NZ730861B2 - Antimycotic compound - Google Patents
Antimycotic compound Download PDFInfo
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- NZ730861B2 NZ730861B2 NZ730861A NZ73086115A NZ730861B2 NZ 730861 B2 NZ730861 B2 NZ 730861B2 NZ 730861 A NZ730861 A NZ 730861A NZ 73086115 A NZ73086115 A NZ 73086115A NZ 730861 B2 NZ730861 B2 NZ 730861B2
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 176
- 230000001857 anti-mycotic effect Effects 0.000 title 1
- 239000002543 antimycotic Substances 0.000 title 1
- 238000011282 treatment Methods 0.000 claims abstract description 60
- 208000031888 Mycoses Diseases 0.000 claims abstract description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 32
- -1 Compound (I) Chemical class 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 21
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 15
- 241001225321 Aspergillus fumigatus Species 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 229940091771 aspergillus fumigatus Drugs 0.000 claims description 14
- 206010017533 Fungal infection Diseases 0.000 claims description 13
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 12
- 239000005711 Benzoic acid Substances 0.000 claims description 11
- 229960004365 benzoic acid Drugs 0.000 claims description 11
- 235000010233 benzoic acid Nutrition 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 9
- 208000024386 fungal infectious disease Diseases 0.000 claims description 9
- 125000003944 tolyl group Chemical group 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 7
- 239000000969 carrier Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 241000228212 Aspergillus Species 0.000 claims description 5
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 5
- 125000004193 piperazinyl group Chemical group 0.000 claims description 5
- 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
- 241000223238 Trichophyton Species 0.000 claims description 4
- 229960004130 itraconazole Drugs 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 241001337994 Cryptococcus <scale insect> Species 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 3
- 229960004413 flucytosine Drugs 0.000 claims description 3
- YKSVGLFNJPQDJE-YDMQLZBCSA-N (19E,21E,23E,25E,27E,29E,31E)-33-[(2R,3S,4R,5S,6R)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-17-[7-(4-aminophenyl)-5-hydroxy-4-methyl-7-oxoheptan-2-yl]-1,3,5,7,37-pentahydroxy-18-methyl-9,13,15-trioxo-16,39-dioxabicyclo[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid Chemical compound CC(CC(C)C1OC(=O)CC(=O)CCCC(=O)CC(O)CC(O)CC(O)CC2(O)CC(O)C(C(CC(O[C@@H]3O[C@H](C)[C@@H](O)[C@@H](N)[C@@H]3O)\C=C\C=C\C=C\C=C\C=C\C=C\C=C\C1C)O2)C(O)=O)C(O)CC(=O)C1=CC=C(N)C=C1 YKSVGLFNJPQDJE-YDMQLZBCSA-N 0.000 claims description 2
- ZMYFCFLJBGAQRS-IRXDYDNUSA-N (2R,3S)-epoxiconazole Chemical compound C1=CC(F)=CC=C1[C@@]1(CN2N=CN=C2)[C@H](C=2C(=CC=CC=2)Cl)O1 ZMYFCFLJBGAQRS-IRXDYDNUSA-N 0.000 claims description 2
- 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 2
- 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 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
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-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
- FRPZMMHWLSIFAZ-UHFFFAOYSA-N 10-undecenoic acid Chemical compound OC(=O)CCCCCCCCC=C FRPZMMHWLSIFAZ-UHFFFAOYSA-N 0.000 claims description 2
- 108010064760 Anidulafungin Proteins 0.000 claims description 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 claims description 2
- 239000005767 Epoxiconazole Substances 0.000 claims description 2
- 229930183931 Filipin Natural products 0.000 claims description 2
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 claims description 2
- 229930195098 Hamycin Natural products 0.000 claims description 2
- YTAOBBFIOAEMLL-REQDGWNSSA-N Luliconazole Chemical compound ClC1=CC(Cl)=CC=C1[C@H](CS\1)SC/1=C(\C#N)N1C=NC=C1 YTAOBBFIOAEMLL-REQDGWNSSA-N 0.000 claims description 2
- 108010021062 Micafungin Proteins 0.000 claims description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 claims description 2
- 241000228143 Penicillium Species 0.000 claims description 2
- AWGBZRVEGDNLDZ-UHFFFAOYSA-N Rimocidin Natural products C1C(C(C(O)C2)C(O)=O)OC2(O)CC(O)CCCC(=O)CC(O)C(CC)C(=O)OC(CCC)CC=CC=CC=CC=CC1OC1OC(C)C(O)C(N)C1O AWGBZRVEGDNLDZ-UHFFFAOYSA-N 0.000 claims description 2
- AWGBZRVEGDNLDZ-JCUCCFEFSA-N Rimocidine Chemical compound O([C@H]1/C=C/C=C/C=C/C=C/C[C@H](OC(=O)[C@@H](CC)[C@H](O)CC(=O)CCC[C@H](O)C[C@@]2(O)O[C@H]([C@@H]([C@@H](O)C2)C(O)=O)C1)CCC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N)[C@@H]1O AWGBZRVEGDNLDZ-JCUCCFEFSA-N 0.000 claims description 2
- XZKWIPVTHGWDCF-KUZYQSSXSA-N amorolfine hydrochloride Chemical compound Cl.C1=CC(C(C)(C)CC)=CC=C1CC(C)CN1C[C@@H](C)O[C@@H](C)C1 XZKWIPVTHGWDCF-KUZYQSSXSA-N 0.000 claims description 2
- 229960003348 anidulafungin Drugs 0.000 claims description 2
- JHVAMHSQVVQIOT-MFAJLEFUSA-N anidulafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC=C(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](C)O)[C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)[C@@H](C)O)=O)C=C1 JHVAMHSQVVQIOT-MFAJLEFUSA-N 0.000 claims description 2
- 229960002206 bifonazole Drugs 0.000 claims description 2
- 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
- 229960002962 butenafine Drugs 0.000 claims description 2
- 229960005074 butoconazole Drugs 0.000 claims description 2
- 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
- 229960004348 candicidin Drugs 0.000 claims description 2
- KHAVLLBUVKBTBG-UHFFFAOYSA-N caproleic acid Natural products OC(=O)CCCCCCCC=C KHAVLLBUVKBTBG-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
- 229960003913 econazole Drugs 0.000 claims description 2
- 229960003937 efinaconazole Drugs 0.000 claims description 2
- NFEZZTICAUWDHU-RDTXWAMCSA-N efinaconazole Chemical compound N1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)CCC(=C)CC1 NFEZZTICAUWDHU-RDTXWAMCSA-N 0.000 claims description 2
- 229960001274 fenticonazole Drugs 0.000 claims description 2
- 229950000152 filipin Drugs 0.000 claims description 2
- IMQSIXYSKPIGPD-NKYUYKLDSA-N filipin Chemical compound CCCCC[C@H](O)[C@@H]1[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@@H](O)C[C@H](O)\C(C)=C\C=C\C=C\C=C\C=C\[C@H](O)[C@@H](C)OC1=O IMQSIXYSKPIGPD-NKYUYKLDSA-N 0.000 claims description 2
- IMQSIXYSKPIGPD-UHFFFAOYSA-N filipin III Natural products CCCCCC(O)C1C(O)CC(O)CC(O)CC(O)CC(O)CC(O)CC(O)C(C)=CC=CC=CC=CC=CC(O)C(C)OC1=O IMQSIXYSKPIGPD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004884 fluconazole Drugs 0.000 claims description 2
- 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 2
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 claims description 2
- 229960002867 griseofulvin Drugs 0.000 claims description 2
- 229950006942 hamycin Drugs 0.000 claims description 2
- 229960004849 isoconazole Drugs 0.000 claims description 2
- 229960004125 ketoconazole Drugs 0.000 claims description 2
- 229960000570 luliconazole Drugs 0.000 claims description 2
- 229960002159 micafungin Drugs 0.000 claims description 2
- 229960004313 naftifine Drugs 0.000 claims description 2
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 claims description 2
- 229960003255 natamycin Drugs 0.000 claims description 2
- 239000004311 natamycin Substances 0.000 claims description 2
- NCXMLFZGDNKEPB-FFPOYIOWSA-N natamycin 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@@H](C)OC(=O)/C=C/[C@H]2O[C@@H]2C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 NCXMLFZGDNKEPB-FFPOYIOWSA-N 0.000 claims description 2
- 235000010298 natamycin Nutrition 0.000 claims description 2
- 229960000988 nystatin Drugs 0.000 claims description 2
- 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
- 229960004031 omoconazole Drugs 0.000 claims description 2
- JMFOSJNGKJCTMJ-ZHZULCJRSA-N omoconazole Chemical compound C1=CN=CN1C(/C)=C(C=1C(=CC(Cl)=CC=1)Cl)\OCCOC1=CC=C(Cl)C=C1 JMFOSJNGKJCTMJ-ZHZULCJRSA-N 0.000 claims description 2
- 229960003483 oxiconazole Drugs 0.000 claims description 2
- 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
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 claims description 2
- 229950004154 ravuconazole Drugs 0.000 claims description 2
- 229960005429 sertaconazole Drugs 0.000 claims description 2
- 229960002607 sulconazole Drugs 0.000 claims description 2
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 claims description 2
- 229960002722 terbinafine Drugs 0.000 claims description 2
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- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 claims description 2
- 229960002703 undecylenic acid Drugs 0.000 claims description 2
- 241000228257 Aspergillus sp. Species 0.000 claims 1
- 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 1
- 239000005822 Propiconazole Substances 0.000 claims 1
- 229920001218 Pullulan Polymers 0.000 claims 1
- TYBHXIFFPVFXQW-UHFFFAOYSA-N abafungin Chemical compound CC1=CC(C)=CC=C1OC1=CC=CC=C1C1=CSC(NC=2NCCCN=2)=N1 TYBHXIFFPVFXQW-UHFFFAOYSA-N 0.000 claims 1
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- 229960000788 isavuconazole Drugs 0.000 claims 1
- DDFOUSQFMYRUQK-RCDICMHDSA-N isavuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC=C(F)C=2)F)=NC=1C1=CC=C(C#N)C=C1 DDFOUSQFMYRUQK-RCDICMHDSA-N 0.000 claims 1
- 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 1
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- 235000019423 pullulan Nutrition 0.000 claims 1
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- 239000007787 solid Substances 0.000 description 58
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
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- 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 description 43
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- 238000000034 method Methods 0.000 description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- 210000004072 lung Anatomy 0.000 description 31
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
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- 208000015181 infectious disease Diseases 0.000 description 29
- 230000000694 effects Effects 0.000 description 26
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 25
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 25
- 238000001914 filtration Methods 0.000 description 24
- 230000002538 fungal effect Effects 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- 208000000785 Invasive Pulmonary Aspergillosis Diseases 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 241000699670 Mus sp. Species 0.000 description 18
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- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- XJYOPIZTZGCDSR-UHFFFAOYSA-N piperazin-1-yl benzoate Chemical compound C=1C=CC=CC=1C(=O)ON1CCNCC1 XJYOPIZTZGCDSR-UHFFFAOYSA-N 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- PXKYXTXYWJKTSQ-UHFFFAOYSA-N tert-butyl 4-[4-(hydroxymethyl)phenyl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(CO)C=C1 PXKYXTXYWJKTSQ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 239000003039 volatile agent Substances 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
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61P31/10—Antimycotics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/14—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 three or more hetero rings
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F1/00—Details not covered by groups G06F3/00 - G06F13/00 and G06F21/00
- G06F1/26—Power supply means, e.g. regulation thereof
- G06F1/32—Means for saving power
- G06F1/3203—Power management, i.e. event-based initiation of a power-saving mode
- G06F1/3234—Power saving characterised by the action undertaken
- G06F1/325—Power saving in peripheral device
- G06F1/3268—Power saving in hard disk drive
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- G—PHYSICS
- G11—INFORMATION STORAGE
- G11C—STATIC STORES
- G11C11/00—Digital stores characterised by the use of particular electric or magnetic storage elements; Storage elements therefor
- G11C11/21—Digital stores characterised by the use of particular electric or magnetic storage elements; Storage elements therefor using electric elements
- G11C11/34—Digital stores characterised by the use of particular electric or magnetic storage elements; Storage elements therefor using electric elements using semiconductor devices
- G11C11/40—Digital stores characterised by the use of particular electric or magnetic storage elements; Storage elements therefor using electric elements using semiconductor devices using transistors
- G11C11/401—Digital stores characterised by the use of particular electric or magnetic storage elements; Storage elements therefor using electric elements using semiconductor devices using transistors forming cells needing refreshing or charge regeneration, i.e. dynamic cells
- G11C11/4063—Auxiliary circuits, e.g. for addressing, decoding, driving, writing, sensing or timing
- G11C11/407—Auxiliary circuits, e.g. for addressing, decoding, driving, writing, sensing or timing for memory cells of the field-effect type
- G11C11/4074—Power supply or voltage generation circuits, e.g. bias voltage generators, substrate voltage generators, back-up power, power control circuits
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
This invention relates to Compound (I), useful in the treatment of mycoses, compositions comprising said compound, and its use in therapy.
Description
COTIC COMPOUND
Field of the Invention
This invention relates to a compound useful in the treatment of s, compositions
containing it and its use in therapy.
ound of the Invention
The nce of fungal infections has increased substantially over the past two decades and
invasive forms are leading causes of morbidity and mortality, especially amongst
immunocompromised or immunosuppressed patients. Disseminated candidiasis, pulmonary
aspergillosis, and emerging opportunistic fungi are the most common agents producing these
serious s. It is a particularfeature of fungi that they are able to generate an extracellular
matrix (ECM) that binds them together and allows them to adhere to their in vitro or in vivo
substrates. These biofilms serve to protect them against the hostile environments of the host
immune system and to resist antimicrobial g (Kaur and Singh, 2013).
Pulmonary aspergillosis can be segmented into those patients suffering with non-invasive
disease versus those with an invasive condition. A further vision is used to characterise
patients who exhibit an allergic component to aspergillosis (known as ABPA; allergic
bronchopulmonary aspergillosis) compared with those that do not. The factors precipitating
pulmonary aspergillosis may be acute, such as exposure to high doses of immuno-
suppressive medicines or to intubation in an intensive care unit. Alternatively, they may be
chronic, such as a previous infection with TB (Denning et al., 2011a). Chronic lung infections
with illus can leave patients with extensive and permanent lung damage, requiring
lifetime treatment with oral azole drugs r et al., 2011).
A growing body of research suggests that aspergillus infection may play an important role in
clinical asthma (Chishimba et al., 2012; Pasqualotto et al., 2009). Furthermore, recently
hed work has correlated aspergillus infection with poorer clinical outcomes in patients
with COPD (Bafadhel et al., 2013). Similarly cross-sectional studies have shown associations
between the presence of Aspergillus spp. and a spp. in the sputum and worsened lung
function (Chotirmall et al., 2010; Agbetile et al., 2012).
Invasive aspergillosis (IA) exhibits high mortality rates in immunocompromised ts, for
example, those undergoing nic stem cell transplantation or solid organ transplants (such
as lung transplants). The first case of IA reported in an compromised patient ed
in 1953. This event was concurrent with the uction of osteroids and cytotoxic
40 chemotherapy into treatment regimens (Rankin, 1953). Invasive aspergillosis is a major
concern in the treatment of leukaemia and other haematological malignancies given its high
incidence and associated mortality. Death rates usually exceed 50% (Lin et al., 2001) and
long term rates can reach 90% in allogeneic hematopoietic stem cell transplantation recipients,
despite the availiability of oral triazole medicines (Salmeron et al., 2012). In patients
undergoing solid organ transplantation (particularly of the lung), the use of high doses of
steroids leaves patients vulnerable to infection (Thompson and Patterson, 2008) which is a
s problem. The disease has also appeared in less severely immunocompromised
patient populations. These include those suffering with underlying COPD or cirrhosis, patients
receiving high dose steroids, and individuals fitted with central venous catheters or supported
by ical ventilation (Dimopoulos et al., 2012).
