JP2020531575A - 新規化合物 - Google Patents
新規化合物 Download PDFInfo
- Publication number
- JP2020531575A JP2020531575A JP2020530727A JP2020530727A JP2020531575A JP 2020531575 A JP2020531575 A JP 2020531575A JP 2020530727 A JP2020530727 A JP 2020530727A JP 2020530727 A JP2020530727 A JP 2020530727A JP 2020531575 A JP2020531575 A JP 2020531575A
- Authority
- JP
- Japan
- Prior art keywords
- mycobacterium
- pharmaceutically acceptable
- acceptable salt
- diazaspiro
- deca
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 146
- 238000011282 treatment Methods 0.000 claims abstract description 50
- 201000008827 tuberculosis Diseases 0.000 claims abstract description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 208000027531 mycobacterial infectious disease Diseases 0.000 claims abstract description 25
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 206010062207 Mycobacterial infection Diseases 0.000 claims abstract description 23
- -1 Fluoro-substituted ethyl Chemical group 0.000 claims description 78
- 150000003839 salts Chemical class 0.000 claims description 68
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 48
- 125000003545 alkoxy group Chemical group 0.000 claims description 44
- 125000001153 fluoro group Chemical group F* 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 35
- 241000186359 Mycobacterium Species 0.000 claims description 22
- 241000124008 Mammalia Species 0.000 claims description 21
- 229960002001 ethionamide Drugs 0.000 claims description 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000001246 bromo group Chemical group Br* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 208000015181 infectious disease Diseases 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 13
- 239000003814 drug Substances 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims description 11
- VRDIULHPQTYCLN-UHFFFAOYSA-N Prothionamide Chemical compound CCCC1=CC(C(N)=S)=CC=N1 VRDIULHPQTYCLN-UHFFFAOYSA-N 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 11
- 229960000918 protionamide Drugs 0.000 claims description 11
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 9
- 229960002049 etravirine Drugs 0.000 claims description 9
- PYGWGZALEOIKDF-UHFFFAOYSA-N etravirine Chemical compound CC1=CC(C#N)=CC(C)=C1OC1=NC(NC=2C=CC(=CC=2)C#N)=NC(N)=C1Br PYGWGZALEOIKDF-UHFFFAOYSA-N 0.000 claims description 9
- 125000001301 ethoxy group Chemical class [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 8
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 8
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 239000000814 tuberculostatic agent Substances 0.000 claims description 7
- 229940121383 antituberculosis agent Drugs 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 229960003350 isoniazid Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 229940124522 antiretrovirals Drugs 0.000 claims description 5
- 239000003903 antiretrovirus agent Substances 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 claims description 4
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 4
