JP7183270B2 - 新規化合物 - Google Patents
新規化合物 Download PDFInfo
- Publication number
- JP7183270B2 JP7183270B2 JP2020530728A JP2020530728A JP7183270B2 JP 7183270 B2 JP7183270 B2 JP 7183270B2 JP 2020530728 A JP2020530728 A JP 2020530728A JP 2020530728 A JP2020530728 A JP 2020530728A JP 7183270 B2 JP7183270 B2 JP 7183270B2
- Authority
- JP
- Japan
- Prior art keywords
- fluoro
- pyridyl
- trifluoromethyl
- trifluoro
- butan
- 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.)
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- 150000001875 compounds Chemical class 0.000 title claims description 186
- 125000001153 fluoro group Chemical group F* 0.000 claims description 103
- 125000001424 substituent group Chemical group 0.000 claims description 82
- -1 chloro, bromo, cyano, methyl Chemical group 0.000 claims description 81
- 150000003839 salts Chemical class 0.000 claims description 79
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 55
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 46
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 42
- 201000008827 tuberculosis Diseases 0.000 claims description 39
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 38
- 125000004076 pyridyl group Chemical group 0.000 claims description 36
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 30
- 229960002001 ethionamide Drugs 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 28
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 27
- 208000027531 mycobacterial infectious disease Diseases 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 241000124008 Mammalia Species 0.000 claims description 19
- 206010062207 Mycobacterial infection Diseases 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- VRDIULHPQTYCLN-UHFFFAOYSA-N Prothionamide Chemical compound CCCC1=CC(C(N)=S)=CC=N1 VRDIULHPQTYCLN-UHFFFAOYSA-N 0.000 claims description 11
- 229960000918 protionamide Drugs 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 208000015181 infectious disease Diseases 0.000 claims description 10
- 239000000814 tuberculostatic agent Substances 0.000 claims description 10
- 229940121383 antituberculosis agent Drugs 0.000 claims description 9
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 7
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical group NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- QTQVXFOSWARYIX-UHFFFAOYSA-N 4,4,4-trifluoro-1-[4-[2-(trifluoromethyl)pyridin-4-yl]piperidin-1-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)C1=CC(=NC=C1)C(F)(F)F)(F)F QTQVXFOSWARYIX-UHFFFAOYSA-N 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
- 238000004519 manufacturing process Methods 0.000 claims description 5
- HEMZQNFJXPYSRX-UHFFFAOYSA-N 4,4,4-trifluoro-1-[4-fluoro-4-[4-(trifluoromethyl)pyridin-2-yl]piperidin-1-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)(C1=NC=CC(=C1)C(F)(F)F)F)(F)F HEMZQNFJXPYSRX-UHFFFAOYSA-N 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
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003926 antimycobacterial agent Substances 0.000 claims description 4
