AU726495B2 - N-benzylazolium derivatives - Google Patents
N-benzylazolium derivatives Download PDFInfo
- Publication number
- AU726495B2 AU726495B2 AU45364/97A AU4536497A AU726495B2 AU 726495 B2 AU726495 B2 AU 726495B2 AU 45364/97 A AU45364/97 A AU 45364/97A AU 4536497 A AU4536497 A AU 4536497A AU 726495 B2 AU726495 B2 AU 726495B2
- Authority
- AU
- Australia
- Prior art keywords
- triazol
- ium bromide
- acetoxy
- bromide
- difluorophenyl
- 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.)
- Ceased
Links
- FNEQHKCQXDKYEO-UHFFFAOYSA-N 1-benzylpyrrole Chemical class C1=CC=CN1CC1=CC=CC=C1 FNEQHKCQXDKYEO-UHFFFAOYSA-N 0.000 title description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 98
- -1 azole compound Chemical class 0.000 claims description 68
- 150000001875 compounds Chemical class 0.000 claims description 42
- YYABOYVMXVMNPF-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrobromide Chemical compound Br.OC(=O)C(F)(F)F YYABOYVMXVMNPF-UHFFFAOYSA-N 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 19
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 208000031888 Mycoses Diseases 0.000 claims description 11
- 239000012453 solvate Substances 0.000 claims description 11
- 150000004677 hydrates Chemical class 0.000 claims description 10
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 206010017533 Fungal infection Diseases 0.000 claims description 5
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 230000000843 anti-fungal effect Effects 0.000 claims description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 4
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 230000004962 physiological condition Effects 0.000 claims description 4
- 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 4
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 3
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 239000012871 anti-fungal composition Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 1
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 1
- 101000816965 Trypanosoma brucei rhodesiense Trypanin Proteins 0.000 claims 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims 1
- 125000004802 cyanophenyl group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000006178 methyl benzyl group Chemical group 0.000 claims 1
- 125000004193 piperazinyl group Chemical group 0.000 claims 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- 239000000843 powder Substances 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 24
- 150000003851 azoles Chemical class 0.000 description 17
- 239000002904 solvent Substances 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000009885 systemic effect Effects 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 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 6
- 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 6
- 201000002909 Aspergillosis Diseases 0.000 description 6
- 208000036641 Aspergillus infections Diseases 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 6
- 229960004130 itraconazole Drugs 0.000 description 6
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 208000015181 infectious disease Diseases 0.000 description 5
- 229960004125 ketoconazole Drugs 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000004212 difluorophenyl group Chemical group 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010006473 Bronchopulmonary aspergillosis Diseases 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000004430 Pulmonary Aspergillosis Diseases 0.000 description 3
- 206010042938 Systemic candida Diseases 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
- 229940121375 antifungal agent Drugs 0.000 description 3
- 239000003429 antifungal agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 201000003984 candidiasis Diseases 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000004188 dichlorophenyl group Chemical group 0.000 description 3
- 125000006182 dimethyl benzyl group Chemical group 0.000 description 3
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- 239000002244 precipitate Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- RLOWRCNOBNILBK-UHFFFAOYSA-N 1h-1,2,4-triazol-1-ium;bromide Chemical compound [Br-].C1=NNC=[NH+]1 RLOWRCNOBNILBK-UHFFFAOYSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- DVQUEUMFZZEIBI-UHFFFAOYSA-N 4-(bromomethyl)-2,6-dimethylphenol Chemical compound CC1=CC(CBr)=CC(C)=C1O DVQUEUMFZZEIBI-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- UYGBSRJODQHNLQ-UHFFFAOYSA-N 4-hydroxy-3,5-dimethylbenzaldehyde Chemical compound CC1=CC(C=O)=CC(C)=C1O UYGBSRJODQHNLQ-UHFFFAOYSA-N 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000223682 Exophiala Species 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241001480037 Microsporum Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
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- 238000010410 dusting Methods 0.000 description 2
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- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- BICAGYDGRXJYGD-UHFFFAOYSA-N hydrobromide;hydrochloride Chemical compound Cl.Br BICAGYDGRXJYGD-UHFFFAOYSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- HWYHDWGGACRVEH-UHFFFAOYSA-N n-methyl-n-(4-pyrrolidin-1-ylbut-2-ynyl)acetamide Chemical compound CC(=O)N(C)CC#CCN1CCCC1 HWYHDWGGACRVEH-UHFFFAOYSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 125000006308 propyl amino group Chemical group 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- CSAROMURJIAFPL-UHFFFAOYSA-N tert-butyl 2-(bromomethyl)-5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]oxybenzoate Chemical compound CC(C)(C)OC(=O)NCC(=O)OC1=CC=C(CBr)C(C(=O)OC(C)(C)C)=C1 CSAROMURJIAFPL-UHFFFAOYSA-N 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 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 2
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 1
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 1
- MDTUWBLTRPRXBX-UHFFFAOYSA-N 1,2,4-triazol-3-one Chemical compound O=C1N=CN=N1 MDTUWBLTRPRXBX-UHFFFAOYSA-N 0.000 description 1
- LZTSCEYDCZBRCJ-UHFFFAOYSA-N 1,2-dihydro-1,2,4-triazol-3-one Chemical compound OC=1N=CNN=1 LZTSCEYDCZBRCJ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- PKDPUENCROCRCH-UHFFFAOYSA-N 1-piperazin-1-ylethanone Chemical compound CC(=O)N1CCNCC1 PKDPUENCROCRCH-UHFFFAOYSA-N 0.000 description 1
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- 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
- FUJSJWRORKKPAI-UHFFFAOYSA-N 2-(2,4-dichlorophenoxy)acetyl chloride Chemical compound ClC(=O)COC1=CC=C(Cl)C=C1Cl FUJSJWRORKKPAI-UHFFFAOYSA-N 0.000 description 1
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 1
- MUTDXQJNNJYAEG-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(dimethylamino)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)N(C)C MUTDXQJNNJYAEG-UHFFFAOYSA-N 0.000 description 1
- XXZCIYUJYUESMD-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(morpholin-4-ylmethyl)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CN1CCOCC1 XXZCIYUJYUESMD-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- 125000006186 3,5-dimethyl benzyl group Chemical group [H]C1=C(C([H])=C(C([H])=C1C([H])([H])[H])C([H])([H])*)C([H])([H])[H] 0.000 description 1
- BIWAJQQHDTXDHM-UHFFFAOYSA-N 4-(1,3-thiazol-4-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1=CSC=N1 BIWAJQQHDTXDHM-UHFFFAOYSA-N 0.000 description 1
- MSVUDMHLPJJTHO-STAPWGBESA-N 5-(2-aminoacetyl)oxy-2-[[1-[(2r,3r)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-2-hydroxybutyl]-1,2,4-triazol-4-ium-4-yl]methyl]benzoic acid;2,2,2-trifluoroacetic acid;bromide Chemical compound [Br-].OC(=O)C(F)(F)F.C=1SC([C@H](C)[C@](O)(CN2N=C[N+](CC=3C(=CC(OC(=O)CN)=CC=3)C(O)=O)=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 MSVUDMHLPJJTHO-STAPWGBESA-N 0.000 description 1
- 241000223600 Alternaria Species 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 241000335423 Blastomyces Species 0.000 description 1
- 241000228405 Blastomyces dermatitidis Species 0.000 description 1
- 241000079253 Byssochlamys spectabilis Species 0.000 description 1
- OOSBCWRSKAZVAV-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NCC(=O)OC=1C=C(C(=O)O)C(=CC1)CBr Chemical compound C(C)(C)(C)OC(=O)NCC(=O)OC=1C=C(C(=O)O)C(=CC1)CBr OOSBCWRSKAZVAV-UHFFFAOYSA-N 0.000 description 1
- REWVSWKTGZPBHR-UHFFFAOYSA-N C(C)(C)(C)OC(=O)NCC(=O)OC=1C=C(C(=O)O)C(=CC1)CO Chemical compound C(C)(C)(C)OC(=O)NCC(=O)OC=1C=C(C(=O)O)C(=CC1)CO REWVSWKTGZPBHR-UHFFFAOYSA-N 0.000 description 1
- 101100290713 Caenorhabditis elegans mef-2 gene Proteins 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 201000007336 Cryptococcosis Diseases 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-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
- 241000228402 Histoplasma Species 0.000 description 1
- 241000228404 Histoplasma capsulatum Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000585693 Homo sapiens Mitochondrial 2-oxodicarboxylate carrier Proteins 0.000 description 1
- 101001041245 Homo sapiens Ornithine decarboxylase Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102100021079 Ornithine decarboxylase Human genes 0.000 description 1
- 241000231139 Pyricularia Species 0.000 description 1
- 241000918585 Pythium aphanidermatum Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000223238 Trichophyton Species 0.000 description 1
- MEUWUBXEOFFOOX-UHFFFAOYSA-N [4-(bromomethyl)phenyl] acetate Chemical compound CC(=O)OC1=CC=C(CBr)C=C1 MEUWUBXEOFFOOX-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- BLAKAEFIFWAFGH-UHFFFAOYSA-N acetyl acetate;pyridine Chemical compound C1=CC=NC=C1.CC(=O)OC(C)=O BLAKAEFIFWAFGH-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960004884 fluconazole Drugs 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
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- ZYCMDWDFIQDPLP-UHFFFAOYSA-N hbr bromine Chemical compound Br.Br ZYCMDWDFIQDPLP-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 238000003898 horticulture Methods 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000749 insecticidal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- OPAHEYNNJWPQPX-RCDICMHDSA-N ravuconazole Chemical compound C=1SC([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 OPAHEYNNJWPQPX-RCDICMHDSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- CDYSICKJYBJTQP-UHFFFAOYSA-N tert-butyl 2-(hydroxymethyl)-5-[2-[(2-methylpropan-2-yl)oxycarbonylamino]acetyl]oxybenzoate Chemical compound CC(C)(C)OC(=O)NCC(=O)OC1=CC=C(CO)C(C(=O)OC(C)(C)C)=C1 CDYSICKJYBJTQP-UHFFFAOYSA-N 0.000 description 1
- WQIGTMLRQSOQJG-UHFFFAOYSA-N tert-butyl 5-hydroxy-2-(hydroxymethyl)benzoate Chemical compound CC(C)(C)OC(=O)C1=CC(O)=CC=C1CO WQIGTMLRQSOQJG-UHFFFAOYSA-N 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
V
S F Ref: 390519D1
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIRCATION FOR A STANDARD PATENT
ORIGINAL
Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: a a.
a a *aa.
F. Hoffmann-La Roche AG 124 Grenzacherstrasse CH-4070 Basel
SWITZERLAND
Shigeyasu Ichihara, Chikako Murasaki, Noriko Ohga, Jun Ohwada, Daisuke Sawada, Nobuo Shimma, Michlo Shiral and Isao Umeda Spruson Ferguson, Patent Attorneys Level 33 St Martins Tower, 31 Market Street Sydney, New South Wales, 2000, Australia N-benzylazolium Derivatives The following statement is a best method of performing it full description known to me/us:of this invention, including the 5845 1 N-benzylazolium Derivatives Although several azole compounds are currently used for synthetic mycoses, none of them fulfils the necessary clinical requirement in full extent, i.e. efficacy against major systemic mycoses including disseminated aspergillosis, safety, and oral or parenteral formulations. Particularly, demand of a parenteral administration of the azole compounds is increasing for the treatment of serious systemic mycoses. Most of the azole compounds on the market as well as under development are highly lipophilic molecules that make the parenteral formulation difficult.
The present invention relates to novel water soluble azole compounds useful for the treatment of systemic mycoses and suitable for both oral and particularly parenteral administration, a process for n tneir manufacture, antifungal compositions containing them and a method for treating mycoses.
More particularly, a first aspect of the present invention relates to novel azole compounds represented by the general formula
R
2 R 1 Z X
DN
P
3 0
R
4
(I)
*.wherein Q is the group of the formula Q 1 or Q 2 7
R
.S
CH2/ H H N
H
H
O
H N CN CH3 or
-CH
2
O
CH
2 0 N N-D
O
R
R 0
(Q
2 wherein D is a lower alkanoyl or the group of the formula, 1ib\ I B II :\l)ayLib\L BA33490.doc:T1 T 0 7 N
N-
N
RI is a halogen atom, and R8 is a straight-chain or branched Cl-C 4 alkyl,
N-Q
or wherein /is a group derived from an azole compound of the group consisting of: dl-i 2 24 -dichlorophenyl)-2-[(2,4..dichlorophenyl)methoxy]ethyl]-i H-imidazole, dl-cis-1 -acetyl- 4 4 2 2 4 dichlorophenyl-2(imidazoli1ylmethyl)i ,3-dioxolan-4yl]methoxy]phenyl]piperazine, dl- 2 -[(PS)-secbutyl4[4[4[4.[(2R4S)2(2-(2,4dichlorophenyl)- 2 1 H-i 2,4-triazol- 1-ylmethyl)- 1, 3 -dioxolan-4-yl]methoxyjphenyl]i1 -piperazinyl]phenyl-3H-[ 2 4 ]triazol-3-one,
R,
2
R)-
2 -(2,4-difluorophenyly2hydroxyi1 -methyl-3-(1 H-i ,2,4-triazol-1 -yI)propyfl-4-[4- 2 3 3 -tetrafluoropropoxy)phenyl]j3(2H 1,2,4-triazolone, (+--24dfurpey)3mty-1-(1 H-i 1,2,4-triazol- 1 1 H-i 1,2,4-triazol-i1 -yl)pyrid azi n- 3-ylthio)butan-2-ol, 2 R)-2-(2,4-difluorophenyl)..i 3 4 2 2 ,3,3-tetrafluoropropoxy)-styryl]-(i,2,4-triazol-i -yI)-3- (1,2,4-triazol- 1 -yl)lpropan-2-ol, dl-th reo- 2 2 ,4-difluorophenyl)3methyl-sulfonyi H-i ,2,4-triazol-1 -yl)-butan-2-oI, 4 4 4 -[5-2,4-difluorophenyl)-5-( 1 H-i 2,4-triazol- 1 -ylmethyl)tetrahydrofuran-3 yl]methoxylphenyllpiperazinyljphenylj-2[(i S,2S)-l1-ethyl-2-hydroxypropyl].3H-1 ,2,4-triazol-3-one, (2R, 3
R)-
3 4 4 -cyanophenyl)thiazok2-yl)]-2-(2,4-difluorophenyl)i H-i 2,4-triazol- 1-yI)-butan- 2-ol, 3-methyI-3-methylthioi- ,2,4-triazol- i-yI)- 2 -(trifluoromethylphenyl-butan-2ol, 1 -fj(l1R,2S, 6
R)-
2 -methoxy-3, 3 -dimethyF-6-(2-p-tolylethyl)cyclohexyl] methyl] 1 2,4]triazol, and (5R,6R)-2,2-dimethyl-6-[(iH-i ,2,4-triazol-i -yl)methyl]-5-[[4- (trifluoromethoxy)phenoxy]methyl]cyclohexanone 0-methyloxime, Z is nitrogen or methine;
R
1 R2 are each independently a hydrogen atom or a group -QY [in which Y is .a group easily S4Ifrolyzable under physiological condition]; I 1:\D yl-ib\I I 13A]33490.doc:TFLTI
R
3
R
4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl; and X-is a pharmaceutically acceptable anion, as well as salts, hydrates or solvates of the compounds of the general formula Preferred among the above azole compounds of formula I are those of formula
R
3 RP-COO- x
NO
N-Q
R
4 wherein
R
5 is a straight-chain or branched Ci-C 5 alkyl, aryl, pyridyl, pyrrolidinyl or a group A-NH-B- (wherein A is a hydrogen atom or a straight-chain or branched Cl-C 5 alkyl; B is a straight-chain or branched C 1
-C
4 alkylene, -CH2-CONH-CH 2 or -CH2CH 2
CH
2
-CH(NH
2
R
3 and R 4 are each independently a hydrogen or halogen atom or a lower alkoxy; and Z, Q and X are as defined above.
