WO2021246455A1 - ヒト用抗真菌剤 - Google Patents
ヒト用抗真菌剤 Download PDFInfo
- Publication number
- WO2021246455A1 WO2021246455A1 PCT/JP2021/021064 JP2021021064W WO2021246455A1 WO 2021246455 A1 WO2021246455 A1 WO 2021246455A1 JP 2021021064 W JP2021021064 W JP 2021021064W WO 2021246455 A1 WO2021246455 A1 WO 2021246455A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- substituted
- groups
- spp
- antifungal agent
- Prior art date
Links
- 229940121375 antifungal agent Drugs 0.000 title claims abstract description 41
- 239000003429 antifungal agent Substances 0.000 title claims abstract description 41
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 125000005843 halogen group Chemical group 0.000 claims description 87
- 125000000217 alkyl group Chemical group 0.000 claims description 81
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- -1 Thiosianat group Chemical group 0.000 claims description 38
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 241000233866 Fungi Species 0.000 claims description 29
- 241000555676 Malassezia Species 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 125000004432 carbon atom Chemical group C* 0.000 claims description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 20
- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 19
- 208000024891 symptom Diseases 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 17
- 241001337994 Cryptococcus <scale insect> Species 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 241000223238 Trichophyton Species 0.000 claims description 15
- 241000228212 Aspergillus Species 0.000 claims description 14
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 13
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 13
- 241001480037 Microsporum Species 0.000 claims description 12
- 208000017520 skin disease Diseases 0.000 claims description 12
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 241000222122 Candida albicans Species 0.000 claims description 10
- 201000007336 Cryptococcosis Diseases 0.000 claims description 10
- 241000221204 Cryptococcus neoformans Species 0.000 claims description 10
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 125000004434 sulfur atom Chemical group 0.000 claims description 8
- 201000002909 Aspergillosis Diseases 0.000 claims description 7
- 208000036641 Aspergillus infections Diseases 0.000 claims description 7
- 206010007134 Candida infections Diseases 0.000 claims description 7
- 201000003984 candidiasis Diseases 0.000 claims description 7
- AHLIZUWPYRQFHY-UHFFFAOYSA-N 5-chloro-4-(4-methylphenyl)-1h-imidazole-2-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=C(Cl)N=C(C#N)N1 AHLIZUWPYRQFHY-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 5
- 125000003107 substituted aryl group Chemical group 0.000 claims description 5
- INKBBDJOWMOPIS-UHFFFAOYSA-N 5-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile Chemical compound CC(C=C1)=CC(Cl)=C1C1=CNC(C#N)=N1 INKBBDJOWMOPIS-UHFFFAOYSA-N 0.000 claims description 4
- MPBMEDQTJJCMAP-UHFFFAOYSA-N 5-(4-methylphenyl)-1h-imidazole-2-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=CNC(C#N)=N1 MPBMEDQTJJCMAP-UHFFFAOYSA-N 0.000 claims description 4
- GROABTSWDRJUQW-UHFFFAOYSA-N 5-chloro-1-hydroxy-4-(4-methylphenyl)imidazole-2-carbonitrile Chemical compound CC(C=C1)=CC=C1C(N=C(C#N)N1O)=C1Cl GROABTSWDRJUQW-UHFFFAOYSA-N 0.000 claims description 4
- ITIOHUVJBZBCRF-UHFFFAOYSA-N 5-chloro-4-(2-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile Chemical compound CC(C=C1)=CC(Cl)=C1C(N=C(C#N)N1)=C1Cl ITIOHUVJBZBCRF-UHFFFAOYSA-N 0.000 claims description 4
- XLAGALVJBBZMKO-UHFFFAOYSA-N 5-chloro-4-(2-methylphenyl)-1H-imidazole-2-carbonitrile Chemical compound CC(C=CC=C1)=C1C(N=C(C#N)N1)=C1Cl XLAGALVJBBZMKO-UHFFFAOYSA-N 0.000 claims description 4
- HIUPGRXMXJDQPM-UHFFFAOYSA-N 5-chloro-4-(3-chloro-4-methylphenyl)-1H-imidazole-2-carbonitrile Chemical compound CC(C=CC(C(N=C(C#N)N1)=C1Cl)=C1)=C1Cl HIUPGRXMXJDQPM-UHFFFAOYSA-N 0.000 claims description 4
- HUTWVYGTQOLAJM-UHFFFAOYSA-N 5-chloro-4-(3-methylphenyl)-1H-imidazole-2-carbonitrile Chemical compound CC1=CC=CC(C(N=C(C#N)N2)=C2Cl)=C1 HUTWVYGTQOLAJM-UHFFFAOYSA-N 0.000 claims description 4
- GXSRPBUGHIGMSB-UHFFFAOYSA-N 5-chloro-4-(4-chloro-3-methylphenyl)-1H-imidazole-2-carbonitrile Chemical compound CC(C=C(C=C1)C(N=C(C#N)N2)=C2Cl)=C1Cl GXSRPBUGHIGMSB-UHFFFAOYSA-N 0.000 claims description 4
- 206010012504 Dermatophytosis Diseases 0.000 claims description 4
- 241001460074 Microsporum distortum Species 0.000 claims description 4
- 208000002474 Tinea Diseases 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- BSQXVCVJVBXWBP-UHFFFAOYSA-N CC(C=C1)=CC=C1C(N(C=N1)O)=C1Cl Chemical compound CC(C=C1)=CC=C1C(N(C=N1)O)=C1Cl BSQXVCVJVBXWBP-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 238000012360 testing method Methods 0.000 description 59
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 239000002504 physiological saline solution Substances 0.000 description 28
- 125000001424 substituent group Chemical group 0.000 description 24
- 239000000725 suspension Substances 0.000 description 22
- 239000002609 medium Substances 0.000 description 21
- 125000004122 cyclic group Chemical group 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- 210000004027 cell Anatomy 0.000 description 17
- 230000000844 anti-bacterial effect Effects 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 241000893980 Microsporum canis Species 0.000 description 12
- 241000223229 Trichophyton rubrum Species 0.000 description 12
- 230000001580 bacterial effect Effects 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 241000894006 Bacteria Species 0.000 description 11
- 239000006159 Sabouraud's agar Substances 0.000 description 11
- 238000005119 centrifugation Methods 0.000 description 11
- 239000012449 sabouraud dextrose agar Substances 0.000 description 11
- 210000003491 skin Anatomy 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 238000012258 culturing Methods 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 239000002994 raw material Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 241000282412 Homo Species 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 208000007712 Tinea Versicolor Diseases 0.000 description 7
- 206010056131 Tinea versicolour Diseases 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 7
- 229920000053 polysorbate 80 Polymers 0.000 description 7
- 229920001214 Polysorbate 60 Polymers 0.000 description 6
- 230000000843 anti-fungal effect Effects 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 206010012438 Dermatitis atopic Diseases 0.000 description 5
- 201000004681 Psoriasis Diseases 0.000 description 5
- 201000008937 atopic dermatitis Diseases 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 229940127557 pharmaceutical product Drugs 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 4
- 201000004624 Dermatitis Diseases 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 210000004209 hair Anatomy 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000006210 lotion Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 206010033072 otitis externa Diseases 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 239000002453 shampoo Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 241001225321 Aspergillus fumigatus Species 0.000 description 3
- 241000228245 Aspergillus niger Species 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000555688 Malassezia furfur Species 0.000 description 3
- 241001291477 Malassezia restricta Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 239000001888 Peptone Substances 0.000 description 3
- 108010080698 Peptones Proteins 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 241000222126 [Candida] glabrata Species 0.000 description 3
- 229940091771 aspergillus fumigatus Drugs 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940095731 candida albicans Drugs 0.000 description 3
- 208000032343 candida glabrata infection Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 3
- 229960005091 chloramphenicol Drugs 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 230000005757 colony formation Effects 0.000 description 3
- 239000002537 cosmetic Substances 0.000 description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 230000002538 fungal effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 235000019319 peptone Nutrition 0.000 description 3
- 239000011593 sulfur Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- QMQZIXCNLUPEIN-UHFFFAOYSA-N 1h-imidazole-2-carbonitrile Chemical class N#CC1=NC=CN1 QMQZIXCNLUPEIN-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 241001480043 Arthrodermataceae Species 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 241001291474 Malassezia globosa Species 0.000 description 2
- 241001048957 Malassezia nana Species 0.000 description 2
- 241001299738 Malassezia pachydermatis Species 0.000 description 2
- 239000004909 Moisturizer Substances 0.000 description 2
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 241000221424 Tremellaceae Species 0.000 description 2
- 241001045770 Trichophyton mentagrophytes Species 0.000 description 2
- WPZSJJJTNREFSV-UHFFFAOYSA-N [Zn].[O-][N+]1=CC=CC=C1S Chemical compound [Zn].[O-][N+]1=CC=CC=C1S WPZSJJJTNREFSV-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000008043 acidic salts Chemical class 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000001332 colony forming effect Effects 0.000 description 2
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 2
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 210000003128 head Anatomy 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000001333 moisturizer Effects 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002374 sebum Anatomy 0.000 description 2
- 229910000338 selenium disulfide Inorganic materials 0.000 description 2
- JNMWHTHYDQTDQZ-UHFFFAOYSA-N selenium sulfide Chemical compound S=[Se]=S JNMWHTHYDQTDQZ-UHFFFAOYSA-N 0.000 description 2
- 229960005265 selenium sulfide Drugs 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 201000004647 tinea pedis Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 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 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- MCCACAIVAXEFAL-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]imidazole;nitric acid Chemical compound O[N+]([O-])=O.ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 MCCACAIVAXEFAL-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004847 2-fluorobenzyl group Chemical group [H]C1=C([H])C(F)=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- HXGDSTCIQXNYBP-UHFFFAOYSA-N 4-chloro-1-hydroxy-5-(4-methylphenyl)imidazole-2-carbonitrile Chemical compound C1=CC(C)=CC=C1C1=C(Cl)N=C(C#N)N1O HXGDSTCIQXNYBP-UHFFFAOYSA-N 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000031295 Animal disease Diseases 0.000 description 1
- 241000893451 Arthroderma Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- IMQLKJBTEOYOSI-UHFFFAOYSA-N Diphosphoinositol tetrakisphosphate Chemical compound OP(O)(=O)OC1C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C(OP(O)(O)=O)C1OP(O)(O)=O IMQLKJBTEOYOSI-UHFFFAOYSA-N 0.000 description 1
- 206010065837 External ear inflammation Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000428512 Malassezia dermatis Species 0.000 description 1
- 241000271955 Malassezia japonica Species 0.000 description 1
- 241001291472 Malassezia obtusa Species 0.000 description 1
- 241001291475 Malassezia slooffiae Species 0.000 description 1
- 241001291478 Malassezia sympodialis Species 0.000 description 1
- 241001350514 Malassezia yamatoensis Species 0.000 description 1
- 241001178059 Malasseziaceae Species 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 206010058667 Oral toxicity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 241000235344 Saccharomycetaceae Species 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241001136486 Trichocomaceae Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000012459 cleaning agent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008406 cosmetic ingredient Substances 0.000 description 1
- 125000006165 cyclic alkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001352 cyclobutyloxy group Chemical group C1(CCC1)O* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000006612 decyloxy group Chemical group 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 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 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- WHWDWIHXSPCOKZ-UHFFFAOYSA-N hexahydrofarnesyl acetone Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)=O WHWDWIHXSPCOKZ-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229960005040 miconazole nitrate Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006611 nonyloxy group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- CKQVRZJOMJRTOY-UHFFFAOYSA-N octadecanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCC(O)=O CKQVRZJOMJRTOY-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000418 oral toxicity Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- BTSZTGGZJQFALU-UHFFFAOYSA-N piroctone olamine Chemical compound NCCO.CC(C)(C)CC(C)CC1=CC(C)=CC(=O)N1O BTSZTGGZJQFALU-UHFFFAOYSA-N 0.000 description 1
- 229940081510 piroctone olamine Drugs 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M thiocyanate group Chemical group [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 235000015961 tonic Nutrition 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 229960000716 tonics Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 239000007222 ypd medium 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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
-
- 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
Definitions
- Malassezia spp. Is a carrier-type yeast that is resident on the skin of humans and animals, and because it proliferates using lipids as a nutrient source, it settles in areas with a lot of sebum, and tinea versicolor, seborrheic dermatitis, and hair follicles. It is known to cause skin diseases such as inflammation, atopic dermatitis and psoriasis vulgaris.
