AU2013203952A1 - Antituberculous composition comprising oxazole compounds - Google Patents

Abstract

Document29- I 1/04/201 3 The present invention provides antituberculous therapeutic drugs with a higher potency. The present invention provides also antituberculous therapeutic drugs containing oxazole compounds represented by (I) general formula (1): 0 2N (1) N O (CH2)nR [wherein RI represents a hydrogen atom or C1-6 alkyl group, n represents an integer of 0-6, and R2 represents general formula (A) or the like, O N R3 (A) wherein R3 represents a phenoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) or the like], optically active forms thereof or salts thereof, and drugs (II) such as primary antituberculous drugs.

Description

Docmnt29-l1/04/2013 DESCRIPTION PHARMACEUTICAL COMPOSITION TECHNICAL FIELD This application is a divisional application of Australian Application No. 2010241497 the specification and drawings of which as originally filed are incorporated herein in their entirety by reference. The present invention relates to a pharmaceutical composition. BACKGROUND ART It is known that 2,3-dihydro-6- nitroimidazo[2,1-b] oxazole compounds represented by the following general formula (1), optically active forms thereof and pharmacologically acceptable salts thereof (hereinafter they are simply referred to as oxazole compounds (I)) have an excellent bactericidal effect against acid-fast bacteria (Mycobacterium tuberculosis, multidrug-resistant Mycobacterium tuberculosis and atypical acid-fast bacteria) (JP-A-2004-149527 and W02005-042542). 0 2 N R1(1) N

(CH

2 )nR 2 wherein R represents a hydrogen atom or C1-6 alkyl group. n represents an integer of 0-6. R2 represents any group of the following general formulas (A)-(G). The group represented by the general formula (A) is: WO 20071043542 PCT/JP2006/020239 0-- -N R~ (A) wherein R. represents any group of the following (1)--(6) (1) a phenoxy group (at least one group selected from ,the group consisting of a halogen atom, an optionally 5 halogen-substituted C1-6 alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring); (2) a phenyl Cl-6 alkoxy group (at least one group selected from the group consisting ofa halogen atom, 10 an optionally halogen-substituted Cl-6 alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring); (3) a' --NR 4 R5 group, wherein pA represents a hydrogen atom or C1-6 alkyl group and R) represents phenyl group 15 (at least one group selected from the group consisting of a halogen atom an optionally halogen-substituted Cl-6 alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring); 20 (4) a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted Cl-6 alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may betsubstituted on the phenyl ring; 25 (5) a phenoxy C1-6 alkyl group (at least one group WO 20071043542 PCT/JP2006/020239 3 selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) ; and 5 (6) a benzofuryl Cl-6 alkyl group (at least one group selected from the group consisting of a halogen atom, ,an optionally halogen-substituted 01-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring); 10 the group represented by the general formula (B) is: /6 -N N-COOCH 2 CH=CH-R. (B) wherein R' represents phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 15 alkoxy group may be substituted on the phenyl ring). The group represented by the general formula (0) is: -O N N-R' (C) wherein R7 represents a phenyl C2-10 alkenyl group- (at least one group selected from the group consisting of a halogen atom, an optionally halogen 20 substituted C1-6 alkyl group and an optionally halogen substituted C1-6 alkoxy group may be substituted on the phenyl ring) or a biphenyl Cl-6 alkyl group (at. least WO 20071043542 PCT/JP2006/020239 4 one group selected from the group consisting of a halogen atom, an optionally halogen-substituted Cl-& alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring) 5 The group represented by the general formula (D) is: - N N-R 8 (D) 8 wherein R represents a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an option ally halogen substituted CI-6 alkyl group and an optionally halogen 10 substituted Cl-G alkoxy group may be substituted on the phenyl ring) The group represented by the general formula (E) is: NN \(E) whrein R 8 is as described above. The group represented by the generaL formula (F) is: -O >-N ' R (F) N 5 wherein R3 is as described above. (F)

N\\~

WO 20071043542 PCT/JP2006/020239 The group represented by the general formula (G) is: -N N-N-C-

R

6 (G) H wherein R is as described above, Among acid-fast bacteria, human Mycobacterium tuberculosis is widely known and one third of human being is said to be infected. In addition, 5 Mycobacterium africanum, Mycobacterium bovis and Mycobacterium microti are known as members of a group of tubercle bacilli together with Mycobacterium tuberculosis and as mycobacteria strongly pathogenic to human beings. 1 To these tuberculosis, a treatment is performed using those ranked as the primary antituberculous drug, i.e. three drugs including antibacterial drug of rifamycin family (e.g. rifampicin, rifabutin, rifapentine etc.), isoniazid and 15 ethambutol hydrochloride (or streptomycin), or four drugs including those above described plus pyrazinamide. However, very long period of medication is required for treatment of tuberculoksis, which lead to 20 poor compliance resulting in failure .of the treatment in considerable number of cases. For multidrug resistance of 'infecting Mycobacterium tuberculosis and WO 20071043542 PCT/JP2006/020239 6 tuberculosis caused by multidrug-resista'nt Mycobacterium tuberculosis, used are secondary antituberculous drugs including kanamycin, enviomycin, capreomycin, paraaminosalicylic acid, cycloserine, 5 thioacetazone; quinolone anti-bacteria! drugs in cluding ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, sparfloxacin etcv due to their in vitro efficacy; and macrolide antibacterial drugs including clarithromycin and azithromycin, etc.. They have, however strong side 10 effects and a low potency. Further, the following side effects are reported for the primary antituberculous (rugs: hepatopathyj full syndrome, drug allergy, incompatibility with other drugs due to enzymatic 15 induction related to P450 for rifamycin and related anti-bacterial drugs; peripheral neuropathy, induction of severe hepatopathy by concomitant use of rifampicin for isoniazid; decreased vision due to optic nerve disorder for ethambutol hydrochloride; decreased 20 hearing ability by 8th cerebral nerve disorder for streptomycin; hepatopathy, gouty attack' associated with increased level of uric acid anidvomiting, etc. for pyrazinamide (A Clinician's Guide To Tuberculosis, Michael D. Iseman 2000 by Lippincott Williams & 25 Wilkins, printed in the USA, ISBN Q-7817-1749-3; Kekkaku 2nd edition (1992), by Humiyqki Kose and Takahide Izumi, Igakushoin; Kekkaku Vol.74: 77-82 (1999)).

WO 20071043542 PCT/JP2006/020239 7 There is a report in fact that cases where standard chemotherapy can not be performed owing to these side effects account for 70% of discontinued medication cases (about 23%, 52 cases) among the total 5 cases (228 inpatient cases in total subjected to Investigation) (Kekkaku Vol.74: 77-82 (1999)). n particular, it is known that a side effect of hepatic toxicity which is common in rifamyc in and related anti-bacterial drug, isoniazid and pyrazinamide 10 among five drugs used concomitantly on the first line described above develops most frequently. On the other hand, Mycobacterium tuberculosis which shq~ws resistance to antituberculous drugs and that has become multidrug resistant is increasing, making treatment more 15 difficult. According to the investigation by WHO (1996 1999), it is announced that among Mycobacterium tuberculosis isolated in the world, the ratio of those which show resistance to any of existing 20 antituberculous drugs reaches 19%., and that of those which show multidrug-resistance is 5.1%. Carriers who are infected with these multidkug-resistant Mycobacterium tuberculosis has assumably reached 60 millionss in the world, and further increase of 25 multidrug-resistant Mycobacterium tperculosis in the future is concerned (April 2001, as a supplement to the journal Tuberculosis, the ".Scient ific Blueprint for TB drug development") WO 20071043542 PCT/JP2006/020239 Further, it is reported chat the mass of death in AIDS patients is caused by tuberculosis and that the number of human beings mixed-infected with tuberculosis and HIV has reached 10.7 millions at the 5 time point of 1997 (Global Alliance for TB drug development). In addition, it is considered that mixed infection involves a higher onset risk of tuberculosis by at least 30 times than otherwise. Further, bacteria known to be pathogenic to 10 human beings include Mycobacterium avium and Mycobacterium intracellulare which cause recently increasing MAC disease (Mycobacterium avium intracellulare complex disease) and other atypical acid-fast bacteria such as Mycobacterium kansasii, 15 Mycobacterium marinum, Mycobacterium simiae, Mycobacterium scrofulaceum,. Mycobacterium szulgai, Mycobacterium xenopi, Mycobacterium malmoense, Mycobacterium haemophilum, Mycobacterium ulcerans, Mycobacterium shimoidei, Mycobacterium fortuitum, 20 Mycobacterium chelonae, Mycobacteriu'm smegmatis, and Mycobacterium aurum. Currently, we are short' of promising therapeutic drugs against these atypical acid-fast bacterial diseases, and in the present state, primary 25 antituberculous drugs such as rifarycin and related affti-bacterial drugs, isoniazid, ethamnbutol, streptomycin and pyrazinamide, and common therapeutic drugs against 'microbism including quinolone WO 20071043542 PCT/JP2006/020239 9 antibacterial drugs or antibiotics are used in combination. DISCLOSURE OF INVENTION .or treatment of acid-fast bacterial disease, S however, longer medication is forced compared with infectious diseases caused by common bacteria, and cases of difficulty in healing and death have been reported. in order to solve such situation, development of drugs which have stronger efficacy is 10 desired. As a result of extensive study to solve the subject described above, the present inventors have found that the subject can be solved by using one or more drugs selected from the primary antituberculous 15 drugs, secondary antituberculous drugs, quinolone antibacterial drugs, macrolide antibacterial drugs, sulfa drugs and anti-HIV viral drugs with a combination of, at least one selected from the group consisting of oxazole compounds (I) described above. Further,. a 20 measurement of antibacterial activity of the oxazole compounds (I) against Mycobacterium tuberculosis showed that they expressed a strong antibacterial effect in a short time and the effect was sustained for a long period. Therefore, it has been found that clinical 25 therapy based on intermittent administration can be practiced. The present invention has been completed WO 20071043542 PCT/JP2006/020239 10 based on such findings. The invention preferably provides antituberculous therapeutic drugs shown in items 1 to 17, drugs for treatment of tuberculosis shown in item 5 18 and kits for treatment of tuberculosis shown in items 24 to 30. Item 1. An antituberculous therapeutic drug comprising: (I) at least one selected from the group consisting of 10 2,3-dihydro-6-nitroimidazo[2,1-b]oxazoie compounds represented by general formula .(1) described above, optically active forms thereof and pharmaclogically acceptable salts thereof, and (IT) at least one drug selected from the group 15 consisting of primary antituberculous drugs, secondary antituberculous drugs, quinoione antibacterial drugs, macrolide antibacterial drugs, sulfa drugs, and anti HIV drugs. Item 2. The antituberculous therapeutic drug 20 according to item 1, wherein the drug of (II) is at least one selected from the group consisting of the primary antituberculous drugs, the secondary antituberculous drugs and the quinolone antibacterial drugs., 25 Item 3. The antituberculous therapeutic drug according to item 2, wherein the drug. selected from the primary antituberculous drug is at least one selected from the group consisting of rifamycin and related WO 20071043542 PCT/JP2006/020239 11 anti-bacterial drugs, isoniazid, ethambutol, streptomycin, pyrazinamide and .salts thereof, and the drug seledted from the secondary antituberculous drug is at least one selected from the group consisting of 5 enviomycin, kanamycin, capreomycin, cycloserine, thioacetazone,cIofazimine and salits thereof. Item 4. The antituberculous therapeutic drug according to item 2, wherein the drug of (II) is at least one selected from the primary antituberculous 10 drugs. Item 5. The antituberculous therapeutic drug according to item 4, wherein the at least one selected from theprimary antituberculous drugs comprises in combination (i) at least one of rifamycin and related 15 anti-bacterial drugs and (ii) at least one selected from-the group consisting of isoniazid, ethambutol, streptomycin, pyrazinamide and salts thereof. Item 6. The antituberculous therapeutic drug according to item 5, wherein the at least one selected 20 from the primary antituberculous drugs comprises in combination (i) at least one of rifamycih and related anti-bacterial drugs and (ii) pyrazinamide. Item 7. The antituberculous therapeutic drug according to item 4, wherein the at least one selected 25 from the primary antituberculous drugs comprises in combination (i) at least one of rifamycin and related anti bacterial drugs, WO 2007/043542 PCT1/P2006/020239 12 (ii) pyrazinamide, and (iii) at least one selected from the group consisting of isoniazid, ethambutol and streptomycin. Item 8. The antituberculous therapeutic drug 5 according to any one of items 3 to 7, wherein the at least one of rifamycin and related anti-bacterial drugs is at least one selected from the group consisting of rifampicin, rifabutin and rifapentine. Item 9. The antituberculous therapeutic drug 10 according to item 8, wherein the at least one of rifamycin and related anti-bacteriai drugs is rifampicin. item 10. The antituberculous therapeutic drug according to item 1, wherein the drug of (II) is 15 at least one selected from the quinolone antibacterial drugs. Item 1I. The antitberculous therapeutic drug according to item 10, wherein the at least one selected from the quinolone antibacterial drugs is at 20 least one selected from the group consisting of gatifloxacin, moxifloxacin and hydrates thereof. Item 12. The antituberculous therapeutic drug according to item 10, wherein the at least one selected from the drugs of (II) comprises in 25 combination at least one selected from the group consisting of gatifloxacin, moxifloxacin and hydrates thereof and at least one primary antituberculous drug. Itei 13. The antituberculous therapeutic WO 20071043542 PCT/JP2006/020239 drug according to item 12, wherein the at least one selected from the. primary antituberculous therapeutic drugs comprises in combination (i) any of rifamycin and related antibacterial drugs and (ii) at least one 5 selected from the group consisting of isoniazid, ethambutol, streptomycin, pyrazinamide and salt .thereof. Item 14. The antituberculous therapeutic drug according to item 13, wherein the at least one selected 10 from the primary antituberculous therapeutic drugs comprises in combination (i) at least one of rifamycin and related antibacterial drugs and (ii) pyrazinamide. tem 15. The antituberculous therapeutic drug according to item 14, wherein the at least one 15 selected from the primary antituberculous drugs comprises in combination (i) at least one of rifamycin and related antibacterial drugs, (ii) pyrazinamide, and 20 (iii) at least one selected from the group consisting of isoniazid, ethambutol and streptomycin. Item 16. The antituberculous therapeutic drug according to any one of items 13 to 15, wherein the at least- one of r:famycin and related antibacterial 25 drugs is at least one selected from. the group consisting of rifamycin, rifabutin and rifapentine. Item 17. The antitubereulous therapeutic drugaccording to item 16, wherein the at least one of WO 2007/043542 PCT1/P2006/020239 14 rifamycin and related antibacterial drugs is rifampicin. Item 18. The antituberculous therapeutic drug according to item 1, wherein the drugs of (II) is 5 least one selected from the macrolide antibacterial drugs. Item 19. The antituberculous therapeutic drug according to item 18, wherein the at least one selected from~the macrolide antibacterialdrugs is at 10 least one selected from the group consisting of clarithromycin, azithromycin and hydrates thereof. Item 20. The antituberculous therapeutic drug according to item 1, wherein the drug of (II) is at least one selected from the sulfa drugs. 15 Item 21. The antituberculous therapeutic drug 'according to item 20, wherein the at least one selected from the sulfa drugs is at least one selected from the group consisting of sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfadimethoxine, 20 sulfamethizole, salazosulfapyridine, sulfadiazine and salts thereof. tem 22. The antituberculcus therapeutic drug according to item 1, wherein the drug of (II) is at least one selected from anti-HIV drugs. 25 Item 23. The antituberculous therapeutic drug according to item 22, wherein the at least one selected from the anti-HIV drugs 'is (a) a reverse transcriptase inhibitor based on a nucleic acid, (b) a WO 20071043542 PCT/JP2006/020239 1 S reverse transcriptase inhibitor based on' a non-nucleic acid or (c) a protease inhibitor. Item 24. A medicament for dosing at an interval of 48 hours or more, wherein the medicament 5 comprises at least one compound as active ingredient which is selected from the group consisting of 2,3 dihydro-6-nitroimidazo[2 ,1-bjoxazole compounds represented by general formula (1), optically active forms thereof and pharmacologically acceptable salts 10 thereof Item 25. A kit for tuberculosis treatment wherein the kit comprises the medicament gf item 24, and at least one drug (II) selected from the group consisting of primary antituberculous drugs, secondary 15 antituberculous drugs, quinolone antibacterial drugs, macrolide antibacterial drugs, sulfa drugs and anti-HIV drugs, and wherein the kit is used to dose the medicament and the drugs at an interval of 48 hours or more. 20 Item 26. The kit according to item 25, wherein the drug of (II) is at least one selected from the group consisting of the primary antituberculous drugs, the secondary antituberculous drugs and the quinolone antibacterial drugs. 25 Item 27. The kit according to item 26, wherein at least one selected from the primary antituberculous drugs is at least) one selected from the group consisting of rifamycin and related anti- WO 20071043542 PCT/JP2006/020239 ±6 bacterial drugs, isoniazid, ethambutol, streptomycin, pyrazinamide and salts thereof, and the secondary antituberdulous drugs are at least one selected from the group consisting of enviomycin, kanamycin, 5 capreomycin, cycloserine, thioacetazone, clofazimine and salts thereof, and at least one selected from the .quinolone antibacterial drugs is at least one selected from the group consisting of gatifloxacin, moxifloxacin and hydrate thereof. 10 item 28. The kit according to item 27, wherein the drug of (IH) is at least one primary antituberculous drug selected from the grqup consisting of rifamycin and related anti-bacterial drugs, isoniazid, ethambutol, streptomycin, pyrazinamide and 15 salts thereof. Item 29. The kit according to item 28, wherein the drug (s) of (II) comprises in combination at least one primary antituberculous drug selected from the groups consisting of rifamycin and. related 20 antibacterial drugs, isoniazid, ethambutol, streptomycin, pyrazinamide and salt thereof, and at least one quinolone antibacterial drug selected from the group consisting of gatifloxacin, moxifloxacin and hydra-te thereof. 25 Item 30. The kit according to any one of items 27 to 29, wherein the at least .one selected from the rifamycin and related anti-babterial drugs is at least one selected from the group consisting of WO 20071043542 PCT/JP2006/020239 17 ri famoic.n, rifabutin and rifapentine. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1-1 is a graph representing the results of in vivo experiment for combined effect of oxazole 5 compounds (I) with other drugs. Fig. 1-2 is a graph representing the results of in vivo experiment for combined effect of oxatole compounds (I) with other drugs. Fig. 2 is a graph representing the effect of 10 oxazole compounds (I)- on intracellular parasitic mycobacterium tuberculosis. BEST MODE FOR CARRYING OUT THE INVENTION Oxazole compounds (I) used in the antituberculous therapeutic drugs of the present 5 invent-ion are at least one selected from the group consisting of 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compounds represented by general formula (1) described above (wherein, RI-R 8 and n are as described above), optically active forms thereof and pharmacologically 20 acceptable salts thereof. wherein, a C1-6 alkyl group may include linear or branched alkyl groups composed of 1 to 6 carbon atoms, more specifically, fQr example, a methyl group, an ethyl group, an n-propyl group, an isopropyl 25 group, an n-butyl group, an isobdtyl group, a tert butyl group, i sec-butyl group, an n-pentyl group, a WO 20071043542 PCT/JP2006/020239 18 neopentyl group, an n-hexyl group, an isohexyl group, a 3-methylpentyl group. A halogen atom may include fluorine, chlorine, bromine and iodine atoms. 5 An optionally halogen-substituted Ci-6 alkyl group is a linear or branched alkyl group composed of I to 6 carbon atoms defined above or the alkyl group substituted with 1-7 a halogen atom, and examples may include: a methyl group, ethyl group, n-propyl group, 10 isopropyl group, n-butyl group, isobutyl group, tert butyl group, sec-butyl group, n-pentyl group, neopentyl group, n-hexyl group, isohexyl group,.3-mthylpentyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, chloromethyl group, 15 dichloromethyl group, trichloromethyl group, bromoYethyl group, dibromomethyl group, dichlorofluoromethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 2-chloroethyl group, 3,3,3 trifluoropropyl group, heptafluoropropyl group, 20 heptafluoroisopropyl group, 3-chloropropyl group, 2 chloxopropyl group, 3-bromopropyl group, 4,4,4 trifluorobutyl group, 4,4,4,3, 3-pentafluorobutyi group, 4-chlorobutyl group, 4-bromobutyl group, 2-chlorobutyl group, 5,5,5-trifluoropentyl group, 5-chloropentyl 25 group, 6, 6, 6-trifluorohexyl group, and 6-chlorohexyl group. A C1-6 alkoxy group is b group composed of a C1-6 alkyl group defined above and an oxygen atom, and WO 20071043542 PCT/JP2006/020239 19 examples may include: a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a tert-butoxy group, a sec butoxy group, an. n-pentoxy group, a neopentoxy group, 5 an n-hexyloxy group, an isohexyloxy group, a 3 methylpentoxy group. An opLionally halogen-substituted Cl-6 alkoxy group is a CI-6 alkoxy group defined above or the alkoxy group substituted with 1-7 a halogen atom, arid 10 examples may include: a methoxy group, ethoxy group, n propoxy group,, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n-pentoxy group, neopentoxy group, n-hexyloxy group, isohexyloxy group, 3-methylpentoxy group, fluoromethoxy 15 group, difluoromethoxy group, trifluoromethoxy group, chloromethoxy group, dichlorQmethoxy group, trichloromethoxy group, bromomethoxy group, dibromomethoxy group, dichlorofluor-omethoxy group, 2,-2,2-triflucroethoxy group, pentafluoroethoxy group, 20 2-chloroethoxy group, 3,3,3-trifluoropropoxy group, heptafluoropropoxy group, heptafluoroisopropoxy group, 3--chloropropoxy group, 2-chloropropoxy group, 3 bromopropoxy group, 4,4,4-trifluorobutoxy 9roup, 4,4,4,3, 3-pentafluorobutoxy group, 4-chlorobutoxy 25 group, 4-bromobutoxy group, 2-chloiobutoxy group, 5,5,5-trifluoropentoxy group, 5-chloropentoxy group, 6,'6, 6-trifluorhexyloxy group, and 6-chlorohexyloxy group.