- 239000003926 antimycobacterial agent Substances 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 229960002656 didanosine Drugs 0.000 claims description 4
- 229960000689 nevirapine Drugs 0.000 claims description 4
- 229960001225 rifampicin Drugs 0.000 claims description 4
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 4
- 229960002599 rifapentine Drugs 0.000 claims description 4
- WDZCUPBHRAEYDL-GZAUEHORSA-N rifapentine Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C(O)=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N(CC1)CCN1C1CCCC1 WDZCUPBHRAEYDL-GZAUEHORSA-N 0.000 claims description 4
- 230000001225 therapeutic effect Effects 0.000 claims description 4
- BWBONKHPVHMQHE-UHFFFAOYSA-N tiocarlide Chemical group C1=CC(OCCC(C)C)=CC=C1NC(=S)NC1=CC=C(OCCC(C)C)C=C1 BWBONKHPVHMQHE-UHFFFAOYSA-N 0.000 claims description 4
- 229960002171 tiocarlide Drugs 0.000 claims description 4
- BJPLNPPYUJGREP-UHFFFAOYSA-N 1-(3-ethoxy-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)-4,4,4-trifluorobutan-1-one Chemical compound C(C)OC1=NOC2(C1)CCN(CC2)C(CCC(F)(F)F)=O BJPLNPPYUJGREP-UHFFFAOYSA-N 0.000 claims description 3
- KIMCGLHTSSZPNS-UHFFFAOYSA-N 2,3-dinitrobenzamide Chemical compound NC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O KIMCGLHTSSZPNS-UHFFFAOYSA-N 0.000 claims description 3
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 3
- ZEAVKHMQTZBUND-UHFFFAOYSA-N 4,4,4-trifluoro-1-[3-(trifluoromethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)C(F)(F)F)CC1)(F)F ZEAVKHMQTZBUND-UHFFFAOYSA-N 0.000 claims description 3
- XZISSTDXPBUCJA-DYESRHJHSA-N ClC1=CC(=C(C(=C1)F)N1C[C@H]([C@](CC1)(O)COC1=C2CCC(NC2=C(C=C1)F)=O)O)F Chemical compound ClC1=CC(=C(C(=C1)F)N1C[C@H]([C@](CC1)(O)COC1=C2CCC(NC2=C(C=C1)F)=O)O)F XZISSTDXPBUCJA-DYESRHJHSA-N 0.000 claims description 3
- 229940034014 antimycobacterial agent Drugs 0.000 claims description 3
- XDAOLTSRNUSPPH-XMMPIXPASA-N delamanid Chemical compound C([C@]1(C)OC2=NC(=CN2C1)[N+]([O-])=O)OC(C=C1)=CC=C1N(CC1)CCC1OC1=CC=C(OC(F)(F)F)C=C1 XDAOLTSRNUSPPH-XMMPIXPASA-N 0.000 claims description 3
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 3
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 3
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 229960003907 linezolid Drugs 0.000 claims description 3
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 claims description 3
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims description 3
- JFIBVDBTCDTBRH-REZTVBANSA-N n'-(2-adamantyl)-n-[(2e)-3,7-dimethylocta-2,6-dienyl]ethane-1,2-diamine Chemical compound C1C(C2)CC3CC1C(NCCNC/C=C(C)/CCC=C(C)C)C2C3 JFIBVDBTCDTBRH-REZTVBANSA-N 0.000 claims description 3
- 229960005206 pyrazinamide Drugs 0.000 claims description 3
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 claims description 3
- 229960003879 tedizolid Drugs 0.000 claims description 3
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 claims description 3
- 229960003231 thioacetazone Drugs 0.000 claims description 3