- imidazole compounds such as selenium disulfide, 2-mercaptopyridine N-oxide zinc, piroctone olamine, myconazole nitrate and ketoconazole, and triazole compounds such as itraconazole and fluconazole. Examples include compounds.
- barrier effects such as the effect of preventing the scalp odor associated with the growth of various germs on the skin and the effect of maintaining a weakly acidic state by moderately decomposing sebum. Since it kills not only pathogenic bacteria but also indigenous bacteria on the skin, there is a concern that the barrier effect of the skin may be destroyed.
- selenium disulfide has side effects such as oral toxicity, hair loss, skin irritation, weakness, malaise, and discoloration of hair, and 2-mercaptopyridin N-oxide zinc has concerns about sulfur odor and environmental hormones.
- imidazole compounds such as miconazole nitrate and triazole compounds such as itraconazole have the effect of inhibiting the lipid synthesis of fungi, but are sufficient due to the property that antibacterial activity is exhibited by inhibiting the biosynthesis of the cell membrane of the fungi. It takes time for the effect to appear, and it is necessary to administer it for a long period of time. It is known that continuous administration of the same drug over a long period of time significantly increases the risk of developing resistant bacteria.
- the lipid synthesis inhibitor does not immediately develop antibacterial activity even when the drug is administered. Therefore, an administration method that requires immediate effect on the expression of antibacterial activity, for example, a medical shampoo. Not suitable for the prevention or treatment of skin diseases caused by. Therefore, there has been a demand for the development of a compound that is highly safe, has an action mechanism different from that of conventional therapeutic agents, and exhibits antibacterial activity immediately.
- Non-Patent Document 1 describes that the mechanism of action of siazofamide, which is a cyanoimidazole compound, is respiratory inhibition.
- Patent Document 1 describes that an imidazole-based compound containing siazofamide is useful as a pest control agent
- Patent Document 2 describes that a control agent containing an imidazole-based compound containing siazofamide as an active ingredient is a parasite. It has been described as useful against animal diseases derived from, for example, parasites such as coxidium. However, imidazole compound antibacterial activity against skin fungi involved in human diseases such as skin malassezia, Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. And Cryptococcus spp. None has been reported about.
- the present disclosures are novel effective cyanoimidazole compounds represented by the formula (I) or (II) described later (hereinafter, also referred to as the compounds of the present disclosure) for dermatophylles involved in human diseases. It has been found that it can be used as an antifungal agent for humans.
- the present disclosure provides a novel antifungal agent for humans.
- R 1 and R 2 are independent of each other. Hydrogen atom, Halogen atom, Hydroxy group, Nitro group, Cyano group, Thiosianat group, Trimethylsilyl group, Alkyl groups that may be substituted, Alkenyl groups that may be substituted, Alkynyl groups that may be substituted, Alkyloxy groups that may be substituted, Alkenyloxy groups that may be substituted, Alkynyloxy groups that may be substituted, Aryl groups that may be substituted, Aryloxy groups that may be substituted, A 5- to 6-membered aromatic heterocyclic group which may be substituted, -SO m R 3 (R 3 is an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, an aryl group which may be substituted, an aromatic complex
- a ring group or -NR 4 R 5 groups (R 4 and R 5 are alkyl groups which may be substituted), or m is an integer of 0 to 2), or.
- W 1 is an oxygen atom or a sulfur atom
- W 2 is an oxygen atom
- a sulfur atom or -NH- n is an integer from 0 to 1 and R 6 is a group represented by a is) optionally substituted alkyl group or an optionally substituted aryl group
- X is a hydrogen atom, a hydroxyl group or -OY
- Y is the formula:
- R 7 is an alkyl group which may be substituted, Alkyloxy groups that may be substituted, Alkenyl groups that may be substituted, Alkenyloxy groups that may be substituted, Aryl groups that may be substituted, Aryloxy groups that may be substituted, A 5- to 6-membered aromatic heterocyclic group which may be substituted
- -NR 8 R 9 groups (R 8 and R 9 are independently hydrogen
- R 8 and R 9 are hydrogen atoms at the same time
- R 10 , R 11 and R 12 are an alkyl group that may be substituted, an alkenyl group that may be substituted, or an aryl group that may be substituted).
- a novel antifungal agent for humans can be provided by using the compound represented by the formula (I) or (II) or a salt thereof.
- the compound represented by the formula (I) or (II) or a salt thereof can be advantageously utilized for immediately exerting excellent antibacterial activity against fungi associated with human diseases.
- halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
- alkyl alkenyl
- alkynyl alkynyl as a group or a part of a group are linear, branched, and cyclic, respectively, unless otherwise specified. Alternatively, it means an alkyl, alkenyl or alkynyl in a combination thereof. Further, for example, in the case of "alkyl having 1 to 6 carbon atoms” as a group or a part of a group, “1 to 6 carbon atoms” means that the alkyl group has 1 to 6 carbon atoms.
- the number of carbon atoms of the linear or branched alkyl group is preferably 1 to 12, and more preferably 1 to 6. It is more preferably 1 to 3.
- Examples of the linear or branched alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group and n-pentyl.
- Examples thereof include a group, an n-hexyl group, a heptyl group, an octyl group, a nonyl group or a decyl group, but a methyl group, an ethyl group, an n-propyl group or an isopropyl group is preferable, and a methyl group or an ethyl group is more preferable. Is.
- the cyclic alkyl group (cycloalkyl group) preferably has 3 to 7 carbon atoms, more preferably 3 to 6 carbon atoms.
- the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
- the alkyl group may be substituted and the substituents include a halogen atom; an alkyloxy group optionally substituted with a halogen atom; an alkylthio group optionally substituted with a halogen atom; a phenyl substituted with a halogen atom.
- examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above-mentioned group.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- an alkyl group represented by R 2 and R 7 are linear or branched, number of carbon atoms in the alkyl group is preferably 1 to 12, more preferably from 1 to 6, Even more preferably, it is 1 to 3.
- Examples of the linear or branched alkyloxy group include a methoxy group, an ethoxy group, an n-propyloxy group, an isopropyloxy group, an n-butyloxy group, a sec-butyloxy group, an isobutyloxy group and a tert-butyloxy group.
- the cyclic alkyl oxy group (cycloalkyl oxy group) preferably has 3 to 7 carbon atoms, more preferably 3 to 6 carbon atoms. be.
- the cycloalkyloxy group include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like.
- the above alkyloxy group may be substituted, and the substituent may be a halogen atom; an alkyloxy group optionally substituted with a halogen atom; an alkylthio group optionally substituted with a halogen atom; or a halogen atom substituted.
- the alkyloxy group is cyclic (cycloalkyloxy group)
- examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above-mentioned group.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the carbon number of the linear or branched chain alkenyl group is , It is preferably 2 to 12, more preferably 2 to 6, and even more preferably 2 to 4.
- Examples of the linear or branched alkenyl group include an allyl group and a geranyl group.
- the number of carbon atoms of the cyclic alkenyl group is preferably 5 to 8. Yes, more preferably 5-6.
- the cycloalkenyl group include a cyclopentenyl group, a cyclohexenyl group, a cyclooctenyl group and the like.
- the alkenyl group may be substituted, and the substituent may be a halogen atom; an alkyloxy group that may be substituted with a halogen atom; an alkylthio group that may be substituted with a halogen atom; or a halogen atom.
- examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above-mentioned ones.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- alkenyloxy groups R 2 and R 7 represents a linear or branched
- number of carbon atoms of the linear or branched alkenyloxy group is preferably 2 to 12, more It is preferably 2 to 6, and even more preferably 2 to 4.