WO 20071043542 PCT/JP2006/020239 20 A phenoxy group (at least one group selected rrom the group consisting of a .halogen atom an option'ally halogen-substituted C1-6 aikyl group and an optionally halogen-substituted C1-6 .alkoxy group may be substituted on the phenyl ring) may include, for example: a phenoxy group, 2-chlorophenoxy group, 2,33 dichIorophenoxy group, 3,4-dichlorophenoxy group, 3,5 dichlorophenoxy group, 2,6-dichlorophenoxy group, 2,4 dichlorophenoxy, group, 2, 5-dichlorophenoxy group, 1 0 2, 4, 6-trichlorophenoxy group, 2-fluorophenoxy group, 2,3-difluorophenoxy group, 3,4-difluorophenoxy group, 3,5-difluorophenoxy group, 2, 6-difluorophenoxy group, 2,4-difluorophenoxy group, 2,5-difluorophenoxy group, 2,4, 6--trifluorophenoxy gro up, 2-bromophenoxy group 15 2,3-dibromophenoxy group, 3, 4-dibromophenoxy group, 3, 5-dibromophenoxy group, 2, 6-dibromophenoxy group, 2,4-dibromophenoxy group, 2, 5-dibromophenoxy group, 2,4, 6-tribromophenoxy group, 2-methylphenoxy group, 2,,3-dimethylphenoxy group, 3, 4-dirmethylphenoxy group, 20 3, 5-dimethylphenoxy group, 2, 6-dimethylphenoxy group 2,4-dimethylphenoxy group, 2,5-dimethylphenoxy group, 2, 4, 6-trimethylphenoxy group, '3, 5 ditri fluoromethyiphenoxy group, 2,4,6 trifluoromethylphenoxy group, 2-trifluoromethylphenoxy 25 group, 3-trifluoromethylphenoxy grcup, 4 trifluoromethylphenoxy group, 2-trifluoronethoxyphenoxy group, 3-trifl"uoromethoxyphenoxy group, 4 trifluormethxyphenoxy group, 3--methoxyphenoxy group, WO 20071043542 PCT/JP2006/020239 21 2, 3-dimethoxyphenoxy group, 3, 4-dimethoxyphenoxy group, 3, 5-dimethoxyphenoxy group, 2, 6-dimethoxyphenoxy group, 2, 4-dimethoxyphenoxy group, 2, 5-dimetnoxyphenoxy group, 2,4, 6-trimethoxyphenoxy group, 2,6 5 ditrifluoromethoxyphenoxy group, 2,3,4 trifluoromethoxyphenoxy group, and 2-trifluoromethyl-3 trifluoromethoxyphenoxy group (1-3 groups selected from the group consisting of a halogen atom an optionally halogen-substit.uted C1-6 alkyl group and an optionally 10 halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring) A phenyl Cl-6 alkoxy group .(at east one group selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 alkyl group 15 and an optionally halogen-substituted C--6 alkoxy group may be substituted on the phenyl. ring) may include, for example: a benzyloxy group, 1-phenylethoxy group, 2 phenylethoxy group, 3-phenylpropoxy group, 2 phenylpropoxy group, 4-phenylbutoxy group, 5 20 phenylpentyloxy group, 4-phenylpentyloxy group, 6 phenylhexyloxy group, 2-chlorobenzyloxy group, 2,3 dichloroben zyloxy group, 3, 4-dichlorobenzyloxy group, 3, 5--dichlorobenzyl oxy group, 2, 6-dichlorobenzyloxy group, 2,4-dichlorobenzyloxy group, 2,5 25 dichlorobenzyloxy group, 2,4, 6-tridhlorobenzyioxy group, 2-fluorobenzyloxy group,. 2, 3-difluorobenzyloxy group, 3,4-difluorobenzyloxy group: , 3,5 diflucrobenzyioxy group, 2, 6-difluorobenzyioxy group, WO 20071043542 PcT1jP2t)06i020239 2 2 2,4'-difluorobenzyiloxy group. 2,5 %difluor-obenzyloxv group. 2,.4, 6-triluorobenzvloxv group, 2-brornobenzyloxy group, 2, 3-dibrornobenzylIoxy groupD, 3, 4 -dibro mobenzyi~oxy group, 3, 5-dibrorniobenzyloxy group, 2, 6-dibromobenzvioxv 5 group, 2, 4-d 4bro-.noberizyloxy group, 2, 5-dibromobenzyloxy group, 2,4, 6-tribro. obenzyloxy group, 2-metklhylbenzyioxy group, 2,3-dimethylbenzyioxy group, 3,4 dimetbhyibenzyloxy group, 3, 5-di-methylbenzyioxy group, 2, G-direthylbenzylioxy group, 2, 4-dirnethylbenzvloxy 10 group, ?,5"'-dirnethylben-zyi~oxy group, 2,4,6 trirnethylbenzyloxy group, 3, 5 d-ft'-rifluoromethylbenzyIoxy group, 2,4.,6£ trifiuoromethy.i.Lenzyiloxy group, 2 trifluoronethylbenzyloxy group, 3 15 trifluoromethylbenzyloxy group, 4 tri4fuoromethylbenzyloxy group, 2 trifiul-oromietlioxybenzyloxv group, 3 tri fiuioromethoxvbe nzyloxy group, 411 t rifluoro-meth oxybenzyloxy group, 3-ret.hoxybenzyloxy 20 group, 2,3-dimetr-hoxybenzyvloxy group, 33,4 dimethoxybenzv'ioxy group, 3, 5-dirnethoxybenzyloxy group, 2,66-dirnethoxybenzy"ioxv' group, 2,4;-d-*imerhoxybenzyIoxy group, 2,S-dimethoxybenizyloxy group, 2,4,6 trimeethoxybenzyioxy group, 2,6 25 d 4 -rifluoromlethoxvbenzvloxy group,t2, 3,4 t rifluoro. ethoxybenzyi'oxy group, 1--( ch'loropheriyl) ethoxy group, 1- (3-chlorophenvJJ ethoxv group, 1- (4-c:hLorophenvl) etho~xv group, 2-lk2- WO 2007/043542 PCT/JP2006/020239 23 chlorophenyl) ethoxy group, 2-(3-chlorophenyl) ethoxy group, 2- (4-chlorophenyl)ethoxy group, 1-(2 fluorophenyl) ethoxy group, 1- (3-fluorophenyl) ethoxy group, 1- ( 4-fiuorophenyl)ethoxy group, 2-(2 5 fluorophenyl)ethoxy group, 2-(3-fluorophenyl)ethoxy group, 2-(4-fluorophenyl)ethoxy group, 1-(2 bromophenyl)ethoxy ,group, 1-- (3-bromophenyl)ethoxy group, 1-(4-bromophenyl)ethoxy group, 2- (2 bromn'ophenyl) ethoxy group, 2-(3-bromophenyl)ethoxy 10 group, 2-(4-bromophenyl)ethoxy group, 1-(2 trifluoromethylphenyl)ethoxy group, 1-(3 tri fluoromethylphenyl) ethoxy group, 1- (4-, trifluoromethylphenyl)ethoxy group, 1-(2 trifluoromethoxyphenyl)ethoxy group, 1-($ 15 trifluoromethoxyphenyl)ethoxy group, 1-(4 trifluoromethoxyphenyl)ethoxy group, 2-(2 trifluoromethylphenyl) ethoxy group, 2- (3 trifluoromethylphenyl)ethoxy group, 2-(4 trifluoromethylphenyl)ethoxy group, 2- (2 20 trifluoromethoxyphenyl)ethoxy group, 2-(3 trifluoromethoxyphenyl)ethoxy group, 2- (4 trifiuoromethoxyphenyl)ethoxy group, 3-(2 chlorophenyl) propoxy group, 3- (3-chlorophenyl) propoxy group, 3- (4-chlorophenyi) propoxy group, 3- (2 25 fluorophenyl)propoxy group, 3-(3-fluorophenyl)propoxy group, 3-(4-fluorophenyl)propoxy group, 3L(2 bromophenyl) propoxy group, 3- (3-Lromophenyl) propoxy group, 3-(4-bromophenyl)propoxy group, 3-(2- WO 20071043542 PCT/JP2006/020239 24 triflucromethylphenyl)propoxy group, 3-(3 tri f luocomethylphenyl) propoxy g roup, 3-(4 trifluobromethylphenyl)propoxy group, 3-(3 5 Lrifluoromethoxyphenv.l)propoxy group, 3-(4 trifluoromethoxyphenyl)3propoxy g group, 4-(3 chlorophenvl) butoxy, group, 4- (3-fl'uoropheny) butoxy group, 4-(3-bromophenyl)butoxy group, 4- (3 trifluoromethylphenyl)butoxy group, 5- 4 chlorophenyl)pentyloxy group, 4-(4 chlorophenyl)pentyloxy group, 5-(4 fluorophenylV1pentyloxy group, 4-(4 Fluorophenyl)pentyloxy group, 5- (4 bromophenyl) pentyloxy group, 4- (4 -bromophenyl) pentyloxy 15 group, 5-(4-trifluoromethylphenvl)pentyloxy group, 4 (4-tr'ifluoromethylphenyl)pentyloxy group, 4- (4 tri fluoromethoxyphenyl) pentlvoxy group, 6-(3 chlorophenyl)hexyloxy group, 6-- (4-chlorophenyl)hexyloxy group, 6-(3-fluorophenyl)hexyloxy group, 6-(4 20 fluorophenyl)hexyloxy group, 6-(3-bromophenyl) hexyloxy group, 6-(4-bromophenyl)hexyloxy group, -(3 t r iflu oromet.h yl phe nyl) hexyloxy' group, 6- (4 tri fluoromethyliphenyl) hexyloxy group, 6-(4 trifuormethoxyphenyl)hexyloxy group, and 2 25 trifluoromethyl-3-trifluo romethoxyhaenzyloxy group (1-3 groups selected from the group consisting'of a halogen atom an optionally halogen-substituted C1-6 alkyl group and an optionally thalogen-substtuted (1-6 alkoxv group WO 20071043542 PCT/JP2006/020239 may be substituted on the phenyl ring) A phenyl group (at least one group selected from the group Consisting of a halogen atom an optionally halogen-substituted C1-6 alky' group and an 5 optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyI ring) may include, for example: a phenyl group, 2-chiorophenyl group, 2,3 dichlorophenyl group, 3, 4-dichilorophenyl group, 3, 5 dichIorophenyl group, 2, 6-dichlorophenyl group, 2,4 10 dichlorophenyl group, 2,5-dichlorophenyl group, 2,4,6 trichlorophenyl group, 2-fluorophenyl' group, 2, 3 di fluorophenyl group, 3, 4-di fluorophenyl group, 3, 5 difluorophenyl group, 2,6-difluorop henyl group, 2,4 difluorophenyl group, 2,5-difluorophenyl group, 2,4,6 15 trifluorophenyl group, 2-bromophenyl group 2,3 dibrdmophenyl group, 3,4-dibromophenyl group, 3,5 dibromophenyl group, 2,6-dibromophenyl group, 2,4 dibromophenyl group, 2, 5-dibromophenyl group, 2,4,6 tribromophenyl group, 2-methylphenyl group, 2,3- 20 dimethylphenyl group, 3, 4-dimethylphenyl group, 3, 5 dimethylphenyl group, 2, 6-dimethylpheny group, 2,4 diLmethviphenJgo.p dmhpnyl group, 2, 5-dimethylphenyl group, 2,4,6 trimethylphenyl group, 3,5-ditrifluoromethylphenyl group, 2,4,6-trifluoromethylphenyl group, 2 25 trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trif'luoromethylphenvl group, 2 trifluoromethoxyphenyl group, 3 -rifluoromethoxyphenyl group, 4-trifluoroTethoxyphenyl group, 3-methoxyphenyl WO 20071043542 PCT/JP2006/020239 group, 2, 3 -dimethoxyphenyl group, 3, 4 -dimethoxyphenyl group, 3, 5-dimethoxyphenyl group, 2, 6-dimethoxyphenyl group, 2, 4 -dimethoxyphenyl group, 2, 5-dimethoxyphenyl group, 2 ,4,6-trimethoxyphenyl, group, 2,6 5 ditrifluoromethoxyphenyl group, .2,3,4 trifluoromethoxyphenyl group, and 2 -trifluoromethyl-3 crifluoromethoxyphenyl group (1-3 groups selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 alkyl group and an optionally 10 halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring). A phenyl Cl-6 alkyl group (at least one group selected from the group consisting of a halogen atom an optionally halogen-substituted Cl-6 alkyl group and an 15 optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) may include, for example: a benzyl group, 1-phenethyl group, 2-phenethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 4 phenylbutyl group, 5-phenylpentyl group, 4-phenylpentyl 20 group, 6-phenylhexyl group, 2-chlorobenzyl group, 2,3 dichlorobenzyl group, 3, 4-dichlorobenzyl group, 3,5 dichlorobenzyl group, 2, 6-dichlorobenzyl group, 2,4 dichlcrobenzyl group, 2,5-dichlorobenzyl group, 2,4,6 trichlorobenzyl group, 2-fluorobenzyl group, 2,3 25 difluorobenzyl group, 3,4-difluorobenzyl group, 3,5 difluorobenzyl group, 2, 6-difluorobenzyl group, 2,4 di fluorobenzyl group, 2,5-difluorcbenzyl group, 2,4,6 trifluorobenzyl group, 2-bromobenzyl group, 2,3- WO 2007/043542 PCTJP2006/020239 27 dibromobenzyl group, 3,4-dibromobenzyl group, 3,5 dibromobenzyl group, 2.,6-dibromobenzyl group, 2,4 dibromobenzyl group, 2, 5-dibronobenzyl group, 2,4,6 tribromobenzyI group, 2-methylbenzyl group, 2,3 5 direthylbenzyl group, 3, 4-dimethylbenzyl group, 3,5 dimethylbenzyl group, 2, 6-dimethylbenzyl group, 2, 4 dimethylbenzyI group,.2,5-dimethylbenzyl group, 2,4,6 trirethylbenzyl group, 3,5-ditrifluoromnethylbenzyI group, 2,4,6-trifluoromethylbenzyl group, 2-- 10 trifluoromethylbenzyl group, 3-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 2 trifluoromethoxybenzyl group, 3-trifluoromethoxybenzyl group, 4-trifluoromethocxybenzyl group, 3-methoxybenzyl group, 2, 3-dimerethoxybenzyl group, 3, 4 -dimethoxybenzyl 15 group, 3,5-dimethoxybenzyl group, 2,6-dimethoxybenzyl group, 2,4-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,4,6-trimethoxybenzyl group, 2,6 ditrifluoromethoxybenzyl group, 2,3,4 trifluoromethoxybenzyl group, 1-(2-chlorophenyl)ethyl 20 group, 1-(3-chloropheny1)ethyl group, 1-(4 chlbrophenyl)ethyl group, 2-(2-chlorophenyl) ethyl group, 2-(3-chlorophenyl)ethyl group, 2-(4 chlorophenyl)ethyl group, 1-(2-fluorophenyI)ethyl group, 1-(3"fluorophenyl)ethyl group, 1-(4 25 fluorophenyl)ethyl group, 2-(2-fluorophenyl)ethyl group, 2--(3-fluorophenyl)ethyl group., 2-(4 fluorophenyl)ethyl group, 1-(2-bkomophenyl)ethyl group, 1- (3-bromophenyl) ethyl group, 1- (4-bromophenyl) ethyl WO 20071043542 PcrijP2t)06i020239 .28 group, 2-(2-bro-nophenyi.)ethyl group, 2-(3 brommcophernyl )ethyi group, 2- (4-brornophenyl) ethyl group, I -(2-trfi.Uorolthyi~pheflyl)ethyI group, l-(3 t~i fluoromethayl'pheflyl) eth yl group, 1-14 5 trifluoromethylpheflyl)eth~d. group, 107(2 trifluronethoxypheiyl)ethyl g.:roup, 1-%3 nrifluoromethoxypheil) ethyl group, 1- (4 tri fluioromethioxypienlyl)ethyJ- group, 2-(2 trifiuoromethylphenli)eth.,.yi group, 2-13 10 trifluoromethyiphienyl) ethyl, group, 2- (4 trifiluoromethylpheiyi) ethyl group, 2-'(2 trifluoomthoxy2p enyl.)eth-yl gro. up, 2> (3-,~ trifuoroirmethoxypheflyl)ethli group, 2-(4 trtluoromethoxypheiyJ) eth-y.l- group, 3-(2 15 chiorophienyl) propyl group, 3- (3-chlorophenyl) propyl group,, 3-(4-chlorophenyl)propyl. group, 3-(2 fluorophenyl)prropyl. group, 3- (3-f luoropheriyl.)propyl group, 3- (4-f luorophenyl.)propyl group, 3- (2 bromophenyl) propyl group, 3- (3-bromophenyl) propyl 20 group, 3--(4-brornopheflyl)propyl group, 3-(2 *trifluo'roipethiyl'ph-efyl)propyI group, 3-1(3 trifluorornethylpheflyl)propyi g:jroup, 3- (4 trifluoromethylphenyl)propyi group, 3-02 trifiuoromsthvlphefyl) propyl group, 3- (3 25 trjfluoromethoxypheriyl)propyl group, 3-(4 trifluoramethoxyphefiyi)propyi, group ,. 