group or an optionally Substituted heterocyclic group, X in the present invention include a compound represented by the above formula (I) or a salt thereof. VEC-162 (Vanda), represents CHR, NR, CO, O or S (wherein, R represents a LY-156735 (Lilly), Agomelatine (Servier), and the like. hydrogenatom, an optionally substituted hydrocarbon group Among them, the compound represented by the above for or hydroxyl group), Y represents C, CH or N. mula (I) or a salt thereof is preferred. represents a single bond or double bond, 0028. Hereinafter, the compound represented by formula ring A represents an optionally substituted 5- to 7-membered (I) or a salt thereof will be illustrated. heterocyclic ring containing an oxygen atom, (0029. In the above formula (I), R' represents an optionally ring B represents an optionally Substituted benzene ring, and Substituted hydrocarbon group, an optionally Substituted m represents an integer of 1 to 4, or a salt thereof; amino group or an optionally substituted heterocyclic group, 0020 4. The method for a prevention or treatment R represents a hydrogen atom or an optionally substituted according to the above-mentioned 3, wherein the com hydrocarbon group, R represents a hydrogen atom, an pound represented by formula (I) or a salt thereof is (S)— optionally Substituted hydrocarbon group or an optionally N-2-(1,6,7,8-tetrahydro-2H-indeno5,4-bfuran-8-yl) substituted heterocyclic group, X represents CHRNR, CO, ethylpropionamide; Oor S (wherein, R represents a hydrogenatom, an optionally 0021 5. Use of a compound represented by formula (I): Substituted hydrocarbon group or hydroxyl group), Y repre sents C, CH or N, represents a single bond or double bond, R2 ring A represents an optionally substituted 5- to 7-membered heterocyclic ring containing an oxygen atom, R1 1. ring B represents an optionally Substituted benzene ring, and (CH2) m represents an integer of 1 to 4. 0030 Preferably, in case that X represents CHY is C or Y. O CH. 0031. In this specification, examples of the “hydrocarbon X group' in the “optionally substituted hydrocarbon group' include an aliphatic hydrocarbon group, a monocyclic Satu rated hydrocarbon group and an aromatic hydrocarbon group, wherein, R' represents an optionally substituted hydrocarbon and preferred is a group having 1 to 16 carbons. Specifically, group, an optionally Substituted amino group or an optionally for example, an alkyl group, an alkenyl group, and an alkynyl substituted heterocyclic group, R represents a hydrogen group, a cycloalkyl group and aryl group are used. atom or an optionally substituted hydrocarbon group, R rep 0032. As the “alkyl group', for example, a lower alkyl resents a hydrogen atom, an optionally Substituted hydrocar group and the like are preferred, and a C- alkyl group Such bon group or an optionally Substituted heterocyclic group, X as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, represents CHR', NR, CO, O or S (wherein, R represents a tert-butyl, pentyl and hexyl is used generally. hydrogenatom, an optionally substituted hydrocarbon group 0033. As the “alkenyl group', for example, a lower alkenyl or hydroxyl group), Y represents C, CH or N. group and the like are preferred, and a Calkenyl group such represents a single bond or double bond, as vinyl, 1-propenyl, allyl, isopropenyl, butenyl and isobute ring A represents an optionally substituted 5- to 7-membered nyl is used generally. heterocyclic ring containing an oxygen atom, 0034. As the “alkynyl group', for example, a lower alky ring B represents an optionally Substituted benzene ring, and nyl group and the like are preferred, and a C- alkynyl group m represents an integer of 1 to 4, or a salt thereof, for the Such as ethynyl, propargyl and 1-propynyl is used generally. manufacture of a pharmaceutical composition for a preven 0035. As the “cycloalkyl group', for example, a lower cycloalkyl group and the like are preferred, and a C tion or treatment of irritable bowel syndrome; cycloalkyl group Such as cyclopropyl, cyclobutyl, cyclopen 0022 6. The use according to the above-mentioned (5), tyl and cyclohexyl is used generally. wherein the compound represented by formula (I) or a salt 0036) As the “aryl group', for example, a Caryl group thereof is (S)-N-2-(1,6,7,8-tetrahydro-2H-indeno5,4- Such as phenyl, 1-naphthyl 2-naphthyl, biphenylyl, 2-anthryl blfuran-8-yl)ethylpropionamide; and the like. and the like are preferred, and for example, phenyl group is used generally. BRIEF DESCRIPTION OF DRAWINGS 0037 Examples of the substituent which the “hydrocar bon group' of the “optionally substituted hydrocarbon 0023 FIG. 1 is a graph showing viscerosensory response group' may have, include a halogen atom (e.g., fluorine, test for compound A. chlorine, bromine, iodine), nitro, cyano, hydroxyl, an option 0024 FIG. 2 is a graph showing restraint stress-induced ally halogenated lower alkyl group (e.g., an optionally halo defecation test for compound A. genated C. alkyl group such as methyl, chloromethyl, dif 0025 FIG.3 is a graph showing normal defecation test for luoromethyl, trichloromethyl, trifluoromethyl, ethyl, compound A. 2-bromoethyl, 2.2.2-trifluoroethyl, pentafluoroethyl, propyl. 0026 FIG. 4 is a graph showing a restraint stress-induced 3,3,3-trifluoropropyl, isopropyl, butyl, isobutyl, sec-butyl, defecation test for melatonin. tert-butyl, 4.4.4-trifluorobutyl, pentyl, isopentyl, neopentyl, US 2010/0267821 A1 Oct. 21, 2010

5.5,5-trifluoropentyl, hexyl, 6.6,6-trifluorohexyl, etc.), a azinyl, phenoxazinyl, and the like are used. Among them, a 5 lower alkoxy group (e.g., C-alkoxy group Such as methoxy, to 7-membered (preferably 5- or 6-membered) heterocyclic ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, group containing 1 to 3 heteroatoms selected from a nitrogen hexyloxy, etc.), amino group, a mono-lower alkylamino atom, an oxygenatom and a Sulfur atom in addition to carbon group (e.g., mono-Cio alkylamino group Such as methy atoms is preferred. lamino, ethylamino, etc.), a di-lower alkylamino group (e.g., 0039 Examples of the substituent which the “heterocyclic di-C alkylamino group Such as dimethylamino, diethy group' of the “optionally substituted heterocyclic group' lamino etc.), a carboxyl group, a lower alkylcarbonyl group may have, include a halogen atom (e.g., fluorine, chlorine, (e.g., C alkyl-carbonyl group Such as acetyl, propionyl, bromine, iodine), a lower alkyl group (e.g., C alkyl group etc.), a lower alkoxycarbonyl group (e.g., Calkoxy-carbo Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec nyl group Such as methoxycarbonyl, ethoxycarbonyl, pro butyl, tert-butyl, pentyl, hexyl, etc.), a cycloalkyl group (e.g., poxycarbonyl, butoxycarbonyl etc.), a carbamoyl group, a C. cycloalkyl group Such as cyclopropyl, cyclobutyl, cyclo mono-lower alkylcarbamoyl group (e.g., mono-Cl alkyl pentyl, cyclohexyl, etc.), a lower alkynyl group (e.g., C. carbamoyl group Such as methylcarbamoyl ethylcarbamoyl, alkynyl group Such as ethynyl, 1-propynyl, propargyl, etc.), a etc.), a di-lower alkylcarbamoyl group (e.g., di-C alkyl lower alkenyl group (e.g., C alkenyl group Such as vinyl, carbamoyl group Such as dimethylcarbamoyl, diethylcar allyl, isopropenyl, butenyl, isobutenyl, etc.), an aralkyl group bamoyl, etc.), an as phenylcarbamoyl, naphthylcarbamoyl, (e.g., C. aralkyl group Such as benzyl, C.