- Examples of the linear or branched alkenyloxy group include 2-propenyloxy group and the like.
- alkenyloxy group represented by R 2 and R 7 is cyclic
- the carbon number of the cyclic alkenyloxy group (cycloalkenyl group) is preferably 5-8, more preferably 5-6 be.
- the cycloalkenyloxy group include a cyclopentenyloxy group, a cyclohexenyloxy group, a cyclooctenyloxy group and the like.
- the alkenyloxy group may be substituted, and the substituent may be a halogen atom; an alkyloxy group that may be substituted with a halogen atom; an alkylthio group that may be substituted with a halogen atom; or a halogen atom.
- examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above-mentioned ones.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the number of carbon atoms of the linear or branched alkynyl group is preferably 2 to 12, more preferably. It is 2 to 6, and even more preferably 2 to 4.
- Examples of the linear or branched alkynyl group include a 2-propynyl group and the like.
- the cyclic alkynyl group (cycloalkynyl group) preferably has 6 to 10 carbon atoms.
- the cycloalkynyl group include a cyclooctynyl group and the like.
- the alkynyl group may be substituted, and the substituent may be a halogen atom; an alkyloxy group which may be substituted with a halogen atom; an alkylthio group which may be substituted with a halogen atom; or a halogen atom.
- examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above-mentioned group.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the carbon number of the linear or branched alkynyloxy group is preferably 2 to 12, more preferably 2. It is ⁇ 6, and even more preferably 2-4.
- Examples of the linear or branched alkynyloxy group include 2-propynyloxy group.
- the cyclic alkynyloxy group (cycloalkynyloxy group) preferably has 6 to 10 carbon atoms.
- the cycloalkynyloxy group include a cyclooctynyloxy group.
- the above alkynyloxy group may be substituted, and the substituent may be a halogen atom; an alkyloxy group which may be substituted with a halogen atom; an alkylthio group which may be substituted with a halogen atom; or an alkylthio group which may be substituted with a halogen atom.
- examples of the substituent include an alkyl group which may be substituted with a halogen atom in addition to the above-mentioned ones.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the aryl group represented by R 1 , R 2 , R 3 , R 6 , R 7 , R 10 , R 11 and R 12 preferably has 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms.
- Examples of the aryl group include a phenyl group and a naphthyl group, but a phenyl group is preferable.
- the aryl portion of the aryloxy group represented by R 1 , R 2 , R 3 , R 6 , R 7 , R 10 , R 11 and R 12 preferably has 6 to 14 carbon atoms, more preferably 6 to 10 carbon atoms. Is.
- Examples of the aryloxy group include a phenyloxy group and a naphthyloxy group, and a phenyloxy group is preferable.
- the aryl group or aryloxy group may be substituted, and the substituent may be a halogen atom; an alkyl group optionally substituted with a halogen atom; an alkyloxy group optionally substituted with a halogen atom; substituted with a halogen atom.
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the 5- to 6-membered aromatic heterocyclic groups represented by R 1 , R 2 , R 3 and R 7 are preferably the same or different, with one or one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur. It is an aromatic heterocycle having a plurality of.
- the number of heteroatoms in the 5- to 6-membered aromatic heterocyclic group is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
- Examples of the 5- to 6-membered aromatic heterocyclic group include a thienyl group, a frill group, a thiazolyl group, a pyridyl group and the like.
- the 5- to 6-membered aromatic heterocyclic group may be substituted, or may be substituted with a halogen atom, a nitro group, a cyano group, an alkyl group which may be substituted with a halogen atom, an alkyloxyalkyl group, or a halogen atom.
- R 15 is an alkyl group that may be substituted with a halogen atom, and p is an integer of 0 to 2).
- the number of these substituents is preferably 0 to 5, more preferably 1 or 2.
- the alkyl moiety contained in R 13 to R 15 may be the same as the alkyl moiety in R 1 to R 12 described above.
- the number of heteroatoms in the 5- to 7-membered saturated heterocycle is preferably 1 to 4, more preferably 1 to 3, and even more preferably 1 or 2.
- Examples of the 5- to 7-membered saturated heterocycle include a piperidine group, a pyrrolidine group, a morpholine group, a thiomorpholin group, and the like.
- R 1 and R 2 are independently hydrogen atom, halogen atom, hydroxyl group, nitro group, cyano group, thiocyanate group, trimethylsilyl group, linear or optionally substituted linear or Branched chain alkyl group, optionally substituted cycloalkyl group, optionally substituted linear or branched alkenyl group, optionally substituted cycloalkenyl group, optionally substituted linear or Branched chain alkynyl group, optionally substituted linear or branched alkyloxy group, optionally substituted phenyloxy group, optionally substituted phenyl group, optionally substituted naphthyl group, substituted A 5- to 6-membered aromatic heterocyclic group which may be substituted, —SO m R 3 (R 3 is a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, Substituentally substituted linear or branched alken
- R 1 and R 2 are independently hydrogen atom, halogen atom, nitro group, cyano group, and the like.
- Alkyl groups that may be substituted with halogen atoms Alkyl groups substituted with alkyloxy groups, which may be substituted with halogen atoms, Alkyl group substituted with phenyl group, Alkyl groups, alkyl groups substituted with phenyl groups substituted with halogen atoms or hydroxyl groups,
- n R 6 (R 6 is an alkyl group which may be substituted with a halogen atom or a phenyl group which may be substituted with a halogen atom, and n is an integer of 0 to 1).
- R 1 is an unsubstituted alkyl group, an alkyl group substituted with a halogen atom, an alkyl group substituted with a phenyl group optionally substituted with a halogen atom, or a halogen.
- R 1 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an n-pentyl group, 3-chloro-n-.
- R 2 is a chlorine atom or a bromine atom.
- R 1 and R 2 are independently hydrogen atoms, halogen atoms or optionally substituted phenyl groups.
- R 1 and R 2 are independently hydrogen atoms or halogen atoms, or are substituted with at least one group of an alkyl group and a halogen atom. It is also a good phenyl group.
- R 1 and R 2 are independently hydrogen atoms or halogen atoms, or at least one of an alkyl group and a halogen atom having 1 to 6 carbon atoms. It is a phenyl group that may be substituted with one group.
- R 1 and R 2 are different groups from each other.
- X is a hydrogen atom, a hydroxyl group or -OY, preferably a hydrogen atom or a hydroxyl group, and more preferably a hydrogen atom.
- Y is the formula: (In the formula, R 7 is a linear or branched alkyl group which may be substituted, a cycloalkyl group which may be substituted, a phenyl group which may be substituted, a thienyl group which may be substituted, a substitution. May be a frill group, or -NR 8 R 9 (R 8 and R 9 are each independently a hydrogen atom, an optionally substituted alkyl group or an optionally substituted alkenyl group, or , Forming a 5- to 7-membered saturated heterocycle with adjacent nitrogen atoms, except when R 8 and R 9 are hydrogen atoms at the same time).
- R 7 may be substituted linear or branched alkyl group may be substituted linear or branched alkyl group
- R 8 and R 9 are independently substituted with hydrogen atoms, respectively. It is an alkyl group or an alkenyl group which may be substituted, or forms a 5- to 7-membered saturated heterocycle with nitrogen atoms adjacent to each other, except that R 8 and R 9 are hydrogen atoms at the same time.
- -CR 10 R 11 R 12 groups R 10 , R 11 and R 12 are each independently substituted alkyl group or optionally substituted phenyl group.
- R 7 is an alkyl group which may be substituted, a phenyl group which may be substituted, an alkyloxy group which may be substituted, or a phenyloxy group which may be substituted.
- R 10 R 11 R 12 groups R 10 , R 11 and R 12 are independently substituted alkyl groups or optionally substituted phenyl groups, respectively).
- the compound represented by the formula (I) or (II) or a salt thereof can be produced by the methods described in JP-A-8-283243 and JP-A-8-225539.
- the compounds of the present disclosure may be used alone or in combination of two or more.
- the compound of the present disclosure may be in the form of a salt.
- the salt is preferably a pharmaceutically or cosmetically acceptable salt.
- the above-mentioned pharmaceutically or cosmetically acceptable salt means a salt that can be used as a medicine.
- the compound represented by the formula (I) or (II) has an acidic group or a basic group, it can be made into a basic salt or an acidic salt by reacting with a base or an acid.
- acidic salts include hydrochloride, hydrobromide, sulfate, nitrate, inorganic acid salts such as phosphate, acetate, propionate, tartrate, fumarate, maleate, and malic acid.
- organic acid salts such as salts, citrates, methanesulfonates, benzenesulfonates and paratoluenesulfonates.
- basic salts include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.
- the compound of the present disclosure or a salt thereof may absorb water and become adsorbed water or become a hydrate when left in the air or recrystallized, and the compound of the present disclosure or a salt thereof may become a hydrate.
- the salt also includes such various hydrates, solvates and polymorphic compounds.
- the compound of the present disclosure or a salt thereof may be used as a drug as it is, but if necessary, it is formulated by a conventional method by combining other additional ingredients such as the above carrier, active ingredient, pharmacological ingredient and cosmetic ingredient. be able to.
- the content of the compound of the present disclosure is usually 0.00001 to 30% by mass, preferably 0.0001 to 10% by mass, and more preferably 0. It is 001 to 0.05% by mass.
- the carrier used in the above-mentioned preparation is preferably a pharmaceutically or cosmetically acceptable carrier, for example, an excipient, a film agent, a binder, a bulking agent, and a disintegration agent.
- a pharmaceutically or cosmetically acceptable carrier for example, an excipient, a film agent, a binder, a bulking agent, and a disintegration agent.
- moisturizers for example, moisturizers, anti-inflammatory agents, bactericidal agents, antibacterial agents, ultraviolet protective agents, cell activators, makeup components and the like may be used.
