US20020049336A1 - Water soluble prodrugs of azole compounds - Google Patents
Water soluble prodrugs of azole compounds Download PDFInfo
- Publication number
- US20020049336A1 US20020049336A1 US09/966,220 US96622001A US2002049336A1 US 20020049336 A1 US20020049336 A1 US 20020049336A1 US 96622001 A US96622001 A US 96622001A US 2002049336 A1 US2002049336 A1 US 2002049336A1
- Authority
- US
- United States
- Prior art keywords
- compound
- thiazol
- difluorophenyl
- cyanophenyl
- triazol
- 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.)
- Granted
Links
- 239000000651 prodrug Substances 0.000 title abstract description 5
- 229940002612 prodrug Drugs 0.000 title abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 35
- 229910001868 water Inorganic materials 0.000 title description 32
- 150000003851 azoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 30
- 230000000843 anti-fungal effect Effects 0.000 claims abstract description 23
- 150000003852 triazoles Chemical class 0.000 claims abstract description 17
- 229940121375 antifungal agent Drugs 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 26
- -1 methylpyrazolyl Chemical group 0.000 claims description 23
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 57
- 239000001273 butane Substances 0.000 description 52
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 52
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 52
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 51
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 45
- 239000000203 mixture Substances 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 34
- 238000006243 chemical reaction Methods 0.000 description 27
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 238000000034 method Methods 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 0 *OC(=O)OCOC(=O)C1=CC=CC=C1.CC.CC.CC.CC.CCC Chemical compound *OC(=O)OCOC(=O)C1=CC=CC=C1.CC.CC.CC.CC.CCC 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- 239000000243 solution Substances 0.000 description 21
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 229910019142 PO4 Inorganic materials 0.000 description 18
- 239000010452 phosphate Substances 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 13
- 239000012043 crude product Substances 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 229940093499 ethyl acetate Drugs 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 229910000105 potassium hydride Inorganic materials 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical compound OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 230000002829 reductive effect Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- 206010017533 Fungal infection Diseases 0.000 description 5
- 208000031888 Mycoses Diseases 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 239000000539 dimer Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 238000002953 preparative HPLC Methods 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 229940095731 candida albicans Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 150000002148 esters Chemical group 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- 239000012258 stirred mixture Substances 0.000 description 4
- 150000003536 tetrazoles Chemical class 0.000 description 4
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 3
- YCAIYRWHKSJKEB-UHFFFAOYSA-N 3-(chloromethyl)benzoyl chloride Chemical compound ClCC1=CC=CC(C(Cl)=O)=C1 YCAIYRWHKSJKEB-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YPESRNGPUZFBJO-WWOZWPLTSA-N [(2r,3r)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-yl]oxymethyl 2-hydroxybenzoate Chemical compound C=1SC([C@H](C)[C@@](CN2N=CN=C2)(OCOC(=O)C=2C(=CC=CC=2)O)C=2C(=CC(F)=CC=2)F)=NC=1C1=CC=C(C#N)C=C1 YPESRNGPUZFBJO-WWOZWPLTSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- IKXCHOUDIPZROZ-LXGUWJNJSA-N (2r,3r,4r,5s)-6-(ethylamino)hexane-1,2,3,4,5-pentol Chemical compound CCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO IKXCHOUDIPZROZ-LXGUWJNJSA-N 0.000 description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical group NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- GNIHNIZUKILDAW-UHFFFAOYSA-N CC(C)C(=O)OCOC(=O)C1=CC=C(COP(=O)(O)O)C=C1 Chemical compound CC(C)C(=O)OCOC(=O)C1=CC=C(COP(=O)(O)O)C=C1 GNIHNIZUKILDAW-UHFFFAOYSA-N 0.000 description 2
- GIWVJAMEKXJGMF-UHFFFAOYSA-N CC(C)C(=O)OCOC(=O)C1=CC=C(OP(=O)(O)O)C=C1 Chemical compound CC(C)C(=O)OCOC(=O)C1=CC=C(OP(=O)(O)O)C=C1 GIWVJAMEKXJGMF-UHFFFAOYSA-N 0.000 description 2
- BNZNIBNSNUACGH-UHFFFAOYSA-N CC(C)C(=O)OCOC(=O)C1=CC=CC(OP(=O)(O)O)=C1 Chemical compound CC(C)C(=O)OCOC(=O)C1=CC=CC(OP(=O)(O)O)=C1 BNZNIBNSNUACGH-UHFFFAOYSA-N 0.000 description 2
- NICQQXBERDNCDE-UHFFFAOYSA-N CC(C)C(=O)OCOC(=O)C1=CC=CC=C1OP(=O)(O)O Chemical compound CC(C)C(=O)OCOC(=O)C1=CC=CC=C1OP(=O)(O)O NICQQXBERDNCDE-UHFFFAOYSA-N 0.000 description 2
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- SGAZSGSBJODEBP-YEJXKQKISA-N C[C@@H](C1=NC(C2=CC=C(O)C=C2)=CS1)[C@](O)(CN1C=NC=N1)C1=CC=C(F)C=C1F Chemical compound C[C@@H](C1=NC(C2=CC=C(O)C=C2)=CS1)[C@](O)(CN1C=NC=N1)C1=CC=C(F)C=C1F SGAZSGSBJODEBP-YEJXKQKISA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001480037 Microsporum Species 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- GXTKEFQZLJWVAH-UHFFFAOYSA-N chloromethyl 3-(chloromethyl)benzoate Chemical compound ClCOC(=O)C1=CC=CC(CCl)=C1 GXTKEFQZLJWVAH-UHFFFAOYSA-N 0.000 description 2
- ADBYXLWUAOQPMW-UHFFFAOYSA-N chloromethyl 3-phenylmethoxybenzoate Chemical compound ClCOC(=O)C1=CC=CC(OCC=2C=CC=CC=2)=C1 ADBYXLWUAOQPMW-UHFFFAOYSA-N 0.000 description 2
- JYWJULGYGOLCGW-UHFFFAOYSA-N chloromethyl chloroformate Chemical compound ClCOC(Cl)=O JYWJULGYGOLCGW-UHFFFAOYSA-N 0.000 description 2
- CHHJDCVKYCVTHD-UHFFFAOYSA-N chloromethyl formate Chemical compound ClCOC=O CHHJDCVKYCVTHD-UHFFFAOYSA-N 0.000 description 2
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
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- 239000012973 diazabicyclooctane Substances 0.000 description 1
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- 239000002270 dispersing agent Substances 0.000 description 1
- YEWZQCDRZRYAEB-UHFFFAOYSA-M ditert-butyl phosphate Chemical compound CC(C)(C)OP([O-])(=O)OC(C)(C)C YEWZQCDRZRYAEB-UHFFFAOYSA-M 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
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- PFWYNUZZFFHPMV-UHFFFAOYSA-N hydroxymethyl benzoate;potassium Chemical compound [K].OCOC(=O)C1=CC=CC=C1 PFWYNUZZFFHPMV-UHFFFAOYSA-N 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
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- 125000002346 iodo group Chemical group I* 0.000 description 1
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- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- YGFLCNPXEPDANQ-UHFFFAOYSA-N n-[bis[(2-methylpropan-2-yl)oxy]phosphanyl]-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C YGFLCNPXEPDANQ-UHFFFAOYSA-N 0.000 description 1
- ANPWLBTUUNFQIO-UHFFFAOYSA-N n-bis(phenylmethoxy)phosphanyl-n-propan-2-ylpropan-2-amine Chemical compound C=1C=CC=CC=1COP(N(C(C)C)C(C)C)OCC1=CC=CC=C1 ANPWLBTUUNFQIO-UHFFFAOYSA-N 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
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- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 150000003333 secondary alcohols Chemical class 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 238000010186 staining Methods 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000003826 tablet Substances 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
Definitions
- This invention relates to a new class of azole derivatives, methods for their use, and processes for their production.
- the compounds described herein are useful for the treatment of fungal infections in humans and other mammals.
- the present invention provides a compound represented by the general formula:
- A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, m can be 0 to 6; p is 1 or 2; R 1 , R 2 , R 3 and R 4 can each independently be hydrogen, C 1 -C 6 alkyl, hydroxy, OR 5 , NH 2 , NR 6 R 7 , or halogen; R 5 , R 6 and R 7 can each independently be hydrogen, C(O)R8, or C 1 -C 6 alkyl; R 8 is C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof.
- Triazole antifungal compounds are well known in the prior art. Of the several known classes of such compounds, one particularly potent class contains a tertiary hydroxyl group.
- U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol has potent anti-fungal activity.
- R′ represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
- EP 829478 discloses compounds of the general formula
- Q is the remainder of an azole compound of the formula
- Z is nitrogen or methine
- 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 condition;
- 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 X ⁇ is a pharmaceutically acceptable anion.
- WO 99/15522 discloses compounds of the general formula
- G is H or PO 3 H 2 .
- WO 98/34934 discloses compounds of the formula
- radicals (a) and (b) may be replaced with a C 1-6 alkyl-radical and up to two hydrogen atoms in radical (c) may be replaced by a C 1-6 alkyl-radical;
- L represents the acyl moiety of an amino acid, and thus —O—L represents an amino acid ester group;
- D is a radical of formula
- X is N or CH
- R 1 is halo
- R 2 is hydrogen or halo.