Existing ungal medicines are inantly dosed either orally or systemically. These
commonly exploited routes of delivery are poor for treating lung ainNays ions, since drug
concentrations achieved at the site of infection tend to be lower than those in organs. This is
especially so for the liver, which is a site of toxicity: up to 15% of patients d with
voriconazole suffer raised minase levels (Levin et al., 2007; Lat and Thompson, 2011).
Exposure of the liver also results in significant drug interactions arising from the the inhibition
of hepatic P450 enzymes (Jeong, et al., 2009; Wexler et al., 2004).
Furthermore, the read use of triazoles, both in the clinic and in agriculture has led to a
growing and problematic emergence of resistant mycoses in some locations (Denning et al.,
2011b; Bowyer and Denning, 2014).
It is clearly evident that an urgent medical need exists for novel anti-fungal medicines that
deliver improved efficacy and better systemic tolerability profiles.
Summary of the Invention
In a first aspect, the invention provides Compound (|)
MN) Me
NWO0 — / \ — HNQF
F F
Compound (I)
which is: 4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)tetrahydro
furanyl)methoxy)methylphenyl)piperaziny|)-N-(4-fluorophenyl)benzamide,
and pharmaceutically acceptable salts thereof (hereinafter sometimes referred to as the
“compound of the invention”).
ical data disclosed herein below reveals that the compound of the invention, Compound
(I), is a potent inhibitor of Aspergi/Ius fumigatus growth in in vitro assays. ln
immunosuppressed mice Compound (I) demonstrated potent inhibition of i/Ius
fumigatus infections. Other desirable properties of Compound (I) are described herein.
Brief Description of the Figures
Figure 1 displays the effects of prophylactic and therapeutic treatment with Compound (I) on
CFU in lung of Aspergi/lus fumigatus ed, immuno-compromised, neutropenic mice.
Figure 2 and Figure 3 show the effects of lactic and therapeutic treatment with
nd (I) on galactomannan concentrations in BALF and serum respectively, in
Aspergi/lus fumigatus infected, immuno-compromised, neutropenic mice.
In s.1-3, the symbol *** indicates significance with P<0.001.
Detailed Description of the Invention
Scheme 1: Preparation of Compound (I) by Routes 1-3.
Buchwald Br
' - — Euchillvald
(XIVa), Rc — H 0Up In9
Route 1 COUPIINQ Route 2
Route 3 (IX)
Ho N\_/N—P W; /—\N@C02Ra
(XI) N “'9
0 V(III)
o F F (IX)
(XIII) l (X)
Q 0T5 BUC W8h IdC0U p I'In9
F F (IX) l
, Wm,
gm<33., Buchwald
Coupling gm<3~cNew
Deprotect— (V;II Rb—— P Ester 7 (I);Ra= AIkyI
_> (V); Rb-— H hydrolysis++0”; Ra_— H
NF)N Amide ng H2NO
mo 0 F
CE“ M2“T<\/> (N 7 (III)
\/ F
Three alternative, convergent routes which have been developed for the generation of
Compound (I) from commercially available starting materials are depicted above (Scheme 1).
These tic ologies differ in the manner in which the advanced benzoate ester
intermediates of formula (IV) are prepared.
Route 1
The Buchwald ng of a suitably protected piperazine derivative (XII) with 4-bromo
methylphenol (XIVa) under conditions typically employed for such reactions provides the
mono N-arylated piperazine (XI). A suitable en protective group for such transformations
is as a urethane, using a Boc group (P = COz‘Bu). Those skilled in the art will appreciate that
a wide variety of conditions may be used for affecting transformations of this kind. In particular,
palladium catalysts and phosphine ligands such as RuPhosG3 and RuPhos are routinely
employed in the presence of a base, for example, cesium carbonate or lithium
hexamethyldisilazide. Alkylation of the resulting phenol (XI), under basic ions, with the
tosylate (IX) generates the ether (VII). The tosylate (IX) is a configurationally stable, non-
volatile (solid) reagent that is widely available, in high enantiomeric purity, from commercial
sources; though other electrophilic derivatives such as the corresponding mesylate, as well
as the halomethyl (e.g. chloromethyl and ethyl) derivatives would be anticipated as
suitable atives for this transformation. Removal of the nitrogen protective group reveals
the mono-substituted piperazine (V). In the case of a Boc derivative (Rb = COz‘Bu), the amine
deprotection step is typically aken by exposure of the carbamate to strong l acid
or a strong organic acid, such as TFA, either neat or in the presence of a solvent, such as
DCM. A second Buchwald coupling of the amine (V) with an alkyl 4-bromobenzoate (VI), under
basic conditions and the agency of a catalyst, gives rise to the N,N'-bisarylated product (IV) in
which R8 represents lower alkyl, such as 01.5 alkyl, for example methyl or ethyl, or else tert-
butyl.
Route 2
The benzoate ester intermediates (IV), may be obtained in an alternative process in which
only a single palladium-mediated coupling is required. Reaction of the bromophenol (XIVa)
with a mono N-arylated piperazine derivative [(X), R8 = lower alkyl, such as 01.5 alkyl, for
e methyl or ethyl, or else tert—butyl], under rd Buchwald ng conditions,
gives rise to a 1,4-bisarylpiperazine (VIII). The O-alkylation of this phenolic product, with the
te (IX), as described above, provides the ether products (IV) ly, in two steps, from
commercially available starting materials.
Route 3
It will be appreciated from the preparative routes outlined above (Scheme 1) that in some
instances it is advantageous to perform the same or similar synthetic transformations in a
40 ent order, so as to improve the overall efficiency of the processes and/or the y of
the materials obtained therefrom. For example, the bromophenol (XIVa) may be transformed
into the compounds of formula (IV) by conducting the two steps, outlined above, in reverse
order. In this manner, ent of the said phenol with the tosylate (IX) provides the ether
derivatives of formula (XIII). This aryl bromide substrate may be reacted with an N-aryl
zine of a (X), under Buchwald coupling conditions as previously described, to
provide the intermediates of formula (IV),
Preparation of Compound (I) from ediate (IV)
In some cases, for example those in which R8 is methyl or ethyl, generation of the free benzoic
acid (II) is conveniently undertaken by treatment of the ester (IV) with a base in the presence
of water. Typical conditions include treatment with an alkali metal hydroxide, such as lithium
hydroxide, in a mixture of water and a suitable aq miscible solvent. In other instances, as in
the case of a tert—butyl ester, it may be advantageous to conduct the hydrolysis step under
acidic conditions. Common reagents for such interconversions include strong inorganic acids,
for example hydrochloric acid, in the presence of a water miscible, organic t such as
IPA.
Treatment of the benzoic acid product (II), with 4-fluoroaniline under standard amide coupling
conditions, widely ble in the art, provides the compound of the invention, Compound (I).
For example the reaction may be undertaken by mixing the acid (II) and 4-fluoroaniline with
the ng agents HOBt and EDCI in a polar, non protic solvent such as DMF in the presence
of a non-nucleophilic organic base, typically DIPEA and the like.
Scheme 2: Preparation of Compound (I) by Route 4.
o O my
fim m
I(I)I WWI“ QF (XII RbNUNWN
Br Amide Buchwald CF
(xx) Formation (XIX Coupling
(XVIII); Rb = P _
b Deprotect
(XVII); R = H <—
>—\ Buchwald
/ \ /—\ 0
c Me0\©\
R°\\//N\/N\\//,j<N/—\F, Coupling
(XVI); R° = Me— (X'Vb)
(XV); R° = H <—
F'?‘
NW) /_N
0 Ni 3
0(w Me
OT5 RJVO0 a m
— o
F F (IX) N\ N _
Route 4
The compound of the t invention may also be assembled using yet another variation of
the preparative technologies described herein (Scheme 2). In this ative process (Route
4) amide bond formation is undertaken as the first step and tion of the ether linkage
constitutes the last synthetic transformation. Acylation of 4-fluoroaniline (III) with 4-
bromobenzoyl chloride (XX) provides the anilide fragment (XIX). As already noted such amidic
products may be prepared from the corresponding amine and benzoic acid directly using a
variety of activating agents, including e coupling reagents, of which a wide choice is
available in the art. Subjecting the aryl bromide product to the Buchwald coupling conditions,
with a suitable mono-protected piperazine (XII), under the agency of a catalyst in the manner
recorded above, gives rise to the intermediates of formula (XVIII). In the case of a Boc
protective group [P = COz‘Bu] the d N—aryl piperazine (XVII) is readily obtained by brief
exposure to a strong acid, for example, by treatment with TFA, which is then conveniently
removed from the reaction medium by evaporation under reduced pressure. The phenolic
precursor to compound (I), [(XV); RC = H], was then derived in two steps from a second
Buchwald coupling with the anisole (XIVb), to give the methyl ether intermediate [(XVI)
RC = Me], followed by an O-dealkylation with boron tribromide. The phenol (XV) was then
converted into Compound (I), by re-alkylation with the tosylate reagent (IX) in the manner
previously described.
Protective groups and the means for their removal are described in “Protective Groups in
Organic sis”, by Theodora W. Greene and Peter G. M. Wuts, published by John Vlfiley
& Sons Inc; 4th Rev Ed., 2006, ISBN-10: 7540. A review of methodologies for the
preparation of amides is d in: “Amide bond formation and peptide coupling” Montalbetti,
N. and Falque, V. edron, 2005, 61, 10852.
Thus the invention also provides a s for preparing Compound (I) or a pharmaceutically
acceptable salt thereof which ses reacting a compound of formula (II):
N//—\N
N Me
\\“'
\“‘ O N N COZRa
F F
(H)
wherein:
R8 represents en;
or an activated derivative f (such as an acid halide e.g. an acid chloride or an acid
anhydride); or a salt thereof;
with a compound of formula (III):
H2N0
(III)
or a salt thereof.
The invention also provides a process for preparing Compound (I) or a pharmaceutically
acceptable salt thereof which comprises reacting a compound of formula (XV):
2015/053731
Hoflflfli\/ \ / \ /
HN Q F
(XV)
or a salt thereof;
with a compound of formula (IX):
N\N)
\\\‘“‘" Z
F F (IX)
wherein:
Z represents a g group such as p-TolylSOzo;
or a salt thereof.
Pharmaceutically acceptable salts of compounds of formula (I) include in particular
ceutically acceptable acid addition salts of said compounds. The pharmaceutically
acceptable acid addition salts of compounds of a (I) are meant to comprise the
therapeutically active non-toxic acid addition salts that the compounds of formula (I) are able
to form. These pharmaceutically acceptable acid addition salts can conveniently be obtained
by treating the free base form with such appropriate acids in a suitable solvent or mixture of
solvents. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids,
e.g. hydrochloric or hydrobromic acid, sulfuric, , phosphoric acids and the like; or organic
acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, malonic, succinic,
maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, esulfonic, p-
toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic acid and the like.
Conversely said salt forms can be converted by treatment with an appropriate base into the
free base form.
The definition of the nd of formula (I) is intended to e all tautomers of said
compound.
The definition of the compound of formula (I) is intended to include all es of said
compound (including solvates of salts of said compound) unless the context specifically
indicates othenNise. Examples of solvates include es.
The compound of the disclosure includes embodiments wherein one or more atoms specified
are naturally occurring or non-naturally ing isotopes. In one embodiment the isotope is
a stable isotope. Thus the compounds of the disclosure include, for example deuterium
containing compounds and the like.
The disclosure also extends to all polymorphic forms of the compound herein d.
Novel ediates, as described , of formula (II), (IV), (V), (VII), (VIII), (XIII) and (XV)
and salts thereof, form a further aspect of the invention. Salts include pharmaceutically
acceptable salts (such as those mentioned above) and non-pharmaceutically acceptable salts.
Salts of acids (e.g. carboxylic acids) e first and second group metal salts including
sodium, potassium, magnesium and calcium salts.
In an embodiment there is provided a ceutical composition comprising the compound
of the invention optionally in ation with one or more pharmaceutically acceptable
diluents or carriers.
Suitably the compound of the invention is administered topically to the lung or nose,
particularly, topically to the lung. Thus, in an embodiment there is ed a pharmaceutical
composition sing the compound of the invention optionally in ation with one or
more topically acceptable diluents or carriers.
Suitable compositions for pulmonary or intranasal administration include s, liquid
solutions, liquid suspensions, nasal drops comprising solutions or suspensions or pressurised
or non-pressurised aerosols.
The compositions may conveniently be administered in unit dosage form and may be prepared
by any of the methods well-known in the pharmaceutical art, for example as described in
ton's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA.,
(1985). The itions may also conveniently be administered in multiple unit dosage form.
Topical administration to the nose or lung may be achieved by use of a non-pressurised
formulation such as an aqueous solution or suspension. Such formulations may be
administered by means of a nebuliser e.g. one that can be hand-held and portable or for home
or hospital use (i.e. non-portable). An example device is a RESPIMAT inhaler. The formulation
may se excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents,
viscosity modifiers, surfactants and co-solvents (such as ethanol). Suspension liquid and
aerosol formulations (whether pressurised or surised) will typically contain the
compound of the invention in finely divided form, for example with a D50 of 05-10 pm e.g.
around 1-5 pm. Particle size distributions may be represented using D10, D50 and D90 values.
The D50 median value of particle size distributions is defined as the particle size in microns
that divides the distribution in half. The measurement derived from laser diffraction is more
accurately described as a volume distribution, and consequently the D50 value obtained using
this procedure is more meaningfully referred to as a Dv5o value (median for a volume
40 bution). As used herein Dv values refer to particle size distributions measured using laser
diffraction. Similarly, D10 and D90 values, used in the context of laser diffraction, are taken to
mean Dvm and Dv90 values and refer to the particle size whereby 10% of the distribution lies
below the D10 value, and 90% of the distribution lies below the D90 value, respectively.
ing to one specific aspect of the invention there is provided a pharmaceutical
composition comprising the compound of the invention in particulate form suspended in an
aqueous medium. The aqueous medium typically comprises water and one or more excipients
selected from buffers, tonicity adjusting agents, pH ing agents, viscosity modifiers and
surfactants.
Topical administration to the nose or lung may also be achieved by use of an aerosol
formulation. Aerosol ations typically comprise the active ingredient suspended or
dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a
hydrofluorocarbon (HFC). Suitable CFC propellants e trichloromonofluoromethane
(propellant 11), dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane
(propellant 12). Suitable HFC propellants include tetrafluoroethane (HFC-134a) and
heptafluoropropane (H FC-227). The propellant typically comprises 40%-99.5% e.g. 40%-90%
by weight of the total inhalation composition. The formulation may comprise excipients
including co-solvents (e.g. l) and surfactants (e.g. lecithin, sorbitan trioleate and the
like). Other possible ents include polyethylene glycol, polyvinylpyrrolidone, glycerine and
the like. Aerosol ations are packaged in canisters and a suitable dose is delivered by
means of a metering valve (e.g. as supplied by Bespak, Valois or 3M or alternatively by Aptar,
Coster or Vari).
Topical administration to the lung may also be achieved by use of a dry-powder formulation.
A dry powder formulation will contain the compound of the disclosure in finely divided form,
typically with an MMD of 1-10 pm or a D50 of 05-10 pm e.g. around 1-5 pm. Powders of the
compound of the invention in finely divided form may be prepared by a micronization process
or r size reduction process. Micronization may be performed using a jet mill such as
those ctured by Hosokawa Alpine. The resultant particle size distribution may be
measured using laser diffraction (e.g. with a Malvern sizer 20008 instrument). The
ation will lly contain a topically acceptable diluent such as lactose, glucose or
ol (preferably lactose), usually of comparatively large particle size e.g. an MMD of 50
pm or more, e.g. 100 pm or more or a D50 of 40-150 pm. As used herein, the term “lactose”
refers to a lactose-containing component, including d-lactose monohydrate, B-lactose
monohydrate, d-lactose anhydrous, B-lactose anhydrous and amorphous lactose. Lactose
components may be processed by micronization, sieving, g, compression, agglomeration
or spray drying. Commercially ble forms of lactose in various forms are also
encompassed, for example Lactohale® (inhalation grade lactose; DFE Pharma), lnhaLac®70
(sieved lactose for dry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose®
(sieved inhalation grade e; DFE Pharma) products. In one embodiment, the lactose
ent is selected from the group consisting of d-lactose monohydrate, d-lactose
ous and amorphous lactose. Preferably, the e is d-lactose monohydrate.