- the pharmaceutical product containing the compound of the present disclosure or a salt thereof can be provided as a pharmaceutical product, a quasi-drug, or a cosmetic product, but is preferably used as a pharmaceutical product.
- the form of the formulation containing the compound of the present disclosure or a salt thereof may be, for example, any of creams, emulsions, lotions, suspensions, gels, powders, packs, sheets, patches, sticks, cakes and the like.
- the form is not particularly limited to these.
- the pharmaceutical product of the present disclosure may be orally or parenterally administered.
- Dosage forms for oral administration include, for example, solid dosage forms such as tablets, coated tablets, granules, powders, capsules, and liquid dosage forms such as elixir, syrup and suspension.
- Dosage forms for parenteral administration include injection, infusion, topical, external, transdermal, transmucosal, nasal, enteral, inhalation, suppository, bolus, patch and the like.
- the preferred form of the preparation is a skin external preparation.
- the pharmaceutical product of the present disclosure is used for ameliorating a symptom or disease caused by a fungus.
- “improvement” includes not only the treatment of an established pathological condition but also the prevention or delay of a pathological condition that may be established in the future.
- the improvement in the present disclosure preferably includes improvement of the symptom or condition of the skin disease, prevention or delay of deterioration of the symptom or condition of the skin disease, and reversal, prevention or delay of the progression of the symptom or condition of the skin disease. ..
- the fungi in the present disclosure are preferably Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. Or Cryptococcus spp., And more preferably Candida spp., Trichophyton spp. It is a genus, Microsporum, Arsroderma, Aspergillus or Cryptococcus.
- the genus Candida is a fungus belonging to the family Saccharomycetaceae, and examples thereof include Candida albicans and Candida glabrata.
- Malassezia a fungus belonging to Malassezia family (Malasseziaceae), for example, Malassezia furfur, Malassezia pachydermatis, Malassezia globosa, Malassezia obtusa, Malassezia restricta, Malassezia sympodialis, Malassezia slooffiae, Malassezia dermatis, Examples include Malassezia yamatoensis, Malassezia japonica , Malassezia nana and the like.
- the Trichophyton genus is a fungus belonging to the family Trichophyton , and examples thereof include Trichophyton rubrum and Trichophyton interdigate.
- the Microsporum is a fungus belonging to the family Arthrodermataceae, and examples thereof include Microsporum canis and the like.
- the Arusuroderuma genus (Arthroderma), a fungus belonging to Arusuroderuma family (Arthrodermataceae), for example, Arthroderma Vanbreuseghemii and the like.
- the genus Aspergillus (Aspergillus), a fungus belonging to Mayuhakitake family (Trichocomaceae), for example, Aspergillus fumigatus, Aspergillus niger, and the like.
- Cryptococcus genus a fungus belonging to tremellaceae (Tremellaceae), for example, Cryptococcus neoformans, and the like.
- the symptom or disease caused by the fungus is a skin disease.
- skin diseases include dermatitis, psoriasis vulgaris, tinea pedis, candidiasis, cutaneous malacetia, aspergillosis, cryptococcosis, atopic dermatitis, external ear inflammation and the like, and skin is preferable.
- skin diseases include dermatitis, psoriasis vulgaris, tinea pedis, candidiasis, cutaneous malacetia, aspergillosis, cryptococcosis, atopic dermatitis, external ear inflammation and the like, and skin is preferable.
- tinea pedis, candidiasis, aspergillosis or cryptococcosis include tinea pedis, candidiasis, aspergillosis or cryptococcosis.
- the administration target of the compound of the present disclosure or a salt thereof is preferably human.
- the administration site of the compound of the present disclosure or a salt thereof is not particularly limited, and may be a tissue such as skin, an organ, or a cell in which the target fungus is present.
- the compound of the present disclosure or a salt thereof can be administered in an effective amount for producing antifungal activity to a subject who needs it to suppress the growth of fungi or sterilize the fungus.
- inhibition of fungal growth comprising administering to a human subject in need of an effective amount of a compound of formula (I) or (II).
- a sterilization method is provided.
- the fungus is Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. Or Cryptococcus spp., More preferably Candida spp., Trichophyton.
- fungus it is a genus Phyton, a genus Microsporum, a genus Arsroderma, a genus Aspergillus, or a genus Cryptococcus. Also, according to another preferred embodiment of the present disclosure, due to a fungus comprising administering to a human subject in need thereof an effective amount of a compound of formula (I) or (II). A method for improving a symptom or a disease is provided.
- the method of the present disclosure is preferably a therapeutic method, but may be a non-therapeutic method. Specifically, it may be used for cosmetic purposes or non-therapeutic use for health promotion purposes. According to one embodiment, according to a preferred embodiment of the present disclosure, the method does not include medical practice, i.e., treatment of an individual by treatment.
- the effective amount of the compound of the present disclosure or a salt thereof varies depending on the animal species, sex, age, body weight, condition and other factors to be administered, but the growth of the target fungus is 50% or less, preferably 50% or less of the control.
- the amount is 40% or less, more preferably 30% or less, still more preferably 20% or less, still more preferably 10% or less.
- the dose, administration route, and administration interval of the compound of the present disclosure vary depending on the animal species, sex, age, body weight, condition, and other factors to be administered, and therefore cannot be unconditionally specified.
- the dose of the compound of the present disclosure is usually 0.005 to 350 mg / day per adult weighing 60 kg, which is preferable per week.
- the dose is 0.01 to 175 mg / week.
- the use of a compound represented by the formula (I) or (II) or a salt thereof is provided in the production of an antifungal agent for humans.
- the fungus is Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. Or Cryptococcus spp.
- the above-mentioned symptom or disease is a skin disease.
- the above-mentioned symptom or disease is tinea versicolor, psoriasis vulgaris, tinea versicolor, candidiasis, malassezia dermatitis, aspergillosis, cryptococcosis, atopic dermatitis or I have otitis externa.
- the antifungal agent is a pharmaceutical.
- the use is cosmetic or non-therapeutic use.
- a compound represented by the formula (I) or (II) or a salt thereof for use as an antifungal agent for humans is provided.
- a compound represented by the formula (I) or (II) or a salt thereof is provided for ameliorating a symptom or a disease caused by Malassezia spp.
- the fungus is Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. Or Cryptococcus spp.
- the above-mentioned symptom or disease is a skin disease.
- the above-mentioned symptom or disease is tinea versicolor, psoriasis vulgaris, tinea versicolor, candidiasis, malassezia dermatitis, aspergillosis, cryptococcosis, atopic dermatitis or I have otitis externa.
- the antifungal agent is a pharmaceutical.
- Hydrogen atom Halogen atom, Hydroxy group, Nitro group, Cyano group, Thiosianat group, Trimethylsilyl group, Alkyl groups that may be substituted, Alkenyl groups that may be substituted, Alkynyl groups that may be substituted, Alkyloxy groups that may be substituted, Alkenyloxy groups that may be substituted, Alkynyloxy groups that may be substituted, Aryl groups that may be substituted, Aryloxy groups that may be substituted, A 5- to 6-membered aromatic heterocyclic group which may be substituted, -SO m R 3 (In the formula, R 3 is an alkyl group which may be substituted, an alkenyl group which may be substituted, an alkynyl group which may be substituted, an aryl group which may be substituted, and 5 to 6 members which may be substituted.
- Aromatic heterocyclic groups or -NR 4 R 5 groups (in the formula, R 4 and R 5 are alkyl groups which may be substituted), or m is an integer of 0 to 2), or.
- W 1 is an oxygen atom or a sulfur atom
- W 2 is an oxygen atom
- a sulfur atom or -NH- n is an integer from 0 to 1 and R 6 is a group represented by a is) optionally substituted alkyl group or an optionally substituted aryl group
- X is a hydrogen atom, a hydroxyl group or -OY
- Y is the formula:
- R 7 is an alkyl group which may be substituted, Alkyloxy groups that may be substituted, Alkenyl groups that may be substituted, Alkenyloxy groups that may be substituted, Aryl groups that may be substituted, Aryloxy groups that may be substituted, A 5- to 6-membered aromatic heterocyclic group which may be substituted, -NR 8 R 9 groups (R 8
- R 1 and R 2 are phenyl groups that are independently hydrogen atoms or halogen atoms, or may be substituted with at least one group of an alkyl group and a halogen atom, [1]. ] Or the antifungal agent according to [2]. [4] R 1 and R 2 are independent hydrogen atoms or halogen atoms, or may be substituted with at least one group of an alkyl group and a halogen atom having 1 to 6 carbon atoms. The antifungal agent according to any one of [1] to [3], which is a group. [5] The antifungal agent according to any one of [1] to [4], wherein R 1 and R 2 are different groups from each other.
- X is a hydrogen atom, a hydroxyl group or -OY;
- Y is the formula:
- R 7 is an alkyl group which may be substituted, a phenyl group which may be substituted, an alkyloxy group which may be substituted, a phenyloxy group which may be substituted, or -CR 10 R 11 R 12 groups.
- R 10 , R 11 and R 12 are independently substituted alkyl groups or optionally substituted phenyl groups), which are the groups represented by [1] to [1] to [ 5]
- the antifungal agent according to any one of.
- the antifungal agent according to any one of [1] to [6], wherein X is a hydrogen atom or a hydroxyl group.
- the compound represented by the formula (I) or (II) is 5-chloro-4- (4-methylphenyl) -1 H - imidazole-2-carbonitrile, 4- (4-methylphenyl) -1 H - imidazole-2-carbonitrile, 5-chloro-4- (3-methylphenyl) -1 H - imidazole-2-carbonitrile, 5-chloro-4- (2-methylphenyl) -1 H - imidazole-2-carbonitrile, 5-chloro-4- (2-chloro-4-methylphenyl) -1 H - imidazole-2-carbonitrile, 5-chloro-4- (3-chloro-4-methylphenyl) -1 H - imidazole-2-carbonitrile, 5-chloro-4- (4-chloro-3-methylphenyl) -1 H - imidazole-2-
- the fungus is at least one selected from Candida spp., Malassezia spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. And Cryptococcus spp., [1] to The antifungal agent according to any one of [9].
