JP2016508968A - ピリドン誘導体および結核の処置におけるその使用 - Google Patents
ピリドン誘導体および結核の処置におけるその使用 Download PDFInfo
- Publication number
- JP2016508968A JP2016508968A JP2015547535A JP2015547535A JP2016508968A JP 2016508968 A JP2016508968 A JP 2016508968A JP 2015547535 A JP2015547535 A JP 2015547535A JP 2015547535 A JP2015547535 A JP 2015547535A JP 2016508968 A JP2016508968 A JP 2016508968A
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- JP
- Japan
- Prior art keywords
- pharmaceutically acceptable
- tuberculosis
- acceptable salt
- compound according
- phenyl
- 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
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- 201000008827 tuberculosis Diseases 0.000 title claims abstract description 68
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 118
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 39
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 18
- 208000035475 disorder Diseases 0.000 claims abstract description 17
- 230000005764 inhibitory process Effects 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 16
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 10
- 108040007096 enoyl-[acyl-carrier-protein] reductase activity proteins Proteins 0.000 claims abstract description 7
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- -1 hydroxy, amino Chemical group 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 66
- 150000003839 salts Chemical class 0.000 claims description 58
- 239000000203 mixture Substances 0.000 claims description 38
- 239000003814 drug Substances 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 206010036790 Productive cough Diseases 0.000 claims description 14
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- 210000003802 sputum Anatomy 0.000 claims description 14
- 208000024794 sputum Diseases 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 239000003937 drug carrier Substances 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 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical group NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 8
- 201000006674 extrapulmonary tuberculosis Diseases 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 208000015181 infectious disease Diseases 0.000 claims description 7
- 244000005700 microbiome Species 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- 239000008177 pharmaceutical agent Substances 0.000 claims description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 239000000814 tuberculostatic agent Substances 0.000 claims description 5
- VCOPTHOUUNAYKQ-WBTCAYNUSA-N (3s)-3,6-diamino-n-[[(2s,5s,8e,11s,15s)-15-amino-11-[(6r)-2-amino-1,4,5,6-tetrahydropyrimidin-6-yl]-8-[(carbamoylamino)methylidene]-2-(hydroxymethyl)-3,6,9,12,16-pentaoxo-1,4,7,10,13-pentazacyclohexadec-5-yl]methyl]hexanamide;(3s)-3,6-diamino-n-[[(2s,5s,8 Chemical compound N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](C)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1.N1C(=O)\C(=C/NC(N)=O)NC(=O)[C@H](CNC(=O)C[C@@H](N)CCCN)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CNC(=O)[C@@H]1[C@@H]1NC(N)=NCC1 VCOPTHOUUNAYKQ-WBTCAYNUSA-N 0.000 claims description 4
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 claims description 4
- 108010065839 Capreomycin Proteins 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 229960004821 amikacin Drugs 0.000 claims description 4
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 claims description 4
- 229940121383 antituberculosis agent Drugs 0.000 claims description 4
- 229960004602 capreomycin Drugs 0.000 claims description 4
- 150000001767 cationic compounds Chemical class 0.000 claims description 4
- 229960000285 ethambutol Drugs 0.000 claims description 4
- 229910001411 inorganic cation Inorganic materials 0.000 claims description 4
- 229960003350 isoniazid Drugs 0.000 claims description 4
- 229930027917 kanamycin Natural products 0.000 claims description 4
- 229960000318 kanamycin Drugs 0.000 claims description 4
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 claims description 4
- 229930182823 kanamycin A Natural products 0.000 claims description 4
- 229960001699 ofloxacin Drugs 0.000 claims description 4
- 150000002892 organic cations Chemical class 0.000 claims description 4
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 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
- 229960001225 rifampicin Drugs 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims description 3
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 claims description 3
- DYDCUQKUCUHJBH-UWTATZPHSA-N D-Cycloserine Chemical compound N[C@@H]1CONC1=O DYDCUQKUCUHJBH-UWTATZPHSA-N 0.000 claims description 3
- DYDCUQKUCUHJBH-UHFFFAOYSA-N D-Cycloserine Natural products NC1CONC1=O DYDCUQKUCUHJBH-UHFFFAOYSA-N 0.000 claims description 3
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 3
- VRDIULHPQTYCLN-UHFFFAOYSA-N Prothionamide Chemical compound CCCC1=CC(C(N)=S)=CC=N1 VRDIULHPQTYCLN-UHFFFAOYSA-N 0.000 claims description 3
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 3
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 claims description 3
