IL105048A - Cyclic peptide antifungal agents and process for preparation thereof - Google Patents
Cyclic peptide antifungal agents and process for preparation thereofInfo
- Publication number
- IL105048A IL105048A IL10504893A IL10504893A IL105048A IL 105048 A IL105048 A IL 105048A IL 10504893 A IL10504893 A IL 10504893A IL 10504893 A IL10504893 A IL 10504893A IL 105048 A IL105048 A IL 105048A
- Authority
- IL
- Israel
- Prior art keywords
- formula
- alkyl
- phenyl
- substituted
- hydrogen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 39
- 230000008569 process Effects 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 9
- 229940121375 antifungal agent Drugs 0.000 title description 29
- 108010069514 Cyclic Peptides Proteins 0.000 title description 12
- 102000001189 Cyclic Peptides Human genes 0.000 title description 12
- 239000003429 antifungal agent Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 42
- 239000001257 hydrogen Substances 0.000 claims abstract description 41
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 30
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 23
- 125000002252 acyl group Chemical group 0.000 claims abstract description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 5
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 5
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims abstract description 3
- -1 C7-C14 tricycloalkyl Chemical group 0.000 claims description 106
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 21
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims description 20
- 244000045947 parasite Species 0.000 claims description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 10
- 125000006711 (C2-C12) alkynyl group Chemical group 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 230000002538 fungal effect Effects 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 230000003071 parasitic effect Effects 0.000 claims description 6
- 125000006710 (C2-C12) alkenyl group Chemical group 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- 241000233872 Pneumocystis carinii Species 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 3
- 208000001388 Opportunistic Infections Diseases 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 2
- 125000002346 iodo group Chemical group I* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical group [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 239000008024 pharmaceutical diluent Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- 241000700159 Rattus Species 0.000 description 19
- 230000000843 anti-fungal effect Effects 0.000 description 17
- 210000004072 lung Anatomy 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 208000015181 infectious disease Diseases 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 208000031513 cyst Diseases 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 241001465754 Metazoa Species 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229910001868 water Inorganic materials 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 8
- FAUOJMHVEYMQQG-HVYQDZECSA-N echinocandin B Chemical compound C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3C[C@H](C)[C@H](O)[C@H]3C(=O)N[C@H](O)[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)CCCCCCC\C=C/C\C=C/CCCCC)[C@@H](C)O)=CC=C(O)C=C1 FAUOJMHVEYMQQG-HVYQDZECSA-N 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000007912 intraperitoneal administration Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 108010049047 Echinocandins Proteins 0.000 description 4
- 206010017533 Fungal infection Diseases 0.000 description 4
- 208000031888 Mycoses Diseases 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000000443 aerosol Substances 0.000 description 4
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 4
- 238000005947 deacylation reaction Methods 0.000 description 4
- 108010062092 echinocandin B Proteins 0.000 description 4
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 4
- 239000007903 gelatin capsule Substances 0.000 description 4
