JP6681894B2 - 抗真菌剤 - Google Patents
抗真菌剤 Download PDFInfo
- Publication number
- JP6681894B2 JP6681894B2 JP2017527340A JP2017527340A JP6681894B2 JP 6681894 B2 JP6681894 B2 JP 6681894B2 JP 2017527340 A JP2017527340 A JP 2017527340A JP 2017527340 A JP2017527340 A JP 2017527340A JP 6681894 B2 JP6681894 B2 JP 6681894B2
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- compound
- dimethyl
- pyrrol
- piperazin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229940121375 antifungal agent Drugs 0.000 title claims description 67
- 239000003429 antifungal agent Substances 0.000 title claims description 65
- 150000001875 compounds Chemical class 0.000 claims description 150
- -1 1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl Chemical group 0.000 claims description 127
- 150000003839 salts Chemical class 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 79
- 239000008194 pharmaceutical composition Substances 0.000 claims description 49
- 208000031888 Mycoses Diseases 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 42
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- SUFPWYYDCOKDLL-UHFFFAOYSA-N 2-(1,5-dimethyl-3-phenylpyrrol-2-yl)-N-[4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]phenyl]-2-oxoacetamide Chemical compound CN1C(=C(C=C1C)C1=CC=CC=C1)C(C(=O)NC1=CC=C(C=C1)N1CCN(CC1)C1=NC=C(C=N1)F)=O SUFPWYYDCOKDLL-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 23
- 241000228212 Aspergillus Species 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 22
- 230000002265 prevention Effects 0.000 claims description 17
- 230000002538 fungal effect Effects 0.000 claims description 16
- 208000006673 asthma Diseases 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 15
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 15
- 206010006474 Bronchopulmonary aspergillosis allergic Diseases 0.000 claims description 14
- 208000006778 allergic bronchopulmonary aspergillosis Diseases 0.000 claims description 14
- 239000003112 inhibitor Substances 0.000 claims description 14
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 11
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 claims description 11
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- 230000008313 sensitization Effects 0.000 claims description 7
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 claims description 6
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- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 6