Dry powder formulations may also contain other excipients such as sodium stearate, calcium
stearate or magnesium stearate.
A dry powder formulation is typically red using a dry powder inhaler (DPI) device.
Example dry powder delivery systems include SPINHALER, LER, ALER,
DISKUS, SKYEHALER, ACCUHALER and CLICKHALER. Further examples of dry powder
delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER,
CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TVVINCAPS, XCAPS
, TURBOSPIN, ELPENHALER, MIATHALER, TVVISTHALER, NOVOLIZER,
IR, A, ORIEL dry powder inhaler, MICRODOSE, AL, EASYHALER,
ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX,
XCELOVAIR and PROHALER.
The compound of the invention might also be administered topically to another al or
al surface (e.g. a mucosal surface or skin) or administered orally. The compound of the
ion may be formulated conventionally for such routes of administration.
The compound of the invention is useful in the treatment of mycoses and for the prevention or
ent of disease associated with mycoses.
In an aspect of the invention there is provided use of the nd of the invention in the
manufacture of a medicament for the treatment of mycoses and for the prevention or treatment
of e associated with mycoses.
In another aspect of the invention there is provided a method of treatment of a subject with a
mycosis which comprises administering to said subject an effective amount of the compound
of the invention.
In another aspect of the invention there is provided a method of prevention or treatment of
disease ated with a mycosis in a subject which comprises administering to said subject
an effective amount of the compound of the invention.
s may, in particular, be caused by Aspergi/Ius spp. such as Aspergi/Ius fumigatus or
Aspergi/Ius pu/lu/ans especially Aspergi/Ius fumigatus Mycoses may also be caused by
Candida spp. e.g. Candida albicans or Candida glabrata, Rhizopus spp. e.g. Rhizopus oryzae,
Cryptococcus spp. e.g. Cryptococcus neoformans, Chaetomium spp. e.g. Chaetomium
globosum, Penicil/ium spp. e.g. Penicil/ium chrysogenum and Trichophyton spp. e.g.
Trichophyton rubrum.
A disease associated with a mycosis is, for example, pulmonary aspergillosis.
The compound of the invention may be used in a prophylactic setting by administering the
40 said compound prior to onset of the mycosis.
Subjects e human and animal subjects, especially human subjects.
The compound of the invention is especially useful for the treatment of mycoses such as
Aspergi/Ius fumigatus infection and for the prevention or treatment of disease associated with
mycoses such as Aspergi/Ius fumigatus infection in at risk subjects. At risk subjects include
ure infants, children with congenital defects of the lung or heart, immunocompromised
subjects (e.g. those ing from HIV infection), asthmatics, subjects with cystic fibrosis,
elderly ts and ts suffering from a chronic health condition affecting the heart or
lung (e.g. congestive heart failure or chronic obstructive pulmonary disease).
The compound of the invention is also useful for the ent of azole resistant mycoses such
as azole resistant Aspergi/Ius fumigatus infection, particularly in ation with
posaconazole.
The compound of the invention may be administered in combination with a second or further
active ient. Second or r active ingredients may, for example, be ed from
other anti-fungal agents (such as voriconazole or posaconazole), amphotericin B, an
echinocandin (such as caspofungin) and an inhibitor of 3-hydroxymethyl-glutaryl-CoA
reductase (such as lovastatin, tatin or fluvastatin).
Second or further active ingredients include active ingredients suitable for the treatment or
prevention of a mycosis such as Aspergi/Ius fumigatus ion or disease associated with a
mycosis such as Aspergi/Ius fumigatus infection or ions co-morbid with a mycosis such
as Aspergi/Ius tus infection.
The compound of the invention may be co-formulated with a second orfurther active ingredient
or the second or further active ingredient may be formulated to be administered separately by
the same or a different route.
For example, the compound of the invention may be administered to patients already being
treated systemically with an anti-fungal, such as voriconazole or posaconazole.
For example, the compound of the invention may be co-administered e.g. co-formulated with
one or more agents selected from amphotericin B, an echinocandin, such as ungin, and
an inhibitor of 3-hydroxymethyl-glutaryl-CoA ase, such as lovastatin, pravastatin or
fluvastatin.
The compound of the invention may alternatively (or in addition) be co-administered e.g. co-
formulated with one or more agents selected from candicidin, filipin, hamycin, natamycin,
nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole,
isoconazole, ketoconazole, luliconazole, zole, omoconazole, oxiconazole.
40 sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole,
fluconazole, onazole, itraconazole, onazole, ravuconazole, terconazole,
gin, amorolfin, butenafine, naftifine, terbinafine, anidulafungin, micafungin, benzoic
acid, ciclopirox, flucytosine (5-fluorocytosine), griseofulvin, tolnaftate and undecylenic acid.
WO 87878
Preferred combination partners include intraconazole, nazole, caspofungin and
posaconazole.
According to an aspect of the invention there is provided a kit of parts comprising (a) a
pharmaceutical composition comprising the compound of the ion optionally in
combination with one or more diluents or carriers; (b) a pharmaceutical composition
comprising a second active ingredient optionally in ation with one or more diluents or
carriers; (c) optionally one or more further ceutical compositions each comprising a
third or further active ingredient optionally in combination with one or more diluents or carriers;
and (d) instructions for the administration of the ceutical compositions to a subject in
need thereof. The subject in need thereof may suffer from or be susceptible to a mycosis such
as Aspergi/Ius fumigatus infection.
The compound of the ion may be stered at a suitable interval, for example once
per day, twice per day, three times per day or four times per day.
A suitable dose amount for a human of average weight (50-70 kg) is expected to be around
50 ug to 10 mg/day e.g. 500 ug to 5 mg/day although the precise dose to be administered
may be determined by a skilled person.
The compound of the invention is expected to have one or more of the ing favourable
attributes:
. potent antifungal activity, particularly activity against Aspergi/Ius spp. such as
Aspergi/Ius fumigatus or activity against Candida spp. e.g. Candida albicans or
Candida glabrata, Rhizopus spp. e.g. Rhizopus oryzae, Cryptococcus spp. e.g.
Cryptococcus neoformans, Chaetomium spp. e.g. Chaetomium globosum, l/ium
spp. e.g. Penicil/ium chrysogenum or Trichophyton spp. e.g. Trichophyton rubrum,
especially following l administration to the lung or nose;
. long duration of action in lungs, preferably consistent with once daily dosing;
. low systemic exposure following topical administration to the lung or nose; and
. an acceptable safety profile, especially following topical administration to the lung or
nose.
2015/053731
EXPERIM ENTAL SECTION
Abbreviations used herein are defined below (Table 1). Any abbreviations not d are
intended to convey their generally accepted meaning.
Table 1: Abbreviations
ABPA allergic bronchopulmonary illosis
aq aqueous
ATCC American Type Culture Collection
BALF bronchoalveolar lavage fluid
BEASZB SV40-immortalised human bronchial lial cell line
Boc tert—butyloxycarbonyl
br broad
BSA bovine serum albumin
CC5o 50% cell cytotoxicity concentration
CFU colony forming unit(s)
CLSI Clinical and Laboratory Standards ute
COI cut off index
conc concentration/concentrated
d doublet
DCM dichloromethane
DFB5o days taken to reach a fungal burden of 50% of control
DIPEA N,N-diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMEM Dulbecco’s Modified Eagle Medium
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DSS dextran sodium sulphate
EBM endothelial basal media
ECM extracellular matrix
EDCI.HC| N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
EGM2 endothelial cell growth media 2
EUCAST European tee on Antimicrobial Susceptibility Testing
(ES+) electrospray ionization, positive mode
Et ethyl
EtsN triethylamine
EtOAc ethyl acetate
FBS foetal bovine serum
GM galactomannan
HPAEC human pulmonary artery endothelial cell
HOBt.H20 1-hydroxybenzotriazole mono-hydrate
2015/053731
HPLC reverse phase high performance liquid chromatography
hr hour(s)
IA invasive aspergillosis
i.n. intranasal
IPA 2-propanol
i.t. intra-tracheal
LC-MS liquid chromatography—mass spectrometry
Li Hep lithium heparin
LiHMDS lithium bis(trimethy|si|y|)amide
m multiplet
(M+H)+ protonated molecular ion
MDA malondialdehyde
Me methyl
MeCN acetonitrile
MeOH methanol
MHz megahertz
MlC5o 50% of minimum inhibitory concentration
MIC75 75% of minimum inhibitory concentration
Mngo 90% of minimum inhibitory concentration
min minute(s)
MMD mass median diameter
MOI multiplicity of infection
MOPS 3-(N-morpholino)propanesulfonic acid
m/z: mass-to-charge ratio
NCPF National Collection of Pathogenic Fungi
NMR nuclear magnetic resonance (spectroscopy)
NT not tested
OD optical density
PBS phosphate buffered saline
P protective group
0| quartet
RT room ature
RP HPLC reverse phase high performance liquid chromatography
RPMI l Park Memorial Institute medium
RuPhos 2-dicyclohexylphosphino-2’, sopropoxybiphenyl
(2-dicyclohexylphosphino-2’, 6’-diisopropoxybiphenyl)[2-(2’-amino-1,
RuPhosG3
1’-biphenyl)]palladium thanesulfonate
s singlet
sat saturated
sc sub-cutaneous
SDS sodium l sulphate
t triplet
TFA trifluoroactic acid
TH F ydrofuran
An Aspergi/Ius fumigatus strain containing a leucine-to-histidine
TR34/L98H
substitution at codon 98 and a 34-bp tandem repeat
General Procedures
All starting materials and solvents were obtained either from commercial sources or prepared
according to the literature citation. Unless othenNise stated all reactions were stirred. Organic
ons were routinely dried over anhydrous magnesium sulfate.
ical Methods
e Phase HPLC Methods:
Waters t CSH C18 XP column, 2.5 pm (4.6 x 30 mm) at 40°C; flow rate 2.5-4.5 mL min'
1 eluted with
a Hzo-MeCN gradient containing either 0.1% v/v formic acid (Method a) or 10
mM NH4HCOs in water d b) over 4 min employing UV detection at 254 nm. Gradient
information: 0-3.00 min, ramped from 95% H20-5% MeCN to 5% H20-95% MeCN; 3.00-3.01
min, held at 5% H20-95% MeCN, flow rate increased to 4.5 mL min'1; 3.01 3.50 min, held at
% H20-95% MeCN; 3.50-3.60 min, returned to 95% H20-5% MeCN, flow rate reduced to
3.50 mL min"; 3.60-3.90 min, held at 95% H20-5% MeCN; 3.90-4.00 min, held at 95% H20-
% MeCN, flow rate d to 2.5 mL min'1.
1H NMR Spectroscopy:
1H NMR spectra were acquired on a Bruker Advance ||| spectrometer at 400 MHz using
residual erated solvent as reference and unless specified othenNise were run in DMSO-
d6.
Synthetic Methods for the Preparation of Compound (I)
tert-butyl 4-(4-hydroxymethylphenyl)piperazinecarboxylate.
HO®Br Me
HN NBoc —> HO N NBoc
RuPhos, RuPhos G3,
(Xlla) LiHMDS, DMF (Xla)
A flask charged with tert—butylpiperazincarboxy|ate (Xlla) (7.44 g, 40.0 mmol), 4-bromo
methylphenol (6.23 g, 33.3 mmol), RuPhos (311 mg, 0.67 mmol) and RuPhos G3 (557 mg,
0.67 mmol) was evacuated and backfilled with nitrogen three times. A solution of LiHMDS (1M
in THF, 100 mL, 100 mmol) was added and the reaction mixture was heated at 70°C for 3 hr.
After cooling to RT the mixture was quenched by the addition of 1M hydrochloric acidl (100
mL) and was then neutralised with 1M aq. NaHCOs (100 mL). The aq layer was extracted with
EtOAc (3 x 100 mL) and the combined c extracts were dried. The les were
removed in vacuo to give a crude product which was purified by flash column chromatography
(SiOz, 120 g, 0-100% EtOAc in isohexanes, gradient elution) to afford the title compound,
intermediate (Xla), as a light brown solid (7.80 g, 78%); Rt 2.07 min (Method b); m/z 293
(M+H)+ (ES+); 1H NMR 6: 1.41 (9H, s), 2.07 (3H, s), .88 (4H, m), 3.41-3.43 (4H, m),
6.58-6.65 (2H, m), 6.71 (1H, d) and 8.72 (1H, s).
((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)tetrahydrofuran
yl)methoxy)—3-methylphenyl)piperazine.
O NUN “‘ OTS \N Me
F F (IX) /—\
\~“ 0 N N—Rb
(Xla) —> \ /
NaOH,DMSO F F
— (Vila); Rb = Boc
TFA,DCM
—> (V);R'°=H
To a solution of intermediate (Xla) (7.80 g, 25.1 mmol) in DMSO (60 mL) was added aq sodium
hydroxide (3.0 mL, 12.5 M, 37.6 mmol). The e was stirred at RT for 10 min and was then
treated portionwise with ((38,5R)—5-((1H—1,2,4-triazolyl)methyl)(2,4-difluoro
)tetrahydrofuranyl)methyl4-methylbenzenesulfonate (IX) (ex APIChem, Catalogue
Number: AC-8330, 12.4 g, 27.6 mmol). The reaction mixture was stirred at 30°C for 18 hr,
cooled to RT and water (200 mL) was added. The resulting mixture was extracted with EtOAc
(3 x 200 mL) and the combined organic extracts were washed with brine (2 x 200 mL), and
then dried and evaporated in vacuo to afford a brown oil. Analysis of the crude, Boc-protected
product (Vlla) by 1H NMR indicated that it contained ~10% of the alkene: (R)—1-((2-(2,4-
difluoropheny|)methylenetetrahydrofuranyl)methy|)-1H-1,2,4-triazole, formed as an
elimination by-product. The crude urethane (Vlla) was taken up into DCM (150 mL) and
treated with TFA (39.0 mL, 502 mmol). After 2 hr at RT the reaction mixture was concentrated
in vacuo to remove most of the volatiles and was then d with EtOAc (200 mL) and washed
with aq. NaOH (2 M, 200 mL). The aq phase was separated and was extracted with EtOAc (2
x 200 mL). The combined organic extracts were washed with brine (2 x 200 mL) and then
dried and evaporated in vacuo to afford a light brown oil. The crude product was purified by
flash column chromatography (SiOz, 80 g, 0-10% 0.7 M NHs/MeOH in DCM, gradient elution)
to afford the title compound, intermediate (V), as a viscous, light brown oil (9.46 g, 80%); Rt
1.91 min (Method b); m/z 470 (M+H)+ (ES+); 1H NMR 6: 2.07 (3H, s), 2.15 (1H, dd), 2.36-2.42
(1H, m), 2.52-2.56 (1H, m), 2.79-2.81 (4H, m), .90 (4H, m), 3.66 (1H, dd), 3.73-3.77 (2H,
m), 4.04 (1H, t), 4.57 (2H, dd), 6.64 (1H, dd), .75 (2H, m), 6.99 (1H, td), 7.25-7.34 (2H,
m), 7.76 (1H, s) and 8.34 (1H, s).
Methyl 4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)tetra
hydrofuranyl)methoxy)methylphenyl)piperazinyl)benzoate.