- 229960004909 aminosalicylic acid Drugs 0.000 claims description 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@](C)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 3
- 229960002626 clarithromycin Drugs 0.000 claims description 3
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 claims description 3
- 229960003324 clavulanic acid Drugs 0.000 claims description 3
- 229960003077 cycloserine Drugs 0.000 claims description 3
- 229960002182 imipenem Drugs 0.000 claims description 3
- 229960003376 levofloxacin Drugs 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
- 229960003702 moxifloxacin Drugs 0.000 claims description 3
- 229960000918 protionamide Drugs 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 229960005322 streptomycin Drugs 0.000 claims description 3
- 229960002784 thioridazine Drugs 0.000 claims description 3
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 2
- 229960003022 amoxicillin Drugs 0.000 claims description 2
- 229960004287 clofazimine Drugs 0.000 claims description 2
- 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 2
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 claims description 2
- 229960002001 ethionamide Drugs 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 2
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- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims 1
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- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940042402 non-nucleoside reverse transcriptase inhibitor Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000002726 nonnucleoside reverse transcriptase inhibitor Substances 0.000 description 1
- 229940072250 norvir Drugs 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000010292 orthophenyl phenol Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000005880 oxathiolanyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000003585 oxepinyl group Chemical group 0.000 description 1
- 235000019371 penicillin G benzathine Nutrition 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 229940068586 prezista Drugs 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical group [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 229960004742 raltegravir Drugs 0.000 description 1
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229940107904 reyataz Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- 102200156911 rs121964886 Human genes 0.000 description 1
- 102200057606 rs231775 Human genes 0.000 description 1
- 102220123008 rs773305645 Human genes 0.000 description 1
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 229940031307 selzentry Drugs 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 229940054565 sustiva Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000005032 thiofuranyl group Chemical group S1C(=CC=C1)* 0.000 description 1
- 125000001806 thionaphthenyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000012070 whole genome sequencing analysis Methods 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229940052255 ziagen Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- 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
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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
- A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
-
- 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
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- 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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- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/58—Pyridine rings
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- Epidemiology (AREA)
- Molecular Biology (AREA)
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- General Chemical & Material Sciences (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本明細書に記載されている化合物は、結核、特に多剤耐性(MDR)および超多剤耐性(XDR)結核の処置に有用であることを示している。
式中、
R1がH、メチルもしくはエチルであり;
R2がフェニル、ピロールもしくはピラゾールであり、前記フェニルが、場合により、フルオロもしくはクロロから独立して選択される1個もしくは複数の置換基で置換され;但し前記置換基がクロロである場合、前記クロロが前記フェニルのメタ位もしくはオルト位に位置し、クロロ置換基の数が1個以下であり;
R3が
(式中、R100およびR200が、H、(C1〜C6)アルキル、シクロアルキル、有機カチオンおよび無機カチオンからなる群からそれぞれ独立して選択される)
からなる群から選択される構造式であり;
R4がHもしくは−C(=O)NH2であり;
R5が(C1〜C6)アルキル、シクロアルキル、フェニル、ヘテロ環およびヘテロアリールからなる群から選択され、場合により1個もしくは複数の独立したR300置換基で置換され;ならびに
R300が、H、(C1〜C6)アルキル、シクロアルキル、ヒドロキシ、アミノおよびFからなる群から選択される;
の化合物、または薬学的に許容されるその塩を提供する。
式中、R1がHである;の化合物、または薬学的に許容されるその塩が提供される。別の実施形態において、式(I)
式中、R2がフェニルである;の化合物、または薬学的に許容されるその塩が提供される。さらに別の実施形態において、式(I)
式中、R3が(Ia)である;の化合物、または薬学的に許容されるその塩が提供される。
式中、R3が(Ic)であり、R100およびR200がいずれもHである;の化合物、または薬学的に許容されるその塩が提供される。別の実施形態において、式(I)
式中、R4がHである;の化合物、または薬学的に許容されるその塩が提供される。さらに別の実施形態において、式(I)
式中、R5が(C1〜C6)アルキル、フェニル、テトラヒドロ−2H−ピランもしくはピリジンである;の化合物、または薬学的に許容されるその塩が提供される。
式中、R5がシクロアルキルである;の化合物、または薬学的に許容されるその塩が提供される。別の実施形態において、式(I)、
式中、R5がシクロヘキサンである;の化合物、または薬学的に許容されるその塩が提供される。さらに別の実施形態において、式(I)
式中、R5がシクロヘキサン((C1〜C6)アルキル、シクロアルキルもしくはFから独立して選択される、1個もしくは複数の置換基で置換される)である;の化合物、または薬学的に許容されるその塩が提供される。さらに別の実施形態において、式(I)
式中、R5がシクロヘキサン(メチル、シクロプロパンもしくはFから独立して選択される、1個もしくは複数の置換基で置換される)である;の化合物、または薬学的に許容されるその塩が提供される。さらに別の実施形態において、式(I)
式中、R5がシクロヘキサン(2個のメチル置換基で置換される)である;の化合物、または薬学的に許容されるその塩が提供される。
(i)請求項1から16に記載の化合物のいずれか1つ、または薬学的に許容されるその塩、および薬学的に許容される担体または賦形剤を含む第1の組成物;ならびに