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 229960005107 darunavir Drugs 0.000 claims description 4
- CJBJHOAVZSMMDJ-HEXNFIEUSA-N darunavir Chemical compound C([C@@H]([C@H](O)CN(CC(C)C)S(=O)(=O)C=1C=CC(N)=CC=1)NC(=O)O[C@@H]1[C@@H]2CCO[C@@H]2OC1)C1=CC=CC=C1 CJBJHOAVZSMMDJ-HEXNFIEUSA-N 0.000 claims description 4
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 claims description 4
- 229960002656 didanosine Drugs 0.000 claims description 4
- 229960002049 etravirine Drugs 0.000 claims description 4
- 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 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229960003350 isoniazid Drugs 0.000 claims description 4
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 claims description 4
- 229960001225 rifampicin Drugs 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- 229960002171 tiocarlide Drugs 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
- 150000003952 β-lactams Chemical class 0.000 claims description 4
- HBUJYEUPIIJJOS-PBHICJAKSA-N (5r)-3-[4-[1-[(2s)-2,3-dihydroxypropanoyl]-3,6-dihydro-2h-pyridin-4-yl]-3,5-difluorophenyl]-5-(1,2-oxazol-3-yloxymethyl)-1,3-oxazolidin-2-one Chemical compound C1N(C(=O)[C@@H](O)CO)CCC(C=2C(=CC(=CC=2F)N2C(O[C@@H](COC3=NOC=C3)C2)=O)F)=C1 HBUJYEUPIIJJOS-PBHICJAKSA-N 0.000 claims description 3
- ZLHZLMOSPGACSZ-NSHDSACASA-N (6s)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5h-imidazo[2,1-b][1,3]oxazine Chemical compound O([C@H]1CN2C=C(N=C2OC1)[N+](=O)[O-])CC1=CC=C(OC(F)(F)F)C=C1 ZLHZLMOSPGACSZ-NSHDSACASA-N 0.000 claims description 3
- QUIJNHUBAXPXFS-UHFFFAOYSA-N 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol Chemical compound COC1=NC2=CC=C(Br)C=C2C=C1C(C(O)(CCN(C)C)C=1C2=CC=CC=C2C=CC=1)C1=CC=CC=C1 QUIJNHUBAXPXFS-UHFFFAOYSA-N 0.000 claims description 3
- VXODFDGBPPOOBB-UHFFFAOYSA-N 1-[3-(5-chloropyridin-3-yl)pyrrolidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC=1C=C(C=NC=1)C1CN(CC1)C(CCC(F)(F)F)=O VXODFDGBPPOOBB-UHFFFAOYSA-N 0.000 claims description 3
- QZIFEXPXICNUGE-UHFFFAOYSA-N 1-[4-(2-chloropyridin-4-yl)-4-fluoropiperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC1=NC=CC(=C1)C1(CCN(CC1)C(CCC(F)(F)F)=O)F QZIFEXPXICNUGE-UHFFFAOYSA-N 0.000 claims description 3
- CSQJUMKUCHUABH-UHFFFAOYSA-N 1-[4-(2-chloropyridin-4-yl)piperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC1=NC=CC(=C1)C1CCN(CC1)C(CCC(F)(F)F)=O CSQJUMKUCHUABH-UHFFFAOYSA-N 0.000 claims description 3
- CUWCLXGQIYBLJR-UHFFFAOYSA-N 1-[4-(5-chloropyridin-3-yl)-4-fluoropiperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC=1C=C(C=NC=1)C1(CCN(CC1)C(CCC(F)(F)F)=O)F CUWCLXGQIYBLJR-UHFFFAOYSA-N 0.000 claims description 3
- UNJDEKIBCSGTOQ-UHFFFAOYSA-N 1-[4-(5-chloropyridin-3-yl)piperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC=1C=C(C=NC=1)C1CCN(CC1)C(CCC(F)(F)F)=O UNJDEKIBCSGTOQ-UHFFFAOYSA-N 0.000 claims description 3
- KJHKRTYCTBFLIK-UHFFFAOYSA-N 1-[4-(5-chloropyridin-3-yl)piperidin-1-yl]-5,5,5-trifluoropentan-1-one Chemical compound ClC=1C=C(C=NC=1)C1CCN(CC1)C(CCCC(F)(F)F)=O KJHKRTYCTBFLIK-UHFFFAOYSA-N 0.000 claims description 3
