JP6681894B2 - 抗真菌剤 - Google Patents

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Publication number

JP6681894B2

JP6681894B2 JP2017527340A JP2017527340A JP6681894B2 JP 6681894 B2 JP6681894 B2 JP 6681894B2 JP 2017527340 A JP2017527340 A JP 2017527340A JP 2017527340 A JP2017527340 A JP 2017527340A JP 6681894 B2 JP6681894 B2 JP 6681894B2

Authority

JP

Japan

Prior art keywords

phenyl

compound

dimethyl

pyrrol

piperazin

Prior art date

2014-11-21

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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• 229940121375 antifungal agent Drugs 0.000 title claims description 67
• 239000003429 antifungal agent Substances 0.000 title claims description 65
• 150000001875 compounds Chemical class 0.000 claims description 150
• -1 1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl Chemical group 0.000 claims description 127
• 150000003839 salts Chemical class 0.000 claims description 96
• 239000000203 mixture Substances 0.000 claims description 79
• 239000008194 pharmaceutical composition Substances 0.000 claims description 49
• 208000031888 Mycoses Diseases 0.000 claims description 42
• 238000011282 treatment Methods 0.000 claims description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
• SUFPWYYDCOKDLL-UHFFFAOYSA-N 2-(1,5-dimethyl-3-phenylpyrrol-2-yl)-N-[4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]phenyl]-2-oxoacetamide Chemical compound CN1C(=C(C=C1C)C1=CC=CC=C1)C(C(=O)NC1=CC=C(C=C1)N1CCN(CC1)C1=NC=C(C=N1)F)=O SUFPWYYDCOKDLL-UHFFFAOYSA-N 0.000 claims description 31
• 238000000034 method Methods 0.000 claims description 25
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 23
• 241000228212 Aspergillus Species 0.000 claims description 22
• 201000010099 disease Diseases 0.000 claims description 22
• 230000002265 prevention Effects 0.000 claims description 17
• 230000002538 fungal effect Effects 0.000 claims description 16
• 208000006673 asthma Diseases 0.000 claims description 15
• 229940079593 drug Drugs 0.000 claims description 15
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 15
• 206010006474 Bronchopulmonary aspergillosis allergic Diseases 0.000 claims description 14
• 208000006778 allergic bronchopulmonary aspergillosis Diseases 0.000 claims description 14
• 239000003112 inhibitor Substances 0.000 claims description 14
• KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 11
• BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 11
• 108010049047 Echinocandins Proteins 0.000 claims description 10
• 150000004291 polyenes Chemical class 0.000 claims description 10
• 229960004740 voriconazole Drugs 0.000 claims description 10
• 241000233866 Fungi Species 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 9
• 239000000417 fungicide Substances 0.000 claims description 8
• 238000002156 mixing Methods 0.000 claims description 8
• 108090000623 proteins and genes Proteins 0.000 claims description 8
• 102000004169 proteins and genes Human genes 0.000 claims description 8
• 206010070834 Sensitisation Diseases 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 229960001589 posaconazole Drugs 0.000 claims description 7
• RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 claims description 7
• 230000008313 sensitization Effects 0.000 claims description 7
• VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 6
• 229920000057 Mannan Polymers 0.000 claims description 6
• APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 6
• 238000001990 intravenous administration Methods 0.000 claims description 6
• 238000004519 manufacturing process Methods 0.000 claims description 6
• 230000035699 permeability Effects 0.000 claims description 6
• APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 5
• 108010020326 Caspofungin Proteins 0.000 claims description 5
• 229940123047 Elongation factor inhibitor Drugs 0.000 claims description 5
• 229930182764 Polyoxin Natural products 0.000 claims description 5
• 229960003942 amphotericin b Drugs 0.000 claims description 5
• JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 claims description 5
• 229960003034 caspofungin Drugs 0.000 claims description 5
• 239000003795 chemical substances by application Substances 0.000 claims description 5