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- JYIKNQVWKBUSNH-WVDDFWQHSA-N caspofungin Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 JYIKNQVWKBUSNH-WVDDFWQHSA-N 0.000 claims description 5
- 229960003034 caspofungin Drugs 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229960004413 flucytosine Drugs 0.000 claims description 5
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 5
- 150000003230 pyrimidines Chemical class 0.000 claims description 5
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 claims description 4
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
- 241001480043 Arthrodermataceae Species 0.000 claims description 4
- 206010020751 Hypersensitivity Diseases 0.000 claims description 4
- 230000000844 anti-bacterial effect Effects 0.000 claims description 4
- 230000037304 dermatophytes Effects 0.000 claims description 4
- 230000000855 fungicidal effect Effects 0.000 claims description 4
- BODYFEUFKHPRCK-ZCZMVWJSSA-N ibrexafungerp Chemical compound N1([C@@H]2C[C@@]34COC[C@]([C@H]2OC[C@](C)(N)C(C)(C)C)(C)[C@@H]3CC[C@@H]2[C@@]3(C)CC[C@]([C@H]([C@]3(C)CC=C24)C(O)=O)(C)[C@H](C)C(C)C)N=CN=C1C1=CC=NC=C1 BODYFEUFKHPRCK-ZCZMVWJSSA-N 0.000 claims description 4
- 229960004130 itraconazole Drugs 0.000 claims description 4
- 239000002213 purine nucleotide Substances 0.000 claims description 4
- 239000002719 pyrimidine nucleotide Substances 0.000 claims description 4
- 229960000580 terconazole Drugs 0.000 claims description 4
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims description 3
- 108010021062 Micafungin Proteins 0.000 claims description 3
- 229960004884 fluconazole Drugs 0.000 claims description 3
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 claims description 3
- 229950003053 icofungipen Drugs 0.000 claims description 3
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- 229960002159 micafungin Drugs 0.000 claims description 3
- PIEUQSKUWLMALL-YABMTYFHSA-N micafungin Chemical compound C1=CC(OCCCCC)=CC=C1C1=CC(C=2C=CC(=CC=2)C(=O)N[C@@H]2C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N[C@H](C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[C@H](O)C2)[C@H](O)CC(N)=O)[C@H](O)[C@@H](O)C=2C=C(OS(O)(=O)=O)C(O)=CC=2)[C@@H](C)O)=O)=NO1 PIEUQSKUWLMALL-YABMTYFHSA-N 0.000 claims description 3
- RKOUGZGFAYMUIO-RITPCOANSA-N pdl 118 Chemical compound N[C@H]1CC(=C)C[C@H]1C(O)=O RKOUGZGFAYMUIO-RITPCOANSA-N 0.000 claims description 3