-methylbenzyl, etc.), an aryl group (e.g., Cao aryl group such as phenyl, phenethyl, etc.), an aryl group (e.g., Co aryl group Such as naphthyl, etc.), an aryloxy group (e.g., Cao aryloxy group phenyl, naphthyl, etc., preferably phenyl group), a lower Such as phenyloxy, naphthyloxy, etc.), an optionally haloge alkoxy group (e.g., C alkoxy group Such as methoxy, nated lower alkylcarbonylamino group (e.g., an optionally ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, halogenated alkyl-carbonylamino group Such as acety ter-butoxy, etc.), an aryloxy group (e.g., Cao aryloxy group lamino, trifluoroacetylamino, etc.), oxo group, and the like. Such as phenoxy, etc.), a lower alkanoyl group (e.g., C. The “hydrocarbon group' of the “optionally substituted alkyl-carbonyl group Such as formyl, acetyl, propionyl, hydrocarbon group' may have 1 to 5, preferably 1 to 3 of the butyryl, isobutyryl, etc.), an arylcarbonyl (e.g., Co aryl above substituents at substitutable positions of the hydrocar carbonyl group Such as benzoyl group, naphthoyl group, etc.), bon group, and when the number of the substituents is 2 or a lower alkanoyloxy group (e.g., C alkyl-carbonyloxy more, the respective substituents may be the same or differ group Such as formyloxy, acetyloxy, propionyloxy, butyry ent. loxy, isobutyryloxy, etc.), an arylcarbonyloxy Caryl-car 0038. In this specification, examples of the "heterocyclic bonyloxy group Such as benzoyloxy, naphthoyloxy, etc.), a group' of the “optionally substituted heterocyclic group' carboxyl group, a lower alkoxycarbonyl group (e.g., C. include a 5- to 14-membered (preferably 5- to 10-membered) alkoxy-carbonyl group Such as methoxycarbonyl, ethoxycar (monocyclic to tricyclic, preferably monocyclic or bicyclic) bonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbo heterocyclic group containing one or two kinds of to 4 (pref nyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), an aralky erably 1 to 3) heteroatoms selected from a nitrogen atom, an loxycarbonyl group (e.g., C. aralkyloxycarbonyl group oxygen atom and a Sulfur atom in addition to carbon atoms. Such as benzyloxycarbonyl, etc.), a carbamoyl group; a For example, 5-membered ring group containing 1 to 4 hetero mono-, di- or tri-halogeno-lower alkyl group (e.g., mono-, di atoms selected from an oxygen atom, a Sulfur atom and a or tri-halogeno-Cl alkyl group Such as chloromethyl, nitrogen atom in addition to carbon atoms. Such as 2- or dichloromethyl, trifluoromethyl, 2.2.2-trifluoroethyl, etc.), 3-thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrro OXO group, amidino group, imino group, amino group, a lidinyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 2-, 4- or mono-lower alkylamino group (e.g., mono-Cl alkylamino 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 3-, 4- or 5-pyrazolyl, 2-, group Such as methylamino, ethylamino, propylamino, iso 3- or 4-pyrazolidinyl, 2-, 4- or 5-imidazolyl, 1-, 2- or 3-tria propylamino, butylamino, etc.), a di-lower alkylamino group Zolyl, 1-, 2- or 4-triazolyl, 1H- or 2H-tetrazolyl, and the like, (e.g., di-C alkylamino group such as dimethylamino, 6-membered ring group containing 1 to 4 hetero atoms diethylamino, dipropylamino, diisopropylamino, dibuty selected from an oxygen atom, a Sulfur atom and a nitrogen lamino, methylethylamino, etc.), a 3- to 6-membered cyclic atom in addition to carbonatoms, such as 2-, 3- or 4-pyridyl, amino group optionally containing 1 to 3 heteroatoms N-oxido-2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, N-oxido selected from an oxygen atom, a Sulfur atom and a nitrogen 2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, pip atom in addition to carbonatom and one nitrogen atom (e.g., eridino, 2-, 3- or 4-piperidyl, thiopyranyl, 1,4-oxazinyl, 1,4- 3- to 6-membered cyclic amino group Such as aziridinyl, thiazinyl, 1.3-thiazinyl, piperazinyl, triazinyl, 3- or aZetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, 4-pyridazinyl, pyrazinyl, N-oxido-3- or 4-pyridazinyl, and pyrazolyl, imidazolidinyl, piperidinyl, morpholinyl, dihydro the like, and a bicyclic ortricyclic fused ring group containing pyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, 1 to 4 hetero atoms selected from an oxygen atom, a Sulfur etc.), alkylene dioxy group (e.g., C alkylene dioxy group atom and a nitrogen atom in addition to carbon atoms (pref Such as methylene dioxy, ethylene dioxy, etc.), hydroxyl erably, a group formed by condensing the above-mentioned group, nitro group, cyano group, mecapto group, Sulfo group. 5- or 6-membered ring with one or two of 5- or 6-membered Sulfino group, phosphono group, Sulfamoyl group, mono ring group optionally containing 1 to 4 hetero atoms selected alkylsulfamoyl group (e.g., mono-Cl alkylsulfamoyl group from an oxygen atom, a Sulfur atom and a nitrogen atom in such as N-methylsulfamoyl N-ethylsulfamoyl N-propylsul addition to carbon atoms), such as indolyl, benzofuryl, ben famoyl N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), di Zothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, iso alkylsulfamoyl group (e.g., di-C alkylsulfamoyl group quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, indoliz such as N,N-dimethylsulfamoyl N,N-diethylsulfamoyl, inyl, quinolizinyl, 1.8-naphthyridinyl, dibenzofuranyl. N,N-dipropylsulfamoyl N,N-dibutylsulfamoyl, etc.), an carbazolyl, acridinyl, phenanthridinyl, chromanyl, phenothi alkylthiogroup (e.g., Calkylthio group Such as methylthio. US 2010/0267821 A1 Oct. 21, 2010 ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio. 10047. In the above-mentioned formula (I), R' represents tert-butylthio, etc.), an arylthio group (e.g., Co arylthio an optionally substituted hydrocarbon group, an optionally group Such as phenylthio, naphthylthio, etc.), a lower alkyl Substituted amino group or optionally Substituted heterocy Sulfinyl group (e.g. C- alkylsulfinyl group Such as methyl clic group. Sulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), an 0048 Preferred examples of the “hydrocarbon group' in arylsulfinyl group (e.g., Co arylsulfinyl group Such as phe the “optionally substituted hydrocarbon group' include an nylsulfinyl, naphthylsulfinyl, etc.), a lower alkylsulfonyl alkyl group (e.g., C alkyl group such as methyl, ethyl, group (e.g. C. alkylsulfonyl group Such as methylsulfonyl: propyl, isopropyl, etc.), an alkenyl group (e.g., C2-alkenyl ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), an arylsul group Such as Vinyl, etc.), an alkynyl group (e.g., C2-alkynyl fonyl group (e.g., Carylsulfonyl group such as phenylsul group Such as ethynyl, etc.), a cycloalkyl group (e.g., C.