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 claims description 3
- 150000003952 β-lactams Chemical class 0.000 claims description 3
- HAJOJKJXQVITPM-UHFFFAOYSA-N 1-(3-ethyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)-4,4,4-trifluorobutan-1-one Chemical compound C(C)C1=NOC2(C1)CCN(CC2)C(CCC(F)(F)F)=O HAJOJKJXQVITPM-UHFFFAOYSA-N 0.000 claims description 2
- GTUIRORNXIOHQR-VIFPVBQESA-N 2-[(3s)-3-methyl-1,4-dioxa-8-azaspiro[4.5]decan-8-yl]-8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one Chemical compound O1[C@@H](C)COC11CCN(C=2SC3=C([N+]([O-])=O)C=C(C=C3C(=O)N=2)C(F)(F)F)CC1 GTUIRORNXIOHQR-VIFPVBQESA-N 0.000 claims description 2
- NMXJUSOTRMIRIQ-UHFFFAOYSA-N 4,4,4-trifluoro-1-(3-hexoxy-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)OCCCCCC)CC1)(F)F NMXJUSOTRMIRIQ-UHFFFAOYSA-N 0.000 claims description 2
- ZVEXKHANVKUKHD-UHFFFAOYSA-N 4,4,4-trifluoro-1-(3-methoxy-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)OC)CC1)(F)F ZVEXKHANVKUKHD-UHFFFAOYSA-N 0.000 claims description 2
- FRTUJJKNFIGXBL-UHFFFAOYSA-N 4,4,4-trifluoro-1-(3-methyl-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)C)CC1)(F)F FRTUJJKNFIGXBL-UHFFFAOYSA-N 0.000 claims description 2
- AIMATYJZSACHSL-UHFFFAOYSA-N 4,4,4-trifluoro-1-(3-propoxy-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)OCCC)CC1)(F)F AIMATYJZSACHSL-UHFFFAOYSA-N 0.000 claims description 2
- FSGOHNBOSAFPGW-UHFFFAOYSA-N 4,4,4-trifluoro-1-[3-(2,2,2-trifluoroethoxy)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)OCC(F)(F)F)CC1)(F)F FSGOHNBOSAFPGW-UHFFFAOYSA-N 0.000 claims description 2
- QMTNXNNTJQITNN-UHFFFAOYSA-N 4,4,4-trifluoro-1-[3-(2-methylpropoxy)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)OCC(C)C)CC1)(F)F QMTNXNNTJQITNN-UHFFFAOYSA-N 0.000 claims description 2
- CGBYTKOSZYQOPV-ASSBYYIWSA-N 5-chloro-3-[[3-[(e)-2-cyanoethenyl]-5-methylphenyl]-methoxyphosphoryl]-1h-indole-2-carboxamide Chemical compound C1([P@](=O)(C=2C3=CC(Cl)=CC=C3NC=2C(N)=O)OC)=CC(C)=CC(\C=C\C#N)=C1 CGBYTKOSZYQOPV-ASSBYYIWSA-N 0.000 claims description 2
- HGGAKXAHAYOLDJ-FHZUQPTBSA-N 6alpha-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid Chemical compound S([C@@H]1[C@H](C(N1C=1C(O)=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 HGGAKXAHAYOLDJ-FHZUQPTBSA-N 0.000 claims description 2
- MDVPOWWMRGIHML-UHFFFAOYSA-N 8-(4,4,4-trifluorobutanoyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-3-carbonitrile Chemical compound FC(CCC(=O)N1CCC2(CC(=NO2)C#N)CC1)(F)F MDVPOWWMRGIHML-UHFFFAOYSA-N 0.000 claims description 2
- JJEGOJPMKLRSPJ-POURPWNDSA-N COc1cc(cc(OC)n1)[C@](O)(CCN(C)C)[C@H](c1cccc(OC)c1F)c1cc2cc(Br)ccc2nc1OC Chemical compound COc1cc(cc(OC)n1)[C@](O)(CCN(C)C)[C@H](c1cccc(OC)c1F)c1cc2cc(Br)ccc2nc1OC JJEGOJPMKLRSPJ-POURPWNDSA-N 0.000 claims description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 2
- ZNBRXLSWXJKKLJ-LBPRGKRZSA-N FC=1C=C(C=CC=1N1CC2(COC2)C1)N1C(O[C@H](C1)CNC(OC)=O)=O Chemical compound FC=1C=C(C=CC=1N1CC2(COC2)C1)N1C(O[C@H](C1)CNC(OC)=O)=O ZNBRXLSWXJKKLJ-LBPRGKRZSA-N 0.000 claims description 2