- an acid or base addition salt thereof or a stereochemically isomeric form thereof wherein A and B taken together form —N ⁇ CH—, —CH ⁇ N—, —CH 2 —CH 2 , CH ⁇ CH—, —C( ⁇ O)—CH 2 —, —CH 2 —C( ⁇ O); D is a radical of formula
- Alk is a C 1-4 alkanediyl radical; R 1 is halo; R 2 is hydrogen or halo; R 3 is hydrogen, C 1-6 alkyl, phenyl or halophenyl; R 4 is hydrogen, C 1-6 alkyl phenyl or halophenyl; R 5 is hydrogen or C 1-6 alkyl; R 6 is hydrogen, C 1-6 alkyl, C 1-6 alkyloxycarbonyl, or R 5 and R 6 taken together with the nitrogen atom to which they are attached form a heterocyclic ring.
- WO 96/38443 discloses compounds of the formula
- R 1 is a straight or branched chain (C 4 -C 5 ) alkyl group substituted by one or two groups convertible in vivo into hydroxy moieties or a pharmaceutically acceptable salt thereof.
- WO 98/43970 discloses a quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo to be converted into an antifungal azole compound.
- the preferred compounds have the formula
- Q is an imidazol-1-yl or 1,2,4-triazol-1-yl group in which one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo;
- Ar is an optionally substituted phenyl group;
- A is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group;
- X 1 is an oxygen atom or a methylene group;
- X 2 is an optionally oxidized sulfur atom;
- m and p respectively represent 0 or 1;
- Y is an anion; and
- R 3 , R 4 and R 5 may be the same or different and represent a hydrogen atom or a lower alkyl group, or (2) R 3 is a hydrogen atom or a lower alkyl group and R 4 and R 5 are combined with each other to form a lower alkylene group, or (3) R 5 is a hydrogen atom or a lower alkyl group and R 3 and R 4 are combined
- WO 99/33846 discloses compounds of the formula
- R 1 , R 2 and R 3 are substituents which comprise the parent secondary or tertiary amine such that one of R 1 , R 2 or R 3 may be hydrogen, R 4 and R 5 are each hydrogen, or an organic or inorganic residue.
- triazole anti-fungal compounds containing a secondary or tertiary hydroxyl group including (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into prodrugs with superior properties to those previously disclosed by attaching a phosphate containing moiety via a linking group.
- the invention covers compounds of the formula:
- A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, m can be 0 to 6; p is 1 or 2; R 1 , R 2 , R 3 and R 4 can each independently be hydrogen, C 1 -C 6 alkyl, hydroxy, OR 5 , NH 2 , NR 6 R 7 , or halogen; R 5 , R 6 and R 7 can each independently be hydrogen, C(O)R8, or C 1 -C 6 alkyl; R 8 is C 1 -C 6 alkyl, or a pharmaceutically acceptable salt thereof.
- the preferred formula I compounds are those where R 1 , R 2 , R 3 and R 4 are each independently hydrogen, C 1 -C 6 alkyl, OR 5 or halogen. Most preferred are the formula I compunds where R 1 , R 2 , R 3 and R 4 are each hydrogen.
- A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
- the various phosphate containing substituents of formula I may be attached in either an ortho, meta, or para relationship to the ester substituent, with the preferred attachment being either meta or para.
- A can be
- R 9 represents phenyl substituted by one or more (preferably 1-3) halogen atoms
- R 10 represents H or CH 3 ;
- R 11 represents H, or taken together with R 10 may represent ⁇ CH 2 ;
- R 12 represents a 5- or 6 membered nitrogen containing ring which may be optionally substituted by one or more groups selected from halogen, ⁇ O, phenyl substituted by one or more groups selected from CN, (C 6 H 4 )—OCH 2 CF 2 CHF 2 and CH ⁇ CH—(C 6 H 4 )—OCH 2 CF 2 CHF 2 , or phenyl substituted by one or more groups selected from halogen and methylpyrazolyl.
- Nitrogen containing heterocycles which R 12 may represent include triazolyl, pyrimidinyl, and thiazolyl.
- Preferred embodiments comprise:
- salts with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, meglumine (N-methylglucamine), eglumine, triethanolamine or tris(hydroxymethyl)aminomethane). Salts with bases such as piperidine or morpholine are also intended to be encompassed by the term “pharmaceutically acceptable salt”.
- halogen includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro, and most preferably fluoro.
- the aliphatic “alkyl” groups may be straight or branched chains having the specified number of carbon atoms, e.g. in the case of C 1 -C 6 alkyl, the alkyl group may have from 1 to 6 carbon atoms.
- Preferred embodiments of the present invention including in each case pharmaceutically acceptable salts thereof are:
- the compounds of the present invention can be made by conventional methods. Three suitable general procedures are summarized by the following reaction schemes. In these schemes, A represented the non-hydroxy portion of a triazole anti-fungal compound of the type containing a secondary or tertiary hydroxyl group.
- the anti-fungal parent compound of interest is converted into ester 2 by reaction with chloride intermediate 1 in the presence of a suitable base, such as potassium hydride.
- a suitable base such as potassium hydride.
- the esterification reaction can be carried out in THF (tetrahydrofuran) or other inert organic solvent and the product may be purified by column chromatography.
- Chloride 1 can be prepared by the method of Iyer et al. found in Syn. Comm. 25, 2739, (1995) (see “Preparation of Starting Materials” herein, Method 1) or by the alternative method disclosed below in “Preparation of Starting Materials,” Method 2.
- Ester 2 can be subsequently converted into phosphate ester 3 by reaction with a dialkyl phosphate in refluxing acetonitrile.
- Phosphate ester 3 can be converted to the phosphate acid 4 in one of two ways. If phosphate 4 is the di-tertiary butyl ester, the free phosphate acid can be liberated by treatment with trifluoroacteic acid. Alternatively, if phosphate 4 is the di-benzyl ester, the free phosphate acid can be obtained by hydrogenation in the presence of palladium on carbon in the presence of a suitable solvent. In either case, the final product can be purified via C-18 column chromatography.
- the anti-fungal parent compound of interest is converted into chloromethylformate 5 by reaction with commercially available chloromethyl chloroformate in the presence of an appropriate base in THF or other solvent at 0° C. to 50° C.
- Appropriate bases include potassium hydride and sodium hydride, among others, with the preferred base being potassium hydride.
- the product 5 may be purified by column chromatography.
- Chloromethylformate 5 is converted to alcohol 7 by reaction with carboxylate salt 6 in acetonitrile or other appropriate organic solvent.
- Carboxylate salt 6 can be prepared by the method disclosed in U.S. Pat. No. 4,623,486.
- Alcohol 7 can be converted to phosphate ester 8 by reaction with a commercially available phosphoramidite in the presence of tetrazole followed by oxidation e.g. by use of hydrogen peroxide or m-chloroperoxybenzoic acid.
- Ester 8 can be purified by column chromatography. Phosphate ester 8 can then be converted to phosphate acid 9 in one of two ways. If phosphate 8 is the di-tertiary butyl ester, the free phosphate acid can be liberated by treatment with trifluoroacteic acid.
- phosphate 8 is the di-benzyl ester
- the free phosphate acid can be obtained by hydrogenation in the presence of palladium on carbon in the presence of a suitable solvent.
- phosphate acid 9 can be prepared from alcohol 7 by reaction with phosphorus oxychloride in an inert organic solvent such as dichloromethane in the presence of an organic base such as pyridine. In either case, the final product can be purified via C-18 column chromatography.
- the benzyloxybenzoic acids 10 are converted to their respective chloromethyl esters 11 using the procedures described for the preparation of compounds 1 in Method 1.
- the anti-fungal parent compound of interest is then converted to either its potassium or sodium salt by reaction with either potassium or sodium hydride respectively, in an inert solvent such as THF (tetrahydrofuran), or DMF (N,N-dimethylformamide), or mixtures of both at 0° C. to 60° C.
- the chloromethyl esters 11 are then introduced to the reaction mixtures to afford the intermediates 12.
- the compounds 12 can be purified by column chromatography on silicic acid.
- the benzyl protecting groups are removed from the compounds 12 by hydrogenation using palladium catalysts in an inert solvent to give the alcohols 13 which can be purified by flash chromatography on silicic acid.
- the alcohols 13 are coverted to the phosphate esters by reaction with a commercially available phosphoramidite in the presence of tetrazole followed by oxidation e.g. by the use of hydrogen peroxide or m-chloroperoxybenzoic acid.
- the phosphate esters 14 are converted to their respective phosphate acids 15 by one of the two methods illustrated in Method 2 for the conversion of 8 to 9.
- A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group; n is 0 or 1; m is 0 to 6; p is 1 or 2; R 1 , R 2 , R 3 and R 4 can each independently be hydrogen, C 1-6 alkyl, hydroxy, OR 5 , NH 2 , NR 6 R 7 or halogen; and X is OH or —OL where L is a conventional leaving group such as tosylate, methanesulfonate or triflate; and pharmaceutically acceptable salts thereof.
- a preferred embodiment comprises the intermediates of formula III wherein A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
- A is preferably a group of the formula II above.
- a most preferred embodiment within this subclass comprises compounds where R 9 in formula II is 2,4-difluorophenyl.
- Another most preferred embodiment comprises compounds where R 9 is 2,4-difluorophenyl, R 10 is methyl and R 11 is hydrogen.
- a still more preferred embodiment of this subclass comprises compounds wherein R 9 is 2,4-difluorophenyl, R 10 is methyl, R 11 is hydrogen and R 12 is 4-(4-cyanophenyl)thiazol-2-yl.
- a preferred embodiment comprises intermediates of formula III wherein n is 0, p is 1, R 1 , R 2 , R 3 and R 4 are hydrogen, m is 0 or 1, and X is OH.
- Another preferred embodiment comprises intermediates of formula III wherein n is 1, p is 1, R 1 , R 2 , R 3 and R 4 are hydrogen, m is 0 or 1 and X is OH.