In the above group Y which is easily hydrolyzable under physiological conditions means preferably the acyl residue of an amino acid or a group represented by the formula, R5CO-, or (R60) 2
PO-
wherein R 5 is hydrogen, lower alkoxy, lower alkyl which may be optionally substituted with carboxyl, amino, lower alkylamino, diloweralkylamino, or aryl; and R6 is hydrogen or lower alkyl.
chi n As used in this specification, the term "lower alkyl" refers to preferably straight or branched chain having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl or tert- S2 butyl.
.I.
The term "lower alkoxy" refers to preferably straight or branched chain having 1 to 4 carbon .atoms such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy.
As used in this specification, the term "aryl" is defined to mean preferably an unsubstituted or substituted aryl radical such as phenyl, methoxyphenyl, pyridyl, pyrazinyl or furyl.
Preferably, Y is formyl, acetyl, propionyl, isobutyryl, pivaloyl, succinoyl, benzoyl, nicotinoyl, phosphoryl, dimethylphosphoryl, aminoacetyl, 3-aminopropionyl, 4-aminobutyryl, (2-aminoacetylamino)-acet, (S)-2,5-diaminopentoyl, (S)-2-aminopropionyl, (S)-pyrrolidine-2-carbonyl, (methylamino)acetyl, (propylamino)acetyl, 2 -(methylamino)propionyl, 3-(methylamino)propionyl, (S)-2-amino-3-methylbutanoyl, (isopropylamino)acetyl, (2S)-2-(ethylamino)propionyl, ,ethylamino)acetyl and the like.
S33490doc:
S/
I \l);iyl.ih\I I A |33490doc:l'liT 3a R3 and R4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl.
The term "halogen" denotes fluorine, chlorine or bromine.
The term "lower alkylthio" refers to preferably straight or branched chain having 1 to 4 carbon atoms such as methylthio, ethylthio, n-propylthio.
The term "lower alkyl" and "lower alkoxy" are the same as described above.
Preferably, R 3 and R 4 are independently methyl, methoxy, or chlorine.
*9
C
C
a Il:\DayLib\LI 3A133490.doc:TLT X- is an anion from a pharmaceutically acceptable inorganic acid, e.g. a mineral acid; such as chloride, bromide or sulfate; or from an organic acid, e.g. an aliphatic, aromatic or araliphatic carboxylic or sulfonic acid such as acetoxy, trifluoroacetoxy, mesyloxy anion and the like.
Particularly preferred compounds in accordance with the present invention are: dl-1 4 -acetoxy- 3 ,5-dimethylbenzyl)-3-[2-(2,4dichlorobenzyoxy)2(2,4dichlorophenyl)ethyl]-3Himidazol-1-ium bromide, dl-1 4 -acetoxy- 3 -methylbenzyl)-3-[2-(2,4-dichlorobenzyloxy)2(2,4dichlorophenyl)ethylp-3Himidazol- 1-ium bromide, dl-1 4 -acetoxybenzyl)-3-[2-(2,4-dichlorobenzyloxy)2(2,4-dichlorophenyl)ethyll-3H-imidazol-l-ium bromide, dl-1 4 -acetoxybenzyl)-3-[(2R,4S)-4-[4-(4-acetylpiperazin-1 -yl)phenoxymethyl]-2-(2,4-dichlorophenyl)- [1 ,3]dioxan-2-ylmethyl]-3H-imidazol-1 -ium bromide, dl-1 4 -acetoxy- 3 ,5-dimethylbenzyl)3[(2R,4S)4[4(4acetylpiperazin-1-yl)phenoxymethylj-2-(2,4dichlorophenyl)-[1 ,3]dioxan-2-ylmethylj-3H-imidazol-1 -ium bromide, dl-1 4 -acetoxy- 3 -methylbenzy)-3-[(2R,4S)4[4(4acetylpiperazin-1-yl)phenoxymethyl]-2-(2,4dichlorophenyl)-[1 ,3]dioxan-2-ylmethyl]-3H-imidazol-1 -ium bromide, dl-1 4 -acetoxy-3-methoxybenzyl)-3[(2R,4S)4[4(4acetylpiperazin-1 -yl)phenoxyinethylJ-2-(2,4dichlorophenyl)-[1 ,3ldioxan-2-ylmethylj-3H-imidazo-1 -ium bromide, dl-3-[(2R,4S)-4-[4-(4-acetylpiperazin.1 -yl)phenoxymethyl]-2-(2,4-dichloropheny)-[1 ,3jdioxan-2ylmethylJ-1 -(4-isobutyryloxy-3,5-dimethylbenzyl)-3H-imidazol-i -ium bromide, dl-3-I(2R,4S)-4-[4-(4-acetylpiperazin-1 -yl)phenoxymethyl]-2-(2,4-dichloropheny)-[1 ,3jdioxan-2ylmethylj-1 -(4-pivaloyloxy-3,5-dimethylbenzyl)-3H-imidazol-l-ium bromide, dl-3-[(2R,4S)-4-[4-(4-acetylpiperazin-1 -yl)phenoxymethyl]-2-(2,4-dichloropheny)-[1 ,3jdioxan-2- 25 ylmethyl]-1 4 2 ,2-dimethylpropionyloxy)benzylJ-3H-imidazol-l-ium bromide, dl-4-(4-benzoyloxy-3,5-dimethylbenzyl)-1 -[4-[4-[4-[4-(l1-(2-butyl-5-oxo-1 ,5-dihydro-[1 ,2,4jtriazol-4yl)phenyl]piperazin-1 -yllphenoxymethyI)-2-(2,4-dichlorophenyl)-[1 ,3]dioxolan-2-ylmethylj-1
H-
[1 ,2,4jtriazol-4-ium bromide, dl- 4 -[4-(pyridine-3-carbonyloxy)..3,5-dimethylbenzyl].1 -(2-butyl-5-oxo-1 [1 2 4 ]triazol-4-yl)phenyljpiperazin-1 -yl~phenoxymethyl]-2-(2,4-dichlorophenyi)[1 ,3]dioxolan-2ylmethyl]-IH-[1,2,4]triazol-4-ium bromide, dl-4-(4-acetoxy-3,5-dimethylbenzyl)-1 -(2-butyl-5-oxo-1 ,5-dihydro-[1 ,2,4]triazol-4yl)phenyllpiperazin-1 -yllphenoxymethylj-2-(2,4-dichlorophenyl)-[1,3]dioxolan-2-ylmethylj-1
H-
[1 ,2,4]triazol-4-ium bromide, dl-4-(4-acetoxy-3-methylbenzyl)-l1-[4-[4-[4-[4-[1 -(2-butyl-5-oxo-1 ,5-dihydro-[1 ,2,4jtriazol-4- 35 yl)phenyl]piperazin-1 -yI]phenoxymethylj-2-(2,4-dich lorophenyl)-[1 ,3]dioxolan-2-ylmethyl]-
IH-
[1 ,2,4]triazol-4-ium bromide, dl-4-(4-acetoxybenzyl)-l -(2-butyl-5-oxo-1 ,5-dihydro-[1 2 ,4]triazol-4-yl)phenyl]piperazin-1 yllphenoxymethyl]-2-(2,4-dichlorophenyl)-[1 ,3]dioxolan-2-ylmethyl-1 H-[1 ,2,4]triazol-4-ium bromide, [N:\LIBC]02679A:MEF dl-1 -sec-butyl-5-oxo-1 ,5-dihydro-[1 2 4 ltriazol-4-yl)-phenyl]-piperazin-I -yl}phenoxymethyl)-2-(2,4..dichloro-phenyl)-[1 3 Idioxolan-2-ymethyi-4-(4-hexanoyloxy3,5 dimethylbenzyl).1H-[1 ,2,4]triazol-4-ium methanesuifonate, 4 -(4-acetoxy-3,5-dimethylbenzyl)-1 2 R3R)-2-(2,4-difluorophenyl)2hydroxy35oxo44(2 2 3 3 tetrafluoropropoxy)phenyl]4,5:*dihydrofl ,2,4Jtriazol-1 -yI~butylj-1 H-fl ,2,4jtriazol-4-ium bromide, 4 4 -acetoxy-3,5-dimethylbenzyl)-1 2
R)-
2 -(2,4-difluoropheny-2hydroxy3methy,3-(6[1 ,2,4Jtriazol- 1 -yI-pyridazin-3-ylsuifanyl)butyl]-1 H-fl ,2,4]triazol-4-ium bromide, 4 4 -acetoxy-3,5-dimethylbenzyl)-1 -[(2R)-2-(2,4-difluoropheny)2hydroxy3(3(Z)24(22, 3 3 tetrafluoropropoxy)phenyllvinyI[1 ,2,4Jtriazol-l -yI)propylj-1 H-fl ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3,5-dimethylbenzyl)-1 i-f( 2
R,
3
R)-
2 2 4 -difluorophenyl)-2.hydroxy3methanesufonylbutyl]I 1 H-[1 ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3,5-dimethylbenzyl).1 -f (2R-cis)-2-(2,4-difluorophenyt)-4..{4-[4-[4f1 S,2S)-1 -ethyl-2hydroxypropyl)-5-oxo-1 ,5-dihydro- 1 2 ,4ltriazoi-4-yllphenyllpiperazin-i yI]phenoxymethyiltetrahydrofuran2ylmethyil] H-fl ,2,4jtriazol-4-ium bromide, 4 4 -acetoxy-3-methylbenzyl).1 -f (2R-cis)-2-(2,4-difluoropheny)-4-4.f4.f4{[ S,2S)-1 -ethyl-2hydroxypropyl)-5-oxo-1 ,5-dihydro-fl 2 ,4ltriazol-4-y]phenyl]piperazin-I ylphenoxymethyltetrahydrofuran-2-ylmethyIl -H-fl ,2,4]triazol-4-ium bromide, 4-(4-acetoxybenzyl)-1 -f (2R-cis)-2-(2,4-difluoropheny)-4[4f[4-[4{-[( 1 S,2S)-1 oxo-1 ,5-dihydro-[1 2 4 ltriazol-4-yllphenyllpiperazin-1 -yllphenoxymethyfltetrahydrofuran2ylmethyjl-
H-
[1 ,2,4jtriazol-4-ium bromide, 4-(4-acetoxy-3,5-dichlorobenzyl)1-f [(2R-cis)-2-(2,4-difluoropheny)4f[4-4-4-[{l-[(1 S,2S)-1 -ethyl-2hydroxypropyl)-5-oxo-1 ,5-dihydro- 1 2 ,4ltriazot-4-yllphenyljpiperazin-1 yllphenoxymethyljtetrahydrofuran-2-ylmethyl]-1 H-fl ,2,4]triazoi-4-ium bromide, 4-(4-acetoxy-3-ch Iorobenzyi)- (2R-cis)-2-(2,4-difluorophenyl)4[4f[4f[4{j-[(1 S,2S)-1 -(ethyl-2hydroxypropyI)]-5-oxo- 1 ,5-dihydro-fl 2 4 ltriazol-4-yl]phenyIjpiperazin- 1 y]phenoxymethyltetrahydrofuran2ylmethyl]lH-fl ,2,4]triazol-4-ium bromide, 4 -(4-acetoxy-3,5-dimethylbenzyl) 1 -[(2R,3R)-2-(2,4-difluoropheny)2hydroxy3f[4(4cyanophenyl)thiazol-2-yljbutyi]-1 H-fl ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3-methylbenzyl)-l 2 Ri 3
R)-
2 2 ,4-difluorophenyl)2hydroxy3f4(4-cyanopheny)thiazol 30 2 -yl]butyil-1H-fl,2,4]triazol-4-ium bromide, 4-(4-acetoxybenzyI)-l 2
R,
3
R)-
2 -(2,4-difluorophenyl)-2hydroxy3f4-(4-cyanopheny)thiazo-2yI]butylj-1 H-fl ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3,5-dichlorobenzyl). 1 -(2R,3R)-2-(2,4-difluorophenyl)-2hydroxy3[4-(4cyanophenyl)thiazol-2-yI]butyIl- H-[1 ,2,4]triazoi-4-ium bromide, 4-(4-acetoxy-3-chlorobenzyl)-1 -f( 2 R,3R)-2-(2,4-difluoropheny)-2-hydroxy3[4(4-cyanophenyl)th iazoi- 2-yi]butyl]-1 H-fl ,2,4jtriazol-4-ium bromide, 2 R,3R)-4-(4-aminoacetoxy-2-carboxybenzyl)-1 -[3-[4-(4-cyano-phenyl)-thiazol2.yI-2(2,4 diftuorophenyl)-2-hydroxybutyj..i H-fl ,2,4jtriazol-4-iumn bromide trifluoroacetic acid salt, 4 -(pyrrolidine-2-carbonyloxy)-benzyl]-1 H-fl ,2,4jtriazol-4-ium bromide trifluoroacetic acid salt, [N:\LIBC]02679A:MEF 2
R,
3
R)
4 -(4-aminoacetoxy35-dimethylbenzyI)l1 3 4 4 -cyano-phenyl)-thiazol2yl-2-(2,4 difluorophenyl)-2-hydroxybutyljlI H-fl 2 4 ltriazol-4-iumbromide trifluoroacetic acid salt, 2
R,
3
R)-
4 4 3 aminopropionyloxy)35dimethylbenzyl]-1 4 4 4 -cyano-phenyl)-thiazol2yl-2-(2,4 difluorophenyl)-2hydroxy3methylbutyll H-fl 2 4 ltriazol-4-ium bromide trifluoroacetic acid salt, 2
R,
3
R)-
4 4 4 aminobutyyloxy)-3,5-dimethylbenzy)- l-f 4 4 4 -cyano-pheny)-thiazol2yll.2(2,4 difiuorophenyl)-2-hydroxy3methylbutyl- H-fl 2 4 ltriazol-4-ium bromide trifluoroacetic acid salt, (2,R--4[2(mnaey~mioaeoy-,-iehlez -1 -f 4 -(4-cyanophenyl)-thiazol.2-yl]- 2 2 4 -difluorophenyl)-2-hydroxybutylp lH-fl 2 ,4ltriazol-4-ium bromide trifluoroacetic acid salt, 1-(R3)3[-4caohnl-hao--l--24dfurpey)2hdoyuy]4[-()25 diaminopentoyloxyl35dimethyl-benzylll1 H-fl ,2,4]triazol-4-ium bromide trifluoroacetic acid salt, 4 -f 4 2 -amino-propionyloxy)3,5-dimethylbenzylll1 2
R,
3 R)-3-[4-(4-cyanophenyl)thiazol2-yi]2 2 4 -difluorophenyl)-2-hydroxybutyll H-fl ,2,4jtriazol-4-ium bromide trifluoroacetic acid salt, [(methylamino)acetoxy]benzyl-l H-[l 2 ,4jtriazol-4-ium bromide trifluoroacetic acid salt, (2R,3R)-I -[-4(-ynpey)tizl2yl2(,-ilurpey)2hdoyuy]4f,-iehl [(propylamino)acetoxylbenzylj.lHf 1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt, 1-(R3)3[-4caohnl-hao--l--24dfurpey)2hdoyuy]4[-()2 1 H-fl ,2,4]triazol-4-ium bromide trifluoroacetic acid salt, (2R,3R)-l 4 -f 4 4 -cyanophenyl)thiazol2yi2-(24difluorophenyl)2hydroxy3methybtl] 4 3 dimethyl-4-f3-(methylamino)-propionyloxylbenzyl-l H-fl ,2,4]triazol-4-ium bromide trifluoroacetate, 4 4 -[(S)-2-amino-3-methylbutanoyoxy3,5dimethylbenzyl]-l 2
R,
3 R)-3-f4-(4-cyanophenyl)thiazol-2 Yl- 2 2 ,4-difluorophenyl)-2-hydroxybutyllH-fl ,2,4jtriazo-4-ium bromide trifluoroacetic acid salt, 1-[ 3 4 4 -cyanophenyl)thiazol2yl-2(2,4difluorophenyl)2hydroxy-butyl]- 4 4 [(isopropylamino)acetoxy-3,5-dimethylbenzyl)l H-[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt, R 3 )3 -y n p e y)th ao. -2 -il o o h ny)2 h d o y uyl S -2 (ethylamino)propionyloxyl3,5-dimethyl-benzyl]pl[,24tizo--u bromide trfuraei acid salt, (2R,3R)-l-[ 3 4 4 -cyanophenyl)thiazol2yl-2(2,4-difluorophenyl)2hydroxybutylj- 4 4 f(ethylamino)acetoxyl35dimethylbenzylll H-fl ,2,4]triazol-4-ium bromide trifluoroacetic acid salt 4 4 -acetoxy-3,5-dimethylbenzyl) 1 -f 2 -hydroxy-3-methyl-3-methylsulfanyl2(4trifluoromethylphenyl)butylp lH-fl ,2,4ltriazol-4-ium bromide, 4 4 -acetoxy-3,5-dimethylbenzyl)-l-ff(l1R,6R)-2-methoxyimino3,3dimethyl-6-(4- *trifluoromethoxyphenoxy)methyllcyclohexyljmethylll H-fl ,2,4ltriazol-4-ium bromide, 4 4 -acetoxy-3,5-d imethylbenzyl)yl 1 R,2S, 6R)-2-methoxy3,3dimethyl6(2-ptolylethyl)cyclohexylmethyll H-fl ,2,4]triazol-4-ium bromide, a a. methylaminoacetoxybenzyl)-l H-fl ,2,4jjtriazol-4-ium bromide hydrochloric acid salt, methylaminoacetoxybenzyl)-l H-fl 2 ,4]triazol-4-ium chloride hydrochloric acid salt, and IN:\LIBC]02679A:MEr 1-[2R,3R)-3-[4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,4-difluoro-phenyl)-2-hydroxy-butyl]-4-(3,5-dimethyl-4methylaminoacetoxy-benzyl)-1 H-[1, 2 ,4]triazol-4-ium bromide hydrobromic acid salt.