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000009885 systemic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000002141 anti-parasite Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 125000001743 benzylic group Chemical group 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000020176 deacylation Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 150000004665 fatty acids Chemical group 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 125000001312 palmitoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 201000000317 pneumocystosis Diseases 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000003442 weekly effect Effects 0.000 description 3
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 241000187840 Actinoplanes utahensis Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010011732 Cyst Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 108010018980 FR 901379 Proteins 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WUPSJTQKGFMDON-UHFFFAOYSA-N Mulundocandin Natural products N1C(=O)C2CC(O)CN2C(=O)C(C(C)O)NC(=O)C(NC(=O)CCCCCCCCCCC(C)CC)CC(O)C(O)NC(=O)C2C(O)C(C)CN2C(=O)C(CO)NC(=O)C1C(O)C(O)C1=CC=C(O)C=C1 WUPSJTQKGFMDON-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WUPSJTQKGFMDON-FUMJLYDLSA-N N-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-6-[(1S)-1,2-dihydroxy-2-(4-hydroxyphenyl)ethyl]-11,20,21,25-tetrahydroxy-15-[(1R)-1-hydroxyethyl]-3-(hydroxymethyl)-26-methyl-2,5,8,14,17,23-hexaoxo-1,4,7,13,16,22-hexazatricyclo[22.3.0.09,13]heptacosan-18-yl]-12-methyltetradecanamide Chemical compound CCC(C)CCCCCCCCCCC(=O)N[C@H]1C[C@@H](O)[C@@H](O)NC(=O)[C@@H]2[C@@H](O)[C@@H](C)CN2C(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H]2C[C@@H](O)CN2C(=O)[C@@H](NC1=O)[C@@H](C)O)[C@H](O)C(O)c1ccc(O)cc1 WUPSJTQKGFMDON-FUMJLYDLSA-N 0.000 description 2
- 238000011887 Necropsy Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 2
- 229920002700 Polyoxyl 60 hydrogenated castor oil Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 150000007854 aminals Chemical class 0.000 description 2
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 2
- 239000003096 antiparasitic agent Substances 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- JRXXLCKWQFKACW-UHFFFAOYSA-N biphenylacetylene Chemical class C1=CC=CC=C1C#CC1=CC=CC=C1 JRXXLCKWQFKACW-UHFFFAOYSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 108010090182 cilofungin Proteins 0.000 description 2
- ZKZKCEAHVFVZDJ-MTUMARHDSA-N cilofungin Chemical compound C1=CC(OCCCCCCCC)=CC=C1C(=O)N[C@@H]1C(=O)N[C@@H]([C@@H](C)O)C(=O)N2C[C@H](O)C[C@H]2C(=O)N[C@@H]([C@H](O)[C@@H](O)C=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)N2C[C@H](C)[C@H](O)[C@H]2C(=O)N[C@H](O)[C@H](O)C1 ZKZKCEAHVFVZDJ-MTUMARHDSA-N 0.000 description 2
- 229950007664 cilofungin Drugs 0.000 description 2
- 229940047766 co-trimoxazole Drugs 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 2
- 125000002669 linoleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 108010084578 mulundocandin Proteins 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 108010023461 pneumocandin A(0) Proteins 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 206010040872 skin infection Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000021286 stilbenes Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 210000003812 trophozoite Anatomy 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 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
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- LHJGJYXLEPZJPM-UHFFFAOYSA-N 2,4,5-trichlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C=C1Cl LHJGJYXLEPZJPM-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- 101100221077 Arabidopsis thaliana CML12 gene Proteins 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 241000222173 Candida parapsilosis Species 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 230000005526 G1 to G0 transition Effects 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