- Another preferred aspect of the present invention comprises the intermediates of the formula
- the desired end-product of formula I may be recovered in the form of a pharmaceutically acceptable acid salt.
- pharmaceutically acceptable salt as used herein is intended to include salts with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)aminomethane), or with bases such as piperidine or morpholine, and meglumine and eglumine.
- suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such
- compositions comprising, in addition to the active triazole ingredient, a pharmaceutically acceptable carrier, adjuvant or diluent.
- the compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection).
- the pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions.
- Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents.
- the compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
- the compounds of the present invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, or cream. Additionally, they may be incorporated (at a concentration up to 10%) into an ointment consisting of a white wax or soft, white paraffin base together with the required stabilizers and/or preservatives.
- the compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans.
- the compounds of the present invention are useful for the treatment or prevention of topical fungal infections, including those caused by species of Candida, Tnchophyton, Microsporum, or Epidermophyton.
- they are useful for the treatment of mucosal infections caused by Candida albicans. They can also be used in the treatment of systemic fungal infections caused, for example, by species of Candida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus , Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces.
- a method of treating a fungal infection which comprises administering a therapeutically effective amount of the compound to a host, particularly a mammalian host and most particularly a human patient.
- a host particularly a mammalian host and most particularly a human patient.
- the use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of fungal infections are also provided.
- the dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 mg/day to about 1.0 g/day. These doses are exemplary of the average case, and there can be individual instances where higher or lower dosages are merited, and such dosages are within the scope of this invention. Furthermore, administration of the compounds of the present inventions can be conducted in either single or divided doses.
- the in vitro evaluation of the antifungal activities of the compounds of the invention can be performed by determining the minimum inhibitory concentration (MIC).
- MIC is the concentration of test compound which inhibits the growth of the test microorganism.
- a series of agar plates, each having the test compound incorporated at a specific concentration is inoculated with a fungal strain and each plate is then incubated for 48 h at 37° C. The plates are examined for the presence or absence of fungal growth, and the relevant concentration is noted.
- Microorganisms which can be used in the test include Candida albicans, Asperigillus fumigatus , Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis , and Torulopsos gaibrata . It should be recognized that, as prodrugs, some compounds of the invention may not be active in the in vitro test.
- the in vivo evaluation of compounds of the present invention can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration to mice which have been inoculated with a strain of fungus (e.g. Candida albicans). Activity is determined by comparing the survival of the treated group of mice at different dosage levels after the death of an untreated group of mice. The dose level at which the test compound provides 50% protection against the lethal effect of the infection is noted.
- a strain of fungus e.g. Candida albicans
- the compounds of the present invention substantially increase the solubility of the parent triazole antifungal compound and also release the bioactive parent compound (i.e. function as a prodrug) in human liver S9 experiments.
- MCPBA m-chloroperoxybenzoic acid
- Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt; doublet of triplets; and app d, apparent doublet, etc.
- Mass spectra were recorded on a Kratos MS50 or a Finnegan 4500 instrument utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron ion spray (ESI).
- DCI direct chemical ionization
- FAB fast atom bombardment
- ESI electron ion spray
- Analytical thin-layer chromatography was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, and/or staining by heating with methanolic phosphomolybdic acid.
- Column chromatography also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures somewhat above atmospheric pressure.
- Tin (IV) Chloride (41.35 g, 18.57 mL, 158 mole, Aldrich)
- reaction mixture was quenched by the addition of 120 mL water via the addition funnel maintaining the internal temperature between 15° C.-20° C.
- reaction mixture (containing some suspended solid particles) was filtered through a sintered glass funnel (polish filtration) and the solids were washed with 120 mL CH 2 Cl 2 . After settling, the two layers clearly separated.
- the combined filtrate and wash containing the product was concentrated via distillation under house vacuum to approximately 100 mL volume.
- the mixture was cooled to 22° C. over a period of one hour with seeding (at 35° C.).
- HPLC Instrument Shimadzu LC-10AS HPLC Detector: Shimadzu SPD M10A Diode Array (260 nm) Column: YMC ODS AQ 4.6 ⁇ 150 mm, S-3 ⁇ m, 120A Injection vol: 10 ⁇ L Flow Rate: 1.5 mL/min Run Time: 25 min Eluent A: CH 3 CN/water 10:90 Eluent B: CH 3 CN/water 90:10 Gradient Table: Time (minutes) % Eluent A % Eluent B (linear gradient) 0 60 40 5 60 40 15 0 100 20 0 100 23 60 40 25 stop
- Solvent A 10% methanol ⁇ 90% water ⁇ 0.1% TFA.
- Solvent B 90% methanol ⁇ 10% water ⁇ 0.1% TFA.
- Trifluoroacetic acid (210 mmol) was added to a mixture of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[[[p-di-t-butylphosphonooxymethyl]benzoyloxy]methoxy]carbonyloxy]butane (10.5 mmol) in 300 mL of CH 2 CL 2 at 0° C. under N 2 . The reaction mixture was then allowed to warm to rt and stirred for 1 h.
- the reaction mixture was then cooled to 0° C. and to it was added 30% aqueous H 2 O 2 (2.0 mL, 17.7 mmol). The reaction mixture was stirred 1 hour at 0° C. then 0.5 hours at room temperature and was then concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 and was washed with water and brine. The organic layer was dried over Na 2 SO 4 and then was concentrated. The residue was then stirred in CH 2 Cl 2 (50 mL) and TFA (25 mL) for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase chromatography on C-18 (CH 3 CN/H 2 O).
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Abstract
Description
- This divisional application claims the priority of U.S. Non-Provisional Application Ser. No. 09/441,541 filed Nov. 16,1999 and U.S. Provisional Application Ser. No. 60/109,184 filed Nov. 20,1998.
- This invention relates to a new class of azole derivatives, methods for their use, and processes for their production. The compounds described herein are useful for the treatment of fungal infections in humans and other mammals. The present invention provides a compound represented by the general formula:
- wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, m can be 0 to 6; p is 1 or 2; R1, R2, R3 and R4 can each independently be hydrogen, C1-C6 alkyl, hydroxy, OR5, NH2, NR6R7, or halogen; R5, R6 and R7 can each independently be hydrogen, C(O)R8, or C1-C6 alkyl; R8 is C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.
- Triazole antifungal compounds are well known in the prior art. Of the several known classes of such compounds, one particularly potent class contains a tertiary hydroxyl group. For example, U.S. Pat. No. 5,648,372 discloses that (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol has potent anti-fungal activity.
- The utility of this class of compounds is limited by their low water solubility. Various prior art methods have attempted to address this problem in order to prepare water-soluble forms of these compounds, e.g. for parenteral administration.
- WO 97/28169 discloses compounds of the general formula
- R′—OP(O)(OH)2
- wherein R′ represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
-
- wherein
-
- possessing antifungal activity;
- Z is nitrogen or methine;
- R1 and R2 are each independently a hydrogen atom or a group —OY in which Y is a group easily hydrolyzable under physiological condition;
- R3 and 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.
-
- wherein G is H or PO3H2.
-
- the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein —A—B— forms a divalent radical of formula:
- —N═CH— (a),
- —CH═N— (b),
- —CH═CH— (c),
- wherein one hydrogen atom in the radicals (a) and (b) may be replaced with a C1-6 alkyl-radical and up to two hydrogen atoms in radical (c) may be replaced by a C1-6 alkyl-radical;
- L represents the acyl moiety of an amino acid, and thus —O—L represents an amino acid ester group;
-
- wherein
- X is N or CH;
- R1 is halo;
- R2 is hydrogen or halo.
-
-
- Alk is a C1-4 alkanediyl radical; R1 is halo; R2 is hydrogen or halo; R3 is hydrogen, C1-6 alkyl, phenyl or halophenyl; R4 is hydrogen, C1-6 alkyl phenyl or halophenyl; R5 is hydrogen or C1-6 alkyl; R6 is hydrogen, C1-6 alkyl, C1-6 alkyloxycarbonyl, or R5 and R6 taken together with the nitrogen atom to which they are attached form a heterocyclic ring.
-
- wherein X is independently both F or both Cl or one X is independently F and the other is independently Cl;
- R1 is a straight or branched chain (C4-C5) alkyl group substituted by one or two groups convertible in vivo into hydroxy moieties or a pharmaceutically acceptable salt thereof.
- WO 98/43970 discloses a quaternized nitrogen-containing imidazol-1-yl or 1,2,4-triazol-1-yl compound wherein one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo to be converted into an antifungal azole compound. The preferred compounds have the formula
- (wherein Q is an imidazol-1-yl or 1,2,4-triazol-1-yl group in which one of the nitrogen atoms constituting an azole ring is quaternized with a substituent capable of being eliminated in vivo; Ar is an optionally substituted phenyl group; A is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X1 is an oxygen atom or a methylene group; X2 is an optionally oxidized sulfur atom; m and p respectively represent 0 or 1; Y is an anion; and (1) R3, R4 and R5 may be the same or different and represent a hydrogen atom or a lower alkyl group, or (2) R3 is a hydrogen atom or a lower alkyl group and R4 and R5 are combined with each other to form a lower alkylene group, or (3) R5 is a hydrogen atom or a lower alkyl group and R3 and R4 are combined with each other to form a lower alkylene group) or a salt thereof.
-
- wherein R1, R2 and R3 are substituents which comprise the parent secondary or tertiary amine such that one of R1, R2 or R3 may be hydrogen, R4 and R5 are each hydrogen, or an organic or inorganic residue.