- cycloalkyl group Such as cyclopropyl, cyclobutyl, cyclopen fonyl, naphthylsulfonyl, etc.), and the like. tyl, cyclohexyl, etc.), and aryl group (e.g., C-14 aryl group 0040. The "heterocyclic group' of the “optionally substi Such as phenyl, etc.), and in particular, an alkyl group (e.g., tuted heterocyclic group' may have 1 to 5, preferably 1 to 3 of C. alkyl group such as methyl, etc.) and a cycloalkyl group the above substituents at substitutable positions of the hetero (e.g., C. cycloalkyl group Such as cyclopropyl, etc.) are used cyclic group, and when the number of the Substituents is 2 or widely. The “alkyl group”, “alkenyl group”, “alkynyl group', more, the respective substituents may be the same or differ “cycloalkyl group' and “aryl group' may have 1 to 5, pref ent. erably, 1 to 3, substituents such as those that the above 0041. In the present specification, the “optionally substi mentioned "hydrocarbon group' may have, preferably, halo tuted amino group' includes an amino group that may have gen atom Such as fluorine, etc. one or two of the above-mentioned “optionally substituted 0049. As the preferred substituent of the “optionally sub hydrocarbon group' and the like as a Substituent. As a pre stituted amino group” represented by R', for example, one or ferred substituent that the “amino group” may have, for two of an optionally Substituted lower alkyl group, an option example, an optionally Substituted C. alkyl group and an ally Substituted aryl group and the like are used, in particular, optionally substituted Caryl group are exemplified. As the one of the optionally substituted lower alkyl group and the like is used. As the “lower alkyl group', for example, Calkyl Substituent that the "Ce alkyl group' and "Coo aryl group' Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec may have, Substituents similar to those that may be possessed butyl and tert-butyl is used. The “lower alkyl group” may have by the above-mentioned “hydrocarbon group' are used. 1 to 3 substituents that may be possessed by, for example, the 0042. In the present specification, the “lower alkyl group' above-mentioned “hydrocarbon group'. As the “aryl group'. of the “optionally substituted lower alkyl group' indicates for example, Co aryl group Such as phenyl group and the C. alkyl group Such as methyl, ethyl, propyl, isopropyl. like is used. The “aryl group' may have 1 to 5, preferably 1 to butyl, isobutyl, sec-butyl and tert-butyl, and may have 1 to 3 3, substituents such as those that the above-mentioned of the substituents that may be possessed by the above-men "hydrocarbon group' may have, preferably, halogen atom tioned “hydrocarbon group', as a Substituent. such as fluorine, chlorine, etc., C alkoxy group such as 0043. In the present specification, the “lower alkoxy methoxy, ethoxy, etc. As the “optionally Substituted amino group' of the “optionally substituted lower alkoxy group' group', for example, phenyl amino group Substituted with 1 indicates a C- alkoxy group Such as methoxy, ethoxy, pro to 3 lower alkoxys (e.g., C alkoxy group Such as methoxy, poxy, isopropoxy, butoxy, isobutoxy, Sec-butoxy and tert etc.) or mono-alkylamino group Substituted with lower alkyl butoxy, and may have 1 to 3 of the substituents that may be group (e.g., C alkyl group Such as methyl, ethyl, propyl. possessed by the above-mentioned "hydrocarbon group', as a butyl and tert-butyl) is used widely. substituent. 0050. As the preferred “heterocyclic group' of the 0044. In the present specification, the “optionally substi “optionally substituted heterocyclic group' represented by tuted benzene ring indicates a benzene ring that may have R", for example, 5- or 6-membered heterocyclic group con one or two Substituents selected from a halogen atom (e.g., taining 1 to 3 heteroatoms selected from a nitrogen atom, an fluorine, chlorine, bromine, iodine), an optionally Substituted oxygen atom and a Sulfur atom in addition to carbon atoms is hydrocarbon group, an optionally Substituted amino group, used. Specifically, 1-, 2- or 3-pyrrolidinyl, 2- or 4-imidazoli an amido group (e.g., O-3 acylamind group Such as forma nyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or 4-piperidyl, mide, acetamide, etc.), hydroxy group, an optionally Substi 1- or 2-piperazinyl, morpholinyl, 2- or 3-thienyl, 2-, 3- or tuted lower alkoxy group and lower alkylene dioxy group 4-pyridyl, 2-furyl or 3-furyl, pyrazinyl, 2-pyrimidinyl, 3-pyr (e.g., C alkylene dioxy group Such as methylene dioxy, rolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, and the ethylene dioxy, etc.), at Substitutable positions. like are exemplified. A 6-membered nitrogen containing-het 0045. As these “optionally substituted hydrocarbon erocyclic group (e.g., pyridyl, etc.) and the like are particu group', 'optionally substituted amino group' and "optionally larly preferably used. Substituted lower alkoxy group', for example, groups similar 0051. As the preferred substituent of the “optionally sub to those detailed above are used. When the number of the stituted heterocyclic group', for example, a halogen atom substituents that these “hydrocarbon group”, “amino group' (e.g., chlorine, fluorine, etc.), a C- alkyl group (e.g., methyl, and “lower alkoxy group' may have is 2 or more, the respec ethyl, etc.), alkoxy group (e.g., methoxy, ethoxy, etc.), aralky tive substituents may be the same or different. loxycarbonyl group (e.g., C-2 aralkyloxy-carbonyl Such as 0046 Preferred examples of the “optionally substituted benzyloxycarbonyl), and the like are used. benzene ring include a benzene ring that may be substituted I0052) R' is preferably, for example, (i) an optionally sub with one or two Substituents selected from a halogen atom stituted lower alkyl group, (ii) an optionally substituted lower (e.g., fluorine, chlorine), a C- alkyl (e.g., methyl, ethyl, cycloalkyl group, (iii) an optionally Substituted lower alkenyl etc.); hydroxy group and mono-Cl alkylamino group. group, (iv) an optionally Substituted aryl group, (v) an option US 2010/0267821 A1 Oct. 21, 2010 ally Substituted mono- or di-lower alkylamino group, (vi) an C2-alkenyl group Such as Vinyl, etc.), alkynyl group (e.g., optionally Substituted arylamino group or (vii) an optionally C- alkynyl group Such as ethynyl, etc.), cycloalkyl group Substituted 5- or 6-membered nitrogen containing-heterocy (e.g., C. cycloalkyl group Such as cyclopropyl, cyclobutyl, clic group. cyclopentyl, cyclohexyl, etc.) and aryl group (e.g., Caryl 0053 Preferred examples of the above-mentioned “lower group such as phenyl, etc.), in particular, alkyl group (e.g., alkyl group' are C alkyl group Such as methyl, ethyl, pro C. alkyl group Such as methyl, etc.) and aryl group (e.g., pyl, isopropyl, butyl, penty1 and hexyl, and the like. Preferred Caryl group Such as phenyl, etc.) are used widely. The examples of the “lower cycloalkyl group' are C. cycloalkyl “alkyl group”, “alkenyl group”, “alkynyl group”, “cycloalkyl Such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, group' and “aryl group' may have 1 to 5, preferably, 1 to 3, and the like. Preferred examples of the “lower alkenyl group' substituents such as those that the above-mentioned “hydro are Calkenyl group such as vinyl, 1-propenyl, butenyl, and carbon group' may have, preferably, halogen atom Such as the like. Preferred examples of the “aryl group' are Caryl fluorine atom, etc. group Such as phenyl, 1-naphthyl 2-naphthyl, and the like. 0060. As the preferred examples of the "heterocyclic Preferred examples of the “lower