The novel azole compounds represented by the general formula as well as salts, hydrates or solvates thereof can be manufactured A) by reacting an azole compound possessing antifungal activity, of the general formula (II) z
N-Q
(II)
with a compound of the general formula (111), R L 3
R
R4 (11) wherein R 1 and R 2 are each independently a hydrogen atom or a group-OY [in which Y is a group easily hydrolyzable under physiological conditions];
R
3 and R 4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower alkylcarbonyl) thiomethyl, carboxy or methoxycarbonyl; and L is a leaving group; or B) by reacting a compound of the general formula (II) as defined above with a compound of the general formula (III) wherein one of R 1 or R 2 is hydroxy, followed by reaction of the resulting compound with a compound of formula RSCOL, or (R 6
O)
2 POL, wherein R 5 CO is the acyl residue of a N-protected amino acid, or R 5 is hydrogen, lower alkoxy, lower alkyl which may be optionally substituted with carboxyl, amino, lower alkyl amino with or without protecting group, di-lower alkyl amino, or aryl; and
R
6 is hydrogen or lower alkyl, and L is a leaving group such as hydroxy, chlorine, bromine, OCOR methanesulfonyl, p-toluenesulfonyl and the like.
20 The reaction of the compound of the general formula (II) with the compound of the general formula (111) can be carried out in a solvent such as methylene chloride, chloroform, benzene, toluene, acetonitrile, tetrahydrofuran, dioxane, or dimethylformamide, preferably chloroform, acetonitrile, or dimethylformamide.
The reaction time in the above benzylation reaction may be varied within a relatively wide range.
In general, the reaction can be carried out at a temperature between 0°C and 1000C, preferably between 0°C and In process B, the acylation or phosphorylation can be performed with either free acid in the presence of a condensation agent such as 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like, or acid halides, acid anhydrides, mixed anhydrides, alkoxycarbonyl halides, .i 30 dialkoxy phosphoryl chloride or phosphoryl chloride in the presence of an acid acceptor such as triethylamine, pyridine, picoline, lutidine, dimethylaminopyridine or alkali metal carbonate by the method known to those skilled in the art.
[N:\LIBC102679A:MEF 8 Preferably, an amino group present in R 5 in the compound of formula III is protected by a suitable amino protecting group as tert-butoxycarbonyl.
The protecting group may, if necessary, be removed after the reaction by procedures known to those skilled in the art.
The compounds of formula I may contain an amino acid ester substituent R 1 and/or R 2 which substituents may form acid addition salts. The term "salts of compounds of formula I" refers to such acid addition salts. These salts may be derived from pharmaceutically acceptable acids as described earlier with reference to the Symbol X. The salt formation can be performed when removing a protecting group, or can be performed ad hoc by procedures known per se.
The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product. Solvates with pharmaceutically acceptable solvents such as ethanol can be obtained for example, during crystallisation.
The novel azole compounds represented by the general formula as well as hydrates or solvates thereof have much higher water solubility than known antimycotic azole compounds represented by the general formula (II) (see table 1).
Table 1
S..
*5 *S
S
S
555.
55
S
Compound (Example No.) Solubility (mg/mL) solvent* 1 1.0 b 2 0.4 b 3 0.4 b 4 >2.0 a >1.0 a 6 6.5 a 7 >1.0 a 8 14.0 a 9 >2.0 a 10 >2.0 a 11 6.0 a 12 5.0 a 13 0.5 b solvent a distilled water, solvent b Melivaine buffer(pH8.02) In addition, the novel azole compounds are chemically stable in aqueous solution at room temperature more than three days, but are efficiently converted into compounds of formula (II) in either mouse, rat, monkey or human plasma.
The conversion of representatives of the new azole compounds of the general formula to ketoconazole and itraconazole, respectively, in human plasma are shown in table 2. The compounds of formula I were incubated with human plasma at a concentration of 10pg/mL at 37 0 C for up to 120min.
IN:\LIBC102679A:MEF Table 2.
Conversion of the new azole compounds to ketoconazole (KCZ) and itraconazole (ICZ) in human plasma Example No. Conversion half-life (min) Incubation time (min) Observed Comp. I KCZ 9 <1 5 <5 89 11 <1 5 <5 100 4 8.4 20 19 74 3.5 10 <5
ICZ
1 53 60 47 28 In vivo efficacy of the compounds of the present invention is shown in Table 3. Male Fisher rats, strain F344/DuCrj, were employed for experimental infection models such as systemic candidiasis, systemic aspergillosis and pulmonary aspergillosis model. Immunocompetent 4 weeks old rats were used for systemic candidiasis or systemic aspergillosis which occurred after infection with Candida albicans conidia of 5xl0 6 /rat or with Aspergillus fumigatus conidia of 6x10 rat via tail vein. Otherwise for pulmonary aspergillosis model, rats had been immunosuppressed with cortisone acetate treatments prior to infection with 2xl0 5 /rat intratrachially. Treatments were given twice on the first day and once daily on following 4 days both for systemic and pulmonary aspergillosis for systemic candidiasis rats were treated at 0, 4, 24, and 48h after infection Effective dose values were determined on day 14 after infection.
Table3 (p.mol/kg) Systemic candidasis Pulmonay aspergillosis Systemic aspergillosis i.v. p.o. i.v. p.o. i.v. p.b.
Example 16 3.5 <2.1 17 18 >35 Example 23 4.6 4.7 8.0 17 17 19 Itraconazole n.t. n.t. n.t. n.t. n.t. 17 Fluconazole n.t. >2.9 n.t. n.t. n.t. n.t.
15 Therefore, the water soluble azole antifungal agents, represented by the general formula as well as salts, hydrates or solvates thereof, according to the present invention, exhibit potent antifungal activity against various fungal infections including Aspergillosis in mice over a very wide range of dosages both orally and parenterally and are useful as antifungal agents.
The present invention further relates to the pharmaceutical compositions containing the azole compound of the general formula as well as salts, hydrates or solvates thereof.
The azole compounds of the formula as well as salts, hydrates or solvates thereof are yery active antimycotic agents. They are active against a variety of fungal species including Candida spp., Cryptotoccus neoformans, Aspergillus spp., Tnchophyton spp., Microsporum spp., Exophiala spp., Blastomyces dermatitidis, and Histoplasma capsulatum.
Thus, the compounds of the present invention are useful for topical and systemic treatment of mycoses in animals as well as in humans. For example, they are useful in treating topical and mucosal fungal infections caused by, among other genera, Candida, Trichophyton, or Microsporum. They may also be used in the treatment of systemic fungal infections caused by, for example, Candida spp., *eee ebee Cb
S
be ebb C be.
C e bbS bb [N:\LIBC0]2679A:MEF Cryptococcus neoformans, Aspergillus spp., Paracoccidiodes spp., Sporotrix spp., Exophiala spp., Blastomyces spp., or Histoplasma spp.
For clinical use, the azole compound of the formula as well as salts, hydrates or solvates thereof can be administered alone, but will generally be administered in pharmaceutical admixture formulated as appropriate to the particular use and purpose desired, by mixing excipient, binding agent, lubricant, disintegrating agent, coating material, emulsifier, suspending agent, solvent, stabilizer, absorption enhancer and/or ointment base. The admixture can be used for oral, injectable, rectal or topical administration.
Pharmaceutical formulation for oral administration may be granule, tablet, sugar coated tablet, capsule, pill, suspension or emulsion. For parenteral injection, for example, intravenously, intramuscularly or subcutaneously, the azoles of formula may be used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose to make the solution isotonic. The azoles can also be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
The daily dosage level of the azole compounds of the formula is from about 0.1 to about (in divided doses) when administered in one, two or more dosages by either the oral or parenteral route. Thus tablets or capsules of the compounds may contain from about 5mg to about of active compound for administration. In any event the actual dosage can be determined by the physician and it may be varied upon the age, weight and response of the particular patient.
In addition, the azole compounds of the formula as well as salts, hydrates or solvates thereof have activity against a variety of plant pathogenic fungi, including for example Pyricularia otyzae, Pythium aphanidermatum, Alternaria spp., and Paecilomyces variotii.
Thus, they can be applied for agricultural and horticultural purposes preferably in the form of a composition formulated as appropriate to the particular use and purpose desired, for example dusting 25 powders, or granules, seed dressings, aqueous solutions, dispersions or emulsions, dips, sprays or aerosols. Such compositions may contain such conventional carriers, diluents or adjuvants as are known and acceptable in agriculture and horticulture. Other compounds having herbicidal or insecticidal, or additional antifungals can be incorporated in the compositions. The compounds and compositions can be applied in a number of ways, for example they can be applied directly to the plant 30 foliage, stems, branches, seeds or roots or to the soil or other growing medium, and they may be used not only to eradicate the disease, but also prophylactically to protect the plants or seeds from attack.
i The following examples illustrate the preferred methods for the preparation of the compounds of the present invention, which are not intended to limit the scope of the invention thereto.