(ii)少なくとも1つの追加の医薬品および薬学的に許容される担体または賦形剤を含む第2の組成物を投与するステップを含む。特に重要な疾患、障害または症候群は結核である。一実施形態において、ヒトは(i)喀痰塗抹陽性、喀痰塗抹陰性または肺外結核;(ii)薬剤耐性結核菌(M. tuberculosis)群の微生物によって引き起こされる結核;または(iii)ヒト免疫不全ウイルス(HIV)感染症に合併する結核を有する。第1および第2の組成物は同時に;または、任意の順序で順次投与され得る。
本明細書で使用されている、「アルキル」という用語は、一般式CnH2n+1の炭化水素基を指す。アルキル(alkane)基は、直鎖または分岐であってよい。例えば、「(C1〜C6)アルキル」という用語は、1から6個の炭素原子(例えば、メチル、エチル、n−プロピル、i−プロピル、n−ブチル、i−ブチル、s−ブチル、t−ブチル、n−ペンチル、1−メチルブチル、2−メチルブチル、3−メチルブチル、ネオペンチル、3,3−ジメチルプロピル、ヘキシル、2−メチルペンチルなど)を含有する、一価の、直鎖または分岐脂肪族基を指す。同様に、アルコキシ、アシル(例えば、アルカノイル)、アルキルアミノ、ジアルキルアミノおよびアルキルチオ基のアルキル部(すなわち、アルキル部分)は、上と同一の定義を有する。
本発明は、結核、特にMDRまたはXDR耐性結核の処置に有用な化合物およびそれらの医薬製剤を提供する。
ヌクレオシド逆転写酵素阻害剤(NRTIs)、例えばアバカビル(Ziagen)、ならびにエムトリシタビンおよびテノフォビル(Truvada)、ならびにラミブジンおよびジドブジン(Combivir)を組み合わせた薬剤;プロテアーゼ阻害剤(PI)、例えばアタザナビル(Reyataz)、ダルナビル(Prezista)、ホスアンプレナビル(Lexiva)およびリトナビル(Norvir);侵入または融合阻害剤、例えばエンフビルチド(Fuzeon)およびマラビロク(Selzentry);ならびにインテグラーゼ阻害剤、例えばラルテグラビル(Isentress)が含まれる。
h 時間
rt 室温
aq. 水溶液
sat. 飽和
Cs2CO3 炭酸セシウム
DCM ジクロロメタン
NMR 核磁気共鳴
MS 質量分析
HPLC 高速液体クロマトグラフィー
DMSO ジメチルスルホキシド
MeOH メタノール
EtOH エタノール
EtOAc 酢酸エチル
MeCN アセトニトリル
DMF ジメチルホルムアミド
THF テトラヒドロフラン
NaH 水素化ナトリウム
Na2SO4 硫酸ナトリウム
NaOH 水酸化ナトリウム
NaHCO3 炭酸水素ナトリウム
NH4OH 水酸化アンモニウム
HCl 塩酸
DMAP 4−ジメチルアミノピリジン
KHSO4 硫酸水素カリウム
(COCl)2 塩化オキサリル
MeI ヨウ化メチル
NaOMe ナトリウムメトキシド
K2CO3 炭酸カリウム
TBAI テトラ−n−ブチルアンモニウムヨージド
DIPEA N,N−ジイソプロピルエチルアミン
SOCl2 塩化チオニル
PCl5 五塩化リン
NH3 アンモニア
NBS N−ブロモスクシンイミド
BnBr 臭化ベンジル
Ag2CO3 炭酸銀
Ac2O 無水酢酸
BBr3 三臭化ホウ素
Pd(PPh3)2Cl2 ビス(トリフェニルホスフィン)パラジウム(II)ジクロリド
方法1〜5で例示されるように、スキーム1〜7(下記)は、式(I)の化合物を生成するための有望な経路について記載している。
方法1で例示されるスキーム1は、US007396936B1に記載の手順に従って、対応する酸または酸塩化物からの、4−置換エチル3−アミノブト−2−エノエートの合成に使用できる。
方法2で例示されるスキーム2は、Org.Lett.9,3469〜3472頁(2007)に記載の手順に従って、マロン酸ジエチルからの、2−置換アリールマロネート(2-substituted aryl malonate)の合成に使用できる。
方法3Aで例示されるスキーム3は、Eur.J.Med.Chem.26,599〜604頁(1991)に記載の手順に従って、対応する4−置換エチル3−アミノブト−2−エノエートおよび2−置換マロネート(2-substituted malonate)からの、置換ピリドンの合成に使用できる。
方法3Bで例示されるスキーム4は、Eur.J.Med.Chem.26,599〜604頁(1991)に記載の手順に従って、対応する4−置換エチル3−アミノブト−2−エノエートおよび2−置換マロネート(2-substituted malonate)からの、置換ピリドンの合成に使用できる。
方法3Cで例示されるスキーム5は、Eur.J.Med.Chem.26,599〜604頁(1991)に記載の手順に従って、対応する4−置換エチル3−アミノブト−2−エノエートおよび2−置換マロネート(2-substituted malonate)からの、置換ピリドンの合成に使用できる。
方法4(4Aおよび4Bを含む)で例示されるスキーム6は、Eur.J.Med.Chem.26,599〜604頁(1991)に記載の手順に従って、置換ピリドンの脱炭酸に使用できる。
2NのNaOH水溶液中のエチル4−ヒドロキシ−2,5−二基置換−6−オキソ−1,6−ジヒドロピリジン−3−カルボキシレートの溶液を、24時間まで130℃で維持した。反応塊を室温に冷却し、1NのHClを用いて酸化させた。形成された固体を濾過し、石油エーテルを用いて洗浄し、乾燥させて、4−ヒドロキシ−3,6−二基置換ピリジン−2(1H)−オンをオフホワイトの固体として得た(沈殿が観察されなかった例の場合、EtOAcを用いて反応混合物を抽出し、水、5%重炭酸ナトリウム水溶液、ブラインを用いて合わせた有機層を洗浄し、無水Na2SO4で脱水し、濃縮して、4−ヒドロキシ−3,6−二基置換ピリジン−2(1H)−オンを固体として得た)。
エチル4−ヒドロキシ−2,5−二基置換−6−オキソ−1,6−ジヒドロピリジン−3−カルボキシレートおよび2NのHClを130℃で24時間まで維持した。反応塊を室温に冷却し、飽和NaHCO3水溶液を用いて中和した。濾過により固体を収集し、石油エーテルを用いて洗浄し、乾燥させて4−ヒドロキシ−3,6−二基置換ピリジン−2(1H)−オンを得た。沈殿が観察されなかった例において、EtOAcを用いて反応混合物を抽出した。水、5%重炭酸ナトリウム水溶液、ブラインを用いて合わせた有機層を洗浄し、無水Na2SO4で脱水し、濃縮して、4−ヒドロキシ−3,6−二基置換ピリジン−2(1H)−オンを固体として得た。
方法5で例示されるスキーム7は、PCT出願国際公開第WO2009/099929A1号パンフレットに記載の手順に従って、2−置換マロン酸からの、ビス(2,4,6−トリクロロフェニル)2−置換マロネート(2-substituted malonate)の合成に使用できる。
対応する市販の酸(スキーム1を参照されたい)を使用して、方法1に従って、以下の4−置換エチル3−アミノブト−2−エノエートを調製した。US2004/0077618A1で報告されている手順を使用して、市販されていない(4,4−ジメチルシクロヘキシル)酢酸を調製し、Tetrahedron 51,10259〜10280頁(1995)およびUS2006/264489で報告されている手順に従って(4,4−ジフルオロシクロヘキシル)酢酸を調製した。
エチル4−(4,4−ジメチルシクロヘキシル)−3−オキソブタノエートの調製
0℃でTHF(1.5L)中のNaH(38.02g、0.990mol、油中に60%)の溶液に、トリエチルホスホノアセテート(157.2mL、0.792mol)を加え、混合物を室温で1時間十分に撹拌した。次いで、4,4−ジメチルシクロヘキサノン(100g、0.792mol)を加え、混合物を60℃で2時間十分に撹拌した。氷冷した飽和NH4Cl水溶液(1L)を用いて反応混合物をクエンチし、EtOAc(3×350mL)を用いて生成物を抽出した。ブライン(3×150mL)を用いて合わせた有機層を洗浄し、無水Na2SO4で脱水し、減圧下で濃縮して、170gの粗エチル2−(4,4−ジメチルシクロヘキシリデン)アセテートを淡黄色の液体として得た。これを、さらに精製することなく、次のステップにてそれ自体を使用した。
1H NMR: (400 MHz, CDCl3): δ 5.50 (s, 1H), 4.16 (q, J = 7.6 Hz, 2H), 2.10-1.95 (br s, 2H), 1.90-1.80 (br s, 2H), 1.50-1.30 (m, 7H), 0.90 (s, 6H).
EtOH(1.2L)中のエチル2−(4,4−ジメチルシクロヘキシリデン)アセテート(155g、789.64mmol)の溶液に、10%Pd/C(13.0g)を加え、50psiの水素圧力で12時間水素化した。セライトを通して反応混合物を濾過し、濃縮して、150g(96%、2ステップ)のエチル2−(4,4−ジメチルシクロヘキシル)アセテートを淡黄色の液体として得た。
1H NMR: (400 MHz, CDCl3): δ 4.12 (q, J = 7.2 Hz, 2H), 2.19 (d, J = 7.2 Hz, 2H), 1.80-1.60 (m, 1H), 1.60-1.50 (m, 2H), 1.40-1.10 (m, 9H), 0.89 (s, 3H), 0.86 (s, 3H).
エチル2−(4,4−ジメチルシクロヘキシル)アセテートの溶液(150g、756.42mmol)に、無水EtOH(800mL)中の50%NaOH水溶液(800mL)を加え、室温で15時間撹拌した。これを、エーテル(3×120mL)を用いて洗浄して、不純物を除去した。次いで、2NのHCl水溶液を使用して、反応混合物をpH2に酸化させた。EtOAc(3×350mL)を用いてHCl溶液および生成物を抽出した。ブライン(3×150mL)を用いて、合わせた有機層を洗浄し、無水Na2SO4で脱水し、減圧下で濃縮して、120g(93%)の2−(4,4−ジメチルシクロヘキシル)酢酸を粘液として得た。
1H NMR: (400 MHz, DMSO-d6): δ 11.98 (s, 1H), 2.10 (d, J = 6.4 Hz, 2H), 1.60-1.40 (m, 3H), 1.40-1.25 (m, 2H), 1.20-1.05 (m, 4H), 0.87 (s, 3H), 0.84 (s, 3H).
0℃で、DCM(1.2L)中の2−(4,4−ジメチルシクロヘキシル)酢酸(120g、0.704mol)の溶液に、メルドラム酸(132.2g、0.92mol)およびDMAP(129.1g、1.06mol)、続いてDCC(218.1g、1.06mol)を加え、混合物を室温で4時間十分に撹拌した。DCM(500mL)を用いて、反応混合物を希釈し、10%クエン酸水溶液(3×150mL)、続いて水(3×150mL)、ブライン(3×150mL)を用いて洗浄し、濃縮して、100gの粗5−(2−シクロヘキシル−1−ヒドロキシエチリデン)−2,2−ジメチル−1,3−ジオキサン−4,6−ジオンを無色の液体として得た。粗5−(2−シクロヘキシル−1−ヒドロキシエチリデン)−2,2−ジメチル−1,3−ジオキサン−4,6−ジオン(100g)を、EtOH(700mL)に溶解し、4時間還流した。反応混合物を減圧下で濃縮した。溶離液としてヘキサン中の15〜20%EtOAcを使用した100〜200のシリカにより、粗化合物を精製して、90g(53%)の純粋なエチル4−(4,4−ジメチルシクロヘキシル)−3−オキソブタノエートを無色の液体として得た。
1H NMR (400 MHz, CDCl3): δ 4.18 (q, J = 7.2 Hz, 2H), 3.41 (s, 2H), 2.44 (d, J = 6.8 Hz, 2H), 1.80-1.70 (m, 1H), 1.56-1.48 (m, 2H), 1.40-1.05 (m, 9H), 0.89 (s, 3H), 0.85 (s, 3H).