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- 108010028921 Lipopeptides Proteins 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 241000233870 Pneumocystis Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- MGVGMXLGOKTYKP-ZFOBEOMCSA-N acetic acid;(6s,8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-17-(2-hydroxyacetyl)-6,10,13-trimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-3-one Chemical compound CC(O)=O.C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 MGVGMXLGOKTYKP-ZFOBEOMCSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000002814 agar dilution Methods 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 125000000304 alkynyl 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
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 150000004074 biphenyls Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 229940055022 candida parapsilosis Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 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
- 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
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=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
- 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
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NSBNXCZCLRBQTA-UHFFFAOYSA-N dibenzyl bis(phenylmethoxy)phosphoryl phosphate Chemical compound C=1C=CC=CC=1COP(OP(=O)(OCC=1C=CC=CC=1)OCC=1C=CC=CC=1)(=O)OCC1=CC=CC=C1 NSBNXCZCLRBQTA-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 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
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 230000007366 host health Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000008629 immune suppression Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- AMZMQXJQIYKBJU-UHFFFAOYSA-N iodo benzoate Chemical compound IOC(=O)C1=CC=CC=C1 AMZMQXJQIYKBJU-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000011694 lewis rat Methods 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- DYUWQWMXZHDZOR-UHFFFAOYSA-N methyl 4-iodobenzoate Chemical compound COC(=O)C1=CC=C(I)C=C1 DYUWQWMXZHDZOR-UHFFFAOYSA-N 0.000 description 1
- 229960001293 methylprednisolone acetate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])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])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 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
- 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
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- NXLOLUFNDSBYTP-UHFFFAOYSA-N retene Chemical compound C1=CC=C2C3=CC=C(C(C)C)C=C3C=CC2=C1C NXLOLUFNDSBYTP-UHFFFAOYSA-N 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])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])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
- 239000008223 sterile water Substances 0.000 description 1
- 150000001629 stilbenes Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000004083 survival effect Effects 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
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl 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])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003981 vehicle Substances 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
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/64—Cyclic peptides containing only normal peptide links
- C07K7/66—Gramicidins S, C; Tyrocidins A, B, C; Related peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/50—Cyclic peptides containing at least one abnormal peptide link
- C07K7/54—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring
- C07K7/56—Cyclic peptides containing at least one abnormal peptide link with at least one abnormal peptide link in the ring the cyclisation not occurring through 2,4-diamino-butanoic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Virology (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL12231593A IL122315A (en) | 1992-03-19 | 1993-03-15 | Cyclic peptides and antifungal pharmaceutical compositions containing them |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US85411792A | 1992-03-19 | 1992-03-19 | |