alkylamino group' are group' in the “optionally substituted heterocyclic group' rep mono- or di-C alkylamino group Such as methylamino, resented by R, a 5- or 6-membered heterocyclic group con ethylamino, propylamino, isopropylamino, butylamino, tert taining 1 to 3 heteroatoms selected from a nitrogen atom, an butylamino, dimethylamino, diethylamino, methylethy oxygenatom and a Sulfur atom in, addition to carbonatoms is lamino, and the like. Preferred examples of the “arylamino used. Specifically, for example, 1-, 2- or 3-pyrrolidinyl, 2- or group' are Co-o arylamino group Such as phenylamino, and 4-imidazolinyl, 2-, 3- or 4-pyrazolidinyl, piperidino, 2-, 3- or the like. Preferred examples of the “5- or 6-membered nitro 4-piperidyl, 1- or 2-piperazinyl, morpholinyl, 2-, or 3-thienyl, gen containing-heterocyclic group' are a 5- or 6-membered 2-, 3- or 4-pyridyl, 2- or 3-furyl, pyrazinyl, 2-pyrimidinyl, nitrogen containing-heterocyclic group Such as 2-, 3- or 4-py 3-pyrrolyl, 3-pyridazinyl, 3-isothiazolyl, 3-isooxazolyl, and ridyl, and the like. These groups may each have 1 to 5 sub the like are exemplified. A 6-membered nitrogen containing stituents such as those the above-mentioned “hydrocarbon heterocyclic group (e.g., pyridyl, etc.) is used particularly group' may have. preferably. 0054. In this specification, - - - - represents a single bond 0061. As the preferred examples of the substituent of the or double bond. “optionally substituted heterocyclic group' represented by 0055. The more preferred examples of R' include i) C. R. for example, a halogenatom (e.g., chlorine, fluorine, etc.), alkyl group which may be substituted with 1 to 4 of halogen, a C- alkyl (e.g., methyl, ethyl, etc.), a C- alkoxy group hydroxy group or Ce alkoxy group, ii) C cycloalkyl (e.g., methoxy, ethoxy, etc.), an aralkyloxycarbonyl group group. iii) C2-alkenyl group, iv) Co-o aryl group which may (e.g., C. aralkyloxy-carbonyl such as benzyloxycarbonyl, be substituted with 1 to 4 of Calkoxy, nitro, halogenoC etc.), amino group, mono-Cio alkylamino group (e.g., alkyl-carbonylamino or halogen atom, v) mono- or di-C methylamino, ethylamino, etc.), di-C alkylamino group alkylamino group, vi) Co. arylamino group which may be (e.g., dimethylamino, diethylamino, etc.), and the like are substituted with 1 to 3 of C alkoxy or vii) 6-membered used. nitrogen containing-heterocyclic group which may be substi 10062 R is preferably, for example, (i) a hydrogen atom, tuted with 1 or 2 of C. aralkyloxycarbonyl group. In par (ii) an optionally Substituted lower alkyl group, (iii) an ticular, an optionally halogenated C. alkyl group (e.g., optionally Substituted aryl group, (iv) an optionally Substi methyl, chloromethyl, difluoromethyl, trichloromethyl, trif tuted 5- or 6-membered heterocyclic group or the like, fur luoromethyl, ethyl 2-bromoethyl, 2.2.2-trifluoroethyl, pen thermore for example, (i) a hydrogen atom, (ii) a lower alkyl tafluoroethyl, propyl. 3,3,3-trifluoropropyl, isopropyl, butyl, group, (iii) an optionally substituted Co aryl group, (iv) an isobutyl, sec-butyl, tert-butyl, 4,4,4-trifluorobutyl, pentyl, optionally Substituted 6-membered nitrogen containing het isopentyl, neopentyl, 5.5.5-trifluoropentyl, hexyl, 6.6,6-trif erocyclic group or the like is preferred. Examples of the luorohexyl, etc.), Cse cycloalkyl group (e.g., cyclopropyl. Substituent include a halogenatom, a Calkyl, a Calkoxy cyclobutyl, cyclopentyl, cyclohexyl, etc.) or mono-Cl alky group, amino group, mono-Cio alkylamino group, di-C- lamino group (e.g., methylamino, ethylamino, propylamino, alkylamino group, and the like. For R, a hydrogen atom, isopropylamino, butylamino, tert-butylamino, etc.) are used phenyl group and 2-, 3- or 4-pyridyl group are more preferred. widely, and among them, an optionally halogenated C Particularly preferred is a hydrogen atom for R. alkyl group or mono-Cl alkylamino group, particularly an 0063. In the above formula (I), X represents CHR, NR, optionally halogenated C. alkyl group, interalia, Calkyl CO, O or S (wherein, R represents a hydrogen atom, a group (e.g., methyl, ethyl, propyl, etc.) is preferred. hydroxyl group or an optionally Substituted hydrocarbon 0056. In the above formula (I), R represents a hydrogen group). atom or an optionally Substituted hydrocarbon group. I0064) Preferred examples of R include a hydrogen atom, I0057. As R, a hydrogenatom or an optionally substituted a hydroxyl group and an optionally Substituted lower (C) lower (C) alkyl group is preferably used, and more prefer alkyl group, and a hydrogen atom is used widely. ably a hydrogen atom or a lower (Ce) alkyl group, in par 0065 X is preferably CHR (R has the same meaning as ticular, a hydrogen atom is used widely. the above-mentioned), CO, O or S. Or X is preferably CHR 0058. In the above formula (I), R represents a hydrogen or NR (R has the same meaning as the above-mentioned). atom, an optionally Substituted hydrocarbon group or an 0066. In the above formula (I), ring A represents an optionally substituted heterocyclic group. optionally substituted 5- to 7-membered heterocyclic ring 0059. As the preferred examples of the “hydrocarbon containing an oxygen atom. group' in the “optionally substituted hydrocarbon group' 0067 Examples of the “5- to 7-membered heterocyclic represented by R. alkyl group (e.g., C. alkyl group such as ring containing an oxygenatom' include a 5- to 7-membered methyl, ethyl, propyl, isopropyl, etc.), alkenyl group (e.g., (preferably 5- or 6-membered) heterocyclic ring optionally US 2010/0267821 A1 Oct. 21, 2010 containing 1 to 3 (preferably 1 or 2) of one or two heteroatoms dino group, imino group, amino group, a mono-lower alky selected from a nitrogen atom, an oxygen atom and a Sulfur lamino group (e.g., mono-Cia alkylamino group Such as atom in addition to carbonatoms and an oxygenatom, and the methylamino, ethylamino, propylamino, isopropylamino, like. As the ring, the ring represented by formula: butylamino, etc.), a di-lower alkylamino group (e.g., di-Ca alkylamino group Such as dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, methyl Ore ethylamino, etc.), a 3- to 6-membered cyclic amino group optionally containing 1 to 3 hetero atoms selected from an oxygenatom, a Sulfur atom and a nitrogenatom in addition to carbon atoms and one nitrogen atom (e.g., 3- to 6-membered cyclic amino group Such as aziridinyl, pyrrolidinyl, pyrroli wherein, E represents (i) CHCH, (ii) CH=CH, (iii) CHO, nyl, pyrrolyl, imidazolyl pyrazolyl, imidazolidinyl, pip (iv) OCH., (v) CHS(O), (q' is an integer of 0 to 2), (vi) eridyl, morpholinyl, dihydropyridyl, pyridyl, N-methylpiper S(O). CH (q' is as defined above), (vii) CH-NH. (viii) azinyl, N-ethylpiperazinyl, etc.), an alkylene dioxy group NHCH, (ix) N=N, (x) CH=N, (xi) N=CH or (xii) CONH, (e.g., alkylene dioxy group Such as methylene dioxy, ethylene and n' represents an integer of 0 to 2, is preferred. dioxy, etc.), hydroxyl group, nitro group, cyano group. 0068. For E, (i) CHCH, (ii) CH=CH, (iii) CHO, (iv) mecapto group, Sulfo group, Sulfino group, phosphono group, OCH, (v) CH-NH. (vi) NHCH (vii) N=N, (viii) CH-N Sulfamoyl group, mono-alkylsulfamoyl group (e.g., mono or (ix) N=CH is preferred, and in particular, (i) CHCH or C. alkylsulfamoyl group Such as N-methylsulfamoyl, (ii) CH=CH is preferred. N-ethylsulfamoyl N-propylsulfamoyl N-isopropylsulfa 0069 Specifically, a 5-membered heterocyclic ring con moyl, N-butylsulfamoyl, etc.), di-alkylsulfamoyl group (e.g., taining an oxygenatom Such as 2.3-dihydrofuran, furan, 1.3- di-C alkylsulfamoyl group Such as N,N-dimethylsulfa dioxole, oxazoline, isoxazole, 1.2.3-oxadiazole and oxazole, moyl N,N-diethylsulfamoyl N,N-dipropylsulfamoyl N,N- and a 6-membered heterocyclic ring containing an oxygen dibutylsulfamoyl, etc.), an alkylthio group (e.g., C alky atom Such as 2H-3,4-dihydropyran, 2H-pyran, 2.3-dehydro lthio group Such as methylthio, ethylthio, propylthio. 1,4-dioxane and 2,3-dehydromorpholine are preferred. isopropylthio, butylthio, sec-butylthio, tert-butylthio, etc.), 0070 More preferred is a ring represented by formula: an arylthio group (e.g., Coo arylthio group Such as phe