Example 1 Preparation of 4 -(4-Acetoxy-3,5-dimethylbenzyl)--[4-(4-{4.[4-(-(2-butyl)-5.oxo-1,5-dihydro-[1,2,4]triazol-4.
yl)pheny]piperazin-1-yl}phenoxymethyl)-2-(2,4-dichlorophenyl)-[1,3]dioxolan-2-ylmethyl]-H-[1,2,4]triazol-4ium bromide To a solution of 1g of 3 ,5-dimethyl-4-hydroxybenzyl bromide in CHCI 3
-CH
3 CN (7/3mL) was added 400mg of Itraconazole and stirring was continued for 15h at room temperature. The solvent was fN:\LIBC]02679A:MEF evaporated in vacuo and the residue was stirred in acetic anhydride-pyridine (4/4mL) for Ah at ambient temperature. The mixture was concentrated and column chromatography on silica gel (200A, solvent:
CH
2
CI
2 /MeOH 10/1) gave 4-(4-acetoxy-3,5-dimethylbenzyl)-1 -(2-butyl)-5-oxo-1 dihydro-[1I,2,4]triazol-4-yl)phenyl]piperazin-1 -yllphenoxymethyl)-2-(2,4-dichlorophenyl)-[1 dioxolan-2ylmethyl]-1 H-fl ,2,4]triazol-4-iumbromide (507mg, 93%, as amorphous powder); FAB-MS: m/z 881 'H-NMR(CDC 3 8 0.90(3H,t,J=7.3Hz), 1 .39(3H,d,J=6.9Hz), 1.69- 1.77(1 I .81.87(1 2.02(3H,s), 2.1 0(3H,s), 2.32(3H,s), 3.22-3.29(2H,m), 3.31-3.38(1 H,m), 5.02(1 H,d,J=14.2Hz), 5.03(1 H,d,J=14.5Hz), 5.13(1 H,d,J=14.5Hz), 5.54(1 H,d,J=14.2Hz), 6.88- 7.04(8H,m), 7.29(lIH,dd,J=2.0,7.3Hz), 7.45(l1H,d,J=8.9), 7.47(1 7.62(l1H,s), 7.68(1 8.02(1 11.5-1 1.6(1 H,brs).
The following compounds in Examples 2-8 were obtained according to a manner analogous to that of Example 1.
Example 2 4-(4-(Pyridine-3-carbonyloxy)-3,5.dimethylbenzyl)-I -(2-butyl).5-oxo-l ,5-dihydro-fl ,2,4]triazol-4yI)phenyl]piperazin-l -yllphenoxymethyl)-2.(2,4.dichlorophenyl)[1 ,3]dioxolan-2-ylmethylJ-l H-fl ,2,4Jtriazol-4lum bromide; Physical form: amorphous powder MALDI-TOF-MS: m/z 945 1
H-NMR(CD
3 OD) 6 0.88(3H,t,J=7.6Hz), 1 .36(3H,d,J=5.3Hz), 1 .73(2H,m), 2.1 6(6H,s), 3.30(8H,m), 3.63-4.44(6H,m), 5.18(2H,s), 5.48(2H,s), 6.84-8.56(18H,m), 9.01 (1H,s).
Example 3 4-(4-Benzoyloxy-3,5-dimethylbenzyl).l -(2-butyl)-5-oxo-1 ,5-dihydro-[1 ,2,4]triazol-4- *6 yI)phenylqpiperazin-l -yI~phenoxym ethl)-2-(2,4-dichloroplienyl)-jl ,3]dioxolan-2-ylmethyl]-l H-fl ,2,4]triazol- 4-ium bromide; Physical form: amorphous powder; FAB-MS mlz 943 1 H-NMR(86-DMSO) 6 0.80(3H,t,J=7.3Hz), 1 .29(3H,d,J=6.6Hz), 1 .67(2H,m), 2.11 3.40(8H,brs), 3.77(2H,m), 3.95(2H,m), 4.12(1H,m), 4.40(1H,m), 5.08(2H,s), 5.42(2H,s), 6.90(2H,brd), 7.11-7.80(14H,m), 8.17(2H,d,J=7.2Hz), 8.35(1H,s) 9.40(IH,s), 10.4(IH,s).
Example 4 30 1 4 -Acetoxy-3,5-dimethyl-benzyl).3-[(2R*,4S*)4.[4(4.aceyIpipera zin-l -yI)-phenoxymethyl]-2-(2,4-dichloro.
phenyl)-fl ,3]dioxolan-2-ylmethyI].3H-imidazoIl -lum bromide; Physical form: pale brown oil; FAB-MS: m/z 707(M-Br)+; 1
H-NMR(CDC
3 6 2.11(6H,s), 2.14(3H,s), 2.33(3H,s), 3.07(4H,m), 3.62(2H,m), 3.68(1H, dd,J=4.6,10.2Hz), 3.77(2H,m), 3.89- 4.02(l1H,dd,J=4.0, 11.6H-z), 4.37( 1H, 4.85(2H,s), 5.08(1H,d,J=14.2Hz), 5.48(1H,d,J=14.2Hz), 6.81(2H,d,J=8.9Hz), 6.91(2H,d,J=8.9Hz), 6.99(1H,s), 7.05(2H,s), 7.18(1H,s), 7.31 (1 H~dd,J=2.0,8.6Hz), 7.47(1 H,d,J=2.OHz), 7.69(1 H,d,J=8.6Hz), 10.42(1 H,s).
[NALIBC102679A:MEF Example 3.[(2R*,4S*)-4-[4-(4AcetyI-piperazin-1 -yi)phenoxymethyl]-2-(2,4.dichloro-phenyl)[1 ,3Jdioxolan-2-ylmethylJ- I -(4-isobutyryloxy-3,5-dimethyl-benzyl).3H-imidazol.1 -lum bromide; Physical form: clear film; FAB-MS: m/z 735 'H-NMR(CDC 3 5 1 .34(6H,d,J=6.9Hz), 2.09(6H,s), 2.14(3H,s), 2.85(lIH, sept,J=6.9Hz), 3.06(4H,m), 3.61 (1 H,dd,J=4.9,5.2Hz), 3.67(1 H,dd,J=4.0, 10.6H-z), 3.97(1 H,dd,J4.9,5.2Hz), 3.90(2H,m), 3.97(1 H,ddJ=4.O,10.6Hz), 4.35(1 4.83(2H,s), 5.15(1 H,d,J=14.5Hz), 5.49(1 H,d,J=14.5Hz), 6.80(2H,d,J=8.9Hz), 6.91 (2H,d,J=8.9Hz), 7.08(2H,s), 7.10(1 H,d,J=2.0Hz), 7.19(1 H,brs), 7.30(1 H,dd,J=2.0,8.3Hz), 7.46(1 H,d,J=2.OHz), 7.67(1 H,d,J=8.3Hz), 10.32(1 H,brs).
Example 6 I .(4.Acetoxy-3,5-dichloro-benzyl).3-[(2R*4S*)-[4-[4-(4.acetyI-piperazin-1-yI)-phefloxymethyl]-2-(2,4.dichloro.
phenyl).[I ,3Jdioxolan-2-ylmethylj-3H-imidazol.li -um bromide; Physical form: pale brown oil; FAB-MS: mlz 747 1 H-NMR(CDCI,) 8 2.14(3H~s), 2.39(3H,s), 3.07(4H,m), 3.62(3H,m), 3.78(2H,m), 3.89(1H,m), 3,97(1H,m), 4.10(1H,m), 4.39(1H,m), 4.75(1 H,d,J=16.2Hz), 4.83(1 H~d,J=16.2Hz), 5.11 (1 H,d,J~l14.81-z), 5.77(1 H,d,J=14.8Hz), 6.79(2H,d,J=9.l Hz), 6.92(2H,d,J=9.l Hz), 7.01 (1 7.22(l1H,s), 7.33(1 H,dd,J=8.6,2.OHz), 7.42(2H,s), 7.48(IH,d,J=2.OHz), 7.68(1H,d,J=8.6Hz), 10.52(1H,s).
Example 7 dI-I 4 -Acetoxy-3,5.dimethyI-benzyl).3.[2-(2,4-dichloro-benzyloxy)-2.(2,4-dichloro-pheny).ethy]3H imidazol-IVumn bromide: Physical form: amorphous powder; FAB-MS m/z 593 1
H-NMR(CD
3 OD) 6 2.15(6H,s), 2.35(3H,s), 4.41--4.58(4H,m), 5.22(1H,dd,J=3.5,7.8Hz), 5.32(2H,s), 7.16(2H~brs), 7.24-7.56(7H,m), 7.66(l1H,d,J=1.OHz), 9.00(lIH, brs).
Example 8 25 4-(4-acetoxy-3,5-dimethyl-benzyl)-I R,2S,6R)-2-methoxy.3,3-dimethyl.6.(2.p-tolyl-ethyl).
cyclohexylmethyl].I H-I ,2,4ltriazol-4-ium bromide; Physical form: colorless oil; MALDI-TOF-MS: m/z 518 1
H-NMR(CDC
3 8 0.84(3H,s), 1.02(3H,s), 1.10--1.30(3H,m), 1.37-1.42 1.45-1..65(IH,m), 1.71 1.93(2H,m), 2.1 5(6H,s), 2.31 2.34(3H,s), 2.51(1 2.71(1 2.83(1 H,d,J=1 0.9Hz), 3.50(3H,s), 30 4.49(1 H~d,J= 18.9Hz), 4.60(1 H,dd,J=1 8.9,5.9Hz), 5.58(1 H,d,J=14.4Hz), 5.66(1 H,d,J=14.4z), 7.08(4H,s), 7.21(2H,s), 8.31 (1 1 1.64(1 H,s).
Example 9 :.Preparation of I .(4-Acetoxybenzyl)41[(2R*,4S*).4[4(4-acetylpiperazin.I -yI)phenoxymethy]-2-(2,4dichlorophenyl)[1 ,3]dioxolan-2.yI-methyl]-3H-imidazol-I-ium bromide To a solution of 28mg of 4-acetoxybenzyl bromide in 1 .5mL of CHC13 was added 30mg of Ketoconazole and the mixture was stirred for 1 6h at room temperature. The solvent was evaporated in vacuo. Column chromatography on silica gel(Wakogel C-200, solvent:CH 2
CI
2 /MeOH=10/1) gave 1-(4- [N:\LIBC]02679A:MEF acetoxybenzyI)-3-[(2R*,4S*)4[4(4acetyI piperazin-1 -yl)phenoxymethyll-2-(2,4-dich lorophenyl)- [1,3]dioxolan-2-yl methyll-3H-imidazok 1 -ium bromide (32mg, 76%, as colorless oil); MALD I-TOF-MS mlz 679 1
H-NMR(CDC
3 6 2.14(3H,s), 2.28(3H,s), 3,05(4H,m), 3.60'..3.89(8H,m), 4.33(l1H,m), 4.80(2H,s), 5.37(1 H,d,J=14.5Hz), 5.61(1 H,d,J=14.5Hz), 6.78(2H,d,J=g.1 Hz), 6.92(2H,d,J=9.1Hz), 7.03(2H,d,J=8.6Hz), l.
2 4-7.63(7H,m), 10.1(1 H,s).
The following compounds in Example 10-14 were obtained according to a manner analogous to that of Example 9.
Example 3 2 R,4S).4-[4-(4-Acetylpiperazin.1 -yl)phenoxymethyll.2-(2,4.dichlorophenyl)-[1 3]dioxolan-2-ylmethyl]-1.
1 0 4 2 2 -dimethylpropionyloxy)benzyl.3Himidazo-i -ium bromide; Physical form: amorphous powder; MALDI-TOF-MS: mlz 721 1 H-NMR (ODC1 3 6 1 .34(9H,s), 2.14(3H,s), 3.06(4H,m), 3.60-4.00(8H,m),4.36,(1 4.81 5.29(1 H,d,J=14.4Hz), 5.62(1 H,d,J=14.4Hz), 6.80(2H,d,J=9.3Hz), 6.92(2H,d,J=9.3Hz), 7.02(2H,d,J=8.6Hz), 7.15(1 H,brs), 7.20(1 H,brs), 7.28(1 H,brs), 7.43(2H,d,J=8.6Hz), 7.46(1 H,brs), 7.65(1 H,d,J=8.3Hz), 10.3(1 H,s).
Example 11 1-4Aeoy3mty-ezl--(RS)4[-4aey-ieai- -yI)-p hen oxymethyfl-2-(2,4-dich Ioro- .phenyI)-[1,3Idioxolan-2.ylmethyl].3H-imidazoI1.-ium bromide; *Physical form clear film; FAB-MS: m/z 693(M-Br)+; 1
H-NMR(CDC
3 6 2.13(6H,s), 2.31(3H,s), 3,06(4H,dt,J=5OHz), 3.62(2H,t,J=5.OHz), 3.66(1 H,dd,J=4.6Hz), 3.76(2H,t,J=9.OHz), 3.88(2H,m), 3.94(l1H,dd,J=4.6Hz), 4.36(1H,m), 4.81(2H,s), 5.26(1 H,d,J~l14.0Hz), 5.55(1H,d,J=14.OHz), 6.79(2H,d,J=9.OHz), 6.91 (2H,d,J=9.OHz), 6.96(1 H,d,J=8.OHz), 7.22(2H,brs), 7.23(1 H,dd,J=2.0,8.OHz), 7.29(1 H,dd,J=2.O,8.OHz), 7.39(1 H,brd), 7.45(1 H~d,J=2.OHz), 7.64(1 H,d,J=8.OHz), 10.21 (1 H,s).
Example 12 1 l( 4 -Acetoxy- 3 -methoxyI-benzyl)3(2R*4S*)4[4(4aceylpiperazin-1-yI)-phenoxymethyl.-2-(2,4-dichloro.
phenyl)-[I ,3-dioxolan-2-ylmethyt]-3H-imidazol.1 -lum bromide; Physical form: amorphous powder; MALDI-TOF-MS m/z 709(M-Br)'; 1
H-NMR(CDC
3 6 2.14(3H,s), 2.30(3H,s), 3.06(4H,m), 3.62(2H,m), 3.65(1H,dd,J=4.6, 10.2H-z), 3.77(2H,m), 3.86(3H,s), 3.88.-3.94(2H,m), 4.03(1 H,dd,J=4.0,1 1.6Hz), 4.36(1 H, 4.80(2H,s), 5.12(1 H,d,J=14.2Hz), 5.54(1 H,d,J=14.2Hz), 6.80(2H,d,J=8.9Hz), 6.81(1 6.92(2H,d,J=8.9Hz), 6.95(1 7.07(1 H,s), 7.17(1 7.31(1 H,dd,J=2.0,8.6Hz), 7.44(1 H,d,J=2.OHz), 7.47(1 H,J=2.0Hz), 7.66(1 H,d,J=8.6Hz), 10.41 (1 H,s).