4- (3 ch cr oprhenyl) butyl group, 4- (3-fluorophefiyl) butyl group, 4- (3-bromophernyl)buty1 group, 4-(3 WO 20071043542 PCT/JP2006/020239 29 trifluoromethylphenyl)butyl group, 5-(4 chlorophenyl) pentyl group, 4- 4-chlorophenyl) pentyl group, 5-(4-fluorophenyl)pentyl group, 4-(4 ,luorophenyl)pent.yl group, 5-(4-bromophenyl)pentyl 5 group, 4-(4-bromophen.yl)pentyI group, 5-(4 trifluoromethylphenyl)pentyl group, 4- (4 trifluoromethylphenyl)pentyl group, 4-(4 trifluoromethoxyphenyl) pentyl group, 6- (3 chlorophenyl) hexyl group, 6- (4-chlorophenyl) hexyl 10 (group, 6- (3-fluorophenyl) hexyl group, 6- (4 fluorophenyl)hexyl group, 6-(3-bromophenyl)hexyl group, 6- (4-bromophenyl)hexyl group, 6-(3 trifluoromethylphenyl).hexyl group, 6-(4 trifluoromethylphenyl)hexyl group, 6- (4 15 trifluoromethoxyphenyl)hexyl group, and 2 trifluoromethyl-3-trifluoromethoxybenzyl group (1-3 groups selected from the group consisting of a halogen atom an optionally halogen-substituted Cl-6 alkyl group and an optionally halogen-substituted CI-6 alkoxy group 20 may be substituted on the phenyl ring). A phenoxy C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 alkyl group and 'an optibnally halogen-substituted CI-6 alkoxy group 25 may be substituted on the phenyl ning) is a group composed of a phenoxy group unsubstiotuted or substituted with 1-5, preferably, 1-3 groups selected from the group consisting of an optionally halogen- WO 20071043542 PCT/JP2006/020239 30 substituted C1-6 aikyl group and an optionally halogen substituted C1-6 alkoxy group and halogen as defined, above and a C1-6 alkyl group, ano may include, for example: a phenoxymethyl group, 2-phenoxyethyl group, 5 3-phenoxypropyl group., 4-phenoxybutyl group, 5 phenoxypentyl group, 6-phenoxyhexyl group, 4 luorophenoxymethyl, group, 2-fluoro-4 bromophenoxymethyl group, 4-chloro-3 fluorophenoxymethyl group, 2,3,4-trichlorophenoxyrethyl 10 group, 3,4,5-trichlorophenoxymethyl group, 2,4,6 trichioropherioxymethyl group, 4 -isopropylphenoxymethyl group, 4-n-butylphenoxymethyl group, 4 methylphenoxymethyl group, 2-methylphenoxymethyl group, 3-methylphenoxymethyl group, 2, 4-dimethylphenoxymethyl 15 group, 2,3-dimethylphenoxymethyl group, 2,6 dimethylphenoxymethyl group, 3, 5-dimethylphenoxymethyl group, 2, 5-dimethylphenoxymethyl group, 2,4, 6 trimethylphenoxymethyl group, 3, 5 ditrifluoromethylphenoxymethyl group, 2,3,4,5,6 20 pentafluorophenoxymethyl group, 4 isopropoxyphenoxymethyl group, 4-n-butoxyphenoxymethyl group, 4-methoxyphenoxymethyl 'group, 2 methoxyphenoxymethyl group, 3-methoxyphenoxymethyl group, 2,4-dimethoxyphenoxymethyl group, 2,3 25 dimethoxyphenoxymethyl group, 2,6-\ dimethoxyphenoxymethyl group, 3, 5 dimethoxyphenoxymethyl group, 2, 9 dimethoxyphenoxymethyl group, 2, 4,6- WO 20071043542 PcT1jP2t)06i020239 31 trinPethoxypherioxymr.eth,'yl-- group, 3, 5 ditrifiuo~omethoxyphenoxymethyl group, 2 isopropoxyphenoxyrnethyl group, 3-chioro-4 mn~thcxyphenoxymethyl group, 2-chloro-4 5 triflu-,oroiethoxype-,oxvmet-ylgop mehl4 fluorophenoxymethyl group, 4-bromo-3 itrifuoromethylphnoxynethy1 group, 2-(4 fluorophenoxy) ethyl group, >- (.-fluoropheno:y) propyl group, 4-(4-fluorophenoxy)buty: group, 5-(4 10 fluorophenoxy) pentyl group, 6- (4-fluorophenoxy) hexyl group, 4-chlorophienoxymethl group, 27,(4 chiorophenoxy) ethyl group, 3- (4-chloropheiloxy) propyl group, 4-(4-chlorbphenoxy)butyl group, 5-(4 chioropherioxy) pentyl group, 6- (4-chiorophenoxy )hexyl 15 group, 4-methyiphenoxymethyl group, 2- (4 methylphernoxy)ethyi group, 3-(4-methylphenoxy)propyl group, 4- (4-1-ethylpheno xy) butyl group, 5- (4 methyiphenoxy) pentyl group, 6- (4-methylpherioxy)-hexyl group, 4-trifiuorompthylpheloxyriethyl group,, 2-(4 20 trifluoromethylphenoxy) ethyl group, 3- (4 trifluoromethyphenoxy) propyl group, 4- (4trifluoronethyphenoxy) butyl- group, 5- (4 trifluoromethylphienioxy)penitlI group, 6- (4 trifiuoromethylphernoxy)hexyi group, 4 25 trifluoromethoxyphenoxymethyl grouO, 2- (4 trifluoromethoxyphenoxy)ethyl group,'3- (4tfifiuoromrethoxherioxy)propyl g-?oup, 4-(4 tra fluoromethoxyphenoxy) butyl group, S- (4- WO 20071043542 PCT/JP2006/020239 32 trifluoromethoxyphenoxy)penity'l group, 6-'(4 trifluoromethoxyphenoxy)hexyl group, 2-(4 methoxyphenoxy)ethyl group, 3-(4-methoxyphenoxy)propyl group, 4- (4-methoxyphenoxy)butyl group, 5- (4 5 methoxyphenoxy)pentyl group, and 6-(4 methoxyphenoxy) hexyl group. A benzofuryl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom an optionally halogen-substituted Cl-6 alkyl group 10 and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring) may include, for example: a benzofuryl Cl-6 alkyl group (at least one group selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 15 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring) wherein, the alkyl moiety is a C1-6 linear or branched alkyl group such as: a [(2-, 3-, 4-, 5-, 6-, or 7-)benzofuryljmethyl group, 1-[(2-, 3-, 4-, 5-, 6-, or 20 7-)benzofuryl]ethyl group, 2- (2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl]ethyl group, 3-[(2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl]propyl group, 2- (2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl]propyl group, 4-[(2-, 3-, 4-, 5-, 6-, or 7-)benzofurgl]butyl group, 5-[(2-, 3-, 4-, 5-, 6-, or 25 7-)benzofuryllpentyl group, 4- (2-1 3-, 4-, 5-, 6-, or 7-)benzofuryl]pentyl group,. 6-[(2-, 3--, 4, 5-, 6-, or 7-)benzofuryl]hexyl group, 2-chl6ro-3-[(2-, 3-, 4-, 5-, 6-, or 7-)benzofuryl]propyl group, 1,1-dichloro-2-[(2-, WO 20071043542 PcT1jP2t)06i020239 3-, 4-, 5-, 6-, or 7-)berizofuryllethyil group, 2-4[iuoro 3q 2-,3-4---, -, or 7-)ben-zofuryiI roy1grup 11,I-dif luo'ro-2-r.(2-, 3-, 4-, 5-, 66, or, 71-,)en.zoru:Lryl]eth.y- group, 2-bromo-3-[r(2-, 3-, 4-,5 56-, or 7-)benzofur l],propyi1 group, 1, -airon-2- [2 3.-f 4-, 5-f 6-, or 7-.)benzofurylljethy- group, 2-methy'l 3-[2,3-, 4-, 5-.,,6-, or '7-)benzofuryllpropyl group, 1,1-dirnethyl-2-[ (2-, 3-, 4-,5-, 6-, or 7-)ben zofuryLlethyi group, 2-trifluoro.-ethyl-(3-, 4---, .~ --,6-~.or7-)benzoflrvirnethvl group, 5 tr-ifluoromethyl- (2-, 3-, 4-, 6-, or 7-) berizofurvlmethvl group, 4-methyi- (2-, 3-, 5-, 6-, or 7-bertaof urylrnethyl group, 2,4-diJ'methyil-(3-, 5-, 6-, or 7)benzof uryllmethyl group, 2,4,6-rimethy---(3-, 5-, or 7-)berizofurylmethyl 15 group, 4-trifiluoromethyl- (2--, 3-, 5-, 6-, or 7I-'benzofurvlrnethyl groupp. -- rfurmtv-(- 3-, 4-, 5c-, or 7-)beizofuryi"methyl' group, 2-,methoxyr-3-((2-, 3-, 4-, 5-, .6-, or 7-)benzofuryl Ipropyl group, 1,1 dimethoxy-2-[ (2>, 3-, 4- -5-, 6-, or 20 7-)benzo'furyl'e-hy1 group, 2-triflioromethoxy-(3-, 4--, 5-, 6-, or 7-)benzofuryime'thyl group, 5 triflioromrethoxy-(2-f 3-, 4-, '6-, or -)ezoriet\ group, 4-methoxy- (2-, 3-, S---,6 or 7') benzofurylmethyl group, 2, 4-dirnethoDxy- (3-, 5-, 25 6-, or 7-)berzofuryimethyi group, 2,4, 6-trimethoxy- (3-, 5-, or 7/-)benzofurylmethyi group, 4-trifuoocmethomy (2'-, 3--, 5--, 6-, or 7-)benz7ofury~imethyl group, and 6 trifiuoromethoxy-(2-, 3-, 4-, 5-, or WO 20071043542 PCT/JP2006/020239 34 7-) benzofurylmethyl group. A phenyl C2-10 alkenlyl group (at least one group selected from the group consisting of a halogen tom an optionally halogen-substituted Cl-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) includes both trans and cis forms, and 1-5, preferably, 1-3 groups selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 alkyl group and an 10 optionally halogen-substituted. C1-6 alkoxy group may be substituted on the phenyl ring which composes the phenyl C2-10 alkenyl group. Examples of such a phenyl C2-10 alkenyl group may include, for example; a 3 phenyl-2-propenyl group (conventional name: a cinnamyl 15 group), a 4-phenyl-2-buteny" group, 4-phenyl-3-butenyl group, 5-phenyl-4-pentenyl group, 5-phenyl-3-pentenyl group, 6-phenyl-5-hexenyl group, 6-phenyl-4-hexenyl group, 6-phenyl-3-hexenyl group, 4-phenyl-1, 3 butadienyl group, 6-phenyl---1,3,5-hexatrienyl group, 2 20 n-penty'l-3-phenyl-2-propenyl group, 9-phenyl-2-nonenyl group, 10-phenyl-2-decenyl group, 8-phenyl-1, 3octadienyl group, 9-phenyl-l,3,5-nonatrienyl group, 10 phenyl-2, 4, 6-decatrienyl group, 3- (2-chlorophenyl) -2 propenyl group, 4-(3-fluorophenylv-2--butenyl group, 4 25 (4-bromophenyl)-3-butenyl group, 5,-(3-chlorophenyl) -4 pentenyl group, 5- (4-fluorophenyl)-3-pentenyl group, 6 (2-bromophenyl) -5-hexenyl group, 6- 4-chlorophenyl) -4 hexenyl group, 6- (2-fluorophenyl) -3-hexenyl group, 4- WO 20071043542 PCT/JP2006/020239 35 (2-chlorophenyl) -1, 3-butadienyl group, 6- (3 fluorophenyl)-1,3,5-hexatrienyl- group, 2-n-pentyl-3-(3 bromophenyl) -2-propenyl group, 9- (3-chlorophenyl) -2 nonenyl group, 1Q-(4-fluorophenyl)-2-decenyl group, 8 5 (4--bromophenyl) -1, 3-octadienyl group, 9- (4 chlorophenyl)-1,3,5-nonatrienyl group, 10-(2 fluorophenyl)-2,4,6-decatrieryl group, 3-(2 methylphenyl) -2-propenyl group, 3- (2, 3-dimethylphenyl) 2-propenyl group, 3- (3, 4-dinethylphenyl) -2-propenyl 10 group, 3- (3,5-dimethylphenyl) -2-propenyI group, 3- (2,6 dimethylphenyl) -2-propenyl group, 3- (2,4 dimethylphenyl)-2-propenyl group, 3-(2,5 dimethylphenyl)-2-propenyl group, 3-(2,4,6 trimethylphenyl) -2-propenyl group, 3- (3,5 15 ditrifluoromethylphenyl)-2-propenyl group, 3-.(2, 4,6 trifIuoromethylphenyl)-2-propenyl group, 3-(2 trifluoromethylphenyl) -2-propenyl group, 3-(3 trifiuoromethylphenyl) -2-propenyl group, 3- (4 trifluoromethyiphenyl) -2-propenyl group, 3- (2 20 trifluoromethoxyphenyl) -2-propenyI group, 3-(3 trifiluoromethoxyphenyl)-2-propenyI group, 3-(4trifluoromethoxyphenyl) -2-propenyl group, 3- (3 methoxyphenyl) -2-propenyl group, 3- (2,3 dimethoxyphenyl) -2-propenyl group, 3- (3,4 25 dimethoxyphenyl)-2-propenyl group, 13-(3,5 dimethoxyphenyl) -2-propenyl group, 3- (2,6 dilethoxyphenyl) -2- propenyl group, 3-(2,4 dimethoxyphenyi) -2-propenyl group, 3- (2,5- WO 20071043542 PCT/JP2006/020239 36 dimethoxyphenyl)-2-propenyl group, 3-(2,4,6 trimethoxyphenyl) -2-prcopenyl group, 3- (2,6 ditri fluoromethoxyphenyl)-2-propenyl group, 3- (2,3,4 trifluoromethoxyphenyl) -2-propenyl group, 3-(2 5 trifluoromethli-3-trifluoromethxyphenyl)-2-propenyl group, 4- (3-tri fluoromethylphenyl) -2-butenyl group, 4 (4-trifluoromethylphenyl)-3-butenyl group, 5-(3 triflucromethylphenyl)-4-pentenyl group, 5-(4-, trifluoromethylphenyl)-3-pentenyl group, 6-(2 10 triflubromethylphenyl) -5-hexenyl. group, 6-(4 trifluoromnethylphenyl)-4-hexenyl group, 6-(2 trifluoromethylphenyl)-3-hexenyl group, 44(2 trifluoromethylphenyl)-1,3-butadienyI group,,6-(3 triflucromethylphenyl)-1,3,5-hexatrienylI group, 2-n 15 pentyl-3- (3-trifluoromethylphenyl) -2-propenyI group, 9 (3-trifluoromethylpheyril) -2-nonenyl group, 10- (4trifluoromethylphenyl) -2-decenyl group, 8- (4 ri fluoromethylphenyl) -1, 3-octadienyl group, 9- (4 trifiuoromethylphenyl) -1,3, 5-nonatrienyl group, and 10 20 (2-trifluoromethylphenyl) -2,4, 6-decatri enyl group. These are all an alkenyl group wherein 1---2 phenyl groups are substituted on the 'C2-10 alkenyl group with 2-10 carbon atoms and 1-3 double bonds (at least one group selected from the group consisting of a halogen 25 atom an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring) . A biphenyls C1-6 alkyl group (at least one WO 2007/043542 PCT/JP2006/020239 37 group selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted Ci-6 alkoxy group may be substituted on the phenyl ring) may include, for 5 example: a b iphenyl C1-6 alkyl group (1-3 groups selected from the group consisting of a halogen atom an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted Cl-6 alkoxy group may be substituted on the phenyl ring) such as: a 4 10 biphenylmethyl group, 1-(4-biphenyl)ethyl group, 2-(4 biphenyl)ethyl group, 3-(4-biphenyl)propyl group, 2-(4 biphenyl)propyl group, 4(4-biphenyl)butyl group, 5-(4 biphenyl)-pentyl group, 4-(4-biphenyl)pentyl group,. 6 (4-biphenyl) hexyl group, 2 -chloro-4-biphenylmtethyl 15 group, 2',3'-dichloro-4-biphenylmethyl group, 3',4' dichloro-4-biphenylmethyi group, 3' , 5' -dichloro-4 biphenylmethyl group, 2', 6' -dichloro-4-biphenvlmnethyl group, 2',4'.