| US99239092A | 1992-12-16 | 1992-12-16 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL105048A0 IL105048A0 (en) | 1993-07-08 |
| IL105048A true IL105048A (en) | 2001-06-14 |
Family
ID=27127211
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10504893A IL105048A (en) | 1992-03-19 | 1993-03-15 | Cyclic peptide antifungal agents and process for preparation thereof |
| IL12231593A IL122315A (en) | 1992-03-19 | 1993-03-15 | Cyclic peptides and antifungal pharmaceutical compositions containing them |
| IL12231597A IL122315A0 (en) | 1992-03-19 | 1997-11-27 | Cyclic peptide antifungal agents |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL12231593A IL122315A (en) | 1992-03-19 | 1993-03-15 | Cyclic peptides and antifungal pharmaceutical compositions containing them |
| IL12231597A IL122315A0 (en) | 1992-03-19 | 1997-11-27 | Cyclic peptide antifungal agents |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP0561639B1 (index.php) |
| JP (3) | JP3519754B2 (index.php) |
| KR (1) | KR100256036B1 (index.php) |
| CN (1) | CN1036715C (index.php) |
| AT (1) | ATE217635T1 (index.php) |
| AU (2) | AU3534193A (index.php) |
| BR (1) | BR9301232A (index.php) |
| CA (1) | CA2091663C (index.php) |
| CZ (1) | CZ288974B6 (index.php) |
| DE (2) | DE122008000006I2 (index.php) |
| DK (1) | DK0561639T3 (index.php) |
| ES (1) | ES2174843T3 (index.php) |
| FI (1) | FI118768B (index.php) |
| HU (2) | HU225783B1 (index.php) |
| IL (3) | IL105048A (index.php) |
| LU (1) | LU91406I2 (index.php) |
| MX (1) | MX9301457A (index.php) |
| MY (1) | MY136593A (index.php) |
| NL (1) | NL300334I2 (index.php) |
| NO (1) | NO930948L (index.php) |
| NZ (3) | NZ247149A (index.php) |
| PT (1) | PT561639E (index.php) |
| RU (1) | RU2129562C1 (index.php) |
| TW (1) | TW264477B (index.php) |
| YU (1) | YU49108B (index.php) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5430018A (en) * | 1991-10-17 | 1995-07-04 | Merck & Co., Inc. | Cyclohexapeptide with basic nitrogen containing alkylamide groups |
| US6743777B1 (en) | 1992-03-19 | 2004-06-01 | Eli Lilly And Company | Cyclic peptide antifungal agents and process for preparation thereof |
| NZ247149A (en) * | 1992-03-19 | 1996-10-28 | Lilly Co Eli | Cyclic peptide antifungal agents and compositions thereof |
| US5378804A (en) * | 1993-03-16 | 1995-01-03 | Merck & Co., Inc. | Aza cyclohexapeptide compounds |
| US5948753A (en) * | 1993-05-04 | 1999-09-07 | Merck & Co., Inc. | Cyclohexapeptidyl propanolamine compounds |
| EP0697879A4 (en) * | 1993-05-04 | 1998-01-14 | Merck & Co Inc | AMINOALKYL ETHER DERIVATIVES OF CYCLOHEXAPEPTIDES |
| WO1995008341A1 (en) * | 1993-09-22 | 1995-03-30 | Merck & Co., Inc. | Antifungal and anti-pneumocystis compounds, compositions containing such compounds, and methods of use |
| US5514651A (en) * | 1994-09-16 | 1996-05-07 | Merck & Co., Inc. | Aza cyclohexapeptide compounds |
| WO1996008266A1 (en) * | 1994-09-16 | 1996-03-21 | Merck & Co., Inc. | Aza cyclohexapeptide compounds |
| US5516757A (en) * | 1994-09-16 | 1996-05-14 | Merck & Co., Inc. | Semi-synthetic lipopeptides, compositions containing said lipopeptides, and methods of use |
| ATE229541T1 (de) * | 1994-10-07 | 2002-12-15 | Fujisawa Pharmaceutical Co | Zyklische hexapeptide mit antibiotischer aktivität |
| US5516756A (en) * | 1994-10-31 | 1996-05-14 | Merck & Co., Inc. | Aza cyclohexapeptide compounds |
| JP2966936B2 (ja) * | 1995-01-26 | 1999-10-25 | メルク エンド カンパニー インコーポレーテッド | 新規抗真菌シクロヘキサペプチド |
| US5646111A (en) * | 1995-04-07 | 1997-07-08 | Eli Lilly And Company | Cyclic peptide antifungal Agents |
| US5786325A (en) * | 1995-05-26 | 1998-07-28 | Eli Lilly And Company | Cyclic peptide antifungal agents and methods of making and using |
| US5652213A (en) * | 1995-05-26 | 1997-07-29 | Eli Lilly And Company | Cyclic peptide antifungal agents |
| US5629290A (en) * | 1995-05-26 | 1997-05-13 | Eli Lilly And Company | Cyclic peptide antifungal agents |