Example 13 dl-i -sec-butyl-5-oxo-1 ,5-dihydro-[1 2 4 ltriazol- 4 -y).phenyl]-piperazini -yI}-phenoxymethyl)-2- (2,4-dichloro-phenyl)-[1 3 ]dioxoan2ymethy1-4(4hexanoyoxy3,5dimethy-benzyj)-1 H-(1 ,2,4]triazol-4-ium methanesulfonate; Physical form: amorphous powder; FAB-MS mlz 937(M-MsO)+; 1
H-NMR(CDC
3 6 0.80- 1 .00(6H,m), 1 .42(3H,d,J=6.6Hz), 1.20-.50(6H,m), 1 2.1 0(9H,s), 2.58(2H,t,J=7.6Hz), 3.26(4H,m), 3.36(4H,m),3.62-3.70(2H,m), 3.75(1 4.10-4.50(3H,m), 4.84(1 H,d,J=14.2Hz), 5.00(1 H,d,J=13.8Hz), 5.12(1 H,d,J=1 3.8Hz), 5.44(1 H,d,J=14.2Hz), 6.90(2H,d,J=8.9Hz), 6.94(2H,s), 6.99(2H,d,J=8.9Hz), 7.03(2H,d,J=8.9Hz), 7.31 (1 H,dd,J=8.6,2.OHz), 7.43(2H,d,J=8.9Hz), 7.48(1 H,d,J=2.OHz), 7.62(1 7.71 (1 H,d,J=8.6Hz), 7.90(1 11.30(1 H,s).
Example 14 (2R,3R)-4-(4-Acetyloxy-3,5-dimethylbenzyl)-l -[3-[4-(4-cyanophenyl)-thiazol-2-yl-2-(2,4-difluorophenyl)-2.
hydroxy-butylJ]l H-fl ,2,4]triazol-4-ium bromide; Physical form amorphous poweder; FAB-MS mlz 614 'H-NMR(CD 3 OD) 8 1 .24(3H ,d,J=6.9Hz), 2.25(6H,s), 2.36(3H,s), 4.30(1 H,q,J=6.9Hz), 4.64(1 H,d,J=1 4.2Hz), 5.10(1 H,d,J=14.2Hz), 5.31 6.75-7.27(3H,m), 7.1 0(2H,s), 7.82(2H,d,J=8.3Hz), 8.09(1 H,s),8.18(2H,d,J=8.2Hz), 8.73(1 9.95(1 H,s) Example (2R,3R)-4-(4-Aminoacetoxy-2.carboxy-benzyl).l -13-f4-(4-cyano-phenyl)-thiazol-2-yl]-2-(2,4-difluorophenyl)2hydroxybutyl]-l H-fl ,2,4]triazol-4-ium bromide trifiuoroacetic acid salt a) Preparation of 3-(tert-butoxycarbonylaminoacetoxy)-6-(bromomethyl)benzoic acid tert-butyl ester A mixture of 200mg of 3-hydroxy-6-(hydroxymethyl)benzoic acid tert-butyl ester, 187mg of Bocglycine, 65mg of 4-dimethylaminopyridine and 245mg of 1 -(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride in 8mL of dichioromethane was stirred for 1 5h at room temperature and was diluted with 4OmL- of dichloromethane. The mixture was washed with IN HCI and dried over anhydrous Na 2
SO
4 Removal of the solvent gave 180mg of 3-(tert-butoxycarbonylaminoacetoxy)-6hydroxymethylbenzoic acid tert-butyl ester.
To a solution of 650mg of 3-(tert-butoxycarbonylaminoacetoxy)-6-hydroxymethylbenzoic acid .~.tert-butyl ester and 250mg of triphenylphosphine was added 848mg of carbon tetrabromide, and the 25 mixture was stirred for 2h at room temperature. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na 2
SO
4 and concentrated in vacuo.
Column chromatography on silica gel gave 322mg of 3-(tert-butoxycarbonylaminoacetoxy)-6- (bromomethyl)benzoic acid tert-butyl ester as a colourless oil; 1
H-NMR(CDC
3 8 1 .34(9H,s), :1.51 4.08(2H,br.d,J=5.6Hz), 4.80(2H,s), 4.95(1H,br.s), 7.12(l1H,dd,J=8.6,2.6Hz), 7.34(1H,d,J=8.6Hz), 7.51 (1H,d,J=2.6Hz) b) (2R,3R)-4-(4-Aminoacetoxy-2-carboxybenzyl)-1 -[3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4difluorophenyl)-2-hydroxybutyl]-1 H-[1,2,4]triazol-4-ium bromide trifluoroacetic acid salt was obtained as a white solid from (1 R,2R)-4-[2-[2-(2,4-difluoro-phenyl)-2-hydroxy-1 -methyl-3-[1 ,2,4]triazol- 1-yl-propyl]thiazol-4-yl]-benzonitrile and 3-(tert-butoxycarbonylaminoacetoxy)-6-(bromomethyl)benzoic acid tert- 35 butyl ester according to a manner analogous to that of Example 1; Physical form: white powder; FAB-MS: m/z 645 1
H-NMR(CD
3 OD) 8 1 .22(3H,d,J=7.3Hz), 4.21 4.28(1 H,q,J=7.3Hz), 4.61(1 H,d,J=14.2Hz), 5.09(1 H,d,J=14.2Hz), 5.68(1 H,d,J1l4.OHz), 5.75(1 H,d,J 1 4.0Hz), 6.78-7.28(3H,m), 7.55(1 H,dd,J=2.3,8.6Hz), [N:\LIBC]02679A:MEF 7.64(1 H,d,J=8.6Hz), 1.81 (2H,d,J=8.5Hz), 8.03(1 H,d,J=2.3Hz), 8.10(1 8.1 7(2H,d,J=8.5Hz), 8.67(l1H,s) 9.80(l1H,s) Example 16 2
R,
3
R)-
3 4 4 -Cyanophenyl)thiazol2yl]2(24difluorophenvl)2hydroxybutyl]4[(S)- 3 dimethyl-4-(pyrrolidine-2-carbonyloxy)-benzyl]1 H-[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid sait was obtained either by the following method A or B.
i) method A: To a solution of 3g of 3,5-dimethyl-4-hydroxybenzyl bromide in CH 3 CN(3OmL) was added 1 .2g of (1 R,2R)-4-[2-[2-(2,4-difluorophenyl)-2-hydroxy-1 -methyl-3-[1 ,2,4]triazol-1 -yl-propyl~thiazol-4yllbenzonitrile and stirring was continued for 2h at room temperature. The precipitate was filtered and washed with ether to give I .37g(81%y.) of l-[(2R,3R)-3-[4-(4-cyanophenyl)thiazol2yl-2-(2,4 difluorophenyl)-2-hydroxybutyl4(35dimethyl4hydroxy)benzyllI H-[1 ,2,4]triazol-4-ium bromide(RoO9-3846) as a white solid.
To a mixture of 30g of 2
R,
3
R)-
3 -[4-(4-cyanophenyl)thiazol-2-ylI2(2,4..difluorophenyl)-2 hydroxybutyll-4-(3,5dimethyl-4hydroxybenzyl) I H-[1 ,2,4jtriazol-4-ium bromide, 1 0.9g of Boc-(L)proline and 2.8g of N,N-dimethylaminopyridine in 1.21- of dichloromethane was added 17.6g of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the mixture was stirred for 1 .5h at room temperature and concentrated in vacuo. The residue was chromatographed on silica gel (Wakogel C- 200, solvent: CH 2
CI
2 /MeOH= 14/1) to give 30.9g(79%y.) of 1 -[(2R,3R)-3-[4-(4-cyanophenyl)thiazol-2yl]- 20 2 2 4 -difiuorophenyl)2hydroxybutyl4(S)3,5dimethyl4(N-tertbutoxycarbonylpyrrolidine-2 carbonyloxy)benzylJ-1 H-[1,2,4]triazol.4-ium bromide as a white solid.
30.9g of 1-(R3)3[-4caohnltizl2y]--24dfurpey)2hdoyuy]4 H-[1 ,2,4]triazol-4-ium bromide was stirred in 600mL- of 10% TFA-dichioromethane for 5h at room temperature and the solvent was removed in vacuo. The residue was diluted with ether and the precipitate was washed *:.with ether to give 2
R,
3
R)-
3 4 4 cyanophenyl)thiazol2yl2(2,4-difluorophenyl)-2hydroxybutyl]-4 3 ,5-dimethy-4(pyrrolidine2carbonyloxy)benzyl]-1 H-[1 ,2,4jtriazol-4ium bromide trifluoroacetic acid salt as a white solid.
ii) method B: A mixture of 1 .06g of (1 R, 2 R)4-[2-[2-(2,4-difluorophenyl)2hydroxylmethyl-3[1 ,2,4]triazol-1-ylpropyl]thiazol-4-yl]benzonitrile and 1.1 g of 3 5 -dimethyl-4-[(S)-N-tert-butoxycarbonylpyrrolidine carbonyloxy]benzyl bromide, prepared from 3,5-dimethyl-4-hydroxybenzaldehyde in 3 steps, in 2OmL of acetonitrile was stirred for 15h at reflux temperature and then concentrated.
The residue was chromatographed on silica gel (Wakogel C-200, solvent: CH 2 01 2 /MeOH=12/1) to give 1 .92g of I 2
R,
3
R)-
3 4 -(4cyanophenyl)thiazol2yl-2(2,4difluorophenyI)-2
H-
[l,2,4]triazol-4-ium bromide as a white solid.
1-(R3 )3[-4C aohnltizl2yl2(,-iloohnl--yrxbtl--()35 dimethyl-4-(pyrrolidine-2-carbonyloxy)benzyl]1 H-[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt [N:\1IBC102679A:MEF was obtained by removal of the protecting group as described in the method A; Physical form: white powder; MALDI-TOF-MS: "mlz 669 'H-NMR(CDOD) 6 1.24(3H,d,J=7.3Hz), 2.18-2.25(2H,m), 2.21 2.36-2.44(1 2.66-2.71 (1 3.43-3.50(2H,m), 4.30(1 H,q,J=7.3Hz), 4.65(1 H,d,J=14.2Hz), 4.88(1 5.12(1 H,d,J=14.2Hz), 5.33(2H,s), 6.73-6.79(1 6.99- 7.06(1 7.14(2H,s), 7.21-7.30(1 7.82(2H,d,J=8.6Hz), 8.10(1 8.18(2H,d,J=8.6Hz), 8.74(IH,s), 1.00(lH,s) Following compounds in Example 17-30 were obtained according to a manner analogous to that of Example 16.
Example 17 2 R,3R)-4-(4-Aminoacetoxy.3,5-dimethylbenzyl)-1 3 4 4 -cyanopheny)thiazo2vJ2-(2,4-difluoropheny)- 2-hydroxybutyl].1 H.[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS: mlz 629 'H-NMR(CD 3 00) 8 1.25(3H,d,J=7.3Hz), 2.21(6H,s), 4.29(1H,q,J=7.3Hz), 4.31(2H,s), 4.66(1H,d,J=14.2Hz), 5.12(1H,d,J=14.2Hz), 5.34(2H,s), 6.72-7.30(3H,m), 7.15(2H,s), 7.81(2H,d,J=6.6Hz), 8.l0(1H,s), 8.17(2H,d,J=6.6Hz), 8.74(1H,s), 10.0(1 H,s) Example 18 2
R,
3 R)-4-[4-(3-Aminopropionyloxy).3,5-dimethylbenzyI.1 -[4-[4-(4cyanophenyl).thiazol.2.y11.2.(2,4 d ifl uoro phenyl)-2-hyd roxy.3-methyl buty].1 H-[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS mlz 643 (M-TFA-Br)+; 'H-NMR(CD 3 OD) 8 20 1.24(3H,t,J=7.3Hz), 2.19(6H,s), 3.09-3.37(4H,m), 4.30(1H, q,J=7.3Hz), 4.66(1H, d, J=14.2Hz), 5.11(IH, d, J=14.2Hz), 5.33(2H, br.s), 6.73-6.81(1H,m), 6.98-7.07(1H,m), 7.12(2H,s), 7.20- 7.3( .12 ,d .H .1 .82 ,d .H ),87 ,s,100 Example 19 2
R,
3 R).4.[4.(4.Aminobutyryloxy)35-dimethylbenzylJ.1 -[4-[4-(4-cyanophenyl)-thiazol-2.yl].2-(2,4 25 difluorophenyl).2-hydroxy-3methylbuty]1 H[124]trazoj.4ium bromide trifluoroacetic acid salt: Physical form: white powder; FAB-MS Mlz 657 (M-TFA-Br) 1
H-NMR(CD
3 OD) 6 1.24(3H, d, J=7.26Hz), 2.03-2.12(2H,m), 2.17(6H,s), 2.87(2H,t,J=7.5Hz), 3.07(2H, t, J=7.5Hz), 4.30(IH, t, 4.65(1H, d, J14.4Hz) 5.10(IH, d, J=14.4Hz), 5.31(2H,s), 6.73-6.80(IH,m), 6.98- 7.07(IH,m), 7.11(2H,s), 7.18-7.28(IH,m), 7.82(2H, d, J8.6Hz), 8.10(1H,s), 8.17(2H, d, J=8.6Hz), 8.73(l1H,s).
Example 2
R,
3
R)-
4 4 [(2Aminoacetylamino)acetoxyl.3,5.dimethylbenzyl]1 3 -[4-(4-cyanophenyl)-thiazal-2.ylj.2-(2.4.
difluorophenyl).2.hydroxybutyl].1 H-[1 ,2,4ltriazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS: Mlz 686 1 H-NMR(DMSO-d 6 8 1 .18(3H,d,J=6.9HZ), 2.08(6H,s), 3.67(2H,brs), 4.14(1 H,q,J=6.9Hz), 4.34(2H,d,J=5.6), 4.69(1H,d,J=14.2Hz), 5.01(1H,d,J=14.2Hz), 5.35(2H,s), 6.58(IH,s), 6.90-6.96(1H,m), 7.07(2H,s), 7.21- IN:\LIBC]02679A:MEF 7.37(2H,m), 7.94(2H,d,J=7.9Hz), 8.07(2H,brs), 8.21 (2H,d,J=7.9Hz), 8.43(1 8.99(1 H,t,J=5.6), 9.02(1H,s), 10.06(1H,s).