- YEBIHIICWDDQOL-YBHNRIQQSA-N polyoxin Polymers O[C@@H]1[C@H](O)[C@@H](C(C=O)N)O[C@H]1N1C(=O)NC(=O)C(C(O)=O)=C1 YEBIHIICWDDQOL-YBHNRIQQSA-N 0.000 claims description 3
- 150000003212 purines Chemical class 0.000 claims description 3
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 claims description 2
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- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 claims description 2
- ZCJYUTQZBAIHBS-UHFFFAOYSA-N 1-[2-(2,4-dichlorophenyl)-2-{[4-(phenylsulfanyl)benzyl]oxy}ethyl]imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C=CC(SC=2C=CC=CC=2)=CC=1)CN1C=NC=C1 ZCJYUTQZBAIHBS-UHFFFAOYSA-N 0.000 claims description 2
- OCAPBUJLXMYKEJ-UHFFFAOYSA-N 1-[biphenyl-4-yl(phenyl)methyl]imidazole Chemical compound C1=NC=CN1C(C=1C=CC(=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 OCAPBUJLXMYKEJ-UHFFFAOYSA-N 0.000 claims description 2
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 claims description 2
- JLGKQTAYUIMGRK-UHFFFAOYSA-N 1-{2-[(7-chloro-1-benzothiophen-3-yl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound ClC1=CC(Cl)=CC=C1C(OCC=1C2=CC=CC(Cl)=C2SC=1)CN1C=NC=C1 JLGKQTAYUIMGRK-UHFFFAOYSA-N 0.000 claims description 2
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- BWMISRWJRUSYEX-SZKNIZGXSA-N terbinafine hydrochloride Chemical compound Cl.C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 BWMISRWJRUSYEX-SZKNIZGXSA-N 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 201000004647 tinea pedis Diseases 0.000 description 1
- 201000005882 tinea unguium Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229960004319 trichloroacetic acid Drugs 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229940010175 vfend Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01G—HORTICULTURE; CULTIVATION OF VEGETABLES, FLOWERS, RICE, FRUIT, VINES, HOPS OR SEAWEED; FORESTRY; WATERING
- A01G7/00—Botany in general
- A01G7/06—Treatment of growing trees or plants, e.g. for preventing decay of wood, for tingeing flowers or wood, for prolonging the life of plants
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- 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
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Description
(a)2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド又はその重水素化誘導体、又は
(b)2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミド又はその重水素化誘導体、又は
(c)(a)又は(b)のプロドラッグ
である化合物、又は(a)、(b)又は(c)の医薬上許容される塩若しくは農業上許容される塩を提供する。
(a)2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド又はその重水素化誘導体、又は