トルエン(750mL)中のエチル4−(4,4−ジメチルシクロヘキシル)−3−オキソブタノエート(90g、644.5mmol)の溶液に、酢酸アンモニウム(144.3g、1.87mol)、AcOH(21.4mL、374.5mmol)を加え、Dean−Stark装置を使用して36時間混合物を還流した。減圧下で反応混合物を濃縮して、75g(84%)のエチル3−アミノ−4−(4,4−ジメチルシクロヘキシル)ブト−2−エノエートを無色の液体として得た。
1H NMR (400 MHz, CDCl3): δ 4.51 (s, 1H), 4.15 (q, J = 6.8 Hz, 2H), 2.08-1.98 (m, 2H), 1.60-1.54 (m, 2H), 1.50-1.34 (m, 3H), 1.26 (t, J = 7.6 Hz, 3H), 1.22-1.05 (m, 4H), 0.89 (s, 3H), 0.86 (s, 3H).
ESI MS:m/z 240.4(M+H)。
6−((4,4−ジメチルシクロヘキシル)メチル)−4−ヒドロキシ−3−フェニルピリジン−2(1H)−オンの調製
ステップ1:エチル2−((4,4−ジメチルシクロヘキシル)メチル)−4−ヒドロキシ−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボキシレートの調製
ダウサム(45mL)中に入れたエチル3−アミノ−4−(4,4−ジメチルシクロヘキシル)ブト−2−エノエート(10g、41.8mmol)およびビス(2,4,6−トリクロロフェニル)−2−フェニルマロネート(22.51g、41.8mmol)の混合物を、予熱した砂浴にて、260℃で30分間加熱した。得られた残渣を石油エーテル中で粉砕し、沈殿した固体を濾過し、石油エーテルを用いて洗浄し、乾燥させて7.3g(46%)のエチル2−((4,4−ジメチルシクロヘキシル)メチル)−4−ヒドロキシ−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボキシレートをオフホワイトの固体として得た。
1H NMR (400 MHz, DMSO-d6): δ 11.85-11.75 (br s, 2H), 7.42-7.30 (m, 5H), 4.35 (q, J = 6.8 Hz, 2H), 2.83 (d, J = 7.2 Hz, 2H), 1.70-1.50 (m, 1H), 1.50-1.05 (m, 11H), 0.88 (s, 6H).
ESI MS:m/z 384.21(M+H)。
封管中のエチル2−((4,4−ジメチルシクロヘキシル)メチル)−4−ヒドロキシ−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボキシレート溶液(55g、143.4mmol)に、2NのNaOH水溶液(550mL)を加え、24時間130℃に加熱した。冷水を用いて反応混合物を希釈し、2NのHCl水溶液を使用してpH2に酸化させ、CHCl3中の10%MeOHに生成物を抽出した。ブライン(3×150mL)を用いて、合わせた有機層を洗浄し、無水Na2SO4で脱水し、真空下で濃縮した。溶離液として、n−ペンタンおよびジエチルエーテルと共に、粗化合物を粉砕することにより精製して、39g(87%)の6−((4,4−ジメチルシクロヘキシル)メチル)−4−ヒドロキシ−3−フェニルピリジン−2(1H)−オンをオフホワイトの固体として得た。
1H NMR (400 MHz, DMSO-d6): δ 11.08 ( s, 1H), 10.20 (s, 1H), 7.38-7.26 (m, 4H), 7.18-7.14 (m, 1H), 5.78 (s, 1H), 2.30 (d, J = 6.1 Hz, 2H), 1.46-1.34 (m, 5H), 1.25 (br s, 4H) 0.87 (d, J = 5.3 Hz, 6H). 13C NMR (100 MHz, DMSO-d6): δ 163.46, 162.82, 146.87, 134.18, 130.77, 126.93, 125.58, 108.39, 98.20, 38.33, 36.76, 32.38, 29.68, 27.99, 24.38.
ESI MS:m/z 312.4[M+H]。C20H26NO2[M+H]のHRMS計算値、312.1958;実測値、312.1956。HPLC純度:>99%。
3−(2−フルオロフェニル)−4−ヒドロキシ−6−イソブチルピリジン−2(1H)−オン
1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.30 (br s, 1H), 7.30-7.22 (m, 2H), 7.14-7.09 (m, 2H), 5.78 (s, 1H), 2.27 (d, J = 7.5 Hz, 2H), 1.96-1.89 (m, 1H), 0.90 (d, J = 6.6 Hz, 6H).
ESI MS:m/z 262.20(M+H)。HPLC純度:97.30%。
1H NMR (400 MHz, DMSO-d6): δ 11.18 (br s, 1H), 10.2 (s, 1H), 7.39-7.26 (m, 4H), 7.18-7.15 (m, 1H), 5.80 (s, 1H), 2.30 (d, J = 7.10 Hz, 2H), 1.95-1.93 (m, 1H), 0.90-0.88 (d, J = 6.42 Hz, 6H).
ESI MS:m/z 244.37(M+H)。HPLC純度:99.95%。
1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.18 (br s, 1H), 7.38 (d, J = 7.50 Hz, 2H), 7.27 (t, J = 7.50 Hz, 2H), 7.17 (t, J = 7.0 Hz, 1H), 5.86 (s, 1H), 2.40 (s, 2H), 2.16-2.10 (m, 1H), 1.70-1.50 (m, 6H), 1.23-1.19 (m, 2H).
ESI MS:m/z 270.1(M+H)。HPLC純度:95.96%。
1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.18 (s, 1H), 7.37 (m, 2H), 7.28 (m, 2H), 7.17 (m, 1H), 5.80 (s, 1H), 2.36 (d, J = 6.6 Hz, 2H), 2.10-1.80 (br. s., 2H), 1.85-1.65 (m, 5H), 1.22 (m, 2H).