-
- as suitable for preparation of pharmaceutical formulations for intravenous use.
- It has now been found that triazole anti-fungal compounds containing a secondary or tertiary hydroxyl group, including (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol, may be converted into prodrugs with superior properties to those previously disclosed by attaching a phosphate containing moiety via a linking group. Specifically, the invention covers compounds of the formula:
- wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group, n is 0 or 1, m can be 0 to 6; p is 1 or 2; R1, R2, R3 and R4 can each independently be hydrogen, C1-C6 alkyl, hydroxy, OR5, NH2, NR6R7, or halogen; R5, R6 and R7 can each independently be hydrogen, C(O)R8, or C1-C6 alkyl; R8 is C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. The preferred formula I compounds are those where R1, R2, R3 and R4 are each independently hydrogen, C1-C6 alkyl, OR5 or halogen. Most preferred are the formula I compunds where R1, R2, R3 and R4 are each hydrogen.
- In a preferred embodiment, A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group.
- The various phosphate containing substituents of formula I may be attached in either an ortho, meta, or para relationship to the ester substituent, with the preferred attachment being either meta or para.
-
- wherein R9 represents phenyl substituted by one or more (preferably 1-3) halogen atoms;
- R10 represents H or CH3;
- R11 represents H, or taken together with R10 may represent ═CH2;
- R12 represents a 5- or 6 membered nitrogen containing ring which may be optionally substituted by one or more groups selected from halogen, ═O, phenyl substituted by one or more groups selected from CN, (C6H4)—OCH2CF2CHF2 and CH═CH—(C6H4)—OCH2CF2CHF2, or phenyl substituted by one or more groups selected from halogen and methylpyrazolyl.
- Nitrogen containing heterocycles which R12 may represent include triazolyl, pyrimidinyl, and thiazolyl.
- Preferred embodiments comprise:
- (1) A compound of formula I where A is a group of formula II and R9 is 2,4-difluorophenyl; or a pharmaceutically acceptable salt thereof;
- (2) A compound of (1) above where R10 is methyl and R11 is hydrogen; or a pharmaceutically acceptable salt thereof;
- (3) A compound of (2) above where R12 is 4-(4-cyanophenyl)-thiazol-2-yl; or a pharmaceutically acceptable salt thereof;
- (4) A compound of (3) above wherein n is 0 or 1, m is 0 or 1, p is 1 and R1, R2, R3 and R4 are each hydrogen; or a pharmaceutically acceptable salt thereof.
-
-
-
-
- The term “pharmaceutically acceptable salt” as used herein is intended to include salts with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, meglumine (N-methylglucamine), eglumine, triethanolamine or tris(hydroxymethyl)aminomethane). Salts with bases such as piperidine or morpholine are also intended to be encompassed by the term “pharmaceutically acceptable salt”.
- The term “halogen” includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro, and most preferably fluoro.
- The aliphatic “alkyl” groups may be straight or branched chains having the specified number of carbon atoms, e.g. in the case of C1-C6 alkyl, the alkyl group may have from 1 to 6 carbon atoms.
- Preferred embodiments of the present invention, including in each case pharmaceutically acceptable salts thereof are:
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[o-phosphonooxy]benzoyloxy]-methoxy]butane (compound of example 1)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-phosphonooxymethyl]benzoyloxy]-methoxy]butane (compound of example 2)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-phosphonooxymethyl]benzoyloxy]-methoxy]butane (compound of example 3)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[[p-phosphonooxymethyl]benzoyloxy]-methoxy]carbonyloxy]butane (compound of example 4)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[[m-phosphonooxy]benzoyloxy]methoxy]butane (compound of example 5)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-phosphonooxy]benzoyloxy]methoxy]butane
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[o-phosphonooxymethyl]benzoyloxy]methoxy]butane
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[[o-phosphonooxymethyl]benzoyloxy]methoxy]carbonyloxylbutane
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-phosphonooxymethyl]benzoyloxy]methoxy]carbonyloxy]butane
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[[m-phosphonooxy]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 6)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[[p-phosphonooxy]benzoyloxylmethoxy]carbonyloxy]butane (compound of example 6)
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[[o-phosphonooxy]benzoyloxy]methoxy]carbonyloxy]butane (compound of example 6)
-
- The compounds of the present invention can be made by conventional methods. Three suitable general procedures are summarized by the following reaction schemes. In these schemes, A represented the non-hydroxy portion of a triazole anti-fungal compound of the type containing a secondary or tertiary hydroxyl group.
- To elaborate on Method 1, the anti-fungal parent compound of interest is converted into ester 2 by reaction with chloride intermediate 1 in the presence of a suitable base, such as potassium hydride. The esterification reaction can be carried out in THF (tetrahydrofuran) or other inert organic solvent and the product may be purified by column chromatography. Chloride 1 can be prepared by the method of Iyer et al. found inSyn. Comm. 25, 2739, (1995) (see “Preparation of Starting Materials” herein, Method 1) or by the alternative method disclosed below in “Preparation of Starting Materials,” Method 2. Ester 2 can be subsequently converted into phosphate ester 3 by reaction with a dialkyl phosphate in refluxing acetonitrile. Phosphate ester 3 can be converted to the phosphate acid 4 in one of two ways. If phosphate 4 is the di-tertiary butyl ester, the free phosphate acid can be liberated by treatment with trifluoroacteic acid. Alternatively, if phosphate 4 is the di-benzyl ester, the free phosphate acid can be obtained by hydrogenation in the presence of palladium on carbon in the presence of a suitable solvent. In either case, the final product can be purified via C-18 column chromatography.
- To elaborate on Method 2, the anti-fungal parent compound of interest is converted into chloromethylformate 5 by reaction with commercially available chloromethyl chloroformate in the presence of an appropriate base in THF or other solvent at 0° C. to 50° C. Appropriate bases include potassium hydride and sodium hydride, among others, with the preferred base being potassium hydride. The product 5 may be purified by column chromatography. Chloromethylformate 5 is converted to alcohol 7 by reaction with carboxylate salt 6 in acetonitrile or other appropriate organic solvent. Carboxylate salt 6 can be prepared by the method disclosed in U.S. Pat. No. 4,623,486. Alcohol 7 can be converted to phosphate ester 8 by reaction with a commercially available phosphoramidite in the presence of tetrazole followed by oxidation e.g. by use of hydrogen peroxide or m-chloroperoxybenzoic acid. Ester 8 can be purified by column chromatography. Phosphate ester 8 can then be converted to phosphate acid 9 in one of two ways. If phosphate 8 is the di-tertiary butyl ester, the free phosphate acid can be liberated by treatment with trifluoroacteic acid. Alternatively, if phosphate 8 is the di-benzyl ester, the free phosphate acid can be obtained by hydrogenation in the presence of palladium on carbon in the presence of a suitable solvent. Alternatively, phosphate acid 9 can be prepared from alcohol 7 by reaction with phosphorus oxychloride in an inert organic solvent such as dichloromethane in the presence of an organic base such as pyridine. In either case, the final product can be purified via C-18 column chromatography.
- To elaborate on Method 3 the benzyloxybenzoic acids 10 are converted to their respective chloromethyl esters 11 using the procedures described for the preparation of compounds 1 in Method 1. The anti-fungal parent compound of interest is then converted to either its potassium or sodium salt by reaction with either potassium or sodium hydride respectively, in an inert solvent such as THF (tetrahydrofuran), or DMF (N,N-dimethylformamide), or mixtures of both at 0° C. to 60° C. The chloromethyl esters 11 are then introduced to the reaction mixtures to afford the intermediates 12. The compounds 12 can be purified by column chromatography on silicic acid. The benzyl protecting groups are removed from the compounds 12 by hydrogenation using palladium catalysts in an inert solvent to give the alcohols 13 which can be purified by flash chromatography on silicic acid. The alcohols 13 are coverted to the phosphate esters by reaction with a commercially available phosphoramidite in the presence of tetrazole followed by oxidation e.g. by the use of hydrogen peroxide or m-chloroperoxybenzoic acid. The phosphate esters 14 are converted to their respective phosphate acids 15 by one of the two methods illustrated in Method 2 for the conversion of 8 to 9.
-
- wherein A is the non-hydroxy portion of a triazole antifungal compound of the type containing a secondary or tertiary hydroxy group; n is 0 or 1; m is 0 to 6; p is 1 or 2; R1, R2, R3 and R4 can each independently be hydrogen, C1-6 alkyl, hydroxy, OR5, NH2, NR6R7 or halogen; and X is OH or —OL where L is a conventional leaving group such as tosylate, methanesulfonate or triflate; and pharmaceutically acceptable salts thereof.
- A preferred embodiment comprises the intermediates of formula III wherein A represents the non-hydroxy portion of a triazole antifungal compound of the type containing a tertiary hydroxy group. Within this preferred embodiment, A is preferably a group of the formula II above. A most preferred embodiment within this subclass comprises compounds where R9 in formula II is 2,4-difluorophenyl. Another most preferred embodiment comprises compounds where R9 is 2,4-difluorophenyl, R10 is methyl and R11 is hydrogen. A still more preferred embodiment of this subclass comprises compounds wherein R9 is 2,4-difluorophenyl, R10 is methyl, R11 is hydrogen and R12 is 4-(4-cyanophenyl)thiazol-2-yl.
- A preferred embodiment comprises intermediates of formula III wherein n is 0, p is 1, R1, R2, R3 and R4 are hydrogen, m is 0 or 1, and X is OH.
- Another preferred embodiment comprises intermediates of formula III wherein n is 1, p is 1, R1, R2, R3 and R4 are hydrogen, m is 0 or 1 and X is OH.