- the fungus is at least one selected from Candida spp., Trichophyton spp., Microsporum spp., Arsroderma spp., Aspergillus spp. And Cryptococcus spp., [1]-[10].
- the symptom or disease is tinea versicolor, psoriasis vulgaris, tinea versicolor, candidiasis, skin malassezia, aspergillosis, cryptococcosis, atopic dermatitis or otitis externa, [12] or [ 13].
- the antifungal agent is tinea versicolor, psoriasis vulgaris, tinea versicolor, candidiasis, skin malassezia, aspergillosis, cryptococcosis, atopic dermatitis or otitis externa, [12] or [ 13].
- Production Example 8 4- (2-Chloro-4-methylphenyl) -1H-imidazol-2-carbonitrile (Compound No. 8) Except for the use of the raw material compound corresponding to the product to be produced, the compound No. 8 was manufactured.
- Test Example 1-1 Antibacterial activity test Test compound: Compound No. 1
- Test strain Candida albicans (TIMM1768 strain)
- Test method Candida bacteria cultured in YPD liquid medium at 37 ° C. for 20 hours were collected by centrifugation (3000 rpm, 5 minutes), washed twice with saline, suspended in saline, and suspended in 2 ⁇ 10 The bacterial solution was prepared so as to be 3 cells / mL. 100 ⁇ L of the bacterial solution was applied to Sabouraud agar to which the test compound dissolved in DMSO was added so as to have a predetermined concentration. After culturing at 37 ° C. for 48 hours, the presence or absence of colony formation was investigated. As a result, compound No. 1 completely inhibited colonization at 50 ppm.
- Test Example 1-2 Antibacterial activity test Test compound: Compound No. 1
- Test strain Candida glabrata (TIMM6054 strain)
- Test method Candida bacteria cultured in YPD liquid medium at 37 ° C. for 20 hours were collected by centrifugation (3000 rpm, 5 minutes), washed twice with saline, suspended in saline, and suspended in 2 ⁇ 10 The bacterial solution was prepared so as to be 3 cells / mL. 100 ⁇ L of the bacterial solution was applied to a YPD medium in which a test compound dissolved in DMSO was added to a predetermined concentration. After culturing at 37 ° C. for 48 hours, the presence or absence of colony formation was investigated. As a result, compound No. 1 completely suppressed colonization at 200 ppm.
- Test Example 1-3 Antibacterial activity test Test compound: Compound No. 1
- Test strain Cryptococcus neoformans (TIMM1316 strain)
- Test method Cryptococcus bacteria cultured in YPD liquid medium at 37 ° C. for 20 hours were collected by centrifugation (3000 rpm, 5 minutes), washed twice with physiological saline, and then physiological. The cells were suspended in saline and the bacterial solution was prepared to a concentration of 2 ⁇ 10 3 cells / mL. 100 ⁇ L of the bacterial solution was applied to Sabouraud agar to which the test compound dissolved in DMSO was added so as to have a predetermined concentration. After culturing at 37 ° C. for 48 hours, the presence or absence of colony formation was investigated. As a result, compound No. 1 completely suppressed colonization at 20 ppm.
- Test Example 1-4 Antibacterial activity test Test compound: Compound No. 1 Test strain: Malassezia nana (CBS95574)
- Colonization inhibition rate (%) [(number of colonies formed in the drug-free group-number of colonies formed in the group of the present invention) / number of colonies formed in the drug-free group] ⁇ 100 As a result, compound No.
- the colonization inhibition rate of 1 was 98.5% at 100 ppm and 99.9% at 200 ppm.
- Test Example 1-5 Antibacterial activity test Test compound: Compound No. 1 Test strain: Malassezia pachydermatis (TIMM10024)
- the number) and the number of colonies in the medium to which the test compound was not added were measured, and the colonization inhibition rate (%) was determined by the same method as in Test Example 1-4. As a result, compound No.
- the colonization inhibition rate of 1 was 98.1% at 100 ppm and 100% at 200 ppm.
- Test Example 1-6 Antibacterial activity test Test compound: Compound No. 1 Test strain: Aspergillus fumigatus (TIMM0063 strain), A. niger (TIMM4968 strain) Test method: Aspergillus bacterium was cultured in PDA medium at 27 ° C. for 3 days, and then spores were added to a physiological saline solution containing Tween80 (polyoxyethylene sorbitan monooleart: manufactured by Kanto Chemical Co., Inc.) (0.05% (v / v)). Was collected and filtered with a cell strainer ( ⁇ 40 ⁇ m).
- Tween80 polyoxyethylene sorbitan monooleart: manufactured by Kanto Chemical Co., Inc.
- Test Example 1-7 Antibacterial activity test Test compound: Compound No. 1 Test strain: Trichophyton rubrum (CBS118892 shares), T. interdegitale (TIMM20065 strain), Microsporum canis (TIMM20080 strain), Arthrodavanbreuseghemii (TIMM2789)
- Test compound Compound No. 6 Test strain: Candida albicans (NBRC1594 strain), Candida glabrata (JCM3761 strain), Cryptococcus neoformans (JCM3685 strain), Aspergillus fumigatus (JCM10253), Aspergillus niger (ATCC6725), Trichophyton rubrum (ATCCMYA4607), Trichophyton interdegitale (ATCC9533), Microsporum canis (NBRC7863), Arthroderma vanbreuseghemii (JCM1891)
- Tween80 polyoxyethylene sorbitan monooleart: Kanto Chemical Co., Ltd.
- PBS containing 8 g of sodium chloride, 2.9 g of disodium hydrogen phosphate, 0.2 g of potassium chloride, 0.2 g of potassium dihydrogen phosphate in 1000 mL
- cell strainer ⁇ 40 ⁇ m
- Test Example 3-1 Antifungal activity test Test compound: Compound No. 6 Test strains: Malassezia furfur (IFM 55951), Malassezia symmodialis (IFM 48588), Malassezia globosa (IFM 51946)
- Malassezia furfur Malassezia symphodias , Malassezia simpodialis, cultured in Chromogar TM Malassezia / Candida raw medium (Peptone, special enzyme substrate mixture, chloramphenicol, olive oil, agar, manufactured by Kanto Kagaku Co., Ltd.) for 5 to 7 days. It was suspended in physiological saline and adjusted to 0.025 at an absorbance of 600 nm.
- test compound dissolved in DMSO was added thereto to a final concentration of 200, 100, 50, 25 ppm, and after 1 minute, 10 ⁇ L of the suspension and 10 mL of physiological saline were added to the syringe and stirred, and the 37 mm quality monitor (Pall) was added. It was connected to (manufactured by the company), filtered, and washed twice with 10 mL of physiological saline. The membrane filter was removed from the quality monitor, the filter was placed on the Chromogar TM Malassezia / Candida raw medium, and the cells were cultured at 32 ° C. for 72 hours, and the presence or absence of colony growth was investigated to determine the minimum fungal killing concentration (MFC100). The results are shown in Table 2-1.
- Test Example 3-2 Antifungal activity test Test compound: Compound No. 6 Test strain: Malassezia restricta (IFM55992)
- Chromogar TM Malassezia / Candida raw medium (Peptone, special enzyme substrate mixture, chloramphenicol, olive oil, agar, manufactured by Kanto Kagaku Co., Ltd.) was cultured for 5 to 7 days and Malassezia restricta was suspended in physiological saline. The mixture was adjusted to 0.025 at an absorbance of 600 nm. The test compound dissolved in DMSO was added thereto to a final concentration of 200, 100, 50, 25 ppm, and after 1 minute, 10 ⁇ L of the suspension and 10 mL of physiological saline were placed in a syringe and stirred, and a 37 mm quality monitor (37 mm quality monitor) was added.
- MLNA medium Leeming & Notman agar Modified medium
- the culture was carried out at 32 ° C. for 72 hours, the presence or absence of colony growth was investigated, and the minimum fungal killing concentration MFC100) was determined. The results are shown in Table 2-2.
- Test Example 4 Antifungal activity test Test compound: Compound No. 6 Test strains: Trichophyton rubrum (ATCCMYA4607), Microsporum canis (IFM63627)
- Trichophyton rubrum was cultured in Sabouraud agar and Microsporum canis was cultured in 1/10 Sabouraud agar at 32 ° C. for 168 hours to form spores.
- the hyphae are peeled off from the surface of the medium and collected in a tube, physiological saline (Otsuka saline injection; 9 g of sodium chloride is contained in 1000 mL) is added, and the whole is used as a disposable loop (type 1 (1 ⁇ L)). The mixture was mixed and dispersed, and a spore suspension containing hyphae was collected.
- Microsporum canis 10 mL of physiological saline was added directly onto the medium, and the surface was rubbed with a disposable loop to recover the spore suspension containing hyphae.
- a spore suspension containing Trichophyton rubrum and Microsporum canis hyphae was filtered through a cell strainer ( ⁇ 40 ⁇ m). Spores centrifugation from the filtrate (3500 rpm, 5 minutes) was recovered by, washed twice with saline, a spore suspension was prepared (1 ⁇ 10 7 cells / mL). 10 ⁇ L of the spore suspension was inoculated into Sabouraud agar to which the test compound dissolved in DMSO was added to a predetermined concentration. Trichophyton rubrum and Microsporum canis were cultured at 32 ° C. for 72 hours, and then the presence or absence of colony growth was investigated to determine the minimum inhibitory concentration (MIC100). The results are shown in Table 3.
- Test Example 5 Antifungal activity test Test compound: Compound No. 6 Test strains: Trichophyton rubrum (ATCCMYA4607), Microsporum canis (IFM63627)
- Trichophyton rubrum was cultured in Sabouraud agar and Microsporum canis was cultured in 1/10 Sabouraud agar at 32 ° C. for 168 hours to form spores.