Example 21 I -[(2R,3R)-3-[4-(4-Cyanophenyl)-thiazol.2-yl]-I -2-(2,4-difluorophenyl)-2-hydroxy-butyl].4-[4.[(S)-2,5 diaminopentoyloxyl]-3,5-dimethylbenzyl].1 H.[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS: m/z 686 'HNMR(CD 3 OD) 6 1.24(3H~d,J=6.9Hz), 1 .95-2.43(4H,m), 2.22(6H,s), 3.09(2H,t,J=7.OHz), 4.30(1 H,q,J=6.9Hz), 4.60(1 H,m), 4.67(1 H,d,J~l14.21-z), 5.12(1 H,d,J=14.2Hz), 5.34(2H,s), 6.76-7.27(3H,m), 7.15(2H,s), 7.82(2H,d,J=8.2Hz), 8.10(1 8.18(2H,d,J=8.2Hz), 8.74(1 10.0(1 H,s).
Example 22 4-[4-[(S)-2-Aminopropionyloxy)-3,5-dimethylbenzyl]-I -[(2R,3R)-3[4-(4-cyanophenyl).thiazol.2-ylj.2-(2,4.
difluorophenyl)-2-hydroxybutyl]-I H.[1 ,2,4Jtriazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS :mlz 643 1
HNMR(CD
3 OD) 8 1 .23(3H,d,J=6.9Hz), 1 .79(3H,d,J=6.9Hz), 2.20(6H,s), 4.29(1 H,q,J=6.9Hz), 4.57(1 H,q,J=6 9Hz), 4.67(1 H,d,J=14.2Hz), 5.12(1 H,d,J=14.2Hz), 5.34(2H,s), 6.70-7.26(3H,m), 7.14(2H,s), 7.80(2H,d,J=8.2Hz), 8.10(1 8.18(2H,d,J=8.2Hz), 8.74(1 10.0(1 H,s) Example 23 .[(methylamino)acetoxyjbenzylJ.I H[1 ,2,4jtriazol-4-ium bromide trifluoroacetic acid salt; Physical form: amorphous powder; FAB-MS: m/z 643 1
H-NMR(CD
3 OD) 8 ~:1.24(3H,d,J=7.3Hz), 2.21(6H,s), 2.84(3H,s), 4.30(1H,qJ=7.3Hz), 4.45(2H,s), 4.65(1H,d,J=14,2Hz), 5.11(1 H,d,J=14.2Hz), 5.33(2H,s), 6.76(1 7.02(1 7.14(2H,s), 7.24(1 H, m), 7.82(2H,dJ8.6Hz), 8.10(1 8.18(2H,d,J=8.6Hz), 8.74(1 9.99(1 H,s).
~:.Example 24 (2R,3R).1 3 4 4 -Cyanophenyl)thiazol2y]-2-(2,4-difluorophenyl)2hydroxybutyl]4.p35-dimethyl.4- [(propylamino)acetoxylbenzyl]l H-[1 ,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS: m/z 671 1
HNMR(CD
3 OD) 6 1 .05(3H,t,J=7.4Hz), 1 .25(3H,d,J=7.3Hz), 1 .77(2H,m), 2.21 3.1 0(2H,m), 4.31 (1 H,q,J=7.4Hz), 4.47(2H,s), 4.66(1 H,d,J=13.9Hz), 5.12(1 H,d,J=13.9Hz), 5,33(2H,s), 6.72-7.29(3H,m), 7.14(2H,s.), 30 7.82(2H,d,J=8.3Hz), 8.09(l 8.18(2H,d,J=8.3Hz), 8.74(lIH,s), 10.0(1IH,s) Example I -[(2R,3R)-3-[4-(4-Cyanophenyl)thiazol.2-yl-2(2,4.difluorophenyl)-2-hydroxybutyl]-4-[4-[(S)-2- H.[I,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder;FAB-MS: m/z 657 'HNMR(CD 3 00) 6 1 .25(3H,d,J=7.3Hz), 1 .83(3H,d,J=7.3Hz), 2.21 2.83(3H,s), 4.26(1 H,q,J=7.3Hz), 4.57(1 H,qJ=7.3Hz), IN:XL1BC)02679A:MEF 4.66(1 H,d,J=14.5Hz), 5.12(1 H,d,J=14.5Hz), 5.34(2H,s), 6.72-7.26(3H,m), 7.1 5(2H,s), 7.82(2H,d,J=8.6Hz), 8.11 (1 8.18(2H,d,J=8.6Hz), 8.75(1 H,s) Example 26 (2R,3R)-l 4 4 4 -cyanophenyl)thiazol.2.yl]-2(2,4difluorophenyl)2hydroxy3methylbutyl].4[3,5dimethyl 4-[3-(methylamino)propionyloxy]benzyl]1 H-fl ,2,4]triazol-4-ium bromide trifluoroacetate: Physical form: white powder; FAB-MS: mlz 657 (M-TFA-Br) 'HNMR(CD 3 OD) 6 1 .24(3H, d, J=6.9Hz), 2.19(6H,s), 2.78(3H,s), 3.21(2H, t, J=6.6Hz), 3.42(2H, t, J6.6Hz) 4.30(IH, q, J=6.9Hz), 4.66(1H, d, J=14.2Hz), 5.11(1H, d, J=14.2Hz), 5.33(2H, 6.73-6.81(1H, in), 6.98.-7.07(1H, in), 7.12(2H, 7.20-7.30(1H, in), 7.82(2H, d, J=8.7Hz), 8.10(IH, 8.18(2H, d,J=8.7Hz), 8.73(1H,s), 9.98(l1H, s) Example 27 4-[4-[(S)-2-Amino-3-methylbutanoyloxy]-3,5-dimethylbenzylj-I -[(2R,3R)-3-[4-(4-cyanophenyl)thiazol.2-yij.2- (2,4-difluorophenyl)-2-hydroxybutyl]-1 H-fl ,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: white powder; FAB-MS: mlz 671 1 H NMR(CD 3 OD) 6 1 .21 (3H,d,J=6.9Hz), 1 .25(3H,d,J=6.9Hz), I .27(3H,d,J=6.9Hz), 2.22(6H,s), 2.66(1H,m), 4.27(1 H,q,J=6.9Hz), 4.49(1 H~d,J=3.6Hz), 4.66(1 H,d,J=14.2Hz), 5.12(1 H,d,J=14.2Hz), 5.35(2H,s), 6.73-7.30(3H,m), 7.1 5(2H,s), 7.82(2H,d,J=8.6Hz), 8. 10(1 8.18(2H,d,J=8.6Hz), 8.75(1 10.0(1 H,s) Example 28 (2R,3R)-l -[3-[4-(4-Cyanophenyl)-thiazol-2-yll-2-(2,4-difluorophenyl)-2.hydroxy-butyl]-4[4.
20 [(isopropylamino)acetoxy-3,5.dimethylbenzyl]-l H-fl ,2,4]triazol-4-ium bromide trifluoroacetic acid salt; Physical form: amorphous powder; FAB-MS mlz 671 1 HNMR(CDOD) 6 1 .24(3H,d,J=6.9Hz), 1.41 (6H,d,J=6.6Hz), 2.22(6H,s), 3.32-3.53(1 4.30(1 H,q,J=7.3Hz), 4.50(2H,s), 4.66(1 H,d,J=14.2Hz), 5.12(1 H,d,J=14.2Hz), 5.34(2H,s), 6.73-6.78(1 6.98-7.06(1 H,m), 7.1 5(2H,s), 7.20-7.29(1 7.82(2H,d,J=8.6Hz), 8.11 (1 8.1 8(2H~d,J=8.6Hz), 8.74(1 H,s).
Example 29 I -(2R,3R)-3-[4-(4Cyanophenyl)thiazol-2-yl]-2-(2,4.difluorophenyl).2-hydroxybutyl]4-(2)4-2 (ethylamino)propionyloxy]-3,5-dimethylbenzyl]1 H-fl ,2,4jtriazol-4-ium bromide trifluoroacetic acid salt; Physical form: amorphous powder; MALDI-TOF-MS mlz 671 'H-NMR(CDOD) I .24(3H,d,J=7.3Hz), 1 .38(3H,t,J=7.3Hz), 1.83(3H,d,J=7.3Hz), 2.21 3.14-3.25(2H,rn), 3oa 4.30(1 H,q,J=7.3Hz), 4.63(1 H,q,J=7.3Hz), 4.66(1 H,d,J=14.2Hz), 5.12(1 H,d,J=1 4.2Hz), 5.35(2H,s), 6.74-6.80(1 6.98-7.07(1 7.1 6(2H,s), 7.21-7.30(1 7.82(2H4d,J=8.6Hz), 8.11(1 H~s), 8.1 8(2H,d,J=8.6Hz), 8.75(1 10.00(1 H,s) Example (2R,3R)-1 -[3-[4-(4-Cyanophenyl)-thiazol.2-yI]-2-(2,4difluorophenyl)-2-hydroxybutyl]-4-[4- [(ethyl am ino)acetoxy]-3,5.d imethylbenzyl]-l H -fl,2,4]triazol1-4-i um bromide trifluoroacetic acid salt; fN:\LIBC]02679A:MEF Physical form: white powder FAB-MS mlz 657 1
H-NMR(CD
3 OD) 8 1.25(3H,d,J=7.3Hz), 1 .38(3H,t,J=7.3Hz), 2.22(6H,s), 3.22(2H,q,J=7.3Hz), 4.27(1 H,q,J=7.3Hz), 4.48(2H,s), 4.67(1 H,d,J=14.2Hz), 5.12(1 H,d,J=14.2Hz), 5.35(2H,s), 6.73-7.29(3H,M), 7.15(2H,s), 7.82(2H,d,J=8.6Hz), 8.10(1 8.18(2H,d,J=8.6Hz), 8.75(1 10.0(1 H,s) Example 31 methylaminoacetoxy-benzyl)1 H-[1 ,2,4]triazol-4.ium bromide hydrochloric acid salt 4 -f 4 [(tert-Butoxycarbonyl-methyl-amino)acetoxy]..3,5-dimethylbenzylll1 -f2R,3R)-3-[4-(4-cyanophenyl)-thiazole-2-yl-2(24difluorophenyl)2hydroxy-butyll H-fl ,2,4J triazoie-4-ium bromide (1:1) was obtained by the similar procedure as described in the method B. To a solution of 4-{4-f(tert- 2
R,
3 R)-3-[4-(4-cyano-phenyl)ythiazole- 2 -yl]- 2 -(2,4-difluoro-phenyl)-2-hydroxybutyq1 lH-fl ,2,4ltriazole-4-ium bromide (1 98.7g, 241 mmol) in EtOAc (lOOOmL), a solution of Hl in EtOAc (4 N, 600mL-) was added at room temperature over a period of 30min with vigorous stirring. The resulting suspension was stirred at room temperature for 3 h. Precipitates were collected on a glass filter (3G) and washed with ether (500mL- x 10) and dried under vacuum at 400C for 2 days and then at 8000 for 12h to yield l-f 2 R,3R)-3-[4-(4-cyano-phenyl)thao--l--24dfurpey)2hdoybtyl4(,-iehl4mtyaioctx-ezl-
H-
[1 ,2,4jtriazol-4-ium bromide hydrochloric acid salt(1 83.3g, 100%) as a colourless powder.
Physical form: amorphous powder; FAB-MS mlz 643 1 H-NMR(DMSO-d 6 6 1.18(3H,d,J=7.3Hz), 2.12(6H,s), 2.64(3H,s), 4.13(1H,q 4.42(2H,s), 4.72(IH,d,J=14.2), 5.01(1 H,d,J=14.2), 5,39(2H,s), 6.70(1 6.90-6.94(1 7.1 3(2H,m), 7.26-7.34(2H,m), 7.94(2H,d,J=8.3), 8.20(2H,d,J=8.3), 8.44(1H,s), 9.07(1H,s), 9.51(2H,brs),.10.17(1H,s) Example 32 The following compounds can be prepared according to a manner similar to Example 1 or 9: 4-4Aeoy35diehlezl- 2 R3R)2-(2,4difluorophenyl)2hydroxy3oxo4[4(223,3 tetrafluoropropoxy)phenyl]4,5-dihydro{[ ,2,4]triazol-1 -yllbutylj-1 H-fl ,2,4]triazol-4-ium bromide, 4 -(4-acetoxy-3,5-dimethylbenzyl)-1 -[2)2(,-ilurpey)2hdox--ehl3 1 ,2,4]triazol- 1 -yl-pyridazin-3-ylsulfanyl)butyljl H-fl ,2,4jtriazol-4-ium bromide, 4 -(4-acetoxy-3,5-dimethylbenzyl)-1 -[(2R)-2-(2,4difluorophenyl)2hydroxy3(3(z)-24(2233 tetrafluoropropoxy)phenyljvinylyf 1 ,2,4]triazol-l -yl)propyl]-1 H-fl ,2,4]triazol-4-ium bromide, 4-4-acetoxy-3,5-dimethylbenzyl)l1 2
R,
3
R)-
2 2 4 difluorophenyl)2hydroxy3methanesulfonylbutyq 1H-fl,2,4]triazol-4-ium bromide, 4 -(4-Acetoxy-3,5-dimethylbenzyl).1-[(2R-cis)-2-(2,4-difluorophenyl)-4[4[4-[4-[1 -f(1S -ethyl-2- ,5-dihydro-[1 ,2,4ltriazol-4-yl]phenyljpiperazin-l-1 yl]phenoxymethyltetrahydrofuran-2ylmethyl]1 H-fl ,2,4]triazol-4-ium bromide, 4 4 -acetoxy-3-methylbenzyl)-I -[(2R-cis)-2-(2,4-difluorophenyl)-4-[4-[4-[f4-fl S,2S)-1 -ethyl-2hydroxylpropyl)-5-oxo-1 ,5-dihydro-[1I,2,4]triazol-4-yl]phenyl]piperazinl1 yllphenoxymethyltetrahydrofuran2ylmethyl]-l H-fl ,2,4]triazol-4-ium bromide, [N:\LIBC]02679A:MEF 4 -(4-acetoxybenzyl)-1 -[(2R-cis)-2-(2,4-difluorophenyl)-4[4[4-[4-[ S,2S)-1 oxo-1 ,5-dihydro-[1 2 4 ltriazol-4-yllphenyljpiperazin-1 -yllphenoxymethyl]tetrahydrofuran2ylmethyl]-1
H-
[1 ,2,4]triazol-4-ium bromide, 4 -(4-acetoxy-3,5-dichlorobenzyl)1 -[(2R-cis)-2-(2,4-difluorophenyl)4[4-[4.{4-[j-[(1 S,2S)-(1 -ethyl-2hydroxypropyl)J-5-oxo-1i,5-dihydro-[1 2 4 ]triazol-4-y]phenyl]piperazin-I yl]phenoxymethyl]tetrahydrofuran-2ylmethyl]1 H-fl ,2,4ltriazol-4-ium bromide, 4-(4-acetoxy-3-chlorobenzyl)1l -[(2R-cis)-2-(2,4-difiuorophenyl)-4[4[4-[4{1 S,2S)- I -ethyl-2hydroxylpropyl)-5-oxo-1 ,5-dihydro-[i 2 4 ltriazol-4-yllphenyllpiperazin-1 yl]phenoxymethyl]tetrahydrofuran.2-ylmethyl]-1 H-fl ,2,4jtriazol-4-ium bromide, 4-(4-acetoxy-3-methylbenzyl)-1 -f( 2
R,
3
R)-
2 2 4 -difuorophenyl)hydroxy3[4(4-cyanophenyl)thiazol- 2-yljbutyl]-1 H-fl ,2,4]triazol-4-ium bromide, 4-(4-acetoxybenzyl)-1 2
R,
3
R)-
2 -(2,4-difluorophenyl)2hydroxy3[4-(4cyanophenyl)thiazol- 2 yl]butyl]-1 H-fl ,2,4]triazol-4-ium bromide, 4 -(4-acetoxy-3,5-dichlorobenzyl)-1 -[(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy3[4-(4cyanophenyl)thiazol-2-ylbutylp1 H-(1 ,2,4jtriazol-4-ium bromide, 4-( 4 -acetoxy-3-chlorobenzyl)-1 -f( 2
R,
3
R)-
2 2 4 -difluorophenyl)2hydroxy3f4-(4-cyanophenyl)thiazol- 2-yl]butylj-l H-[1 ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3, 5-dimethylbenzyl)-1 -[2-hydroxy-3-methyl-3-methylsulfanyl2(4trifiuoromethylphenyl)butylj-lIH-[1 ,2,4jtriazol-4-ium bromide, and 20 4 -(4-acetoxy-3,5-dimethyl-benzyl)-l -[[(5R,6R)-2-methoxyimino-3,3dimethyl-6[(4- :::.trifluoromethoxyphenoxy)methyllcyclohexyl-1 H-fl ,2,4]triazol-4-ium bromide.