- SKGYIHLXAQNRLQ-UHFFFAOYSA-N 1-[4-(6-chloropyrazin-2-yl)piperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC1=CN=CC(=N1)C1CCN(CC1)C(CCC(F)(F)F)=O SKGYIHLXAQNRLQ-UHFFFAOYSA-N 0.000 claims description 3
- KIMCGLHTSSZPNS-UHFFFAOYSA-N 2,3-dinitrobenzamide Chemical class 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 class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 3
- MJNPHLBKHKJDEF-UHFFFAOYSA-N 2h-1$l^{4},2-benzothiazine 1-oxide Chemical class C1=CC=C2S(=O)NC=CC2=C1 MJNPHLBKHKJDEF-UHFFFAOYSA-N 0.000 claims description 3
- YVMGQODAKAHLHB-UHFFFAOYSA-N 3-nitroimidazo[4,5-e]oxazine Chemical compound O1N=C([N+](=O)[O-])C=C2N=CN=C21 YVMGQODAKAHLHB-UHFFFAOYSA-N 0.000 claims description 3
- JANUJOVYUHEXTD-UHFFFAOYSA-N 4,4,4-trifluoro-1-(4-fluoro-4-pyridin-2-ylpiperidin-1-yl)butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)(C1=NC=CC=C1)F)(F)F JANUJOVYUHEXTD-UHFFFAOYSA-N 0.000 claims description 3
- ZDWARSILNSGGEQ-UHFFFAOYSA-N 4,4,4-trifluoro-1-(4-fluoro-4-pyridin-3-ylpiperidin-1-yl)butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)(C=1C=NC=CC=1)F)(F)F ZDWARSILNSGGEQ-UHFFFAOYSA-N 0.000 claims description 3
- TVTGYVWCNVZNTA-UHFFFAOYSA-N 4,4,4-trifluoro-1-[4-(2-fluoropyridin-4-yl)piperidin-1-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)C1=CC(=NC=C1)F)(F)F TVTGYVWCNVZNTA-UHFFFAOYSA-N 0.000 claims description 3
- IDTYRLFCTDMAIF-UHFFFAOYSA-N 4,4,4-trifluoro-1-[4-(5-fluoropyridin-2-yl)piperidin-1-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)C1=NC=C(C=C1)F)(F)F IDTYRLFCTDMAIF-UHFFFAOYSA-N 0.000 claims description 3
- XQLJHAIWXSIYHF-UHFFFAOYSA-N 4,4,4-trifluoro-1-[4-(5-fluoropyridin-3-yl)piperidin-1-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)C=1C=NC=C(C=1)F)(F)F XQLJHAIWXSIYHF-UHFFFAOYSA-N 0.000 claims description 3
- DAXJZDGDVQQKGJ-UHFFFAOYSA-N 4,4,4-trifluoro-1-[4-(6-fluoropyridin-3-yl)piperidin-1-yl]butan-1-one Chemical compound FC(CCC(=O)N1CCC(CC1)C=1C=NC(=CC=1)F)(F)F DAXJZDGDVQQKGJ-UHFFFAOYSA-N 0.000 claims description 3
- AZOFJHATIPDIER-UHFFFAOYSA-N 6-[[4-(2,3-dimethylphenoxy)piperidin-1-yl]methyl]-1h-pyrimidine-2,4-dione Chemical compound CC1=CC=CC(OC2CCN(CC=3NC(=O)NC(=O)C=3)CC2)=C1C AZOFJHATIPDIER-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
- 229960004287 clofazimine Drugs 0.000 claims description 3
- WDQPAMHFFCXSNU-BGABXYSRSA-N clofazimine Chemical compound C12=CC=CC=C2N=C2C=C(NC=3C=CC(Cl)=CC=3)C(=N/C(C)C)/C=C2N1C1=CC=C(Cl)C=C1 WDQPAMHFFCXSNU-BGABXYSRSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 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
- PEASPLKKXBYDKL-FXEVSJAOSA-N enfuvirtide Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(C)=O)[C@@H](C)O)[C@@H](C)CC)C1=CN=CN1 PEASPLKKXBYDKL-FXEVSJAOSA-N 0.000 claims description 3
- 229960000285 ethambutol Drugs 0.000 claims description 3
- 125000006379 fluoropyridyl group Chemical group 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
- 229960003907 linezolid Drugs 0.000 claims description 3
- 229960003702 moxifloxacin Drugs 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
- 229950004447 posizolid Drugs 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