-
- It will be understood that where the substituent groups used in the above reactions contain certain reaction sensitive functional groups such as amino or carboxylate groups which might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated, for example, inProtective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, 1991). It is intended that such “protected” intermediates and end-products are included within the scope of the present disclosure and claims.
- The desired end-product of formula I may be recovered in the form of a pharmaceutically acceptable acid salt. As defined previously, the term “pharmaceutically acceptable salt” as used herein is intended to include salts with such counterions as ammonium, alkali metal salts, particularly sodium or potassium, alkaline earth metal salts, particularly calcium or magnesium, and salts with suitable organic bases such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, and the like) or with substituted lower alkylamines (e.g. hydroxyl-substituted alkylamines such as diethanolamine, triethanolamine or tris(hydroxymethyl)aminomethane), or with bases such as piperidine or morpholine, and meglumine and eglumine.
- It will be appreciated that certain products within the scope of formula I may have substituent groups which can result in formation of optical isomers. It is intended that the present invention include within its scope all such optical isomers as well as epimeric mixtures thereof, i.e. R- or S- or racemic forms.
- The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active triazole ingredient, a pharmaceutically acceptable carrier, adjuvant or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
- Alternatively, the compounds of the present invention can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, or cream. Additionally, they may be incorporated (at a concentration up to 10%) into an ointment consisting of a white wax or soft, white paraffin base together with the required stabilizers and/or preservatives.
- The compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. Specifically, the compounds of the present invention are useful for the treatment or prevention of topical fungal infections, including those caused by species of Candida, Tnchophyton, Microsporum, or Epidermophyton. Additionally, they are useful for the treatment of mucosal infections caused by Candida albicans. They can also be used in the treatment of systemic fungal infections caused, for example, by species ofCandida albicans, Cryptococcus neoformans, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidiodes, Histoplasma, or Blastomyces.
- Thus, according to another aspect of the invention, there is provided a method of treating a fungal infection which comprises administering a therapeutically effective amount of the compound to a host, particularly a mammalian host and most particularly a human patient. The use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of fungal infections are also provided.
- The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 5 mg/day to about 1.0 g/day. These doses are exemplary of the average case, and there can be individual instances where higher or lower dosages are merited, and such dosages are within the scope of this invention. Furthermore, administration of the compounds of the present inventions can be conducted in either single or divided doses.
- The in vitro evaluation of the antifungal activities of the compounds of the invention can be performed by determining the minimum inhibitory concentration (MIC). The MIC is the concentration of test compound which inhibits the growth of the test microorganism. In practice, a series of agar plates, each having the test compound incorporated at a specific concentration, is inoculated with a fungal strain and each plate is then incubated for 48 h at 37° C. The plates are examined for the presence or absence of fungal growth, and the relevant concentration is noted. Microorganisms which can be used in the test includeCandida albicans, Asperigillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis, and Torulopsos gaibrata. It should be recognized that, as prodrugs, some compounds of the invention may not be active in the in vitro test.
- The in vivo evaluation of compounds of the present invention can be carried out at a series of dose levels by intraperitoneal or intravenous injection or by oral administration to mice which have been inoculated with a strain of fungus (e.g. Candida albicans). Activity is determined by comparing the survival of the treated group of mice at different dosage levels after the death of an untreated group of mice. The dose level at which the test compound provides 50% protection against the lethal effect of the infection is noted.
- The compounds of the present invention substantially increase the solubility of the parent triazole antifungal compound and also release the bioactive parent compound (i.e. function as a prodrug) in human liver S9 experiments.
- The following examples illustrate the invention, but are not intended as a limitation thereof. The abbreviations used in the examples are conventional abbreviations well-known to those skilled in the art. Some of the abbreviations used are as follows:
- h=hour(s)
- rt=room temperature
- mol=mole(s)
- mmol=mmole(s)
- g=gram(s)
- THF=tetrahydrofuran
- L=liter(s)
- mL=milliliter(s)
- Et2O=diethyl ether
- EtOAc=ethyl acetate
- MeOH=methanol
- DMF=dimethylformamide
- DABCO=1,4-Diazabicyclo[2.2.2]octane
- TFA=trifluoroacetic acid
- DMAP=dimethylaminopyridine
- MCPBA=m-chloroperoxybenzoic acid
- Ph=phenyl
- CH3CN=acetonitrile
- EtOH=ethanol
- Bn=benzyl
- KH=potassium hydride
-
- In the following examples, all temperatures are given in degrees Centigrade. Melting points were determined on an electrothermal apparatus and are not corrected. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a Bruker AM-300 or a Varian Gemini 300 spectrometer. All spectra were determined in CDCl3, DMSO-d6, CD3OD, or D2O unless otherwise indicated. Chemical shifts are reported in 8 units relative to tetramethylsilane (TMS) or a reference solvent peak and interproton coupling constants are reported in Hertz (Hz). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad peak; dd, doublet of doublets; dt; doublet of triplets; and app d, apparent doublet, etc. Mass spectra were recorded on a Kratos MS50 or a Finnegan 4500 instrument utilizing direct chemical ionization (DCI, isobutene), fast atom bombardment (FAB), or electron ion spray (ESI).
- Analytical thin-layer chromatography (TLC) was carried out on precoated silica gel plates (60F-254) and visualized using UV light, iodine vapors, and/or staining by heating with methanolic phosphomolybdic acid. Column chromatography, also referred to as flash chromatography, was performed in a glass column using finely divided silica gel at pressures somewhat above atmospheric pressure.
- The preparative HPLC purifications were carried out using a Shimadzu LC-8A preparative liquid chromatograph with a 20×100 mm YMCS5 ODS column. The compounds were eluted with CH3OH and water with 0.1% of TFA.
- Preparation of (3-Chloromethyl)Benzoic Acid Chloromethyl Ester
-
- To a cooled (0° C.) mixture of paraformaldehyde (0.79 g, 26.4 mmol) and zinc chloride (72 mg, 0.53 mmol) in benzene (10 mL) was added dropwise the acid chloride (5.0 g, 26.4 mmol) over a period of 15 minutes. The mixture was then heated at 55° C. overnight. The mixture was then filtered and the filtrate concentrated. Purification of the crude product via flash chromatography (100% Hexanes) yielded 2.7 g of the title compound as a colorless oil.
-
- MATERIALS:
- 3-Chloromethylbenzoyl chloride: 30 g (0.159 mole, 22.6 mL, Aldrich)
- Tin (IV) Chloride: (41.35 g, 18.57 mL, 158 mole, Aldrich)
- 1,3,5-trioxane (14.29 g of 99% purity, 0.158 mole, Aldrich)
- Dichloromethane (120 mL, EM Science, HPLC grade, KF=0.2 mG/mL)
- Heptane (470 mL, EM Science, HPLC grade)
- Ethylacetate (4.5 mL, EM Science, HPLC grade)
- Aq. NaHCO3 solution (saturated); 100 ml
- Water (Deionised, 220 mL)
- PROCEDURE:
- A 500 ml three neck round bottom flash equipped with a nitrogen inlet, reflux condenser, addition funnel, mechanical stirrer and immersion thermometer was charged with 60 mL CH2Cl2 (KF=0.2 mg/mL) and 3-chloromethylbenzoylchloride. Tin (IV) chloride was added via the addition funnel with stirring over a period of 2 minutes maintaining a temperature of 20° C.-22° C. 1,3,5-trioxane was added to the stirred mixture. The majority of the 1,3,5-trioxane remains undissolved.
- The stirred suspension was kept at 20° C.-22° C. for 24 hours at the end of which the conversion was 99% (L.C. area percent). Approximately 10% of the dimer (2) was also observed by HPLC.
- The reaction mixture was quenched by the addition of 120 mL water via the addition funnel maintaining the internal temperature between 15° C.-20° C.
- The reaction mixture (containing some suspended solid particles) was filtered through a sintered glass funnel (polish filtration) and the solids were washed with 120 mL CH2Cl2. After settling, the two layers clearly separated.
- The lower CH2Cl2 layer containing the product was separated from the top aqueous layer. The organic layer was washed with 100 mL water and the lower CH2Cl2 layer containing the product was separated from the top aqueous layer.
- The lower CH2Cl2 layer containing the product was separated from the top aqueous layer. The organic layer was washed with 100 mL saturated aq. NaHCO3 solution and the lower CH2Cl2 layer containing the product was separated from the top aqueous layer.
- The lower CH2Cl2 layer containing the product was separated from the top aqueous layer. The CH2Cl2 was then replaced by heptane via distillation (under atmospheric pressure) maintaining a total volume of approximately 450 mL.
- 1. Distillation was discontinued when the batch temperature reached approximately 80° C. NMR analysis of the mixture indicated complete removal of CH2Cl2 at this point.
- 2. Approximately 470 mL heptane was used.
- The mixture was cooled down to 22° C. Ethylacetate (4.5 mL) was added to the stirred mixture and the stirred mixture was kept at 22° C. for 18 h.
- 1. The less soluble methanediol bis [3-chloromethyl)benzoate] (2) is crystallized out in this process. Addition of ethylacetate helps to keep the desired product (1) in solution.
- 2. When the heptane solution is cooled down to approximately 30-40° C., some crystallization of the dimer was observed and a seed bed is formed.
- 3. If the dimer does not crystallize by cooling down to 22° C., additional cooling to 0-5° C. may be necessary for the seed bed to be formed.
- The crystals (dimer 2) were filtered and washed with 60 mL heptane.
- 1. Approximately 4.4 gm of the dimer, methanediol bis [3-chloromethyl)benzoate] was obtained.