Example A: Manufacture of dry ampoules for intramuscular administration: A lyoph ilizate of 0.5g 4-(4-acetoxy-3,5-dimethyl-benzyl)-l -[f(1R,6R)-2-methoxyimino-3,3dimethyl-6-[(4-trifluoromethoxyphenoxy)methyllcyclohexylj methyl]-1 H-fl triazol-4-ium bromide is prepared in the usual manner and filled into an ampoule. Prior to the administration the lyophilizate is treated with 2.5 mL of a 2% aqueous lidocaine hydrochloride solution.
Example B SHard gelatin capsules each containing the following ingredients were manufactured in the .conventional manner per se: a..
4 -(4-Acetoxy-3,5-dimethyl-benzyl-l 6
R)-
2 -methoxyimino-3,3dimethyl6[(4-tdfluoromethoxy- 100 mg henoxy meth iylcyclohexyI methylI-i H-[1,2,41triazol-4-iumn bromide Lactose 56 mg Crystalline Cellulose 30 mg Silicic acid, Light Anhydrous l0 in Talc 3 Magnesium stearate im IN:\LIBC)02679A:MEF 21 Example C: Tablets each containing the following ingredients were manufactured in the conventional manner per se: 4 -(4-Acetoxy-3,5-dimethyl-benzyl)1 -[[(5R,6R)-2-methoxyimino-3,3-dimethyl.6-[(4- 100 mg trifiuoromethoxyphenoxy)methy l ]cy clohexyllmethyl]-l H-fl ,2,4]triazol-4-iumn bromide Lactose 60 m Corn starch 20 M Sodium Starch Glycolate 10 Mg Po2) Lyinylpyrrolidone 6m Talc 3 mg Magnesium stearate 1 mg Total [N:\LIBC102679A:MEF
Claims (4)
1. A compound of the general formula R 2 wherein 0 is the group of the formula Q 1 or Q 2 RP 7 CHj CH CH N 0 NN CH 3 Q or -CH 2 0 H 2 a' /.C2 N N-D /7 P see. (Q 2 wherein D is a lower alkanoyl or the group of the formula, a a0 *a 0 -N RI is a halogen atom, and R8~ is a straight-chain or branched 0 1 -C 4 alkyl, or wherein /is a group derived from an azole compound of the group consisting of: dI-1 -[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-1 H-imidazole, KJ dl-cis-1 -acetyl-4-[4-[2-(2,4-dichlorophenyl)-2-(imidazoll -ylmethyl)-1 ,3-dioxolan-4- I 6e~hoxy]phenyljpiperazine, 11 \1)aiyl-ib\I 13A I3'3490.doc:'ITT 23 d l- 2 -[(RS)-sec-butyl-444[4-[4[(2R,4S)-2-(2-(2,4-dichlorophenyl)2-(1 H- 1,2,4-triazol- 1 -ylmethyl)- 1, 3 -dioxolan-4-yl~methoxyjphenyl]-1 -piperazinyl]phenyl-3H-i 2 ,4]triazol-3-one, R, 2 R)- 2 2 4 -difluorophenyl2ydroxy1methyl3-( H-i 2 ,4-triazol-i -yl) pro pyl]-4-[4- 2 23 3 -tetraflIu oropropoxy) phen yl]3(2H4H)- 1, 2 ,4-triazolone, 2 2 4 -difluorophenyl)3-methyli1 H-i ,2,4-triazol-1 H-i ,2,4-triazol-1 -yl)pyridazin-
3-ylthio)butan-2-ol, (2P)-2-(2,4-difluorophenyl)-i 3 4 2 2 3 ,3-tetrafluoropropoxy)-styryl] (1 ,2,4-triazol-i -yl)-3- (1 2 4 -triazol-i -yl)]propan-2-ol, dl-threo-2-(24-difluorophenyl-3methyl-sulfonyli H-i ,2,4-triazol- I -yl)-butan-2-ol, 4 4 4 4 -[[5-(24difluorophenyl)y5.( 1 H-i 2,4-triazol- 1 -ylmethyl)tetrahydrofuran-3- yl]methoxyjphenyl]piperazinyl]phenyl]2[(I S,2S)-i -ethyl-2-hydroxypropyl].3Hi 2 ,4-triazol-3-one, 2 R, 3 R)- 3 4 4 -cyanophenyl)thiazol2yl)]2(2,4difluorophenyl)i1 H-i ,2,4-triazol-i -yl)-butan- 2-ol, 3-methyl-3-methylthio-I ,2,4-triazol- i -yl)- 2 -(trifluoromethylphenyl)-butan2ol, 1 R, 2 S, 6 R)- 2 -methoxy-3, 3 -dimethyl-6-(2-ptolylethyl)cyclohexyl] methyl]-1 2,4]triazol, and (5R,6R)-2,2-dimethyl-6-[( H-i ,2,4-triazol-i -yl)methylj-5-[[4- (trifluoromethoxy)phenoxylmethyl]cyclohexanone 0-methyloxime, Z is nitrogen or methine;
99.: 2)R 1 R2 are each independently a hydrogen atom or a group -QY [in which Y is a group easily hydrolyzable under physiological condition]; R 3 R4 are each independently a hydrogen or halogen atom, lower alkyl, lower alkoxy, lower alkylthio, (lower alkylcarbonyl)thiomethyl, carboxy or methoxycarbonyl; and X- is a pharmaceutically acceptable anion, n as well as salts, hydrates or solvates of the compounds of the general formula 2. The compound of claim 1, wherein the easily hydrolyzable group Y is the acyl residue of an amino acid or Y is selected from the group consisting of: (R60) 2 P0- wherein R5 is hydrogen, lower alkoxy, lower alkyl which may be optionally substituted with carboxyl, amino, lower alky amino, diloweralkylamino, or aryl; and R6 is hydrogen or lower alkyl. 3. The compound of claim 1 of the formula 1', II s\I)iylib\L113A]33490.dIoc:TILT 24 R 3 R-COO 0NO in erein Is a straight-chain or branched Cl-C5 alkyl, aryl, pyridyl, pyrrolidinyl or a group A-NH-B- (wherein A is a hydrogen atom or a straight-chain or branched 01-05 alkyl;' B is a straight-chain or branched C 1 -C 4 alkylene, -CH2-CONH-CH 2 or -CH2CH2CH 2 -CH(NH 2 R 3 and R4 are each independently a hydrogen or halogen atom or a lower alkoxy;- and Z, Q and X- are as defined in claim 1. 4. A compound of claim 1 which is selected from the group consisting of: dl-1 4 -acetoxy- 3 5-dimethylbenzyl)3[2-(2,4dichorobenzyloxy)-2(24dichoropheny)etyl]- 3H-irnidazol-1-ium bromide, dl-1 tx eh le z l--2(,-ihoo e z lx )2(,-ihoo h n leh l-H imidazol-1-umn bromide, dl- l-( 4 -acetoxybenzyi)- 3 2 (2,4dichlorobenzyloxy-2(24dichlorophenyl)ethyl]-3H-imidazo,1- urn bromide, I dl-l1-( 4 -acetoxybenzyi)-3-[(2R,4S)-4-[4(4-acetylpiperazin-1 -yl)phenoxymethyl]-2-(2,4- Iichlorophenyl)-[1 ,3]dioxan-2-ylmethly]-3H-imidazoll-ium bromide, l-( 4 -acetoxy- 3 ,5-dimethybenzyl)3[(2R,4S)4[4-(4acetylpiperazi n-i -yl)phenoxymethyl]-2- 4-dichlorophenyl)-[1 ,3]dioxan-2-ylmethly]-3H-imidazol-1 -ium bromide, d i-i-( 4 -acetoxy- 3 -methylbenzy)3[(2,4S-4-[4-(4acetylpiperazin-1 -yl)phenoxymethyl]-2-(2,4- 2dichlorophenyl)-[1 3 ldioxan-2-ylmethyl]-3H-imidazol-ium bromide, dl- l-( 4 -acetoxy- 3 -methoxybenzy3[(2R,4s-4-44(4-acetylpiperazin-1-yI)phenoxymethylj-2- '?.4-dichlorophenyl)-[1 3 ]dioxan-2-ylmethyl]-3H-imidazol-ium bromide, dl- 3 21 4 S)-4-[4-(4-acetylpiperazinl1 -yI)phenoxymethyl]-2-(2,4-dichlorophenyl)>[1 ,3]dioxan-2- ylmethyl]-1 4 -iouyyloxy-3,5-dimethylbenzyl3Himidazoll-ium bromide, dl- 3 2 1,4S)-4-[4-(4-acetylpiperazinl -yI)phenoxymethyl]-2-(2,4-dichlorophenyl)>[1 ,3]dioxan-2- y Imeth yl]- 1 4 2 2 -d imethylpropion yloxy)benzyl]-3H-imid azol 1 -i um bromide, d 1- 4 (4-ben zoyloxy-3,5-d imethyl ben zyl) 1 -(2-butyl-5-oxo-1, ,5-d ihyd ro-[1, ,2,4]tri azol- 4-yl)phenyl]piperazin-1 -yl]phenoxymethyl]-2-(2,4-dichlorophenyl)>[1 ,3]dioxolan-2-ylmethyl]-1 H- (1 ,2,4ltriazol-4-ium bromide, I 1\I )ay~ib\LI B A ).doc:TLTF dl-4-[4-(pyridine-3 -carbonyloxy)-3 ,5-dirnethylbenzyl]- I I-(2-butyI-5 -oxo- 1,5 dihydro-[ 1 2 4 ]triazol-4-yl)pheniyl]piperazin- 1 -yl]phenoxymethyl]-2-(2,4-dichlorophenyl)- [1 ,3 ]doxolan-2-ylrnethiyl] 1H-[l ,2, 4 ]triazol-4-iurn bromide, dl-4-(4-acetoxy-3 ),5-dimethylbenzyl1)-1- 1-(2-butyl-5-oxo- [1 ,2 ,4]triazol-4-yl)phienyllperazini-1I-yllhenoxymnethyll-2-(2,4-dichiloroplhenyl) [1 21 dioxolan-2-ylmethyl]- 11 -[1I, 2 4 ]triazol-4-iuim bromide, dl-4-(4-acetoxy-3-methylbenzyl)- I-(2-butyl-5-oxo-1I,5-dihydro-[1 ,2,4]triazol- 4 -yl)pheniyl]piperazin- 1-yllphenoxymeth-yl] -2-(2,4-dichilorophenyl)- [1 I dioxolan-2- ylmethyl]- 1H-[ 1,2,4]triazol-4-ium bromide, dl-4-(4-acetoxybenizyl)- I -(2-butyl-5-oxo-1I,5-dihydro-[1I,2,4]triazol-4- yl)pheniyl]piperazin-1I-yl]phenoxymiethiyl]-2-(2,4-d ichlorophenyl)- [1 ,31Idioxolan-2-ylmethiyl)- 1 H-Li ,2,4]triazol-4-ium bromide, dl-1- I-sec-butyl-5-oxo- 1,5 -dihydro- [1 ,2,4ltriazol-4-yl)-phenyll -piperazlin- -yI phenoxymethyl)-2-(2,4-diehloro-phenyl) [1,3 ]dioxolan-2-ylmethyl]-4-(4-hexanoyloxy-3 dimethylbenzyl)- 1 1,2,4]triazol-4-ium methanesulfonate, 4-(4-acetoxy-3 ,5-dimethylbenzyl)- 1-( 2 R,3R)-2-(2,4-difluorophenyl)-2-lhydroxy-3 {5-oxo-4- ,3 -tetrafluoropropoxy)phenyl]-4,5-dihydro [1 ,2,4]triazol- l-yl }butyl]-l1H- [1,2,4] triazol-ium bromide, 4-(4-acetoxy-3 ,5-dimethylbenzyl)- 2 R)-2-(2,4-difluorophenyl)-2-hydroxy-3-methyl-3-(6- :20 [1 ,2,4]triazol-1I-yl-pyridazin-3 -ylsulfanyl)butyl j- 1H-[ 1,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3 ,5-dimethylbenzyl)- 1-[(2R)-2-(2,4-difluorophenyl)-2-hydroxy-3 [4- (2,2,3,3 -tetrafluoropropoxy)phenyl]vinyl ,2,4]triazol-1 -yl)propyl] -1H-ri ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3 ,5 -dimethylbenzyl)-1- [(2R,3R)-2-(2,4-difluorophenyl)-2-hydroxy-3 :25 methanesulfonylbutyl] -1H-[1I, 2 ,4]triazol-4-ium bromide, :4-(4-acetoxy- 3,5 -dimethylbenzyl)- 1 [(2R-cis)-2-(2,4-difluorophenyl)-4- 1- S,2 S)- 1 -ethyl-2-hydroxypropyl)-5 -oxo- 1, ,5-dihydro- 1, 2 4 triazol-4-yl]phenyl]piperazin- 1 yllphenoxymethyl]tetrahydrofuran-2-ylmethyl] -1H-[i ,2,4]triazol-4-ium bromide, 4-(4-actoxy-3-methylbenzyl)- I -[(2R-cis)-2-(2,4-difluorophenyl)-4-[4-[4-[4-[ 1( S,2 1 ethyl -2-hydroxypropy 5-oxo- 1, ,5-dihydro- 1, 2 4 triazol1-4-yl]phenyllpiperazin- 1 yllphenoxymethyl]tetrahydrofuran-2-ylmethyl 1-1H-[l ,2,4]triazol-4-ium bromide, 4-(4-acetoxybenzyl)- 1 -[(2R-cis)-2-(2,4-difluorophenyl)-4-[4-[4-[4-[I S,2S)- 1 -ethyl-2- 1 ,5-dihydro- [1 ,2,4]triazol-4-yl]phenyl lpiperazin- 1 yllphenoxymethyl]tetrahydrofuran-2-ylmethyl]- 1H- [1,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3 ,5-dichlorobenzyl)- 1-Ii(2R-cis)-2-(2,4-difluorophenyl)-4-[4-[4-[4-[ 1- S,2S)- (1 -ethyl-2-hydroxypropyl)]-5-oxo- 1,5-dihydro-[1 2 4 ]triazol-4-yl]phenyl]piperazin- 1- yllphenoxymethyl]tetrahydrofuran-2-ylmethyl] -1H-[i ,2,4]triazol-4-ium bromide, 4-(4-acetoxy-3 -chlorobenzyl)-1- [(2R-cis)-2-(2,4-difluorophenyl)-4- S,2 -oxo- 1,5-dihydro- [1 2 4 ]triazol-4-yl]phenyl]piperazin- 1- .401,, yl]phenoxymethyl]tetrahydrofuran-2-ylmethyl] -1H- [1 ,2,4]triazol-4-ium bromide, 26 4-(4-acetoxy-3 ,5 -dimethylbenzyl)- 1 R)- 2 2 ,4-difluorophenyl)-2-lydroxy-3 cyanophenyl)thiiazoh2-yl]butyl]y I FI-[ 1, 2 4 ]triazol-4-ium bromide, 4 4 -acetoxy-3 -methylbenzyl> 4 -diifuoropheny1)-2-hiycroxy-3 f4-(4- cyanophienyl)thiazol-2yl]butvl1] -I H-[l 2 4 ltriazol-4-ium bromide, 4 4 -acetoxybenzyl)> 1 R,3 R)- 2 2 4 -difluoropheiiy)>2ydroxy-3 cyanoplhenyl)thiazol2-)IbutNrly 1 H-[l 2 4 ]triazol-4-jun bromide, 4 4 -acetoxy-3 ),5-dichlorobenzyl)- lil( 2 R, 3 R)-2-(2,4-difiuoropheny).)