nylthio, naphthylthio, etc.), a lower alkylsulfinyl group (e.g. Calkylsulfinyl group Such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), an arylsulfinyl group (e.g., Co arylsulfinyl group Such as phenylsulfinyl, naphthyl sulfinyl, etc.), a lower alkylsulfonyl group (e.g. Calkylsul fonyl group Such as methylsulfonyl, ethylsulfonyl, propylsul fonyl, butylsulfonyl, etc.), an arylsulfonyl group (e.g., Co wherein, in represents an integer of 0 to 2, and arylsulfonyl group Such as phenylsulfonyl, naphthylsulfonyl, etc.), and the like are used. represents a single bond or double bond. (0073. The “lower alkyl group”, “lower alkenyl group', 0071 Specifically, for example, 2,3-dihydrofuran, furan, “lower alkynyl group”, “lower cycloalkyl group' and “aryl 2H-3,4-dihydropyran and 2H-pyran are used widely. group' may have 1 to 5, preferably 1 to 3, of the substituents 0072. As the substituent for ring A, for example, a halogen that may be possessed by the above-mentioned “hydrocarbon atom (e.g., fluorine, chlorine, bromine, iodine), an optionally group'. Substituted lower alkyl group, an optionally Substituted cycloalkyl group, an optionally Substituted lower alkynyl 0074 Examples of the substituent for ring A include a group, an optionally substituted lower alkenyl group, an halogen atom, an optionally Substituted C. alkyl group, an optionally Substituted aryl group, a lower alkoxy group (e.g., optionally substituted C. alkoxy group, hydroxyl group, Calkoxy group Such as methoxy, ethoxy, propoxy, isopro nitro group, cyano group, an optionally Substituted amino poxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), an group, oxo group, and the like. The Substituent of the “option aryloxy group (e.g., Cao aryloxy group such as phenoxy, ally substituted C. alkyl group”, “optionally substituted etc.), a lower alkanoyl group (e.g., formyl, Ce alkyl-carbo Calkoxy group' and "optionally substituted amino group' nyl group Such as acetyl, propionyl, butyryl, isobutyryl, etc.), may be the substituents that may be possessed by the above an arylcarbonyl group (e.g., Co-o aryl-carbonyl group Such as mentioned “hydrocarbon group'. benzoyl group, naphthoyl group; etc.), a lower alkanoyloxy (0075. The ring A may have 1 to 4, preferably 1 to 2 of the group (e.g., formyloxy, Calkyl-carbonyloxy group Such as above-mentioned substituents at substitutable positions acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, etc.), an depending on the ring size, and when the number of the arylcarbonyloxy group (e.g., Co-o aryl-carbonyloxy group Substituents is 2 or more, the respective Substituents may be Such as benzoyloxy, naphthoyloxy, etc.), a carboxyl group, a the same or different. lower alkoxycarbonyl group (e.g., C alkoxy-carbonyl 0076 Examples of ring A include group Such as methoxycarbonyl, ethoxycarbonyl, propoxy carbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy carbonyl, tert-butoxycarbonyl, etc.), an aralkyloxycarbonyl (1/s group (e.g., C. aralkyloxy-carbonyl group such as benzy O loxycarbonyl, etc.), a carbamoyl group, a mono-, di- or tri halogeno-lower alkyl group (e.g., mono-, di- or tri-halogeno C. alkyl group Such as chloromethyl, dichloromethyl, trifluoromethyl, 2.2.2-trifluoroethyl, etc.), oxo group, ami US 2010/0267821 A1 Oct. 21, 2010 wherein, R represents a hydrogen atom or 1 or 2 of the substituents represented by the above-mentioned “preferable -continued substituent for ring A', and the other symbols are as defined above, and the like. Among them, a ring wherein R is a hydrogen atom, hydroxyl group or an optionally substituted B B Calkyl group, in particular, R is a hydrogenatom (unsub O O stituted ring A), is used widely. 0077. In the formula, n represents an integer of 0 to 2, and N n is preferably an integer of 0 or 1. Particularly, preferred is R4' the case when n is G. O 0078. In the above formula (I), ring B represents an optionally substituted benzene ring. 0079. Examples of the substituent for ring B include the “substituent of the above-mentioned “optionally substituted benzene ring. Interalia, a halogen atom, hydroxyl group or an optionally substituted lower (C) alkyl group is pre ferred, in particular, a halogen atom, hydroxyl group or a O)- lower (Ce) alkyl group (preferably methyl) is used widely. The “substituent of the “optionally substituted lower (C) O alkyl group' may be the Substituents that may be possessed by the above-mentioned “hydrocarbon group'. wherein, R' represents an optionally substituted hydrocarbon 0080. The ring B may have 1 or 2, preferably 1 of the group or hydroxyl group, and the other respective symbol is above-mentioned substituents at Substitutable positions, and as defined above. when the number of the substituents is 2, the respective sub stituents may be the same or different. 0084 R" is preferably an optionally substituted lower (C. I0081 Preferred examples of ring B include 3) alkyl. I0085. Other preferred examples of the moiety represented by the formula

r B B A4 O Y O w X R include O) R3, wherein, R represents a hydrogen atom, hydroxyl group, a X halogen atom; an optionally Substituted lower (Ce) alkyl group oran optionally Substituted lower (Ce) alkoxy group. R is preferably a hydrogen atom, hydroxyl group, a halogen B B atom or lower (Ce) alkyl group (preferably methyl). R is O O more preferably a hydrogen atom. 0082 In the above formula (I), m represents an integer of 1 to 4. Preferably m is an integer of 1 to 3. More preferably, m N is 2 or 3, and in particular, preferred is the case when m is 2. H 0083 Preferred examples of the moiety represented by the formula B O Y-R B B N O Y O H w R include O) R3, x wherein, each symbol is as defined above. Among them, preferred is R4'

B B O O A A O O O)-R. N R3, R4' O) R3 ) R3 s US 2010/0267821 A1 Oct. 21, 2010

or vii) 6-membered nitrogen-containing heterocyclic group -continued optionally substituted with 1 to 2 of Czaralkyloxy-carbo nyl group, R is a hydrogen atom or a lower (Ce) alkyl group, R is (i) a hydrogenatom, (ii) a lower (Cl-) alkyl group or (iii) a C-14 aryl group, X is CHR or NR (R represents a hydrogen atom or lower N H (Ce) alkyl group optionally Substituted with oxo group), Y is C, CH or N (provided that, when X represents CHY is C or CH), wherein, each symbol is as defined above. represents a single bond or double bond, ring A is 0086 Interalia,