- The combined filtrate and wash containing the product was concentrated via distillation under house vacuum to approximately 100 mL volume. The mixture was cooled to 22° C. over a period of one hour with seeding (at 35° C.).
- 1. Crystallization begins at approximately 30° C. to 35° C.
- 2. Since the compound melts at 42° C., the mixture should not be seeded above 40° C.
- The stirred mixture was cooled to 0-5° C. over a period of 30 minutes and then kept at 0-5° C. for 2 hours. The crystals were filtered, washed with 20 mL of cold (10° C.) heptane, and dried in a vacuum oven at 20-22° C. with a flow of nitrogen for 18 hours to yield 25.8 g (74% yield).
- ANALYSES:
- M.P. 41-42° C.
- NMR=consistent with the structure.
- HPLC
Instrument: Shimadzu LC-10AS HPLC Detector: Shimadzu SPD M10A Diode Array (260 nm) Column: YMC ODS AQ 4.6 × 150 mm, S-3 μm, 120A Injection vol: 10 μL Flow Rate: 1.5 mL/min Run Time: 25 min Eluent A: CH3CN/water 10:90 Eluent B: CH3CN/water 90:10 Gradient Table: Time (minutes) % Eluent A % Eluent B (linear gradient) 0 60 40 5 60 40 15 0 100 20 0 100 23 60 40 25 stop - Retention Times:
- 3-Chloromethylbenzoyl chloride 12.28 min.
- 3-Chloromethylbenzoic acid (formed by hydrolysis of the acid chloride) 3.46 min.
- (3-Chloromethyl)benzoic acid chloromethyl ester 11.67 min.
- Methanediol bis [3-chloromethyl)benzoate] (2) 14.67 min.
-
- To the potassium salt of 3-benzyloxybenzoic acid (2.39 g, 8.91 mmol) was added the bromochloromethane (8.7 ml, 15 eq.) and DMF (10.7 mL). The mixture was then stirred at room temperature for 12-18 hours. The mixture was then filtered and the filtrate concentrated. Purification of the crude product via flash chromatography (EtOAc: Hexanes 1:10) yielded 1.2 g of the title compound as a light yellow oil.1H NMR (300 MHz, CDC13)δ=5.12 (s, 2H), 5.96 (s, 2H), 7.22-7.25 (m, 1H), 7.26-7.47 (m, 6H), 7.68-7.72 (m, 2H), MS(ESI) 276.
-
-
- (2R, 3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1.0 mmol) was added to a suspension of potassium hydride (1.1 mmol) in THF (20 mL) at 0° C. The heterogeneous mixture was stirred for 15 minutes and chloromethyl ester (1.1 mmol) was added. The reaction was allowed to stir at r.t. for 5 h. Excess base was carefully quenched with water, and the crude mixture was extracted into ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. Purification of the crude product via flash chromatography (Hexanes/EtOAc) yielded 200 mg of the subtitled compound as a colorless oil.1H NMR (300 MHz, CDCl3)δ=1.27 (d, 3H), 4.06 (q, 1H), 4.87-5.04 (m, 4H), 5.99 (d, 1H), 6.23 (d, 1H), 6.80 (m, 2H), 6.95 (m, 2H), 7.24-7.45 (m, 8H), 7.66-7.77 (m, 4H), 7.95 (d, 2H), 8.15 (s, 1H). MS (ESI) 677.
-
- A suspension of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(o-(benzyloxy)benzoyloxyl methoxylbutane (0.22 mmol) in ethanol (100 mL) was hydrogenated over 10% Palladium on carbon (150 mg) at r.t. at 1 atmosphere for 2.5 h. The crude reaction was concentrated and the filtrate was collected. Purification of the crude product via flash chromatography (Hexanes/EtOAc 3/1) yielded 120 mg of the subtitled compound as a colorless oil.1H NMR (300 MHz, CDCl3) δ=1.27 (d, 3H), 4.12 (m, 1H), 5.02 (d, 1H), 5.28-5.38 (m, 2H), 6.21(dd, 2H), 6.61 (t, 1H), 6.77-6.94 (m, 3H), 7.42 (m, 4H), 7.65 (m, 3H), 7.88 (d, 2H), 8.08 (s, 1H). MS (ESI) 587.
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[o-hydroxy]benzoyloxy]methoxy]butane (0.22 mmol), 1H-tetrazole (0.66 mmol), 4-dimethylaminopyridine (10.7 mg, 0.088 mmol) and dibenzyl diisopropylphosphoramidite (0.44 mmol) in methylene chloride (10 mL) were refluxed under a nitrogen atmosphere for 12 h. The mixture was then cooled to 0° C., and hydrogen peroxide (0.25 mL, 30% solution in water) was added dropwise at a rate which maintained the reaction temperature below 20° C. The resulting mixture was stirred at 20° C. for 30 minutes before separating the organic layer, which was washed with water, dried over Na2SO4. Purification of the crude product via flash chromatography (Hexanes/EtOAc) yielded 140 mg of the subtitled compound as a colorless oil. 1H NMR (300 MHz, CDCl3) d=1.28 (d, 3H), 4.10 (q, 1H), 4.96 (d,1H), 5.13-5.21 (m, 4H), 5.27 ( d, 1H), 6.07 (d, 1H), 6.14 (d, 1H), 6.76-6.85 (m, 2H), 7.04 (t, 1H), 7.29-7.44 (m, 14H), 7.62-7.67 (m, 4H), 7.90 (d, 2H), 8.10 (s, 1H). MS (ESI) 847.
-
- A suspension of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[o-dibenzylphosphonooxy]benzoyloxy]methoxy]butane (0.17 mmol) in ethanol (100 mL) was hydrogenated over 10% Palladium on carbon (140 mg) at room temperature at 1 atmosphere for one hour. The crude reaction was filtered and the filtrate was collected. Purification of the crude product via flash chromatography (MeOH/CH2Cl2) yielded 80 mg of the titled compound as a white solid. 1H NMR (300 MHz, DMSO) d=1.14 (d, 3H), 4.07 (q, 1H), 4.36 (d, 1H), 4.58 (br. s, 2H), 4.85 (d, 2H), 6.94 (t, 1H), 7.08-7.32 (m, 4H), 7.63 (t, 2H), 7.86-7.93(m, 3H), 8.20 (t, 3H), 8.41(s, 1H). MS (ESI) 667.
-
-
- The benzyl chloride (made in by the method disclosed in example C) (300 mg, 0.48 mmol), di-benzyl phosphate (270 mg, 0.97 mmol), and silver oxide (115 mg, 0.48 mmol) were disolved in acetonitrile and the rection was allowed to reflux for 7 h. The mixture was cooled, filtered, and the filtrate was diluted with ethyl acetate. This solution was washed with water (2×) and brine, dried over Na2SO4. Purification of the crude product via flash chromatography (Hexanes/EtOAc) yielded 100 mg of the subtitled compound as a white solid. 1H NMR (CDC13) d 1.31 (d, 3H), 4.13 (q, 1H), 4.97-5.09 (m, 7H), 5.33 (d, 1H), 6.18 (ab, 2H), 6.78 (m, 2H), 7.22-7.46 (m, 17H), 7.68-7.70 (m, 2H), 7.80 (d, 2H), 7.92 (d, 2H), 8.15 (s, 1H). MS: 861.
-
- A suspension (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[p-dibenzylphosphonooxymethyl]benzoyloxy]methoxy]butane (0.12 mmol) in EtOAc (100 mL) was hydrogenated over 10% Palladium on carbon (100 mg) at r.t. and 1 atmosphere for 24 h. The crude reaction was filtered and the filtrate was concentrated. Purification of the crude product via prepation HPLC yielded 20 mg of the subtitled compound as a white solid.1H NMR (DMSO) d 1.24 (br. s, 3H), 4.05 (q, 1H), 4.79 (d, 2H), 5.15 (d, 1H), 5.34 (d, 1H), 6.02 (ab, 2H), 7.01 (m, 1H), 7.22 (m, 1H), 7.29(m, 1H), 7.41(d, 2H), 7.77 (d, 2H), 7.84 (s, 1H), 7.88 (d, 2H), 8.06 (d, 2H), 8.20 (s, 1H), 8.51(s, 1H). MS: 681.
-
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl] -2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (13.9 mmol) was added to a suspension of potassium hydride (15.3 mmol) in THF (100 mL) at 0° C. The heterogeneous mixture was stirred for 15 minutes and the chloromethyl ester (16.8 mmol, prepared by the method disclosed in Houben-Weyl, Methoden Der Organischen Chemie, Band E14a/3, 85, 1992) was added. The reaction was allowed to stir at 0° C. for 2 h and then warmed to r.t. and stirred for 2 h. Excess base was carefully quenched with water, and the crude reaction was extracted into ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. Purification of the crude product via flash chromatography (Hexanes/EtOAc) yielded 4.6 g of the subtitled compound as a colorless oil. 1H NMR (CDCl3): δ 1.29 (m, 3H), 4.14 (m, 1H), 5.03 (d, J=16.0, 2H), 5.35 (d, J=18.0, 2H), 6.20 (s, 2H), 6.85 (m, 2H), 7.29(m, 1H), 7.42(m, 2H), 7.56(d, J=7.7, 1H), 7.70(m, 3H), 7.79(d, J=7.8, 1H), 7.88(s, 1H), 7.94(d, J=8.5, 2H), 8.11(s, 1H).