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 claims description 2
- RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 claims description 2
- ZWBTYMGEBZUQTK-PVLSIAFMSA-N [(7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,32-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-1'-(2-methylpropyl)-6,23-dioxospiro[8,33-dioxa-24,27,29-triazapentacyclo[23.6.1.14,7.05,31.026,30]tritriaconta-1(32),2,4,9,19,21,24,26,30-nonaene-28,4'-piperidine]-13-yl] acetate Chemical compound CO[C@H]1\C=C\O[C@@]2(C)Oc3c(C2=O)c2c4NC5(CCN(CC(C)C)CC5)N=c4c(=NC(=O)\C(C)=C/C=C/[C@H](C)[C@H](O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H](OC(C)=O)[C@@H]1C)c(O)c2c(O)c3C ZWBTYMGEBZUQTK-PVLSIAFMSA-N 0.000 claims description 2
- 229960004748 abacavir Drugs 0.000 claims description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 claims description 2
- 229950005846 amdoxovir Drugs 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 2
- 229940098164 augmentin Drugs 0.000 claims description 2
- 229960000508 bedaquiline Drugs 0.000 claims description 2
- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical compound C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 claims description 2
- 229960003496 delamanid Drugs 0.000 claims description 2
- XNHZXMPLVSJQFK-UHFFFAOYSA-O dimethyl-[[4-[[3-(4-methylphenyl)-8,9-dihydro-7h-benzo[7]annulene-6-carbonyl]amino]phenyl]methyl]-(oxan-4-yl)azanium Chemical compound C1=CC(C)=CC=C1C1=CC=C(CCCC(=C2)C(=O)NC=3C=CC(C[N+](C)(C)C4CCOCC4)=CC=3)C2=C1 XNHZXMPLVSJQFK-UHFFFAOYSA-O 0.000 claims description 2
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- 125000006005 fluoroethoxy group Chemical group 0.000 claims description 2
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 2
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- GSNHKUDZZFZSJB-QYOOZWMWSA-N maraviroc Chemical compound CC(C)C1=NN=C(C)N1[C@@H]1C[C@H](N2CC[C@H](NC(=O)C3CCC(F)(F)CC3)C=3C=CC=CC=3)CC[C@H]2C1 GSNHKUDZZFZSJB-QYOOZWMWSA-N 0.000 claims description 2
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims description 2
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- 229960000885 rifabutin Drugs 0.000 claims description 2
- YIBOMRUWOWDFLG-ONEGZZNKSA-N rilpivirine Chemical compound CC1=CC(\C=C\C#N)=CC(C)=C1NC1=CC=NC(NC=2C=CC(=CC=2)C#N)=N1 YIBOMRUWOWDFLG-ONEGZZNKSA-N 0.000 claims description 2
- 229960001852 saquinavir Drugs 0.000 claims description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 claims description 2
- 229960001203 stavudine Drugs 0.000 claims description 2
- 229960004556 tenofovir Drugs 0.000 claims description 2
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 2
- QRPZBKAMSFHVRW-UHFFFAOYSA-N 1-(4-benzoylpiperazin-1-yl)-2-[4-methoxy-7-(3-methyl-1,2,4-triazol-1-yl)-1h-pyrrolo[2,3-c]pyridin-3-yl]ethane-1,2-dione Chemical compound C1=2NC=C(C(=O)C(=O)N3CCN(CC3)C(=O)C=3C=CC=CC=3)C=2C(OC)=CN=C1N1C=NC(C)=N1 QRPZBKAMSFHVRW-UHFFFAOYSA-N 0.000 claims 1