• 229960004413 flucytosine Drugs 0.000 claims description 5
• XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 5
• 150000003230 pyrimidines Chemical class 0.000 claims description 5
• BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 claims description 4
• VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 4
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
• 241001480043 Arthrodermataceae Species 0.000 claims description 4
• 206010020751 Hypersensitivity Diseases 0.000 claims description 4
• 230000000844 anti-bacterial effect Effects 0.000 claims description 4
• 230000037304 dermatophytes Effects 0.000 claims description 4
• 230000000855 fungicidal effect Effects 0.000 claims description 4
• BODYFEUFKHPRCK-ZCZMVWJSSA-N ibrexafungerp Chemical compound N1([C@@H]2C[C@@]34COC[C@]([C@H]2OC[C@](C)(N)C(C)(C)C)(C)[C@@H]3CC[C@@H]2[C@@]3(C)CC[C@]([C@H]([C@]3(C)CC=C24)C(O)=O)(C)[C@H](C)C(C)C)N=CN=C1C1=CC=NC=C1 BODYFEUFKHPRCK-ZCZMVWJSSA-N 0.000 claims description 4
• 229960004130 itraconazole Drugs 0.000 claims description 4
• 239000002213 purine nucleotide Substances 0.000 claims description 4
• 239000002719 pyrimidine nucleotide Substances 0.000 claims description 4
• 229960000580 terconazole Drugs 0.000 claims description 4
• XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 3
• 108010021062 Micafungin Proteins 0.000 claims description 3
• 229960004884 fluconazole Drugs 0.000 claims description 3
• RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 3
• 229950003053 icofungipen Drugs 0.000 claims description 3
• 230000001939 inductive effect Effects 0.000 claims description 3
• 229960004125 ketoconazole Drugs 0.000 claims description 3
• 229960002159 micafungin Drugs 0.000 claims description 3
• PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 claims description 3
• RKOUGZGFAYMUIO-RITPCOANSA-N pdl 118 Chemical compound N[C@H]1CC(=C)C[C@H]1C(O)=O RKOUGZGFAYMUIO-RITPCOANSA-N 0.000 claims description 3
• YEBIHIICWDDQOL-YBHNRIQQSA-N polyoxin Polymers O[C@@H]1[C@H](O)[C@@H](C(C=O)N)O[C@H]1N1C(=O)NC(=O)C(C(O)=O)=C1 YEBIHIICWDDQOL-YBHNRIQQSA-N 0.000 claims description 3
• 150000003212 purines Chemical class 0.000 claims description 3
• MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 claims description 2
• MPIPASJGOJYODL-SFHVURJKSA-N (R)-isoconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@@H](OCC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 MPIPASJGOJYODL-SFHVURJKSA-N 0.000 claims description 2
• AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 claims description 2
• ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 claims description 2
• OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 claims description 2
• LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 2
• JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 claims description 2
• BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 claims description 2
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• ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 claims description 2
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• SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 claims description 2
• 229960004022 clotrimazole Drugs 0.000 claims description 2
• VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 claims description 2
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• VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 claims description 2
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• QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 claims description 2
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• OGGVRVMISBQNMQ-MDGIRFSOSA-N sordarin Chemical compound O[C@H]1[C@H](O)[C@H](OC)[C@@H](C)O[C@H]1OC[C@]1([C@@]2(C(C(C)C)=C3)C(O)=O)[C@H]3C[C@]2(C=O)[C@@H]2CC[C@@H](C)[C@H]2C1 OGGVRVMISBQNMQ-MDGIRFSOSA-N 0.000 claims description 2
• OGGVRVMISBQNMQ-UHFFFAOYSA-N sordarin Natural products OC1C(O)C(OC)C(C)OC1OCC1(C2(C(C(C)C)=C3)C(O)=O)C3CC2(C=O)C2CCC(C)C2C1 OGGVRVMISBQNMQ-UHFFFAOYSA-N 0.000 claims description 2
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• OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 description 21
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