-
- Acetonitrile (160 mL) was added to a mixture of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-chloromethyl]benzoyloxy]methoxy]butane (0.0161mol), di-tert-butyl phosphate (0.0352mol), and silver oxide (0.0177mol). The mixture was stirred under argon and refluxed for 6 hours. The mixture was cooled, filtered, and filtrate was concentrated. The resulting viscous material was dissolved in ethyl acetate. The solution was sequentially washed (dilute sodium bicarbonate followed by saturated brine), dried (magnesium sulfate) and concentrated to afford 12.5 g of the subtitled compound as a viscous oil which was of sufficient purity to carry forward.
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[[m-di-t-butylphosphonooxymethyl]benzoyloxy]methoxy]butane (11 g) was dissolved in methylene chloride (120 mL). TFA (30 mL) was added and the solution stirred for 15 min. The solution was concentrated to leave a gum. a Ice cold saturated sodium bicarbonate (60 mL) was added and the gum worked to give a soft solid. Additional saturated sodium bicarbonate (about 30 mL) was added to give a pH of 6.6 and a largely granular solid. The crude material (2.4g) was dissolved in hot water (about 60° C., 30-40 mL). The hazy solution was filtered (0.45 cm membrane) and applied to a Michel-Miller column (21×250 mm) packed with C18. The column was eluted with water and then with water-acetonitrile (60:40) to elute the product containing fractions. The acetonitrile was removed, and the aqueous solution lyophilized to leave the purified monosodium salt of the title compound (1.53g) as a colorless solid.1H NMR (CD30D) δ 1.35 (d, J=7, 3H), 4.19 (q, J=7, 14, 1H), 4.93 (m, 2H), 5.22 (d, J=16, 1H), 5.48 (d, J-16, 1H), 6.19 (m, 2H), 6.97 (m, 2H), 7.28 (m, 1H), 7.49 (m, 1H), 7.68 (m, 2H), 7.71 (m, 3H), 7.91 (s, 1H), 7.96 (s, 1H), 8.00 (m, 2H), 8.00 (m, 2H), and 8.50 (s, 1H); IR (cm-1) 2226 (CN) and 1724 (CO); MH+=682; Anal. Calcd for C31H26F2N5O7PS: C,54.63:H,3.84:N,10.27:S,4.70. Found: C,54.01:H,4.08:N,10.00:S,4.99 and 5.13: Na, 0.33 and 0.37: KF(HOH), 0.69 and 0.80.
- Crystallization
- A sample of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-(di-t-butylphosphonooxy)benzoyloxy]methoxy]butane prepared as in Example 3 was dissolved in methylene chloride (75 ml). Trifluoroacetic acid (TFA) (25 ml) was added and the solution was stirred for 15 minutes. The solution was concentrated and diluted with CCl4. The mixture was reconcentrated and diluted with 100 ml of ice cold water. The resulting mixture was extracted with ethyl acetate (150 ml). The ethyl acetate layer was washed (water, brine), dried (sodium sulfate) and concentrated to leave the free acid as an oil which turned granular when stirred with ether.
- A sample of this crude acid (600 mg) was purified using a Shimadzu Prep HPLC (YMC ODS 30×100 mm column and eluting with a gradient starting with 40% B-60% A and proceeding to 100% B over 10 minutes). The solvents were removed by lyophilization to leave the title compound as a white solid (400 mg). The solid was dissolved in acetonitrile (175 mL) at 80° C. The clear solution was kept at 80° C. and then slowly cooled and allowed to stand at ambient temperatures for 18 hours to afford the crystalline title material (280 mg, 70% recovery).
- A single crystal X-ray was obtained which confirmed the structure.
- 1. Purity about 90%.
- 2. Solvent A=10% methanol−90% water−0.1% TFA. Solvent B=90% methanol−10% water−0.1% TFA.
-
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (5.8 mmol) was added to a suspension of potassium hydride (7 mmol) in THF at 0° C. and was allowed to stir for 0.5 hours. Choromethyl chloroformate (5.8 mmol, in 2 mL THF) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 4 hours. The crude reaction was diluted with EtoAc, and was sequentially washed with H2O, 0.1N HCl, H2O , and brine. The organic layer was dried over MgSO4 and was concentrated to afford 3.43 g of the subtitled product as a pale yellow solid. 1H NMR (DMSO) δ 8.47 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 7.97 (d, 2H, J=8), 7.88 (d, 2H, J=8), 7.26-7.12 (m, 3H), 5.93 (d, 1H, J=6), 5.90 (d, 1H, J=6), 5.70 (d, J=1H, J=15), 5.36 (d, 1H, J=15), 4.02 (q, 1H, J=7), and 1.48 (d, 3H, J=7); MS (MH+=530).
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[chloromethyl]methyloxy]butane (23.6 mmol) was added to an acetonitrile solution of hydroxymethyl benzoate potassium salt (28.3 mmol, prepared by the method of Lombardino et al, U.S. Pat. No. 4,623,486) and 18-crown-6 (23.6 mmol), and the reaction was allowed to warm to 60° C. and stir overnight under N2. After cooling at rt, the mixture was filtered and the solution was concentrated at reduced pressure. The residue was purified via column chromatography on silica yielding 9.5 g (62%) of the subtitled compound as a white solid. 1H NMR (DMSO-d6) δ 8.45 (s, 1H), 8.24 (s, 1H), 7.94 (dd, 4H, J=8, 2), 7.85 (s, 1H), 7.84 (d, 2H, J=8), 7.49 (d, 2H, J=8), 7.21-7.03 (m, 3H), 5.95 (s, 2H), 5.67 (d, 1H, J=15), 5.42 (br s, 1H), 5.35 (d, 1H, J=15), 4.60 (s, 2H), 4.01 (q, 1H, J=7), 1.45 (d, 3H, J=7).
-
- A mixture of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[[p-hydroxymethyl]benzoyloxy]methoxy]carbonyloxy]butane (14.7 mmol), di-tert-butylphosphorous amidite (29.4 mmol) and tetrazole (73.5 mmol) in 150 mL of THF was stirred at rt overnight. It was then cooled to −78° C. and MCPBA (32.3 mmol) in CH2CL2 was added via a syringe under N2. After addition, it was warmed to rt and stirred for another hour. Aqueous NaHSO3 was then added and the mixture was stirred at rt for 15 min. The crude reaction was diluted with EtOAc, and was sequentially washed with NaHSO3, NaHCO3 and water. The organic layer was dried over Na2SO4 and then was concentrated. The residue was purified via column chromatography on silica (Hexane/EtoAc) to afford 8.8 g (71%) of the subtitled compound as a white solid. 1H NMR (DMSO-d6) δ 8.25 (s, 1H), 8.22 (s, 1H), 7.96 (d, 2H, J=8), 7.93 (d, 2H, J=8), 7.84 (s 1H), 7.82 (d, 2H, J=8), 7.54 (d, 2H, J=8), 7.30-7.01 (m, 3H), 5.96 (s, 2H), 5.67 (d, 1 H, J=15), 5.35 (d, 1H, J=15), 5.04 (d, 2H, J=8), 4.01 (q, 1H, J=7), 1.45 (d, 3H, J=7), 1.42 (s, 9H).
-
- Trifluoroacetic acid (210 mmol) was added to a mixture of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[[[p-di-t-butylphosphonooxymethyl]benzoyloxy]methoxy]carbonyloxy]butane (10.5 mmol) in 300 mL of CH2CL2 at 0° C. under N2. The reaction mixture was then allowed to warm to rt and stirred for 1 h. After evaporation of volatiles in vacuo, the residue was dissolved in a minimum amount of CH3CN and basified with saturated aqueous NaHCO3 until pH was 8.5. It was then purified via C-18 column chromatography (H2O to 20% H2O/CH3CN to CH3CN). After lyopholization, 2.0 g (25%) of the product was obtained as a white solid. 1H NMR (DMSO-d6) δ 8.45 (s, 1H), 8.23 (s, 1H), 7.98 (d, 2H, J=8), 7.93 (d, 2H, J=8), 7.85 (s, 1H), 7.84 (d, 2H, J=8), 7.55 (d, 2H, J=8), 7.18-7.04 (m, 3H), 5.95 (s, 2H), 5.67 (d, 1H, l=15), 5.34 (d, 1H, J=15), 4.99 (d, 2H, J=7), 4.01 (q, 1H, J=7), 3.37 (br s, 2H), 1.45 (d, 3 H, J=7).
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4triazol-1yl)-2-[[[[m-phosphonooxy]benzoyloxy]methoxy]butane
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (1.4 mmol) was added to a suspension of potassium hydride (1.5 mmol) in THF (10 mL) at room temperature. The mixture was stirred for 10 minutes and chloromethyl ether (1.6 mmol) was added. The reaction was allowed to stir at 32° C. for 5 hours. Excess base was carefully quenched with water, and the crude mixture was extracted into ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. Purification of the crude product via flash chromatography (Hexanes/EtOAc 3/1) yielded 350 mg of the subtitled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.29 (d, 3H), 4.12 (q, 1H), 4.99-5.03 (m, 3H), 5.32 (d, 1H), 6.19 (m, 2H), 6.76-6.88 (m, 2H), 7.08-7.38 (m, 3H), 7.32-7.48 (m, 8H), 7.88 (d, 2H), 8.14 (s, 1H). MS(ESI) 677.
-
- A suspension of (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-(benzyloxy)benzoyloxy]methoxy]butane (0.40 mmol) in ethanol (150 mL) was hydrogenated over 10% Palladium on carbon (150 mg) at room temperature at 1 atmosphere for 12 hours. The mixture was then filtered and the filtrate concentrated. Purification of the crude product via flash chromatography (Hexanes/EtOAc 3/1) yielded 170 mg of the subtitled compound as a white solid.1H NMR (300 MHz, CDC13) δ=1.29 (d, 3H), 4.10 (m, 1H), 5.09 (d, 2H), 5.33 (d, 2H), 5.94 (d, 2H), 6.14 (dd, 2H), 6.85 (m, 2H), 7.01 (d, 1H), 7.18-7.27 (m, 2H), 7.32-7.44 (m, 2H), 7.50 (s, 1H), 7.69 (d, 2H), 7.77 (m, 1H), 7.95 (d, 2H), 8.42 (s, 1H). MS(ESI) 587.