- the hyphae are peeled off from the surface of the medium and collected in a tube, physiological saline (Otsuka saline injection; 9 g of sodium chloride is contained in 1000 mL) is added, and the whole is used as a disposable loop (type 1 (1 ⁇ L)). The mixture was mixed and dispersed, and a spore suspension containing hyphae was collected.
- Microsporum canis 10 mL of physiological saline was added directly onto the medium, and the surface was rubbed with a disposable loop to recover the spore suspension containing hyphae.
- a spore suspension containing Trichophyton rubrum and Microsporum canis hyphae was filtered through a cell strainer ( ⁇ 40 ⁇ m). Spores centrifugation from the filtrate (3500 rpm, 5 minutes) was recovered by, washed twice with saline, a spore suspension was prepared (1 ⁇ 10 7 cells / mL). 10 ⁇ L of the spore suspension was inoculated into 90 ⁇ L physiological saline solution in which the test compound dissolved in DMSO was added to a predetermined concentration.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
R1及びR2は、それぞれ独立して、
水素原子、
ハロゲン原子、
水酸基、
ニトロ基、
シアノ基、
チオシアナート基、
トリメチルシリル基、
置換されてもよいアルキル基、
置換されてもよいアルケニル基、
置換されてもよいアルキニル基、
置換されてもよいアルキルオキシ基、
置換されてもよいアルケニルオキシ基、
置換されてもよいアルキニルオキシ基、
置換されてもよいアリール基、
置換されてもよいアリールオキシ基、
置換されてもよい5~6員の芳香族複素環基、
-SOmR3
(R3は、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいアリール基、置換されてもよい5~6員の芳香族複素環基又は-NR4R5基(R4及びR5は、置換されてもよいアルキル基である)であり、mは0~2の整数である)、又は
W1は、酸素原子又は硫黄原子であり、
W2は、酸素原子、硫黄原子又は-NH-であり、
nは0~1の整数であり、
R6は、置換されてもよいアルキル基又は置換されてもよいアリール基である)で表される基
であり;
Xは、水素原子、水酸基又は-OYであり;
Yは、式:
R7は、置換されてもよいアルキル基、
置換されてもよいアルキルオキシ基、
置換されてもよいアルケニル基、
置換されてもよいアルケニルオキシ基、
置換されてもよいアリール基、
置換されてもよいアリールオキシ基、
置換されてもよい5~6員の芳香族複素環基、
-NR8R9基(R8及びR9は、それぞれ独立して、水素原子、置換されてもよいアルキル基又は置換されてもよいアルケニル基であるか、又は、互いに隣接している窒素原子とともに5~7員の飽和複素環を形成し、但し、R8及びR9が同時に水素原子である場合を除く)又は
-CR10R11R12基(R10、R11及びR12は、それぞれ独立して、置換されてもよいアルキル基、置換されてもよいアルケニル基又は置換されてもよいアリール基である))である。]
ハロゲン原子で置換されてもよいアルキル基、
ハロゲン原子で置換されてもよいアルキルオキシ基で置換されたアルキル基、
フェニル基で置換されたアルキル基、
アルキル基、ハロゲン原子もしくは水酸基で置換されたフェニル基で置換されたアルキル基、
ハロゲン原子で置換されてもよいアルケニル基、
ハロゲン原子で置換されてもよいアルキルオキシ基、
ハロゲン原子で置換されてもよいフェニル基、
ハロゲン原子で置換されてもよいアルキル基で置換されたフェニル基、
ハロゲン原子で置換されてもよいアルキルオキシ基で置換されたフェニル基、
ハロゲン原子で置換されてもよいチエニル基、
ピリジル基、
フリル基、
-S(O)mR3基(R3は、フェニル基で置換されてもよいアルキル基、ハロゲン原子で置換されてもよいフェニル基、ハロゲン原子で置換されたアルキル基で置換されてもよいピリジル基、アルケニル基又は-NR4R5基(R4及びR5は、アルキル基である)であり、mは0~2の整数である)、又は
-C(=O)-(NH)nR6(R6はハロゲン原子で置換されてもよいアルキル基、又はハロゲン原子で置換されてもよいフェニル基であり、nは0~1の整数である)である。
5-クロロ-4-(3-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、5-クロロ-4-(2-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、5-クロロ-4-(2-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(3-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(4-クロロ-3-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
4-(2-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、5-クロロ-1-ヒドロキシ-4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、及び
4-クロロ-1-ヒドロキシ-5-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル
から選択されるものである。
[1]式(I)又は(II)で表される化合物又はその塩を含有する、ヒト用抗真菌剤。
R1及びR2は、それぞれ独立して、
水素原子、
ハロゲン原子、
水酸基、
ニトロ基、
シアノ基、
チオシアナート基、
トリメチルシリル基、
置換されてもよいアルキル基、
置換されてもよいアルケニル基、
置換されてもよいアルキニル基、
置換されてもよいアルキルオキシ基、
置換されてもよいアルケニルオキシ基、
置換されてもよいアルキニルオキシ基、
置換されてもよいアリール基、
置換されてもよいアリールオキシ基、
置換されてもよい5~6員の芳香族複素環基、
-SOmR3
(式中、R3は、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいアリール基、置換されてもよい5~6員の芳香族複素環基又は-NR4R5基(式中、R4及びR5は、置換されてもよいアルキル基である)であり、mは0~2の整数である)、又は
W1は、酸素原子又は硫黄原子であり、
W2は、酸素原子、硫黄原子又は-NH-であり、
nは0~1の整数であり、
R6は、置換されてもよいアルキル基又は置換されてもよいアリール基である)で表される基
であり;
Xは、水素原子、水酸基又は-OYであり;
Yは、式:
R7は、置換されてもよいアルキル基、
置換されてもよいアルキルオキシ基、
置換されてもよいアルケニル基、
置換されてもよいアルケニルオキシ基、
置換されてもよいアリール基、
置換されてもよいアリールオキシ基、
置換されてもよい5~6員の芳香族複素環基、
-NR8R9基(R8及びR9は、それぞれ独立して、水素原子、置換されてもよいアルキル基又は置換されてもよいアルケニル基であるか、又は、互いに隣接している窒素原子と共に5~7員の飽和複素環を形成し、但し、R8及びR9が同時に水素原子である場合を除く)又は
-CR10R11R12基(式中、R10、R11及びR12は、それぞれ独立して、置換されてもよいアルキル基、置換されてもよいアルケニル基又は置換されてもよいアリール基である))である。]
[2]R1及びR2は、それぞれ独立して、水素原子、ハロゲン原子又は置換されてもよいフェニル基である、[1]に記載の抗真菌剤。
[3]R1及びR2は、それぞれ独立して、水素原子又はハロゲン原子であるか、あるいは、アルキル基及びハロゲン原子のうち少なくとも1つの基で置換されてもよいフェニル基である、[1]又は[2]に記載の抗真菌剤。
[4]R1及びR2は、それぞれ独立して、水素原子又はハロゲン原子であるか、あるいは、炭素数1~6のアルキル基及びハロゲン原子のうち少なくとも1つの基で置換されてもよいフェニル基である、[1]~[3]のいずれかに記載の抗真菌剤。
[5]R1及びR2は、互いに異なる基である、[1]~[4]のいずれかに記載の抗真菌剤。
[6]Xは、水素原子、水酸基又は-OYであり;
Yは、式:
[7]Xは、水素原子又は水酸基である、[1]~[6]のいずれかに記載の抗真菌剤。
[8]前記式(I)又は(II)で表される化合物は、
5-クロロ-4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(3-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(2-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(2-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(3-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(4-クロロ-3-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
4-(2-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-1-ヒドロキシ-4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、及び
4-クロロ-1-ヒドロキシ-5-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル
から選択されるものである、[1]~[7]のいずれかに記載の抗真菌剤。
[9]医薬である、[1]~[8]のいずれかに記載の抗真菌剤。
[10]前記真菌が、カンジダ属菌、マラセチア属菌、トリコフィトン属菌、ミクロスポルム属菌、アルスロデルマ属菌、アスペルギルス属菌及びクリプトコッカス属菌から選択される少なくとも1つのものである、[1]~[9]のいずれかに記載の抗真菌剤。
[11]前記真菌が、カンジダ属菌、トリコフィトン属菌、ミクロスポルム属菌、アルスロデルマ属菌、アスペルギルス属菌及びクリプトコッカス属菌から選択される少なくとも1つのものである、[1]~[10]のいずれかに記載の抗真菌剤。
[12]前記真菌に起因する症状または疾患の改善のための、[1]~[11]のいずれかに記載の抗真菌剤。
[13]前記症状又は疾患が、皮膚疾患である、[12]に記載の抗真菌剤。
[14]前記症状又は疾患が、癜風、尋常性乾癬、皮膚糸状菌症、カンジダ症、皮膚マラセチア症、アスペルギルス症、クリプトコックス症、アトピー性皮膚炎又は外耳炎である、[12]又は[13]に記載の抗真菌剤。
[15]前記症状又は疾患が、皮膚マラセチア症、皮膚糸状菌症、カンジダ症、アスペルギルス症又はクリプトコックス症である、[12]~[14]のいずれかに記載の抗真菌剤。
特開平8-225539号の実施例1~5に記載の方法に準じて5-クロロ-4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル(化合物No.1)を製造した(CAS番号:120118-14-1)。
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.2を製造した(CAS番号:120118-10-7)。
MS:184.2[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.3を製造した(CAS番号:120118-18-5)。
MS:218.2[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.4を製造した。
MS:218.1[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.5を製造した(CAS番号:2167064-69-7)。
MS:252.2[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.6を製造した(CAS番号:120118-82-3)。
MS:252.1[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.7を製造した。
MS:251.0[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.8を製造した。
MS:218.1[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.9を製造した。
MS:234.1[M+H]+
製造目的物に対応する原料化合物を用いること以外、特開平8-225539号の記載と同様の手法に準じて化合物No.10を製造した(CAS番号:177762-70-8)。
MS:234.1[M+H]+
供試化合物:化合物No.1
供試菌株:Candida albicans(TIMM1768株)