- BTTNOGHPGJANSW-IBGZPJMESA-N radezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C1=CC=C(C=2C=CC(CNCC=3NN=NC=3)=CC=2)C(F)=C1 BTTNOGHPGJANSW-IBGZPJMESA-N 0.000 claims description 3
- 229950009965 radezolid Drugs 0.000 claims description 3
- 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 3
- 229960002599 rifapentine 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
- 229960003879 tedizolid Drugs 0.000 claims description 3
- CNPVJJQCETWNEU-CYFREDJKSA-N (4,6-dimethyl-5-pyrimidinyl)-[4-[(3S)-4-[(1R)-2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl]-3-methyl-1-piperazinyl]-4-methyl-1-piperidinyl]methanone Chemical compound N([C@@H](COC)C=1C=CC(=CC=1)C(F)(F)F)([C@H](C1)C)CCN1C(CC1)(C)CCN1C(=O)C1=C(C)N=CN=C1C CNPVJJQCETWNEU-CYFREDJKSA-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 description 2
- OKGPFTLYBPQBIX-CQSZACIVSA-N 1-[(2r)-4-benzoyl-2-methylpiperazin-1-yl]-2-(4-methoxy-1h-pyrrolo[2,3-b]pyridin-3-yl)ethane-1,2-dione Chemical compound C1=2C(OC)=CC=NC=2NC=C1C(=O)C(=O)N([C@@H](C1)C)CCN1C(=O)C1=CC=CC=C1 OKGPFTLYBPQBIX-CQSZACIVSA-N 0.000 claims description 2
- VPFMXKXMTVMSAW-UHFFFAOYSA-N 1-[4-(2,6-difluoropyridin-3-yl)piperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound FC1=NC(=CC=C1C1CCN(CC1)C(CCC(F)(F)F)=O)F VPFMXKXMTVMSAW-UHFFFAOYSA-N 0.000 claims description 2
- FUAJZZVGAQHHPU-UHFFFAOYSA-N 1-[4-(3,5-difluoropyridin-2-yl)piperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound FC=1C(=NC=C(C=1)F)C1CCN(CC1)C(CCC(F)(F)F)=O FUAJZZVGAQHHPU-UHFFFAOYSA-N 0.000 claims description 2
- DRSRNHXFFDRSKW-UHFFFAOYSA-N 1-[4-(5,6-difluoropyridin-3-yl)piperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound FC=1C=C(C=NC=1F)C1CCN(CC1)C(CCC(F)(F)F)=O DRSRNHXFFDRSKW-UHFFFAOYSA-N 0.000 claims description 2
- IWCSWONEDZMFKV-UHFFFAOYSA-N 1-[4-(6-chloropyrazin-2-yl)-4-fluoropiperidin-1-yl]-4,4,4-trifluorobutan-1-one Chemical compound ClC1=CN=CC(=N1)C1(CCN(CC1)C(CCC(F)(F)F)=O)F IWCSWONEDZMFKV-UHFFFAOYSA-N 0.000 claims description 2
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- UDXYSITZZMTXMH-UHFFFAOYSA-N tert-butyl 4-pyrimidin-2-yl-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC(C=2N=CC=CN=2)=C1 UDXYSITZZMTXMH-UHFFFAOYSA-N 0.000 description 1
- ISNSIRJTXRMJAP-UHFFFAOYSA-N tert-butyl 4-pyrimidin-2-ylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1=NC=CC=N1 ISNSIRJTXRMJAP-UHFFFAOYSA-N 0.000 description 1
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- NZPXPXAGXYTROM-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(O)=C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)C1)CC1=CC=CC=C1 NZPXPXAGXYTROM-FYBSXPHGSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000607 toxicokinetics Toxicity 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 229940075466 undecylenate Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 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
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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Description
本発明は、化合物、それらを含有する組成物、および療法、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の感染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1,500万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。
nは、1もしくは2であり;