ESI MS:m/z 320.2(M+H)。HPLC純度:99.68%。
対応する2−置換マロネート(2-substituted malonate)および方法1または市販の供給源を使用して調製した4−置換エチル3−アミノブト−2−エノエートを使用した方法3A(スキーム3を参照されたい)に従って、式(I)の以下の化合物を調製した。
3−(3−クロロフェニル)−4−ヒドロキシ−6−イソブチルピリジン−2(1H)−オン
1H NMR (400 MHz, DMSO-d6): δ 11.13 (br s, 1H), 10.59-10.36 (m, 1H), 7.47 (t, J = 1.76 Hz, 1H), 7.43-7.38 (m, 1H), 7.31 (t, J = 7.91 Hz, 1H), 7.24-7.19 (m, 1H), 5.79 (s, 1H), 2.26 (d, J = 7.28 Hz, 2H), 1.98-1.86 (m, 1H), 0.89 (d, J = 6.78 Hz, 6H).ESI MS:m/z 278[M+H]。HPLC純度:99.0%。
1H NMR (400 MHz, DMSO-d6): δ 11.06 (br s, 1H), 10.25 (br s, 1H), 7.46-7.39 (m, 1H), 7.31-7.24 (m, 2H), 7.22-7.18 (m, 1H), 5.76 (s, 1H), 2.27 (d, J = 7.53 Hz, 2H), 1.98-1.84 (m, 1H), 0.90 (d, J = 6.50 Hz, 6H).ESI MS:m/z 278[M+H]。HPLC純度:96.4%。
1H NMR (400 MHz, DMSO-d6): δ 11.08 (br s, 1H), 10.32 (br s, 1H), 7.49-7.38 (m, 2H), 7.17-7.04 (m, 2H), 5.78 (s, 1H), 2.25 (d, J = 7.28 Hz, 2H), 1.98-1.86 (m, 1H), 0.89 (d, J = 6.53 Hz, 6H).ESI MS:m/z 262[M+H]。HPLC純度:99.2%。
1H NMR (400 MHz, DMSO-d6): δ 11.10 (br s, 1H), 7.33-7.28 (m, 2H), 7.24 (d, J = 8.53 Hz, 1H), 7.02-6.94 (m, 1H), 5.79 (s, 1H), 2.26 (d, J = 7.53 Hz, 2H), 1.92 (td, J = 6.93, 13.49 Hz, 1H), 0.89 (d, J = 6.53 Hz, 6H).ESI MS:m/z 262[M+H]。HPLC純度:99.6%。
1H NMR (400 MHz, DMSO-d6): δ 11.18 (br s, 1H), 10.68 (br s, 1H), 7.13-7.09 (m, 2H), 5.77 (s, 1H), 2.28 (d, J = 7.60 Hz, 2H), 1.96-1.89 (m, 1H), 0.89 (d, J = 6.40 Hz, 6H).ESI MS:m/z 298[M+H]。HPLC純度:99.4%。
1H NMR (400 MHz, DMSO-d6): δ 11.05 (br s, 1H), 10.17 (br s, 1H), 7.37 (d, J = 6.80 Hz, 2H), 7.28 (t, J = 7.20 Hz, 2H), 7.16 (t, J = 7.20 Hz, 1H), 5.82 (s, 1H), 2.71-2.66 (m, 1H), 1.17 (d, J = 7.20 Hz, 6H).ESI MS:m/z 230[M+H]。HPLC純度:98.4%。
1H NMR (400 MHz, DMSO-d6): δ 11.09 (br s, 1H), 10.16 (br s, 1H), 7.38 (d, J = 7.03 Hz, 2H), 7.28 (t, J = 7.53 Hz, 2H), 7.16 (t, J = 8.00 Hz, 1H), 5.81 (s, 1H), 2.39 (t, J = 8.00 Hz, 2H), 1.55 (td, J = 6.56, 13.24 Hz, 1H), 1.50-1.41 (m, 2H), 0.90 (d, J = 6.53 Hz, 6H).ESI MS:m/z 258[M+H]。HPLC純度:99.0%。
1H NMR (400 MHz, DMSO-d6): δ 10.92 (br s, 1H), 10.22 (br s, 1H), 7.40 (d, J = 6.80 Hz, 2H), 7.28 (t, J = 7.60 Hz, 2H), 7.16 (t, J = 7.20 Hz, 1H), 5.77 (s, 1H), 2.31 (s, 2H), 0.94 (s, 9H).ESI MS:m/z 258[M+H]。HPLC純度:95.7%。
1H NMR (400 MHz, DMSO-d6): δ 11.08 (br s, 1H), 7.42-7.35 (m, 2H), 7.32-7.23 (m, 2H), 7.20-7.13 (m, 1H), 5.94 (s, 1H), 2.30 (d, J = 7.03 Hz, 2H), 1.06-0.94 (m, 1H), 0.55-0.45 (m, 2H), 0.25-0.18 (m, 2H).ESI MS:m/z 242[M+H]。HPLC純度:99.3%。
1H NMR (400 MHz, DMSO-d6): δ 11.04 (br s, 1H), 10.16 (br s, 1H), 7.40-7.35 (m, 2H), 7.27 (t, J = 7.65 Hz, 2H), 7.19-7.13 (m, 1H), 5.77 (s, 1H), 2.62-2.52 (m, 1H), 2.08-1.99 (m, 2H), 1.88-1.79 (m, 2H), 1.74-1.63 (m, 2H).ESI MS:m/z 256[M+H]。HPLC純度:99.8%。
1H NMR (400 MHz, DMSO-d6): δ 11.00 (br s, 1H), 10.19 (s, 1H), 7.39 (d, J = 7.03 Hz, 2H), 7.27 (t, J = 7.53 Hz, 2H), 7.19-7.12 (m, 1H), 5.76 (s, 1H), 2.26 (d, J = 6.78 Hz, 2H), 1.73-1.52 (m, 6H), 1.27-1.09 (m, 3H), 0.85-0.99 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 163.45, 162.73, 146.75, 134.13, 130.76, 126.92, 125.59, 108.39, 98.17, 36.82, 32.24, 25.82, 25.52.HPLC純度:>99%。ESI MS:m/z 284[M+H]。C18H22NO2[M+H]+のHRMS計算値、284.1645;実測値、284.1647。
1H NMR (400 MHz, DMSO-d6): δ 11.27 (br s, 1H), 10.18 (br s, 1H), 7.40-7.31 (m, 6H), 7.27 (t, J = 7.65 Hz, 3H), 7.19-7.13 (m, 1H), 5.70 (s, 1H), 3.75 (s, 2H).ESI MS:m/z 278[M+H]。HPLC純度:98.9%。