A A ( -- O O)- O CC O wherein, each symbol is as defined above, wherein, each symbol is as defined above, is preferred. Par ring B is ticularly preferred is

O)- wherein, R" represents a hydrogen atom, a halogen atom or wherein, each symbol is as defined above. a lower (Ce) alkyl group, and 0087. In addition, preferred examples of compound (I) m is 1 or 2, and the like. include a compound wherein I0089 Among these, a compound represented by formula R" is (i) an optionally substituted lower alkyl group, (ii) an

optionally Substituted lower cycloalkyl group, (iii) an option ally Substituted lower alkenyl group, (iv) an optionally Sub stituted aryl group, (v) an optionally Substituted mono- or di-lower alkylamino group, (vi) an optionally Substitutedary lamino group or (vii) an optionally Substituted 5- or 6-mem bered nitrogen-containing heterocyclic group, R’ is a hydrogen atom or an optionally substituted lower (Ce) alkyl group, R is (i) a hydrogenatom, (ii) an optionally substituted lower alkyl group or (iii) an optionally Substituted aryl group, X is CHR or NR (R represents a hydrogen atom or lower wherein, R' represents a C- alkyl group optionally having (Ce) alkyl group optionally Substituted with oxo group), a hydroxyl group, R' represents a hydrogen atom or a halo Y is C, CH or N (provided that, when X represents CHY is gen atom, n represents 0 or 1, C or CH), represents a single bond or double bond, ring A is an optionally substituted 5- to 7-membered hetero cyclic ring containing an oxygenatom, ring B is an optionally Substituted benzene ring, and m is 1 or 2, and the like. represents a single bond or double bond, and when X repre 0088 More preferably, a compound wherein sents CH, R" is i) C alkyl group optionally substituted with 1 to 4 of halogen, hydroxyl group or C- alkoxy group, ii) Cs. cycloalkyl group, iii) Coalkenyl group, iv) Co. aryl group optionally Substituted with 1 to 4 of Calkoxy group, nitro, halogenoC alkyl-carbonylamino or halogen atom, V) mono- or di-C alkylamino group, (vi) Coo arylamino represents a single bond or double bond and when X repre group optionally substituted with 1 to 3 of Calkoxy group sents NH,

US 2010/0267821 A1 Oct. 21, 2010

salts with inorganic acid include salts with hydrochloric acid, table bowel syndrome, and thus the side effects caused by the hydrobromic acid, nitric acid, Sulfuric acid, phosphoric acid, other prophylactic or therapeutic agents for irritable bowel and the like. Preferred examples of the salts with organic acid syndrome can be reduced by lowering the dose of such drugs. include salts with formic acid, acetic acid, trifluoroacetic 0104 Examples of such prophylactic ortherapeutic agents acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, for irritable bowel syndrome include alosetron, tegaserod, maleic acid, citric acid, Succinic acid, malic acid, methane polycarbophil calcium and trimebutine. Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 0105. In addition, since the compound represented by for and the like. Preferred examples of the salts with basic amino mula (I) or a salt thereof is extremely low toxic, it may be used acid include salts witharginine, lysine, ornithine, and the like, in combination with one or more of other gastrointestinal and preferred examples of a salt with acidic amino acid motilityStimulant, sedative drug, antidepressant, and/or anti include salts with asparaginic acid, glutamic acid, and the anxiety drug. like. 0106 Examples of the “gastrointestinal motility stimu 0095 Among these, a pharmaceutically acceptable salt is lant include domperidone, metoclopramide, mosapride, ito preferred, and as examples thereof, in case that the compound pride, tegaserod, and the like. represented by formula (I) has a basic functional group within 0107 Examples of the “antidepressant’ include tricyclic the molecule, a salt with inorganic acid such as hydrochloric antidepressants e.g., Doxepin, Imipramine hydrochloride, acid, hydrobromic acid, nitric acid, Sulfuric acid, phosphoric Amitriptyline, Clomipramine, tetracyclic antidepressants acid, and the like and a salt with organic acid such as acetic e.g., Mianserine, Setiptiline, Maprotiline, SSRI e.g., Flu acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, oxetine, Sertraline, Paroxetine, Citalopram, Escitalopram, citric acid, Succinic acid, methanesulfonic acid, p-toluene Fluvoxamine. SNRI e.g., Milnacipran, Duloxetine, Ven sulfonic acid, and the like are exemplified, furthermore in lafaxine, Trazodone, Nefazodone, Minaprine, Mirtazapine, case that the compound represented by formula (I) has a triple uptake inhibitors (e.g., DOV-216303, NS-2359, NK1 acidic functional group, alkali metal salts such as Sodium salt receptor antagonist, and drugs having both melatonin recep and potassium salt, alkaline earth metal salts such as calcium tor agonistic action and serotonin 2 receptor antagonistic salt and magnesium salt, ammonium salt, and the like are action e.g., Agomelatine, and the like. exemplified. 0.108 Examples of the “antianxiety drug include 0096. In addition, the compound represented by formula GABA-A agonistic antianxieties e.g., Diazepam, Fluta (I) of the present invention may be a hydrate or non-hydrate. Zolam, Lorazepam, Ethyl loflazepate, Flutoprazepam, Mex 0097. As the compound represented by formula (I) or a azolam, Clotiazepam, Etizolam, Hydroxyzine, Alprazolam, salt thereof, particularly preferred is (S)-N-2-(1,6,7,8-tet Fludiazepam, Chlordiazepoxide, Cloxazolam, CloraZepate, rahydro-2H-indeno5,4-bfuran-8-yl)ethylpropionamide Oxazolam, serotonin antianxieties e.g., Buspirone, Tan (generic name: Ramelteon) (hereinafter, sometimes referred doSpirone, and the like. to as compound A). 0109. In addition, the compound represented by formula 0098. The compound represented by formula (I) or a salt or a salt thereof may be used in combination with the follow thereof is a known therapeutic agent for sleep disorder dis ing drugs. closed in U.S. Pat. No. 6,034,239 and the like, and can be produced by a known method such as the method described in (a) 5-HT receptor antagonist: for example, dolasetron, pal said reference. onosetron, alosetron, aZasetron, ramosetron, mitrazapine, 0099. In addition, the compound represented by formula granisetron, tropisetron, E-3620, ondansetron and indisetron; (I) of the present invention can be synthesized according to (b) 5-HT, receptor agonist: for example, tegaserod, the production method described in JP 10-287665A or an mosapride, cinitapride and oXtriptane; analogous method thereto, and if desired, a combination of (c) laxative agent: for example, Trifyba (trade name), Fybogel the method and a conventional oxidation method. (trade name), Konsyl (trade name), Isogel (trade name), 0100. The compound represented by formula (I) or a salt Regulan (trade name), Celevac (trade name) and Normacol thereof can be used for a prevention or treatment of irritable (trade name); Amitiza (trade name) bowel syndrome, and for a prevention or treatment of (d) dopamine receptor antagonist: for example, metoclopra abdominal pain associated with irritable bowel syndrome and mide, domperidone and levoSulpiride bowel movement disorder associated with irritable bowel (e) tachykinin (NK) receptor antagonist (in particular, NK-3, syndrome. NK-2 and NK-1 antagonist): for example, nepadutant, 0101. In addition, since the compound represented by for saredutant, talnetant, (O.R.9R)-7-3,5-bis(trifluoromethyl) mula (I) or a salt thereof has an antianxiety action, it can be benzyl-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)- used as a prophylactic or therapeutic agent for irritable bowel 7H-1,4-diazocino.2.1-g1.7naphthyridin-6,13-dione, syndrome known for involvement of mental stress. 