(b)2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミド又はその重水素化誘導体、又は
(c)(a)又は(b)のプロドラッグ
である医薬化合物、又は(a)、(b)又は(c)の医薬上許容される塩である。
(a)2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド、又は
(b)2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミド
である農業用化合物、又は(a)又は(b)の農業上許容される塩である。
本発明は、
(a)
(b)
(c)化合物(a)のプロドラッグ又は化合物(b)のプロドラッグ
である化合物、又は(a)、(b)又は(c)の医薬上許容される塩又は農業上許容される塩を提供する。
また、本発明は、化合物(a)のプロドラッグ又は化合物(b)のプロドラッグを提供する。化合物は、例えば、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミドのプロドラッグであってもよく、或いは化合物は、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミドのプロドラッグであってもよい。プロドラッグは、例えば、高い溶解度、透過性、吸着、分布及び製剤、及び/又は低い毒性をもたらすことができる。
を有し得る。
本発明の化合物は、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミド又は2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミドの重水素化誘導体であってもよい。本発明の化合物の重水素化誘導体は、高活性の抗真菌剤であることが見出されている。
(a) ピペラジニル環上の水素原子の全てが、重水素に置き換えられていてもよく
(b) ピペラジニル環に隣接したフェニル環上の水素原子の全てが、重水素に置き換えられていてもよく
(c) ピリミジニル環上の水素原子の全てが、重水素に置き換えられていてもよい。
(a) ピペラジニル環上の水素原子の全てが、重水素に置き換えられていてもよく
(b) ピペラジニル環に隣接したフェニル環上の水素原子の全てが、重水素に置き換えられていてもよく
(c) ピリミジニル環上の水素原子の全てが、重水素に置き換えられていてもよい。
ある実施形態では、本発明の化合物は、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド、又はその医薬上許容される塩である。
ある実施形態では、本発明は、1種以上の医薬上許容される担体及び/又は賦形剤と共に本発明の医薬化合物を含む医薬組成物を提供する。
また、本発明は、(i)本発明の医薬化合物、及び(ii)第二の抗真菌剤を含む医薬配合物を提供する。
ある実施形態では、(i)本発明の医薬化合物(例えば、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド又はその医薬上許容される塩)、(ii)本明細書に定義の医薬組成物又は(iii)本明細書に定義の医薬配合物は、治療によるヒト又は動物体の治療方法に用いられるためのものであってもよい。
また、本発明は、植物の菌類病を防ぐ方法であって、植物のローカスに、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド又はその農業上許容される塩、又は2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)−3−ヒドロキシフェニル)−2−オキソアセトアミド又はその農業上許容される塩である化合物を塗布することを含む方法を提供する。場合により、第二の抗真菌剤も存在していてもよい。
1.実施例1:2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミドの合成
実施例3:2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル−2,2,3,3,5,5,6,6−d8)フェニル)−2−オキソアセトアミド
2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミドが多種多様な菌類の増殖を阻害することを証明するデータを以下に示す。このピロール化合物と構造的に類似の化合物との間の比較も提供する。化合物は以下の通り:
2−(1,5−ジメチル−3−フェニル−1H−ピロロ−2−イル)−N−{4−[4−(5−フルオロ−ピリミジン−2−イル−ピペラジン−1イル]−フェニル}−2−オキソ−アセトアミド
1〜5mgの化合物を滅菌エッペンチューブに正確に量り取った。化合物をDMSOに溶解し、5mg/mLを含む溶液を得た。必要になるまでチューブを−20℃で保存した。
以下のMICの結果は、各グレードにまとめられている。例えば、Fグレードは、MICが0.06mg/Lより大きいことを示す。Eグレードは、MICが0.04mg/Lより大きく0.06mg/L以下であることを示す。Dグレードは、MICが0.02mg/Lより大きく0.04mg/L以下であることを示す。Cグレードは、MICが0.01mg/Lより大きく0.02mg/L以下であることを示す。Bグレードは、MICが0.005mg/Lより大きく0.01mg/L以下であることを示す。Aグレードは、MICが0.005mg/L以下であることを示す。
以下のMICの結果は、上記定義の各グレードにまとめられている。