mは、0もしくは1であり;
R1は、HもしくはFであり;
R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択される1もしくは2個の置換基により置換されていてもよいピリジルであるか、または
R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから選択される置換基によりメタ位で置換されていてもよいピラジニルであるか、または
R2は、フルオロもしくはクロロによりパラ位で置換されていてもよいピラジニルであり、
ここで、R1がHである場合、R2は置換されており、mが0である場合、R1はHである。]
の化合物またはその薬学上許容可能な塩が提供される。
上記のように、本発明の一側面は、式(I):
nは、1もしくは2であり;
mは、0もしくは1であり;
R1は、HもしくはFであり;
R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択される1もしくは2個の置換基により置換されていてもよいピリジルであるか、または
R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから選択される置換基によりメタ位で置換されていてもよいピラジニルであるか、または
R2は、フルオロもしくはクロロによりパラ位で置換されていてもよいピラジニルであり、
ここで、R1がHである場合、R2は置換されており、mが0である場合、R1はHである。]
の化合物またはその薬学上許容可能な塩に関する。
R2が2-ピリジルまたは4-ピリジルである場合、置換基は、クロロ、フルオロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択され;
R2が3-ピリジルである場合、置換基は、クロロ、フルオロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択され、ここで、置換基がトリフルオロメチルである場合、それはピリジン環の5位に結合しており、置換基がメトキシである場合、それはピリジン環の6位に結合している。
R2が2-ピリジルである場合、置換基は、クロロ、フルオロおよびトリフルオロメチルから独立に選択され;
R2が3-ピリジルである場合、置換基は、クロロ、フルオロ、メトキシおよびトリフルオロメチルから独立に選択され、ここで、置換基がトリフルオロメチルである場合、それはピリジン環の5位に結合しており、置換基がメトキシである場合、それはピリジン環の6位に結合しており;
R2が4-ピリジルである場合、置換基は、フルオロ、クロロ、メチルおよびトリフルオロメチルから独立に選択される。
4,4,4-トリフルオロ-1-[4-フルオロ-4-(3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(5-フルオロ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(6-フルオロ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[6-(トリフルオロメチル)-3-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[4-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[5-(トリフルオロメチル)-3-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[6-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(6-フルオロ-2-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(6-メトキシ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[2-(トリフルオロメチル)-3-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(5-メトキシ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
1-[4-(3,5-ジフルオロ-2-ピリジル)-1-ピペリジル]-4,4,4-トリフルオロ-ブタン-1-オン;
1-[4-(2,6-ジフルオロ-3-ピリジル)-1-ピペリジル]-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-[4-(5-フルオロ-2-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(2-(トリフルオロメチル)ピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(2-フルオロピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(5-(トリフルオロメチル)ピラジン-2-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(2-メチルピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(5,6-ジフルオロピリジン-3-イル)ピペリジン-1-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-(4-(6-(トリフルオロメチル)ピラジン-2-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(2-クロロピリジン-4-イル)ピペリジン-1-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-(4-(3-フルオロピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(6-クロロピリジン-2-イル)ピペリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;
1-(4-(5-クロロピリジン-3-イル)-4-フルオロピペリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;
1-(4-(5-クロロピリジン-3-イル)ピペリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;
1-(4-(5-クロロピリジン-3-イル)ピペリジン-1-イル)-5,5,5-トリフルオロペンタン-1-オン;