試験方法:YPD液体培地で37℃、20時間培養したカンジダ菌を遠心分離(3000rpm、5分)にて回収し、生理食塩水で2回洗浄後、生理食塩水に懸濁させ、2×103cells/mLとなるように菌液を調製した。そこへDMSOに溶解した試験化合物を所定の濃度となるように加えたサブロー培地に、前記菌液100μLを塗布した。37℃で48時間培養後、コロニー形成の有無を調査した。
その結果、化合物No.1は50ppmでコロニー形成を完全に阻害した。
供試化合物:化合物No.1
供試菌株:Candida glabrata(TIMM6054株)
試験方法:YPD液体培地で37℃、20時間培養したカンジダ菌を遠心分離(3000rpm、5分)にて回収し、生理食塩水で2回洗浄後、生理食塩水に懸濁させ、2×103cells/mLとなるように菌液を調製した。そこへDMSOに溶解した試験化合物を所定の濃度となるように加えたYPD培地に、前記菌液100μLを塗布した。37℃で48時間培養後、コロニー形成の有無を調査した。
その結果、化合物No.1は200ppmでコロニー形成を完全に抑制した。
供試化合物:化合物No.1
供試菌株:Cryptococcus neoformans(TIMM1316株)試験方法:YPD液体培地で37℃、20時間培養したクリプトコッカス菌を遠心分離(3000rpm、5分)にて回収し、生理食塩水で2回洗浄後、生理食塩水に懸濁させ、2×103cells/mLとなるように菌液を調製した。そこへDMSOに溶解した試験化合物を所定の濃度となるように加えたサブロー培地に、前記菌液100μLを塗布した。37℃で48時間培養後、コロニー形成の有無を調査した。
その結果、化合物No.1は20ppmでコロニー形成を完全に抑制した。
供試化合物:化合物No.1
供試菌株:Malassezia nana(CBS95574)
コロニー形成阻害率(%)=[(薬剤無処理区のコロニー形成数-本発明区のコロニー形成数)/薬剤無処理区のコロニー形成数]×100
その結果、化合物No.1のコロニー形成阻害率は100ppmで98.5%、200ppmで99.9%であった。
供試化合物:化合物No.1
供試菌株:Malassezia pachydermatis(TIMM10024)
その結果、化合物No.1のコロニー形成阻害率は100ppmで98.1%、200ppmで100%であった。
供試化合物:化合物No.1
供試菌株:Aspergillus fumigatus(TIMM0063株)、A. niger(TIMM4968株)
試験方法:アスペルギルス菌をPDA培地で27℃、3日間培養後、Tween80(ポリオキシエチレンソルビタンモノオレアート:関東化学株式会社製)(0.05%(v/v))含有生理食塩水で胞子を採取し、セルストレーナー(φ40μm)でろ過した。ろ液から胞子を遠心分離(3500rpm、5分)にて回収し、生理食塩水で2回洗浄後、胞子懸濁液を調製した(1×107個/mL)。DMSOに溶解した化合物No.1を所定の濃度となるように加えたサブロー培地に、前記胞子懸濁液を10μL接種した。28℃で48時間培養後、菌の発育の有無を調査し、最小発育阻止濃度を求めた。
その結果、化合物No.1の2菌株に対する最小発育阻止濃度はいずれも100ppmであった。
供試化合物:化合物No.1
供試菌株:Trichophyton rubrum(CBS118892株)、T. interdegitale(TIMM20065株)、Microsporum canis(TIMM20080株)、Arthroderma vanbreuseghemii(TIMM2789)
その結果、化合物No.1の4菌株に対する最小発育阻止濃度はいずれも10ppmであった。
供試化合物:化合物No.6
供試菌株:Candida albicans(NBRC1594株)、Candida glabrata(JCM3761株)、Cryptococcus neoformans(JCM3685株)、Aspergillus fumigatus(JCM10253)、Aspergillus niger(ATCC6725)、Trichophyton rubrum(ATCCMYA4607)、Trichophyton interdegitale(ATCC9533)、Microsporum canis(NBRC7863)、Arthroderma vanbreuseghemii(JCM1891)
その結果は、第1表に示した。
供試化合物:化合物No.6
供試菌株:Malassezia furfur(IFM 55951)、Malassezia sympodialis(IFM 48588)、Malassezia globosa(IFM 51946)
供試化合物:化合物No.6
供試菌株:Malassezia restricta(IFM55992)
供試化合物:化合物No.6
供試菌株:Trichophyton rubrum(ATCCMYA4607)、Microsporum canis(IFM63627)
その結果を第3表に示した。
供試化合物:化合物No.6
供試菌株:Trichophyton rubrum(ATCCMYA4607)、Microsporum canis(IFM63627)
その結果を第4表に示した。
Claims (15)
- 式(I)又は(II)で表される化合物又はその塩を含有する、ヒト用抗真菌剤。
R1及びR2は、それぞれ独立して、
水素原子、
ハロゲン原子、
水酸基、
ニトロ基、
シアノ基、
チオシアナート基、
トリメチルシリル基、
置換されてもよいアルキル基、
置換されてもよいアルケニル基、
置換されてもよいアルキニル基、
置換されてもよいアルキルオキシ基、
置換されてもよいアルケニルオキシ基、
置換されてもよいアルキニルオキシ基、
置換されてもよいアリール基、
置換されてもよいアリールオキシ基、
置換されてもよい5~6員の芳香族複素環基、
-SOmR3
(式中、R3は、置換されてもよいアルキル基、置換されてもよいアルケニル基、置換されてもよいアルキニル基、置換されてもよいアリール基、置換されてもよい5~6員の芳香族複素環基又は-NR4R5基(式中、R4及びR5は、置換されてもよいアルキル基である)であり、mは0~2の整数である)、又は
W1は、酸素原子又は硫黄原子であり、
W2は、酸素原子、硫黄原子又は-NH-であり、
nは0~1の整数であり、
R6は、置換されてもよいアルキル基又は置換されてもよいアリール基である)で表される基
であり;
Xは、水素原子、水酸基又は-OYであり;
Yは、式:
R7は、置換されてもよいアルキル基、
置換されてもよいアルキルオキシ基、
置換されてもよいアルケニル基、
置換されてもよいアルケニルオキシ基、
置換されてもよいアリール基、
置換されてもよいアリールオキシ基、
置換されてもよい5~6員の芳香族複素環基、
-NR8R9基(式中、R8及びR9は、それぞれ独立して、水素原子、置換されてもよいアルキル基又は置換されてもよいアルケニル基であるか、又は、互いに隣接している窒素原子と共に5~7員の飽和複素環を形成し、但し、R8及びR9が同時に水素原子である場合を除く)又は
-CR10R11R12基(式中、R10、R11及びR12は、それぞれ独立して、置換されてもよいアルキル基、置換されてもよいアルケニル基又は置換されてもよいアリール基である)である。] - R1及びR2は、それぞれ独立して、水素原子、ハロゲン原子又は置換されてもよいフェニル基である、請求項1に記載の抗真菌剤。
- R1及びR2は、それぞれ独立して、水素原子又はハロゲン原子であるか、あるいは、アルキル基及びハロゲン原子のうち少なくとも1つの基で置換されてもよいフェニル基である、請求項1又は2に記載の抗真菌剤。
- R1及びR2は、それぞれ独立して、水素原子又はハロゲン原子であるか、あるいは、炭素数1~6のアルキル基及びハロゲン原子のうち少なくとも1つの基で置換されてもよいフェニル基である、請求項1~3のいずれか一項に記載の抗真菌剤。
- R1及びR2は、互いに異なる基である、請求項1~4のいずれか一項に記載の抗真菌剤。
- Xは、水素原子又は水酸基である、請求項1~6のいずれか一項に記載の抗真菌剤。
- 前記式(I)又は(II)で表される化合物は、
5-クロロ-4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(3-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(2-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(2-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(3-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-4-(4-クロロ-3-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
4-(2-クロロ-4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、
5-クロロ-1-ヒドロキシ-4-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル、及び
4-クロロ-1-ヒドロキシ-5-(4-メチルフェニル)-1H-イミダゾール-2-カルボニトリル
から選択されるものである、請求項1~7のいずれか一項に記載の抗真菌剤。 - 医薬である、請求項1~8のいずれか一項に記載の抗真菌剤。
- 前記真菌が、カンジダ属菌、マラセチア属菌、トリコフィトン属菌、ミクロスポルム属菌、アルスロデルマ属菌、アスペルギルス属菌及びクリプトコッカス属菌から選択される少なくとも1つのものである、請求項1~9のいずれか一項に記載の抗真菌剤。
- 前記真菌が、カンジダ属菌、トリコフィトン属菌、ミクロスポルム属菌、アルスロデルマ属菌、アスペルギルス属菌及びクリプトコッカス属菌から選択される少なくとも1つのものである、請求項1~10のいずれか一項に記載の抗真菌剤。
- 前記真菌に起因する症状または疾患の改善のための、請求項1~11のいずれか一項に記載の抗真菌剤。
- 前記症状又は疾患が、皮膚疾患である、請求項12に記載の抗真菌剤。
- 前記症状又は疾患が、癜風、尋常性乾癬、皮膚糸状菌症、カンジダ症、皮膚マラセチア症、アスペルギルス症、クリプトコックス症、アトピー性皮膚炎又は外耳炎である、請求項12又は13に記載の抗真菌剤。
- 前記症状又は疾患が、皮膚マラセチア症、皮膚糸状菌症、カンジダ症、アスペルギルス症又はクリプトコックス症である、請求項12~14のいずれか一項に記載の抗真菌剤。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP21817674.1A EP4162939A4 (en) | 2020-06-03 | 2021-06-02 | ANTIFUNGAL AGENT INTENDED FOR USE IN HUMAN BEINGS |
MX2022015292A MX2022015292A (es) | 2020-06-03 | 2021-06-02 | Agente antifungico para uso en humanos. |
AU2021284446A AU2021284446A1 (en) | 2020-06-03 | 2021-06-02 | Antifungal agent for use in humans |
BR112022024702A BR112022024702A2 (pt) | 2020-06-03 | 2021-06-02 | Agente antifúngico para ser humano |
CA3181160A CA3181160A1 (en) | 2020-06-03 | 2021-06-02 | Antifungal agent for human |
KR1020237000059A KR20230035028A (ko) | 2020-06-03 | 2021-06-02 | 사람용 항진균제 |
CN202180041539.XA CN115996714A (zh) | 2020-06-03 | 2021-06-02 | 人用抗真菌剂 |
JP2022528876A JPWO2021246455A1 (ja) | 2020-06-03 | 2021-06-02 | |
US18/000,434 US20230233527A1 (en) | 2020-06-03 | 2021-06-02 | Antifungal Agent for Human |
ZA2022/13318A ZA202213318B (en) | 2020-06-03 | 2022-12-08 | Antifungal agent for use in humans |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2020097174 | 2020-06-03 | ||
JP2020-097174 | 2020-06-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2021246455A1 true WO2021246455A1 (ja) | 2021-12-09 |
Family
ID=78831184
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2021/021064 WO2021246455A1 (ja) | 2020-06-03 | 2021-06-02 | ヒト用抗真菌剤 |
Country Status (12)
Country | Link |
---|---|
US (1) | US20230233527A1 (ja) |
EP (1) | EP4162939A4 (ja) |
JP (1) | JPWO2021246455A1 (ja) |
KR (1) | KR20230035028A (ja) |
CN (1) | CN115996714A (ja) |
AU (1) | AU2021284446A1 (ja) |
BR (1) | BR112022024702A2 (ja) |
CA (1) | CA3181160A1 (ja) |
MX (1) | MX2022015292A (ja) |
TW (1) | TW202214234A (ja) |
WO (1) | WO2021246455A1 (ja) |