アスペルギルス・フミガタス感染症の生存モデルの概要
マウス生存モデルは、しばしば、アスペルギルスに対する抗真菌剤の有効性を評価するために用いられる。実施例1の開発で用いられたモデルは、抗真菌剤の評価の広範な経験を有する開発業務受託機関(CRO)であるEuprotec社(マンチェスター)で行った。代表的なモデルは、処置群あたり6〜10匹の雄CD−1マウスのグループの使用を含む。マウスに200mg/kgシクロホスファミドを感染3日前に腹腔内注射して免疫抑制する。A.フミガタス菌株A1163を35℃で4〜6日間サブロー寒天培地で培養する。胞子をリン酸緩衝食塩水(PBS)/Tweenに採取し、懸濁液を希釈し、胞子の数を数える。次いで、マウスに側面尾静脈を介してA.フミガタス胞子を静脈注射して感染させる。代表的な接種は、6〜8x104cfu/マウスであり、4〜6日目までに全ての未処置の動物を殺すのに十分である。動物がIAで死ぬとアスペルギルス生物が多くの体組織で検出され得る。処置は、通常、感染後すぐに開始するが、感染後24時間までの遅延は、より困難なモデルを生み出す。処置は、7〜9日間継続する。経口投与により1日3回まで処置してもよい。処置停止後、動物を1〜2日間観察し、次いで犠牲にする。経口薬剤不含ビヒクルで処置した関連対照は常に含まれる。このグループには生存マウスが存在しないのが理想的である。参考例10のような抗真菌剤からなる陽性対照が用いられた。この化合物は、経口経路で投与された場合、10mg/kg b.i.d.の用量で一貫して100%の生存率を示す。多くのモデルが一時的な好中球減少モデルとして実行され、シクロホスファミドの単回投与のみがなされる。
ガラクトマンナンは、アスペルギルスの細胞壁に存在する炭水化物である。生物が増殖するにつれ、ガラクトマンナンが細胞外培地に分泌される。それは、感染したヒト及び動物の血漿において見出され、その存在は、活動性疾患の強力な指標である。ヒト血漿におけるガラクトマンナンの検出は、現在、ヒトのアスペルギルス症の重要な診断検査とみなされている。より最近では、ボリコナゾールのような薬剤でアスペルギルス症の治療が成功すれば、ヒト及び動物両方の血清におけるガラクトマンナン濃度を低下させることができ、連続的なガラクトマンナン指数が、治療効果の尺度として使用できることが示されている。ガラクトマンナン測定は、潜在的に、臨床試験における抗真菌治療の応答を評価するための有用なバイオマーカーであり得る。レベルの上昇は、治療の失敗を示し、その一方で、レベルの低下は、治療の成功を示す。しかしながら、カスポファンギンのようなエキノカンジン剤は、アスペルギルス症の動物モデルにおいて有効であるが、ガラクトマンナンレベルを低下させない。この研究の目的は、実施例1がマウスのアスペルギルス感染症モデルにおいてガラクトマンナンレベルを低下させるかどうか、これが将来の作業における有効性を予測するためのマーカーとして用いることができるかどうかを決定することであった。
生存率試験を実施し、実施例1の用量反応を評価した。10mg/kg b.i.d.及び3mg/kg b.i.d.の2つの用量レベルで、A.フミガタスに感染したマウスに実施例1を経口投与した。感染24時間後に処置を開始し、治療を8日間継続した。試験の終わりに、生き残った動物について腎臓負荷を測定した。さらに、試験の終わりに全ての生き残った動物及び試験の過程で死亡した各動物から血清試料を採取した。ガラクトマンナン測定のためにこれらを−80℃で凍結保存した。生存曲線を図5に示す。
培養
L.プロリフィカンス(スケドスポリウム・プロリフィカンス又はS.プロリフィカンスとしても知られる)を、35℃で5日間ポテトデキストロース寒天培地(PDA)上で増殖させた。感染当日に、培養物を滅菌生理食塩水に浸し、滅菌ガーゼでろ過し、生子及び菌糸の塊を除去した。得られた懸濁剤を、血球計のカウントによって、そして、生存率を確認するために、連続プレーティングによって調整した。
30gの平均体重を有する雄OF−1マウスを実験に用いた。マウスを食物及び水を自由にした標準的な箱に収容した。全ての動物の手順は、ロビライビルジリ大学動物福祉倫理委員会により監督及び承認された。
感染2日前に、200mg/kgのシクロホスファミドを腹腔内(i.p.)注射することにより(その後5日に1回)、マウスを好中球減少症にした(Clemons et al,2005)。
0.2mlの体積の滅菌生理食塩水中の5x104CFU/動物のL.プロリフィカンスFMR3569を用いてマウスの側面尾静脈にチャレンジした。
処置は、(a)強制飼養QDによる25mg/kg p.oのボリコナゾール(VRC)(Vfend;ファイザーS.A.、スペイン・マドリッド);(b)強制飼養BIDによる20mg/k、p.oの実施例1;及び(c)処置なしからなった。感染3日前から、VRCを与えたマウスに水の代わりにグレープフルーツジュースを与えた(Sugar & Liu,2001)。全ての処置は、チャレンジ1日後に開始し、治療を9日間継続した。対照は処置しなかった。
平均生存期間(MST)をカプランマイヤー法により評価し、ログランク検定を用いることによりグループ間を比較した。組織負荷研究では、WindowsのGraph Pad Prism5を用いて、コロニー数をlog10変換し、両側マンホイットニーのU検定により比較した。P値≦0.05は、統計的に有意であるとみなされた。
生存率の結果を図7に示す。示されたデータから、対照と比較して、ボリコナゾールの使用が生存率の有意な増加をもたらさないということが明白である。対照的に、実施例1により生存率の向上がもたらされた。
Claims (27)