0com2. o
(Vla) \N
Br Me
(V) N‘ ‘N <_> co Me (lVa)
RuPhos,RuPhosG3, mo <3 2
\ / \ /
C52C03, DMF F F
A flask charged with intermediate (V) (9.00 g, 19.2 mmol), methylbromobenzoate (Vla)
(4.95 g, 23.0 mmol), RuPhos (0.18 g, 0.38 mmol, 2 mol%), RuPhosG3 (0.32 g, 0.38 mmol, 2
mol%) and cesium carbonate (9.99 g, 30.7 mmol) was evacuated and refilled with nitrogen
three times before DMF (150 mL) was added. The mixture was heated at 80°C for 22 hr and
then, whilst still hot, was poured into water (150 mL) to form a brown gum. More water (300
mL) was added and the aq. phase was extracted with DCM (2 x 200 mL). The organic extracts
were ed and concentrated in vacuo to give a brown oil which was poured into water
(100 mL). The resulting itate was collected by filtration and then re-suspended in THF
(100 mL). The mixture was heated at reflux for 1 hr during which time a cream suspension
was formed. The mixture was cooled to RT and the resulting itate was collected by
filtration, washed with THF (2 x 50 mL) and then dried in vacuo to afford the title compound,
intermediate (lVa), as a light yellow solid (9.48 g, 79%); Rt 2.79 min (Method b); m/z 604
(M+H)+ (ES+); 1H NMR 6: 2.09 (3H, s), 2.16 (1H, dd), 2.37-2.43 (1H, m), 2.52-2.58 (1H, m),
3.11-3.14 (4H, m), 3.43-3.46 (4H, m), 3.68 (1H, dd), 3.74-3.79 (5H, s overlapping over m),
4.05 (1H, dd), 4.58 (2H, dd), 6.75 (2H, br s), 6.85 (1H, br d), 7.00 (1H, td), 7.04 (2H, d), 7.25-
7.34 (2H, m), 7.76 (1H, s), 7.81 (2H, d) and 8.34 (1H, s).
Ethyl 4-(4-(4-hydroxymethylphenyl)piperazinyl)benzoate.
H0®Br Me
/—\ (XIVa)
HN HOQ/—\N
\_/N®C02Et —> \_/N®C02Et
R_uPhos G3,
(Xa) LIHMDS, DMF (Vllla)
A flask charged with a solution of ethyl 4-(piperaziny|)benzoate (Xa) (20.0 g, 85.0 mmol)
and 4-bromomethylphenol (19.2 g, 102 mmol) in DMF (213 mL) was evacuated and
backfilled with nitrogen three times. RuPhos G3 (1.43 g, 1.71 mmol) was added and the flask
was evacuated and backfilled with nitrogen. The reaction e was cooled to 0°C and
LiHMDS (17.1 g, 102 mmol) was added. The reaction was stirred at RT for 10 min, then cooled
in a water bath and LiHMDS (20.0 g, 120 mmol) added in equal portions (7 x 2.85 g) at 5 min
intervals. The ing solution was stirred at RT for 30 min and was then cooled to 0°C and
d with 2M hydrochloric acid (200 mL) resulting in a pH of 6-7. The mixture was d
for 15 min at RT and was then extracted with EtOAc (220 mL). The aq layer was separated
2015/053731
and extracted with EtOAc (4 x 50 mL) and the combined organics were washed with brine (6
x 50 mL), and then dried and evaporated in vacuo to afford a cream solid. A mixture of
anes and IPA (1:1, 150 mL) was added and the suspension was stirred at RT for 30
min. The solid was collected by filtration, and the filter cake was washed with a mixture of
anes and IPA (1:1, 2 x 10 mL) followed by isohexanes (4 x 10 mL) and dried in vacuo
at 40°C for 18 hr to afford the title compound, intermediate (Vllla), as a cream solid (15.3 g,
50%); Rt 2.29 min d b); m/z 341 (M+H)+ (ES+); 1H NMR 6:1.29 (3H, t), 2.09 (3H, s),
3.06-3.09 (4H, m), 3.42-3.44 (4H, m), 4.24 (2H, dd), 6.66 (2H, br s), 6.76 (1H, br s), 7.03 (2H,
d), 7.80 (2H, d), 8.72 (1H, s).
Ethyl 4-(4-(4-(((3R,5R)((1H-1,2,4-triazoly|)methyl)(2,4-difluorophenyl)tetrahydro
furanyl)methoxy)methylpheny|)piperaziny|)benzoate.
Ni/—N2
N Me
(IX) 0
(Vllla)—> e“
o N1 ‘N COzEt
NaOEt,DMF
F F
(IVb)
To a solution of intermediate (Vllla) (15.3 g, 44.9 mmol) in DMF (110 mL) cooled to 0°C was
added sodium ethoxide (3.13 g, 46.1 mmol) and the mixture stirred at 0°C for 10 min and then
treated with the tosylate (IX) (20.2 g, 44.9 mmol). The reaction mixture was d to warm
to RT, heated to 50°C for 1 hr and then cooled to RT. Hydrochloric acid (1M, 60 mL) and water
(200 mL) were added and the mixture was stirred for 30 min at RT and then extracted with
DCM (150 mL). The aq layer was separated and extracted with DCM (2 x 50 mL) and the
combined organics were washed with brine (4 x 30 mL) and then dried and evaporated in
vacuo to afford a cream solid. The solid was suspended in an equal mixture of isohexanes
and IPA (80 mL) and d at RT for 1 hr. The solid was collected by filtration, washed with
a mixture of iso-hexanes and IPA 1:1 (3 x 20 mL) and then dried in vacuo at 40°C for 18 hr to
afford the title compound, intermediate (IVb) as a white solid (16.4 g, 56%); Rt 2.92 min
(Method b); m/z 618 (M+H)+ (ES+); 1H NMR 6: 1.29 (3H, t), 2.10 (3H, s), 2.16 (1H, dd), 2.37-
2.42 (1H, m), 2.52-2.58 (1H, m), 3.12-3.14 (4H, m), 3.43-3.46(4H, m), 3.68 (1H, dd), 3.74-3.79
(2H, m), 4.05 (1H, dd), 4.24 (2H, dd), 4.58 (2H, dd), 6.76 (2H, br s), 6.86 (1H, br s), 6.98-7.05
(3H, m), 7.26-7.34 (2H, m), 7.77 (1H, s), 7.81 (2H, d), 8.34 (1H, s).
1-(((2R,4R)((4-bromomethylphenoxy)methy|)(2,4-difluorophenyl)tetrahydro
furanyl)methyl)-1H-1,2,4-triazole.
//—N
N\ )
Me N Me
(IX) 0
HO Br > 0 Br
NaOH, DMSO/HZO
F F
(XIVa) (XIII)
To a solution of 4-bromomethyl phenol (920 mg, 4.89 mmol) in DMSO (10 mL) was added
aq sodium hydroxide (0.39 mL, 12.5 M, 4.89 mmol) and the mixture stirred at RT for 10 min
and then treated with the tosylate (IX) (2.00 g, 4.45 mmol). The reaction mixture was stirred
at 60°C for 72 hr then cooled to RT and partitioned between water (25 mL) and EtOAc (20
mL). The c phase was separated and retained and the aq layer was extracted with
EtOAc (3 x 25 mL). The combined organic extracts were washed with brine (3 x 15 mL) and
then dried and evaporated in vacuo. The crude product was purified by flash column
chromatography (SiOz, 12 g, 0-30% EtOAc in DCM, gradient elution) to give the title compound,
intermediate (XIII), as a colourless oil (1.84 g, 86%); Rt 2.78 min (Method a); m/z 464 (M+H)+
(ES+);1H NMR 6: 2.09 (3H, s), 2.17 (1H, dd), 2.37-2.43 (1H, m), 2.52-2.60 (1H, m), 3.72-3.78
(2H, m), 3.82 (1H, dd), 4.00-4.06 (1H, m), 4.57 (2H, dd), 6.82 (1H, d), 7.00 (1H, td), 7.25-7.34
(4H, m), 7.76 (1H, s), 8.34 (1H, s).
Ethyl 4-(4-(4-(((3R,5R)((1H-1,2,4-triazoIy|)methyI)(2,4-difluorophenyl)tetrahydro
furanyl)methoxy)methylpheny|)piperaziny|)benzoate.
(XIII)
RuPhos,RuPhos G3, wT©7NUN4©7COZE
Cszcog, DMF (IVb)
A vial charged with ethyl 4-(piperaziny|)benzoate (X) (103 mg, 0.44 mmol), intermediate
(XIII) (170 mg, 0.37 mmol), RuPhos (8.5 mg, 18 umol), RuPhos G3 (14.2 mg, 18 umol) and
cesium carbonate (191 mg, 0.59 mmol) was ted and backfilled with nitrogen three times
before DMF (3.0 mL) was added. The mixture was heated at 80°C for 18 h and then at 100°C
for 24 hr. The reaction e was cooled to RT and ioned between water (10 mL) and
EtOAc (10 mL). The organic phase was separated and retained and the aq layer was extracted
with EtOAc (3 x 10 mL). The combined organics were washed with brine (3 x 10 mL) and then
dried and ated in vacuo. The crude product was purified by flash column
chromatography (SiOz, 12 g, 0-100% EtOAc in isohexane, nt elution) to give the title
compound, intermediate (IVb), as a white solid (100 mg, 43%).
4-(4-(4-(((3R,5R)((1H-1,2,4-triazoly|)methyI)(2,4-difluorophenyl)tetrahydrofuran-
ethoxy)methylpheny|)piperaziny|)benzoic acid.
Hydrolysis of the Methyl Ester (IVa)
N me
LiOH OTGN/—\ (IVa) —> \““‘o
\_/N@COZH
(ll)
DMSO, H20
F F
WO 87878
To a suspension of intermediate (lVa) (9.00 g, 14.9 mmol) in DMSO (370 mL) was added a
solution of lithium hydroxide (1.79 g, 74.5 mmol) in water (37.0 mL). The mixture was heated
at 70°C for 22 hr and was then cooled to RT, diluted with water (1000 mL) and ied (to ~
pH 2) by the addtion of 1M aq hydrochloric acid (80 mL). The mixture was cooled in an ice
bath for 2 hr and the resulting precipitate was collected by filtration. The filter cake was washed
with water (3 x 80 mL) and dried in vacuo at 50°C to give the title compound, intermediate (II)
as a white solid (4.66 g, 54%); Rt 2.21 min d 1a); m/z 590 (M+H)+ (ES+); 1H NMR 6:
2.10 (3H, s), 2.16 (1H, dd), 2.37-2.43 (1H, m), 2.52-2.58 (1H, m), .14 (4H, m), 3.42-3.45
(4H, m), 3.68 (1H, dd), 3.74-3.79 (2H, m), 4.05 (1H, dd), 4.58 (2H, dd), 6.76 (2H, br s), 6.86
(1H, br d), 6.97-7.03 (3H, m), 7.25-7.34 (2H, m), 7.77-7.80 (3H, m), 8.34 (1H, s) and 12.31
(1H, s).
Hydrolysis of the Ethyl Ester (lVb)
To a suspension of intermediate (lVb) (16.4 g, 26.6 mmol) in DMSO (375 mL) was added a
solution of lithium hydroxide (3.18 g, 74.5 mmol) in water (50 mL). The mixture was heated at
70°C for 22 hr and was then cooled to RT, poured into water (500 mL) and acidified (to ~ pH
-6) by the n of 2M hydrochloric acid (70 mL). The mixture was stirred at RT for 30 min
and the resulting solid was collected by filtration and washed with water (2 x 20 mL) and with
diethyl ether (3 x 30 mL) and then dried in vacuo at 40°C for 18 hr to afford the title compound,
ediate (II) as a tan solid (14.2 g, 84%); Rt 2.26 min (Method 1a); m/z 590 (M+H)+ (ES+);
1H NMR 6: 2.09 (3H, s), 2.16 (1H, dd), 2.37-2.42 (1H, m), 2.52-2.58 (1H, m), 3.12-3.14 (4H,
m), 3.42-3.44 (4H, m), 3.68 (1H, dd), .79 (2H, m), 4.05 (1H, dd), 4.58 (2H, dd), 6.75 (2H,
br s), 6.86 (1H, br s), 6.97-7.03 (3H, m), 7.26-7.34 (2H, m), 7.77-7.80 (3H, m), 8.34 (1H, s),
12.31 (1H, br s).
4-Bromo-N-(4-fluorophenyl)benzamide.
Et3N, DMAP, THF (XIX)
(XX)
To a on of 4-fluoroaniline (|||) (0.85 mL, 9.00 mmol), triethylamine (1.88 mL, 13.5 mmol)
and DMAP (0.11 g, 0.90 mmol) in THF (15 mL) was added 4-bromobenzoyl chloride (XX)
(2.37 g, 10.8 mmol). The reaction mixture was maintained at RT for 1 hr and was then
partitioned between EtOAc (100 mL) and 1M hydrochloric acid (100 mL). The organic phase
was separated and was washed sequentially with 1M hydrochloric acid (100 mL), sat. aq.
NaHCOs (100 mL) and brine (100 mL) and then dried and evaporated in vacuo. The crude
residue was triturated from warm DCM (100 mL) and the mixture was heated at reflux to give
a white suspension which was allowed to cool to RT. The resulting precipitate was collected
by filtration to afford the title compound, intermediate (XIX), as white solid (1.81 g, 65%); Rt
2.23 min; m/z 294/296 (M+H)+ (ES+); 1H NMR 6: 7.20 (2H, t), 7.74-7.79 (4H, m), 7.90 (2H, d)
and 10.36 (1H, s).
tert-Butyl 4-(4-((4-f|uorophenyl)carbamoyl)pheny|)piperazinecarboxylate.
BocN NH (XII)
\_/ O
I \
(XIX) —> BocN N
w 131@F
, RuPhos G3, HN
LiHMDS, THF (XVIII)
A flask charged with tert—butyl piperazinecarboxylate (Xll) (4.00 g, 215 mmol), intermediate
(XIX) (6.63 g, 22.6 mmol), RuPhos (100 mg, 0.215 mmol) and RuPhos G3 (180 mg, 0.215
mmol) was evacuated and lled with en three times. A solution of LiHMDS (1M in
THF, 75.0 mL, 75.0 mmol) was added and the reaction mixture was heated at 70°C for 5 hr.
After cooling to RT the e was partitioned n EtOAc (150 mL) and 1M hydrochloric
acid (150 mL). The organic phase was separated and retained and the aq phase was ted
with EtOAc (3 x 150 mL). The combined organics were dried and concentrated in vacuo to
afford a brown solid which was triturated in a mixture of isohexanes and diethyl ether (1:1, 100
mL). The product so obtained was ted by filtration, washed with a e of isohexanes
and diethyl ether (1:1, 25 mL) and then dried in vacuo at 40°C to provide the title compound,
intermediate (XVIII) as a tan solid (6.44 g, 85%); Rt 2.40 min (Method a); m/z 400 (M+H)+; 1H
NMR 6: 1.43 (9H, s), 3.27-3.30 (4H, m), 3.45-3.48 (4H, m), 7.03 (2H, d), 7.14-7.18 (2H, m),
7.74-7.79 (2H, m), 7.88 (2H, d), 9.99 (1H, s).
N-(4-fluoropheny|)(piperaziny|)benzamide.
/—\ 0 TFA /—\ o
B°°_N “Q4HN®F —> HN NW _
\—/ \ /
DCM — HN <\ /> F
(XVIII) (XVII)
To a solution of intermediate (XVIII) (6.44 g, 16.1 mmol) in DCM (200 mL) was added TFA
(24.7 mL, 322 mmol). The reaction was stirred at RT for 2 hr and was then evaporated in
vacuo. Toluene (5.0 mL) was added and the mixture was again evaporated in vacuo. The
resulting oil was taken up in a mixture of DCM (90 mL) and methanol (10 mL) and was then
extracted with a mixture of water (50 mL) and sat. aq NaHCOs (50 mL). The organic phase
was separated and retained and the aq layer was extracted with a mixture of DCM and
methanol (9:1, 3 x 100 mL). The combined organic layers were dried and concentrated in
vacuo to afford the title compound, intermediate (XVII), as a brown solid (3.74 g, 70%); Rt 1.02
min (Method a); m/z 300 (M+H)+; 1H NMR 6: 2.81-2.83 (4H, m), 3.18-3.20 (4H, m), 6.99 (2H,
d), 7.14-7.18 (2H, m), 7.74-7.80 (2H, m), 7.85 (2H, d), 9.99 (1H, s).