-dichloro--biphenylmethyl group, 2',5' dichloro-4-biphenylmethyl group, 2',4', 6 -trichloro-4 20 biphenylmethyl group, 2'-fluoro-4-biphenylmethyl group, 2',3'-difluoro-4-biphenylmethyl group, 3',4'-difluoro 4-biphenylmethyl group, 3' 5' -cifluoro-4-biphenylmethyl group, 2',6'-diluoro-4-biphenylmethyl group, 2',4' diflUoro-4-biphenylmethyl group, 2',5'-difluoro-4 25 biphenylmethyl group, 2',4',6'-trif-luoro-4 biphenyimet hyl group, 2'-bromo-4-biphenylmrethyl group, 2'', 3' -dibromo'-4-biphenylimethyl group, 3',4 '-dibromo-4 biphenylmethyl group, 3', 5'-dibromo--biphenylmethyl WO 20071043542 PCT/JP2006/020239 38 group, 2' ,6'-dibromo-4-biphenylmethyl group, 2' ,4 dibromo-4-biphenylmethyl group,. 2',5'.-dibromo-4 biphenvimethl. group, 2',4',6'-tribromo-4 biphenylmethyl group, 2'-methyl-4-biphenylmethyl group, 5 2', 3'-dimethy'-4-biphenylmethyl group, 3',4'-dimethyl 4-biphenylmethyl group, 3' , 5' -dimethyl-4-biphenylmethyl group, 2',6'- direthyi.l-4-biphenylmethyl group, 2',4 dimethyl-4-biphenylmethyl. group, 2' , 5' -di methYl-4 biphenylmethyl group, 2',4',6'-trimethyl-4 10 biphenylmethyl group, 3' ,-ditrifluoromethyl-4 b-phenylmethyl. group, 2' ,41 , 6'-triffluoroethyl-4 biphenylmethyl group, 2-tr 4f' uoromethyy--l biphenylmethyl group, 3 -trifluoromethyl-4 irphenylmethyl group, 4 '-trifluorornethyl-4 biphenylmethyl group, 2 -trifluoroimethoxy-4 biphenylmethyl group, 3' -trifluoromethoxy-4 biphenylmethyl group, 4'-trifuoromethoxy-4 biphenylmethyl group, 3' -methoxy-4 -biphenylmethyI group, 2',3' -dimethoxy-4-biphenyl methyl group, 3',4 20 dimethoxy-4-biphenyImethyl group, 3',5'-dimethoxv-4 biphenylmethyl group, 2', 6' -dimethoxy-4- iphenylmethyl group, 2',4'-dimethoxy-4-biphdnylmethyl group, 2',5' dimethoxy-4-biphenvmethv group, 2', 4', 6' -trimethoxy 4-biphenylmethyl group, 2',6'-ditrifluoromethoxy-4 25 biphenylmethyl group, 2' ,3', 4'-triiluoromethoxy-4 bipheriylmethyl group, 1- (2'-chloro-4-biphenyl ethyl group, 1- (3'-chloro-4 -biphenv1) ethyl group, 1- (4' chloro-4-biphenyl) ethyl group, 2- (2' -chloro-4- WO 20071043542 PcT1jP2t)06i020239 blphenyl)ethyL group, 2-(3'-chloro-4-b'.phienyl) ethyl1 group, 2-( -horo-4 -biphenyl) ethyl group, 1 - (2' t1luoro-4-biphenvy-L*Il) ehyi group, 1-\(31-fluoro- 4iphenyl)ethyi' Qroup, 1- (4 '-fiuoro-4-b-Lphiernl),ethyv-l 5 group, 2- (2L'-fl-uoro-4,-bipheriyl)ethiyl group, 2- (3' fluoro-4--biphnery ) eth--.yl gro up, 2- (4'-fluoro-4 biphenyl) ethyl group;' 1- (2' -bromo-4-bLphLL ernv.) ethLyl group, 1- (3'--bromo)-4-biphenvI.)ethyl group, 1- t4'--brrno- 4-biphenyl) ethryl group, 2- (2'-bromo--4-bipheniyl) e+ thyl+ 10 grtobp, 2- (3'-bromo-4-biphnyi) )ethyl group,2- 4-bo 4-biphenyl)ethy! group, 1-(2s-'trifluorornethIyl-4 biphenyl; ethyl group, 1 3 tilooehl4 biphenyl)ethyl group, 1-(4'-tLri'-luorrnet hyi-4 biphenyl)ethyl group, 1-12-,i.' tlluoromethoxy-4 15 biphenyl)ethyi group,i-3trfuomhxy4 biphenyl) ethyl. group, 1- (4'-t rifloroietoxy-4 biphenyl)ethyl group, 2-(2-'--trif -luoromne-thvl-4 blphenyl)ethyl group, .2- (3'-riffluoromethyl-4 biphenyl) ethyl-4 grc)u-,p, 2- (4 -triflIuoromethyl-4 20 biphenyl') ethyl group, 2- (' -tri fluoromethoxy-4 biphenyl) ethyl group, 2- (3' -tri uoromethoxy--4 biphenyli) ethyl gro up, 2- (4 '-tr fluoronethoxy-4 biphenyl) ethyl Qroup, 3- (2 ' -chl oro-4-biphenyl) propyl group, 3- (3.'-ch-lor-o-4-bl-phen-yl) propyl. group, 3--(4j' 25 chloro-4-biphenyl)propyl group, 3 2' fiuoro-4 blpheny'l) propyl group, 3- (3' -fl-uoro-4-bipphen-Iyl .)propyil group, 3- (4' -fluioro-4-b, .Iihenyl)p ropyl group, 3-(2' brom-.o--4-b,-".phenyl' propel. group, 3--(3'--brorno-4- WO 20071043542 PCT/JP2006/020239 40 biphenyl) propyl group, 3- (4 '-bromo-4-biphertyl) propyl group, 3-(2'-trifluorormethyl-4 -biphenyl)propyl group, 3-(3'-trifluoromethyl-4-biphenyl)propyl group, 3-(4' trifiuoromethyl-4-biphenyl)propyl group, 3-(2' 5 trifluoromethyl-4-biphernyl)propy1 group, 3-(3' t-rifluoromethoxy-4-biphenyl)propyl group, 3-(4' trifluoromethoxy-4-biphenyl) propyl group, 4-(3'-chloro 4-biphenyl)butyl group, 4- (3'-fluoro-4-biphenyl.) butyi group, 4-(3'-bromo-4--biphenyl)butyl group, 4-(3' 10 trifluorometylv-4-biphernyl)buty1 group, 5-(4'-chloro-4 biphenyl)pentyl group, 4- (4'-chloro- 4-biphenyl) pentyl group, 5-(4'-fluor -- biphenyl)pentyl group, 4-(4' fluoro-4-biphenyl)pentyl group, 5-(4'-bromo-4 biphenyl)pentyl group, 4-(4'-bromo-4-biphenyl)pentyl 5 group, 5-(4'-trifluoromethyl-4-biphenyl)pentyl group, 4-(4''-trifluoromethyl-4 biphenyl)pentyl group, 4-(4' tri fluoromethoxy-4 -biphenyl)pentyl group, 6-(3'-chloro 4-biphenyl) hexyl group, 6- (4 '-chloro-4-biphenyl) hexyl group, 6-(3'-fiuoro-4-biphenyl)hexyl group, 6-(4' 20 fluoro-4--biphenyl)hexyl group, 6-(3'-bromo--4 biphenyl) hexyl group, 6- (4 '-bromo-4-biphenyl) hexyl group, 6- (3' -trifluoromethyI-4-biphenyl) hexyl group, 6 (4'-trifluoromethyl-4-biphenyl) hexyl group, 6-(4' trif'luoromethoxy-4-biphen-yl)hexyl group, and 2' 25 trifluoromethyl-3'-trifluoromethoky-4-biphenylmethyl group Oxazole compounds repr sented by the general formula (1) include, for example, the following WO 20071043542 PCT/JP2006/020239 compounds: (R) -2-methyl- 6-nitro-2-(4--[4-(4 tri fluoromethoxyphenoxy)piperidin-1-y1]phenoxymethyi) 2 1 3-dihydroimidazo(2,1-boxazole (hereinafter referred 5 to as "compound (A-R).") (S)-2-methyl-6-nitro-2-(4-[4-(4 -trifluoromethoxyphenoxy)piperidin-1-ylphenoxymethyil 2,3-dihydroimidazo[2,1-b]oxazole (hereinafter referred to as "compound (A--S)") 10 (RS)-2-methy-6-nitro-2-{4-[4-(4 trifIuoromethxyphenoxy) piperidin-1-yl ] phenoxymethyl ) 2,3-dihydroimidazo[2,1-b]oxazole (hereinat.ter referred to as "compound (A-RS) ") 3-(4-trifluoromethyipheriyi) -2-propenyl (R)-4-(2-methyi 15 6-nitro-2, 3-dihydroirmidazo2, 1-b]oxazol-2 ylmet'hyl)piperazine-1-carboxylate (hereinafter referred to as "compound (B-R)") 3- (4-trifluoromethylpheryl) -2-propenyl (S) -4- (2-methyl 6-nitro-2, 3-dihydroimnidazo [2, i-b] oxa zol-2 20 ylmethyl)piperazine-1-carboxylate (hereinafter referred to as "compound (B-S) 3-(4-trifluromethylphenyl)-2-'propenyl (RS)-4-(2 methyl-6-nit ro-2,3-dihydroimidazo[2,1-b]oxazol-2 ylmethyl)piperazine-1-carboxylate (hereinafter referred 25 to as "compound (B-RS)") (R)-2-(4-(4-[N-(4-chlorophenyl) -N-met-hyl aminopiperidin-1-ylp henoxynmethyj)-2-methyl-6-nitro 2,3-dihydroimidazo[2,1-b]oxazcle (hereinafter referred WO 20071043542 PcT1jP2)06i020239 43 FI -- S-214-[4-34:--dichriorobenzy! piperid.in-l yvilphenioxymeth~yl-2-methyl-6-nitro-2, 3 * ihydroirnidazo [2,1I-b] oxazole (Iee ferrfre o 5as "compoundI tE-RS)?? trifluor-oreth- oxvph enoxy) pipe idin- I- yilphenoxynethyi-1 2,--dihydroiridazo[2,i-bloxazol'Je (hereiLna-fter- referred 'to as "compound. (F-R)") 1l0 (S) --6--nitro--2-- 1 4--4tri4 fluoromethoxy~thenoxy )piperidin-1-y ljphenoxyrnethyi- 2,3~diydrimiaz(2,-b~xaz~e(hereinafter referred to as "comnpound (F-S)".) (RS)-6nto-2(-4(4 15 trifiooethoxyphenoxy) pi peridin--i--.yi I ph-enoxymethyl } 2, 3-dih-ydro:-imi-dazo [-2, i-b]oxazol]e (her'einaf ter re.fer-red t-o as "compound (F-RS)") (R) -6-(24-methyi-6-n,' -ro-2, 3-dihyvdroim-r.idazo [2,1 b]oxazol--2--yimethoxy---2--1[4--(4-- 20 t-rifluorometho xybe-nzyi-)piperaz" n-1-y1]ben-zot--hiazole (herieinafter- referred to as "compound (G-R) "' (S) -6-(2-methyl-6-i tr'o-2,3-dihyvdroimidcAzo[2,i b] oxazoi,-2-ylmethoxy) -2- [4- (4t-ri-FluoromethioxybenzyiL)pl.peraz,'nr-1-yllbenzo-hiazole 25 (hereinafter referred to as ",compound (G-S), (RS) -6- (2-mlethyi-6-niLtro-2,3-iy r idazo [2, 1 b'icxazol-2-ylmethoxy)-2-['4-(4 trifluoromiethoxybenizyI~ pi*-perazirn-1-yl] bezoc-hiazoi1e WO 2007/043542 PCT/JP2006/020239 42 to as "compound (C-R1 )-2- (4-( 4-[N- (4-chloropheny) -N-methy amino] pi peridin-1-yl ) phenoxymethyl) -2- methyl1-6-nitro 2, 3-dihydroimidazo[2,1-b]oxazole (hereinafter referred 5 to as "compound (C-S) ") (RS) -2- (4-( 4- [N- (4-chlorophenyl) -N-methyl -amino] piperidin--yJ.l phenoxymethyl) -2-methyl-6-nitro 2,3-dihydroimidazo[2,1-b]oxazole (hereinafter referred to as "compound (C-RS) ") 10 (R)-2-methyl-6-nitro-2-{4-[4-(4 trifluoromethoxybenzyi)piperidin-1-yl]phenoxyrmethyi} 2, 3-dihydroimidazo[2, 1-b~loxazole (hereinafter referred to as "compound (D-R)") (S) -2-methyI--6- nitro-2--2 4-- 4- (4- 15 tr ifluoromethoxybenzyil)piper idin-1-ylphenoxyme tyl} 2, 3-dihydroimidazo [2, 1-b] oxazole (hereinafter referred to as "compound (D-S) ") (RS) -2-methyl-6-nitro- 2-(4- [4- (4 trifliuoromethoxybenzyl)piperidin---y'Iphenoxymethyl} 20 2, 3-dihydroimidazo [2, 1-b} oxazole (hereinafter referred to as "compound (D---RS) (R) -2-{4-[4 - (3,4-dichlorobenzy.)piperidin-1 yl]phenoxymethyl } -2-methyl-6-nitrco---2, 3 dihydroimidazo[2, 1-b]oxazole (hereinafter referred to 25 as "compound (E-R)") (S) -2-( 4- [4- (3, 4 -d ich loroben zyl)piperidin yl'] phenoxymethyl }-2--methyl-6-nitLo-2, 3 dihydroimidazo[2,1-bioxazole (hereinafter referred to WO 20071043542 PcT1jP2t)06i020239 44 (her-einafter referred~ to as "compound (G-RS)" (R) -6-nitro-2-{ 4-[4-(4 triflorcmethoxybenzyioxy( /pi,.eridin-1-1 yjlphenioxymeLhl-2,-dihiydroimidazo[2,1-blioxazol~e 5 (hereinafter referred to as "c-omp-ound -)" tri-fioromethoxyberlzy,.Ioxy), pioerl din-I yli phenoxy~r.ethy 1'1-2, 3-dihydro imi azo [2, 1-b] oxa-zole (tEereiina after referred to as compoundd (H-S)" trif'Llorometl hoxybenzyl-oxy( pip-eridin-i yl]!Lhenoxvmethy1),-2,3--dihydroirpidL-,azo('2,1-b,]oxazole (htereinafter referred to as "compound (H-RS)" tr rif'LuoromerLhoxyphenyiL)ethyi-'piper -icii-lI YUlphenoxymethvl) -2, 3-d hydro" m,' dazo [2, 1-b) oxa role (I herein-after refer-red to as "compound (I-Pd ) trifluorometlhoxyphenyl 'eth~yl piper-'di,-l 20 yl~phenoxvrethyl)-2,3 -dhydroimrn-idazot2,1-bloxazole hereinlaftLer referred to as compoundd (I-S~ ) (R S)--2 -me th y-1-n it r o -2 -(4 -4 2 (i trifluoromectlhoxyphnlehy]iprdyi }p Heno xyrnt;hyi1) - 2, 3 d h yd r o irmJd a zo 2, I -b] o x aZoe 25 (hereinafter referred to as "compodnrd (I-RS)") (R)-2-(-1-f4-(4-chlorophenoxymet-hyl-'J)tperidinyi']phenoxyniethy 1} -2-methylr6-nitro-2 , 3 dhdoimid zo[2,1-bloxazole (her-,atrreerdt WO 20071043542 PcT1jP2)06i020239 4 5 as "COrnPou-nd (J-RU) (S) -2{(4i4-(4-chorophenoxymnethyi)pip)eridini-l yl] phenoxymethyJ. -2-methyi-6--nitro-2,3 dihydroi..midazo [2,1'-b' oxazol-e (hereinafter referred to 5 as "compound .(J-S) ') (,PS) -2-1{ 4- [4-(4-chior ophe n.oxy-me- zhy1) piperidin-1 y1]phenoxymethy1 i 27-methy-6-nitro-2,3 dihydrormidazo[2,1-blcxazole (h-iereinafter referred to as ?compound (J-RS)") 10 (R)-6-nitro-2-{4-[4-(4 trifiuormethoxyphenoxymethyi) piperidin- -. y.1]phenoxymethyI-2,3-dihydroimidazo[2,1-, ]oxazole (hereinafter referred to as~ "compound (K-R)") (S)-6-nitro-2-j4-[4-(4 15 trifluoro iethoxyphen~oxymethyi)piperidinyl Iph.enoxym ethy1 -2,3 -dihydroimidazo[2,1-b~oxazole (hereinafter referred to as "compound (K-S)'') trifluoromethoxyph enoxyrethyl.)piperidin-1 20 yl phenOxym ethy) (-2, 3-dihydroimidazo (2, I-b] oxazole (hereinafter referred to as "'compound(K-)" (R) -6-nitro-2-{ 4- [4- (4 trif luoromethoxybenzyi) piperidin-i-yl] phenoxyrnethyl' } 2, 3-dihydroQimidazo[2, 1-b~oxazole (hereinafter referred 25 to as "compound (L-.) trifluoromethoxybenzyI)piperidini1-y1]phenoxymethy}) 2,3-dihvdroimidazo[2, 1-b]oxazole (hereinafter referred WO 20071043542 PcT1jP2t)06i020239 46 to as "comnpound (L-S)") (RS) -E3-n'tro-2-{4-"- (4triafl':u(Drornethoxvbenzy ) piperidi4n-1-yii phenoxymethyi} 2,di hvYd.o mid Tzo [2, 1 -b o x azol e (her e in after re Ze rreci 5 to as "compound (L-RS)") (-R--methvi,.-6--nitro--2-{4-[4-(4 tri-fluoromethoxybenzyioxvipe-ridiri-1 yij1 phenoxymethyl1} -2, 3 -di hydroini da zo[ 2, 1-b oxa zole (h'ereiniaf 'er referred to as "comTpound C -R)) 10 (S)-2-m~ethyl.-6-niro-2---i4-(4 t r ifluorone IChoxyben z yioxy) piperidin-1 yl hnxmthl1-,3d4 yr-mlao[,14 xzl (hereinafter referred to as "compound (1-S)" (PS) -2 -methvL--6--ni'-tro--2-- 4- [4-(4 151 t-rifluoromethoxybe z 'Ioxy)piper,-din-i yl]ph'enoxymethyi}1-2, 3-dihiydroimi'dazo[2, 1-b]oxazoie (hereinafter referred to as "compound (M-RS)") tri.fluoronethoxyphenyl) -2--propenyipipera i-1 20 yll}phenoxy-methyi) -2, 3-dihydroimidazo [2, 1-b] oxazole (h-ereinafter ref--err-ed to as "compound (tJ--R)" (5) -2-methyi-6-nitro-2- (4- (4-[3- (4 tr-ifluorramethoxyphiEnryl) -2-propenyl] pilperazin-1 y1}lphenoxymethyl) -2, 3-dihydroimidazo [2, 1--b] oxazole 25 (hereinafter referred to as "compound (N-S)"), ~rifluorome-hoxyphenyi) --2--propenyI'pip-"erazin-' yi- pbenoxymeth~yl) -2, 3-dihy-droimidazol,2, 1.--b] oxazole WO 20071043542 PCT/JP2006/020239 !hereinafter referred to as "compound (N-RS)")