5-(2R,3S)-2-[(1R)-1-3,5-bis(trifluoromethyl)phenyl 0102 The compound represented by formula (I) or a salt ethoxy-3-(4-fluorophenyl)-4-morpholinyl)methyl-1,2-di thereof can also be used for a prevention or treatment of hydro-3H-1,2,4-triazole-3-one (MK-869), lanepitant, dapi inflammatory bowel disease (IBD), functional dyspepsia and tant and 3-2-methoxy-5-(trifluoromethoxy)phenyl gastroesophageal reflux disease (GERD). methylamino-2-phenyl-piperidine (2S,3S); 0103) Further, since the compound represented by formula (f) vanilloid receptor 1 antagonist: for example, AMG-517 (I) or a salt thereof is extremely low toxic, it can be used for and GW-705498: a prevention or treatment of irritable bowel syndrome, and for (g) ghrelin receptor agonist: for example, capromorelin and a prevention or treatment of abdominal pain associated with TZP-101; irritable bowel syndrome and bowel movement disorder asso (h) AchE release stimulant: for example, Z-338 and ciated with irritable bowel syndrome by combining with one KW-5092; or more of other prophylactic or therapeutic agents for irri (i) CRF antagonist: for example, CP-316311 and TS-041: US 2010/0267821 A1 Oct. 21, 2010

(j) vasopressin antagonist: for example, SSR1494.15 and on a total weight of the composition. The content of other SRX251: melatonin agonist can be decided according to compound A. (k) glucocorticoid receptorantagonist: for example, mifepris 0116. The dose of the melatonin agonist to be used in the tone and Org-34517; present invention differs depending on melatonin agonist to (1) cannabinoid receptor agonist: for example, A9-THC, be used, administration Subject, administration route, and the CP-55940, WIN-55212-2, HU-210; like. For example, when compound A is administered to an (m) FAAH inhibitor: for example, OL-135, LY2077855 and adult as an oral agent, the dose is about 0.0005 to 2 mg/kg URB-597 body weight, preferably about 0.001 to 1 mg/kg body weight, 0110. These drugs to be used in combination (concomitant more preferably about 0.01 to 1 mg/kg body weight as an drugs) may be a free form or a pharmaceutically acceptable active ingredient. The pharmaceutical composition may be salt. administered once to several times in divided doses per day. 0111. In this case, timing of administration of the prophy The dose of other melatoninagonist can be decided according lactic or therapeutic agent for irritable bowel syndrome of the to compound A. present invention and the concomitant drugs is not limited, and these can be administered to the Subjects simultaneously EXAMPLES or at different times. 0117 The present invention will be described in detail 0112 Examples of administration forms include through the following Preparation Example and Test (1) administration of a single preparation obtained by formu Examples. However, the present invention is not limited by lating the melatonin agonist to be used in the present inven these examples. tion and concomitant drug simultaneously, Preparation Example 1 (2) simultaneous administration via the same administration route of two preparations obtained by formulating the mela 0118 Compound A (160 g), lactose (4064 g), and corn toninagonist to be used in the present invention and concomi starch (640 g) are mixed uniformly in a fluidized bed granu tant drug respectively, lation dryer, and the mixture is granulated with spraying a (3) separate administration at an interval via the same admin solution of hydroxypropyl cellulose (160 g) in water in the istration route of two preparations obtained by formulating dryer, followed by drying in said drier. The resulting granu the melatonin agonist to be used in the present invention and lated material is crushed by 1.5 mmcp punching screen using concomitant drug respectively, a power mill apparatus to obtain uniform granules. To the (4) simultaneous administration via different routes of two uniform granules (3894 g) are added corn starch (124 g) and preparations obtained by formulating the melatonin agonist magnesium Stearate (12.4 g), and the mixture is mixed to give to be used in the present invention and concomitant drug granules fortableting. These granules are tableted in a weight respectively, of 130 mg per tablet with a 7.0 mmdD die using a tableting (5)-separate administration at an interval via different routes machine to prepare bare tablets. The obtained bare tablets are of two preparations obtained by formulating the melatonin sprayed with a solution of hydroxypropylmethylcellulose agonist to be used in the present invention and concomitant 2910 and copolividone wherein titanium oxide and yellow drug respectively (for example, administration in the order of ferric oxide are dispersed, in a film coating machine, to give compound of the present invention concomitant drug, or in about 25000 tablets which are film-coated tablets each con the inverse order) and the like. taining 4 mg of compound A per tablet and having a prescrip 0113 Dosage of concomitant drug can be appropriately tion shown in Table 1. selected on the basis of the clinically used dosage. In addition, the combination ratio of the compound of the present inven TABLE 1 tion and concomitant drug can be appropriately selected Composition Blending Quantity (mg) depending on a Subject to be administered, an administration Compound A 4.0 route, targeted diseases, symptoms, combinations thereof or Lactose 101.6 the like. For example, when the subject to be administered is Corn Starch 2O.O a human, the concomitant drug may be used with an amount Hydroxypropyl Cellulose 4.0 of 0.01 to 100 parts by weight based on 1 part by weight of Magnesium stearate 0.4 compound A. In case of other melatonin agonist, dosage of Bare Tablet 13O.O the concomitant drug can be decided according to compound Hydroxypropylmethylcellulose 2910 3.74 A Copolividone 0.75 0114. The melatonin agonist to be used in the present Titanium Oxide O.S invention can be safely administered orally or parenterally Yellow Ferric Oxide O.O1 (e.g. topically, rectally, intravenously etc.) as it is or as a Total 13S.O pharmaceutical composition mixed with pharmacologically acceptable carriers according to a conventional method (e.g., method described in Japanese Pharmacopoeia, etc.). Such as tablets (including Sugar-coated tablets, film-coated tablets), Test Example 1 powders, granules, capsules, solutions, emulsions, Suspen Action of Compound A on Viscerosenditivity sions, injectables, suppositories, Sustained-release agents (controlled-release preparation), adhesive preparations, and Method the like. 0119 For the experiment, 7 to 8 week-old male SD rats 0115 The content of compound A in the pharmaceutical (CREA Japan, Inc.) were used. Under ether anesthesia, the composition is usually about 0.01 to 100% by weight based rats were sutured with a force transducer (F12-IS-SL, Star US 2010/0267821 A1 Oct. 21, 2010