N-(4-fluorophenyl)(4-(4-methoxymethylphenyl)piperaziny|)benzamide.
MeOQBr (XIVb) Me
Me04<\ O
(XVII) >7N\—/N4< H
RuPhos, RuPhos G3,
LiHMDS, THF HN®F
(XVI)
A flask charged with 4-bromomethoxymethylbenzene (XIVb) (406 mg, 2.02 mmol),
intermediate (XVII) (550 mg, 1.84 mmol), RuPhos (43 mg, 0.092 mmol) and RuPhos G3 (77
mg, 0.092 mmol) was evacuated and lled with nitrogen three times. A solution of
LiHMDS (9.2 mL, 1M in THF, 9.2 mmol) was added and the reaction mixture was heated at
70°C for 8 hr. After cooling to RT the mixture was quenched by the addition of 1M aq.
hydrochloric acid (9.0 mL) and then partitioned between water (15 mL) and EtOAc (15 mL).
The organic layer was separated and retained and the aq layer was extracted with EtOAc (2
x 15 mL). The ed organics were washed with brine (20 mL) and then dried and
evaporated in vacuo. The crude product so obtained was purified by flash column
chromatography (SiOz, 12 g, 0-100% EtOAc in isohexane, gradient elution) to afford a yellow
solid. This material was repurified by flash column chromatography (SiOz, 4 g, 0-10% EtOAc
in DCM, gradient elution) to afford the title compound, intermediate (XVI), as an off-white solid
(83 mg, 11%); R‘ 2.27 min (Method a); m/z 420 (M+H)+ (ES+); 1H NMR 6: 2.13 (3H, s), 3.13-
3.16 (4H, m), 3.42-3.45 (4H, m), 3.72 (3H, s), 6.77-6.88 (3H, m), 7.08 (2H, d), 7.17 (2H, t),
7.75-7.80 (2H, m), 7.89 (2H, d), 10.02 (1H, s).
N-(4-fluorophenyl)(4-(4-hydroxymethylphenyl)piperaziny|)benzamide.
BBI‘3 /—\ O
(XVI) —> Ho N NW
DCM 46F
(XV)
To a suspension of intermediate (XVI) (83 mg, 0.20 mmol) in DCM (5.0 mL) at 0°C was added
a solution of boron tribromide (0.59 mL, 1M in DCM, 0.59 mmol). The reaction mixture was
stirred at 0°C for 30 min, d to warm to RT for 8 hr and was then ioned between.
water (15 mL) and DCM (10 mL). The organic layer was separated and retained and the aq
layer was extracted with a mixture of DCM and MeOH (90:10, 5 x 15 mL). The ed
organics were dried and evaporated in vacuo to give a crude product which was purified by
flash column chromatography (SiOz, 4.0 g, 0-3% MeOH in DCM, gradient elution) to afford the
title nd, intermediate (XV), as a beige solid (61 mg, 72%); Rt 1.73 min (Method a); m/z
406 (M+H)+ (ES+); 1H NMR 6: 2.10 (3H, s), 3.08-3.11 (4H, m), 3.41-3.43 (4H, m), 6.67 (2H, br
s), 6.77 (1H, br s), 7.07 (2H, d), 7.17 (2H, t), 7.76-7.80 (2H, m), 7.89 (2H, d), 8.73 (1H, s),
10.01 (1H, s).
4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)tetrahydrofuran-
ethoxy)methylphenyl)piperaziny|)-N-(4-fluorophenyl)benzamide.
1. Preparation of Compound (I) from the Benzoic Acid ediate (ll).
OF /—N
( III ) REV
PO 0
(II) \ / QNWNG
EDCI, DMAP,
Pyridine
To a suspension of intermediate (II) (2.50 g, 4.24 mmol), EDCI (1.63 g, 8.48 mmol) and DMAP
(30 mg, 0.21 mmol) in pyridine (30 mL) was added 4-fluoroaniline (0.41 mL, 4.3 mmol) and
the reaction mixture heated at 60°C for 2 hr and then cooled to RT. Dilution of the mixture with
water (60 mL) and stirring for 5 min produced a solid, which was collected by filtration and
then washed with water (3 x 10 mL) and with diethyl ether (2 x 15 mL) to give a tan coloured
. The crude product so obtained was purified by flash column chromatography (SiOz,
40 g, 0-3% MeOH in DCM, gradient elution) to afford Compound (I) as a yellow solid (2.47 g,
85%); Rt 2.60 min (Method a); m/z 683 (M+H)+ (ES+); 1H NMR 6: 2.10 (3H, s), 2.15 (1H, dd),
2.37-2.43 (1H, m), 2.53-2.58 (1H, m), 3.13-3.16 (4H, m), 3.42-3.44 (4H, m), 3.68 (1H, dd),
3.74-3.79 (2H, m), 4.05 (1H, dd), 4.58 (2H, dd), 6.76 (2H, br s), 6.86 (1H, br s), 6.99 (1H, td),
7.08 (2H, d), 7.16 (2H, t), 7.25-7.35 (2H, m), 7.76-7.80 (3H, m), 7.89 (2H, d), 8.34 (1H, s) and
.00 (1H, s).
2. Preparation of nd (I) from the Phenol Intermediate (XV).
F’ : ‘F
(Ix) REVM<:\N/—l)\
(XV) —’ //N N\\// <0
NaOH, DMSO/H20 HN <\—/> F
To a solution of ediate (XV) (19 mg, 0.047 mmol) in DMSO (1.5 mL) was added aq
sodium hydroxide (1M, 98 uL, 0.098 mmol). The mixture was stirred at RT for 10 min and then
treated with a solution of tosylate (IX) (ex APlChem, Catalogue Number: AC-8330, 23.2 mg,
0.052 mmol) in DMSO (0.5 mL). The reaction mixture was stirred at 60°C for 2 hr, cooled to
RT and water (10 mL) was added. The resulting mixture was extracted with EtOAc (3 x 10
mL) and the combined organic extracts were dried and ated in vacuo to afford a brown
oil. The crude product so obtained was purified by flash column chromatography (SiOz, 4 g,
0-2% MeOH in DCM, gradient elution) to afford a beige solid (23 mg). The product was
fied by flash column chromatography (SiOz, 4.0 g, 0-50% EtOAc in DCM, gradient
n) to afford nd (I), as an off-white solid (14 mg, 42%); Rt 2.60 min (Method a);
m/z 683 (M+H)+ (ES+).
4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)tetrahydrofuran-
3-yl)methoxy)methylphenyl)piperaziny|)-N-(4-fluorophenyl-2,3,5,6-d4)benzamide.
Preparation of a Tetra-deuterio tive of Compound (I)
Fwwzl: N/_\N D
D D REV “it?“\ F
o / NW0”N 3% (ll)—> \
(I)4[2H1
To a suspension of intermediate (II) (200 mg, 0.34 mmol), EDCI (130 mg, 0.68 mmol) and
DMAP (2.1 mg, 0.02 mmol) in ne (1.5 mL) was added a solution of 4-fluoroaniline-
2,3,5,6-d4 (43 mg, 0.37 mmol) in pyridine (0.5 mL) and the reaction mixture heated at 60°C for
1 h. The reaction mixture was cooled to RT, diluted with water (10 mL) and stirred for 5 min,
which produced a precipitate. The solid was collected by filtration, washed with water (3 x 2.0
mL) and then taken up in a mixture of DCM and MeOH (9:1, 5.0 mL). The mixture was passed
through a phase separator and the organic solution was evaporated in vacuo to give a tan
coloured solid (200 mg). The crude product so obtained was purified twice by flash column
chromatography (SiOz, 12 g, 0-2% MeOH in DCM, gradient elution; SiOz, 40 g, 0-2.5% MeOH
in DCM, gradient elution) to afford an ite coloured .
The solid was suspended in DMSO (0.75 mL) and heated to 60°C for 5 min until dissolution
was complete. The resulting solution was cooled to RT and treated with water (1.0 mL) which
gave a precipitate. The suspension was stirred at RT for 20 min and the solid was collected
by filtration, rinsed with water (3 x 0.5 mL) and dried in vacuo at 50°C or three days) to afford
the title compound, (I) 4[2H] as a white solid (147 mg, 62%); Rt 2.59 min d 1a); m/z 687
(M+H)+ (ES+); 1H NMR 6: 2.10 (3H, s), 2.16 (1H, dd), .43 (1H, m), 2.52-2.60 (1H, m),
3.13-3.16 (4H, m), 3.42-3.44 (4H, m), 3.68 (1H, dd), .79 (2H, m), 4.05 (1H, dd), 4.58
(2H, dd), 6.76 (2H, br s), 6.86 (1H, br s), 7.00 (1H, td), 7.08 (2H, d), 7.25-7.35 (2H, m), 7.77
(1H, s), 7.89 (2H, d), 8.34 (1H, s) and 10.01 (1H, s).
Scale-up of the Preparation of nd (I) by Route 2
The synthetic methodology described above for Route 2, (Scheme 1), has been successfully
exploited to prepare the compound of the present invention on a scale of over 1.0 kg of API
(Scheme 3). Two variants of the methodology have been developed in which the 4-piperazinyl
benzoate [Intermediate (V|||)] comprises of either the ethyl ester (Vllla) or the corresponding
tert—butyl ester (Vlllb). Both of these compounds may be coupled with the tosylate (IX) to give
the corresponding ester precursors to the benzoic acid (II). In the case of the ethyl ester the
free acid is obtained by fication, whilst the tert—butyl derivative is de-esterified by
acidolysis. The ures adopted for this synthetic campaign are depicted below and are
described herein.
Scheme 3: Scale-up of the Synthesis of Compound (I).
H0®Br (XIVa) “'9
N‘ ‘N C02Ra > H0 N
\_/N4©7C02Ra
RuPhos G3, LiHMDS, DMF
(Xa); Ra =Et (Vllla,b)
(Xb); Ra=tBu
N//—NN
NaOEt, DMF
— (lVb); Ra: Et
KOH’
DMSO, H20 6 (ll); Ra = H <— Conc aq HCI,
(Ive); Ra = 1:3" _ IPA, H20
HMO/F NFN
HOBt, EDCI, DIPEA
Analytical and Spectroscopic Methods
The analytical and spectroscopic s pertaining to this experimental section are as set
out below.
Reverse Phase HPLC Conditions for LCMS Analysis:
XBridge BEH Phenyl 4.6 x 150 mm column; 2.5 pm (Ex. Waters #186006720) at 40°C; flow
rate 1.0 mL.min'1 eluted with a purified Hzo-MeCN gradient containing 0.1% formic acid over
min employing UV detection at 300 nm. Injection volume 5 uL. nt information: 0-2
min, held at 95% H20-5% MeCN; 2—15 min, ramped from 95% H20-5% MeCN to 10% H20-
90% MeCN; 15-25 min, held at 10% H20-90% MeCN.
1H NMR Spectroscopy:
1H NMR spectra were ted using a JOEL ECX 400MHz spectrometer. Residual
undeuterated solvent was used as reference and, unless specified otherwise, samples were
run in DMSO-ds.
Ethyl 4-(4-(4-hydroxymethylphenyl)piperaziny|)benzoate.
H0®Br Me
/—\ (XlVa) /—\
HN HO N
02Et —> \_/N®C02Et
R_uPhos G3,
(Xa) LIHMDS, DMF (Villa)
A solution of ethyl 4-(1-piperazinyl)benzoate (Xa) (500 g, 2.13 mol) and 4-bromomethyl
phenol (479 g, 2.56 mol) in anhydrous DMF (5.0 L) was degassed by placing the e
alternately under vacuum and then a nitrogen here three times.The mixture was then
treated with RuPhos G3 (35.7 g, 0.043 mol) and a on of LiHMDS (1 .0M in THF, 2560 mL,
2.56 mol) whilst maintaining the al temperature below 35°C (water bath cooling). A
solution of LiHMDS (1.0M in THF) was then added in fourteen equal portions at two min
intervals (14 x 213 mL, total 2.98 L, 2.98 mol) at 20-35°C. The resulting solution was stirred
at 18-25°C for 30 min after which analysis by HPLC indicated 0.6% of the ethyl 4-(1-
piperazinyl) benzoate remained the reaction was deemed complete.
The reaction mixture was adjusted to pH 7.6 by the addition of 2M hydrochloric acid (5.50 L)
whilst maintaining the temperature below 40°C, after which EtOAc (3.00 L) was added and
the resulting phases separated. The aq phase was extracted with EtOAc (2 x 3.00 L and then
2 x 2.00 L) and the combined organics were washed with sat brine (8 x 1.00 L), dried over
MgSO4 and then evaporated in vacuo to give a light brown oily solid. The crude product was
slurried in IPA (2.50 L) at 20-25°C for 30 min and the resulting solid was ted by filtration.
The filter cake was washed with IPA (2 x 500 mL) and pulled dry and the solids then dried
under vacuum at 50°C to provide the title compound, intermediate (Vllla), as a light tan solid
(380.0 g, 52%, HPLC purity ; Rt 11.01 min; m/z 341.3 (M+H)+ (ES+).
In order to control the level of palladium residues, the products from several batches were
combined (1900 g, residual Pd 108 ppm), taken up into THF (19.0 L) and treated with MP-
TMT resin (250 g) at 18-25°C. The mixture was stirred at this temperature for 24 hr and the
resin was then removed by filtration and washed with THF (3.49 L). The filtrate was evaporated
to dryness in vacuo and the resulting solid was slurried in IPA (4.75 L) at C for 1 hr and
collected by filtration. The filter cake was washed with IPA (500 mL), pulled dry and was then
dried in vacuo at 50°C to give the title compound, intermediate (Vllla), as an off-white solid
(1789 g, 94%, residual Pd 17 ppm).
Ethyl 4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)-tetrahydro
furanyl)methoxy)methylphenyl)piperazinyl)benzoate.
HO N N COzEt
(Vllla)
F'1'
(IX) NaOEt, ”\N
0 Me
0 N N COzEt
F F
( IVb)
To a solution of intermediate (Villa) (1780 g, 5.23 mol) in anhydrous DMF (17.8 L) at C
was added sodium ethoxide (391 g, 5.75 mol). After 45 min the tosylate (IX) (2586 g, 5.75
mol) was added in one portion and stirring was continued at C for 5 hr. Analysis by
HPLC indicated that the on was essentially complete (1.67% starting material remaining).
The mixture was cooled to 18-25°C and the resulting suspension was treated with water (18.0
L) whist ining the temperature below 30°C. After cooling to 15-25°C for 45 min the solid
was collected by filtration and washed with water (2 x 7.14 L). The damp filter cake was slurried
in ethanol (8.92 L) at reflux for 2 hr and the mixture was then cooled to 15-25°C and stirred
for 18 hr. The solids so ed were collected by filtration, washed with l (2 x 1.78 L)
and then dried in vacuo at 50°C to provide the title compound, intermediate as an off-
white solid (2855 g, 88%, HPLC purity 95.97%); Rt 14.99 min; m/z 618.5 (M+H)+ (ES+).
4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)-tetrahydrofuran
yl)methoxy)methylphenyl)piperazinyl)benzoic acid mono-hydrochloride.
N\ B
0 Me
00FM»<IVb> ; Ra: Et — (u); Ra : H DMSO, H20
F F
To a suspension of intermediate (lVb) (1467 g, 2.38 mol) in mixture of DMSO (1.45 L) and
water (5.90 L) at 18-25°C was added a 50% w/w solution of KOH in water (2.93 L). The
suspension was heated at 90-95°C for 18 hr after which time HPLC analysis indicated that the
reaction was complete (0.16% starting material remaining, 97.9% product). The reaction
mixture was cooled to 40-50°C and a mixture of IPA (14.9 L) and water (4.42 L) was added.