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- 239000012312 sodium hydride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- FNDDDNOJWPQCBZ-ZDUSSCGKSA-N sutezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCSCC1 FNDDDNOJWPQCBZ-ZDUSSCGKSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- GWWKNKUBRWLTRV-UHFFFAOYSA-N tert-butyl 2-ethylnon-7-enoate Chemical compound CCC(CCCCC=CC)C(=O)OC(C)(C)C GWWKNKUBRWLTRV-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 125000005500 uronium group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
Description
本発明は、新規化合物、それらを含有する組成物、および治療、例えば、マイコバクテリア感染症の治療または結核(TBとしても知られる)などのマイコバクテリウムにより生じる疾患の治療におけるそれらの使用に関する。
2014年に世界保健機関により発表された報告書によれば、毎年ほぼ1,000万人が結核(TB)に感染し、毎年150万例の死亡が生じている。結核に対する治療が利用可能であるにもかかわらず、この疾患の発生率は、TBの原因となる細菌病原体である結核菌(Mycobacterium tuberculosis)による感染症のために依然として上昇し始めており、この結核菌(Mycobacterium tuberculosis)は、イソニアジドおよびリファンピシンなどの多くの第一選択治療に対して耐性を示すようになってきている。
上記のように、本発明の一つの側面は、式(I)の化合物またはその薬学的に許容可能な塩:
4,4,4−トリフルオロ−1−[3−(2,2,2−トリフルオロエトキシ)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル]ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−プロポキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−イソブトキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−ヘキシルオキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
1−(3−ブロモ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)−4,4,4−トリフルオロブタン−1−オン;
1−(3−エトキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)−4,4,4−トリフルオロブタン−1−オン;
4,4,4−トリフルオロ−1−(3−メトキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−(トリフルオロメチル)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−メチル−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
1−(3−エチル−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)−4,4,4−トリフルオロブタン−1−オン;
8−(4,4,4−トリフルオロブタノイル)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−3−カルボニトリル;および
4,4,4−トリフルオロ−1−(3−フルオロ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン
を含む。
本明細書で使用する場合、用語「ハロゲン」は、フルオロ、クロロ、ブロモまたはヨードを指す。しかしながら、より詳しくは、それは、フルオロ、クロロまたはブロモを指すものとする。
本発明の化合物は、標準化学を含む多様な方法により調製してよい。先に定義されたいずれの変数も、特に断りのない限り、先に定義された意味を継続して有する。例示的な一般的合成法を以下のスキームにおいて説明するが、これらは、本発明の他の化合物を調製するために容易に適合することができる。本発明の特定の化合物は、実施例の項に開示される実験手順に従って調製することができる。
アルキルスピロ化合物である式(Ib)の化合物は、4,4,4−トリフルオロブタン酸との式(IV)の化合物のカップリングにより、スキーム3(下記)に従って調製してよい。式(IV)の化合物は、式(V)のオキシム化合物による市販の4−メチレンピペリジン−1−カルボン酸tert−ブチルの環化、およびさらに塩化水素などの酸によるN−Boc保護基の切断により、調製してよい。
式(Ic)のシアノ化合物は、スキーム4(下記)に従って、DMFなどの好適な溶媒中で、例えばシアン化ナトリウムによる化合物(IIIa)の求核置換により、調製してよい。
式(Id)のフッ素化合物は、スキーム5(下記)に従って、DMSOなどの好適な溶媒中で、例えばフッ化カリウムによる化合物(IIIa)のハロゲン置換により、調製してよい。
式(V)のオキシム中間体は、スキーム6(下記)に示されるように、NBSまたはNCSなどのN−ハロゲンスクシンイミドとの式(VI)の中間体化合物のハロゲン化反応により、調製してよい。Rがメチルまたはエチルである、式(VI)のオキシム中間体は、例えばヒドロキシルアミンとの式(VII)の対応するアルデヒドの反応により、調製してよい。あるいは、Rがトリフルオロメチルである、トリフルオロメチルオキシム中間体は、ヒドロキシルアミンとの2,2,2−トリフルオロ−1−メトキシエタノールの反応により、調製することができる。
一つの側面では、本発明は、治療での使用のための、式(I)の化合物またはその薬学的に許容可能な塩に関する。
式(I)の化合物およびその薬学的に許容可能な塩は、通常、必ずしもそうではないが、患者に投与する前に医薬組成物に処方される。従って、別の側面では、式(I)の化合物またはその薬学的に許容可能な塩と、薬学的に許容可能な賦形剤とを含んでなる医薬組成物が提供される。
以下の一覧は、本明細書で使用される特定の略語および記号の定義を示す。この一覧は網羅的ではないが、本明細書で以下に定義されない略語および記号の意味は、当業者には容易に明らかであろうと認識されるであろう。本発明の記載において、化学元素は、元素周期表に従って同定される。
anh 無水
CDCl3 重水素化クロロホルム(Deuterated chlorofom)
CD2Cl2 重水素化ジクロロメタン