1H NMR (400 MHz, DMSO-d6): δ 11.08 (br s, 1H), 10.18 (br s, 1H), 7.40-7.35 (m, 2H), 7.31-7.24 (m, 2H), 7.20-7.13 (m, 1H), 5.80 (s, 1H), 3.83 (dd, J = 3.01, 11.54 Hz, 2H), 3.30-3.22 (m, 2H), 2.33 (d, J = 7.28 Hz, 2H), 1.82 (br. s., 1H), 1.52 (d, J = 12.30 Hz, 2H), 1.28-1.15 (m, 2H).ESI MS:m/z 286[M+H]。HPLC純度:98.5%。
対応する2−アリールマロネート(2-aryl malonate)および方法1または市販の供給源を使用して作られた4−置換エチル3−アミノブト−2−エノエートを使用した方法3Bおよび方法4B(スキーム4およびスキーム6)に従って、式(I)の以下の化合物を調製した。
4−ヒドロキシ−3−フェニル−6−(ピリジン−4−イルメチル)ピリジン−2(1H)−オン
1H NMR (400 MHz, DMSO-d6): δ 11.39 (s, 1H), 10.3 (br s, 1H), 8.54 (d, J = 4.8 Hz, 2H), 7.36-7.26 (m, 6H), 7.18 (m, 1H), 5.75 (s, 1H), 3.8 (s, 2H).ESI MS:m/z 279.1(M+H)。HPLC純度:94.77%。
対応する2−アリールマロネート(2-aryl malonate)および方法1または市販の供給源を使用して調製した4−置換エチル3−アミノブト−2−エノエートを使用した方法3C(スキーム5)に従って、式(I)の以下の化合物を調製した。1ステップで、塩基および酸なしでの環化および脱炭酸を観察した。
3−(2,4−ジフルオロフェニル)−4−ヒドロキシ−6−イソブチルピリジン−2(1H)−オン(NV−035−PD−54−C)
1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 10.60 (br s, 1H), 7.29-7.25 (m, 1H), 7.16-6.99 (m, 2H), 5.77 (s, 1H), 2.26 (d, J = 7.0 Hz, 2H), 1.90-1.94 (m, 1H), 0.89 (d, J = 6.1 Hz, 6H).ESI MS:m/z 280.23(M+H)+。HPLC純度:99.03%。
4−ヒドロキシ−6−イソブチル−1−メチル−3−フェニルピリジン−2(1H)−オンの調製
0℃に冷却した1,4−ジオキサン(3mL)中のピリドン1の懸濁液(50.8mg、0.209mmol)に、塩化アセチル(16μL、0.219mmol)およびピリジン(18.5μL、0.230mmol)を加えた。混合物を徐々に室温まで温め、室温で2時間撹拌した。反応混合物を真空で濃縮し、残渣をDCM(3mL)中に取り込んだ。水、ブラインを用いて有機層を洗浄し、Na2SO4で脱水し、真空で濃縮して、淡黄色の残渣を得た。カラムクロマトグラフィー(ISCO Combiflash(登録商標)、4gのシリカゲルカラム、0〜40%EtOAc/シクロヘキサン)により残渣を精製して、化合物2を白色固体(37.6mg、63%収率)として得た。
1H NMR (400 MHz, CDCl3): δ 7.47-7.33 (m, 5H), 6.21 (s, 1H), 2.50 (d, J = 7.28 Hz, 2H), 2.15-2.09 (m, 1H), 2.07 (s, 3H), 1.00 (d, J = 6.53 Hz, 6H).ESI MS:m/z 286[M+H]。
乾燥MeCN(2mL)中のピリドン2(37.6mg、0.132mmol)の溶液に、K2CO3(18.2mg、0.132mmol)およびMeI(11μL、0.172mmol)を加えた。生じた混合物を、Biotageマイクロ波反応器中で、30分間にわたり100℃に加熱した。反応混合物を冷却し、EtOAc(4mL)を用いて希釈した。有機物を、水およびブラインを用いて連続して洗浄し、Na2SO4で脱水し、濾過し、真空で濃縮して、無色の油を得た。カラムクロマトグラフィー(ISCO Combiflash(登録商標)、4gのシリカゲルカラム、0〜50%EtOAc/シクロヘキサン)により、粗材料を精製して、化合物3(26mg、65%収率)を得た。
6−イソブチル−1−メチル−2−オキソ−3−フェニル−1,2−ジヒドロピリジン−4−イルアセテート(3):1H NMR (400 MHz, CDCl3): δ 7.16 - 7.32 (m, 5H), 5.83 (s, 1H), 3.45 (s, 3H), 2.42 (d, J = 7.20 Hz, 2H), 1.91 (s, 3H), 1.83 - 1.88 (m, 1H), 0.94 (d, J = 6.40 Hz, 6H).ESI MS:[M−Ac]m/z 258。
MeOH(2mL)中の3(26mg、0.087mmol)の溶液に、室温でMeOH(0.2mL、10%v/v)中の30%NaOMeを加えた。生じた混合物を、真空下で濃縮する前に、室温で30分間にわたり撹拌して、白色の残渣を得た。白色の残渣をEtOAc(3mL)中に取り込み、10%クエン酸溶液を用いて洗浄し、Na2SO4で脱水し、濾過し、真空で濃縮して白色の残渣を得た。粗材料をMeOHに溶解し、H2O中の20〜95%MeCN/0.1%ギ酸の溶媒グラジエントを使用した逆相HPLCで精製して、望ましい生成物5を白色の固体として得た(10.3mg、46%収率)。
1H NMR (400 MHz, DMSO-d6): δ 7.35 (d, J = 7.20 Hz, 2H), 7.28 (t, J = 7.60 Hz, 2H), 7.17 (t, J = 7.20 Hz, 1H), 5.89 (s, 1H), 3.36 (s, 3H), 2.47 (s, 2H), 1.94-1.87 (m, 1H), 0.97 (d, J = 6.80 Hz, 6H)).ESI MS:m/z 258[M+H]。HPLC純度:>99%。
[実施例6]
0.5NのNaOH中の、200mgのエチル4−ヒドロキシ−2−イソブチル−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボキシレートの懸濁液を、還流温度で加熱した。4時間後、氷水を用いて反応塊を希釈し、1NのHClを用いて酸化し、生じた固体を濾過した。固体塊を酢酸エチルに溶解し、飽和NaHCO3溶液(4×30mL)を用いて抽出した。濃縮HClを用いて、合わせた重炭酸塩溶液を酸化させ、生じた固体を濾過し、水を用いて洗浄し、乾燥させて、20mgの4−ヒドロキシ−2−イソブチル−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボン酸3をオフホワイトの固体として得た。
1H NMR (400 MHz, DMSO-d6): δ 13.6-13.2 (br s, 1H), 11.78 (s, 1H), 7.42-7.3 (m, 4H), 7.27-7.2 (m, 1H), 2.91 (d, J = 6.6 Hz, 2H), 1.61 (br s, 1H), 1.42-1.05 (m, 8H), 0.87 (s, 6H).