1-(4-(6-クロロピラジン-2-イル)ピペリジン-1-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-(4-フルオロ-4-(ピリジン-2-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-フルオロ-4-(5-(トリフルオロメチル)ピリジン-3-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-フルオロ-4-(2-(トリフルオロメチル)ピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(6-クロロピラジン-2-イル)-4-フルオロピペリジン-1-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-(4-フルオロ-4-(2-フルオロピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-フルオロ-4-[4-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-フルオロ-4-[4-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
1-(3-(5-クロロピリジン-3-イル)ピロリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;および
1-[4-(2-クロロ-4-ピリジル)-4-フルオロ-1-ピペリジル]-4,4,4-トリフルオロ-ブタン-1-オン
を含む。
nは、1または2であり;
mは、0または1であり;
R1は、HまたはFであり;
R2は、ピリジル、ピラジニル、ピリミジニルまたはピリダジニルであり、その各々は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択される1または2個の置換基により置換されていてもよく、
ここで、R1がHであり、R2がピリジルである場合、ピリジルは置換されており、mが0である場合、R1はHである。]
の化合物またはその薬学上許容可能な塩も本明細書に開示されるが、
ただし、化合物は、
本明細書で使用する場合、用語「ピリジル」は、2-ピリジル、3-ピリジルおよび4-ピリジルを含むピリジン置換基を指す。疑義を避けるために、2-ピリジル、3-ピリジルおよび4-ピリジルに関して以下のIUPACナンバリング体系を用いる:
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。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。
m=1であり、n=1または2であり、R1がHであり、R2が前述の定義の通りである式(I)の化合物は、塩化水素を用いた式(III)のアミノ化合物のBOC脱保護、次いで、市販の4,4,4-トリフルオロブタン酸もしくは5,5,5-トリフルオロペンタン酸(5,5,5-trifluoropentanoic)との、または式(IV)の中間体との式(II)の対応するHCl塩のカップリングにより、スキーム1に従って調製してよい。あるいは、式(I)の化合物は、4,4,4-トリフルオロブタノイルベンゾトリアゾールとの、式(II)のHCl塩としての対応する市販のアミノ化合物の反応により調製することができる。
式(IV)の中間体は、塩化チオニルの存在下で、1H-ベンゾトリアゾールとの市販の4,4,4-トリフルオロブタン酸のカップリングにより、スキーム8に従って調製することができる。
一側面において、本発明は、療法に使用するための、式(I)の化合物またはその薬学上許容可能な塩に関する。
式(I)の化合物およびその薬学上許容可能な塩は、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上許容可能な塩と、薬学上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
aq. 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
DAST 三フッ化ジエチルアミノ硫黄
DCM ジクロロメタン
DIPEA ジイソプロピルエチルアミン
DMAP 4-ジメチルアミノピリジン
DME ジメトキシエタン
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
dppf 1,1’-ビス(ジフェニルホスフィノ)フェロセン
EDC.HCl N-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド塩酸塩
EtOAc 酢酸エチル
EtOH エタノール
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
HOBt 1-ヒドロキシベンゾトリアゾール水和物
HPLC 高速液体クロマトグラフィー
lnt. 中間体
M モル
MeOH メタノール
MS 質量分析
min 分
N 規定
NaH 水素化ナトリウム
NaHMDS ナトリウムビス(トリメチルシリル)アミド
NMR 核磁気共鳴
pet 石油
Ref. Ex. 参考例
rt 室温
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
中間体1:1-(ベンゾトリアゾール-1-イル)-4,4,4-トリフルオロ-ブタン-1-オン
参考例1:4,4,4-トリフルオロ-1-(4-ピラジン-2-イル-1-ピペリジル)ブタン-1-オン
アッセイ1
げっ歯動物比較データ
以下のプロトコールを用いて、ラットにおける経口バイオアベイラビリティ(F%)を決定した。その値は、以下の表12に報告する。
0.25、0.5(注入終了直前)、0.58、0.75、1、1.5、2、3、5、7、および24時間;n=3匹(静脈内注入投与)
0.25、0.5、1、2、4、6、8、および24時間;n=3匹(強制経口投与)
化合物 mg/Kg
WO2014/096378のBDM_44751 100
実施例30 50
実施例18 100
エチオナミド(ETH)と実施例1~41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量を補償した。
ヒトマクロファージTHP-1阻害アッセイ(細胞内アッセイ)における結核菌(Mycobacterium tuberculosis)in vitro H37Rv
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 (32)
- 式(I):
nは、1もしくは2であり;
mは、0もしくは1であり;
R1は、HもしくはFであり;
R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択される1もしくは2個の置換基により置換されていてもよいピリジルであるか、または
R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから選択される置換基によりメタ位で置換されていてもよいピラジニルであるか、または
R2は、フルオロもしくはクロロによりパラ位で置換されていてもよいピラジニルであり、