-lydroxy-'-[ 4 4 cyanopheflyl)thiazo[-2y]btt,1 -1H-Ill, 2 4 ]triazol-4-jum bromide, 4 -(4-acctoxy-3 -chilorobenzyl)-I -Il(2R,3 R)- 2 2 ,4-difluorophenyI>-2-yclroxy- cyainophenyl)thiazol-2-y Ilbutyl] -1H-Ill, 2 4 ltriazol-4-ium bromide, 4 -(4-acetoxy-3 ,5-dimethylbenzyl)- I -Il2-hydroxy-3 -m-ethyl-3 -methlylsulfanlyl (4- tri fluoromethylphenyl)butyl] [1, 2 4 ]triazol-4-ium bromide, 4 -(4-acetoxy-3 ,5-dimethylbcnzyl)> I -[I(5R, 6 R)-2-methoxyimino3- -dimethy] -6-j(4- tr-ifluoromethoxyphenoxy)methy1cyclohexyl]lmethyl] I H-[1I, 2 ,4]triazol -4-ium bromide, and 4-(4-acetoxy-3 ,5-dimethylbenzyl> 1 R,2S,6R)-2-mi-ethoxy-3 ,3 -dimicthlyl-6-(2.-, tolylethyl)cyclohexylmethylp 1 H-Ill, 2 4 ]triazol-4-ium bromide. A compound of claim I which is selected from the group consisting of (2R,3)R)-4- 4 -aminoacetoxy-2-carboxybeiizyl) aophnl-lizl--l--2 difluorophenyl)-2-hydroxybutyl]- 1 H-Ill, 2 4 ]triazol-4-ium bromide trifluoroacetic acid salt, 1-Il(2R,3R)-3-[-4caohnl haol2yl2(,-iloohey)2hdoyuy]4 -dimethyl-4-(pyrroidi ne2-carbonyl oxy)-benzyl l-Il 2 4 1]triazo 1-4- ium bromide trifluoro acetic acid salt, (2R,3 R)-4-(4-aminoacetoxy-3 5-dimethylbenzyl)- 1-[I3 -[I 4 -(4-cyano-pheny1)-thiazo1-2-y1] -2- 2 4 -difluorophenyl)-2-hydroxybutyl] -1H-Ill, 2 4 ]triazol-4-ium bromide trifluoroacetic acid salt, (2R,3R)-4-[Il-(3 -aminopropionyloxy)-3, 5-dimethylbenzyl]- -Il 4 -Il 4 4 -cyanophenyl)-thiazol 2 -yl]- 2 2 4 -difluorophenyl)-2-hydroxy-3-methylbutyl] -Ill 1, 2 4 ]triazol-4-ium bromide trifluoroacetic acid salt, *e~s 2 R, 3 R)-4-Il4-(4-amino-butyryloxy-3 ,5 -dimethylbenzyl] 1 -Il 4 -Il 4 4 -cyano-phenyl)-thiazol-2- yl 2(,-iioohnl--yrx- mtybtl -1I H-Ill 2 4 ]triazol-4-ium bromide trifluoroacetic acid salt, 2 R, 3 R)- 4 -Il 4 2 -(aninoacety)am Ino] acetoxy]-3 ,5 -dimethylIbellzyl] -Il 3-Il4-(4- cynpey)tizl2y]2(,-iloohnl--yrx-uy] H-Ill, 2 ,4]triazol-4-iumn bromide trifluoroacetic acid salt, 1-(R3)3[-4eaopey)tizl2y]2( 2 ,4difluorophenyl)2hydrxbutl] -4-Il4- I(S)- 2 ,5-diaminopentoyloxy]-3,5-dimethyl-benzyl] -1 H-Ill, 2 4 ]triazol-4-ium bromide trifluoroacetic acid salt, 4-Il4-[(S)-2-amino-propionyloxy)-3 ,5-dimethylbenzyl]- l-Il( 2 R,3R-3-[4-(4cyanophenyl)> thiazol-2-yl] 2 2 4 -difluorophenyl)-2-hydroxy-buty]- -1 Ill, 2 4 ]triazol-4-ium bromide 4 :-,,trifluoroacetic acid salt, I- [(2R,3 R)-3 4 4 yanophenyI)zoth-Iazo2yi2 4dforphlorophenroyl) 2 ldl]- 4 [3 5 -d imethyl 4 [(inethyl am ino)acetoxy] benzyl]- 111-r 1, 2 4 ]triazo1-4-iuim bromide trifluoroacetic acid salt, 3 4 4 -cyanopheniyl)-thiazol-2yl 1 2-( 2 4 -difluoropheniyl)2-lydroxybutv1 1 4 13 5 -dimethiyI- 4 -[(propylainio)acetoxy] beoizylI I- 2 ,4]triazol-4-iuin1 bromide trifluoroacetic acid salt, R)-3 4 4 -cyanopienylthiazol2yl-2-(2, 4 -difluoroph enyl--1)2ldxbtl 1-4- [4- [(S)-2-(methiylam-ino)proplinyloxy]y3 ,5 -di methyl-benzyl
111-1 [1,2,4]JtriazoI -4-mm11 bromide trifluoroacetic acid salt, (2R 1- 4 4 4 -cyanopleyIthiazo2ylp2-(2,4-difluor-ophenyl) 2 -hvdroxy,-3 -miethl,- buttyl_1-4-[3 5 -dinmethyl- 4 -[3)-(mietlhyla1iniio)-propioniyloxylbenizylj] 2 .4]triazol-4-im bromide triflu oro acetate, 4 4 2 -amino-3-methylbutanoyloxy-3,5dimethylbenzyly 1 -f4-(4- cyanophenyl)thiazol2yl2(24difluoroplieyl)2hydroxbt Iii 4 ]triazol-4-iumi 1 5 bromide trifluoroacetic acid salt, (2R,3R)- 1-[3 4 4 cyanophenyl)thiazol2y1-2-(2, 4 -difluorophenyl>-2-lydroxybutlj [(isopropylamino)acetoxy]-3 ,5-dimyethylbcnzyl)- 1H-[1I,2,4]triazol-4-ium bromide trifluoroacetic acid salt, 4 4 cyanophenyl)thiazol2yI 2-2,4-difluorophenyI-2-hydroxybutyl] -4- 2 S)-4-[2-(ethylarnino)propionyloxy-3 ,5-dimethyl-benzyl] IH-[ 1, 2 4 ]triazol-4-ium bromide trifluoroacetic acid salt, (2 R, 3R)- 1 [3 4 4 -cyanopheny)thiazo 2 yl 2(24difluorophenyl)>2..lydroxybuty 4 4 [(ethylamino)acetoxy] -3 ,5-dimethylbenzyl] -1H-[i 2 ,4]triazol-4-ium bromide trifluoroacetic acid salt, and particularly 250 1 -[2R,3R)-3-[-4caopey)t zl2y]2(,4dfur-hnl--yrx-uy]4 3 5 -dimethyl-4-methylamiinoacetoxy-benzyl> I-[,z,4]triazol-4-lum romd hydrochloric acid salt. A process flor the manufacture of a compound of the general formula R z N wherein R to R Q, X and Z have the same meaning as in claim I, as well as salts, hydrates of' solvates thereof, which comprises reacting an azole compound possessing antifungal activity of the general formnula (11), N-- W-1,th a compound of the general formula (111), 0N R 1 R3 R 4 wherein Ri to R4 are the same as in claim 1 and wherein an amino group present in R 1 or R 2 may be in protected form; and L is a leaving group followed if necessary, by removal of a protecting group and/or by salt formation. 7. A process according to claim 6 for the manufacture of a compound of claim 2, which comprises reacting a compound of the general formula (II) as defined in claim 6 with a compound of the general formula (il1) as defined in claim 6, in which one of R 1 or R2 is hydroxy, followed by reaction ui the resulting compound with a compound of formula RCOL, or (R60)2POL, wherein RsCO is the acyl residue of a N-protected amino acid, or R5 is hydrogen, lower alkoxy, lower alkyl which may be S optionally substituted with carboxyl, amino, lower alkyl amino with or without protecting group, di-lower alkyl amino, or aryl; and R6 is hydrogen or lower alkyl, and L is a leaving group. 8. A process for preparing an N-benzylazolium compound, substantially as hereinbefore described with reference to any one of the examples. 9. An N-benzylazolium compound prepared by the process of any one of claims 6 to 8. 10. An N-benzylazolium compound having antifungal activity, substantially as hereinbefore described with reference to any one of the examples. 11. An antifungal composition comprising a compound as defined in any one of claims 1 to 9 or 10 and a carrier. 12. A method for the therapy of fungal infections, which method comprises administering to the infected organism an effective amount of a compound as defined in any one of claims 1 to 5, 9 or 0 or a composition as defined in claim 11. 13 The use of a compound as defined in any one of claims 1 to 5, 9 or 10 for the production of medicaments for the therapy of fungal infections. Dated 8 August, 2000 F. Hoffmann-La Roche AG Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON I 1:\Day.ib\I13 33490,docTL.I
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| AU45364/97A AU726495B2 (en) | 1996-09-09 | 1997-11-24 | N-benzylazolium derivatives |
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| EP97114246 | 1997-08-18 | ||
| AU36850/97A AU3685097A (en) | 1996-09-09 | 1997-09-05 | N-benzylazolium derivatives |
| AU45364/97A AU726495B2 (en) | 1996-09-09 | 1997-11-24 | N-benzylazolium derivatives |
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| AU36850/97A Division AU3685097A (en) | 1996-09-09 | 1997-09-05 | N-benzylazolium derivatives |
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| WO1999045008A1 (en) * | 1998-03-06 | 1999-09-10 | F. Hoffmann-La Roche Ag | 3-[4-(4-cyanophenyl)thiazol-2-y)]-1-(1h-1,2,4-triazol-1-yl)-butan-2-ol derivatives having antifungal activity |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1519132A (en) * | 1966-04-29 | 1968-03-29 | Basf Ag | Agents to fight algae and fungi |
| DE2531031A1 (en) * | 1975-07-11 | 1977-01-20 | Schuelke & Mayr Gmbh | Benzyl octyl (or decyl) imidazolium salts - used as biocides in low foaming disinfectants and preservatives |
| GB1489112A (en) * | 1974-01-31 | 1977-10-19 | Janssen Pharmaceutica Nv | Imidazolium salts |
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1997
- 1997-11-24 AU AU45364/97A patent/AU726495B2/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1519132A (en) * | 1966-04-29 | 1968-03-29 | Basf Ag | Agents to fight algae and fungi |
| GB1489112A (en) * | 1974-01-31 | 1977-10-19 | Janssen Pharmaceutica Nv | Imidazolium salts |
| DE2531031A1 (en) * | 1975-07-11 | 1977-01-20 | Schuelke & Mayr Gmbh | Benzyl octyl (or decyl) imidazolium salts - used as biocides in low foaming disinfectants and preservatives |
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