ESI MS:m/z 356.4(M+H)。HPLC純度:92.3%。
4−ヒドロキシ−2−イソブチル−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボン酸3(400mg、13.94mmol)、DCM(20mL)中のDMF(4滴)の冷溶液に塩化オキサリル(1.2mL、139.4mmol)を0℃で徐々に加え、室温で2時間撹拌した。1,4−ジオキサン中のNH3を用いて反応塊をクエンチし、10分間にわたり撹拌し、濃縮した。分取HPLCにより粗生成物を精製して、28mg(7%)の4−ヒドロキシ−2−イソブチル−6−オキソ−5−フェニル−1,6−ジヒドロピリジン−3−カルボキサミドをオフホワイトの固体として得た。
1H NMR (400 MHz, DMSO-d6): δ 10.85 (br s, 1H), 8.17 (s, 1H), 7.43-7.34 (m, 2H), 7.28-7.13 (m, 3H), 2.7 (d, J = 6.7 Hz, 2H), 1.99-1.90 (m, 1H), 0.86 (d, J = 6.4 Hz, 6H).ESI MS:m/z 287.19(M+H)。HPLC純度:94.32%。
((6−((4,4−ジメチルシクロヘキシル)メチル)−2−オキソ−3−フェニル−1,2−ジヒドロピリジン−4−イル)オキシ)メチルジハイドロジェンホスフェートの調製
DMF(20mL)およびTHF(20mL)中の6−((4,4−ジメチルシクロヘキシル)メチル)−4−ヒドロキシ−3−フェニルピリジン−2(1H)−オン8(4g、12.84mmol)およびCs2CO3(4.59g、14.12mmol)の混合物を、140℃で1時間加熱した。反応混合物を、室温に冷却し、DMF−THF(1:1、4mL)中のジベンジルクロロメチルホスフェートの溶液(4.88g、14.97mmol)を、徐々に滴加した。反応混合物を室温で12時間撹拌した。冷水を用いて、すべての反応混合物を希釈し、EtOAc(3×50mL)を用いて抽出した。水(3×50mL)、ブラインを用いて合わせた有機層を洗浄し、Na2SO4で脱水し、濃縮して、7.5gの粗ジベンジル(6−((4,4−ジメチルシクロヘキシル)メチル)−2−オキソ−3−フェニル−1,2−ジヒドロピリジン−4−イルオキシ)メチルホスフェート9を得た。粗生成物にさらなる精製をせずに、次のステップを施した。
9:ESI MS:m/z 602.21[M+H]+& 603.23[M+H]+
EtOH(150mL)中のジベンジル(6−((4,4−ジメチルシクロヘキシル)メチル)−2−オキソ−3−フェニル−1,2−ジヒドロピリジン−4−イルオキシ)メチルホスフェート9(7.5g、粗製)の溶液に、10%Pd/C(2.2g)を加えた。生じた混合物を、水素バルーン圧力下で1時間撹拌した。セライトベッドを通して反応混合物を濾過し、MeOHを用いて洗浄した。減圧下で濾液を濃縮して、5gの粗材料を得た。H2O中の0〜95%MeCN/0.05%TFAの溶媒グラジエントを使用したXBridgeカラム(C−18、150×30mm ID5)を使用して、逆相HPLCで、この粗材料を精製して、表題化合物を白色の固体(840mg、2ステップの15.5%)として得た。
((6−((4,4−ジメチルシクロヘキシル)メチル)−2−オキソ−3−フェニル−1,2−ジヒドロピリジン−4−イル)オキシ)メチルジハイドロジェンホスフェート:1H NMR (400 MHz, DMSO-d6): δ 11.7-11.3 (br, 1H), 7.37 (d, J = 7.2 Hz, 2H), 7.30 (dd, J = 7.6, 7.2 Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 6.17 (s, 1H), 5.47 (s, 1H), 5.45 (s, 1H), 2.40 (d, J = 6.8 Hz, 2H) 1.60-1.42 (m, 3H), 1.40-1.30 (m, 2H), 1.20-1.10 (m, 4H), 0.90 (s, 3H), 0.87 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 163.1 (1C), 161.7 (1C), 148.5 (1C), 133.1 (1C), 130.9 (2C), 127.25 (2C), 126.3 (1C), 111.9 (1C), 95.4 (1C), 86.8 (1C), 38.4 (1C), 37.1 (1C), 32.5 (1C), 29.8 (2C), 28.1 (2C), 24.4 (1C).ESI MS:m/z 422.20[M+H]。HPLC純度:96.9%。
6−((4,4−ジメチルシクロヘキシル)メチル)−2−オキソ−3−フェニル−1,2−ジヒドロピリジン−4−イルジハイドロジェンホスフェートの調製
乾燥DMF(10mL)中のピリドン1(614.7mg、1.974mmol)の懸濁液を0℃に冷却し、K2CO3(818mg、5.92mmol)、続いてジベンジルホスホロクロリデート(11.7mL、3.965mmol、ベンゼン中で10%w/v)を加えた。生じた混合物を室温まで徐々に温め、室温で18時間撹拌した。EtOAc(15mL)を用いて、反応混合物を希釈し、水(10mL)を加えた。有機物を分離し、EtOAc(3×8mL)を用いて水液層を抽出した。水およびブラインを用いて合わせた有機物を洗浄し、Na2SO4で脱水し、濾過し、真空で濃縮して、黄色の油を得た。カラムクロマトグラフィー(ISCO Combiflash(登録商標)、40gのシリカゲルカラム、0〜30%EtOAc/シクロヘキサン)により、粗材料を精製して、ピリドン7を白色の固体(1.45g、89%収率)として得た。
1H NMR (400 MHz, CDCl3): δ 7.44-7.28 (m, 17H), 7.25-7.21 (m, 4H), 7.21-7.13 (m, 4H), 7.07 (s, 1H), 5.11-5.02 (m, 4H), 4.87-4.75 (m, 4H), 2.56 (d, J = 7.03 Hz, 2H), 1.47 (br s, 2H), 1.43 (s, 1H), 1.34-1.27 (m, 2H), 1.19-1.03 (m, 4H), 0.86 (s, 6H).ESI MS:m/z 832[M+H]+。
10%Pd/C(150mg、15%w/w)を加える前に、2:1EtOH/EtOAc(45mL)中の二リン酸化した材料6の溶液(1.00g、1.326mmol)をアルゴンでパージした。生じた混合物を放置して、室温で、水素雰囲気下で3時間撹拌した。反応混合物を、セライトのプラグを通して濾過する前に、アルゴンでパージし、MeOHを用いて洗浄した。濾液を真空で濃縮して、褐色の残渣を得た。粗材料をDMSOに溶解し、H2O中の10〜95%MeCN/0.1%ギ酸の溶媒グラジエントを使用して逆相HPLCで精製して、表題化合物を白色の固体(280.5mg、54%収率)として得た。
1H NMR (400 MHz, DMSO-d6): δ 11.59 (br s, 1H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 2H), 7.27-7.20 (m, 1H), 6.36 (s, 1H), 2.37 (d, J = 6.78 Hz, 2H), 1.47 (br s, 3H), 1.35 (d, J = 8.53 Hz, 2H), 1.21-1.08 (m, 4H), 0.89 (s, 3H), 0.87 (s, 3H).ESI MS:m/z 392[M+H]+。HPLC純度:95%。C20H25NO5P[M−H]−のHRMS計算値390.1476;実測値、390.1487。
本発明の化合物の実用性は、本明細書で下に記載されているアッセイのいずれか1つを使用することで、証拠立てることができる。
Mtb:結核菌(Mycobacterium tuberculosis)
TB:結核
H37Rv:ATCCからのMtbの実験室株(カタログ#27294)
ATCC:American type culture collection
ADS:アルブミン:デキストロース:塩化ナトリウム
DMSO:ジメチルスルホキシド
MoA:作用機序
MIC:最小発育阻止濃度
0.05%Tween80および10%ADS supplementを添加したMiddlebrook 7H9肉汁培地中で、結核菌(Mycobacterium tuberculosis)H37Rv(ATCC#27294)(Mtb)株を維持した。ADS supplementは、5%ウシ血清アルブミン分画V、2%D−デキストロースおよび0.8%の塩化ナトリウムを含有する。10%OADC(オレイン酸、アルブミン、デキストロースおよびカタラーゼ)を添加したMiddlebrook 7H11の寒天培地を、Mtbを成長させる固体培地として使用した。90%DMSOを使用して、化合物の保存溶液を調製した。