ここで、R1がHである場合、R2は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから独立に選択される1もしくは2個の置換基により置換されているピリジルであるか、または、R 2 は、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから選択される置換基によりメタ位で置換されているピラジニルであるか、または、R 2 は、フルオロもしくはクロロによりパラ位で置換されているピラジニルであり、mが0である場合、R1はHである。]
の化合物またはその薬学上許容可能な塩。 - nが1である、請求項1に記載の化合物またはその薬学上許容可能な塩。
- mが1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上許容可能な塩。
- R2が、フルオロ、クロロ、メチル、トリフルオロメチル、およびメトキシから独立に選択される1もしくは2個の置換基により置換されていてもよいピリジルであって、置換基がトリフルオロメチルである場合、それはピリジン環のメタ位に結合している前記ピリジルであるか;または、R2が、フルオロ、クロロおよびトリフルオロメチルから独立に選択される1もしくは2個の置換基によりメタ置換されたピラジニルであるか;または、R2が、フルオロもしくはクロロによりパラ置換されたピラジニルである、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上許容可能な塩。
- R1がH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上許容可能な塩。
- R2が置換されている場合、それはメタ位で置換されている、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上許容可能な塩。
- R2が、フルオロ、クロロ、メチル、トリフルオロメチル、およびメトキシから独立に選択される1もしくは2個の置換基により置換されたピリジルであって、置換基がトリフルオロメチルである場合、それはピリジン環のメタ位に結合している前記ピリジルであるか;または、R2が、フルオロ、クロロおよびトリフルオロメチルから独立に選択される1もしくは2個の置換基によりメタ置換されたピラジニルであるか;または、R2が、フルオロもしくはクロロによりパラ置換されたピラジニルである、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上許容可能な塩。
- R2が、フルオロ、クロロ、ブロモ、シアノ、1個以上のフルオロにより置換されていてもよいメチル、および1個以上のフルオロにより置換されていてもよいメトキシから選択される1個の置換基により置換されたピリジルである、請求項5に記載の化合物またはその薬学上許容可能な塩。
- R2が、クロロ、フルオロ、メチル、メトキシおよびトリフルオロメチルから選択されるメタ位の1個の置換基により置換されたピリジルである、請求項1~8のいずれか一項に記載の化合物またはその薬学上許容可能な塩。
- R2が、フルオロ、クロロ、メチルまたはトリフルオロメチルにより置換された4-ピリジルである、請求項8または9に記載の化合物またはその薬学上許容可能な塩。
- R2が、トリフルオロメチルにより置換された4-ピリジルである、請求項10に記載の化合物またはその薬学上許容可能な塩。
- R2が、クロロ、フルオロ、メトキシまたはトリフルオロメチルにより置換された3-ピリジルであって、置換基がトリフルオロメチルである場合、それはピリジン環の5位に結合しており、置換基がメトキシである場合、それはピリジン環の6位に結合している前記3-ピリジルである、請求項8または9に記載の化合物またはその薬学上許容可能な塩。
- mが0である、請求項2または請求項4~12のいずれか一項に記載の化合物またはその薬学上許容可能な塩。
- R2が、クロロおよびトリフルオロメチルから選択される1個の置換基により置換された3-ピリジルである、請求項13に記載の化合物またはその薬学上許容可能な塩。
- R1がF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上許容可能な塩。
- R2が、1個の置換基により置換された3-ピリジルまたは4-ピリジルであって、置換基が、請求項1に定義された通りである前記3-ピリジルまたは4-ピリジルである、請求項15に記載の化合物またはその薬学上許容可能な塩。
- R2が、1個の置換基により置換された3-ピリジルまたは4-ピリジルであって、置換基が、クロロ、フルオロまたはトリフルオロメチルである前記3-ピリジルまたは4-ピリジルである、請求項15または16に記載の化合物またはその薬学上許容可能な塩。
- 4,4,4-トリフルオロ-1-[4-フルオロ-4-(3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(5-フルオロ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(6-フルオロ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[6-(トリフルオロメチル)-3-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[4-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[5-(トリフルオロメチル)-3-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[6-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(6-フルオロ-2-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(6-メトキシ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-[2-(トリフルオロメチル)-3-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-(5-メトキシ-3-ピリジル)-1-ピペリジル]ブタン-1-オン;
1-[4-(3,5-ジフルオロ-2-ピリジル)-1-ピペリジル]-4,4,4-トリフルオロ-ブタン-1-オン;