After cooling to 15-25°C, the pH was adjusted to 1-2 by the on of concentrated
hloric acid (3.12 L) whilst maintaining the internal temperature below 40°C. The
resulting suspension was cooled to 15-25°C and the solids were collected by filtration, pulled
dry and then slurried in water (7.40 L) at 90-95°C for 30 min. After cooling to 15-25°C, the
solids were collected by filtration, washed with water (2 x 1.48 L) and pulled dry. Further drying
in vacuo at 50°C yielded the title compound, intermediate (II), as a white solid (1329 g, 89%,
HPLC purity 99.0%; chlorine content: 6.61 w/w % [theory 5.66 w/w %]; Rt 12.92 min; m/z 590.4
(M+H)+ (ES+).
tert-Butyl 4-(4-(4-hydroxymethylphenyl)piperaziny|)benzoate.
:>%—Br Me
::>—cogBu (xwh) /—\
HN 44444444444» HO N
x_/ x_/N—<::>—co;Bu
RuPhos G3,
(Xb) LiHMDS, DMF (Vlllb)
A solution of utyl 4-(piperaziny|)benzoate (Xb) (100 g, 381 mmol) and 4-bromo
methylphenol (85.5 g, 457 mmol) in anhydrous DMF (1.00 L) was degassed by placing the
mixture alternately under vacuum and then a nitrogen atmosphere three times. Following this
procedure, RuPhos G3 (6.38 g, 7.62 mmol) was added at 15-25°C followed by a solution of
LiHMDS in THF (1.06 M, 432. mL, 457 mmol) over 5 min whilst maintaining the temperature
within 15-30°C, (water bath cooling). After stirring for 5 min additional aliquots of the solution
of LiHMDS (1.06 M in TH F) was added to the reaction mixture in en equal portions (14
x 36 mL, total 504 mL, 533 mmol) at 2 min intervals, resulting in an exotherm from 16°C-
he reaction was stirred at 15-25°C overnight (at which point HPLC showed the
formation of 72.% of the d product) and the pH of the mixture was adjusted to 7.3 by the
addition of 2M hydrochloric acid (~900 mL). The aq phase was ted and was extracted
repeadtedly with EtOAc (1.0 L, 500 mL and 2 x250 mL). The combined organics were washed
with brine (6 x 400 mL), dried over MgSO4 and concentrated in vacuo to give a sticky yellow
solid. The solid so obtained was suspended in IPA (500 mL) and was stirred at 15-25°C for 1
hr. The suspension was filtered and the filter cake was washed with IPA (250 mL, 200 mL)
and pulled dry. Further drying of the product in vacuo at 50°C provided the title compound,
intermediate (Vlllb) as an off-white solid (105.6 g, 75%, HPLC purity 97.1%); Rt 12.23 min;
m/z 369.3 (M+H)+ (ES+)
tert-Butyl 4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)—tetra
hydrofuranyl)methoxy)—3-methylphenyl)piperaziny|)benzoate.
’ ‘
HO N N C02 But
(vmb)
MTKN
0X) N
NaOEt
DMF 0 Me
’ ‘
o N N cmBut
F F
(We)
WO 87878
To a solution of intermediate (Vlllb) (100 g, 271 mmol) in DMF (500 mL) under a nitrogen
atmosphere was added sodium de (22.2 g, 325 mmol) resulting in a mild exotherm (from
to 220°C). After stirring at 15-25°C for 45 min the reaction mixture was treated with the
tosylate (IX) (146.4 g, 325 mmol) and was then heated at 60-65°C for 2 hr. Analysis of the
resulting mixture by HPLC indicated that the reaction was essentially complete (4.4% phenol
remaining, 14.6% tosylate, 77.6% product) and the mixture was cooled to 40-45°C and IPA
(800 mL) was added. Water was then added drop-wise at 40-45°C until a slight haze persisted
(required 500 mL) at which point a small sample of the product (100 mg, 0.15 mmol) was
added as a seed and the mixture stirred for 10 min at 40-45°C to ensure precipitation was
initiated. Water (500 mL) was added drop-wise at 40-45°C and the suspension then cooled to
-25°C. The resulting solid was collected by filtration, washed with water (3 x 200 mL) and
then dried in vacuo at 50°C give the crude product as an off-white solid (155.9 g, 89%, HPLC
purity 94.8%). A n of this material (85.0 g) was taken up in IPA (510 mL) by heating at
65-75°C until dissolution was te. The solution was then cooled to 15-25°C and stirred
for 30 min. The resulting solid was collected by filtration, washed with IPA (2 x 85 mL) and
dried in vacuo at 50°C to give the title compound, intermediate (IVc) as a white solid (83.4g,
87% overall yield, HPLC purity 98.2%); Rt 15.74 min; m/z 646.6 (M+H)+ (ES+)
4-(4-(4-(((3R,5R)((1H-1,2,4-triazoly|)methy|)(2,4-difluorophenyl)-tetrahydrofuran
y|)methoxy)methylphenyl)piperaziny|)benzoic acid mono-hydrochloride.
N//—N
— (IVc), Ra:
Conc aq HCI,
0 4» (u); Ra: H (HCI salt)
To a suspension of the tert—butyl te (IVc) (83.4 g, 129 mmol) in a mixture of water (250
mL) and IPA (417 mL) was added a solution of conc hydrochloric acid (167 mL) in water (167
mL) whilst maintaining the al temperature below 35°C. The resulting on was then
kept at 35°C for 24 hr (solid formation observed after 2-3 hr) at which point HPLC is
indicated the reaction was essentially complete (0.6% ester remaining, 98.1% product) The
mixture was cooled to 15-25°C, IPA (417 mL) was added and the pH was adjusted ~10 by the
addition of aq NaOH (10 M, 200 mL) at <40°C to give a solution. The pH was then re-adjusted
to 1-2 by the on of conc hydrochloric acid (25 mL) at <40°C. The resulting suspension
was cooled to 15-25°C and the solids were collected by filtration. The filter cake was
resuspended in water (834 mL), heated to C and then stirred for 30 min. The
suspension was then cooled to 15-25°C and the solids collected by filtration, washed with
water (2 x 83 mL) and dried in vacuo at 50°C to provide the title compound, intermediate (II),
(as the mono-hydrochloride salt) as a white solid (64.6 g, 80%, HPLC purity 97.6%); Rt 12.92
min; m/z 590.4 (M+H)+ (E9).
C:\Interwoven\NRPortbl\DCC\BAS\19270341_1.docx-04/09/2019
4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4-difluorophenyl)-tetrahydrofuran
methoxy)methylphenyl)piperazinyl)-N-(4-fluorophenyl)benzamide.
To a stirred suspension of the benzoic acid (II) as its mono-hydrochloride salt (1001 g, 1.60
mol) and HOBt.H2O (216. g, 1.41 mol) in DMF (5020 mL) at <40°C was added DIPEA (840
mL, 4.823 mol) followed by 4-fluoroaniline (181 mL, 1.91 mol) and then EDCI.HCl (368 g, 1.92
mol). The mixture was heated at 60-65°C for 17 hr at which time analysis by HPLC indicated
the reaction was te (no starting material or reaction intermediate detected, 82.63%
product). The resulting solution was cooled to 15-25°C and was quenched with water (15.2 L)
at <35°C, then cooled again to 15-25°C and stirred for 1 hr. The resulting solid was ted
by filtration, washed with water (2 x 2.00 L) and pulled dry. The filter cake was re-slurried in
water (5.00 L) at 15-25°C for 45 min and the solids were collected by filtration, washed with
water (2 x 2.00 L) and dried in vacuo to afford the title compound, Compound (I), as an offwhite
solid (1101 g, ~100%, HPLC purity 95.8%); Rt 14.46 min; m/z 683.5 (M+H)+ (ES+); 1H
NMR δ: 2.10 (3H, s), 2.16 (1H, dd), 2.37-2.43 (1H, m), 2.50-2.58 (1H, m), 3.13-3.15 (4H, m),
3.41-3.44 (4H, m), 3.67 (1H, dd), 3.74-3.78 (2H, m), 4.05 (1H, t), 4.55 (1H, d), 4.61 (1H, d),
6.76 (2H, s), 6.86 (1H, s), 7.00 (1H, d,t), 7.08 (2H, d), 7.17 (2H, t), .35 (2H, m), 7.76-
7.80 (2H, m), 7.77 (1H, s), 7.89 (2H, d), 8.35 (1H, s) and 10.02 (1H. S).
Biological Testing: Experimental s
Assessment of planktonic fungus growth
a. Resazurin-microtitre assay
This assay was conducted using a modified, published method (Monteiro et al., 2012). Spores
of illus fumigatus (NCPF2010, Public Health England, Wiltshire) were cultured in
Sabouraud dextrose agar for 3 days. A stock spore suspension was ed from a
Sabouraud dextrose agar culture by washing with PBS-tween (10 mL; PBS containing 0.05%
Tween-20, 100 U/mL Penicillin and 100 U/mL Streptomycin). The spore count was assessed
using a Neubauer haemocytometer and, using PBS, adjusted to 106 spores/mL. A working
suspension of spores (104 spores/mL) was prepared in filter sterilised MOPS RPMI-1640 (50
mL; RPMI-1640 containing 2 mM amine, 2% glucose and 0.165 M MOPS, buffered to
pH 7 with NaOH). rin sodium salt (100 µL of 1% solution; Sigma-Aldrich, Dorset, UK)
was added to the spore suspension and mixed well. The spore suspension-resazurin mixture
(100 uL/well) was added to 384-well plates (Catalogue number 353962, BD Falcon, Oxford,
UK). Simultaneously, test nds (0.5 uL DMSO solution) were added to 100 uL of the
spore-resazurin mixture in quadruplicate to provide a final DMSO solution of 0.5% using an
lntegra VlAFLO 96 (lntergra, Zizers, Switzerland). For non-spore control wells, MOPS-RPMI-
resazurin solution (100 uL) was added instead of the spore-resazurin mixture. The plate was
covered with a Breathe Easier membrane (Catalogue No Z763624, Sigma-Aldrich, Dorset,
UK), and incubated (35°C, 5% C02) until fluorescence in the inoculated wells was double that
of the control wells (around 24 hr). The fluorescence of each well (545 nm (excitation) / 590
nm (emission), gain 800, focal height 5.5mm) was determined using a scanner
(Clariostar: BMG, Buckinghamshire, UK). The tage inhibition for each well was
calculated and the MIC50, M|C75 and MIC90 values were calculated from the concentration-
se curve generated for each test compound.
b. Broth microdilution assay
This assay was conducted using a modified method published by EUCAST (Rodriguez-
Tudela et al., 2008). Spores of Aspergi/Ius tus (NCPF2010, NCPF7010 (Methionine
220 mutation), 99 ne G54 mutation) from Public Health England, Wiltshire;
TR34/L98H mutants from St Louis Hospital, Paris, France) were cultured in Sabouraud
dextrose agar for 3 days. A stock spore suspension was prepared from a Sabouraud dextrose
agar culture by washing with een (10 mL; PBS containing 0.05% Tween-20, 100 U/mL
llin and 100 U/mL Streptomycin). The spore count was assessed using a Neubauer
haemocytometer and then adjusted to ‘106 /mL with PBS. A working suspension of
spores (2 x ‘105 spores/mL) was prepared in filter sterilised, BSA MOPS RPMl-1640 (50 mL;
RPMl-1640 containing 2 mM L-glutamine, 0.5% BSA, 2% glucose, 0.165 M MOPS, buffered
to pH 7 with NaOH). Forthe assay, BSA MOPS RPMl-1640 (50 uL/well) was added throughout
the 384-well plate (Catalogue number 353962, BD Falcon, Oxford, UK) first. Test compounds
(0.5 uL DMSO solution) were then added in quadruplicate using an a VlAFLO 96 (lntegra,
Zizers, Switzerland), and mixed well using a plate mixer. Subsequently 50 uL of the working
spore suspension prepared above was added to all wells except non-spore control wells. For
non-spore control wells, BSA PMI on (50 uL/well) was added d. The plate
was covered with a plastic lid, and incubated (35°C with ambient air) for 48 hr. The OD of each
well at 530 nm was determined using a multi-scanner (Clariostar: BMG, Buckinghamshire,
UK). The percentage inhibition for each well was calculated and the MIC50, M|C75 and MIC90
values were calculated from the concentration-response curve generated for each test
Fungus panel screening was conducted by Eurofins Panlabs Inc. The MIC and M|C5o values
40 of the test articles were ined following the guidelines of the Clinical and Laboratory
Standards Institute, broth microdilution methods for yeast (CLSl M27-A2), (CLSI, 2002) and
for filamentous fungi (CLSl M38-A), (CLSI, 2008).
Aspergillus fumigatus infection of ial epithelial cells
BEAS2B cells were seeded in 96-well plates (100 uL; 30,000 cells /we|l; Catalogue No 3596,
Sigma Aldrich, Dorset, UK) in 10% FBS RPMl-1640 and were then incubated (37°C, 5% CO2)
for one day before experimentation. Test compounds (0.5 uL DMSO on) or vehicle
(DMSO) were added to each well to give a final DMSO concentration of 0.5%. BEAS2B cells
were incubated with test compounds for 1 hr (35°C, 5% C02) before infection with Aspergillus
fumigatus (20 uL; Public Health d) conidia suspension (0.5x105 /ml in 10% FBS RPMI-
1640). The plate was incubated for 24 hr (35°C, 5% C02). Supernatant (50 uL) was collected
and transferred to a PCR plate (Catalogue No L1402-9700, Starlab, Milton Keynes, UK), which
was frozen ) until use. After thawing, supernatant (5 uL) was d 1:20 by adding R7-
PBS solution (95 uL; 1:4 R7 to PBS; Bio-Rad Laboratories, Redmond, WA, USA). GM levels
in these samples (50 uL) were measured using Platelia GM-EIA kits ad Laboratories,
Redmond, WA, USA). The tage inhibition for each well was calculated and the |C5o
value was calculated from the concentration-response curve generated for each test
compound.
Aspergillus fumigatus infection of human alveoli bilayers
In vitro models of human alveoli, consisting of a bilayer of human alveolar lial cells and
endothelial cells, were ed as usly described (Hope et al., 2007). This system
allows administration of a test nd to the upper (“air” space) and/or lower (“systemic”
space) compartments. This flexibility has been exploited to explore the effects of combination
treatments by dosing Compound (I) to the upper chamber and posaconazole or other anti-
fungal agents to the lower chamber. Primary human pulmonary artery endothelial cells
(HPAEC) were harvested and diluted to 106 cells/mL in EGM-2 media (Lonza, Basel,
Switzerland). Transwells were inverted and the cell suspension (100 uL/well) was applied to
the base of each transwell. The inverted transwells were incubated at RT within a flow hood
for 2 hr after which they were turned upright. EGM-2 media was added to the lower (700
uL/well) and upper (100 uL/well) compartments and the transwells were incubated for 48 hr
(37°C, 5% C02). The EGM-2 media in the lower compartment was then replaced with fresh
EGM-2 media. A549 cells were ted and diluted to 5x105 cells/mL in 10% EBM, then
added to the upper compartment (100 l) of all transwells and the plates incubated for
72 hr (37°C, 5% C02). Conidia of Aspergillus fumigatus (the itraconazole sensitive strain
NCPF2010 and the itraconazole resistant strain TR34-L98H) were cultured separately in
Sabouraud dextrose agar for 3 days. A stock conidia suspension of either strain was prepared
from a Sabouraud dextrose agar culture by washing with PBS-tween (10 mL; PBS containing
0.05% Tween-20, 100 U/mL Penicillin and 100 U/mL Streptomycin). The conidia count was
assessed using a Neubauer haemocytometer and ed to 106 conidia/mL with PBS. A
40 working stock of conidia was prepared in EBM (cone of 105 conidia/mL) immediately prior to
use.