ZA (1) | ZA202213318B (ja) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63255269A (ja) * | 1987-03-21 | 1988-10-21 | シエーリング・アグロケミカルズ・リミテツド | 抗真菌剤 |
JPH01131163A (ja) | 1987-03-13 | 1989-05-24 | Ishihara Sangyo Kaisha Ltd | イミダゾール系化合物及びそれらを含有する有害生物防除剤 |
JPH08225539A (ja) | 1994-10-28 | 1996-09-03 | Ishihara Sangyo Kaisha Ltd | 2−シアノイミダゾール系化合物の製造方法 |
JPH08283243A (ja) | 1994-09-08 | 1996-10-29 | Ishihara Sangyo Kaisha Ltd | イミダゾール系化合物の製造方法 |
WO2001014341A1 (fr) | 1999-08-19 | 2001-03-01 | Ishihara Sangyo Kaisha, Ltd. | Agents permettant de luter contre les maladies animales engendrees par des parasites |
JP2002193710A (ja) * | 2000-12-25 | 2002-07-10 | Kumiai Chem Ind Co Ltd | ピリミジン又はトリアジン誘導体及び農園芸用殺菌剤 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PH26182A (en) * | 1987-03-13 | 1992-03-18 | Ishihara Sangyo Kaisha | Intermediate compounds for biocidal imidazole compounds |
CA1339133C (en) * | 1987-03-13 | 1997-07-29 | Rikuo Nasu | Imidazole compounds and biocidal composition comprising the same for controlling harmful organisms |
US5045557A (en) * | 1987-03-20 | 1991-09-03 | Schering Agrochemicals Ltd. | Imidazable fungicides and use thereof |
US6713500B2 (en) * | 1999-08-19 | 2004-03-30 | Ishihara Sangyo Kaisha Ltd. | Agent for controlling animal diseases caused by parasites |
JP5502354B2 (ja) * | 2008-03-28 | 2014-05-28 | 石原産業株式会社 | 農園芸用殺菌剤組成物及び植物病害の防除方法 |
-
2021
- 2021-06-02 AU AU2021284446A patent/AU2021284446A1/en active Pending
- 2021-06-02 BR BR112022024702A patent/BR112022024702A2/pt unknown
- 2021-06-02 JP JP2022528876A patent/JPWO2021246455A1/ja active Pending
- 2021-06-02 MX MX2022015292A patent/MX2022015292A/es unknown
- 2021-06-02 US US18/000,434 patent/US20230233527A1/en active Pending
- 2021-06-02 CN CN202180041539.XA patent/CN115996714A/zh active Pending
- 2021-06-02 WO PCT/JP2021/021064 patent/WO2021246455A1/ja active Application Filing
- 2021-06-02 KR KR1020237000059A patent/KR20230035028A/ko active Search and Examination
- 2021-06-02 CA CA3181160A patent/CA3181160A1/en active Pending
- 2021-06-02 EP EP21817674.1A patent/EP4162939A4/en active Pending
- 2021-06-03 TW TW110120204A patent/TW202214234A/zh unknown
-
2022
- 2022-12-08 ZA ZA2022/13318A patent/ZA202213318B/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01131163A (ja) | 1987-03-13 | 1989-05-24 | Ishihara Sangyo Kaisha Ltd | イミダゾール系化合物及びそれらを含有する有害生物防除剤 |
JPS63255269A (ja) * | 1987-03-21 | 1988-10-21 | シエーリング・アグロケミカルズ・リミテツド | 抗真菌剤 |
JPH08283243A (ja) | 1994-09-08 | 1996-10-29 | Ishihara Sangyo Kaisha Ltd | イミダゾール系化合物の製造方法 |
JPH08225539A (ja) | 1994-10-28 | 1996-09-03 | Ishihara Sangyo Kaisha Ltd | 2−シアノイミダゾール系化合物の製造方法 |
WO2001014341A1 (fr) | 1999-08-19 | 2001-03-01 | Ishihara Sangyo Kaisha, Ltd. | Agents permettant de luter contre les maladies animales engendrees par des parasites |
JP2002193710A (ja) * | 2000-12-25 | 2002-07-10 | Kumiai Chem Ind Co Ltd | ピリミジン又はトリアジン誘導体及び農園芸用殺菌剤 |
Non-Patent Citations (4)
Title |
---|
CAS , no. 120118-82-3 |
CAS, no. 120118-18-5 |
PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY, vol. 71, 2001, pages 107 - 115 |
See also references of EP4162939A4 |
Also Published As
Publication number | Publication date |
---|---|
KR20230035028A (ko) | 2023-03-10 |
CN115996714A (zh) | 2023-04-21 |
ZA202213318B (en) | 2024-04-24 |
JPWO2021246455A1 (ja) | 2021-12-09 |
US20230233527A1 (en) | 2023-07-27 |
AU2021284446A1 (en) | 2023-01-19 |
EP4162939A4 (en) | 2024-06-26 |
EP4162939A1 (en) | 2023-04-12 |
CA3181160A1 (en) | 2021-12-09 |
MX2022015292A (es) | 2023-03-06 |
TW202214234A (zh) | 2022-04-16 |
BR112022024702A2 (pt) | 2023-02-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2861573B1 (en) | Oxathiazine derivatives as antibacterial and anticancer agents. | |
KR20140129030A (ko) | 캔디다증 및 아스퍼질러스 감염을 치료하기 위한 화합물 및 방법 | |
JP2023011847A (ja) | 真菌感染の処置のための組成物及び方法 | |
CN109503510B (zh) | 一种防龋抗菌的噻唑类化合物及其制备方法 | |
CA2211161A1 (fr) | Medicament destine au traitement des troubles obsessifs compulsifs, de l'apnee du sommeil, des dysfonctions sexuelles, de l'emese et du mal des transports | |
US20200361874A1 (en) | Compositions and methods for the treatment of oral infectious diseases | |
WO2023106320A1 (ja) | 5-クロロ-4-(3-クロロ-4-メチルフェニル)-1h-イミダゾール-2-カルボニトリルの水和物結晶 | |
RU2056416C1 (ru) | Производные тиомочевины, фармацевтическая композиция и способ лечения | |
WO2021246455A1 (ja) | ヒト用抗真菌剤 | |
US8987277B2 (en) | Fungicide | |
WO2021246453A1 (ja) | 非ヒト動物用抗菌剤 | |
US7704976B2 (en) | Use of N-acetyl-D-glucosamine for preparing medicines for urogenital tract infection's treatment and prevention | |
AU679305B2 (en) | Substituted cyclohexanol esters, their use for treating diseases, and pharmaceutical preparations | |
EP3954370B1 (en) | Anti-fungal agent | |
JPH0372468A (ja) | トリアゾール化合物及びこれを含有する抗真菌剤 | |
US8022072B2 (en) | Azolylmethylidenehydrazine derivative and use thereof | |
FI70705B (fi) | Foerfarande foer framstaellning av nya farmakologiskt verkandedekahydrokinolinolderivat | |
JP6553961B2 (ja) | 美白剤 | |
BG108032A (bg) | Азолови съединения като противогъбични средства | |
JPH01153635A (ja) | 抗真菌剤 | |
EP3782702A1 (en) | Compounds and use thereof for the treatment of infectious diseases and cancer | |
KR20190054423A (ko) | 메틸렌비스 및 관련 화합물의 자가포식 조절 기전을 이용하여 dna 토포이소머라제1 억제제의 항암 효능 증진 방법 | |
El Zein | Derivatives of Rhodanine as Potential Antifungal Drugs | |
JP2012224592A (ja) | 神経芽細胞腫に対する抗腫瘍薬 | |
JP2000034285A (ja) | 抗真菌剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21817674 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 3181160 Country of ref document: CA |
|
ENP | Entry into the national phase |
Ref document number: 2022528876 Country of ref document: JP Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112022024702 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202217073550 Country of ref document: IN |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2021817674 Country of ref document: EP Effective date: 20230103 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2022134445 Country of ref document: RU |
|
ENP | Entry into the national phase |
Ref document number: 2021284446 Country of ref document: AU Date of ref document: 20210602 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112022024702 Country of ref document: BR Kind code of ref document: A2 Effective date: 20221202 |