1-[4-(2,6-ジフルオロ-3-ピリジル)-1-ピペリジル]-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-[4-(5-フルオロ-2-ピリジル)-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(2-(トリフルオロメチル)ピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(2-フルオロピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(5-(トリフルオロメチル)ピラジン-2-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-(2-メチルピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(5,6-ジフルオロピリジン-3-イル)ピペリジン-1-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-(4-(6-(トリフルオロメチル)ピラジン-2-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(2-クロロピリジン-4-イル)ピペリジン-1-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-(4-(3-フルオロピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(6-クロロピリジン-2-イル)ピペリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;
1-(4-(5-クロロピリジン-3-イル)-4-フルオロピペリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;
1-(4-(5-クロロピリジン-3-イル)ピペリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;
1-(4-(5-クロロピリジン-3-イル)ピペリジン-1-イル)-5,5,5-トリフルオロペンタン-1-オン;
1-(4-(6-クロロピラジン-2-イル)ピペリジン-1-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-(4-フルオロ-4-(ピリジン-2-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-フルオロ-4-(5-(トリフルオロメチル)ピリジン-3-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-(4-フルオロ-4-(2-(トリフルオロメチル)ピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
1-(4-(6-クロロピラジン-2-イル)-4-フルオロピペリジン-1-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-(4-フルオロ-4-(2-フルオロピリジン-4-イル)ピペリジン-1-イル)ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-フルオロ-4-[4-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
4,4,4-トリフルオロ-1-[4-フルオロ-4-[4-(トリフルオロメチル)-2-ピリジル]-1-ピペリジル]ブタン-1-オン;
1-(3-(5-クロロピリジン-3-イル)ピロリジン-1-イル)-4,4,4-トリフルオロブタン-1-オン;および
1-[4-(2-クロロ-4-ピリジル)-4-フルオロ-1-ピペリジル]-4,4,4-トリフルオロ-ブタン-1-オン
から選択される、請求項1~17のいずれか一項に記載の化合物またはその薬学上許容可能な塩。 - 療法に使用するための、請求項1~19のいずれか一項に記載の式(I)の化合物またはその薬学上許容可能な塩。
- マイコバクテリア感染症の治療に使用するための、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使用するための、請求項1~19のいずれか一項に定義される式(I)の化合物またはその薬学上許容可能な塩。
- 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21に記載の使用のための化合物またはその薬学上許容可能な塩。
- 結核の治療に使用するための、請求項1~19のいずれか一項に定義される式(I)の化合物またはその薬学上許容可能な塩。
- 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使用するための医薬の製造における、請求項1~19のいずれか一項に記載の化合物またはその薬学上許容可能な塩の使用。
- (a)請求項1~19のいずれか一項に定義される式(I)の化合物またはその薬学上許容可能な塩と、(b)薬学上許容可能な賦形剤とを含んでなる医薬組成物。
- 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に使用される、請求項25に記載の医薬組成物。
- 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に使用される、請求項25に記載の医薬組成物。
- (a)請求項1~19のいずれか一項に定義される式(I)の化合物またはその薬学上許容可能な塩と、(b)少なくとも1種の他の抗マイコバクテリア剤とを含む組合せ医薬。
- 少なくとも1種の他の抗マイコバクテリア剤が抗結核剤である、請求項28に記載の組合せ医薬。
- 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、ジアリルキノリン系、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)、オキサゾリジノン系、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、ベンゾチアジノン系、例えば、BTZ043もしくはPBTZ169、アザインドール系、例えば、TBA-7371、ジニトロベンズアミド、またはβラクタム系、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ラクタム系の組合せ、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29に記載の組合せ医薬。
- 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28~30のいずれか一項に記載の組合せ医薬。
- 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31に記載の組合せ医薬。
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WO2013060744A2 (en) | 2011-10-25 | 2013-05-02 | Universite De Droit Et De La Sante De Lille 2 | Compounds having an ethr inhibiting activity - use of said compounds as drugs - pharmaceutical composition and product containing said compounds |
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