(R)-

2

-{

4

-[

4 -(4-chlorophenoxymethyl)piperidin-1 yl] phenoxymethyl}-6-nitro-2,3-dihydroimidazo[2,1 b]oxazole (hereinafter referred to as "compound (0-R)") 5 (S)-2--(4-[4-(4-chlorophenoxymethyl)piperidin-1i yl] phenoxymethyl 6-nitro-2, 3-dih ydroimi dazo [2,1 b]oxazole (hereinafter referred to as "compound (0-S)") (RS)-2-{4-[4-(4-chlorophenoxyrmethyl)piperidin-1 yl]phenoxym nethyl}-6-nitro-2,3-dihydroimidazo[2,1 10 b]oxazole (hereinafter referred to as "compound (0 RS)") (R) -.- nitro-2-{4-[4-(4 trifluoromethy1phenoxymethyl)piperidin-1yl]phenoxymethyl)-2, 3-dihydroimidazo [2, 1-b]oxazole 15 (hereinafter referred to as "compound (P-R)") (S) -- nitro-2-{4-[4-(4 trifluoromethylphenoxymethyl) piperidin-1 yI]phenoxymethyl}-2,3-dihydroimidazo[2, 1-bioxazole (hereinafter .referred to as "compound (P-S)") 20 (RS)-6-nitro-2-{4-[4-(4 trifiuoromethylphenoxymethyl) piperidinyliphenoxymethyi }-2, 3-dihydro'iridazo[2,1-b]oxazole (hereinafter referred to as "compound (P-RS) ") (R) -2-methyl-6-nitro-2- {4- [4- (4 25 trifluoromethylphenoxymethyl)piperidin-1 y phenoxymethyl }-2, 3-dihydroimidazo[2,1-b]coxazole (hereinafter referred to as "compbund (Q-R) (S)'-2-methyl'- -nitro-2-{4-[4-(4- WO 20071043542 PCT/JP2006/020239 4F trifluoromethylphenoxymethyl)piperidin-1 yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (hereinafter referred to as "compound (Q-S) ") (RS) -2-methyl-6-nitro-2-{ 4- [4- (4 5 trifluoromethylphenoxymethyl)piperidin-1 yl] phenoxymethyl }-2, 3-dihydroimidazo[2,1-b]oxazole (hereinafter referred to as "compound (Q-RS)") (R) -2-methyl-6-nitro-2-{ 4- [,4- (4 trifluoromethoxyphenoxyrmethyl) piperidin-1 10 v]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (hereinafter referred to as "compound (R-R)") (S)-2-rethyl-6-nitro-2-{4-[4-(4 trifluoromethoxyphenoxymethyl)piperidin-1 yl]phenoxymethyl )-2, 3-dihydroimidazo [2, 1-b] oxazole 15 (hereinafter referred to as "compound (R-S)") RS) :2--methyl-6-nitro-2-{4-[4-(4 trifluoromethoxyphenoxymethyli piperidin-1 yl]phenoxymet-hyl)-2,3-dihydroimidazo[2,1-b]oxazoie (hereinafter referred to as "compound (R-RS)") 20 (R)-6-nitro-2-(4-(4-[3-(4 trifluoromethoxyphenyl)propylipiperidin'-1 yl)phenoxymethyl) -2, 3-dihydroimidazo [2, 1-b] oxazole (hereinafter referred to as "compound (S-R)") (S)-6-nitro-2-(4-{4-[3 -(4 25 trifluoromethoxyphenyl)propyljpipetidin-1 yi phenoxymethyl) -2, 3-dihydroimidazo{2,1-]oxazole (hereinafter referred to as compoundd (S-S)") (R.7S) -6-nitro-2-(4-{14-[3-(4- WO 20071043542 PcT1jP2t)06i020239 49 tr~llfioromethoxypheny1) prop~yl- 'piperidlin-i yl phenoxymethyi) --2, 3-dihydrcimJ a~o [2, 1--b oxazole (here ina after referred to as "com-vpound fS-RS)"* (R) -5-- (2-methyI-6-rnitro-2, 3-dihydroimidazo [2,4 5 -b]oxazol -2--ylrethoxy)--2--r4--(4 -rfuoroethoxybenzI) pliperidin-ly]-prdn (he reinafter referred -to as "compound (T-R)") (S) -5-(2-methnyi--6--nitro--2,3--di-hydroinidazoFL2,l bjoxt'.zoI-2-yimet-.hoxy) -2-[4-'(4 IC trif~luoromethoxybenzypipeidn----.yli--pyridine (hereinafter referred to as "compound (T-Sc)") (RS)-5-(2-methyl-6-nit- ro-2, 3-di'hvdr-oi'mi daao[2,1 b] oxazol-2-yi-methoxy) -72- [4- (4 trifiuoronet-hoxybenzyil) piperidin-l-yl] -pyridine 15 ('hereinafter referred .to as."compound (T-RS) tri.flur.methylbenizo*fura-1-2-yimTethyi)piper-"d'nyI)phenoxymethyi}-2, 3-dihydroimidao[,Ib xzl (hereinafter refer red to as compoundd (U-R)") 20 (S)-2-mrethyl-6-nit-ro-2-{4-(L4-(5 t+Irifuoromethvi.benizofur.-an,-2--y-imetLhyl) piperidi -n-i yiljphenoxyeth'i-2',3-dihiydro,'-mnl'dazo[241--b]oxazo.e (hereiLnafter referred to as "compound (U-S)") (RS) -2 -met hy--6-ni-tro-2-{ 4- [4- (5 25, tri-*f uorohetlhylbenzof uran-2-ymrethAI) piperidinyv-Iiphenoxvmetbyi} -2, 3-dihydr.oimidazo [ 2, -b] oxazol-e (herei-nafter referred to as "compound (JR)" (R) -6- (2-=nvethi -6-n.itro-2,3--dihdroim-idazo[2,1- WO 20071043542 PcT1jP2t)06i020239 50 bioxazo--2-yimethoxy) -2- [4- (4 tiloroief-hoxybenzy.i.) piperidi n-11-yl quino'_Line (hereinafter referred to as "compollnd0 (V-R)" 'IS)- 6 -(2 -met hyl - 6-n illro--2, 3-dihydroirnida zo [2,1 Sblcoxazol-2-yi"meth-oxy),-2-[4- (4 trifuorometh7oxybenzy-) pi peridin--1 .-- yiJ quinoiiin-e (hereinafter referred to as "compound (V-S)") (RS) -6- (2-methyi-6-nitro-2, 3-dihydroimidazo [2,1 b] oxazoi-2-yimethoxy) -2- [4- ( 10 riluoromethoxybenzyl) pipe ridin -1 -l] qu ino Iine (h1-ereinafter referred to as "compound (V-RS)") ("R) -.6-nitro -2-{ 4- [4- (4 '-trifluoronethyibiphenyl-4 yimethyl) pi-'erazin-1--yi] phenoxymethvyl }-2 3'-I dinyaroimnidazo['2,1-b]oxazole (h ereinafter referred to, 15as "compound (W-R)) (S)-6-nitro-2-('4-[4-(4'-r rifiuoroneth-y.ibipLhenyl-4 yimethyl) piperazin-1-yi 3 pnox' ethyl) -2, 3 dihydroL idazo r2, 1-b' oxazole (hereinlaf ter ref erred to as, "compound (WP-S) 20 (RS)-6-niitro-2--(4- [4-(4'---zLrifiorometybiphenvi--4 ylmethy)piper-azin-l -yi-)phenoxymethyi}-2/-,3 dihydroimidazol.2, 1-b",oxa zole ,(hereiniafter- ref erred to as "compound (W-RS)". (P-4--,(2-rethy-6-nitro-2, 33-dihydroi rtidazo [2, 1_ 25 billoxazoi-2-YI) methyl. I-N- [(E) -4 1-f~ifuoromethylbenzylidenie]p'pera-zin7l-aminie (hereinafter referred to as "COM~f.OUrld (X-R," (S)- 4-'i (2-mretffi-6-nitro--2,3-dihydr-oimidazo[2, 1- WO 20071043542 PCT/JP2006/020239 51 bjoxazol-2-yl) methyl]-Nl- [(E) -4 trifluoromethylbenzylidenejpiperazin-l-amine (hereinafter referred to as "compound (X-S)") (RS) -4-[ (2-methyl-6-nitro-2, 3-dihydrdimidazo[2, I 5 b~oxazol--2-yllmethyl]-N-[(E)-4 trifluoromethylbenzylidenelpiperazin-l-amine (hereinafter referred to as "compound (X-RS)") (R) -2-methyl-6-nitro-2-(4-{4-[(E)-3- (4trifluoromethylphenyl)-2-propenyl] piperazin-l 10 yl)phenoxymethyl)-2,3-dihydroimidazo[2,1--b]oxazole (hereinafter referred to as "compound (Y-R)") (S) -2-methyl-6-nitro-2- (4-(4-[(E)-3-(A trifluoromethylphenyl)-2-propenyijpiperazin-1 yl) phenoxymethyl) -2, 3-dihydroimidazo[2,1-b]oxazole 15 (hereinafter referred to as "compound (Y-S)") RS)-'2-me-thyl-6-niitro-2- (4-(4.-[(E) -3-(4 tri-fluoromethylphenyl) -2-propenyl ] piperazin-l y1)phenoxymethyl) -2,3-dihydroimidazo[2,1-b]oxazole (hereinafter referred to as "compound (Y-RS)") 20 The present invention preferably uses at least one selected from the group consisting of the oxazole compounds described above, optically active forms thereof and pharmacologically acceptable salts thereof. 25 Optically active forms oft oxazole compounds include R and S forms. Pharmacologically accepIable salts include, for example, inorganic acid salts such as sulfate, WO 20071043542 PCT/JP2006/020239 52 nitrate, hydrochloride,. phosphate and hydrobromide, sulfonic acid salts such as p-toluenesulfonate, methanesulfonate and ethanesulfonate, and organic acid salts such as oxalate, maleate, fumarate, malate, 5 tartrate, citrate, succinate and benzoate. The more preferred oxazole compounds (1) are .at least one selected. from the group consisting of compounds (A-R), compounds (Q-R), optically active forms thereof and pharmacologically acceptable salts. .0 thereof. The above oxazole compounds, optically active forms thereof and pharmacologically acceptable salts thereof (I), their manufacturing method, doses in their use, etc. are disclosed in JP-A-2004-149527 and WO2005 15 042542, the disclosures of which are incorporated hereih by reference as a part of the specification. The drugs (II) which may be combined with oxazole compounds (I) in the present invention include, for example, drugs selected from the followings. One 20 or more drugs (QI) may be used in combination. it is preferred that one or more drugs selected from antituberculous drugs of the following (1) are used in combination. (1) Primary antituberculous drugs 25 The primary antituberculolUs drugs include, for example, rifamycin and related anti-bacterial drugs (rifampicin, rifabutin, rifapent.i e, etc.), isoniazid, ethambutol, streptomycin, pyrazinamide, etc. These WO 20071043542 PCT/JP2006/020239 53 primary antituberculous drugs may be in the form of salts such as sodium methanesulfonate and hydrochloride. The specific examples include, for example, isoniazid sodium methanesulfonate, ethambutol 5 hydrochloride,, streptomycin sulfate, etc. (2) Secondary antituberculous drugs The secondary antituberculous drugs include, for example, p-aminosalicylic acid, alumino-p amindsalicylic acid, ethionamide, prothionamide, 10 enviomycin, kanamycin, capreomycin, cycloserine, thioacetazone, clofazimine, diaphenylsulfone, etc. These secondary antituberculous drugs may be in the form of salts such as calcium salt, sulfate, etc. The specific examples include, for example, calcium p 15 aminosalicylate, calcium alumino-p-aminosalicylate, enviohycin sulfate, kanamycin sulfate, etc. (3) Quinolone antibacterial drugs The quinolone antibacterial drugs include, for example, gatifloxacin, moxifloxacin, grepafioxacin, 20 nadifloxacin, nalidixic acid, pipemidic acid, piromidic acid~, enoxacin, norfloxacin, ofloxacin, tosufloxacin, ciprofloxacin, lomefloxacin, sparfloxacin, fleroxacin, levofloxacin, prulifloxacin, pazufloxacin, linezolid, etc. These .uinolone antibacterial drugs may be in the 25 form of salts such as tosylate, hydrochloride and mesylate, and hydrates. The specifdic- examples include, for example, tosufloxacin tosylath, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, pazufloxacin WO 2007/043542 PCT/JP2006/020239 54 mesylate, gatifloxacin hydrate, pipemidic acid trihydrate, etc. (4) Macrolide antibacterial drugs The macrolide antibacterial drugs include, 5 for example, clarithromycin, azithromycin erythromycin, etc. These macrolide antibacterial drugs .may be in the form of hydrates. The specific examples include, for example, azithromycin hydrate, etc (5) 8ulfa drugs 10 The sulfa drugs include, for example, sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfadimethoxine, sulfamethizole, sal-azoswlfapyridine, sulfadiazine, etc. These sulfa drugs may be in the form of salts such as silver salt etc.. The specific 15 examples include, for example, sulfadiazine silver, etc. (6) Anti-HIV drugs The anti-HIV drugs include, for example, (a) a reverse transcriptase inhibitor based on a 20 nucleic acid (zidovudine, didanosine, zalcitabine, lamivudine, stavudine, abacavir, adefovir, adefovir dipivoxil, fozivudine tidoxil, etc.], (b) a reverse transcriptase inhibitor based on a non nucleic acid [nevirapine, delavirdine, efavirenz, 25 loviride, immunocal, oltipraz, etc,], (c) a protease inhibitor [saquinavir; ritonavir, indinavir, nelfinavir, amprenavii, palinavir, lasinavir, lopinavir, etc.], etc. These anti-HIV drugs WO 2007/043542 PCT/JP2006/020239 may be in the form of salts. The antituberculous therapeutic drugs of the present invention combined with the oxazole compounds (I) and the above. drugs (II) include preferably the 5 following (1) to (11) () antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with at least one selected from the group consisting of the primary antituberculous drugs (preferably, rifamycin 10 and related anti-bacterial drugs (preferably, at Least one selected from the group consisting of rifampicin, rifabutin and rifapentine, and. more preferably rifampicin), at least one selected from the group consisting of isoniazid, ethambutol, streptomycin, 15 pyrazinamide and salts thereof) and the secondary antithberculous drugs (preferably, at least one selected from the group consisting of