Test and nce compounds (or neat DMSO as the vehicle) were added to the appropriate
wells of 24-well plates (3 uL/well ning 600 uL of 2% FBS EBM) for lower compartment
2015/053731
treatment and to 96-well plates (1 uL/well ning 200 uL of 2% FBS EBM) for the ent
of the upper tment, to provide a final DMSO concentration of 0.5%. The media in the
upper compartment was aspirated and that containing the riate test and reference
compounds, or vehicle, were added (100 uL/well). Transwells were then transferred into the
24-well plate containing the test and reference compounds or DMSO vehicle. After tion
for 1 hr (35°C, 5% C02) the conidia suspension (10 uL/well) was added to the upper
compartment of each transwell. Plates were then incubated for 24 hr (35°C, 5% C02).
Supernatants from each compartment (5 uL/compartment) were collected and stored (-20°C).
Media was replaced daily after collection of the supernatants and all wells were treated with
test and reference compounds or with DMSO, as described above, for 3 days. Samples
continued to be collected until fungal growth was visible by eye in all transwells. The levels of
GM in the supernatant in lower compartment were then measured by ELISA (BioRad, CA,
USA) as an index of Aspergillus fumigatus invasion.
Cell Viability: Resazurin Assay
BEAS2B cells were seeded in 384-well plates (100 uL; 3000 / well /; BD Falcon, Catalogue
No 353962) in RPMl-LHC8 (RPMl-1640 and LHC8 media combined in equal proportions) one
day before experimentation. For cell-free control wells, RPMl-LHC8 (100 uL) was added. Test
compounds (0.5 uL of a DMSO solution) were added to give a final DMSO tration of
0.5% using an lntegra VIAFLO 96 (lntegra, Zizers, rland). BEAS2B cells were incubated
with each test compound for 1 day (37°C / 5% COzin RPMl-LHC8). After addition of resazurin
stock solution (5 uL, 0.04%) the plates were incubated for a further 4 hr (37°C / 5% C02). The
fluorescence of each well at 545 nm (excitation) and 590 nm (emission) was determined using
a multi-scanner (Clariostar: BMG Labtech). The percentage loss of cell viability was calculated
for each well relative to vehicle (0.5% DMSO) treatment. Where appropriate, a CC5o value was
ated from the concentration-response curve ted from the concentration-response
curve for each test compound.
In Vivo Anti-fungal Activity
Aspergillus fumigatus (ATCC 13073 [strain: NIH 5233], American Type Culture Collection,
Manassas, VA, USA) was grown on Malt agar (Nissui Pharmaceutical, Tokyo, Japan) plates
for 6—7 days at RT (24 1r 1°C). Spores were aseptically dislodged from the agar plates and
suspended in sterile distilled water with 0.05% Tween 80 and 0.1% agar. On the day of
infection, spore counts were assessed by haemocytometer and the inoculum was adjusted to
obtain a concentration of 1.67 x 108 spores mL'1 of physiological saline.
To induce immunosuppression and penia, A/J mice (males, 5 weeks old) were dosed
40 with hydrocortisone (Sigma H4881; 125 mg/kg, sc,) on days 3, 2 and 1 before infection, and
with cyclophosphamide (Sigma C0768; 250 mg/kg, ip) 2 days before ion. On day 0,
animals were infected with the spore suspension (35 uL intra-nasally).
Test nds were administered intra-nasally (35 uL of a suspension of 0.08-2.00 mg/mL
45 in physiological saline) once daily, 30 min before infection on day 0 and then on days 1, 2 and
3 (representing prophylactic treatment) or on days 1, 2 and 3 only senting therapeutic
treatment). For extended prophylactic treatment, test compounds (35 uL of a suspension of
0.0032 or 0.016 mg/mL in physiological saline) were administered nasally once daily for
seven days; then 30 min before infection on day 0, and thereafter, either on days 1, 2 and 3
after infection, or on day 0 only. The effects of these treatment paradigms were compared with
those obtained when treatment was restricted to one day and 30 min before inoculation and
then on days 1, 2 and 3 post infection; or reduced still further to one day and 30 min before
infection only. Animal body s were monitored daily and those exhibiting a reduction
220%, compared with their body weight on day 0, were culled.
Six hours after the last dose, animals were etised, the a was cannulated and
BALF was collected. The total number of alveolar cells was determined using a
haemocytometer, and the numbers of alveolar macrophages and neutrophils were determined
by FACS analysis (EPICS® ALTRA ll, Beckman Coulter, lnc., Fullerton, CA, USA) using anti-
mouse MOMA2-FITC (macrophage) or anti-mouse 7/4 (neutrophil), respectively, as previously
reported (Kimura et a/., 2013). The levels of lFN-y and lL-17 in BALF, and lL-6 and TNFo in
serum were determined using Quantikine® mouse lFN-y, lL-17, lL-6 or TNF-d ELISA kit (R&D
systems, Inc, Minneapolis, MN, USA) respectively. MDA, an ive stress marker, was
assayed using OxiSelect® TBARS Assay Kits (MDA Quantitation; Cell Biolabs Inc, San Diego,
CA, USA). Aspergillus GM in serum was determination using Platelia GM-EIA kits (Bio-Rad
Laboratories, Redmond, WA, USA). Cut-off index was calculated by the a: Cut-off index
= OD in sample / OD in cut-off control provided in kit. For tissue fungal load assays, 100 mg
of lung tissue was removed aseptically and homogenized in 0.2 mL of 0.1% agar in sterile
distilled water. Serially diluted lung homogenates were plated on Malt agar plates (50 uL/plate),
and ted at 24i1°C for 72 to 96 h. The colonies of A. fumigatus on each plate was
counted and the fungal titre presented as CFU per gram of lung tissue.
Severely immunosuppressed, neutropenic A/J mice (males, 5 weeks old), which had been
dosed with hydrocortisone (Sigma H4881; 125 mg/kg, sc,) daily for three days before infection
and with cyclophosphamide (Sigma C0768; 250 mg/kg, ip) two days before ion were
used to evaluate the s of the combined treatment of Compound (I) administered
intranasally and posaconazole dosed orally. On day 0, s were infected intranasally with
uL of the spore suspension (1.67 x 108 spores/mL in logical saline) of Aspergillus
fumigatus (ATCC 13073 [strain: NIH . Compound (I) prepared as a suspension in
isotonic saline (0.4 mg/mL) was dosed once daily by an intra-nasal injection (35 uL/mouse)
on days 1-6 after infection. Posaconazole (1 mg/kg) was given orally once daily on days 1-6
after infection. Body weight and survival were monitored daily up to day 7.
y of Screening Results
Compound (I) demonstrates potent inhibitory activity against both azole sensitive Aspergillus
fumigatus fungal growth, as evaluated by the resazurin assay, and fungal infection of bronchial
epithelial cells (Table 2). In these assay s Compound (I) showed significantly greater
potency than nazole and amphotericin B, and similar potency to posaconazole.
Incubation with Compound (I) had no or little effect on the viability of BEAS2B bronchial
epithelial cells at concentrations up to, at least, 10 uM.
Table 2 The effects of treatment with Voriconazole, Posaconazole, ericin B and
Compound (I) on Aspergi/lus fumigatus (NCPF2010) planktonic fungal growth, on fungal
infection of BEAS2B ial epithelial cells and on BEAS2B cell viability.
Mlcso I MIC75 I CC50 Values in assay system indicated (nM)
Planktonic fungal Infection of BEASZB
Treatment growth1 BEAS2B cells2 Cell Viability3
(Test Compound)
MIC50 MIC75 MIC50 CC50
Voriconazole 90.8 168 154 >28600
Posaconazole 3.64 6.94 4.48 >14300
Amphotericin B 28.5 64.4 nt 977
Compound (I) 1.98 5.02 5.43 >12200
Compound (l).4[2H] nt nt 3.15 >14600
Table Footnotes: 1. Resazurin-microtitre assay; 2. Bronchial lial cells; 3. n = 1-5;
Compound (I) also exhibits potent inhibitory activity against onic fungal growth as
evaluated in a broth microdilution assay (Table 3). In this assay, Compound (I) showed
significantly greater potency versus both posaconazole-resistant strains (NCPF7099,
NCPF7100 and TR34/L98H) and a posaconazole-sensitive strain (NCPF2010) than
posaconazole, voriconazole and Amphotericin B.
Table 3 The Effects of ent with Voriconazole, Posaconazole, Amphotericin B and
Compound (I) on planktonic fungal growth of es of Aspergi/lus fumigatus.
MIC75 Values (nM)
Treatment t the indicted Aspergillus fumigatus isolates1
(Test nd)
NCPF2010 NCPF7099 NCPF7100 L98H
Voriconazole 496 96.7 596 >2860
Posaconazole 15.3 112 71.5 150
Amphotericin B 382 365 >1080 209
Compound (I) 13.6 16.5 19.7 56.7
Compound (l).4[2H] 14.7 13.7 28.6 70.0
Table tes: 1. Broth microdilution assay, n =1-3
The s of Compound (I) on the growth of wide range of fungal pathogens were ted
using the CLSI broth microdilution methods. Compound (I) was found to be a potent inhibitor
of the growth of Rhizopus oryzae, Cryptococcus neoformans, Chaectomimum globosum,
Penicillium chrysogenum and Trichophyton rubrum as well as some Candida Spp (Table 4).
Table 4 The effects of Compound (I) on the growth of a range of fungi species.
Compound (I) Voriconazole Posaconazole
Fungal Mleo MlC1oo Mleo M|C1oo Mleo M|C1oo
Strain_
Agent (Hg/mL) (Hg/mL) (Hg/mL)
Aspergi/lus
ATCC204304 1.0 >8.0 1.0 2.0 0.063 0.13
flavus
Aspergi/lus
ATCC9348 >80 >80 >80 >80 0.25 1.0
pul/u/ans
20240.04? 0.031 >8.0 0.031 >8.0 0.031 >8.0
ATCC10231 0.13 >8.0 0.25 >8.0 0.13 >8.0
Candida_
albicans
20183.073 0.5 >8.0 4.0 >8.0 0.25 >8.0
20186.025 >80 >80 >8 0 >8 0 >8 0 >8 0
ATCC36583 0.5 >8.0 0.25 >8 0 0.5 >8.0
Candida_
glabrata
R363 0.5 >8.0 >8 0 >8 0 0.5 >8.0
Rhizooryzgeus
ATCC11145 0.063 2.0 8.0 >8.0 0.13 >8.0
forman:tococc s
ATCC24067 0.008 1.0 0.016 1.0 0.016 0.25
mium
ATCC44699 0.063 >8.0 0.5 1.0 0.13 0.25
globosum
Penicillium
ATCC9480 0.031 >8.0 1.0 2.0 0.063 0.13
chrysogenum
Trichophyton
218 <0.008 0.031 <0.008 0.063 <0.008 0.031
rubrum
Table footnotes: MICso/ M|C1oo = concentration required for 50% and 100% tion of fungal growth
by visual inspection (CLSI).
Monotherapy with either Compound (I) (0.1 ug/mL in the upper chamber) or posaconazole
(0.01 ug/mL in the lower chamber) inhibited GM production on day 1 in human alveoli bilayers.
However, the inhibitory effects of these treatments were lost rapidly thereafter (Table 5). In
contrast, combination treatment of Compound (I) with posaconazole showed sustained
inhibition of invasion post infection. Consequently, the DFB5o for the combination treatment
was 5.48 days, much longer than the values for either compound alone. This synergistic or
additive effect of combination therapy was also confirmed when treatment with Compound (I)
was combined with that of onazole, voriconazole or caspofungin (results not shown).
Table 5 Effects of Compound (I), Posaconazole and the ent combination on Aspergi/Ius
fumigatus (NCPF2010) invasion into the lower r in human alveoli bilayers (transwells).
GM Levels in the Lower Chamber for Treatments Indicated
OD value (% inhibition vs.control)l
Treatment nd (I)1 Posaconazole2 Combination
Vehicle
Day Upper Chamber Lower Chamber Treatment
0 0 0 0 0
1 0.68 0.091 (86) 0.064 (91) 0.007 (99)
2 1.19 1.15 (3.4) 1.01 (15) 0.011 (99)
3 1.19 1.14 (3.7) 1.14 (4.1) 0.025 (98)
4 1.18 1.13 (4.5) 1.17 (1.1) 0.11 (91)
1.18 1.18 (0.3) 1.18 (-0.6) 0.42 (64)
6 1.18 1.18 (-0.3) 1.19 (-1.1) 0.73 (38)
7 1.18 1.16 (0.9) 1.17 (0.3) 1.15 (2.0)
8 1.16 1.13(2.8) 1.15(0.8) 1.12(3.7)
DFBso Values for
1'13 1-45 5.48
treatments indicated
Table footnotes: 1. Dosed at 0.1 ug/mL; 2. Dosed at 0.01 ug/mL; DFBso: Days taken to reach a fungal
burden of 50% of control
In on, this combination treatment has been tested in bilayers ed with the azole
resistant strain of Aspergi/Ius fumigatus: TR34-L98H. (Table 6) Monotherapy with Compound
(I) (1 ug/mL) in the upper chamber or with posaconazole (0.1 ug/mL) in the lower chamber
showed limited benefit. In st, the combination of Compound (I) and posaconazole
showed marked tory effects on fungal invasion into the lower chamber. The beneficial
effect of the combination treatment was observed on day 1 post infection, but disappeared
after day 2.
Table 6 Effects of nd (I), Posaconazole and the treatment combination on Aspergi/lus
fumigatus (TR34-L98H strain) invasion into the lower chamber in the alveolar bilayer cell
system (transwells).
GM Levels in the Lower Chamber for Treatments Indicated
OD value (% inhibition vs.control)l
Compound (I)1 Posaconazole2 Combination
Treatment Day
Upper r Lower Chamber Treatment
0 0 0 0
1 0.35 0.039 (88) 0.013 (96)
2 0.99 1.02 (-2.7) 0.082 (92)
3 0.99 0.97 (1.7) 0.54 (45)
4 1.01 1.02 (-1.4) 1.09 (-8.8)
DFB“ va'ues f°r
1.10 1.64 2.93
treatments indicated
Table footnotes: 1. Dosed at 1 ug/mL; 2. Dosed at 0.1 ug/mL; DFBso: Days taken to reach a fungal
burden of 50% of control
When given intranasally to immunocompromised, neutropenic mice, on days 0 and 1-3
following innoculation (Prophylactic Treatment) in a head-to-head comparison, nd (I)
showed superior s to posaconazole on reducing body weight loss, measured over 3 days,
caused by infection with Aspergi/lus fumigatus. (Table 7).
Table 7: Comparison of the Effects of Treatment with Compound (I) and Posaconazole on the
body weight loss of compromised, neutropenic mice caused by infection with
Aspergi/lus fumigatus.
Body weight loss caused by ion with A. fumigatus2
Drug (% Inhibition of weight loss)
Treatment1
Day 1 Day 2 Day 3
Vehicle plus Spores 9.2 1r 1.5 14.3 1r 1.9 19.3 1r 1.4
Posaconazole 7.3 1r 2.0 (21) 13.4 1r 1.9 (6) 18.1 1r 2.0 (6)
Compound (I) 6.1 1r 1.8 (34) 8.7: 2.5 (39) 11.1 1r 5.6 (42)
Table footnotes: 1. Dosed at 0.4 mg/mL intra-nasally; 2. % weight loss compared with animal weight
on day 0.
Furthermore, prophylactic and therapeutic treatment with Compound (I), showed superior
effects to posaconazole on fungal load in the lung, as well as on GM trations in both
BALF and serum, post infection. The data for Compound (I) used in prophylactic and
therapeutic dosing regimens are shown in Table 8 and Figs. 1, 2 and 3 (lD5o values presented
in Table 9).
Table 8: The Effects of Prophylactic and Therapeutic Treatment with Compound (I) on CFU
in lung and galactomannan concentrations in BALF and serum in i/Ius fumigatus
infected, immuno-compromised, neutropenic mice.