CyHex シクロヘキサン
DCM ジクロロメタン
DIPEA ジイソプロピルエチルアミン(Diisoproylethylamine)
DMAP 4−ジメチルアミノピリジン
DMF ジメチルホルムアミド
DMSO−d6 重水素化ジメチルスルホキシド
EDC 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
EtOAc 酢酸エチル
Ex. 例
HBTU ヘキサフルオロリン酸N,N,N’,N’−テトラメチル−O−(1H−ベンゾトリアゾール−1−イル)ウロニウム
HPLC 高速液体クロマトグラフィー
lnt. 中間体
M モル
MS 質量分析
min 分
N 規定
NaH 水素化ナトリウム
NMR 核磁気共鳴
TFA トリフルオロ酢酸
TEA トリエチルアミン
THF テトラヒドロフラン
TLC 薄層クロマトグラフィー
rt 室温
UPLC 超高速液体クロマトグラフィー
中間体1:3−ブロモ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−カルボン酸tert−ブチル
例1:4,4,4−トリフルオロ−1−[3−(2,2,2−トリフルオロエトキシ)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル]ブタン−1−オン
b HPLC(pH3.8、アイソクラティックグラジエント、ACN/H2Oギ酸アンモニウム:39/61)による精製
c HPLC(pH3.8、アイソクラティックグラジエント、ACN/H2Oギ酸アンモニウム:54/46)による精製
エチオナミド(ETH)と例1〜11の組合せによる結核菌(M. tuberculosis)GFP株の成長阻害の測定
1. マイコバクテリア組換え株の構築
結核菌(M. tuberculosis)H37Rv−GFP株。緑色蛍光タンパク質を発現する結核菌(M. tuberculosis)H37Rvの組換え株(H37Rv−GFP)を、組込みプラスミドpNIP48のトランスフォーメーションにより得た(Abadie et al., 2005; Cremer et al., 2002)。Ms6マイコバクテリオファージに由来するこのプラスミドにおいて、GFP遺伝子を強力マイコバクテリアプロモーターpBlaFの下でクローン化し、GFPを構成的に発現させた。このプラスミドは、ハイグロマイシン耐性遺伝子も含有していた。
−80℃で保存した細菌ストックを用いて、25cm2組織培養フラスコ中で、オレイン酸−アルブミン−デキストロース−カタラーゼ(OADC、Difco、スパークス、メリーランド州、米国)および50μg ml−1ハイグロマイシン(Invitrogen、カールスバッド、カリフォルニア州、米国)を添加したミドルブルック7H9培地5mlを接種した。フラスコを振り混ぜずに37℃で7日間インキュベートした。次に、培養液を新鮮培養培地で希釈し、OD600を0.1とした。培養フラスコ(75cm2)をこの希釈培養液50mlで満たし、振り混ぜずに37℃で7日間培養した。
エチオナミド(Sigma、E6005)を、0.1mg/mLおよび0.8mg/mlでDMSOに希釈し、アリコートを−20℃で凍結保存した。試験化合物を終濃度10μMでDMSOに再懸濁した。エチオナミドおよび試験化合物を384ウェル低容量ポリプロピレンプレート(Corning、no.3672)に移し、これを用いて、アッセイプレートを調製した。化合物の10回の3倍段階希釈(一般に、30〜4.5e−3μMの範囲)を、Echo 550 Liquid Handler(Labcyte)を用いて、黒色のGreiner384ウェル透明ボトムポリスチレンプレート(Greiner、no.781091)の中に行った。全ウェルにわたる濃度が等しくなる(0.3%)ように、DMSO量を補った。
EC50_H37Rvは、H37Rv株に対するエチオナミド活性を増強する本発明の化合物の能力を測定し、一方、EC50_変異体は、エチオナミドに耐性を示すTBの株に対するエチオナミド活性を増強する本発明の化合物の能力を測定する。
細胞内スクリーニングは、ヒトマクロファージにおいて活性を示す新規抗結核化合物を同定するために有用なツールである。この生体外アッセイは、疾患を模倣し、宿主細胞の好ましい寄与を考慮した生理学的条件を表し得る(Sorrentino, F. et al. (2016) Antimicrob. Agents Chemother. 60 (1), 640-645.)。
Claims (22)
- R1が、フルオロ、クロロもしくはブロモ;シアノ;C1−6直鎖アルキル;C3−4分岐アルキル;C1−6直鎖アルコキシ;C3−4分岐アルコキシ;1以上のフルオロにより置換されたメチル;1以上のフルオロにより置換されたエチル;1以上のフルオロにより置換されたメトキシ;または1以上のフルオロにより置換されたエトキシである、請求項1に記載の化合物またはその薬学的に許容可能な塩。
- R1が、フルオロ、クロロもしくはブロモ;シアノ;C1−6直鎖アルキル;C3−4分岐アルキル;C1−6直鎖アルコキシ;C3−4分岐アルコキシ;モノ、ジもしくはトリフルオロメチル;モノ、ジもしくはトリフルオロメトキシ;2−フルオロエチル;2,2−ジフルオロエチル;2,2,2−トリフルオロエチル;2−フルオロエトキシ、2,2−ジフルオロエトキシ;または2,2,2−トリフルオロエトキシである、請求項1または2に記載の化合物またはその薬学的に許容可能な塩。
- R1が、フルオロ、クロロ、ブロモ、シアノ、C1−6直鎖アルキル、C3−4分岐アルキル、C1−6直鎖アルコキシ、C3−4分岐アルコキシ、トリフルオロメチル、トリフルオロメトキシ、2,2,2−トリフルオロエチルまたは2,2,2−トリフルオロエトキシである、請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- R1が、フルオロ、クロロ、ブロモ、シアノ、C1−6直鎖アルキル、C3−4分岐アルキル、C1−6直鎖アルコキシ、C3−4分岐アルコキシ、トリフルオロメチル、2,2,2−トリフルオロエチルまたは2,2,2−トリフルオロエトキシである、請求項1〜4のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- R1が、フルオロ、ブロモ、シアノ、C1−4直鎖アルキル、C1−6直鎖アルコキシ、C4分岐アルコキシ、トリフルオロメチル、2,2,2−トリフルオロエチルまたは2,2,2−トリフルオロエトキシである、請求項1〜5のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- R1が、フルオロ、ブロモ、シアノ、メチル、エチル、トリフルオロメチル、2,2,2−トリフルオロエトキシ、メトキシ、エトキシ、n−プロポキシ、イソ−ブトキシまたはヘキシルオキシである、請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- 4,4,4−トリフルオロ−1−[3−(2,2,2−トリフルオロエトキシ)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル]ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−プロポキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−イソブトキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−ヘキシルオキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