enviomycin, kanamycin, capreomycin, cycloserine, thioacetazone, clofazimine and salts thereof); 20 (2) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with at least one primary antituberculous drug selected from the group consisting of rifamycin and related anti bacte'ial drugs (preferably, at least one selected from 25 the group consisting of rifampicin,t rifabutin and rifapentine, and more preferably rifampicin), isoniazid, isoniazid sodium methakesulfonate, ethambutol hydrochloride, streptomycin, and WO 2007/043542 PCT/JP2006/020239 pyrazinamide; (3) antituberculous therapeutic drugs comprising a combination of oxazole corripounds (I), (i) rifamycin and related anti-bacterial drugs (preferably, 5 at least one selected from the group consisting of rifampicin, rifabutin and rifapentine, and more ,preferably rifampicin) with (ii) at least one primary antituberculous drug selected from the group consisting of isoniazid, ethambutol hydrochloride, streptomycin 10 and pyrazinamide; (4) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I), (i) rifamycin aid related anti-bacterial drugs (preferably, at least one selected from the group consisting of 15 rifampicin, rifabutin and rifapentine, and more preferably rifampicin) with (ii) pyrazinamide; (5) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with at least one primary antituberculous drug selected from 20 the group consisting of (i) rifarrycin and related anti bacterial drugs (preferably, at least one selected from the group consisting of rifampicin, rifabutin and rifapentine, and more preferably rifampicin), (ii) pyrazinamide and (iii) isoniazid, isoniazid sodium 25 methanesulfonate, ethambutol hydro chloride, and streptomycin; (6) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with WO 2007/043542 PCT/JP2006/020239 S) 7 at least one quinolone antibacterial drug selected from the group consisting of gatifloxacin hydrate, moxifloxacin, and grepafloxacin; (7) antituberculous therapeutic drugs 5 comprising a combination of oxazole compounds (I), (A) at least one quinolone antibacterial drugs selected .rrom the group consisting of gatifloxacin hydrate and moxifloxacin and (B) at least one primary antituberculous therapeutic drug selected from the 10 group consisting of rifamycin and related antibacterial drugs (preferably, at least one selected from the group cons,ting of rifampicin, rifabutin and rifapentine, and more preferably rifampicin), isoniazid, isoniazid sodium methanesulfonate, ethambutol hydrochloride, 15 streptomycin and pyrazinamide. (8) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I), (A) at least one quinolone antibacterial drug selected from the group consisting of gatifloxacin hydrate and 20 moxifloxacin, (B-i) rifamycin and. related antibacterial drugs (preferably, at least one selected from the group consisting of rifampicin, rifabutin and rifapentine, and more preferably rifampicin) and (B-ii) at least one primary antituberculous therapeutic drug selected from 25 the group consisting of isoniazid, iethambutol hydrochloride, streptomycin. and. pyrazinamide. (9) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I), (A) WO 2007/043542 PCT/JP20061020239 58 noxifloxacin, (B-i) rifanpicin and (B-ii) pyrazinamide. (10) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with at least one quinolone antibacterial drug selected from 5 the group consisting of gatifloxacin hydrate and moxifloxacin; 11) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with at least one macrolide antibacterial drug selected from 10 the group consisting of clarithromycin and azithromycin hydrate; and (12) antituberculous therapeutic drugs comprising a combination of oxazole compounds (I) with anti-HIV drugs which are (a) a reverse. transcriptase 15 inhibitor based on a nucleic acid, (b) a reverse transcriptase inhibitor based on a non-nucleic acid or (c) a protease inhibitor. The above oxazole compounds (1) and the above drugs (II) may be administered orally or parenterally. 20 wherein, when using a medicament comprising a combination of oxazole compounds (T) of the present invention and drugs (II) described above, administration period of oxazole compounds (I) of the present invention and drugs (II) described above is not 25 limited, therefore, oxazole compounds (I) of the present invention or their pharmaceutical compositions and drugs (I!) described above or their pharmaceutical compositions may be administered to the subject WO 2007/043542 PCT/JP2006/020239 59 concomitantly or- with time difference. When administering oxazole compounds (s ) and drugs (II), while they may. be administered concomitantly, drugs (II) may be administered earlier followed by 5 administration of oxazole compounds (I) or oxazole compounds (I) may be administered earlier followed by administration of drugs (II) . When administering with time difference, the .time difference varies. depending on active ingredients, formulations and methods of 10 administration. When administering drugs (II) earlier for example, the method includes administration of oxazole compounds (I) within I minute to 3 days, preferably within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour after administration of 15 drugs (TI) The dose of diugs (II) described above may conform the dose used clinically and may be appropriately selected depending on a subject to be administered, an administration route, a disease, a 20 combination etc. The administration form of drugs of the present invention used in combination is not particularly limited only if oxazole compounds (I) of the present.invention are administered with drugs (II) 25 described above. Such administration forms include, for example, (1) administration of si-ngle preparations obtained by formulating oxazole, compounds (I) and drugs (I described above simultaneously, (2) simultaneous WO 2007/043542 PCT/JP2006/020239 60 administration in the same administration route of two preparations obtained by formulating oxazole compounds (I) and drugs (II) described above separately, (3) administrationn with time difference in the same 5 administration route of two preparations obtained by formulating oxazole compounds (I) and drugs (II) described above separately (for example, administration in the order of oxazole compounds (I); one or more drugs (IT) described above, or in the reversed order), 20 (4) simultaneous administration in the different administration. route of two preparations obtained by formulating oxazole compounds (I) and' druds (IT) described above separately, (5) administration with time difference in the different administration route 15 of one or more preparations obtained by formulating oxazole compounds (I) and drugs (II) described above separately (for example, administration in the order of oxazole compounds (I); one or more drugs (IT) described above, or. in the reversed order). 20 Further, when using a medicament of a single oxazole compound (I) or that comprising a combination of oxazole compounds (I) with drugs for concomitant use, administration is performed, for example, intermittently with interval periods set in order to 25 relieve and eliminate side effects of the existing drugs for concomitant use being used 'in combination. When administering intermittently, while interval. period of the present invention will vary corresponding WO 2007/043542 PCT/JP2006/020239 to different situations and be determined as needed by the physician's judgment, oxazole compounds (I) are desirably administered at regular intervals. Therefore, in an embodiment of the present 5 invention, oxazole compounds (I) are administered at intervals of about 48 hours or more (preferably, about 72 hours or more, more preferably, about 7 days or more). Further, in an embodiment of the present 10 invention, oxazole compounds (I) are administered not more than 5 times, preferably not more than 3 times, preferably not more than 2 times, more preferably one time a week. The medication mode of 3 times a week includes such a procedure that medication is dosed 15 continuously for 3 days from initiation of administration followed by other 4 days of interval in 7 days. The medication mode ofF 2 times a week includes such a procedure that medication is dosed continuously or 2 days from initiation of administration followed 20 by other 5 days of interval in 7 days. Further, the treatment mode of 5 times a week includes such a procedure that medication is dosed continuously for 5 days per week followed by the other 2 days of interval. Any of oxazole compounds (I) which are 25 components of the present invention, drugs (IT) and/or medicaments of the present invention 'comprising a combination of oxazole compounds (I) with drugs (II) have low toxicity, and oxazole compounds (I) and/or WO 2007/043542 PCT/JP2006/020239 62 drugs (II) may be mixed with pharmacologically acceptable carriers according to known methods and administered safely as pharmaceutical compositions, for example, tablets (including sugar-coated and film 5 coated tablets), powders, granules, capsules (including soft capsules), solutions, injections, suppositories, sustained drugs orally or parenterally (for example, topically, rectally, intravenously etc.). Injections may be administered intravenously, intramuscularly, 10 subcutaneously or intraorganly, or directly into the lesion. Pharmacologically acceptable carriers which may be used in production of drugs to be &sed concomitantly of the present invention include excipients, disintegrators, binders, glidants, 15 lubricants, coating agents, coloring agents, suspending agents, sweeteners or surfactants, which are used as needed to make common forms of pharmaceutical preparations according to known methods. Forms of pharmaceutical preparations include, for example, 20 powders, tablets, pills, capsules, etc. The excipients include, for example, lactose, anhydrous lactose, sucrose, saccharose, D-mannitol, D sorbitol, xylitol, erythritol, dextrin, crystalline cellulose, sticrocrystalline cellulose corn starch, 25 potato starch, anhydrous calcium hydrogenphosphate, etc. The disintegrators include, for example, sodium carboxymethylstarch, carmellose, carmellose WO 2007/043542 PCT/JP2006/020239 63 calcium, carmellose sodium, croscarmellose sodium, crospovidone, low substituted .hydroxypropylcellulose, partially pregelatinized starch, etc. The binders include, for example, 5 hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch, syrup, .starch syrup, etc. The glidants include, for example, light anhydrous silicic acid,, synthetic aluminum. silicate, 10 hydrous silicon dioxide, calcium stearate, metasilicate magnesium aluminate, talc, etc. The lubricants include, for. example, magnesium stearate, calcium stearate, magnesium silicate, magnesium oxide, talc, hydrogenated oil, 15 sucrose fatty acid ester, sodium fumarate stearyl, etc. The coating agents include, for example, hydroxypropylmethylcellulose, polyvinyl alcohol, polysorbate, macrogol, talc, etc. The coloring agents include, for example, 20 yellow iron sesquioxide, brown iron oxide, iron sesquioxide, titanium oxide, Food Blue No. 1, Food Red No. 2, Food Red No. 3, Food Yellow No. 4, etc. The suspending agents include, for example, polysorbate; polyethyleneglycol, acacia gum, glycerin, 25 gelatin, etc. The sweeteners include, for exa ple, aspartame, saccharin, sodium sac hari-n, starch syrup, fructose, etc.