下の表2では、MIC50は、非処理の対照と比較して、野生型株の50%の増殖を阻害する化合物の最低濃度と定義される。試験化合物を、連続的に2回または3回繰り返して希釈し、mosquito HTSにより、384ウェルクリアプレートに配置し、各化合物の10倍の希釈度とした。50μlの体積のMtb培養物(0.02の最終OD600)を各ウェルに加え、アッセイプレートを37℃で5日間インキュベートした。Spectramax M2分光計を使用して、600nMで吸光度を読み取ることにより、細菌の増殖を測定した。Activity Baseソフトウェアを使用することにより、MIC50値を測定した。
作用様式の研究。
式(I)の化合物の作用様式を評価するために、選択した式(I)の化合物(例えば化合物の番号PD12、PD10およびPD2)に対して、Mtbの自然耐性変異体を発生させた。簡潔には、7.5および10μMの濃度のPD12、PD10およびPD2を含有する7H11のプレートに、109コロニー形成単位のMtb H37Rvを蒔いた。これらのプレートを37℃のインキュベータで3週間インキュベートした。プレート上に形成したコロニーを、抗生物質なしでさらに二次培養し、MIC測定によりPD12、PD10およびPD2への耐性を確認した。選択した6種の自然耐性分離株のゲノムDNAを単離し、Pethe Kら、「A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy」、Nat. Commun、1(57)、1〜8頁(2010)において報告されているようにSolexaシステムを使用して、全体のゲノムシークエンシングを施した。コンピュータ分析、およびさらにキャピラリーシークエンシングの結果により、すべての自然耐性変異体における変異がinhAをコードするRv1484遺伝子にマップされることが明らかになった。変異体のうち5種は、単一ヌクレオチド多型を示し、inhAにおける以下のアミノ酸変化、すなわちD148G、S94A、G96VおよびD148Vの変化のうち1つを引き起こす(下の表3を参照されたい)。
Claims (34)
- 式(I)
式中、
R1がH、メチルもしくはエチルであり;
R2がフェニル、ピロールもしくはピラゾールであり、前記フェニルが、場合により、フルオロもしくはクロロから独立して選択される1個または複数の置換基で置換され;但し前記置換基がクロロである場合、前記クロロが前記フェニルのメタ位もしくはオルト位に位置し、クロロ置換基の数が1個以下であり;
R3が、
からなる群から選択される構造式であり;
R4がHもしくは−C(=O)NH2であり;
R5が(C1〜C6)アルキル、シクロアルキル、フェニル、ヘテロ環およびヘテロアリールからなる群から選択され、場合により1個または複数の独立したR300置換基で置換され;ならびに
R300が、H、(C1〜C6)アルキル、シクロアルキル、ヒドロキシ、アミノおよびFからなる群から選択される;
の化合物、または、薬学的に許容されるその塩。 - R1がHである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R2がフェニルである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R3が(Ia)である、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R3が(Ic)であり、R100およびR200がいずれもHである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R4がHである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R5が(C1〜C6)アルキル、フェニル、テトラヒドロ−2H−ピランまたはピリジンである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R5がシクロアルキルである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R5がシクロヘキサンである、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R5がシクロヘキサン((C1〜C6)アルキル、シクロアルキルもしくはFから独立して選択される、1個もしくは複数の置換基で置換される)である、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R5がシクロヘキサン(メチル、シクロプロパンもしくはFから独立して選択される、1個もしくは複数の置換基で置換される)である、請求項1に記載の化合物、または薬学的に許容されるその塩。
- R5がシクロヘキサン(2個のメチル置換基で置換される)である、請求項1に記載の化合物、または薬学的に許容されるその塩。
-
からなる群から選択される、請求項1に記載の化合物、または薬学的に許容されるその塩。 - 以下の構造
を有する、請求項1に記載の化合物、または薬学的に許容されるその塩。 - 以下の構造
を有する、請求項1に記載の化合物、または薬学的に許容されるその塩。 - 以下の構造
を有する、請求項1に記載の化合物、または薬学的に許容されるその塩。 - 請求項1から請求項16のいずれか一項の式(I)の化合物、または薬学的に許容されるその塩、および薬学的に許容される担体または賦形剤を含む、医薬組成物。
- 少なくとも1つの追加の医薬品をさらに含む、請求項17に記載の医薬組成物。
- 前記少なくとも1つの追加の医薬品が、抗結核剤である、請求項18記載の医薬組成物。
- 前記抗結核剤が、イソニアジド、リファンピシン、ピラジンアミド、エタンブトール、ストレプトマイシン、カナマイシン、アミカシン、カプレオマイシン、オフロキサシン、レボフロキサシン、モキシフロキサシン、シクロセリン、パラアミノサリチル酸、エチオナミド、プロチオナミド、チオアセタゾンクロファジミン、クラブラン酸を伴うアモキシシリン、イミペネム、リネゾリド、クラリスロマイシンおよびチオリダジンからなる群から選択される、請求項19に記載の医薬組成物。
- 結核菌(M. tuberculosis)のエノイルアシルキャリアータンパク質還元酵素(InhA)の阻害を通じたミコール酸生合成の阻害により介在される疾患、障害または症候群を処置する方法であって、それを必要とする患者に、請求項1から16のいずれか一項に記載の化合物、または薬学的に許容されるその塩を投与するステップを含む方法。
- 前記患者がヒトである、請求項21に記載の方法。
- 前記疾患、障害または症候群が結核である、請求項21に記載の方法。
- 前記ヒトが(i)喀痰塗抹陽性、喀痰塗抹陰性または肺外結核;(ii)薬剤耐性結核菌(M. tuberculosis)群の微生物によって引き起こされる結核;または(iii)ヒト免疫不全ウイルス(HIV)感染症に合併する結核を有する、請求項22に記載の方法。
- 結核を処置する方法であって、それを必要とする患者に、請求項17に記載の医薬組成物を投与するステップを含む、方法。
- 前記患者がヒトである、請求項25に記載の方法。
- 前記ヒトが(i)喀痰塗抹陽性、喀痰塗抹陰性または肺外結核;(ii)薬剤耐性結核菌(M. tuberculosis)群の微生物によって引き起こされる結核;または(iii)ヒト免疫不全ウイルス(HIV)感染症に合併する結核を有する、請求項26に記載の方法。
- 治療に使用する、請求項1から16に記載の化合物。
- 前記治療が、結核菌(M. tuberculosis)のエノイルアシルキャリアータンパク質還元酵素(InhA)の阻害を通じたミコール酸生合成の阻害により介在される疾患、障害または症候群を処置するためのものである、請求項28に記載の化合物。
- 結核菌(M. tuberculosis)のエノイルアシルキャリアータンパク質還元酵素(InhA)の阻害を通じたミコール酸生合成の阻害により介在される疾患、障害または症候群を処置するための方法が、それを必要とする患者に、
(i)請求項1から16に記載の化合物のいずれか1つ、または薬学的に許容されるその塩、および薬学的に許容される担体または賦形剤を含む第1の組成物;ならびに
(ii)少なくとも1つの追加の医薬品、および薬学的に許容される担体または賦形剤を含む第2の組成物
を投与するステップを含む、方法。 - 前記患者がヒトである、請求項30に記載の方法。
- 前記ヒトが(i)喀痰塗抹陽性、喀痰塗抹陰性または肺外結核;(ii)薬剤耐性結核菌(M. tuberculosis)群の微生物によって引き起こされる結核;または(iii)ヒト免疫不全ウイルス(HIV)感染症に合併する結核を有する、請求項31に記載の方法。
- 前記第1および第2の組成物が同時に投与される、請求項30、31または32に記載の方法。
- 前記第1および第2の組成物が、任意の順序で順次投与される、請求項30、31または32に記載の方法。
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