% Inhibition of response
Drug
Treatment
Conc
Regimen CFU GM in BALF GM in serum
(mglmL)
(lmg of lung) (COI) (COI)
veh'c'e +
None 28.4 i 16.9 4.8 i 0.40 5.3 i 1.1
Spores
0.08 15.2 1r 13.7 (46) 0.70 1r 0.39 (85) 0.81 1r 0.52 (85)
Compound (I):
lactic 0.4 2.1 1r 1.6 (93) 0.37 1r 0.46 (92) 0.24 1r 0.18 (95)
Treatment
2 0.8 1r 0.7 (97) 0.13 1r 0.02 (97) 0.18 1r 0.07 (97)
0.4 3.8 1r 1.0 (87) 0.24 1r 0.06 (95) 0.29 1r 0.11 (95)
Compound (I):
Therapeutic 2 1.9 1r 1.7 (93) 0.22 1r 0.14 (95) 0.25 1r 0.19 (95)
Treatment
0.5 1r 0.3 (98) 0.11 1r 0.05 (98) 0.24 1r 0.11 (95)
Table footnotes: The data for fungal load are shown as the mean i standard error ofthe mean (SEM;
n = 5-6).
Table 9: |D5o values for Prophylactic Treatment with Posaconazole and nd (I) on
fungal load in the lung and on galactomannan concentrations in BALF and in serum, in
Aspergi/Ius fumigatus infected, immuno-compromised, neutropenic mice.
Drug substance IDso Values for response indicated (mglmL)
ylactic
Regimen) Lung Fungal Load GM in BALF GM in serum
Compound (I) 0.086 <0.08 <0.08
Posaconazole 0.24 1.3 0.47
Prophylactic treatment with Compound (I), inhibited inflammatory cell accumulation in BALF
(Table 10), in a similar fashion to posaconazole. In addition, prophylactic treatment with
Compound (I) showed superior inhibitory effects to posaconazole versus lL-17, lFNy and MDA
trations in BALF, and the comparative |D5o values for Compound (I) and for
posaconazole in ndent experiments are displayed in Table 11.
Table 10: The Effects of Prophylactic and eutic Treatment with Compound (I) on
macrophage and neutrophil accumulation into the BALF of Aspergi/Ius fumigatus infected,
immunocompromised, neutropenic mice.
Cell numbers in BAL L
Drug Conc
Treatment (% inhibition)
(mglmL)
Macrophage Neutrophil
Vehicle + Spores 0.65 1r 0.14 0.49 1r 0.09
0.08 0.40 1r 0.15 (38) 0.37 1r 0.04 (24)
Compound (I)
Prophylactic 0.4 0.32 1r 0.07 (51) 0.26 1r 0.12 (47)
Treatment
2 0.26 1r 0.05 (60) 0.22 1r 0.04 (55)
0.4 0.43 1r 0.05 (34) 0.38 1r 0.04 (22)
nd (I)
Therapeutic 2 0.40 1r 0.11 (38) 0.34 1r 0.05 (31)
Treatment
0.32 1r 0.07 (51) 0.27 1r 0.08 (45)
Table footnotes: The data for cell number are shown as the mean i standard error of the mean (SEM),
N = 5-6.
Table 11: |D5o values for Prophylactic Treatment with Posaconazole and Compound (I) on IL-
17, lFNy and MDA levels in BALF in Aspergi/Ius fumigatus infected, immuno-compromised,
neutropenic mice.
Drug substance IDso Values for biomarkers indicated (mglmL)
(Prophylactic
Regimen) lL-17 lFNy MDA
nd (I) 0.074 <0.08 0.11
Posaconazole 0.61 0.22 0.69
rmore, data showing the effects of Compound (I) on lFNv, lL-17 and MDA levels in the
BALF, when administered either prophylactically or therapeutically, are shown in Table 12 and
the effects on serum, lL-6 and TNFd are shown in Table 13.
Table 12: The Effects of Prophylactic and Therapeutic Treatment with Compound (I) on lFNv,
lL-17 and MDA levels in the BALF of Aspergi/Ius fumigatus infected, compromised,
neutropenic mice.
Biomarker Concentrations in BALF
(% Inhibition)
Treatment Drug Conc
Regime" e lFNy lL-17 MDA
(pglmL) (pglmL) (uglmL)
Vehicle + Spores 9.2 1r 1.0 19.8 1r 3.6 1.8 1r 0.2
0.08 3.7 i 1.7 (60) 9.8 i 5.3 (51) 0.96 i 0.32 (47)
C°mp°”"d.(') 0.4 3.0 i 0.8 (67) 6.7: 4.9 (66) 0.57 i 0.22 (68)
prophylactic
2 2.5 i 0.3 (73) 3.2 i 0.8 (84) 0.34 i 0.05 (81)
0.4 4.3 i 2.2 (53) 8.5 i 2.9 (57) 0.45 i 0.10 (75)
C°mp°”"d. (D 2 3.3 i 0.8 (64) 4.0 i 0.8 (80) 0.37 i 0.10 (79)
therapeutic
2.1 i 0.3 (77) 2.9 i 0.7 (85) 0.25 i 0.05 (86)
Table tes: The data for biomarker concentrations are shown as the mean i standard error of
the mean (SEM), N = 5-6.
Table 13: The Effects of Prophylactic and Therapeutic Treatment with Compound (I) on lL-6
and TNFd levels in the serum of i/Ius fumigatus infected, immunocompromised,
neutropenic mice
Conc of Biomarkers )
Treatment Drug Conc (% Inhibition)
Regimen (mglmL)
lL-6 TNF01
Vehicle + Spores 284 1r 112 25.6 1r 8.0
0.08 159 1r 73.3 (44) 11.8 1r 5.9 (54)
Compound (I)
Prophylactic 0.4 86.3 1r 46.9 (70) 7.3 1r 3.5 (71)
Treatment
2 44.5 1r 12.2 (84) 4.7 1r 0.4 (82)
0.4 51.7 1r 16.8 (82) 6.2 1r 0.5 (76)
Compound (I)
Therapeutic 2 44.2 1r 11.4 (84) 5.5 1r 0.7 (79)
Treatment
35.9 1r 10.4 (87) 4.9 1r 0.6 (81)
Table footnotes: The data for biomarker concentrations are shown as the mean i standard error of
the mean (SEM), N = 5-6.
Therapeutic treatment with Compound (I) was also found to maintain potent tion of lung
fungal load, serum galactomannan levels and on BALF cytokine concentrations in Aspergi/lus
fumigatus infected, immunocompromised, neutropenic mice. (Tables 7, 8 9 and 10 and Figs.
1, 2 and 3).
The effects of extended prophylactic dosing with Compound (I) on biomarkers in Aspergi/lus
fumigatus infected, immuno-compromised, neutropenic mice were also ted. Extended
prophylaxis with Compound (I) was found to inhibit fungal load in the lung, as well as the GM
concentrations in both BALF and serum, at 25 fold lower doses than those used in a us
biomarker study (Table 14). Furthermore, the data suggest an accumulation of anti-fungal
effects in the lung on repeat dosing since seven days of prophylaxis produced r anti-
fungal effects than did prophylactic treatment for a single added day. The compounds
persistence of action in the lung is suggested by the finding that treatment on days -7 to day
0 generated superior anti-fungal effects on day 3 than those resulting from treatment on days
-1 and 0, only. Nevertheless this abbreviated dosing protocol was still protective
Table 14 Effects of extended prophylactic dosing of Compound (I) on fungal load (CFU) in
lung and GM concentrations in BALF and serum in Aspergi/lus fumigatus infected, immunocompromised
, neutropenic mice.
ent Dose of Values and % Inhibition of response3
Reg'me"' 1 C°m|°°und “I CFU GM in BALF GM in Serum
(Days d°sed) (”9’le
(Img of lung) (COI) (COI)
Vehicle plus
Sporesz None 3475107 51:09 43:10
-7 to +3 3.2 8.3:2.0 (78) 2.6iO.36 (49) 43 (58)
-1 to +3 3.2 95:33 (73) 2.8:071 (45) 2.2:069 (49)
-7 to +3 18 50:23 (88) 1.75039 (87) 1.45020 (87)
-1 to +3 18 6.1:2.8 (82) 1 (57) 41 (83)
-7 to o 18 6.7:17 (81) 23:052 (55) 1.75059 (80)
-1, o 18 13.1:26 (82) 4.54.050 (12) 4.0:0.88 (7)
Table footnotes: 1. The N value was six for all drug treated groups; 2. The N value was five for the
vehicle treated group; 3. The data for fungal load and GM levels are shown as the mean i standard
error ofthe mean and the percentage inhibition, with respect to vehicle.
The influence on survival of combining the treatments of nd (I), dosed lly, with
oral Posaconazole, was ted in severely immuno-compromised, neutropenic mice after
inoculation with Aspergi/lus tus. Monotherapy with Compound (I) (0.4 mg/mL, given
intranasally) or with Posaconazole (1.0 mg/kg, dosed orally) showed only a very limited
therapeutic benefit. In contrast, the combination of Compound (I) and Posaconazole
demonstrated a marked se on survival time following infection (Table 15).
Table 15 Effects of Compound (I) and Posaconazole as erapy or in combination on
survival in severely immune-compromised, neutropenic mice ed with Aspergillus
fumigatus.
No. of Median Log-rank test
Treatment
Dose (Route) . . .
survuvors al
Regimen for_survu_val
on day 7 (%) (days) fect|on)
Vehicle none 0/6 (0) 5 -
Compound (I) 0.4 mg/mL (in) 0/6 (0) 6 p<0.05
Posaconazole 1 mg/kg, (po) 0/6 (0) 6.5 Not significant
Compound (I) 0.4mg/mL (in)
plus 5/6 (83) Undefined p<0.001
Posaconazole 1mg/kg (I00)
Table footnotes: N = 8 per group.
In Vivo Pharmacokinetics
It is a commonly used procedure for pulmonary, therapeutic agents to be dosed into the lungs
of animals, for example mice, and plasma collected at various time points after dosing in order
to characterise the ing systemic exposure to the administered compound. The
compound of the invention may be tested in such in vivo systems.
Summary of the Biological Profile of Compound (I)
Compound (I) has been found to be a potent inhibitor of illus fumigatus planktonic
growth and bronchial epithelial cell ion. Compound (I) also ted the growth of
posaconazole-resistant and nazole-resistant Aspergillus fumigatus isolates,
trating greater potency than posaconazole, voriconazole and intraconazole against
these strains. Compound (I) was also found to be a potent inhibitor of the growth of Rhizopus
oryzae, Cryptococcus neoformans, Chaetomimum globosum, Penicil/ium chrysogenum and
Trichophyton rubrum as well as some Candida Spp. In an in vitro model of alveoli, Compound
(I) showed impressive activity against Aspergillus invasion, both as monotherapy and when
dosed in combination with posaconazole. In vivo, in Aspergillus fumigatus infected,
immunocompromised, neutropenic mice, nd (I), demonstrated potent inhibition of
Aspergillus fumigatus infection, as well as the associated lung immune response whether
dosed prophylactically or as a treatment. Compound (I) was also highly efficacious in reducing
infection-dependent body weight loss. These inhibitory effects were superior to those of
posaconazole. It is significant that the beneficial ungal effects of Compound (I) are
observed in both a prophylactic and a therapeutic setting.
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Throughout the specification and the claims which follow, unless the t requires
otherwise, the word ‘comprise’, and ions such as ‘comprises’ and ‘comprising’, will be
understood to imply the inclusion of a stated integer, step, group of integers or group of steps
but not to the exclusion of any other integer, step, group of integers or group of steps.
21339411.1:DCC - 26/03/2021
Claims (8)
- Claims 1. A compound, namely Compound (I), which is: 4-(4-(4-(((3R,5R)((1H-1,2,4-triazolyl)methyl)(2,4- difluorophenyl)tetrahydrofuranyl)methoxy)methylphenyl)piperazinyl)-N-(4- fluorophenyl)benzamide; 10 or a ceutically acceptable salt thereof.
- 2. Use of a compound according to claim 1 in the manufacture of a medicament for the treatment of mycoses or for the prevention or ent of disease associated with mycoses. 15
- 3. The use according to claim 2 wherein the s is caused by Aspergillus spp.
- 4. The use according to claim 3 wherein the Aspergillus sp. is Aspergillus fumigatus or Aspergillus pullulans especially Aspergillus fumigatus. 20
- 5. The use ing to claim 3 wherein the illus sp. is an azole resistant Aspergillus fumigatus.
- 6. The use according to claim 2 wherein the mycosis is caused by Candida spp., us spp., Cryptococcus spp., Penicillium spp., or Trichophyton spp.
- 7. A pharmaceutical composition comprising a compound according to claim 1 in combination with one or more pharmaceutically acceptable diluents or carriers.
- 8. A pharmaceutical composition according to claim 7 which comprises a second or 30 further active ingredient. [Link] https://en.m.wikipedia.org/wiki/Candicidin [Link] https://en.m.wikipedia.org/wiki/Filipin [Link] https://en.m.wikipedia.org/wiki/Hamycin [Link] //en.m.wikipedia.org/wiki/Natamycin [Link] https://en.m.wikipedia.org/wiki/Nystatin [Link] https://en.m.wikipedia.org/w/index.php?title=Rimocidin&action=edit&redlink=1 [Link] https://en.m.wikipedia.org/wiki/Bifonazole [Link] https://en.m.wikipedia.org/wiki/Butoconazole [Link] https://en.m.wikipedia.org/wiki/Clotrimazole [Link] https://en.m.wikipedia.org/wiki/Econazole [Link] https://en.m.wikipedia.org/wiki/Fenticonazole [Link] //en.m.wikipedia.org/wiki/Isoconazole [Link] https://en.m.wikipedia.org/wiki/Ketoconazole [Link] https://en.m.wikipedia.org/wiki/Luliconazole [Link] https://en.m.wikipedia.org/wiki/Miconazole [Link] //en.m.wikipedia.org/wiki/Omoconazole [Link] https://en.m.wikipedia.org/wiki/Oxiconazole [Link] https://en.m.wikipedia.org/wiki/Sertaconazole [Link] https://en.m.wikipedia.org/wiki/Sulconazole [Link] https://en.m.wikipedia.org/wiki/Tioconazole [Link] https://en.m.wikipedia.org/wiki/Efinaconazole [Link] https://en.m.wikipedia.org/wiki/Epoxiconazole [Link] https://en.m.wikipedia.org/wiki/Fluconazole [Link] https://en.m.wikipedia.org/wiki/Isavuconazole [Link] https://en.m.wikipedia.org/wiki/Itraconazole [Link] https://en.m.wikipedia.org/wiki/Propiconazole [Link] https://en.m.wikipedia.org/wiki/Ravuconazole [Link] https://en.m.wikipedia.org/wiki/Terconazole [Link] https://en.m.wikipedia.org/wiki/Abafungin [Link] https://en.m.wikipedia.org/wiki/Amorolfin [Link] https://en.m.wikipedia.org/wiki/Butenafine [Link] https://en.m.wikipedia.org/wiki/Naftifine [Link] https://en.m.wikipedia.org/wiki/Terbinafine [Link] https://en.m.wikipedia.org/wiki/Anidulafungin [Link] https://en.m.wikipedia.org/wiki/Micafungin [Link] https://en.m.wikipedia.org/wiki/Benzoic_acid [Link] https://en.m.wikipedia.org/wiki/Flucytosine [Link] https://en.m.wikipedia.org/wiki/Griseofulvin [Link] https://en.m.wikipedia.org/wiki/Tolnaftate [Link] https://en.m.wikipedia.org/wiki/Undecylenic_acid 11.1:DCC -
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14196662.2 | 2014-12-05 | ||
EP14196662 | 2014-12-05 | ||
PCT/GB2015/053731 WO2016087878A1 (en) | 2014-12-05 | 2015-12-04 | Antimycotic compound |
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NZ730861A NZ730861A (en) | 2021-04-30 |
NZ730861B2 true NZ730861B2 (en) | 2021-08-03 |
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