| US5618787A (en) * | 1995-05-26 | 1997-04-08 | Eli Lilly And Company | Cyclic peptide antifungal agents |
| US5629289A (en) * | 1995-07-25 | 1997-05-13 | Eli Lilly And Company | Cyclic peptide antifungal agents |
| AU1851797A (en) * | 1996-02-01 | 1997-08-22 | Eli Lilly And Company | Cyclic peptide antifungal agents |
| US5693611A (en) * | 1996-02-01 | 1997-12-02 | Eli Lilly And Company | Cyclic peptide antifungal agents |
| JPH09227422A (ja) * | 1996-02-12 | 1997-09-02 | Rolic Ag | シクロペンチル誘導体 |
| US5696084A (en) * | 1996-08-16 | 1997-12-09 | Abbott Laboratories | Amino-lipopetide antifungal agents |
| AUPO381496A0 (en) * | 1996-11-25 | 1996-12-19 | Fujisawa Pharmaceutical Co., Ltd. | New compound |
| FR2784993B1 (fr) * | 1998-10-26 | 2002-10-31 | Hoechst Marion Roussel Inc | Nouveaux derives de l'echinocandine, leur procede de preparation et leur application comme fongicides |
| AU2003200556B2 (en) * | 1997-12-10 | 2005-12-01 | Novexel | Echinocandin derivative and their preparation method |
| UA72200C2 (uk) * | 1997-12-10 | 2005-02-15 | Авентіс Фарма С.А. | Похідні ехінокандину, спосіб їх одержання, їх застосування, проміжні сполуки та фармацевтична композиція |
| AUPP172898A0 (en) * | 1998-02-09 | 1998-03-05 | Fujisawa Pharmaceutical Co., Ltd. | New compound |
| WO1999047551A1 (en) * | 1998-03-16 | 1999-09-23 | Fujisawa Pharmaceutical Co., Ltd. | Wf14573 or its salt, production thereof and use thereof |
| WO2000011023A2 (en) | 1998-08-20 | 2000-03-02 | Eli Lilly And Company | Ring modified cyclic peptide analogs |
| JP2003511345A (ja) | 1998-12-09 | 2003-03-25 | イーライ リリー アンド カンパニー | Ｅｃｈｉｎｏｃａｎｄｉｎシクロペプチド化合物の精製 |
| DE19907904A1 (de) | 1999-02-24 | 2000-08-31 | Clariant Gmbh | Verfahren zur Herstellung von [1,1':4',1"]-Terphenylverbindungen |
| JP4272359B2 (ja) | 1999-03-03 | 2009-06-03 | イーライ リリー アンド カンパニー | エキノカンジン／炭水化物複合体 |
| CN1345230A (zh) | 1999-03-03 | 2002-04-17 | 伊莱利利公司 | 口服ecb药物制剂和药物组合物的制备方法 |
| IL145186A0 (en) | 1999-03-03 | 2002-06-30 | Lilly Co Eli | Formation and anion-exchange of crystalline echinocandin ammonium salts |
| IL145185A0 (en) | 1999-03-03 | 2002-06-30 | Lilly Co Eli | Echinocandin pharmaceutical formulations containing micelle-forming surfactants |
| AU2001232319B2 (en) * | 2000-02-18 | 2005-01-13 | Meiji Seika Kaisha, Ltd. | Phenoxyalkylamine derivates useful as opioid delta receptor ligands |
| FR2833596B1 (fr) * | 2001-12-14 | 2005-02-18 | Aventis Pharma Sa | Procede de preparation de derives d'echinocandine |
| US6991800B2 (en) | 2002-06-13 | 2006-01-31 | Vicuron Pharmaceuticals Inc. | Antifungal parenteral products |
| CN1812978A (zh) * | 2003-04-30 | 2006-08-02 | 药物研发有限责任公司 | 作为蛋白酪氨酸磷酸酶－1b抑制剂的苯基取代羧酸 |
| KR101551207B1 (ko) * | 2008-09-04 | 2015-09-08 | 롬엔드하스전자재료코리아유한회사 | 신규한 유기 발광 화합물 및 이를 발광재료로서 채용하고 있는 유기 발광 소자 |
| CN102464704B (zh) * | 2010-11-05 | 2013-12-11 | 上海医药工业研究院 | 一种化合物及其制备方法和用途 |
| KR102236462B1 (ko) * | 2012-03-19 | 2021-04-08 | 시다라 세라퓨틱스, 인코포레이티드 | 에키노칸딘 계열의 화합물에 대한 투여 용법 |
| ES2694561T3 (es) | 2015-02-23 | 2018-12-21 | Selectchemie Ag | Composición de anidulafungina |
| JP6866583B2 (ja) * | 2016-07-05 | 2021-04-28 | Dic株式会社 | 液晶化合物 |
| CN116903706B (zh) * | 2023-06-13 | 2024-05-17 | 深圳市祥根生物有限公司 | 一种棘白菌素类药物及其制备方法和用途 |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE886576A (fr) * | 1979-12-13 | 1981-06-10 | Lilly Co Eli | Derives de noyaux peptidiques cycliques, leur preparation et leur utilisation comme agents antifongiques |
| BE886575A (fr) * | 1979-12-13 | 1981-06-10 | Lilly Co Eli | Derives de noyaux peptidiques cycliques, leur preparation et leur utilisation comme agents antifongiques |
| CA2037957A1 (en) * | 1990-03-12 | 1991-09-13 | Merck & Co., Inc. | N-acylated cyclohexapeptide compounds |
| GB2241956A (en) | 1990-03-16 | 1991-09-18 | Merck & Co Inc | N-acylated cyclohexapeptide compounds |
| US5330973A (en) * | 1990-03-19 | 1994-07-19 | Merck & Co., Inc. | Lipopeptide derivatives |
| IL97347A0 (en) * | 1990-03-19 | 1992-05-25 | Merck & Co Inc | Lipopeptide derivatives and antimicrobial compositions containing them |