Medical Inc.) on the abdominal oblique muscle, and used for tonin did not inhibit the restraint stress-induced defecation in the experiment after waiting at least one day or more postop the 10 and 30 mg/kg administration. eratively for recovery of the animals. 0120. After fasting for 18 hours, 1% acetic acid was INDUSTRIAL APPLICABILITY instilled into the colon to produce a hypersensitive condition. One hour after the instillation of acetic acid, a balloon was I0128. According to the present invention, a prophylactic inserted into the colon, fixed, and colonic distension stimulus or therapeutic agent for irritable bowel syndrome is provided. was loaded for 10 minutes by inflating the balloon. The 1. A pharmaceutical composition for a prevention or treat colonic distension stimulus was loaded two times before and ment of irritable bowel syndrome, which comprises a com after administration of compound A, and the observed con pound represented by formula (I): traction number of the abdominal oblique muscle was counted. The result was expressed as inhibition percent. Determination of the abdominal muscle contraction was con ducted with the naked eye and waveform of force transducer. 0121 Compound A was suspended in a 0.5% methylcel lulose, and administered orally with a volume of 4 mL/kg 30 minutes before the second colonic distension stimulus (0.3.3 and 30 mg/kg). Result 0122) The result was shown in FIG. 1 (n=4 to 5, **Ps0. 025 vs. control group, Williams test). As is clear from this wherein, R' represents an optionally substituted hydrocarbon figure, compound A shows a dose-dependent significant inhi group, an optionally Substituted amino group or an optionally bition action on viscerosensory response. Substituted heterocyclic group, Test Example 2 R represents a hydrogenatom or an optionally substituted hydrocarbon group, Method R represents a hydrogen atom, an optionally substituted 0123 For the experiment, 10 week-old male Wistar rats hydrocarbon group or an optionally Substituted hetero (SLC) were used. Compound A (0.3, 3, 10 and 30 mg/kg) or cyclic group, a vehicle (control group, 0.5% methylcellulose) was admin X represents CHR, NR, CO, O or S (wherein, R repre istered orally with a dose of 4 ml/kg, and after 15 minutes, a sents a hydrogen atom, an optionally substituted hydro restraint stress was loaded. Fecal pellets were retrieved 2 carbon group or hydroxyl group), hours after the beginning of the restraint stress loading, and Y represents C, CH or N, the number of feces was counted. In addition, as for normal . . . . . represents a single bond or double bond, group, rats were left in their individual cages without any after ring A represents an optionally substituted 5- to 7-mem administration of vehicle, and the number of feces for 2 hours bered heterocyclic ring containing an oxygenatom, ring was counted. B represents an optionally Substituted benzene ring, and 0.124. Further, a study on normal defecation was also con m represents an integer of 1 to 4, or a' Salt thereof. ducted. Until the day before the experiment, two rats were 2. The pharmaceutical composition for a prevention or kept in a cage and accustomed to the measuring condition. On treatment of irritable bowel syndrome according to claim 1, the day of experiment, compound A or vehicle (control group, wherein the compound represented by formula (I) or a salt 0.5% methylcellulose) was administered orally with a dose of thereof is (S)- N-2-(1,6,7,8-tetrahydro-2H-indeno5,4-b 4 ml/kg, and after 15 minutes, the measurement of defecation furan-8-yl)ethylpropionamide. was commenced. The number of feces was counted two hours 3. A method for a prevention or treatment of irritable bowel after the initiation of measurement, and the result was syndrome, which comprises administering an effective expressed by the number of feces per two rats. amount of a compound represented by formula (I: Result 0.125. The result was shown in FIG. 2 (***P0.001 vs. normal group (Student's t-test), #P-0.025 vs. control group (Parametric Williams test) and FIG. 3. As seen from FIG. 2, compound A inhibited significantly the restraint stress-in duced defecation in the 30 mg/kg administered group. On the other hand, as is clear from FIG.3, normal defecation was not inhibited even in the administration of 30 mg/kg. Test Example 3 Comparison Example Method wherein, R' represents an optionally substituted hydrocarbon group, an optionally Substituted amino group or an optionally 0126 Experiment was carried out according to Test Substituted heterocyclic group, Example 2, wherein melatonin (10 and 30 mg/kg) instead of R represents a hydrogenatom or an optionally substituted compound A was administered orally. hydrocarbon group, Result R represents a hydrogen atom, an optionally substituted 0127. The result was shown in FIG. 4 (***Ps0.001 vs. hydrocarbon group or an optionally Substituted hetero normal group (Student's t-test)). As shown in FIG. 4, mela cyclic group, US 2010/0267821 A1 Oct. 21, 2010

X represents CHR, NR, CO, O or S (wherein, R repre wherein, R' represents an optionally substituted hydrocarbon sents a hydrogen atom, an optionally substituted hydro group, an optionally Substituted amino group or an optionally carbon group or hydroxyl group), Substituted heterocyclic group, Y represents C, CH or N, R represents a hydrogenatom or an optionally substituted - - - - - represents a single bond or double bond, hydrocarbon group, ring A represents an optionally Substituted 5- to 7-mem R represents a hydrogen atom, an optionally substituted bered heterocyclic ring containing an oxygenatom, ring hydrocarbon group or an optionally Substituted hetero B represents an optionally Substituted benzene ring, and cyclic group, m represents an integer of 1 to 4, or a salt thereof. X represents CHR, NR, CO, O or S (wherein, R repre 4. The method for a prevention or treatment according to sents a hydrogen atom, an optionally substituted hydro claim3, wherein the compound represented by formula (I) or carbon group or hydroxyl group), a salt thereof is (S)-N-2-(1,6,7,8-tetrahydro-2H-indeno5, Y represents C, CH or N, 4-bfuran-8-yl)ethylpropionamide. - - - - - represents a single bond or double bond, 5. Use of a compound represented by formula (I): ring A represents an optionally substituted 5- to 7-mem bered heterocyclic ring containing an oxygen atom, ring B represents an optionally Substituted benzene ring, and m represents an integer of 1 to 4, or a salt thereof, for the manufacture of a pharmaceutical composition for a prevention or treatment of irritable bowel syndrome. 6. The use according to claim 5, wherein the compound represented by formula (I) or a salt thereof is (S) —N-2-(1,6,7,8-tetrahydro-2H-indeno5,4-bfuran-8-yl) ethylpropionamide.