1−(3−ブロモ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)−4,4,4−トリフルオロブタン−1−オン;
1−(3−エトキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)−4,4,4−トリフルオロブタン−1−オン;
4,4,4−トリフルオロ−1−(3−メトキシ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−(トリフルオロメチル)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
4,4,4−トリフルオロ−1−(3−メチル−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン;
1−(3−エチル−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)−4,4,4−トリフルオロブタン−1−オン;
8−(4,4,4−トリフルオロブタノイル)−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−3−カルボニトリル;および
4,4,4−トリフルオロ−1−(3−フルオロ−1−オキサ−2,8−ジアザスピロ[4.5]デカ−2−エン−8−イル)ブタン−1−オン
から選択される、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。 - 治療での使用のための、請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- マイコバクテリア感染症の治療における使用のための、またはマイコバクテリウムの感染により生じる疾患の治療における使用のための、請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- マイコバクテリア感染症が結核菌(Mycobacterium tuberculosis)感染症である、請求項11に記載の使用のための化合物またはその薬学的に許容可能な塩。
- 結核の治療における使用のための、請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- それを必要とする哺乳動物におけるマイコバクテリア感染症の治療のための方法であって、治療上有効な量の請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を前記哺乳動物に投与することを含んでなる、方法。
- それを必要とする哺乳動物におけるマイコバクテリウムの感染により生じる疾患の治療のための方法であって、治療上有効な量の請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を前記哺乳動物に投与することを含んでなる、方法。
- マイコバクテリア感染症またはマイコバクテリウムの感染により生じる疾患の治療における使用のための薬剤の製造における、請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩の使用。
- (a)請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩と、(b)薬学的に許容可能な賦形剤と
を含んでなる医薬組成物。 - (a)請求項1〜9のいずれか一項に記載の化合物またはその薬学的に許容可能な塩と、(b)さらなる抗マイコバクテリア剤との組合せ。
- 少なくとも1つの他の抗マイコバクテリア剤が抗結核剤である、請求項18に記載の組合せ。
- 抗結核剤が、イソニアジド、リファンピン、ピラジナミド、エタンブトール、モキシフロキサシン、リファペンチン、クロファジミン、エチオナミド、プロチオナミド、イソキシル、チアセタゾン、リファブチン、ジアリルキノリン、例えば、ベダキリン(TMC207)もしくはTBAJ−587、ニトロイミダゾ−オキサジンPA−824、デラマニド(OPC−67683)、オキサゾリジノン、例えば、リネゾリド、テジゾリド、ラデゾリド、ステゾリド(PNU−100480)、ポジゾリド(AZD−5847)もしくはTBI−223、EMB類似体SQ109、OPC−167832、GSK3036656(GSK070としても知られる)、GSK2556286、GSK3211830、ベンゾチアジノン、例えば、BTZ043もしくはPBTZ169、アザインドール、例えば、TBA−7371、ジニトロベンズアミド、またはβラクタム、例えば、メロペネム、ファロペネム、エルタペネム、テビペネムまたはβラクタムの組合せ、例えば、オーグメンチン(アモキシシリン−クラブラン酸)から選択される、請求項19に記載の組合せ。
- 抗レトロウイルス剤を含む抗ウイルス剤をさらに含んでなる、請求項18〜20のいずれか一項に記載の組合せ。
- 抗レトロウイルス剤が、ジドブジン、ジダノシン、ラミブジン、ザルシタビン、アバカビル、スタブジン、アデホビル、アデホビルジピボキシル、ホジブジン、トドキシル、エムトリシタビン、アロブジン、アムドキソビル、エルブシタビン、ネビラピン、デラビルジン、エファビレンツ、ロビリデ、イムノカル、オルチプラズ、カプラビリン、レルシビリン、GSK2248761、TMC−278、TMC−125、エトラビリン、サキナビル、リトナビル、インジナビル、ネルフィナビル、アンプレナビル、ホスアンプレナビル、ブレカナビル、ダルナビル、アタザナビル、チプラナビル、パリナビル、ラシナビル、エンフビルチド、T−20、T−1249、PRO−542、PRO−140、TNX−355、BMS−806、BMS−663068およびBMS−626529、5−ヘリックス、ラルテグラビル、エルビテグラビル、GSK1349572、GSK1265744、ビクリビロック(Sch−C)、Sch−D、TAK779、マラビロク、TAK449、ジダノシン、テノホビル、ロピナビル、またはダルナビルから選択される、請求項21に記載の組合せ。
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