-
2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド、又は
その医薬上許容される塩。 - 1種以上の医薬上許容される担体及び/又は賦形剤と共に請求項1に定義の化合物を含む医薬組成物。
- (i) 請求項1に定義の化合物;及び
(ii) 第二の抗真菌剤
を含む医薬配合物。 - 化合物(i)及び第二の抗真菌剤(ii)を個別投与、同時投与又は連続投与のために製剤化した請求項3に記載の医薬配合物。
- 第二の抗真菌剤が、アゾール、ポリエン、プリンヌクレオチド阻害剤、ピリミジンヌクレオチド阻害剤、マンナン阻害剤、タンパク質伸長因子阻害剤、エキノカンジン、アリルアミン、抗HSP90抗体、殺菌性/透過性誘導タンパク質産物又はポリオキシンからなる群から選ばれるもの、或いは化合物5−フルオロ−1,3−ジヒドロ−1−ヒドロキシ−2,1−ベンゾキサボラル、5−クロロ−1,3−ジヒドロ−1−ヒドロキシ−2,1−ベンゾキサボラル、イコフンギペン、VT116又はSCY078の何れか1つである請求項3又は請求項4に記載の医薬配合物。
- 第二の抗真菌剤が、(a.i)クロトリマゾール、エコナゾール、ビホナゾール、ブトコナゾール、フェンチコナゾール、フルコナゾール、イソコナゾール、イトラコナゾール、ケトコナゾール、ミコナゾール、オキシコナゾール、セルタコナゾール、スルコナゾール、チオコナゾール、イサブコナゾール、ラブコナゾール、ポサコナゾール、テルコナゾール及びボリコナゾールから選ばれるアゾール;(a.ii)アニデュラファンギン、カスポファンギン及びミカファンギンから選ばれるエキノカンジン;(a.iii)テルビナフィン、ブテナフィン、アモロルフィン及びナフチフィンから選ばれるアリルアミン;(a.iv)アンフォテリシンB及びナイスタチンから選ばれるポリエン;(a.v)フルシトシンであるプリン又はピリミジンヌクレオチド阻害剤;(a.vi)プラディマイシンであるマンナン阻害剤;(a.vii)ソルダリン及びその類似体から選ばれるタンパク質伸長因子阻害剤;又は(a.viii)ニコマイシンZであるポリオキシンである請求項5に記載の医薬配合物。
- (i)請求項1に定義の化合物、(ii)請求項3〜6の何れか1項に定義の第二の抗真菌剤、及び(iii)1種以上の医薬上許容される担体及び/又は賦形剤を含む請求項2に記載の医薬組成物。
- 請求項1に記載の化合物、又は請求項3〜6の何れか1項に記載の医薬配合物を活性成分として含む医薬組成物。
- 請求項1に記載の化合物、請求項2又は7に記載の医薬組成物、又は請求項3〜6の何れか1項に記載の医薬配合物を含む菌類病の予防又は治療のための薬剤。
- 薬剤が静脈内投与のための請求項9に記載の薬剤。
- 疾患がアスペルギルス種により引き起こされる請求項9又は請求項10に記載の薬剤。
- 疾患が真菌の皮膚糸状菌により引き起こされるか或いは疾患がアレルギー性気管支肺アスペルギルス症(ABPA)又は喘息である請求項9又は請求項10に記載の薬剤。
- 請求項1に記載の化合物、請求項2又は7に記載の医薬組成物、又は請求項3〜6の何れか1項に記載の医薬配合物を含む真菌の感作を伴う重度の喘息(SAFS)の予防又は治療のための薬剤。
- 請求項1に記載の化合物、請求項2又は7に記載の医薬組成物、又は請求項3〜6の何れか1項に記載の医薬配合物を含む、喘息を有している対象における菌類が悪化させるアレルギー反応の予防又は治療のための薬剤。
- 薬剤が真菌の感作を伴う重度の喘息(SAFS)の予防又は治療のための請求項14に記載の薬剤。
- 薬剤が静脈内投与のための請求項13〜15の何れか1項に記載の薬剤。
- 混合容器又は別々の容器において、請求項1に定義の化合物及び請求項3〜6の何れか1項に定義の第二の抗真菌剤を含むキット。
- 植物の菌類病を防ぐ方法であって、
2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド又はその農業上許容される塩である化合物;及び
任意で第二の抗真菌剤
を植物のローカスに塗布することを含む方法。 - 任意で第二の抗真菌剤を伴う、2−(1,5−ジメチル−3−フェニル−1H−ピロール−2−イル)−N−(4−(4−(5−フルオロピリミジン−2−イル)ピペラジン−1−イル)フェニル)−2−オキソアセトアミド又はその農業上許容される塩である化合物の農業殺菌剤としての使用。
- 菌類病の予防又は治療のための医薬の製造における請求項1に定義の化合物、請求項2又は7に記載の医薬組成物、又は請求項3〜6の何れか1項に記載の医薬配合物の使用。
- 疾患が真菌の皮膚糸状菌により引き起こされる請求項20に記載の使用。
- 疾患がアレルギー性気管支肺アスペルギルス症(ABPA)である請求項20に記載の使用。
- 疾患が喘息である請求項20に記載の使用。
- 真菌の感作を伴う重度の喘息(SAFS)の予防又は治療のための医薬の製造における請求項1に定義の化合物、請求項2又は7に記載の医薬組成物、又は請求項3〜6の何れか1項に記載の医薬配合物の使用。
- 喘息を有している対象における菌類が悪化させるアレルギー反応の予防又は治療のための医薬の製造における請求項1に定義の化合物、請求項2又は7に記載の医薬組成物、又は請求項3〜6の何れか1項に記載の医薬配合物の使用。
- 医薬が真菌の感作を伴う重度の喘息(SAFS)の予防又は治療のための請求項25に記載の使用。
- 静脈内投与のための形態である医薬の製造における請求項20〜26の何れか1項に記載の使用。
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