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- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-(hydroxy)benzyloxy]methoxy]butane (220 mg, 0.37 mmol), 1H-tetrazole (78 mg, 1.12 mmol), 4-dimethylaminopyridine (18 mg, 0.15 mrnol) and di-t-butyl diisopropylphosphoramidite (0.24 mL, 0.75 mmol) in methylene chloride were refluxed under a nitrogen atmosphere for 12 hours. The mixture was then cooled to 0° C., and hydrogen peroxide (0.38 mL, 30% solution in water) was added dropwise at a rate which maintained the reaction temperature below 10° C. The resulting mixture was stirred at 20° C. for 30 minutes before separating the organic layer, which was washed with water, dried over Na2SO4. Purification of the crude product via flash chromatography (Hexanes/EtOAc) yielded 200 mg of the subtitled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ=1.29 (d, 3H), 1.53 (s, 9H), 1.54 (s, 9H), 4.13 (q, 1H), 4.98 (d, 1H), 5.34 (dd, 1H), 6.20 (dd, 2H), 6.77-6.92 (m, 2H), 7.19-7.24 (m, 1H), 7.36-7.45 (m, 2H), 7.55-7.58 (m, 2H), 7.67 (s, 1H), 7.69 (d, 2H), 7.79 (m, 1H), 7.95 (dd, 2H), 8.12 (s, 1H). MS(ESI) 779.
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- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-[[(m-(di-t-butylphosphonooxy)benzoyloxy]methoxy]butane (180 mg) was dissolved in methylene chloride (20 mL). TFA (5 mL) was added and the solution stirred for 15 minutes. The solution was concentrated to leave a gum. Purification of the crude product via Prep-HPLC (MeOH/H20) yielded 120 mg of the titled compound as a white solid.1H NMR (300 MHz, CDCl3) δ=1.39 (d, 3H), 4.13 (q, 1H), 5.32 (dd, 2H), 5.66 (d, 1H), 5.93 (d, 1H), 6.79-6.92 (m, 2H), 7.22-7.25 (m, 3H), 7.59 (s, 1H), 7.62-7.66 (m, 4H), 7.84 (s, 1H), 7.94 (d, 2H), 8.82 (s, 1H). MS(ESI) 667.
-
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[chloromethyl]methyloxy]carbonyloxy]butane (1.06g, 2.0 mmol), 3-hydroxybenzoic acid sodium salt (0.32 g, 2.0 mmol) and 18-crown-6 (0.10 g) were stirred under nitrogen in CH3CN (20 mL) and DMF (10 mL) at 65° C. for 20 hours. After cooling to room temperature the mixture was concentrated at reduced pressure. The residue was dissolved in CH3CN and was purified by preparative HPLC to yield 1.0 g crude subtitled compound as an off white solid (79%). 1H NMR (DMSO-d6) δ 9.93 (s, 1H), 8.48 (s, 1H), 8.25 (m, 4H), 7.95 (d, 2H, J=8), 7.83 (m, 2H), 7.49-7.08 (m, 5H), 5.95 (s, 2H), 5.68 (d, 1H, J=15), 5.37 (d, 1H, J=15), 4.00 (q, 1H, J=7), 1.45 (d, 3H, J=7). LC/MS (ESI+(MH+) 632 obs).
- In a similar manner, p-hydroxy and o-hydroxy derivatives were also prepared.
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[p-hydroxy]benzoyloxy]methoxy]carbonyloxy]butane:
-
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[o-hydroxy]benzoyloxy]methoxy]carbonyloxy]butane:
-
-
- The crude (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[m-hydroxy]benzoyloxy]methyloxy]carbonyloxy]butane (792 mg, 1.26 mmol) was dissolved in CH2Cl2 (15 mL) and was cooled to 0° C. To this solution was added pyridine (0.38 mL, 4.74 mmol) followed by phosphorus oxychloride (0.16 mL, 1.79 mmol). Mixture was stirred 0.5 hours at 0° C. then 2 hours at room temperature. Water (15 mL) was added to the mixture and stirred for 0.25 hours. The mixture was then concentrated under reduced pressure. The residue was dissolved in CH3CN (16 mL) and was purified by preparative HPLC resulting in 0.128 g (14%) of the subtitled compound as a white solid. 1H NMR (DMSO-d6) δ 8.47 (s, 1H), 8.22 (s, 1H), 8.05 (d, 1H, J=9), 7.96-7.75 (m, 6H), 7.59 (t, 1H, J=7), 7.48 (d, 1H, J=7), 7.21-7.03 (m, 3H), 5.96 (s, 2H), 5.68 (d, 1H, J=15), 5.35 (d, 1H, J=15), 4.00 (q, 1H, J=7), 1.46 (d, 3H, J=7). MS (ESI+(MH+) 712 obs).
- Similarly, p-phosphonooxy derivative was prepared.
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[p-phosphonooxy]benzoyloxy]methoxy]carbonyloxy]butane, disodium salt:
-
- The o-phosphonooxy analog was prepared by phosphoamidite reaction followed by oxidation.
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)4-(1H-1,2,4-triazol-1yl)-2-[[o-phosphonooxy]benzoyloxy]methoxy]carbonyloxy]butane:
- (2R,3R)-3-[4-(4-cyanophenyl)thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)-2-[[o-hydroxy]benzoyloxy]methoxy]carbonyloxy]butane (1.04 g, 1.65 mmol), di t-butoxy diisopropyl phosphoramidite (0.91 g, 3.29 rnmol), tetrazole (0.35 g, 4.95 mmol) and 4-dimethyamino pyridine (0.08 g, 0.66 mmol was refluxed in THF (25 mL) for 18 hours. The reaction mixture was then cooled to 0° C. and to it was added 30% aqueous H2O2 (2.0 mL, 17.7 mmol). The reaction mixture was stirred 1 hour at 0° C. then 0.5 hours at room temperature and was then concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and was washed with water and brine. The organic layer was dried over Na2SO4 and then was concentrated. The residue was then stirred in CH2Cl2 (50 mL) and TFA (25 mL) for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase chromatography on C-18 (CH3CN/H2O). The product containing fractions were concentrated under reduced pressure, frozen and lyophilized to afford 0.22 g (19%) of the subtitled compound as a white solid. 1H NMR (DMSO-d6) δ 8.50 (s, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.94 (d, 2H, J=9), 7.85 (d, 2H, J=9), 7.75 (d, 1H, J=7), 7.63 (dd, 1H, J=7,7), 7.42 (d, 1H, J=7), 7.26 (dd, 1H, J=7), 7.21-7.02 (m, 3H), 5.90 (s, 2H), 5.70 (d, 1H, J=15), 5.37 (d, 1H, J=15), 4.00 (q, 1H, J=7), 1.46 (d, 3H, J=7). MS (ESI+(MH+) 712 obs).
Claims (8)
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US09/965,755 Expired - Fee Related US6620934B2 (en) | 1998-11-20 | 2001-09-28 | Water soluble prodrugs of azole compounds |
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US6362172B2 (en) * | 2000-01-20 | 2002-03-26 | Bristol-Myers Squibb Company | Water soluble prodrugs of azole compounds |
US6448401B1 (en) * | 2000-11-20 | 2002-09-10 | Bristol-Myers Squibb Company | Process for water soluble azole compounds |
HUP0303249A3 (en) * | 2001-02-22 | 2007-03-28 | Sankyo Co | Water-soluble triazole fungicide compounds and pharmaceutical compositions containing them |
JP4989225B2 (en) * | 2003-09-25 | 2012-08-01 | コーリー ファーマシューティカル グループ,インコーポレイテッド | Nucleic acid lipophilic conjugate |
JO2691B1 (en) * | 2005-05-03 | 2013-03-03 | ايساي آر آند دي مانجمنت كو.، ليمتد | Mono-lysine salts of azole compounds |
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US5714490A (en) * | 1993-12-21 | 1998-02-03 | Schering Corporation | Tetrahydrofuran antifungals |
SI0741737T1 (en) * | 1994-01-24 | 2000-02-29 | Janssen Pharmaceutica N.V. | Watersoluble azole antifungals |
NZ270418A (en) | 1994-02-07 | 1997-09-22 | Eisai Co Ltd | Polycyclic triazole & imidazole derivatives, antifungal compositions |
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US6407129B1 (en) | 1997-03-31 | 2002-06-18 | Takeda Chemical Industries, Ltd. | Azole compounds, their production and their use |
US6043245A (en) * | 1997-09-25 | 2000-03-28 | Schering Corporation | Tetrahydrofuran antifungal phosphate |
PT1027349E (en) | 1997-09-25 | 2005-05-31 | Schering Corp | TETRA-HYDROFURANE PHOSPHATE AND HYDROXYL ESTERS, AS PRO-DRUGS FOR THE CORRESPONDING ANTIFUNGAL AGENTS |
KR20010033811A (en) | 1997-12-31 | 2001-04-25 | 토마스 안 빅토리아 | Water soluble prodrugs of secondary and tertiary amine containing drugs and methods of making thereof |
US5883097A (en) | 1998-04-16 | 1999-03-16 | Schering Corporation | Soluble azole antifungal salt |
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