WO 20071043542 PCT/JP2006/020239 The surfactants include, for example, sodium laurate, polysorbate, polyoxyethylene hydrogenated castor oil, etc. Capsules are prepared by packing into hard 5 capsules including gelatin capsules, hydroxypropylmethylcellulose capsules and polyvinylalcohol capsules as well as gelatin soft capsules according to known methods. Pharmaceutical materials include conventional different organic and, 10 inorganic carrier substances, for example, excipients, lubricants, binders and disintegrators in solid preparations, or dispersants, solubilizer$, suspending agents, agents for isotonicity, buffering agents and agents for analgesia in liquid preparations. In 15 addition, additives including common preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents may be used in appropriate amount as needed. In the present invention, using ratio of 20 oxazole compounds (I) and drugs (II) described above may be usually about 0.01-100 parts by weight of the latter based on 1 part by weight of the former, preferably about J.1-60 parts by weight, more preferably about 1-60 parts by weight. 25 Further, in the case wheAe drugs (II) described above comprise in combination (i) rifampicin with (ii) at least one antituberculous drug selected from. the group consisting of isoniazid, ethambutol WO 2007/043542 PCT/JP2006/020239 65 hydrochlorae, streptomycin and pyrazinamide, using ratio of (i) rifampicin and the antituberculous drug of (ii) may be about 0.1-10 parts by weight of the latter based on I part by weight of the former, preferably 5 about 0.3-2.5 parts by weight. Further, in the case where drugs (II described above comprise in combination (i) rifampicin, (ii) pyrazinamide and (iii) at least one antituberculousdrug selected from the group consisting 10 of isoniazid, ethambutol and streptomycin, using ratio of (i) rifampicin and (ii) pyrazinamide may be usually about 1-10 parts by weight of the latter based on 1 part by the weight of the former, preferably about 1.5 4 par-ts by weight, and using ratio of (i) rifampicin 15 and antituberculous drugs of (iii) may be usually about 0.1-10 parts by weight of the latter based on i part by weight- of the former, preferably about 0.1-5 parts by weight, more preferably about 0.3-3 parts by weight. Combining, ratio of oxazole compounds (I) to 20 drugs (II) in the antituberculous therapeutic drugs of the present invention may be selected appropriately depending on a subject to be administered, administration route, disease etc. For example, while total ratioof oxazole compounds (I) and drugs (II) in 25 the antituberculous therapeutic drigs of the present invention differs depending on the form of preparations, it is usually in the range of about 0.01 99.99% by weight, preferably about 0.1-99.9% by weight, WO 20071043542 PCT/JP2006/020239 66 more preferably about 1--30% by weight based on the total preparation. In the residual part, pharmacologically acceptable carriers described above are used. 5 Additionally, in the cases where oxazole compounds (I) and drugs (II) are formulated separately, the contents may be, similar. While the dosage of the antituberculous therapeutic drugs of the present invention will vary 10 depending on the. type of oxazole compounds (I), age, weight, symptom, dosage form, administration method, administration period etc., usually, for example, about 0.01-about 1000 mg/kg, preferably about 0.01-about 100 mg/kg, more preferably about 0.1-about. 100 mg/kg, 15 especially about 0.1-about 50 mg/kg, most especially about 1.5-about 30 mg/kg a day per patient (adult, about 60 kg of weight) as oxazole compounds (I) and drugs (I!) are administered intravenously from once to several times in divided amounts a day. Dosage w 20 of .course, vary depending on different conditions as described above, the amounts less than the above described dose may be adequate or those exceeding the limit may be required. For drugs (I), it is possible to set any amount within the range where side effects 25 are nonproblematic. While daily dosage with respect to drugs (II) will vary depending on degree of symptoms, ag'e of the subject to be administered, sex, weight, difference of sensitivity, period of administration, WO 2007/043542 PCT/JP2006/020239 67 interval, property of the pharmaceutical preparations, dispensing, type, type of active ingredients etc., it is administered as the amount of the drug, usually in the range of, but not particularly limited to, about 5 0.001-2000 mg per kg weight of a mammal, for example, orally, preferably about 0.01-500 mg, more preferably -about 0.1-100 mg, 4 times a day in divided amounts. Therefore, the present invention provides the kit for treatment of tuberculosis comprising a 10 medicament containing oxazole compounds (I) described above as active ingredients and one or more drugs (II) selected from the group consisting of. antituberculous drugs, quinolone antibacterial drugs, macrolide antibacterial drugs and anti-HIV drugs, and used to 15 administer them at intervals of 48 hours or more. Dosage forms of the medicament containing oxazole compounds (I) as active ingredients and drugs (II), carriers used in them, ratio of each ingredient, interval of administration may be used similarly as 20 described above. Preferred drugs (II) include, for example, primary antituberculous drugs, secondary antituberculous drugs and quinolone antibacterial drugs quindlone antibacterial drugs described above. Herein, 25 preferred primary antituberculous drugs include at least one selected from the group consisting of isoniazid, isoniazid sodium methalnesulfonate, pyrazinamide, rifampicin, streptomycin, streptomycin WO 2007/043542 PCT/JP2006/020239 68 sulfate, ethambutol and ethambutol hydrochloride, more preferably at least one selected from the group consisting of rifampicin, pyrazinamide, isoniazid, ethambutol and streptomycin. Preferred secondary 5 antituberculous drugs include at least one selected from the group, consisting of enviomycin, enviomycin sulfate, kanamycin, kanamycin sulfate, capreomycin, cycloserine, thioacetazone and clofazimine. P referred quinolone antibacterial drugs'include at least one 10 selected from the group consisting of gatifloxacin hydrate and maxifloxacin. n the present invention, a combination of oxazole compounds (I) with drugs (II) which are ahtitubercuious drugs used concomitantly having a IS different action mechanism exerts effects shown below compared with those in the case where oxazole compounds (I) or antituberculous drugs for concomitant use are administered singly. (1) Oral administration is possible and the 20 dosage can be reduced. (2) A shorter treatment period can be set i.e. a short-term chemotherapy becomes possible. (3) Side effects can be reduced. (4) Sustained therapeutic effect can be 25 attained. (5) Synergistic effects can be obtained. (6) Antituberculous drigs for concomitant use to be used in combination with oxazole compounds (I) WO 20071043542 PCT/JP2006/020239 69 can be selected corresponding to symptoms in patients (mild, severe or other) (7) It is active against Mycobacterium tuberculosis, multidrug-resistant Mycobacterium 5 tuberculosis and atypical acid-fast bacteria. (8) Efficacy is shown against Mycobacterium tuberculosis infecting latently (latent Mycobacterium tuberculosis). Such superior effects can be obtained. 10 Further, by using a medicament of single oxazole compounds (1) or that comprising a combination of oxazole compounds (I) with drugs for concomitant use, it is possible, for example, to administer the above' described drugs for concomitant use intermittently 15 setting interval period of at least about 48 hours in order to relieve or eliminate side effects of existing antituberculous drugs being used in combination. The following examples illustrate more clearly the present invention in detail. 20 Example 1 In Vitro experiment on the combined effect of an oxazole compound (I) and another agent The synergistic effect of an oxazole compound (I) and a known antituberculous drug, rifampicin (RFP) 25 or ethambutol (EB) on a clinical isolate of tubercle bacillus was examined. Specifically, each 7H1ll agar plate containing the compound (A-R) at a final concentration of 0.1 - 0.0002 pg/ml (a 2-fold dilution WO 2007/043542 PCT/JP2006/020239 70 series), each agar plate of the same agar containing rifampicin at a final concentration of 1.56 - 0.0015 pg/ml, and each agar plate containing both drugs at each set of concentrations were prepared. A suspension of tubercle bacillus was prepared at about 106 CrU/ml (for clinical isolates of tubercle bacillus, TBT-9 and TBT-14). About 10 pl aliquots thereof were inoculated on respective plates by using a multipoint inoculator. The plates were incubated at 37'C for 2 weeks to .0 determine minimum inhibitory concentrations (MIC) for cell growth. A similar test was performed by using ethambutol at concentrations of 12.5 ' 0.024 ptg/ml, and MIC was determined for each set of concentrations. From these results, an FIC Index ( (MIC for a 15 combination of compound (A-R) plus RFP or EB)/(MIC of compound (A--R) alone) + (MIC for a combination of RFP or EB plus the compound (A-R) ) / (MIC of RFP or EB alone)) was calculated for the set of concentrations with the least MIC. Results are shown in Table 1. 20 When compound (A-R) and rifampicin or ethambutol were combined with each other, FIC Index indicated 0.375 in both cases, as a result, a strong synergistic effect was demonstrated in a combination of both 'agents.