| US5310726A (en) * | 1990-03-19 | 1994-05-10 | Merck & Co., Inc. | Lipopeptide compounds |
| NZ247149A (en) * | 1992-03-19 | 1996-10-28 | Lilly Co Eli | Cyclic peptide antifungal agents and compositions thereof |
-
1993
- 1993-03-15 NZ NZ247149A patent/NZ247149A/en not_active IP Right Cessation
- 1993-03-15 CZ CZ1993416A patent/CZ288974B6/cs not_active IP Right Cessation
- 1993-03-15 TW TW082101890A patent/TW264477B/zh not_active IP Right Cessation
- 1993-03-15 CA CA002091663A patent/CA2091663C/en not_active Expired - Lifetime
- 1993-03-15 MY MYPI93000458A patent/MY136593A/en unknown
- 1993-03-15 NZ NZ512085A patent/NZ512085A/en not_active IP Right Cessation
- 1993-03-15 IL IL10504893A patent/IL105048A/en active Protection Beyond IP Right Term
- 1993-03-15 IL IL12231593A patent/IL122315A/en not_active IP Right Cessation
- 1993-03-15 NZ NZ299314A patent/NZ299314A/en not_active IP Right Cessation
- 1993-03-16 NO NO93930948A patent/NO930948L/no not_active Application Discontinuation
- 1993-03-16 MX MX9301457A patent/MX9301457A/es unknown
- 1993-03-17 KR KR1019930004076A patent/KR100256036B1/ko not_active Expired - Lifetime
- 1993-03-18 CN CN93103587A patent/CN1036715C/zh not_active Expired - Lifetime
- 1993-03-18 DK DK93302064T patent/DK0561639T3/da active
- 1993-03-18 YU YU18593A patent/YU49108B/sh unknown
- 1993-03-18 PT PT93302064T patent/PT561639E/pt unknown
- 1993-03-18 JP JP05852993A patent/JP3519754B2/ja not_active Expired - Lifetime
- 1993-03-18 HU HU9300785A patent/HU225783B1/hu unknown
- 1993-03-18 DE DE200812000006 patent/DE122008000006I2/de active Active
- 1993-03-18 EP EP93302064A patent/EP0561639B1/en not_active Expired - Lifetime
- 1993-03-18 AT AT93302064T patent/ATE217635T1/de active
- 1993-03-18 DE DE69331922T patent/DE69331922T2/de not_active Expired - Lifetime
- 1993-03-18 BR BR9301232A patent/BR9301232A/pt not_active Application Discontinuation
- 1993-03-18 RU RU93004787A patent/RU2129562C1/ru active
- 1993-03-18 FI FI931202A patent/FI118768B/fi not_active IP Right Cessation
- 1993-03-18 ES ES93302064T patent/ES2174843T3/es not_active Expired - Lifetime
- 1993-03-19 AU AU35341/93A patent/AU3534193A/en not_active Abandoned
-
1995
- 1995-06-22 HU HU95P/P00378P patent/HU211562A9/hu active Protection Beyond IP Right Term
-
1996
- 1996-09-09 AU AU65529/96A patent/AU689391B2/en not_active Expired
-
1997
- 1997-11-27 IL IL12231597A patent/IL122315A0/xx unknown
-
2002
- 2002-01-10 JP JP2002003969A patent/JP3520071B2/ja not_active Expired - Lifetime
-
2003
- 2003-12-10 JP JP2003412638A patent/JP2004115540A/ja active Pending
-
2008
- 2008-01-09 LU LU91406C patent/LU91406I2/fr unknown
- 2008-01-21 NL NL300334C patent/NL300334I2/nl unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0561639B1 (en) | Cyclic peptide antifungal agents and process for preparation thereof | |
| US5965525A (en) | Cyclic peptide antifungal agents | |
| EP0744405B1 (en) | Cyclic peptide antifungal agents | |
| EP0736541B1 (en) | Cyclic hexapeptide antifungal agents | |
| US6384013B1 (en) | Cyclic peptide antifungal agents and process for preparation thereof | |
| DE69624167T2 (de) | Zyklische Peptide mit fungizider Wirkung | |
| US5386010A (en) | Lipopeptide compounds | |
| US6743777B1 (en) | Cyclic peptide antifungal agents and process for preparation thereof | |
| DE69623387T2 (de) | Zyklische Peptide mit fungizider Wirkung | |
| JPH11510165A (ja) | 環状ペプチド抗真菌薬 | |
| CA2220944A1 (en) | Cyclic peptide antifungal agents | |
| EP1254161A2 (en) | Aerothricin analogs, their preparation and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| EXTF | Application for patent extension filed | ||
| KB | Patent renewed | ||
| PEL | Intention of commissioner to extend period of protection | ||
| EXTG | Extension of patent term granted |
Extension date: 20160720 |
|
| EXTN | Extension order renewed | ||
| EXTN | Extension order renewed | ||
| EXTN | Extension order renewed | ||
| EXTN | Extension order renewed | ||
| EXTN | Extension order renewed |