WO 2007/043542 PCT/JP2006/020239 71 Table 1 Minimum inhibitory concentration (MIC) against tubercle bacillus FTC Compound (A-R) RFP Compound (A-R) & RFP inex 0.375 0.006(0 024) 0.05(0.39) FIC Compound (A-R EB Compound (A-R) & EB index 0.375 0.003(0.012) 0.2(1,56p 0 Unit: ug/ml * Numerical values in the Table: MIC in combination (MIC in alone) - FIC index: Synergistic effect ; O 5 Example 2-1 In vivo experiments on the combined effect of the oxazole compound (I) and other agents Therapeutic effect in combinations of multiple agents 5 Tubercle bacillus, Kurono strain with 455 CFU was inoculated transtracheally in ICR mice and allowed to leave for 4 weeks to prepare an experimental mouse model of chronic tuberculosis. A combination of 2.5 mg/kg of the compound (A-R) (in Fig. 1-1, indicated as 10 "O") with 5 mg/kg of rifampicin (in Fig. 1-1, indicated as "R") and 100 mg/kg of pyrazinamide (in Fig. 1-1, indicated as "Z") was given to this model. The dos ing was conducted once a day for 56 days and the results were . compared with those from a conventional regimen .5 used for treatment of tuberculosis. The conventional regimen was dosing of rifampicin, isoniazid (in Fig. 1 1,' indicated as "H"), ethambutol (in Fig. 1-1, indicated as ''E) and pyrazinamide, 5 mg/kg, 10 mg/kg, WO 2007/043542 PCT/JP2006/020239 72 100 mg/kg and 100 mg/kg, respectively, once a day for 56 days to the model mice hereinabove. To confirm decreasing viable cell counts of pulmonary tubercle bacillus with time, the mice were euthanized by 5 venesection from the inferior vena cava under anesthesia on the next day after dosing for 28 days (4 W) and 56 days (8W), and the lungs were extirpated aseptically. The extirpated lung in 2 ml of sterilized water was ground homogeneously with a glass homogenizer 10 and diluted stepwise. Then, 0.1 ml of each diluted sample was smeared on the 7HII agar plate medium and incubated until colonies appeared to calculate viable cell counts in the lung after the treatment. As shown in Fig. 1-1, the triple therapy 15 containing the compound (A-R) (in Fig. 1-1, indicated as "ORZ") was confirmed to show a stronger effect in spite of a smaller number of combined drugs than the known quadruple therapy regimen (in Fig. 1-1, indicated as. "RHEZ"). Further, since the viable cell count of 20 tubercle bacillus decreased in the early stage, the chemotherapy could be expected to be effective in a shorter time than that of the conventional antituberculous drugs. Example 2-2 25 In vivo experiments on the combined effect of the oxazole compound (I) and other agents Therapeutic effect in combinations of multiple agents (2) WO 2007/043542 PCT/JP2006/020239 73 Tubercle bacillus, -H37Rv strain with 2750 CPU was inoculated in ICR mice and allowed to leave for ' weeks to prepare an experimental mouse model of chronic tuberculosis. Three drug combinations "ORZ", "OREZ" 5 and "ORZM" selected from 2.5 mg/kg of the compound (A R-) (in Fig. 1-2, indicated as "0"), 10 mg/kq of rifampicin (in Fig., 1-2, indicated as "R"), 150 mg/kg of pyrazinamide (in Fig. 1-2, indicated as "Z"), 100mg/kg of ethambutol (in Fig. 1-2, indicated as "E") 10 and 100mg/kg of moxifloxacin (in Fig. 1-2, indicated as "M") were given to this model. The dosing was conducted once a day for 56 days and the results were compared with those from a conventional regimen used for treatment of tuberculosis. The conventional 15 regimen was dosing of rifampicin, isoniazid (in Fig'. 1 1, indicated as "H"), ethambutol and pyrazinamide, i mg/kg, 25 mg/kg, 100 mg/kg and 150 mg/kg, respectively, once a day for 56 days to the model mice hereinabove. To confirm decreasing viable cell counts of pulmonary 20 tubercle bacillus with time, the mice were euthanized by venesection from the inferior vena cava under anesthesia on the next day after dosing for and 56 days (8W), and the lungs were extirpated aseptically. The extirpated lung in 2 ml of sterilized water was ground 25 homogeneously with a glass homogenizer and diluted stepwise. Then, 0.1 ml of each diluted sample was smeared on the 7Hll agar plate medium and incubated until colonies appeared to calculate viable cell counts WO 2007/043542 PCT/JP2006/020239 74 'n the lung after the treatment. As shown in Fig, 1-2, all combination groups containing the compound (A-R) (in Fig. 1-2, indicated as "0 RZ", 'OREZ" .and "ORZM") was confirmed to show a 5 stronger effect in spite of a smaller number of combined drugs than the known quadruple therapy regimen (in Fig. 1-2, indicated as "RHEZ") . Further, since the viable cell count of tubercle bacillus decreased in the early stage, the chemotherapy could be expected to be 10 effective in a shorter time than that of the conventional antituberculous drugs. Example 3 Evaluation of the effect of the oxazole compound (I) on intracellular parasitic tubercle bacillus 15 Evaluation of the effect of the oxazole compound (I) on intracellular parasitic tubercle bacillus was performed below. 3-1. Infection of tubercle bacillus in THP-1 A suspension of THP-1 cells with a cell 20 density adjusted to 106 cells/0.9 ml of RPMIl640 - 10% FBS medium (hereinafter abbreviated as RPMIl640 medium) was added in each well of a 24-well cell culture plate. A solution of phorbol 12-myristate 13-acetate (PMA) (0.1 ml) was added into the well containing added cells 25 to the final concentration of 100 ng/ml. The plate was incubated at 37'C for 48 hours under 5% CO 2 atmosphere to differentiate THP-1 cells into macrophage-like cells. The differentiated THP-1 cells were washed once WO 2007/043542 PCT/JP2006/020239 .75 with RPMIl640 medium to remove PMA solution. After replacing the medium in each well with fresh RPMIl640 medium 0.9 ml, prepared microbial suspension (M. tuberculosis H37Rv) 0.1 ml was added into each well. 5 The plate was incubated at 37 0 C for 4 hours under 5% CO 2 atmosphere to i-nfect the bacteria into cells. Each well was washed twice with RPMI1640 medium for removing uninfected bacteria remaining in RPMIl640 medium. Further, RPMI1640 medium containing streptomycin 10 (hereinafter designates as SM) 20 pig/ml was added and incubated for 20 hours in order to remove remaining external bacteria. After incubation, each well of the plate was washed twice with RPMII640 medium to remove SM. After removing the washing medium from each well, 15 it was replaced by fresh RPMI1640 medium 0.99 ml, at which time point was set as time 0 hour. For counting intracellular viable count before addition of test substance, the objective well in the plate was washed three times with phosphate buffer saline (PBS) . After 20 removing the final PBS washing solution, 0.1% SDS solution 0.5 ml was added into each well and allowed to stand at room temperature for 10 minutes or more to decompose cells. After neutralizing SDS by adding and mixing RPMI1640 medium 0.5 ml to each well, cell lysate 25 was collected in test tubes. Ten-fold dilution series of the collected cell lysate with addition of distilled water were prepared, and each dilution solution 0.1 ml was smeared on 7H11 agar plate to prepare 3 plates, WO 2007/043542 PCT/JP2006/020239 76 which were smeared with the collected cell lysate with bacteria having different dilution series. The smeared plates were sealed with vinyl tape to avoid drying and further incubated at 37*C for 2 - 3 weeks. Number of 5 appeared colonies was counted to calculate intracellular viable bacterial counts at time 0 hour according to judgment. criterion. 3-2. Addition of test substance Diluted solution oftest substance 0.01 ml 10 was' added to each well of 24 well plate containing infected cells. The plate added with test substance was incubated at 37*C under 5% CO 2 atmosphere, and after affecting for 2 or 4 hours by adding test substance, each well was washed three times with RPM1l640 medium 15 for removal- of the test substance. After removal 6f the test substance, fresh RPMI1640 medium 1 ml was added to each well and continued incubation. 3-3. Recovery, dilution and smearing on 7H11 agar plate of intracellular bacteria 20 Intracellular bacteria were collected from plates incubated for 3 days (72 hours) after adding test substance by the following procedures. Specifically, each well in the plate was washed three times with PBS. After removing the final PBS washing 25 solution, 0.1% SDS solution 0.5 ml was added into each well and allowed to stand at room temperature for 10 minutes or more to decompose cells. SDS solution was neutralized by adding RPMI1640 medium 0.5 ml to each WO 2007/043542 PCT/JP2006/020239 '77 well, and cell lysate, total volume of i ml, was collected in test tubes, Ten-fold dilution series of the collected cell lysate were prepared by using distilled water. Each diluted solution 0.1 ml was 5 smeared on 71-11 agar plate to prepare 3 plates, which were smeared with the collected cell lysate with bacteria having different dilution series. The smeared plates were sealed with vinyl tape to avoid drying and further incubated at 374C for 2 - 3 weeks to count 10 numbers of appeared colonies. Log reduction of bacterial counts compared with the bacterial counts at time 0 hour before addition-of test substance was shown based on experimental results (Fig. 2). As a result, in the 15 group adding compound (A--R), stronger effect against intracellular parasitic tubercle bacillus was confirmed than in the group adding other ant ituberculous drugs. Although RFP showed the strongest effect in the conventional drugs, the compound (A-R) was found to 20 exhibit the equivalent effect of the maximum concentration 3 pg/ml of RFP, even at the lowest test dose of the compound (A-R) 0.1' pg/ml in concentration employed in the study. in addition, strong effect was confirmed even in short term action for 2 hours, and 25 this result suggests that the compound (A-R) has strong post antibiotic effect (PAE) against tubercle bacilli. Consequently, it is conceivable that the compound (A-R) can be a drug having sufficient effect even in the WO 2007/043542 PCT/JP2006/020239 -'8 intermittent administration in the clinical field. Example 4 Evaluation of drug interaction between oxazole compound I) and other drugs 5 Since there are many cases in metabolism related drug interaction involved in cytochrome P450 (CYP) enzyme, elucidation of CYP molecular species involved in metabolism of antituberculous drug oxazole compound (I) is, essential for, safety use of the above 10 described drug. In addition, since there is a possibility to occur drug interaction on the condition that multiple a combination of antituberculous drugs is conventionally applied, inhibitory action of oxazole compound (I) against each CYP enzyme is important to 15 study. Various CYP enzymes are confirmed in the hepatic microsomal enzyme, and drug metabolism using, the hepatic microsomal enzyme and inhibitory action of drug against each CYP enzyme can be tested in vitro. Therefore, in vitro metabolism of oxazole compound (I) 20 using hepatic microsomal enzyme of human and various animals (mouse, rat, dog, rabbit and monkey), and in vitro inhibitory action of oxazole compound (I) against each CYP enzyme using human hepatic microsomal enzyme were examined. 25 4-1. In vitro metabolism of oxazole compound (I) Studies on in vitro metabolism of oxazole compound (I) (compound (A-R)) were performed using hepatic microsomal enzyme of human and various animals WO 20071043542 PCT/JP2006!020239 79 (mouse, rat, dog, rabbit and monkey) Human microsome was obtained from Attached Primate Research Institute, HAB Discussion Group (Chiba, Japan). Reaction composition (0.5 ml) was consisting of 100 mM phosphate 5 buffer (pH 7.4), 100 pM compound (A-R), 2.5 rHl'P-NADPH, 2-.5 mM P-NADH and microsome protein 1 mg/ml, and the reaction was performed at 37*C for 2 hours. The reaction was terminated by adding organic solvent (acetonitrile or ethyl acetate) and generated 10 metabolites were extracted. The extracted metabolites were detected by using high perform ance liquid chrpmatography and liquid chromatograph electrosprav ionization tandem mass spectrometry to confirm amount of generation. As a result of in vitro metabolism of the compound (A-R) using hepatic microsomal enzyme of human and various animals (mouse, rat, dog, rabbit and monkey), almost no generated metabolites were confirmed. Consequently, the compound (A-R) might not 20 be metabolized by an action of CYP enzyme. 4-2. Effect of the oxazole compound (I) on the enzymatic activity of each molecular species of cytochrome P450 (CYP) Inhibitory action of the oxazole compound (I) 25 (compound (A-R): I - 100 pM) on each molecular species of GYP in human hepatic microsome was assayed by measuring ethoxyresorufin deethylation activity (CYPlA1/2), coumarin hydroxylation activity (CYP2A6), WO 2007/043542 PCT/JP2006/020239 80 7-benzyloxyresorufin debenzylation activity (CYP2B6), tolbutamide hydroxylation activity (CYP2C8/9) S mephenytoin hydroxylation activity (CYP2CI9), bufuralol hydroxylation activity (CYP2D6) , chlorzoxazone 5 nydroxylation activity (CYP2E1), testosterone 6p hydroxylation activity (CYP3A4) and nifedipine oxidation activity (CYP3A4) Basic reaction composition (0.5 ml) was consisting of microsome protein 0.2 - 1 mg/ml, 100 mM 10 phosphate buffer (pH 7.4), 0.1 T.M EDTA, NADPH generation system (2.5 mM -NADP, 25 mM glucose-6 phosphate, 2 units glucose-6-phosphate dehydrogenase and 10 mM magnesium chloride), with or without each substrate and inhibitor, and the reaction was performed 15 at 37*C for 10 - 60 minutes. Each substrate and its concetration used were 7-ethoxyresorufin (0.5 pM) coumarin (2 pM), 7-benzyloxyresorufin (1.5 pM), tolbutamide (400 -pM), S-mephenytoin (100 ptM), bufuralol (2,0 pM), chlorzoxazone (100 pM), testosterone (100 p) 20 and nifedipine (50 pM). 7,8-benzoflavone (IAl), furafylline (lA2), orphenadrine (26), quercetin (2C8), suifaphenazole (2C9), tranylcypromine (2C19), quinidine (2D6) ; diethyldithiocarbamine (2A6 and 2E1) and ketoconazole (3A4) were used as specific inhibitors for 25 each CYP activity. Generated products after the metabolic response were measured by using high performance liquid chromatography after extraction.

WO 2007/043542 PCT/JP2006/020239 81 The results of the above experiments indicated that the compound (A-R) did not exhibit inhibitory action and stimulation action against each CYP enzymre (CYP1A/2, CYP2A6, CYP2B6 CYP2C8/9, CYP2C19, 5 CYP2D6, CYP2EI and CYP3.A4) activity up to 100 ptM (Table 2) Table 2 shows the effect of the oxazole compound (1) on the enzymatic activity of each molecular species of cytochrome P450 (CYP).

WO 20071043542 P(TI.JP2006!020239 8~2 4-Jm >00 C 43 cm41 (0~~~~ Pmcc m 5-. c ~ ~ ~ ~ O cmL;1 (1' 1 000 (D 01' o'-'W"'~~- wN ( (0 ' - c (N Q (n 1-) 1.o a- 0 L0 C-D1 CD C,) 0* 4I '0 r~.1 1-3 03'' cm cm o' (( 0 0m n . 0 -4 C) TiW ) N ' 0 020 1 4) 4j0' 31' 0 31 0 (, t 100'. 4-) 44 ,A -A .) m~ 4J 4-) 4-j cm . ) .0 ) C0 0 I) 00 xH -C a I 0 -0 0 D 'H > - -oC I~ -) 4 I 0' -(7 _47 0 -- 0 :L 00 73 4 '0)0 ' 04 : 1 0~ 0(0 0.4 -4 -,A (vI~ CUl -. -- N0 v - 0 I'4-'. TU C) >4 t31 >) a, 43 ll (40 30 U ' CIQcN)C) N4 u4( .5.t 4). u' V..5 ~~ 11 LI) I 4<13~. j 40-U ' WO 2007/043542 PCT/JP2006/020239 83 Considering the above data, when oxazole compound (I) and other drug, which is metabolized mainly by CYP, are used in combination at the concentration of oxazole compound in clinical use, in 5 which effect can be expected, there may be a little possibility to inhibit metabolic activity of the combined drug (II) by an action of oxazole compound (I) and to increase blood level of the combined drug (II), namely causing drug interaction. 10 Example 5 In vivo E:xperiments for intermittent administration Experimental mouse tuberculosis model was prepared and treated by once a day administration of the compound (A-R) alone or for a combination of other 15 conventional drugs. Maintaining an index of the therapeutic effect equivalent to such the effect, the compound (A-R) alone or for a combination of other conventional antituberculous drugs was administered, for example, three times a week, twice a week or once a 20 week in order to obtain the same effect as above. The equivalent effect was confirmed to be exhibited and the compound (A-R) was confirmed to be available used for intermittent administration in vivo.

Docum ent29-I1/04/2013 - 83A Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims (16)

1. An antituberculous therapeutic drug comprising: (I) at least one selected from the group consisting of 2,3-dihydro-6-nitroimidazo[2,1 b]oxazole compounds represented by general formula (1): 0 2 N (1) N O (CH 2 )nR 2 [wherein RI represents a hydrogen atom or C1-6 alkyl group, n represents an integer of 0-6, and R2 represents any group of the following general formulas (A)-(G), wherein the group represented by the general formula (A) is: O\/NR3 (A) wherein R 3 represents any group of the following (1)-(6): (1) a phenoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (2) a phenyl C1-6 alkoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (3) -NR 4 R 5 group, wherein R 4 represents a hydrogen atom or C1-6 alkyl group and R 5 represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (4) a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted Cl-6 alkyl group and an optionally Document29-l1/04/2013 - 85 halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (5) a phenoxy C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); and (6) a benzofuryl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring); the group represented by the general formula (B) is: N N- COOCH 2 CH=CH-R 6 (B) wherein R represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); the group represented by the general formula (C) is: 0 N N N- R 7 (C) wherein R 7 represents a phenyl C2- 10 alkenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) or a biphenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); the group represented by the general formula (D) is: Document29-l1/04/2013 -86 N N--R 8 (D) wherein R 8 represents a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); the group represented by the general formula (E) is: N N R8 (E) (wherein R 8 is as described above); and the group represented by the general formula (F) is: - N R6 (F) N (wherein R is as described above), the group represented by the general formula (G) is: - N N--N C - R 6 H (G) (wherein R is as described above), optically active forms thereof and pharmacologically acceptable salts thereof, and (II) at least one drug selected from the group consisting of secondary antituberculous Document29-l1/04/2013 - 87 drugs, quinolone antibacterial drugs, macrolide antibacterial drugs, sulfa drugs, and anti HIV drugs.

2. The antituberculous therapeutic drug according to claim 1, wherein the drug of (II) is at least one selected from the group consisting of the secondary antituberculous drugs and the quinolone antibacterial drugs.

3. The antituberculous therapeutic drug according to claim 2, wherein the drug selected from the secondary antituberculous drug is at least one selected from the group consisting of enviomycin, kanamycin, capreomycin, cycloserine, thioacetazone, clofazimine and salts thereof.

4. The antituberculous therapeutic drug according to claim 2, wherein the drug of (II) is at least one selected from the secondary antituberculous drugs.

5. The antituberculous therapeutic drug according to claim 1, wherein the drug of (II) is at least one selected from the quinolone antibacterial drugs.

6. The antituberculous therapeutic drug according to claim 5, wherein the at least one selected from the quinolone antibacterial drugs is at least one selected from the group consisting of gatifloxacin, moxifloxacin and hydrates thereof.

7. The antituberculous therapeutic drug according to claim 1, wherein the drugs of (II) is at least one selected from the macrolide antibacterial drugs.

8. The antituberculous therapeutic drug according to claim 7, wherein the at least one selected from the macrolide antibacterial drugs is at least one selected from the group consisting of clarithromycin, azithromycin and hydrates thereof.

9. The antituberculous therapeutic drug according to claim 1, wherein the drug of (II) is at least one selected from the sulfa drugs.

10. The antituberculous therapeutic drug according to claim 9, wherein the at least one selected from the sulfa drugs is at least one selected from the group consisting of sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfadimethoxine, sulfamethizole, salazosulfapyridine, sulfadiazine and salts thereof.

11. The antituberculous therapeutic drug according to claim 1, wherein the drug of (II) is at least one selected from the anti-HIV drugs.

12. The antituberculous therapeutic drug according to claim 11, wherein the at least one selected from the anti-HIV drugs is (a) a reverse transcriptase inhibitor based on a Document29-l1/04/2013 - 88 nucleic acid, (b) a reverse transcriptase inhibitor based on a non-nucleic acid or (c) a protease inhibitor.

13. A medicament for dosing at an interval of 48 hours or more, wherein the medicament comprises at least one compound as active ingredient which is selected from the group consisting of: (I) 2,3-dihydro-6-nitroimidazo[2,1-b]oxazole compounds represented by general formula (1): 0 2 N (1) N O (CH 2 )nR 2 [wherein RI represents a hydrogen atom or C1-6 alkyl group, n represents an integer of 0-6, and R2 represents any group of the following general formulas (A)-(G), wherein the group represented by the general formula (A) is: O\/NR3 (A) wherein R 3 represents any group of the following (1)-(6): (1) a phenoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (2) a phenyl C1-6 alkoxy group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (3) -NR 4 R 5 group, wherein R 4 represents a hydrogen atom or C1-6 alkyl group and R 5 represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (4) a phenyl C1-6 alkyl group (at least one group selected from the group consisting of Document29-l1/04/2013 - 89 a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); (5) a phenoxy C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); and (6) a benzofuryl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the benzofuran ring); the group represented by the general formula (B) is: N N- COOCH 2 CH=CH-R 6 (B) wherein R represents a phenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); the group represented by the general formula (C) is: 0 N N N- R 7 (C) wherein R 7 represents a phenyl C2- 10 alkenyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring) or a biphenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); the group represented by the general formula (D) is: Document29-l1/04/2013 -90 N N--R 8 (D) wherein R 8 represents a phenyl C1-6 alkyl group (at least one group selected from the group consisting of a halogen atom, an optionally halogen-substituted C1-6 alkyl group and an optionally halogen-substituted C1-6 alkoxy group may be substituted on the phenyl ring); the group represented by the general formula (E) is: N N R8 (E) (wherein R 8 is as described above); and the group represented by the general formula (F) is: - N R6 (F) N (wherein R is as described above), the group represented by the general formula (G) is: - N N--N C - R 6 H (G) (wherein R is as described above), optically active forms thereof and pharmacologically acceptable salts thereof.

14. A kit for tuberculosis treatment, wherein the kit comprises the medicament of claim Document29-11/04/2013 - 91 13, and at least one drug (II) selected from the group consisting of secondary antituberculous drugs, quinolone antibacterial drugs, macrolide antibacterial drugs, sulfa drugs and anti-HIV drugs, and wherein the kit is used to dose the medicament and the drugs at an interval of 48 hours or more.

15. The kit according to claim 14, wherein the drug of (II) is at least one selected from the group consisting of the secondary antituberculous drugs and the quinolone anti bacterial drugs.

16. The kit according to claim 15, wherein the at least one selected from the secondary antituberculous drugs are at least one selected from the group consisting of enviomycin, kanamycin, capreomycin, cycloserine, thioacetazone, clofazimine and salts thereof, and the at least one selected from the quinolone antibacterial drugs is at least one selected from the group consisting of gatifloxacin, moxifloxacin and hydrate thereof.